Rhodium catalyzed C2-selective cyanation of indoles and pyrroles

Article abstract of DOI:10.1021/acs.joc.5b00142

An efficient and general rhodium(III) catalyzed C2-selective cyanation of indoles and pyrroles was accomplished employing easily accessible and environmentally friendly cyanating reagent, NCTS. This methodology tolerates various functional groups, uses re

Full text of DOI:10.1021/acs.joc.5b00142

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Rhodium Catalyzed C2-Selective Cyanation of Indoles and Pyrroles
Manthena Chaitanya, and Pazhamalai Anbarasan
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 12 Mar 2015
Downloaded from http://pubs.acs.org on March 13, 2015
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The Journal of Organic Chemistry
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Rhodium Catalyzed C2ꢀSelective Cyanation of Indoles
and Pyrroles
Manthena Chaitanya and Pazhamalai Anbarasan*
Department of Chemistry, Indian Institute of Technology Madras, Chennai ꢀ 600036, India
Eꢀmail: anbarasansp@iitm.ac.in
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FAX: +91ꢀ44ꢀ22574202
Abstract: An efficient and general rhodium(III) catalyzed C2ꢀselective cyanation of indoles and
pyrroles was accomplished employing easily accessible and environmentally friendly cyanating reagent,
NCTS. This methodology tolerates various functional groups, uses readily removable directing groups
and allows the synthesis of various 2ꢀcyanoindoles and pyrroles in good to excellent yield.
Cyano heteroarenes, particularly 2ꢀcyanoindoles and pyrroles, are important structural motifs present
1
in various therapeutically important natural products. Also, they are widely used as building blocks for
construction of various pharmaceuticals, agrochemicals (Figure 1) and dyes as well as incorporation of
2
these moiety in polymer provides an unique physical properties to them. Thus, efficient and selective
synthesis of 2ꢀcyanoindoles and pyrroles are highly desirable in both organic and medicinal chemistry.
Figure 1: Examples of bioactive molecules synthesized from 2ꢀcyanoindole.
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Although traditionally cyano(hetero)arenes were synthesized from corresponding aldehydes and its
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derivatives or halides, over fast few decades, selective and direct cyanation of highly abundant CꢀH
bonds of (hetero)arenes has emerged as a powerful tool to achieve atom and stepꢀeconomy in organic
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synthesis. In this context, the most documented direct cyanation of indoles is the transition metal
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mediated/catalyzed C3ꢀselective cyanation, which is probably due to the inherent property of indoles
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(
Scheme 1). Typically, C3ꢀcyanation of indoles can be achieved using isocyanatophosphoric acid
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dichloride, or triphenylthiocyanogen (TPPT) as cyanating reagent. Recently, these strategies were
t
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replaced with transition metal catalyzed cyanation of indoles employing BuNC, TMEDA/NH ,
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DMF, DMF/NH I, DMSO/NH HCO , metal cyanides, BnCN, 3,5ꢀ(CF ) C H I(OTf)CN and
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3 2
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NꢀcyanoꢀNꢀphenylꢀpꢀtoluenesulfonamide (NCTS) . However, the closely related C2ꢀselective
cyanation of indoles and related heteroarenes are rather limited.
Scheme 1: Synthesis of diarylacetic acid derivatives.
The known C2ꢀselective cyanation of indoles (pyrroles) includes the directing group assisted
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,18
palladiumꢀcatalyzed cyanation using tertꢀbutyl isocyanide
equivalent of copper salt and the substoichiometric copper catalyzed cyanation employing acetonitrile
as “CN” source along with additive such as AgOAc or (Me Si) (Scheme 2). These reactions suffer
as “CN” source in combination with 3
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3
2
from the use of high catalyst loading, super stoichiometric amount of expensive additives, harsh reaction
conditions and limited substrate scopes. Thus, the efficient catalytic C2ꢀselective cyanation of indoles
(
pyrroles) is highly warranted. Based on the need of catalytic cyanation and our interest in the CꢀH
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functionalization and cyanation employing readily accessible and environmentally benign NCTS as a
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The Journal of Organic Chemistry
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cyanating reagent , we herein reveal the general rhodium catalyzed chelation assisted selective C2ꢀ
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cyanation of indoles and pyrroles with NCTS.
Initially, we investigated the C2ꢀcyanation of indole derivatives. The C2ꢀcyanation of Nꢀ(2ꢀ
pyridyl)indole 1a with NCTS (2 equiv) in the presence of [Cp*RhCl ] (1 mol%) as a catalyst and
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AgSbF (10 mol%) as an additive in toluene at 100 ˚C for 36 h. To our delight, 2ꢀcyanoꢀNꢀ(2ꢀ
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pyridyl)indole 3a was observed in 20% isolated yield (Table 1, entry1). No reaction was observed in the
absence of either [Cp*RhCl ] or AgSbF , which shows the cyanation is catalyzed and promoted by
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2
2
rhodium and silver complex, respectively. Next, slight improvement in yield was observed while the
temperature increasing to 120 ˚C (Table 1, entry 2). Increasing the ratio of rhodium to silver complex by
adding 2 mol% of rhodium complex gave the better conversion with 56% isolated yield of 3a, but the
opposite effect was observed when the silver complex was reduced to 5 mol% to increase the ratio of
Rh(III)/Ag(I) (Table 1, entries 3 and 4).
