1380

1380▌ PAPER

7
N -Tosyltheophylline (TsTh): A Highly Efficient Reagent for the One-Pot
paper

Synthesis of N7-Alkyltheophyllines from Alcohols

Mohammad Navid Soltani Rad,* Somayeh Behrouz,* Hosnieh Najafi
One-Pot Synthesis of N7-Alkyltheophyllines

Department of Chemistry, Shiraz University of Technology, Shiraz 71555-313, Iran

Fax +98(711)7354520; E-mail: [email protected]; E-mail: [email protected]
Received: 21.12.2013; Accepted after revision: 25.02.2014

and their corresponding therapeutic properties are given

Abstract: A convenient and highly efficient one-pot N-alkylation
of theophylline from alcohols via N7-tosyltheophylline (TsTh) is
in Figure 1.
described. In this protocol, the treatment of primary and/or second- To access N7-alkyltheophyllines, theophylline is normally
ary alcohols with a mixture of TsTh and 1,8-diazabicyclo[5.4.0]un- treated with different carbon electrophiles, particularly al-
dec-7-ene in refluxing acetonitrile affords the corresponding N7- kyl halides, in basic media.7
alkyltheophylline in good to excellent yields; the reaction was opti-
mized for solvent and base. This methodology is highly efficient for The direct N-alkylation of theophyllines via alcohols
various structurally diverse primary and secondary alcohols. A would be a highly advantageous and attractive strategy,
plausible mechanism for the one-pot N-alkylation of theophylline since alcohols are versatile reagents that are readily avail-
with alcohols via TsTh has been suggested.

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able in comparison with their corresponding alkyl ha-
Key words: N-alkylation, alcohol, theophylline, TsTh, DBU lides.8
Furthermore, alcohols are less toxic than alkyl halides and
they can be easily handled. However, there are few meth-
Xanthine alkaloids are critically important compounds in ods that have been established for the one-pot N-alkyl-
human healthcare.1 Methylxanthines including theophyl- ation of purine nucleobases, which are close related
line, caffeine, and theobromine are well known, since they scaffolds to theophylline. The most distinguished protocol
are significant ingredients in food stuffs that are major di- for the N-alkylation of purine nucleobases uses the
etary sources, such as coffee, tea, cola beverages, energy Mitsunobu conditions.9 However, this method is accom-
drinks, and chocolates.2 It is well known that methylxan- panied by several drawbacks including utilizing toxic, ex-
thines show remarkable pharmacological activity.3 pensive, and explosive reagents such as diethyl
Among methylxanthines, theophylline has a greater bind- azodicarboxylate and diisopropyl azodicarboxylate. Fur-
ing efficacy with DNA compared to theobromine and caf- thermore, the presence of unreacted triphenylphosphine
feine and it has been used in the design of new therapeutic and also the formation of triphenylphosphine oxide causes
agents.4 Although the combination of theophylline with the workup and separation process to become tedious.
various drugs has been widely used for the treatment for Therefore, the development of a method for the N-alkyla-
both chronic obstructive pulmonary disease (COPD) and tion of theophylline using alcohols is still required. Re-
asthma, the limitations and side effects of theophylline re- cently, we developed protocols for the direct N-alkylation
lated to its narrow therapeutic index has restricted the of nucleobases and theophylline using alcohols.8 In con-
applications of the parent compound.5 N7-Alkyltheophyl- tinuation of our ongoing research on the direct N-alkyla-
lines, however, show more specific chemotherapeutic ac- tion of nucleobases and theophylline via alcohols, herein,
tivity with lower toxicity and side effects;6 their we report the one-pot N-alkylation of theophylline with
chemotherapeutic activity includes bronchodilator activi- alcohols via N7-tosyltheophylline (TsTh) as an efficient
ty (with consequent efficacy in the treatment of asthma), reagent in the presence of 1,8-diazabicyclo[5.4.0]undec-
analeptic, diuretic, cardiotonic, CNS stimulant, etc.6 The 7-ene in refluxing acetonitrile (Scheme 1). To the best of
structures of some N7-alkyl derivatives of theophylline

R1
O O O
O R2
R2 S Me
Me DBU, MeCN N
N N
+ N
R1 OH reflux, 3–15 h
O N N
O N N
Me
R1 = alkyl, aryl Me TsTh 1a–s
R2 = H, alkyl

Scheme 1 One-pot N-alkylation of theophylline with alcohols via TsTh (DBU, MeCN, reflux)

SYNTHESIS 2014, 46, 1380–1388

Advanced online publication: 25.03.20140039-78 1 437-210X
DOI: 10.1055/s-0033-1341026; Art ID: SS-2013-Z0828-OP
© Georg Thieme Verlag Stuttgart · New York
PAPER One-Pot Synthesis of N7-Alkyltheophyllines 1381

OH O N

O O O O
CO2H O
Me OH Me Me N
Me N N N
N N N N

N O N N O N N
O N N O N
Me Me Me
Me
acefylline diprophylline doxofylline etamiphylline
(cardiotonic, diuretic, (expectorant, bronchodilator) (antiasthmatic, bronchodilator) (cardiotonic, diuretic)
antispasmodic
bronchodilator)
O
HN HN
O O O ( )3 O
Me OH Me
N N Me Me
N N N N
N N N
O N N
O N N O N N N
O N
Me
Me Me Me
etofylline fenethylline lomifylline pimefylline
(cardiotonic, bronchodilator) (CNS stimulant) (vasodilator) (vasodilator)
Cl

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OH

OH
O
HN
O N
O O O
O O Me
OH
OH Me Me HO Me N
Me N N N N OH
N N N

N N
N N N O N N O
O N O
Me
Me Me Me
proxyphylline theofibrate theodrenaline xanthinol
(cardiotonic, bronchodilator) (antihyperlipoproteinemic) (circulary analeptic, diuretic, (vasodilator)
cardiotonic)

