Cyanation of indoles with benzyl cyanide as the cyanide anion surrogate

Article abstract of DOI:10.1016/j.tet.2013.03.089

A copper-mediated direct cyanation of indoles with benzyl cyanide as the cyanide anion surrogate has been achieved. The cascade reaction furnished 3-cyanoindoles under mild reaction conditions in good to excellent yields with various functional groups tolerance.

Full text of DOI:10.1016/j.tet.2013.03.089

Tetrahedron 69 (2013) 4236e4240
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Cyanation of indoles with benzyl cyanide as the cyanide anion
surrogate
*
*
Lianpeng Zhang, Qiaodong Wen, Jisong Jin, Chen Wang, Ping Lu , Yanguang Wang
Department of Chemistry, Zhejiang University, Hangzhou 310027, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 January 2013
Received in revised form 15 March 2013
Accepted 22 March 2013
Available online 26 March 2013
A copper-mediated direct cyanation of indoles with benzyl cyanide as the cyanide anion surrogate has
been achieved. The cascade reaction furnished 3-cyanoindoles under mild reaction conditions in good to
excellent yields with various functional groups tolerance.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Copper catalysis
Cyanation
Benzyl cyanide
3-Cyanoindoles
1. Introduction
cyano group of 3-cyanoindole derives from the relevant aldehyde,10
aldoximine,11 hydroxymethyl,12 and ester.13 Another one is the di-
The importance of indole derivatives comes from their unique
presence in natural products and pharmaceutical compounds.
Among this field, 3-cyanoindoles particularly functioned as the key
intermediates in the preparations of the most fascinating indole
containing compounds. For instance, based on the versatile trans-
formations of cyano group, they are useful in the synthesis of indolyl
1,2,4-triazoles1 and 3,5-bis(indolyl)-1,2,4-thiadiazoles2 as potent
and selective anticancer agents, indole oxadiazoles as 5-HT3 an-
tagonists,3 and oxadiazole-5-carboxamide as inhibitors of glycogen-
synthase-kinase-3 (GSK-3).4 Beyond of these, modification of the
NeH bond of 3-cyanoindoles also leads to a great amount of indole
containing compounds with special bioactivities, such as indole-3-
carbinol analogues,5 oncrasin-1 analogues as inhibitors of the C-
terminal domain of RNA polymerase II,6 1H-benzylindole derivatives
as HIV-integrase inhibitors,7 and indole-fused piperazinones and
piperazines acting as antagonists of the histamine 3 (H3) receptor.8
Further, it is noticeable that 3-cyanoindoles play a key role in the
construction of tremendous natural products, such as strychnos
alkaloids.9 Therefore, the development of new methods leading to
simple and rapid introduction of cyano group onto the 3-position of
indole remains a challenge in the organic synthesis.
rect installation of cyano group through activation of CeH bond of
3-hydroindole or CeX bond of 3-haloindole, which is catalyzed by
transition metals. Among these advance methods, cyano source can
be a single component, such as MCN (with extremely toxic),14
K2Fe(CN)4 (with solubility obstacle),15 acetone cyanohydrin (with
stability problem),16 malononitrile,17 TMSCN,18 nitromethane,19a
DMF19b and so on. Combinations of DMFþNH3,20 DMSOþNH4
HCO3,21 and DMFþNH4HCO3,22 providing ‘C’ and ‘N’, respectively,
can also be efficiently used for cyanation of AreH or AreX.
Encouraged by our previous works on benzyl cyanide as an
operator-benign cyanation reagent that could be used for
palladium-catalyzed cyanation of AreX,23 and copper-catalyzed
cyanation of AreH with directing group,24 we were interested in
exploring the cyanation of electron-rich aromatics with benzyl
cyanide through CeH bond activation without directing group. We
herein report the detail of this effort.