[
a]
Table 1. Rhodium catalyzed C2ꢀselective cyanation of Nꢀ(2ꢀpyridyl)indole 1a: Optimization
[b]
[c]
Entry
X
2
2
2
2
2
2
2
2
Y
1
1
2
2
2
2
2
1
1
1
1
Solvent
Toluene
Toluene
Toluene
Toluene
C H Cl
Time (h)
36
36
36
36
36
36
18
18
Conv. (%)
ꢀ
60
81
35
Yield (%)
20
32
56
<10
33
18
82
84
82
[
d]
1
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8
9
[
e]
72
62
6
5
1,2ꢀDCE
t
AmOH
AmOH
AmOH
AmOH
100
100
100
100
100
t
t
1.5
1.2
1
18
18
18
t
10
82
92
[f]
t
1
1
AmOH
[
a] Reaction conditions: Nꢀ(2ꢀpyridyl)indole 1a (1 equiv), NCTS 2 (X equiv), [Cp*RhCl ] (Y mol%),
2 2
AgSbF (10 mol%), solvent (1.5 mL), 120 °C, time; [b] Based on the recovered starting material; [c]
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isolated yield; [d] 100 °C; [e] 5 mol% of AgSbF ; [f] 1.2 equiv of 1a and the yield is based on cyanating
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reagent.
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Although cyanation in solvents like chlorobenzene and 1,2ꢀDCE were inferior to toluene, AmOH
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gave the formation of product 3a in 82% isolated yield with complete conversion of 1a in 18 h (Table 1,
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entres 5ꢀ7). Interestingly, decreasing the catalyst loading to 1 mol% in AmOH did not affect the
reaction. Most importantly, similar effect was observed when the equivalents of cyanating reagent were
reduced to 1 equivalent and the product 3a was isolated in comparable yield (Table 1, entries 8ꢀ10).
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Finally, using 1 equivalent of NCTS and 1.2 equivalent of 1a in AmOH at 120 ˚C with 1 mol% of
[
Cp*RhCl ] and 10 mol% of AgSbF afforded the product 3a in the best isolated yield of 92%.
2 2 6
After identifying the optimal reaction conditions, we studied the scope and generality of the Rh(III)ꢀ
catalyzed C2ꢀcyanation with various substituted indoles. As shown in Scheme 2, the optimized
conditions tolerates functional groups at various position (C3, C4 and C5) of Nꢀ(2ꢀpyridyl)indoles to
afford the corresponding product in good to excellent yield. Simple aryl and readily functionalizable
bromoꢀsubstituted cyanoindoles (3b and 3c) were achieved in 76 and 77% yield respectively.
Interestingly, the reaction tolerates both electron donating (methoxy and benzyloxy) and electronꢀ
withdrawing groups (tosyloxy and cyano) on the indole moiety and led to the formation of
corresponding 2ꢀcyanoindoles (3dꢀ3h) in good yields. Sterically demanding CꢀH possessing 3ꢀmethyl
and 3ꢀ(carbomethoxy)methyl substituted indoles were also readily converted to corresponding cyanated
product (3i and 3j) in 96 and 82% yield, respectively. Similarly, substitutions on the directing group
were also examined. All the pyridine derivatives that were examined helped the chelationꢀassisted
cyanation and led to the formation of cyanated product (3kꢀ3m) in good yield. Instead of pyridine, other
chelating groups like quinoline and pyrimidine were also studied. Nꢀ(2ꢀquinolyl)indole and Nꢀ(2ꢀ
pyrimidyl)indole underwent smooth reaction to afford the product 3n and 3o in 71% and 46% yield,
respectively. However, substrate having an additional coordination site gave comparatively lower
yields.
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Scheme 2: Rhodium catalyzed C2ꢀselective cyanation of indoles. [a] 2 mol% [Cp*RhCl ] ; [b] 3
2
2
mol% [Cp*RhCl ] .
2
2
Subsequently, we extended the optimized conditions to pyrroleꢀbased derivatives. Initial attempts with
Nꢀ(pyridyl)pyrrole 4a afforded only moderate yield of 2ꢀcyanoꢀNꢀ(pyridyl)pyrrole 5a. By changing the
catalyst loading, the reaction conditions was optimized to afforded the product 5a in 81% yield, with 3
mol% of rhodium catalyst, 10 mol% of AgSbF in tertꢀamyl alcohol at 120 °C (Scheme 3 and see
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supporting information).
Scheme 3. Rhodium catalyzed C2ꢀselective cyanation of Nꢀpyridylpyrrole 4a.
Next, diverse pyrrole derivatives 4 were examined for C2ꢀselective cyanation under the optimized
conditions (Scheme 4). Simple alkyl and arylꢀsubstituted pyrrole derivatives were readily converted
under the optimized conditions to corresponding cyanated product (5c and 5d) in good yield. 2ꢀMethyl
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and 2,3ꢀfused pyrroles, sterically demanding pyrrole derivatives, underwent smooth reaction to give the
product 5a and 5e in 67 and 76% yield, respectively. Interestingly, the optimized reaction tolerates
various functional groups, like benzoyl, acetyl and ester, to afford the corresponding products (5fꢀ5h) in
moderate yield. Furthermore, cyanation of pyrrole containing various chelating pyridines derivatives
were also furnished the product (5iꢀ5l) in good to excellent yield.
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Scheme 4: Rhodium catalyzed C2ꢀselective cyanation of pyrroles. H NMR yield.
After the successful development of rhodium catalyzed C2ꢀselective cyanation of indoles and pyrroles,
the utility of the synthesized 2ꢀcyanoheteroarenes was demonstrated through the conversion into
synthetically useful building blocks. First, we envisioned the removal of directing group form the 2ꢀ
cyanoindole moiety. Thus, the reaction of 3o and sodium methoxide in DMSO at 110 °C furnished the
simple 2ꢀcyanoindole 7, an important building blocks for the synthesis of bioactive molecules shown in
Scheme 1, in 81% yield. Similarly, the treatment of 3a with sodium methoxide afforded the hydrolyzed
product 6 in good yield. The combined deprotection and hydrolysis of cyano compound 3a to indoleꢀ2ꢀ
carboxylic acid 8 was achieved through the initial reaction with methyltriflate followed by treatment
with sodium hydroxide.
