Synthesis of 3-cyanoindole derivatives mediated by copper(I) iodide using benzyl cyanide

Article abstract of DOI:10.1021/jo3028278

Copper-mediated direct and regioselective C3-cyanation of indoles using benzyl cyanide as the cyanide anion source is presented. A wide range of indoles undergo cyanation smoothly by employing a reaction system of copper(I) iodide under open-to-air vessels.

Full text of DOI:10.1021/jo3028278

Note
pubs.acs.org/joc
Synthesis of 3‑Cyanoindole Derivatives Mediated by Copper(I) Iodide
Using Benzyl Cyanide
On Ying Yuen, Pui Ying Choy, Wing Kin Chow, Wing Tak Wong, and Fuk Yee Kwong*
State Key Laboratory of Chirosciences and Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic
University, Hung Hom, Kowloon, Hong Kong
S
* Supporting Information
ABSTRACT: Copper-mediated direct and regioselective C3-
cyanation of indoles using benzyl cyanide as the cyanide anion
source is presented. A wide range of indoles undergo cyanation
smoothly by employing a reaction system of copper(I) iodide under
open-to-air vessels.
Scheme 1. Examples of Useful Substituted 3-Cyanoindole-
Containing Molecules
he indole scaffold is exemplified as an important subunit
Tnot only in pharmaceutical and agrochemical products but
also basic constituents of dyes and herbicides.1 In particular, 3-
cyanoindole is a key building block in pharmaceutical syntheses
that can be applied in medicinal chemistry and drug discovery.
With the nitrile moiety, further transformations of this group
into a broad range of functional groups, such as amines,
aldehydes, acids, amides, ketones, and heterocycles, can be
made.2 In fact, 3-cyanoindole scaffold containing structures
have been well-known for their use as therapeutic estrogen
receptor ligands,3 acetyl-CoA carboxylase inhibitors for type 2
diabetes,4 xanthine−oxidase inhibitors,5 antiviral hepatitis C
virus inhibitors,6 aldosterone synthase modulator for cardio-
vascular diseases,7 anticancer agents,8 and antithrombotics
factor Xa inhibitors (Scheme 1).9
Aryl nitriles are generally prepared from classical organic
transformations, such as Sandmeyer10 and Rosenmund−von
Braun reaction,11 in which prefunctionalized starting materials
are often required. Palladium- and copper-catalyzed cyanations
of aryl halides and sulfonates are also well-documented
methods.12 Yet, there has been no example reported for the
conversion of 3-bromoindole to 3-cyanoindole. In fact, organic
transformations from a modified Madelung reaction,13 metal-
free oxidative synthesis from N-aryl enamines14 (Scheme 2A),
palladium-catalyzed N-heterocyclization,15 and propylphos-
phonic anhydride-promoted conversion of aldehydes16 are
alternative approaches to afford 3-cyanoindoles. Indeed,
emerging methods for facile synthesis of 3-cyanoindoles using
a direct C−H functionalization protocol are highly desirable.
Lewis acid, Fe, Cu, and Pd salts are usually employed as the
catalyst for accessing 3-cyanoindole using various metal
cyanides and other cyanide anion (CN−) surrogates (Scheme
2B).17
of indole would be highly favorable. In 2012, Wang and co-
workers first reported palladium-catalyzed cyanation of aryl
halides and CuBr-mediated cyanation of arenes using benzyl
cyanide as a CN− surrogate.18 This notable reagent is
commercially available, hazardless, inexpensive, and highly
soluble in common organic solvents. In view of the beneficial
features associated with this CN− source as well as our current
interest in cyanation reactions,19 herein we disclose our efforts
on copper-mediated direct cyanation of indole using benzyl
cyanide in a highly regioselective manner.
