Review

pubs.acs.org/CR

Arylglyoxals in Synthesis of Heterocyclic Compounds

Bagher Eftekhari-Sis,*,† Maryam Zirak,‡ and Ali Akbari†
†
Department of Chemistry, Faculty of Science, University of Maragheh, Golshahr, P.O. Box. 55181-83111, Maragheh, Iran
‡
Department of Chemistry, Payame Noor University, P.O. Box 19395-3697, Tehran, Iran
5.6.1. Dioxophospholanes 2990
6. Synthesis of Six-Membered Heterocycles 2991
6.1. N-Heterocyclic Compounds 2991
6.1.1. Tetrahydropyridines 2991
6.1.2. Pyridines 2992
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6.1.3. Tetrahydroquinolines and Quinolines 2994

6.1.4. Isoquinolines 2995
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6.1.5. β-Carbolines 2996

6.1.6. Pyridazines 2998
CONTENTS 6.1.7. Fused Pyridazines 3000
1. Introduction 2959 6.1.8. Pyrimidines 3002
2. Arylglyoxals 2959 6.1.9. Piperazinones and Pyrazinones 3002
2.1. Physical Properties and Reactivity of Aryl- 6.1.10. Pyrazines 3004
glyoxals 2959 6.1.11. Quinoxalines 3005
2.2. Synthesis of Arylglyoxals 2960 6.1.12. Fused Pyrazines and Pteridines 3006
3. Synthesis of Three-Membered Heterocycles 2960 6.1.13. Triazinones 3008
3.1. Aziridines 2960 6.1.14. Triazines 3009
3.2. Oxiranes 2961 6.1.15. Fused Triazines 3010
4. Synthesis of Four-Membered Heterocycles 2961 6.2. O-Heterocyclic Compounds 3011
4.1. Azetidines and β-Lactams 2961 6.2.1. Pyrans and Pyranones 3011
4.2. β-Lactones 2962 6.2.2. Dioxanes 3012
5. Synthesis of Five-Membered Heterocycles 2963 6.3. S-Heterocyclic Compounds 3013
5.1. N-Heterocyclic Compounds 2963 6.3.1. Thiopyrans 3013
5.1.1. Pyrrolidines and Pyrrolines 2963 6.4. N,O-Heterocyclic Compounds 3013
5.1.2. Pyrroles 2964 6.4.1. 1,3-Oxazines 3013
5.1.3. Pyrrolizidines, Pyrrolizines, and Indolizi- 6.4.2. Morpholines 3014
dines 2967 6.4.3. Oxadiazines 3016
5.1.4. Pyrazolines and Pyrazoles 2968 6.5. N,S-Heterocyclic Compounds 3016
5.1.5. Imidazolidin-2,4-diones and Imidazolin- 6.5.1. 1,4-Thiazines and 1,4-Benzothiazines 3016
2-ones 2970 6.5.2. Benzothiadiazines 3017
5.1.6. Imidazoles 2973 6.6. S,O-Heterocyclic Compounds: Benzoxathiin 3017
5.1.7. Fused Imidazopyridines, -Pyrimidines, 7. Synthesis of Seven-Membered Heterocycles 3018
and -Pyrazines 2976 7.1. N-Heterocyclic Compounds 3018
5.1.8. 1,2,3-Triazoles and Tetrazoles 2977 7.1.1. Tetrahydroazepines 3018
5.2. O-Heterocyclic Compounds 2978 7.1.2. Diazepines and Benzodiazepines 3018
5.2.1. Tetrahydro- and Dihydrofurans 2978 7.2. N,O-Heterocyclic Compounds: Oxazepanes 3019
5.2.2. Furans 2980 8. Miscellaneous Heterocycles 3019
5.2.3. Benzofurans and Furofurans 2981 8.1. Porphyrins 3019
5.2.4. Dioxolanes 2983 8.2. Cyclens 3019
5.3. S-Heterocyclic Compounds 2983 9. Conclusion 3020
5.3.1. Thiophenes 2983 Author Information 3021
5.4. N,O-Heterocyclic Compounds 2984 Corresponding Author 3021
5.4.1. Isoxazoles 2984 Notes 3021
5.4.2. Oxazolidines, Oxazolines, and Benzox- Biographies 3021
azolines 2985 Acknowledgments 3021
5.4.3. Oxazoles 2986 Dedication 3022
5.5. N,S-Heterocyclic Compounds 2987 Abbreviations 3022
5.5.1. Thiazolidines and Thiazolines 2987 References 3022
5.5.2. Thiazoles and Benzothiazoles 2988
5.5.3. Thiadiazolidines and Thiadiazoles 2989 Received: April 28, 2012
5.6. O,P-Heterocyclic Compounds 2990 Published: January 25, 2013

© 2013 American Chemical Society 2958 dx.doi.org/10.1021/cr300176g | Chem. Rev. 2013, 113, 2958−3043
Chemical Reviews Review

1. INTRODUCTION Publishing, Thieme Chemistry, and other sites with the

keywords phenylglyoxal, arylglyoxal, glyoxal, α-ketoaldehyde,
Heterocycles are an extraordinarily important class of
and 1,2- or α-dicarbonyl compounds and from a selection of
compounds, making up more than half of all known organic
papers related to the synthesis of heterocyclic compounds
compounds. Heterocycles are present in a wide variety of drugs,
starting with AGs and their derivatives. Some references are
most vitamins, many natural products, biomolecules, and
more recent that were available to us during the elaboration of
biologically active compounds, including antitumor, antibiotic,
this manuscript. We have arranged the data in terms of the type
anti-inflammatory, antidepressant, antimalarial, anti-HIV, anti-
of heterocycle formed, starting with three-, four-, five-, six-, and
microbial, antibacterial, antifungal, antiviral, antidiabetic, seven-membered and miscellaneous rings in the heteroatom
herbicidal, fungicidal, and insecticidal agents. Also, they have order of N, O, S, N,O, N,S, O,S, and O,P in the order of an
been frequently found as a key structural unit in synthetic increasing number of heteroatoms, that is, first with one
pharmaceuticals and agrochemicals. Some of these compounds heteroatom, two heteroatoms, and three heteroatoms.
exhibit a significant solvatochromic, photochromic, and bio-
and chemiluminescence properties. Most of the heterocycles 2. ARYLGLYOXALS
possess important applications in materials science such as
dyestuff, fluorescent sensor, brightening agents, information 2.1. Physical Properties and Reactivity of Arylglyoxals
storage, plastics, and analytical reagents. In addition, they have Phenylglyoxal (PG),9 the simplest AG, is a yellow liquid that
applications in supramolecular and polymer chemistry, polymerizes upon standing. Upon heating, the polymeric
especially in conjugated polymers. Moreover, they act as material cracks to give back the yellow aldehyde. PG is
organic conductors, semiconductors, molecular wires, photo- recrystallized in hot water to form a colorless crystalline
voltaic cells, organic light-emitting diodes (OLEDs), light hydrate. The AG-hydrate appears to contain either one or one-
harvesting systems, optical data carriers, chemically controllable half molecule of water and presumably has the structure 1 or 2
switches, and liquid crystalline compounds. Heterocycles are (Scheme 1), which upon heating loses a molecule of water and
also of considerable interest because of their synthetic utility as regenerates the anhydrous AG.
synthetic intermediates, protecting groups, chiral auxiliaries,
organocatalysts, and metal ligands in asymmetric catalysts in Scheme 1. Hydrate Forms of AG
organic synthesis. Therefore, substantial attention has been paid
to develop efficient new methods to synthesize heterocycles.
1,2-Dicarbonyl compounds are among the most attractive
precursors that are used to synthesize heterocyclic compounds.
Arylglyoxals (ArCOCHO, AGs), aromatic α-keto aldehydes
containing both aldehyde and ketone functional groups with
different reactivity, play an important role in this area. To the
best of our knowledge, there is no review on synthesis of
heterocyclic compounds using AGs and their derivatives.
However, there have been many published articles on different
reactions of AGs and their derivatives, such as allylation,1
arylation,2 Cannizzaro,3 Henry,4 Mannich,5 reductive amina-
tion,6 reductive coupling with dienes,7 and Wittig8 reactions; in The data of conformational analysis of PG, studied with gas-
this review, AGs were considered as precursors in reactions that phase electron diffraction, revealed that two carbonyl groups of
led to construction of the heterocycles. In addition to some PG are nonplanar with the torsional angle OCCO of
common heterocyclic compounds, other uncommon hetero- about 130°. Moreover, the phenyl ring is nearly coplanar with
cycles such as pyrrolizidine, indolizidine, furofuran, dioxophos- the carbonyl group.10
pholane, β-carboline, benzoxathiin, fused heterocycles, and AGs possessing adjacent aldehyde and ketone functional
some seven membered heterocycles such as azepine, diazepine, groups with different reactivity show interesting chemical
and oxazepane are also reported starting with AGs and their properties. Due to existence of an electron-withdrawing ketone
derivatives. Hence, the main purpose of this review is to show group, the reactivity of the aldehyde of AG is greater than that
the application of AGs in heterocyclic syntheses, all types of of benzaldehyde, a simple aromatic aldehyde. AG forms hydrate
reactions, such as cyclocondensation, cycloaddition, Pictet− 1, which is unstable in the case of most simple aldehydes.
Spengler, and any sequences of other reactions such as Ugi− Frequently, the aldehyde group of AG reacts rapidly with
Wittig, Ugi cyclocondensation, aldol-Paal−Knorr, and Wittig different nucleophiles, which then undergo cyclization either by
dehydrative cyclization are included. The reactions in which the aldehyde group residue, which provides one atom of
AGs or their derivatives were produced in situ and then heterocycle along with producing an aroyl substituent on the
converted into heterocyclic compounds are also included. obtained rings, or by ketone of AG to provide two atoms of the
While the preparation of phenylglyoxal (PG) and its use date heterocyclic rings. In addition, AGs and AG-imines can act as
back to 1887, the synthesis of heterocyclic compounds using dienophiles in [4 + 2] and [2 + 2] cycloaddition reactions via
AGs and their derivatives have increased in recent years. So, CO and CN bonds, respectively. In some cases, AG-
about half of reviewed articles have been published in the past hydrates act as nucleophile via oxygen atom of OH group.
decade (2000−2011). This review has the aim of covering the Additionally, PG selectively modifies the amino acid arginine
literature up to the end of 2011, showing the distribution of residues in proteins.11a AGs such as 4-hydroxy-3-hydroxyme-
publications involving use of arylglyoxals for preparing of thylphenylglyoxal and 3,5-dihydroxyphenylglyoxal are used for
heterocycles, which was elaborated using the Web of Science, preparation of selective bronchodilators such as salbutamol and
ACS Publications, Wiley Online Library, Science Direct, RSC terbutaline. Also, some AG-hydrates, such as 4-hydroxy-3-
2959 dx.doi.org/10.1021/cr300176g | Chem. Rev. 2013, 113, 2958−3043
Chemical Reviews Review

Table 1. Synthesis of Arylglyoxals

method condition prepared AG (Ar) ref
oxidation of aryl methyl SeO2, dioxane−water, reflux Ph, 4-BrC6H4, 4-ClC6H4, 4-OHC6H4, 4-OH-3-MeOC6H3,4- 11b,
ketones MeOC6H4, 3-MeOC6H4, 4-NO2C6H4, 4-AcNHC6H4, 4- 13
MeO2CC6H4, 4-HO2CC6H4, 2-furyl, 2-thienyl, 2,4,6-Me3C6H2
H2SeO3, dioxane−water, reflux, 4 h 5-Me-2-furyl, 5-Me-4-NO2-2-furyl 14
SeO2, EtOH, 10% HNO3 (aq), 90 °C, 1 h Ph 15
(PhSe)2, (NH4)2S2O8, MeOH, reflux, 1−4 h ArCOCH(OMe)2: Ph, 2-OHC6H4, 4-MeC6H4, 4-NO2C6H4, 4- 19
PhC6H4, 2-furyl, 2-naphthyl, 2-thienyl, 3-thienyl
48% HBr (aq), DMSO, 55 °C, 0.5−24 h 2-PhC6H4, 4-BrC6H4, 4-MeOC6H4, 4-NO2C6H4, 4-PhC6H4 16
oxidation of phenacyl DMSO, rt, 9 h Ph, 4-BrC6H4, 4-ClC6H4, 4-NO2C6H4, 4-PhC6H4 18
bromide
Et2NOH, MeOH, reflux, 2 h Ph, 4-BrC6H4, 3-MeOC6H4, 4-PhC6H4, 2-naphthyl 22
α-picoline N-oxide, 0 °C, then Na2CO3, water Ph 23
oxidation of phenacyl NaOAc·3H2O, DMSO, 20−25 °C, 25−55 min 4-BrC6H4, 4-ClC6H4, 4-NO2C6H4, 4-PhC6H4 20
nitrate esters
oxidation of α-diazo DMDO, acetone, rt Ph, 2-furyl, 2-pyridyl, 3-pyridyl, 2-thienyl 21
ketones
oxidation of aryl acetylene (HMPA)MoO(O2)2, Hg(OAc)2, DCE-MeOH, 0 °C, 15 min Ph 24
NBS, dry DMSO, rt, 20 h Ph 25
(PhSe)2, (NH4)2S2O8, water−CH3CN, 60 °C, then ArCOCH(OH)OR: Ar = Ph, 4-BrC6H4, 4-MeOC6H4; R = Me, 26
chromatographed on SiO2, DCM-ROH (99/1) menthyl, i-Pr
reaction of methyl (1) DMSO, KOt-Bu, t-BuOH, rt, 4 h, then HCl, water, rt, 30 h; Ph, 4-BrC6H4, 4-MeOC6H4, 4-MeC6H4 17
benzoate with KDMSO (2) Cu(OAc)2·H2O, CHCl3, rt, 1 h
then oxidation
reaction of organolithium piperidine-1-yl-COCH(OEt)2, p-Me2NC6H4Li, ether, reflux, 2 h, p-Me2NC6H4 11b
compound with then HCl, water, N2 (atm.), rt, 41 h
diethoxyacetylpiperidine
chlorination of aryl methyl 1,3-Cl2-5,5-Me2hydantoin, Cu(OTf)2, CHCl3, reflux, 5−8 h ArCOCHCl2: Ph, 4-BrC6H4, 4-ClC6H4, 4-FC6H4, 4-MeOC6H4, 3,4- 27
ketones (MeO)2C6H3, 3,4,5-(MeO)3C6H2, 4-MeC6H4, 4-NO2C6H4, 2-
naphthyl

methoxyphenylglyoxal hydrate, 4-acetamidophenylglyoxal hy- oxidation of corresponding α-diazo ketones by dimethyl

drate, and 2-furylglyoxal hydrate, show antiviral activity in the dioxirane in 85−100% yields.21 Also, AGs were synthesized
embryonated egg against several viruses, including influenza by reaction of phenacyl bromides with N,N-diethylhydroxyl-
(PR-8) and Newcastle disease (NJKD strain) viruses.11b,c amine in MeOH under reflux conditions in 55−90% yields.22
2.2. Synthesis of Arylglyoxals Similar conversion of phenacyl bromide to PG using α-picoline
N-oxide was reported. These methods offer a useful and mild
Various methods are reported in the literature for the nonoxidative route to AGs.23 p-Dimethylaminophenylglyoxal
production of AGs. PG was first prepared by thermal was prepared by the hydrolysis of its diethylacetal, which was
decomposition of the sulfite derivative of the PG-oxime.12 prepared by the action of p-(Me2N)C6H4Li on diethoxyace-
Oxidation of aryl methyl ketones by SeO2 is one of the most tylpiperidine.11b PG was also prepared by oxidation of phenyl
important methods for the preparation of AGs. Riley and co- acetylene with metal−peroxide complex, (HMPA)MoO(O2)2,
workers13 dealt with the general aspect of this reaction and in the presence of Hg(OAc)2 in DCE at 0 °C,24 or by NBS
reported good efficiency of utilization of SeO2 for the formation induced DMSO oxidation of phenyl acetylene at room
of PG. Also, oxidation of aryl methyl ketones to AGs by temperature.25 AG-hemiacetals were prepared by oxidation of
selenious acid (H 2 SeO 3 ) was reported.14 Sharma and terminal alkynes using (NH4)2S2O8 and (PhSe)2 as catalyst in
Chandalia15 reported the oxidation of acetophenone by aqueous media under heating at 60 °C, followed by purification
aqueous HNO3 in the presence of SeO2 as a selective catalyst with chromatography on silica gel using a mixture of 1:99
in a redox cycle, with a view to changing the use of SeO2 as a ROH−DCM as eluent.26 α,α-Dichloroketones, possessing
stoichiometric oxidizing agent. Floyd et al.16 described the similar structure with AG-hydrates, were readily synthesized
synthesis of AG by the reaction of acetophenones with aqueous by Cu(OTf)2-catalyzed α-chlorination of methyl ketones with
HBr in DMSO in good to high yields. Also conveniently, AG 1,3-dichloro-5,5-dimethylhydantoin in CHCl3 under reflux
can be prepared from methyl benzoates by reaction with condition in high yields.27 The methods to synthesize of
KCH2S(O)CH3 to give ArC(O)CH(SCH3)(OH), followed by AGs, along with experimental procedures and synthesized AGs
oxidation with Cu(OAc) 2.17 Alternatively, oxidation of are summarized in Table 1.
phenacyl bromides with DMSO at room temperature afforded
AGs in 48−95% yields.18 Treatment of aryl and heteroaryl 3. SYNTHESIS OF THREE-MEMBERED HETEROCYCLES
methyl ketones with catalytic amounts of (PhSe)2 and an excess
amount of (NH4)2S2O8 in MeOH under reflux conditions 3.1. Aziridines
afforded AG-acetals in 60−95% yields.19 Kornblum et al.20 Aziridines, the smallest saturated azaheterocycles, are structur-
reported the synthesis of AGs via nitrate esters in 82−86% ally unique and possess many interesting chemical properties.28
yields. Nitrate esters were obtained by reaction of phenacyl They are versatile building blocks for the synthesis of diverse
bromide derivatives with silver nitrate in CH3CN and were nitrogen-containing compounds,29 such as chiral amino acids,30
converted to AGs using NaOAc in DMSO at room temper- tetrahydropyridines, indolizidine, and alkaloids,31 via ring-
ature. PG and some heteroarylglyoxals such as 2-furyl, 2-thienyl, opening and ring-expansion reactions.32 Moreover, the aziridine
2-pyridyl, and 3-pyridylglyoxals were conveniently prepared by moiety is present in a wide variety of natural biologically active
2960 dx.doi.org/10.1021/cr300176g | Chem. Rev. 2013, 113, 2958−3043
Chemical Reviews Review

compounds,33 such as antitumor and antibiotic agents,33c,34 and much attention has been paid to the development of new
has been frequently found as a key structural unit in synthetic methods for the synthesis of epoxides such as epoxidation of
pharmaceuticals.35 Two of the most important methods for the alkenes,53 dehydrochlorination of chlorohydrins,54 and prep-
synthesis of aziridines are the aziridination by carbene transfer aration from carbonyl compounds using sulfur ylides.55
to imines and the nitrene or nitrene equivalents transfer to There is one report on synthesis of oxirane starting from an
olefins.36 Ring closure of amino alcohols,37 aminolysis of AG in the literature, in which, Fuson et al.56 reported the
epoxides,38 functionalization of aziridines,39 and aza-Darzens synthesis of sym-dibenzoyloxirane 7 in low yield by the reaction
reactions40 are among the other reported routes to preparation of PG with phenacyl bromide 6 in 10% NaOH solution at room
of aziridines. temperature for 15 min (Scheme 3). Also, sym-dibenzoyloxir-
In this context, Akiyama et al.41 described the three- ane was synthesized by epoxidation of sym-dibenzoylethylene
component synthesis of aroylaziridine 4 via enantioselective using 10% NaOH and NaOCl solutions.
and stereoselective aza-Darzens reaction catalyzed by a chiral
phosphoric acid 5 (Scheme 2). AG-imines 3, in situ generated Scheme 3. Synthesis of sym-Dibenzoyloxirane 7

Scheme 2. Synthesis of Aroylaziridines 4 via Aza-Darzens

Reactiona

4. SYNTHESIS OF FOUR-MEMBERED HETEROCYCLES

4.1. Azetidines and β-Lactams
The azetidine moiety is found in the structure of many natural
products such as nicotianamine,57 medicanine,58 antifungal and
antibiotic polyoxins,59 or pharmacologically important mole-
cules, such as thrombin inhibitor melagatran,60 which exhibit a
broad range of biological activities.61 2-Azetidinones, the β-
lactam skeletons, are the key structural element of the most
widely used class of drugs for the treatment of bacterial
infections.62 They exhibit a wide range of biological activities
such as antidepressant,63 anti-inflammatory,64 anticancer,65
antimicrobial,66 antitubercular,67 cholesterol absorption inhib-
ition,68 and antibiotic69 activity. Also, 2-azetidinones were
employed as synthons for synthesis of many biologically
important classes of organic compounds.70 However, there are
a
Ar = Ph, 4-BrC6H4, 4-ClC6H4, 4-FC6H4, 4-CF3C6H4, 4-MeOC6H4, 4- different methods for construction of azetidine and β-lactam
MeC6H4, 4-biphenyl, 1-naphthyl, 2-thienyl; 91−100%; ee = 92−97%. structures;71 Staudinger [2 + 2] cycloaddition of ketenes with
imines is one of the most important routes to β-lactams.72
Accordingly, Pedrosa et al.73 described the synthesis of
from AG-hydrates and p-anisidine in the presence of 5 and
azetidin-3-ols 10 in 56−58% yields via Yang photocyclization
MgSO4 in toluene at room temperature, underwent aziridina-
reaction of perhydrobenzoxazines 9 that were prepared by
tion by addition of α-diazoacetate at −30 °C to furnish 4 in
heating of amino menthol derivatives 8 with AG-hydrate in
91−100% yields with 92−97% ee. The stereochemistry of 4 was
toluene or benzene at reflux conditions. Transformation of 10
determined as cis using 1H NMR technique, and the trans
into the final azetidine derivatives 12 was achieved in five steps.
isomer was not observed. At the same condition, aziridination
The protection of the hydroxyl group as benzyl ether, followed
did not occur with aldimine derived from benzaldehyde and p-
by reductive ring-opening of the N,O-ketal moiety using in situ
anisidine.
generated AlH3 by reaction of AlCl3 with LiAlH4 in THF at
Also, one example of the Yb(OTf)3 catalyzed three
reflux conditions afforded the menthol derivatives 11. The
component reaction of PG with diphenylmethylamine and α-
overall yields for two steps are 80−82%. Oxidation of 11 with
diazoacetate in the presence of 4 Å MS in hexane at room
PCC in the presence of 3 Å MS in DCM at room temperature
temperature was reported to afford the corresponding aziridine
for 5−12 h resulted in 8-aminomenthone derivatives, which,
in 85% yield with high stereoselectivity (syn/anti = 94/6).42
without isolation, were treated with KOH in THF−MeOH−
3.2. Oxiranes H2O (2:1:1) at room temperature for 6−8 days to give
Oxiranes (epoxides), the smallest oxygen-containing saturated azetidine derivatives that were isolated as N-tosyl derivatives 12
heterocycles, are broadly found in many natural products, such by treatment with TsCl and DIPEA in EtOAc at room
as azinomycins A and B,43 cryptophycin A and B,44 triptolide temperature for 3 days followed by addition of 15% HCl
and triptonid,45 epoxomicin,46 and psorospermin,47 which solution. The overall yields for three steps are 25−31%
exhibit biological activity such as antitumor,45,48 antileukemic,49 (Scheme 4).
anti-inflammatory,50 and immunosuppressive51 activities. Also, Tanaka et al.74 described the stereoselective synthesis of 4-
epoxides are among the most versatile intermediates in organic benzoyl-3-vinylazetidin-2-ones 14 via Pd-catalyzed carbon-
synthesis because they can be converted into highly valuable ylation of an allyl phosphate 13 in the presence of PG-imines
products via ring-opening or rearrangement reactions.52 Thus, 3 and c-Hex2NMe, a tertiary amine, under CO pressure in 50−
2961 dx.doi.org/10.1021/cr300176g | Chem. Rev. 2013, 113, 2958−3043
Chemical Reviews Review

Scheme 4. Synthesis of Azetidin-3-ols 12

63% yields with high syn selectivity. Different reaction Scheme 6. Synthesis of 4-Benzoylazetidin-2-one 18 and 19
conditions were examined and 2 mol % Pd2dba3CHCl3, 8 via Staudinger Cycloaddition Reactiona
mol % Ph3P, and 1 mmol of c-Hex2NMe under 30 kg cm−2
pressure of CO for 0.5 mmol of PG-imine, and 0.75 mmol of
13 in THF at room temperature was selected as optimum
condition. In the case of 3 with R = 4-MeOC6H4 and R = n-Pr,
only cis isomer was obtained. Treatment of benzoyl lactam 14a
with PhSiH3 in the presence of 5 mol % Co(acac)2 under an O2
atmosphere in THF at room temperature for 3 h resulted in the
formation of hemiacetal 15, a useful intermediate for the
synthesis of carbapenams (Scheme 5).

Scheme 5. Stereoselective Synthesis of 4-Benzoylazetidin-2-

ones 14

a
For a, ∗ = (R); SiR3 = Si(i-Pr)3; conditions DIPEA, −20 °C, 83%,
18a/19a = 20/80. For b, ∗ = (S); SiR3 = SiMe2Ph; conditions Et3N,
40 °C, 75%, 18b/19b = 75/25.

