A facile synthesis of 1-phenylsulfonyl-3-substituted-2-cyanoindoles, 1-phenylsulfonyl-2-methyl-3-cyanoindoles, and bifunctional 1- phenylsulfonylindoles

Article abstract of DOI:10.1055/s-2006-942449

A facile 'one-pot' introduction of the cyano group into the 2/3-position of indole has been developed from the corresponding aldehydes using anhydrous aluminum chloride and sodium azide. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-942449

PAPER
2413
A Facile Synthesis of 1-Phenylsulfonyl-3-substituted-2-cyanoindoles,
1-Phenylsulfonyl-2-methyl-3-cyanoindoles, and Bifunctional 1-Phenyl-
sulfonylindoles
A
F
acile Synth
i
esis of
c
C
yanoindo
h
les amuthu Jaisankar, P. C. Srinivasan*
Department of Organic Chemistry, University of Madras, Guindy Campus, Chennai-25, India
E-mail: pancol2000@yahoo.co.in; E-mail: vjpshankar@yahoo.co.in
Received 2 November 2005; revised 20 December 2005
tended to other aromatic aldehydes. Herein, we wish to re-
port the successful extension of this methodology to
indole aldehydes for the synthesis of N-protected cy-
anoindoles directly, in particular the synthesis of 1-phe-
nylsulfonyl-2-methyl-3-cyanoindole, 1-phenylsulfonyl-
3-substituted-2-cyanoindole and their derivatives. We
also attempted unsuccessfully to apply these conditions to
the synthesis of 2,3-dicyanoindoles.
Abstract: A facile ‘one-pot’ introduction of the cyano group into
the 2/3-position of indole has been developed from the correspond-
ing aldehydes using anhydrous aluminum chloride and sodium
azide.
Key words: indole aldehydes, aluminum chloride, sodium azide,
cyanoindoles, bifunctional indoles
Our first targets were 3-cyanoindoles; in particular, we
looked at the conversion of indole-3-aldehydes12 into the
corresponding 3-cyanoindoles 2a and 2b. Treatment with
sodium azide and anhydrous aluminum chloride in reflux-
ing anhydrous THF for five to six hours (Scheme 1), fur-
nished 2a and 2b in 75% and 72% yields, respectively.
Then 2a and 2b were converted into their corresponding
N-phenylsulfonyl derivatives, 3a and 3b, under PTC con-
ditions in 84% and 87% yields, respectively.
Cyanoindoles are an important class of compounds in
pharmacology as some derivatives show antiviral activi-
ty,1,2 they are also used as intermediates in the synthesis of
drugs and agrochemicals.3 Cyanoindoles have been
prepared4 from oximes of indole-3-aldehydes using re-
agents such as 2,4,6-trichloro-s-triazine, acetic anhydride,
and thionyl chloride. 7-Substituted-3-cyanoindoles were
reported5 as starting materials for the synthesis of azepi-
no[3,4,5-cd] indole, which is of biological interest. Meth-
yl indole-3-carboxylate has been converted into 3-
cyanoindole by sodium bis(trimethylsilyl)amide.6
We were interested in applying this reaction to N-protect-
ed indole-3-aldehydes. 2-Methylindole-3-aldehyde (1b)
underwent N-methylation with excess methyl iodide un-
der PTC conditions to give 1,2-dimethylindole-3-
aldehyde13 (4a) in 61% yield and methyl 1,2-dimethylin-
dole-3-carboxylate14 (4b) as a by product in 32% yield
(Scheme 2). The ester 4b probably arises by a Cannizaro
type mechanism.
A number of other routes to access cyanoindoles have
been developed, such as, the reaction of indole with chlo-
rosulfonyl isocyanate and triethylamine which afforded 3-
cyanoindole;7 the reaction of indole-3-aldehyde with sodi-
um acetate and nitroethane in refluxing acetic acid also
gave 3-cyanoindole5 while treatment of 2- or 3-methylin-
dole with triphenylphosphine thiocyanate (TPPT)
yielded8 the corresponding cyanoindoles in high yield.