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Scheme 5: Representative reaction of 2ꢀcyanoindoles 3.
In conclusion, we have developed an efficient and direct rhodium catalyzed C2ꢀcyanation of indoles and
pyrroles employing readily available and environmentally benign NꢀcyanoꢀNꢀphenylꢀpꢀ
toluenesulfonamide (NCTS, 2) as a cyanating reagent. The developed reaction tolerated various
functional groups and allowed the synthesis of diverse 2ꢀcyanoindoles and pyrroles in good to excellent
yield. Additionally, the reaction utilizes the readily modifiable chelating groups like pyridine,
pyrimidine and quinoline. Furthermore, the potential of the synthesized cyano compounds was
successfully demonstrated by converting into highly important building blocks.
Experimental Section:
General procedure for rhodium catalyzed C2 cyanation N-pyridyl indole (3): A dry reaction tube
(
10 mL) was charged with heteroarene 1 (0.24 mmol), NꢀcyanoꢀNꢀphenylꢀpꢀtoluenesulfonamide 2 (54
mg, 0.2 mmol), [Cp*RhCl ] (1.2 mg, 0.002 mmol, 1 mol%), AgSbF (6.8 mg, 0.02 mmol, 10 mol%)
2 2
6
t
and dry AmOH (1.5 mL) under nitrogen atmosphere. The reaction tube was sealed under nitrogen
o
atmosphere and the reaction mixture was stirred at 120 C for 18 h. After the completion of the reaction,
as monitored by TLC analysis, the reaction mixture was cooled to room temperature and purified by
column chromatography using mixture of hexane and ethyl acetate as eluent to afford the pure cyanated
product 3.
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3a: 49 mg, 92% yield; colorless liquid; H NMR (400 MHz, CDCl , 24 °C): δ 8.69ꢀ8.67 (m, 1H), 7.96ꢀ
3
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7
7
.91 (m, 1H), 7.76 (dd, 1H, J = 8.72, 0.64 Hz), 7.70 (d, 1H, J = 8.0 Hz), 7.58 (d, 1H, J = 8.2 Hz), 7.43ꢀ
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.35 (m, 3H), 7.29ꢀ7.25 (m, 1H); C{ H} NMR (100 MHz, CDCl , 24 °C): δ 149.7 (CH), 149.6 (C),
3
138.9 (CH), 137.1 (C), 127.0 (CH), 126.9 (C), 122.9 (CH), 122.8 (CH), 124.4 (CH), 118.8 (CH), 117.4
(CH), 113.8 (C), 112.3 (CH), 109.1 (C); HRMS: calcd. for C H N +H: 220.0875; found: 220.0886.
14 9 3
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b: 54 mg, 76% yield; white solid; H NMR (400 MHz, CDCl , 24 °C): δ 8.72ꢀ8.70 (m, 1H), 7.99ꢀ7.94
3
(m, 1H), 7.90 (d, 1H, J = 1.09 Hz), 7.85 (d, 1H, J = 8.76 Hz), 7.69ꢀ7.62 (m, 4H), 7.48ꢀ7.45 (m, 3H),
13
1
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.41ꢀ7.34 (m, 2H); C{ H} NMR (100 MHz, CDCl , 24 °C): δ 149.8 (CH), 141.1 (C), 139 (CH), 136.6
3
(C), 136.4 (C), 129 (C), 128.9 (CH), 127.5 (C), 127.4 (CH), 127.2 (CH), 126 .9 (CH), 122.9 (CH), 120.5
(CH), 118.7 (CH), 117.7 (CH), 113.7 (C), 112.7 (CH), 109.7 (C); HRMS: calcd. for C H N +H:
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3
2
96.1188; found: 296.1199.
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c: 55 mg, 77% yield; colorless liquid; H NMR (400 MHz, CDCl , 24 °C): δ 8.69ꢀ8.67 (m, 1H), 7.96
3
(m, 1H), 7.84 (d, 1H, J = 1.57 Hz), 7.67 (d, 1H, J = 8.8 Hz), 7.57 (d, 1H, J = 8.18 Hz), 7.49ꢀ7.47 (m,
13
1
1
H), 7.42ꢀ7.38 (m, 1H), 7.32 (s, 1H); C{ H} NMR (100 MHz, CDCl , 24 °C): δ 149.8 (CH), 149.4
3
(C), 139.1 (CH), 135.7 (C),129.9 (CH), 128.4 (C), 124.7 (CH), 123.2 (CH), 118.8 (CH), 116.3 (CH),
1
16 (C), 114.1 (CH), 113.2 (C), 110 (C); HRMS: calcd. for C H N Br+H: 297.9980; found: 297.9969.
14 8 3
9
1
3
d: 38 mg, 64% yield; white solid; H NMR (400 MHz, CDCl , 24 °C): δ 8.67ꢀ8.66 (m, 1H), 7.95ꢀ7.91
3
(m, 1H), 7.70 (dd, 1H, J = 9.88, 0.54 Hz), 7.58 (m, 1H), 7.34 (ddd, 1H, J = 7.50, 4.88, 0.89 Hz), 7.31 (d,
1
3
1
1
H, J = 0.6 Hz), 7.08ꢀ7.05 (m, 2H), 3.86 (s, 3H); C{ H} NMR (100 MHz, CDCl , 24 °C): δ 156.0 (C),
3
1
49.8 (C), 149.6 (CH), 139 (CH),132.4 (C), 127.5 (C), 122.7 (CH), 118.5 (CH), 118.2 (CH), 117 (CH),
113.9 (C), 113.5 (CH), 109 (C), 102.3 (CH), 55.8 (CH ); HRMS: calcd. for C H N O+H: 250.0980;
3
15 11
3
found: 250.0981.
