A general catalyst for the β-selective C - H bond arylation of thiophenes with iodoarenes

Article abstract of DOI:10.1002/anie.201005082

Open access: The normally less-reactive β position of thiophenes was previously inaccessible to direct functionalization. However, the β selectivity observed with the catalytic system PdCl₂/P{OCH(CF ₃)₂}₃/Ag₂CO₃ in the arylation of thiophenes with iodoarenes (see scheme) is a remarkably general phenomenon applicable to unsubstituted, monosubstituted, and disubstituted thiophene derivatives, as well as thiophene-containing fused aromatic compounds.

Full text of DOI:10.1002/anie.201005082

Communications
DOI: 10.1002/anie.201005082
À
C H Functionalization
A General Catalyst for the b-Selective C–H Bond Arylation of
Thiophenes with Iodoarenes**
Kirika Ueda, Shuichi Yanagisawa, Junichiro Yamaguchi, and Kenichiro Itami*
The functionalization of thiophenes is an important and
fundamental transformation in organic chemistry.[1] Repre-
sentative examples include electrophilic substitution and
b selectivity observed in the arylation of the methoxy-
substituted thiophene 1a with iodobenzene (2) under the
catalysis of PdCl2/P{OCH(CF3)2}3/Ag2CO3 (Table 1, entry 1)
base-mediated metalation followed by reaction with an
[2,3]
À
Table 1: Generality of the reaction in terms of the thiophene coupling
partner.
electrophile. The direct functionalization of C H bonds
of thiophenes under the catalysis of transition metals is a
rapidly growing area of extensive research. However, most of
these reactions are known to occur preferentially at the
a position of thiophene rings when both a and b positions are
available, and a general method for selective functionaliza-
tion of the b position has not been forthcoming.[4] Herein we
Entry
1
Major product
Yield [%]
(regioselectivity)
report the first general catalytic system for the b-selective
[3]
À
arylation of thiophene C H bonds. This new methodology
for direct functionalization will significantly streamline the
synthesis of b-aryl thiophenes: in the current multistep
approach, a sequence of a,b dibromination, a debromination,
and organometallic cross-coupling is typically required
(Scheme 1).
1
2
81 (96:4)[a]
69 (>99:1)
66 (>99:1)
48 (97:3)[a,b]
76 (84:16)[a,b]
56 (>99:1)
46 (95:5)[b,c]
56 (>99:1)[b]
40 (83:17)[c]
60 (95:5)[c]
À
As an application of catalytic C H-bond arylation tech-
3
nology[5] to the synthesis of useful classes of compounds, we
recently established a general protocol for the programmed
synthesis of tetraarylthiophenes.[5d] During that study, the
4
5
6
7
8
9
Scheme 1. Comparison of synthetic approaches to b-aryl thiophenes:
the method presented herein for direct functionalization, and the
multistep route typically used for the b arylation of thiophenes.
10
11
53 (95:5)[b,c]
[*] K. Ueda, S. Yanagisawa, Dr. J. Yamaguchi, Prof. Dr. K. Itami
Department of Chemistry, Graduate School of Science
Nagoya University, Chikusa, Nagoya 464-8602 (Japan)
Fax: (+81)52-788-6098
12
13
14
61 (88:12)[b,c,d]
86 (88:12)[b,c,e]
30 (88:12)[c,f]
E-mail: itami@chem.nagoya-u.ac.jp
Homepage: http://synth.chem.nagoya-u.ac.jp
[a] The minor isomer is the C5-phenylation product. [b] The reaction was
carried out with 10 mol% PdCl2 and 20 mol% P{OCH(CF3)2}3. [c] The
minor isomer is the C2-phenylation product. [d] The reaction was carried
out with 10 equivalents of 1l. [e] The reaction was carried out with
25 equivalents of 1l. [f] The reaction was carried out with 1 mol% PdCl2,
2 mol% P{OCH(CF3)2}3, and 6 equivalents of 1l. The reaction time was
20 h.
[**] We thank Dr. Yasutomo Segawa and Hiromi Sekizawa for exper-
imental assistance and fruitful discussions. This research was
supported by a Grant-in-Aid for Scientific Research from MEXT and
the JSPS. K.U. and S.Y. thank the JSPS for predoctoral fellowships.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201005082.
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was an intriguing phenomenon, since the transition-metal-
À
catalyzed arylation of thiophene C H bonds generally
proceeds at a positions (C2 and/or C5) according to the
typical reactivity profile of the thiophene ring.[3–5]
Following this discovery, we considered the critical ques-
tion as to whether the observed b selectivity was due to
substrate control (directing effect of the methoxy group)[6] or
catalyst control. To answer this question and determine the
generality of the protocol, we subjected a range of thiophene
derivatives to arylation in the presence of the PdCl2/P{OCH-
(CF3)2}3/Ag2CO3 catalytic system (Table 1).
