Synthesis of substituted 3-cyano- and 3-(arenesulfonyl)indoles from o-nitrobenzyl cyanides and sulfones

Article abstract of DOI:10.1055/s-0030-1289515

Formation of enamines, in the reaction of o-nitrophenyl-acetonitriles with Vilsmeier reagents, followed by reductive cyclization using Zn in acetic acid, leads to variously substituted 3-cyanoindoles, possessing aryl, alkyl, and aminoalkyl substituents at C-2. The method, when starting from the appropriate o-nitrobenzylsulfones, allows the synthesis of substituted 3-(arenesulfonyl)- indoles. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0030-1289515

LETTER
2567
Synthesis of Substituted 3-Cyano- and 3-(Arenesulfonyl)indoles from
o-Nitrobenzyl Cyanides and Sulfones
S
ynthesis of Su
b
d
3-C
i
yano-
a
g
nd 3-(Arene
n
sulfonyl)indo
i
le
s
ew Wróbel, Krzysztof Wojciechowski*
Institute of Organic Chemistry, Polish Academy of Sciences, ul. Kasprzaka 44, POB 58, 01-224 Warszawa 42, Poland
Fax +48(22)6326681; E-mail: krzysztof.wojciechowski@icho.edu.pl
Received 19 May 2011
R
Abstract: Formation of enamines, in the reaction of o-nitrophenyl-
acetonitriles with Vilsmeier reagents, followed by reductive cy-
NO2
clization using Zn in acetic acid, leads to variously substituted 3-
cyanoindoles, possessing aryl, alkyl, and aminoalkyl substituents at
C-2. The method, when starting from the appropriate o-nitrobenzyl-
sulfones, allows the synthesis of substituted 3-(arenesulfonyl)-
indoles.
CN
N
H
G
[H]
R
X
G
R
b
NO2
a
d
Key words: indoles, amides, cyclization, nitriles, sulfones
RCHO
CN
G
c
R
Indoles form an important class of organic compounds
and there is continuous interest in new methods for their
preparation; including derivatives bearing electron-with-
drawing substituents such as cyano and arenesulfonyl
groups at C-3. 3-Cyanoindole derivatives have received
attention as inosine monophosphate dehydrogenase
inhibitors1 and antitumor agents.2,3 3-Cyano-4-azaindoles
have been tested as therapeutic agents against overactive
bladder.4 3-Cyanoindoles have also been used as starting
materials for the synthesis of bis(indole)-1,2,4-triazinones
of potential biological activity5 as well as for the synthesis
of nortopsentins, alkaloids of marine origin.6
CN
NO2
CN
R
N
G
OH
G
[H]
[H]
CN
e
R
N
H
G
Scheme 1
The latter approach is of substantial value, as the cyano
group can be subjected to further transformations, being a
potential source of carboxylic acid derivatives, formyl or
other carbonyl groups, and amines. The cyano group is
particularly important for the construction of polycyclic
structures comprising two or more similar pyrrole rings.9b
From the stage at which vicarious nucleophilic substitu-
tion (VNS) was found to be a simple method for the prep-
aration of o-nitrophenylacetonitriles,7 they became
valuable substrates for the synthesis of substituted indoles
(Scheme 1).8 The best known and most popular transfor-
mation is a direct catalytic hydrogenation leading to in-
doles substituted on the benzene ring.9 In this process, the
nitrogen atom of the cyano group is incorporated into the
new pyrrole ring; thus C-2 of the indole remains unsubsti-
tuted. Alkylation of the methylene group in o-nitrophenyl-
acetonitrile furnishes starting materials that, after
hydrogenation, form indoles substituted at C-3 following
a combination of path a and b shown in Scheme 1.9a,c,10
Another approach to the synthesis of the indole core from
alkylated o-nitrophenylacetonitriles employs an interac-
tion of the alkyl substituent with the nitro group for the
construction of the new pyrrole ring. In this case, the cy-
ano group of the arylacetonitrile becomes a substituent at
C-3 of the indole (path c).11
The two known ways for the synthesis of 3-cyanoindoles
from o-nitrophenylacetonitriles, depicted in Scheme 1, al-
low for the synthesis of 2-substituted-3-cyanoindoles,
provided the appropriate substituent R is present in the
starting nitrobenzylic cyanide. Following the combined
path a and c, N-hydroxyindoles may be produced, requir-
ing an additional reduction step.11 The approach following
path d and e has been accomplished by two methods. The
original approach, which leads directly to 2-aryl-3-cy-
anoindoles,12 employs iron powder in acetic acid for the
cyclization of various arylidene derivatives of o-nitroaryl-
acetonitriles (R = Ar). Recently, an efficient palladium-
catalyzed reductive N-heteroannulation of a-substituted
o-nitrostyrenes with carbon monoxide has been pub-
lished.13 However, the reaction requires the use of toxic
gas at six atmospheres and elevated temperature, condi-
tions which are not convenient in every-day laboratory
practice.
