Oxidant-controlled regioselectivity in the oxidative arylation of N-acetylindoles

Article abstract of DOI:10.1016/j.tetlet.2008.04.073

N-Acetylindoles can be oxidatively coupled with arenes such as benzene or pentafluorobenzene in dioxane. The use of Cu(OAc)₂ as the stoichiometric oxidant produces selective arylation at the 3-position of indole while AgOAc produces selective a

Full text of DOI:10.1016/j.tetlet.2008.04.073

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 4050–4053
Oxidant-controlled regioselectivity in the oxidative
arylation of N-acetylindoles
Shathaverdhan Potavathri, Ashley S. Dumas, Timothy A. Dwight
Gregory R. Naumiec, Jeffrey M. Hammann, Brenton DeBoef *
Department of Chemistry, University of Rhode Island, Kingston, RI 02881, United States
Received 27 March 2008; accepted 10 April 2008
Available online 15 April 2008
Abstract
N-Acetylindoles can be oxidatively coupled with arenes such as benzene or pentafluorobenzene in dioxane. The use of Cu(OAc)2 as
the stoichiometric oxidant produces selective arylation at the 3-position of indole while AgOAc produces selective arylation at indole’s
2-position.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Indole; Palladium; Oxidative coupling; Regioselective; Arylation; C–H functionalization
The World Drug Index contains forty-six 2-arylindoles
and twenty-eight 3-arylindoles (Fig. 1).1 These molecules
are often synthesized by coupling preactivated arenes and
indole substrates or by intramolecular cyclizations to con-
struct the heterocycle. Recently, several methods have
emerged that allow for the direct coupling of unfunctional-
ized indoles to halogenated arenes using palladium,2 rho-
dium,3 or copper catalysts.4 Our group,5 along with that
of Fagnou,6 has recently disclosed the seminal examples
of palladium-catalyzed oxidative coupling of benzofurans
and indoles with unfunctionalized arenes.7,8 In each of
these cases, the reactions were preformed at high tempera-
tures in acidic solvents. Herein, we report that milder, non-
acidic conditions can be used, and that judicious choice of
oxidants can control the regioselectivity of the reactions.
Moreover, we hypothesize that the formation of catalytic
polymetallic clusters accounts for the unique, oxidant-con-
trolled regioselectivity.
Our previous work with oxidative coupling showed that
different oxidants effect the regioselectivity of the reaction
(Scheme 1).5 The use of Cu(OAc)2 as a stoichiometric
oxidant produced exclusive oxidative arylation of benzo-
furan’s 2-position, while AgOAc produced nearly an
even mixture of 2- and 3-arylated products. Ultimately,
we discovered that aerobic conditions using catalytic
amounts of H4PMo11VO40 (HPMV) exclusively produced
Fig. 1. Examples of biologically active compounds containing arylated
indoles.
*
Corresponding author. Tel.: +1 401 874 9480; fax: +1 401 874 5072.
E-mail address: bdeboef@chm.uri.edu (B. DeBoef).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.04.073

