A versatile catalyst for intermolecular direct arylation of Indoles with benzoic acids as arylating reagents

Article abstract of DOI:10.1002/chem.201000529

(Figure Presented) Coupled together: With a versatile catalyst system (Pd(TFA)₂/Ag₂CO₃/propionic acid) both electron-rich and -deficient benzoic acids serve as arylating reagents for the direct functionalization of a wide rage of indoles by a combination of decarboxylation and C-H bond activation. Depending on the nature of the benzoic acids, the reaction occurs selectively at either the C2- or C3-position of indoles, which may arise from two different catalytic pathways (see scheme; TFA = trifluoroacetate).

Full text of DOI:10.1002/chem.201000529

DOI: 10.1002/chem.201000529
A Versatile Catalyst for Intermolecular Direct Arylation of Indoles with
Benzoic Acids as Arylating Reagents
Jun Zhou, Peng Hu, Min Zhang, Shijun Huang, Min Wang, and Weiping Su*[a]
The development of new methods for the synthesis of val-
uable compounds from simple and readily available starting
materials through concise steps is of intense interest to the
chemical community. In this context, metal-catalyzed direct
pling sequences would allow the use of benzoic acids as
starting materials for the synthesis of complex molecules.[10]
The high availability of benzoic acids renders these transfor-
mations very attractive.
À
functionalizations of C H bonds are currently a very active
Despite remarkable advances in both direct functionaliza-
À
area because these transformations have great potential to
offer highly efficient synthetic routes and minimize wasteful
byproducts by precluding the need for preactivation of the
substrates.[1] Because of the prevalence of C2- and C3-aryl-
tion of C H bonds and decarboxylative cross-coupling reac-
tions, reactions that combine these two chemistries, that is,
the decarboxylative cross-coupling of carboxylic acids with
À
C H bonds, are still scarce. The realization of this class of
indole structural units in biologically active molecules and
reaction would take advantage of both the high efficiency of
pharmaceuticals,[2] considerable efforts have been devoted
to the development of the metal-catalyzed direct arylation
of indoles with various arylating reagents, leading to signifi-
cant advances in this area.[3]
C H functionalization processes and the wide diversity of
À
carboxylic acids, providing an attractive alternative to tradi-
tional metal-catalyzed cross-coupling reactions. Crabtree
À
et al. reported, for the first time, four examples of C H ary-
Recently, pioneering studies by the groups of Goossen,[4]
Myers[5] and others[6] demonstrated that benzoic acids can
be used as arylating reagents for the decarboxylative cross-
coupling reaction, in which the organometallic intermediates
generated from metal-mediated decarboxylation served as
either nucleophiles or electrophiles depending on the nature
of the metal ions used. The groups of Tunge[7a–d] and
Schaus[7e] independently developed the palladium-catalyzed
intramolecular decarboxylation of allylic esters for the for-
lation reactions with 2,6-dimethoxybenzoic acid as an arylat-
ing reagent, which occurred under harsh conditions (2008C)
in low to moderate yields.[11] Later, Glorious et al. realized
the intramolecular direct arylation of benzoic acids by
À
tandem decarboxylation/C H activation for the synthesis of
dibenzofuran derivatives.[12] During the preparation of this
manuscript, Larrosa et al. reported
a Pd/Ag-catalyzed
method for the intermolecular decarboxylative direct C3 ar-
ylation of indoles with electron-deficient benzoic acids.[13]
This achievement by Larrosa and co-workers represented a
À
mation of C C bonds, constituting an appealing approach to
complex molecules. The groups of Yu[8] and Daugulis,[9] in
their elegant studies, disclosed that benzoic acids can under-
big stride in the development of reaction involving C H ac-
À
tivation/decarboxylation sequences, nevertheless, there is
still significant room for improvement with regard to the
limited scope of benzoic acids. From the standpoints of both
practical applications and fundamental research, the devel-
À
go carboxylate-directed C H functionalizations. Seminal
work by Miura et al. on coupling reaction of benzoic acids
with alkynes for construction of fused-rings implied that
À
À
ortho-C H functionalization and decarboxylative cross-cou-
opment of versatile catalysts for C H arylation reactions
with a broad range of benzoic acids as arylating reagents is
highly desirable. To this end, we describe herein 1) the es-
tablishment of a versatile catalyst system that enables the
use of both electron-rich and -deficient ortho-substituted
benzoic acids as arylating reagents for the direct arylation of
a variety of indoles, 2) demonstrate the high regioselectivity
achieved in this reaction: 2-arylindoles were formed selec-
tively from electron-rich benzoic acids and 3-arylindoles
were generated exclusively from electron-deficient benzoic
acids,[14] and 3) present the results of preliminary mechanism
[a] J. Zhou, P. Hu, M. Zhang, S. Huang, M. Wang, Prof. W. Su
State Key Laboratory of Structural Chemistry
Fujian Institute of Research on the Structure of Matter
Chinese Academy of Sciences, Fuzhou, Fujian 350002 (China)
Fax : (+86)591-83771575
E-mail: wpsu@fjirsm.ac.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201000529.