However, all these routes suffer from some disadvantag-
es.9,10
CHO
Me
COOMe
Me
PTC/NaOH
C6H6/MeI
1b
+
N
N
Me
Me
A thorough survey of the literature revealed that the cyano
group had been introduced onto benzaldehyde by the re-
action of sodium azide and aluminum chloride in boiling
THF affording benzonitrile.11 This reaction was not ex-
4a
4b
60%
32%
Scheme 2
CN
CN
CHO
NaN3/AlCl3
PTC/NaOH
C6H6/PhSO2Cl
THF/reflux
for 5–6 h
N
R
N
H
R
N
H
R
SO2Ph
3a: 84%
3b: 87%
2a: 75%
2b: 72%
2c: 72%
1a,b
a: R = H
b: R = Me
Scheme 1
SYNTHESIS 2006, No. 14, pp 2413–2417
x
x.
x
x
.
2
0
0
6
Advanced online publication: 29.06.2006
DOI: 10.1055/s-2006-942449; Art ID: Z21505SS
© Georg Thieme Verlag Stuttgart · New York

2414
P. Jaisankar, P. C. Srinivasan
PAPER
1,2-Dimethylindole-3-aldehyde (4a) was converted into
1,2-dimethyl-3-cyanoindole9 (5a) in 65% yield by treat-
ment with sodium azide and aluminum chloride in THF
(Scheme 3).
Table 1 Synthesis of 1-Phenylsulfonyl-3-substituted-cyanoindoles
Com-
pound
R
Indole-2-aldehydes 8 2-Cyanoindoles 9
Reaction Yield (%) Reaction Yield (%)
time (h)
time (h)
CHO
Me
CN
Me
NaN3/AlCl3
a
b
c
Cl
6
5
7
6
7
60
84
74
71
66
6
5
8
7
9
72
80
68
68
72
THF/reflux
for 9 h
N
N
Br
Me
Me
70%
SPh
CH3
CH2Ph
5a
4a
d
e
Scheme 3
Similarly, 1-phenylsulfonyl-3-cyanoindoles, 3a and 3b,
were synthesized from 1-phenylsulfonylindole-3-alde-
hydes,20 6a and 6b, in comparable yields (Scheme 4).
have great potential as starting materials for the synthesis
of indole alkaloids and medicinally important indole de-
rivatives. Such indoles with two functional groups at both
the 2- and 3-positions are not easily accessible.
CHO
CN
NaN3/AlCl3
Recently, drugs containing an indole ring have been intro-
duced, which may be due to the fact that an indole ring
system may not survive long in vivo due to its facile bio-
degradation. It is well known that even the essential amino
acid tryptophan is degraded and excreted as 3-methylin-
dole. Therefore, a drug with an indole chromophore may
not offer severe side effects, which may be promising for
this type of bifunctional indoles as useful reagents in com-
binatorial synthesis.
N
R
N
R
THF, reflux for 5–6 h
SO2Ph
SO2Ph
6a,b
a: R = H
b: R = Me
3a: 84%
3b: 87%
Scheme 4
The structure of the compound 3b was confirmed by sin-
gle crystal X-ray diffraction studies.
In fact, 1-phenylsulfonyl-3-cyanoindole-2-aldehyde (11)
was easily synthesized from 1-phenylsulfonyl-2-methyl-
3-cyanoindole (3b) in two steps (Scheme 6). Smooth al-
lylic bromination of 3b gave the 1-phenylsulfonyl-2-bro-
momethyl-3-cyanoindole (10) in 93% yield, which was in
turn oxidized to 11 in 76% yield. The structure of com-
pound 11 was confirmed by single crystal X-ray diffrac-
tion studies.
Synthetic elaboration of the 2-position of indoles is an
area of ongoing interest. We planned to synthesize a vari-
ety of 3-substituted-2-cyanoindoles 9a–e (Cl, Br, SPh,
CH3, CH2Ph) from 3-substituted-indole-2-aldehydes 8a–e
by the same methodology (Scheme 5). These aldehydes
could be prepared from the corresponding 3-substituted-
2-bromomethyl-1-phenylsulfonylindoles 7a–e15 which, in
turn, were prepared from the corresponding 3-sustituted-
2-methylindoles in 80–85% yield by a procedure we de-
veloped previously (Table 1).15–19 The structures of com-
pounds 8a, 8b, and 8c were confirmed by single crystal X-
ray diffraction studies. All 3-substituted-indole-2-alde-
hydes 8a–e were converted into the corresponding 3-sub-
stituted-2-cyanoindoles 9a–e by the procedure described
above. The structure of compound 9c was confirmed by
single crystal X-ray diffraction studies. The progress of
the reaction was monitored by TLC, which indicated that
the formation of 2-cyanoindoles was much slower than
the corresponding 3-cyanoindoles.
