Synthesis of N-functionalized/NH-multisubstituted indoles, thienopyrroles, pyrroloindoles, and pyrazolopyrroles via sequential one-pot base-mediated and copper-catalyzed inter- and intramolecular amination of 2-[2-bromo(het)aryl]-3-(het)aryl-3-(methylthio)acrylonitriles

Article abstract of DOI:10.1021/jo501114a

A novel, efficient route to substituted 1-N-(het)aryl/NH-2-(het)aryl-3-cyanoindoles and related pyrrolo-fused heterocycles such as thienopyrroles, pyrroloindoles, and pyrazolopyrroles has been reported. The overall protocol involves sequential cycloamination of readily available 2-[2-bromo(het)aryl]-3-(het)aryl-3-(methylthio)acrylonitrile precursors with primary amines or amides via two key C-N bond-forming processes, one base-mediated intermolecular and the other Cu-catalyzed intramolecular arylamination leading to N(1)-C(2) and N(1)-C(7a) bond formation, respectively, in a two-step one-pot procedure.

Full text of DOI:10.1021/jo501114a

Article
pubs.acs.org/joc
Synthesis of N‑Functionalized/NH-Multisubstituted Indoles,
Thienopyrroles, Pyrroloindoles, and Pyrazolopyrroles via Sequential
One-Pot Base-Mediated and Copper-Catalyzed Inter- and
Intramolecular Amination of 2‑[2-Bromo(het)aryl]-3-(het)aryl-3-
(methylthio)acrylonitriles
S. Vijay Kumar,† B. Saraiah,† G. Parameshwarappa,† H. Ila,*,† and Girijesh K. Verma‡
†New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur, Bangalore 560064, India
‡Department of Chemistry, Banaras Hindu University, Varanasi 221005, India
S
* Supporting Information
ABSTRACT: A novel, efficient route to substituted 1-N-(het)aryl/NH-2-(het)aryl-3-cyanoindoles and related pyrrolo-fused
heterocycles such as thienopyrroles, pyrroloindoles, and pyrazolopyrroles has been reported. The overall protocol involves
sequential cycloamination of readily available 2-[2-bromo(het)aryl]-3-(het)aryl-3-(methylthio)acrylonitrile precursors with
primary amines or amides via two key C−N bond-forming processes, one base-mediated intermolecular and the other Cu-
catalyzed intramolecular arylamination leading to N(1)−C(2) and N(1)−C(7a) bond formation, respectively, in a two-step one-
pot procedure.
alkynation.6h,i Palladium-catalyzed reaction of o-haloanilines
INTRODUCTION
■
with internal alkynes2e,5,8 based on Larock’s protocol8a provides
direct synthesis of 2,3-substituted indoles, which, although it is
an efficient protocol for the synthesis of complex indoles,8d
frequently displays poor regioselectivity for many substrates,
requiring fine-tuning of individual reaction conditions and
ligands to obtain optimal results.8,8b Synthesis of 2-substituted
indoles by palladium-catalyzed tandem intramolecular C−N
and intermolecular C−C bond formation cross-coupling
strategy,9a−c using o-gem-dihalovinylaniline substrates, has also
been reported.9 With emerging interest in the Ullman Goldberg
reaction10 and also due to the lower cost of copper catalysts,
several new efficient routes to indole synthesis have also been
developed via copper-catalyzed reactions.11 Significant break-
throughs have also been made in recent years by several
research groups12 for developing direct approaches for indole
synthesis by transition-metal-catalyzed oxidative C−H activa-
The indole structural motif1 has been generally recognized as a
“privileged structure” in medicinal chemistry because of the
presence of this heterocyclic scaffold in numerous therapeutic
agents,2 as well as in natural products,3 displaying a wide range
of biological and pharmacological activity. Therefore, the
development of new efficient and practical methods for
synthesis of functionalized indoles has attracted the attention
of synthetic organic chemists over the past several decades.4
While classical approaches to indoles are based on a
condensation and cyclization sequence, transition-metal-cata-
lyzed C−C and C−N bond-formation reactions have recently
enabled the development of alternative methodogies toward
modular indole synthesis.4,5 In this context, palladium-catalyzed
transformations for the synthesis of indole backbone starting
from o-alkynylanilines,5,6 as well as Pd-catalyzed coupling of o-
haloanilines with terminal alkynes,5,7 have been studied
extensively. These methods generally afford 3-unsubstituted
indoles; however, in some cases, subsequent functionalization
of the 3-position can be performed in a one-pot manner, via
either Pd-catalyzed arylation,6c,d alkenylation,6e alkylation,6f,g or
Received: May 20, 2014
Published: July 29, 2014
© 2014 American Chemical Society
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Scheme 1. 2-[2-Bromo(het)aryl]-3-(het)aryl-3-(methylthio)acrylonitriles as Versatile Synthons for Heterocyclic Synthesis
tion. However, the synthesis of N-functionalized multi-
substituted indoles has not received much attention.2e,6f,12d,13
Ackermann and co-workers14 have reported a useful route to
indole framework via palladium-catalyzed tandem N-arylation−
hydroamination of o-alkynylhaloarene precursors. Willis and co-
workers15 have reported an efficient route to N-functionalized
indoles via palladium-catalyzed inter- and intramolecular
alkenyl−arylamination reaction of a broad range of 2-(2-
haloalkenyl)aryl halides as well as the corresponding alkenyl
triflates. Application of Cu-catalyzed amination methodology
for construction of the indole ring via a key N(1)−C(7a) bond
formation has also been demonstrated by several workers.11a,c,16
As part of our own research efforts directed toward design
and development of new synthetic methods for substituted and
fused five- and six-membered heterocycles, utilizing polarized
ketene dithoacetals and other newly developed organosulfur
synthons,17 we have recently reported in a series of papers
synthesis and application of a new class of organosulfur building
blocks such as 2-[2-bromo(het)aryl]-3-(het)aryl/alkyl-3-
(methylthio)acrylonitriles with the general structures 1A and
1B (Scheme 1). Thus, we have previously shown that these
intermediates (1A) undergo a novel unexpected anionic
domino rearrangement in the presence of n-butyllithium,
leading to a general synthesis of 2-(het)aryl/alkyl-1-(o-cyano)-
arylacetylenes 2.18a Also, we have developed an efficient route
for synthesis of 2-(het)aryl/alkyl-3-cyanobenzothiophenes 318b
and the corresponding thienoheterocycles 418c by intra-
molecular radical cyclization of these intermediates (Scheme
1). It was further demonstrated that Pd(0)-catalyzed direct
intramolecular (het)arylation of these intermediates provides
facile access to functionalized phenanthrenes and a variety of
novel angularly fused polycyclic heteroarenes 518d in good
yields (Scheme 1). During the course of these studies, we
became interested in employing intermediates 1A and 1B in a
cascade inter- and intramolecular C−N bond formation−
cyclization process with various primary amines, with a view to
develop a novel synthesis of substituted indoles and hetero-
fused pyrroles such as 6 and 7, respectively (Scheme 1). We
have successfully achieved this goal and herein describe a two-
step one-pot protocol, involving base-mediated intermolecular
N(1)−C(2) and Cu-catalyzed intramolecular N(1)−C(7a)
bond formation with primary amines, which allows direct
transformation of these easily accessible intermediates 1 into a
variey of N-functionalized/NH multisubstituted indoles and
their hetero-fused analogues.
RESULTS AND DISCUSSION
■
The desired 2-[2-bromo(het)aryl]-3-(het)aryl-3-(methylthio)-
acrylonitrile precursors 1a−l (Table 2), 13a−e (Table 6), 16a−
e (Table 7), and 19a−d (Table 8) were prepared according to
previously developed methods in our laboratory,18 by base-
induced condensation of the corresponding 2-bromo-(het)-
arylacetonitriles with (het)aryl dithioesters, followed by in situ
S-methylation of the resulting enethiolate intermediates
(Scheme 2).
Scheme 2. Synthesis of 2-[2-Bromo(het)aryl]-3-(het)aryl-3-
(methylthio)acrylonitrile Precursors
The general strategy for one-pot indole synthesis from 1 is
shown in Scheme 3. The major expectation was that treatment
of 1 with primary amines will furnish, under optimized
conditions, enaminonitrile 8 via conjugate addition−elimina-
tion of amine on activated β-(methylthio)acrylonitrile double
bond of 1. The ortho bromo substituent in the benzene ring of
8 should offer the possibility to convert them (in situ or in two
steps) into indole 6 by a copper- (or palladium-) catalyzed
intramolecular N-arylamination−cyclization process.
Cyclization of acrylonitrile 1a with 4-methoxyaniline was
selected as a test reaction for optimization of reaction
conditions for the synthesis of indole 6a (Scheme 4, Table
1). We first focused on devising reaction conditions for a two-
step process, that is, synthesis and isolation of enaminonitrile
8a by conjugate addition−elimination on 1a with 4-
methoxyaniline and its subsequent copper- (or palladium-)
catalyzed intramolecular arylamination to indole 6a (Scheme 4,
route a). Thus, optimization studies revealed that 1a remained
unaffected when reacted with 4-methoxyaniline in the
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Scheme 3. Designed Strategy for Synthesis of Indole 6 from 1
Scheme 4. Synthesis of Indole 6a from 1a via Enaminonitrile 8a
a
Table 1. Optimization of Reaction Conditions for Synthesis of 6a from 8a
entry
Cu catalyst (10 mol %)
ligand (20 mol %)
L-proline
base
solvent
DMF
temp, °C/time, h
% yield 6a
1
CuI
t-BuOK
t-BuOK
NaH
120/12
120/10
120/8
65
78
90
78
73
75
68
78
70
55
78
75
75
2
CuI
DMF
DMF
DMF
DMF
DMF
2-propanol
DMF
DMF
DMF
DMF
DMF
DMF
3
CuI
L-proline
4
CuI
phenanthroline
DMEDA
NaH
120/9
5
CuI
NaH
120/10
120/10
80/12
6
CuI
cyclohexane 1,2-diamine
ethylene glycol
ethylene glycol
L-proline
NaH
7
CuI
K3PO4
K3PO4
Cs2CO3
K2CO3
NaH
8
CuI
120/10
120/12
120/12
120/10
120/10
120/15
9
CuI
10
11
12
13
CuI
L-proline
CuBr
CuOAc
CuI (5 mol %)
L-proline
L-proline
NaH
L-proline
NaH
a
Reactions were performed with 8a (1 mmol) in 5 mL of solvent with 10 mol % Cu catalyst, 20 mol % ligand, and 1 equiv of base.
presences of bases like K2CO3 or Cs2CO3 in solvents like
toluene, acetonitrile, or N,N-dimethylformamide (DMF), even
at higher temperature, whereas with potassium t-butoxide in
DMF at 120 °C, enaminonitrile 8a could be obtained in
maximum yield of 35% only, upon prolonged heating (24 h).
On the other hand, when sodium hydride was employed as
base in DMF at 90 °C, the reaction was complete within 8 h,
furnishing enaminonitrile 8a in 80% yield (Scheme 4). The 1H
and 13C NMR spectra and X-ray crystallographic data of 8a
revealed that it exists as a single (E) stereoisomer.
Having established the reaction conditions for formation of
enaminonitrile 8a, we next set out to examine its intramolecular
arylamination cross-coupling to indole 6a under the influence
of various catalysts and ligands. In view of the lower costs of
copper salts and related ligands, in comparison to palladium
catalysts and phosphine ligands, we first evaluated copper-
catalyzed intramolecular cyclization of 8a to indole 6a,10,11,16
and these results are summarized in Table 1.
Copper-catalyzed “nitrogen ligand free” amination reactions
are shown to proceed efficiently in the presence of t-BuOK as
base.14a,16a We therefore first explored the possibility of
accomplishing intramolecular aminoarylation of 8a with
inexpensive CuI as catalyst under these conditions, which
afforded the desired indole 6a in 65% yield (Table 1, entry 1).
On the other hand, promising results could be achieved with
proline ligand, affording indole 6a in increased yield of 78%
under identical conditions (entry 2). Furthermore, use of
sodium hydride as base was found to be superior, furnishing
indole 6a in 90% yield within 8 h (entry 3). Preliminary studies
revealed that DMF, among a variety of other solvents [toluene,
dimethyl sulfoxide (DMSO), acetonitrile, N-methylpyrrolidone
(NMP), and tetrahydrofuran (THF)], proved to give rise to
optimal results. Use of representative ligands [phenanthroline,
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a
Table 2. One-Pot Two-Step Synthesis of 1,2,3-Trisubstituted Indoles 6 from 1
a
Reactions were performed with 1 (1 mmol) plus amine (1.1 mmol) in 10 mL of solvent and 2 equiv of 100% NaH, followed by addition of 10 mol
% CuI and 20 mol % L-proline.
N,N′-dimethylethylenediamine (DMEDA), and cyclohexane-
1,2-diamine] generally employed in Cu-catalyzed N-arylation
also furnished the indole 6a in 73−78% yield (entries 4−6).
Similarly, ethylene glycol in the presence of K3PO4 as base in
either 2-propanol or DMF was also found to be effective,11c
providing 6a in reasonably good yields (entries 7 and 8). Bases
like Cs2CO3 and K2CO3 were found to be inferior in
comparison to sodium hydride (entries 9 and 10), whereas
alternative Cu sources could also be employed, with both CuBr
and CuOAc found to be effective, although with reduced
efficiency compared to CuI (entries 11 and 12 vs entry 3).
Reducing the catalytic loading (5 mol %) resulted in decreased
yield of 6a even after 15 h of heating (entry 13).
With optimized reaction conditions for the two-step
synthesis of indole 6a from 2-(2-bromoaryl)acrylonitrile 1a in
hand (Table 1, entry 3), we next attempted one-pot sequence
by subjecting in situ generated enaminonitrile 8a to intra-
molecular arylamination by adding CuI (10 mol %) and proline
(20 mol %) to the reaction mixture (from 1a and 4-
methoxyaniline in the presence of NaH in DMF) and further
heating it at 120 °C (monitored by TLC). To our delight, the
reaction was complete within 8 h and workup of the reaction
mixture afforded indole 6a in 80% yield (Scheme 4, route b).
Despite the slightly reduced yield of indole 6a in comparison
with the two-step process, this sequential one-pot procedure
was followed throughout our subsequent studies for the
synthesis of 1-N-aryl-2-(het)arylindoles 6 (Table 2).