2. Results and discussion
In our primary investigation, indole was selected as the substrate
and tested. As we expected, 3-cyanoindole (3a) was isolated in 75%
yield when indole (1a) reacted with 2 equiv of benzyl cyanide (2a) in
the presence of 2 equiv of CuI under air in DMF at 100 ꢀC for 34 h
(Scheme 1). With the above result, we optimized the reaction con-
ditions (Table 1). By screening the copper sources, CuI presented the
best among CuI, CuBr, and CuCl (Table 1, entries 1e3). Other Cu(I)
source, such as Cu2O, provided only a detectable product although
Traditional methods for the preparation of 3-cyanoindoles in-
clude two strategies. One is related to the 1C chemistry in which the
* Corresponding authors. Tel./fax: þ86 571 87952543; e-mail addresses: pinglu@
zju.edu.cn (P. Lu), orgwyg@zju.edu.cn (Y. Wang).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.03.089

L. Zhang et al. / Tetrahedron 69 (2013) 4236e4240
4237
indole was completely consumed after 34 h (Table 1, entry 4). Cu(II)
did not work for this transformation (Table 1, entries 5 and 6). By
screening the solvents, DMF was found to be the optimal among
polar aprotic solvents, such as DMF, DMAc, DMSO, HMPA, and NMP
(Table 1, entries 7e10). Acetonitrile, toluene, p-xylene, and 1,4-
dioxane did not work for this reaction with the recovery of indole
(Table 1, entries 11e14). By decreasing the amount of CuI to 1.2 equiv,
80% yield of 3a was observed (Table 1, entry 15). Further decreasing
the amount of CuI to 1 equiv, indole was consumed completely after
reaction and 3a was isolated in 70% yield (Table 1, entry 16). When
the amount of CuI dropped to 0.5 equiv, yield of 3a was decreased to
36% with a 52% recovery of indole (Table 1, entry 17). When the
reaction was carried out with the stoichiometric amount of iodine
and catalytic amount of CuI, only trace amount of 3a could be
detected by TLC (Table 1, entry 18). The optimal amount of benzyl
cyanide was found to be 1.2 equiv (Table 1, entries 15 and 17e19).
Finally the optimal reaction temperature and reaction time were
selected to be 100 ꢀC and 34 h (Table 1, entries 15 and 20e23). When
the reaction was conducted under nitrogen, no desired product was
detected with the recovery of indole (Table 1, entry 24). When the
reaction was carried out without benzyl cyanide, 3-formylindole and
indolo[2,1-b]quinazoline-6,12-dione25 were isolated in 16% and 46%
yields, respectively (Scheme 2).
Scheme 2. Reaction of indole without benzyl cyanide.
and 3c were obtained in relatively lower yields. Conversely, sub-
stituents with electron-withdrawing property benefitted the re-
action. Thus, 3c, 3d, 3e, and 3f were obtained in good to excellent
yields (81e93%). By altering 5-chloroindole to 4-chloroindole,
a higher yield of 3h was observed. With the ester group on 6-
position of indole, 3i was isolated in 82% yield. It was noticeable
that cyanation still occurred smoothly on 3-position of 2-substituted
indoles. Beyond of these, this transformation could be operated in
gram scale. For example, 1.13 g (7 mmol) of 5-nitroindole was cya-
nated to give 1.15 g of 5-nitroindole-3-carbonitrile (3e) in 88% yield.
Scheme 1. Cu-catalyzed cyanation of indole with benzyl cyanide.
Table 1
Optimization of the reaction conditionsa
Entry
Catalyst (equiv)
Solvent
Benzyl
cyanide
(equiv)
Temp
(ꢀC)
Time
(h)
Yieldb
(%)
Reaction conditions: 1 (0.5 mmol), 2a (0.6 mmol), CuI (0.6 mmol), air, 100
°C, DMF (3 mL), 34 h.
1
2
3
4
5
6
7
8
CuI (2.0)
DMF
DMF
DMF
DMF
DMF
DMF
DMAc
DMSO
HMPA
NMP
CH3CN
Toluene
p-Xylene
1,4-Dioxane
DMF
DMF
DMF
DMF
DMF
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.5
1.0
1.2
1.2
1.2
1.2
1.2
100
100
100
100
100
100
100
100
100
100
81
100
100
100
100
100
100
100
100
100
120
80
34
34
34
34
34
34
34
34
34
34
34
34
34
34
34
34
34
34
34
34
34
34
24
36
34
75
33
27
Trace
0
CuBr (2.0)
CuCl (2.0)
Cu2O (2.0)
CuBr2 (2.0)
Cu(OAc)2 (2.0)
CuI (2.0)
CuI (2.0)
CuI (2.0)
CuI (2.0)
CuI (2.0)
CuI (2.0)
CuI (2.0)
CuI (2.0)
CuI (1.2)
CuI (1.0)
CuI (0.5)
Scheme 3. Structures and yields of prepared 3-cyanoindoles.
0
When N-alkyl indoles were used as the substrates, yields of the
cyanation products were significantly improved, especially in the
case of 1-ethyl-2-phenyl-1H-indole (Scheme 4). From the pair of
59
54
35
30
0
0
0
0
80
70
36
Trace
80
75
75
45
62
80
0c
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
CuI (0.5)þI2 (1.0)
CuI (1.2)
CuI (1.2)
CuI (1.2)
CuI (1.2)
CuI (1.2)
CuI (1.2)
CuI (1.2)
DMF
DMF
DMF
DMF
DMF
DMF
100
100
100
a
Reaction conditions: 1a (0.5 mmol), solvent (3 mL), air.
Isolated yield.