CN
CN
[Bu4N]2Cr2O7
NBS/AIBN
3b
CHCl3/reflux
76%
Br
CCl4/reflux
93%
N
CHO
SO2Ph
11
N
SO2Ph
10
Scheme 6
Similarly the isomeric 1-phenylsulfonyl-2-cyanoindole-
3-aldehyde (13) was synthesized from the corresponding
1-phenylsulfonyl-2-cyano-3-methylindole (9c) via inter-
mediate 1-phenylsulfonyl-3-bromomethyl-2-cyanoin-
dole (12), whose structure was confirmed by single crystal
X-ray diffraction studies.
Bifunctional indoles, such as, 1-phenylsulfonyl-3-cy-
anoindole-2-aldehyde, 1-phenylsulfonyl-2-cyanoindole-
3-aldehyde, and 1-phenylsulfonylindole-2,3-dialdehyde
R
R
R
NaN3/AlCl3
[Bu4N]2Cr2O7
Br
CHCl3
N
THF/reflux
5–9 h
N
CN
SO2Ph
9a–e
N
CHO
SO2Ph
8a–e
reflux 5–7 h
SO2Ph
68–80%
60–84%
7a–e
Scheme 5
Synthesis 2006, No. 14, 2413–2417 © Thieme Stuttgart · New York

PAPER
A Facile Synthesis of Cyanoindoles
2415
CHO
CN
N-Methylation of 2-Methylindole-3-aldehyde under PTC Con-
ditions
Br
NBS/AIBN
[Bu4N]2Cr2O7
9c
CCl4/reflux
for 2–4 h
CHCl3
To a solution of 2-methylindole-3-aldehyde (1.59 g, 10 mmol) in
benzene (50 mL) and a 50% solution of NaOH (50 mL), tetrabutyl-
ammonium hydrogen sulfate (100 mg) and MeI (20 mmol) in ben-
zene were added. The mixture was stirred for 2 h, poured over
crushed ice (75 g), and extracted with EtOAc (3 × 50 mL). The or-
ganic layer was separated, washed with H2O (3 × 25 mL), and dried
(MgSO4). Removal of the solvent under reduced pressure followed
by column chromatography (EtOAc–hexane, 2: 8) gave 4a and 4b.
N
N
CN
SO2Ph
12
reflux for 8 h
SO2Ph
92%
75%
13
Scheme 7
Finally, we looked at preparing 2,3-dicyanoindole 15
from indole-2,3-dialdehyde 14.15 Initially 14 was synthe-
sized from 1-phenylsulfonyl-2,3-dimethylindole, which
was converted into 1-phenylsulfonyl-2,3-dibromometh-
ylindole in 87% yield; this was in turn oxidized to 14 in
74% yield. We then attempted to prepare 15 by the meth-
odology described above (Scheme 8). TLC monitoring of
the reaction indicated a mixture of products, however,
workup of the reaction mixture gave only the starting al-
dehyde in 70–78% yield. We also attempted to prepare 15
from aldehydes 11 and 13, but all attempts were in vain.
We believe that both functional groups present coordinate
with aluminum chloride, thereby preventing attack of so-
dium azide on the aldehyde group.
1,2-Dimethylindole-3-aldehyde (4a)
Yield: 1.04 g (61%); mp 125 °C (Lit.13 126 °C).
IR (KBr): 1643 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.66 (s, 3 H, CH3), 3.68 (s, 3 H,
NCH3), 7.26–7.29 (m, 3 H, ArH), 8.24–8.26 (m, 1 H, indole-7H),
10.14 (s, 1 H, CHO).
13C NMR (100 MHz, CDCl3): d = 10.53, 29.58, 109.10, 109.13,
114.18, 120.80, 122.74, 123.04, 125.67, 136.93, 147.68, 184.05.