SYNLETT 2011, No. 17, pp 2567–2571
x
x
.x
x
.2
0
1
1
Advanced online publication: 06.10.2011
DOI: 10.1055/s-0030-1289515; Art ID: D15411ST
© Georg Thieme Verlag Stuttgart · New York

2568
Z. Wróbel, K. Wojciechowski
LETTER
There are also a few routes leading to 3-cyanoindoles cases they were prepared separately prior to the reaction
from nonindole substrates that do not employ o-nitroary- with the nitroarene.18
lacetonitriles. For example, 2-aryl-3-cyanoindoles have
The reductive cyclization of the cyanoenamines 3a–g
leads to 3-cyanoindoles bearing substituents originated
from the starting amide at C-2. In one instance, however,
in addition to 3, another product, possessing a dialkyl-
amine group at C-2 was isolated (5). Formation of dialkyl-
aminoindoles 5 is possible only with unsubstituted
been prepared from substituted phenylaminoacrylonitrile
derivatives utilizing hypervalent iodine reagents.14a,b In
another approach an intramolecular Heck reaction of 3-
(arylamino)acrylonitriles substituted with bromine or io-
dine in the requisite position has been performed.14c The
modified Madelung reaction14d has found application in
cyanoenamines derived from dimethylformamide, appar-
solid-phase synthesis of a variety of 2-substituted 3-cy-
ently as a result of elimination of water from intermediate
anoindoles.14e It can be considered as an alternative meth-
6 competing with eliminaton of the dialkylamine moiety
od for the utilization of o-cyanomethylnitroarenes, as the
starting N-acylated o-cyanomethylanilines could be easily
obtained from the former materials.
(Scheme 3). Intermediate hydroxylamines (6, R2 ≠ H) cy-
clize exclusively with loss of the dialkylamine, forming
intermediate N-hydroxyindoles 7, which undergo further
In this paper we present another route to 3-cyanoindoles reduction to the final indole 4. However, the reaction can
and their 2-substituted derivatives starting from o-nitro- be terminated at the stage of the 3-cyano-1-hydroxyindole
phenylacetonitriles, which is, in part, an adaptation of the 7. When the reduction of 3e was carried out under milder
well-known Leimgruber–Batcho indole synthesis.15 The conditions at ambient temperature, hydroxyindole 7e was
original reaction is limited to producing indoles unsubsti- obtained as a sole product in 80% yield. Subsequently, the
tuted in the pyrrole ring. Its extension allows the introduc- latter was converted into 4e by reduction with Zn powder
tion of certain substituents at position 3, 2, or 1 by means in refluxing acetic acid. This result supports the reaction
of functionalization of the intermediate enamine.16 The pathway discussed above, and an alternative pathway to 4,
two-step method presented here involves the formation of which would involve exhaustive reduction of the nitro
enamines from o-nitrophenylacetonitriles and Vilsmeier group to the corresponding aniline prior to the addition–
reagents,17 followed by their reductive cyclization using elimination cyclization, can be discarded.
