Copper-mediated direct C2-cyanation of indoles using acetonitrile as the cyanide source

Article abstract of DOI:10.1021/jo4014904

A copper-mediated C2-cyanation of indoles using cheap and commercially available acetonitrile as the nonmetallic cyanide source was achieved through sequential C-C and C-H bond cleavages. The installation of a removable pyrimidyl group on the indole nitrogen atom is the key for this C2 selectivity. This approach provides a novel and alternative route leading to indole-2-carbonitrile.

Full text of DOI:10.1021/jo4014904

Note
pubs.acs.org/joc
Copper-Mediated Direct C2-Cyanation of Indoles Using Acetonitrile
as the Cyanide Source
Changduo Pan,†,‡ Hongming Jin,† Pan Xu,† Xu Liu,† Yixiang Cheng,† and Chengjian Zhu*,†
†State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing
210093, P. R. China
‡Wenzhou Institute of Industry & Science, Wenzhou 325000, P. R. China
S
* Supporting Information
ABSTRACT: A copper-mediated C2-cyanation of indoles using
cheap and commercially available acetonitrile as the “nonmetallic”
cyanide source was achieved through sequential C−C and C−H
bond cleavages. The installation of a removable pyrimidyl group on
the indole nitrogen atom is the key for this C2 selectivity. This
approach provides a novel and alternative route leading to indole-2-
carbonitrile.
ndoles are common structural motifs in a series of natural
one example on the direct C2-cyanation of indole was reported
by Xu, using tert-butyl isocyanide as the cyano-group source.39
Our interest in the cyanation40 and C2-functionalization of
indole41 spurred us to test the feasibility of chelation effect of a
pyrimidyl group in the cyanation of the C−H bond. Herein, we
disclosed a copper-mediated C2-cyanation of indole with
commercially available acetonitrile as the nonmetallic cyano-
group source.
Initially, we examined the reaction of 1-(pyrimidin-2-yl)-1H-
indole (1a) with acetonitrile (2) using Cu(OAc)2 as the catalyst
under O2. To our delight, a 32% yield of the cyanated product
3a was obtained (Table 1, entry 1). After surveying a series of
oxidants, such as AgNO3, AgOAc, Ag2O, K2S2O8, PhI(OAc)2,
and DDQ, AgOAc was found to be most efficient (Table 1,
entry 2). Cu(OAc)2 was the best among the screened copper
sources, while CuBr2 showed very poor activity for this
transformation. The yield decreased to 25% under air. No
product was obtained without a copper source (Table 1, entry
12).
To evaluate the substrate scope of this protocol, the
optimized reaction conditions were applied to a range of
indoles. As illustrated in Scheme 1, N-pyrimidyl indoles bearing
a series of substitutions at the C3-, C4-, C5- C6-, or C7-
positions were compatible in this reaction with good yields.