Nevertheless, most commonly available metal cyanides are
extremely toxic. Although K4[Fe(CN)6] is exceptionally
nontoxic, its low solubility in organic solvent limited its
applicability. Despite these limited CN− sources, an exploration
of other user-friendly organic CN− sources for direct cyanation
Received: January 6, 2013
© XXXX American Chemical Society
A
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Note
Scheme 2. Selected Synthetic Methods for 3-Cyanoindole Preparation Using Different Cyanide Sources
In order to achieve the C-3 indole functionalization for
cyanation, a series of reaction parameter optimizations were
deployed (Table 1). N-Methylindole was chosen as the
Having the optimized reaction conditions in hand, we next
examined the substrate scope of this cyanation reaction (Table
2). N-Alkylated indoles proceeded smoothly to give the
corresponding products in good yields (entries 1 and 2). The
allyl group remained intact during the course of the reaction
(entry 3). Disappointingly, unprotected NH indole showed
poor conversion under these reaction conditions (entry 4). It is
possibly due to the decomposition of unprotected indole. N-
Table 1. Initial Optimization of Direct C3-Cyanation of N-
a
Methylindole
a
Table 2. Copper-Mediated Direct C3-Cyanation of Indoles
b
entry
[Cu] (equiv)
solvent
time (h)
% yield
c
1
CuI (1)
DMF
20
20
20
20
20
24
24
24
24
24
24
24
24
24
trace
51
2
CuI (1)
DMF
3
Cu2O (1)
Cu(OAc) (1)
Cu(OAc)2 (1)
CuI (1)
DMF
0
4
DMF
trace
trace
89
5
DMF
6
DMF
7
CuBr (1)
CuCl (1)
CuI (1)
DMF
trace
0
8
DMF
9
CH3CN
dioxane
toluene
DMSO
DMF
0
10
11
12
CuI (1)
0
CuI (1)
0
CuI (1)
trace
79
d
13
CuI (1)
14
CuI (1.5)
DMF
91
a
Reaction conditions: copper source (0.5 mmol, 1 equiv), N-
methylindole (0.5 mmol), PhCH2CN (0.75 mmol), and solvent (2.0
mL) were stirred under air at 130 °C for the indicated period of time.
b
Calibrated GC yields were reported using pentadecane as the internal
c
d
standard. 110 °C was used. 140 °C was used.
benchmark substrate. Commercially available copper salts
were investigated (entries 2−8). CuI showed successful
cyanation of indole while other Cu complexes did not. A
screening of solvent revealed that DMF was the solvent of
choice (entries 6 and 9−12). When the reaction temperature
was increased from 110 to 130 °C and the reaction time was
extended to 24 h, the product yield was improved (entries 1
and 2, 2 and 6).
a
Reaction conditions: CuI (0.5 mmol), N-substituted indole (0.5
mmol), PhCH2CN (0.75 mmol), and DMF (2.0 mL) were stirred
under air at 130 °C for indicated time. Isolated yield. 1.5 equiv of
CuI was used.
b
c
B
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Note
Arylindoles were also tested (entries 5−7). Moderate yields
were generally obtained.
To further test the generality of the reaction system, a series
of substituted N-benzylindoles was probed in this cyanation
system (Table 3). Functional groups such as fluoro, chloro, and
Scheme 3. Copper-Mediated Direct C3-Cyanation of N-
Methylindoles (Reaction Conditions Were the Same as in
a
Table 2, Entry 5)
Table 3. Copper-Mediated Direct C3-Cyanation of
a
Benzylindoles
a
1.0 mmol of PhCH2CN was used.
EXPERIMENTAL SECTION
■
General Information. Unless otherwise noted, all reagents were
purchased from commercial suppliers and used without purification.
All cyanations were performed in an open vessel, a vial (approximately
60 mL volume), fitted with an air condenser, and equipped with
Teflon coated magnetic stir bar (4 mm × 10 mm). All indole
derivatives except indole, N-methylindole, and N-methyl-2-phenyl-
indole were synthesized according to the literature methods.21 Silica
1
gel (230−400 mesh) was used for column chromatography. H NMR
spectra were recorded on a 400 MHz spectrometer. Spectra were
referenced internally to the residual proton resonance in CDCl3 (δ
7.26 ppm) or with TMS (δ 0.00 ppm) as the internal standard.