Reactions of 2,3-disubstituted thiophenes, 1b–1d, did
indeed afford C4-arylated products with very high regiose-
lectivity (Table 1, entries 2–4). The fact that b selectivity was
observed without the methoxy group on the thiophene ring
clearly indicates that the observed regioselectivities are a
result of catalyst control. Arylation of the 2-substituted
thiophenes 1e and 1 f proceeded at the 4-position (Table 1,
entries 5 and 6). In fact, the 4-position is generally the least
reactive site in thiophenes when the 2-position is occupied by
ortho/para-directing groups, such as Ph or Cl (Scheme 2). The
Scheme 3. Generality of the reaction with respect to the iodoarene
coupling partner. Product yield given in parentheses.
the cross-coupling of Cl- and Br-containing iodoarenes with 2-
À
À
cholorothiophene (1 f) left the C Cl and C Br bonds intact
(in products 4g and 4i), which is attractive for further
synthetic elaboration. In all cases examined, the reaction took
place exclusively at the 4-position.
Scheme 2. Unique regioselectivity of Pd/P{OCH(CF3)2}3 catalysis.
This investigation of substrate scope clearly showed that
the b selectivity observed with PdCl2/P{OCH(CF3)2}3/Ag2CO3
is a remarkably general phenomenon, and that the b selec-
tivity is catalyst-based. Thus, we next examined the effect of
the reaction parameters, including the Pd source, the ligand,
additives, the solvent, and the temperature, in the phenylation
of thiophene (Table 2; see also Tables S1–S5 in the Supporting
Information).
PdCl2, PdBr2, PdI2, and 2NaCl·PdCl2 performed equally
well as the Pd source. The complex [Pd2(dba)3] (dba = diben-
zylideneacetone) also promoted the b-selective arylation,
albeit in lower yield. On the other hand, Pd(OAc)2, Pd-
(OCOCF3)2, and [Pd(CH3CN)4](BF4)2 preferentially cata-
lyzed the formation of 2-phenylthiophene. The effect of the
supporting ligand was most striking. The extremely electron-
withdrawing ligand P{OCH(CF3)2}3 was found to be the best
ligand for the b-selective arylation of thiophenes (Table 2,
entry 1). Albeit less efficiently, PhP{OCH(CF3)2}2 also pro-
moted the reaction with good b selectivity (Table 2, entry 2).
These results clearly implicate the importance of the
1,1,1,3,3,3-hexafluoro-2-propoxy group on phosphorus for
the b-selective arylation of thiophenes. Among various silver-
based additives examined, Ag2CO3 and AgO promoted the b-
selective arylation with reasonable efficiency. Quite interest-
ingly, the b-selective arylation occurred in a wide variety of
solvents (m-xylene, toluene, hexafluorobenzene, chloroben-
arylation of 3-substituted thiophenes, 1g–1i, one of the most
problematic substrate classes,[7] also occurred selectively at
the 4-position (Table 1, entries 7–9). Interestingly, the
observed selectivities override the inherent influence of
ortho/para- (OPh, Cl) and meta-directing groups (Ac), as
well as that of the thiophene ring itself (Scheme 2). Thio-
phene-containing fused aromatic compounds, such as ben-
zo[b]thiophene (1j) and thieno[3,2-b]thiophene (1k), as well
as thiophene itself (1l), were also arylated with high
b selectivity (Table 1, entries 10–14). Although we typically
used relatively high catalyst loadings (5–10 mol% of Pd), the
arylation also took place with 1 mol% of Pd (Table 1,
entry 14). In this particular reaction, the turnover number
reached 30.
We next examined the scope of the reaction with respect
to the iodoarene coupling partner. Representative results are
summarized in Scheme 3. Various iodoarenes reacted with 2-
chlorothiophene (1 f) to give the corresponding arylated
thiophenes 4 in good yields. Both electron-rich (in products
4a–4c, 4h, and 4j) and electron-deficient aryl groups (in
products 4d–4g and 4i) could be installed on the thiophene
ring. Aryl iodides with electron-withdrawing groups showed
higher reactivity. Severe steric hindrance imposed by ortho
substitution (in 4a and 4k) was tolerated, as were functional
groups such as ester and nitro groups (in 4e and 4 f). Notably,
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Communications
Table 2: Effect of the ligand.
to the preferred substrate (acidic versus nucleophilic) and the
regioselectivity (a versus b) indicate that the present catalytic
system may react by a mechanism distinct from that proposed
by Fagnou and co-workers.