Under N2.
b
c
With the optimized reaction conditions in hand, we tested the
Reaction conditions: 1 (0.5 mmol), 2a (0.6 mmol), CuI (0.6 mmol), air, 100
°C, DMF (3 mL), 34 h.
scope of indoles (Scheme 3). A variety of functional groups tolerated
this reaction. Indoles with substituent on 5-position were firstly
investigated. With the electron-donating nature of 5-substituent, 3b
Scheme 4. Cyanation products of N-alkyl indoles.

4238
L. Zhang et al. / Tetrahedron 69 (2013) 4236e4240
the 3t and 3u, a preliminary conclusion could be made that the
impact of the electronic effect on the reaction efficiency is larger
than that of the steric effect.
We also tested N-phenyl, N-acetyl, and N-tosyl indoles. All of
these three substrates did not participate in the reaction with the
quantitative recoveries of the starting materials.
showed 15% only. The amount of 3a kept going as the reaction
proceeding and finally reached a maximum at 34 h (Fig. 1). 4 was
isolated and characterized by its spectroscopy (see ESD). Under the
established reaction conditions, 4 could be converted to 3a with
82% yield.
Because of the importance of pyrrole in medicinal and material
science, we tried the pyrrole as substrates. Unfortunately, no iso-
lable cyanated products were obtained although pyrrole and 2,4-
dimethylpyrrole consumed completely in NMP at 100 ꢀC for 15 h.
By decreasing the electron density of pyrrole, both N-tosylpyrrole
and N-tosyl 2,4-dimethylpyrrole did not work with the recoveries
of starting materials. N-Boc pyrrole could react, but no isolable
product was obtained. To our delight, N-Boc 2,4-dimethylpyrrole
could react to afford 5-cyano-2,4-dimethyl-pyrrole (3v)26 in 94%
yield (Scheme 5).
3a
100
1a
4
80
60
40
20
0
0
5
10
15
20
25
30
35
Time(h)
Fig. 1. Reaction profile of 1a and 2a (recorded by GC).
Scheme 5. Cyanation of N-Boc-2,4-dimethylpyrrole.
Based on these results, we proposed a possible mechanism
for the formation of 3a (Scheme 7). As we presented in our
previous paper,24 CNꢁ is released from benzaldehyde cyanohy-
drin and/or benzoyl cyanide in situ generated via a copper-
catalyzed aerobic CeH oxidation of benzyl cyanide. Existence
of free CNꢁ was indicated by the stripe test.20 Meanwhile, CeH
bond of indole is activated in the presence of Cu(I) and air that
formed the key intermediated A. If reductive elimination of A
occurs directly, 3-iodoindole is obtained. If A is further con-
verted into B through anion exchange, followed by reductive
elimination, 3a is formed. It is interesting to note that formation
of 4 is kinetically favored and it can be detected and isolated
during the reaction, while formation of 3a is thermodynamically
favored.
In order to have a good insight into the mechanism, we tested
other cyanation reagents 2bef (Scheme 6). Substituted benzyl cy-
anides, either with electron-donating (2b) or with electron-
withdrawing (2c), provided 3a in lower yields than the naked
benzyl cyanide (2a) did. The nature of the electron-withdrawing
group on the para position of benzyl cyanide is beneficial to the
copper-catalyzed benzylic CeH aerobic activation, but retarded the
release of cyanide anion from cyanohydrin, which was obtained in
situ from the oxidation of benzyl cyanides in the presence of cop-
per. One support to this hypothesis is that 2e could give 3a in 81%
yield. However, when benzaldehyde cyanohydrin (2f) was used as
the surrogate of the cyanide anion, which should have the fastest
rate of releasing cyanide anion in comparison with benzyl cyanides
2aee because the oxidation step from benzyl cyanide to 2f was
eliminated, 3a was only isolated in 15% yield although indole was
completely consumed after the reaction. Similarly, benzoyl cyanide
provided 3a in a trace amount. These might be ascribed to the
relatively slow rate of the copper-catalyzed activation of CeH bond
of indole. Therefore, it is obvious that balancing the rates of re-
leasing cyanide anion and activating the indole CeH bond is critical
to a successful transformation.
Scheme 7. Possible mechanism for the formation of 3a.
Scheme 6. Substituent effect of benzyl cyanides.