Chemical shifts (δ) were reported as parts per million (ppm) on the δ
scale downfield from TMS. 13C NMR spectra were recorded on a 100
MHz spectrometer, and the spectra were referenced to CDCl3 (δ 77.0
ppm, the middle peak). Coupling constants (J) are reported in hertz
(Hz). Mass spectra (EI-MS and ES-MS) were recorded on a mass
spectrometer. High-resolution mass spectra (HRMS) were obtained
on an ESIMS mass spectrometer. GC−MS analysis was conducted on
a GCD system. Products described in GC yield were accorded to the
authentic samples/pentadecane calibration standard from GC-FID
system.
General Procedure for Reaction Condition Screenings. All
reagents were weighed in air, and the reactions were performed in an
open-to-air vessel. Copper salt (0.5−0.75 mmol), N-methylindole (0.5
mmol), and PhCH2CN (0.75 mmol) were loaded into a 60 mL vial
equipped with a Teflon-coated magnetic stir bar. The solvent (2 mL)
was added at room temperature. The vial was fitted with an air
condenser and then placed into a preheated oil bath with vigorous
stirring for the indicated time. After the completion of reaction, the
vial was allowed to cool at room temperature. Ethyl acetate (∼20 mL)
and pentadecane (internal standard) were added. The organic layer
was subjected to GC analysis.
General Procedure for Cyanation of Indoles with Benzyl
Cyanide. Copper(I) iodide (0.5−0.75 mmol), PhCH2CN (0.75−1.0
mmol), indole derivatives (0.5 mmol), and DMF (2.0 mL) were
loaded into a 60 mL vial equipped with an air condenser and Teflon-
coated magnetic stir bar under air. The vial was then placed into a
preheated oil bath at the temperature indicated in Table 2 and
vigorously stirred in an open system for the indicated time. After
completion of reaction, the reaction vial was allowed to cool at room
temperature. Ethyl acetate (∼20 mL) was added for dilution. The
organic layer was subjected to GC analysis. After analysis of the GC
spectra, the crude product was further extracted with ethyl acetate (2 ×
10 mL). The filtrate was concentrated under reduced pressure. The
crude product was purified by flash column chromatography on silica
gel to afford the desired product.
a
Reaction conditions: CuI (0.5 mmol), substituted benzylindole (0.5
mmol), PhCH2CN (0.75 mmol), and DMF (2.0 mL) were stirred
under air at 130 °C for the indicated time. Isolated yield. 1.5 equiv of
CuI was used.
b
c
methoxy were compatible under these reaction conditions
(entries 2−4). The intact chloro group is beneficial for later
functionalization using other coupling protocols.20 In fact, these
nitrile-containing products can undergo further organic trans-
formations to afford a variety of potential xanthine oxidase
inhibitors, HCV inhibitors, and therapeutic estrogen receptor
ligands.3,5,6 N-Benzylindoles with 5- and 7-substitutents
furnished the desired product smoothly with extended reaction
times (entries 5−7). Azaindole and sterically hindered 2-
methyl-N-benzylindole were found to be feasible substrates for
the cyanation (entries 8 and 9).
Highly sterically congested 2-aryl-N-methylindoles were
applicable substrates for direct cyanation (Scheme 3). 2-(1-
Naphthyl)-N-methylindole afforded the desired product in
lower yield presumably due to the large steric hindrance of the
o-naphthyl moiety.
In summary, we have developed a simple protocol for facile
preparation of 3-cyanoindoles. This inexpensive reaction
system, copper(I) iodide and benzyl cyanide, is found to
effectively promote regioselective cyanation of indoles in open-
to-air vessels. This protocol potentially provides a more direct
and complementary access to pharmaceutically useful inter-
mediates.