Having accomplished the optimal conditions for the two-step
one-pot base-mediated amination−Cu-catalyzed intramolecular
arylamination protocol, we set out to evaluate the scope and
generality of this novel indole synthesis by varying the
substituents on acrylonitrile precursors 1, as well as on N-
coupling partners, that is, anilines, following these optimized
reaction conditions (Table 2). Thus, the reaction was equally
facile with electron-donating and electron-withdrawing sub-
stituents on the aromatic ring of 1 (1a−d), yielding indoles
6a−d in high yields (Table 2, entries 1−4). Also, by employing
appropriate 3-(het)aryl-substituted acrylonitrile precursors
(1c−k), the protocol could also be extended for synthesis of
2-(het)arylindoles bearing 2-thienyl (6c), 2-furyl (6d and 6e),
2-(N-methylpyrrolyl) (6f−h), 3-(N-methylindolyl) (6i and 6j),
and 3-pyridyl (6k) moieties in good to excellent yields (entries
3−11). It should be noted that despite the broad application of
palladium- (or copper-) catalyzed C−N cross-coupling/
cyclization protocol for synthesis of 2-substituted indoles
from the relevant acetylene precursors, not much attention
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a
Table 3. Synthesis of 3-Cyano-2-alkyl-N-arylindoles 6m−o and 3-Cyano-2-(het)aryl-N-alkylindoles 6p and 6q
a
AcOH/reflux, 6−7 h (for 8m−o). bMeCN/rt, 5−6 h (for 8p and 8q). cReactions were performed with 8 (1 mmol) in 5 mL of solvent with 10 mol
% CuI, 20 mol % L-proline, and 1 equiv of Cs2CO3.
has been paid to extending this methodology for synthesis of
biologically important 2-(het)arylindoles from the correspond-
ing o-halo(het)arylacetylene substrates.14g,16a Also, extension of
the reaction to a range of commercially available anilines, as N-
coupling partners in the cyclization reaction, revealed that a
wide variety of substitution pattern and functionalities are
tolerated, as shown in Table 2. Thus, N-arylindoles containing
both electron-donating (6a; entry 1) and electron-withdrawing
groups (6b−d, 6f, and 6h; entries 2−4, 6, and 8) or bearing
sterically constrained o-substituent (6g; entry 7) on the N-aryl
moiety could be prepared efficiently in good yields following
this procedure (Table 2). When the pyridyl-2- (or 3-) amines
were used as the amine coupling partners, the corresponding N-
pyridylindoles (6e and 6i−k; entries 5 and 9−11) were also
obtained in good yields (Table 2).
desired indole 6l, furnishing only an intractable reaction
mixture (Table 2, entry 12). We therefore synthesized few 2-
alkyl- (6m−o) and 1-N-alkyl- (6p and 6q) indoles via the two-
step procedure as depicted in Table 3. Thus, enaminonitriles
8m−q were prepared by reaction of either α-ketonitriles19 9m
and 9o or the corresponding thiocarbonyl analogues 9p and 9q
with appropriate primary amines under varying conditions
(Table 3). However, enaminonitriles 8m−q failed to yield
indoles 6m−q when subjected to Cu-catalyzed intramolecular
aminoarylation under previously described conditions (NaH/
CuI/proline/DMF), affording only complex mixture of
products. Optimization of reaction conditionsusing weaker
base such as Cs2CO3 instead of NaH in the presence of CuI
catalyst and proline as ligandafforded the corresponding 2-
alkyl (6m−o) and 1-N-alkyl (6p and 6q) indoles in moderate
to good yields (Table 3).
Further elaboration of the methodology for the synthesis of
2-alkylindole by treatment of 2-(2-bromophenyl)-3-
(methylthio)hept-2-enenitrile (1l) with aniline under two-step
one-pot conditions (NaH/CuI/proline) did not yield the
In view of the importance of free N−H indoles among
biologically active compounds,2,20 besides the ease with which
less nucleophilic amides can be N-arylated under copper
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Scheme 5. Synthesis of N-Acylenaminonitriles and Their Cu-Catalyzed Intramolecular N-Arylation−Hydrolysis to Indole 12a
Table 4. Attempted Intramolecular N-Arylation of N-Acylenaminonitriles 10
entry
substrate
Cu catalyst (10 mol %)
ligand (20 mol %)
base (equiv)
solvent
temp, °C/time, h
% yield 12a
1
2
3
4
5
6
7
8
10a
10b
10a
10a
10b
10a
10b
10c
CuI
L-proline
L-proline
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
NaH (1)
DMF
120/12
120/12
110/24
80/12
75
74
70
62
66
70
68
64
CuI
NaH (1)
DMF
CuI
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
toluene
THF
CuI
CuI
toluene
toluene
toluene
toluene
110/12
110/12
110/12
110/12
CuTC
CuTC
CuI
catalysis,10a−c we further conceived of extending this protocol
for the synthesis of N-acylindoles 11 and their subsequent
hydrolysis to the corresponding NH indoles 12 (Scheme 5 and
Table 4).16a Thus, the acrylonitrile substrate 1a was reacted
with either benzamide, trimethylacetamide, or propionamide in
the presence of NaH/DMF (120 °C/10 h), yielding the
corresponding N-acylenaminonitriles 10a−c in good yields
(Scheme 4). However, subsequent copper-catalyzed intra-
molecular N-arylation of 10a−c under earlier described
reaction conditions (CuI/proline/NaH) did not provide the
expected N-acylindoles 11a−c, but the product isolated from all
these reactions was characterized as the hydrolyzed NH indole
12a (Scheme 5). Attempted intramolecular N-arylation of N-
acylenaminonitriles 10a−c in the presence of various copper
catalysts/ligands/bases under varying conditions also resulted
in the formation of only NH indole 12a, without any trace of
the corresponding N-acylindoles 11a−c (Table 4).
In view of our failure to isolate N-acylindoles 11, we
therefore focused our attention toward direct one-pot synthesis
of N-unsubstituted 2-(het)arylindoles 12a−e by reaction of the
respective acrylonitrile precursors 1 with either benzamide or t-
butylamide in the presence of sodium hydride in DMF and
subsequent in situ treatment of the resulting N-acylenaminoni-
trile intermediates 10a−e with CuI/proline in a one-pot
procedure (Table 5). Following this protocol, 1-N-unsubsti-
tuted 3-cyanoindoles bearing various 2-(het)aryl moieties such
as 2-(3-indolyl) (12b and 12c), 2-(3-pyridyl) (12d), and 2-(2-
thienyl) (12e) groups could be obtained in good to excellent
overall yields (65−74%) (Table 5, entries 2−5).
With the successful synthesis of substituted indoles, we
sought to extend our methodology to the synthesis of other
heteroarylpyrroles such as thieno[2,3-b]pyrroles,21 pyrrolo[2,3-
b]indoles,22 and pyrazolo[3,2-c]pyrroles,23 which have impor-
tant optical and electronic properties.24 Also, bioisosteric
replacement of indole arene ring by other heteroarenes in
these pyrrolo-fused heterocycles is known to alter their
biological profile by changing the binding sites as well as
their bioavailability.21a,25 Thus, thienopyrroles21a,b,25 and
pyrazolopyrroles23a are known to display a broad range of
biological activity, whereas the hexahydropyrrolo[2,3-b]indole
ring system is present in many biologically important alkaloids
and in several marketed drugs and drug candidates.26,27 It
should be noted that these fused pyrroles are less stable than
the corresponding indole derivatives and they cannot be
synthesized by the usual classical methods employed for indole
synthesis.21
Synthesis of Thieno[2,3-b]pyrroles 14a−f. We began
this segment of our studies by examining the reaction of 2-(2-
bromo-3-thienyl)-3-(methylthio)-3-(4-methoxyphenyl)-
acrylonitrile 13a with 4-methoxyaniline under the previously
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a
Table 5. Synthesis of 3-Cyano-2-(het)aryl-1-unsubstituted Indoles 12
a
Reaction was performed with 1 (1 mmol) plus amide (1.1 mmol) in 10 mL of solvent and 2 equiv of 100% NaH, followed by addition of 10 mol %
CuI and 20 mol % L-proline.
described two-step one-pot double C−N amination reaction
conditions (Table 6), which furnished the desired 4-cyano-5,6-
bis(4-methoxyphenyl)thieno[2,3-b]pyrrole 14a in 69% yield
(Table 6). Similarly, the other substituted thieno[2,3-b]pyrroles
14b−e, bearing a diverse range of 5-(het)aryl groups and N-aryl
or N-(2-pyridyl) substituents, could also be prepared in 65−
73% overall yields from the respective acrylonitrile precursors
13b−e and approppriate anilines/pyridylamine (Table 6,
entries 2−5). By subjecting one of the (2-bromothienyl)-
acrylonitriles (13e) to one-pot inter- and intramolecular
amination with benzamide under previously described con-
ditions (Scheme 4, Table 5), it was also possible to synthesize
6-unsubstituted NH thieno[2,3-b]pyrrole 14f in 72% yield
(Table 6, entry 6).
Synthesis of Pyrrolo[2,3-b]indoles 18a−e. The scope of
this novel pyrrole annulation protocol was next extended for
the synthesis of pyrrolo-fused indoles 18 by employing the
corresponding 2-[(2-bromo-1-N-methyl)-3-indolyl]acrylonitrile
substrates 16a−e and substituted anilines (Table 7). Under
previously optimized reaction conditions, the corresponding 3-
cyano-2-het(aryl)pyrrolo[2,3-b]indoles 18a−e were obtained in
moderate to good yields (58−67%) through intermediacy of
enaminonitrile 17, and no further attempts were made to
improve the yields of the products (Table 7).
Synthesis of Substituted Pyrrolo[3,2-c]pyrazoles 21a−
e. Further elaboration of the methodology revealed that the
above reaction conditions and catalytic system are equally
effective for the synthesis of annulated pyrrolopyrazoles such as
21, which are shown to be useful subunits present in
biologically relevant structures.23a Thus, 6-cyano-1,3-bis-
(phenyl)-4,5-(het)arylpyrrolo[3,2-c]pyrazoles 21a−d could be
readily accessed in 62−80% overall yields by sequential inter-
and intramolecular Cu-catalyzed amination of the correspond-
ing 2-(4-bromo-1,3-bisphenyl-5-pyrazolyl)acrylonitrile precur-
sors 19a−d with various primary amines (Table 8, entries 1−4)
through intermediacy of enaminonitrile 20. The corresponding
4-N-unsubstituted pyrrolo[3,2-c]pyrazole derivative 21e could
also be prepared in good yield by cycloannulation of
acrylonitrile precursor 19c with benzamide under earlier
described conditions (Table 8, entry 5).
CONCLUSION
■
In summary, we have developed an efficient protocol for
assembly of N-functionalized/NH-multisubstituted indoles
from easily accessible acyclic 2-(2-bromoaryl)-3-[(methyl-
thio)-(het)aryl]acrylonitrile precursors and primary amines,
involving two key N(1)−C(2) and N(1)−C(7a) bond-forming
processes, one base-mediated intermolecular conjugate addition
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a
Table 6. Synthesis of Thieno[2,3-b]pyrroles 14
a
Reactions were performed with 13 (1 mmol) plus amine (1.1 mmol) in 10 mL of DMF and 2 equiv of 100% NaH, followed by addition of 10 mol
b
% CuI and 20 mol % L-proline. In this reaction, benzamide (1.1 mmol) was used rather than amine.
and the other Cu-catalyzed intramolecular arylamination, in a
sequential two-step one-pot procedure. The synthetic method-
ology is compatible with a variety of electronically and
structurally varied primary amines including primary alkyl-
amines by tuning the reaction conditions, thus allowing
installation of a broad range of functionalized N units. The
cyclization precursors 1 are assembled by condensation of 2-
bromo(het)arylacetonitriles and (het)aryl dithioesters with
variation of both components well tolerated, thus allowing
efficient synthesis of diversely functionalized indoles. Of
particular importance is the synthesis of indoles bearing a
wide range of 2-(het)aryl moieties such as 2-thienyl, 2-furyl, 2-
pyrrolyl, 3-pyridyl, and 3-indolyl groups, since most of the
established palladium- (or copper-) catalyzed methods from
either 2-amino(or 2-halo)arylacetylenes usually lead to 2-aryl-
(or 2-alkyl-) indoles, with only a few exceptions.7b,16a Similarly,
there are only a few reports of the synthesis of indoles bearing
reactive functionalities at either 2- or 3- positions, prepared by
earlier reported cross-coupling reactions. The 3-nitrile moiety
in these newly synthesized indoles provides a useful
functionality, which can undergo a rich array of chemical
transformations to form other functional groups. 1,2-Disub-
stituted and 1,2,3-trisubstituted indoles generally display a
broad range of biological activities (COX-II inhibitors, estrogen
agonists and antagonists) and also find a range of applications
in material science (electroluminescence) industries.9a N-
substituted skeletons, especially N-arylindoles, represent an
important subclass, due to their presence in many synthetically
challenging pharmaceutically active compounds; however,
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a
Table 7. Synthesis of Pyrrolo[2,3-b]indoles 18
a
Reactions were performed with 16 (1 mmol) plus amine (1.1 mmol) in 10 mL of DMF and 2 equiv of 100% NaH, followed by addition of 10 mol
% CuI and 20 mol % L-proline.
strategic approaches to the N-aryl pattern of indole compounds
are limited.28a,b
EXPERIMENTAL SECTION
■
General Information. All chemicals were commercially purchased
and used without further purification. Solvents were dried according to
standard procedures. All reactions were monitored by thin-layer
chromatography (TLC) on silica gel plates and visualized with UV
light. Column chromatography was performed with Merck 100−200
mesh silica gel. Nuclear magnetic resonance spectra were recorded on
a (400 MHz) Fourier transform NMR spectrometer with CDCl3,
DMSO-d6, or acetone-d6 as solvent. Chemical shifts were reported in δ
ppm (parts per million) with residual solvent protons as internal
standard (δ 7.26 for CDCl3, δ 2.50 for DMSO-d6, and δ 2.05 for
acetone-d6 in 1H NMR, δ 77.16 for CDCl3, δ 39.5 for DMSO-d6 and δ
29.84 for acetone-d6 in 13C NMR). Coupling constant (J) values are
given in Hertz (Hz). Splitting patterns are designated as s (singlet), d
(doublet), t (triplet), q (quartet), dd (double doublet), dt (doublet of
triplet), ddd (doublet of doublet of doublet), m (multiplet), and br
(broad). Infrared spectra were recorded on a Fourier transform
infrared (FTIR) instrument, and high-resolution mass spectra
(HRMS) were measured on a quadrupole time-of-flight (Q-TOF)
spectrometer. Melting points were recorded on an electrothermal
The broad scope of the methodology was further illustrated
with the synthesis of biologically relevant N−H indoles by
employing primary amides as coupling partners in this
sequential one-pot C−N bond-forming reaction. We are still
not in a position to give a rational explanation for our failure to
isolate the corresponding N-acylindoles 11, which may
probably be due to steric hindrance by 2-(het)aryl group,
thus facilitating the hydrolysis of 11 to the corresponding NH-
indoles 12 during workup under these conditions.29
The protocol also enables the facile and efficient synthesis of
hetero-fused pyrroles such as thieno[2,3-b]pyrrole, pyrrolo[2,3-
b]indole, and pyrrolopyrazole structural motifs by subjecting
the corresponding 2-[2-bromo(het)aryl)]acrylonitriles to se-
quential two-step one-pot cycloamination with various primary
amines under identical conditions.