By tracking the reaction between 1a and 2a with gas chroma-
tography, we observed the formation and disappear of 3-
iodoindole (4) during the reaction process. As the time occurred
about 12 h, about 70% of 4 was detected, while both indole and 3a
3. Conclusion
In conclusion, we developed a convenient method for the syn-
thesis of 3-cyanoindoles from indoles using benzyl cyanide as

L. Zhang et al. / Tetrahedron 69 (2013) 4236e4240
4239
cyanation reagent. The cascade reaction involves
a
copper-
8.56 (s, 1H), 8.49 (s, 1H), 8.17 (d, J¼9.0 Hz,1H), 7.77 (d, J¼9.0 Hz,1H);
catalyzed aerobic CeH oxidation, a CeCN bond cleavage, and
a copper-catalyzed aerobic oxidative CeH functionalization with-
out directing group. The cyanation reagent is environmentally be-
nign and the reaction is palladium-free and ligand-free. Beyond of
these advantageous, the reaction could be operated in gram scale.
Further exploration of the copper-catalyzed cyanations and their
applications are undergoing.
13C NMR (100 MHz, DMSO)
115.9, 114.8, 87.8.
d 143.5, 139.4, 139.3, 127.0, 119.6, 116.0,
4.3.6. 5-Fluoro-1H-indole-3-carbonitrile (3f).29 Yield 81%; yellow
solid; mp 151e153 ꢀC; 1H NMR (400 MHz, DMSO)
12.34 (s, 1H),
d
8.35 (s, 1H), 7.60 (dd, J¼8.9 Hz, JHeF¼4.6 Hz, 1H), 7.45 (dd, J¼9.2 Hz,
JHeF¼2.2 Hz, 1H), 7.18 (dd, J¼9.2 Hz, JHeF¼2.2 Hz, 1H); 13C NMR
(100 MHz, DMSO)
d
160.4 (d, JCeF¼235 Hz), 137.1, 132.8, 128.2 (d,
4. Experimental
4.1. General
JCeF¼11 Hz), 116.8, 115.3 (d, JCeF¼9 Hz), 112.9 (d, JCeF¼26 Hz), 104.6
(d, JCeF¼24 Hz), 85.5.
4.3.7. 5-Chloro-1H-indole-3-carbonitrile (3g).30 Yield 82%; white
Unless stated otherwise, reactions were conducted in flame-
solid; mp 165e167 ꢀC; 1H NMR (400 MHz, DMSO)
d 12.42 (s, 1H),
dried glassware using anhydrous solvents (dried by Molecular
sieves 4 A). Commercially available reagents and solvents were
8.36 (s, 1H), 7.70 (s, 1H), 7.61 (d, J¼8.8 Hz, 1H), 7.33 (d, J¼8.8 Hz,1H);
13C NMR (100 MHz, DMSO)
116.7, 115.6, 85.1.
d 137.0, 134.7, 128.8, 127.5, 124.5, 118.7,
ꢀ
used as received. Flash column chromatography was performed
using 200e300 mesh silica gel. Visualization on TLC was achieved
by the use of UV light (254 nm). NMR spectra were obtained at
400 or 500 MHz for 1H NMR and 100 or 125 MHz for 13C NMR.
Chemical shifts were quoted relative to tetramethylsilane (TMS)
as internal standard and reported in parts per million. The fol-
lowing abbreviations were used to describe peak splitting pat-
terns when appropriate: s¼singlet, d¼doublet, t¼triplet,
m¼multiple. High-resolution mass spectra (HRMS) were recorded
using TOF-EI.
4.3.8. 4-Chloro-1H-indole-3-carbonitrile (3h).31 Yield 88%; yellow
solid; mp 223e225 ꢀC; 1H NMR (400 MHz, DMSO)
d 12.55 (s, 1H),
8.41 (s, 1H), 7.65e7.40 (m, 1H), 7.30 (d, J¼7.6 Hz, 2H); 13C NMR
(100 MHz, DMSO)
113.2, 84.6.
d 137.6, 137.4, 125.3, 125.2, 124.5, 122.8, 117.2,
4.3.9. Methyl 3-cyano-1H-indole-6-carboxylate (3i). Yield 82%;
white solid; mp 240e242 ꢀC; 1H NMR (400 MHz, DMSO)
12.60 (s,
1H), 8.51 (s, 1H), 8.20 (s,1H), 7.85 (d, J¼8.4 Hz,1H), 7.77 (d, J¼8.4 Hz,
1H), 3.91 (s, 3H); 13C NMR (100 MHz, DMSO)
167.5, 138.6, 135.6,
131.3, 125.5, 123.1, 119.5, 116.7, 115.7, 85.8, 53.1.
d
4.2. General procedure for the synthesis of 3
d
A mixture of CuI (0.6 mmol), indoles (0.5 mmol) and benzyl
cyanide (0.6 mmol) in DMF (3.0 mL) was stirred under air at 100 ꢀC
for 34 h and then cooled to room temperature. After the reaction
mixture was quenched with 10 mL of water, it was extracted with
DCM (3ꢂ10 mL). The combined organic layers were washed with
the saturated aqueous solution of sodium chloride and dried over
MgSO4. The solution was concentrated under reduced pressure and
purified by column chromatography to afford 3-cyanoindoles.