1-Methyl-1H-indole-3-carbonitrile (Example from Table 2,
Entry 1).17f Eluents (DCM/hexane = 1:1, Rf = 0.5) were used for
1
flash column chromatography: 67.1 mg, 86% yield, brown liquid; H
NMR (400 MHz, CDCl3) δ 3.85 (s, 3H), 7.29−7.42 (m, 3H), 7.55 (s,
1H), 7.76 (d, J = 7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 33.6,
85.3, 110.3, 115.9, 122.1, 123.8, 127.7, 135.5, 136.0. (See the
Supporting Information for copies of the spectra.)
1-Isopropyl-1H-indole-3-carbonitrile (Table 2, Entry 2).
Eluents (DCM/hexane = 1:1, Rf = 0.35) were used for flash column
1
chromatography: 64.4 mg, 70% yield, brown liquid; H NMR (400
C
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The Journal of Organic Chemistry
Note
MHz, CDCl3) δ 1.59 (d, J = 6.8 Hz, 6H), 4.70−4.77 (m, 1H), 7.29−
7.38 (m, 2H), 7.48 (d, J = 8.0 Hz, 1H), 7.74 (s, 1H), 7.78 (d, J = 7.6
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 22.6, 48.4, 85.6, 110.7,
116.2, 119.9, 122.1, 123.6, 128.0, 131.2, 135.0; HRMS (ESI) calcd. for
C12H13N2 [M + H+] 185.1079, found 185.1083.
chromatography: 97.3 mg, 73% yield, orange solid; mp 117.9−120.0
1
°C; H NMR (400 MHz, CDCl3) δ 5.35 (s, 2H), 7.15 (d, J = 6.0 H,
2H), 7.25−7.31 (m, 2H), 7.36−7.41 (m, 3H), 7.63 (s, 1H), 7.75 (s,
1H); 13C NMR (100 MHz, CDCl3) δ 51.0, 85.7, 112.0, 115.0, 119.2,
124.4, 127.0, 128.2, 128.5, 128.8, 129.1, 133.8, 134.7, 135.9; HRMS
(ESI) calcd for C16H12N2Cl [M + H+] 267.0689, found 267.0684.
1-Benzyl-5-methyl-1H-indole-3-carbonitrile (Table 3, Entry
5).17d Eluents (DCM/hexane = 1:1, Rf= 0.45) were used for flash
1-Allyl-1H-indole-3-carbonitrile (Table 2, Entry 3).17i Eluents
(DCM/hexane = 1:1, Rf = 0.35) were used for flash column
1
chromatography: 64.4 mg, 73% yield, brown liquid; H NMR (400
1
column chromatography: 94.5 mg, 77% yield, light orange solid; H
MHz, CDCl3) δ 4.79 (d, J = 5.6 Hz, 2H), 5.18 (d, J = 17.2 Hz, 1H),
5.33 (d, J = 10.4 Hz, 1H), 5.96−6.06 (m, 1H), 7.30−7.39 (m, 2H),
7.42 (d, J = 7.4 Hz, 1H), 7.63 (s, 1H), 7.79 (d, J = 7.6 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 49.4, 86.0, 110.7, 115.8, 119.0, 119.9,
122.2, 123.8, 127.9, 131.6, 134.6, 135.4.
NMR (400 MHz, CDCl3) δ 2.50 (s, 3H), 5.33 (s, 2H), 7.14−7.17 (m,
3H), 7.26 (d, J = 8.4 Hz, 1H), 7.34−7.39 (m, 3H), 7.58 (d, J = 7.2 Hz,
2H); 13C NMR (100 MHz, CDCl3) δ 21.4, 50.9, 85.6, 110.5, 116.0,
119.6, 125.7, 127.1, 128.3, 128.4, 129.1, 132.1, 134.0, 134.9, 135.4.