19b in 75% yield via Staudinger [2 + 2] cycloaddition reaction

of ketene 17b derived from (S)-3-(dimethylphenylsilyloxy)-
butanoyl chloride 16b with PG-imine 3. The reaction was
carried out in the presence of Et3N in DCM at 40 °C for 20−24
h (Scheme 6).
Also, the synthesis of α-phenylthio-β-lactams 22 as only cis
isomer was reported through [2 + 2] cycloaddition reaction of
PG-imines 3 with ketene, which was in situ prepared from a
mixture of the potassium salt of (phenylthio)acetic acid, Et3N,
and cyanuric chloride 20 in CCl4 at room temperature via
intermediate 21. The benzoyl substituent in 3 obviously
influences the syn-stereoselectivity on β-lactam formation
(Scheme 7).77
There are other reports on the construction of 4-benzoyl-β-
lactam ring via [2 + 2] cycloaddition reaction of PG-imines
with ketene generated in situ by reaction of propionyl chloride78
or arylacetyl chloride79 with Et3N in DCM.
As shown in Scheme 6, a diastereoselective route to synthesis
of the carbapenem antibiotic intermediates 18a and 19a was 4.2. β-Lactones
developed by Lynch and co-workers75 via the reaction of PG- β-Lactones are attractive intermediates in natural product and
imine 3 and acid chloride 16a. The reaction was carried out in polymer synthesis.80 The important reactions of β-lactones
the presence of DIPEA in DCM at −20 °C for 16 h to give cis involve ring opening, including polymerization, to yield poly(β-
4-benzoylazetidin-2-ones 18a and 19a in a 1:4 ratio via ketene hydroxyalkanoate)s (PHAs).81 The most important routes to
intermediate 17a. Palomo et al.76 reported the similar synthesize β-lactones are nucleophile-catalyzed aldol-lactoniza-
procedure for synthesis of 4-benzoylazetidin-2-ones 18b and tions and Lewis acid-catalyzed [2 + 2] cycloadditions.80c,82
2962 dx.doi.org/10.1021/cr300176g | Chem. Rev. 2013, 113, 2958−3043
Chemical Reviews Review

Scheme 7. Synthesis of α-Phenylthio-β-lactams 22 via [2 + 2] 5. SYNTHESIS OF FIVE-MEMBERED HETEROCYCLES

Cycloaddition Reaction
5.1. N-Heterocyclic Compounds
5.1.1. Pyrrolidines and Pyrrolines. Pyrrolidines are an
important class of heterocycles found in numerous natural
products,84 pharmaceuticals,85 and bioactive molecules86 with
antibacterial, antifungal, and cytotoxic activities.87 They also
serve as neuroexcitatory agents,88 antibiotics89 and glycosidase
inhibitors.90 They have a wide range of applications as
organocatalysts,91 building blocks in organic synthesis,92 chiral
auxiliaries, and ligands for asymmetric synthesis.93 Many
syntheses of pyrrolidines have been reported.94 Additionally,
pyrrolines are common structural scaffolds in natural products
and pharmaceutical agents95 that exhibit biological activity96
and serve as useful synthetic intermediates97 especially in the
synthesis of biologically active pyrroles and pyrrolidines.98
There are different methods for construction of pyrroline
derivatives.98,99
In this context, the synthesis of β-lactones 25 was reported As shown in Scheme 9, Pedrosa and co-workers100 described
by He et al.83 via chiral N-heterocyclic carbene 23b catalyzed the synthesis of 3-phenyl-1-tosyl-4-vinylpyrrolidin-3-ols 30 in
enantioselective [2 + 2] cycloaddition reactions of alkyl(aryl)- six steps, starting from PG and (−)-8-aminomenthol 26. By
ketenes 24 with AGs (Scheme 8). Treatment of AGs with condensation of PG with 26 in DCM at room temperature 2-
benzoyl-1,3-oxazine 27 was obtained in quantitative yield. A
Scheme 8. Chiral NHC Catalyzed Synthesis of β-Lactones mixture of diastereomeric 3-hydroxypyrrolidines 28a,b or
25a 28a′,b′ were formed by alkylation of 27 with prenyl or crotyl
bromide in the presence of K2CO3 in refluxing acetonitrile,
followed by carbonyl−ene reaction under thermal conditions.
Different thermal conditions were examined, and in the case of
N-crotyl derivative (R = H), the best results were obtained
when reaction was carried out in xylene under reflux conditions
for 218 h; the corresponding 3-hydroxypyrrolidines 28a,b were
obtained in 80% yield with 88:12 ratio of 28a/28b. But in the
case of N-prenyl derivative (R = Me), reaction at 170 °C for 21
h without using any solvent afforded the 3-hydroxypyrrolidines
28a′,b′ in 80% yield with 75:25 ratio of 28a′/28b′. The
conversion of 28a,a′ into mentone derivatives 29a,a′ was
achieved by reductive ring opening of 28a,a′ with AlH3, in situ
generated by treatment of AlCl3 with LiAlH4, in THF at −10
°C for 10 min, followed by oxidation with PCC in the presence
of 4 Å MS in DCM at room temperature for 6−8 h. Mentone
derivatives 29a,a′, without isolation, were converted into the
final pyrrolidines 30 by elimination with KOH in H2O−
a
Ar′ = Ph, 2-ClC6H4, 4-ClC6H4; Ar′-R = (CH2)6; R = Et, i-Pr, Ph; Ar MeOH−THF (1:1:2) at room temperature and tosylation with
= Ph, 4-BrC6H4, 4-MeOC6H4, 4-MeC6H4, 1-naphthyl, 2-naphthyl; TsCl in the presence of DIPEA in EtOAc at room temperature
55−99%, dr (trans/cis) = 80−100%; ee = 4−99%. for 36 h. The overall yields for three last steps are 39−45%.
A similar procedure using different AGs, such as p-Me-, p-
MeO-, o-NO2-, or p-NO2-PG, was reported by Andrés et al.101
in which the keto−ene cyclization sequence was investigated
different ketenes 24 in the presence of NHC 23b (10−12 mol using different Lewis acids. The best results were obtained
%) in THF at room temperature and stirring overnight afforded when 1.5 equiv of Me2AlCl or Et2AlCl in DCM was used.
25 in 63−99% yields with 4−99% ee. AGs having electron- The 1,3-dipolar cycloaddition reaction of azomethine ylides
donating groups as well as electron-withdrawing substituents 33, derived from N-(cyanomethyl)- and N-(α-cyanobenzyl)-
worked well and the corresponding β-lactones 25 were imines 32, with N-methylmaleimide 34 or dimethyl fumarate
obtained in high yields with excellent diastereo- and 35, was described in refluxing CHCl3 (Scheme 10). Reactions
enantioselectivities. The symmetric cyclic ketene, cycloheptyli- were conducted via in situ generation of imines 32 by the
reaction of PG with 31 in CHCl3 under heating conditions
denemethanone, gave the corresponding β-lactone in only 63%
followed by adding of dipolarophiles 34 or 35 to furnish
yield with very low enantioselectivity (4% ee). NHC 23b was corresponding pyrrolidines 36 or 37 in quantitative yields with
generated in situ from the action of Cs2CO3 on triazolium salt endo/exo ratio of 100/0. Pyrroline 38 was obtained in
23a in THF at room temperature in 1 h. Under similar quantitative yield when 36b was chromatographed over silica
conditions, the cycloaddition reaction of ethyl(2- gel with CHCl3−Et2O (3:1) via elimination of HCN.102
chlorophenyl)ketene with 4-chlorobenzaldehyde did not afford The synthesis of N-substituted 4-cyano-2,5-dihydro-5-
the corresponding β-lactone. oxopyrrole-2-carboxamides 40 was reported by Bossio et
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Scheme 9. Synthesis of Pyrrolidin-3-ols 30 via Carbonyl−Ene Reactiona

a
a, R = H; a′, R = Me.

Scheme 10. Synthesis of Pyrrolidines 36 and 37 via 1,3- 5-methoxypyrrole-2-carboxamides 41 were obtained in 73−
Dipolar Cycloaddition Reaction 89% yields (Scheme 11).

Scheme 11. Synthesis of 4-Cyano-5-oxodihydropyrroles 40

via Ugi Reactiona

a
R = c-Hex, n-Hex; Ar = Ph, 4-ClC6H4; Ar′ = Ph, 3-ClC6H4, 4-
ClC6H4, 4-MeC6H4; 40, 40−60%; 41, 73−89%.

Beck et al.104 described the synthesis of highly substituted 5-

oxo-2,5-dihydro-1H-pyrrole-2-carboxamides 44 via four-com-
ponent reaction of AGs, isocyanides, primary amines, and
phosphono acetic acids 42 in MeOH at room temperature to
afford Ugi products 43, followed by Wittig ring-closing reaction
[using the Horner/Wadsworth/Emmons variant (HWE)]
al.103 via Ugi reaction among AGs, anilines, isocyanides, and using 10 equiv of Et3N as base in the presence of 4.5 equiv
cyanoacetic acid. The reactions were carried out by in situ of LiCl in THF at room temperature for 12 h (Scheme 12).
generation of AG-imines 3, via reaction of AGs with anilines in 5.1.2. Pyrroles. Pyrroles are an important class of
toluene at reflux conditions by removal of water using a Dean− heterocycles that are broadly found in natural products,105
Stark apparatus, followed by stirring with isocyanides and pharmaceuticals,106 and bioactive molecules107 and also used in
cyanoacetic acid in Et2O at room temperature for 6 days to give material science.108 Many methods have been developed for
Ugi adducts 39. The obtained mixture was treated with Et3N in pyrrole synthesis,109 which include Knorr, Paal−Knorr, and
EtOH to afford 40 in 40−60% yields. By treatment of a Hantzsch syntheses and 1,3-dipolar cycloaddition reactions.
saturated solution of 40 in CHCl3 with a large excess of CH2N2 Trost et al.110 reported the synthesis of two isomeric
in Et2O and stirring at room temperature for 10 h, the 4-cyano- pyrroles, 1-benzyl-2-phenylpyrrole 50 and 1-benzyl-3-phenyl-
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Scheme 12. Synthesis of Dihydropyrroles 44 via Ugi−HWE Scheme 13. Synthesis of Two Isomeric Pyrroles 46 and 47
Reactionsa

a
R = allyl, t-Bu, c-Hex, MeO2CCH2, PhCH2CH(CO2Me), 2-
pyridylCH2; R′ = Bn, n-Pentyl, i-Pentyl, n-Pr, c-Pr, Me3CCH2CH2,
BocNHCH2CH2CH2, 3,4-(MeO)2C6H3CH2CH2; R″ = H, Ph; Ar =
Ph, 4-MeOC6H4, 3,4-(MeO)2C6H3, 4-morpholino-C6H4, 4-biphenyl,
2-naphthyl; 7−95%.

pyrrole 51, by cyclization of 1-phenyl-2-acetoxy-3-buten-1-one

47 and 2-acetoxy-2-phenyl-3-butenal 49 with benzylamine in
the presence of a catalytic amount of Pd(PPh3)4 in dry THF
under reflux conditions in 65% and 9% yields, respectively. The
PG-ketal 46 was prepared from α,α-dichloroacetophenone 45
upon treatment with methanolic NaOMe. By Grignard addition
of vinylmagnesium bromide to 46 and acetylation of the
resultant alcohol using Ac2O in the presence of DMAP in dry
pyridine at room temperature and finally by deketalization
using a few drops of 60% aqueous solution of HClO4 in Scheme 14. Synthesis of 3-Hydroxypyrroles 54 Using
acetone, 47 was obtained. Alternatively, 49 was obtained by Enamino Esters and Nitrilea
Grignard addition of vinylmagnesium bromide to PG-acetal 48
in THF at room temperature, followed by hydrolysis with p-
TsOH in acetone, and then acetylation using Ac2O in the
presence of DMAP and pyridine in DCM (Scheme 13). PG-
acetal 48 is readily available by direct acetalization of PG.
The synthesis of 3-hydroxypyrroles 54 via reaction of
enamino esters and nitrile 52 with PG-hydrate was investigated
by Feliciano et al.111 (Scheme 14). The reaction was conducted
in refluxing MeOH to afford corresponding 3-hydroxypyrroles
54 in 52−62% yields. In the proposed reaction mechanism,
C3−C4 bonds of the pyrroles were formed by nucleophilic
addition of enamino esters 52, through the C atom, to the
aldehyde group of PG; then by regeneration of the enamine,
intermediates 53 were produced. By condensation of the amino a
Y = CO2Me, CO2Et, CN; 54, 52−62%.
group with the ketone along with removal of a molecule of
water, intermediates 53 were converted into the corresponding
pyrroles 54. 3-Hydroxypyrroles 54 were acetylated to acetate only product. However, the 2-pyrrolin-5-one 57c was detected
55 using Ac2O in pyridine at room temperature. as initial product of the reaction, but converted into 58c at
A similar reaction was carried out using N-hydroxyalkyl room temperature via equilibrium with starting materials and
substituted enamino methyl esters 56a,b in MeOH under reflux recombination to 58c. Interestingly, the reaction with methyl 3-
conditions, which resulted in pyrrolinones 57a,b in 45−60% p-tolylaminocrotonate 56d resulted to methoxypyrrole 59 in
yields, while corresponding 3-hydroxypyrroles 58a,b were not 30% yield, via intermediate 57d, by addition of MeOH to the
isolated. This can be attributed to the formation of hydrogen carbonyl group of pyrrolinone 57d, followed by lose of a
bonds between the hydroxyl group of hydroxyalkyl substituent molecule of water (Scheme 15).112
and the carbonyl group of the pyrrolinone, which induced Khalili and co-workers113 described a new interesting one-
relative stabilization to pyrrolinones 57a,b. Unlikely, steric pot method for synthesis of 2-alkyl-5-aryl-(1H)-pyrrole-4-ols
hindrance between the hydroxyalkyl substituent and the phenyl 60 via three-component reaction of 1,3-dicarbonyl compounds
group at the C2-position of pyrroles induced destabilization to with AGs in the presence of an excess amount of NH4OAc in
the 3-hydroxypyrroles 58a,b. This statement was proven when water at room temperature. The reaction mixture solidified
reaction was carried out using unsubstituted enamino ester 57c, rapidly (in 10−30 min) and afforded 60 in 20−98% yields
in which 5-phenyl-4-hydroxypyrrole 58c was isolated as the (Scheme 16). β-Ketoesters and acetylacetone worked well in
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Scheme 15. Synthesis of Pyrrolines 57 Using N-Hydroxyalkyl Enamino Esters

Scheme 16. Synthesis of 3-Hydroxypyrroles 60a Scheme 17. Synthesis of Pyrrole-3-ols 64 via Aldol-Paal−
Knorr Reaction Sequencea

a
R = Me, n-Pr; R' = Ot-Bu, OEt, OMe, Me; Ar = Ph, 4-BrC6H4, 4-
ClC6H4, 4-FC6H4, 4-MeOC6H4, 4-biphenyl; 60, 20−98%. a
R = Bn, n-Pr, Ph, 4-ClC6H4, 4-MeOC6H4; 61−82%.

this reaction, but in the case of 1,3-dicarbonyl compounds

possessing phenyl substitution at the carbonyl group, those acetophenones (Scheme 18). A plausible reaction mechanism
were recovered and 4- or 5-aryl-2-aryloyl-(1H)-imidazole 61 involves the formation of AGs by DMSO-induced oxidation of
was obtained as a two-isomer mixture via condensation of two α-iodoacetophenones, which were in situ generated by
molecules of PG with NH4OAc. Also, the similar three- iodination of acetophenones by action of CuO and I2, and
component reaction was carried out under ultrasound then conversion into 2-(methylthio)-1,4-diaryl-2-butene-1,4-
irradiation to afford the corresponding pyrroles 60 in high diones 66 in 65−94% yields via aldol-type reaction with sulfur
yields in very short reaction times.114 The Vilsmeier−Haack ylides 65, followed by loss of MeI and then dehydration. The Z-
reaction of 60 (R = R′ = Me) with POCl3/DMF was or E-isomer of 66 was reacted with KI and conc. HCl in
investigated, and indole-5,7-dicarbaldehydes were obtained in acetone at room temperature to give saturated 1,4-diketones,
31−53% yields.115 which were transformed to the corresponding pyrroles 67 in
Recently, we reported a method to synthesize N-alkyl(aryl)- 80−92% yields when heated in the presence of ammonium
2,4-diaryl-2-methyl-1H-pyrrole-3-ol derivatives 64 in 61−82% formate in AcOH under reflux conditions for 2−4 h.
yields via an aldol-Paal−Knorr reaction sequence (Scheme 17). As shown in Scheme 19, a three-component reaction
1,4-Dicarbonyl compound 63 was synthesized in 89% yield via between dialkyl acetylenedicarboxylates (DAAD), anilines,
aldol reaction of 1-(p-methoxyphenyl)propan-2-one 62 with and AGs to synthesize polysubstituted pyrrole derivatives 69
PG-hydrate in the presence of a catalytic amount of DABCO in was described by Anary-Abbasinejad et al.118 The reaction was
water at room temperature. Then conversion of 63 to various carried out by addition of AGs to a mixture of DAAD, Ph3P,
fully substituted pyrroles 64 was performed by refluxing a and an aniline derivative in DCM at room temperature to
solution of primary amines and 63 in toluene in the presence of afford 69 in 84−90% yields. It is illustrated that ylide 68 was
a catalytic amount of p-TsOH.116 produced in situ as a reaction intermediate and underwent
A facile route for the synthesis of 3-methylthio-substituted Wittig reaction with the AG, which then cyclizes to 69 by losing
pyrroles 67 was developed by Yin et al.117 starting from a molecule of water.
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Scheme 18. Synthesis of 3-Methylthiopyrroles 67a Quiroga et al.119 reported the three-component reaction
between dimedone 70, 6-aminopyrimidines 71, and AGs to
synthesize fused pyrido[2,3-d]pyrimidines 75. Reaction was
conducted by heating of the equimolar amounts of AG, 70, and
71 in EtOH in the presence of a catalytic amount of AcOH for
9 h. Interestingly, the unexpected cyclization process led to
pyrrolo[2,3-d]pyrimidine derivatives 72−74 in 38−60% yields
(Scheme 20).
Also, the three-component condensation of an enaminone
with PG and morpholine leading to tetrahydroindoles was
reported.120
By reaction of N-silyl-1-azaallyl anion 77 with PG in THF at
−75 °C for 1 h, then warming to room temperature for 2 h
under N2 atmosphere, followed by reduction with NaBH4 at
room temperature and then treatment with conc. HCl, 2H-
pyrrole 78 was obtained in 21% yield. When reduction was
carried out using LiAlH4 under reflux conditions, 2H-pyrrole 78
and pyrrole 79 were obtained in 20% and 44% yields,
respectively.121 N-Silyl-1-azaallyl anion 77 was prepared by
a reaction of benzonitrile and 2-(trimethylsilyl)methyl pyridine
Ar = Ph, 4-MeOC6H4, 4-MeC6H4, 2-benzofuryl, 2-thienyl; 80−92%.
76 in the presence of a base such as LDA or n-BuLi in THF at
−75 °C (Scheme 21).122
Scheme 19. Synthesis of Pyrroles 69 via Wittig−Dehydrative
Cyclization Reactionsa 5.1.3. Pyrrolizidines, Pyrrolizines, and Indolizidines.
Bridgehead nitrogen heterocycles are of interest because they
constitute an important class of natural and unnatural
products,123 which display biological and pharmacological
activities,124 and are important as precursors in the synthesis
of many biologically active compounds. Consequently, there
has been an ongoing interest in the synthesis of pyrrolizi-
dine,125 pyrrolizines,126 and indolizidine127 heterocycles.
Accordingly, Felluga et al.128 recently reported the reaction
of PG with β-nitrostyrene 80 and an equimolar amount of L-
proline 81 in i-PrOH at room temperature that gives
substituted pyrrolizidine 82 in 80% yield as a single
regioisomer. The reaction mechanism involves the in situ
a
R = t-Bu, Et, Me; Ar = 4-BrC6H4, 4-NO2C6H4; Ar′ = Ph, 4-ClC6H4, generation of 1,3-azomethine ylide 83 derived from PG and 81
4-MeC6H4; 84−90%. by decarboxylation, then 1,3-dipolar cycloaddition reaction with
80 (Scheme 22).

Scheme 20. Synthesis of Pyrrolo[2,3-d]pyrimidines 72−74

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Scheme 21. Synthesis of 2H-Pyrrole 78 and Pyrrole 79 via Scheme 23. Synthesis of Dihydropyrrolizines 86−88
Azaallyl Anion 77

Scheme 22. Synthesis of Pyrrolizidine 82 via 1,3-Dipolar

Cycloaddition Reaction

due to their occurrence in a number of biologically active

molecules131 with antibacterial, antiviral,132 antiamoebic,
antidiabetic,133 antitumor,134 anti-inflammatory,135 antidepres-
sant,136 and MAO-inhibitory activities. In addition pyrazolines
possess important applications as dyestuffs, analytical reagents,
and agrochemicals.137 Pyrazolines are synthesized by the
condensation/addition of hydrazines onto α,β-unsaturated
carbonyl compounds138 and cycloaddition of azomethine
imines with alkynes.139 Additionally, pyrazoles are a motif
Treatment of 2-nitromethylenpyrrolidine 84 with PG in found in a number of small molecules that possess a wide range
EtOAc at room temperature for 2 h gave product 85 in 92% of agricultural and pharmaceutical activities such as herbicidal,
yield, which transformed to substituted dihydro-1H-pyrrolizines fungicidal, insecticidal, analgesic, antipyretic, and anti-inflam-
86 by heating in various alcohols in the presence of conc. HCl matory properties.140 Also they have applications in supra-
in 75−87% yields. Interestingly, by heating of 85 in molten molecular and polymer chemistry and as ligands for transition
phenol in the presence of HCl, nucleophilic substitution metal-catalyzed reactions.141 Conventional approaches for the
occurred at C-4 of phenol, and 4-hydroxyphenyl substituted preparation of substituted pyrazoles involve either condensa-
pyrrolizines 87 were obtained in 41% yield. Cyclization reaction tion of hydrazines with 1,3-dicarbonyl compounds or 1,3-
in a 2,2,2-trifluoroethanol/HCl solution afforded the chloro dipolar cycloaddition reactions.142
derivative 88 in 88% yield (Scheme 23).129 Del Buttero et al.143 described a route for synthesis of
Grigg et al.130 described the 1,3-dipolar cycloaddition dihydropyrazoles 97 via 1,3-dipolar cycloaddition of 3(R)-
reaction between N-methylmaleimide 34 and azomethine phenyl-4(S)-(4-benzoyl-E,E-1,3-butadienyl)-2-azetidinone with
ylides, which were in situ prepared by condensation reaction nitrilimines 99, in situ generated by reaction of hydrazonoyl
of PG with α-amino esters 89−91 (Scheme 24). The reaction chloride 98 with 1 equiv of AgOAc in dioxane at room
was conducted by heating of a solution of 89−91, PG, and 34 temperature (Scheme 25). Reaction was carried out in the dark
in CH3CN or dry DMF at 80 or 120 °C, respectively. Reaction for 24 h to afford a complex mixture of the four isomeric
of 89 and 90 in refluxing CH3CN afforded single cycloadducts dihydropyrazoles 97 via site-selective and regioselective but not
pyrroloisoquinoline 92 and indolizinoindole 93 in 78% and stereoselective cycloaddition. The 2-azetidinone derivative was
73% yields, respectively, while in the case of the reaction prepared in 48% yield by a three-step synthetic sequence as
between 91, PG, and 34 in DMF at 120 °C for 16 h, outlined in Scheme 25. By treatment of PG with
pyrrolothiazole 94 was obtained in 73% yield with a 2.7/1/1 (triphenylphosphoranylidene)-acetaldehyde 95 in Wittig re-
ratio of 94a/94b/94c cycloadducts. action, followed by reaction with p-anisidine in EtOH at room
5.1.4. Pyrazolines and Pyrazoles. Pyrazolines are one of temperature for 5 min, imine derivative 96 was obtained, which
the most important five membered heterocyclic compounds, was converted into 2-azetidinone by reaction with phenylacetyl
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Scheme 24. Synthesis of Pyrroloisoquinoline 92, Indolizinoindole 93, and Pyrrolothiazole 94 via 1,3-Dipolar Cycloaddition
Reaction

Scheme 25. Synthesis of Dihydropyrazoles 97 via 1,3-Dipolar Cycloaddition Reactiona

a
Ar = 4-MeC6H4, 4-BrC6H4.

chloride in the presence of Et3N in DCM in the Staudinger [2 under heating at 110 °C for 1 h. 3-Benzoyl-4-hydroxy-5-
+ 2] cycloaddition reaction. phenylpyrazoles 103 were obtained, when the reaction was
Begtrup et al.144 reported the synthesis of 4-hydroxypyrazoles performed in the presence of water, by cyclocondensation of
101 in 15−86% yields via reaction of aldehyde hydrazones 100 PG with PG-hydrazones 102, which were generated in situ by
with PG under anhydrous conditions in n-BuOAc containing transhydrazonation of PG with 100 (Scheme 26). To prove this
AcOH in the presence of MgSO4. Reactions were performed statement, oxohydrazones 102 were prepared separately and
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treated with PG under same reaction conditions and produced Scheme 27. Synthesis of Pyrazole 107 and Pyridazinone 110
the corresponding benzoylpyrazoles 103.

Scheme 26. Synthesis of 4-Hydroxy-5-phenylpyrazoles 101

and 103a

a
R = Me, Ph; R′ = H, Me, Ph; 101, 15−86%; 103, 52−100%.

Meanwell et al.145 reported the Wittig reaction of the

Horner−Wadsworth−Emmons type reagents, phosphonates
104, with PG in the presence of NaOEt to produce C-5
unsaturated hydantoin derivatives 105a,b in 89−100% yields.
The spiro substituted pyrazoline 106 was obtained in 85% yield
by treatment of 105a with hydrazine in EtOH at room
temperature. Pyrazoline 106 was transformed to pyrazole 107
in 77% yield when heated in AcOH under reflux conditions for
4.5 h. The compound 105b was converted to pyridazinone 110
by reduction using zinc in AcOH, followed by treatment of 108
with an excess amount of hydrazine in ethanol, then by loss of Scheme 28. Synthesis of 3-Benzoylpyrazole 114
an urea molecule from 109 (Scheme 27).
3-Benzoyl-4-phenyl-1-methylpyrazole 114 was synthesized
by condensation of PG with protected 1-methyl-1-phenacylhy-
drazine 111 in the presence of AcOH in EtOH, followed by
treatment with 75% H2SO4 at room temperature for 2 weeks.
By reaction of 111 with PG, hydrazone 112 was produced,
which underwent deketalization to 113 in treatment with 75%
H2SO4 and then intramolecular condensation to yield 114 in
56% yield. Aldol type condensation of the methylene with the
carbonyl group of PG to produce 5-benzoyl-4-phenyl-1-
methylpyrazole 115 did not occur (Scheme 28).146 A similar
reaction was reported using phenyl-, p-bromophenyl-, and p-
methylphenylglyoxals to furnish the corresponding 3-aroylpyr-
azoles.147
5.1.5. Imidazolidin-2,4-diones and Imidazolin-2-ones.
Imidazolin-2-one and imidazolidin-2,4-dione (hydantoin) de-
rivatives have received great attention because of their
interesting biological activities,148 such as antioxidant,149
cardiotonic,150 herbicidal,151 aldose reductase inhibitors,152
antitubercular,153 antitumor,154 antiarrhythmics,155 anticonvul-
sants,156 anti-inflammatory,157 and antiandrogens activity.158
There are many known methods in the literature for the polyphosphoric ester (PPE) as a reaction mediator (Scheme
synthesis of imidazolin-2-ones159 and hydantoins160 via reaction 29). Also, the synthesis of 117 using PPE under neat conditions
of carbodiimides with α-bromoaryl acetic acids,160c α-amino was investigated using an oil bath (3 min and 120 °C), in which
amides with triphosgene,160d and α-amination process of the yields were low in comparison to microwave irradiation.
esters.160e The advantages of this protocol include a simple reaction setup,
Paul et al.161 developed a facile and efficient microwave- high product yields, short reaction times, and elimination of
induced solvent-free synthesis of 1,5-disubstituted hydantoins solvents and acid.
and thiohydantoins 117 in 80−95% yields via condensation of A similar reaction was carried out using a fluorine containing
the AGs with phenylurea or phenylthiourea 116 using AG, 2,4-dichloro-5-fluorophenylglyoxal, with different arylureas
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Scheme 29. Synthesis of Hydantoins and Thiohydantoins Scheme 30. Synthesis of 1,3,4-Thiadiazol-2-yl Substituted
117 via Condensation of Urea Derivatives with AGa Hydantoin 120

a
R, R′ = c-Hex, H, Ph, 4-BrC6H4, 3-ClC6H4, 4-ClC6H4, 3,4-Cl2C6H3,
4-HOC6H4, 3-IC6H4, 4-IC6H4, 4-MeOC6H4, 4-MeC6H4, 4-Me-
CONHC 6 H 4 , 3-NO 2 C 6 H 4 , 4-NO 2 C 6 H 4 , 2,4-(NO 2 ) 2 C 6 H 3 , 4-
HO3SC6H4; Ar = Ph, 4-BrC6H4, 4-ClC6H4, 2,4-Cl2-5-FC6H2, 2-Cl-4-
FC6H3, 3-Cl-4-FC6H3, 4EtOC6H4, 4-FC6H4, 2-F-5-MeC6H3, 4-F-3-
MeC6H3, 3-F-4-MeOC6H3, 2,4-F2C6H3, 4-MeC6H4, 4-MeOC6H4, 4-
NO2C6H4; X = O, S; ref 161, cond. = PPE, MW, 2.5−3.5 min, 80−
95%; ref 162, cond. = acidic alumina, MW, 7−10 min, 9−95%; ref 163,
cond. = HCl−AcOH, EtOH, reflux, 4 h, 59−85%; ref 164, cond. =
HCl−AcOH (15/0.5), reflux, 4−10 h, 59−64%; ref 165, cond. = 50%
KOH, reflux, 3 min, 26−85%.