4.3.10. 2-Methyl-1H-indole-3-carbonitrile (3j).32 Yield 37%; yellow
solid; mp 208e210 ꢀC; 1H NMR (400 MHz, DMSO)
12.12 (s, 1H),
d
7.55 (d, J¼7.6 Hz, 1H), 7.47 (d, J¼7.8 Hz, 1H), 7.27e7.17 (m, 2H), 2.58
(s, 3H); 13C NMR (100 MHz, DMSO)
118.6, 117.4, 113.0, 83.7, 13.5.
d 146.9,135.7,128.1,123.6, 122.3,
4.3.11. 2-Phenyl-1H-indole-3-carbonitrile (3k).33 Yield 48%; white
solid; mp 245e247 ꢀC; 1H NMR (400 MHz, DMSO)
12.65 (s, 1H),
8.03 (d, J¼7.6 Hz, 2H), 7.68 (m, 3H), 7.59 (d, J¼7.4 Hz, 2H),
7.41e7.26 (m, 2H); 13C NMR (100 MHz, DMSO)
145.7, 136.5,
d
4.3. Characterization data
d
4.3.1. 1H-Indole-3-carbonitrile (3a).27 Yield 80%; yellow solid; mp
130.9, 130.3, 130.3, 129.3, 128.0, 124.9, 123.0, 119.4, 118.0, 113.6,
82.4.
178e180 ꢀC; 1H NMR (400 MHz, CDCl3)
d 8.80 (s, 1H), 7.78 (d,
J¼8.2 Hz, 1H), 7.76 (s, 1H), 7.48 (d, J¼8.2 Hz, 1H), 7.39e7.28 (m, 2H);
13C NMR (125 MHz, CDCl3)
116.0, 112.2, 87.5.
d
135.0, 132.0, 127.1, 124.4, 122.5, 119.8,
4.3.12. 2-(4-Fluorophenyl)-1H-indole-3-carbonitrile
55%; white solid; mp 239e241 ꢀC; 1H NMR (400 MHz, DMSO)
12.64 (s, 1H), 8.06 (dd, J¼8.4 Hz, JHeF¼5.6 Hz, 2H), 7.68 (d,
J¼7.8 Hz,1H), 7.60 (d, J¼8.0 Hz,1H), 7.52 (dd, J1¼J2¼8.8 Hz, 2H), 7.32
(m, 2H); 13C NMR (100 MHz, DMSO)
(3l).34 Yield
d
4.3.2. 5-Methyl-1H-indole-3-carbonitrile (3b). Yield 53%; white
solid; mp 132e134 ꢀC; 1H NMR (400 MHz, DMSO)
12.12 (s, 1H),
d
d
165.1 (d, JCeF¼247 Hz), 144.8,
8.21 (s, 1H), 7.47 (d, J¼8.4 Hz, 2H), 7.13(d, J¼8.4 Hz, 1H), 2.45(s, 3H);
136.5, 130.4 (d, JCeF¼8 Hz), 129.2, 126.9 (d, JCeF¼3 Hz), 124.9, 123.0,
13C NMR (100 MHz, DMSO)
117.5, 113.6, 84.6, 22.0.
d 135.2, 134.5, 131.7, 128.0, 125.9, 118.9,
119.3, 117.9, 117.5 (d, JCeF¼21 Hz), 113.6, 82.4.
4.3.13. 1-Methyl-1H-indole-3-carbonitrile (3m).15b Yield 86%; white
4.3.3. 5-Methoxy-1H-indole-3-carbonitrile (3c).28 Yield 43%; white
solid; mp 154e156 ꢀC; 1H NMR (400 MHz, DMSO)
12.10 (s, 1H),
solid; mp 53e55 ꢀC; 1H NMR (400 MHz, CDCl3)
d
7.70 (d, J¼7.8 Hz,
d
1H), 7.48 (s, 1H), 7.38e7.30 (m, 2H), 7.27 (d, J¼11.2 Hz, 1H), 3.78 (s,
8.20 (s, 1H), 7.48 (d, J¼8.8 Hz, 1H), 7.12 (s, 1H), 6.94 (d, J¼8.8 Hz, 1H),
3H); 13C NMR (100 MHz, CDCl3)
119.5, 116.0, 110.4, 85.0, 33.5.
d 135.9, 135.6, 127.6, 123.7, 122.0,
3.85 (s, 3H); 13C NMR (100 MHz, DMSO)
117.6, 114.8, 100.7, 84.9, 56.3.