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Chem. Eur. J. 2010, 16, 5876 – 5881

COMMUNICATION
studies, which suggest that electron-rich and -deficient ben-
zoic acids might take two different reaction pathways due to
their difference in reactivity towards decarboxylation.
Initially, we examined the reaction of N-acetylindole 1
with 2,4-dimethoxybenzoic acid (2a; 2 equiv) in DMF at
palladation on indole. As expected, the addition of propion-
ic acid (0.25 equiv) gave rise to an improvement in yield
(Table 1, entry 8). However, as the amount of propionic acid
increased, the yield of the desired product decreased be-
cause too much propionic acid slowed decarboxylation. In-
terestingly, an increase in the amount of 2,4-dimethoxyben-
zoic acid not only promoted the conversion of indole but
also improved the yield (Table 1, entry 10). Gratifyingly, fur-
ther optimization disclosed that the treatment of N-acetylin-
dole with 2,4-dimethoxybenzoic acid (5 equiv) in dioxane
(1.5 mL) at 808C in the pres-
808C in the presence of PdACTHNUTRGNE(UNG TFA)2 (5 mol%, TFA=trifluor-
oacetate) as a catalyst, Ag2CO3 (2 equiv) as an oxidant and
DMSO (3.5 equiv) as a ligand (1:70 ratio of Pd to DMSO),
and observed that this reaction offered the desired C2-aryla-
tion product in 9% yield (Table 1, entry 1). Under otherwise
ence of Pd
Ag2CO3
ACHTUNGTRENNUNG
Table 1. Optimization studies for Pd/Ag-catalyzed arylation of indoles(1) with 2,4-dimethoxybenzoicACTHNUTRGNEUNG
(2a).[a]
(1.5 equiv), and propionic acid
(0.25 equiv) resulted in almost
total conversion of indole, af-
fording the desired product in
78% yield with 16.4:1 C2/C3
ratio (Table 1, entry 13). The
effect of an N-protecting group
on the reactivity of indole has
also been investigated under
the optimal conditions. N-Piva-
loylindole generated the corre-
Entry Pd
G
2a
[equiv]
R[b] Solvent
Ligand
([equiv])
EtCOOH
[equiv]
Yield
[%][c]
Ratio (3/
4)[d]
[mol%]
1
5
2
2
2
2
2
2
2
2
2
4
5
5
5
5
5
5
5
5
Ac DMF
DMSO (3.5)
DMSO (3.5)
DMSO (3.5)
DMSO (3.5)
DMSO (7.0)
DMSO (1.0)
TMSO (1.0)
TMSO (1.0)
TMSO (1.0)
TMSO (1.0)
TMSO (1.0)
TMSO (1.5)
9
39
15
4
>99:1
8.0:1
>99:1
>99:1
10:1
2
5
Ac dioxane
Ac toluene
Ac NMP
3
5
4
5
5
5
Ac dioxane
Ac dioxane
Ac dioxane
Ac dioxane
Ac dioxane
Ac dioxane
Ac dioxane
Ac dioxane
26
43
49
57
49
65
33
70
78
0
sponding product in
comparable to that of N-acetyl-
indole with a lower selectivity
(2.1:1 C2/C3 ratio), and N-
tosylindole was less reactive
a yield
6
5
9.7:1
7
5
11.4:1
16.9:1
20.4:1
19.2:1
>99:1
17.4:1
16.4:1
AHCTUNGTRENNUNG
8
5
0.25
1
9
5
10
11
12
13
14
15
16
17
18
5
5
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
ACHTUNGTRENNUNG
than N-acetylindole, providing
a moderate yield, whereas free
N-H indole, N-methylindole,
7.5
7.5
7.5
7.5
7.5
7.5
7.5
Ac dioxane[e] TMSO (1.5)
H
dioxane[e] TMSO (1.5)
CH3 dioxane[e] TMSO (1.5)
Piv dioxane[e] TMSO (1.5)
<5
72
42
trace
and
N-tert-butyloxycarbonyl
2.1:1
>99:1
(Boc) indole gave no product.
