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Synthesis of Chromones via Palladium-Catalyzed ever, most of the methods suffer from harsh reaction condi-
Ligand-Free Cyclocarbonylation of o-Iodophenols with tions, poor substituent tolerance, and low to moderate yields.
During the past two decades, the palladium-catalyzed carbo-
Terminal Acetylenes in Phosphonium Salt Ionic Liquids nylation of o-iodophenols with terminal acetylenes has become
an attractive method to synthesize chromones.4 In some
Qian Yang and Howard Alper* situations, this reaction produces a mixture of six-membered
Centre for Catalysis Research and Innovation, Department of chromones 1 and five-membered aurones 2 (Scheme 1).5
Chemistry, University of Ottawa, 10 Marie Curie, Ottawa,
Ontario K1N 6N5, Canada SCHEME 1. Pd-Catalyzed Cyclocarbonylation of o-Iodo-
phenols and Terminal Acetylenes
[email protected]
Received October 16, 2009

Ionic liquids (ILs), because of their low volatility, non-

flammability, capability to dissolve various organic and in-
organic compounds, and potentially recyclable properties,
have attracted considerable attention as environmentally
friendly reaction media. Many transition metal-catalyzed reac-
tions in task-specific ionic liquids (TSILs) have established
some highly effective and easily separable catalytic systems.6
The highly efficient and selective palladium-catalyzed Imidazolium-based ionic liquids are most commonly used as
ligand-free cyclocarbonylation reaction of o-iodophenols these alternative solvents.7 In recent years, phosphonium
with terminal acetylenes and CO in the phosphonium salt salt ionic liquids (PSILs) have been the subject of some
ionic liquid, C14H29(C6H13)3PþBr-, affords diversified chro-
(4) (a) Awuah, E.; Capretta, A. Org. Lett. 2009, 11, 3210. (b) Ma, W.; Li, X.;
mones in good to excellent yields under atmospheric CO Yang, J.; Liu, Z.; Chen, B.; Pan, X. Synthesis 2006, 2489. (c) Liang, B.; Huang,
pressure. The ionic liquid, as the reaction medium, enhances M.; You, Z.; Xiong, Z.; Lu, K.; Fathi, R.; Chen, J.; Yang, Z. J. Org. Chem. 2005,
70, 6097. (d) Miao, H.; Yang, Z. Org. Lett. 2000, 2, 1765. (e) Bhat, A. S.;
the efficiency of the cyclocarbonylation reaction. Whetstone, J. L.; Brueggemeier, R. W. Tetrahedron Lett. 1999, 40, 2469. (f) Torii,
S.; Okumoto, H.; Xu, L.-H.; Sadakane, M.; Shostakovsky, M. V.; Ponomaryov,
A. B.; Kalinin, V. N. Tetrahedron 1993, 49, 6773. (g) An, Z. W.; Catellani, M.;
Chiusoli, G. P. J. Organomet. Chem. 1990, 397, 371. (h) Kalinin, V. N.;
Flavones, also known as 2-phenylchromones, represent a Shostakovsky, M. V.; Ponamaryov, A. B. Tetrahedron Lett. 1990, 31, 4073.
major class of naturally occurring products, biologically active (5) Ciattini, P. G.; Morera, E.; Ortar, G.; Rossi, S. S. Tetrahedron 1991,
47, 6449.
substances, and drugs.1 Because of their broad range of (6) (a) Cao, H.; Xiao, W. J.; Alper, H. J. Org. Chem. 2007, 72, 8562.
significant biological activities,2 synthetic approaches to this (b) Fukuyama, T.; Inouye, T.; Ryu, I. J. Organomet. Chem. 2007, 692, 685.
(c) Li, Y.; Yu, Z.; Alper, H. Org. Lett. 2007, 9, 1647. (d) Ye, F.; Alper, H. J. Org.
family of products have been extensively investigated.3 How- Chem. 2007, 72, 3218. (e) Li, Y.; Alper, H.; Yu, Z. K. Org. Lett. 2006, 8, 5199.
(f) Ye, F.; Alper, H. Adv. Synth. Catal. 2006, 348, 1855. (g) Zhao, X.; Alper, H.;
(1) (a) Harborne, J. B.; Baxter, H. The Handbook of Natural Flavonoids: Yu, Z. J. Org. Chem. 2006, 71, 3988. (h) Calo, V.; Nacci, A.; Monopoli, A. Eur.