Methyl 1,2-Dimethylindole-3-carboxylate (4b)
Yield: 0.64g (32%); mp 141 °C (Lit.14 140 °C).
3-Cyanoindoles from Indole-3-aldehydes; General Procedure
To a stirred solution of anhyd AlCl3 (2.70 g, 20 mmol) in anhyd
THF (100 mL), NaN3 (3.90 g, 60 mmol) and indole-3-aldehyde (10
mmol) were added and the resulting reaction mixture was refluxed.
The progress of the reaction was monitored by TLC. The suspen-
sion gradually turned pale yellow after 5–6 h. When the reaction
was complete excess THF was removed by distillation and the res-
idue was diluted with 10% HCl (10 mL). The aqueous layer was ex-
tracted with CHCl3 (2 × 50 mL), the organic layer was separated,
and dried (Na2SO4). The solvent was removed under reduced pres-
sure and the residue was purified by column chromatography
(EtOAc–hexane, 2:8) to give 3-cyanoindoles in 70–87% yield.
CN
NaN3/AlCl3
X
anhyd THF/reflux
N
CHO
SO2Ph
11
CHO
CN
CN
NaN3/AlCl3
X
N
CN
anhyd THF/reflux
N
SO2Ph
SO2Ph
13
15
CHO
N-Phenylsulfonylation of 3-Cyanoindoles
NaN3/AlCl3
To a solution of 3-cyanoindole (10 mmol) in benzene (50 mL) and
a 50% solution of NaOH (25mL), tetrabutylammonium hydrogen
sulfate (100 mg) and PhSO2Cl (1.25 mL, 10 mmol) in benzene were
added in one portion. The reaction mixture was stirred for 5–6 h,
poured over crushed ice (75 g), and extracted with EtOAc (3 × 50
mL). The organic layer was separated, washed with H2O (3 × 35
mL), and dried (MgSO4). The solvent was removed under reduced
pressure and the residue was purified by column chromatography
(EtOAc–hexane, 2:8) to give N-phenylsulfonyl-3-cyanoindoles.
X
anhyd THF/reflux
N
CHO
SO2Ph
14
Scheme 8
Indole aldehydes were prepared by Vilsmeyer formylation of the
corresponding indole by a known procedure.12 1-Phenylsulfonylin-
dole-3-aldehyde (6a)20a and 1-phenyl sulfonyl-2-methylindole-3-al-
dehyde (6b)20b were synthesized by known procedures; analytical
data were in agreement with those previously published. Bromina-
tion of cyanoindoles was adopted from the published procedure;18
the reaction was carried out on a 5 mmol scale with one equivalent
of NBS.
3-Cyanoindole (2a)
Yield: (75%); mp 183 °C (Lit.7 183–184 °C).
IR (KBr): 3213, 2221 cm–1.
2-Methyl-3-cyanoindole (2b)
Yield: 1.12g (72%); mp 204 °C (Lit.8 204–206 °C).
IR (KBr): 3236, 2213 cm–1.
1NMR spectra were recorded on Bruker DPX (200 MHz), Bruker
(300 MHz), Jeol GSX (400 MHz), Jeol FX (90 MHz) and Varian
(90 MHz) instruments with TMS as the internal standard. Mass
spectra were recorded on a Jeol-JMS-DX-303HF instrument under
70 eV. IR spectra were recorded with a Shimadzu 8300 FT-IR spec-
trometer. Elemental analyses were performed on a Perkin Elmer se-
ries II CHNS/O Analyzer. All the melting points are uncorrected.
Acme 200 mesh silica gel was thoroughly washed with distilled wa-
ter and oven-dried at 150 °C prior to use. All solvents were purified
by standard methods.
MS: m/z (%) = 156 (M+, 9), 155 (22), 141 (57), 128 (9), 78 (9), 77
(100), 51 (14).
1,2-Dimethyl-3-cyanoindole (5a)
Yield: 1.19 g (70%); mp 103 °C (Lit.8 104–105 °C).
1-Phenylsulfonyl-3-cyanoindole (3a)
Yield: 2.02 g (84%); mp 151–152 °C.
