Direct C-H bond arylation: Selective palladium-catalyzed C2-arylation of N-substituted indoles

Article abstract of DOI:10.1021/ol0490072

(Equation Presented) We present a new, practical method by which N-substituted indoles may be selectively arylated in the C2-position with good yields, low catalyst loadings, and a high degree of functional group tolerance. Our investigation found that two competitive processes, namely, the desired cross-coupling and biphenyl formation, were operative in this reaction. A simple kinetic model was formulated that proved to be instructive and provided useful guidelines for reaction optimization; the approach described within may prove to be useful in other catalytic cross-coupling processes.

Full text of DOI:10.1021/ol0490072

ORGANIC
LETTERS
2004
Vol. 6, No. 17
2897-2900
Direct C−H Bond Arylation: Selective
Palladium-Catalyzed C2-Arylation of
N-Substituted Indoles
Benjamin S. Lane and Dalibor Sames*
Department of Chemistry, Columbia UniVersity, 3000 Broadway,
New York, New York 10027
sames@chem.columbia.edu
Received May 29, 2004
ABSTRACT
We present a new, practical method by which N-substituted indoles may be selectively arylated in the C2-position with good yields, low
catalyst loadings, and a high degree of functional group tolerance. Our investigation found that two competitive processes, namely, the
desired cross-coupling and biphenyl formation, were operative in this reaction. A simple kinetic model was formulated that proved to be
instructive and provided useful guidelines for reaction optimization; the approach described within may prove to be useful in other catalytic
cross-coupling processes.
Indoles represent important structural units frequently found
in natural products, pharmaceuticals, and other synthetics.
Current methods for C2-arylation of N-substituted indoles
require functionalization of the heteroarene substrate, i.e.,
synthesis of the corresponding stannane or boronate, prior
to a palladium-catalyzed C-C coupling.1 However, there is
little precedent for the direct intermolecular reaction of
N-substituted indoles with aryl halides currently limited to
low-yielding reactions with specialized chloropyrazine do-
nors.2 In this context, we came to appreciate that indoles
were significantly less reactive in comparison to other five-
membered heteroarenes. Consequently, we directed our
attention to this problem and found critical roles for
the base and catalyst loading in these coupling reactions.
As a result, we herein present a new, practical method
by which (N-R)-indoles may be arylated in the C2-posi-
tion selectively in good to excellent yields, with low cata-
lyst loadings and a high degree of functional group
tolerance.
Our initial investigations demonstrated that the standard
conditions developed for palladium-catalyzed arylation of
five-membered heteroarenes were not suitable for (N-R)-
indole substrates. These conditions often used carbonate or
acetate bases at higher temperatures as well as relatively high
catalyst loadings (entry 3 and 4, Table 1).3 Furthermore, in
contrast to furan, pyrrole, oxazole, and related systems, indole
arylation does not follow the “electrophilic” regiochemistry
but instead shows high C-2 selectivity.4 We also examined
the conditions recently developed in our group for the
arylation of free (N-H)-heteroarenes (Table 1, entry 1).5 It
became apparent that MgO was not a suitable base for (N-
R)-indole substrates, confirming the importance of the
magnesium salt (N-MgX) formation in the case of free
(3) (a) Miura, M.; Nomura, M. Top. Curr. Chem. 2002, 219, 211-241.
(b) Yokooji, A.; Okazawa, T.; Satoh, T.; Miura, M.; Nomura, M.
Tetrahedron 2003, 59, 5685-5689 and references therein. (c) Sezen, B.;
Sames, D. Org. Lett. 2003, 5, 3607-3610.
(4) “Nonelectrophilic palladation” and carbopalladation represent two
reasonable mechanistic alternatives consistent with the observed regio-
selectivity; see ref 5.
(1) Labadie, S. S.; Teng, E. J. Org. Chem. 1994, 59, 4250-4254.
(2) Akita, Y.; Itagaki, Y.; Takizawa, S.; Ohta, A. Chem. Pharm. Bull.
1989, 37, 1477-1480.
(5) (a) Sezen, B.; Sames, D. J. Am. Chem. Soc. 2003, 125, 10580-10585.
(b) Sezen, B.; Sames, D. J. Am. Chem. Soc. 2003, 125, 5274-5275.
10.1021/ol0490072 CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/30/2004