or arylthioureas 116 under microwave irradiation on acidic

alumina as a solid support, and the corresponding hydantoins of water by hydride rearrangement to yield 5-aryl-3-
or thiohydantoins 117 were obtained in 9−95% yields in short hydroxyhydantoins 124 in 46−77% yields (Scheme 31). The
reaction times. Also, the synthesis of 117 was investigated using reaction was carried out by addition of AG-hydrate to the
acidic alumina under conventional heating (80−100 °C), in solution of 122 in water at room temperature.
which 117 was formed in poor yields in long reaction time. The
antibacterial activity of the products against Escherichia coli and Scheme 31. Synthesis of 3-Hydroxyhydantoins 124a
Streptococcus was investigated, and compounds having 4-Cl, 4-
Me, and 2,4-(NO2)2 substitutions exhibited the highest degree
of inhibition.162
Also, the synthesis of fluoroaryl containing hydantoins 117
was reported by condensation of 116 with fluoroarylglyoxals, 4-
F-, 2-Cl-4-F-, 3-Cl-4-F-, 2-F-5-Me-, 4-F-3-Me-, 3-F-4-MeO-,
and 2,4-F2-phenylglyoxal, using HCl−AcOH as catalyst in
refluxing absolute EtOH. The corresponding hydantoins 117
were obtained in 59−85% yields.163
Also, Muccioli and co-workers164 described the synthesis of
1,5-diaryl- and 1,3,5-triarylhydantoin derivatives 117 in 59−
64% yields. The 1,5-diphenyl derivatives were synthesized by
refluxing a mixture of PG and 116 for 4 h in glacial AcOH in
the presence of HCl. Also, 1,3,5-triphenyl derivatives were
obtained using 1,3-diarylurea or 1,3-diarylthiourea by the same
procedure. 1,3-Dicyclohexyl-5-phenylhydantoin was synthe-
sized from 1,3-dicyclohexylurea and PG. The 1,3,5-triphenyl- a
Ar = Ph, 4-ClC6H4, 4-MeC6H4, 2-thienyl; 46−77%.
hydantoin derivatives and their thio isosteres exhibited
interesting affinity and selectivity for the human CB 1
cannabinoid receptor. Also, the condensation reactions of PG Kostyanovsky et al.168 studied the reaction of PG with N-
with urea, phenyl urea, and methyl urea were carried out in alkoxy-N′-arylurea 125 and 126. The reaction was carried out
basic solution under thermal conditions.165 in DCM at room temperature. When N-benzyloxy-N′-(2-
As outlined in Scheme 30, one example of the condensation bromophenyl)urea was used, because of retardation of the
of PG-hydrate with urea having 5-t-butyl-1,3,4-thiadiazol-2-yl further cyclization into expected 5-phenylimidazolidin-2-one
substituent 118 was reported using aqueous NaOH in EtOH at derivative by the bulky o-bromo substituent, only acyclic N-
room temperature to afford dihydroxyimidazolidin-2-one 119, [(benzoyl)(hydroxy)methyl]-N-benzyloxy-N′-(2-
which was converted to the corresponding hydantoin 120 by bromophenyl)urea was obtained in 80% yield. But reaction
refluxing in the presence of p-TsOH in CH3CN in 87% yield. with 125 and 126 led to cyclic products, hydantoins 127b and
Treatment of hydantoin 120 with NaBH4 in EtOH afforded the 128b in 46% and 6% yields, respectively. In addition to 128b,
4-hydroxyimidazolidin-2-one 121 in 76% yield as only trans dihydroxyimidazolidinone 128a was produced in the reaction
isomer.166 of 126 with PG in 56% yield as the major product (Scheme
Shtamburg et al.167 reported the condensation reaction of 32). Probably, this can be attributed to participation of N-1,
AG-hydrate with N-hydroxyurea 122 in water via 3,4,5- containing aryl substituent, in 127a and 128a to removal of the
trihydroxy-5-arylimidazolidin-2-ones 123b as reaction inter- hydroxy group to give 129, which regenerated to enol 130 that
mediate, which underwent intramolecular proton transfer under tautomerization transformed to hydantoins 127b and
resulting in zwitterion 123c, followed by removal of a molecule 128b. In the case of 128a, p-nitro substituent on phenyl group
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Scheme 32. Synthesis of 3-Alkoxyhydantoins 127b and 128b

with electron-withdrawing characteristic retarded the gener- Kolos et al.170 studied the one-pot condensation reaction of
ation of 129 with positive charge on N-1 atom, leading to low 4-hydroxycoumarin 133 with AG and 116 to synthesize aroyl
yield of 128b. derivatives of chromeno[4,3-d]pyrimidines 135 via Biginelli
Recently, an efficient synthesis of hydantoins 132 has been reaction. The reaction was carried out by heating of a mixture
developed from the condensation reaction of 1,3-dicarbonyl of 133, AGs, and 116 in EtOH in the presence of a catalytic
compounds and acetophenones in the presence of CuO and I2 amount of AcOH under reflux conditions for 15−50 min, and
in DMSO at 70 °C, followed by addition of ureas 116 and interestingly, imidazol-2-ones 134 were obtained in 45−70%
heating at 100 °C (Scheme 33). This protocol involves an yields (Scheme 34).
Gozalishvili et al.171 described a similar reaction using 1,3-
Scheme 33. Synthesis of Hydantoins 132 via Two Coupled dimethylbarbituric acid 136. The reaction was conducted by
Domino Processesa heating the solution of equimolar amounts of 136, AGs, and

Scheme 34. Synthesis of Coumarin-3-yl Substituted

Imidazol-2-ones 134a

a
R = Ph, 4-ClC6H4, 4-FC6H4, 3,4,5-(MeO)3C6H2, 4-NO2C6H4, 2-
furyl; R′ = OEt, OMe, Ph; R″ = H, Et, Me, n-Pr; Ar = Ph, 4-BrC6H4, 4-
ClC6H4, 4-FC6H4, 4-HOC6H4, 4-MeOC6H4, 4-MeC6H4, 4-NO2C6H4,
2-benzofuryl, 2-furyl, 2-naphthyl, 2-thienyl; 42−76%.

integration of two coupled domino processes: iodine-promoted

synthesis of unsymmetrical 1,4-enediones 131 via Knoevenagel
condensation of the in situ generated AG with 1,3-dicarbonyl
compounds (domino I) and the sequential transformation into
132 via aza-Michael addition of urea and cyclocondensation
with carbonyl group, followed by oxidative dehydrogenation
and 1,2-rearrangement of aryl groups (domino II).169 Oxidative a
Ar = Ph, 4-BrC6H4, 4-ClC6H4, 4-IC6H4, 4-MeC6H4, 2-thienyl; R = H,
dehydrogenation occurred by action of I2. Me, Ph; R′ = H, Me; 45−70%.

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116 in MeOH in the presence of a catalytic amount of AcOH Scheme 37. Synthesis of Imidazolin-4-one 141
under reflux conditions for 25−40 min to produce imidazol-4-
yl-pyrimidine-2,4,6-triones 137 in 62−87% yields (Scheme 35).

Scheme 35. Synthesis of 4-[(Pyrimidine-2,4,6-trione)-5-

yl]imidazole-2-ones 137a

Scheme 38. Synthesis of 2-Iminoimidazolidin-4-one 143 via

Condensation of PG with 142

a
Ar = 4-C6H4, 4-IC6H4, 4-MeC6H4; 62−87%.

Another similar reaction was carried out using 1,3-dicarbonyl

compounds, in which by treatment of PG with N,N′-dimethyl compounds such as cimetidine, losartan, 178 fungicides,
urea 116 in the presence of ZnCl2 under reflux conditions or in herbicides,179 plant growth regulators,180 and therapeutic
the presence of ZnCl2/AlCl3 (1:3) on silica gel under agents.181 Due to their wide range of biological, industrial,
microwave irradiation, the multisubstituted imidazolin-2-one and synthetic applications, there are several methods reported
derivatives 138 were produced in 50−66% or 35−46% yields, in the literature for the synthesis of imidazoles.182
respectively (Scheme 36).172 By Ugi four component reaction of AGs, primary amines,
carboxylic acids, and isocyanides 144 on Wang resin,
ketoamides 145 were obtained, which underwent further
Scheme 36. Synthesis of Imidazol-2-ones 138a
cyclization to the corresponding imidazoles 146 in 16−56%
overall yields, when treated with 60 equiv of NH4OAc in AcOH
at 100 °C for 20 h, followed by reaction with 10% TFA-DCM
at 23 °C for 20 min (Scheme 39). The Ugi reaction was carried
out in a mixture of CHCl3−MeOH−pyridine (1:1:1) at 65 °C
for 3 days.183

Scheme 39. Synthesis of Imidazoles 146 via Ugi Reaction on

Wang Resina

a
R = OEt, OMe, Me; reflux, 50−66%; MW, 35−46%.

Waugh et al.173 described the condensation reaction between

PG-hydrate and benzamidine 139 in water in the presence of
KOH at room temperature to produce hydroxyphenacylbenza-
midine 140, which was cyclized to imidazole derivative 141
under heating in 64% yield (Scheme 37). Also, the reaction of
PG with aliphatic amidines was reported.174 Treatment of
guanidine hydrochloride 142 with PG-hydrate in the presence
of TFA in refluxing benzene by azeotropic removal of water
using Dean−Stark apparatus afforded the trifluoroacetate salt of
2-imino-5-phenylimidazolidin-4-one 143 (Scheme 38).175
5.1.6. Imidazoles. The imidazole moiety is present in a
wide range of naturally occurring molecules176 and has broadly
been found in biomolecules, including biotin, the essential
a
amino acid histidine, histamine, and the pilocarpine alka- n = 2, 10; Ar = Ph, 4-FC6H4, 4-MeOC6H4; R = Bn, i-Bu, Ph, 4-
loids.177 Imidazole structures are present in important synthetic MeOC6H4; R′ = Bn, n-Bu, Ph, 4-FC6H4; 16−56%.

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Sung et al.184 reported a similar procedure to synthesize Scheme 41. Synthesis of Two Isomeric Aroylimidazoles 150a
alternating benzene/imidazole systems in solution media by
multicomponent reaction of c-hexylisocyanide, benzoic acid, n-
butylamine, and PG-hydrate in MeOH at room temperature,
then by cyclization of obtained α-amido-β-ketoamide with in
situ generated NH3 by heating of (NH4)2CO3 in AcOH under
nitrogen atmosphere for 2 h in 55% yield. Also, the reaction
was carried out using isophthalic acid 147a and terephthalic a
Ar = Ph, 4-BrC6H4, 4-ClC6H4, 4-FC6H4, 4-MeOC6H4, 3,4-
acid 147b and corresponding bis-imidazoles 149a,b with five (MeO)2C6H3, 3,4-(OCH2O)C6H3, 4-biphenyl; 46−86%; a/b = 2.8−
consecutive aromatic rings were synthesized via Ugi products 7.5.
148 as intermediate in 40% and 43% yields, respectively
(Scheme 40). Because of the large steric hindrance, an attempt S4N4 in dioxane at reflux conditions for 6−15 h afforded the 2-
to use o-phthalic acid failed. aroyl-5-arylimidazoles 150b in 10−33% yields. In some cases,
depending on the substitution on the AG (Ar = Ph, 4-MeC6H4,
Scheme 40. Synthesis of Bis-imidazoles 149 via Ugi Products 4-MeOC6H4, and 4-CNC6H4), 2-aroyl-5-aryloxazoles 151 were
148a obtained in 17−32% yields, in addition to 150b. Imidazoles
150b and oxazoles 151 were synthesized via AG-imine, as an
intermediate, which was formed by the reaction of AG with
NH3 formed by decomposition of S4N4 at refluxed dioxane
(Scheme 42).

Scheme 42. Synthesis of 2-Aroylimidazoles 150b via

Reaction of AG with S4N4a

a
Ar = Ph, 4-BrC6H4, 4-ClC6H4, 4-NCC6H4, 4-MeOC6H4, 4-MeC6H4,
2-thienyl; 150b, 10−33%; 151, 0−32%.

The electrochemical reduction of phenacyl azides in the

presence of LiClO4 in DMF188 and pyrolysis of phenacyl azides
at 180−240 °C189 resulted in aroylimidazoles 150 via AG-imine
as intermediate of the reaction.
Bratulescu190 reported one example of the conversion of PG
to 4-phenylimidazoles 152 in reaction with urotropine as an in
vitro source of formaldehyde in the presence of NH4OAc and a
few drops of AcOH under solvent free microwave irradiation in
a
a, meta; b, para.
79% yield (Scheme 43).

Scheme 43. Synthesis of 4-Phenylimidazole 152 via Reaction

Recently, Khalili and co-workers185 reported a green and
of AG with Urotropine
simple method for the synthesis of two isomeric aroylimida-
zoles 150 by treatment of AG-hydrate with an excess amount of
NH4OAc in water at room temperature in 48−86% yields
(Scheme 41). The desired imidazoles 150 were obtained in
30−45 min. The isomeric ratio was determined by 1H NMR
using NH signal intensities of two isomers. Also the thermo-
tauto-isomerization process between two isomers was studied
by NMR techniques. The short reaction time and obtaining
pure products directly by filtration are some advantages of this Zuliani et al.191 reported the reaction of AG with aldehydes
method. A similar procedure was used for the synthesis of a in the presence of NH4OAc in MeOH at room temperature,
naturally occurring and biologically active alkaloid, 2-(p- which selectively resulted in 2,4(5)-diarylimidazoles 153 in 52−
hydroxybenzoyl)-4-(p-hydroxyphenyl)imidazole, isolated from 83% yields, suffering from the formation of unwanted 2-aroyl-
the red ascidian Botryllus leachi.186 4(5)-arylimidazoles 150 (Scheme 44). The reaction of PG with
Kong et al.187 reported the reaction of AG-hydrate with benzaldehyde in the presence of NH4OAc was investigated
tetrasulfur tetranitride (S4N4). Heating a mixture of AG and under different conditions, and it was observed that the
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Scheme 44. Synthesis of 2,4(5)-Diarylimidazoles 153a A similar procedure was used to synthesize the imidazole
moiety of L-733,725, 156, a new immunosuppressant drug
candidate. Different aldehydic components such as glycolalde-
hyde dimer 157, chloroacetaldehyde 160, glyoxalic acid 162,
and hemiacetal of methyl glyoxalate 163 were treated with 3,5-
dimethoxyphenylglyoxal or PG in the presence of NH4OAc to
obtain the precursor of the imidazole alcohol 166 (Scheme 45).
By treatment of 157 with 3,5-dimethoxyphenylglyoxal hydrate
in the presence of NH4OH, a 2/1 mixture of the desired
imidazole 158 and the imidazole 159 was produced. When 160
was used, only the hydrated oxazole 161 was isolated. Reaction
with 162 afforded the decarboxylated imidazole 152 in 61%
yield. But, when 163 was used, the desired aryl imidazole ester
a
164 was obtained in 75% yield. The ester group of the THF-
153: Reference 191: Ar and Ar' = Ph, 3-ClC6H4, 4-ClC6H4, 3- protected imidazole was reduced to the alcohol 166 in high
CF3C6H4, 4-CF3C6H4, 3-MeOC6H4, 4-MeOC6H4, 3-NO2C6H4, 4-
NO2C6H4; 52−83%. Reference 193: Ar = Ph, Ar' = Ph, 2-benzofuryl,
yield using LiBH4 in the presence of MeOH in THF at 10−15
2-furyl, 3-furyl, c-Hex, 3-pyridyl, 4-pyridyl, 3-thienyl. °C for 2 h, which was subjected to further reactions to yield L-
733,725.195 Also, the synthesis of 164 was investigated in large
scale using 5.0 mol of 3,5-dimethoxyphenylglyoxal hydrate, and
850 g (63%) of 164 was obtained.
selectivity of the reaction was affected by solvent. MeOH at The condensation reaction of acetate salt of 3-hydroxyamino-
room temperature afforded the best yield of 153 (83%). The 2-butanone oxime 167 with AG-hydrate was studied by
evaluation of 153 for inhibition of the human neuronal Nav1.2 Amitina et al.196 The reaction was carried out in MeOH at
sodium channel isoform192 and hNav1.2 sodium channel193 was room temperature leading to α-aroylnitrone 168, which upon
investigated, and m-CF3 substituted derivative 154 showed high heating in the presence of AcOH, underwent cyclization−
activity for Nav1.2 sodium channel. A similar procedure for dehydration sequences to afford 1-hydroxyimidazoles 170 in
synthesis of 153 was applied by Husain et al. using NH4OAc in 46−84% yields via intermediate 169 (Scheme 46). In the case
AcOH.194 of 4-methoxy-, 4-ethoxy-, and 3,4-diethoxyphenylglyoxal, when

Scheme 45. Synthesis of Imidazole Moiety of L-733,725

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Scheme 46. Synthesis of 1-Hydroxyimidazoles 170a Synthesis of 2,2-dimethyl-4-phenyl-2H-imidazole 176 was

reported via condensation reaction of PG with acetone in the
presence of NH3 in 72% yield. The reaction was carried out by
bubbling of NH3(g) through a solution of acetone in Et2O,
following by dropwise addition of the solution of PG in dry
Et2O, in which the carbonyl carbon of acetone provided the C-
2 of imidazole 176 (Scheme 48).198

Scheme 48. Synthesis of 2,2-Dimethyl-4-phenyl-2H-

imidazole 176

Spongotine A and B, bisindole alkaloids isolated from marine

sponges possessing an imidazole moiety, have been synthesized
by different groups using 3-indolylglyoxal as starting material or
intermediate.199
a
Ar = Ph, 4-ClC6H4, 4-EtOC6H4, 3,4-(EtO)2C6H3, 4-MeOC6H4, 4- 5.1.7. Fused Imidazopyridines, -Pyrimidines, and
NO2C6H4; 46−84%. -Pyrazines. Substituted fused heterocycles can be found in
many types of synthetic and naturally occurring medicinal
substances200 such as coelenterazine, an imidazolopyrazinone
reaction was carried out by heating in MeOH in the presence of derivative.201 It was found that imidazo[1,2-a]pyrazinones
AcOH for 2 h, directly afforded corresponding 1-hydroxyimi- exhibit a significant solvatochromism 202 and bio- and
dazoles 170. In the case of 4-chloro- and 4-nitrophenylglyoxal chemiluminescence.201a,203 Imidazo[1,5-a]pyridines204 possess
in addition to 170, the pyrazine 1,4-dioxides 171 were obtained various applications such as dyes,205 optical data carriers,206
in 8−12% yields. pesticides, fungicides,207 hypoglycemic agents,208 and com-
Also, a similar reaction was carried out by heating of acetate pounds exhibiting antitumor,209 anti-inflammatory, antipyretic,
salts of 2-hydroxyaminocyclohexanone and cyclopentanone and analgesic activity.210 Oxidative condensation−cyclization of
oxime 172 with pentafluorophenylglyoxal hydrate in MeOH to aldehydes with 2-aminomethylpyridines211b−d or Pictet−
afford 174 in 26−30% yields via cyclization of intermediate 173 Spengler strategy211e−g are among the most important routes
with elimination of HF (Scheme 47). In addition to 174, to synthesize of these types of fused heterocycles.211
pyrazine 1,4-dioxides 175 were obtained in low yields.197 The reaction of 2-amino-N-heterocyclic compounds 177
with AG-hydrates was investigated by Alcaide et al.212
Scheme 47. Synthesis of Benzo[e]imidazo[1,2- Reactions were carried out by addition of AG-hydrates to a
b][1,2]oxazin-10-one 174 solution of 177 in DCM in the presence of BF3·OEt2 or in
benzene without using any catalyst at room temperature for 7−
264 h, and corresponding bicyclic imidazo[l,2-a]-derivatives
181−183 were obtained in 35−100% yields. Pyridone imine
179 was proposed as reaction intermediate, which was
generated either by the rearrangement of intermediate
carbinolamine 178 or by direct reaction of 177 with the
aldehyde group of the AG through the N atom of heterocyclic
ring, which then cyclized to 180 and dehydrated to 181−183
(Scheme 49). There are other reports on condensation
reactions of 177 with PG.213
Devillers and co-workers214 reported the synthesis of
imidazopyrazinones 183, substituted at C-2 or C-2 and C-6
by condensation reaction of 2-aminopyrazines 177 (X = CH, Y
= N) with AGs or AG-acetals in the presence of HCl in
refluxing EtOH under argon atmosphere for 4 h (Scheme 50).
Antioxidant activity of the obtained products was investigated,
and they behaved as quenchers of superoxide anion.215 Also the
solvatochromism of 183 was investigated by Fujio et al.216
A similar condensation reaction with PG was reported by
Barlin et al.217 using 177 in an ethanolic solution of conc. HCl
to yield 183 and 184 in 46−62% yields (Scheme 51).
The synthesis of 5-acylamido-6-phenylimidazo[2,1-b]-
thiazoles 187 and 2-phenyl-3-acylamidoimidazo[1,2-a]-
pyridines 188 was described by Drach et al.218 through the
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Scheme 49. Synthesis of Bicyclic Imidazo[1,2-a]pyridine, Scheme 52. Synthesis of Imidazothiazoles 187 and
Pyrimidine, and Pyrazines 181−183a Imidazopyridines 188a

a
R = Me, MeO; 187, 55−62%; 188, 60−68%.

(phenylamino)methylpyrrolidine 189, which was conducted

in refluxing toluene by azeotropic removal of water in 83% yield
(Scheme 53).219 Then, obtained 190 was subjected to reaction
a
Conditions = benzene, rt, or BF3·OEt2, DCM, rt; 7−264 h. 181: X = Scheme 53. Synthesis of Pyrroloimidazole 190
Y= CH; Ar = Ph, 4-ClC6H4, 4-MeOC6H4, 4-MeC6H4, 4-NO2C6H4; R
= H, 6-Cl, 8-MeO, 5-Me, 6-Me, 7-Me, 8-Me; 35−100%. 182: X = N, Y
= CH; Ar = Ph, 4-ClC6H4, 4-MeC6H4; 40−72%. 183: X = CH, Y = N;
Ar = Ph, 4-ClC6H4, 4-MeOC6H4; 53−100%.

Scheme 50. Synthesis of C-2 and C-6 Disubstituted

Imidazopyrazinones 183a

a
Ref 214, R = Ph, 4-HOC6H4, 4-MeOC6H4; ref 215, R = H.

Scheme 51. Synthesis of Imidazopyridazines 184a

with metalated methyldiphenylphosphine oxides to give

a
X, Y = N, CH; R= H, Cl; 184, 46−62%; 183, 49%. hydroxyl aminal 191, which was converted into diol 192 by
hydrolysis with 2% HC1 followed by reduction with LiAlH4
with >97% ee.220 Also, the reaction of 190 with Grignard
reaction of 2-aminothiazole 186 and 2-aminopyridine 177 (X = reagents was reported, which followed by hydrolysis with 2%
Y = CH) with ω-chloro-ω-acylaminoacetophenones 185, which HCl afforded the corresponding α-hydroxyaldehydes in 67−
were prepared by condensation of PG with amides, followed by 82% yields with 94−96% ee.219
reaction with thionyl chloride or phosphorus pentachloride. 5.1.8. 1,2,3-Triazoles and Tetrazoles. 1,2,3-Triazole has
The reaction was carried out by standing of a solution of 185 become one of the most important heterocycles in current
and 186 or 177 in THF at room temperature for 24 h, followed chemistry research,221 due to its important industrial, agro-
by evaporation of THF and reflux of the residue in MeOH for 1 chemical, and pharmaceutical applications,222 especially in
h (Scheme 52). biological science,223 material chemistry,224 and medicinal
There is a report on synthesis of hexahydro-1H-pyrrolo[1,2- chemistry.225 One of the most attractive ways to prepare
c]imidazole 190 via reaction of PG-hydrate with 2- these compounds involves the thermal 1,3-dipolar cyclo-
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addition of azides with alkynes.221b,226 Additionally, the Scheme 55. Synthesis of Benzoyltetrazole 201
chemistry of the tetrazole ring is gaining increasing attention
due to its importance in a variety of synthetic and industrial
processes227 and excellent properties as a metabolically stable
isosteric replacement for the carboxylic acid moiety228 and as a
cis-peptide bond mimetic.229 Tetrazoles have also been used as
precursors to other heterocycles230 and in high energy
compounds.231 The synthesis of tetrazoles from a cycloaddition
reaction between a nitrile and an azide is well documented.232
The reaction of α-hydroxyacetophenones 193 and phenyl-
hydrazines was studied by Tang and Hu233 leading to 2,4-
diaryl-1,2,3-triazoles 196. The reaction occurred via CuCl2-
catalyzed oxidative cyclization reaction in refluxing glacial
AcOH. Similar to the formation of sugar osazone, by treatment
of 193 with phenylhydrazine, PG-bisphenylhydrazone 194 was
obtained, which underwent oxidative cyclization using CuCl2 to
give intermediates 195. Finally, intermediates 195 were
transformed to 196 by losing an arylnitrene molecule under
thermal conditions in 52−86% yields (Scheme 54).

Scheme 54. Synthesis of 1,2,3-Triazoles 196a Scheme 56. Synthesis of Tetrahydrofurans 203 via [3 + 2]
Cycloaddition Reaction of 202a

a
SiR3 = Sit-BuPh2, SiMe2Ph, Si(i-Pr)2Ph; Ar = Ph, 4-ClC6H4, 4-
a MeOC6H4, 4-MeC6H4, 2-furyl, 2-naphthyl, 2-thienyl; temp = 0 °C,
Ar = Ph, 4-BrC 6 H4 , 4-ClC 6 H 4 , 4-FC 6 H 4 , 4-HOC 6 H 4 , 3,4-
56−90%, trans/cis = 59/41−99/1; temp = −78 °C, 57%-quant., trans/
(HO)2C6H3, 4-MeOC6H4, 3,4-(MeO)2C6H3; Ar′ = Ph, 4-ClC6H4, 4-
cis = 26/74−48/52.
MeOC6H4, 2-MeC6H4; 52−86%.

while at −78 °C, products cis-203 were obtained, stereo-

One example of the construction of tetrazole 201, using PG-
selectively.
monohydrazone 198, was reported by Yates et al.234 via base-
Beck et al.241 reported the synthesis of 5-acylamino
catalyzed reaction with α-diazoacetophenone 197 in MeOH at
butenolides 205 by a sequence of a Passerini reaction and an
room temperature for 1 h. The PG-monohydrazone 198 was
intramolecular Horner−Wadsworth−Emmons (HWE) mod-
formed in situ by reduction of 197 by methanolic NaOMe. The
ification of the Wittig reaction. The reaction was carried out via
resulting intermediate 199 underwent cyclization to 200 which
multicomponent reaction of AGs, isocyanides, and 42 in Et2O
by elimination of acetophenone resulted in 201 (Scheme 55).
or THF to afford Passerini adducts 204, which underwent
5.2. O-Heterocyclic Compounds intramolecular HWE reaction using LiBr and Et3N in THF to
5.2.1. Tetrahydro- and Dihydrofurans. Tetrahydrofuran furnish 205 in 13−87% yields (Scheme 57). The reaction was
and dihydrofuran skeletons are frequently found in natural performed either in one pot or with the isolation of the
products,235 biologically active compounds,236 and valuable Passerini products 204.
intermediates for organic synthesis.237 Thus, much attention By treatment of AGs, isocyanides, and cyanoacetic acid in
has been paid to the development of new methods for the Passerini reaction, N-substituted 3-aryl-2-cyanoacetoxy-3-oxo-
synthesis of tetrahydrofuran237f,238 and dihydrofurans,239 propionamides 206 were obtained, which were cyclized to 207
including [3 + 2] cycloaddition reactions, oxidative cyclization in the presence of Et3N. The reaction was conducted by
reactions and cyclization of alkenols and alkynols. treatment of a solution of AGs and isocyanides with cyanoacetic
Fuchibe et al.240 reported the [3 + 2] cycloaddition reactions acid in Et2O at room temperature for 6 h, followed by addition
of cyclopropylmethylsilanes 202 and AGs in the presence of of a solution of Et3N or piperidine in MeOH to a solution of
SnCl4 to afford 2-silylmethyl substituted tetrahydrofurans 203. obtained solid 206 in MeOH and stirring at room temperature
The reaction of 202 with PG was examined using different for 10 min. Acidification of the reaction mixture with 6 N HCl
Lewis acids in different solvents, and SnCl4 in DCM was until pH = 4 afforded the dihydrofuran-2-ones 207 in 78−85%
selected as optimum conditions based on high yields of 203 yields. The reaction of 207 (Ar = 4-ClC6H4, R = c-Hex) with an
(Scheme 56). The stereoselectivity of the reactions was excess amount of CH2N2 in Et2O−CHCl3 at room temperature
dependent on the reaction temperature. When reaction was in 6 h yielded corresponding 5-methoxy furan 208b via hydroxy
carried out at 0 °C, products trans-203 were the major isomer, furan 208a in 73% yield (Scheme 58).242
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Scheme 57. Synthesis of Dihydrofuran-2-ones 205 via Scheme 59. Synthesis of 5-Hydroxy Dihydrofurans 211a
Passerini−HWE Reactionsa

a
R = allyl, n-Bu, t-Bu, c-Hex, t-BuO2CCH(Me), t-BuO2CCH2CH2,
MeO2CCH(CH2CHMe2); R′ = H, Ph, 4-FC6H4, 3-MeOC6H4; Ar =
Ph, 4-HOC6H4, 4-biphenyl, 2-naphthyl, 2-thienyl; 13−87%.

Scheme 58. Synthesis of Dihydrofuran-2-ones 207 via

Passerini Reactiona
a
R = t-Bu, Et, Me; Ar = Ph, 4-BrC6H4, 4-NO2C6H4; 71−85%; cis/trans
= 10/90−62/38.

Scheme 60. Synthesis of Formoins 212 via Benzoin

Condensation of AGa

a
Ar = Ph, 4-MeC6H4, 2-furyl, selenophen-2-yl, 2-thienyl; 27−71%.

Scheme 61. Synthesis of Formoin Diacetate 216

a
R = c-Hept, c-Hex, c-Pent; Ar = Ph, 4-ClC6H4, 4-MeC6H4, 2-thienyl;
206, 78−82%; 207, 78−85%.