S. Potavathri et al. / Tetrahedron Letters 49 (2008) 4050–4053
4051
Table 2
Scope of regioselective arylation reactions
Substrate Oxidant Temp Product
Yield
(%)
(°C)
AgOAc
120
43
Cu(OAc)2 120
53
AgOAc
AgOAc
100
100
33
22
Scheme 1. Evidence of oxidant-controlled regioselectivity.
2-phenylbenzofuran in high yield, but these conditions
were incompatible with indole substrates, due to over-
oxidation. These oxidant effects seem counterintuitive
when simplistic mechanisms are considered, in which the
oxidant only serves to regenerate catalytically active Pd(II)
from Pd(0). In fact, these observations show that the
oxidant must be involved in the C–H functionalization
process. When N-acetylindoles were subjected to the
Cu(OAc)2/AcOH conditions, which showed regioselecti-
vity for benzofuran, a mixture of 2-arylated and 3-arylated
regiomers was formed. This loss of regioselectivity was
even more pronounced for N-methylindole (Scheme 1).
As shown in Table 1, switching solvents from acetic acid
to dioxane allowed for regioselective control. In the pres-
ence of Cu(OAc)2, N-acetylindole selectively underwent
oxidative coupling with benzene at its 3-position. This
observation contrasts with our previous studies with ben-
AgOAc
AgOAc
AgOAc
AgOAc
100
55
56
25a
38
60
100
100
Table 1
Lead discovery and control reactions in dioxane
AgOAc
AgOAc
AgOAc
60
52
0b
Entry Solvent
Oxidant
X mol % Y mol % Yield 6 Yield 8
Pd(OAc)2 Oxidant (%)
(%)
100
100
1
2
3
4
5
6
AcOH
Cu(OAc)2
25
25
25
100
0
400
400
400
0
400
400
38
13
43
13
0
8
53
12
18
0
Dioxane Cu(OAc)2
Dioxane AgOAc
Dioxane None
Dioxane AgOAc
Dioxane Cu(OAc)2
30
0
0
0
Standard reactions conditions: 0.1 mmol substrate, 25 mol % Pd(OAc)2,
(continued on next page)
4 equiv oxidant, 2 mL AcOH, 3 mL PhH, 120 °C, 1 atm N2.

4052
S. Potavathri et al. / Tetrahedron Letters 49 (2008) 4050–4053
Table 2 (continued)
carbamate (28) resulted in the decomposition of the sub-
strate. The reactions are also prone to the formation of
palladium black. Consequently, higher Pd(OAc)2 loadings
(25 mol %) were required compared to our prior work with
HPMV/O2 oxidants (10 mol %).5
Substrate
Oxidant
AgOAc
Temp
(°C)
Product
Yield
(%)
100
0c
With respect to the other arene substrate, electron-rich
moieties such as p-xylene and anisole failed to react, but
pentaflurorobenzene cleanly cross-coupled (31). This also
contrasts with our previous work using the HPMV/O2 oxi-
dant system.5
AgOAc
100
38
We propose that the oxidant-controlled selectivity is a
consequence of the formation of polymetallic, catalytically
active clusters. The formation of [Cu2Pd(OAc)6] and
[Cu2Pd4(OAc)12] had been previously described by both
Claridge and Thornton.11 Interestingly, Claridge observed
that complexes of this type do not form with alkali metal
acetates, such as KOAc. This trend may extend to other
mono-valent metal acetates, such as AgOAc. Alternatively,
mixtures of AgOAc and Pd(OAc)2 may form novel clus-
ters. We hypothesize that the Cu(OAc)2 oxidant forms a
polymetallic cluster with Pd(OAc)2 that selectively couples
to the 3-position of N-acetylindole, while the AgOAc oxi-
dant forms either a different polymetallic cluster or ‘naked’
Pd(OAc)2 that selectively arylates the 2-position of N-
acetylindole.
In light of the substrate scope and assumed polymetallic
cluster formation, we propose the following mechanism
(Scheme 2). Initially, the electron-rich indole is metallated
at its nucleophilic 3-position (33). Deprotonation of this
intermediate occurs when Cu(OAc)2 is present, leading to
the formation of the 3-aryl product 8. When AgOAc is
the oxidant, palladium migration from the indole’s 3- to
the 2-position occurs, followed by deprotonation of the
indole’s 2-position (34).2a,9 As this migration, or lack
thereof, is the regiochemistry-determining step, the oxidant
must be intimately involved at this point.
Standard reaction conditions. See Scheme 1 for details. (a) 1:1 mixture of
2- and 3-phenylated products. (b) No appreciable conversion was
observed. (c) Substrate decomposition was observed.
zofuran (Scheme 1), but is congruent with the observations
of both Fagnou6 and Gaunt,9 in which arenes and olefins
couple to the 3-position of indoles in acidic media with
Pd(II)/Cu(II) catalyst/oxidant systems. Contrastingly, in
the presence of AgOAc, N-acetylindole selectively arylated
at its 2-position. Reactions using stoichiometric amounts of
palladium produced a 3:2 mixture of 3-phenyl- and 2-phen-
ylindole, thus showing that the copper and silver oxidants
were intimately involved in the selective arylation reac-
tions. Furthermore, control reactions containing no palla-
dium and stoichiometric amounts of the oxidants failed
to convert the indole starting material.
The scope of the reaction was explored with respect to
the indole substrate (Table 2). In light of the importance
of 2-arylindoles,1 we chose to focus primarily on the reac-
tion using AgOAc. Aldehydes, esters, and ethers were all
tolerated, and, with one exception (19), near exclusive reg-
ioselectivities were observed.
Following the electrophilic palladation that forms 34,
the electron-poor arene (e.g., benzene or pentafluorobenz-
ene) is deprotonated via an intramolecular abstraction
process.12 This hypothesis is supported by the fact that
N-Tosylindole (26) was also a viable substrate for oxida-
tive arylation. Thus, allowing for a synthesis of N-H-2-aryl-
indoles, following tosyl deprotection.10 Unfortunately,
indoles protected with carbamate groups such as t-butyl-
H
H
N
H
PdII(M)x(OAc)y
33
Ac
PdII(M)x(OAc)y-1
N
H
8
Oxidation
Ac
N
Ac
Electrophilic
Palladation
H
34
Migration/
Pd0(M)x(OAc)y-2
Deprotonation
37
M = AgI, CuII, or PdII
H
H
H
PdII(M)x(OAc)y-1
PdII(M)x(OAc)y-2
N
Ac
N
Ac
Proton
Abstraction
Reductive
N
Ac
35
Elimination
36
6
Scheme 2. Proposed mechanism.