Figure 1 The structures of some N7-alkyltheophylline derivatives and their corresponding therapeutic activity

our knowledge, this current research is the first reported depicted in Table 1. Of the solvents examined, acetonitrile
application of TsTh in organic transformations. (entry 4) afforded the best result and, hence, it was solvent
TsTh was prepared by the reaction of anhydrous theoph- of choice for all further reactions. The use of N,N-dimeth-
ylline with tosyl chloride and triethylamine in acetonitrile ylformamide, dimethyl sulfoxide, N-methylpyrrolidin-2-
at reflux for three hours (Scheme 2). TsTh was obtained one, and anhydrous acetone (entries 1, 3, 5, and 8) led to
in almost quantitative yield (ca. 96%) and it was recrystal- N7-butyltheophylline (1i) in reasonable yields. However,
lized from hot dichloromethane–hexane (1:1) solution as the yield of 1i using hexamethylphosphoramide was poor
white cotton-like needles. TsTh is quite stable and can be (entry 6), and the use of THF, toluene, and water failed to
stored in a refrigerator for many months.10 generate 1i even after a reaction time of 24 hours (entries
2, 7, and 9).
The first step of this synthetic approach was initiated by
optimizing the reaction conditions. As a model reaction, With acetonitrile as the solvent, next the model reaction
we examined the reaction of butan-1-ol with TsTh to give was examined for the most suitable base (Table 2); in ab-
N7-butyltheophylline (1i). The optimization began by sence of a base, the reaction failed, even after 24 hours
studying the influence of various aprotic and other sol- (entry 1). DBU proved to be the most appropriate base in
vents on the model reaction in the presence of freshly pre- the model reaction and it was utilized in all further reac-
pared ThTs with DBU as the base. The results are tions (entry 4). Additionally, the use of triethylamine,
DBN, and 4-(dimethylamino)pyridine gave satisfactory

O O O
H O
Me N O S
N Et3N, MeCN Me N
+ S Cl N
O N N O reflux, 3 h
O N N
Me
Me TsTh

Scheme 2 Preparation of TsTh from theophylline and TsCl

© Georg Thieme Verlag Stuttgart · New York Synthesis 2014, 46, 1380–1388
1382 M. N. Soltani Rad et al. PAPER

Table 1 Effect of Various Solvents on the Reaction of TsTh with Butan-1-ol To Give N7-Butyltheophylline

O O O
O
S
Me Me N
N DBU, solvent N
N
OH +
reflux, 3–15 h N
O N N O N

Me Me
1i

Entry Solvent Time (h) Yielda (%)

1 DMF 5 69

2 THF 24 –b

3 DMSO 5 62

4 MeCN 3 90

5 NMP 6 53

6 HMPA 7 41

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7 toluene 24 –b

8 acetonec 8 60

9 H2O 24 –b
a
Isolated yield.
b
No reaction.
c
Anhydrous solvent.

Table 2 Effect of Various Bases on the Reaction of TsTh with Butan-1-ol To Give N7-Butyltheophylline

O O O
O
S
Me Me N
N base, MeCN N
N
OH +
reflux, 3–15 h N
O N N O N

Me Me
1i

Entry Base Time (h) Yielda (%)

1 – 24 –b

2 Et3N 5 80

3 K2CO3 8 47

4 DBU 3 90

5 KOH 12 10

6 MgO 10 35

7 Cs2CO3 8 52

8 DBN 4 84

9 DMAP 5 68

10 DABCO 7 56
a
Isolated yield.
b
No reaction.

Synthesis 2014, 46, 1380–1388 © Georg Thieme Verlag Stuttgart · New York
PAPER One-Pot Synthesis of N7-Alkyltheophyllines 1383

yields of 1i (entries 2, 8, and 9), whereas potassium car- The optimized stoichiometric ratio of reactants was found
bonate, cesium carbonate, and DABCO afforded moder- to be 1.2:1:2 for alcohol, TsTh, and DBU, respectively.
ate yields of 1i (entries 3, 7, and 10). Other bases Various alcohols were next examined under the optimized
examined gave 1i in low yield. one-pot reaction conditions with TsTh to give the corre-
sponding N7-alkyltheophyllines (Table 3); structurally di-

Table 3 One-Pot N-Alkylation of Theophylline with Alcohols via TsTh (DBU, MeCN)a
R1
O O O
O R2
R2 S Me
Me DBU, MeCN N
N N
+ N
R1 OH reflux, 3–15 h
O N N
O N N
Me
R1 = alkyl, aryl Me TsTh 1a–s
R2 = H, alkyl

Entry R1R2CHOH Time (h) Yieldb (%)

1 BnOH 5 94
2 Ph(CH2)2OH 3 92

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3 Ph(CH2)3OH 5 90
4 Cy(CH2)2OH 10 84
O
OH
5 9 86

6 Me2C=CHCH2OH 5 92
7 NC(CH2)2OH 5 81
8 Me(CH2)9OH 8 87
9 BuOH 3 90
O
OH
10 6 80
Cl
N

11 N 9 87
OH

OH
O2N N
12 4 92
N

13 i-PrOH 11 76
14 Ph(Me)CHOH 10 79
15 Me(CH2)5(Me)CHOH 14 69
16 Et(Me)CHOH 15 79
17 H2C=CHCH2OH 7 87
Cl Cl

18 OH 4 82
O

O
OH
19 O 7 84

20 t-BuOH 48 –c
a
All products were characterized by 1H and 13C NMR, IR, CHN, and MS analysis.
b
Isolated yield.
c
No reaction.