Anary-Abbasinejad et al.243 described the reaction between

AG-hydrates, DAAD, and Ph3P to give dihydrofuran derivatives
211. Treatment of DAAD with Ph3P and AG-hydrates in DCM
at room temperature gave rise to DAAD−PPh3 zwitterions 209,
which by protonation and conjugate addition with AGs to give
210 followed by intramolecular Wittig reaction afforded 211 in
71−85% yields (Scheme 59). The dihydrofurans 211 were
isolated as two diastereomers. The cis/trans ratio was
determined to be 10/90 to 62/38 using 1H NMR spectroscopy. The synthesis of [2-alkoxy-5-amino-4-cyanofuran-3(2H)-
Peter et al.244 worked on the benzoin condensation of AGs ylidene]malononitriles 221 was reported by Bardasov et al.246
using potassium cyanide in aqueous EtOH. The reaction was via reaction of 3-aroylcyclopropane-1,1,2,2-tetracyanides 217
carried out by adding of a solution of KCN in 50% aqueous with NaOMe or sodium 2-hydroxyethoxide in the correspond-
EtOH to an ice-cold solution of AGs in EtOH and stirring. The ing alcohols in 42−85% yields. Also, the reaction was
reaction was solidified and corresponding formoins 212 were investigated with sodium salts of acetone and acetaldehyde
prepared in 27−71% yields (Scheme 60). oximes, in which corresponding 221 were obtained in 19−87%
Also, formoin diacetate 216 was prepared by refluxing of PG yields (Scheme 62). The reaction was performed by adding of a
in Ac2O containing pyridine in good yield via benzoin suspension of cyclopropane derivative 217 in appropriate
condensation. The plausible reaction mechanism involves the solvent to a solution of either NaOMe in MeOH,
removal of a proton from the diacetyl derivative 213 by NaOCH2CH2OH in ethylene glycol, or sodium salts of oximes
pyridine to generate an anion 214 and its reaction with another in CH3CN with stirring at room temperature for 24 h, then
molecule of PG to afford intermediate 215, which then cyclized neutralization with 5% H2SO4. The 217 was transformed to
to 216 (Scheme 61).245 220 via dianion intermediates 218 and 219. The precursor 217
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Scheme 62. Synthesis of Furanylidene Malononitriles 221a Reduction of 223 to 225 occurred by action of CH2O·BF3, in
situ generated in the conversion of 223 to 224. To trap the
furfuryl carbocation intermediate 223, the BF3·OEt2-catalyzed
reaction of 222a in the presence of an electron-rich furan
derivative such as 225 (Ar = 4-MeC6H4) was investigated in the
presence of water in THF at 23 °C for 30 min, in which a
dimeric furan 226 was obtained in 49% yield (Scheme 64).
Compounds 222 were prepared by Knoevenagel condensation
of AGs with acetylacetone in boiling CH3CN without any
catalyst in 98% yield. By treatment of 222a with Ph3P in CHCl3
under reflux conditions for 30 min, deoxygenation occurred to
give 225a (Ar = Ph) in 88% yield (Scheme 64). When
pentenedione 222a was treated with conc. HCl in THF at 23
°C chloromethylfurane 229 was produced in 87% yield, which
was transformed into 2-ethoxymethylfuran 230a in boiling
ethanol for 30 min or converted into the corresponding furfuryl
alcohol 230b by hydrolysis in refluxing water−THF for 3 h
(Scheme 63). Diels−Alder (DA) reaction of 222a with
cyclopentadiene was also carried out in EtOAc at 23 °C for 2
a
h, and 2-oxabicyclo[3.3.0]octene 227 was obtained together
Ar = Ph, 4-BrC6H4, 4-MeOC6H4, 3,4-(MeO)2C6H3, 3-NO2C6H4, 2- with the corresponding DA cycloadduct 228 (Scheme 64).
thienyl; R/solvent = Me/MeOH, HOCH2CH2/HOCH2CH2OH, On the other hand, the BF3·OEt2-catalyzed condensation of
MeCHN- or Me2CN-/CH3CN; 42−85%.
222 with acetylacetone or ethyl acetoacetate afforded 231
(50%) together with isomeric 232 or corresponding furan
was prepared by three-component reaction of AG with 2- carboxylate 233 (31%), respectively (Scheme 65).260,261
bromomalononitrile and malononitrile in i-PrOH at room The 1,4-diones 66 were converted into 3-methylthio-
temperature in 68−82% yields. substituted furans 234 using SnCl2 in a mixture of conc. HCl
5.2.2. Furans. Furans and their derivatives are very useful as and AcOH (4/6, mL/mL) under reflux conditions in 69−90%
starting materials to produce pharmaceutically and industrially yields. Removal of the methylthio group using Raney-Ni in
important compounds.247 Furan moieties exist in numerous refluxing EtOH gave the 2,5-diaryl furans 235 in 85−91%
bioactive natural products, such as kallolides,248 cembrano- yields. Also, by treatment of the 1,4-diones 66 with a solution
lides,249 calicogorgins, furan fatty acids,250 cytotoxic furanocem- of 30% HBr in AcOH in the presence of a drop of H2SO4 in
branes,251 gersolanes,252 pseudopteranes,253 rosefuran,254 agas- CHCl3 at 0 °C, the corresponding bromofurans 236 were
sizin, furodysin,255 and α-clausenan,256 and are frequently used obtained in 58−92% yields (Scheme 66).262
as intermediates in organic synthesis.257 Although a variety of Yang and co-workers263 provided an efficient synthesis of
furan syntheses are known,258 especially Paal−Knorr reac- indole−furan conjugates from the reaction of indoles, aryl
tion,259 the development of new and convenient strategies is of methyl ketones, and 1,3-dicarbonyl compounds (Scheme 67).
considerable interest. Aryl methyl ketones were converted into 66 and 131 via AG
Onitsuka and co-worker260 studied the BF3·OEt2-catalyzed intermediates using CuO, I2, and DMSO by self-condensation
reaction of 3-acetyl-1-aryl-2-pentene-1,4-diones 222 in the or condensation with 1,3-dicarbonyl compounds, respectively
presence of water in THF under reflux conditions, which (Schemes 18 and 33). Treatment of indoles with obtained 66
afforded bis-furans 224, with a small amount of 225 via and 131 afforded the 3-(furan-3-yl)indole derivatives 237 via
intramolecular cyclization reaction. It is known that relatively linear domino Friedel−Crafts alkylation/Paal−Knorr cycliza-
stable furfuryl carbocation 223 is the intermediate of the tion. Different Lewis and Brønsted acids and solvents were
reaction of 222 under wet reaction conditions (Scheme 63). investigated for construction of the furan skeleton, and MsOH

Scheme 63. Synthesis of Furan Derivatives via BF3·OEt2-Catalyzed Reaction of 1,4-Diones 222a

a
Ar = Ph, 4-FC6H4, 4-ClC6H4, 4-MeC6H4, 4-MeOC6H4; 224, 21−79%; 225, 3−10%.

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Scheme 64. Synthesis of Furan Derivatives via Reactions of 1,4-Diones 222

Scheme 65. BF3·OEt2-Catalyzed Synthesis of Furans 231− Scheme 66. Synthesis of 2,5-Diarylfurans 234−236a
233a

a
Ar = Ph, 4-BrC6H4, 4-ClC6H4, 4-EtOC6H4, 4-MeOC6H4, 4-MeC6H4,
2-benzofuryl, 1-naphthyl, 2-naphthyl, 2-thienyl, 3-thienyl; 234, 69−
90%; 235, 85−91%; 236, 58−92%.

tautomeric form 243b led to the formation of 2,5-diphenylfuran

a
Ar = Ph, 4-ClC6H4, 4-FC6H4, 4-MeOC6H4, 4-MeC6H4; 231, 15− 244 in water. But, when PG was heated in cyclohexane, only
77%; 232, 8−59%. the reduced forms 245 and 246 were prepared. In water at 200
°C after 6 h, only a small amount of 245 was obtained (Scheme
69).
in refluxing CH3CN was selected for good efficiency, which 5.2.3. Benzofurans and Furofurans. Benzofuran moieties
gave the desired indole−furan conjugates 237a and 237b in are widely presented in many naturally occurring and
24−99% and 47−97% yields, respectively. biologically active compounds, which display various pharma-
3-Alkylthiofurans 241 were synthesized via photoaddition of cological activities266 and antifungal,267 antibacterial,268 anti-
PG with 1-alkylthio-1-propynes 238 in benzene, followed by neoplastic,269 antiviral,270 antioxidative,271 anti-inflammatory272
treatment of the obtained 1,4-enediones 240 with SnC12 and and angiogenesis inhibitory273 properties. Substituted benzo-
HCl in AcOH at 80 °C for 10 min. Irradiation of the PG with furans have wide range of applications such as of fluorescent
238 gave 240, through oxete intermediates 239, in 20−25% sensors,274 oxidants,275 brightening agents, and a variety of
yields. The intermediates 239 were produced via [2 + 2] drugs and in other fields of chemistry and agriculture.276
cycloaddition of the alkyne’s triple bond with the aldehyde Therefore, a number of routes leading to substituted
group of PG (Scheme 68).264 benzofurans have been described in the literature,277 such as
The high-temperature chemistry of PG in water and Pd-catalyzed coupling/cyclization reactions of alkynes with o-
cyclohexane was studied at 200 °C by Katritzky et al.265 hydroxyaryl halides,277k,l carbonylative annulation of o-hydrox-
Disproportionation of PG produced benzoylmethanol 243, yarylacetylenes,277m tandem Michael addition/cyclization of
which converted to acetophenone and starting PG via further quinones with 1,3-dicarbonyl compounds,277n SmI2 or Bu3SnH-
disproportionation. Condensation of acetophenone with mediated radical cyclization,277o,p and Claisen rearrangement
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Scheme 67. Synthesis of Indole−Furan Conjugates 237 via Additionally, furofurans exhibit a wide variety of biological
Domino Friedel−Crafts/Paal−Knorr Reactionsa activities including antitumor,278 antimitotic,279 antiviral,280
antioxidant,281 and antihypertensive activities,282 inhibition of
platelet activating factor (PAF)283 and Ca2+ channels,284 cAMP
phosphodiesterase inhibition,285 sodium-selective diuretic
properties,286 and microsomal monooxygenase inhibitory
effects for insects.287 Several synthetic approaches to furofurans
have been reported in the literature.288
Talinli et al.289 studied the reaction of AGs with phenolic
compounds such as resorcinol and 2-naphthol under acidic
conditions, in which the reaction products were changed
depending on the type of the phenolic compounds. By
treatment of AGs with 2 equiv of resorcinol in toluene in the
presence of p-TsOH at 70−80 °C, 2-phenyl-3-(2,4-dihydroxy)-
6-hydroxy-benzo[b]furans 248 were obtained in 52−60% yields
via a sequence of Friedel−Crafts semiacetalization reactions
followed by removal of a molecule of water (Scheme 70).

a Scheme 70. Synthesis of Benzofurans 248a

237a: R = Ph, 4-ClC6H4, 4-FC6H4, 3,4,5-(MeO)3C6H2, 4-MeC6H4, 3-
NO2C6H4, 4-NO2C6H4, 2-furyl; R′ = OEt, OMe, Me, Ph; R″ = H, Me;
Ar = Ph, 4-BrC6H4, 4-ClC6H4, 3,4-Cl2C6H3, 4-FC6H4, 4-OHC6H4, 4-
MeOC6H4, 4-MeC6H4, 4-NO2C6H4, 2-benzofuryl, 1-naphthyl, 2-
naphthyl, 3-thienyl; reflux, 8−10 h, 24−99%. 237b: Ar = Ph, 4-
BrC6H4, 4-ClC6H4, 4-FC6H4, 4-MeOC6H4, 4-MeC6H4, 4-NO2C6H4, 2-
naphthyl, 3-thienyl; reflux, 5 h, 47−97%.

Scheme 68. Synthesis of 3-Alkylthiofurans 241a

a
Ar = Ph, 4-ClC6H4; 52−60%.

Compounds 247 were proposed as reaction intermediates. But

reaction of AGs with 2-naphthol resulted in formation of
benzo[b]naphtho[2,1-f ]oxepin-13-ones 249 (Scheme 71),

Scheme 71. Reaction of AG with 2-Naphthol and Synthesis

of Benzooxepine 249a
a
R = t-Bu, Et, Me, Ph; 240, 20−25%; 241, 80−95%.

Scheme 69. High-Temperature Chemistry of PG

a
X = H, Br; Y = H, Cl, OMe; 35−60%.

which was attributed to prevention of semiacetalization step

by the steric bulk of the naphthol ring. The reaction was carried
out by heating the mixture of AGs with 2 equiv of 2-naphthol in
AcOH in the presence of H2SO4 as catalyst at 50 °C and
compounds 249 were obtained in 35−60% yields.
followed by Pd-catalyzed intramolecular oxidative cycliza- An InCl3-catalyzed three-component reaction of phenols,
tion.277q AG-hydrates, and p-TsNH2 was reported by Chen et al.290 that
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afforded 2-aryl-3-aminobenzofuran derivatives 250. The re- Scheme 74. Synthesis of Hexahydrofurofurandiones 255 via
action of p-(t-Bu)phenol with PG-hydrate was examined using Reformatsky Reactiona
different Lewis acids, and the best results were obtained when
InCl3 was used as catalyst. Reactions were carried out by mixing
of AG-hydrate, p-TsNH2, and catalytic amounts of InCl3 in
DCM at room temperature and stirring for 30 min, then by
addition of phenols and heating at 40 °C for 6−16 h to give
250 in 45−94% yields (Scheme 72). Reaction of phenols

Scheme 72. InCl3-Catalyzed Synthesis of 3-

Aminobenzofurans 250a

a
R = H, Me; Ar = Ph, 4-BrC6H4, 4-t-BuC6H4, 4-ClC6H4, 4-EtC6H4, 4-
FC6H4, 4-MeC6H4; 28−85%.
a
Ar = Ph, 4-ClC6H4, 4-MeOC6H4; R = H, 4-Br, 4-t-Bu, 2,4-di-t-Bu, 4-
Cl, 4-F, 4-MeO, 4-Ph; 45−94%. (258) and furo[2′,3′:2,3]furo[5,4-c]isoquinoline-10-carboni-
trile 262 via route b (259) and intermediate 261 in a ratio of
containing electron-donating groups led to the corresponding 2:3 (Scheme 75).293 The compound 257 was prepared by the
250 in high yields, while phenols with electron-withdrawing condensation of 2-methyl-1,3-(2H,4H)-isoquinolinedione 256
substituents afforded the 250 in moderate yields. with PG.294
A one-pot three-component reaction of 4-hydroxycoumarin 5.2.4. Dioxolanes. 1,3-Dioxolanes are found in biologically
133 or dimedone 70 with AGs and isocyanides was reported, active compounds such as dioxolane nucleosides with
which afforded furocoumarins 251 or benzofurans 252, anticancer295 activity and act as inhibitors of herpes simplex
respectively. The reactions were carried out in refluxing viruses (HSV)296 and isozyme-selective heme oxygenase
CH3CN without any catalyst for 5 h to give corresponding (HO).297 In the literature, some synthetic routes, starting
products in 88−92% yields (Scheme 73).291 from tartaric acid and carbohydrate derivatives,298 dicarbonyl
compounds via radical addition to the carbonyl carbon,299
Scheme 73. Synthesis of Furocoumarins 251 and carbonyl ylides via 1,3-dipolar cycloaddition to aromatic
Benzofurans 252a aldehydes,300 and 2-hydroxyethyl vinyl ethers via Pd-catalyzed
cyclization,301 are commonly used to obtain dioxolanes. In
addition, 1,3-dioxolanes were synthesized widely for protection
of carbonyl groups.302
Shao and Li303 have described the synthesis of hemialdals
263 by direct oxidation of acetophenones using DMSO in the
presence of a catalytic amount of I2, in which the AG-hydrate
was produced as reaction intermediate, which on further
heating in toluene using Dean−Stark apparatus to remove
produced water resulted in 263. Hemialdals 263 were
converted into 2,4,5-triacyl-1,3-dioxolanes 264 in 43−70%
yields with excellent stereoselectivity, when treated with α-
bromoacetophenone and Et3N in the presence of LiBr in THF
at room temperature for 15−60 min (Scheme 76). Also the
reaction of AG-hydrates with α-bromoketones under similar
conditions to produce 264 in 35−61% yields with excellent anti
a
Ar = Ph, 4-BrC6H4, 4-ClC6H4, 4-NO2C6H4; R = t-Bu, c-Hex; 88− selectivity were reported. As the authors mentioned, the
92%. reactions proceeded via 263 as intermediate. Hemiacetal 265
was also employed in the reaction with α-bromoacetophenone
to give the corresponding dioxolane 264 in moderate yield and
Shchepin et al.292 described the Reformatsky reaction of AGs
excellent stereoselectivity (anti/syn > 99:1) (Scheme 77).304
with methyl 2-bromopropionate and methyl 2-bromo-2-
Manning et al.305 described the reaction of acetophenone
methylpropionate in ether−HMPA mixture under heating
with nitrosyl chloride in the presence of l,2-propanediol. The
conditions. The both carbonyl groups of the AGs were
reaction was performed by slowly adding the nitrosyl chloride
attacked by initially arising Reformatsky reagent 253 to provide
to the solution of acetophenone in benzene in the presence of 8
zinc bromide alcoholate 254, which spontaneously cyclized to
equiv of 1,2-propanediol. PG was in situ generated and
bicyclic products, hexahydrofurofurandiones 255, under the
underwent reaction with 1,2-propanediol to produce bis-
reaction conditions in 28−85% yields. (Scheme 74).
dioxolane 266 in 36% yield (Scheme 78).
The Michael reaction of 2-methyl-4-phenacylidene-1,3-
(2H,4H)-isoquinolinedione 257 with malononitrile was 5.3. S-Heterocyclic Compounds
described in the presence of Et2NH as a catalyst in a 5.3.1. Thiophenes. Thiophenes and their polycyclic
benzene−EtOH solvent mixture at 60 °C to furnish a mixture derivatives comprise an important heterocyclic class that exhibit
of 1H-pyrano[2,3-c]isoquinoline-2-carbonitrile 260 via route a remarkable electrochemical,306 optical,307 physical,308 and
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Scheme 75. Synthesis of Furofuran 262

Scheme 76. Synthesis of 2,4,5-Triaroyl-1,3-dioxolanes 264a Scheme 78. Synthesis of Bis-dioxolane 266 via PG
Intermediate

Mac Dowell et al.318 reported the synthesis of 8H-

indeno[2,1-b]thiophene 270 by the method shown in Scheme
78. 3-Phenyl-2,5-thiophenedicarboxylic acid 268 was prepared
in 57% yield by the Hinsberg−Stobbe type of condensation
a
Ar = Ph, 4-AcOC6H4, 4-CbzNHC6H4, 4-ClC6H4, 4-FC6H4, 4- between PG and diethyl thiodiglycolate 267 using NaOEt
MeOC6H4, 4-MeC6H4; Ar′ = Ph, 4-AcOC6H4, 4-ClC6H4, 4-FC6H4, followed by saponification. The 268 was converted into 270 via
4-MeC6H4, Et, 2-furyl, Me, 2-thienyl, styryl; 263, 32−53%; 264, 43− intermediate 269 by ring closure with AlCl3, followed by
70%; a/b = 68/32−75/25; anti/syn > 99/1. Wolff−Kishner reduction, which caused both decarboxylation
and reduction in 64% yield (Scheme 79).
Scheme 77. Synthesis of 2,4,5-Triaroyl-1,3-dioxolanes 264 A similar synthesis of 2,5-di-p-toluoyl-3-phenylthiophene 272
via Hemiacetal 265 was reported by reaction of diketo sulfide 271 with PG in warm
MeOH in the presence of NaOMe in 67.8% yield (Scheme
80).319
1,4-Diones 66 prepared through AGs (Scheme 18) were
converted into saturated 1,4-diketones in the presence of KI
and conc. HCl in acetone at room temperature, which afforded
3-methylthio-substituted thiophenes 273 by treatment with
Lawesson’s reagent in refluxing toluene for 2 h in 75−88%
yields (Scheme 81).320
biological309 properties. Also, thiophenes have wide range of
applications in advanced materials310 such as conjugated 5.4. N,O-Heterocyclic Compounds
polymers,306b,311 organic conductors,312 semiconductors,313 5.4.1. Isoxazoles. The isoxazole nucleus is a prominent
and light emitting devices314 and in treatment of various structural motif found in numerous natural products and
diseases315 as pharmaceuticals.316 Thiophene derivatives have synthetic compounds with vital medicinal value.321 Also,
been prepared by various methods,317 such as Gewald317d,e and isoxazoles have applications in functional materials,322 such as
Paal−Knorr317i,j reactions. liquid crystalline compounds,323 and exhibit GABAA antago-
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Scheme 79. Synthesis of Indenothiophene 270 Scheme 82. Synthesis of Isoxazoles 276a

a
Ar= Ph, 4-ClC6H4, 4-MeOC6H4; Ar′ = Ph, 4-ClC6H4, 4-FC6H4, 4-
MeOC6H4; 39−63%.

Scheme 80. Synthesis of 2,5-Ditolylthiophene 272

5.4.2. Oxazolidines, Oxazolines, and Benzoxazolines.
Oxazolidines and oxazolines are common useful metal ligands
in asymmetric catalysts336 and also are utilized in organic
synthesis as synthetic intermediates337 or protecting groups.338
Oxazolidines and oxazolines appear in numerous medicinally
active compounds and natural products of biological signifi-
cance,339 such as quinocarcin.340 A number of methods exist for
preparation of oxazolidine and oxazoline derivatives,341 such as
1,3-dipolar cycloaddition of vinyl epoxides with imines,341i−k
carboamination of O-vinyl-1,2-amino alcohol,341m aminohy-
droxylations of alkenes,341f cyclization of β-hydroxyami-
des,341c,n,o and acid-catalyzed reaction of aldehydes with 1,2-
hydroxyalkyl azides.341p
Scheme 81. Synthesis of 3-Methylthiothiophenes 273a (R)-Piperidin-3-ol 277 was reported as a chiral auxiliary for
stereoselective synthesis of α-hydroxy aldehydes 280 by Choi
and co-workers.342 (5R,7R)-7-Benzoyl-6-oxa-1-azabicyclo-
[3.2.1]-octane 278 was obtained by condensation of PG-
hydrate with 277 in the presence of 4 Å MS in dry DCM under
reflux conditions in 85% yield. The reactions of 278 with
Grignard reagent to give carbinols 279 showed excellent
a
Ar = Ph, 4-MeC6H4, 2-benzofuryl, 2-furyl; 75−88%. stereoselectivity, because of the chelation of the metal between
the carbonyl oxygen and the ether oxygen. The stereoselectivity
was low when RLi or RMgCl was used, while RMgBr led to
nist,324 analgesic,325 antibacterial,326 anti-inflammatory,325a,327 excellent stereoselectivity. Hydrolysis of the 279 to α-hydroxy
hypoglycemic,328 COX-2 inhibitory,329 antinociceptive,330 and aldehydes 280 was carried out by stirring in the presence of
anticancer331 activity. Isoxazole derivatives have served as silica gel in DCM at room temperature for 2 h (Scheme 83).
versatile building blocks in organic synthesis.332 Many synthetic Agami et al.343 have reported the synthesis of N-Boc-2-
methods, including 1,3-dipolar cycloaddition of nitrile benzoyloxazolidine 282 as a chiral auxiliary to enantiopure 1,2-
oxides333e−h and condensation of hydroxylamine with 1,3- diols 284 via diastereoselective nucleophilic additions by
dicarbonyl compounds333q and α,β-unsaturated carbonyl Grignard reagents. The 282 was prepared either by stirring of
compounds,333b have been employed in the synthesis of a solution of (1R,2S)-norephedrine 281 and PG-hydrate in
isoxazoles.333 THF in the presence of anhydrous MgSO4 at room
Juhász-Tóth et al.334 reported the synthesis of 5-substituted- temperature for 0.5 h or by stirring of a solution of 281 and
3-acylisoxazoles 276 from 2-azido-3-hydroxy-1,4-diketones 275 PG in the presence of 4 Å MS in DCM at room temperature
in 39−63% yields. By treatment of α-azido acetophenones 274 for 0.5 h, followed by refluxing of a solution of obtained
with various AG-hydrates in the presence of DBU at 0 °C in oxazolidine with Boc2O in EtOAc. The Grignard reaction was
dry THF, products 275 were obtained in good yields. Further carried out in THF or Et2O at 0 °C. Hydrolysis of 283 using
reaction of 275 with a slight excess amount of MsCl in the TFA in DCM followed by reduction with NaBH4 furnished
presence of Et3N at −15 °C in dry DCM resulted in the enantiopure 284 (Scheme 84).
formation of 276, presumably via the corresponding nitrene Also the addition reaction of organometallic compounds to
intermediate (Scheme 82). the chiral 2-benzoyl-3-oxa-1-azabicyclo[3.3.0]octane 286, which
An attempt at silylation of 275 (Ar = 4-ClC6H4, Ar′ = Ph) was prepared via condensation of PG-hydrate and (S)-prolinol
using TBDMS-Cl in the presence of imidazole in DMF at room 285 in DCM in the presence of 4 Å MS, was reported. The
temperature did not produced the TBDMS-protected product, reactions were performed in Et2O, THF, or THF−HMPA to
but only the corresponding 276 was obtained in 44% yield.335 afford the corresponding carbinols 287 in over 80% yields. The
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Scheme 83. Stereoselective Synthesis of α-Hydroxy Scheme 85. Synthesis of Fused Oxazolidines 286a
Aldehydes 280 via Oxazolidine 278a

a
R = n-Bu, c-Hex, Me; M = MgBr, Et2O, −78 °C, 287a/b = 88/12−
96/4; M = Ti(i-OPr3), Et2O, −78 °C → rt, 287a/b = 96/4−99/1; M
= Li, THF−HMPA, −78 °C, 287a/b = 10/90−21/79; M = Li−CeCl3,
THF, −78 or −85 °C, 287a/b = 16/84−28/72.

Scheme 86. Synthesis of Oxazolones 289 via Ugi Reactiona

a
R = n-Bu, Et, Me, i-Pr, vinyl; M = MgBr, MgCl, Li; 279, 62−85%; M
= Li, 279a/b = 39/61−40/60; M = MgBr, MgCl, 279a/b = 77/23−
98/2.

Scheme 84. Synthesis of Enantiopure Diols 284 via N-Boc-

Oxazolidine 282a

a
Ar = Ph, 4-ClC6H4, 4-FC6H4, 4-MeOC6H4, 4-MeC6H4, 6-MeO-
naphth-2-yl; Ar′ = Ph, 3-ClC6H4, 4-ClC6H4, 4-MeOC6H4, 4-MeC6H4;
61−89%.

benzoxazine 291 and dibenzoxazolines 294 were produced.

The product distribution was affected by the AG/o-amino-
phenol molar ratio. With a 1/2 molar ratio of AG/o-
aminophenol, the reaction led to 294 as major products,
while with a molar ratio of 1/1, 291 was the major product.
The products 291 were obtained via initial condensation of the
a amine with the keto group of the AGs, 290, but 294 were
RMgX = allylMgBr, EtMgBr, MeMgI, vinylMgCl; 283, 54−70%, de =
2−95; 284, 51−61%. produced via condensation of two o-aminophenol molecules
with both aldehyde and ketone groups, 293 (Scheme 87). It is
known that 294 is in equilibrium with tautomeric ketimine
reaction conditions and diastereoselectivity are illustrated in form 295.347
Scheme 85.344 5.4.3. Oxazoles. Oxazoles are a common structural motif
A one-pot Ugi four-component synthesis of 2(3H)- found in numerous molecules that display antiviral (i.e.,
oxazolone 4-carboxamides 289 was reported by Garcia- ́ hennoxazole A),348 antifungal (i.e., leucascandrolide A),349
Valverde et al.345 by treatment of AGs with anilines in the and antibacterial activities350 and also are contained in the
presence of activated 3 Å MS in DCM at room temperature, structure of disorazole A,351 anti-inflammatory drug oxapro-
then addition of cyclohexyl isocyanide and anhydrous zin,352 virginiamycin M2,353 and antibiotic ostreogrycin A354 as
trichloroacetic acid. The products 289 were obtained in 61− well as in the immunosuppressant merimepodib (VX-497),355
89% yields. The proposed reaction mechanism involves initially which display attractive biological activities.356 General
formation of the Ugi products 288 followed by nucleophilic synthetic methods for them include the condensation of
addition of the ketone enolate onto the chloroacetate carbonyl carboxylic acids with 2-aminoethanol followed by dehydrative
group, and finally elimination of chloroform to give the cyclization to obtain 2-oxazolines357 and then oxidation to the
corresponding 289 (Scheme 86). oxazoles358 and cyclodehydration of α-acylaminoketone and
The condensation reaction of AG with o-aminophenol was Robinson−Gabriel synthesis.359p,q There are other alternative
investigated by Belgodere et al.,346 and a mixture of 1,4- methods to construction of the oxazole ring.359
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Scheme 87. Synthesis of Dibenzoxazolines 294a

a
Ar = Ph, 4-ClC6H4, 4-MeOC6H4, 4-MeC6H4, 4-NO2C6H4; AG/o-aminophenol molar ratio = 1:2; 291/294 = 10/90−20/80; AG/o-aminophenol
molar ratio = 1:1; 291/294 = 23/77−65/35.