1-Benzyl-7-methoxy-1H-indole-3-carbonitrile (Table 3,
Entry 6). Eluents (DCM/hexane = 1:1, Rf= 0.2) were used for flash
column chromatography: 90.4 mg, 69% yield, light orange solid; mp
142.8−146.9 °C; 1H NMR (400 MHz, CDCl3) δ 3.89 (s, 3H), 5.66 (s,
2H), 6.75 (d, J = 8.0 Hz, 1H), 7.15 (d, J = 7.2 Hz, 2H), 7.21 (t, J = 8.0
Hz, 1H), 7.31−7.38 (m, 4H), 7.50 (s, 1H); 13C NMR (100 MHz,
CDCl3) δ 53.4, 55.4, 86.4, 104.7, 112.3, 115.8, 122.9, 125.4, 126.9,
127.9, 128.8, 130.2, 135.4, 137.2, 147.9; HRMS (ESI) calcd. for
C17H15N2O [M + H+] 263.1184, found 263.1191.
1H-Indole-3-carbonitrile (Table 2, Entry 4).17f Eluents (DCM/
hexane = 6:1, Rf = 0.20) were used for flash column chromatography:
1
12.1 mg, 17% yield, yellow solid; H NMR (400 MHz, CDCl3) δ
7.31−7.42 (m, 2H), 7.51 (d, J = 8.4 Hz, 1H), 7.76 (s, 1H), 7.81 (d, J =
6.4 Hz, 1H), 8.86 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 87.5,
112.0, 115.7, 119.6, 122.3, 124.3, 126.9, 131.7, 134.8.
1-Phenyl-1H-indole-3-carbonitrile (Table 2, Entry 5).17i
Eluents (DCM/hexane = 1:1, Rf = 0.5) were used for flash column
1
chromatography: 65.4 mg, 60% yield, light orange solid: H NMR
1-Benzyl-7-methyl-1H-indole-3-carbonitrile (Table 3, Entry
7). Eluents (DCM/hexane = 1:1, Rf = 0.45) were used for flash
column chromatography: 71.3 mg, 58% yield, yellow solid; mp 153.7−
(400 MHz, CDCl3) δ 7.35−7.39 (m, 2H), 7.49−7.56 (m, 4H), 7.59−
7.63 (m, 2H), 7.82 (s, 1H), 7.84−7.86 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 88.0, 111.5, 115.4, 119.9, 122.7, 124.5, 124.8, 127.9, 128.3,
130.0, 134.6, 135.5, 137.2.
1
154.5 °C; H NMR (400 MHz, CDCl3) δ 2.57 (s, 3H), 5.63 (s, 2H),
6.97 (d, J = 7.2 Hz, 2H), 7.04 (d, J = 7.2 Hz, 1H), 7.20 (t, J = 7.6 Hz,
1H), 7.32−7.38 (m, 3H), 7.56 (s, 1H), 7.67 (d, J = 8.0 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 19.2, 52.9, 86.4, 115.6, 117.9, 122.1, 122.4,
125.5, 126.8, 128.0, 128.9, 129.1, 130.7, 134.4, 136.4, 137.1; HRMS
(ESI) calcd for C17H15N2 [M + H+] 247.1235, found 247.1226.
1-Benzyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (Table 3,
Entry 8). Eluents (DCM/hexane = 1:1, Rf = 0.2) were used for flash
column chromatography: 75.7 mg, 65% yield, yellow solid; mp 90.3−
91.6 °C; 1H NMR (400 MHz, CDCl3) δ 5.56 (s, 2H), 7.28−7.38 (m,
6H), 7.71 (s, 1H), 8.12 (dd, J = 1.6, 6.4 Hz, 1H), 8.51 (dd, J = 1.6, 4.8
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 48.7, 85.0, 118.3, 120.1,
127.9, 128.4, 128.5, 129.0, 134.9, 135.6, 145.2, 146.4; HRMS (ESI)
calcd for C15H12N3 [M + H+] 234.1031, found 234.1041.
1-(4-Methoxyphenyl)-1H-indole-3-carbonitrile (Table 2,
Entry 6).17i Eluents (DCM/hexane = 1:1, Rf = 0.25) were used for
1
flash column chromatography: 81.8 mg, 66% yield, white solid; H
NMR (400 MHz, CDCl3) δ 3.92 (s, 3H), 7.09 (d, J = 8.8 Hz, 2H),
7.34−7.36 (m, 2H), 7.40 (d, J = 8.8 Hz, 2H), 7.43−7.46 (m, 1H), 7.76
(s, 1H), 7.82−7.84 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 55.6,
87.4, 111.4, 115.0, 115.6, 119.8, 122.5, 124.3, 126.3, 127.7, 130.5,
134.9, 136.0, 159.4.