1
3
e: 57 mg, 73% yield; colorless liquid; H NMR (400 MHz, CDCl , 24 °C): δ 8.67ꢀ8.65 (m, 1H), 7.94ꢀ
3
7
.90 (m, 1H), 7.71 (d, 1H, J = 9.97 Hz), 7.7 (d, 1H, J = 8.04 Hz), 7.45 (d, 2H, J = 7.07 Hz), 7.40ꢀ7.32
1
3
1
(m, 4H), 7.29 (s, 1H), 7.17ꢀ7.14 (m, 2H), 5.1 (s, 2H); C{ H} NMR (100 MHz, CDCl , 24 °C): δ 155.1
3
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(
C), 149.8 (C), 149.6 (CH), 139 (CH),136.9 (C), 132.5 (C), 128.7 (CH), 128.1 (CH), 127.6 (CH), 127.4
C), 122.7 (CH), 118.7 (CH), 118.5 (CH), 117 (CH), 113.9 (C), 113.5 (CH), 109 (C), 103.9 (CH), 70.6
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2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
(OCH ); HRMS: calcd. for C H N O+H: 326.1293; found: 326.1279.
2
21 15
3
1
3
f: 54 mg, 58% yield; colorless liquid; H NMR (400 MHz, CDCl , 24 °C): δ 8.59 (d, 1H, J = 4.58 Hz),
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
7
.90ꢀ7.86 (m, 1H), 7.64ꢀ7.60 (m, 3H), 7.49 (d, 1H, J = 7.95 Hz), 7.34ꢀ7.31 (m, 1H), 7.26ꢀ7.18 (m, 4H),
1
3
1
6.97 (d, 1H, J = 9.15 Hz), 2.36 (s, 3H); C{ H} NMR (100 MHz, CDCl , 24 °C): δ 149.8 (CH), 149.4
3
(C), 145.5 (C), 145.3 (CH), 139.2 (CH),135.4 (C), 132.3 (C), 130.9 (C), 129.9 (CH), 128.7 (CH), 126.9
(
C), 123.3 (CH), 121.9 (CH), 118.9 (CH), 117.1 (CH), 115.5 (CH), 113.1 (C), 110.7 (C), 21.8 (CH3);
HRMS: calcd. for C H N O S+H: 390.0912; found: 390.0926.
2
1
15
3
3
9
1
3
g: 23 mg, 39% yield; white solid; H NMR (400 MHz, CDCl , 24 °C): δ 8.72ꢀ8.71 (m, 1H), 8.10ꢀ8.09
3
13
1
(m, 1H), 8.03ꢀ7.99 (m, 1H), 7.88ꢀ7.86 (m, 1H), 7.64ꢀ7.60 (m, 2H), 7.48ꢀ7.45 (m, 2H); C{ H} NMR
(100 MHz, CDCl , 24 °C): δ 150.0 (CH), 148.9 (C), 139.4 (CH), 138.4 (C), 129.2 (CH), 128.0 (CH),
3
1
26.6 (C), 123.8 (CH), 119.2 (C), 119.2 (CH), 117.1 (CH), 113.9 (CH), 112.6 (C), 111.8 (C), 106.6 (C);
HRMS: calcd. for C H N +H: 245.0827; found: 245.0832.
15
8
4
1
3h: 18 mg, 30% yield; white solid; H NMR (400 MHz, CDCl , 24 °C): δ 8.72ꢀ8.71 (m, 1H), 8.06ꢀ7.99
3
(m, 2H), 7.66 (dd, 1H, J = 7.28, 0.72 Hz), 7.63ꢀ7.61 (m, 1H), 7.59 (d, 1H, J = 0.72 Hz), 7.51ꢀ7.45 (m,
1
3
1
2
H); C{ H} NMR (100 MHz, CDCl , 24 °C): δ 150.0 (CH), 149.0 (C), 139.4 (CH), 136.7 (C), 128.3
3
(CH), 127.7 (C), 126.6 (CH), 123.8 (CH), 119.2 (CH), 117.7 (CH), 117.2 (C), 114.9 (CH), 112.6 (C),
1
11.6 (C), 105.4 (C); HRMS: calcd. for C H N +H: 245.0827; found: 245.0836.
