A simple phenylation of heteroaromatic compounds using diphenyliodonium triflate

Article abstract of DOI:10.1007/s11164-011-0453-1

In this study a novelmethod for direct synthesis of 2-phenyl heteroaromatic arenes was successfully developed. The title compounds were synthesized by reaction of heteroaromatic compoundswith diphenylene iodonium trifluoromethanesulfonate in the presence of 5 mol% Pd(OAc)₂ under mild reaction conditions (THF, 60 °C, 24 h). The proposed reaction mechanism was studied by HPLC. Springer Science+Business Media B.V. 2011.

Full text of DOI:10.1007/s11164-011-0453-1

Res Chem Intermed (2012) 38:1335–1340
DOI 10.1007/s11164-011-0453-1
A simple phenylation of heteroaromatic compounds
using diphenyliodonium triflate
Qi Yang
•
Jiao Chang
•
Qun Wu Bianxiang Zhang
•
Received: 3 November 2011 / Accepted: 5 December 2011 / Published online: 29 December 2011
Ó Springer Science+Business Media B.V. 2011
Abstract In this study a novel method for direct synthesis of 2-phenyl heteroaromatic
arenes was successfully developed. The title compounds were synthesized by reaction
of heteroaromatic compounds with diphenylene iodonium trifluoromethanesulfonate in
the presence of 5 mol% Pd(OAc) under mild reaction conditions (THF, 60 °C, 24 h).
2
The proposed reaction mechanism was studied by HPLC.
Keywords Heteroaromatic compounds Á Diphenyliodonium triflate Á Phenylation
Introduction
Heteroaromatic compounds are among the most important heterocyclic compounds
[
1, 2]. 2-Arylheteroaromatic compounds are important intermediates used not only
as building blocks in the synthesis of natural products but also as key structural units
of compounds with interesting biological activity [3–7]. Many traditional
approaches to synthesis of these compounds have involved cross-coupling between
2
-functionalized heterocyclic compounds and functionalized arene derivatives.
Palladium-catalyzed arylation of heteroaromatic compounds is one of the most
powerful methods for preparation of aryl-substituted heteroarenes. Several palla-
dium and/or nickel-catalyzed cross-coupling reactions have been reported as
efficient methods for reaction of aryl halides with an electron-rich heterocycles, for
example thiophenes, furans, thiazoles, and oxazoles [8–15]. These reactions
Electronic supplementary material The online version of this article
(doi:10.1007/s11164-011-0453-1) contains supplementary material, which is available to authorized
users.
Q. Yang Á J. Chang Á Q. Wu Á B. Zhang (&)
School of Chemistry and Chemical Engineering, Shanxi University,
92 Wucheng Road, Taiyuan 030006, People’s Republic of China
e-mail: zbxthh@sxu.edu.cn
123

1336
Q. Yang et al.
generally require multi-step sequences for preparation of the functionalized
heterocyclic compounds, harsh conditions, for example high temperature, long
reaction time, anhydrous and strongly-basic environment, and Cu/Ag salts as co-
oxidants, often in stoichiometric amounts. Moreover, for such coupling, preparation
of an organometallic derivative is required [16–22]. Therefore, it is necessary to
seek new optimum reaction conditions for efficient arylation of heterocyclic
aromatic rings. Diaryliodonium salts have recently emerged as viable coupling
partners because of their low toxicity, easy handling, and high reactivity [23–26]. In
this paper we report a simple, direct, and efficient method for synthesis of
2-phenylheteroaromatic compounds by use of diphenyliodonium triflate in the
presence of Pd(OAc) as catalyst under unprecedentedly mild conditions.
2
Experimental results and discussion
Our initial study focused on the reaction of benzofuran 1a with diphenyliodonium
triflate using a variety of oxidants; the results were summarized in Table 1. In the
absence of catalysis no reaction was observed. The expected product 2a was
selectively obtained in a 40–60% isolated yield in the presence of 5 mol%
Pd(OAc) as catalyst and THF as solvent at 60 °C, using BQ (benzoquinone),
2
Ph(OAc) , and Cu(OAc) as oxidants. In contrast, the expected product 2-phen-
ylbenzofuran 2a was obtained selectively, in 85% yield, by use of Ph IOTf (0.2
2
2
2
equiv) as the oxidant under otherwise similar conditions.
These results indicated that diphenyliodonium triflate can be regarded not only as
a viable coupling partner but also as an oxidant in the reaction system. In addition,
this transformation was not sensitive to air and moisture. Importantly, these
Table 1 Screening different oxidants for oxidative cross-coupling
O
O
Pd(OAc)2
THF
+
-
+
Ph I OTf
2
Ph
+
PhI
2a
1a
TfOH;
a
Entry
Oxidant (equiv)
Yield (%)
1
2
3
4
5
6
BQ(0.2)
53
40
63
85
69
86
PhI(OAc)
2
(0.2)
Cu(OAc) (0.2)
2
?
I OTf (0.2)
?
I OTf (0.05)
?
I OTf (0.3)
-
Ph
Ph
Ph
2
2
2
-
-
Reaction conditions: benzofuran (1 mmol), Ph
2
IOTf (1.2 mmol), Pd(OAc)
2
(5 mmol%), THF (3 mL),
6
a
0 °C, 24 h
Yield of pure, isolated product
1
23

