Efficient access to azaindoles and indoles

Article abstract of DOI:10.1021/ol061232r

An expedient, catalytic method for the synthesis of diverse azaindoles and indoles, starting from readily available and inexpensive starting materials, is described. Conditions were developed for effective reductive alkylation of electron-deficient o-chlo

Full text of DOI:10.1021/ol061232r

ORGANIC
LETTERS
2006
Vol. 8, No. 15
3307-3310
Efficient Access to Azaindoles and
Indoles
Mark McLaughlin,* Michael Palucki, and Ian W. Davies
Department of Process Research, Merck Research Laboratories, P.O. Box 2000,
Rahway, New Jersey 07065
mark_mclaughlin@merck.com
Received May 19, 2006
ABSTRACT
An expedient, catalytic method for the synthesis of diverse azaindoles and indoles, starting from readily available and inexpensive starting
materials, is described. Conditions were developed for effective reductive alkylation of electron-deficient o-chloroarylamines, substrates previously
viewed as poor partners in this reaction. The derived N-alkylated o-chloroarylamines were elaborated to N-alkylazaindoles and N-alkylindoles
via a novel one-pot process comprising copper-free Sonogashira alkynylation and a base-mediated indolization reaction.
Indole and azindole heterocycles are prevalent substructures
in naturally occurring and synthetic molecules displaying
biological activity.1 Consequently, the development of ef-
ficient ways to prepare these compounds continues to be an
active area of research.2 Aside from the vast array of more
traditional methods, there exists a variety of organometallic
techniques for indole synthesis.3 In particular, the cyclization
of o-alkynylanilines, normally prepared from o-haloanilines
via the Sonogashira reaction,4 has been widely documented.5
Although this method has proven valuable, examination of
the literature reveals considerable scope for refinement of
the existing procedures. Significantly, the o-haloaniline
starting materials most often used for the initial Sonogashira
step are iodo or bromo species.6 Therefore, an indolization
process capable of utilizing less expensive o-chloroanilines
would be useful.
A recent report described the synthesis of indoles starting
from 1,2-dihaloarenes via sequential Sonogashira and ami-
nation reactions, allowing access to indoles bearing nitrogen
substituents.7 However, potentially significant drawbacks of
this method are the fairly harsh reaction conditions (>100
°C) and the use of relatively high loadings of transition-
metal catalysts (10 mol % of Cu and 5 mol % of Pd). Given
that 1-bromo-2-iodobenzenes and 1-chloro-2-iodobenzenes
are normally prepared via Sandmeyer iodination of the
corresponding o-haloanilines, an alternative approach to
N-substituted indoles starting from o-haloanilines appeared
potentially more direct. Thus, a sequence based around
reductive alkylation of o-haloanilines followed by Sono-
gashira coupling/indole construction was envisaged (Figure
1). In view of the ready availability and inexpense of
3-amino-2-chloropyridine and 2-chloroanilines, the develop-
ment of efficient methods for their transformation into
substituted azaindoles/indoles was investigated.
(1) For leading references on the biological activity associated with the
indole substructure, see: (a) Kuethe, J. T.; Wong, A.; Qu, C.; Smitrovich,
J.; Davies, I. W.; Hughes, D. L. J. Org. Chem. 2005, 70, 2555-2567. (b)
Van Zandt, M. C.; Jones, M. L.; Gunn, D. E.; Geraci, L. S.; Jones, J. H.;
Sawicki, D. R.; Sredy, J.; Jacot, J. L.; DiCioccio, A. T.; Petrova, T.;
Mitschler, A.; Podjarny, A. D. J. Med. Chem. 2005, 48, 3141-3152.
(2) For a recent review, see: Gribble, G. W. J. Chem. Soc., Perkin Trans.
1 2000, 1045-1075.
(3) For a review of the Pd-catalyzed synthesis of heterocycles, see: Zeni,
G.; Larock, R. C. Chem. ReV. 2004, 104, 2285-2309.
(4) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
4467-4470.
(5) Originally, the Cu-promoted Castro reaction: (a) Castro, C. E.;
Stevens, R. D. J. Org. Chem. 1963, 28, 2163. (b) Stevens, R. D.; Castro,
C. E. J. Org. Chem. 1963, 28, 3313-3315. For early work on the Pd-
catalyzed version, see: Sakamoto, T.; Kondo, Y.; Yamanaka, H. Hetero-
cycles 1988, 27, 2225-2249.
(6) For example, see: (a) Yue, D.; Larock, R. C. Org. Lett. 2004, 6,
1037-1040. (b) Amjad, M.; Knight, D. W. Tetrahedron Lett. 2004, 45,
539-541. For recent examples where o-chloroanilines were used in
alternative indolization processes, see: (c) Nazare´, M.; Schneider, C.;
Lindenschmidt, A.; Will, D. W. Angew. Chem., Int. Ed. 2004, 43, 4526-
4528. (d) Shen, M.; Li, G.; Lu, B. L.; Hossain, A.; Roschangar, F.; Farina,
V.; Senanayake, C. H. Org. Lett. 2004, 6, 4129-4132. (e) Ackermann, L.;
Kaspar, L. T.; Gschrei, C. J. Chem. Commun. 2004, 2824-2825.
(7) Ackermann, L. Org. Lett. 2005, 7, 439-442.
10.1021/ol061232r CCC: $33.50
© 2006 American Chemical Society
Published on Web 06/22/2006