The indoles possessing electron-donating groups (3b−3f,
Scheme 1) gave higher yields than those with electron-
withdrawing groups (3g−3j, Scheme 1). Steric hindrance on
the indole had obvious effect on the reaction. For example,
methyl at C3 of indole could inhibit the efficiency and afforded
lower yield (3b vs 3d, Scheme 1). Furthermore, for those
substrates with an ethyl or fluoro group at the pyrimidine ring,
indole-2-carbonitriles could be isolated with good yields (3k
1
Iproducts and drugs. Therefore, the selective and efficient
functionalizations of such framework are highly desired in
synthesis. In the past few years, direct transformation of the
indole C−H bond has become the most straightforward
method leading to functionalized indoles.2 The C3-selective
C−H functionalizations of indole, such as formylation,
alkynylation, and alkenylation, were widely studied owning to
its inherent property.2 In order to alter the regioselectivity of
C3 toward C2 C−H bonds, some easily removable directing
groups are usually required to install to the indole nitrogen
atom.3−9
The nitrile unit is widely present in dyes, herbicides, drugs,
and natural products.10 Traditional Sandmeyer reaction,
Rosenmund−von Braun reactions,11 and transition-metal-
catalyzed cyanation of aryl halides were developed to access
nitrile.12 Recently, the direct cyanation of C−H bonds has
emerged as an alternatively attractive method.13−15,32−38 With
regards to cyano source,16 one is metallic cyano-group sources,
such as CuCN, KCN, NaCN, Zn(CN)2. The other is
“nonmetallic” organic cyano-group sources, such as acetone
cyanohydrin, BnSCN, N-cyano-N-phenyl-p-toluenesulfona-
mide, DDQ, tert-butyl isocyanide, ethyl cyanoacetate, benzyl
cyanide, malononitrile, DMF, or combined cyanide source.17−29
The metallic cyano-group sources employed are generally toxic
and not environmentally benign. Thus, the nonmetallic cyano-
group sources becomes a promising alternative. As far as this is
concerned, acetonitrile is a very ideal choice since it is cheap
and commercially produced. In 1998, Cheng developed a
palladium and zinc species-mediated cyanation of aryl halides
with acetonitrile.30 Recently, Li reported a copper-catalyzed
oxidative cyanation of aryl halides using acetonitrile as the
cyanide source.31 However, to our knowledge, direct cyanation
of the aromatic C−H bond with acetonitrile is not disclosed in
the literature. Although direct C3-cyanations of indole with
different cyanide sources have been well developed,32−38 only
Received: July 12, 2013
© XXXX American Chemical Society
A
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The Journal of Organic Chemistry
Note
a
To increase the reaction practicability, we attempted to
remove the pyrimidinyl group (Scheme 2). Upon treatment of
3a with NaOEt in DMSO at 110 °C,42 1H-indole-2-carbonitrile
4a was isolated in 95% yield, which is the key intermediate for
pharmaceutical products.43−45
Table 1. Screening the Optimized Reaction Conditions
In order to confirm the origin of the cyano group in this
cyanation procedure, an array of experiments were performed.
CuI or CuCl2 instead of Cu(OAc)2 provided the cyanide
product (Table 1, entries 9 and 11), and replacing AgOAc with
AgNO3, Ag2O, or K2S2O8 also provided the desired product
(Table 1, entries 1−6). These results ruled out the possibility of
the carbon atom in the cyano group deriving from Cu(OAc)2
or AgOAc. According to these results, the unique possibility of
the CN unit comes from CH3CN.
Moreover, when 1-methyl-1H-indole or 1-phenyl-1H-indole
instead of 1-(pyrimidin-2-yl)-1H-indole (1a) was submitted to
the procedure, only a trace of cyanated product was detected by
GC−MS. These results revealed that the directing group was
crucial for this selectivity.
Although the detailed mechanism remained unclear at the
current stage, a possible mechanism based on the above results
is outlined in Scheme 3. First, coordination of the N atom of 1a
to Cu(II) and directed cyclometalation affords a Cu(II)
intermediate A. The intermediate A chelates with the C−N
triple bond in MeCN to form intermediate B. Then, the
carbon−cyano σ-bond is cleaved to form intermediate C,46−48
and intermediate C is oxidized to the Cu(III) intermediate D in
the presence of oxidant.49,50 Finally, the reductive elimination
of intermediate C gives the product 3a along with Cu(I), which
is oxidized to regenerate Cu(II).
entry
Cu
oxidant
yield (%)
1
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
CuI
AgNO3
AgOAc
AgF
32
b
c
2
70(25) (40)
3
10
25
57
23
12
0
4
Ag2CO3
Ag2O
5
6
K2S2O8
PhI(OAc)2
DDQ
7
8
9
AgOAc
AgOAc
AgOAc
AgOAc
50
trace
36
0
10
11
12
13
CuBr2
CuCl2
Cu(OAc)2
41
a
Reaction conditions: 1a (0.2 mmol), Cu (50 mol %), oxidant (0.4
mmol), CH3CN (2 mL), O2, 130 °C in a sealed tube. Air. 20 mol %
of Cu(OAc)2.
b
c
a
Scheme 1. Substrate Scope
In conclusion, we have developed a copper-mediated C2-
cyanation of indoles using cheap and commercially available
acetonitrile as the nonmetallic cyano-group source through
sequential C−C bond and C−H bond cleavage. The key to this
C2-cyanation is the installation of a pyrimidyl group on the
indole nitrogen atom. This approach provides a novel and
alternative route for preparation of indole-2-carbonitrile.