John Wiley & Son: Chichester, UK, 1999; Vols. 1 and 2. (b) Harborne, J. B. The J. Org. Chem. 2006, 3791. (i) Xue, H.; Verma, R.; Shreeve, J. M. J. Fluorine
Flavonoids: Advances in Research since 1986; Chapman and Hall: London, UK, Chem. 2006, 127, 159. (j) Davis, J. H. Task-specific ionic liquids. In. Chem. Lett.
1994. (c) Harborne, J. B. The Flavonoids: Advances in Research since 1980; 2004, 33, 1072. (k) Shi, F.; Gu, Y.; Zhang, Y.; Deng, Y. Catal. Surv. Asia 2004, 8,
Chapman and Hall: London, UK, 1988. 179. (l) Calo, V.; Giannoccaro, P.; Nacci, A.; Monopoli, A. J. Organomet. Chem.
(2) (a) Lewis, K.; Stermitz, F. R.; Collins, F. Proc. Natl. Acad. Sci. U.S.A. 2002, 645, 152. (m) Mizushima, E.; Hayashi, T.; Tanaka, M. Green Chem. 2001,
2000, 97, 1433. (b) Costantino, L.; Rastelli, G.; Gamberini, M. C.; Vinson, 3, 76.
J. A.; Bose, P.; Iannone, A.; Staffieri, M.; Antolini, L.; Corso, A. D.; Mura, U.; (7) (a) Welton, T. Coord. Chem. Rev. 2004, 248, 2459. (b) Wilkes, J. S.
Albasini, A. J. Med. Chem. 1999, 42, 1881. (c) Fert
e, J.; K€ uhnel, J.-M.; Green. Chem. 2002, 4, 73. (c) Wasserscheid, P.; Welton, T. Ionic Liquid in
Chapuis, G.; Rolland, Y.; Lewin, G.; Schwaller, M. A. J. Med. Chem. 1999, Synthesis; Wiley-VCH & CoKGaA: Weinheim, Germany, 2002. (d) Dupont, J.;
42, 478. (d) Artico, M.; Santo, R. D.; Costi, R.; Novellino, E.; Greco, G.; De Souza, R. F.; Suarez, P. A. Z. Chem. Rev. 2002, 102, 3667. (e) Sheldon, R. A.
Massa, S.; Tramontano, E.; Marongiu, M. E.; Montis, A. D.; Colla, P. L. Chem. Commun. 2001, 2399. (f) Wasserscheid, P.; Keim, W. Angew. Chem., Int.
J. Med. Chem. 1998, 41, 3949. (e) Akama, T.; Ueno, K.; Saito, H.; Kasai, M. Ed. 2000, 39, 3772. (g) Earle, M. J.; Seddon, K. R. Pure Appl. Chem. 2000, 72,
Synthesis 1997, 1446. (f) Fesen, M. R.; Pommier, Y.; Leteurtre, F.; Hiroguchi, 1391. (h) Welton, T. Chem. Rev. 1999, 99, 2071.
S.; Yung, J.; Kohn, K. W. Biochem. Pharmacol. 1994, 48, 595. (8) (a) McNulty, J.; Nair, J. J.; Robertson, A. J. Org. Lett. 2007, 9, 4575.
(3) (a) Tabaka, A. C.; Murthi, K. K.; Pal, K.; Teleha, C. A. Org. Process Res. (b) McNulty, J.; Cheekoori, S.; Bender, T. P.; Coggan, J. A. Eur. J. Org. Chem.