Table 1. Critical Role of Base in the Indole C2-Arylation
Reactionsa
yield %
Figure 1. Proposed kinetic model of the reaction system.
entry
base
MgO
ZnO
CS2CO3
KOAc
solvent
product
biphenyl
1
2
3
4
5
6
dioxane/DMF (1:2)
dioxane/DMF (1:2)
DMA
3
8
21
27
48
11
12
24
28
34
28
37
then undergo two competing pathways: (1) cross-coupling
with the substrate to furnish the desired product or (2)
formation of byproduct biphenyl. Although the mechanistic
details of these processes have not been elucidated,5 we made
an informed assumption that biphenyl formation required a
bimolecular transmetalation of the aryl-palladium species
(Figure 1).11
DMA
DMA
DMA
CsOAc
CsOTFA
a All yields were determined by HPLC versus an internal standard. For
complete data, see Supporting Information.
Despite its simplicity, this model predicts several features
of significant practical consequence. For instance, decreasing
the catalyst loading should increase the rate ratio V3/V2 and
thus faVor production of the desired product. To test this
hypothesis, arylation of N-methylindole with iodobenzene
was conducted over a range of catalyst loading; in these
experiments, the concentration of the substrate was kept
constant (Figure 2). Indeed, decreasing the amount of catalyst
indoles. A significant improvement was accomplished via a
systematic investigation of the base, which ultimately led
us choose cesium acetate as the optimum reagent (Table 1,
entry 5). Although the importance of the carboxylate ion/
ligand in the palladation of both sp3 and sp2 C-H bonds
has been recognized,6 in this case both the cation and anion
play an essential role.7 For example, both potassium acetate
and cesium trifluoroacetate provided low amounts of the
product (Table 1, entries 4 and 6, respectively).8 However,
even with CsOAc the reaction efficiency was low, affording
48% yield of the desired product as well as 28% yield of
biphenyl. It became clear that biphenyl formation represented
a key competitiVe process responsible for consuming the
iodobenzene before full conVersion of the substrate could
occur.
The palladium-catalyzed Ullmann coupling is a well-
established protocol;9 moreover, it represents a frequently
encountered problem in hetero cross-coupling reactions such
as the Heck reaction and related processes.10 Surprisingly,
this issue has not been previously addressed in this context,
and thus there are no general guidelines available to mitigate
biphenyl byproduct formation. Consequently, we proposed
a qualitative kinetic model of the reaction system presented
here, which in turn guided our optimization studies (Figure
1).
Figure 2. Chemical yield and TON as a function of catalyst loading
in reaction of N-methylindole and Ph-I: Pd(OAc)2/PPh3 (1:4), 2.54
M in substrate, CsOAc, DMA, 125 °C, 24 h.
(starting from 5 mol % Pd) led to a steady increase of the
product yield at the expense of biphenyl formation, reaching
a maximum at 0.5 mol % Pd (Figure 2). The inverse
relationship between the catalyst loading and the chemical
yield is highly desirable, particularly at the lower range of
catalyst loading as observed herein.12
Lowering the catalyst amount below 0.5 mol % led to a
sharp decline in yield, which was accompanied by a dramatic
increase in the catalyst turnover number (Figure 2). At such
low concentrations, catalyst decomposition processes, includ-
ing biphenyl formation were suppressed. However, the
reaction rates were too slow to afford practical yields within
We surmised that the first step, namely, oxidative addition,
proceeds to an aryl-palladium halide intermediate, which may
(6) (a) Dangel, B. D.; Godula, K.; Youn, S. W.; Sezen, B.; Sames, D. J.
Am. Chem. Soc. 2002, 124, 11856-11857. (b) Sezen, B.; Franz, R.; Sames,
D. J. Am. Chem. Soc. 2002, 124, 13372-13373.
(7) Campo, M. A.; Larock, R. C. J. Am. Chem. Soc. 2002, 124, 14326-
14327.
(8) See Supporting Information for a broader exploration of the base
dependence.
(9) (a) Dyker, G.; Kellner, A. J. Organomet. Chem. 1998, 555, 141-
144. (b) Albanese, D.; Landini, D.; Penso, M.; Petricci, S. Synlett 1999,
199-200. (c) Hassan, J.; Penalva, V.; Lavenot, L.; Gozzi, C.; Lemaire, M.
Tetrahedron 1998, 54, 13793-13804.
(10) (a) Mitsudo, T.; Fischetti, W.; Heck, R. F. J. Org. Chem. 1984, 49,
1640-1646. (b) Andersson, C. M.; Larsson, J.; Hallberg, A. J. Org. Chem.
1990, 55, 5757-5761. (c) Dyker, G. J. Org. Chem. 1993, 58, 234-238.
(d) Padmanabhan, S.; Gavaskar, K. V.; Triggle, D. J. Synth. Commun 1996,
26, 3109-3113. (e) Shmidt, A. F.; Khalaika, A. Kinet. Catal. 1998, 39,
803-809. (f) Shmidt, A. F.; Smirnov, V. V.; Starikova, O. V.; Elaev, A.
V. Kinet. Catal. 2001, 42, 199-204.
(11) (a) Amatore, C.; Carre, E.; Jutand, A. Acta Chem. Scand. 1998, 52,
100-106. (b) Ozawa, F.; Hidaka, T.; Yamamoto, T.; Yamamoto, A. J.
Organomet. Chem. 1987, 330, 253-263.
(12) Penalva, V.; Lavenot, L.; Gozzi, C.; Lemaire, M. Appl. Catal., A.
Gen. 1999, 182, 399-405.
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Org. Lett., Vol. 6, No. 17, 2004