Zn in AcOH (Scheme 2).18 The Vilsmeier reagents were
A similar reaction sequence can also be applied to ni-
trobenzylic sulfones, readily available by VNS reaction of
generated in situ from N-methylpyrrolidone or DMF ac-
cording to the procedure described previously.17 In other
nitroarenes with chloromethyl aryl sulfones.19 Thus, 2-
X
R2
NR1
2
HN
NO2
NO2
O
EWG
POCl3
POCl3
EWG
+
EWG
R2
NR1
2
Ar
Ar
Ar
1
2: R1 = Me; R2 = Ph
N-methylpyrrolidone
1 = Me; R2 = H
R1 = -(CH2)4-; R2 = Et
4: X = R2
3
R
5: X = NR1
2
EWG = CN, TolSO2
2
Scheme 2 Two-step synthesis of 3-cyano- and 3-(toluenesulfonyl)indoles from o-nitrobenzyl cyanides or sulfones
R2
+
R2
NO2
R2
R2
HO
G
HO
G
HO
NR1
CN
NR1
CN
NR1
NR1
CN–
2
2
2
2
CN
NH
NH
N
– HNR1
[H]
H+
2
R2
C
N–
N
G
G
G
OH
7e: G = 5-Cl,
2 = Et
7
3
6
R
R2 = H
– H2O
CN
[H]
CN
NR1
R2
2
N
H
N
H
G
G
5
4
Scheme 3 Mechanistic scheme of the reductive cyclization of enamines 3 leading to differently substituted 3-cyanoindoles
Synlett 2011, No. 17, 2567–2571 © Thieme Stuttgart · New York

LETTER
Synthesis of Substituted 3-Cyano- and 3-(Arenesulfonyl)indoles
2569
nitrobenzyl sulfones were treated with Vilsmeier reagent, analogues, that were tested as norepinephrine reuptake
and the enamines formed after reduction cyclized to 3- inhibitors and 5-HT2A receptor antagonists,21 as ‘flipped’
(arenesulfonyl)indoles. The results are appended in serotonergic ligands,22,23 and as 5-HT6 receptor modula-
Table 1.
tors.23
Earlier we described a method for the synthesis of nitro In conclusion, the methodology presented herein can be
derivatives of 3-(arenesulfonyl)indoles via VNS reaction useful for the preparation of variously substituted 3-
of 3-nitrobenzeneisonitriles and chloromethyl sulfones.20a cyano- and 3-(arenesulfonylo)indoles, possessing aryl,
In an alternative approach amines obtained from 2- alkyl, and aminoalkyl substituents at position 2, starting
nitrobenzyl sulfones could be condensed with orthoesters, from readily available substrates.
and the so-formed imidates cyclized to 3-(arenesulfo-
nyl)indoles.20b The latter method was recently employed
in the synthesis of 3-(arenesulfonyl)indoles and their aza
Table 1 Two-Step Synthesis of 3-Cyano- and 3-(Arenesulfonyl)indoles from o-Nitrobenzyl Cyanides or Sulfones
Nitroarene 1
Amide 2
3, 4 Enamine 3
Yield (%) Indole 4
Yield (%)
83
NO2
CN
NO2
CN
NMe2
O
Cl
CN
a
b
c
85
Ph
Ph
NMe2
Ph
N
H
Cl
Cl
NO2 CN
NO2
CN
Me
N
O
Cl
6324
87
CN
N
N
H
Me
NHMe
Cl
Cl
CN
NO2
NO2 CN
O
6117
41a
NMe2
CN
N
NMe2
H
H
MeN
CN
CN
MeHN
NC
O2N
O
N
db
52
95
O2N
N
Me
N
N
N
PMB
PMB
PMB
NO2
NO2 CN
CN
O
N
Cl
72c
CN
CN
e
42
N
O
N
H
Cl
Cl
NO2
NO2 CN
CN
Me
N
Br
f
4424
51
32
N
N
N
Me
H
NHMe
Br
Br
NHMe
NO2
CN
H
NO2
CN
O
N
g
49
N
MeO
N
Me
MeO
N
MeO
N
Me
CN
SO2Tol
NO2 SO2Tol
NO2
O
F3C
4217
45
SO2Tol
h
NMe2
NMe2
H
N
H
CF3
CF3
Synlett 2011, No. 17, 2567–2571 © Thieme Stuttgart · New York

2570
Z. Wróbel, K. Wojciechowski
LETTER
Table 1 Two-Step Synthesis of 3-Cyano- and 3-(Arenesulfonyl)indoles from o-Nitrobenzyl Cyanides or Sulfones (continued)
Nitroarene 1
Amide 2
3, 4 Enamine 3
Yield (%) Indole 4
Yield (%)
33
NO2 SO2Tol
NO2
SO2Tol
O
Cl
SO2Tol
i
91
NMe2
NMe2
H
N
H
Cl
NO2 SO2Tol
Ph
Cl
NO2
SO2Tol
Ph
O
Cl
SO2Tol
k
51
35
NMe2
NMe2
Ph
N
H
Cl
Cl
a Additionally, 5% of 2-(N,N-dimethylamino) derivative 5 was isolated.
