Synthesis of 2-acylthiophenes by palladium-catalyzed addition of thiophenes to nitriles

Article abstract of DOI:10.1002/adsc.201300843

A direct synthesis of 2-acylthiophenes has been developed through palladium-catalyzed addition of thiophenes to nitriles. The reaction proceeded well under the palladium(II) acetate/2,2'-bipyridine system and using d-(+)-camphorsulfonic acid as the additive. In addition, the obtained 2-acylthiophenes could undergo further coupling reactions to generate novel products.

Full text of DOI:10.1002/adsc.201300843

COMMUNICATIONS
DOI: 10.1002/adsc.201300843
Synthesis of 2-Acylthiophenes by Palladium-Catalyzed Addition
of Thiophenes to Nitriles
Tao-Shan Jianga and Guan-Wu Wanga,*
a
CAS Key Laboratory of Soft Matter Chemistry, Hefei National Laboratory for Physical Sciences at Microscale, and
Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, Peopleꢀs Republic of
China
E-mail: gwang@ustc.edu.cn
Received: September 18, 2013; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300843.
Abstract: A direct synthesis of 2-acylthiophenes has
been developed through palladium-catalyzed addi-
tion of thiophenes to nitriles. The reaction proceed-
ed well under the palladium(II) acetate/2,2’-bipyri-
dine system and using d-(+)-camphorsulfonic acid
as the additive. In addition, the obtained 2-acylthio-
phenes could undergo further coupling reactions to
generate novel products.
multiple steps for their installation. Thus, the develop-
ment of a simple and direct method for the synthesis
of 2-acylthiophenes from thiophenes is a highly de-
sired goal in synthetic chemistry.
In recent years, the transition metal-catalyzed syn-
thesis of aryl ketones through addition reaction of or-
ganometallics to nitriles has emerged as a powerful
synthetic method. This methodology was first report-
ed in the 1970s,[10] then attracted much attention from
the Larock group,[11] the Lu group,[12] and others.[13]
We have recently reported the palladium-catalyzed
acylation of free (N-H) indoles with nitriles.[14] In con-
tinuation of our work along this line, we envisioned
that the addition of thiophenes to nitriles catalyzed
by a Pd(II) species may lead to 2-acylthiophenes. In
Keywords: 2-acylthiophenes; metalation; nitriles;
palladium(II) acetate; thiophenes
Molecules containing the thiophene substructure play this paper, we report the direct synthesis of 2-acyl-
a significant role in natural products,[1] pharmaceuti-
ACHTUNGTRENtNGNU hiophenes through palladium-catalyzed addition of
cals,[2] and functional organic materials used for con- thiophenes to nitriles and further transformation to
ductivity, photoelectricity, and liquid crystalline pur- other novel products.
poses.[3] Hence, the derivatization of thiophene has at-
Based on our previously optimized reaction condi-
tracted much attention among chemists. 2-Acylthio- tions and the fact that d-(+)-camphorsulfonic acid (d-
phenes are a privileged class of thiophene derivatives CSA) was the best additive compared to other
and are versatile starting materials for the synthesis of acids,[14] we directly performed the reaction of 2-meth-
other types of thiophene derivatives since their car- ylthiophene 1a (38.7 mL, 0.4 mmol) with 4-methylben-
bonyl groups can easily undergo a variety of transfor- zonitrile 2a (1.5 equiv.) in the presence of PdACHTUNGTRENNUNG
À
À
mations such as C C and C N coupling reactions and (5 mol%),
2,2’-bipyridine
(6 mol%),
reductions.[4] Traditional approaches to the synthesis (1.5 equiv.), and H2O (2 equiv.) in 0.5 mL of N-meth-
of 2-acylthiophenes mainly include Friedel–Crafts ylacetamide (NMA) at 1208C for 36 h. To our pleas-
acylation,[5] transition metal-catalyzed cross-coupling ure, the desired product 2-acylthiophene 3a was ob-
of (hetero)aryl iodides with arylboronic acids and tained in 55% isolated yield. Varying the reaction
carbon monoxide,[6] and others.[7] Friedel–Crafts acyla- temperature, a better result could be achieved at
tion requires excess amounts of Lewis acid and strict 1108C, and the yield was improved to 67% (Table 1,
reaction conditions.[8] The commonly used acylated entry 2 vs. entries 1 and 3). Then the reaction time
reagents like acid chlorides and some other substi- was investigated. The yield decreased to 58% when
tutes are usually unstable and sometimes difficult to the time was shortened to 24 h (Table 1, entry 4). Pro-
prepare. The transition metal-catalyzed cross-coupling longing the reaction time to 48 h gave a comparable
reaction of organometallic reagents with (hetero)aryl result to that for 36 h (Table 1, entry 5 vs. entry 2).
halides is an efficient tool in organic synthesis.[9] How- Similar efficiency could be attained when the amount
ever, the need for dual preactivation in this method is of d-CSA was decreased from 1.5 equiv. to 1.0 equiv.
inherently wasteful since these groups may require (Table 1, entry 7 vs. entries 2 and 6). However, 0.5
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
ÞÞ
These are not the final page numbers!