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a
Table 8. Synthesis of Pyrrolo[3,2-c]pyrazoles 21a−e
a
Reactions were performed with 19 (1 mmol) plus amine (1.1 mmol) in 10 mL of solvent and 2 equiv of 100% NaH, followed by addition of 10 mol
b
% CuI and 20 mol % L-proline. In this reaction, benzamide (1.1 mmol) was used rather than amine.
capillary melting point apparatus and are uncorrected. X-ray single-
crystal data of 8a, 6d, and 18c were collected on a diffractometer using
Mo Kα radiation (λ = 0.7107 Å), at room temperature. The structure
was solved by direct methods (SHELXS-97) and refined by full-matrix
least-squares against F2 by use of SHELXL-97 software
analytical data for the unknown enaminonitriles 8m and 8n are given
below, whereas the enaminonitrile 8o (obtained from ketonitrile 9o
and aniline) was found to be unstable and used as such without
purification for further transformation. The corresponding thioketoni-
triles 9p and 9q were obtained by condensation of the respective 2-
bromoarylacetonitrile and dithioesters in the presence of of sodium
hydride in DMF17e and used as such without further purification.
2-(2-Bromo-5-methoxyphenyl)-3-(4-methoxyphenyl)-3-
(methylthio)acrylonitrile (1a). Obtained as a 4:1 inseparable mixture
of geometrical isomers, off-white solid (1.65 g, 85%): mp 66−68 °C;
Rf 0.5 (1:4 EtOAc/hexane); IR (KBr, cm−1) 2926, 2207, 1608, 1249,
1028, 833; 1H NMR (400 MHz, CDCl3) δ 7.55 (d, J = 8.8 Hz, 0.2H),
7.48 (d, J = 8.8 Hz, 0.4H), 7.35 (d, J = 8.8 Hz, 0.8H), 7.11 (d, J = 8.8
Hz, 1.6H), 7.02 (d, J = 8.8 Hz, 0.4H), 6.94 (d, J = 3.2 Hz, 0.2H), 6.83
(dd, J = 8.8 Hz, 3.2 Hz, 0.2H), 6.74 (d, J = 8.8 Hz, 1.6H), 6.62 (dd, J =
8.8 Hz, 3.2 Hz, 0.8H), 6.49 (d, J = 3.2 Hz, 0.8H), 3.87 (s, 0.6H), 3.83
(s, 0.6H), 3.75 (s, 2.4H), 3.60 (s, 2.4H), 2.11 (s, 2.4 H), 1.91 (s,
0.6H); 13C NMR (100 MHz, CDCl3) δ 163.2, 161.4, 161.1, 160.5,
159.2, 158.7, 136.1, 135.3, 133.9, 133.6, 130.9, 130.5, 127.1, 126.4,
Precursors Prepared According to Literature. The desired
acrylonitrile precursors 1a−n, 13a−e, 16a−e, and 19a−d were
prepared according to our earlier reported procedure18 by reaction
of the corresponding 2-bromo(het)arylacetonitrile (5.0 mmol) with
the appropriate (het)aryl dithioester (5.0 mmol) by use of NaH (0.44
g, 11.0 mmol, 60%) in THF (15 mL), and subsequent alkylation with
MeI (0.46 mL, 7.5 mmol). The known acrylonitrile precursors 1c, 1e,
1f, 1h, 13b−e, 16b−d, 19a, 19b, and 19d were characterized by
comparison of their spectral and analytical data with reported data,18
whereas spectral and analytical data for the unknown precursors 1a,
1b, 1d, 1g, 1i−m, 13a, 16a, 16e, and 19c are given below.
Enaminonitriles 8m−o were prepared according to a reported
procedure19a by refluxing corresponding ketonitriles 9m or 9o and
the appropriate anilines in glacial acetic acid for 6−7 h. Spectral and
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117.63, 117.58, 117.1, 116.8, 116.7, 116.3, 114.7, 114.4, 114.1, 113.9,
107.9, 106.9, 55.7, 55.5, 55.4, 55.2, 16.51, 16.45; HRMS (ESI) m/z
calcd for C18H16BrNO2S [M + H]+ 390.0163 and 392.0143, found
390.0160 and 392.0145.
133.3, 133.2, 132.78, 132.75, 131.61, 131.57, 131.3, 131.2, 126.23,
126.19, 124.96, 124.86, 124.8, 124.7, 123.0, 121.4, 120.9, 120.6, 120.5,
120.4, 120.2, 118.0, 118.8, 115.4, 115.2, 115.0, 110.2, 109.9, 109.7,
109.3, 104.6, 103.5, 33.5, 33.3, 16.93, 16.86; HRMS (ESI) m/z calcd
for C19H14BrFN2S [M + H]+ 401.0123 and 403.0103, found 401.0128
and 403.0110.
2-(2-Bromo-4-fluorophenyl)-3-(4-fluorophenyl)-3-(methylthio)-
acrylonitrile (1b). Obtained as a single geometrical isomer, white solid
(1.46 g, 80%); mp 91−92 °C; Rf 0.6 (1:4 EtOAc/hexane); IR (KBr,
cm−1) 2926, 2207, 1602, 1482, 1230, 845; 1H NMR (400 MHz,
CDCl3) δ 7.259 (dd, J = 8.0, 2.8 Hz, 1H), 7.138 (dd, J = 8.8, 5.2 Hz,
2H), 6.97−6.91 (m, 3H), 6.82 (td, J = 8.8, 2.8 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 164.4, 163.4, 161.9, 161.2, 160.9, 133.7, 133.6,
131.24, 131.19, 131.1, 130.2, 130.1, 124.8, 124.7, 120.6, 120.4, 116.6,
116.2, 116.0, 115.3, 115.0, 108.0, 16.5; HRMS (ESI) m/z calcd for
C16H10BrF2NS [M + H]+ 365.9764 and 367.9743, found 365.9760 and
367.9739
2-(2-Bromo-4-fluorophenyl)-3-(furan-2-yl)-3-(methylthio)-
acrylonitrile (1d). Obtained as a 2:1 inseparable mixture of
geometrical isomers, brown semisolid (1.26 g, 75%): Rf 0.5 (1:4
EtOAc/hexane); IR (KBr, cm−1) 2918, 2199, 1480, 1206, 876, 742; 1H
NMR (400 MHz, CDCl3) δ 7.66−7.65 (m, 0.33H), 7.43 (dd, J = 8.0,
2.4 Hz 0.33H), 7.38−7.32 (m, 1.67H), 7.19 (dd, J = 8.8, 5.6 Hz,
0.67H), 7.14−7.10 (m, 0.67H), 7.00 (td, J = 8.4, 2.4 Hz, 0.67H), 6.59
(dd, J = 2.8, 1.6 Hz, 0.33H), 6.47 (d, J = 3.6 Hz, 0.67H), 6.36 (dd, J =
2.8, 1.2 Hz, 0.67H), 2.47 (s, 2H), 2.13 (s, 1H); 13C NMR (100 MHz,
CDCl3) δ 163.9, 163.7, 161.4, 161.2, 149.9, 148.4, 147.8, 147.1, 145.7,
145.4, 132.9, 132.8, 132.6, 132.5, 131.9, 131.8, 131.13, 131.10, 124.6,
124.5, 124.4, 124.3, 121.0, 120.73, 120.72, 120.5, 117.5, 117.3, 116.3,
115.6, 115.40, 115.35, 115.2, 112.4, 112.3, 108.3, 105.8, 17.9, 17.0;
HRMS (ESI) m/z calcd for C14H9BrFNOS [M + H]+ 337.9651 and
339.9630, found 337.9645 and 339.9624.
2-(2-Bromo-5-methoxyphenyl)-3-(methylthio)-3-(pyridin-3-yl)-
acrylonitrile (1k). Obtained as a single geometrical isomer, pale yellow
solid (1.08 g, 60%): mp 105−106 °C; Rf 0.4 (2:3 EtOAc/hexane); IR
(KBr, cm−1) 2932, 2200, 1589, 1463, 1236, 1016, 770; 1H NMR (400
MHz, CDCl3) δ 8.48 (d, J = 4.0 Hz, 1H), 8.41 (s, 1H), 7.54 (dt, J =
7.6, 2.4 Hz, 1H), 7.34 (d, J = 9.0 Hz, 1H), 7.21 (dd, J = 7.6, 5.2 Hz,
1H), 6.64 (dd, J = 9.0, 3.2 Hz, 1H), 6.54 (d, J = 3.2 Hz, 1H), 3.63 (s,
3H), 2.14 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 159.0, 157.5,
150.6, 149.7, 136.7, 135.0, 134.0, 130.8, 123.3, 117.7, 116.9, 116.4,
114.5, 110.4, 55.7, 16.6; HRMS (ESI) m/z calcd for C16H13BrN2OS
[M + H]+ 361.001 and 362.9990, found 361.0005 and 362.9990.
2-(2-Bromophenyl)-3-(methylthio)hept-2-enenitrile (1l). Obtained
as a single geometrical isomer, pale yellow liquid (1.01 g, 65%): Rf 0.7
(1:4 EtOAc/hexane); IR (KBr, cm−1) 2963, 2207, 1558, 1469, 1028,
1
757; H NMR (400 MHz, DMSO-d6) δ 7.56−7.73 (m, 1H), 7.49−
7.45 (m, 1H), 7.38−7.34 (m, 2H), 2.81−2.79 (m, 2H), 2.33 (s, 3H),
1.63 (quintet, J = 7.2 Hz, 2H), 1.48 (sextet, J = 7.2 Hz, 2H), 0.975 (t, J
= 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 165.3, 133.6, 133.0,
131.9, 131.1, 128.5, 123.2, 116.8, 104.0, 33.1, 30.8, 21.6, 13.7, 13.6;
HRMS (ESI) m/z calcd for C14H16BrNS [M + H]+ 310.0265 and
312.0245, found 310.0256 and 312.0236.
2-(2-Bromo-5-methoxyphenyl)-3-(methylthio)-3-(thiophen-2-yl)-
acrylonitrile (1m). Obtained as a 9:1 inseparable mixture of
geometrical isomers, pale yellow solid (1.50 g, 82%): mp 62−64 °C;
Rf 0.6 (1:3 EtOAc/hexane); IR (KBr, cm−1) 2932, 2200, 1564, 1463,
1236, 1016, 713; 1H NMR (400 MHz, CDCl3) δ 7.59−7.54 (m,
0.3H), 7.43 (d, J = 8.4 Hz, 0.9H), 7.39 (dd, J = 5.2, 1.2 Hz, 0.9H), 7.17
(dd, J = 4.8, 3.2 Hz, 0.1H), 7.03 (dd, J = 3.6, 1.2 Hz, 0.9H), 6.94 (d, J
= 2.8 Hz, 1H), 6.91 (dd, J = 5.2, 3.6 Hz, 0.9H), 6.84 (dd, J = 8.8, 3.2
Hz, 0.1H), 6.76−6.71 (m, 1.8H), 3.83 (s, 0.1H), 3.70 (s, 0.9H), 2.43
(s, 0.9H), 2.08 (s, 0.1H); 13C NMR (100 MHz, CDCl3) δ 159.2,
151.8, 137.4, 135.7, 133.9, 131.6, 130.9, 130.6, 130.0, 127.9, 127.6,
117.3, 117.0, 116.9, 116.8, 116.6, 114.7, 110.1, 55.7, 55.6, 18.1, 17.2;
HRMS (ESI) m/z calcd for C15H12BrNOS2 [M + H]+ 365.9622 and
367.9601, found 365.9620 and 367.9602.
2-(2-Bromothiophen-3-yl)-3-(4-methoxyphenyl)-3-(methylthio)-
acrylonitrile (13a). Obtained as a single geometrical isomer, off-white
solid (1.42 g, 78%): mp 101−102 °C; Rf 0.6 (1:4 EtOAc/hexane); IR
(KBr, cm−1) 2926, 2200, 1602, 1255, 827; 1H NMR (400 MHz,
CDCl3) δ 7.10 (d, J = 9.2 Hz, 2H), 7.03 (d, J = 5.8 Hz, 1H), 6.79 (d, J
= 9.2 Hz, 2H), 6.45 (d, J = 5.8 Hz, 1H), 3.79 (s, 3H), 2.13 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 162.1, 160.9, 134.6, 131.3, 129.3, 126.6,
126.3, 117.0, 114.2, 113.2, 102.0, 55.4, 16.8; HRMS (ESI) m/z calcd
for C15H12BrNOS2 [M + H]+ 365.9622 and 367.9601, found 365.9618
and 367.9599.
2-(2-Bromo-1-methyl-1H-indol-3-yl)-3-(4-methoxyphenyl)-3-
(methylthio)acrylonitrile (16a). Obtained as a 2:1 inseparable mixture
of geometrical isomers, pale yellow solid (1.34 g, 65%): mp 86−88 °C;
Rf 0.4 (1:4 EtOAc/hexane); IR (KBr, cm−1) 2926, 2200, 1608, 1457,
1249, 739; 1H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 8.0 Hz, 0.33H),
7.53 (d, J = 8.8 Hz, 0.67H), 7.44 (d, J = 8.0 Hz, 0.67H), 7.34 (d, J =
8.0 Hz, 0.33H), 7.30−7.27 (m, 0.33H), 7.22−7.15 (m, 3H), 7.09−7.02
(m, 1.32H), 6.66 (d, J = 8.8 Hz, 1.32H), 3.88 (s, 0.99H), 3.83 (s,
0.99H), 3.71 (s, 2.01H), 3.66 (s, 2.01H), 2.16 (s, 2.01H), 1.89 (s,
0.99H); 13C NMR (100 MHz, CDCl3) δ 163.6, 161.0, 160.4, 160.1,
136.9, 136.7, 131.2, 128.0, 127.4, 126.4, 125.8, 122.8, 122.6, 120.8,
119.3, 118.9, 118.2, 118.1, 115.8, 115.6, 114.5, 113.9, 110.0, 109.8,
109.6, 109.0, 100.6, 99.6, 55.5, 55.3, 31.9, 31.8, 17.0, 16.7; HRMS
(ESI) m/z calcd for C20H17BrN2OS [M + H]+ 413.0323 and 415.0303,
found 413.0326 and 415.0305.