a reasonable reaction time. The same trends were observed
when the substrate concentration was decreased 10-fold from
2.54 to 0.254 M. Virtually identical yields for both 2-phen-
yl-1-methylindole and biphenyl were obtained at the two
different concentrations.13 These experiments demonstrated
that the substrate/catalyst ratio (and not the absolute con-
centration) determine the yield and product distribution,
lending further support for the kinetic model introduced
earlier.
Table 3. Reaction Scope: Substitution on Indolea
As a result of this exercise, the protocol requiring only
0.5 mol % catalyst (optimized for the parent coupling
partners) was subsequently applied to a broad range of
substrates in order to investigate the substrate scope.
First, we investigated the scope of N-substitution on the
indole nucleus (Table 2). Both N-alkyl and N-arylindoles
Table 2. Reaction Scope: Substitution at Nitrogen
entry
R
yield %a entry
R
yield %a
1
2
3
CH3 88 (54)b
Bn 81
iPr 92
4
5
6
Ph
68
55
0
p-(CN)-C6H4
SO2Ph, SO2CH3, COCH3
a All values based on isolated yields; conditions were the same as in
Table 2. b Performed with 0.1 mol % Pd(OAc)2, 0.4 mol % PPh3; reaction
time was 48 h.
a All values based on isolated yields. b Chlorobenzene was used as donor
and dicyclohexylphenylphosphine as a ligand at 150 °C.
proved to be suitable substrates, while N-sulfonyl or N-
acetylindole were inert. These results clearly indicated the
need for sufficient electron density on the pyrrole ring to
facilitate substitution.
ing the catalyst load and increasing the reaction time to
compensate for a slower product formation afforded a 2-fold
enhancement of the isolated yield of 10 (24f50%, Table
3).
Subsequently, we examined more complex substrates
bearing various substituents on both the indole and the
haloarene components (Tables 3 and 5). To our delight, many
functional groups were well tolerated in these reactions. The
modest yields observed in some cases may be ascribed to
two main factors: (1) the low stability of the substrate and
the corresponding product (cf. entries 3 and 4, Table 3) or
(2) the low reactivity of the substrate. The latter case may
be illustrated by 5-sulfonamido-1-methylindole 5, a slow yet
stable substrate, which furnished only a 31% yield of product
10 and a 10% yield of biphenyl (Table 4). In such instances,
the kinetic model discussed above (Figure 1) may once again
prove to be instructive. The slow V3 rate will favor biphenyl
formation and unproductive consumption of iodobenzene.
In resonance with this analysis, increasing the reaction time
from 24 to 48 h led only to a minor improvement in the
yield of product 10 (31f34%), while the yield of biphenyl
was doubled (10f22%), Table 4. According to our model,
this should be correctable by further lowering the catalyst
concentration. Indeed, this proved to be the case, as decreas-
ing the loading from 0.5 to 0.1 mol % Pd(OAc)2 resulted in
a significant increase in the production of 10 at the expense
of biphenyl formation (Table 4). In practical terms, decreas-
C2-arylation was generally preferred unless the haloarene
donor contained a substituent in the ortho-position. In these
circumstances, a mixture of C2- and C3-arylation products
was obtained. Since biphenyl homocoupling is not an issue
a
Table 4. Optimization of Substrates with Slow V3
yield %
entry
time (h)
mol % Pd(OAc)2
product
biphenyl
1
2
3
24
48
48
0.5
0.5
0.1
31
34
52
10
22
13
a All values based on HPLC yields versus an internal standard.
(13) See Supporting Information for data.
Org. Lett., Vol. 6, No. 17, 2004
2899

the reaction temperature, provided the substrates and products
are sufficiently stable (cf. 15, 41f67% combined yield,
Table 5).
Table 5. Reaction Scope: Substitution on Arene Donor
Last, it is notable that similar reactivity trends were found
employing chlorobenzene in place of Ph-I, although the
chemical yields were lower (cf. 54% with N-methylindole,
Table 2, entry 1). Future studies will address the use of other
haloarene donors.
In conclusion, a practical new, method has been developed
for the selective C2-arylation of N-substituted indoles.
Careful evaluation of the reaction conditions identified the
base and the catalyst loading as two key factors. Reducing
the catalyst loading suppressed the formation of biphenyl
byproduct and enhanced product formation. Good functional
group tolerance was demonstrated, and a simple kinetic
model was used to guide optimization of complex indole
substrate arylation. We believe that this kinetic model may
prove to be valuable for optimization of other cross-coupling
reactions.
Acknowledgment. Funding was provided by the National
Science Foundation, GlaxoSmithKline, Johnson & Johnson,
and Merck Research Laboratories. D.S. is a recipient of the
Alfred P. Sloan Fellowship, Camille Dreyfus Teacher-
Scholar Award, and AstraZeneca Excellence in Chemistry
Award. We thank Bengu¨ Sezen (insightful conversations),
Dr. J. B. Schwarz (editorial assistance), and Vitas Votier
Chmelar (intellectual support).
a All values based on isolated yields; conditions were the same as in
Table 2. b Performed at 150 °C.
Supporting Information Available: Experimental pro-
cedures, spectral data, base optimization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
with these particular donors (V2 is very slow), the desired
cross-coupling yield could in fact be improved by increasing
OL0490072
2900
Org. Lett., Vol. 6, No. 17, 2004