Palladium-catalyzed domino C-S coupling/carbonylation reactions: An efficient synthesis of 2-carbonylbenzo[ b ]thiophene derivatives

Article abstract of DOI:10.1021/ol200880m

A facile and selective palladium-catalyzed domino procedure has been developed for the preparation of 2-carbonylbenzo[b]thiophene derivatives from 2-gem-dihalovinylthiophenols. This protocol involves intramolecular C-S coupling/intermolecular carbonylatio

Full text of DOI:10.1021/ol200880m

ORGANIC
LETTERS
2011
Vol. 13, No. 11
2868–2871
Palladium-Catalyzed Domino CꢀS
Coupling/Carbonylation Reactions:
An Efficient Synthesis of
2-Carbonylbenzo[b]thiophene Derivatives
Fanlong Zeng and Howard Alper*
Centre for Catalysis Research and Innovation, Department of Chemistry,
University of Ottawa, 10 Marie Curie, Ottawa, Ontario, Canada, K1N 6N5
howard.alper@uottawa.ca
Received April 4, 2011
ABSTRACT
A facile and selective palladium-catalyzed domino procedure has been developed for the preparation of 2-carbonylbenzo[b]thiophene derivatives
from 2-gem-dihalovinylthiophenols. This protocol involves intramolecular CꢀS coupling/intermolecular carbonylation cascade sequences and
allows access to various highly functionalized benzo[b]thiophenes in moderate yields.
The transition-metal-catalyzed CꢀS coupling reaction
has recently attracted considerable attention, as it can
provide a more efficient, practical, and straightforward
approach to valuable sulfur-containing compounds.1
Since Migita and co-workers first reported the Pd(PPh3)4-
catalyzed CꢀS coupling of stannyl sulfides and aryl
bromides,2 a number of catalytic systems based on transi-
tion metals, such as palladium,3 nickel,4 copper,5 cobalt,6
indium,7 and iron,8 have been developed for this purpose.
In contrast to amination9 and etherification10 reactions of
aryl and vinyl halides, this transformation still represents a
challenge due to two main disadvantages: first, the sulfur-
containing compounds may deactivate the catalysts owing
to their strong coordination and absorption properties;
second, thiols are prone to affording the corresponding
(5) (a) Ma, D.; Lu, X.; Shi, L.; Zhang, H.; Jiang, Y.-G.; Liu, X.-Q.
Angew. Chem., Int. Ed. 2011, 50, 1118. (b) Kabir, M. S.; Lorenz, M.; Van
Linn, M. L.; Namjoshi, O. A.; Ara, S.; Cook, J. M. J. Org. Chem. 2010,
75, 3626. (c) Firouzabadi, H.; Iranpoor, N.; Gholinejada, M. Adv. Synth.
Catal. 2010, 352, 119. (d) Chen, C.-K.; Chen, Y.-W.; Lin, C.-H.; Lin,
H.-P.; Lee, C.-F. Chem. Commun. 2010, 282. (e) Ma, D.; Xie, S.; Xue, P.;
Zhang, X.; Dong, J.; Jiang, Y. Angew. Chem., Int. Ed. 2009, 48, 4222. (f)
Jiang, Y.; Qin, Y.; Xie, S.; Zhang, X.; Dong, J.; Ma, D. Org. Lett. 2009,
11, 5250. (g) Bhadra, S.; Sreedhar, B.; Ranu, B. C. Adv. Synth. Catal.
2009, 35, 2369. (h) Gan, J.; Ma, D. Org. Lett. 2009, 11, 2788. (i) Kabir,
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3363. (j) Carril, M.; SanMartin, R.; Domınguez, E.; Tellitu, I. Chem.;
Eur. J. 2007, 13, 5100. (k) Rout, L.; Sen, T. K.; Punniyamurthy, T.
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Venkataraman, D. Org. Lett. 2002, 4, 2803. (m) Kwong, F. Y.;
Buchwald, S. L. Org. Lett. 2002, 4, 3517.