b PMB = para-methoxybenzyl.
c Under milder reaction conditions N-hydroxyindole 7e was formed in 86% yield.
Makara, G. M.; Pera, P. J.; Anderson, W. K. Bioorg. Med.
Chem. 2004, 12, 2867. (d) Orlemans, E. O. M.; Schreunder,
A. H.; Conti, P. G. M.; Verboom, W.; Reinhoudt, D. N.
Tetrahedron 1987, 43, 3817. (e) Wacker, D. A.; Kasireddy,
P. Tetrahedron Lett. 2002, 43, 5189.
Acknowledgment
This research was supported by the Ministry of Science and Higher
Education, Grant NN 204 193 038.
(15) (a) Batcho, A. D.; Leimgruber, W. Org. Synth. 1985, 63,
214; Org. Synth., Coll. Vol. VII 1990, 34. (b) Clark, R. D.;
Repke, D. B. Heterocycles 1984, 22, 195. (c) Gribble, G.
W. J. Chem. Soc., Perkin Trans. 1 2000, 1045.
(16) (a) Clark, C. I.; White, J. M.; Kelly, D. P.; Martin, R. F.;
Lobachevsky, P. Aust. J. Chem. 1998, 51, 243. (b) Prashad,
M.; Vecchia, L. L.; Prasad, K.; Repic, O. Synth. Commun.
1995, 25, 95. (c) Coe, J. W.; Vetelino, M. G.; Bradlee, M. J.
Tetrahedron Lett. 1996, 37, 6045.
References and Notes
(1) Dhar, T. G. M.; Shen, Z.; Gu, H. H.; Chen, P.; Norris, D.;
Watterson, S. H.; Ballentine, S. K.; Fleener, C. A.; Rouleau,
K. A.; Barrish, J. C.; Townsend, R.; Hollenbaugh, D. L.;
Iwanowicz, E. J. Bioorg. Med. Chem. Lett. 2003, 13, 3557.
(2) Owa, T.; Yoshino, H.; Okauchi, T.; Okabe, T.; Ozawa, Y.;
Sugi, N. H.; Yoshimatsu, K.; Nagasu, T.; Koyanagi, N.;
Kitoh, K. Bioorg. Med. Chem. Lett. 2002, 12, 2097.
(3) Yokoi, A.; Kuromitsu, J.; Kawai, T.; Nagasu, T.; Sugi,
N. H.; Yoshimatsu, K.; Yoshino, H.; Owa, T. Mol. Cancer
Ther. 2002, 1, 275.
(4) Turner, S. C.; Carroll, W. A.; White, T. K.; Gopalakrishnan,
M.; Coghlan, M. J.; Shieh, C.-C.; Zhang, X.-F.; Parihar,
A. S.; Buckner, S. A.; Milicic, I.; Sullivan, J. P. Bioorg. Med.
Chem. Lett. 2003, 13, 2003.
(5) Garg, N. K.; Stoltz, B. M. Tetrahedron Lett. 2005, 46, 1997.
(6) Miyake, F. Y.; Yakushijin, K.; Horne, D. A. Org. Lett. 2000,
2, 2121.