© Georg Thieme Verlag Stuttgart · New York Synthesis 2014, 46, 1380–1388
1384 M. N. Soltani Rad et al. PAPER

OH
OH
OH
+
OH +

MeCN, reflux MeCN, reflux

15 h 10 h

O O
O O
Me N Me N
N + N Me Me
N N
N N
N N +
O N O N
O N N O N N
Me Me
Me Me
1i 82% 1p 12%
1b 75% 1n 22%

Scheme 3 Competitive one-pot N-alkylation of TsTh with primary and secondary alcohols

verse alcohols including primary and secondary alcohols droxy group was replaced with theophylline and
were used. In general, good to excellent yields were ob- proxyphylline was obtained as the sole product in 56%

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tained when both primary and secondary alcohols were yield (Scheme 4).
applied. This protocol works well with benzylic (entries 1 A plausible mechanism for the one-pot N-alkylation of
and 14), allylic (entries 6 and 17), secondary alcohols (en- theophylline with alcohols via TsTh with DBU as the base
tries 13, 15, and 16), and primary alcohols with various is suggested (Scheme 5). In this mechanism, DBU first
functionalities (entries 5, 7, 10–12, 18, and 19). However, scavenges a proton from the alcohol, and then the activat-
the use of tertiary alcohols, such as tert-butyl alcohol, did ed alcohol (alkoxide ion) attacks TsTh at the tosyl site to
not lead to the desire product (entry 20). give an alkyl tosylate and the anion of theophylline. Next,
The selectivity of this method was examined by perform- the theophylline anion attacks the electrophilic carbon in
ing a competitive reaction between a mixture of primary the in situ produced alkyl tosylate to afford the corre-
and secondary alcohols with TsTh under the optimized sponding N7-alkyltheophylline. The experimental obser-
conditions. For this purpose, a mixture consisting of an vations confirmed that the reaction, indeed, progresses by
equimolar ratio of two isomeric alcohols, butan-1-ol and the proposed mechanism. For example, the generation of
butan-2-ol, was treated with an equimolar amount of TsTh the corresponding alkyl tosylate and theophylline was
in the presence of DBU (2 equiv). As shown in Scheme 3, readily observed during the early stages of the reaction
entry 1, TsTh reacts with apparent selectivity with the pri- process. The in situ generated theophylline and the corre-
mary alcohol and 1i was predominantly obtained; com- sponding alkyl tosylate were confirmed by comparing
pound 1p was generated in trace amounts. A competitive them with authentic samples.
reaction between a mixture of two isomeric alcohols 1- In conclusion, a convenient protocol for the one-pot N-al-
phenylethanol (1 equiv) and 2-phenylethanol (1 equiv) kylation of theophylline using primary and secondary al-
with TsTh (1 equiv) in the presence of DBU (2 equiv), cohols starting from TsTh and using DBU in refluxing
gave 1b as the major product (entry 2). acetonitrile has been developed. In this method various
To further assess the selectivity in the reaction of TsTh primary and secondary alcohols reacted with TsTh to af-
with primary and secondary hydroxy groups, we reacted ford N7-alkyltheophylline derivatives in good to excellent
TsTh with propane-1,2-diol to obtain proxyphylline, a yields. However, this method was not effective for the N-
well-known and in-use drug with cardiotonic and bron- alkylation of theophylline by tertiary alcohols. A plausible
chodilator activity (Figure 1), under the optimized condi- mechanism has also been suggested in which the reaction
tions with the ratio of propane-1,2-diol, TsTh, and DBU proceeds through the simultaneous tosylation and nucleo-
(1.2:1:2) (Scheme 4). Of the primary and secondary hy- philic attack on alcohol via TsTh.
droxy groups in propane-1,2-diol, only the primary hy-

O O O
O
S OH
Me Me N
N DBU, MeCN N
OH N
+
OH reflux, 12 h O N
O N N N

Me Me
proxyphylline

Scheme 4 Selectivity of TsTh with propane-1,2-diol; synthesis of proxyphylline

Synthesis 2014, 46, 1380–1388 © Georg Thieme Verlag Stuttgart · New York
PAPER One-Pot Synthesis of N7-Alkyltheophyllines 1385

O O
O ••
S R2 N – DBUH+
Me N + +
N H
R1 O N
O N N
TsTh R1 = alkyl, aryl DBU
Me
R2 = H, alkyl
R1 O
O
R2 Me – R2 O O
Me N
N –
N + S
N – TsO
R1 O
O N N
O N N
Me
Me

Scheme 5 A plausible mechanism for one-pot N-alkylation of theophylline with alcohols via TsTh using DBU

All chemicals reagents were purchased from either Fluka or Merck. 7-Benzyl-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione (1a)8a
Solvents were purified by standard procedures, and stored over 3-Å Column chromatography (silica gel, EtOAc–n-hexane, 1:1) afford-
molecular sieves.11 Reactions were followed by TLC using ed a white solid; yield: 2.53 g (94%); mp 159–160 °C; Rf = 0.48
SILG/UV 254 silica gel plates. Column chromatography was per- (EtOAc).
formed on silica gel 60 (0.063–0.200 mm, 70–230 mesh; ASTM). IR (KBr): 3100, 2980, 2895, 1720, 1705, 1451 cm–1.