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Chem. Soc., Perkin Trans. 1 2001, 335. (b) Kondo, T.; Mitsudo, T.-A.
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K. R. J. Org. Chem. 2009, 74, 3189.
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ꢀ
r
10.1021/ol200880m
Published on Web 05/05/2011
2011 American Chemical Society

disulfides as accompanying products. Therefore, the devel-
opment of new and efficient catalytic procedures to cir-
cumvent these limitations is a highly desirable goal.
powerful transformation for the synthesis of carbonyl-
containing compounds.19 As part of our ongoing efforts
to develop more efficient and environmentally benign
strategies to synthesize carbonyl-containing heterocycles
via carbonylation reactions,20 we herein report a novel and
straightforward domino protocol for the preparation of
2-carbonylbenzo[b]thiophene derivatives, which entails
the consecutive formation of multiple new bonds in a
single step, and potentially minimize the amounts of
requisite reagents, separation steps, and chemical waste.
2-Carbonylbenzo[b]thiophene derivatives are an impor-
tant class of ring-fused compounds from both synthetic
and biological points of view. For instance, they have good
biological activities as anti-inflammatory,11 antimitotic,12
and antitumor13 agents, FimH antagonists,14 and PIM
kinases inhibitors.15 However, there are only a few efficient
procedures which have been developed to synthesize them
based on the oxidation of cinnamic acids and derivatives
by a strong oxidant,16 metalation at the C-2 position of
benzo[b]thiophenes by organometallic reagents,17 or cy-
clodehydration of ortho-formylphenylthioacetate and
derivatives.18 These procedures often suffer from harsh
reaction conditions, poor availability of the requisite o-
formylphenylthioacetate derivatives, and low yields.
Transition-metal-catalyzed carbonylation, particularly
palladium-catalyzed, is a fundamental, practical, and
Table 1. Optimization of the Reaction Conditions Using 2-gem-
Dibromovinylthiophenol and Methanola
CO
yield
(%)b
(9) For reviews on catalytic amination, see: (a) Hartwig, J. F. Acc.
Chem. Res. 2008, 41, 1534. (b) Surry, D. S.; Buchwald, S. L. Angew.
Chem., Int. Ed. 2008, 47, 6338. (c) Barluenga, J.; Valdes, C. Chem.
Commun. 2006, 4891. (d) Ley, S. V.; Thomas, A. Angew. Chem., Int. Ed.
2003, 42, 5400.
entry
ligand
base
solvent
(psi)
36c
45
ꢀ
1
2
3
4
5
6
7
8
9
Johnphos
Johnphos
Johnphos
Johnphos
Johnphos
Johnphos
Johnphos
Johnphos
Johnphos
cyclohexyl
Johnphos
Ruphos
K2CO3
K2CO3
K2CO3
Et3N
THF
500
500
500
500
500
500
300
150
50
MeOH
THF/MeOH
THF/MeOH
THF/MeOH
THF/MeOH
THF/MeOH
THF/MeOH
THF/MeOH
58d
29d
52d
42d
56d
58d
traced
(10) (a) Burgos, C. H.; Barder, T. E.; Huang, X.; Buchwald, S. L.
Angew. Chem., Int. Ed. 2006, 45, 4321. (b) Vorogushin, A. V.; Huang, X.;
Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 8146. (c) Torraca, K. E.;
Huang, X.; Parrish, C. A.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123,
10770. (d) Shelby, Q.; Kataoka, N.; Mann, G.; Hartwig, J. F. J. Am.
Chem. Soc. 2000, 122, 10718. (e)Gujadhur, R.;Bates, C. G.; Venkataraman,
D. Org. Lett. 2001, 3, 4315.
(11) Radwan, M. A. A.; Shehab, M. A.; El-Shenawy, S. M. Monatsh.
Chem. 2009, 140, 445.