COMMUNICATIONS
Tao-Shan Jiang and Guan-Wu Wang
Table 1. Optimization of the reaction conditions.[a]
Entry
Additive (equiv.)
Time [h]
Temperature [oC]
Yield [%]
1
2
3
4
5
6
7
8
d-CSA (1.5)
d-CSA (1.5)
d-CSA (1.5)
d-CSA (1.5)
d-CSA (1.5)
d-CSA (1.2)
d-CSA (1.0)
d-CSA (0.5)
d-CSA (1.0)
d-CSA (1.0)
36
36
36
24
48
36
36
36
36
36
120
110
100
110
110
110
110
110
110
110
55
67
48
58
69
66
69
48
79
0
9[b]
10[c]
[a]
Unless otherwise specified, all reactions were carried out using 1a (0.4 mmol), PdCATHUNGTREN(NUGN OAc)2 (5 mol%), ligand (6 mol%), and
H2O (0.8 mmol) in 0.5 mL solvent for 36 h.
[b]
[c]
Pd
ACHTUNGTRENNUNG
The reaction was carried out without Pd
AHCTUNGTRENNUNG
equiv. of d-CSA gave the product in only 48% yield methylthiophene (87% for 3o vs. 86% for 3e), where-
(Table 1, entry 8). Gratifyingly, the yield could be fur- as those with 2-methoxythiophene and 2-iodothio-
ther improved to 79% by employing 10 mol% of phene gave products 3p and 3q in low yields due to
Pd
The reaction did not occur in the absence of a palladi- phenes with electron-withdrawing groups like 2-ace-
um catalyst (Table 1, entry 10). tylthiophene provided no product in our catalytic
ACHTUNGTRENNUNG
(OAc)2 and 12 mol% of ligand (Table 1, entry 9). side reactions under our reaction conditions.[15] Thio-
Using the optimized conditions (Table 1, entry 9), system. Notably, thiophene-based p-conjugated sys-
we next explored the scope and limitation of this pro- tems such as bithiophene, which are widely studied in
cess. As shown in Table 2, the substrate scope with re- material science,[3] could be easily transformed into
spect to the nitriles was examined first. In reactions monoacylated products 3r–u in 57–73% yields by
with 2-methylthiophene, aromatic nitriles with both means of this protocol. It should be pointed out that
electron-withdrawing and electron-donating substitu- 3-methylthiophene gave the acylation products in
ents on the phenyl rings could furnish the desired 82% yield, yet with two regioisomers in a ratio of 4:1.
products 3a–h in generally good to excellent yields Furthermore, replacing the nitriles with 1 mL of ace-
(54–86%). The electron-withdrawing groups on the
aromatic ring exhibited relatively higher efficiency
than the electron-donating groups (3e–h vs. 3a–c),
which is in accordance with our earlier observation.[14]
However, the reaction with 2-methylbenzonitrile gave
the desired product in very low yield (<10%) due to
the steric hindrance effect. Intriguingly, thiophene-2-
carbonitrile could react with 2-methylthiophene to
afford the novel dithiophenyl ketone 3i in 61% yield.
Aliphatic nitriles such as phenylacetonitrile and 4-
phenylbutanenitrile could also be employed and af-
forded products 3j and 3k in 71% and 78% yields, re-
spectively. It is noteworthy that the reaction with phe-
nylacetonitrile required a mixture of NMA and tolu-
ene as the solvent. Then the scope of the thiophene
partners was explored. Thiophene itself could react
with representative 4-bromobenzonitrile, 3-methyl-
benzonitrile, and thiophene-2-carbonitrile to furnish
the monoacylated products 3l–n in moderate yields.
The reaction of 4-bromobenzonitrile with 2-phenyl-
thiophene provided a comparable yield to that with 2- acylthiophenes.
Scheme 1. Proposed mechanism for the formation of 2-
2
asc.wiley-vch.de
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