1-(3,5-Dimethylphenyl)-5-methoxy-1H-indole-3-carbonitrile
(Table 2, Entry 7). Eluents (DCM/hexane = 1:1, Rf = 0.25) were
used for flash column chromatography: 78.7 mg, 57% yield, light
1
orange solid; mp 140.7−141.8 °C; H NMR (400 MHz, CDCl3) δ
2.43 (s, 6H), 3.91 (s, 3H), 6.97 (d, J = 8.8 Hz, 1H), 7.08 (s, 2H), 7.11
(s, 1H), 7.23 (s, 1H), 7.41 (d, J = 8.8 Hz, 1H), 7.72 (s, 1H); 13C NMR
(100 MHz, CDCl3) δ 21.3, 55.8, 87.2, 100.8, 112.7, 115.1, 122.3,
128.9, 129.9, 130.5, 134.5, 137.8, 139.9, 156.3; HRMS (ESI) calcd. for
C18H17N2O [M + H+] 277.1341, found 277.1332.
1-Benzyl-2-methyl-1H-indole-3-carbonitrile (Table 3, Entry
9).17d Eluents (DCM/hexane = 1:1, Rf = 0.45) were used for flash
1
column chromatography: 68.9 mg, 56% yield, yellow liquid; H NMR
(400 MHz, CDCl3) δ 2.55 (s, 3H), 5.35 (s, 2H), 7.00 (d, J = 6.4 Hz,
2H), 7.26−7.33(m, 6H), 7.73 (d, J = 7.2 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 12.1, 47.3, 85.7, 110.3, 116.5, 119.1, 122.2, 123.4,
126.0, 127.2, 128.0, 129.1, 135.7, 136.2, 145.8.
1-Benzyl-1H-indole-3-carbonitrile (Table 3, Entry 1).17i
Eluents (DCM/hexane = 1:1, Rf = 0.5) were used for flash column
1
chromatography: 95.1 mg, 82% yield, brown liquid; H NMR (400
1-Methyl-2-phenyl-1H-indole-3-carbonitrile (Scheme 3,
Compound 1).17h Eluents (DCM/hexane = 1:1, Rf = 0.4) were
used for flash column chromatography: 88.2 mg, 76% yield, yellow
MHz, CDCl3) δ 5.36 (s, 2H), 7.16−7.19 (m, 2H), 7.32−7.41 (m, 6H),
7.62 (s, 1H), 7.80−7.82 (m, 1H); 13C NMR (100 MHz, CDCl3) δ
50.8, 86.1, 110.7, 119.9, 122.2, 123.9, 127.0, 127.9, 128.3, 129.0, 134.9,
135.1, 135.5.
1
liquid; H NMR (400 MHz, CDCl3) δ 3.76 (s, 3H), 7.37−7.44 (m,
3H), 7.58 (s, 5H), 7.80 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 31.6,
85.2, 110.5, 119.2, 119.2, 122.2, 123.7, 127.4, 128.5, 128.8, 129.7,
136.7, 147.9.
1-Benzyl-5-methoxy-1H-indole-3-carbonitrile (Table 3,
Entry 2).22 Eluents (DCM/hexane = 1:1, Rf = 0.2) were used for
1
flash column chromatography: 102.2 mg, 78% yield, white solid; H
1-Methyl-2-(o-tolyl)-1H-indole-3-carbonitrile (Scheme 3,
Compound 2). Eluents (DCM/hexane = 1:1, Rf = 0.6) were used
for flash column chromatography: 73.8 mg, 60% yield, yellow solid;
NMR (400 MHz, CDCl3) δ 3.88 (s, 3H), 5.30 (m, 2H), 6.95 (dd, J =
2.4, 9.2 Hz, 1H), 7.14−7.17 (m, 2H), 7.19 (s, 1H), 7.24 (d, J = 9.2 Hz,
1H), 7.34−7.37 (m, 3H), 7.56 (s, 1H); 13C NMR (100 MHz, CDCl3)
δ 50.9, 55.6, 85.5, 100.8, 111.7, 114.6, 126.9, 128.3, 128.8, 129.0, 130.4,
134.8, 135.2, 156.0.