Dev. 1999, 3, 256. (b) Lokshin, V.; Heynderickx, A.; Samat, A.; Pepe, G.; 2007, 9, 1423. (c) McNulty, J.; Nair, J. J.; Cheekoori, S.; Larichev, V.; Capretta,
Guglielmetti, R. Tetrahedron Lett. 1999, 40, 6761. (c) Dekermendjian, K.; A.; Robertson, A. J. Chem.;Eur. J. 2006, 12, 9314. (d) Vygodskii, Y. S.;
Kahnberg, P.; Witt, M.-R.; Sterner, O.; Nielsen, M.; Liljefors, T. J. Med. Chem. Shaplov, A. S.; Lozinskaya, E. I.; Filippov, O. A.; Shubina, E. S.; Bandari, R.;
1999, 42, 4343. (d) Costantino, L.; Rastelli, G.; Gamberini, M. C.; Vinson, J. A.; Buchmeiser, M. R. Macromolecules 2006, 39, 7821. (e) McNulty, J.; Cheekoori,
Bose, P.; Iannone, A.; Staffieri, M.; Antolini, L.; Corso, A. D.; Mura, S.; Nair, J. J.; Larichev, V.; Capretta, A.; Robertson, A. J. Tetrahedron Lett. 2005,
U.; Albasini, A. J. Med. Chem. 1999, 42, 1881. (e) Marder, M.; Viola, H.; 46, 3641. (f) McNulty, J.; Capretta, A.; Cheekoori, S.; Clyburne, J. A. C.;
Bacigaluppo, J. A.; Colombo, M. I.; Wasowski, C.; Wolfman, C.; Medina, J. H.; Robertson, A. J. Chim. Oggi 2004, 22, 13. (g) Gerritsma, D. A.; Robertson, A. J.;
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(f) Riva, C.; Toma, C. D.; Donadel, L.; Boi, C.; Pennini, R.; Motta, G.; Leonardi, M. J.; Robertson, A. J. PCT Int. Appl., 2003, 24 (i) McNulty, J.; Capretta, A.;
A. Synthesis 1997, 195. (g) Pinto, D. C. G. A.; Silva, A. M. S.; Cavaleiro, J. A. S. Wilson, J.; Dyck, J.; Adjabeng, G.; Robertson, A. J. Chem. Commun. 2002, 1986.
J. Heterocycl. Chem. 1996, 33, 1887. (h) McGarry, L. W.; Detty, M. R. J. Org. (j) Karodia, N.; Guise, S.; Newlands, C.; Andersen, J.-A. Chem. Commun. 1998,
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948 J. Org. Chem. 2010, 75, 948–950 Published on Web 01/12/2010 DOI: 10.1021/jo902210p
r 2010 American Chemical Society
Yang and Alper
JOC Note
TABLE 1. Palladium-Catalyzed Cyclocarbonylation of o-Iodophenol TABLE 2. Palladium-Catalyzed Cyclocarbonylation of o-Iodophenols
with Phenyl Acetylenea with Terminal Acetylenesa

temp yieldb
entry cat. base CO (°C) sol. of 5a
1 Pd(PPh3)2Cl2 Et3N 200 110 PSIL102 95
psi
c
2 Pd(PPh3)4 K2CO3 200 110 PSIL102 ND
psi
3 Pd(PPh3)2Cl2 Et3N 1 atm 110 PSIL102 74
4 Pd(PPh3)2Cl2 Et3N 1 atm rt PSIL102 trace
5 Pd(OAc)2 Et3N 1 atm 110 PSIL102 91
6 PdCl2 Et3N 1 atm 110 PSIL102 95
7 PdCl2 Et2NH 1 atm 110 PSIL102 58
8d PdCl2 Et3N 1 atm 110 PSIL101 50
9e PdCl2 Et3N 1 atm 110 PSIL110 41h
10f PdCl2 Et3N 1 atm 110 PSIL109 43i
11 PdCl2 Et3N 1 atm 110 [BMIM]NTf2 35j
12g PdCl2 Et3N 1 atm 110 Et3N 28k
a
Reaction conditions: o-iodophenol (1 mmol), phenyl acetylene (2 a
Reaction conditions: o-iodophenols (1 mmol), terminal acetylenes (2
mmol), Pd cat. (5 mol %), Et3N or Et2NH (3 mmol) or K2CO3 (4 mmol),
mmol), PdCl2 (5 mol %), Et3N (3 mmol), C14H29(C6H13)3PþBr- (1.5 g),
PSIL or [BMIM]NTf2 (1.5 g). bIsolated yield. cNeither product 5a nor
110 °C, 24 h. bIsolated yield. cUse of [BMIM]NTf2 as reaction medium
5b was detected. The only detected product was 2-(2-phenylethynyl)-
under identical reaction conditions afforded 41% of 19a and 26% of 2-
phenol. dPSIL101: C14H29(C6H13)3PþCl-. ePSIL110: C14H29Pþ PF6-.
heptylidenebenzofuran-3(2H)-one. dMethyl 3-hydroxy-4-iodobenzoate
f
PSIL109: C14H29(C6H13)3PþNTf2-. gReaction was run in 3 mL of
was used as the substrate.