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Melting points were measured using Electrothermal IA 9000 melt- 1
ing point apparatus in open capillary tubes and are uncorrected. IR H NMR (250 MHz, CDCl3): δ = 3.31 (s, 3 H, N3-CH3), 3.49 (s, 3
spectra were obtained using a Shimadzu FT-IR-8300 spectropho- H, N1-CH3), 5.32 (s, 2 H, NCH2), 7.12–7.31 (m, 5 H, HAr), 7.54 (s,
tometer. 1H and 13C NMR spectra were recorded on Brüker Avance- 1 H, H8theo).
DPX-250/400 spectrometer operating at 250/62.5 and/or 400/100 13
C NMR (62.5 MHz, CDCl3): δ = 27.9, 29.6, 50.1, 106.8, 127.3,
MHz, respectively, relative to TMS as an internal standard. GC/MS 127.8, 128.6, 135.3, 140.8, 148.7, 151.5, 155.1.
was performed on a Shimadzu GC/MS-QP 1000-EX apparatus. El-
MS (EI): m/z (%) = 270 (31.4) [M+].
emental analyses were performed on a Perkin–Elmer 240-B micro-
analyzer. Anal. Calcd for C14H14N4O2: C, 62.21; H, 5.22; N, 20.73. Found: C,
62.32; H, 5.35; N, 20.81.
N7-Tosyltheophylline (TsTh)10
To a two-necked round-bottom flask (100 mL) equipped with a con- 1,3-Dimethyl-7-phenethyl-3,7-dihydro-1H-purine-2,6-dione
denser was added a mixture of theophylline (1.8 g, 0.01 mol), TsCl (1b)
(2.47 g, 0.013 mol), and Et3N (2.0 g, 0.02 mol) in MeCN (40 mL). Column chromatography (silica gel, EtOAc–n-hexane, 1:2) afford-
The mixture was refluxed for 3–4 h. The solvent was evaporated un- ed a white foam; yield: 2.61 g (92%); Rf = 0.36 (EtOAc–n-hexane,
der vacuum and the remaining solid was diluted with CHCl3 (100 2:1).
mL) and subsequently washed with distilled H2O (2 × 100 mL). The IR (liquid film): 3070, 2965, 2871, 1715, 1702, 1475 cm–1.
organic layer was dried (Na2SO4), filtered, and evaporated. The re- 1
maining solid was recrystallized (CH2Cl2–n-hexane, 50:50, 50 mL). H NMR (250 MHz, CDCl3): δ = 2.94 (t, J = 7.0 Hz, 2 H, CH2Ph),
After flash filtration, white cotton-like needle crystals were ob- 3.21 (s, 3 H, N3-CH3), 3.31 (s, 3 H, N1-CH3), 4.28 (t, J = 7.0 Hz, 2
tained; yield: 3.2 g (96%); mp 198–201 °C; Rf = 0.47 (EtOAc– H, NCH2), 6.90–7.07 (m, 5 H, HAr), 7.14 (s, 1 H, H8theo).
13
n-hexane, 2:1). C NMR (62.5 MHz, CDCl3): δ = 27.5, 29.3, 36.8, 48.2, 106.1,
IR (KBr): 3130, 2966, 2927, 1715, 1703, 1531, 1437, 1386 cm–1. 126.5, 128.3, 128.4, 136.9, 141.0, 148.5, 151.1, 154.5.
1
H NMR (400 MHz, CDCl3): δ = 2.45 (s, 3 H, CH3C6H4), 3.35 (s, 3 MS (EI): m/z (%) = 284 (15.9) [M+].
H, N3-CH3), 3.56 (s, 3 H, N1-CH3), 7.37 (d, J = 8.4 Hz, 2 H, HAr), Anal. Calcd for C15H16N4O2: C, 63.37; H, 5.67; N, 19.71. Found: C,
8.12 (d, J = 8.4 Hz, 2 H, HAr), 8.31 (s, 1 H, H8theo). 63.28; H, 5.75; N, 19.79.
13
C NMR (100 MHz, CDCl3): δ = 21.8, 28.5, 30.1, 106.8, 129.4, 1,3-Dimethyl-7-(3-phenylpropyl)-3,7-dihydro-1H-purine-2,6-
130.0, 133.2, 142.0, 147.0, 150.4, 151.1, 152.8. dione (1c)
MS (EI): m/z (%) = 334 (17.5) [M+]. Column chromatography (silica gel, EtOAc–n-hexane, 1:3) afford-
ed a white foam; yield: 2.68 g (90%); Rf = 0.30 (EtOAc–n-hexane,
Anal. Calcd for C14H14N4O4S: C, 50.29; H, 4.22; N, 16.76; S, 9.59. 1:1).
Found: C, 50.38; H, 4.27; N, 16.68; S, 9.50.
IR (liquid film): 3050, 2987, 2870, 1718, 1704, 1462 cm–1.
7-Alkyl-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-diones 1; 1
H NMR (250 MHz, CDCl3): δ = 2.09 (quint, J = 7.2 Hz, 2 H,
General Procedure
To a two-necked round-bottom flask (100 mL) equipped with a con- CH2CH2CH2), 2.53 (t, J = 7.2 Hz, 2 H, CH2Ph), 3.31 (s, 3 H, N3-
denser was added a mixture, consisting of an alcohol (0.012 mol), CH3), 3.48 (s, 3 H, N1-CH3), 4.16 (t, J = 7.2 Hz, 2 H, NCH2), 7.05–
TsTh (3.3 g, 0.01 mol), and DBU (3.0 g, 0.02 mol) in MeCN (50 7.21 (m, 5 H, HAr), 7.40 (s, 1 H, H8theo).
13
mL). The mixture was heated at reflux and heating was continued C NMR (62.5 MHz, CDCl3): δ = 28.9, 30.9, 32.2, 33.2, 50.5,
until TLC indicated no further improvement in the conversion (Ta- 105.6, 127.9, 128.2, 129.0, 135.8, 147.7, 151.6, 152.1, 155.9.
ble 3). The solvent was evaporated under vacuum and the remaining MS (EI): m/z (%) = 298 (24.6) [M+].
foam was dissolved in CHCl3 (100 mL) and subsequently washed
with H2O (2 × 100 mL). The organic layer was dried (Na2SO4) and Anal. Calcd for C16H18N4O2: C, 64.41; H, 6.08; N, 18.78. Found: C,
evaporated. The crude product was purified by recrystallization 64.52; H, 6.16; N, 18.71.
and/or column chromatography (silica gel).

