Divergent reactivity in palladium-catalyzed annulation with diarylamines and α,β-unsaturated acids: Direct access to substituted 2-quinolinones and indoles

Article abstract of DOI:10.1002/chem.201501208

A palladium-catalyzed C-H activation strategy has been successfully employed for exclusive synthesis of a variety of 3-substituted indoles. A [3+3] annulation for synthesizing substituted 2-quinolinones was recently developed by reaction of α,β-unsaturate

Full text of DOI:10.1002/chem.201501208

DOI: 10.1002/chem.201501208
Communication
&
Synthetic Methods
Divergent Reactivity in Palladium-Catalyzed Annulation with
Diarylamines and a,b-Unsaturated Acids: Direct Access to
Substituted 2-Quinolinones and Indoles
Rajesh Kancherla, Togati Naveen, and Debabrata Maiti*[a]
Abstract: A palladium-catalyzed CÀH activation strategy
has been successfully employed for exclusive synthesis of
a variety of 3-substituted indoles. A [3+3] annulation for
synthesizing substituted 2-quinolinones was recently de-
veloped by reaction of a,b-unsaturated carboxylic acids
with diarylamines under acidic conditions. In the present
work, an analogous [3+2] annulation is achieved from the
Scheme 1. Divergent reactivity in heterocycle synthesis.
same set of starting materials under basic conditions to
generate 1,3-disubstituted indoles exclusively. Mechanistic
studies revealed an ortho-palladation–p-coordination–b-
thesis would be dependent on a decarboxylation (ÀCO2) reac-
migratory insertion–b-hydride elimination reaction se-
tion. Successful implementation of this hypothesis for the re-
gioselective synthesis of 1,3-diarylindole would require a CÀC
bond formation between a,b-unsaturated acid and diarylamine
(Fujiwara–Moritani-type coupling[10]). Preliminary studies with
palladium catalyst in acetic acid gave a mixture of 3-indole
and 2-quinolinone in moderate yields. This particular observa-
tion further supported the presumption that a common inter-
mediate could deliver these two heterocycles.
quence to be operative under the reaction conditions.
Indoles are a highly significant class of heterocycles with
a wide range of biological activities[1] and, as such, numerous
methods for their synthesis have been reported.[2] Recent de-
velopments for their access includes the use of transition
metal-catalyzed heteroannulation of amines with different cou-
pling partners using a directing group.[2i–t] Recently, 1,3-disub-
stitituted indoles have been of particular interest, owing to the
limited reports of their synthesis and their unique biological
activities.[3]
By replacing acetic acid with a combination of trifluoroacetic
acid (76 mL, 4 equiv) and methanol (2 mL) was previously
found to suppress the decarboxylation and thereby allow the
formation of 4-substituted-2-quinolinones exclusively.[9] In the
present work, we set out to synthesize 3-substituted-N-arylin-
doles regioselectively from diarylamines and a,b-unsaturated
acids. Exclusive formation of 3-substituted-N-arylindoles was
particularly challenging because of the possibility of generat-
ing 4-substituted-2-quinolinone and 2-substituted-N-arylin-
doles. Formation of 4-substituted-2-quinolinone can be pre-
vented by carrying out the reaction under basic conditions.
However, a mixture of 2- and 3-substituted indoles was gener-
ated. Finally, use of Pd(OAc)2/K2CO3 in methanol prevented the
formation of 2-substituted indole completely.
Methods for the synthesis of 3-arylated indoles involve
metal-catalyzed C3 arylation using Pd catalysis.[4] To synthesize
1,3-diarylindoles, in 2015, Greaney and co-workers have report-
ed a tandem arylation of indole with diaryliodonium salts.[5]
Even so, methods for the regioselective synthesis of 3-substiti-
tuted indoles using readily accessible starting materials are still
in great demand, due to their relevance in pharmaceuticals
and in medicinal chemistry.[6]
Inspired by our recent successes in heteroannulation reac-
tions via CÀH activation[2i,7] and by progress in CÀH activation
of anilines,[8] we hypothesized an ortho-olefinated intermediate
(IM; Scheme 1) as the common platform for generating indoles
and 2-quinolinones. Our previous work showed that synthesis
of 2-quinolinones would require a net dehydration (ÀH2O) of
IM (Scheme 1).[9] Subsequently, we envisioned that indole syn-
The optimized reaction conditions with diphenylamine (1a,
1.0 mmol), cinnamic acid (2a, 0.25 mmol), palladium acetate
(Pd(OAc)2, 10 mol%), 1,10-phenanthroline (20 mol%), and
K2CO3 (3 equiv) in 20:1 MeOH/H2O (1 mL) and using Cu(OAc)2
(1.0 equiv) as oxidant produced 1,3-diphenylindole 3a exclu-
sively in 84% yield (isolated in 80% yield).[11] Therefore, the
CO2H moiety of the a,b-unsaturated acid is acting as a traceless
directing group during exclusive formation of the 1,3-diarylin-
dole. The scope of the reaction was investigated by systematic
variation of the substituents on the cinnamic acids (3a–s;
Table 1). Substituents at para (3b–i), meta (3j, k), and ortho (3l,
m) positions were incorporated successfully. Functional groups
such as 4-CN, 4-CO2Me, 4-NMe2, 3-NO2, and 3-CF3 (3g–k) on
[a] Dr. R. Kancherla, T. Naveen, Prof. D. Maiti
Department of Chemistry, Indian Institute of Technology Bombay
Powai, Mumbai-400076 (India)
E-mail: dmaiti@chem.iitb.ac.in
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201501208.
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Table 1. N-aryl-3-substituted indoles:[a] aromatic variants.[11]
Table 2. N-aryl-3-substituted indoles:[a] Aliphatic and heterocyclic var-