Scheme 88. Synthesis of Oxazole Phosphonic Acid Derivatives 297 and 299a

a
299a: Ar = Ph, 4-MeC6H4; X = Y = OH, cond. water, 20−25 °C, 5 h, 63−76%. 299b: Ar = 4-MeC6H4; X = Y = NHR (R = Et, n-Pr), cond. 2.5
equiv of RNH2, dry dioxane, 20−25 °C, 5 h, 63−76%. 299c: Ar = 4-MeC6H4; X = BnNH, Y = OMe, conds. 2 equiv of BnNH2, dry dioxance, 20−25
°C, 1 h, then MeONa, MeOH, 20−25 °C, 12 h, 64%. 299d: Ar = 4-MeC6H4; X = O(CH2CH2)2N, Y = OH, cond. 2 equiv of morpholine, dry
dioxane, 20−25 °C, 4 h, then water, 20−25 °C, 12 h, 57%.

Belyuga et al.360 described the synthesis of methyl (2-aryl-5- reactions as chiral auxiliaries.364 There are a number of
phenyl-1,3-oxazol-4-yl)phosphonates 297 in 69−73% yields by approaches for construction of the thiazolidine and thiazoline
treatment of Arbuzov products 296 with excess amounts of rings,365 such as cycloaddition reactions of 2-vinylthiirane with
SOCl2 under reflux conditions for 2 h. α-Chloro-α-acylamino various heterocumulenes,365k intramolecular cyclization of
ketones 185, which were generated by reaction of PG with aminoethyl thiolesters 3 6 5 g and N-(β-hydroxyethyl)-
amides followed by action of SOCl2, were transformed to 296 thioamides,365o−q and condensation of thioethanol amine
in 76−82% yields, when treated with trimethyl phosphite in with nitriles,365l esters,365m and imines.365n
refluxing benzene for 4 h. (1,3-Oxazol-4-yl)phosphonates 297 One example of the condensation of aminothiol 300 (X =
were converted into corresponding phosphonic acid 299a, SH) with PG was reported in refluxing CH3CN producing 2-
phosphonic dialkylamides 299b, methyl N-benzyl phosphona- benzoylthiazolidine 301 as a mixture of two diastereoisomers.
midate 299c, and phosphonic morpholide 299d via phosphonic Interestingly, N-methylphenylglycinol 300 (X = OH) afforded
dichlorides 298 in further reactions as illustrated in Scheme 88. morpholinone 303 under the same conditions via phenyl
5.5. N,S-Heterocyclic Compounds migration within intermediate 302 (Scheme 89).366
5.5.1. Thiazolidines and Thiazolines. Thiazolidine and The reaction of p-MeO−PG and PG with L-cysteine methyl
thiazoline moieties occur in a variety of natural and non-natural ester was reported by Pinho e Melo et al.367 to yield a mixture
products,361 with anticonvulsant, sedative, antidepressant, anti- of diastereoisomeric thiazolidines 304a,b and 305a,b, respec-
inflammatory, antihypertensive, antihistaminic, and antiarthritic tively. Treatment of thiazolidine 304a with prop-2-ynylox-
activities.362 In addition, these compounds are useful in yacetyl chloride 306 in the presence of K2CO3 in dry DCM
synthetic organic chemistry,363 especially in diastereoselective under N2 atmosphere at room temperature for 18 h, followed
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Scheme 89. Synthesis of 2-Benzoylthiazolidine 301a under reflux conditions for 6 h, two products, the chiral 1H,3H-
pyrrolo[1,2-c]thiazole 310 and pyrrolo[1,2-c][1,4]thiazine 311
were obtained in 17% and 29% yields, respectively (Scheme
90).
Pearson et al.368 described the synthesis of 6-substituted-3-
benzoylpenems 316 in four steps, by condensation of PG with
azetidinones 313 in toluene followed by conversion of obtained
314 to chloro derivatives. Subsequent treatment with
triphenylphosphine in the presence of 2,6-lutidine in dioxane
at room temperature afforded the phosphorane derivatives 315,
which were converted into penems 316 by ozonolysis in the
presence of TFA followed by heating to 105 °C in toluene.
a
Also, transformation of phosphoranes 315 to penems 316 was
X= OH, SH. performed using silver nitrate in the presence of DMAP in
CH3CN, and then formylation by acetic formic anhydride in
by reaction with 4 equiv of LiI in refluxing EtOAc for 6 h, and the presence of DMAP and NaI, followed by heating at 85 °C
then acidification with aqueous HCl, afforded the N- in toluene, in which, in addition to penem 316, cis-isomer was
acylthiazolidine 307. By heating of 307 in refluxing Ac2O for isolated in 15% yield (Scheme 91).
6 h, chiral 3-benzoyl-1H,3H-pyrrolo[1,2-c]thiazole derivative 5.5.2. Thiazoles and Benzothiazoles. Thiazole is an
308 was obtained in 42% yield via intramolecular 1,3-dipolar important scaffold in heterocyclic chemistry and is present in
cycloaddition of intermediate 312. By a similar procedure on many pharmacologically active substances369 with anti-inflam-
304b, the enantiomer of 308 was obtained. In contrast, the matory,370 herbicidal,371 antitumoral,372 cardiodepressant,373
acylation reaction of 305a,b led to same thiazolidine, which antiviral,374 antifungal,375 antiprion,376 and antibacterial activ-
reacted with LiI in EtOAc followed by treatment with aqueous ities.377 Also they have wide range applications in organic
HCl to give thiazolidine 309. With heating of 309 in Ac2O functional materials such as fluorescent dyes378 and liquid

Scheme 90. Synthesis of Pyrrolothiazolidines 308 and 310

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Scheme 91. Synthesis of Penems 316 Containing Fused Thiazoline Structurea

a
R= H, Et, MeCH(OSit-BuMe2); R′ = CHCHCO2Et (cond. a); R′ = CPh3 (cond. b).

crystals.379 Widely used routes to thiazoles synthesis, such as Scheme 92. Synthesis of Thiazoles 318 and 319a
Hantzsch thiazole synthesis,380o dehydrative cyclization of α-
amidoketones using Lawesson’s reagent,380j,k reaction of thio-
amides or thioureas with α-haloketone derivatives,380a−g,l,m and
propargyl alcohols or bromides380h,i,n are reported in the
literature.380 Additionally, substituted benzothiazole is an
important class of heterocyclic compound that exhibits a wide
range of biological properties such as antitumor381 and
antimicrobial,382 and also histamine H3-receptor antagonists.383
Many reports have appeared in the literature describing the
formation of benzothiazoles,384 including condensation reac-
tion of o-aminothiophenol with carboxylic acid derivatives or
aldehyde followed by oxidation384h−j and intramolecular
cyclization of thioanilides.384f,k−o
Kolos et al.385 reported the reaction of thioureas and
thioacetamide with 317, which were obtained by Knoevenagel
condensation of 136 with AGs. The thioureas or thioacetamide
were treated with 317 in refluxing EtOH or MeOH and the
corresponding 2-aminothiazoles 319 or 2-methylthiazoles 318
were obtained in 45−76% or 37−56% yields, respectively
(Scheme 92). Also, the one-pot three-component reactions of
136 and AGs with thioureas or thioacetamides were carried out
in refluxing EtOH or MeOH for 1 h to give corresponding a
R = H, Me; R′ = H, 2-BrC6H4CO; Ar = Ph, 4-BrC6H4, 4-FC6H4, 4-
thiazoles in 39−40% or 73−75% yields, respectively.
MeOC6H4, 2-thienyl; X = O, S; 318, 37−56%; 319, 45−76%.
Also, the reaction of 185 with thioamides was investigated to
give substituted thiazoles 320 containing acylamide residues in
Scheme 93. Synthesis of 5-Acylamidothiazoles 320 and 5-
64−94% yields (Scheme 93). Deprotection of the acyl group
Aminothiazoles 321a
was carried out using saturated solution of HBr in glacial AcOH
to afford 5-amino-4-phenylthiazole 321 in 87−90% yields.218
The condensation reaction of o-aminothiophenol with AG
was carried out in the presence of 5 mol % cetyltrimethyl
ammonium bromide (CTAB) in water under reflux conditions
for 4 h, and the corresponding 2-aroylbenzothiazoles 323 were
prepared in 80−85% yields. As the authors mentioned, oxygen
from the air can act as oxidant for oxidation of thiazoline to the
thiazole ring (Scheme 93).386 Also, products 323 were prepared
by Cu(I)-catalyzed reaction of disulfide arylamines 322 with
PG in AcOH at 80 °C in the open-air system in 66−85% yields a
(Scheme 94).387 R = BnO, MeO, Me, Ph; R′ = Me, Ph; 320, 64−94%; 321, 87−90%.
5.5.3. Thiadiazolidines and Thiadiazoles. Thiadiazoles
exhibit wide biological behavior,388 such as anti-HIV,389 anti- dioxides are important heterocycles due to pharmacological
inflammatory,390 anticancer,391 antituberculosis,392 anticonvul- properties.396
sant,393 and antihypertensive activities.394 As a result of these The method for synthesis of 3-imino-1,2,5-thiadiazolidine 1,l-
applications, 1,3,4-thiadiazole395 derivatives have been targets dioxides 325 was described by the reaction of PG-hydrate with
of a number synthetic studies. Additionally, thiadiazolidine 1,1- sulfamide 324 in the presence of NaCN. The reaction was
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Scheme 94. Synthesis of 2-Aroylbenzothiazoles 323a Scheme 96. Synthesis of 2-Amino-1,3,4-thiadiazole 329 and
Imino-1,3,4-thiadiazoline 330a

a
Reference 386: cond. = CTAB (5 mol %), water, reflux, 4 h; X = H,
Ar = Ph, 4-BrC6H4, 4-ClC6H4, 4-MeC6H4; 80−85%. Reference 387:
cond. = Cu(I) 5 mol %, AcOH, air, 80 °C, 5 h; X = 6-Br, 5-CN, 6-
MeO; Ar = Ph; 66−85%.

carried out by refluxing the solution of PG-hydrate and NaCN

with an excess amount of 324 in aqueous ethanol to produce
325 in 20% yield. Probably, the cyanide-mediated cleavage of
PG furnished benzaldehyde, which condensed with 324 and
cyanide anion to yield 325, which converted to 3-oxo-1,2,5- a
thiadiazolidine 1,1-dioxides 327 when heated with ethanolic R = H, Me; R′ = H, Me; R″ = H, Me, Ph.
HC1 for 24 h to give ethyl 2-sulfamido-substituted ester 326,
followed by reaction with NaOMe in MeOH under reflux thione 334 were obtained through nucleophilic attack of
conditions for 3 h, in 54% overall yield (Scheme 95).397 terminal nitrogen atom to the carbonyl group. But in the case
of thiosemicarbazone 328e, thiadiazole 329 was produced via
Scheme 95. Synthesis of 3-Oxo-1,2,5-thiadiazolidine 1,1- oxidative cyclization along with nucleophilic attack of sulfur
Dioxide 327 atom to the CN bond (Scheme 97).399

Scheme 97. Behavior of 328 in aq. NaOH and Synthesis of

Thiadiazole 329a

a
328a,b: R = R′ = H; R″ = H, Me; 2 N NaOH, rt, 24 h. 328c,d: R =
H; R′ = Me; R″ = H, Me; 2 N NaOH, rt, 15 min, or 5% NaOH, reflux,
5 min, then 10% HCl. 328e: R = R′ = Me; R″ = H; 2 N NaOH, rt, 15
min.

Werber and co-workers398 reported the FeCl3-mediated

oxidative cyclization of thiosemicarbazones 328, which were
5.6. O,P-Heterocyclic Compounds
prepared by reaction of PG-hydrate with corresponding
thiosemicarbazide in very dilute and cold aqueous solution. 5.6.1. Dioxophospholanes. Ramirez et al.400 reported the
The reactions were carried out by heating of the mixture of 328 synthesis of unsaturated dioxophospholane 335 via reaction of
and FeCl3 in water, and depending on the R and R′ PG with a large excess amount of trimethyl phosphite (TMP)
substituents on 328, thiadiazoles 329 (with R = H) and in DCM under N2 atmosphere at 0 °C. Pentaoxyphosphorane
thiadiazolines 330 (with R = Me and R′ = H) were obtained. 335 was obtained in 48% yield, which was transformed to 2:1
The benzoyl group on 329 and 330 was removed by adduct 336 in quantitative yield when reacted with a second
nucleophilic attack of NaOH in refluxing EtOH to give 331 molecule of PG. Dioxophospholane 336 was obtained as two
and 332, respectively (Scheme 96). diastereoisomers, meso-336b and racemic-336a, in 65/35 ratio.
Also, the behavior of 328 was investigated in aq. NaOH at Also the reaction of biacetyl-TMP 1:1 adduct 337 with PG was
room temperature and different cycloadducts were obtained investigated, and dioxophospholane 338 was obtained in
according to the substituent on the terminal nitrogen atom. In quantitative yield as two diastereoisomers, 338a and 338b
the case of 328a−d (R = H), the corresponding dihydro-1,2,4- (Scheme 98). Also, the same products 338a,b were obtained by
triazine-3-thione 333 and 5-hydroxytetrahydro-1,2,4-triazine-3- the reaction of biacetyl with 335.
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Scheme 98. Synthesis of Dioxophospholanes 335, 336, and 338

6. SYNTHESIS OF SIX-MEMBERED HETEROCYCLES elimination reaction of the hydroxylamine obtained from

6.1. N-Heterocyclic Compounds
reaction of silyl enol ether 342 with nitrosobenzene (Scheme
100).
6.1.1. Tetrahydropyridines. Tetrahydropyridines are one
of the fundamental heterocycles due to their biological
Scheme 100. In Situ Generation of AG-imines 3 via Reaction
activity401 and wide range of applications in pharmaceuticals
of 342 with Nitrosobenzene and Their Aza-DA Reactiona
and synthetic intermediates.402 Consequently, their synthesis
has received much attention.403 The aza-DA reaction is
potentially one of the most versatile and rapid routes to
substituted piperidines.404
The aza-DA reaction of different dienes with PG-imine 3,
which was in situ generated by reaction of p-anisidine and PG-
hydrate, was reported using lanthanide triflates, such as
Yb(OTf)3 and Sc(OTf)3, in the presence of MgSO4 in
CH3CN at room temperature. When 2,3-dimethyl-1,3-
butadiene was used, corresponding tetrahydropyridine 339
was isolated in 44% yield. In the case of Danishefsky’s diene (R′
= R‴ = H, R = OMe, R″ = OSiMe3), the corresponding 2,3-
dihydropyridin-4(1H)-one 340 was obtained in 76% yield. But a
R = Ph, R′ = H, Ar = Ph; 25%; R = H, R′ = Me, Ar = Ph, 4-BrC6H4,
in the case of cyclopentadiene, the PG-imine 3 acted as diene 4-MeOC6H4, 4-MeC6H4, 2-furyl, 2-pyridyl; 7−52%.
and tetrahydro-1H-cyclopenta[c]quinoline 341 was obtained in
94% yield (Scheme 99).405 Also the same authors reported a
similar reaction with aniline, p-anisidine, and p-chloroaniline in Zhang et al.408 described the Yb(OTf)3-catalyzed solid phase
very high to quantitative yield.406 aza-DA reaction of PG-hydrate, dienes, and immobilized
Sasaki et al.407 reported the aza-DA reaction of AG-imines 3 benzylamine 344 in DCM at room temperature. After cleavage
with dienes in the presence of BF3·OEt2 at room temperature of products from the solid support 345, the tetrahydropyridine
to afford tetrahydropyridine derivatives 343 in 7−52% yields. derivatives 346 were obtained in excellent yields with high
The AG-imines 3 were in situ generated by Et3N-catalyzed levels of purity. Cleavage of resin support was achieved using 5
equiv of 1-chloroethyl chloroformate (Scheme 101).
Scheme 99. Synthesis of Tetrahydropyridine 339 and The aza-DA reaction of diene 348 with imines, derived from
Pyridone 340 via Aza-DA Reaction amine hydrochloride and PG, was reported by Chou et al.;409
the reaction was accomplished by stirring of a mixture of 348,
amine, and PG in DMF at room temperature to afford N-
substituted 2-benzoyl-4-(phenylthio)-1,2,3,6-tetrahydropyri-
dines 349 in 63−95% yields. The diene 348 was prepared by
desulfonylation of 3-(phenylthio)-3-sulfolene 347 (R = H),
using NaHCO3 in the presence of hydroquinone (HQ) in
toluene under reflux condition (Scheme 102). In the case of 2-
methyl-4-(phenylthio)-3-sulfolene 347 (R = Me), the reactions
were dependent on temperature, and in the case of benzyl-
amine at room temperature only trans isomer was obtained in
60% yield. The reaction temperature and diastereoselectivity
are illustrated in Scheme 102.410
Cycloaddition reactions of methanol addition adducts of PG-
imines 350, prepared by reaction of PG-hydrate with anilines in
MeOH, with different dienes was reported by Lucchini et al.411
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Scheme 101. Synthesis of Tetrahydropyridines 346 via Solid major products in 59−70% yields (exo/endo = 44/15−57/13),
Phase Aza-DA Reaction but with electron-releasing groups such as Me (350c)
substituents, hexahydrophenanthridine derivative 341c′ was
isolated as major product in 61% yield. Heating of 343 (R′ =
Me and R″ = H or Me) in refluxing toluene with a
stoichiometric amount of BF3·OEt2 for 4 h led to pyrido[1,2-
a]indole derivatives 354a,b or 355a,b, respectively (Scheme
103). There is also another report on HAD reaction of PG-
imine with 1,3-butadiene, cyclopentadiene, and cyclohexadiene
using BF3·OEt2.412
6.1.2. Pyridines. Pyridines are found as skeletal moieties of
many biologically active compounds and natural products,413
which exhibit anti-HBV,414 antibacterial,415 and anti-ischemic
activity,416 and as potassium channel openers,417 agonists for
adenosine A1 receptor,418 and agonists for human adenosine
A2B receptor.419 Moreover, they have many applications in
supramolecular chemistry, due to their π-stacking ability along
with H-bonding capacity.420 Thus, the synthesis of pyridines
has attracted much attention, and a number of procedures have
been developed.421 Among these, very convenient approaches
Scheme 102. Desulfonylation of 347 and Their Aza-DA were the oxidative aromatization of 1,4-DHPs,422 multi-
Reactiona component reaction of aldehydes with malononitrile423 or
acetophenone derivatives424 in the presence of nitrogen source
and catalyst, and Bohlmann−Rahtz pyridine synthesis.425 Also,
a combination of the wide variety of methods for the synthesis
of substituted 1,2,4-triazines, coupled with the aza-DA reaction
with various dienophiles, allows the synthesis of functionalized
pyridines.
Diring et al.426 described a protocol for the efficient synthesis
of substituted 6-phenyl-2,2′-bipyridine derivatives 358, which
were suitable ligands for the synthesis of cyclometalated
complexes. 2,6-Disubstituted 1,2,4-triazine derivatives 357a,
which were synthesized by the condensation reaction of PG
with 2-pyridyl amidrazone 356, were converted into 6-phenyl-
a 2,2′-bipyridine derivatives 358 via [4 + 2] cycloaddition
349a: R = H; R′ = Me, Bn, Ph; rt, 63−95%. 349b: R = Me; R′ = Bn;
reaction with monofunctionalized alkynes in o-dichlorobenzene
rt, 60%, trans only; 0 °C, 60%, cis/trans = 2/7; −20 °C, 52%, cis/trans
= 2/5. 349c: R = R′ = Me; 90 °C, 78%, cis/trans = 2/7; 60 °C, 88%, at high temperature followed by reverse-DA reaction. When 4-
cis/trans = 1/2; rt, 76%, cis/trans = 1/3; −10 °C, 52%, cis/trans = 3/4; ethynyltoluene, 2-ethynyl-9,9-dimethylfluorene, and 3-ethynyl-
−20 °C, 75%, cis/trans = 1/1. 9-methylcarbazole were used, the major products were the 3-
aryl isomers 358b (9−42% yields), whereas the 4-aryl isomers
358a were isolated in low yield (8−13%). Electron-rich
Reactions were carried out by adding of 1.5 equiv of diene to a terminal alkynes, such as 3-ethynylperylene and 1-ethynylpyr-
stirred solution of 350 and 1 equiv of BF3·OEt2 in DCM at ene, provided almost exclusively the 3-aryl isomers 358b. Also,
room temperature for a few minutes to produce the benzyne was treated with 357a to give the fused isoquinoline
corresponding substituted tetrahydropyridines 343. When 1,3- molecule 359 in low yield. Benzyne was prepared in situ from
butadiene was subjected to the DA reaction with 350a,b, 6- anthranilic acid and isoamyl nitrite (Scheme 104).
benzoyltetrahydropyridines 343a,b were isolated in 0−16% The synthesis of terpyridines and higher oligopyridines 364
yields, while tetrahydroquinoline derivatives 351a,b were was reported by Pabst et al.427 via [4 + 2] cycloaddition
isolated as major products in 40−77% yields, in which PG- reaction of aryl or heteroaryl substituted 1,2,4-triazines 361 and
imines act as diene component. With 2-methyl-1,3-butadiene 362 with bicyclo[2.2.1]hepta-2,5-diene 363, followed by [4 +
and 2,3-dimethyl-1,3-butadiene, the corresponding tetrahydro- 2] cycloreversions of nitrogen and cyclopentadiene in o-
pyridines 343a′−b″ were obtained in 65−88% yields as major dichlorobenzene at 140 °C in 50−79% yields. Intermediates
products. In addition to 343a′, tetrahydrofurane derivative 352 361 and 362 were prepared via condensation reaction of 2-
was isolated as two stereoisomers only in 7% yield, in the case pyridylglyoxal with amidrazone 356 or bis-amidrazone 360 in
of 2-methyl-1,3-butadiene. By treatment of cyclopentadiene aqueous EtOH at room temperature (Scheme 105).
with 350a,b, the corresponding 341a,b were isolated in 87− Also, a similar procedure was used for preparing of
88% yields. When AlCl2OMenth was used as catalyst at −20 superbranched oligopyridines 366 starting from condensation
°C, only 3-benzoylazabicyclo[2.2.1]hept-5-ene 353a was of pyridine-2,4,6-tricarboxtrisamidrazone 365 with 2-pyridyl-
isolated in low yield (8%). In treatment of 1,3-cyclohexadiene and 2-thienylglyoxals (Scheme 106).428
with 350a−c, the product distribution was affected by the A similar reaction was reported for synthesis of bipyridine
substituent on 350. With electron-withdrawing groups such as derivatives in which triazines were synthesized by cyclo-
nitro and chloro substituents (350 a,b), the 3- condensation reaction of 2-pyridylamidrazone with arylglyox-
benzoylazabicyclo[2.2.2]oct-5-enes 353a′,b′ were obtained as al-1-hydrazono-2-oximes, which were prepared by nitrosation
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Scheme 103. Aza-DA Reaction of 350 with Different Dienes

of acetophenones, then by treatment with hydrazine hydrate in nolines 374b (n = 2) via 1,2,4-triazines 368 in 41−84% yields.
good yields.429 Similarly, the 2-thienyl pyridine was synthe- Substitution of methyl sulfinate with anions of active methylene
sized.430 compounds 373 afforded alkyne tethered to C-3 of the 1,2,4-
An efficient method for synthesis of polysubstituted 2,3- triazines, which underwent the intramolecular inverse electron
dihydrofuro[2,3-b]pyridines (n = 0) and 3,4-dihydro-2H- demand DA reaction (Scheme 108). Also, the condensation
pyrano[2,3-b]pyridines (n = 1) 371−372 from 1,2,4-triazines reaction of PG with acylhydrazide 375 in the presence of
368 was reported by Hajbi et al.431 via inverse electron demand NH4OAc in refluxing AcOH was investigated, in which in situ
DA reaction under microwave irradiation. The 3-methylsulfon- generated 1,2,4-triazine underwent the intramolecular inverse
yl-1,2,4-triazine 368 was synthesized by condensation of PG electron demand DA reaction to afford 374a (X = Y = H) in
with S-methylthiosemicarbazide 367, followed by MCPBA 35% yield as a 1:1 mixture of two regioisomers (Scheme 109).
oxidation. The 368 was transformed to 1,2,4-triazine The intramolecular inverse electron demand DA reaction
substituted alkynols 369 and 370 in three or four steps. The between imidazole and 1,2,4-triazines linked by a trimethylene
intramolecular inverse electron demand DA reaction of 369 tether from the imidazole N-1 position, 378, to produce
and 370 was carried out by heating of the solution of 369 or cycloadducts 381 was studied by Lahue et al.434 Reactions were
370 in chlorobenzene under microwave irradiation, and carried out in either refluxing tri-iso-propylbenzene or refluxing
corresponding pyridines 371 or 372 were obtained in 91− Ph2O and afforded unexpected product 1,2,3,4-tetrahydro-1,5-
93% or 67−99% yields, respectively (Scheme 107). Also, a naphthyridines 380 in 75−89% yields. The reactions proceeded
similar procedure was applied by Taylor and Macor.432 by a cycloaddition with subsequent loss of nitrogen, followed
Taylor and co-workers433 reported the synthesis of 2,3- by presumed stepwise loss of a nitrile (intermediate 379). 1,2,4-
cyclopentanopyridines 374a (n = 1) and 5,6,7,8-tetrahydroqui- Triazines 378 were prepared by either condensation of
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Scheme 104. Synthesis of Bipyridines 358 via Inverse Electron Demand DA Reaction of Triazines 357a

a
Ar = 4-MeC6H4, 9-Me-carbazole-3-yl, 9,9-Me2-fluorene-2-yl, perylene-3-yl, pyrene-1-yl; 358a, 8−13%; 358b, 9−42%.

Scheme 105. Synthesis of Oligopyridines 364 via DA−Inverse DA Reactions of Triazines

acylhydrazide 376 with PG in the presence of NH4OAc in 3,4-dihydrofuran 165, catalyzed by salen−AlCl complex 383.
AcOH or condensation of amidrazone 377 with AGs (Scheme The reaction was carried out by addition of 165 and 383 to a
110). mixture of PG-hydrate and aniline in dry CH3CN and stirring
6.1.3. Tetrahydroquinolines and Quinolines. Quino- at room temperature for 7 h to afford the cycloaddition product
lines and the related tetrahydroquinolines constitute a group of 382 in the endo/exo ratio of 10:90 (Scheme 111).
heterocycles largely occurring in natural products,435 which The three-component aza-DA reaction of PG-hydrate,
exhibit broad biological activity436 such as antibacterial,437 anilines, and 165 or cyclopentadiene catalyzed with
fungicidal,438 pesticidal,439 antimalarial,440 antioxidant,441 anti- Ph3P·HClO4 was reported by Nagarajan et al.447 The reactions
depressive,442 anti-inflammatory,443 and antidiabetic activ- were carried out in CH3CN at room temperature to produce
ities.444 A variety of approaches, such as aza-DA reac- the isomeric mixture of furoquinolines 382 in the ratio of 35:65
tion,445d,o−r Friedländer annulation,445s−u alkynylation−cycliza- in an overall yield of 77%. Reaction with cyclopentadiene
tion reactions,445v,w Combes synthesis,445x and Döbner−Von resulted in the corresponding 341 in 82−93% yields. Also,
Miller and Conrad−Limpach445y reactions have been devel- reaction of PG-imine with cyclopentadiene using KHSO4 as
oped for the synthesis of tetrahydroquinoline and quinoline catalyst in MeOH448 or Nafion-Sc as catalyst in a water−
skeletons.445 EtOH−toluene (1:7:4) solvent system449 at room temperature
Magesh et al.446 described the DA reaction of PG-imine 3, in was reported. There is another report on aza-DA reaction of
situ generated from reaction of PG-hydrate and aniline, with cyclopentadiene with imines derived from PG.450
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Scheme 106. Synthesis of Superbranched Oligopyridines 366 Scheme 108. Synthesis of Cyclopentanopyridines and
via Triazinesa Tetrahydroquinolines 374 via Triazinesa

a
a, n = 1; b, n = 2; Ar = Ph, 4-ClC6H4, X = COMe, CO2Me, CN; Y =
CO2Me, CO2Et, CN; 41−84%.

Scheme 109. Synthesis of Cyclopentanopyridine 374 (X = Y

= H) via Triazine
a
Het = 2-pyridyl; cond. = p-xylene, reflux, 6 d, 46%. Het = 2-thienyl;
cond. = o-Cl2C6H4, 145−150 °C, 1 d, 30%.