COMMUNICATIONS
Synthesis of 2-Acylthiophenes by Palladium-Catalyzed Addition
Table 2. Palladium-catalyzed addition of thiophenes to nitriles.[a]
[a]
Reaction conditions: 1 (0.4 mmol), 2 (0.6 mmol), PdACTHNUTRGENUN(G OAc)2 (10 mol%), 2,2’-bipyridine
(12 mol%), d-CSA (0.4 mmol), and H2O (0.8 mmol) in 0.5 mL of NMA at 1108C for
36 h.
[b]
[c]
[d]
[e]
[f]
Reaction was run at 1208C.
The reaction was run for 48 h.
Using 0.5 mL of toluene and 0.5 mL of NMA as the solvent.
C-2/C-5=4:1 as determined by H NMR.
1 mL of CH3CN was used.
1
À
À
tonitrile allowed the reaction to proceed smoothly, reactive C Br bond (3e, 3f, 3l, 3o–q, 3t, 3v) and C I
and provided 2-acylthiophenes 3w and 3x in good bond (3q) were tolerated, and provided an attractive
yields. In our present catalytic system, the potentially route for further coupling reactions.
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3
ÞÞ
These are not the final page numbers!

COMMUNICATIONS
Tao-Shan Jiang and Guan-Wu Wang
Scheme 2. Further transformations of 2-acylthiophenes.
(+)-camphorsulfonic acid (92.9 mg, 0.4 mmol), and H2O
(14.4 mL, 0.8 mmol) in N-methylacetamide (0.5 mL) was
stirred at 110 or 1208C for 36 or 48 h. After the reaction
was finished, the mixture was filtered through a silica gel
plug with ethyl acetate (30 mL) as the eluent. The filtrate
was washed with saturated brine (3ꢂ10 mL), and the organ-
ic phase was dried over Na2SO4, filtered, and concentrated
under reduced pressure. The residue was purified by flash
column chromatography on a silica gel using petroleum
ether/EtOAc (40:1 to 10:1) as the eluent to give the desired
product 3.
The possible reaction mechanism of palladium-cata-
lyzed 2-acylation of thiophenes with nitriles is depict-
ed in Scheme 1 based on the previous literature prec-
edents.[14] The catalytic pathway may involve the fol-
lowing key steps: (i) palladation at C-2 of a thiophene
to form a palladium intermediate A; (ii) an active cat-
ionic palladium complex B is generated under the
acidic conditions;[16] (iii) coordination of the nitrile
gives the intermediate C; (iv) carbopalladation of the
nitrile forms ketimine complex D; (v) protonation of
the complex D and subsequent hydrolysis leads to 2-
acylthiophene. Nevertheless, the possibility that the
whole reaction cycle is mediated by Pd+ species
cannot be excluded due to the strong acidity of d-
CSA.
It should be emphasized that only monoacylated
products were obtained when thiophene was used as