© Georg Thieme Verlag Stuttgart · New York Synthesis 2014, 46, 1380–1388
1386 M. N. Soltani Rad et al. PAPER

7-(2-Cyclohexylethyl)-1,3-dimethyl-3,7-dihydro-1H-purine- 7-Decyl-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione (1h)

2,6-dione (1d) Column chromatography (silica gel, EtOAc–n-hexane, 1:3) afford-
Column chromatography (silica gel, EtOAc–n-hexane, 1:2) afford- ed a white foam; yield: 2.78 g (87%); Rf = 0.50 (EtOAc–n-hexane,
ed a white solid; yield: 2.43 g (84%); mp 86–88 °C; Rf = 0.36 1:1).
(EtOAc–n-hexane, 1:1).
IR (liquid film): 3100, 2982, 1718, 1705, 1557, 1450 cm–1.
IR (KBr): 3111, 2941, 2852, 1718, 1702, 1444 cm–1. 1
H NMR (250 MHz, CDCl3): δ = 0.49 (t, J = 6.7 Hz, 3 H, CH3),
1
H NMR (250 MHz, CDCl3): δ = 0.97–1.01 (m, 2 H, CH2), 1.17– 0.89–0.96 (m, 14 H, 7CH2), 1.50–1.55 (m, 2 H, NCH2CH2), 3.05 (s,
1.26 (m, 4 H, 2 CH2), 1.68–1.82 (m, 7 H, 3 CH2, CH), 3.41 (s, 3 H, 3 H, N3-CH3), 3.23 (s, 3 H, N1-CH3), 3.91 (t, J = 7.2 Hz, 2 H, NCH2),
N3-CH3), 3.59 (s, 3 H, N1-CH3), 4.29 (t, J = 7.5 Hz, 2 H, NCH2), 7.24 (s, 1 H, H8theo).
7.58 (s, 1 H, H8theo). 13
C NMR (62.5 MHz, CDCl3): δ = 13.0, 20.3, 25.0, 26.3, 26.4, 26.7,
13
C NMR (62.5 MHz, CDCl3): δ = 25.7, 27.9, 29.9, 31.3, 32.6, 33.8, 27.5, 29.5, 30.1, 32.5, 34.2, 49.4, 105.1, 140.1, 147.3, 151.6, 156.2.
34.2, 48.4, 106.9, 142.5, 149.7, 152.2, 154.6.
MS (EI): m/z (%) = 320 (18.7) [M+].
MS (EI): m/z (%) = 290 (18.2) [M+].
Anal. Calcd for C17H28N4O2: C, 63.72; H, 8.81; N, 17.48. Found: C,
Anal. Calcd for C15H22N4O2: C, 62.05; H, 7.64; N, 19.30. Found: C, 63.79; H, 8.73; N, 17.54.
62.17; H, 7.57; N, 19.39.
7-Butyl-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione (1i)
7-(Furan-2-ylmethyl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6- Recrystallization (CH2Cl2–MeOH) afforded a cream solid; yield:
dione (1e) 2.12 g (90%); mp 88–90 °C; Rf = 0.30 (EtOAc–n-hexane, 2:1).
Column chromatography (silica gel, EtOAc–n-hexane, 1:3) afford-
ed a bright brown solid; yield: 2.23 g (86%); mp 137–140 °C; Rf = IR (KBr): 3105, 2956, 2875, 1718, 1702, 1549, 1476 cm–1.
1
0.27 (EtOAc–n-hexane, 1:1). H NMR (400 MHZ, CDCl3): δ = 0.86 (t, J = 7.2 Hz, 3 H, CH3),

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IR (KBr): 3086, 2957, 1717, 1701, 1546, 1473 cm . –1 1.23–1.32 (m, 2 H, CH2CH3), 1.75 (quint, J = 7.6 Hz, 2 H,
NCH2CH2CH2), 3.34 (s, 3 H, N3-CH3), 3.51 (s, 3 H, N1-CH3), 4.20
1
H NMR (250 MHz, CDCl3): δ = 3.31 (s, 3 H, N3-CH3), 3.47 (s, 3 (t, J = 7.2 Hz, 2 H, NCH2), 7.47 (s, 1 H, H8theo).
H, N1-CH3), 5.42 (s, 2 H, NCH2), 6.26 (br s, 1 H, H3furyl), 6.43 (br 13
s, 1 H, H4furyl), 7.31 (br s, 1 H, H5furyl), 7.56 (s, 1 H, H8theo). C NMR (100 MHz, CDCl3): δ = 14.3, 21.1, 29.6, 31.5, 32.8, 51.5,
105.3, 143.7, 149.2, 151.2, 156.4.
13
C NMR (62.5 MHz, CDCl3): δ = 29.2, 32.2, 44.7, 105.1, 107.5,
112.0, 141.9, 143.8, 148.6, 150.6, 156.2, 158.0. MS (EI): m/z (%) = 236 (24.9) [M+].

MS (EI): m/z (%) = 260 (17.4) [M+]. Anal. Calcd for C11H16N4O2: C, 55.92; H, 6.83; N, 23.71. Found: C,
56.03; H, 6.91; N, 23.85.
Anal. Calcd for C12H12N4O3: C, 55.38; H, 4.65; N, 21.53. Found: C,
55.47; H, 4.76; N, 21.62. 7-[2-(4-Chlorophenoxy)ethyl]-1,3-dimethyl-3,7-dihydro-1H-
purine-2,6-dione (1j)
1,3-Dimethyl-7-(3-methylbut-2-enyl)-3,7-dihydro-1H-purine- Recrystallization (EtOAc–MeOH) afforded a white solid; yield:
2,6-dione (1f) 2.67 g (80%); mp 80–83 °C; Rf = 0.29 (EtOAc–n-hexane, 7:1).
Column chromatography (silica gel, EtOAc–n-hexane, 1:3) afford-
ed a white solid; yield: 2.28 g (92%); mp 130–133 °C; Rf = 0.27 IR (KBr): 3120, 2956, 2884, 1720, 1705, 1479, 1248, 743 cm–1.
1
(EtOAc–n-hexane, 1:1). H NMR (400 MHz, CDCl3): δ = 3.33 (s, 3 H, N3-CH3), 3.51 (s, 3
IR (KBr): 3121, 2967, 2921, 1725, 1708, 1545, 1490 cm–1. H, N1-CH3), 4.20 (t, J = 4.8 Hz, 2 H, NCH2), 4.60 (t, J = 4.8 Hz, 2
H, OCH2), 6.68 (d, J = 8.8 Hz, 2 H, HAr), 7.12 (d, J = 8.8 Hz, 2 H,
1
H NMR (250 MHz, CDCl3): δ = 1.72 (s, 6 H, 2 CH3), 3.32 (s, 3 H, HAr), 7.62 (s, 1 H, H8theo).
N3-CH3), 3.49 (s, 3 H, N1-CH3), 4.82 (d, J = 7.5 Hz, 2 H, NCH2), 13
5.36–5.37 (m, 1 H, =CH), 7.49 (s, 1 H, H8theo). C NMR (100 MHz, CDCl3): δ = 28.7, 32.0, 50.3, 71.1, 104.8,
116.7, 128.3, 131.1, 142.5, 150.9, 153.3, 156.4, 156.8.
13
C NMR (62.5 MHz, CDCl3): δ = 18.8, 24.1, 28.6, 32.0, 37.5,
105.5, 116.1, 132.2, 144.1, 149.9, 152.3, 156.2. MS (EI): m/z (%) = 334 (28.1) [M+].