EXPERIMENTAL SECTION
■
General Information. 1H NMR and 13C NMR spectra were
measured on 300, 400, or 600 MHz NMR spectrometers using CDCl3
or DMSO-d6 as the solvent with tetramethylsilane (TMS) as the
internal standard. Chemical shifts are given in δ relative to TMS, the
coupling constants J are given in Hz. HRMS were recorded on a TOF
LC/MS equipped with electrospray ionization (ESI) probe operating
in positive or negative ion mode.
All the 2-pyrimidylindoles were prepared according to the
literature.42 The 2-pyrimidylindoles 1f, 1k, 1l are unknown.
4-(Benzyloxy)-1-(pyrimidin-2-yl)-1H-indole (1f). White solid;
1
mp 98−100 °C; H NMR (CDCl3, 400 MHz) δ 8.68 (d, J = 4.8 Hz,
2H), 8.42 (d, J = 8.4 Hz, 1H), 8.18 (d, J = 3.6 Hz, 1H), 7.51 (d, J = 7.2
Hz, 2H), 7.42−7.38 (m, 2H), 7.35−7.32 (m, 1H), 7.25−7.22 (m, 1H),
7.02 (t, J = 4.8 Hz, 1H), 6.89 (dd, J = 3.6 Hz, 1H), 6.74 (d, J = 7.8 Hz,
1H), 5.24 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 158.1, 157.9,
152.1, 137.5, 136.8, 128.5, 127.8, 127.4, 124.4, 122.0, 116.2, 109.8,
104.2, 104.1, 70.1. HRMS (ESI) m/z calcd for C19H16N3O (M + H)+
302.1288, found 302.1290.
1-(5-Ethylpyrimidin-2-yl)-1H-indole (1k). White solid; mp 44−
1
46 °C; H NMR (CDCl3, 400 MHz) δ 8.78 (d, J = 8.8 Hz 1H), 8.53
a
Reaction conditions: 1 (0.2 mmol), Cu(OAc)2 (50 mol %), AgOAc
(s, 2H), 8.25 (d, J = 3.6 Hz, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.33−7.31
(m, 1H), 7.24−7.22 (m, 1H), 6.68 (d, J = 3.3 Hz, 1H), 2.64 (q, J = 7.6
Hz, 2H), 1.29 (t, J = 7.6 Hz, 2H); 13C NMR (100 MHz, CDCl3):
157.4, 156.4, 135.3, 131.2, 131.1, 125.8, 123.4, 121.8, 120.7, 116.0,
106.4, 23.0, 15.1. HRMS (ESI) m/z calcd for C14H14N3 (M + H)+
224.1182, found 224.1179.
(0.4 mmol), CH3CN (2 mL), O2, 130 °C.
and 3l, Scheme 1). Notably, N-pyridyl indoles also worked well
in this cyanation reaction (3m−3o, Scheme 1).
B
dx.doi.org/10.1021/jo4014904 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
a
Scheme 2. Removal of Directing Group to 1H-Indole-2-carbonitrile and Its Application
a
Reaction conditions: 3a (0.15 mmol), NaOEt (0.6 mmol), DMSO (1.5 mL), argon, 110 °C.
Scheme 3. Proposed Mechanism
1-(5-Fluoropyrimidin-2-yl)-1H-indole (1l). White solid; mp
113−115 °C; H NMR (CDCl3, 400 MHz) δ 8.71 (d, J = 8.4 Hz,
7.54−7.48 (m, 1H), 7.37−7.27 (m, 1H), 7.19 (t, J = 4.8 HZ, 1H), 2.59
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 158.2, 156.6, 136.5, 131.6,
128.7, 127.7, 123.0, 120.1, 117.4, 116.3, 114.0, 107.2, 9.9.