the starting material in our catalytic process. To dem-
onstrate the utility of 2-acylthiophenes, the arylation
and olefination of acylated products were performed
under Suꢀs conditions (Scheme 2).[17] The desired cou-
Acknowledgements
We are grateful for financial support from the National Natu-
ral Science Foundation of China (91021004), National Basic
Research Program of China (2011CB921402), and the Key
Project of Science and Technology of the Department of
Education, Anhui Province, China (KJ2010ZD05).
pling products 4 and 5 were obtained in 52% and References
59% yields, respectively.
In summary, the direct synthesis of 2-acylthio-
phenes from thiophenes and nitriles was accomplished
[1] a) W. Carruthers, A. G. Douglas, J. Chem. Soc. 1959,
2813; b) S. Nakajima, K. Kawazu, Agric. Biol. Chem.
1980, 44, 1529; c) F. Bohlmann, M. Ahmed, M. Grenz,
R. M. King, H. Robinson, Phytochemistry 1983, 22,
2858.
in the PdACHTUNGTRENNUNG(OAc)2/2,2’-bipyridine and d-(+)-camphor-
sulfonic acid system. Different thiophenes could suc-
cessfully react with aromatic and aliphatic nitriles to
form 2-acylthiophenes in moderate to good yields. In
addition, the synthesized 2-acylthiophenes could be
further transformed into other novel derivatives
through cross-coupling reactions.
[2] a) K. R. Romines, G. A. Freeman, L. T. Schaller, J. R.
Cowan, S. S. Gonzales, J. H. Tidwell, C. W. Andrews,
D. K. Stammers, R. J. Hazen, R. G. Ferris, S. A. Short,
J. H. Chan, L. R. Boone, J. Med. Chem. 2006, 49, 727;
b) S. Conde, D. I. Perez, A. Martinez, C. Perez, F. J.
Moreno, J. Med. Chem. 2003, 46, 4631.
[3] For selected examples: a) M. S. Sunitha, A. V. Adhi-
kari, K. A. Vishnumurthy, N. Smijesh, R. Philip, Chem.
Lett. 2012, 41, 234; b) I. C. Wu, C. H. Lai, D. Y. Chen,
C. W. Shih, C. Y. Wei, B. T. Ko, C. Ting, P. T. Chou, J.
Mater. Chem. 2008, 18, 4297; c) C. J. Shi, Y. Yao, Y.
Yang, Q. B. Pei, J. Am. Chem. Soc. 2006, 128, 8980.
[4] For selected examples: a) A. Berlicka, L. Latos-Gra-
zynski, T. Lis, Angew. Chem. 2005, 117, 5422; Angew.
Chem. Int. Ed. 2005, 44, 5288; b) S. N. Greszler, J. S.
Johnson, Angew. Chem. 2009, 121, 3743; Angew. Chem.
Experimental Section
General Procedure for the Addition of Thiophenes to
Nitriles
A mixture of thiophene 1 (0.4 mmol), nitrile 2 (0.6 mmol,
1 mL when acetonitrile was used), Pd
0.04 mmol), 2,2’-bipyridine (7.5 mg, 0.048 mmol), d-
ACHTUNGRTENUN(NG OAc)2 (9.0 mg,
4
asc.wiley-vch.de
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