iants[11]
[a] Yields refer to isolated product.
aryl)-N-phenylindoles (5d–h) were successfully synthesized
with complete selectivity and in synthetically useful yields
(Table 2). The decrease in yields for 5d–h was due to the in-
complete conversion of the starting materials. Efforts to incor-
porate ArNHR (R=H, Me, Et, iPr, Ts, Ac) in place of ArNH(Ar’),
gave low yields of the desired products.
Series of competition experiments have were carried out be-
tween electronically different acrylic acids and diphenylamines
to understand the reactivity and reaction mechanism of 1,3-
disubstituted indole synthesis.[14] Based on these competition
experiments and the results in Tables 1 and 2, we found that
electron-rich acrylic acids and electron-rich diarylamines were
cyclized preferentially over neutral and electron-deficient ana-
logues (Scheme 2).
[a] Yields refer to isolated product.
the arene ring were retained. Although reactions with all of
the substrates were successful, electron-rich cinnamic acids
gave better yields, which revealed electronic and steric de-
pendence (e.g., 3b vs. 3d and 3m). The halides F, Cl, and Br at
the ortho or para position were well tolerated (3d–f and 3m).
As expected, substituted diarylamines gave 1,3-disubstituted
indoles in excellent yields (3p–r).
Olefin reaction partners are often problematic in Pd-cata-
lyzed coupling reactions, giving rise to undesired side products
due to their tendency to undergo b-hydride elimination.[12] In-
terestingly, aliphatic acrylic acids also gave the 3-substituted
indole with complete selectivity (5a–c; Table 2). Reactivity of
the acrylic acids was found to increase with chain length (5a–
c).
To probe the reaction mechanism, intra- and intermolecular
competition experiments with deuterium-labeled diphenyl-
amines were also carried out (Scheme 3). Cyclization on the
undeuterated arene ring was observed preferentially with re-
spect to the [D5]aryl moiety in [D5]diphenylamine ([PH1]/[PD1]=
4.5; Scheme 3a). Additionally, intermolecular competition be-
tween [D10]- and simple (undeuterated) diphenylamine also
gave the product distribution values of 4.7 ([PH2]/[PD2],
Scheme 3b).[14] These higher values indicate that CÀH bond
cleavage is irreversible and may be involved in the turnover-
limiting step.[14]
Isolation of the intermediate IV (Scheme 4) was difficult due
to its effective annulation in the presence of trifluoroacetic
acid (TFA) to give 2-quinolinone VIII.[9] In the absence of TFA,
ortho-olefinated intermediate IV underwent decarboxylative
Presence of nitrogen and sulfur atoms in heterocyclic sub-
strates may lead to the strong co-ordination of the heteroatom
with metal catalysts, which can cause catalyst poisoning or CÀ coupling to produce 1,3-diarylindole V instead of 2-quinoli-
H functionalization at an undesired position. This limits the ap-
plicability of CÀH activation reactions in heterocycle-based
drug discovery. Efforts were made to overcome these limita-
tions in directed CÀH functionalizations of heterocycles.[13] No-
tably, under the present reaction conditions, various 3-(hetero-
none VIII.
Based on these findings, ortho-palladation of diarylamine is
proposed for the generation of intermediate I (Scheme 4),
which is an irreversible step. Interaction of I with a,b-unsatu-
rated acids will lead to species II. Subsequently, b-migratory in-
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of palladium, another catalytic cycle will be operative at VI to
give intermediate VII, which can then undergo b-hydride elimi-
nation to provide indole V.
In summary, a palladium-catalyzed CÀC and CÀN bond for-
mation between diarylamines and a,b-unsaturated acids has
been discovered for the synthesis of indoles. Exclusive forma-
tion of 3-substituted indoles was achieved under basic condi-
tions (K2CO3). The present method complements our recently
developed strategy for 2-quinolinone synthesis.[9] The versatili-
ty and the generality of the method was demonstrated by pre-
paring a variety of N-arylindoles with aromatic, aliphatic, and
heterocyclic substituents. Preliminary mechanistic understand-
ing was presented based on competition experiments and
deuterium labeling studies.
Acknowledgements
Scheme 2. Competition experiments.[11]
This activity was supported by the Science and Engineering Re-
search Board, India (No. SB/S5/GC-05/2013). Financial support
received from DST under the Fast Track Scheme (R.K.) and CSIR
(T.N.) is gratefully acknowledged. Palladium catalysts were ob-
tained as a gift from Johnson Matthey Chemicals, MIDC Taloja,
India.
Keywords: amines
indoles · palladium
·
carboxylic acids
·
CÀH activation
·
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Received: March 27, 2015
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Communication
COMMUNICATION
&
Synthetic Methods
R. Kancherla, T. Naveen, D. Maiti*
&& – &&
Divergent Reactivity in Palladium-
Catalyzed Annulation with
Diarylamines and a,b-Unsaturated
Acids: Direct Access to Substituted 2-
Quinolinones and Indoles
A basic diversion: A palladium-cata-
lyzed CÀH activation strategy is success-
fully employed for exclusive synthesis of
27 different 3-substituted indoles from
a,b-unsaturated carboxylic acids and di-
arylamines under basic conditions in
yields up to 89%. Mechanistic studies
revealed an ortho-palladation–p-coordi-
nation–b-migratory insertion–b-hydride
elimination reaction sequence.
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