15 8 4
9
1
3
i: 54 mg, 96% yield; white solid; H NMR (400 MHz, CDCl , 24 °C): δ 8.56 (s, 1H), 7.83ꢀ7.80 (m,
3
1H), 7.70 (d, 1H, J = 8.34 Hz), 7.56 (d, 1H, J = 7.94 Hz), 7.47 (d, 1H, J = 7.94 Hz), 7.32ꢀ7.31 (m, 1H),
13
1
7
1
.23ꢀ7.16 (m, 2H), 2.48 (s, 3H); C{ H} NMR (100 MHz, CDCl , 24 °C): δ 150.0 (C), 149.5 (CH),
3
38.8 (CH), 137.0 (C), 128.6 (C), 127.5 (C), 127.2 (CH), 122.3 (CH), 122.1 (CH), 120.6 (CH), 118.3
(CH), 113.7 (C), 112.3 (CH), 107.6 (C), 9.9 (CH ); HRMS: calcd. for C H N +H: 234.1031; found:
3
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34.1033.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
3
j: 57 mg, 82% yield; colorless liquid; H NMR (400 MHz, CDCl , 24 °C): δ 8.69ꢀ8.67 (m, 1H), 7.96ꢀ
3
7.92 (m, 1H), 7.79ꢀ7.76 (m, 1H), 7.71ꢀ7.69 (m, 1H), 7.61ꢀ7.59 (m, 1H), 7.45ꢀ7.41 (m, 1H), 7.37 (ddd,
1
3
1
1
H, J = 7.49, 4.88, 0.95 Hz), 7.31ꢀ7.27 (m, 1H), 4.02 (s, 2H), 3.74 (s, 3H); C{ H} NMR (100 MHz,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
CDCl , 24 °C): δ 170.1 (C), 149.7 (CH), 139.0 (CH), 137.0 (C), 127.4 (CH), 126.8 (C), 124.0 (C), 122.8
3
(CH), 122.7 (CH), 120.9 (C), 120.8 (CH), 118.7 (CH), 113.0 (C), 112.4 (CH), 108.9 (C), 52.5 (OCH3),
3
1.1 (CH ); HRMS: calcd. for C H N O +H: 292.1086; found: 292.1079.
2 17 13 3 2
1
3
k: 40 mg, 72% yield; colorless liquid; H NMR (400 MHz, CDCl , 24 °C): δ 8.45 (d, 1H, J = 5.17 Hz),
3
7.66 (dd, 1H, J = 8.61, 0.86 Hz), 7.63ꢀ7.61 (m, 1H), 7.35ꢀ7.30 (m, 3H), 7.20ꢀ7.16 (m, 1H), 7.12ꢀ7.11
13
1
(m, 1H), 2.41 (s, 3H); C{ H} NMR (100 MHz, CDCl , 24 °C): δ 150.7 (C), 149.8 (C), 149.3 (CH),
3
1
37.2 (C), 128.5 (C), 126.9 (CH), 124.0 (CH), 122.7 (CH), 122.3 (CH), 119.7 (CH), 117.2 (CH), 113.8
(C), 112.4 (CH), 109.2 (C), 21.34 (CH ); HRMS: calcd. for C H N +H: 234.1031; found: 234.1029.
3
15 11
3
1
3
l: 53 mg, 95% yield; colorless liquid; H NMR (400 MHz, CDCl , 24 °C): δ 8.40 (m, 1H), 7.65ꢀ7.59
3
1
3
1
(m, 3H), 7.38ꢀ7.36 (m, 1H), 7.33ꢀ7.28 (m, 2H), 7.18ꢀ7.14 (m, 1H), 2.34 (s, 3H); C{ H} NMR (100
MHz, CDCl , 24 °C): δ 149.9 (CH), 147.4 (C), 139.4 (CH), 137.2 (C), 132.9 (C), 128.4 (C), 126.8 (CH),
3
1
22.5 (CH), 122.3 (CH), 118.5 (CH), 116.8 (CH), 113.8 (C), 112.2 (CH), 109.1 (C), 18.13 (CH3);
HRMS: calcd. for C H N +H: 234.1031; found: 234.1041.
15 11
3
1
3m: 49 mg, 82% yield; colorless liquid; H NMR (400 MHz, CDCl , 24 °C): δ 7.79ꢀ7.75 (m, 2H), 7.71ꢀ
3
7
.69 (m, 1H), 7.43ꢀ7.38 (m, 2H,), 7.29ꢀ7.25 (m, 1H), 7.13 (d, 1H, J = 7.44 Hz), 6.78 (d, 1H, J = 8.33
1
3
1
Hz), 4.05 (s, 3H); C{ H} NMR (100 MHz, CDCl , 24 °C): δ 164.0 (C), 147.1 (C), 140.7 (CH), 136.7
3
(C), 127.0 (C), 126.8 (CH), 122.6 (CH), 122.4 (CH), 117.3 (CH), 114.1 (C), 112.2 (CH), 112.2 (CH),
1
09.9 (CH), 109.3 (C), 54.3 (OCH ); HRMS: calcd. for C H N O+H: 250.0980; found: 250.0983.
3 15 11 3
1
3
n: 46 mg, 71% yield; white solid; H NMR (400 MHz, CDCl , 24 °C): δ 8.40 (d, 1H, J = 8.68 Hz),
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7
.17 (d, 1H, J = 8.35 Hz), 7.96ꢀ7.91 (m, 2H), 7.83ꢀ7.79 (m, 1H), 7.76ꢀ7.73 (m, 2H), 7.64ꢀ7.60 (m, 1H),
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
13
1
.48ꢀ7.44 (m, 2H), 7.33ꢀ7.29 (m, 1H); C{ H} NMR (100 MHz, CDCl , 24 °C): δ 148.6 (C), 147.4 (C),
3
139.5 (CH), 137.2 (C), 130.9 (CH), 129.1 (CH), 127.8 (CH), 127.3 (CH), 127.2 (C), 127.2 (CH), 127.2
C), 123 (CH), 122.5 (CH), 118.0 (CH), 117.0 (CH), 113.9 (C), 112.7 (CH), 109.2 (C); HRMS: calcd.
for C H N +H: 270.1031; found: 270.1033.