(7) Mąkosza, M.; Winiarski, J. J. Org. Chem. 1984, 49, 1494.
(8) Mąkosza, M.; Wojciechowski, K. Chem. Rev. 2004, 104,
2631.
(9) (a) Mąkosza, M.; Danikiewicz, W.; Wojciechowski, K.
Liebigs Ann. Chem. 1988, 203. (b) Macor, J. E.; Forman, J.
T.; Post, R. J.; Ryan, K. Tetrahedron Lett. 1997, 38, 1673.
(c) Macor, J. E.; Wehner, J. M. Tetrahedron Lett. 1993, 34,
349. (d) Marino, J. P.; Hurt, C. R. Synth. Commun. 1994, 24,
839.
(10) Macor, J. E.; Wehner, J. M. Tetrahedron Lett. 1991, 32,
7195.
(11) (a) Wróbel, Z.; Mąkosza, M. Synlett 1993, 597. (b) Wróbel,
Z.; Mąkosza, M. Tetrahedron 1997, 53, 5501.
(17) Mąkosza, M.; Wróbel, Z. Rev. Roum. Chim. 1991, 36, 563;
Chem. Abstr. 1992, 117, 26036.
(18) General Procedure for the Synthesis of Enamines 3a,e,k
The amide 2 (3 mmol) dissolved in dry MeCN (10 mL) was
cooled to –40 °C and treated with oxalyl chloride (3 mmol).
The cooling bath was removed, and the reaction mixture
allowed to reach r.t. After evolution of gas ceased (ca. 30
min) the reaction mixture was cooled to –40 °C and treated
with a solution of substrate 1 (1 mmol) and Et3N (5 mmol)
in dry MeCN (10 mL). (In the case of less soluble sulfones
they were added in powdered form to the cooled Vilsmeier
reagent followed by the addition of Et3N). After stirring for
1 h the reaction mixture was poured into sat. NH4Cl solution
(20 mL), extracted with EtOAc (3 × 20 mL), the extract was
dried (Na2SO4), filtered, evaporated and purified by
chromatography.
Enamines 3b–d and 3f–i were synthesized according to the
procedure described previously.17
General Procedure for the Synthesis of 3-Cyanoindoles 4
Enamine 3 (1 mmol) in glacial AcOH (20 mL) was treated
with Zn powder (10 mmol) (Note: a slight exotherm was
observed). After stirring for 1 h at r.t. the mixture was heated
to reflux for 1 h. After cooling the solvent was evaporated to
dryness, the residue was dissolved in EtOAc (20 mL), and
treated cautiously with sat. NaHCO3 (3 mL). After filtering
through Celite® the solution was evaporated, and the residue
purified by chromatography.
(12) (a) Suh, J. T.; Puma, B. M. J. Org. Chem. 1965, 30, 2253.
(b) Suh, J. T. US 3370063, 1968.
(13) (a) Söderberg, B. C. G.; Banini, S. R.; Turner, M. R.; Minter,
A. R.; Arrington, A. K. Synthesis 2008, 903. (b) Banini, S.
R.; Turner, M. R.; Cummings, M. M.; Söderberg, B. C. G.
Tetrahedron 2011, 67, 3603.
(14) (a) Yu, W.; Du, Y.; Zhao, K. Org. Lett. 2009, 11, 2417.
(b) Li, X.; Du, Y.; Liang, Zh.; Li, X.; Pan, Y.; Zhao, K. Org.
Lett. 2009, 11, 2643. (c) El-Araby, M. E.; Bernacki, R. J.;
Representative Analytical Data
(2E,Z)-2-(5-Chloro-2-nitrophenyl)-3-(dimethylamino)-3-
phenylacrylonitrile (3a)
White solid, mp 103–106 °C. 1H NMR (600 MHz, DMSO-
d6): two isomers, M (major)/N (minor) = 1.2. d = 2.65 (s, 6
H, M), 3.18 (s, 6 H, N), 7.07 (dd, J = 8.7, 2.2 Hz, 1 H, M),
Synlett 2011, No. 17, 2567–2571 © Thieme Stuttgart · New York

LETTER
Synthesis of Substituted 3-Cyano- and 3-(Arenesulfonyl)indoles
2571
7.10–7.12 (m, 2 H, M), 7.20–7.24 (m, 2 H, M), 7.29–7.32 (m,
136.1, 147.1, 158.7. MS (EI, 70 eV): m/z (%) = 386 (39),
355 (12), 121 (100). HRMS (EI): m/z calcd for C24H26N4O:
386.2107; found: 386.2098.