MS (EI): m/z (%) = 248 (25.8) [M+]. Anal. Calcd for C15H15ClN4O3: C, 53.82; H, 4.52; Cl, 10.59; N,
16.74. Found: C, 53.89; H, 4.42; Cl, 10.51; N, 16.82.
Anal. Calcd for C12H16N4O2: C, 58.05; H, 6.50; N, 22.57. Found: C,
57.94; H, 6.58; N, 22.47. 7-[2-(1H-Benzimidazol-1-yl)ethyl]-1,3-dimethyl-3,7-dihydro-
1H-purine-2,6-dione (1k)
3-(1,3-Dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7- Column chromatography (silica gel, EtOAc–MeOH, 14:1) afforded
yl)propanenitrile (1g) a pale-yellow solid; yield: 2.81 g (87%); mp 244–246 °C; Rf = 0.24
Column chromatography (silica gel, EtOAc–n-hexane, 1:2) afford- (EtOAc–MeOH, 5:1).
ed a white solid; yield: 1.88 g (81%); mp 153–155 °C; Rf = 0.30
(EtOAc–n-hexane, 3:1). IR (KBr): 3094, 2952, 1718, 1702, 1479 cm–1.
1
IR (KBr): 3138, 2971, 2253, 1715, 1702, 1549, 1472 cm–1. H NMR (250 MHZ, CDCl3): δ = 3.44 (s, 3 H, N3-CH3), 3.54 (s, 3
H, N1-CH3), 4.67–4.71 (m, 4 H, NCH2CH2N), 6.98 (s, 1 H,
1
H NMR (250 MHz, CDCl3): δ = 3.03 (t, J = 5.5 Hz, 2 H, CH2CN), H2benzimid), 7.28–7.42 (m, 4 H, Hbenzimid), 7.59 (s, 1 H, H8theo).
3.34 (s, 3 H, N3-CH3), 3.54 (s, 3 H, N1-CH3), 4.45 (t, J = 5.5 Hz, 2 13
H, NCH2), 7.64 (s, 1 H, H8theo). C NMR (62.5 MHz, CDCl3): δ = 29.4, 31.4, 50.3, 56.2, 105.9,
115.1, 117.1, 124.3, 126.2, 133.0, 136.1, 142.6, 146.1, 149.6, 152.0,
13
C NMR (62.5 MHz, CDCl3): δ = 18.1, 27.8, 32.0, 33.8, 107.5, 155.7.
120.2, 145.5, 150.0, 152.1, 155.4.
MS (EI): m/z (%) = 324 (20.4) [M+].
MS (EI): m/z (%) = 233 (19.5) [M+].
Anal. Calcd for C16H16N6O2: C, 59.25; H, 4.97; N, 25.91. Found: C,
Anal. Calcd for C10H11N5O2: C, 51.50; H, 4.75; N, 30.03. Found: C, 59.37; H, 5.06; N, 25.98.
51.62; H, 4.87; N, 30.12.

Synthesis 2014, 46, 1380–1388 © Georg Thieme Verlag Stuttgart · New York
PAPER One-Pot Synthesis of N7-Alkyltheophyllines 1387

1,3-Dimethyl-7-[2-(2-methyl-4-nitro-1H-imidazol-1-yl)ethyl]- 7-sec-Butyl-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione (1p)