this point, the use of alternative stronger acids was studied.
The use of 100 mol % of TFA resulted in a yield comparable
to that obtained with AcOH as the solvent (Table 1, entry
9). Further development led to optimal conditions (Table 1,
entry 11).10,11 The reaction did not function well in the
presence of 200 mol % of MeSO3H (Table 1, entry 12).
Gratifyingly, the developed conditions gave good results
across a range of aldehyde and ketone substrates (Table 2).12
Figure 1. Alternative routes to substituted indoles.
Reductive alkylation of electron-deficient arylamines is
known to be difficult8 and there are no reports of this reaction
using 3-amino-2-chloropyridine as the amine partner. Indeed,
our initial efforts to conduct this reaction between 3-amino-
2-chloropyridine 1a and ethyl 4-piperidone carboxylate 2a
using NaBH(OAc)3 (STAB) were thwarted by insufficient
imine/iminium concentration and competing direct reduction
of the carbonyl (Table 1, entry 1). Even with 300 mol % of
Table 2. Reductive Amination Reactionsa
Table 1. Optimization of the Reductive Alkylation Processa
ketone STAB
(mol %) (mol %) conv (%)
amine assay yieldb
entry
acid (mol %)
(%)
1
2
3
4
5
6
7
8
9
AcOH (0)
AcOH (50)
100
100
100
100
100
100
100
150
120
120
110
110
120
120
120
120
120
120
120
170
150
150
120
120
36
34
39
46
52
55
60
99
97
100
99
6
15
15
19
20
22
34
54
97
94
99
98
3
AcOH (100)
AcOH (200)
AcOH (300)
AcOH (1000)
AcOH (solvent)
AcOH (solvent)
TFA (100)
TFA (200)
TFA (200)
MeSO3H (200)
10
11
12
a Reaction conditions: All reactions conducted at rt using amine 1a as
the limiting reagent. b Conversion and assay yields were determined by LC
versus purified standards.
the ketone, the conversion of the amine remained below 50%.
The standard literature recommendation8 for poorly nu-
cleophilic amines is to add 100-150 mol % of AcOH, along
with a concomitant increase in the amounts of carbonyl
component and STAB. In the present case, poor yields were
still obtained with added AcOH, although a trend toward
increasing yield with increasing quantities of acid was clear
(Table 1, entries 2-6).
With this observation in mind, AcOH was used as solvent
for this reaction and a high assay yield was obtained, with
150 mol % of ketone and 170 mol % of STAB necessary
for total consumption of the amine (Table 1, entry 8).9 At
a Reaction conditions: amine (100 mol %), carbonyl (110 mol %), TFA
(200 mol %), and STAB (120 mol %) in i-PrOAc at rt. b Yields refer to
isolated material. c 130 mol % of ketone used.
The ability to use aldehydes under these acid-promoted
conditions is notable since competing carbonyl reduction was
reported to be a significant issue with these more reactive
substrates.8 Application of the same conditions to 2-chlo-
roaniline reductive alkylations also led to high yields (Table
2). In certain instances, the reductively alkylated products
could be directly crystallized in high purity following
(8) Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.;
Shah, R. D. J. Org. Chem. 1996, 61, 3849-3862.
3308
Org. Lett., Vol. 8, No. 15, 2006