Tarantin et al.451 described the reaction of methyl 12-

aminodehydroabietate with AGs to afford 384 and its aza-DA
reaction with ethyl vinyl ether, cyclopentadiene, and indene.
The reactions were carried out in 2,2,2-trifluoroethanol in the
presence of BF3·OEt2 at room temperature. With ethyl vinyl
ether, as shown in Scheme 112, quinolines 386 were obtained
by elimination of EtOH molecule from intermediate 385,
followed by oxidation with atmospheric oxygen, in 20−37%
yields. In the reaction with cyclopentadiene and indene,
quinolines 387a,b were isolated in 38−96% yields. The (6R)/ The condensation reaction of o-aminophenylglyoxal-dime-
(6S) ratio of 387a and 387b was determined using 1H NMR thylacetal 391 with several cyclic and acyclic ketones was
spectra as 1:1−2:1 and 1:1−3:2, respectively. reported in the presence of sodium in absolute EtOH to give
Saggiomo and co-workers452 reported the Doebner reactions quinoline-4-carbaldehyde-dimethylacetal derivatives 392 in 85−
of AG-hydrates, p-chloroanilines, and pyruvic acid 388 to 97% yields, which were hydrolyzed to corresponding aldehydes
produce 2-benzoylcinchoninic acids 389 in 21−39% yields. The 393 using 2 N HCl. Also the reaction of 391 with ethyl
reaction was carried out by addition of pyruvic acid 388 to a acetoacetate and diethyl malonate was carried out at 150−160
suspension of an aniline and an AG-hydrate in AcOH and °C to afford 394 in 70−94% yields (Scheme 114).453
H2SO4 and heating to 115 °C for 50 min. Products 389 were 6.1.4. Isoquinolines. The isoquinoline ring system is found
converted to 2-benzoyl-4-quinolinemethanols 390 (which in pharmaceuticals454 and in a variety of natural products such
exhibit moderate antimalarial activity, especially in the case of as alkaloids.455 Due to their substantial applicability, the
Cl and CF3 substitution on benzoyl moiety) in four steps in 5− synthesis of isoquinoline derivatives has received considerable
59% yields, as illustrated in Scheme 113. attention.456 The most common routes to isoquinolines are

Scheme 107. Synthesis of Furo[2,3-b]- and Pyrano[2,3-b]pyridines 371 and 372 via Triazines 369 and 370a

a
n = 0, 1; 371, R = H, 220 °C, 0.75−2 h, 91−93%; 372, Ar = 4-MeOC6H4, 4-MeC6H4, 4-NO2C6H4, 2-thienyl, 180−240 °C, 2.5−8 h, 67−99%.

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Scheme 110. Synthesis of Tetrahydro-1,5-naphthyridines 380 via Triazines

Scheme 111. Synthesis of Hexahydro-Furoquinolines 382 via Pictet−Spengler reaction,456e−g Bischler−Napieralski reac-
Aza-DA Reaction tion,456h,i and recently, catalyzed cyclization of o-halobenzyl-
amines and o-alkynyl benzyl azides.456j−l
Nimgirawath et al.457 described a method for synthesis of 1-
aroyl-1,2,3,4-tetrahydroisoquinolines 396 via Pictet−Spengler
reaction between AG-hydrates and 2-arylethylamine 395. The
reaction was studied under various conditions, and it was found
that refluxing with 3 N aq. HCl for 5 h afforded 396 in 25−75%
yields (Scheme 115), but formic acid was less effective than 3 N
HCl, while AcOH, TFA, and p-TsOH were completely
ineffective.
Treatment of PG with cysteine methyl ester resulted in
thiazolidine 305, which was converted to isoquinoline 398 and
399 with pyrrolidinocyclohexene in the presence of AgCO3 and
DBU via aza-diene 397 in 35% and 14% yields, respectively
(Scheme 116).458
6.1.5. β-Carbolines. β-Carbolines are present in numerous
natural and synthetic organic compounds and possess various
biological activities459 such as hypnotic, anxiolytic, antimicro-

Scheme 112. Aza-DA Reaction of AG-Imines 384 with Different Dienesa

a
Ar = Ph, 4-ClC6H4, 4-MeOC6H4, 4-MeC6H4.

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Scheme 113. Synthesis of Quinolinemethanols 390a Scheme 115. Synthesis of Tetrahydroisoquinolines 396a

a
R = H, OMe; R′ = H, OMe; R, R′ = OCH2O; Ar = Ph, 4-ClC6H4, 4-
MeOC6H4, 3,4-(MeO)2C6H3, 4-MeC6H4; 25−75%.

Scheme 116. Synthesis of Hydroisoquinolines through Aza-

Diene 397

a
R = Cl, CF3; Ar = Ph, 4-ClC6H4, 3,4-Cl2C6H3, 3,5-Cl2C6H3, 3-
CF3C6H4, 4-CF3C6H4, 3,5-(CF3)2C6H3; 5−59%.

bial, anti-HIV, antiviral, antitumor,460 anticonvulsant,461 and

antioxidant activity462 and inhibition of topoisomerase I.463
Carboline derivatives are also useful as intermediates for natural
product synthesis.464 There are a number of reports for
synthesis of β-carbolines in the literature,465 using Pictet−
Spengler reaction methodology,465n−p and Pd-catalyzed
iminoannulation of indolcarbaldehydes with alkynes.465q−s
The synthesis of 1-substituted β-carbolines 401−403 was
described by Yang et al.466 via modified Pictet−Spengler
reaction between L-tryptophan 400 and AG-hydrates. Different of 401 via a condensation/cyclization/dehydrogenation
solvents, such as MeOH, acetone, CH3CN, THF, 1,4-dioxane, sequence, involving coupling of 400 with AGs using Pd/C/
DMSO, and DMF, and various acids, such as H2SO4, p-TsOH, K-10 catalyst system in 79−96% yields in 2−12 min.
and HCl, were examined as reaction conditions, and p-TsOH in Treatment of iminophosphorane 405 with AGs in toluene at
MeOH was selected for the best results. The reaction was 160 °C afforded l-aroyl-β-carboline derivatives 406 in 60−65%
carried out by addition of 1.0 equiv of PG-hydrate to a stirred yields via aza-Wittig−electrocyclic ring-closing reactions,
suspension of 1.3 equiv of 400 and 1.0 equiv of p-TsOH·H2O followed by dehydrogenation under the reaction conditions.
in MeOH with heating at 50 °C for 2 h (Scheme 117). This Compounds 406 (X = F, Cl), under treatment with either
methodology was applied for the synthesis of luzongerine A HCO2H or pyridinium hydrochloride at 170 °C, underwent
404, isolated from Illigera luzonensis. Also, Kulkarni et al.467 cyclization through the indole nitrogen atom leading to 407 in
developed a three-step, one-pot, microwave-assisted synthesis 90% yield. Hydrolysis of 406 (X = NO2) with LiOH in THF/

Scheme 114. Synthesis of Quinoline-4-carbaldehydes 393 and 394

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Scheme 117. Synthesis of β-Carbolines 401−403 via Pictet−Spengler Reactiona

a
R = H, CO2H; R' = H, 5-F, 5-MeO; Ar = Ph, 4-BrC6H4, 4-FC6H4, 4-CF3C6H4, 4-MeOC6H4, 4-MeC6H4, 5-MeO-naphth-2-yl; cond. = p-TsOH,
MeOH, 50 °C, 2 h; 401, 15−20%; 402, trace−40%; 403, 3−6%; cond. = Pd/C/K-10, MW, 130 °C, 2−12 min; 401, 79−96%.

Scheme 118. Synthesis of β-Carbolines 406 and Their Conversion into 407 and 408

H2O at room temperature followed by selective reduction of N2 atmosphere in EtOH in 87% yield, with 34:1 ratio of two
the nitro group by catalytic hydrogenation in the presence of regioisomers 410a/410b (Scheme 119).
PtO2, provided the amino derivative in 80% yield, which was Benson and co-workers470 reported the intramolecular
transformed to fascaplysin 408 in 60% yield by diazotization inverse electron demand DA reaction between indole and
and further heating of the resulting diazonium salt (Scheme 1,2,4-triazine linked by a trimethylene tether from the indole N-
118).468 1 position, which was prepared either by condensation of PG
The inverse electron demand DA reaction between indole with acylhydrazide intermediate 420 in the presence of
and 1,2,4-triazine 410 was reported by Benson et al.469 using NH4OAc or by condensation of PG with amidrazone 421. By
small amount of diglyme as solvent at 180 °C. β-Carboline 415 heating of 422a or 422b at 232 °C in tri-iso-propylbenzene for
was obtained via cycloaddition−reversion adduct 414, as 1.5 h, the corresponding canthine skeleton 423a or 423b was
intermediate, in 50% yield. 2-Phenyl-β-carboline 416 was obtained in 87% or 93% yield, respectively (Scheme 120).
produced by hydrolysis of the ester group in 415, with 6.1.6. Pyridazines. The pyridazine ring is broadly present
subsequent decarboxylation in very low yield. The yield of 416 in biologically471 and pharmacologically active compounds472
was increased when reaction was carried out in wet diglyme. In such as antidepressants. Pyridazines are also of considerable
addition to 415, the rearranged adduct 413 was obtained via interest because of their synthetic utility473 and applications in
intermediates 411 and 412 in 5% yield. Quinoline 419 was also physical organic chemistry.474 A number of pyridazine
obtained in 21% isolated yield through the ring-opened diimine syntheses, including cycloaddition reactions of 1,2,4,5-tetrazines
417, followed by hydrolysis to 418 with subsequent ring with different dienophiles475a,b,l and cyclocondensation of 1,4-
closure. 1,2,4-Triazine 410 was prepared by condensation dicarbonyl compounds with hydrazine,475m,n are reported in the
reaction of PG-hydrate with ethyl oxalamidrazonate 409 under literature.475
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Scheme 119. Synthesis of β-Carboline 415 and Quinoline 419 via Triazines

Scheme 120. Synthesis of Canthine 423 via Triazines

Rimaz et al.476 recently described an efficient three- Scheme 121. Also a similar reaction was performed using
component one-pot method for synthesis of pyridazine-4- ultrasound irradiation to produce the corresponding pyrida-
carboxylates 424 in 70−97% yields via reaction of hydrazine
hydrate (5 equiv), 1,3-dicarbonyl compounds (1 mmol), and zines 424 in good yields in short reaction times in contrast to
AGs (1 mmol) in water at room temperature as shown in the conventional procedure.114
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Scheme 121. Synthesis of Pyridazine-4-carboxylate 424a Scheme 123. Synthesis of 3,5-Disubstituted Pyridazines 430a

a
R = t-Bu, Et, Me; Ar = Ph, 4-BrC6H4, 4-ClC6H4, 4-FC6H4, 3,4-
(MeO)2C6H3, 3,4-(OCH2O)C6H3; 70−97%.

The synthesis of steroidal pyridazine derivatives 427 from 2-

acetylestradiol 425 was reported by Ismail and co-workers.477
Treatment of 425 with AGs in refluxing Ac2O afforded the
a
corresponding 1,4-dicarbonyl compounds 426, which were R = H, Me; Ar = Ph, 2-(N-Me-pyrrolyl), 2-naphthyl, 2-thienyl; 31−
transformed to the corresponding 427 when heated with 62%.
hydrazine hydrate in EtOH in the presence of a few drops of
glacial AcOH under reflux conditions (Scheme 122). aminopyridazine 435 in 75% yield (Scheme 124).479 A similar
reaction was carried out by Bourotte et al.480 using benzylamine
Scheme 122. Synthesis of Steroidal Pyridazines 427a or 2,4-dimethoxybenzylamine (DMB). Two regioisomers, 433
and 434, were obtained by cyclocondensation of PG with the
enamine intermediate 432. The 6-phenyl derivative 433 was
obtained as the major product. The conversion of 433b,c into
the corresponding 4-bromo derivatives was achieved by
treatment with HBr/AcOH under reflux conditions. Under
these conditions, the protecting group DMB was also removed,
whereas the benzyl group was not removed. Obtained 4-bromo
pyridazines underwent Suzuki and Sonogashira coupling
reactions with various reagents to give 3-aminopyridazines
436 substituted at position 4 (Scheme 124).
6.1.7. Fused Pyridazines. Due to the wide range of
biological and pharmacological activity,481 such as monoamine
oxidase inhibitory,482 cytotoxic,483 anthelmintic,484 antiviral,485
and antibacterial486 activities, some synthetic routes for
construction of fused pyridazines are found in the liter-
ature.484,485,487
Morrison and co-workers488 described the cyclizations of
AG-hydrates with 6-hydrazinoisocytosines 437 to give
pyrimido[4,5-c]pyridazines 438. Reactions were carried out
by heating the mixture of 437 and AG-hydrate in different
solvents such as water, MeOH, and AcOH. In the case of PG-
hydrate in MeOH, only 4-phenyl isomer 438a was isolated in
a
Ar = Ph, 4-BrC6H4, 4-MeC6H4; R = H, 18−25%; R = OAc, 30−38%. 50% yield, while using m-HOC6H4COCHO, two isomers,
438a,b were obtained in a/b = 5/1 ratio. In water as solvent,
only 438b was isolated in 49% yield. Also the PG-oxime was
Marriner and co-workers478 reported the reaction of AG- subjected to this reaction in AcOH and afforded the 3-phenyl
hydrates with in situ generated aldehyde enolates via rhodium- isomer 438b in 58% yield (Scheme 125).
catalyzed enal hydrogenation of 428 to afford β-hydroxy-γ-keto The method for synthesis of 3- and 4-substituted pyrimido-
aldehydes 429, which were converted into 3,5-disubstituted [4,5-c]pyridazines 441 from reaction of uracil 439 with AG-
pyridazines 430 by treatment with excess hydrazine in MeOH. hydrates was reported by Turbiak et al.489 The reaction was
By treatment of 1 equiv of KOAc, AG-hydrate (1 mmol), and conducted by treatment of AG-hydrates with 439 under
then 5 equiv of 428 with a solution of Rh(COD)2OTf (1 mol different conditions. By treatment of 439 with PG-hydrate in
%) and Ph3P (2.4 mol %) in DCE under an Ar atmosphere refluxing EtOH or water, hydrazone 440 was obtained. When
followed by flushing with H2 and stirring under 1 atm of H2 at reaction was carried out in DCE, solely 441b was obtained,
ambient temperature, intermediates 429 were obtained, which while reactions in aqueous NaOAc resulted in a mixture of both
in reaction with excess hydrazine in MeOH at room regioisomers, 3- and 4-substituted pyrimidopyridazinedione
temperature for 45 min provided pyridazines 430 in 30−62% 441a,b (Scheme 126).
yields (Scheme 123). A one-pot procedure was reported to synthesize of 3-
Also, another example of the construction of pyridazine ring arylpyrimido[4,5-c]pyridazines 442 by stirring a mixture of 136
433a (R = morpholino) was described by nucleophilic addition with AGs in the presence of pyridine in water at room
of 1-aminoethylmorpholine and then hydrazine hydrate onto temperature for 20 min, followed by addition of an excess
the 1,1-bis(thiomethyl)-2-nitroethylene 431 in refluxing EtOH amount of hydrazine hydrate and stirring for additional
followed by condensation with PG in 51% yield. The catalytic minutes. The products 442 were obtained in 43−93% yields
hydrogenation of the nitro group of 433a with H2/Pd/C gave (Scheme 127).490
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Scheme 124. Synthesis of 3-Aminopyridazines 435 and 436a

a
R′ = Ph, 2-BrC6H4, 4-ClC6H4, 2-MeOC6H4, 4-MeC6H4, 2-thienyl, CR″ (R″ = TMS, Ph, (CH2)3OBn, CH2NHBoc); cond. = R′B(OH)2,
Pd(Ph3P)4, Na2CO3, EtOH−toluene, Ar (atm.), 110 °C, 20 h, or alkyne, PdCl2, CuI, Ph3P, Et3N, CH3CN, Ar (atm.), 70 °C, 12 h. 433 + 434, 70−
76%; 433/434 = 60/40−70/30; 436b, R = Bn, 40−79%; 436c, R = H, 45−92%.

Scheme 125. Synthesis of Pyrimido[4,5-c]pyridazines 438a Scheme 127. Synthesis of 3-Arylpyrimido[4,5-c]pyridazines

442a

a
X = O, S; Ar = Ph, 4-BrC6H4, 4-ClC6H4, 4-FC6H4, 4-MeOC6H4, 3,4-
(MeO)2C6H3, 3,4-(OCH2O)C6H3, 4-NO2C6H4; 43−93%.

(6H,8H)-diones 443 were obtained in 76−92% yields. The

AG-hydrazones 198, in situ prepared by condensation of AGs
a
with hydrazine, was proposed as the reaction intermediate
X = O·H2O, R = Me, solvent = MeOH, reflux, 3−4 h: Ar = Ph, 438a, (Scheme 128).491
50%; Ar = 3-HOC6H4, 86%, 438a/438b = 5/1. X = O·H2O, R = H,
solvent = water, reflux, 1 h: Ar = Ph, 438b, 49%. X = NOH, R = Me,
solvent = AcOH, 55 °C, 20 h: Ar = Ph, 438b, 58%. Scheme 128. Synthesis of 4-Arylpyrimidopyridazie-diones
443a
Scheme 126. Synthesis of Pyrimido[4,5-c]pyridazinediones
441a

a
Ar = Ph, 3-BrC6H4, 4-BrC6H4, 4-ClC6H4, 4-FC6H4, 3-MeOC6H4, 4-
MeOC6H4, 3,4-(MeO)2C6H3, 3,4-(OCH2O)C6H3, 4-NO2C6H4; 76−
92%.

a
Ar = Ph, cond. = EtOH, reflux, 24 h, 440, 50%; Ar = Ph, 4-ClC6H4, 4-
Cl-3-NO2C6H3, 3-FC6H4, 4-FC6H4, 4-CF3C6H4, 4-MeOC6H4, cond. = One example of the conversion of PG to pyrazolo[3,4-
DCE, reflux, 1.5−24 h, 441b, 22−85%; cond. = NaOAc, water, reflux, c]pyridazines 447 in four steps was reported. The pyridazinone
1 h, 441, 43−65%, b/a = 0.2−1. 445 was obtained via condensation reaction of PG and
cyanoacetohydrazide 444 in EtOH at room temperature
By treatment of 1,3-dimethylbarbituric acid 136 with AGs in followed by treatment with sodium in EtOH. Compound 445
the presence of NH2NH2·2HCl in EtOH under reflux was transformed into 447, in 88% yield, by treatment with
conditions, 4-aryl-6,8-dimethylpyrimido[4,5-c]pyridazine-5,7- excess POCl3 in dioxane under reflux conditions to produce
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446, followed by reaction of 446 with hydrazine hydrate in Scheme 131. Synthesis of Aroyl-HHP 450 and
refluxing absolute EtOH (Scheme 129).492 Tetrahydropyrimidine 451a

Scheme 129. Synthesis of Pyrazolo[3,4-c]pyridazines 447

a
Cond. = ether, reflux, 40 min; 450, 89%. Cond. = EtOH, 65 °C (5
min) → rt (1 d); 451, 17%.

antifungal,505 antidepressant,506 antimigraine,507 antithrom-

botic,508 antiaggregating,509 and nootropic activity.510 Further-
more, these heterocyclic compounds are present in several
biologically active compounds, such as μ-opioid receptor
agonists,511 NNRTI’s (non-nucleoside reverse transcriptase
inhibitors),512 Leu-enkephalin analogs,513 cholecystokinin
receptor antagonists,514 RGD mimetics,515 and the neuro-
kinin-2 receptor ligand.516 Some progress has recently been
6.1.8. Pyrimidines. Hexahydropyrimidines (HHPs) and made toward the development of synthetic methods for these
dihydropyrimidinones (DHPMs) constitute an important class heterocycles,517 such as condensation of ethylenediamine
of natural and unnatural products, many of which exhibit derivatives with α-haloacetic acids,517i−l and from dipeptidyl
biological493 and pharmacological activity,494 such as para- chloromethyl ketones.517m,n
siticides,495 antifungals, antibacterials,496 antihypertensives,497 The condensation reaction of tetraamines 452, 456, and 460
mitotic kinesin inhibitors,498 α1a-adrenergic receptor antago- with PG-hydrate was reported by Tripier and co-workers.518
nists,499 and hepatitis B virus replication inhibitors.500 The The reactions were carried out by slowly adding a solution of
HHP skeleton is present in a number of alkaloids.501 These PG-hydrate in absolute EtOH to a solution of the convenient
findings make it highly necessary to develop efficient methods linear tetraamines 452 and 456 or tetraazamacrocycle 460 in
for the synthesis of HHPs502 and DHPMs.503 The Biginelli absolute EtOH at room temperature under vigorous stirring. In
reaction is one of the most useful methods to access DHPMs. the case of linear polyamines 452 and 456, depending on the
The synthesis of aroyl derivatives of DHPMs 448 was nature (lateral or central) of the diiminium intermediates 453
reported by Balalaie et al.172 via Biginelli reaction of PG-hydrate and 457, gem/cis 454 and vic/cis or trans 458 were produced by
with 1,3-dicarbonyl compounds and urea in the presence of intramolecular nucleophilic addition of amine to intermediates
ZnCl2 in EtOH at reflux conditions in 59−73% yields or in the 453 and 457, respectively. With cyclic tetraamines 460,
presence of ZnCl2/AlCl3 (1:3) on silica gel under microwave tetracyclic bis-aminals 462 with cis configuration at the bis-
irradiation in 26−42% yields (Scheme 130). However, the aminal bridge were obtained via six-membered diiminium rings
condensation reaction with N,N′-dimethylurea led to the 461. Piperazinone derivatives 455, 459, and 463 were prepared
preparation of multisubstituted imidazolin-2-one derivatives from 454, 458, and 462 in boiling water in good yields
138 (Scheme 36). (Scheme 132). However, condensation of PG with 452, 456,
and 460 in boiling water gave directly 455, 459, and 463,
Scheme 130. Synthesis of Aroyl-DHPMs 448 via Biginelli respectively.
Reactiona Mukaiyama et al.519 reported the synthesis of 5-arylimidazo-
[1,5-a]pyrazine derivatives 467 in six steps. By treatment of
AGs with glycinamide hydrochloride 464 in MeOH−water at
−20 °C,520 the pyrazin-2-one derivatives 465 were prepared in
61−73% yields. Imidazo[1,5-a]pyrazine core 466 was synthe-
sized by protection of the nitrogen in the pyrazine ring with p-
methoxybenzyl chloride (PMB-Cl) in the presence of NaH and
n-Bu 4 NI in DMF−THF solvent mixture, followed by
condensation with tosylmethyl isocyanide (TsMIC) in the
presence of NaH in THF at room temperature. Cleavage of the
PMB group using TfOH/TFA and then treatment with POCl3
under reflux conditions for 1.5 h yielded the 8-chloro
a
R= Me, OMe, OEt; reflux, 59−73%; MW, 26−42%. derivatives, in which the chloride at the 8-position was
substituted with various anilines in the presence of sodium
bis(trimethylsilyl)amide (NaHMDS) in THF at 60 °C for 2 h
Mibu and co-workers504 described the reaction of 1,3- to produce the 5-arylimidazo[1,5-a]pyrazine 467 in 20−83%
propanediamine 449 with PG to give 3-pyrimidine derivatives yields (Scheme 133).
450 and 451. When reaction was carried out in ether, the HHP Also, the condensation reaction of 2-(hydroxyamino)-
derivative 450 was obtained as a sole product (89%), while acetamide 468 with AG-hydrates was reported in MeOH in
reaction in EtOH afforded a tetrahydropyrimidine derivative the presence of NaOH (12.5 N) to give 6-aryl-2(1H)-
451 in 17% yield (Scheme 131). pyrazinone 4-oxides 469 in 24−50% yields (Scheme 134).521
6.1.9. Piperazinones and Pyrazinones. The piperazine The Ugi four-component reaction between AGs, amines,
or piperazinone core is present in compounds possessing benzoylformic acid 470, and isocyanides was reported to afford
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Scheme 132. Synthesis of Pyrazinones 455, 459, and 463

Scheme 133. Synthesis of Imidazo[1,5-a]pyrazinones 466 Scheme 134. Synthesis of Pyrazinone 4-Oxide 469a
and Imidazo[1,5-a]pyrazines 467a

a
Ar = Ph, 4-BrC6H4, 4-ClC6H4, 3,4-Cl2C6H3, 4-MeOC6H4, 3-
NO2C6H4, 4-NO2C6H4, 4-PhOC6H4; 24−50%.

the products 471, which upon heating with an excess of

NH4OAc in AcOH for 3 h cyclized to pyrazinones 472 in good
yields (Scheme 135).522
The cyclocondensation reaction of 3-indolylglyoxals 473
with aminoamide 474 to produce the pyrazine core 475 of
dragmacidin D 476 was investigated; however this method was
not reported as a suitable route to synthesis of 476 (Scheme
136).523 3-Indolylglyoxals 473 were synthesized by modified
Rosenmund reduction of corresponding acid chloride by the
action of Bu3SnH.
a Similarly, treatment of PG-hydrate with 2-amino amides in
Ar = Ph, 4-MeOC6H4; Ar′ = Ph, 2,4-Cl2C6H3, 2,4-F2C6H3, 2-Me-4- the presence of NaOH in water−MeOH at −40 °C for
MeOC6H3, 2-MeC6H4, 2,4-Me2C6H3.
synthesis of the 2-pyrazinone moiety was reported.524 There are
other reports on construction of pyrazinone rings through
condensation reactions of AGs.525
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Scheme 135. Synthesis of Pyrazinones 472 via Ugi Reactiona DMSO at 44−46 °C with 110 min half-life. Product 481 was
synthesized by reaction of 478 with α-amino propionitrile in
the presence of TiCl4 in CHCl3 (Scheme 137).

Scheme 137. Synthesis of 2-Aminopyrazine 1-Oxide 481

a
R = 3-ClC6H4, 4-ClC6H4, 4-MeOC6H4, 4-MeC6H4, 4-ClC6H4CH2,
Me2CHCH2; R′ = c-Hex, n-Hex, 4-MeC6H4; Ar = Ph, 4-ClC6H4, 4-
MeOC6H4, 4-MeC6H4; 471, 42−77%; 472, 67−85%.

6.1.10. Pyrazines. Pyrazines are important pharmaco-

phores present in a number of biologically active compounds
such as antimycobacterial, antibacterial, antidiabetic, and
hypnotic/sedative agents.526 Some pyrazines have been
known as flavor components in foods527 and as pheromones
in various species of insects528 and ants.529 Also, they have
applications as versatile synthetic intermediates530 and in metal
coordination chemistry as N,N′-bidentate ligands.531 Accord-
ingly, the synthetic methods, such as condensation of α-
diketones with 1,2-diamines or α-aminoketones followed by
oxidation532m−q leading to the substituted pyrazines have been
developed.532
The preparation of 2-amino-3-methyl-6-phenylpyrazine 1-
oxide 481, a model for structural elucidation of Cypridina
etioluciferamine, was developed by Karpetsky et al.533 using Condensation of p-methoxyphenylglyoxal with 2,3-diamino-
PG-2-oxime 478. The conversion of the PG-acetal to 477 was propionic acid hydrobromide 482 to synthesize pyrazine
accomplished by hydroxylamine in the presence of NaOAc in carboxylic acid 483 in methanolic NaOH solution was the
MeOH in 93% yield. The next step, the acidic hydrolysis of 477 first step of the synthesis of botryllazine B 484, a naturally
to 478, was carried out in glyme using pH = 3.5 buffer (1 N occurring alkaloid that was first isolated from the red ascidian
AcOH, 0.1 N NaOAc) under reflux conditions in which 2,5- Botryllus leachi (Scheme 138).186
dihydroxy-3,6-diphenyl-5,6-dihydropyrazine 1,4-dioxide 480, Vogl and Taylor534 described the synthesis of 2-amino-
the dimer of 478, was obtained as product via 479. pyrazine-3-carboxamides 486 by the condensation of PG with
Intermediate 478 was reproduced by heating of 480 in aminomalonamidamidine dihydrochloride 485. Reaction was

Scheme 136. Synthesis of Pyrazinone Core of Dragmacidin D 476a

a
475: R = H, OMe; R' = H, CH2CH2OBn, CH(Me)OBn, CH(Me)CO2Me; R" = H, Br.