d 156.2, 135.3, 131.0, 128.5,
4.3.14. 1,5-Dimethyl-1H-indole-3-carbonitrile (3n).21 Yield 86%;
yellow solid; mp 80e82 ꢀC; 1H NMR (400 MHz, DMSO)
8.27 (s,
4.3.4. 1H-Indole-3,5-dicarbonitrile (3d). Yield 91%; yellow solid;
d
mp 257e259 ꢀC; 1H NMR (400 MHz, DMSO)
d
12.73 (s, 1H), 8.52 (s,
1H), 7.61 (d, J¼8.4 Hz,1H), 7.53 (s, 1H), 7.28 (d, J¼8.4 Hz,1H), 3.95 (s,
1H), 8.24 (s, 1H), 7.76 (d, J¼8.4 Hz, 1H), 7.69 (d, J¼8.4 Hz, 1H); 13C
3H), 3.49 (s, 3H); 13C NMR (100 MHz, DMSO)
128.3, 125.9, 119.1, 117.1, 112.1, 83.4, 34.3, 21.9.
d 138.3, 135.2, 132.1,
NMR (100 MHz, DMSO)
116.1, 115.3, 105.1, 86.4.
d 138.3, 138.0, 127.3, 127.2, 125.0, 120.6,
4.3.15. 5-Methoxy-1-methyl-1H-indole-3-carbonitrile (3o).15b Yield
55%; yellow solid; mp 103e105 ꢀC; 1H NMR (400 MHz, DMSO)
4.3.5. 5-Nitro-1H-indole-3-carbonitrile (3e). Yield 93%; yellow
solid; mp 186e188 ꢀC; 1H NMR (400 MHz, DMSO)
12.86 (s, 1H),
d
d
7.29 (s, 1H), 6.67 (d, J¼8.8 Hz, 1H), 6.24 (s, 1H), 6.11 (d,

4240
L. Zhang et al. / Tetrahedron 69 (2013) 4236e4240
J¼8.8 Hz, 1H), 2.98 (s, 3H), 2.98 (s, 3H); 13C NMR (100 MHz,
Supplementary data
DMSO)
d 156.5, 138.3, 131.8, 128.9, 117.2, 114.6, 113.3, 100.9, 83.6,
56.4, 34.4.
General experimental procedures, optimization of reaction
conditions, kinetic data and copies of 1H and 13C NMR spectra for all
products. Supplementary data related to this article can be found at
http://dx.doi.org/10.1016/j.tet.2013.03.089. These data include MOL
files and InChiKeys of the most important compounds described in
this article.
4.3.16. 1-Methyl-1H-indole-3,5-dicarbonitrile (3p).21 Yield 93%;
yellow solid; mp 163e165 ꢀC; 1H NMR (400 MHz, DMSO)
d 7.57 (s,
1H), 7.28 (s, 1H), 6.95 (d, J¼8.6 Hz, 1H), 6.83 (d, J¼8.6 Hz, 1H), 3.05
(s, 3H); 13C NMR (100 MHz, DMSO)
120.5, 115.8, 113.9, 105.3, 85.4, 34.7.
d 141.4, 138.4, 127.5, 127.1, 125.1,
References and notes
4.3.17. 1-Methyl-5-nitro-1H-indole-3-carbonitrile (3q).21 Yield 96%;
yellow solid; mp 159e160 ꢀC; 1H NMR (400 MHz, DMSO)
7.62
d
1. Kumar, D.; Narayanam, M. K.; Chang, K. H.; Shah, K. Chem. Biol. Drug Des. 2011,
77, 182e188.
2. Kumar, D.; Kumar, N. M.; Chang, K. H.; Gupta, R.; Shah, K. Bioorg. Med. Chem.
Lett. 2011, 21, 5897e5900.
3. Swain, C. J.; Baker, R.; Kneen, C.; Moseley, J.; Saunders, J.; Seward, E. M.; Ste-
venson, G.; Beer, M.; Stanton, J.; Watling, K. J. Med. Chem. 1991, 34, 140e151.
4. Ryzhova, E. A.; Koryakova, A. G.; Bulanova, E. A.; Mikitas, O. V.; Karapetyan, R. N.;
Lavrovskii, Y. V.; Ivashchenko, A. V. Pharm. Chem. J. 2009, 43, 148e153.