aqueous workup. When the products were oils, chromatog-
raphy was necessary to obtain analytically pure material. In
general, however, the crude products from these reductive
alkylations were sufficiently pure for direct use in the
subsequent indolization chemistry.
Table 3. Azaindole Synthesisa
Having secured access to a range of N-substituted inter-
mediates, attention was focused on the planned indole
synthesis. For the Sonogashira coupling step, the goal was
to realize economical and mild reaction conditions. Based
on observations13 made during the course of a concurrent
study of Pd-catalyzed reactions using related 2-chloropyridine
compounds, a novel protocol for Sonogashira coupling of
these derivatives was developed. It was found that 2 mol %
of Pd(OAc)2 and 4 mol % of dppb with K2CO3 as the base
in MeCN at 80 °C was an effective, copper-free catalyst
system for Sonogashira coupling of 3-amino-2-chloropy-
ridines with various alkynes. To our knowledge, this is the
first report of this simple and inexpensive catalyst system
for this transformation. Attempts to extend these conditions
to the chloroaniline substrates led to incomplete conversion,
which prompted utilization of alternative conditions. In this
regard, it was found that a slight modification of Buchwald’s
excellent copper-free conditions14 was successful across all
substrates in this report. For the 2-chloropyridine series,
successful coupling was achieved at 60 °C using K2CO3 as
the base, MeCN as the solvent, and only a small excess of
the alkyne component (105 mol %).15 Significantly, under
these conditions, alkyne decomposition was negligible,
obviating the need for slow addition of this reaction partner.16
In accord with previous observations,14 the more electron-
rich chloroaniline series required more elevated temperatures
(80 °C) to achieve full conversion.
Knochel has reported17 the cyclization of o-alkynylanilines
using superstoichiometric quantities (130-210 mol %) of
(9) 1H NMR (AcOH-d4) analysis of a mixture of amine 1a and ketone
2a indicated <5% equilibrium imine/iminium concentration.
(10) 1H NMR study of the TFA system again indicated <5% equilibrium
imine/iminium concentration.
(11) The direct use of NaBH4 was investigated for the conversion of 1a
to 2a, although competing carbonyl reduction was anticipated to be a serious
issue. Nevertheless, complete conversion of the amine partner was achieved
with a 130-140 mol % charge of the carbonyl partner and slow addition
(∼5 h) of the reductant, affording a 95% assay yield of 2a. Depending
upon the application, this procedure could prove more economical since
NaBH4 is substantially cheaper than commercial STAB. However, the
operational simplicity and decreased quantities of alcohol byproduct
associated with the STAB-mediated process made this the preferred method.
(12) Certain carbonyl substrates such as aromatic/unsaturated ketones
and sterically hindered ketones are known8 to perform poorly in reductive
alkylation reactions. Under the conditions developed here, the following
carbonyl compounds exhibited poor reactivity (<10% conversion): ac-
etophenone, R-tetralone, pinacolone, and methyl isobutyl ketone.
(13) See the accompanying paper: McLaughlin, M.; Paluki, M.; Davies,
I. W. Org. Lett. 2006, 8, 3311-3314.
a Reaction conditions: substrate (100 mol %), alkyne (110 mol %),
Pd(OAc)2 (2 mol %), dppb (4 mol %), K2CO3 (300 mol %), MeCN (10
mL/g), 80 °C, 16 h, then 1 M t-BuOK in THF (50 mol %), rt. b Yields
refer to isolated material using the Pd(OAc)2/dppb system. Alternatively,
substrate (100 mol %), alkyne (105 mol %), PdCl2(MeCN)2 (1 mol %),
X-Phos (3 mol %), K2CO3 (300 mol %), MeCN (10 mL/g), 60 °C, 16 h,
then 1 M t-BuOK in THF (50 mol %), rt afforded similar yields.
(14) (a) Anderson, K. W.; Buchwald, S. L. Angew. Chem., Int. Ed. 2005,
44, 6173-6177. (b) Gelman, D.; Buchwald, S. L. Angew. Chem., Int. Ed.
2003, 42, 5993-5996.
KH or t-BuOK in NMP; however, no examples of the
cyclization of N-substituted substrates were included. In the
present work, the prepared substrates bearing additional
N-substitution were studied, and modified conditions were
developed. It was not critical to use NMP as solvent and the
reaction proceeded equally well in THF or MeCN. The
absence of an indolic NH proton in the products raised the
possibility of using catalytic amounts of base. Indeed, while
truly catalytic quantities of base were insufficient, sub-
(15) In the current work, the more economical K2CO3 was found to
perform equally as well as the recommended Cs2CO3.
(16) In the original Buchwald study, unproductive consumption of
arylalkynes was observed in reactions conducted at more elevated temper-
atures (90 °C), necessitating a slow addition protocol.
(17) (a) Koradin, C.; Dohle, W.; Rodriguez, A. L.; Schmid, B.; Knochel,
P. Tetrahedron 2003, 59, 1571-1587. (b) Rodriguez, A. L.; Koradin, C.;
Dohle, W.; Knochel, P. Angew. Chem., Int. Ed. 2000, 39, 2488-2490. The
authors of these reports indicate that excess base was necessary due to
formation of unreactive potassium salts of the product indoles.
Org. Lett., Vol. 8, No. 15, 2006
3309