(12) Romagnoli, R.; Baraldi, P. G.; Carrion, M. D.; Lopez Cara, C.;
Preti, D.; Fruttarolo, F.; Pavani, M. G.; Tabrizi, M. A.; Tolomeo, M.;
Grimaudo, S.; Di Antonella, C.; Balzarini, J.; Hadfield, J. A.; Brancale,
A.; Hamel, E. J. Med. Chem. 2007, 50, 2273.
(13) Valderrama, J. A.; Espinozaa, O.; Rodriguezb, J.; Theoduloz, C.
Lett. Org. Chem. 2009, 6, 278.
(14) Han, Z.; Pinker, J. S.; Ford, B.; Obermann, R.; Nolan, W.;
Wildman, S. A.; Hobbs, D.; Ellenberger, T.; Cusumano, C. K.; Hultgren,
S. J.; Janetka, J. W. J. Med. Chem. 2010, 53, 4779.
(15) Tao, Z.-F.; Hasvold, L. A.; Leverson, J. D.; Han, E. K.; Guan,
R.; Johnson, E. F.; Stoll, V. S.; Stewart, K. D.; Stamper, G.; Soni, N.;
Bouska, J. J.; Luo, Y.; Sowin, T. J.; Lin, N.-H.; Giranda, V. S.;
Rosenberg, S. H.; Penning, T. D. J. Med. Chem. 2009, 52, 6621.
(16) (a) Campaigne, E.; Cline, R. E. J. Org. Chem. 1956, 21, 39. (b)
Higa, T.; Krubsack, A. J. Org. Chem. 1976, 41, 3399.
(17) (a) Kudo, H.; Castle, R. N.; Lee, M. L. J. Heterocycl. Chem.
1985, 22, 215. (b) Takaya, J.; Tadami, S.; Ukai, K.; Iwasawa, N. Org.
Lett. 2008, 10, 2697.
KHCO3
K3PO4
K2CO3
K2CO3
K2CO3
10
K2CO3
THF/MeOH
150
40d
11
12
13
K2CO3
K2CO3
K2CO3
THF/MeOH
THF/MeOH
THF/MeOH
150
150
150
73d
52d
59d
Xphos
Davephos
a All reactions were carried out with 0.5 mmol of 1a, 4 mol % of
Pd(OAc)2 and ligand, 3.0 equiv of base, and 6 mL of solvent, at 110 °C,
for 15 h. b Isolated yield based on 2-gem-dibromovinylthiophenol. c 4.0
equiv of MeOH. d MeOH/THF (v/v = 1:1).
Initially, the 2-gem-dibromovinylthiophenol (1a) and
methanol (2a) were chosen as model substrates to explore
the feasibility and efficiency of the new domino protocol.
Table 1 outlines the results of optimization experiments.
Notably, the performance of this transformation signifi-
cantly depended on the nature of solvents, and a 1:1
mixture of MeOH/THF was found to be the ideal solvent
for the reaction providing thiophene 3a in 58% yield,
which is consistent with our previous report about the
synthesis of 2-carboxylindoles (Table 1, entries 1ꢀ3).20i It
should be mentioned that performing this reaction under
the pressure of carbon monoxide as low as 50 psi only gave
trace amounts of the desired product 3a (Table 1, entry 9).
The ligands employed in this process played an impor-
tant role, and bulky electron-rich 2-dicyclohexylphosphi-
no-20,60-diisopropoxybiphenyl (Ruphos) was the most
effective ligand, which furnished the anticipated product
3a in 73% isolated yield. Other bulky electron-rich
phosphine ligands, e.g., 2-di-tert-butylphosphinobiphenyl
(18) Hirota, T.; Tashima, Y.; Sasaki, K.; Namba, T.; Hayakawa, S.
Hetercycles 1987, 26, 2717.