With a set of optimized con-
ditions in hand (Table 1,
entry 13), we evaluated the
scope of substituents on the N-
acetylindole. As shown in
Table 2, both electron-with-
Ts
dioxane[e] TMSO (1.5)
Boc dioxane[e] TMSO (1.5)
[a] Reaction conditions: indole (0.20 mmol, 1.0 equiv), Ag2CO3 (2 equiv), solvent (1.0 mL), 24 h, 808C.
[b] Ac=acetyl, Piv=pivaloyl, Ts=tosyl, Boc=tert-butoxycarbonyl. [c] Isolated yields. [d] Determined by GC–
MS. [e] Dioxane (1.5 mL).
identical conditions, screening solvents showed that dioxane
is the solvent of choice (Table 1, entry 2–4). The reaction
conducted in dioxane exhibited a good selectivity at the 2-
position of indole with an 8.0:1 C2/C3 ratio. Increasing the
amount of DMSO to seven equivalents retarded the decar-
boxylation process and led to a decrease in yield (Table 1,
entry 5). In contrast, when the amount of DMSO was re-
duced to one equivalent (1:20 ratio of Pd to DMSO), 2,4-di-
methoxybenzoic acid smoothly underwent decarboxylation
and provided an improved yield (Table 1, entry 6). Tetra-
methylene sulfoxide (TMSO) was observed to be more ef-
fective than DMSO (Table 1, entry 7). Although the use of
one equivalent of DMSO or TMSO led to complete decar-
boxylation of 2a, only moderate yields were obtained due to
incomplete conversion of indole. We speculated that the in-
troduction of additional carboxylic acids, such as propionic
acid, to the reaction system would facilitate the electrophilic
drawing and -donating substituents were compatible, afford-
ing synthetically useful yields in most cases. Importantly,
high selectivity can be obtained for 2-arylindoles. Although
substituents on the indole core can influence the yields of
this reaction, no clear trend was observed for the depend-
ence of the reaction yield on the nature of the substituents.
For example, the electron-withdrawing fluoro-substituent at
the C5-position provided a good yield (Table 2, 3 f), whereas
electron-withdrawing nitro and ester groups at the 5-posi-
tion of the indole core led to lower yields (Table 2, 3j, 3k).
The position of the substituent on the indole core was also
observed to affect both the reaction yield and selectivity, as
illustrated by the reactions of three isomers of methoxy-sub-
stituted N-acetylindole (Table 2, 3c–e). Notably, the reac-
tions were tolerant of halogen substituents (Table 2, 3 f–i),
providing the complementary platform for further transfor-
mations by Pd0-catalyzed cross-coupling reactions.
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W. Su et al.
Table 2. Reaction scope: Substitution on indole.[a]
the Pd-catalyzed cross-coupling
reaction of N-acetylindole with
1,3-dimethoxybenzene,[3a] which
was generated in situ from the
protodecarboxylatioon of 2,6-
dimethoxybenzoic acid. In the
cases of electron-deficient ben-
zoic acids, N-pivaloylindole ex-
hibited higher reactivity than
N-acetylindole. The reactions of
N-pivaloylindole with benzoic
acids (3 equiv) conducted in
DMF at 1208C in the presence
of Pd
ACHTUNGTRENNUNG
Ag2CO3
(1.5 equiv), and propionic acid
(0.25–1.5 equiv) gave the de-
sired products in good yields
(Table 3, 4s–y). These reactions
occurred exclusively at the C3-
position of indole, exhibiting an
inversion in regioselectivity
compared with those of elec-
tron-rich benzoic acids. Since
the reaction of electron-rich
2,4-dimethoxybenzoic acid with
N-acetylindole in DMF pre-
dominately formed the C2-ary-
lation product regardless of the
presence or absence of propion-
ic acid, and the reaction of N-
acetylindole with electron-defi-
cient 2-nitrobenzoic acid oc-
[a] Reaction conditions: indole (0.2 mmol, 1.0 equiv), benzoic acids (5.0 equiv), PdACHTNURTGEN(UNG TFA)2 (7.5 mol%),
Ag2CO3 (2.0 equiv), EtCOOH (0.25 equiv), TMSO(1.5 equiv), dioxane (1.5 mL), 24 h, 808C. The yields of 3
were isolated yields, the ratio of 3/4 was determined by GC–MS.