1
1H), 8.57 (s, 2H), 8.19 (d, J = 3.6 Hz, 1H), 7.62 (d, J = 7.7 Hz, 1H),
7.34−7.32 (m, 1H), 7.25−7.22 (m, 1H), 6.70 (d, J = 3.6 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 154.5 (d, JC−F = 256.2 Hz), 154.1 (d, JC−F
= 2.2 Hz), 145.7 (d, JC−F = 21.9 Hz), 135.2, 131.1, 126.0, 123.7, 122.2,
120.9, 115.7, 107.0. HRMS (ESI) m/z calcd for C12H9FN3 (M + H)+
214.0775, found 214.0772.
7-Methyl-1-(pyrimidin-2-yl)-1H-indole-2-carbonitrile (3c).
1
White solid (33.7 mg, 72%); mp 128−129 °C; H NMR (CDCl3,
300 MHz) δ 8.92 (d, J = 4.8 Hz, 2H), 7.59−7.56 (m, 1H), 7.43−7.39
(m, 2H), 7.24−7.23 (m, 2H), 2.16 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 158.7, 156.6, 136.5, 129.8, 127.8, 123.6, 123.2, 120.2, 120.0,
118.5, 113.4, 111.1, 20.7. HRMS (ESI) m/z calcd for C14H11N4 (M +
H)+ 235.0978, found 235.0977.
General Procedure for the Direct C2-Cyanation of Indole
with Acetonitrile as Cyanide Source. A sealed reaction tube was
charged with 1 (0.2 mmol), Cu(OAc)2 (18 mg, 50 mol %), AgOAc
(66.8 mg, 0.4 mmol), and dry CH3CN (2 mL). After stirring at 130 °C
for 48 h under an O2 atmosphere, the reaction mixture was
concentrated and purified by flash column chromatography on silica
gel to give the desired products 3m−3p.
4-Methyl-1-(pyrimidin-2-yl)-1H-indole-2-carbonitrile (3d).
1
White solid (33.2 mg, 71%); mp 158−160 °C; H NMR (CDCl3,
300 MHz) δ 8.83 (d, J = 4.8 Hz, 2H), 8.60 (d, J = 8.6 Hz, 1H), 7.51 (s,
1H), 7.43−7.37 (m, 1H), 7.24 (d, J = 4.8 Hz, 1H), 7.22−7.10 (m,
1H), 2.58 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 158.3, 156.6,
136.5, 131.6, 127.7, 127.7, 123.7, 119.5, 117.9, 114.3, 113.6, 108.3,
18.4. HRMS (ESI) m/z calcd for C14H11N4 (M + H)+ 235.0978, found
235.0978.
1-(Pyrimidin-2-yl)-1H-indole-2-carbonitrile (3a).39 White solid
1
(30.8 mg, 70%); H NMR (CDCl3, 300 MHz) δ 8.83 (d, J = 4.6 Hz,
2H), 8.69 (d, J = 8.6 Hz, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.53−7.47 (m,
2H), 7.35−7.30 (m, 1H), 7.25−7.21 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 158.3, 156.5, 136.6, 127.7, 127.5, 123.5, 122.0, 121.0, 118.0,
116.2, 114.2, 108.9.
5-Methoxy-1-(pyrimidin-2-yl)-1H-indole-2-carbonitrile
(3e).39 White solid (37.5 mg, 75%); H NMR (CDCl3, 300 MHz) δ
1
8.80 (d, J = 4.8 Hz, 2H), 8.60 (d, J = 9.2 Hz, 1H), 7.37 (s, 1H), 7.21 (t,
J = 4.8 Hz, 1H), 7.14−7.05 (m, 2H), 3.87 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 158.2, 156.5, 156.3, 131.6, 128.5, 120.5, 117.9, 117.8,
117.3, 114.3, 109.0, 102.5, 55.6.