IR (KBr): 2224, 1385, 1176 cm–1.
MS: m/z (%) = 282 (M+, 18), 141 (51), 114 (34), 80 (100).
Synthesis 2006, No. 14, 2413–2417 © Thieme Stuttgart · New York

2416
P. Jaisankar, P. C. Srinivasan
PAPER
1-Phenylsulfonyl-2-methyl-3-cyanoindole (3b)
Yield: 2.57 g (87%); mp 154 °C.
IR (KBr): 2224, 1378, 1186 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.18–7.98 (m, 8 H, ArH), 8.11–
8.14 (d, J = 9.0 Hz, 1 H, indole-7H).
IR (KBr): 2233, 1388, 1180 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.81 (s, 3 H, CH3), 7.26–7.87 (m,
8 H, ArH), 8.20–8.22 (d, J = 9 Hz, 1 H, indole-7H).
13C NMR (75 MHz, CDCl3): d = 115.34, 117.86, 124.00, 125.13,
127.16, 129.57, 131.48, 134.67, 136.54, 141.37, 158.67.
13C NMR (100 MHz, CDCl3): d = 14.80, 94.63, 113.86, 114.51,
119.10, 124.76, 125.84, 126.49, 126.80, 129.66, 134.66, 135.38,
138.04, 146.07.
Anal. Calcd for C15H9N2O2SCl : C, 56.88; H, 2.84; N, 8.85. Found:
C, 57.08; H, 2.69; N, 8.57.
1-Phenylsulfonyl-3-bromo-2-cyanoindole (9b)
Yield: 0.722 (80%); mp 188–190 °C.
MS: m/z (%) = 296 (M+, 11), 278 (10), 256 (10), 183 (22), 167 (25),
154 (76), 148 (44), 142 (11), 114 (18), 90 (49), 81 (30) 72 (38), 69
(54), 57 (100), 56 (14.0).
IR (KBr): 2221, 1373, 1180 cm–1.
Anal. Calcd for C16H12N2O2S: C, 64.86; H, 4.05; N, 9.46. Found: C,
64.49; H, 3.92; N, 9.24.
1H NMR (300 MHz, CDCl3): d = 7.27–8.06 (m, 8 H, ArH), 8.24–
8.27 (d, J = 9.0 Hz, 1 H, indole-7H).
13C NMR (75 MHz, CDCl3): d = 109.14, 114.65, 121.46, 124.88,
125.36, 126.56, 127.58, 128.43, 129.46, 129.79, 135.03, 157.64.
1-Phenylsulfonyl-3-substituted-indole-2-aldehydes 8; General
Procedure
MS: m/z (%) = 362 (M + 2, 22), 360 (M+, 20), 219 (26), 141 (94),
113 (21), 84 (100), 62 (18), 51 (99).
To a solution of 1-phenylsulfonyl-2-bromomethyl-3-substituted in-
dole (5 mmol) in anhyd CHCl3 (60 mL), bistetrabutylammonium
dichromate21 (5.0 mmol) was added. The resulting solution was re-
fluxed for 8 h. The reaction mixture was filtered through a plug of
celite or silica gel (10 g) to remove inorganic material and unreacted
tetrabutylammonium salts. The celite or silica gel was washed with
Et2O (75 mL). The ethereal residues were dried (MgSO4), the sol-
vent was removed, and the residue was purified by column chroma-
tography (hexane–EtOAc, 7:3) to afford the appropriate indole-2-
aldehyde as a pure crystalline solid in 60–84% yield.
Anal. Calcd for C15H9N2O2SBr: C, 49.86; H, 2.49; N, 7.76. Found:
C, 50.12; H, 2.55; N, 7.71.
1-Phenylsulfonyl-3-phenylthio-2-cyanoindole (9c)
Yield: 0.69g (68%); mp 120 °C.
IR (KBr): 2110, 1371, 1175 cm–1.
1H NMR (400 MHz, CDCl3): d = 6.95–7.89 (m, 13 H, ArH), 8.19–
8.22 (d, J = 12.0 Hz, 1 H, indole-7H).
1-Phenylsulfonyl-3-chloroindole-2-aldehyde (8a)
Yield: 0.91g (60%); mp 154 °C.