S. Potavathri et al. / Tetrahedron Letters 49 (2008) 4050–4053
4053
Table 3
Kinetic isotope effects
Acknowledgments
Substrate
Oxidant
AgOAc
Product
KIE
The authors thank Brett Lucht for editorial assistance.
This work was supported by the University of Rhode Is-
land, the URI Foundation, the New England Green Chem-
istry Consortium, and the Petroleum Research Fund.
J.M.H. is an awardee of the Jugend Forscht competition
and a visiting international student sponsored by the
URI International Engineering Program.
N-acetylindole 4
6 (C2, major)
8 (C3, minor)
6 (C2, minor)
8 (C3, major)
2.4
3.7
3.9
4.0
Cu(OAc)2
Benzofuran 1
AgOAc
2 (C2, minor)
3 (C3, major)
2 (C2, major)
3 (C3, minor)
2 (C2, exclusive)
3.2
3.4
4.0
4.2
1.9
Cu(OAc)2
HPMV/O2
Supplementary data
Supplementary data (experimental procedures as well as
characterization of previously unknown compounds) asso-
ciated with this article can be found, in the online version,
at doi:10.1016/j.tetlet.2008.04.073.
electron-rich arenes such as anisole failed to react, while
benzene and pentafluorobenzene readily coupled with N-
acetylindole.
Following this step, reductive elimination of the diaryl
palladium intermediate 35 affords the product and a
Pd(0) species 36, and turnover is achieved by oxidation
with the organometallic oxidant. Alternatively, the two
key steps in the proposed mechanism, electrophilic substi-
tution and proton abstraction, could occur in reverse order
(not shown).
References and notes
1. World Drug Index 2007. Thompson Scientific (accessed August 2007).
2. For examples see: (a) Lane, B. S.; Brown, M. A.; Sames, D. J. Am.
Chem. Soc. 2005, 127, 8050. and references cited therein; (b) Park, C.-
H.; Ryabova, V.; Seregin, I. V.; Sromek, A. W.; Gevorgyan, V. Org.
Lett. 2004, 6, 1159; (c) Deprez, N. R.; Kalyani, D.; Andrew Krause,
A.; Sanford, M. S. J. Am. Chem. Soc. 2006, 128, 4972.
The rate-determining step of the process is the proposed
proton abstraction. The kinetic isotope effects for both the
major and minor products of reactions oxidized by both
AgOAc and Cu(OAc)2 were determined using GC/MS
analysis of benzene/benzene-d6 (1:1 mol/mol) competition
experiments (Table 3). Interestingly, the KIE for the
formation of 2-phenyl-N-acetylindole (6) for reactions
employing Ag(I) and Cu(II) oxidants was significantly dif-
ferent. Consequently, we believe that the oxidant is not
only present in the metallation of the indole substrate,
but is involved in the proton abstraction step as well.
Benzofuran substrates also demonstrated significant oxi-
dant-modulated KIEs. Interestingly, the KIEs of reactions
oxidized by both AgOAc and Cu(OAc)2 differed from that