Et3N. h15% 5b was obtained. i28% 5b was obtained. j23% 5b was
obtained. k35% 5b was obtained.
further investigations. When the CO pressure was reduced
publications. They have higher thermal stability than the nitro- from 200 psi to 1 atm, the yield decreased from 95% to 74%
gen-based analogues. McNulty and co-workers, as well as several (Table 1, entry 3). Running the reaction at room temperature
other groups, described several different reactions in PSILs instead of 110 °C afforded trace quantities of the product
affording products in good to excellent yields.8 Recently, we (Table 1, entry 4). To our surprise, without any phosphine
reported several palladium-catalyzed reactions in PSILs.9 ligand, both Pd(OAc)2 and PdCl2 catalyzed the reaction very
Kalini and Torii et al. reported the syntheses of chromones efficiently with PSIL102 as the reaction medium and 5a was
via palladium-catalyzed cyclocarbonylation of o-iodophe- obtained in 91% and 95% yields, respectively (Table 1,
nols with terminal acetylenes, the yields of the products were entries 5 and 6). A reaction carried out under similar condi-
based on rather unreliable TLC and UV spectroscopy yields. tions but with conventional solvent did not give any of the
Several of the chromones were isolated in quite low yields desired product.4f When the reaction was carried out with
(45-63%).4f,h These results encouraged us to investigate the Et2NH as the base instead of Et3N, the isolated yield was
utility of PSILs for the cyclocarbonylation of o-iodophenols reduced from 95% to 58% (Table 1, entry 7). From the above
with terminal acetylenes to give 2-substituted chromones. results, PdCl2 was chosen as the optimal catalyst and Et3N as
We now report that the ionic liquid, PSIL102, C14H29- the base. Other ionic liquids were also investigated for the
(C6H13)3PþBr-, can be employed as a very efficient re- cyclocarbonylation reaction (Table 1). When the reaction
action medium for the selective synthesis of chromones by was carried out in PSIL101, C14H29(C6H13)3PþCl-, the iso-
palladium-catalyzed cyclocarbonylation of o-iodophenols lated yield of 5a was only 50% (Table 1, entry 8). Running the
with terminal acetylenes. The reaction affords high yields reaction in other ionic liquids gave the expected product and
of the desired products. its isomer in low selectivity (Table 1, entries 9, 10, and 11).
Initially, the cyclocarbonylation of o-iodophenol with With Et3N as the base and solvent, two isomers were isolated
phenyl acetylene was chosen as the model reaction. The in 63% total yield (Table 1, entry 12). Hence, a pronounced
results are presented in Table 1. counteranion effect was observed showing the increase in
The results in Table 1 show that cyclocarbonylation of selectivity and yield of 5a when moving from bistriflamide
o-iodophenol with phenyl acetylene can be performed in to bromide: Br- >Cl- > NTf2-.
PSIL102, C14H29(C6H13)3PþBr-, affording 5a in 95% iso- The optimal reaction conditions for the cyclocarbonyla-
lated yield when Pd(PPh3)2Cl2 was used as the catalyst and tion reaction in PSIL102 were then applied to a variety of
Et3N as the base under 200 psi of CO pressure and 110 °C aromatic and aliphatic terminal acetylenes. The results are
(Table 1, entry 1). In contrast, when Pd(PPh3)4 was used as summarized in Table 2.
the catalyst and K2CO3 as the base, neither 5a nor 5b was The results in Table 2 show that by the use of simple PdCl2
formed (Table 1, entry 2). So Pd(PPh3)2Cl2 was used for as catalyst, Et3N as base, and PSIL102 as the ionic liquid, the
cyclocarbonylation of o-iodophenol with both aromatic and
aliphatic terminal acetylenes proceeded well, affording pro-
(9) (a) Cao, H.; McNamee, L.; Alper, H. Org. Lett. 2008, 10, 5281.