13C NMR (100 MHz, CDCl3): d = 70.54, 115.10, 117.86, 121.16,
123.06, 124.69, 126.19, 126.97, 127.45, 128.39, 129.21, 129.59,
130.53, 133.53, 135.15, 136.52, 137.55.
IR (KBr): 1677, 1357, 1176 cm–1.
MS: m/z (%) = 391(M+, 7), 350 (14), 284 (3), 244 (9), 209 (26), 163
(21), 128 (74), 101 (35), 84 (100), 51 (80).
1H NMR (400 MHz, CDCl3): d = 7.26–7.79 (m, 8 H, ArH), 8.25–
8.27 (d, J = 8.0 Hz, 1 H, indole-7H), 10.49 (s, 1 H, CHO).
MS: m/z (%) = 321 (M + 2, 7), 319 (M+, 15), 178 (20), 150 (18), 140
(30), 122 (17), 114 (17), 84 (100), 51 (45).
1-Phenylsulfonyl-3-methy-2-cyanoindole (9d)
Yield: 0.50g (68%); mp 182–184 °C.
IR (KBr): 2233, 1378, 1175 cm–1.
1-Phenylsulfonyl-3-bromoindole-2-aldehyde (8b)
Yield: 1.52g (84%); mp 172 °C.
1H NMR (400 MHz, CDCl3): d = 2.43 (s, 3 H, CH3), 7.26–8.00 (m,
8 H, ArH), 8.19–8.21 (d, J = 12.0 Hz, 1 H, indole-7H).
IR (KBr): 1674, 1367, 1186 cm–1.
13C NMR (100 MHz, CDCl3): d = 10.12, 114.76, 120.73, 124.48,
127.06, 128.69, 128.86, 129.53, 134.50.
1H NMR (200 MHz, CDCl3): d = 7.24–7.78 (m, 8 H, ArH), 8.22–
8.27 (d, J = 10.0 Hz, 1 H, indole-7H), 10.42 (s, 1 H, CHO).
MS: m/z (%) = 296 (M+, 31), 231 (5), 155 (56), 141 (44), 128 (18),
101 (9), 84 (100).
13C NMR (50 MHz, CDCl3): d = 111.89, 115.53, 122.32, 125.36,
126.82, 129.00, 129.29, 130.09, 132.16, 134.44, 137.07, 181.96.
MS: m/z (%) = 365 (M + 2, 4), 363 (M+, 4), 224 (27), 196 (33), 169
(26), 141 (73), 114 (100), 77 (6).
Anal. Calcd for C16 H12 N2O2S: C, 64.86; H, 4.05; N, 9.46. Found:
C, 65.15; H, 3.78; N, 9.05.
1-Phenylsulfonyl-3-benzyl-2-cyanoindole (9e)
Yield: 0.70g (72%) mp 120 °C.
1-Phenylsulfonyl-3-phenylthioindole-2-aldehyde (8c)
Yield: 1.45g (74%); mp 118 °C (Lit.15 120 °C).
IR (KBr): 2102, 1367, 1173 cm–1.
1-Phenylsulfonyl-3-methylindole-2-aldehyde (8d)
Yield: 1.06g (71%); mp 206 °C (Lit.18 208 °C).
1H NMR (300 MHz, CDCl3): d = 4.79 (s, 2 H, CH2), 7.23– 8.16 (m,
13 H, ArH), 8.17– 8.20 (d, J = 9.0 Hz, 1 H, indole-7H).
13C NMR (100 MHz, CDCl3): d = 105.92, 114.83, 120.34, 120.41,
121.15, 124.50, 125.23, 126.73, 127.02, 128.22, 129.01, 129.25,
129.31, 131.21, 132.75, 134.23, 135.77, 138.01.
1-Phenylsulfonyl-3-benzylindole-2-aldehyde (8e)
Yield: 1.24 g (66%); mp 123 °C (Lit.19 124 °C).
1-Phenylsulfonyl-3-substitute-2-cyanoindoles; General Proce-
dure
The procedure was exactly the same as that described for 3-cy-
anoindoles except the procedure was carried out on a 10 mmol
scale.
Anal. Calcd for C22H16N2O2S: C, 70.96; H, 4.30; N, 7.52. Found: C,
71.22; H, 4.13; N, 7.17.