5. Zedda, G.; Simbula, G.; Begala, M.; Pibiri, M.; Floris, C.; Casu, M.; Casu, L.; Tocco,
G. Arch. Pharm. 2012, 345, 195e202.
(s, 1H), 7.51 (s, 1H), 7.27 (d, J¼8.0 Hz, 1H), 6.95 (d, J¼8.0 Hz, 1H), 3.07
(s, 3H); 13C NMR (100 MHz, DMSO)
116.1, 115.5, 113.5, 86.7, 34.9.
d 143.6, 142.5, 139.7, 127.1, 119.4,
4.3.18. 1-Ethyl-2-methyl-1H-indole-3-carbonitrile
65%; brown solid; mp 89e91 ꢀC; 1H NMR (400 MHz, CDCl3)
(3r).15b Yield
7.66
d
(d, J¼7.2 Hz, 1H), 7.33 (d, J¼7.6 Hz, 1H), 7.30e7.24 (m, 2H), 4.16 (q,
J¼7.3 Hz, 2H), 2.58 (s, 3H), 1.38 (t, J¼7.3 Hz, 3H); 13C NMR (100 MHz,
6. Wu, S.; Wang, L.; Guo, W.; Liu, X.; Liu, J.; Wei, X.; Fang, B. J. Med. Chem. 2011, 54,
2668e2679.
7. Ferro, S.; Grazia, S. D.; Luca, L. D.; Barreca, M. L.; Debyser, Z.; Chimirri, A. Het-
erocycles 2009, 78, 947e959.
CDCl3)
d 145.0, 135.3, 127.3, 123.0, 121.9, 119.2, 116.8, 109.9, 85.0,
38.8, 15.0, 11.8.
8. Trost, B. M.; Osipov, M.; Dong, G. J. Am. Chem. Soc. 2010, 132, 15800e15807.
9. (a) Beemelmanns, C.; Lentz, D.; Reissig, H. U. Chem.dEur. J. 2011, 17, 9720e9730;
(b) Beemelmanns, C.; Reissig, H.-U. Org. Biomol. Chem. 2009, 7, 4475e4480.
10. (a) Pomeroy, J. H.; Carolyn, C. A. J. Am. Chem. Soc. 1959, 81, 6340e6341; (b) Hwu,
J. R.; Wong, F. F. Eur. J. Org. Chem. 2006, 11, 2513e2516; (c) Sridhar, M.; Reddy, M.
K. K.; Sairam, V. V.; Raveendra, J.; Godala, K. R.; Narsaiah, C.; Ramanaiah, B. C.;
Reddy, C. S. Tetrahedron Lett. 2012, 53, 3421e3424.
11. Singh, M. K.; Lakshman, M. K. J. Org. Chem. 2009, 74, 3079e3084.
12. (a) Rokade, B. V.; Malekar, S. K.; Prabhu, K. R. Chem. Commun. 2012, 5506e5508; (b)
Oishi, T.; Yamaguchi, K.; Mizuno, N. Angew. Chem., Int. Ed. 2009, 48, 6286e6288.
13. Hwu, J. R.; Hsu, C. H.; Wong, F. F.; Chung, C. S.; Hakimelahi, G. H. Synthesis 1998,
3, 329e332.
14. (a) Zanon, J.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125,
2890e2891; (b) Yang, C.; Williams, J. M. Org. Lett. 2004, 6, 2837e2840; (c)
Buono, F. G.; Chidambaram, R.; Mueller, R. H.; Waltermire, R. E. Org. Lett. 2008,
10, 5325e5328; (d) Jia, X.; Yang, D.; Zhang, S.; Cheng, J. Org. Lett. 2009, 11,
4716e4719; (e) Chatani, N.; Hanafusa, T. J. Org. Chem. 1986, 51, 4714e4716; (f)
Nair, V.; Purdy, D. F.; Sells, T. B. J. Chem. Soc., Chem. Commun. 1989, 878e879.
15. (a) Schareina, T.; Zapf, A.; Beller, M. Chem. Commun. 2004, 1388e1389; (b) Yan,
G.; Kuang, C.; Zhang, Y.; Wang, J. Org. Lett. 2010, 12, 1052e1055; (c) Yeung, P. Y.;
So, C. M.; Lau, C. P.; Kwong, F. Y. Angew. Chem., Int. Ed. 2010, 49, 8918e8922.
16. Sundermeier, M.; Zapf, A.; Beller, M. Angew. Chem., Int. Ed. 2003, 42, 1661e1664.
17. Jiang, Z.; Huang, Q.; Chen, S.; Long, L.; Zhou, X. Adv. Synth. Catal. 2012, 354,
589e592.
4.3.19. 1-Ethyl-2-phenyl-1H-indole-3-carbonitrile (3s). Yield 89%;
yellow solid; mp 108e110 ꢀC; 1H NMR (400 MHz, DMSO)
d 7.77
(d, J¼8.2 Hz, 1H), 7.72 (d, J¼7.8 Hz, 1H), 7.65 (m, 5H), 7.42 (dd,
J1¼J2¼7.6 Hz, 1H), 7.35 (dd, J1¼J2¼7.4 Hz, 1H), 4.25 (q, J¼7.2 Hz,
2H), 1.24 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, DMSO)
d 166.9,
142.9, 141.8, 138.9, 134.8, 131.3, 128.6, 127.3, 126.4, 118.7, 115.4,
114.8, 112.7, 86.1, 34.2, 26.6.