We next turned our attention to the reactions of various
benzoic acids. Considering that varying the substituent of
the benzoic acids directly gives rise to a change in acidity
and decarboxylation rate, which would further affect the ef-
ficiency of cross-coupling reactions between indoles and
benzoic acids, we reasoned that the reaction conditions
should be adjusted to different benzoic acids to achieve effi-
cient transformations. We were pleased to find that slight
modifications of the optimal reaction conditions enabled the
use of a variety of benzoic acids (Table 3). The optimal con-
ditions obtained with 2,4-dimethoxybenzoic acid worked
well for electron-rich benzoic acids (Table 3, 3m–q). Due to
low reactivity towards decarboxylation at 808C, elevated
temperature and a higher Pd loading were required to ach-
ieve good yields in the reactions involving 2-methoxy-4-
methylbenzoic acid and 3-methylbenzofuran-2-carboxylic
acid (Table 3, 3o, 3p). These reactions of electron-rich ben-
zoic acids were observed to produce exclusively C2-arylation
products. As an exception, the reaction of 2,6-dimethoxy-
benzoic acid, in which 7.5 equiv of propionic acid was re-
quired for reducing the rate of decarboxylative and activat-
ing indole, generated not only the regular product in 31%
yield with 6.8:1 C2/C3 ratio but also 3a in 26% yield
(Table 3, 3q). The product 3a was likely to be formed from
curred exclusively at the C3 position of indole, we can rule
out the possibilities that the nature of the solvent,[14a] the
concentration of the carboxylic acids[14a] and the N-protect-
ing groups[14b] are major factors controlling the regioselectiv-
ity of this reaction. Accordingly, we speculate that the high
selectivity of this reaction may be closely related to the
nature of the benzoic acids.
Although both experimental[5,6l] and theoretical studies[6j]
established that PdACTHNUTRGNE(UNG TFA)2 can efficiently promote the decar-
boxylation of electron-rich benzoic acids in the absence of
other metal salts, studies by Larrosa et al. disclosed that Pd-
AHCTUNGRTEG(NNUN TFA)2 is incapable of catalyzing the decarboxylation of
electron-deficient benzoic acids in DMSO at 1208C.[15a] The
groups of Goossen[15b] and Larrosa[15a,c] independently dem-
onstrated that silver salts are versatile catalysts for protode-
carboxylation of a wide spectrum of benzoic acids. These
previous results prompted us to investigate the roles of Pd
and Ag in this Pd/Ag-catalyzed decarboxylative arylation of
indoles. We observed that in the absence of Ag2CO3, stoi-
chiometric amounts of PdACTHNUTRGNE(NUG TFA)2 enabled the reaction of N-
acetylindole with electron-rich 2,4-dimethoxybenzoic acid in
dioxane at 808C to generate arylindoles in 52% yield (5.9:1
C2/C3 ratio), accompanied by decarboxylative dimerization
(6a, <5% yield) and protodecarboxylation of benzoic acid
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Chem. Eur. J. 2010, 16, 5876 – 5881

Catalyst for Intermolecular Direct Arylation of Indoles
Table 3. Reaction scope with respect to benzoic acids.[a]
COMMUNICATION
(5m) in 13 and 51% yield re-
spectively, accompanied by de-
carboxylative dimerization (6m,
11% yield) (Scheme 2), indicat-
ing that an arylpalladium inter-
mediate can arylate indole by
electrophilic palladation. In the
absence of PdACHTNUTRGNENG(U TFA)2, the use
of Ag2CO3 alone was ineffec-
tive for the decarboxylation of
electron-rich 2,4-dimethoxyben-
zoic acid in dioxane, clearly il-
lustrating that in the indole ary-
lation reaction involving elec-
tron-rich benzoic acids Ag2CO3
was not responsible for the de-
carboxylation.[16] In the case of
electron-deficient benzoic acids,
however, the decarboxylation
was observed to arise from
Ag2CO3 rather than Pd-
AHCTUNGTRENNUNG
(TFA)2.[16] Based on these ob-
servations, we speculated that
there might be two different
catalytic pathways for the Pd/
Ag-catalyzed decarboxylative
arylation of indoles (Scheme 3).