3-Methyl-1-(pyrimidin-2-yl)-1H-indole-2-carbonitrile (3b).39
White solid (24.3 mg, 52%); 1H NMR (CDCl3, 300 MHz) δ 8.81 (d, J
= 4.8 Hz, 2H), 8.70 (d, J = 8.6 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H),
C
dx.doi.org/10.1021/jo4014904 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
4-(Benzyloxy)-1-(pyrimidin-2-yl)-1H-indole-2-carbonitrile
(3f). White solid (41.7 mg, 64%); mp 169−171 °C. 1H NMR (CDCl3,
300 MHz) δ 8.84 (d, J = 4.8 Hz, 2H), 8.26 (d, J = 8.6 Hz, 1H), 7.66 (s,
1H), 7.51−7.38 (m, 6H), 7.26 (d, J = 9.2 Hz, 1H), 6.77 (d, J = 7.9 Hz,
1H), 5.25 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 158.3, 156.7,
152.6, 137.9, 136.6, 128.7, 128.7, 128.1, 127.4, 119.3, 118.6, 118.0,
114.3, 109.0, 107.5, 104.3, 70.2. HRMS (ESI) m/z calcd for
C20H14N4NaO (M + Na)+ 349.1060, found 349.1061.
(dd, J = 4.9, 1.1 Hz, 1H), 7.94 (td, J = 8.0, 1.9 Hz, 1H), 7.82 (d, J = 8.5
Hz, 1H), 7.64 (dd, J = 26.3, 8.1 Hz, 2H), 7.49−7.40 (m, 1H), 7.38−
7.28 (m, 2H), 2.60 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 150.0,
149.5, 138.8, 137.0, 128.6, 127.5, 127.1, 122.2, 122.1, 120.5, 118.3,
113.7, 112.3, 107.6, 9.9.
1-(Pyrimidin-2-yl)-1H-pyrrole-2-carbonitrile (3p).39 White
1
solid (18.4 mg, 54%); H NMR (CDCl3, 300 MHz) δ 8.75 (d, J =
4.8 Hz, 2H), 8.0 (dd, J = 3.0 Hz, 1.7 Hz, 1H), 7.25 (t, J = 4.5 Hz, 1H),
7.10−7.08 (m, 1H), 6.38 (t, J = 3.4 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 158.6, 155.2, 126.2, 125.0, 118.9, 114.1, 111.8, 102.9.
Procedure for Removal of 2-Pyrimidyl Director.42 Under
argon, a mixture of 1-(pyrimidin-2-yl)-1H-indole-2-carbonitrile 3a (33
mg, 0.15 mmol), EtONa (40.8 mg, 0.6 mmol), and DMSO (1.5 mL)
was stirred in a reaction tube at 110 °C for 24 h. The resulting mixture
was then quenched with water. The mixture was extracted with ethyl
acetate, and the combined organic layer was dried by sodium sulfate.
The solvent was evaporated under reduced pressure, and the residue
was purified by flash column chromatography on silica gel to give the
product 1H-indole-2-carbonitrile 4a.
6-Fluoro-1-(pyrimidin-2-yl)-1H-indole-2-carbonitrile (3g).
1
White solid (32.4 mg, 68%); mp 178−180 °C; H NMR (CDCl3,
300 MHz) δ 8.85 (d, J = 4.8 Hz, 2H), 8.47 (dd, J = 10.7 Hz, 2.1 Hz,
1H), 7.62 (dd, J = 8.7 Hz, 5.5 Hz, 1H), 7.45 (s, 1H), 7.28−7.25 (m,
1H), 7.14−7.07 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 162.8 (d,
JC−F = 182.1 Hz), 158.3, 156.4, 136.8 (d, JC−F = 10.1 Hz), 124.2, 123.0
(d, JC−F = 7.6 Hz), 120.8 (d, JC−F = 1.0 Hz), 118.2, 113.9, 112.7 (d,
JC−F = 18.7 Hz), 109.4, 103.3 (d, JC−F = 22.0 Hz). HRMS (ESI) m/z
calcd for C13H8FN4 (M + H)+ 239.0728, found 239.0726.