1-Phenylsulfonyl-2-bromomethyl-3-cyanoindole (10)
Yield: 1.74g (93%); mp 144 °C.
IR (KBr): 2234, 1372, 1183 cm–1.
1-Phenylsulfonyl-3-chloro-2-cyanoindole (9a)
Yield: 0.53g (72%); mp 206 °C.
Synthesis 2006, No. 14, 2413–2417 © Thieme Stuttgart · New York

PAPER
A Facile Synthesis of Cyanoindoles
2417
1H NMR (400 MHz, CDCl3): d = 5.14 (s, 2 H, CH2), 7.26–8.11 (m,
8 H, ArH), 8.23–8.25 (d, J = 8.0 Hz, 1 H, indole-7H).
heated at gentle reflux for 6–9 h (with bisaldehyde 14, twice the
amount of reagents were added). The reaction was monitored by
TLC, which indicated a mixture of products. The excess THF was
removed and the residue was diluted with 10% HCl (5 mL). The
aqueous layer was extracted with CHCl3 (2 × 25mL). The organic
layer was separated, dried over anhyd Na2SO4, and concentrated un-
der reduced pressure to give the starting bifunctional indole-alde-
hydes, which were identified by their mp and IR spectra; yield: 70–
78%.
13C NMR (100 MHz, CDCl3): d = 20.21, 97.07, 112.62, 114.95,
120.14, 125.36, 126.56, 127.03, 127.36, 127.47, 129.87, 135.05,
135.65, 137.57, 144.01.
MS: m/z (%) = 376 (M + 2, 52), 374 (M+, 56), 297 (79), 232 (62),
203 (44), 179 (55), 154 (79), 141(83), 127 (89), 117 (39), 100 (53),
84 (100), 57 (40).
Anal. Calcd for C16H11N2O2SBr: C, 51.20; H, 2.93; N, 7.47. Found:
C, 50.80; H, 2.85; N, 7.44.
Acknowledgment
1-Phenylsulfonyl-3-bromomethyl-2-cyanoindole (12)
Yield: 1.72 g (92%); mp 144 °C.
Pichamuthu Jaisankar thanks UGC-SAP and CSIR for providing fi-
nancial assistance in the form of Technical Assistant and Senior Re-
search Fellowship grants, respectively. We also thank UGC-SAP
for instrument grants to the Department.
IR (KBr): 2213, 1372, 1179 cm–1.
1H NMR (400 MHz, CDCl3): d = 4.66 (s, 2 H, CH2), 7.25–8.04 (m,
8 H, ArH), 8.21–8.23 (d, J = 8.0 Hz, 1 H, indole-7H).
13C NMR (125 MHz, CDCl3): d = 19.80, 107.55, 110.94, 114.87,
121.10, 126.51, 127.29, 129.42, 129.87, 132.56, 135.06, 136.80,
137.31.
References
(1) Almerico, A. M.; Lauria, A.; Diana, P.; Barraja, P.;
Cirrincione, G.; Dattolo, G. ARKIVOC 2000, (iv), 486.
(2) Almerico, A. M.; Barraja, P.; Diana, P.; Cirrincione, G.;
Mingoia, F.; Musiu, C.; Perra, G.; Putzolu, M.; Marongiu,
M. E. Farmaco 1998, 53, 409.
(3) Sasaki, T.; Yanai, H. Chem. Abstr. 1994, 111, 15326.
(4) Chakrabarti, J. K.; Hotton, T. M. J. Chem. Soc., Chem.
Commun. 1972, 1226.
MS: m/z (%) = 376 (M + 2, 11), 374 (M+, 12), 295 (58), 235 (5), 154
(100), 141 (79), 127 (19), 115 (4), 102 (23), 84 (92), 51 (35).
Anal. Calcd for C16H11N2O2SBr: C, 51.20; H, 2.93; N, 7.47. Found:
C, 50.90; H, 2.92; N, 7.42.
1-Phenylsulfonyl-3-cyanoindole-2-aldehyde (11)
Synthesized, on a 5 mmol scale with bistetrabutylammonium
dichromate (1 equiv), by a similar procedure used for the prepara-
tion of 8.