The reaction of electron-rich
benzoic acid is thought to begin
by the generation of arylpalla-
dium intermediate I by Pd-pro-
[a] Reaction conditions: indole (0.2 mmol, 1.0 equiv), Pd
(0.25 equiv), TMSO (1.5 equiv), benzoic acids (5 equiv), dioxane (1.5 mL), 24 h, 808C. The yields of 3 were iso-
lated yields, the ratios of 3/4 were determined by GC–MS. [b] Pd(TFA)2 (15 mol%), 1408C. [c] Pd(TFA)2
(15 mol%), 1008C. [d ] 7.5 equiv of EtCOOH. [e] Pd(TFA)2 (15 mol%), Ag2CO3 (3.0 equiv), EtCOOH
(1.5 equiv), TMSO (1.5 equiv), benzoic acids (2.5–3 equiv), DMF (1.5 mL), 24 h, 115–1208C.
ACHTUGNTERN(NUNG TFA)2 (7.5 mol%), Ag2CO3 (2 equiv), EtCOOH
moted
decarboxylation
A
ACHTUNGTRENNUNG
(path A). Next, the electrophilic
attack of arylpalladium I on
indole occurs at C3, where the
electrophilic attack takes place
AHCTUNGTRENNUNG
preferentially, forming
a C3-
(5a, 62%) (Scheme 1). Furthermore, the arylpalladium(II)
trifluoroacetate complex, which was generated from the de-
palladated species II. Following the migration of aryl–Pd
fragment from C3 to C2, the deprotonation for rearomatiza-
tion of indole leads to an intermediate III that further un-
dergoes reductive elimination to release the cross-coupling
product and Pd0 species. The reoxidation of Pd0 to PdII by
AgI ion completes the catalytic cycle. In contrast, the reac-
tion of electron-deficient ben-
carboxylation of 2,4,5-trimethoxybenzoic acid by PdACTHNUTRGNEUNG(TFA)2
in DMSO,[5c] was treated with a solution of an equivalent of
N-acetylindole in dioxane and propionic acid (1.5 equiv) to
generate 2-arylindole (3m) and 1,2,4-trimethoxybenzene
zoic acid might be initiated by
the electrophilic palladation on
indole and the formation of ar-
ylsilver complex by Ag-promot-
ed decarboxylation, followed by
transmetalation from Ag to Pd
through transition-state com-
plex T (similar complexes con-
taining an iminium double
bond coordinated to copper or
ruthenium centers were also
proposed as intermediates in
Scheme 1.
the oxidative coupling reaction
Chem. Eur. J. 2010, 16, 5876 – 5881
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W. Su et al.
Experimental Section
General procedure for decarboxylative
cross-couplings of benzoic acids with
indoles: All coupling reactions were
performed on a 0.2 mmol scale (indole
substrate) at 0.13m unless otherwise
stated. PdACTHNUGTRNEUNG(TFA)2 (0.015–0.030 mmol,
7.5–15 mol%), indoles (0.2 mmol,
1 equiv), benzoic acid (0.5–1.0 mmol,
2.5–5 equiv), Ag2CO3 (0.4–0.6 mmol,
2–3 equiv),
EtCOOH
(0.0037 g,
0.05 mmol, 0.25 equiv; stored in 0.25m
dioxane or DMF), tetramethylene sulf-
oxide (0.0313 g, 0.3 mmol, 1.5 equiv)
were weighed into a 25 mL glass vial.
Dioxane (1.3 mL) or DMF (1.3 mL)
was added. Then the mixture was
heated under nitrogen for several
hours. Upon completion, the crude re-
action mixture was analyzed by GC–
MS and showed a C2/C3 product dis-
tribution. Then the reaction mixture
was diluted with ethyl ether (10 mL),
filtered through a pad of silica gel, fol-
lowed by washing with ethyl acetate
(30 mL). The filtrate was washed with
water (3ꢁ15 mL). The organic phase
was dried over Na2SO4, filtered, and
concentrated under reduced pressure.