A potential mechanism that takes into account the
importance of the p-accepting P{OCH(CF3)2}3 ligand, the
preferential reaction of nucleophilic thiophenes, and the
unprecedented b selectivity is shown in Scheme 5. The
Entry
Ligand
b/a
86:14
Yield [%]
1
2
3
4
5
6
7
8
P{OCH(CF3)2}3
PhP{OCH(CF3)2}2
P{OCH(CH3)2}3
P(OCH2CF3)3
P(OCH3)3
P(OPh)3
P(OC6H4(o-CH3))3
PPh3
86
61
18
18
15
14
37
75
63:37
30:70
34:66
18:82
38:62
45:55
4:96
9
P(C6H4(p-CF3))3
P(C6F5)3
PCy3
Ph2P(CH2)2PPh2
none
31:69
31:69
<1:99
<1:99
–
58
66
>99
73
10
11
12
13
2
zene, 1,2,4-trichlorobenzene, cyclooctane, cyclopentyl methyl
ether, and 1,4-dioxane) in the presence of PdCl2/P{OCH-
(CF3)2}3/Ag2CO3.
To better understand the characteristics of the present
reaction, we compared it with the Pd0/PdII catalytic system
described by Fagnou and co-workers[7] (one of the most
reliable systems to date) through intermolecular competition
experiments (Scheme 4). Fagnou and co-workers demon-
strated that their Pd/PCy3/tBuCO2H/K2CO3 catalytic system
not only favors arylation at the a position but also reacts
preferentially with acidic 2-chlorothiophene (1 f) over nucle-
ophilic 2-methylthiophene (1m).[7b] These observations are in
line with their proposal of a Pd0/PdII redox cycle involving not
an electrophilic aromatic substitution mechanism but a
concerted metalation–deprotonation pathway.[7] When the
competition reaction was conducted with the present catalytic
system, arylation occurred preferentially with nucleophilic 2-
methylthiophene (1m). These contrasting results with respect
Scheme 5. Possible mechanism.
proposed mechanism involves 1) oxidative addition of ArI
to the Pd complex A, 2) silver-mediated generation of the
cationic and electrophilic aryl palladium species B, 3) coor-
dination of the thiophene to Pd to give C[8] and/or D,[9] 4) Ca
À
Pd bond formation to give E, 5) migration of the aryl group
from Pd to the b carbon atom to form a formal Ar Pd-
À
insertion intermediate F,[10] and 6) proton abstraction to
produce a b-aryl thiophene with the regeneration of A. The
observed electronic preferences of the present system, such as
1) the requirement for the extremely electron-withdrawing
P{OCH(CF3)2}3 ligand, 2) the preferential reactivity with
nucleophilic thiophenes, and 3) the positive influence of
electron-withdrawing substituents on the iodoarene coupling
partner, are all likely to promote the otherwise weak
thiophene–palladium interaction, for example, in C or D.[11]
In summary, we have established a general catalytic
system that promotes the b-selective arylation of thiophene
derivatives with iodoarenes. This previously inaccessible
selective b functionalization of thiophenes should have sig-
nificant synthetic utility in materials science as well as
pharmaceuticals and natural products synthesis.
Received: August 13, 2010
Published online: October 8, 2010
À
Keywords: C C coupling · homogeneous catalysis · palladium ·
regioselectivity · thiophenes
.
Scheme 4. Comparison with the Pd0/PdII catalytic system developed by
Fagnou and co-workers. Cy=cyclohexyl, DMAc=N,N-dimethylacet-
amide.
[1] S. Gronowits, A.-B. Hꢀrnfeldt, Thiophenes, Elsevier, Oxford,
2004.
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[2] For recent reviews, see: a) X. Chen, K. M. Engle, D.-H. Wang, J.-
Q. Yu, Angew. Chem. 2009, 121, 5196; Angew. Chem. Int. Ed.
2009, 48, 5094; b) C.-J. Li, Acc. Chem. Res. 2009, 42, 335; c) F.
Kakiuchi, T. Kochi, Synthesis 2008, 3013.
K. Hirano, T. Satoh, M. Miura, Angew. Chem. 2010, 122, 2248;
Angew. Chem. Int. Ed. 2010, 49, 2202.
[4] For an excellent up-to-date treatment of thiophene b arylation,
see: J. Roger, A. L. Gottumukkala, H. Doucet, ChemCatChem
2010, 2, 20.
[5] a) S. Yanagisawa, T. Sudo, R. Noyori, K. Itami, J. Am. Chem.
Soc. 2006, 128, 11748; b) J. Canivet, J. Yamaguchi, I. Ban, K.
Itami, Org. Lett. 2009, 11, 1733; c) B. Join, T. Yamamoto, K.
Itami, Angew. Chem. 2009, 121, 3698; Angew. Chem. Int. Ed.
2009, 48, 3644; d) S. Yanagisawa, K. Ueda, H. Sekizawa, K.
Itami, J. Am. Chem. Soc. 2009, 131, 14622.
[6] For examples of the b arylation of thiophenes with metal-
coordinating groups, see: a) T. Okazawa, T. Satoh, M. Miura, M.