5-Fluoro-1-(pyrimidin-2-yl)-1H-indole-2-carbonitrile (3h).
1
White solid (31.4 mg, 66%); mp 218−219 °C; H NMR (CDCl3,
300 MHz) δ 8.84 (d, J = 4.8 Hz, 1H), 8.70 (dd, J = 9.3, 4.6 Hz, 1H),
7.42 (s, 1H), 7.33 (dd, J = 8.4, 2.5 Hz, 1H), 7.30−7.20 (m, 1H); 13C
NMR (150 MHz, CDCl3) δ 159.4 (d, JC−F = 240.1 Hz), 158.4, 156.4,
133.1, 128.4 (d, JC−F = 10.4 Hz), 120.3 (d, JC−F = 4.7 Hz), 118.2, 117.7
(d, JC−F = 8.8 Hz), 116.0 (d, JC−F = 25.2 Hz), 113.7, 110.4, 106.7 (d,
JC−F = 23.7 Hz). HRMS (ESI) m/z calcd for C13H8FN4 (M + H)+
239.0728, found 239.0727.
1H-Indole-2-carbonitrile (4a).39 White solid (20.2 mg, 95%); 1H
NMR (CDCl3, 400 MHz) δ 8.78 (s, 1H), 8.67 (d, J = 8.1 Hz, 1H),
7.43−7.36 (m, 2H), 7.24−7.19 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 136.9, 126.3, 126.2, 122.1, 121.8, 114.5, 114.2, 111.8, 106.2.
ASSOCIATED CONTENT
■
S
* Supporting Information
5-Chloro-1-(pyrimidin-2-yl)-1H-indole-2-carbonitrile (3i).
1H and 13C NMR spectra of compounds 3a−3p and 4a. This
material is available free of charge via the Internet at http://
pubs.acs.org.
1
White solid (31.5 mg, 62%); mp 193−195 °C; H NMR (CDCl3,
300 MHz) δ 8.85 (d, J = 3.6 Hz, 2H), 8.77 (s, 1H), 7.60 (d, J = 6.4 Hz,
1H), 7.42−7.25 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 158.4,
156.3, 136.7, 133.7, 126.2, 124.4, 122.7, 120.6, 118.3, 116.4, 113.8,
109.6. HRMS (ESI) m/z calcd for C13H7ClN4Na (M + Na)+
277.0251, found 277.0252.
AUTHOR INFORMATION
Corresponding Author
*E-mail: cjzhu@nju.edu.cn.
■
1-(Pyrimidin-2-yl)-1H-indole-2,5-dicarbonitrile (3j). White
1
solid (32.8 mg, 67%); mp 228−230 °C; H NMR (d6-DMSO, 400
Notes
MHz) δ 9.02 (d, J = 4.9 Hz, 2H), 8.72 (d, J = 8.9 Hz, 1H), 8.38 (s,
1H), 7.96−7.90 (m, 1H), 7.60 (t, J = 4.9 Hz, 1H); 13C NMR (100
MHz, d6-DMSO) δ 159.1, 155.1, 137.3, 129.6, 127.8, 127.1, 120.6,
119.7, 119.0, 116.8, 112.9, 110.5, 105.8. HRMS (ESI) m/z calcd for
C14H8N5 (M + H)+ 246.0774, found 246.0776.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the National Natural Science
Foundation of China (21172106, 21074054), the National
Basic Research Program of China (2010CB923303), and the
Research Fund for the Doctoral Program of Higher Education
of China (20120091110010) for their financial support. C.P. is
thankful the support of Natural Science Foundation of China
(21272178).