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Scheme 138. Synthesis of Pyrazine Carboxylic Acid 483 Scheme 140. Synthesis of Thieno[2,3-b]pyrazine 489

VCl3, AlCl3) in the presence of (NH4)6Mo7O24·4H2O as

carried out in dilute NH4OH (pH = 8−9) at 0−20 °C. The catalyst in refluxing o-dichlorobenzene. Dicyanopyrazines 495
yield was 36.6%, and only the 5-phenyl-2-aminopyrazine were prepared by condensation of diaminomaleonitrile 494
regioisomer was isolated (Scheme 139). with AGs. The reaction was carried out by refluxing of a
mixture of AGs with 494 in dioxane/water solvent system for 2
Scheme 139. Synthesis of 2-Aminopyrazine-3-carboxamide h (Scheme 142).
486 Taylor et al.538 described the intramolecular nitrile/1,2,4-
triazine DA cycloaddition to synthesize benzopyrano[3,4-
b]pyrazine 500. 3-(o-Hydroxyphenyl)-1,2,4-triazines 498 were
prepared by three-component condensation of salicylic acid
hydrazide 497 with PG-hydrate in the presence of excess
NH4OAc and then alkylated with bromoacetonitrile using NaH
in the presence of 15-crown-5 in THF under reflux conditions
to give cyanomethyl phenyl ethers 499 in 40−43% yields. By
heating of 499 in refluxing Ph2O for 13 h, 500 was obtained in
39% yield via cycloaddition−cycloreversion of N2 (Scheme
143).
6.1.11. Quinoxalines. Quinoxalines display a broad
spectrum of biological539 and pharmacological540 activities
such as insecticides, fungicides, herbicides, anthelmintics,
antibacterial,541 antimycobacterial, antiprotozoal, anticancer,542
Zhang et al.535 reported the regioselective condensation and antibiotic properties. Quinoxaline derivatives have found
reaction of 2,3-diamino-3-phenylthioacrylonitrile 487 with PG- applications in dyes,543 electron luminescent materials,544 and
acetal to produce 3-cyano-5-phenyl-3-phenylthiopyrazine 488a. chemically controllable switches,545 as building blocks for the
When reaction was conducted in i-PrOH in the presence of synthesis of anion receptors,546 cavitands,547 dehydroannu-
excess TFA, 488a was obtained in high selectivity. Using lenes,548 and organic semiconductors,543,549 and as electron-
mineral acids or weak acids in MeOH and EtOH resulted in transport materials in multilayer OLEDs.550 A number of
low yield and low selectivity. When PG was employed, the synthetic strategies have been developed for the preparation of
regioisomers 488a,b were obtained in 30−60% yields without substituted quinoxalines,551 including condensation of aryl-1,2-
selectivity. Product 488a was converted into thieno[2,3- diamines with α-functionalized ketones, usually dicarbonyl
b]pyrazine 489 via activation of the phenylthio group in 488a compounds or their equivalents.551f−j
as the sulfone using a 3:1 mixture of AcOH and chloroacetic Ayaz et al.552 reported a facile procedure to prepare 2,3-
acid with 3.1 equiv of sodium perborate, followed by treatment diarylquinoxalines 503 via a two-step Petasis deprotection−
of the obtained crude mixture with 1.1 equiv of methyl cyclodehydration−oxidation sequence. The Petasis reaction
thioglycolate in EtOH with Hunig’s base in 93% yield (Scheme between AGs, 501, and arylboronic acid was conducted under
140). MW irradiation at 120 °C to afford 502, which under
The synthesis of thienopyrazine isocyanate 492, the synthetic deprotection−cyclodehydration−oxidation using 20% TFA in
intermediate of fiduxosin 493, was reported by Haight et al.536 DCE at room temperature afforded 503 in 35−98% yields
involving the condensation of aminomalononitrile with PG- (Scheme 144).
oxime in i-PrOH to produce 2-amino-3-cyano-5-phenylpyr- The synthesis of thermostable polyquinoxalines 505 was
azine N-oxide 490, which was converted into 492 in four steps reported by Banihashemi et al.553 via condensation of 2,2′-
through 491 (Scheme 141). diiodobiphenyl-4,4′-diglyoxal dihydrate 504 with several
Jaung and co-workers537 reported the synthesis of the aromatic tetraamine compounds either in HMPA solution or
tetrapyrazinoporphyrazinato metal complexes 496 by reaction as a melt condensation at 300−350 °C under nitrogen
of dicyanopyrazines 495 with the appropriate metal salt (CuCl, atmosphere (Scheme 145). Also different model compounds
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Scheme 141. Synthesis of Thienopyrazine Isocyanate 492

Scheme 142. Synthesis of Tetrapyrazinoporphyrazinato Scheme 143. Synthesis of Benzopyrano[3,4-b]pyrazine 500

Metal Complexes 496a via Triazine 499b

a
M = Al(OH), V(O), Cu; Ar = 4-i-BuC6H4, 4-n-C8H17C6H4, 4-n-
C12H25C6H4, 4-n-C16H33C6H4; 64−84%.
Scheme 144. Synthesis of 2,3-Diarylquinoxalines 503 via
Petasis Reactiona
were prepared by the condensation of 504 with diamines such
as 2-phenylenediamine, 3,4-diaminobenzoic acid, and 3,4-
diaminopyridine in refluxing EtOH or AcOH.
Also, Wrasidlo et al.554 reported the synthesis of the high
molecular weight polyquinoxalines via condensations of either
3,3′,4,4′-tetraaminodiphenyl sulfone or benzophenone with
various bisglyoxals by heating in m-cresol, then quenching with
MeOH.
As illustrated in Scheme 146, 1,4-di-N-oxide-quinoxaline-2-
carboxamide derivatives 508 were prepared by Moreno et al.555
By treatment of the PG and benzyl isocyanide under Passerini a
R = H, Me; Ar = Ph, 4-FC6H4, 4-CF3C6H4; Ar′ = 3-FC6H4, 2,4,6-
reaction, the β-ketoamide 506 was obtained, which underwent F3C6H2, 3-CF3C6H4, 2-MeOC6H4, 4-MeC6H4, 2-naphthyl, trans-β-
the Beirut reaction with appropriate benzofuroxanes 507 in the styryl; 35−98%.
presence of CaCl2 and ethanolamine as catalysts. Synthesized
508 were evaluated for in vitro antituberculosis activity against 6.1.12. Fused Pyrazines and Pteridines. Heterocyclic
Mycobacterium tuberculosis strain H37Rv. Results indicate that compounds possessing a fused pyrazine moiety show important
compounds provide an efficient approach for further develop- biological activities,557 including anti-HIV,558 antimalarial,559
ment of antituberculosis agents. antiviral,560 anticancer,561 psychotropic,562 and aldose reductase
There are several other reports on the condensation of AGs inhibitor activities.563 Additionally, the pteridine structures are
with different 1,2-diamines for construction of pyrazine or present in natural products such as folic acid, biopterin, and
quinoxaline rings and application of them.556 neopterin and are also found in synthetic anticancer drug
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Scheme 145. Synthesis of Thermostable Polyquinoxalines 505

Scheme 146. Synthesis of Quinoxaline-2-carboxamides 508a Scheme 147. Synthesis of Pyrazinothiadiazine 2,2-Dioxide
510a

a
X = O, NOH.

Scheme 148. Synthesis of Pyrazino[2,3-c]pyridazine 512

a
R = H, Cl; R′ = H, Cl, F, OMe, CH3, CF3; 6−36%.

an unusual methylation under acidic conditions in 68% yield

methotrexate.564 While condensation reaction of 5,6-diamino- (Scheme 149).568
pyrimidines with 1,2-dicarbonyl compounds is commonly used The cyclocondensation reaction of the amino-substituted
to prepare of pteridine derivatives,565e there are a number of heterocycles such as 5,6-diaminopyrimidines 515 or 2,3-
alternative methods to prepare this class of heterocycles in the diamino- or 3,4-diaminopyridines 516 and 517 with AG-
literature.565 hydrates forming the pyrazine ring 518−520 was reported in
Campillo et al.566a described the synthesis of pyrazino[2,3- single step. The regioselectivity of the reaction was controlled
c][1,2,6]thiadiazine 2,2-dioxide 510 via condensation between
3,4,5-triamino-2H-1,2,6-thiadiazine 1,1-dioxide 509 and PG. Scheme 149. Synthesis of Dihydropyrazinotriazine 514
Two possible isomers having phenyl substituted at positions 6
and 7 can be obtained. By reaction of 509 with PG-oxime,
exclusively, the 6-phenyl-7H-pyrazinothiadiazines was obtained.
However, when PG was used, the 7-phenyl-6H-derivative was
obtained (Scheme 147).566
Similarly, as shown in Scheme 148, the condensation
reaction of PG with 3,4-diaminopyridazine 511 to give 6(7)-
phenylpyrazino[2,3-c]pyridazine 512 in ethanolic HCl was
reported.567
7-Methoxy-8-methyl-6-phenyldihydropyrazine 514 was pre-
pared by ring closure of 5,6-diaminotriazine 513 with PG in
MeOH via addition of the MeOH at C(7) and N(8) through
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Scheme 150. Regioselective Synthesis of Pyrimido- and Pyridinopyrazines 518−520a

a
X, Y = H, OH, NH2; Ar = Ph, 3-HOC6H4, 4-HOC6H4, 3,4-(HO)2C6H3; cond. = NaOH, MeOH−water, pH = 9−10, rt (3 h) → reflux (3 h),
518a−520a; cond. = Me2CNOH, HCl, water, pH = 3−4, rt (3 h) → reflux (6 h), 518b−520b.

by pH and also by using AGs or AG-oximes. Reactions were Scheme 152. Synthesis of Regioisomers 6- or 7-
conducted in two different conditions, (a) using AG-hydrates in Arylpteridines 523a
MeOH−water at pH = 9−10 (using NaOH), which afforded
518a−520a, and (b) via in situ generation of AG-oximes from
AG-hydrates using Me2CNOH and their reaction in water at
pH = 3−4 (using HCl) to afford regioisomers 518b−520b
(Scheme 150).569
Ma and co-workers570 described the synthesis of the
substituted 2,4-diaminopteridine derivatives 518b by treatment
of 515 (X = NH2, Y = NRR′) with different substituted PG-
oxime under N2 atmosphere in refluxing MeOH. The inhibitory
activity of the compounds 518b against iNOS were evaluated,
and the results indicated that 518b with Y = NHi-Pr and Ar =
p-Me and p-MeOC6H4 exhibited potent inhibitory activity
similar to that of methotrexate (MTX). A similar reaction was
reported using 2-amino- and 2-methylthio-4,5,6-triaminopyr- a
R = H, Me; Ar = Ph, 4-ClC6H4; acidic alumina, 523a, 63−70%;
imidine dihydrohalides in refluxing MeOH.571 neutral alumina, 523b, 71−75%.
The condensation reaction of PG-oxime and its o-methoxy
derivative with aminomalononitrile gave 490 (Scheme 141),
which was converted into 2,4-diamino-6-substituted pteridine 6.1.13. Triazinones. Due to the biological activity of
8-oxides 521 upon cyclization with guanidine 142 in refluxing triazinone derivatives,574 such as antagonists at the cortico-
MeOH in quantitative yield (Scheme 151).572 tropin releasing factor receptor,574a anticancer activity,574b,c
anti-HIV,574d and inhibitory activity of 5-lipoxygenase,574e a
Scheme 151. Synthesis of Pteridine 8-Oxides 521a number of methodologies have been reported for synthesis of
1,2,4-triazinones.575
Lalezari576 reported the cyclization and rearrangement
reactions of substituted arylglyoxalaldoxime semicarbazones
524 to 6-substituted 1,2,4-triazine-3,5(2H,4H)-diones 525. The
reaction was carried out by refluxing of 524 in water in the
presence of K2CO3. Compounds 524 underwent cyclization
with loss of ammonia to produce 6-aryl-1,2,4-triazine-3(2H)-
a
Ar = Ph, 2-MeOC6H4. one 4-oxide, in which the oxygen atom of the N-oxide was
shifted to the neighboring carbon atom to form 525 in 45−67%
yields (Scheme 153). Also, Lalezari and co-workers577 reported
Reaction of 5,6-diaminouracils 522 with AGs over acidic and the conversion of 524 to 6-aryl-1,2,4-triazine-3(2H)-ones using
neutral Al2O3 under MW irradiation was reported by Singh and 5% HCl under reflux conditions, which on boiling with
Geetanjali. When the condensation reaction was carried out by hydrogen peroxide in glacial AcOH was converted into 525 in
using acidic alumina under MW irradiation 6-arylpteridines 65% yield.
523a were obtained in 63−70% yields, but using neutral By reaction of PG with 2,4-disubstituted thiosemicarbazide
alumina afforded the corresponding regioisomer, 7-arylpter- 526 in water at room temperature, the corresponding
idines 523b in 71−75% yields (Scheme 152).573 semicarbazone 527 was synthesized, which was cyclized to 5-
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Scheme 153. Synthesis of 1,2,4-Triazine-3,5-diones 525a As shown in Scheme 156, the condensation reaction of AGs
with arylamidrazones 536 was carried out in MeOH to produce

Scheme 156. Synthesis of 3,6-Diaryl-1,2,4-triazines 357a

a
Ar = Ph, 4-BrC6H4, 4-ClC6H4, 4-FC6H4, 4-MeOC6H4, 4-MeC6H4, 4-
MeSC6H4, 4-NO2C6H4; 45−67%.

hydroxy-l,2,4-triazine-3-thione 528 when treated with TFA in

benzene at room temperature for 15 h. Refluxing of 527 in
alcohols such as MeOH and EtOH in the presence of TFA for
8 h gave corresponding 5-alkoxy-1,2,4-triazine-3-thione deriv- a
Ar = Ph, 2-ClC6H4, 3-ClC6H4, 4-ClC6H4, 2-MeC6H4, 3-MeC6H4, 4-
atives 529 in 73−76% yields. Compound 527 was converted MeC6H4, 3-CF3C6H4; Ar′ = Ph, 4-BrC6H4, 4-ClC6H4, 2-FC6H4, 3-
into 1,3,4-thiadiazolium cation 530 in the presence of TFA FC6H4, 4-FC6H4, 4-CF3C6H4, 2-pyridyl; 357a, 39−76%; 357b, 1−
(Scheme 154).578 16%.

Scheme 154. Synthesis of Triazine-3-thiones 528 and 529a 1,2,4-triazine derivatives 357 as two regioisomers, in which 3,5-
disubstituted 1,2,4-triazines 357a were obtained as major
regioisomers in 39−76% yields588 and were investigated as
potential anti-inflammatory588a and herbicidal agents.588b
Limanto and co-workers589 reported the regioselective
synthesis of 5-substituted 3-amino-1,2,4-triazines 535a by
condensation of aminoguanidine 534 with ketoaminals 533,
prepared by nucleophilic displacement of α,α-dibromoaceto-
phenones with excess morpholine. The reactions were
performed in MeOH in the presence of AcOH, and products
535 were obtained in 45−76% yields with >95% regioselectivity
(Scheme 157). Directly using PG-hydrate in reaction with

Scheme 157. Synthesis of Aryl-Substituted 3-Amino-1,2,4-

triazines 535a

a
Cond. = TFA, benzene, rt, 15 h; 528, 78%; Cond. = TFA, ROH,
reflux, 8 h; 529, 73−76%.

Also, as outlined in Scheme 155, the reaction of PG-hydrate

with thiocarbohydrazide 531 in water gave the 4-amino-1,2,4-
triazine-3-thione 532 in 72% yield.579

Scheme 155. Synthesis of 4-Amino-1,2,4-triazine-3-thione

532

a
Ar = Ph, 4-BrC6H4, 4-MeOC6H4, 6-MeOnaphth-2-yl; X = Cl, Br;
45−76%, 98−99% regioselectivity.

6.1.14. Triazines. 1,2,4-Triazines are a well-known class of

nitrogen heterocycles with a range of applications,580 aminoguanidine acetate in either THF or H2O afforded a 1:1
particularly in pharmaceuticals,581 herbicides, pesticides, and regioisomeric mixture of the corresponding aminotriazines
dyes.582 They exhibit physical, biological, and chemical 535a,b (Ar = Ph) in 50% yield, while reaction in MeOH,
properties,580,582a such as antitumor,583 antiviral,584 and slightly improved the ratio of products a/b to 3:1.
antifungal585 activities. The chemistry of 1,2,4-triazines has Matikainen et al.590 reported the intramolecular cyclization
been extensively studied.586 3-Pyridyl-1,2,4-triazines are inter- reaction of phenylglyoxal bis(amidinohydrazone) into the
esting compounds due to their application in transition metal isomeric mixture of 535a,b. The reaction was conducted
analysis.587 Condensation of the amidrazones with 1,2- under Ar atmosphere at 210 °C without using solvent, and 535
dicarbonyl compounds provides one of the most straightfor- was obtained in 60% yield. The ratio of the two isomers was
ward syntheses of 1,2,4-triazines.580 not studied.
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Triazine 537 was isolated from reaction of PG-hydrate with Scheme 160. Synthesis of Bis-triazines 541 and 542a
aniline in AcOH−EtOH (10/50) under heating conditions in
13% yield via DA reaction between PG-imine 3 and PG-
bisimine 536 (Scheme 158).591

Scheme 158. Synthesis of 1,2,4-Triazines 537 via DA

Reaction

Bruce and co-workers592 developed a synthetic approach to a

series of 5,5′-linked bis-(1,2,4-triazine)s 540, which are a
potential monomers in DA polymerization processes. Ar- Ar = Ph, 4-HOC6H4, 4-NO2C6H4.
ylene-bisglyoxals 539 were synthesized by oxidation of bis(α-
bromophenylacetyl)-substituted aromatic compounds with
There are other reports on similar condensation reactions of
DMSO or by reaction of diacetyl-substituted aromatic
AGs with substituted amidrazones for construction of 1,2,4-
compounds 538 with HBr in DMSO. Conversion of 539 into
triazines in the literature.594
540 was carried out by reaction with S-methylthiosemicarbazi-
dium iodide in aqueous EtOH in the presence of NaHCO3 at 6.1.15. Fused Triazines. Fused triazine moiety can be
room temperature (Scheme 159). considered as a bioisostere, which also displayed pharmaco-
logical and biological activities,595 such as anticancer activity595j
and antagonistic activity against A1 and A2A adenosine
Scheme 159. Synthesis of 5,5′-Linked Bis-(1,2,4-triazine)s receptors.595k−m Fused triazines have been synthesized
540 generally by a previously reported method.596
By treatment of 1-NH-Boc-protected 1,2-diaminopyrroles
543 with PG-hydrate in the presence of conc. HCl in THF at 0
°C, followed by standing at room temperature for 22−72 h,
highly substituted pyrrolo[1,2-b]-1,2,4-triazines 544 were
obtained as two regioisomers, 544a and 544b, in 11−44%
and 8−75% yields, respectively. Reactions were carried out by
one-pot cleavage of the protecting group and subsequent
condensation with PG-hydrate (Scheme 161).597
The preparation of imidazo[1,2-b]-1,2,4-triazines 546 were
reported by Lalezari et al.598 via treatment of PG-oxime with 4-

Scheme 161. Synthesis of Pyrrolotriazines 544a

Also, the condensation reaction of AG-hydrates and 539a

with amidrazone 356 (Ar′ = 2-pyridyl) and bis-amidrazone
360a was reported in refluxing absolute EtOH to give the
corresponding mono- and bis-triazines 357, 541, and 542 in a
R = 4-NO2C6H4, CN, piperidin-1-ylcarbonyl, (EtO)2OP; a, 11−44%;
78−89% yields (Scheme 160).593 b, 8−75%.

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substituted 1,2-diaminoimidazoles 545. The reactions were Scheme 164. Synthesis of Pyrido[1,2-b]-1,2,4-triazinium
conducted by refluxing a solution of PG-oxime and 545 in Salts 551−554a
EtOH for 1 h, followed by addition of HCl and refluxing for
additional 4 h to give 546a in 31−59% yields. When HCl was
added at the beginning of the reaction, a mixture of two
regioisomers, 546a,b, was produced. When reactions were
carried out using PG-hydrate in water under reflux conditions,
546b were obtained in 40−83% yields (Scheme 162).

Scheme 162. Synthesis of Imidazotriazines 546a

a
Ar = Ph, 4-BrC6H4, 4-ClC6H4, 2-naphthyl; X = NOH, EtOH, reflux
(1 h), then dil. HCl, reflux (4 h); 546a, 31−59%; X = O·H2O, HCl,
water, reflux, 10 h; 546b, 40−83%; 546a, minor product.

A similar reaction between PG and 7,8-diamino-1,3-

dimethylxanthine 547 was carried out in the presence of
boric acid in AcOH at 100 °C and 1,3-dimethyl-7-phenyl- a
Ar = Ph, 4-ClC6H4, 4-BrC6H4.
[1,2,4]triazino[2,3-f ]purine-2,4(1H,3H)-dione 548 was ob-
tained in 96% yield (Scheme 163).599
6.2. O-Heterocyclic Compounds
Scheme 163. Synthesis of Triazinopurinedione 548
6.2.1. Pyrans and Pyranones. Pyrans and pyranones are
versatile building blocks that have been extensively used in
natural products601 and for the synthesis of many biologically
active compounds,602 such as pheromones, terpenoids,603
antibiotics,604 and immunosuppressive,605 antitumor,606 anti-
ulcer,607 antiproliferative,608 and antiparasitic609 agents. There
are a number of methods for construction of these heterocycles,
such as hetero-DA (HDA) reactions of aldehydes with dienes
or α,β-unsaturated carbonyl compounds with electron-rich
carbon−carbon unsaturated bonds.610
Oi and co-workers611 studied the HDA reaction of different
dienes with AGs using cationic chiral BINAP−palladium or
−platinum complexes as catalyst to produce 2-benzoyl-3,6-
dihydro-2H-pyrans 555. A variety of chiral diphosphine ligands
were tested for the HDA reaction of 2,3-dimethyl-1,3-butadiene
with PG, and (S)-BINAP was selected as the ligand due to high
yield of cycloadduct with high ee. The reaction was carried out
by stirring a mixture of a diene with an AG in CDCl3 in the
Reaction of AG-hydrates with 1,2-diaminopyridinium salt presence of 3 Å MS and a catalytic amount of [Pt(S-
549 under different conditions was reported by Hajós et al.600 BINAP)(PhCN)2](BF4)2 at 0 °C for 24 h, which afforded
Under basic conditions, using NaOH in CH3CN at room pyrans 555 in 21−80% yields (Scheme 165). Heteroene612
temperature, 2,5-dihydro-2-hydroxypyridotriazines 550 were products were not observed under these reaction conditions.
produced, which were converted into the covalent hydrate salt Also, one example of the HDA reaction of PG with
552 when treated with 70% HClO4 in 65−78% yields. Salts 552 cyclohexadiene was investigated using a different chiral
underwent dehydration when dissolved in TFA, and 3- palladium catalyst, [(S)-MeObiphepPd(NCAr)2(SbF6)2], in
arylpyrido[l,2-b]-1,2,4-triazinium salt 553 was detected using DCM at 0 °C in the presence of 4 Å MS, and corresponding
NMR spectra. When a suspension of 550 (Ar = 4-ClC6H4) in cycloadduct was obtained in 55−80% conversion with 98−99%
DCM was treated with Me3O·PF6 at room temperature, 551 ee and a 98:2 diastereomeric ratio.613
was prepared in 77% yield. Reaction of 549 with AG-hydrates Tonoi et al.614 described the HDA reaction of TIPS-
in acidic media [70% HClO4−MeOH, 1:2 (v/v)] at room substituted Danishefsky’s diene 556 with AGs catalyzed with
temperature resulted in 2-arylpyrido[l,2-b]-1,2,4-triazinium salt DPENTf. The reaction was carried out by addition of AGs and
554 in 70−82% yields (Scheme 164). 556 to a solution of DPENTf in toluene at −78 °C, followed by
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Scheme 165. Synthesis of Pyrans 555 via HDA Reactiona Et2O−EtOAc (3:1). The reaction between 559a and AGs
occurred exclusively at the aldehyde group to afford zinc
bromide alcoholates 560a, which were cyclized to 561a in 80−
93% yields under the reaction conditions (Scheme 167). Also, a
similar reaction of AGs with zinc enolate 559b,c was
investigated to form 3-aroyl-4,4-dimethyl-2-oxaspiro[5.5]-
undecane-1,5-diones 561b and 1-aroyl-4,4-dimethyl-2-
oxaspiro[5.5]undecane-3,5-diones 561c. The reactions were
carried out by dropwise addition of bromo derivatives in ether
to fine zinc turnings and a catalytic amount of HgCl2 in Et2O−
EtOAc solvent mixture. After completion of the reaction, a
solution of the AG in ethyl acetate was added and refluxed for
30 min. Then upon cooling and hydrolyzing with 5% HCl, the
products were obtained in 50−65% yields (Scheme 167).616
6.2.2. Dioxanes. The dioxane moiety is a common
structural motif in several bioactive molecules.617 Also 1,3-
dioxane is one of the most important protecting group of
carbonyl compounds. There are a number of methodologies,
a
Ar = Ph, 4-ClC6H4, 4-MeOC6H4, 4-MeC6H4. such as reaction of carbonyl compounds with 1,3-diols, for
preparing dioxane derivatives.618
hydrolysis with TFA to give 2-aroyl-2H-pyran-4(3H)-ones 557 Reactions of optically pure 1-aryl-2,2-dimethylpropane-1,3-
in 46−74% yields with 77−87% ee (Scheme 166). diols 562 with AGs were carried out in refluxing benzene
catalyzed with p-TsOH with azeotropic removal of water.
Scheme 166. Synthesis of Pyran-4-ones 557 via HDA When BF3·OEt2 was used as Lewis acid, products 563 were
Reactiona obtained in low yields along with a polymeric material. The
products were obtained as diastereomerically pure cyclic ketals
563 in 40−72% yields. Reactions took place at the keto group
(Scheme 168).619

Scheme 168. Synthesis of Cyclic Ketals 563a

a
Ar = Ph, 4-CF3C6H4, 4-MeOC6H4; 46−74%; ee = 77−87%.
a
X = H, Cl; Ar = Ph, 2-ClC6H4, 4-MeC6H4; 40−72%.
Shchepin et al.615 reported the Reformatsky reaction of
methyl 4-bromo-3-oxo-2,2,4-trimethylpentanoate 558a with
zinc and AGs to produce 2,3,5,6-tetrahydropyran-2,4-diones ́ et al.620 reported a synthesis of 2-acyl-1,3-
Becerra-Martinez
561a containing an aroyl group in the 6 position. The reaction dioxanes 565 by the reaction of 3,10-pinanediol derivatives 564
was performed in two steps: first zinc enolate 559a was with PG-acetal, which were subjected to nucleophilic addition
prepared and then the AG was added to the solution of 559a in using MeMgBr to afford carbinols 566 in 88−98% yields with

Scheme 167. Synthesis of 6-Aroylpyran-2,4-diones 561 via Reformatsky Reactiona

a
561a: R = R' = Me; Ar = Ph, 4-BrC6H4, 4-t-BuC6H4, 4-ClC6H4, 4-EtC6H4, 4-FC6H4, 4-MeC6H4, 2,4,6-Me3C6H2, 2,3,5,6-Me4C6H, 4-PhC6H4; 80−
93%; 561b: R = Me; R'−R' = (CH2)5; Ar = Ph, 4-BrC6H4; 63−65%; 561c: R−R = (CH2)5; R' = Me; Ar = Ph, 4-BrC6H4; 50−54%.

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≥87:13 dr. Synthesis of 2-acyl-1,3-dioxanes 565 was conducted butadiene or 1,3-cyclohexadiene, corresponding thiopyrans, 2-
using p-TsOH in benzene with azeotropic removal of water benzoyl-4,5-dimethyl-3,6-dihydro-2H-thiopyran 571a or 3-
(Scheme 169). benzoyl-2-thiabicyclo[2.2.2]oct-5-ene 571b, were obtained in
85% or 89% yields, respectively. The reactions were carried out
Scheme 169. Synthesis of Dioxanes 565 and Their Reaction in CH3CN at room temperature, in which thioaldehyde 570
with MeMgBra was produced as reaction intermediate, which was trapped with
dienes via HDA reaction. HDA reaction with cyclohexadiene
occurred with very high selectivity in favor of the endo isomer
(Scheme 171).626

Scheme 171. Synthesis of Dihydrothiopyrans 571 via HDA

Reaction

a
R = H, Me; 88−98%, a/b ≥ 13/87.