1-Benzyl-5-fluoro-1H-indole-3-carbonitrile (Table 3, Entry
3). Eluents (DCM/hexane = 1:1, Rf = 0.25) were used for flash
column chromatography: 77.5 mg, 62% yield, orange solid; mp 93.4−
95.2 °C; 1H NMR (400 MHz, CDCl3) δ 5.35 (s, 2H), 7.05 (td, J = 2.4,
8.8 Hz, 1H), 7.17 (d, J = 6.8 Hz, 2H), 7.29−7.34 (m, 1H), 7.36−7.42
(m, 4H), 7.65 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 51.1, 86.1,
104.9, 105.2, 111.9, 112.5, 112.8, 115.2, 127.0, 128.5, 129.1, 132.0,
134.8, 136.1, 157.9, 160.3; 19F NMR (400 MHz, CDCl3) δ −120.3;
HRMS (ESI) calcd for C16H11N2F [M + Na+] 273.0804, found
273.0810.
1
mp 113.9−114.9 °C; H NMR (400 MHz, CDCl3) δ 2.26 (s, 3H),
3.60 (s, 3H), 7.34−7.44 (m, 5H), 7.46−7.50 (m, 2H), 7.83 (d, J = 8.4
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 19.7, 31.0, 86.2, 110.6,
116.3, 119.5, 122.4, 123.7, 126.2, 127.5, 128.4, 130.3, 130.6, 130.7,
136.4, 138.0, 148.1; HRMS (ESI) calcd for C17H15N2 [M + H+]
247.1235, found 247.1229.
1-Methyl-2-(naphthalen-1-yl)-1H-indole-3-carbonitrile
(Scheme 3, Compound 3).17k Eluents (DCM/hexane = 1:1, Rf =
0.45) were used for flash column chromatography: 70.8 mg, 50% yield,
orange liquid; 1H NMR (400 MHz, CDCl3) δ 3.55 (s, 3H), 7.39−7.44
(m, 1H), 7.46−7.55 (m, 4H), 7.59 (t, J = 7.6 Hz, 1H), 7.65−7.67 (m,
2H), 7.89 (d, J = 7.8 Hz, 1H), 8.00 (d, J = 8.0 Hz, 1H), 8.08 (m, 1H);
13C NMR (100 MHz, CDCl3) δ 31.5, 110.5, 119.7, 122.5, 123.9, 124.9,
1-Benzyl-5-chloro-1H-indole-3-carbonitrile (Table 3, Entry
4). Eluents (DCM/hexane = 1:1, Rf = 0.4) were used for flash column
125.4, 126.6, 127.5, 128.8, 129.6, 130.8, 133.6.
D
dx.doi.org/10.1021/jo3028278 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
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cyanide sources, see: (a) Dohi, T.; Morimoto, K.; Kiyono, Y.; Tohma,
H.; Kita, Y. Org. Lett. 2005, 7, 537. (b) Dohi, T.; Morimoto, K.;
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(19) For our recent references in cyanation and related reactions, see:
(a) Yeung, P. Y.; So, C. M.; Lau, C. P.; Kwong, F. Y. Angew. Chem., Int.
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ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H NMR, 13C NMR, 19F NMR, and HRMS spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: fuk-yee.kwong@polyu.edu.hk.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Research Grants Council of Hong Kong (GRF:
PolyU5010/11P), PolyU Development Grant (1BD07), and
State Key Laboratory of Chirosciences (BBX-3) for financial
support. We are grateful to Prof. Albert S. C. Chan’s research
group (PolyU Hong Kong) for sharing GC−FID and GC−MS
instruments.
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