(b) Yang, Q.; Robertson, A.; Alper, H. Org. Lett. 2008, 10, 5079. (c) Cao, ducts in good to excellent yields. Acetylenes containing
H.; McNamee, L.; Alper, H. J. Org. Chem. 2008, 73, 3530. methyl or electron-withdrawing substituents on the aromatic
J. Org. Chem. Vol. 75, No. 3, 2010 949
JOC Note Yang and Alper

ring react quite efficiently with o-iodophenol to form the cyclocarbonylation of o-iodophenols with terminal acety-
corresponding chromones in 64-94% yields (Table 2, entries lenes. By using PSIL102 as the ionic liquid, the reaction
2-5). The heteroaromatic substituted acetylene 14 could proceeds in a highly efficient and selective way to give
also give 2-thiophene-substituted chromone in 92% yield various chromones in good to excellent yields under
(Table 2, entry 6). All three aliphatic acetylenes reacted with atmospheric CO pressure and no phosphine ligand is re-
o-iodophenol affording 2-alkyl-substituted chromones in quired.
good yields (Table 2, entries 7-9). Note that for entry 8,
use of an N-based ionic liquid affords significantly reduced Experimental Section
yield of 19a (41%), as well as the formation of a substantial
amount of 2-heptylidenebenzofuran-3(2H)-one (26%). When General Procedure for the Cyclocarbonylation of o-Iodophe-
nols with Terminal Acetylenes. A mixture of o-iodophenol (1.0
methyl 3-hydroxy-4-iodobenzoate was used as the substrate
mmol), terminal acetylene (2 mmol), PdCl2 (0.05 or 0.01 mmol),
for the reaction with phenyl acetylene, the anticipated pro- Et3N (3 mmol), and PSIL102 [trihexyl(tetradecyl)phosphonium
duct was obtained in 79% yield (Table 2, entry 10). Thus, our bromide] (1.5 g) was added to the autoclave with magnetic
method can be considered as a valuable alternative to the stirring. The autoclave was closed, purged three times with
existing methods,4a,c as it affords better yields for some of the CO, and pressurized with CO at room temperature at 15 psi,
2-alkyl-substituted chromones,4c and hetero-aryl-substituted and then the autoclave was immersed in an oil bath preheated at
chromones 5a, 7a, and 15a.4a In addition, our method does 110 °C for 24 h. Excess CO was discharged at room temperature.
not require the use of phosphine ligand. The reaction mixture was purified by flash chromatography on
We have also briefly investigated if the catalyst loading can silica gel with hexane/EtOAc (v/v, 10:1) as the eluant to give the
be reduced to further improve the efficiency of the reaction. corresponding chromones in 64-96% yields.
2-Phenyl-4H-chromen-4-one (5a). The title compound was
Thus, exposure of o-iodophenol and phenyl acetylene to our
prepared from the cyclocarbonylation of o-iodophenol with
optimized cyclocarbonylation conditions using 1 mol % phenyl acetylene according to the general procedure, and the
PdCl2 as catalyst led to the desired product 5a in 81% desired product was obtained in 95% yield after flash chromato-
isolated yield (eq 1). Therefore, the product is isolated in graphy on silica gel. 1H NMR (400 MHz, CDCl3) δ 8.09 (dd, 1H,
good yield using this reduced loading of the catalyst. J = 8.0 and 1.6 Hz), 7.76 (d, 1H, J = 1.6 Hz), 7.74 (d, 1H,
J = 2.0 Hz), 7.56-7.52 (m, 1H), 7.41-7.34 (m, 4H), 7.28-7.24
(m, 1H), 6.66 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 177.9,
162.9, 155.8, 133.4, 131.3, 128.7, 125.9, 125.2, 124.8, 123.6,
117.8, 107.1; HRMS (EI) m/z calcd for C15H10O2 (Mþ)
222.0681, found 222.0679.

The recyclability of the reaction mixture containing active Acknowledgment. We are grateful to Cytec Canada, Inc.
catalyst and PSIL102 in the cyclocarbonylation reaction of and to the Natural Sciences and Engineering Research
o-iodophenol with 1-octyne (Table 2, entry 8) was also Council for support of this work. We benefited from discus-
investigated, and 78% isolated yield of 19a was obtained in sions with Dr. A. Robertson on this work.
the second run (see experimental details in the Supporting
Information). Supporting Information Available: Detailed experimental
In conclusion, PSIL102, C14H29(C6H13)3PþBr-, is a highly procedures and spectral data for all compounds. This material is
effective reaction medium for the palladium-catalyzed available free of charge via the Internet at http://pubs.acs.org.

950 J. Org. Chem. Vol. 75, No. 3, 2010