2-(2-Bromo-5-methoxyphenyl)-3-(1-methyl-1H-pyrrol-2-yl)-3-
(methylthio)acrylonitrile (1g). Obtained as a single geometrical
isomer, off-white solid (1.45 g, 80%): mp 105−106 °C; Rf 0.45 (1:4
EtOAc/hexane); IR (KBr, cm−1) 2932, 2200, 1577, 1469, 1293, 1022,
1
726; H NMR (400 MHz, CDCl3) δ 7.37 (d, J = 9.0 Hz, 1H), 6.65
(dd, J = 9.0, 2.8 Hz, 1H), 6.59 (dd, J = 2.4, 2.0 Hz, 1H), 6.47 (d, J =
2.8 Hz, 1H), 6.13 (dd, J = 3.6, 2.0 Hz, 1H), 6.04 (dd, J = 3.6, 2.4 Hz,
1H), 3.60 (s, 3H), 3.43 (s, 3H), 2.13 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 158.9, 153.0, 136.0, 134.1, 133.8, 126.4, 125.3, 117.1, 116.7,
114.8, 114.1, 109.1, 108.4, 55.6, 34.7, 16.3; HRMS (ESI) m/z calcd for
C16H15BrN2OS [M + H]+ 363.0167 and 365.0146, found 363.0168
and 365.0151
2-(2-Bromo-4,5-dimethoxyphenyl)-3-(1-methyl-1H-indol-3-yl)-3-
(methylthio)acrylonitrile (1i). Obtained as a 3:1 inseparable mixture
of geometrical isomers, pale yellow solid (1.66 g, 75%): mp 80−82 °C;
Rf 0.4 (2:3 EtOAc/hexane); IR (KBr, cm−1) 2932, 2194, 1507, 1211,
745; 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 8.0 Hz, 0.77H), 7.82
(d, J = 8.0 Hz, 0.23H), 7.57 (s, 0.77H), 7.39 (d, J = 8.0 Hz, 0.77H),
7.32 (td, J = 6.8, 2.8 Hz, 0.77H), 7.28−7.23 (m, 1.54H), 7.18−7.14
(m, 1H), 6.94 (s, 0.77H), 6.93 (s, 0.23H), 6.78 (s, 0.23H), 6.45 (m,
0.23H), 3.921 (s, 2.31H), 3.919 (s, 2.31H), 3.88 (s, 2.31H), 3.80 (s,
0.69H), 3.65 (s, 0.69H), 3.41 (s, 0.69H), 2.15 (s, 0.69H), 2.00 (s,
2.31); 13C NMR (100 MHz, CDCl3) δ 157.1, 155.4, 150.0, 149.4,
148.8, 148.2, 137.4, 137.1, 131.1, 130.7, 128.4, 127.2, 126.5, 126.3,
122.9, 122.8, 121.2, 120.6, 120.2, 119.1, 118.1, 115.7, 115.3, 114.8,
114.7, 114.3, 114.1, 110.1, 109.9, 109.8, 109.6, 106.0, 104.5, 56.4, 56.3,
56.2, 55.9, 33.4, 33.3, 16.8, 16.7; HRMS (ESI) m/z calcd for
C21H19BrN2O2S [M + H]+ 443.0429 and 445.0408, found 443.0425
and 445.0407.
2-(2-Bromo-4-fluorophenyl)-3-(1-methyl-1H-indol-2-yl)-3-
(methylthio)acrylonitrile (1j). Obtained as a 3:1 inseparable mixture
of geometrical isomers, off-white solid (1.56 g, 78%): mp 95−97 °C;
Rf 0.5 (1:4 EtOAc/hexane); IR (KBr, cm−1) 2919, 2200, 1589, 1467,
1
1200, 745; H NMR (400 MHz, CDCl3) δ 7.88−7.86 (m, 0.75H),
7.74 (dt, J = 8.0, 0.8 Hz, 0.25H), 7.53 (s, 0.75H), 7.42−7.39 (m,
1.5H), 7.36−7.34 (m, 0.75H), 7.28 (td, J = 6.8, 0.8 Hz, 0.75H), 7.24−
7.20 (m, 1.75H), 7.14−7.06 (m, 1H), 6.95 (dd, J = 8.8, 6.0 Hz,
0.25H), 6.74 (s, 0.25H), 6.72−6.67 (m, 0.25H), 3.84 (s, 2.25H), 3.61
(s, 0.75H), 2.12 (s, 2.25H), 1.95 (s, 0.75H); 13C NMR (100 MHz,
CDCl3) δ 163.7, 163.1, 161.2, 160.6, 157.8, 156.1, 137.5, 137.2, 133.4,
2-(2-Bromo-1-methyl-1H-indol-3-yl)-3-(4-fluorophenyl)-3-
(methylthio)acrylonitrile (16e). Obtained as a 3:2 inseparable mixture
of geometrical isomers, off-white solid (1.45 g, 73%): mp 134−136 °C;
Rf 0.5 (1:4 EtOAc/hexane); IR (KBr, cm−1) 2168, 1467, 1223, 740; 1H
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NMR (400 MHz, CDCl3) δ 7.59−7.55 (m, 1.2H), 7.42 (d, J = 8.0 Hz,
0.6H), 7.37 (d, J = 8.0 Hz, 0.4H), 7.29 (dd, J = 7.2, 1.2 Hz, 0.4H),
7.24−7.16 (m, 3.6H), 7.08 (ddd, J = 8.0, 6.8, 1.6 Hz, 0.6H), 6.85 (t, J =
8.8 Hz, 1.2H), 3.84 (s, 1.2H), 3.66 (s, 1.8H), 2.14 (s, 1.8H), 1.88 (s,
1.2H); 13C NMR (100 MHz, DMSO-d6) δ 164.0, 163.4, 163.0, 161.5,
160.9, 159.9, 136.4, 136.2, 131.64, 131.60, 131.33, 131.29, 131.24,
131.20, 130.63, 130.60, 125.2, 124.7, 122.5, 122.4, 120.58, 120.56,
118.6, 117.8, 117.4, 117.1, 116.2, 116.0, 115.8, 115.74, 115.66, 115.4,
110.7, 110.5, 108.2, 107.4, 100.1, 99.1, 31.8, 31.7, 16.0, 15.7; HRMS
(ESI) m/z calcd for C19H14BrFN2S [M + H]+ 401.0123 and 403.0103,
found 401.0110 and 403.0091.
give pure 8a: off-white solid (0.348 g, 75%): mp 118−120 °C; Rf 0.4
(3:7 EtOAc/hexane); IR (KBr, cm−1) 3296, 2932, 2193, 1582, 1514,
1252, 1030, 835; 1H NMR (400 MHz, CDCl3) δ 7.53−7.50 (m, 3H),
7.03 (d, J = 3.2 Hz, 1H), 6.87 (d, J = 8.8 Hz, 2H), 6.76 (dd, J = 8.8, 3.2
Hz, 1H), 6.64−6.58 (m, 4H), 6.10 (br s, 1H), 3.82 (s, 3H), 3.81 (S,
3H), 3.68 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.4, 159.8,
157.3, 156.4, 134.7, 133.0, 131.7, 125.0, 124.6, 121.6, 117.7, 116.1,
114.2, 114.1, 84.7, 55.8, 55.5, 55.4; HRMS (ESI) m/z calcd for
C24H21BrN2O3 [M + Na]+ 487.0633 and 489.0613, found 487.0638
and 489.0702.
Procedure for Copper-Catalyzed Cyclization of Enaminoni-
trile 8a to 5-Methoxy-1,2-bis(4-methoxyphenyl)-1H-indole-3-
carbonitrile (6a). To a stirred solution of enaminonitrile 8a (232 mg,
0.5 mmol) in DMF (5 mL) were added CuI (9 mg, 0.05 mmol), L-
proline (12 mg, 1.0 mmol), and NaH (20 mg, 0.5 mmol, 100%), and
the reaction mixture was heated at 120 °C with constant stirring for 8
h (monitored by TLC). It was then poured into ice-cold water (20
mL), extracted with EtOAc (3 × 10 mL), washed with brine (1 × 10
mL), and dried over Na2SO4, followed by removal of the solvent. The
resulting crude product was purified by column chromatography over
silica gel with 12% EtOAc/hexane as eluent to give pure 6a: white
solid (0.172 mg, 90%): mp 141−142 °C; Rf 0.4 (1:4 EtOAc/hexane);
2-(4-Bromo-1,3-diphenyl-1H-pyrazol-5-yl)-3-(1-methyl-1H-pyr-
rol-2-yl)-3-(methylthio)acrylonitrile (19c). Obtained as a 1:1
inseparable mixture of geometrical isomers, brown solid (1.54 g,
65%): mp 72−74 °C; Rf 0.35 (1:4 EtOAc/hexane); IR (KBr, cm−1)
1
2926, 2207, 1495, 1306, 959, 694; H NMR (400 MHz, CDCl3) δ
8.03−8.01 (m, 1H), 7.96−7.94 (m, 1H), 7.63−7.61 (m, 1H), 7.52−
7.36 (m, 6H), 7.20−7.19 (m, 1H), 6.80 (t, J = 2.0 Hz, 0.5 H), 6.80 (t, J
= 2.0 Hz, 0.5H), 6.55 (t, J = 2.0 Hz, 0.5H), 6.41 (dd, J = 4.0, 1.6 Hz,
0.5H), 6.21 (dd, J = 3.6, 2.8 Hz, 0.5H), 5.93 (dd, J = 3.6, 2.8 Hz,
0.5H), 5.77 (dd, J = 3.6, 2.0 Hz, 0.5H), 3.62 (s, 1.5H), 2.94 (s, 1.5H),
2.03 (s, 1.5H), 1.83 (s, 1.5H); 13C NMR (100 MHz, CDCl3) δ 160.2,
157.8, 149.9, 149.4, 139.6, 139.1, 135.6, 135.1, 131.62, 131.55, 129.4,
129.2, 128.83, 128.78, 128.7, 128.6, 128.5, 128.4, 128.0, 127.9, 127.90,
127.8, 127.4, 125.4, 124.8, 124.45, 124.47, 116.5, 116.4, 115.5, 114.8,
109.7, 109.3, 97.6, 97.1, 96.4, 95.1, 34.7, 34.1, 16.4, 16.1; HRMS (ESI)
m/z calcd for C24H19BrN4S [M + H]+ 475.0592 and 477.0572, found
475.0586 and 477.0566
1
IR (KBr, cm−1) 2930, 2205, 1607, 1470, 1246, 1021, 814; H NMR
(400 MHz, CDCl3) δ 7.30 (d, J = 8.8 Hz, 2H), 7.22 (d, J = 2.4 Hz,
1H), 7.13 (d, J = 8.8 Hz, 2H), 7.08 (d, J = 9.2 Hz, 1H), 6.93 (d, J = 8.8
Hz, 2H), 6.88 (dd, J = 9.2, 2.4 Hz, 1H), 6.85 (d, J = 8.8 Hz, 2H), 3.90
(s, 3H), 3.84 (s, 3H), 3.80 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
160.4, 159.5, 156.5, 147.4, 132.9, 131.3, 129.7, 129.2, 128.5, 121.4,
117.3, 115.0, 114.6, 114.3, 112.6, 100.6, 85.9, 56.0, 55.7, 55.4; HRMS
(ESI) m/z calcd for C24H20N2O3 [M + H]+ 385.1552, found 385.1533.
General Procedure for Two-Step One-Pot Synthesis of
Indoles 6a−k, Thieno[2,3-b]pyrroles 14a−e, Pyrrolo[2,3-b]-
indoles 18a−c, and Pyrrolo[3,2-c]pyrazoles 21a−d. A solution
of respective 2-[2-bromo(het)aryl]-3-(het)aryl/(methylthio)-
acrylonitriles 1, 13, 16, or 19 (1.0 mmol) in dry DMF (5 mL) was
added to a stirred suspension of the corresponding aniline (1.1 mmol)
and NaH (80 mg, 2.0 mmol, 100%) in DMF (10 mL) at room
temperature, followed by further heating at 120 °C for 8−10 h
(monitored by TLC). After consumption of starting materials, CuI (19
mg, 0.1 mmol) and L-proline (23 mg, 0.2 mmol) were added to the
reaction mixture and it was further heated at the same temperature for
8−9 h (monitored by TLC). It was then cooled to room temperature,
poured into ice-cold water (50 mL), and extracted with EtOAc (2 ×
50 mL), and the combined extracts were washed with water (2 × 50
mL) and brine (1 × 50 mL), dried over Na2SO4 and evaporated under
reduced pressure. The resulting crude products were purified by
column chromatography over silica gel with EtOAc/hexane as eluent.
6-Fluoro-1,2-bis(4-fluorophenyl)-1H-indole-3-carbonitrile (6b).
Obtained from acrylonitrile 1b and 4-fluoroaniline, white solid (295
mg, 85%): mp 167−168 °C; Rf 0.7 (1:4 EtOAc/hexane); IR (KBr,
( E ) - 2 - ( 2 - B r o m o - 4 , 5 - d i m e t h o x y p h e n y l ) - 3 - ( 4 -
methoxyphenylamino)but-2-enenitrile (8m). Obtained from ketoni-
trile 9m and 4-methoxyaniline, off-white solid (261 mg, 65%): mp
119−120 °C, Rf 0.4 (1:3 EtOAc/hexane); IR (KBr, cm−1) 3329, 2939,
1
2179, 1600, 1508, 1245, 1023, 781; H NMR (400 MHz, CDCl3) δ
7.10 (s, 1H), 6.99 (d, J = 8.8 Hz, 2H), 6.89 (s, 3H), 6.83 (d, J = 8.8
Hz, 2H), 6.01 (br s, 1H), 3.88 (s, 6H), 3.79 (s, 3H), 2.19 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 158.3, 156.6, 150.0, 149.4, 131.4, 127.7,
124.8, 121.4, 116.3, 116.2, 115.0, 114.5, 81.4, 56.37, 56.35, 55.6, 17.9;
HRMS (ESI) m/z calcd for C19H19BrN2O3 [M + H]+ 403.0657 and
405.0637, found 403.0656 and 405.0638.