1-(5-Ethylpyrimidin-2-yl)-1H-indole-2-carbonitrile (3k). Yel-
1
lowish liquid (36.2 mg, 73%); H NMR (CDCl3, 300 MHz) δ 8.68−
8.62 (m, 3H), 7.69 (d, J = 8.0 Hz, 1H), 7.52−7.45 (m, 2H), 7.34−7.26
(m, 1H), 2.73 (q, J = 8.0 Hz, 2H), 1.35 (t, J = 7.6 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 157.6, 154.9, 136.6, 133.4, 127.6, 127.3, 123.3,
122.0, 120.3, 115.8, 114.3, 108.9, 23.1, 14.9. HRMS (ESI) m/z calcd
for C15H13N4 (M + H)+ 249.1135, found 249.1134.
1-(5-Fluoropyrimidin-2-yl)-1H-indole-2-carbonitrile (3l).
White solid (30.9 mg, 65%); mp 140−142 °C. H NMR (CDCl3,
1
DEDICATION
■
400 MHz) δ 8.68 (s, 2H), 8.56−8.54 (m, 1H), 7.67 (d, J = 8.0 Hz,
1H), 7.52−7.47 (m, 1H), 7.45 (s, 1H), 7.34−7.30 (m, 1H); 13C NMR
(100 MHz, CDCl3) δ 155.3 (d, JC−F = 260.3 Hz), 152.5 (d, JC−F = 2.8
Hz), 146.0 (d, JC−F = 22.2 Hz), 136.4, 127.6, 127.6, 123.6, 122.1,
120.9, 115.5, 113.9, 109.0. HRMS (ESI) m/z calcd for C13H8FN4 (M
+ H)+ 239.0728, found 239.0726.
Dedicated to Professor Irina Petrovna Beletskaya for her
contribution to metal-catalyzed reactions.
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■
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1-(Pyridin-2-yl)-1H-indole-2-carbonitrile (3m).39 White solid
1
(27.6 mg, 63%); H NMR (CDCl3, 300 MHz) δ 8.71 (d, J = 3.2 Hz,
1H), 8.00−7.94 (m, 1H), 7.79 (d, J = 8.5 Hz, 2H), 7.73 (d, J = 8.0 Hz,
1H), 7.63−7.38 (m, 3H), 7.30 (d, J = 7.7 Hz, 1H); 13C NMR (150
MHz, CDCl3) δ 149.7, 149.7, 138.9, 137.1, 127.0, 126.9, 122.8, 122.7,
122.4, 118.8, 117.4, 113.7, 112.3, 109.1.
5-Methoxy-1-(pyridin-2-yl)-1H-indole-2-carbonitrile (3n).39
1
White solid (32.9 mg, 66%); H NMR (CDCl3, 300 MHz) δ 8.69
(7) Garca-Rubia, A.; Arrays, R. G.; Carretero, J. C. Angew. Chem., Int.
Ed. 2009, 48, 6511.
(8) Pan, S.; Ryu, N.; Shibata, T. J. Am. Chem. Soc. 2012, 134, 17474.
(9) Qin, X.; Liu, H.; Qin, D.; Wu, Q.; You, J.; Zhao, D.; Guo, Q.;
Huang, X.; Lan, J. Chem. Sci. 2013, 4, 1964.
(d, J = 4.8 Hz, 1H), 7.98−7.92 (m, 1H), 7.72 (d, J = 9.4 Hz, 1H), 7.60
(d, J = 8.1 Hz, 1H), 7.40−7.32 (m, 2H), 7.11−7.07 (m, 2H), 3.88 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 156.0, 149.8, 149.6, 138.9,
132.3, 127.5, 122.6, 118.5, 118.2, 116.9, 113.8, 113.5, 109.0, 102.3,
55.7.
3-Methyl-1-(pyridin-2-yl)-1H-indole-2-carbonitrile (3o).39
(10) The Chemisty of the Cyano Group; Rappoport, Z., Ed.;
Interscience: London, 1970.
1
White solid (23.3 mg, 50%); H NMR (CDCl3, 300 MHz) δ 8.68
D
dx.doi.org/10.1021/jo4014904 | J. Org. Chem. XXXX, XXX, XXX−XXX

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