3,7-dihydro-1H-purine-2,6-dione (1l) Column chromatography (silica gel, EtOAc–n-hexane, 1:3) afford-
Recrystallization (EtOAc–MeOH) afforded a white solid; yield: ed a bright brown solid; yield: 1.86 g (79%); mp 81–82 °C; Rf = 0.27
3.02 g (92%); mp 254–257 °C; Rf = 0.37 (EtOAc–MeOH, 6:1). (EtOAc–n-hexane, 3:1).
IR (KBr): 3109, 2954, 1720, 1706, 1542, 1473, 1336 cm–1. IR (KBr): 3062, 2931, 2859, 1721, 1707, 1438 cm–1.
1
H NMR (250 MHZ, DMSO-d6): δ = 2.19 (s, 3 H, imid-CH3), 3.19 1
H NMR (400 MHZ, CDCl3): δ = 0.78 (t, J = 7.2 Hz, 3 H, CH2CH3),
(s, 3 H, N3-CH3), 3.38 (s, 3 H, N1-CH3), 4.54–4.59 (m, 4 H, 1.12–1.24 (m, 3 H, NCHCH2CH3), 1.50 (d, J = 6.8 Hz, 3 H,
NCH2CH2N), 7.81 (s, 1 H, H5imid), 8.04 (s, 1 H, H8theo). NCHCH3), 3.36 (s, 3 H, N3-CH3), 3.54 (s, 3 H, N1-CH3), 7.60 (s, 1
13
C NMR (62.5 MHz, DMSO-d6): δ = 15.1, 27.6, 31.6, 49.6, 52.0, H, H8theo).
105.3, 121.1, 140.1, 146.7, 149.1, 151.0, 153.2, 156.2. 13
C NMR (100 MHz, CDCl3): δ = 11.1, 23.5, 28.3, 29.7, 33.5, 47.2,
MS (EI): m/z (%) = 333 (26.7) [M ].+ 107.7, 143.8, 149.9, 152.1, 158.1.
Anal. Calcd for C13H15N7O4: C, 46.85; H, 4.54; N, 29.42. Found: C, MS (EI): m/z (%) = 236 (25.9) [M+].
46.93; H, 4.59; N, 29.51. Anal. Calcd for C11H16N4O2: C, 55.92; H, 6.83; N, 23.71. Found: C,
55.87; H, 6.91; N, 23.82.
7-Isopropyl-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione
(1m) 7-Allyl-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione (1q)8b
Recrystallization (EtOAc–MeOH) afforded a bright brown solid; Column chromatography (silica gel, EtOAc–n-hexane, 1:1) afford-
yield: 1.68 g (76%); mp 180–184 °C; Rf = 0.33 (EtOAc–n-hexane, ed a white solid; yield: 1.91 g (87%); mp 102–104 °C; Rf = 0.38
3:1). (EtOAc).
IR (KBr): 3109, 2979, 2940, 1719, 1704, 1545, 1456 cm–1. IR (KBr): 3050, 2987, 2890, 1722, 1708, 1448 cm–1.
1
H NMR (250 MHZ, CDCl3): δ = 1.13 (d, J = 6.8 Hz, 6 H, 2 CH3),

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1
H NMR (250 MHz, CDCl3): δ = 3.17 (s, 3 H, N3-CH3), 3.36 (s, 3
2.95 (s, 3 H, N3-CH3), 3.13 (s, 3 H, N1-CH3), 4.57–4.62 (m, 1 H, H, N1-CH3), 4.73 (d, J = 5.2 Hz, 2 H, NCH2), 5.00–5.13 (m, 2 H,
NCH), 7.22 (s, 1 H, H8theo). =CH2), 5.77–5.93 (m, 1 H, =CH), 7.40 (s, 1 H, H8theo).
13
C NMR (62.5 MHz, CDCl3): δ = 25.7, 30.4, 33.1, 47.3, 106.5, 13
C NMR (62.5 MHz, CDCl3): δ = 27.8, 29.6, 48.8, 106.7, 119.1,
143.5, 149.4, 152.3, 156.8. 132.0, 140.7, 148.6, 151.5, 154.9.
MS (EI): m/z (%) = 222 (21.3) [M+]. MS (EI): m/z (%) = 220 (25.4) [M+].
Anal. Calcd for C10H14N4O2: C, 54.04; H, 6.35; N, 25.21. Found: C, Anal. Calcd for C10H12N4O2: C, 54.54; H, 5.49; N, 25.44. Found: C,
54.12; H, 6.42; N, 25.32. 54.62; H, 5.40; N, 25.51.
1,3-Dimethyl-7-(1-phenylethyl)-3,7-dihydro-1H-purine-2,6-di- 7-[2-(2,4-Dichlorophenyl)-2-oxoethyl]-1,3-dimethyl-3,7-di-
one (1n) hydro-1H-purine-2,6-dione (1r)
Column chromatography (silica gel, EtOAc–n-hexane, 1:3) afford- Column chromatography (silica gel, EtOAc–n-hexane, 3:1) afford-
ed a yellow foam; yield: 2.24 g (79%); Rf = 0.29 (EtOAc–n-hexane, ed a creamy solid; yield: 3.01 g (82%); mp 193–194 °C; Rf = 0.61
2:1). (EtOAc–n-hexane, 6:1).
IR (liquid film): 3070, 2964, 2921, 1718, 1702, 1553, 1471 cm–1. IR (KBr): 3065, 2983, 2958, 1723, 1715, 1709, 1569, 1481, 750
1
H NMR (250 MHZ, CDCl3): δ = 1.54 (d, J = 7.1 Hz, 3 H, cm–1.
NCHCH3), 3.18 (s, 3 H, N3-CH3), 3.32 (s, 3 H, N1-CH3), 4.36 (q, J = 1
H NMR (250 MHz, DMSO-d6): δ = 3.23 (s, 3 H, N3-CH3), 3.36 (s,
7.1 Hz, 1 H, NCH), 6.93–7.14 (m, 5 H, HAr), 7.82 (s, 1 H, H8theo). 3 H, N1-CH3), 5.55 (s, 2 H, NCH2), 7.22 (d, J = 6.4 Hz, 1 H, HAr),
13
C NMR (62.5 MHz, CDCl3): δ = 22.9, 29.9, 33.1, 55.1, 106.3, 7.24 (d, J = 6.4 Hz, 1 H, HAr), 7.52 (s, 1 H, HAr), 7.83 (s, 1 H, H8theo).
123.0, 125.1, 127.0, 142.1, 145.7, 148.8, 150.5, 154.1. 13
C NMR (62.5 MHz, DMSO-d6): δ = 27.3, 29.2, 41.3, 106.2, 126.1,
MS (EI): m/z (%) = 284 (29.8) [M ].+ 126.2, 128.2, 128.8, 133.6, 142.4, 147.5, 150.6, 151.9, 154.7, 180.1.
Anal. Calcd for C15H16N4O2: C, 63.37; H, 5.67; N, 19.71. Found: C, MS (EI): m/z (%) = 366 (19.3) [M+].
63.45; H, 5.74; N, 19.83. Anal. Calcd for C15H12Cl2N4O3: C, 49.07; H, 3.29; Cl, 19.31; N,
15.26. Found: C, 49.19; H, 3.36; Cl, 19.18; N, 15.39.
1,3-Dimethyl-7-(octan-2-yl)-3,7-dihydro-1H-purine-2,6-dione
(1o) Benzyl 2-(1,3-Dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-
Column chromatography (silica gel, EtOAc–n-hexane, 1:2) afford- 7-yl)acetate (1s)
ed a pale yellow liquid; yield: 2.01 g (69%); Rf = 0.34 (EtOAc– Column chromatography (silica gel, EtOAc–n-hexane, 2:1) afford-
n-hexane, 2:1). ed a creamy solid; yield: 2.75 g (84%); mp 124–125 °C; Rf = 0.56
IR (liquid film): 3100, 2985, 1715, 1701, 1561, 1443 cm–1. (EtOAc–n-hexane, 4:1).
1
H NMR (400 MHZ, CDCl3): δ = 1.49–1.56 (m, 5 H, CH2CH3), IR (KBr): 3100, 2976, 2942, 1738, 1720, 1705, 1574, 1451 cm–1.
1.61–1.69 (m, 6 H, 3 CH2), 2.38 (s, 3 H, N3-CH3), 2.44 (s, 3 H, N1- 1
H NMR (250 MHz, DMSO-d6): δ = 3.15 (s, 3 H, N3-CH3), 3.29 (s,
CH3), 2.78 (q, J = 6.4 Hz, 2 H, NCHCH2), 3.22–3.24 (m, 1 H, 3 H, N1-CH3), 5.34 (s, 2 H, NCH2), 5.72 (s, 2 H, OCH2), 7.29–7.33
NCH), 3.36 (d, J = 7.4 Hz, 3 H, NCHCH3), 7.73 (s, 1 H, H8theo). (m, 5 H, HAr), 7.82 (s, 1 H, H8theo).
13
C NMR (100 MHz, CDCl3): δ = 14.0, 22.5, 26.3, 27.2, 29.0, 29.1, 13
C NMR (62.5 MHz, DMSO-d6): δ = 27.5, 29.3, 41.6, 65.1, 106.2,
31.76, 33.4, 35.2, 48.8, 105.0, 140.7, 148.5, 151.0, 157.4. 126.8, 127.6, 129.6, 137.1, 142.5, 147.6, 150.6, 153.4, 165.7.
MS (EI): m/z (%) = 292 (18.1) [M+]. MS (EI): m/z (%) = 328 (15.8) [M+].
Anal. Calcd for C15H24N4O2: C, 61.62; H, 8.27; N, 19.16. Found: C, Anal. Calcd for C16H16N4O4: C, 58.53; H, 4.91; N, 17.06. Found: C,
61.72; H, 8.36; N, 19.23. 58.69; H, 5.02; N, 17.14.