The residue was then purified by flash
chromatography on silica gel to pro-
vide the corresponding product.
Scheme 2.
Scheme 3. Two possible reaction pathways.
Acknowledgements
Financial support from the 973 Pro-
gram (2006CB932903, 2009CB939803),
NSFC (20821061, 20925102), “The Distinguished Oversea Scholar Proj-
ect”, “One Hundred Talent Project”, and Key Project from CAS is great-
ly appreciated.
of amines[6m,17]) to form the Pd complex V that delivers C3
arylation product by reductive elimination (path B). If
path B is operative, the coordination of AgI ion to C=N
double bond in complex T might block the migration of the
Pd fragment from C3 to C2, determining the C3 selectivity
of this reaction.
Keywords: decarboxylation · direct arylation · indoles ·
palladium · regioselectivity
In summary, the combination of PdACHTNURGTNE(UNG TFA)2, Ag2CO3, and
propionic acid proved to be an efficient catalyst system for
highly regioselective arylation of a wide range of indoles
with both electron-rich and -deficient benzoic acids as ary-
lating reagents, which provides an attractive complement to
the existing methods for the direct arylation of indoles. Pre-
liminary mechanistic studies suggested that the difference in
reactivity towards decarboxylation between electron-rich
and -deficient benzoic acids might result in two different
catalytic pathways for the decarboxylative arylation of in-
doles, and therefore, leading to the inversion of the reaction
regioselectivity. Current efforts are devoted to a more de-
tailed mechanistic investigation and improvement of effi-
ciency and substrate scope of this reaction.
[1] For recent reviews, see: a) F. Kakiuchi, N. Chatani, Adv. Synth.
Catal. 2003, 345, 1077–1107; b) L.-C. Campeau, D. R. Stuart, K.
Fagnou, Aldrichimica Acta 2007, 40, 35–41; c) A. R. Dick, M. S.
Sanford, Tetrahedron 2006, 62, 2439–2463; d) I. V. Seregin, V. Ge-
vorgyan, Chem. Soc. Rev. 2007, 36, 1173–1193; e) K. Godula, D.
Sames, Science 2006, 312, 67–72; f) X. Chen, K. M. Engle, D.-H.
Wang, J.-Q. Yu, Angew. Chem. 2009, 121, 5196–5217; Angew. Chem.
Int. Ed. 2009, 48, 5094–5115; g) B.-J. Li, S.-D. Yang, Z.-J. Shi, Synlett
2008, 949–957; h) C.-J. Li, Acc. Chem. Res. 2009, 42, 335–344.
[2] a) S. Cacchi, G. Fabrizi, Chem. Rev. 2005, 105, 2873–2920; b) L.
Joucla, L. Djakovitch, Adv. Synth. Catal. 2009, 351, 673–714; c) P. N.
Craig in Comprehensive Medicinal Chemistry, Vol. 8 (Ed.: C. J.
Drayton), Pergamon, New York, 1991.
[3] For the direct arylation of indoles, see: a) D. R. Stuart, K. Fagnou,
Science 2007, 316, 1172–1175; b) D. R. Stuart, E. Villemure, K.
Fagnou, J. Am. Chem. Soc. 2007, 129, 12072–12073; c) R. J. Phipps,
N. P. Grimster, M. J. Gaunt, J. Am. Chem. Soc. 2008, 130, 8172–
8174; d) N. Lebrasseur, I. Larrosa, J. Am. Chem. Soc. 2008, 130,
5880
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Catalyst for Intermolecular Direct Arylation of Indoles
COMMUNICATION
2926–2927; e) N. R. Deprez, D. Kalyani, A. Krause, M. S. Sanford,
J. Am. Chem. Soc. 2006, 128, 4972–4973; f) S.-D. Yang, C.-L. Sun,
Z. Fang, B.-J. Li, Y.-Z. Li, Z.-J. Shi, Angew. Chem. 2008, 120, 1495–
1498; Angew. Chem. Int. Ed. 2008, 47, 1473–1476; g) X. Wang, D. V.