A simple phenylation of heteroaromatic compound
1337
oxidative arylations typically proceeded with very high selectivity for formation of
2
-phenylated products.
To determine the most suitable conditions for this reaction, we studied the effects
of different catalytic systems and reaction temperatures on the yield (Table 2). By
use of 0.5 mol% Pd(OAc) at 60 °C, the desired product 2a was obtained in low
2
yield after a longer reaction time. When 1 mol% Pd(OAc) was used the yield of
2
product 2a was 32% (entry 2). However, the fact that use of longer reaction time
and/or elevated temperature did not afford increased yields suggested that catalyst
deactivation might occur in this system (entries 4 and 6). On the other hand, use of
other catalysts, for example Cu(OAc) , or PdCl under similar conditions resulted in
2
2
very low yields of 2a. The best results were obtained with 5 mol% Pd(OAc) in
2
THF at 60 °C for 24 h, when product 2a in 85% isolated yield.
Using the most suitable reaction conditions, we next examined the scope and
limitation of the reaction using a variety of heteroaromatic substrates with
diphenyliodonium triflate as the phenylating and oxidizing reagent (Table 3).
Benzothiophene and benzothiazole gave the coupling products 2b and 2h in 62 and
6
5% yield, respectively. The reaction of indole provided 2c in 68% isolated yield at
room temperature, without competing N-arylation or other side reactions (entry 2).
Similarly reaction of N-methylindole furnished 2d in 75% isolated yield at room
temperature. Finally, arylation of benzimidazole afforded the phenylated product in
6
5% yield (entry 4). Importantly, these oxidative arylations typically proceeded
with very high ([20:1) selectivity for formation of 2-phenylated products.
Furthermore, the arylated products 2f and 2g of benzoxazole and N-phenylbenz-
imidazole were not isolated after 96 h at 60 °C (entries 5 and 7).
A plausible mechanism for this reaction is depicted in Scheme 1 [20, 23, 27]. The
initial step is probably reaction of the hypervalent iodine(III) reagent Ph IOTf with
2
2
Pd(II), in which a phenyl group is transferred with cleavage of a C(sp )–I bond and
formation of Pd intermediate (A). Subsequent ligand-directed C–H activation then
affords the Pd (IV) species (B). Finally, C–C bond forming reductive elimination
gives the arylated product 2.
We also studied the amount of 2-phenylated product 2a and PhI in the reaction
system. The amount of 2a increased with decreasing amount of PhI. The molar ratio of
Table 2 Optimization of the
reaction conditions for the
arylation
a
Entry Catalyst (equiv)
Temp. (°C) Time (h) Yield (%)
1
2
3
4
5
6
7
8
9
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
2
2
2
2
2
2
(0.005) 60
36
24
18
32
85
15
77
65
–
(0.01)
(0.05)
(0.05)
(0.1)
60
60
rt
24
110
24
60
90
60
60
60
(0.05)
24
PdCl
2
2
(0.05)
(0.05)
18
PdCl
48
9
Cu(OAc)
2
(0.05)
24
–
a
Yield of pure, isolated product
123

1338
Q. Yang et al.
Table 3 Scope and limitation
s
Y
Y
X
Pd(OAc)2
THF
+
-
+
Ph I OTf
2
X
1
a-h
2a-h
a
Entry
1
1
Product
Yield (%)
62
S
S
Ph
Ph
2
3
1b
1c
2b
2c
68
H
N
H
N
75
CH3
N
CH3
N
Ph
4
5
1d
1e
2d
2e
65
H
N
H
N
Ph
N
N
0
Ph
N
Ph
N
Ph
Ph
Ph
N
S
N
N
1
1
f
6
7
2f
65
S
N
h
2
h
0
O
N
O
N
1g
2g
Conditions: 1(1 mmol), Ph
a
2
IOTf (1.2 mmol), Pd(OAc)
2
(5 mmol%), THF (3 mL), 60 °C, 24 h
Yield of pure, isolated product
2a and PhI under these conditions (THF at 60 °C for 24 h) was determined by high-
performance liquidchromatographyto be 1:1(Fig. 1). Moreover, an equimolaramount
of PhI is readily available in a state of purity sufficient for synthesis of Ph IOTf .
2
1
23