COMMUNICATIONS
Synthesis of 2-Acylthiophenes by Palladium-Catalyzed Addition
Int. Ed. 2009, 48, 3689; c) Y. Z. Sui, X. C. Zhang, J. W.
Wu, S. Li, J. N. Zhou, M. Li, W. Fang, A. S. C. Chan, J.
Wu, Chem. Eur. J. 2012, 18, 7486.
kami, Chem. Commun. 2007, 2855; c) J. Lindh, P. J. R.
Sjoerg, M. Larhed, Angew. Chem. 2010, 122, 7899;
Angew. Chem. Int. Ed. 2010, 49, 7733; d) Y.-C. Wong,
K. Parthasarathy, C.-H. Cheng, Org. Lett. 2010, 12,
1736; e) G. C. Tsui, Q. Glenadel, C. Lau, M. Lautens,
Org. Lett. 2011, 13, 208; f) M. Behrends, J. Sꢃvmarker,
P. J. R. Sjçberg, M. Larhed, ACS Catal. 2011, 1, 1455;
g) J. Liu, X. Zhou, H. Rao, F. Xiao, C.-J. Li, G.-J. Deng,
Chem. Eur. J. 2011, 17, 7996; h) T. Miao, G.-W. Wang,
Chem. Commun. 2011, 47, 9501; i) F. Svensson, R. S.
Mane, J. Sꢃvmarker, M. Larhed, C. Skçld, Organome-
tallics 2013, 32, 490.
[5] W. Su, C. Jin, J. Chem. Res. (S) 2003, 694.
[6] a) M. Dai, B. Liang, C. Wang, Z. You, J. Xiang, G.
Dong, J. Chen, Z. Yang, Adv. Synth. Catal. 2004, 346,
1669; b) P. J. Tambade, Y. P. Patil, A. G. Panda, B. M.
Bhanage, Eur. J. Org. Chem. 2009, 3022; c) H. Li, M.
Yang, Y. Qi, J. Xue, Eur. J. Org. Chem. 2011, 2662.
[7] a) A. R. Katritzky, K. N. B. Le, L. Khelashvili, P. P. Mo-
hapatra, J. Org. Chem. 2006, 71, 9861; b) T. T. Nguyen,
N. Marquise, F. Chevallier, F. Mongin, Chem. Eur. J.
2011, 17, 10405; c) G. Karthikeyan, K. Parthasarathy,
C.-H. Cheng, Chem. Commun. 2011, 47, 10461.
[8] G. Sartori, R. Maggi, Chem. Rev. 2006, 106, 1077.
[9] For reviews on this topic, see: a) F. Diederich, P. J.
Stang, (Eds.) Metal-catalyzed Cross-coupling Reactions,
Wiley-VCH, New York, 1998; b) J. Hassan, M. Sev-
ignon, C. Gozzi, E. Shulz, M. Lemaire, Chem. Rev.
2002, 102, 1359.
[14] T.-S. Jiang, G.-W. Wang, Org. Lett. 2013, 15, 788.
[15] 2-Methoxythiophene easily decomposed under strong
acid conditions and no starting material was detected
by TLC after the reaction was complete. 2-Iodothio-
phene had low reactivity and still could be identified
on the TLC, and the main byproduct was due to hy-
drolysis of the nitrile for a long reaction time.
À
[16] A cationic aryl Pd species could be formed under
[10] K. Garves, J. Org. Chem. 1970, 35, 3273.
acidic conditions, see: S. Kirchberg, S. Tani, K. Ueda, J.
Yamaguchi, A. Studer, K. Itami, Angew. Chem. 2011,
123, 2435; Angew. Chem. Int. Ed. 2011, 50, 2387.
[17] a) P. Hu, M. Zhang, X. Jie, W. Su, Angew. Chem. 2012,
124, 231; Angew. Chem. Int. Ed. 2012, 51, 227; b) Y.
Shang, X. Jie, J. Zhou, P. Hu, S. Huang, W. Su, Angew.
Chem. 2013, 125, 1337; Angew. Chem. Int. Ed. 2013, 52,
1299.
[11] a) R. C. Larock, Q. Tian, A. A. Pletnev, J. Am. Chem.
Soc. 1999, 121, 3238; b) A. A. Pletnev, Q. Tian, R. C.
Larock, J. Org. Chem. 2002, 67, 9276; c) C. Zhou, R. C.
Larock, J. Am. Chem. Soc. 2004, 126, 2302; d) C. Zhou,
R. C. Larock, J. Org. Chem. 2006, 71, 3551.
[12] a) B. Zhao, X. Lu, Tetrahedron Lett. 2006, 47, 6765;
b) X. Lu, B. Zhao, Org. Lett. 2006, 8, 5987.
[13] a) K. Ueura, S. Miyamura, T. Satoh, M. Miura, J. Orga-
nomet. Chem. 2006, 691, 2821; b) H. Shimizu, M. Mura-
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
5
ÞÞ
These are not the final page numbers!

COMMUNICATIONS
6 Synthesis of 2-Acylthiophenes by Palladium-Catalyzed
Addition of Thiophenes to Nitriles
Adv. Synth. Catal. 2014, 356, 1 – 6
Tao-Shan Jiang, Guan-Wu Wang*
6
asc.wiley-vch.de
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!