(
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
18 11
3
9
1
3o: 24 mg, 46% yield; white solid; H NMR (400 MHz, CDCl , 24 °C): δ 8.83 (d, 2H, J = 4.67 Hz),
3
8
.69 (d, 1H, J = 8.57 Hz), 7.68 (d, 1H, J = 8.01 Hz), 7.52ꢀ7.47 (m, 2H), 7.34ꢀ7.31 (m, 1H), 7.23 (t, 1H,
1
3
1
J = 4.8 Hz); C{ H} NMR (100 MHz, CDCl , 24 °C): δ 158.4 (CH), 156.7 (C), 136.7 (C), 127.9 (C),
3
1
27.6 (CH), 123.6 (CH), 122.1 (CH), 121.1 (CH), 118.1 (CH), 116.2 (CH), 114.3 (C), 109.1 (C);
HRMS: calcd. for C H N +H: 221.0827; found: 221.0830.
1
3
8
4
General procedure for rhodium catalyzed C2 cyanation of N-pyridyl pyrrole (5): A dry reaction
tube (10 mL) was charged with heteroarene 4 (0.24 mmol), NꢀcyanoꢀNꢀphenylꢀpꢀtoluenesulfonamide 2
(54 mg, 0.2 mmol), [Cp*RhCl ] (3.7 mg, 0.006 mmol, 3 mol%), AgSbF (6.8 mg, 0.02 mmol, 10
2
2
6
t
mol%) and dry AmOH (1.5 mL) under nitrogen atmosphere. The reaction tube was sealed under
o
nitrogen atmosphere and the reaction mixture was stirred at 120 C for 18 h. After the completion of the
reaction, as monitored by TLC analysis, the reaction mixture was cooled to room temperature and
purified by column chromatography using mixture of hexane and ethyl acetate as eluent to afford the
pure cyanated product 5.
9
1
5
a: 33 mg, 81% yield, colorless liquid; H NMR (400 MHz, CDCl , 24 °C): δ 8.46ꢀ8.44 (m, 1H), 7.79ꢀ
3
7.75 (m, 1H), 7.54ꢀ7.52 (m, 1H), 7.50 (dd, 1H, J = 2.95, 1.65 Hz), 7.22ꢀ7.19 (m, 1H), 6.96 (dd, 1H, J =
1
3
1
3
1
.79, 1.64 Hz), 6.29ꢀ6.28 (m, 1H); C{ H} NMR (100 MHz, CDCl , 24 °C): δ 149.8 (C), 149.2 (CH),
3
39.1 (CH), 125.5 (CH), 124.4 (CH), 122.6 (CH), 114.9 (CH), 114.2 (C), 111.2 (CH), 102.4 (C);
HRMS: calcd. for C H N +H: 170.0718; found: 170.0720.
1
0
7
3
1
5
b: 30 mg, 67% yield; colorless liquid; H NMR (400 MHz, CDCl , 24 °C): δ 8.56ꢀ8.54 (m, 1H), 7.83
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(
td, 1H, J = 7.81, 1.89 Hz), 7.35ꢀ7.30 (m, 2H), 6.83 (d, 1H, J = 3.84 Hz), 6.01 (dd, 1H, J = 3.78, 0.73
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
3
1
Hz), 2.22 (s, 3H); C{ H} NMR (100 MHz, CDCl , 24 °C): δ 149.7 (C), 149.5 (CH), 138.8 (CH), 136.4
3
(C), 123.7 (CH), 121.8 (CH), 120.7 (CH), 114.3 (C), 110.1 (CH), 103.4 (C), 13.59 (CH ); HRMS: calcd.
3
for C H N +H: 184.0875; found: 184.0871.
1
1
9
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
5
e: 49 mg, 76% yield; colorless liquid; H NMR (400 MHz, CDCl , 24 °C): δ 8.64ꢀ8.62 (m, 1H), 7.94ꢀ
3
7.90 (m, 1H), 7.46 (dt, 1H, J = 7.99, 0.79 Hz), 7.43ꢀ7.37 (m, 2H), 7.26 (s, 1H), 7.25ꢀ7.19 (m, 2H), 7.16ꢀ
13
1
7
.12 (m, 1H), 3.02ꢀ2.93 (m, 4H); C{ H} NMR (100 MHz, CDCl , 24 °C): δ 149.5 (CH), 149.2 (C),
3
1
38.9 (CH), 136.5 (C), 133.5 (C), 130.8 (C), 128.2 (CH), 127.1 (CH), 126.4 (CH), 123.5 (CH), 122.4
(CH), 121.3 (C), 119.6 (CH), 117.1 (CH), 114.4 (C), 103.6 (C), 29.1 (CH ), 22.0 (CH ); HRMS: calcd.
2 2
for C H N +H: 272.1188; found: 272.1178.
1
8
13
3
1
5
f: 27 mg, 41% yield; colorless liquid; H NMR (400 MHz, CDCl , 24 °C): δ 8.60ꢀ8.58 (m, 1H), 8.12
3
(d, 1H, J = 1.81 Hz), 7.95ꢀ7.91 (m, 1H), 7.88ꢀ7.86 (m, 2H), 7.72ꢀ7.70 (m, 1H), 7.62ꢀ7.58 (m, 1H), 7.53ꢀ
13
1
7
.49 (m, 3H), 7.41ꢀ7.38 (m, 1H); C{ H} NMR (100 MHz, CDCl , 24 °C): δ 189.1 (C), 149.6 (CH),
3
1
49.1 (C), 139.5 (CH), 138.4 (C), 132.6 (CH), 130.0 (CH), 129.1 (CH), 128.7 (CH), 125.8 (C), 125.1
(CH), 123.8 (CH), 115.5 (CH), 113.0 (C), 104.3 (C); HRMS: calcd. for C H N O+H: 274.0980;
17 11 3
found: 274.0989.