Nomura, J. Am. Chem. Soc. 2002, 124, 5286; b) T. Vogler, A.
Studer, Org. Lett. 2008, 10, 129; c) M. Nakano, H. Tsurugi, T.
Satoh, M. Miura, Org. Lett. 2008, 10, 1851.
[7] a) B. Liꢁgault, D. Lapointe, L. Caron, A. Vlassova, K. Fagnou, J.
Org. Chem. 2009, 74, 1826; b) B. Liꢁgault, I. Petrov, S. I.
Gorelsky, K. Fagnou, J. Org. Chem. 2010, 75, 1047; c) S. I.
Gorelsky, D. Lapointe, K. Fagnou, J. Am. Chem. Soc. 2008, 130,
10848.
À
[3] For an excellent recent review on the catalytic arylation of C H
bonds of aromatic and heteroaromatic compounds, see: a) L.
Ackermann, R. Vincente, A. R. Kapdi, Angew. Chem. 2009, 121,
9976; Angew. Chem. Int. Ed. 2009, 48, 9792; for selected recent
breakthroughs, see: b) D. R. Stuart, K. Fagnou, Science 2007,
316, 1172; c) R. J. Phipps, M. J. Gaunt, Science 2009, 323, 1593;
d) J. C. Lewis, R. G. Bergman, J. A. Ellman, Acc. Chem. Res.
2008, 41, 1013; e) J. Norinder, A. Matsumoto, N. Yoshikai, E.
Nakamura, J. Am. Chem. Soc. 2008, 130, 5858; f) H.-Q. Do,
R. K. M. Khan, O. Daugulis, J. Am. Chem. Soc. 2008, 130, 15185;
g) L. Ackermann, A. Althammer, S. Fenner, Angew. Chem.
2009, 121, 207; Angew. Chem. Int. Ed. 2009, 48, 201; h) L.-C.
Campeau, D. R. Stuart, J. P. Leclerc, M. Bertrand-Laperle, E.
Villemure, H.-Y. Sun, S. Lasserre, N. Guimond, M. Lecavallier,
K. Fagnou, J. Am. Chem. Soc. 2009, 131, 3291; i) C. Wang, I. Piel,
F. Glorius, J. Am. Chem. Soc. 2009, 131, 4194; j) K. L. Hull, M. S.
Sanford, J. Am. Chem. Soc. 2009, 131, 9651; k) C. Huang, V.
Gevorgyan, J. Am. Chem. Soc. 2009, 131, 10844; l) M. Tobisu, I.
Hyodo, N. Chatani, J. Am. Chem. Soc. 2009, 131, 12070; m) M.
Kim, J. Kwak, S. Chang, Angew. Chem. 2009, 121, 9097; Angew.
Chem. Int. Ed. 2009, 48, 8935; n) C.-L. Sun, B.-J. Li, Z.-J. Shi,
Chem. Commun. 2010, 46, 677; o) B. Xiao, Y. Fu, J. Xu, T.-J.
Gong, J.-J. Dai, J. Yi, L. Liu, J. Am. Chem. Soc. 2010, 132, 468;
p) T. Nishikata, A. R. Abela, B. H. Lipshutz, Angew. Chem.
2010, 122, 793; Angew. Chem. Int. Ed. 2010, 49, 781; q) M. Wasa,
B. T. Worrell, J.-Q. Yu, Angew. Chem. 2010, 122, 1297; Angew.
Chem. Int. Ed. 2010, 49, 1275; r) F. Vallꢁe, J. J. Mousseau, A. B.
Charette, J. Am. Chem. Soc. 2010, 132, 1514; s) W. Liu, H. Cao,
A. Lei, Angew. Chem. 2010, 122, 2048; Angew. Chem. Int. Ed.
2010, 49, 2004; t) P. Xi, F. Yang, S. Qin, D. Zhao, J. Lan, G. Gao,
C. Hu, J. You, J. Am. Chem. Soc. 2010, 132, 1822; u) H. Hachiya,
[8] For examples of thiophene–palladium complexes with S coordi-
nation, see: a) O. Clot, M. O. Wolf, B. O. Patrick, J. Am. Chem.
Soc. 2001, 123, 9963; b) X. Fang, J. G. Watkin, B. L. Scott, G. J.
Kubas, Organometallics 2001, 20, 3351.
[9] For examples of thiophene–platinum complexes with h2-C,C
coordination, see: T. A. Atesin, W. D. Jones, Organometallics
2008, 27, 53.
[10] Although unlikely,
a concerted insertion mechanism (syn
carbopalladation) cannot be excluded for the formation of F
from B.
[11] The differing strengths of thiophene–palladium and pyrrole–
palladium interactions might explain the a selectivity and low
reactivity observed when pyrroles were used as substrates.
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