(E)-2-(2-Bromo-4,5-dimethoxyphenyl)-3-(4-chlorophenylamino)-
but-2-enenitrile (8n). Obtained from ketonitrile 9m and 4-chloroani-
line, off-white solid (284 mg, 70%): Rf 0.4 (1:3 EtOAc/hexane); IR
(KBr, cm−1) 3327, 2926, 2190, 1608, 1497, 1206, 1026, 776; 1H NMR
(400 MHz, CDCl3) δ 7.28 (d, J = 8.8 Hz, 2H), 7.10 (s, 1H), 6.96 (d, J
= 8.8 Hz, 2H), 6.86 (s, 1H), 6.07 (br s, 1H), 3.88 (s, 3H), 3.87 (s,
3H), 2.28 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 155.1, 150.2,
149.4, 137.3, 131.6, 129.5, 126.4, 124.4, 120.8, 116.2, 116.1, 114.7,
83.9, 56.40, 56.36, 18.0; HRMS (ESI) m/z calcd for C18H16BrClN2O2
[M + H]+ 407.0162 and 409.0141, found 407.0153 and 409.0131.
General Procedure for Synthesis of Enaminonitriles 8p and
8q. A solution of thioketonitrile 9p or 9q (1.0 mmol) and aliphatic
amine (1.0 mmol) in CH3CN (10 mL) was stirred at room
temperature for 5−6 h (monitored by TLC). The reaction mixture
was concentrated under reduced pressure and the residue was diluted
with ice-cold water (20 mL), extracted with EtOAc (2 × 20 mL), and
dried over Na2SO4, followed by removal of the solvent to give crude
8p or 8q. These were found to be unstable and were utilized for the
next step without purification.
Procedure for Synthesis of (E)-2-(2-Bromo-5-methoxyphen-
yl)-3-(4-methoxyphenyl)-3-(4-methoxyphenylamino)-
acrylonitrile (8a). A solution of 1a (390 mg, 1.0 mmol) in dry DMF
(5 mL) was added to a stirred suspension of 4-methoxyaniline (135
mg, 1.1 mmol) and NaH (44 mg, 1.1 mmol, 100%) in DMF (10 mL)
at room temperature, followed by heating at 120 °C for 8 h
(monitored by TLC). The reaction mixture after cooling was poured
into ice-cold water (50 mL) and extracted with EtOAc (2 × 50 mL),
and the organic layer was washed with water (2 × 50 mL) and brine (1
× 50 mL) and dried over Na2SO4. The solvent was removed under
reduced pressure to give the crude product, which was purified by
column chromatography over silica gel with 30% EtOAc/hexane to
1
cm−1) 3070, 2220, 1608, 1507, 1230, 1155, 845, 757; H NMR (400
MHz, CDCl3) δ 7.75 (dd, J = 8.8, 5.2 Hz, 1H), 7.33 (dd, J = 8.8, 5.2
Hz, 2H), 7.20−7.09 (m, 5H), 7.08−7.03 (m, 2H), 6.90 (dd, J = 9.2,
2.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 164.7, 163.7, 162.4,
162.2, 161.2, 160.0, 146.88, 146.85, 138.0, 137.9, 132.23, 132.20,
131.9, 131.8, 129.8, 129.7, 124.6, 124.5, 123.7, 121.0, 120.9, 117.4,
117.1, 116.4, 116.2, 115.9, 112.3, 112.3, 112.1, 98.4, 98.1, 87.8; HRMS
(ESI) m/z calcd for C21H11F3N2 [M + H]+ 349.0953, found 349.0948.
1-(4-Chlorophenyl)-5,6-dimethoxy-2-(thiophen-2-yl)-1H-indole-
3-carbonitrile (6c). Obtained from acrylonitrile 1c and 4-chloroani-
line, white solid (291 mg, 74%): mp 195−196 °C; Rf 0.6 (1:4 EtOAc/
hexane); IR (KBr, cm−1) 2936, 2207, 1486, 1275, 710; 1H NMR (400
MHz, CDCl3) δ 7.52 (d, J = 8.8 Hz, 1H), 7.35 (s, 1H), 7.34 (dd, J =
2.8, 1.2 Hz, 1H), 7.28 (d, J = 8.8 Hz, 2H), 7.18 (s, 1H), 7.03 (dd, J =
5.2, 3.6 Hz, 1H), 6.50 (s, 1H), 3.98 (s, 3H), 3.81 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 149.2, 147.9, 138.9, 135.7, 135.2, 132.4, 130.4,
130.2, 129.9, 129.6, 128.6, 127.6, 120.8, 116.8, 100.6, 94.2, 86.9, 56.6,
56.5; HRMS (ESI) m/z calcd for C21H15ClN2O2S [M + H]+ 395.0621
and 397.0592, found 395.0597 and 397.0560.
7972
dx.doi.org/10.1021/jo501114a | J. Org. Chem. 2014, 79, 7961−7978

The Journal of Organic Chemistry
Article
1-(4-Chlorophenyl)-6-fluoro-2-(furan-2-yl)-1H-indole-3-carboni-
trile (6d). Obtained from acrylonitrile 1d and 4-chloroaniline, white
solid (252 mg, 75%): mp 180−182 °C; Rf 0.4 (1:9 EtOAc/hexane); IR
(KBr, cm−1) 2938, 2220, 1621, 1489, 1192, 757; 1H NMR (400 MHz,
CDCl3) δ 7.72 (dd, J = 8.8, 4.8 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.46
(d, J = 1.2 Hz, 1H), 7.30 (d, J = 8.4 Hz, 2H), 7.08 (td, J = 8.8, 2.0 Hz,
1H), 6.73 (dd, J = 8.8, 2.0 Hz, 1H), 6.41 (dd, J = 3.6, 2.0 Hz, 1H), 6.33
(d, J = 3.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 162.5, 160.1,
144.4, 143.3, 138.4, 138.3, 137.39, 137.36, 135.9, 135.2, 130.4, 129.5,
123.9, 120.9, 120.8, 115.7, 112.7, 112.3, 112.1, 111.9, 98.1, 97.9, 85.5;
HRMS (ESI) m/z calcd for C19H10ClFN2O [M + H]+ 337.0544 and
339.0514, found 337.0532 and 339.0508.
6.90 (t, J = 7.2 Hz, 1H), 4.0 (s, 3H), 3.90 (s, 3H), 3.84 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 151.3, 149.2, 148.4, 147.5, 140.5, 138.5,
137.1, 131.1, 130.3, 125.9, 122.7, 122.6, 121.6, 121.2, 120.7, 120.0,
117.5, 109.7, 104.4, 100.4, 96.0, 87.7, 56.5, 56.4, 33.4; HRMS (ESI)
m/z calcd for C25H20N4O2 [M + H]+ 409.1665, found 409.1655.
6-Fluoro-2-(1-methyl-1H-indol-3-yl)-1-(pyridin-3-yl)-1H-indole-3-
carbonitrile (6j). Obtained from acrylonitrile 1j and 3-aminopyridine,
pale yellow solid (285 mg, 78%): mp 190−192 °C; Rf 0.4 (2:3 EtOAc/
hexane); IR (KBr, cm−1) 2926, 2220, 1583, 1489, 1243, 1028, 745; 1H
NMR (400 MHz, DMSO) δ 8.60 (d, J = 2.4 Hz, 1H), 8.56 (dd, J = 4.8,
1.6 Hz, 1H), 7.99 (ddd, J = 8.4, 2.4, 1.6 Hz, 1H), 7.78 (dd, J = 8.8, 5.2
Hz, 1H), 7.62 (s, 1H), 7.51−7.47 (m, 2H), 7.29−7.24 (m, 2H), 7.18
(td, J = 8.0, 0.8 Hz, 1H), 7.14 (dd, J = 9.6, 2.0 Hz, 1H), 6.99 (td, J =
7.6, 0.8 Hz, 1H), 3.83 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 162.2,
159.8, 149.5, 148.4, 137.5, 137.4, 137.1, 134.6, 134.0, 130.8, 125.6,
124.4, 124.2, 122.9, 121.0, 120.6, 120.5, 119.9, 116.3, 112.0, 111.8,
110.0, 102.9, 98.0, 97.8, 88.0, 33.4; HRMS (ESI) m/z calcd for
C23H15FN4 [M + Na]+ 389.1178, found 389.1177.
2-(Furan-2-yl)-1-(pyridin-2-yl)-1H-indole-3-carbonitrile (6e). Ob-
tained from acrylonitrile 1e and 2-aminopyridine, white solid (213 mg,
75%): mp 120−121 °C; Rf 0.4 (1:3 EtOAc/hexane); IR (KBr, cm−1)
1
3052, 2919, 2220, 1476, 1445, 1244, 1022, 745; H NMR (400 MHz,
CDCl3) δ 8.81 (dd, J = 4.8, 1.2 Hz, 1H), 8.68 (d, J = 2.0 Hz, 1H), 7.82
(dd, J = 7.6, 1.2 Hz, 1H), 7.74 (dq, J = 8.0, 1.6 Hz, 1H), 7.54 (ddd, J =
8.0, 4.8, 0.4 Hz, 1H), 7.40 (dd, J = 1.6, 0.4 Hz, 1H), 7.36 (td, J = 7.2,
1.2 Hz, 1H), 7.30 (td, J = 7.2, 1.2 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H),
6.58 (dd, J = 3.2, 0.4 Hz, 1H), 6.44 (dd, J = 3.2, 1. Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 150.5, 149.4, 144.4, 143.3, 138.1, 136.8, 135.9,
134.1, 127.7, 125.2, 124.3, 123.6, 119.9, 115.9, 113.3, 112.0, 111.0,
86.2; HRMS (ESI) m/z calcd for C18H11N3O [M + H]+ 286.0980,
found 286.0979.
5, 6-Dimethoxy-2-(1-methyl-1H-pyrrol-2-yl)-1-(4-
(trifluoromethyl)phenyl)-1H-indole-3-carbonitrile (6f). Obtained
from acrylonitrile 1f and 4-(trifluoromethyl)aniline, white solid (290
mg, 68%): mp 184−185 °C; Rf 0.6 (1:4 EtOAc/hexane); IR (KBr,
cm−1) 2944, 2215, 1494, 1329, 1164, 718; 1H NMR (400 MHz,
CDCl3) δ 7.72 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 7.22 (s,
1H), 6.75 (s, 1H), 6.69 (t, J = 2.4 Hz, 1H), 6.13−6.12 (m, 2H), 4.0 (s,
3H), 3.85 (s, 3H), 3.42 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
149.1, 147.9, 140.3, 137.4, 131.0, 130.6, 130.2, 127.5, 127.0, 126.93,
126.89, 125.3, 125.1, 120.7, 120.4, 116.2, 114.5, 109.1, 100.8, 94.3,
90.0, 56.57, 56.55, 34.8; HRMS (ESI) m/z calcd for C23H18F3N3O2
[M + H]+ 426.1429, found 426.1423.
1-(2-Bromophenyl)-5-methoxy-2-(1-methyl-1H-pyrrol-2-yl)-1H-
indole-3-carbonitrile (6g). Obtained from acrylonitrile 1g and 2-
bromoaniline, white solid (315 mg, 78%): mp 188−190 °C; Rf 0.4 (1:9
EtOAc/hexane); IR (KBr, cm−1) 2950, 2207, 1489, 1205, 1028, 732;
1H NMR (400 MHz, CDCl3) δ 7.67 (dd, J = 8.4, 1.2 Hz, 1H), 7.43
(td, J = 7.2, 1.2 Hz, 1H), 7.35−7.31 (m, 2H), 7.24 (d, J = 2.4 Hz, 1H),
6.92 (dd, J = 9.2, 2.4 Hz, 1H), 6.86 (d, J = 9.2 Hz, 1H), 6.73 (dd, J =
2.4, 1.6 Hz, 1H), 6.03 (dd, J = 3.6, 2.4 Hz, 1H), 5.95 (dd, J = 3.6, 1.6
Hz, 1H), 3.91 (s, 3H), 3.77 (s, 3H) ; 13C NMR (100 MHz, CDCl3) δ
156.6, 140.0, 136.3, 134.0, 132.0, 131.2, 130.9, 128.6, 128.3, 125.8,
123.2, 120.8, 116.6, 115.1, 114.0, 112.7, 108.7, 100.7, 88.0, 56.0, 35.4;
HRMS (ESI) m/z calcd for C21H16BrN3O [M + H]+ 406.0555 and
408.0535, found 406.0556 and 408.0538.
5-Methoxy-1-(pyridin-2-yl)-2-(pyridin-3-yl)-1H-indole-3-carboni-
trile (6k). Obtained from acrylonitrile 1k and 2-aminopyridine, pale
yellow solid (215 mg, 66%): mp 190−192 °C; Rf 0.4 (4:1 EtOAc/
hexane); IR (KBr, cm−1) 3064, 2938, 2220, 1589, 1465, 1211, 1022,
1
705; H NMR (400 MHz, CDCl3) δ 8.617 (ddd, J = 8.8, 2.0, 0.8 Hz,
1H), 8.61 (br s, 1H), 8.49 (s, 1H), 7.85 (dt, J = 8.0, 2.0 Hz, 1H), 7.77
(td, J = 8.0, 2.0 Hz, 1H), 7.44 (dd, J = 8.8, 0.4 Hz, 1H), 7.37 (dd, J =
4.8, 0.8 Hz, 1H), 7.35 (dd, J = 4.8, 0.8 Hz, 1H), 7.24 (d, J = 2.4 Hz,
1H), 7.05 (dt, J = 8.0, 0.8 Hz, 1H), 6.99 (dd, J = 9.2, 3.6 Hz, 1H), 3.92
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 157.0, 150.2, 150.1, 150.0,
149.98, 142.8, 138.9, 136.9, 132.2, 128.6, 125.8, 123.7, 122.1, 116.2,
115.9, 113.3, 100.8, 89.5, 56.0; HRMS (ESI) m/z calcd for C20H14N4O
[M + H]+ 327.1246, found 327.1233.