4.3.20. 5-Methoxy-1-methyl-2-phenyl-1H-indole-3-carbonitrile
(3t). Yield 41%; canary yellow solid; mp 253e255 ꢀC; 1H NMR
(400 MHz, DMSO)
d
7.71 (d, J¼7.4 Hz, 2H), 7.65 (m, 3H), 7.15 (s, 1H),
7.04 (d, J¼8.8 Hz, 1H), 3.88 (s, 3H), 3.77 (s, 3H); 13C NMR (100 MHz,
DMSO)
d 156.7, 148.5, 132.5, 130.8, 130.7, 129.9, 129.4, 128.5, 117.5,
114.9, 113.7, 100.7, 84.4, 56.4, 32.8; HRMS (EI) calcd for C17H14N2O:
262.1106 ([M]þ), found: 262.1111.
4.3.21. 1-Methyl-2-phenyl-1H-indole-3-carbonitrile (3u).15b Yield
52%; white solid; mp 113e115 ꢀC; 1H NMR (400 MHz, CDCl3)
18. Chen, F. X.; Feng, X. M.; Qin, B.; Zhang, G. L.; Jiang, Y. Z. Org. Lett. 2003, 5,
949e952.
d
7.77 (d, J¼8.0 Hz, 1H), 7.59e7.50 (m, 5H), 7.42 (d, J¼8.0 Hz, 1H),
7.37 (dd, J1¼J2¼8.0 Hz, 1H), 7.33 (dd, J1¼J2¼8.0 Hz, 1H), 3.76 (s,
3H); s13C NMR (100 MHz, CDCl3)
148.21, 136.97, 130.02, 129.96,
19. (a) Chen, X.; Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc. 2006, 128,
6790e6791; (b) Ding, S.; Jiao, N. J. Am. Chem. Soc. 2011, 133, 12374e12377.
20. Kim, J.; Chang, S. J. Am. Chem. Soc. 2010, 132, 10272e10274.
21. Ren, X.; Chen, J.; Chen, F.; Cheng, J. Chem. Commun. 2011, 6725e6727.
22. Zhang, G.; Ren, X.; Chen, J.; Hu, M.; Cheng, J. Org. Lett. 2011, 13, 5004e5007.
23. Wen, Q.; Jin, J.; Hu, B.; Lu, P.; Wang, Y. RSC Adv. 2012, 2, 6167e6169.
24. Jin, J.; Wen, Q.; Lu, P.; Wang, Y. Chem. Commun. 2012, 9933e9935.
25. Jao, C. W.; Lin, W. C.; Wu, Y. T.; Wu, P. L. J. Nat. Prod. 2008, 71, 1275e1279.
26. Alberola, A.; Andres, J. M.; Gonzalez, A.; Pedrosa, R.; Vicente, M. Heterocycles
1990, 31, 1049e1058.
d
129.14, 128.85, 127.70, 124.00, 122.55, 119.67, 116.76, 110.64, 85.67,
31.85.
4.3.22. 3,5-Dimethyl-1H-pyrrole-2-carbonitrile (3v).26 Yield 94%;
white solid; mp 68e70 ꢀC; 1H NMR (400 MHz, CDCl3)
d
8.41 (s, 1H),
5.80 (s, 1H), 2.25 (s, 3H), 2.19 (s, 3H); 13C NMR (100 MHz, DMSO)
137.0, 133.9, 115.1, 98.5, 69.9, 14.8, 14.2.
27. Den Hertog, H. J.; Buurman, D. J. Tetrahedron Lett. 1967, 8, 3657e3659.
28. Banini, S. R.; Turner, M. R.; Cummings, M. M.; Soederberg, B. C. G. Tetrahedron
2011, 67, 3603e3611.
d
29. Pedras, M. S. C.; Liu, J. Org. Biomol. Chem. 2004, 2, 1070e1076.
30. Reddy, B. V. S.; Begum, Z.; Reddy, Y. J.; Yadav, J. S. Tetrahedron Lett. 2010, 51,
3334e3336.
31. Lee, K. Y.; Lee, H. S.; Kim, J. N. Bull. Korean Chem. Soc. 2007, 28, 333e335.
32. Mehta, G.; Dhar, D. N.; Suri, S. C. Synthesis 1978, 374e376.
33. Bergman, J.; Pelcman, B. Tetrahedron 1988, 44, 5215e5228.
34. Swamy, N. K.; Yazici, A.; Pyne, S. G. J. Org. Chem. 2010, 75, 3412e3419.
Acknowledgements
We thank the National Nature Science Foundation of China (No.
21272203, 21032005) for financial support to this work.