1
5
g: 12 mg, 22% yield; white solid; H NMR (400 MHz, CDCl , 24 °C): δ 8.69ꢀ8.67 (m, 1H), 7.99ꢀ7.94
3
(m, 1H), 7.49 (ddd, 1H, J = 7.56, 4.91, 0.88 Hz), 7.40 (d, 1H, J = 7.96 Hz), 7.31 (s, 1H), 2.53 (s, 3H),
13
1
2
.47 (s, 3H); C{ H} NMR (100 MHz, CDCl , 24 °C): δ 193.9 (C), 150.1 (CH), 148.6 (C), 141.0 (C),
3
139.1 (CH), 124.8 (CH), 122.6 (CH), 122.5 (C), 121.5 (CH), 112.9 (C), 103.8 (C), 28.8 (CH ), 13.3
3
(CH ); HRMS: calcd. for C H N O+H: 226.0980; found: 226.0989.
3 13 11 3
1
5
h: 26 mg, 42% yield; colorless liquid; H NMR (400 MHz, CDCl , 24 °C): δ 8.68ꢀ8.66 (m, 1H), 7.95
3
(td, 1H, J = 7.72, 2.01 Hz), 7.48ꢀ7.45 (m, 1H), 7.40 (m, 1H), 7.36 (s, 1H), 4.31 (q, 2H, J = 7.11 Hz),
1
3
1
2
.53 (s, 3H), 1.36 (t, 3H, J = 7.22 Hz); C{ H} NMR (100 MHz, CDCl , 24 °C): δ 163.7 (C), 150.0
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(
CH), 148.9 (C), 141.6 (C), 139.1 (CH), 124.6 (CH), 122.8 (CH), 121.4 (C), 114.8 (CH), 113.0 (C),
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
03.9 (C), 60.3 (CH ), 14.5 (CH ), 12.7 (CH ); HRMS: calcd. for C H N O +H: 256.1086; found:
2 3 3 14 13 3 2
256.1075.
1
5
i: 40 mg, 84% yield; colorless liquid; H NMR (400 MHz, CDCl , 24 °C): δ 8.43ꢀ8.42 (m, 1H), 7.70ꢀ
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
7
.67 (m, 1H), 7.28 (d, 1H, J = 8.17 Hz), 6.87 (d, 1H, J = 3.83 Hz), 6.06 (dd, 1H, J = 3.84, 0.77 Hz), 2.41
1
3
1
(s, 3H), 2.26 (s, 3H); C{ H} NMR (100 MHz, CDCl , 24 °C): δ 149.8 (CH), 147.5 (C), 139.2 (CH),
3
1
36.3 (C), 133.7 (C), 121.4 (CH), 120.2 (CH), 114.4 (C), 109.8 (CH), 103.5 (C), 18.1 (CH ), 13.4
3
(CH ); HRMS: calcd. for C H N +H: 198.1031; found: 198.1025.
3 12 11 3
1
5j: 27 mg, 62% yield; colorless liquid; H NMR (400 MHz, CDCl , 24 °C): δ 8.352ꢀ8.350 (m, 1H),
3
7
.67ꢀ7.64 (m, 1H), 7.53ꢀ7.49 (m, 2H), 7.03ꢀ7.02 (m, 1H), 6.35 (dd, 1H, J = 3.77, 3.02 Hz), 2.38 (s, 3H);
1
3
1
C{ H} NMR (100 MHz, CDCl , 24 °C): δ 149.3 (CH), 147.9 (C), 139.5 (CH), 132.6 (C), 125.6 (CH),
3
124.0 (CH), 114.8 (CH), 114.3 (C), 111.0 (CH), 102.5 (C), 18.0 (CH ); HRMS: calcd. for C H N +H:
3
11
9
3
1
84.0875; found: 184.0877.
1
5
k: 31 mg, 71% yield; colorless liquid; H NMR (400 MHz, CDCl , 24 °C): δ 8.37 (d, 1H, J = 5.01 Hz),
3
7.54ꢀ7.53 (m, 1H), 7.40 (s, 1H), 7.10 (d, 1H, J = 5.01 Hz), 7.03ꢀ7.01 (m, 1H), 6.35ꢀ6.33 (m, 1H), 2.43
13
1
(s, 3H); C{ H} NMR (100 MHz, CDCl , 24 °C): δ 150.8 (C), 150.0 (C), 148.8 (CH), 125.6 (CH),
3
1
24.2 (CH), 123.8 (CH), 115.7 (CH), 114.3 (C), 111.0 (CH), 102.4 (C), 21.3 (CH ); HRMS: calcd. for
3
C H N +H: 184.0875; found: 184.0880.
11
9
3
1
5
l: 34 mg, 65% yield; colorless liquid; H NMR (400 MHz, CDCl , 24 °C): δ 8.32 (d, 1H, J = 8.75 Hz),
3
8
.10 (d, 1H, J = 8.53 Hz), 7.87ꢀ7.85 (m, 1H), 7.79ꢀ7.72 (m, 3H), 7.59ꢀ7.55 (m, 1H), 7.10 (dd, 1H, J =
13
1
3.79, 1.63 Hz), 6.43 (dd, 1H, J = 3.73, 3.06 Hz); C{ H} NMR (100 MHz, CDCl , 24 °C): δ 148.4 (C),
3
1
47.0 (C), 139.8 (CH), 130.9 (CH), 129.0 (CH), 127.7 (CH), 127.2 (C), 127.0 (CH), 125.6 (CH), 124.8
(CH), 114.3 (C), 113.5 (CH), 111.5 (CH), 102.9 (C); HRMS: calcd. for C H N +H: 220.0875; found:
14
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20.0877.