5,6-Bis(4-methoxyphenyl)-6H-thieno[2,3-b]pyrrole-4-carbonitrile
(14a). Obtained from acrylonitrile 13a and 4-methoxyaniline, white
solid (248 mg, 69%): mp 89−90 °C; Rf 0.6 (1:4 EtOAc/hexane); IR
(KBr, cm−1) 2920, 2215, 1619, 1517, 1243, 1031, 835; 1H NMR (400
MHz, DMSO-d6) δ 7.33−7.24 (m, 6H), 7.02 (d, J = 8.8 Hz, 1H), 6.97
(d, J = 9.2 Hz, 2H), 3.78 (s, 3H), 3.77 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 160.0, 159.2, 131.2, 130.9, 130.0, 126.6, 121.8, 120.1, 117.0,
116.9, 115.0, 114.9, 114.22, 114.16, 85.9, 55.5, 55.3; HRMS (ESI) m/z
calcd for C21H16N2O2S [M + H]+ 361.1011, found 361.1025.
5-(1-Methyl-1H-pyrrol-2-yl)-6-(pyridin-2-yl)-6H-thieno[2,3-b]-
pyrrole-4-carbonitrile (14b). Obtained from acrylonitrile 13b and 2-
aminopyridine, white solid (203 mg, 67%); mp 104−105 °C; Rf 0.4
(1:4 EtOAc/hexane): IR (KBr, cm−1) 2928, 2230, 1588, 1462, 1439,
1
1360, 718; H NMR (400 MHz, CDCl3) δ 8.58 (d, J = 3.6 Hz, 1H),
7.57 (t, J = 7.0 Hz, 1H), 7.23−7.14 (m, 3H), 6.83 (br s, 1H), 6.48 (br
s, 1H), 6.30 (d, J = 8.0 Hz, 2H), 3.3 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 150.1, 148.4, 138.8, 134.9, 129.6, 125.2, 123.7, 121.5, 121.2,
115.8, 115.7, 113.7, 113.2, 112.5, 109.4, 92.8, 34.5; HRMS (ESI) m/z
calcd for C17H12N4S [M + H]+ 305.0861, found 305.0855.
6-Fluoro-2-(1-methyl-1H-pyrrol-2-yl)-1-[4-(trifluoromethyl)-
phenyl]-1H-indole-3-carbonitrile (6h). Obtained from acrylonitrile 1h
and 4-(trifluoromethyl)aniline, white solid (272 mg, 71%): mp 131−
132 °C; Rf 0.6 (1:9 EtOAc/hexane); IR (KBr, cm−1) 2932, 2220, 1615,
1489, 1325, 1161, 1060, 732; 1H NMR (400 MHz, CDCl3) δ 7.76 (dd,
J = 8.8, 5.2 Hz, 1H), 7.73 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H),
7.14 (td, J = 8.8, 2.4 Hz, 1H), 7.00 (dd, J = 9.2, 2.4 Hz, 1H), 6.72 (dd,
J = 2.4, 1.6 Hz, 1H), 6.17 (dd, J = 3.6, 1.6 Hz, 1H), 6.14 (dd, J = 3.6,
2.4 Hz, 1H), 3.44 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 162.5,
160.1, 140.1,140.0, 139.7, 137.1, 137.0, 131.0, 130.7, 127.5, 127.11,
127.07, 127.03, 127.0, 125.9, 123.9, 121.1, 121.0, 119.9, 115.5, 115.0,
112.5, 112.2, 109.4, 98.4, 98.1, 90.3, 35.0; HRMS (ESI) m/z calcd for
C21H13F4N3 [M + H]+ 384.1124, found 384.1112.
5-(Furan-2-yl)-6-[4-(trifluoromethyl)phenyl]-6H-thieno[2,3-b]-
pyrrole-4-carbonitrile (14c). Obtained from 13c and 4-
(trifluoromethyl)aniline, white solid (240 mg, 67%); mp 158−160
°C; Rf 0.6 (1:9 EtOAc/hexane): IR (KBr, cm−1) 2215, 1314, 1125,
734; 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.4 Hz, 2H), 7.51 (d,
J = 8.4 Hz, 2H), 7.37 (dd, J = 2.0, 0.4 Hz, 1H), 7.17 (d, J = 5.2 Hz,
1H), 7.04 (d, J = 5.2 Hz, 1H), 6.62 (dd, J = 3.6, 0.4 Hz, 1H), 6.46 (dd,
J = 3.6, 2.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 143.6, 142.9,
141.6, 138.4, 135.5, 131.0, 130.8, 127.1, 127.09, 127.05, 127.02,
126.98, 125.6, 121.4, 117.1, 115.6, 111.8, 111.7, 87.1; HRMS (ESI) m/
z calcd for C18H9F3N2OS [M + H]+ 359.0466, found 359.0445.
5-(1-Methyl-1H-indol-3-yl)-6-phenyl-6H-thieno[2,3-b]pyrrole-4-
carbonitrile (14d). Obtained from acrylonitrile 13d and aniline, brown
solid (257 mg, 73%); mp 191−192 °C; Rf 0.5 (1:4 EtOAc/hexane); IR
(KBr, cm−1) 2920, 2215, 1596, 1510, 1235, 734; 1H NMR (400 MHz,
CDCl3) δ 7.38−7.27 (m, 6H), 7.25 (s, 1H), 7.19−7.14 (m, 3H), 7.01
(d, J = 5.2 Hz, 1H), 6.95 (dd, J = 7.6, 5.2 Hz, 1H), 3.81 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 141.3, 139.0, 137.1, 136.8, 130.4, 129.9,
129.6, 127.9, 126.0, 124.5, 122.3, 120.3, 120.2, 119.8, 117.14, 117.06,
5,6-Dimethoxy-2-(1-methyl-1H-indol-3-yl)-1-(pyridin-2-yl)-1H-in-
dole-3-carbonitrile (6i). Obtained from acrylonitrile 1i and 2-
aminopyridine, off-white solid (306 mg, 75%): mp 213-215 °C; Rf
0.4 (2:3 EtOAc/hexane); IR (KBr, cm−1) 2932, 2207, 1589, 1469,
1
1236, 745; H NMR (400 MHz, CDCl3) δ 8.68 (dd, J = 4.8, 1.2 Hz,
1H), 7.47 (td, J = 8.0, 2.0 Hz, 1H), 7.45 (s, 1H), 7.30−7.28 (m, 2H),
7.22−7.14 (m, 3H), 7.04 (d, J = 8.0 Hz, 1H), 6.96 (d, J = 8.0 Hz, 1H),
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109.5, 104.4, 86.9, 33.29; HRMS(ESI) m/z calcd for C22H15N3S [M +
H]+ 354.1065, found 354.1055.
118.4, 117.7, 117.2, 116.5, 116.3, 114.0, 110.3, 105.4, 82.6, 55.2, 30.1;
HRMS (ESI) m/z calcd for C25H18FN3O [M + H]+ 396.1512, found
396.1505.
6-Phenyl-5-(thiophen-2-yl)-6H-thieno[2,3-b]pyrrole-4-carboni-
trile (14e). Obtained from acrylonitrile 13e and aniline, pale yellow
solid (198 mg, 65%): mp 206−207 °C; Rf 0.6 (1:9 EtOAc/hexane); IR
(KBr, cm−1) 3125, 2922, 2218, 1495, 714; 1H NMR (400 MHz,
CDCl3) δ 7.48−7.46 (m, 3H), 7.36−7.32 (m, 3H), 7.22 (dd, J = 3.6,
0.8 Hz, 1H), 7.16 (d, J = 5.2 Hz, 1H), 7.02−7.00 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ 139.4, 138.9, 138.0, 130.5, 130.2, 130.1, 129.32,
129.31, 128.3, 127.5, 126.4, 121.0, 117.1, 116.5, 87.2; HRMS (ESI) m/
z calcd for C17H10N2S2 [M + H]+ 307.0364, found 307.0354.
2-(4-Methoxyphenyl)-8-methyl-1-phenyl-1,8-dihydropyrrolo[2,3-
b]indole-3-carbonitrile (18a). Obtained from acrylonitrile 16a and
aniline, off-white solid (230 mg, 61%): mp 180−181 °C; Rf 0.5 (1:9
EtOAc/hexane); IR (KBr, cm−1) 2932, 2220, 1495, 1255, 751;
1HNMR (400 MHz, CDCl3) δ 7.94 (d, J = 8.0 Hz, 1H), 7.47−7.46
4-(4-Fluorophenyl)-5-(4-methoxyphenyl)-1,3-diphenyl-1,4-
dihydropyrrolo[3,2-c]pyrazole-6-carbonitrile (21a). Obtained from
acrylonitrile 19a and 4-fluoroaniline, white solid (387 mg, 80%); mp
225−226 °C; Rf 0.7 (1:4 EtOAc:hexane); IR (KBr, cm−1) 2920, 2223,
1604, 1517, 1251, 1181, 789; 1H NMR (400 MHz, DMSO-d6) δ 7.90
(dd, J = 8.8, 1.2 Hz, 2H), 7.62 (br t, J = 7.6 Hz, 2H), 7.43−7.39 (m,
3H), 7.34 (d, J = 8.8 Hz, 2H), 7.30−7.25 (m, 1H), 7.24−7.16 (m, 4),
7.10 (d, J = 8.0 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 3.77 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 163.5, 161.0, 160.7, 150.0, 139.8, 136.2,
134.9, 133.4, 133.3, 131.7, 131.0, 129.8, 129.7, 129.6, 128.7, 128.2,
128.1, 128.0, 126.6, 120.89, 120.85, 116.4, 116.2, 116.1, 114.4, 78.0,
55.5; HRMS (ESI) m/z calcd for C31H21FN4O [M + H]+ 485.1778,
found 485.1771.
(m, 3H), 7.36−7.33 (m, 2H), 7.28−7.24 (m, 3H), 7.21 (d, J = 9.2 Hz,
1H), 6.79 (d, J = 9.2 Hz, 2H), 3.78 (s, 3H), 3.34 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 159.7, 141.2, 140.7, 139.8, 136.5, 131.2, 129.7,
129.5, 129.0, 122.1, 122.0, 120.3, 119.6, 119.3, 117.9, 114.1, 109.5,
107.2, 84.2, 55.4, 30.6; HRMS (ESI) m/z calcd for C25H19N3O [M +
H]+ 378.1606, found 378.1599.
5-(1-Methyl-1H-indol-3-yl)-1,3-diphenyl-4-[4-(trifluoromethyl)-
phenyl]-1,4 dihydropyrrolo[3,2-c]pyrazole-6-carbonitrile (21b). Ob-
tained from acrylonitrile 19b and 4-(trifluoromethyl)aniline, white
solid (373 mg, 67%); mp 261−263 °C; Rf 0.6 (1:9 EtOAc/hexane); IR
(KBr, cm−1) 2920, 2223, 1486, 1321, 1133, 1062, 741; 1H NMR (400
MHz, CDCl3) δ 7.99 (dd, J = 8.4, 1.2 Hz, 2H), 7.56 (dd, J = 8.8, 7.6
Hz, 2H), 7.40 (br d, J = 8.4 Hz, 2H), 7.37−7.32 (m, 2H), 7.248−7.245
(m, 1H), 7.23−7.10 (m, 9H), 7.01 (dd, J = 7.6, 7.2 Hz, 1H), 3.83 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 145.3, 140.5, 139.8, 137.0,
136.1, 135.2, 131.0, 130.9, 130.5, 130.1, 129.6, 128.9, 128.4, 128.1,
127.8, 127.4, 126.6, 126.23, 126.19, 126.16, 126.13, 122.9, 121.0,
120.9, 120.0, 116.2, 110.0, 103.3, 79.4, 33.5; HRMS (ESI) m/z calcd
for C34H22F3N5 [M + H]+ 558.1906, found 558.1902.
5-(1-Methyl-1H-pyrrol-2-yl)-1,3-diphenyl-4-(pyridin-2-yl)-1,4-
dihydropyrrolo[3,2-c]pyrazole-6-carbonitrile (21c). Obtained from
acrylonitrile 19c and 2-aminopyridine, white solid (286 mg, 65%); mp
202−204 °C; Rf 0.5 (3:7 EtOAc/hexane); IR (KBr, cm−1) 3053, 2223,
1580, 1502, 1470, 749; 1H NMR (400 MHz, CDCl3) δ 8.25 (ddd, J =
4.8, 2.0, 0.8 Hz, 1H), 7.96 (d, J = 8.4 Hz, 2H), 7.63 (td, J = 7.8, 2.0 Hz,
1H), 7.56 (dd, J = 8.4, 7.6 Hz, 2H), 7.34 (t, J = 7.6 Hz, 1H), 7.25−7.22
(m, 2H), 7.20−7.15 (m, 4H), 6.88 (dt, J = 8.0, 0.8 Hz, 1H), 6.68 (dd, J
= 2.8, 1.4 Hz, 1H), 6.30 (dd, J = 3.6, 1.4 Hz, 1H), 6.14 (dd, J = 3.6, 2.8
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 149.9, 149.2, 141.3, 139.8,
138.3, 136.7, 134.6, 131.7, 129.6, 128.7, 128.1, 127.9, 127.4, 126.6,
125.3, 123.4, 120.94, 120.92, 120.3, 115.3, 114.8, 108.9, 81.4, 34.8;
HRMS (ESI) m/z calcd for C28H20N6 [M + Na]+ 463.1647, found
463.1643.
4-(4-Chlorophenyl)-5-(furan-2-yl)-1,3-diphenyl-1,4-
dihydropyrrolo[3,2-c]pyrazole-6- carbonitrile (21d). Obtained from
acrylonitrile 19d and 4-chloroaniline, off-white solid (285 mg, 62%);
mp 128−130 °C; Rf 0.6 (1:4 EtOAc/hexane); IR (KBr, cm−1) 3058,
2226, 1489, 1085, 1016, 694; 1H NMR (400 MHz, CDCl3) δ 7.93 (td,
J = 7.6, 1.2 Hz, 2H), 7.56 (dd, J = 8.4, 7.6 Hz, 2H), 7.43 (dd, J = 1.4,
0.6 Hz, 1H), 7.39−7.33 (m, 3H), 7.24−7.20 (m, 3H), 7.18−7.11 (m,
4H), 6.51 (dd, J = 3.4, 0.6 Hz, 1H), 6.44 (dd, J = 3.4, 1.4 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 144.3, 143.0, 139.6, 139.2, 136.3, 136.2,
135.5, 135.0, 130.7, 129.65, 129.59, 129.4, 128.8, 128.4, 128.3, 128.2,
126.8, 121.0, 115.4, 113.3, 111.8, 77.4; HRMS (ESI) m/z calcd for
C28H17ClN4O [M + H]+ 461.1169 and 463.1140, found 461.1163 and
463.1128.