(19) (a) Negishi, E., de Meijere, A., Eds. Handbook of Organopalla-
dium Chemistry for Organic Synthesis; John Wiley & Sons: New York,
2002; Vol. 2, p 2309. (b) Skoda-Foldes, R.; Kollar, L. Curr. Org. Chem.
2002, 6, 1097. (c) Beller, M.; Cornils, B.; Frohning, C. D.; Kohlpaintner,
C. W. J. Mol. Catal. A 1995, 104, 17. (d) Tsuji, J. Palladium Reagents and
Catalysis: Innovation in Organic Synthesis; John Wiley & Sons: Chichester,
U.K., 1995. (e) Colquhoun, H. M.; Thompson, D. J.; Twigg, M. V. Carbon-
ylation, Direct Synthesis of Carbonyl Compounds; Plenum Press: New York,
1991.
(20) (a) Cao, H.; Vieira, T. O.; Alper, H. Org. Lett. 2011, 13, 11. (b)
Zeng, F. L.; Alper, H. Org. Lett. 2010, 12, 5567. (c) Zeng, F. L.; Alper, H.
Org. Lett. 2010, 12, 3642. (d) Zeng, F. L.; Alper, H. Org. Lett. 2010, 12,
1188. (e) Chouhan, G.; Alper, H. Org. Lett. 2010, 12, 192. (f) Cao, H.;
Alper, H. Org. Lett. 2010, 12, 4126. (g) Chouhan, G.; Alper, H. J. Org.
Chem. 2009, 74, 6181. (h) Zheng, Z.; Alper, H. Org. Lett. 2009, 11, 3278.
(i) Vieira, T. O.; Meaney, L. A.; Shi, Y.-L.; Alper, H. Org. Lett. 2008, 10,
4899. (j) Zheng, Z.; Alper, H. Org. Lett. 2008, 10, 829. (k) Zheng, Z.;
Alper, H. Org. Lett. 2008, 10, 4903. (l) Chouhan, G.; Alper, H. Org. Lett.
2008, 10, 4987.
Org. Lett., Vol. 13, No. 11, 2011
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Table 2. One-Step Synthesis of Benzo[b]thiophene-2-carboxy-
lates and Benzo[b]thiophene-2-carboxamidesa
Scheme 1. Possible Reaction Mechanism
biphenyl (Xphos), and 2-dicyclohexylphosphino-20-(N,N-
dimethylamino)biphenyl (Davephos) were effective as
well, albeit giving lower yields (Table 1, entries 8, 10, 12,
and 13). Furtherstudies showed thatthe organicbaseEt3N
was much less useful than inorganic bases, such as K2CO3,
KHCO3, and K3PO4 (Table 1, entries 3ꢀ6).
With the optimized reaction conditions in hand, the
generality of the present domino strategy was explored,
and the results are summarized in Table 2. First, the
reactions of 2-gem-dibromovinylthiophenol (1a) with
methanol, ethanol, and n-butanol generated the corre-
sponding target products 3aꢀ3c in 73%, 65%, and 51%
yields, respectively, which indicates increasing the chain
length of alcohols reduces the efficiency of this transforma-
tion(Table2, entries1ꢀ3). Using phenol as the nucleophile,
the desired product 3d was isolated in low yield (24%),
owing to the weaker nucleophilicity of the phenols relative
to aliphatic alcohols. When primary amines, including n-
hexylamine, isopropylamine, tert-butylamine, and allyla-
mine, were employed as the nucleophiles, the anticipated
amides 3eꢀ3h were obtained in moderate yields (Table 2,
entries 5ꢀ8). However, the reaction of diethylamine using
the standard conditions afforded the desired amide 3i in
44% yield, demonstrating the steric hindrance of two ethyl
groups modestly affects the outcome of this process. The
influence of substituents on the aryl groups of the thiophe-
nol derivatives was also investigated, and the electronic
properties of the substituents had a significant effect on the
efficiency of this reaction. The thiophenols with electron-
donating groups (1e and 1f) gave similar results to that of
the unfunctionalized substrate 1a (Table 2, entries 13 and 14).