of our previously studied oxidant system of HPMV/O2.
This may imply that polymetallic clusters also form in
the presence of HPMV, or that this reaction is following
a different mechanism altogether.
In summary, we have demonstrated that both 3- and 2-
arylindoles can be formed by the oxidative cross-coupling
of unfunctionalized substrates, and that the regioselectivity
of these processes is controlled by the oxidant. We propose
that catalytically active polymetallic clusters are involved in
all of the C–H cleaving and C–C bond forming steps of the
oxidative coupling. Our future efforts in this field will
include further exploration of the mechanism of these
cross-couplings as well as the characterization of these
unique catalysts.
3. Wang, X.; Lane, B. S.; Sames, D. J. Am. Chem. Soc. 2005, 127, 4996.
4. Do, H.-Q.; Daugulis, O. J. Am. Chem. Soc. 2007, 129, 12404.
5. (a) DeBoef, B. Aerobic Oxidative Coupling for the Formation of Bis-
Arenes. U.S. Patent Application 60/867,641, November 29, 2006; (b)
Dwight, T. A.; Rue, N. R.; Charyk, D.; Josselyn, R.; DeBoef, B. Org.
Lett. 2007, 9, 3137.
6. (a) Stuart, D. R.; Fagnou, K. Science 2007, 316, 1172; (b) Stuart, D.
R.; Villemure, E.; Fagnou, K. J. Am. Chem. Soc. 2007, 129, 12072.
7. For examples of other oxidative couplings employing palladium salts,
see: (a) van Helden, R.; Verberg, G. Recl. Trav. Chim. Pays-Bas 1965,
84, 1263; (b) Itahara, T. J. Org. Chem. 1985, 50, 5272; (c) Itahara, T.
Heterocycles 1986, 24, 2557; (d) Burton, H. A.; Kozhevnikov, I. V. J.
Mol. Catal. A 2002, 185, 285; (e) Takahashi, M.; Masui, K.;
Sekiguchi, H.; Kobayashi, N.; Mori, A.; Funahashi, M.; Tamaoki,
N. J. Am. Chem. Soc. 2006, 128, 10930; (f) Li, R.; Jiang, L.; Lu, W.
Organometallics 2006, 25, 5973; (g) Hull, K. L.; Lanni, E. L.; Sanford,
M. S. J. Am. Chem. Soc. 2006, 128, 14047; (h) Hull, K. L.; Sanford,
M. S. J. Am. Chem. Soc. 2007, 129, 11904.
8. Biaryl synthesis via oxidative gold and copper catalysis have also been
reported: (a) Kar, A.; Mangu, N.; Kaiser, H. M.; Beller, M.; Tse, M.
K. Chem. Commun. 2008, 386; (b) Chen, X.; Hao, X. S.; Goodhue, C.
E.; Yu, J.-Q. J. Am. Chem. Soc. 2006, 128, 6790.
9. Grimster, N. P.; Gauntlett, C.; Godfrey, C. R. A.; Gaunt, M. J.
Angew. Chem., Int. Ed. 2005, 44, 3125.
10. Haskins, C. M.; Knight, D. W. Tetrahedron Lett. 2004, 45, 599.
11. (a) Brandon, R. W.; Claridge, D. V. Chem. Commun. 1968, 677; (b)
Sloan, O. D.; Thornton, P. Inorg. Chim. Acta 1986, 120, 173.
12. (a) Lafrance, M.; Rowley, C. N.; Woo, T. K.; Fagnou, K. J. Am.
Chem. Soc. 2006, 128, 8754; (b) Garcia-Cuadrado, D.; Braga, A. A.
C.; Maseras, F.; Echavarren, A. M. J. Am. Chem. Soc. 2006, 128,
1066.