1
2
3
4
5
6
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8
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1
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1
1
1
1
1
1
2
2
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Synthesis of 6: A mixture of 1ꢀ(pyridinꢀ2ꢀyl)ꢀ1Hꢀindoleꢀ2ꢀcarbonitrile 3a (45 mg, 0.2 mmol), NaOMe
(43 mg, 0.8 mmol) in DMSO (3 mL) was stirred at 110 °C for 24 h. After completion of the reaction as
monitored by TLC analysis, the reaction mixture was cooled to room temperature, diluted with EtOAc
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(10 mL) and extracted with water. The aqueous layer was washed with EtOAc (3 x 10 mL). The
combined organic layer was dried over Na SO . After filtration and concentration in vacuo, the crude
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product was purified by column chromatography using mixture of hexane/ethylacetate (85:15) as an
1
eluent to afford the pure product 6 as colorless liquid. 32 mg, 66% yield; H NMR (400 MHz, CDCl ,
3
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4 °C): δ 9.93 (s, 1H), 9.19 (s, 1H), 8.43ꢀ8.35 (m, 2H), 7.76ꢀ7.73 (m, 1H), 7.65 (d, 1H, J = 8.03 Hz),
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.45ꢀ7.43 (m, 1H), 7.31 (t, 1H, J = 7.42 Hz), 7.25ꢀ7.22 (m, 1H), 7.17ꢀ 7.09 (m, 2H); C{ H} NMR (100
MHz, CDCl , 24 °C): δ 160.1 (C), 151.4 (C), 147.8 (CH), 138.8 (CH), 137.0 (C), 130.4 (C), 127.7 (C),
3
1
25.3 (CH), 122.5 (CH), 121.0 (CH), 120.1 (CH), 114.6 (CH), 112.1 (CH), 104.6 (CH); HRMS: calcd.
for C H N O +H: 239.0821; found: 239.0824.
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Synthesis of 7: A mixture of 1ꢀ(pyrimidinꢀ2ꢀyl)ꢀ1Hꢀindoleꢀ2ꢀcarbonitrile 3o (43 mg, 0.2 mmol),
NaOMe (43 mg, 0.8 mmol) in DMSO (3 mL) was stirred at 110 °C for 24 h. After completion of the
reaction as monitored by TLC analysis, the reaction mixture was cooled to room temperature, diluted
with EtOAc (10 mL) and washed with water. The aqueous layer was extracted with EtOAc (3 x 10 mL).
The combined organic layer was dried over Na SO . After filtration and concentration in vacuo, the
2
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crude product was purified by column chromatography using mixture of hexane/ethyl acetate (95:5) as
1
an eluent to afford the pure product 7 as white solid. 23 mg, 81% yield; H NMR (400 MHz, CDCl , 24
3
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1
°
C): δ 8.82 (br, 1H), 7.68 (dd, 1H, J = 8.12, 0.87 Hz), 7.44ꢀ7.38 (m, 2H), 7.24ꢀ7.20 (m, 2H); C{ H}
NMR (100 MHz, CDCl , 24 °C): δ 137.0 (C), 126.4 (CH), 126.3 (C), 122.2 (CH), 121.8 (CH), 114.5
3
(CH), 114.4 (C), 111.9 (C), 106.3 (C); HRMS: calcd. for C H N +H: 143.0609; found: 143.0610.
9 6 2
23
Synthesis of 8: Methyl trifluoromethanesulfonate (39 mg, 0.24 mmol) was added dropwise to a
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solution of 1ꢀ(pyridinꢀ2ꢀyl)ꢀ1Hꢀindoleꢀ2ꢀcarbonitrile 3a (45 mg, 0.2 mmol) in dry 1,2ꢀdichloroethane (5
mL) at room temperature, and the reaction mixture was stirred at room temperature for 24 h. Then the
solvent was removed under vacuum, and the residue was dissolved in MeOH (2.5 mL). A 2N NaOH
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(1.2 mL) was added and stirred at 60 °C for 12 h. The solvent was removed and the resulting mixture
was extracted with EtOAc (3 x 10 mL). The combined organic layer was dried over Na SO . After
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filtration and concentration in vacuo, the crude product was purified by column chromatography using
mixture of hexane/ethyl acetate (70:30) as an eluent to afford the pure product 8 as white solid. 10 mg,
1
24% yield; H NMR (400 MHz, DMSOꢀd , 24 °C): δ 12.9 (br, 1H), 11.7 (s, 1H), 7.67 (d, 1H, J = 7.93
6
1
3
1
Hz), 7.48 (d, 1H, J = 8.26 Hz), 7.27 (t, 1H, J = 7.60 Hz), 7.13ꢀ 7.07 (m, 2H); C{ H} NMR (100 MHz,
DMSOꢀd , 24 °C): δ 163.7 (C), 138.1 (C), 129.3 (C), 127.8 (C), 125.2 (CH), 122.8 (CH), 120.8 (C),
6
113.4 (C), 108.2 (C); HRMS: calcd. for C H NO +H: 162.0555; found: 162.0557.
9
7
2
Acknowledgments: We thank the Indian Institute of Technology Madras (Project No. CHY/11ꢀ
2/569/NFSC/ANBA), and Board of Research in Nuclear Sciences (BRNS) through DAE Young
1
Scientist Award (Project No. 2012/20/37C/14/BRNS) for financial support. M.C. thanks Council of
Scientific & Industrial Research (CSIR) for a fellowship.
Supporting information: Optimization and spectral data. This material is available free of charge via
the Internet at http://pubs.acs.org.
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(
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