General Procedure for Synthesis of 3-Cyano-2-alkyl-N-
arylindoles 6m−o and 3-Cyano-2-(het)aryl-N-alkylindoles 6p
and 6q from Enaminonitriles 8m−q. To a stirred solution of either
pure (8m or 8n) or crude (8o−q) enaminonitrile (0.5 mmol) in DMF
(5 mL) were added CuI (9 mg, 0.05 mmol), L-proline (12 mg, 0.1
mmol), and Cs2CO3 (163 mg, 0.5 mmol, 1 equiv), and the reaction
mixture was heated at 90 °C with constant stirring for 9−10 h
(monitored by TLC). It was then poured into ice-cold water (20 mL)
and extracted with EtOAc (3 × 10 mL), and the combined extracts
were washed with water (2 × 10 mL) and brine (1 × 10 mL) and
dried over Na2SO4 followed by removal of the solvent. Th resulting
crude products were purified by column chromatography over silica
gel with EtOAc/hexane as eluent.
1-(4-Chlorophenyl)-8-methyl-2-(thiophen-2-yl)-1,8-
dihydropyrrolo[2,3-b]indole-3-carbonitrile (18b). Obtained from
acrylonitrile 16b and 4-chloroanilne, off-white solid (224 mg, 61%):
mp 255−256 °C; Rf 0.6 (1:9 EtOAc/hexane); IR (KBr, cm−1) 2932,
1
2213, 1558, 1482, 1085, 739; HNMR (400 MHz, acetone-d6) δ 7.84
(br d, J = 8.0 Hz, 1H), 7.78 (d, J = 8.8 Hz, 2H), 7.72 (d, J = 8.8 Hz,
2H), 7.55 (dd, J = 5.2, 0.8 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.33 (td,
J = 7.2, 1.2 Hz, 1H), 7.28−7.25 (m, 2H), 7.11 (dd, J = 5.2, 3.6 Hz,
1H), 3.47 (s, 3H); 13C NMR (100 MHz, acetone-d6) δ 141.8, 141.1,
136.6, 135.5, 134.5, 132.3, 131.2, 130.7, 129.6, 128.7, 128.0, 123.0,
120.9, 119.8, 119.1, 117.3, 110.8, 107.6, 85.5, 30.6; HRMS (ESI) m/z
calcd for C22H14ClN3S [M + H]+ 388.0675 and 390.0646, found
388.0667 and 390.0630.
2-(Furan-2-yl)-1-(4-methoxyphenyl)-8-methyl-1,8-
dihydropyrrolo[2,3-b]indole-3-carbonitrile (18c). Obtained from
acrylonitrile 16c and 4-methoxyaniline, pale yellow solid (245 mg,
67%): mp 225−226 °C; Rf 0.6 (1:4 EtOAc/hexane); IR (KBr, cm−1)
2963, 2213, 1526, 1249, 745; 1H NMR (400 MHz, CDCl3) δ 7.93 (dt,
J = 4.0, 1.6 Hz, 1H), 7.39−7.37 (m, 3H), 7.27−7.20 (m, 3H), 7.05 (d,
J = 8.8 Hz, 2H), 6.30 (dd, J = 3.6, 1.6 Hz, 1H), 5.90 (d, J = 3.6, 0.4 Hz,
1H), 3.92 (s, 3H), 3.28 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ
160.3, 144.1, 143.2, 140.5, 140.2, 130.3, 130.2, 127.8, 122.0, 120.0,
118.3, 117.9, 116.7, 114.9, 111.7, 110.3, 108.5, 106.1, 81.1, 55.6, 29.8;
HRMS (ESI) m/z calcd for C23H17N3O2 [M + H]+ 368.1399, found
368.1398.
1-(4-Fluorophenyl)-8-methyl-2-(1-methyl-1H-indol-3-yl)-1,8-
dihydropyrrolo[2,3-b]indole-3-carbonitrile (18d). Obtained from
acrylonitrile 16d and 4-fluoroaniline, brown solid (250 mg, 60%):
mp 250−251 °C; Rf 0.5 (1:4 EtOAc/hexane); IR (KBr, cm−1) 2924,
2211, 1505, 1214, 735; 1H NMR (400 MHz, DMSO-d6) δ 7.73 (d, J =
7.2 Hz, 1H), 7.65 (dd, J = 8.8, 4.8 Hz, 2H), 7.52 (d, J = 8.0 Hz, 1H),
7.43 (t, J = 8.8 Hz, 2H), 7.38 (s, 1H), 7.30−7.24 (m, 3H), 7.19 (q, J =
7.6 Hz, 2H), 7.03 (t, J = 7.2 Hz, 1H), 3.77 (s, 3H), 3.37 (s, 3H); 13C
NMR (100 MHz, DMSO-d6) δ 163.1, 160.7, 139.9, 139.4, 136.2,
136.0, 131.99, 131.96, 131.1, 131.0, 126.5, 121.8, 121.4, 119.80,
119.75, 119.4, 118.5, 117.6, 117.3, 116.2, 116.0, 110.23, 110.19, 105.4,
102.6, 83.6, 32.7, 30.2; HRMS (ESI) m/z calcd for C27H19FN4 [M +
H]+ 419.1672, found 419.1684.
2-(4-Fluorophenyl)-1-(4-methoxyphenyl)-8-methyl-1,8-
dihydropyrrolo[2,3-b]indole-3-carbonitrile (18e). Obtained from
acrylonitrile 16e and 4-fluoroaniline, off-white solid (256 mg, 65%):
mp 220−221 °C; Rf 0.4 (1:4 EtOAc/hexane); IR (KBr, cm−1) 2920,
2215, 1519, 1219, 744; 1H NMR (400 MHz, DMSO-d6) δ 7.72 (d, J =
6.8 Hz, 1H), 7.65 (dd, J = 8.8, 4.8 Hz, 2H), 7.51 (d, J = 8.0 Hz, 1H),
7.36 (t, J = 8.8 Hz, 1H), 7.26 (d, J = 8.8 Hz, 2H), 7.25−7.23 (m, 1H),
7.19 (td, J = 7.2, 0.8 Hz, 1H), 6.93 (d, J = 8.8 Hz, 2H), 3.75 (s, 3H),
3.34 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 163.3, 160.8, 159.3,
141.1, 140.1, 139.6, 131.9, 131.8, 131.5, 131.4, 121.6, 121.2, 119.8,
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5,6-Dimethoxy-1-(4-methoxyphenyl)-2-methyl-1H-indole-3-car-
bonitrile (6m). Obtained from enaminonitrile 8m, white solid (128
mg, 80%); mp 131−132 °C; Rf 0.6 (2:3 EtOAc/hexane); IR (KBr,
cm−1) 2919, 2220, 1608, 1482, 1224, 1022, 820; 1H NMR (400 MHz,
CDCl3) δ 7.23 (d, J = 8.8 Hz, 2H), 7.11 (s, 1H), 7.07 (d, J = 8.8 Hz,
2H), 6.49 (s, 1H), 3.95 (s, 3H), 3.90 (s, 3H), 3.77 (s, 3H), 2.37 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 160.1, 147.9, 147.1, 144.4 131.8,
128.98, 128.92, 119.76, 116.9, 115.3, 100.5, 94.5, 85.7, 56.5, 56.4, 55.8,
12.7; HRMS (ESI) m/z calcd for C19H18N2O3 [M + H]+ 323.1396,
found 323.1383.
3H), 3.61 (s, 3H), 1.36 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
165.4, 164.6, 161.9, 161.2, 159.9, 159.1, 152.1, 134.7, 134.01, 133.96,
133.7, 133.2, 133.1, 132.9, 130.7, 130.4, 129.2, 129.1, 127.8, 127.5,
125.4, 125.1, 118.7, 118.0, 117.8, 117.2, 116.8, 116.6, 115.4, 114.3,
114.2, 114.0, 99.3, 98.3, 55.9, 55.7, 55.5, 55.4; HRMS (ESI) m/z calcd
for C24H19BrN2O3 [M + H]+ 463.0657 and 465.0637, found 463.0659
and 465.0639
(E)-N-[2-(2-Bromo-5-methoxyphenyl)-2-cyano-1-(4-
methoxyphenyl)vinyl]pivalamide (10b). Obtained as a single geo-
metrical isomer, white solid (345 mg, 78%): mp 184−186 °C; Rf 0.4
(3:7 EtOAc/hexane); IR (KBr, cm−1) 3237, 2969, 2208, 1677, 1598,
1-(4-Chlorophenyl)-5,6-dimethoxy-2-methyl-1H-indole-3-car-
bonitrile (6n). Obtained from enaminonitrile 8n, white solid (127 mg,
78%): mp 185−186 °C; Rf 0.65 (1:4 EtOAc/hexane); IR (KBr, cm−1)
1
1507, 1467, 1255, 1178, 1024, 834; H NMR (400 MHz, CDCl3) δ
7.83 (br s, 1H), 7.40 (d, J = 8.8 Hz, 2H), 7.05 (d, J = 8.8 Hz, 2H), 6.71
(d, J = 8.8 Hz, 2H), 6.69 (m, 1H), 6.57 (d, J = 2.8 Hz, 1H), 3.75 (s,
3H), 3.61 (s, 3H), 1.37 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
176.9, 161.1, 159.0, 152.0, 134.0, 130.4, 125.4, 117.9, 117.1, 116.8,
115.3, 113.9, 99.4, 55.6, 55.3, 40.2, 27.5; HRMS (ESI) m/z calcd for
C22H23BrN2O3 [M + H]+ 443.0970 and 445.0950, found 443.0954 and
445.0937.
(E)-N-(2-(2-Bromo-5-methoxyphenyl)-2-cyano-1-(4-
methoxyphenyl)vinyl)propionamide (10c). Obtained as 2:1 insepa-
rable mixture of geometrical isomers, off-white solid (290 mg, 70%):
mp 104−107 °C; Rf 0.3 (3:7 EtOAc/hexane); IR (KBr, cm−1) 3234,
2929, 2203, 1687, 1595, 1251, 1023, 828; 1H NMR (400 MHz,
DMSO-d6) δ 10.21 (s, 0.33H), 9.67 (s, 0.67H), 7.59−7.53 (m, 2.34H),
7.06 (dd, J = 8.8 Hz, 2.01H), 6.94−6.91(m, 1.32H), 6.86 (dd, J = 8.8,
2.4 Hz, 0.33H), 6.81 (d, J = 8.8 Hz, 0.67H), 6.66 (d, J = 2.4 Hz,
0.33H), 3.83 (s, 2.01H), 3.76 (s, 2.01H), 3.71 (s, 0.99H), 3.62 (s,
0.99H); 13C NMR (100 MHz, DMSO-d6) δ 172.0, 171.6, 161.1, 160.6,
158.7, 158.6, 152.0, 150.4, 135.1, 134.9, 133.9, 133.8, 130.9, 130.6,
126.8, 126.2, 119.1, 118.1, 117.0, 116.3, 115.4, 114.2, 113.7, 113.62,
113.59, 100.9, 98.4, 55.5, 55.45, 55.35, 55.22, 29.1, 28.9, 9.3, 9.2;
HRMS (ESI) m/z calcd for C20H19BrN2O3 [M + H]+ 415.0657 and
417.0637, found 415.0677 and 417.0642
1
2935, 2218, 1489, 1281, 1163, 831; H NMR (400 MHz, CDCl3) δ
7.57 (d, J = 8.8 Hz, 2H), 7.28 (d, J = 8.8 Hz, 2H), 7.12 (s, 1H) 6.49 (s,
1H), 3.95 (s, 3H), 3.78 (s, 3H), 2.39 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 148.2, 147.3, 143.7, 135.3, 134.9, 131.6, 130.5, 129.1, 119.9,
116.6, 100.6, 94.2, 86.7, 56.5, 56.4, 12.7; HRMS (ESI) m/z calcd for
C18H15ClN2O2 [M + H]+ 327.0900 and 329.0871, found 327.0880 and
329.0855.
5-Methoxy-1-phenyl-2-propyl-1H-indole-3-carbonitrile (6o). Ob-
tained from enaminonitrile 8o, colorless liquid (87 mg, 60%); Rf 0.65
(1:4 EtOAc/hexane); IR (KBr, cm−1) 2967, 2211, 1480, 1248, 700; 1H
NMR (400 MHz, CDCl3) δ 7.57−7.53 (m, 3H), 7.32−7.30 (m, 2H),
7.15 (d, J = 2.4 Hz 1H), 6.90 (d, J = 8.6 Hz, 1H), 6.82 (dd, J = 8.6, 2.4
Hz, 1H), 3.87 (s, 3H), 2.78 (t, J = 7.6 Hz, 2H), 1.57 (sextet, J = 7.2
Hz, 2H), 0.87 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
156.3, 150.1, 136.3, 132.5, 130.0, 129.3, 128.1, 127.9, 116.7, 113.8,
112.1, 100.5, 85.8, 56.0, 28.4, 22.5, 13.8; HRMS (ESI) m/z calcd for
C19H18N2O [M + H]+ 291.1497, found 291.1485.
1-Benzyl-5-methoxy-2-(4-methoxyphenyl)-1H-indole-3-carboni-
trile (6p). Obtained from enaminonitrile 8p, white solid (101 mg,
55%): mp 108−109 °C; Rf 0.6 (1:4 EtOAc/hexane); IR (KBr, cm−1)
2932, 2207, 1608, 1489, 1255, 1028, 833; 1H NMR (400 MHz,
CDCl3) δ 7.43 (d, J = 8.8 Hz, 2H), 7.32−7.28 (m, 3H), 7.215 (d, J =
2.4 Hz 1H), 7.08 (d, J = 8.8 Hz, 1H), 6.99−6.97 (m, 4H), 6.88 (dd, J =
8.8, 2.4 Hz, 1H), 5.32 (s, 2H), 3.88 (s, 3H), 3.85 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 160.9, 156.2, 148.4, 136.5, 131.3, 131.0, 129.03,
128.7, 127.76, 125.8, 121.0, 117.0, 114.6, 114.4, 112.3, 100.8, 85.6,
55.8, 55.4, 48.4; HRMS (ESI) m/z calcd for C24H20N2O2 [M + H]+
369.1603, found 369.1603.