Gribkov, D. Sames, J. Org. Chem. 2007, 72, 1476–1479; h) Z. Zhang,
Z. Hu, Z. Yu, P. Lei, H. Chi, Y. Wang, R. He, Tetrahedron Lett.
2007, 48, 2415–2419; i) B. B. Tourꢂ, B. S. Lane, D. Sames, Org. Lett.
2006, 8, 1979–1982; j) F. Bellina, S. Cauteruccio, R. Rossi, Eur. J.
Org. Chem. 2006, 1379–1382; k) X. Wang, B. S. Lane, D. Sames, J.
Am. Chem. Soc. 2005, 127, 4996–4997; l) C. Bressy, D. Alberico, M.
Lautens, J. Am. Chem. Soc. 2005, 127, 13148–13149; m) L. Acker-
mann, S. Barfuesser, Synlett 2009, 808–812; n) G. Cusati, L. Djako-
vitch, Tetrahedron Lett. 2008, 49, 2499–2502; o) F. Bellina, F. Benel-
li, R. Rossi, J. Org. Chem. 2008, 73, 5529–5535.
k) M. Yu, D. Pan, W. Jia, W. Chen, N. Jiao, Tetrahedron Lett. 2010,
51, 1287–1290; l) P. Hu, J. Kan, W. Su, M. Hong, Org. Lett. 2009, 11,
2341–2344; m) H.-P. Bi, L. Zhao, Y.-M. Liang, C.-J. Li, Angew.
Chem. 2009, 121, 806–809; Angew. Chem. Int. Ed. 2009, 48, 792–
795; n) Z. Duan, S. Ranjit, P. Zhang, X. Liu, Chem. Eur. J. 2009, 15,
3666–3669.
[7] a) S. R. Waetzig, J. A. Tunge, J. Am. Chem. Soc. 2007, 129, 14860–
14861; b) E. C. Burger, J. A. Tunge, J. Am. Chem. Soc. 2006, 128,
10002–10003; c) D. K. Rayabarapu, J. A. Tunge, J. Am. Chem. Soc.
2005, 127, 13510–13511; d) S. R. Waetzig, D. K. Rayabarapu, J. D.
Weaver, J. A. Tunge, Angew. Chem. 2006, 118, 5099–5102; Angew.
Chem. Int. Ed. 2006, 45, 4977–4980; e) S. Lou, J. A. Westbrook,
S. E. Schaus, J. Am. Chem. Soc. 2004, 126, 11440–11441.
[8] a) D.-H. Wang, T.-S. Mei, J.-Q. Yu, J. Am. Chem. Soc. 2008, 130,
17676–17677; b) R. Giri, N. Maugel, J.-J. Li, D.-H. Wang, S. P.
Breazzano, L. B. Saunders, J.-Q. Yu, J. Am. Chem. Soc. 2007, 129,
3510–3511; c) Y.-H. Zhang, B.-F. Shi, J.-Q. Yu, Angew. Chem. 2009,
121, 6213–6216; Angew. Chem. Int. Ed. 2009, 48, 6097–6100; d) R.
Giri, J.-Q. Yu, J. Am. Chem. Soc. 2008, 130, 14082–14083.
[9] H. A. Chiong, Q.-N. Pham, O. Daugulis, J. Am. Chem. Soc. 2007,
129, 9879–9884.
[4] a) L. J. Goossen, G. Deng, L. M. Levy, Science 2006, 313, 662–664;
b) L. J. Goossen, N. Rodriguez, B. Melzer, C. Linder, G. Deng,
L. M. Levy, J. Am. Chem. Soc. 2007, 129, 4824–4833; c) L. J. Goos-
sen, B. Melzer, J. Org. Chem. 2007, 72, 7473–7476; d) L. J. Goossen,
T. J. Knauber, J. Org. Chem. 2008, 73, 8631–8634; e) L. J. Goossen,
B. Zimmermann, T. Knauber, Angew. Chem. 2008, 120, 7211–7214;
Angew. Chem. Int. Ed. 2008, 47, 7103–7106; f) L. J. Goossen, N. Ro-
driguez, C. Linder, J. Am. Chem. Soc. 2008, 130, 15248–15249;
g) L. J. Goossen, F. Rudolphi, C. Oppel, N. Rodriguez, Angew.