A simple phenylation of heteroaromatic compound
1339
Y
H
Ph
2
I+OTf-
OAc
X
Y
X
Y
X
-
Pd
Ph
Pd(OAc)
2
Ph Pd OTf
OAc
Pd
Ph
PhI
TfOH
A
B
2
Scheme 1 Proposed mechanism of the coupling reaction
O
Ph
PhI
Fig. 1 Relative amounts of 2a and PhI determined by use of HPLC
Conclusions
We have demonstrated that diphenyliodonium triflate is a useful coupling partner in
C–H bond activation. In the presence of Pd(OAc) , reaction of heteroaromatic
2
derivatives with phenyliodonium triflate leads to the coupling products in low to
relatively high yields. These reactions proceed under remarkably mild conditions,
are compatible with ambient air and/or moisture, and no metal-containing co-
catalyst is required. The reaction is, therefore, very interesting from the perspectives
of atom-economy and nontoxic waste. The synthetic utility of these reactions is
further enhanced by their high selectivity for arylation at C-2. In ongoing work we
will seek further insight into the mechanism of these reactions and to expand their
scope to the arylation of unactivated arenes and alkanes.
Acknowledgment This work was financially supported by the Shanxi Scholarship Council of China
(no. 2011-001).
References
1
2
3
4
. B.H. Lipshutz, Chem. Rev. 86, 795 (1986)
. P.A. Jacobi, K.M. Touchette, H.G.J. Selnick, Org Chem 57, 6305 (1992)
. S. Cacchi, G. Fabrizi, Chem. Rev. 105, 2873 (2005)
. B.S. Lane, M.A. Brown, D. Sames, J. Am. Chem. Soc. 127, 8050 (2005)
123

1340
Q. Yang et al.
5
6
7
8
9
. B.S. Lane, D. Sames, Org. Lett. 6, 2897 (2004)
. B. Sezen, D. Sames, J. Am. Chem. Soc. 125, 5274 (2003)
. C. Bressy, D. Alberico, M. Lautens, J. Am. Chem. Soc. 127, 13148 (2005)
. S. Yanagisawa, K. Itami, Tetrahedron 67, 4425 (2011)
. S. Yasuike, W.W. Qin, Y. Sugawara, J. Kurita, Tetrahedron Lett. 48, 721 (2007)
1
1
1
0. T. Truong, O. Daugulis, J. Am. Chem. Soc. 133, 4243 (2011)
1. D.L. Wen, M.J. Wu, Tetrahedron Lett. 63, 356 (2007)
2. K. Xie, Z.Y. Yang, X.J. Zhou, X.J. Li, S.Z. Wang, Z. Tan, X.Y. An, C.C. Guo, Org. Lett. 12, 1564
2010)
(
1
1
1
1
1
3. H. Hitoshi, H. Koji, S. Tetsuya, M. Masahiro, Org. Lett. 11, 1737 (2009)
4. S. Tamba, Y. Okubo, S. Tanaka, D. Monguchi, A. Mori, J. Org. Chem. 75, 6998 (2010)
5. H.A. Chiong, O. Daugulis, Org. Lett. 9, 1449 (2007)
6. N.T. Vo, R.D.M. Pace, F. O’Hara, J. Am. Chem. Soc. 130, 404 (2008)
7. J.A. Jordan-Hore, C.C.C. Johansson, M. Gulias, E.M. Beck, M.J. Gaunt, J. Am. Chem. Soc. 130,
16184 (2008)
18. N.R. Deprez, M.S. Sanford, J. Am. Chem. Soc. 131, 11234 (2009)
19. D. Kalyani, N.R. Deprez, L.V. Desai, M.S. Sanford, J. Am. Chem. Soc. 127, 7330 (2005)
20. A.J. Canty, J. Patel, T. Rodemann, J.H. Ryan, B.W. Skelton, A.H. White, Organometallics 23, 3466
(2004)
2
2
2
2
2
2
2
1. M. Hussain, I. Malik, A. Villinger, P. Langer, Synlett 16, 2691 (2009)
2. E. Nakamura, N. Yoshikai, J. Org. Chem. 75, 6061 (2010)
3. U. Radhakrishnan, P.J. Stang, Org. Lett. 3, 859 (2001)
4. T. Kitamura, M. Yamane, B.X. Zhang, Y. Fujiwara, Bull. Chem. Soc. Jpn. 71, 1215 (1998)
5. T. Kitamura, B.X. Zhang, Y. Fujiwara, Org. Lett. 1, 257 (1999)
6. B.X. Zhang, Y. Fujiwara, T. Kitamura, Heterocycles 64, 199 (2004)
7. N.R. Deprez, D. Kalyani, A. Krause, M.S. Sanford, J. Am. Chem. Soc. 128, 4972 (2006)
1
23