5-Methoxy-1-phenethyl-2-(thiophen-2-yl)-1H-indole-3-carboni-
trile (6q). Obtained from enaminonitrile 8q, yellow semisolid (103 mg,
58%): Rf 0.55 (1:4 EtOAc/hexane); IR (KBr, cm−1) 2926, 2207, 1451,
1243, 1028, 707; 1H NMR (400 MHz, CDCl3) δ 7.54 (dd, J = 5.2, 1.2
Hz, 1H), 7.28 (d, J = 8.8 Hz, 1H), 7.226−7.19 (m, 4H), 7.17−7.14
(m, 2H), 6.99−6.94 (m, 3H), 4.44 (t, J = 7.6 Hz, 2H), 3.88 (s, 3H),
3.03 (t, J = 7.6 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 156.3, 140.3,
137.3, 131.1, 130.5, 128.93, 128.9, 128.73, 128.7, 128.0, 127.2, 116.7,
115.1, 111.8,100.8, 87.09, 55.9, 46.5, 36.3; HRMS (ESI) m/z calcd for
C22H18N2OS [M + H]+ 359.1218, found 359.1218.
General Procedure for Copper-Catalyzed Cyclization of N-
Acylenaminonitriles 10a−c. N-Acylenaminonitriles 10a−c (0.5
mmol) were subjected to copper-catalyzed cyclization under identical
conditions as described for enaminonitrile 8a in the presence of CuI (9
mg, 0.05 mmol), L-proline (12 mg, 0.1 mmol), and NaH (20 mg, 0.5
mmol, 100%) in DMF. Workup of the reaction mixture as described
for 8a afforded in all three reactions 5-methoxy-2-(4-methoxyphenyl)-
1H-indole-3-carbonitrile (12a): off-white solid (73−75%, Scheme 4):
mp 224−225 °C; Rf 0.4 (2:3 EtOAc/hexane); IR (KBr, cm−1); 3201,
1
2960, 2225, 1469, 1248, 1026, 818; H NMR (400 MHz, CDCl3) δ
8.60 (br s, 1H), 7.80 (d, J = 8.8 Hz, 2H), 7.30 (d, J = 2.4 Hz, 1H), 7.16
(d, J = 2.4 Hz, 1H), 7.03 (d, J = 8.8 Hz, 2H), 6.92 (dd, J = 8.8, 2.4 Hz,
1H), 3.89 (s, 3H), 3.88 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
161.1, 156.2, 145.2, 130.0, 129.8, 128.3, 122.2, 117.5, 115.0, 114.8,
112.5, 100.8, 83.1, 56.0, 55.6; HRMS (ESI) m/z calcd for C17H14N2O2
[M + H]+ 279.1134, found 279.1122.
General Procedure for Two-Step One-Pot Synthesis of 3-
Cyano-2-(het)aryl-1-NH-indoles 12, 14f, and 21e. To a stirred
suspension of NaH (80 mg, 2.0 mmol, 100%) in dry DMF (5 mL) was
added the appropriate amide (1.1 mmol) in DMF (5 mL) dropwise at
room temperature, followed by addition of acrylonitrile 1, 13e, or 19c
(1.0 mmol) in DMF (10 mL). The reaction mixture was heated at 120
°C with stirring for 10 h, and after consumption of starting materials
(monitored by TLC), CuI (19 mg, 0.1 mmol) and L-proline (23 mg,
0.2 mmol) were added and the reaction mixture was further heated
(120 °C) for 9−10 h (monitored by TLC). Workup of the reaction
mixture as described for preparation of N-arylindoles 6 afforded crude
NH-indoles 12, 14f, and 21e, which were further purified by column
chromatography over silica gel with EtOAc/hexane as eluent.
General Procedure for Synthesis of N-Acylenaminonitriles
10a−c from 1a. To a stirred suspension of NaH (40 mg, 1.0 mmol,
100%) in dry DMF (10 mL) was added a solution of the appropriate
amide (1.1 mmol) in DMF (5 mL) dropwise, followed by addition of
1a (0.39 g, 1.0 mmol) in DMF (5 mL) at room temperature. The
reaction mixture was heated at 120 °C with stirring for 9−11 h
(monitored by TLC). It was then poured into ice-cold water (50 mL),
extracted with EtOAc (2 × 50 mL), washed with water (2 × 50 mL)
and brine (1 × 50 mL), and dried (Na2SO4), and the solvent was
removed under reduced pressure. The resulting crude N-acylenami-
nonitriles were purified by column chromatography over silica gel with
EtOAc/hexane as eluent.
(E)-N-[2-(2-Bromo-5-methoxyphenyl)-2-cyano-1-(4-
methoxyphenyl)vinyl]benzamide (10a). Obtained as a 70:30 mixture
of geometrical isomers, white solid (324 mg, 76%): mp 140−144 °C;
Rf 0.4 (3:7 EtOAc/hexane); IR (KBr, cm−1) 3293, 2941, 2212, 1691,
1606, 1469, 1261, 1026, 714; 1H NMR (400 MHz, CDCl3) δ 7.83 (br
s, 1H), 7.40 (d, J = 8.8 Hz, 2H), 7.05 (d, J = 8.8 Hz, 1H), 6.71 (d, J =
8.8 Hz, 1H), 6.67 (d, J = 2.8 Hz, 1H), 6.57 (d, J = 2.8 Hz, 1H), 3.74 (s,
5,6-Dimethoxy-2-(1-methyl-1H-indol-3-yl)-1H-indole-3-carboni-
trile (12b). Obtained from 1i and trimethylacetamide; white solid (244
mg, 74%): mp 138−140 °C; Rf 0.3 (1:3 EtOAc/hexane); IR (KBr,
cm−1) 3335, 2931, 2203, 1639, 1452, 1205, 1017, 742; 1H NMR (400
MHz, DMSO-d6) δ 11.83 (s, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.92 (s,
1H), 7.59 (d, J = 8.0 Hz, 1H), 7.32 (t, J = 7.2 Hz, 1H), 7.24 (t, J = 7.2
Hz, 1H), 7.06 (s, 2H), 3.93 (s, 3H), 3.84 (s, 3H), 3.82 (s, 3H); 13C
7975
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Article
NMR (100 MHz, CDCl3) δ 147.2, 146.2, 139.8, 136.7, 129.62, 129.58,
127.4, 124.6, 122.3, 120.9, 120.3, 119.9, 117.8, 110.5, 104.6, 99.8, 95.9,
55.8, 55.7, 32.9; HRMS (ESI) m/z calcd for C20H17N3O2 [M + H]+
332.1399, found 332.1391.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
6-Fluoro-2-(1-methyl-1H-indol-3-yl)-1H-indole-3-carbonitrile
(12c). Obtained from 1j and benzamide; off-white solid (187 mg,
65%): mp 255−256 °C; Rf 0.35 (2:3 EtOAc/hexane); IR (KBr, cm−1)
3293, 2205, 1424, 1130, 740; 1H NMR (400 MHz, DMSO-d6) δ 12.23
(s, 1H), 8.0 (s, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H),
7.58 (dd, J = 8.8, 5.2 Hz, 1H), 7.36−7.25 (m, 3H), 7.09 (td, J = 8.8,
2.4 Hz, 1H), 3.94 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 160.5,
158.1, 142.7, 136.8, 135.6, 135.5, 130.5, 124.7, 124.5, 122.5, 120.6,
119.9, 118.9, 117.1, 110.7, 110.0, 109.8, 104.0, 98.8, 98.6, 80.0, 33.0;
HRMS (ESI) m/z calcd for C18H12FN3 [M + H]+ 290.1094, found
290.1077
5-Methoxy-2-(pyridin-3-yl)-1H-indole-3-carbonitrile (12d). Ob-
tained from 1k and trimethylacetamide; white solid (174 mg, 70%);
mp 160−162 °C; Rf 0.3 (4:6 EtOAc/hexane); IR (KBr, cm−1) 3458,
2925, 2212, 1598, 1474, 1212, 801; 1H NMR (400 MHz, DMSO-d6) δ
9.02 (d, J = 2.0 Hz, 1H), 8.75 (dd, J = 4.6, 5.2 Hz, 1H), 8.25 (ddd, J =
8.6, 2.4, 1.6 Hz, 1H), 8.06 (d, J = 9.0 Hz, 1H), 7.65 (ddd, J = 8.6, 4.6,
0.8 Hz, 1H), 7.31 (d, J = 2.4 Hz, 1H), 7.20 (ddd, J = 9.0, 2.4, 0.8 Hz,
1H), 3.89 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 158.7, 152.0,
151.3, 148.2, 139.4, 135.6, 129.7, 127.4, 124.4, 124.3, 117.1, 114.5,
103.7, 102.3, 55.6; HRMS (ESI) m/z calcd for C15H11N3O [M + H]+
250.0980, found 250.0978.
5-Methoxy-2-(thiophen-2-yl)-1H-indole-3-carbonitrile (12e). Ob-
tained from 1m and benzamide; off-white solid (178 mg, 70%); mp
190−192 °C; Rf 0.4 (2:3 EtOAc/hexane); IR (KBr, cm−1) 3234, 2941,
2205, 1463, 1222, 1033, 811, 707; 1H NMR (400 MHz, CDCl3) δ 8.62
(br s, 1H), 7.74 (dd, J = 3.6, 1.2 Hz, 1H), 7.47 (dd, J = 4.8, 1.2 Hz,
1H), 7.30 (d, J = 8.8 Hz, 1H), 7.19 (dd, J = 4.8, 3.6 Hz, 1H), 7.14 (d, J
= 2.4 Hz, 1H), 6.94 (dd, J = 8.8, 2.4 Hz, 1H), 3.88 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 156.4, 139.2, 131.5, 129.8, 129.6, 128.7, 127.4,
127.3, 116.8, 115.4, 112.6, 100.8, 83.7, 55.9; HRMS (ESI) m/z calcd
for C14H10N2OS [M + H]+ 255.0592, found 255.0588.
We thank Professor C. N. R. Rao, FRS, for encouragement;
JNCASR, Bangalore, and the Council of Scientific and
Industrial Research (CSIR, New Delhi) for financial assistance;
and CSIR-SRF (to S.V.K. and B.S.) and Indian National
Science Academy, New Delhi, for INSA Senior Scientist
position (to H.I.). We also thank Girijesh K. Verma and Amar
Hosamani for their help in the X-ray crystal structure
determination of 8a, 6d, and 18c.
DEDICATION
■
This paper is dedicated to Professor C. N. R. Rao, JNCASR, on
the occasion of his 80th birthday.
REFERENCES
■
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1
3224, 2213, 1450, 694; H NMR (400 MHz, CDCl3) δ 9.05 (br s,
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(dd, J = 5.2, 3.6 Hz, 1H), 7.08 (d, J = 5.2 Hz, 1H), 7.0 (d, J = 5.2 Hz,
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benzamide, brown solid (225 mg, 60%); mp 120−122 °C; Rf 0.35 (2:3
EtOAc/hexane): IR (KBr, cm−1) 3404, 3064, 2953, 2211, 1601, 1497,
1275, 755; 1H NMR (400 MHz, CDCl3) δ 8.56 (br s, 1H), 7.93 (d, J =
8.0 Hz, 2H), 7.87 (d, J = 8.0 Hz, 2H), 7.55−7.52 (m, 2H), 7.50−7.46
(m, 2H), 7.38 (tt, J = 8.0, 1.2 Hz, 1H), 7.31 (tt, J = 8.0, 1.2 Hz, 1H),
6.86 (dd, J = 2.4, 1.6 Hz, 1H), 6.56 (dd, J = 3.6, 1.6 Hz, 1H), 6.27 (dd,
J = 3.6, 2.4 Hz, 1H), 3.83 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
141.4, 139.9, 135.9, 134.9, 131.8, 129.6, 129.1, 128.5, 126.5, 126.4,
126.2, 125.7, 122.7, 120.6, 116.1, 113.1, 109.2, 77.8, 35.5; HRMS
(ESI) m/z calcd for C23H17N5 [M + H]+ 364.1562, found 364.1549.
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ASSOCIATED CONTENT
■
S
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(b) Ackermann, L. Synlett 2007, 507. (c) Kruger, K.; Tillack, A.; Beller,
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* Supporting Information
Fifty-nine figures showing ORTEP X-ray crystal structure
displays for 8a, 6d, and 18c and H NMR and 13C NMR
1
spectra for all compounds (PDF); crystallographic data for 8a,
6d, and 18c (CIF). This material is available free of charge via
the Internet at http://pubs.acs.org.
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29, 1799. (b) Review: Battistuzzi, G.; Cacchi, S.; Fabrizi, G. Eur. J.
Org. Chem. 2002, 2671 and references therein. (c) Arylation: Cacchi,
S.; Fabrizi, G.; Goggiamani, A.; Perboni, A.; Sferrazza, A.; Stabile, P.
AUTHOR INFORMATION
Corresponding Author
*E-mail hila@jncasr.ac.in.
■
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The Journal of Organic Chemistry
Article
Desai, P. J.; Jiang, W.; Nguyen, S.; Ling, P.; Wilson, S. J.; Dunford, P.
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(28) Recently, Zhao and co-workers have reported synthesis of N-
aryl/alkyl-2-alkyl-3-cyanoindoles by PIFA-mediated intramolecular
oxidative cyclization of the corresponding N-aryl/alkylenaminonitriles.
However, substituent diversity at the 2-position of product indoles is
limited to 2-methyl group with only one exception; besides, these 2-
aryl-3-aryl/alkylamino-2-alkenenitriles are unstable and their isolation
in pure form is experimentally difficult. (a) Du, Y.; Liu, R.; Linn, G.;
Zhao, K. Org. Lett. 2006, 8, 5919. For NBS-induced similar
transformation, see (b) Yan, Q.; Luo, J.; Zhang-Negrerie, D.; Li,
H.; Qi, X.; Zhao, K. J. Org. Chem. 2011, 76, 8690.
(29) Attempted isolation of N-acylindole 11a by directly evaporating
the reaction mixture [either with NaH as base (Scheme 4) or with
K2CO3 (Table 4, entry 3)] under reduced pressure, showed a new spot
on the TLC plate; however, workup of this residue by pouring over
water or by direct column chromatography of the residue furnished
only NH-indole 12a.
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