stoichiometric amounts (50 mol %) of 1 M t-BuOK in THF
solution were found to effectively promote the indolization
process.
However, a definite electronic effect was observed for the
base-promoted indolization of the alkynylated intermediates.
It was found that all pyridine-based substrates and other
electron-deficient alkynylated arylamines performed satis-
factorily in the indolization, regardless of the substituent on
the incipient indole nitrogen atom.
In contrast, more electron-rich intermediates were either
sluggish or unreactive under the standard conditions. As
shown in Table 3, alkynes other than phenylacetylene also
afforded good yields.
In summary, an expedient method for the synthesis of
azaindoles and indoles is described. An effective procedure
was developed for the reductive alkylation of amine sub-
strates normally viewed as poor partners in this process.
Under these conditions, there is no requirement for a large
excess of either the carbonyl coupling partner or the reducing
agent. Additionally, the direct use of simple NaBH4 for these
reductive alkylations is relatively uncommon and leads to a
particularly economical process.
Having demonstrated that both the Sonogashira and base-
mediated cyclization reactions were clean and high yielding,
a one-pot process appeared feasible. For the majority of
substrates, direct treatment of the Sonogashira reaction
mixture with 50 mol % of t-BuOK resulted in rapid and clean
cyclization to the indole at rt. Isolation of the products in
good yield was normally accomplished following aqueous
workup and chromatography. Tables 3 and 4 summarize the
Table 4. Indole Synthesisa
The derived N-substituted o-chloroarylamines can be
converted into azaindoles or indoles via one-pot processes
comprised of a novel combination of Sonogashira coupling
and base-promoted indolization. These procedures are notable
for the following reasons: (a) the use of cheaply available
o-chloroarylamines rather than the more commonly docu-
mented o-bromo- or o-iodoarylamines, (b) the novel use of
the economical Pd(OAc)2/dppb combination as a copper-
free Sonogashira coupling catalyst system for 2-chloropy-
ridines, and (c) the relative mildness and high efficiency of
the overall processes, which leads to good yields of the
products.
Taken as a whole, the described chemistry outlines a
method by which a range of highly functionalized azaindole
or indole cores can be rapidly accessed in high yield in two
steps starting from inexpensive materials with minimal
purification. The ubiquity of the indoles in natural products
combined with the pharmaceutical relevance of this hetero-
cyclic substructure should render this approach broadly
useful.
a Reaction conditions: substrate (100 mol %), alkyne (110 mol %),
PdCl2(MeCN)2 (1 mol %), X-Phos (3 mol %), K2CO3 (300 mol %), MeCN
(10 mL/g), 80 °C, 16 h, then 1 M t-BuOK in THF (50 mol %), rt. b Yields
refer to isolated material unless otherwise noted. c Complete Sonogashira
coupling, incomplete indolization after 200 mol % of t-BuOK and 50 °C,
NMR yield quoted. d 100 mol % of t-BuOK required for complete
indolization. e Complete Sonogashira coupling; indolization failed even with
excess base and heat.
Acknowledgment. We thank Robert A. Reamer and Tom
J. Novak (Department of Process Research, Merck and Co.,
Inc.) for assistance with NMR data and mass spectrometry
data acquisition, respectively.
Supporting Information Available: Experimental pro-
cedures, characterization data, and NMR spectra for all
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
results of application of these protocols to the series of
N-substituted arylamines prepared via the reductive alkylation
chemistry. All substrates performed well in the Sonogashira
coupling using one or other of the described procedures.
OL061232R
3310
Org. Lett., Vol. 8, No. 15, 2006