1 H, M), 7.33 (dd, J = 8.7, 2.2 Hz, 1 H, N), 7.43 (d, J = 2.2
Hz, 1 H, M), 7.48–7.55 (m, 5 H, N), 7.51 (d, J = 8.7 Hz, 1 H,
M), 7.58 (d, J = 2.2 Hz, 1 H, N), 7.79 (d, J = 8.7 Hz, 1 H, N).
MS (EI, 70 eV): m/z (%) = 327 (36), 283 (9), 187 (55), 148
(20), 118 (100), 105 (40). HRMS (EI): m/z calcd for
C17H14N3O235Cl: 327.0774; found: 327. 0771.
2-{1-[(4-Methoxyphenyl)methyl]-2-methyl-5-nitro-1H-
indol-4-yl}-2-[(2E,Z)-1-methylpyrrolidin-2-ylidene]-
acetonitrile (3d)
Yellow crystals, mp 165–166 °C (hexane–EtOAc).
1H NMR (500 MHz, DMSO-d6): two isomers, M (major)/N
(minor) = 2.5. d = 7.74 (d, J = 8.9 Hz, 1 H, M), 7.70 (d,
J = 8.9 Hz, 1 H, N), 7.57 (d, J = 8.9 Hz, 1 H, M), 7.56 (d,
J = 8.9 Hz, 1 H, N), 6.97–7.01 (m, 2 H, N), 6.93–6.97 (m, 2
H, M), 6.85–6.89 (m, 2 H, M + 2 H, N), 6.45–6.46 (m, 1 H,
N), 6.39–6.40 (m, 1 H, M), 5.37–5.47 (m, 2 H, M + 2 H, N),
3.70 (s, 3 H, N), 3.69 (s, 3 H, M), 3.42–3.55 (m, 2 H, M + 2
H, N), 3.34 (s, 3 H, N), 2.92–3.08 (m, 2 H, M), 2.41 (d,
J = 0.9 Hz, 3 H, N), 2.41 (d, J = 0.9 Hz, 3 H, M), 2.18 (s, 3
H, M), 2.08–2.22 (m, 2 H, N), 1.96–2.05 (m, 2 H, M), 1.70–
1.76 (m, 2 H, N). MS (EI, 70 eV): m/z (%) = 416 (11), 121
(100). HRMS (EI): m/z calcd for C24H24N4O3: 416.1848;
found: 416.1860.
5-Chloro-2-ethyl-1H-indole-3-carbonitrile (4e)
White crystals, mp 176–182 °C. 1H NMR (500 MHz,
DMSO-d6): d = 1.33 (t, J = 7.6 Hz, 3 H), 2.91 (t, J = 7.6 Hz,
2 H), 7.23 (dd, J = 8.6, 2.0 Hz, 1 H), 7.47 (d, J = 8.6 Hz, 1
H), 7.54 (d, J = 2.0 Hz, 1 H), 12.28 (br s, 1 H). 13C NMR
(125 MHz, DMSO-d): d = 13.1, 20.4, 81.7, 113.7, 115.7,
117.1, 122.8, 126.1, 128.3, 133.3, 152.8. MS (EI, 70 eV):
m/z (%) = 204 (46), 189 (100). HRMS (EI): m/z calcd for
C11H9N235Cl: 204.0454; found: 204.0463
2-(Dimethylamino)-1H-benzo[g]indole-3-carbonitrile
(5)27
Yellow solid. MS (EI, 70 eV): m/z (%) = 235 (100), 220
(54), 192 (24), 164 (8). HRMS (EI): m/z calcd for C15H13N3:
235.1110; found: 325.1103.