(5) Klohr, S. E.; Cassady, J. M. Synth. Commun. 1988, 18, 671.
(6) Hwu, R.; Hsu, C. H.; Wong, F. F.; Chung, C.-S.;
Hakimelahi, G. H. Synthesis 1998, 329.
(7) Vorbrüggen, H.; Krolikiewicz, K. Tetrahedron 1994, 50,
6549.
(8) Tamura, Y.; Adachi, M.; Kawasaki, T.; Yasuda, H.; Kita, Y.
J. Chem. Soc., Perkin Trans. 1 1980, 1132.
(9) Tamura, Y.; Kawasaki, T.; Adachi, M.; KitaY, Tetrahedron
Lett. 1977, 50, 4417.
Yield: 1.84 g (76%); mp 160 °C.
IR (KBr): 2231, 1669, 1370, 1182 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.37–7.82 (m, 8 H, ArH), 8.22–
8.24 (d, J = 10.0 Hz, 1 H, indole-7H), 10.42 (s, 1 H, CHO).
MS: m/z (%) = 310 (M+, 17), 282 (8), 228 (6), 190 (5), 170 (55), 141
(77), 114 (100), 84 (100).
(10) Barnet, G.; Anderson, H.; Loader, C. Can. J. Chem. 1980,
58, 409.
(11) Suzuki, H.; Nagaya, C. Synthesis 1991, 641.
(12) James, P. N.; Snyder, J. Org. Synth., Coll. Vol. IV; Wiley:
New York, 1963, 539.
(13) (a) Leete, E. J. J. Am. Chem. Soc. 1959, 81, 6023.
(b) Comins, D. L.; Killpack, M. O. J. Org. Chem. 1987, 52,
104.
1-Phenylsulfonyl-2-cyanoindole-3-aldehyde (13)
Synthesized, on a 5 mmol scale with bistetrabutylammonium
dichromate (1 equiv), by a similar procedure used for the prepara-
tion of 8.
Yield: 1.72 g (75%); mp 308 °C.
(14) Kieslich, K. Tetrahedron 2001, 57, 781.
(15) Suhana, H.; Srinivasan, P. C. Synth. Commun. 2003, 33,
3097.
(16) Arumugam, N.; Srinivasan, P. C. Synth. Commun. 2003,
2313.
IR (KBr): 2231, 1672, 1378, 1181 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.34 –8.05 (m, 8 H, ArH), 8.26–
8.28 (d, J = 8.0 Hz, 1 H, indole-7H), 10.26 (s, 1 H, CHO).
1-Phenylsulfonylindole-2,3-dialdehyde (14)
Synthesized, on a 5 mmol scale with bistetrabutylammonium
dichromate (2 equiv), by a similar procedure used for the prepara-
tion of 8.
(17) Mohanakrishnan, A. K.; Srinivasan, P. C. Tetrahedron Lett.
1996, 36, 2659.
(18) Mohanakrishnan, A. K.; Srinivasan, P. C. Synth. Commun.
1995, 25, 2407.
(19) Suresh Babu, N. PhD Thesis; University of Madras: India,
2004.
Yield: 1.15g (74%); mp 158 °C (Lit.18 160 °C).
IR (KBr): 1665, 1372, 1185 cm–1.
(20) (a) Hibino, S.; Sugino, E.; Yamochi, T.; Kuwata, M.;
Hashimoto, H.; Sato, K.; Amanuma, F.; Karasawa, Y. Chem.
Pharm. Bull. 1987, 35, 2261. (b) Mohanakrishnan, A. K.;
Srinivasan, P. C. J. Org. Chem. 1995, 60, 1939.
(21) Landini, D.; Rola, F. Chem. Ind. (London) 1979, 213.
Attempted Synthesis of 1-Phenylsulfonyl-2,3-dicyanoindole
(15)
To a stirred solution of anhyd AlCl3 (1.35 g, 10 mmol) and NaN3
(1.95 g, 30 mmol) in anhyd THF (50 mL), bifunctional indole-alde-
hyde (11/13, 5 mmol), was added and the resulting solution was
Synthesis 2006, No. 14, 2413–2417 © Thieme Stuttgart · New York