The thiophenols with mildly electron-withdrawing groups,
a All reactions were carried out with 0.5 mmol of 1, 4 mol % of
Pd(OAc)2 and Ruphos, 3.0 equiv of base, and 6 mL of MeOH/THF (v/v
= 1:1), at 110 °C, 150 psi, for 15 h. b Isolated yield based on 1. c 6 mL of
EtOH/dioxane (v/v = 1:1). d 2.0 equiv of phenol, 6 mL of THF. e 4.0
equiv of amine, 6 mL of THF.
(Johnphos), 2-dicyclohexylphosphinobiphenyl (cyclohexyl
Johnphos), 2-dicyclohexylphosphino-20,40,60-triisopropyl-
2870
Org. Lett., Vol. 13, No. 11, 2011

i.e., chloride and fluoride, furnished the corresponding
products, but in slightly reduced yields (Table 2, entries
10 and 11). In contrast, the thiophenol 1d with a strongly
electron-withdrawing CF3 group only gave trace amounts
of the target product 3l. We were pleased to find that our
synthetic strategy was also suitable for 2-gem-dichlorovi-
nylthiophenol (1g), providing the corresponding ben-
zothiophene 3a in 52% yield.
A possible mechanism for the formation of 2-car-
bonylbenzo[b]thiophenes 3 is depicted in Scheme 1. Oxi-
dative addition of 1 to the in situ formed palladium(0)
species21 gives the palladium complex 4, which is followed
by the formation of the palladacycle 5 via base-catalyzed
intramolecular cyclization. Reductive elimination of 5
affords the intermediate 2-halobenzo[b]thiophene 6 and
releases the palladium(0) species. Oxidative addition of 6
to palladium(0) leads to complex 7, followed by CO
insertion into the carbonꢀpalladium bond to provide 8.
Base-catalyzed intermolecular nucleophilic attack on the
aroylpalladium complex 8 then gives the intermediate 9.
Reductive elimination of 9 furnishes the product 3 and
regenerates the active palladium(0) species.
Under a CO atmosphere, the intermediate 5 has the
potential to form the six-membered thiolactone 60 via CO
insertion into the carbonꢀpalladium bond. However the
thiolactone 60 was not detected in all cases, which may be
because the seven-membered transition state is unfavor-
able relative to the formation of five-membered 2-halobenzo-
[b]thiophene 6. The conversion of 2-halobenzo[b]thiophene 6
to the product 3 was not quantitative, and the corresponding
compound 6 was detected as a byproduct,22 which provides
insight to the mechanism of this process.
In summary, a novel strategy for the synthesis of
2-carbonylbenzo[b]thiophene derivatives has been devel-
oped based on a one-pot palladium-catalyzed intramole-
cular CꢀS coupling/intermolecular carbonylation reaction
sequence. This procedure tolerates significant variation of
both nucleophiles and the thiophenol backbone and pro-
vides a general, straightforward, and practical approach to
benzo[b]thiophene-2-carboxylates and benzo[b]thiophene-
2-carboxamides.
Acknowledgment. We are grateful to the Natural
Sciences and Engineering Research Council of Canada
(NSERC) for support of this research
(21) (a) Amatore, C.; Jutand, A.; M’Barki, M. Organometallics 1992,
11, 3009. (b) Amatore, C.; Carre, E.; Jutand, A.; M’Barki, M. Organo-
metallics 1995, 14, 1818.
(22) For instance, the reactions of 1a with methanol and hexylamine
gave the intermediate 2-bromobenzo[b]thiophene in 8% and 14% yields,
respectively. The reaction of 1b with methanol furnished 2-bromo-6-
chlorobenzo[b]thiophene in 15% yield.
Supporting Information Available. Experimental pro-
cedures, characterization data, and NMR spectra for the
starting materials and products. This material is available
free of charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 11, 2011
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