5-Chloro-2-ethyl-1-hydroxy-1H-indole-3-carbonitrile
(7e)
Colorless crystals, mp 177–183 °C (hexane–EtOAc). 1H
NMR (500 MHz, DMSO-d6): d = 1.32 (t, J = 7.6 Hz, 3 H),
2.93 (q, J = 7.6 Hz, 2 H),7.31 (dd, J = 8.7, 2.0 Hz, 1 H), 7.55
(dd, J = 8.7, 0.6 Hz, 1 H), 7.60 (dd, J = 2.0, 0.6 Hz, 1 H),
12.07 (s, 1 H). 13C NMR (125 MHz, DMSO-d): d = 13.1,
18.6, 77.4, 111.7, 115.7, 117.8, 123.7, 124.2, 127.2, 131.7,
149.5. MS (EI, 70 eV): m/z (%) = 220 (100), 205 (46), 189
(46). HRMS (EI): m/z calcd for C11H9N235ClO: 220.0403;
found: 220.0405.
(2E,Z)-2-(5-Chloro-2-nitrophenyl)-3-pyrrolidin-1-
ylpent-2-enenitrile (3e)
Brown oil. 1H NMR (500 MHz, DMSO-d6): two inseparable
isomers, d = 1.14–1.24 (m, 3 H), 1.68–1.82 (m, 5 H), 2.50–
2.70 (m, 2 H), 2.90–3.15 (m, 3 H), 7.45 (br s, 1 H), 7.53–7.59
(m, 1 H), 7.94 (d, J = 8.4 Hz, 1 H). MS (EI, 70 eV): m/z
(%) = 305 (31), 235 (12), 165 (100), 110 (15). HRMS (EI):
m/z calcd for C15H16N335ClO2: 305.0931; found: 305.0933.
5-Chloro-2-phenyl-1H-indole-3-carbonitrile (4a)
Pale yellow solid, mp >260 °C. 1H NMR (500 MHz, DMSO-
d6): d = 7.33 (dd, J = 8.6, 1.9 Hz, 1 H), 7.56–7.60 (m, 2 H),
7.62–7.68 (m, 3 H), 7.96–7.99 (m, 2 H), 12.80 (br s, 1 H). 13C
NMR (125 MHz, DMSO-d):25 d = 81.7, 114.8, 116.8, 118.0,
124.5, 127.2, 127.6, 129.4, 129.8, 130.8, 134.6, 146.6. MS
(EI, 70 eV): m/z (%) = 252 (100), 217 (11), 190 (14). HRMS
(EI): m/z calcd for C15H9N235Cl: 252.0454; found: 252.0449.
6-[(4-Methoxyphenyl)methyl]-7-methyl-2-[3-(methyl-
amino)propyl]-3H,6H-pyrrolo[3,2-e]indole-1-
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Synlett 2010, 2435.
carbonitrile (4d)
Pale yellow crystals, mp 177 °C (dec., EtOH). 1H NMR (500
MHz, DMSO-d6):26 d = 1.87–1.94 (m, 2 H), 2.32 (s, 3 H),
2.41 (s, 3 H), 2.58 (t, J = 7.0 Hz, 2 H), 2.93 (t, J = 7.4 Hz, 2
H), 3.67 (s, 3 H), 5.36 (s, 2 H), 6.55 (s, 1 H), 6.82–6.85 (m,
2 H), 6.89–6.93 (m, 2 H), 7.10 (d, J = 8.7 Hz, 1 H), 7.23 (d,
J = 8.7 Hz, 1 H). 13C NMR (125 MHz, DMSO-d): d = 13.0,
25.1, 28.6, 35.7, 45.9, 50.5, 55.5, 81.6, 97.7, 106.0, 106.9,
114.4, 118.3, 118.5, 119.1, 127.8, 129.6, 130.8, 132.4,
(25) One carbon resonance was not observed.
(26) N–H signals not visible.
(27) Compound 5 was isolated in insufficient quantities to obtain
full analytical data.
Synlett 2011, No. 17, 2567–2571 © Thieme Stuttgart · New York

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