© Georg Thieme Verlag Stuttgart · New York Synthesis 2014, 46, 1380–1388
1388 M. N. Soltani Rad et al. PAPER

Acknowledgement (4) Nafisi, S.; Manouchehri, F.; Tajmir-Riahi, H.-A.;

Varavipour, M. J. Mol. Struct. 2008, 875, 392.
We wish to thank Shiraz University of Technology Research Coun- (5) Theophylline; Wikipedia, the Free Encyclopedia,
cil for partial support of this work. http://en.wikipedia.org/wiki/Theophylline. Accessed 26
September 2013.
(6) Kleeman, A.; Engel, J.; Kutscher, B.; Reichert, D. In
Supporting Information for this article is available online at Pharmaceutical Substances, 3rd ed; Thieme: Stuttgart,
http://www.thieme-connect.com/ejournals/toc/synthesis.SmonurIfgiptSa 1999.
(7) (a) Ananthalakshmi, K. V. V.; Bartl, T.; Aziza, M. H.;
References Novotný, L.; Marek, R.; Beneš, L.; Kombian, S. B. Bioorg.
Med. Chem. 2008, 16, 8142. (b) Pascal, J.-C.; Beranger, S.;
(1) Troy, D. B.; Beringer, P. In Remington: The Science and Pinhas, H.; Poizot, A.; Desilest, J.-P. J. Med. Chem. 1985,
Practice of Pharmacy, 21st ed.; Lippincott Williams & 28, 647.
Wilkins: Philadelphia, 2006. (8) (a) Soltani Rad, M. N.; Khalafi-Nezhad, A.; Behrouz, S.;
(2) (a) Roberts, M. F.; Wink, M. In Alkaloids: Biochemistry, Asrari, Z.; Behrouz, M.; Amini, Z. Synthesis 2009, 3067.
Ecology, and Medicinal Applications; Plenum Press: New (b) Soltani Rad, M. N.; Khalafi-Nezhad, A.; Behrouz, S.;
York, 1998. (b) Fattorusso, E.; Taglialatela-Scafa, O. In Faghihi, M. A.; Zare, A.; Parhami, A. Tetrahedron 2008, 64,
Modern Alkaloids: Structure, Isolation, Synthesis, and 1778.
Biology; Wiley-VCH: Weinheim, 2008. (c) Scheindlin, S. (9) Mitsunobu, O. Synthesis 1981, 1.
Mol. Interventions 2007, 7, 236. (10) Bodor, N.; Sloan, K. B.; Kuo, Y.-N.; Higuchi, T. J. Pharm.
(3) Wilson, C. O.; Gisvold, O.; Block, J. H. In Wilson and Sci. 1978, 67, 1045.
Gisvold’s Textbook of Organic Medicinal and (11) Vogel, A. I. In Practical Organic Chemistry; Longmans,

Downloaded by: State University of New York at Binghamton. Copyrighted material.

Pharmaceutical Chemistry, 11th ed.; Block, J. H.; Beale, J. Green: London, 1954, Chap. 2, 161–176.
M. Jr, Eds.; Lippincott Williams & Wilkins: Philadelphia,
2004.

Synthesis 2014, 46, 1380–1388 © Georg Thieme Verlag Stuttgart · New York