Chem. 2008, 120, 3085–3088; Angew. Chem. Int. Ed. 2008, 47, 3043–
3045; h) L. J. Goossen, N. Rodriguez, P. P. Lange, C. Linder, Angew.
Chem. 2010, 122, 1129–1132; Angew. Chem. Int. Ed. 2010, 49, 1111–
1114.
[10] M. Yamashita, H. Horiguchi, K. Hirano, T. Satoh, M. Miura, J. Org.
Chem. 2009, 74, 7481–7488.
[11] A. Voutchkova, A. Coplin, N. E. Leadbeater, R. H. Crabtree, Chem.
Commun. 2008, 6312–6314.
[12] C. Wang, I. Piel, F. Glorius, J. Am. Chem. Soc. 2009, 131, 4194–
4195.
[5] a) A. G. Myers, D. Tanaka, M. R. Mannion, J. Am. Chem. Soc. 2002,
124, 11250–11251; b) D. Tanaka, A. G. Myers, Org. Lett. 2004, 6,
433–436; c) D. Tanaka, S. P. Romeril, A. G. Myers, J. Am. Chem.
Soc. 2005, 127, 10323–10333.
[13] L. Cornella, P. Lu, I. Larrosa, Org. Lett. 2009, 11, 5506–5509.
[14] For selective functionalization of indoles or pyrroles, see: a) N. P.
Grimster, C. Gauntlett, C. R. A. Godfrey, M. J. Gaunt, Angew.
Chem. 2005, 117, 3185–3189; Angew. Chem. Int. Ed. 2005, 44, 3125–
3129; b) E. M. Beck, N. P. Grimster, R. Hatley, M. J. Gaunt, J. Am.
Chem. Soc. 2006, 128, 2528–2529.
[15] a) J. Cornella, C. Sanchez, D. Banawa, I. Larrosa, Chem. Commun.
2009, 7176–7178; b) L. J. Goossen, C. Linder, N. Rodrꢃguez, P. P.
Lange, A. Fromm, Chem. Commun. 2009, 7173–7175; c) P. Lu, C.
Sanchez, J. Cornella, I. Larrosa, Org. Lett. 2009, 11, 5710–5713.
[16] The detailed experimental results for the mechanism studies are
provided in Table S2 in the Supporting Information.
[6] a) P. Forgione, M. C. Brochu, M. St-Onge, K. H. Thesen, M. D.
Bailey, F. Bilodeau, J. Am. Chem. Soc. 2006, 128, 11350–11351; b) J.
Moon, M. Jeong, H. Nam, J. Ju, J. H. Moon, H. M. Jung, S. Lee,
Org. Lett. 2008, 10, 945–948; c) J. Moon, M. Jang, S. Lee, J. Org.
Chem. 2009, 74, 1403–1406; d) J.-M. Becht, C. Le Drian, Org. Lett.
2008, 10, 3161–3164; e) J.-M. Becht, C. Catala, C. Le Drian, A.
Wagner, Org. Lett. 2007, 9, 1781–1783; f) Z. Y. Wang, Q. P. Ding,
X. D. He, J. Wu, Org. Biomol. Chem. 2009, 7, 863–865; g) Z. Y.
Wang, Q. P. Ding, X. D. He, J. Wu, Tetrahedron 2009, 65, 4635–
4638; h) R. Shang, Y. Fu, J.-B. Li, S.-L. Zhang, Q.-X. Guo, L. Liu, J.
Am. Chem. Soc. 2009, 131, 5738–5739; i) R. Shang, Y. Fu, Y. Wang,
Q. Xu, H.-Z. Yu, L. Liu, Angew. Chem. 2009, 121, 9514–9518;
Angew. Chem. Int. Ed. 2009, 48, 9350–9354; j) S.-L. Zhang, Y. Fu,
R. Shang, Q.-X. Guo, L. Liu, J. Am. Chem. Soc. 2010, 132, 638–646;
[17] a) Z. Li , C.-J. Li, J. Am. Chem. Soc. 2005, 127, 6968–6969; b) S.-I.
Murahashi, N. Komiya, H. Terai, T. Nakae, J. Am. Chem. Soc. 2003,
125, 15312–15313.
Received: March 1, 2010
Published online: April 15, 2010
Chem. Eur. J. 2010, 16, 5876 – 5881
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5881