Griffiths and Gutsche 621 described the synthesis of

mandelaldehyde dimers 569 via hydrolysis of dimethyl acetals
567, which were synthesized by reduction of the AG-acetals
with LiAlH4 (using NaBH4 in the case of nitro substituent) in
refluxing THF. AG-acetals were prepared by the action of 6.4. N,O-Heterocyclic Compounds
trimethyl orthoformate and methanol on AGs in the presence 6.4.1. 1,3-Oxazines. 1,3-Oxazines are an intermediate for
of NH4Cl at room temperature for 24 h. The hydrolysis step the synthesis of medicinally active molecules627 that exhibit
was carried out using 0.5 N HCl at room temperature to afford biological and pharmacological activities such as analgesic,628
568, which were converted into dimers 569 in 20−75% yields antitubercular,629 anticancer,630 anti-HIV,631 antihyperten-
(Scheme 170). sive,632 antibiotic,633 antithromobotic,634 anticonvulsant,635
and antiulcer.636 Moreover, certain kinds of 1,3-oxazines are
Scheme 170. Synthesis of Mandelaldehyde Dimers 569a of interest as photochromic compounds.637 A number of
methods for construction of the 1,3-oxazine structure including
the reaction of a diol638 or olefin639 with a nitrile under acidic
conditions, cyclodehydration of hydroxyl amides,640 elimination
of water from β-acylamino-aldehydes641 or ketones642 are
reported in the literature.643
The nucleophilic addition to 2-benzoyl-1,3-oxazines, which
were prepared by condensation of 3-amino alcohols with PG,
were investigated by different research groups. Ko et al.644
reported the stereoselective reduction of chiral N-tosyl-2-
benzoyl-1,3-oxazines 573a,b, prepared by condensation of D-
glucose 572 with PG-hydrate in refluxing benzene in the
a
Ar = Ph, 4-ClC6H4, 4-CF3C6H4, 4-MeOC6H4, 4-MeC6H4, 4- presence of p-TsOH. Protection of carbinols 574a,b using BnBr
NO2C6H4; 567, 27−80%; 569, 20−75%. or Ac2O followed by acidic hydrolysis (5% HCI/EtOH 1:5)
gave the corresponding 2-benzyloxy aldehyde or 2-hydroxy
aldehyde in 96% or 92% yields, respectively, which reduced to
6.3. S-Heterocyclic Compounds corresponding diols 575 or 576 using LiAlH4 or NaBH4
6.3.1. Thiopyrans. The sulfur-containing six-membered (Scheme 172).
heterocyclic compounds display a wide range of biological Also, as shown in Scheme 173, chiral N-tosyl-2-benzoyl-1,3-
activities622 and have applications for the synthesis of oxazine 578, which was prepared by condensation of 1,3-amino
heterocyclic compounds623 and organic materials for electronic alcohol 577, derived from (1R)-(+)-camphor, with PG-hydrate
devices.624 The HDA reaction of dienes with thiocarbonyl was subjected to reduction to 579 using various reducing
compounds is one of the most important methods for the agents, and high diastereoselectivity was observed in the case of
synthesis of thiopyran derivatives.625 chelating reducing agents such as LiAlH4 and L-Selectride.645 A
By treatment of bis(trimethylsilyl)sulfide and CoCl2·6H2O similar reaction was investigated by addition of Grignard and
with PG-hydrate in the presence of dienes, 2,3-dimethyl-1,3- organolithium reagents to and hydride reduction of benzoyl-
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Scheme 172. Synthesis of 1,3-Oxazines 573 and Their Conversion into Diols 575 and 576a

a
[Red] = NaBH4, LiAlH4, L-Selectride, LiAlH(Ot-Bu)3, n-Bu4NBH4, DIBAL; solvent = EtOH, ether, THF, DCM, toluene; temp = −78, 0 or 20 °C;
574a,c: R = Me; 83−98%; de = 0−98%; 574b,d: R = pivaloyl; 89−98%; de = 0−68%.

Scheme 173. Synthesis of 1,3-Oxazines 578 Derived from The reaction of PG with 3-amino-1-propanol in the presence
(1R)-(+)-Camphor and Their Reduction to 579a of K2CO3 in refluxing benzene with removal of water using
Dean−Stark apparatus was also reported.648
6.4.2. Morpholines. The morpholine skeleton is present in
a number of pharmacologically active molecules649 that exhibit
anti-inflammatory activity650 and have a wide range of
applications in the treatment of depression,651 obesity652 and
asthma. Also, they are chiral building blocks for the synthesis of
variety of pharmacologically active compounds.653 The most
important methods for preparation of morpholines include the
reaction of aminoethanol with 1,2-electrophiles such as α-
ketoaldehydes, epoxides, allyl halide, and α-halo esters and α-
chloroacetyl chloride, with further reactions,654 and reaction of
amines with diethanol amine or its equivalents.655
A protocol for synthesis of 2-hydroxymorpholines 585 was
reported by Berrée et al.656 via a one-pot three-component
Petasis coupling reaction. The reaction was carried out by
stirring of a mixture of 1,2-amino alcohol 584, PG, and
arylboronic acid in EtOH at room temperature for 24 h to give
corresponding 585 in 53−92% yields with 83/17−89/11
diastereoselectivity (Scheme 175).
The reactions of PG-hydrate with (R)-phenylglycinol 586a
a
and (1S,2R)-norephedrine 586b were investigated in the
[Red] = NaBH4, KBH4, LiAlH4, LiAlH(Ot-Bu)3, LiEt3BH, NaEt3BH, presence of excess MgSO4 in DCM to give the corresponding
DIBAL, n-Bu4NBH4, L-Selectride; solvent = EtOH, ether, toluene, oxazolidines 587, in which initially formed 587 underwent a
THF, DCM; temp = 0 or −70 °C; de = 8−98%.
fast stereospecific rearrangement to the corresponding 2-
1,3-benzoxazine derived by reaction of PG with 8-benzylami- hydroxy-3-phenyl-1,4-oxazines 588 in 87−91% yields (Scheme
nomenthol.646 176).657
Condensation reaction between cis-piperidine ethanol 580a By treatment of PG-hydrate with L-ephedrine 589 under
and PG-hydrate in refluxing DCM in the presence of 4 Å MS different conditions such as in the presence of 4 Å MS in ether
afforded one isomer of perhydro-2-benzoyl-1,3-oxazine 581a in at 20 °C or 4 Å MS in EtOH at 20 °C or Amberlyst-15 in
85% yield. 1,3-Oxazine 581b was obtained by a similar refluxing toluene, regiospecifically, 2-benzoyloxazolidine 590
condensation with trans-piperidine ethanol 580b in 86% was obtained with a quantitative yield via condensation of 589
yield. The reaction of 581a,b with Grignard, organolithium, with the more reactive aldehyde group of PG. 2-Benzoylox-
or reducing reagents at −78 °C gave the corresponding azolidine 590 was obtained as two diastereomers, which
carbinols 582 and 583 in high diastereomeric excess (Scheme rearranged to 4,5-dimethyl-3,6-diphenylmorpholin-2-one 591
174).647 at ambient temperature after 12 days (Scheme 177).658
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Scheme 174. Synthesis of 1,3-Oxazines 581 Derived from Piperidine Ethanols 580a

a
Reagents = RMgX, RLi, DIBAL; R = n-Bu, t-Bu, Et, Me, c-pentyl, n-Pr, i-Pr, vinyl; X = Br, Cl; 582, >80%, a/b = 53/47−95/5; 583, >80%, a/b =
95/5.

Scheme 175. Synthesis of 2-Hydroxymorpholines 585 via Scheme 177. Synthesis of Diphenylmorpholine-2-one 591a
Petasis Coupling Reactiona

a
Ar = Ph, 92%, dr = 89/11; Ar = 2-MeOC6H4, 53%, dr = 83/17.
a
Conditions: 4 Å MS, Et2O, 20 °C or 4 Å MS, EtOH, 20 °C or
Scheme 176. Synthesis of 2-Hydroxymorpholines 588 via Amberlyst-15, toluene, reflux.
Oxazolidines 587a
Scheme 178. Synthesis of Oxazine Core of Aprepitant 593

a
a, R = Ph, R′ = H; b, R = Me, R′ = Ph; 588a, X = OH, X′ = H, 87%;
588b, X = H, X′ = OH, 91%.

A protocol for synthesis of aprepitant, 594, a potent

substance P (SP) receptor antagonist, was described by Zhao
and co-workers. The enantiopure oxazinone 593 starting
material was synthesized via condensation reaction of 4-
fluorophenylglyoxal hydrate with amino alcohol 592 in the room temperature, to produce β-amino alcohol 596. By
presence of AcOH under reflux conditions and azeotropic treatment of 596 with Ph3P in the presence of DEAD in
removal of produced water in 90% yield with >98% dr. The THF at room temperature for 24 h, 1,2-ethylenediaziridine 597
conversion of oxazinone 593 to 594 was carried out in further was obtained in 78% yield, which was used as ligand in the Pd-
steps (Scheme 178).659 catalyzed allylic alkylation of dimethyl malonate.
As shown in Scheme 179, Gualandi et al.660 reported the Preparation of morpholine derivatives 600 was reported by
diborane-induced reduction of fused oxazino-oxazine 595, Pedrosa et al.661 through selenocyclofunctionalization of chiral
which was prepared by condensation of PG-hydrate and (S)- 3-allyl-2-hydroxymethyl-substituted perhydro-1,3-benzoxazine
phenylglycinol 596a in DCM in the presence of MgSO4 at derivatives 598. As illustrated in Scheme 180, the chiral
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Scheme 179. Synthesis of Oxazino-oxazine 595 601. The reactions were carried out in the presence of TFA in
MeOH at room temperature for 2 days, and 6-aroyl-5-hydroxy-
5,6-dihydro-4H-1,2,5-oxadiazines 603 were produced in 54−
97% yields via intermediate 602 (Scheme 181).

Scheme 181. Synthesis of Oxadiazines 603a

a
R = Ph, 4-ClC6H4; R′ = H, Me; Ar = Ph, 4-BrC6H4, 4-ClC6H4, 4-
perhydro-1,3-benzoxazines 598 were prepared in three steps, MeOC6H4; 54−97%.
starting from PG.662 Selenocyclofunctionalization of alcohols
598 was carried out using PhSeCl in DCM in the presence of
SnCl4 or in THF with methanol as an additive. Then by 6.5. N,S-Heterocyclic Compounds
reductive deselenenylation using Ph3SnH in the presence of 6.5.1. 1,4-Thiazines and 1,4-Benzothiazines. 1,4-
catalytic amounts of AIBN in refluxing toluene, morpholines Thiazine and 1,4-benzothiazine derivatives possess a wide
599 were produced. N-Tosyl derivatives 600 were produced by spectrum of biological667 and pharmacological activities, such as
treatment of 599 with AlH3, in situ generated by action of calcium channel blockers,668 phosphodiesterase 7 inhibitors,669
LiAlH4 on AlCl3 in THF, followed by elimination of the 5-HT3 antagonists,670 antipsychotics agents,671 sedatives,672
menthol moiety using PCC in DCM at room temperature, then and Na+/H+ exchange inhibitors.673 There are a number of
KOH in THF−MeOH−H2O, which afforded the enantiopure published reports on synthesis of 1,4-thiazine structures using
morpholines that were converted into 600 by treatment with aminothiophenols or reaction of amines with sulfur powder in
TsCl and DIPEA in EtOAc (Scheme 180). the presence of I2.674
6.4.3. Oxadiazines. Oxadiazines are important heterocycles 2H-1,4-Thiazines 607 were synthesized via HDA reaction of
due to their key biological activities.663 They are also synthetic acrylic dienophiles with hydrazono thioketones 605, which
intermediate for other heterocyclic compounds.664 On the were prepared in two steps starting from AG-hydrates.
other hand, 1,2,5-oxadiazines are not very general heterocyclic Monohydrazones 604 were synthesized by reaction of 1,1-
systems.665 dimethylhydrazide or 1-aminopiperidine with AG-hydrates in
Accordingly, Amitina and co-workers666 reported the EtOH at room temperature; then by treatment of 604 with
reactions of AGs with Z-isomers of hydroxylamino oximes Lawesson’s reagent in benzene at room temperature,

Scheme 180. Synthesis of Enantiopure Morpholines 600a

a
R, R′ = H, Me; R−R′ = (CH2)4; R″ = H, Me.

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corresponding thiocarbonyl compounds 605 were obtained in Scheme 183. Synthesis of 1,4-Benzothiazines 609 and 610a
25−55% yields. Compounds 605 were used as heterodienes in
DA cycloaddition reactions with acrylic dienophiles using
benzene as solvent in the presence of HQ as additives to afford
3,4-dihydro-2H-1,4-thiazines 606, which converted to 2H-1,4-
thiazines 607 under heating via elimination of an amine
molecule in 26−58% yields (Scheme 182).675

Scheme 182. Synthesis of 1,4-Thiazines 607 via HDA

Reactiona

a
Ar = Ph, 4-MeOC6H4.

Scheme 184. Synthesis of Acylamido-1,4-benzothiazines

611a

a
Ar = Ph, 4-BrC6H4, 4-ClC6H4; NR2 = NMe2, piperidine; EWG =
CHO, COMe, CO2Me, CN; 26−58%.
a
R = Me, Ph, MeO; 60−86%.
676
MacKenzie et al. described the synthesis of benzothiazines
609 by condensation of PG-hydrazonyl bromides 608 with o- Scheme 185. Synthesis of 1,2,4-Benzothiadiazine 1,1-
aminothiophenol. The reaction was conducted by addition of Dioxide 614
608 to a solution of o-aminothiophenol in EtOH containing
NaOEt and stirring for 30 min to afford desired product in 72−
84% yields, which exists predominantly in its tautomeric
hydrazone form 609a. For investigation of existence of
tautomeric forms, the condensation reaction of o-N-methyl-
aminothiophenol with 608 to produce 4-methyl-3-phenyl-2-
phenylazo-4H-1,4-benzothiazine 610 was also carried out in
EtOH in the presence of NaOEt (Scheme 183).
Treatment of 185, obtained from reaction of PG with amides
followed by SOCl2 (Scheme 52) with o-aminothiophenol
afforded 1,4-benzothiazines 611 in 60−86% yields (Scheme
184).218
6.5.2. Benzothiadiazines. Benzothiadiazine 1,1-dioxide
derivatives exhibit wide biological and pharmacological
activities.677 Accordingly, several methods have been developed
for the synthesis of benzothiadiazines 1,1-dioxides deriva-
tives.678
Topliss et al.679 reported the synthesis of 3-hydroxybenzyl-
3,4-dihydro-1,2,4-benzothiadiazine 1,1-dioxide 614 by con-
densation of a substituted orthanilamide 612 with PG-acetal
in the presence of HCl in EtOH. The condensation reaction
gave 614 rather than 3-benzoyl-3,4-dihydrobenzothiadiazine
613. It seems that 613a was first formed, which was
transformed to 614 by enolization of the carbonyl group and
migration of the double bond to the 3,4-position via Grivas.680 Reaction was carried out by passing of dry HCl (g)
intermediate 613b (Scheme 185).
through a solution of 615 and PG-hydrate in ethanol at 50 °C.
6.6. S,O-Heterocyclic Compounds: Benzoxathiin
Unexpectedly, the reaction yielded 2-benzoyl-4H-3,1-benzox-
In an attempt to synthesize 616, the reaction of PG-hydrate
with 2-mercaptobenzamide 615 was investigated by John C. athiin-4-one 617 in 28% yield (Scheme 186).
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Scheme 186. Synthesis of 3,1-Benzoxathiin-4-one 617 biological686 and pharmacological activities687 such as anti-
biotic,688 antimalarial,689 anti-HIV,690 and anticancer agents.691
The benzodiazepines are the most widely prescribed minor
tranquilizers in current use, and they are known to act on the
central nervous system. A variety of methods exist in the
literature for the preparation of these heterocycles,692 such as
the condensation reaction of 1,2-diamines with 1,3-dielectro-
philic compounds,692f,h intramolecular cycloadditions of (o-
azidobenzamido)alkenes and alkynes,692i,j aza-Wittig ring
closure of [o-(iminophosphoranyl)benzamido]carbonyls,692k
intramolecular Michael additions of (o-aminobenzamido)-
enones.692l
Sañudo and co-workers693 reported the synthesis of 5-
oxobenzo[e][1,4]diazepine-3-carboxamides 624 by Ugi reac-
tion−Staudinger/aza-Wittig cyclization sequences. The Ugi
7. SYNTHESIS OF SEVEN-MEMBERED HETEROCYCLES reaction between AGs, para-substituted benzylamines, cyclo-
hexyl isocyanide, and 2-azidobenzoic acid 622 was conducted in
7.1. N-Heterocyclic Compounds MeOH at room temperature to afford products 623 in 45−90%
7.1.1. Tetrahydroazepines. Due to the occurrence of yields, which was converted into 624 by stirring with Ph3P (1.5
tetrahydroazepines in natural products681 and biologically and equiv) under nitrogen in toluene at room temperature in 59−
pharmaceutically active compounds,682 various approaches, 99% yields (Scheme 188).
mainly ring-closing metathesis (RCM) reaction,683o−q have
been developed to prepare tetrahydroazepine derivatives.683 Scheme 188. Synthesis of 5-Oxobenzo[e][1,4]diazepine-3-
Pedrosa et al.684 described the synthesis of enantiopure carboxamides 624a
2,3,4,7-tetrahydro-1H-azepin-3-ols 621a and 1,2,3,4,5,8-hexahy-
droazocin-3-ols 621b through diastereoselective addition of
allylic or homoallylic Grignard reagents 619 to N-allyl-2-
acylperhydro-1,3-benzoxazines 618 followed by RCM reaction.
The starting 618 was prepared in two steps by condensation of
(−)-8-aminomenthol 26 with PG followed by alkylation with
allylic bromides in the presence of K2CO3 in refluxing CH3CN.
By treatment of an excess of 619 with 618 in ether at −10 °C,
the corresponding alcohols were produced, which were
subjected to RCM using ruthenium(II) complex to give
azepines 620a (n = 1) and azocines 620b (n = 2). Compounds
620a,b were transformed to the final 621 via reductive ring-
opening of the N,O-acetal moiety by treatment with in situ
generated AlH3 in THF at reflux followed by oxidation with
PCC in DCM at room temperature and then treatment with
KOH in THF/MeOH (Scheme 187).
a
7.1.2. Diazepines and Benzodiazepines. The 1,4- Ar = Ph, 4-FC6H4, 4-CF3C6H4, 4-MeOC6H4, 3,4-(MeO)2C6H3, 3,4-
diazepine and 1,4-benzodiazepine structures have been found (OCH2O)C6H3, 4-MeC6H4, 6-MeO-2-naphthyl; Ar′ = Ph, 4-ClC6H4,
in the naturally occurring antibiotics and are important 4-FC6H4, 4-MeOC6H4, 4-MeC6H4.
biomolecules in medicinal chemistry685 with a wide range of

Scheme 187. Synthesis of Tetrahydroazepine-3-ols 621a and Hexahydroazocin-3-ols 621ba

a
R, R′, R″ = H, Me; a, n = 1; b, n = 2.

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Recently, a similar reaction was reported by Lecinska et al.694 presence of SnCl4 at −78 °C afforded a mixture of products
using 3-azido-(S)-2-(N-Boc-amino)propanoic acid 625 to 631 and 630 in ratio of 93/7. Compound 631 was converted
produce enantiomerically pure tetrahydro-1,4-diazepine-3- into 1,4-oxazepane 632 by nucleophilic ring-opening of the
carboxamides 627 via Ugi products 626 in 61−98% yields N,O-acetal moiety using AlH3 (Scheme 191).662
(Scheme 189).
Scheme 191. Synthesis of 1,4-Oxazepane 632
Scheme 189. Synthesis of 5-Oxotetrahydro-1,4-diazepines
627a

a
R = H, (S)-NHBoc, (R/S)-Me; Ar = Ph, 4-FC6H4, 4-CF3C6H4, 4-
MeOC6H4; R′ = n-Bu, Bn, 4-ClC6H4CH2, 4-MeOC6H4CH2, 4-
MeC6H4CH2.

One example of the condensation of PG with 3-amino-

quinazolinone 628 was reported by Tolkunov and Bogza695 via
8. MISCELLANEOUS HETEROCYCLES
Pictet−Spengler reaction. Reaction was carried out either in
refluxing TFA or by heating in HCl to give quinazolino[3,2- 8.1. Porphyrins
c][2,3]benzodiazepin-14(6H)-one 629 in 65% yield (Scheme Porphyrins are important building blocks in many multi-
190). component systems developed for artificial photosynthesis,699
molecular electronics700 such as molecular wires,701 photo-
Scheme 190. Synthesis of Quinazolino[3,2- voltaic cells,702 and organic light-emitting diodes (OLEDs),703
c][2,3]benzodiazepin-14(6H)-one 629 as functional elements of light-harvesting systems,704 photo-
therapy,705 and coordination networks.706 Porphyrins are also
one of the most studied DNA binding agents.707 There are
many methodologies for synthesis of porphyrins in the
literature, commonly condensation of dipyrromethanes or
pyrroles with aldehydes along with oxidation.708
Trans-substituted porphyrin 634 was prepared by con-
densation reaction of dipyrromethane 633 with PG-hydrate in
the presence of BF3·OEt2 in DCM at room temperature,
followed by adding of DDQ, in 14% yield (Scheme 192).709
Thermal behavior of hetaryl analogs of the unsymmetrical
benzoins 635 and 636, obtained from reaction of PG-hydrate
with N-methylpyrrole and indoles,710 was investigated. When
the pyrrole 635 was heated at 150 °C, tetramerization occurred,
and the porphyrin 638 was isolated. In the case of the indole
636 (R = H), the dimer 639 is isolated in a small yield, whereas
There is one report on the synthesis of seven-membered O- the N-methylindole 636 (R = Me) resulted in a high yield of
heterocylic compounds starting from AGs in the literature the dimer 639 (Scheme 193).711
(Scheme 71).289 8.2. Cyclens
7.2. N,O-Heterocyclic Compounds: Oxazepanes Cyclic tetraamines have attracted increasing attention due to
1,4-Oxazepanes are found as an important structural framework their versatile coordination properties. 1,4,7,10-Tetraazacyclo-
in natural products like neurotoxin batrachotoxin.696 Oxaze- dodecane (cyclen or [12]aneN4) and its N-functionalized
panes are important in diverse fields of biochemistry owing to derivatives have been extensively used in medical purposes712
their wide range of biological activities.697 While there is no and pursued713 because the generated metal chelates have wide
common route for synthesis of oxazepane, a number of applications as contrast agents in MRI,714 radiodiagnostic and
synthetic routes have been reported till date.698 radiotherapeutic agents,715 luminescent probes,716 fluorescent
Selenocyclofunctionalization of the secondary alcohol 598, sensors,717 molecular recognition, catalysis compounds,718 and
prepared starting with PG (Scheme 180), using PhSeCl in the anti-HIV and anticancer agents.719 The synthesis of such 12-
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Scheme 192. Synthesis of Porphyrin 634 Using Scheme 194. Synthesis of Tetrasubstituted-[12]aneN4 641a
Dipyrromethane 633

a
Ar = Ph, 3-CNC6H4, 2-fluorenyl, 3-phenanthryl; X = CO2H,
PMeO2H.

compounds. We have started with the methods for synthesis

membered tetraaza rings has been achieved using high-dilution of AGs, followed by presenting of their applications in
syntheses.720 heterocycle syntheses in order of number of atoms in
The cyclo-condensation of triethylenetetramine 452 with heterocyclic rings with consideration of the heteroatom.
AGs in the presence of FeCl3 was reported to afford [12]aneN4 Reactions of AGs were performed in two different ways: (a)
type diimine complex intermediates, which were reduced and reactions took place in the more reactive aldehyde group and
demetalated in situ with NaBH4 to give the [12]aneN4 640 in AGs provided one atom in the ring of the heterocycles to
up to 60% overall yields. The reactions were carried out in dry produce a benzoyl substituent or (b) both aldehyde and ketone
methanol, followed by addition of excess NaBH4. Compounds groups of AG contributed to the reaction to provide two atoms
640 were transformed into the corresponding tetraacetate or of the heterocyclic rings. Moreover, AG derivatives such as AG-
tetramethylphosphinate derivatives 641 via reaction with acetals, -imines, -oximes, and -hydrazones, which show different
ClCH2CO2− or with (CH2O)n−MeP(OEt)2 followed by acidic reactivity and selectivity in contrast with AGs, also worked well
hydrolysis (Scheme 194).721 in construction of heterocyclic compounds. From the
Nucleophilic trifluoromethylation of AG-imines with Rup- perspective of the application of AGs in this field, AGs and
pert−Prakash reagent (CF3SiMe3) gave the corresponding O- their derivatives are unique structures that led to a broad
silylated β-imino-α-(trifluoromethyl)alcohols, which underwent spectrum of heterocycles. While different types of reactions
reduction and desilylation with NaBH4 to yield the β-amino-α- such as cyclocondensation, cycloaddition, Pictet−Spengler and
(trifluoromethyl)alcohols 642. The β-amino alcohols 642 were Ugi−Wittig, Ugi-cyclocondensation, aldol−Paal−Knorr and
used to synthesize diverse trifluoromethylated heterocycles, Wittig−dehydrative cyclization sequences were demonstrated
including aziridines 643, 1,3-oxazolidin-2-ones 644, 1,2,3- for synthesis of five- and six-membered heterocycles, the future
oxathiazolidine 2-oxides 645, 1,3-oxazolidines 646, 1,3,2- evolution of other methodologies promises new approaches to
oxazaphospholidine 2-oxides 647, and morpholine-2,3-diones synthesize new heterocylic systems, especially seven-membered
648 as outlined in Scheme 195.722 and fused heterocycles, previously thought to be inaccessible.
Recently considerable interest has been shown to one-pot
9. CONCLUSION domino reactions via in situ generation of AGs or their
In this review, we have presented an overview of the use of AGs derivatives (domino 1) followed by transformation to hetero-
and their derivatives in the synthesis of heterocyclic cycles (domino 2). Because of the broad spectrum of

Scheme 193. Synthesis of Porphyrin 638 and Indolo[3,2-b]carbazole 639

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Chemical Reviews Review

Scheme 195. Synthesis of Different Heterocycles Using AG- Bagher Eftekhari-Sis was born in 1980 in Sis, Shabestar, Iran. He
Imines through β-Amino Alcohols 642a obtained his B.Sc. in Applied Chemistry from University of Tabriz in
2004 and M.Sc. in Organic Chemistry from Sharif University of
Technology with Prof. Mohammed M. Hashemi in 2006. Also, He
received his Ph.D. under the supervision of Prof. Mohammed M.
Hashemi in 2009 and then joined the Chemistry Department of the
University of Maragheh. His research field involves the synthetic utility
of arylglyoxals, especially in synthesis of heterocycles, and recently on
polymer-supported catalysts, OLEDs, dual sensor polymers, and
bioimaging.

Maryam Zirak was born in Til, Shabestar, Iran. She received her B.Sc.
in Pure Chemistry and M.Sc. in Organic Chemistry from University of
Tabriz. She obtained her Ph.D in 2010 from University of Tabriz on
the topic of pyrone-based heterocycles and its applications in
Medicinal Chemistry under the advisement of Prof. Aziz Shahrisa.
Recently, she joined the Chemistry Department of the Payame Noor
University of Mahabad-West Azerbaijan, Iran, and her research field
a
Ar = Ph, 4-CF3C6H4, 4-MeOC6H4, 4-NO2C6H4; R = t-Bu, i-Pr, (S)- involves the development of new methodologies for synthesis of
PhCH(Me). heterocycles.

synthesized heterocycles using AGs and their derivatives, the

reported methods could be of interest in material science and
medicinal and natural products synthesis.

AUTHOR INFORMATION
Corresponding Author
*E-mail: [email protected]; [email protected].
Notes
The authors declare no competing financial interest.
Biographies
Ali Akbari was born in 1981 in Naghadeh, Iran. He received his B.Sc.
in Applied Chemistry from the University of Tabriz in 2005 and
completed his M.Sc. in the field of Organic Chemistry at the
Chemistry and Chemical Engineering Research Center of Iran in 2009.
Then he joined the group of Dr. Eftekhari-Sis as a research assistant at
the University of Maragheh until summer 2011.

ACKNOWLEDGMENTS
The corresponding author thanks Dr. M. Amini (University of
Maragheh), M. Razzaghi (Southern Illinois University Edwards-
ville), M. Samet (University of Minnesota), M. G. Nazari, H.
Abbasi (University of Tabriz), and Prof. A. Rahimi (University
of Maragheh) for kind help. We would also thank the
anonymous reviewers for their constructive comments.
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Chemical Reviews Review

DEDICATION TFA trifluoroacetic acid

TFAA trifluoroacetic anhydride
Dedicated to Professors M. M. Hashemi, F. Matloubi
Tf trifluoromethanesulfonyl
Moghaddam, A. Pourjavadi, M. R. Saidi, and A. Shahrisa. TfOH trifluoromethanesulfonic acid or triflic acid
THF tetrahydrofuran
ABBREVIATIONS TIPS triisopropylsilyl
acac acetylacetone TMP trimethyl phosphite
AcO acetate TsCl p-toluenesulfonyl chloride
AGs arylglyoxals TsMIC p-toluenesulfonylmethyl isocyanide
AIBN 2,2′-azoisobutyronitrile p-TsOH p-toluenesulfonic acid
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