Detosylation of 3-amino-1-tosylindole-2-carbonitriles using DBU and thiophenol

Article abstract of DOI:10.1016/j.tet.2010.02.058

Attempted detosylation of the 3-amino-1-(p-tosylamino)indole-2-carbonitriles 4a-c using either K₂CO₃ in EtOH or DBU in PhH at reflux gives unexpectedly the 3-(N-p-tosylamino)indole-2-carbonitriles 5a-c, respectively in high yields. Nevertheless, treatment of 1-(p-tosylamino)indoles 4a-c with thiophenol and DBU in PhH at reflux gives the detosylated 3-aminoindole-2-carbonitriles 5a-c. Reaction mechanisms supporting the tosyl migration (4→5) and the reductive detosylation (4→2) are proposed. All new compounds are fully characterised.

Full text of DOI:10.1016/j.tet.2010.02.058

Tetrahedron 66 (2010) 3016–3023
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Detosylation of 3-amino-1-tosylindole-2-carbonitriles using DBU and thiophenol
*
Sophia S. Michaelidou, Panayiotis A. Koutentis
Department of Chemistry, University of Cyprus, PO Box 20537, 1678 Nicosia, Cyprus
a r t i c l e i n f o
a b s t r a c t
Article history:
Attempted detosylation of the 3-amino-1-(p-tosylamino)indole-2-carbonitriles 4a–c using either K2CO3
in EtOH or DBU in PhH at reflux gives unexpectedly the 3-(N-p-tosylamino)indole-2-carbonitriles 5a–c,
respectively in high yields. Nevertheless, treatment of 1-(p-tosylamino)indoles 4a–c with thiophenol and
DBU in PhH at reflux gives the detosylated 3-aminoindole-2-carbonitriles 5a–c. Reaction mechanisms
supporting the tosyl migration (4/5) and the reductive detosylation (4/2) are proposed. All new
compounds are fully characterised.
Received 30 November 2009
Received in revised form 23 January 2010
Accepted 15 February 2010
Available online 18 February 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
a synthesis of 3-aminoindole-2-carbonitriles 2 from the known 3-
amino-1-tosylindole-2-carbonitrile 4, however, detosylation proved
Indolesareimportantinboththebiologicalandmaterialsciences.1
More specifically, several substituted 2-cyanoindoles are important
intermediates in the synthesis of heteroaromatic molecules and bi-
ologically active compounds.2,3 We recently developed two new
routes to 3-aminoindole-2-carbonitriles 2: The first a non classical
difficult. Surprisinglyoureffortstodetosylate3-amino-1-tosylindole-
2-carbonitriles4inthepresenceofethoxideatrefluxinethanolfailed,
while at higher temperatures (sealed tube) the unexpected 3-(N-
tosyamino)indole-2-carbonitriles 5 were obtained in high yield
(Scheme 1).
CN
NH2
CN
PPh3, H2O
MW or Δ
N
Cl
CN
N
N
CN
R
R
R
S
N
H
H
S
1
2
3
NHTs
CN
NH2
Base
CN
N
N
R
H
R
Ts
4
5
Scheme 1.
route starting from 2-(4-chloro-1,2,3-dithiazolylidenamino)benzo-
nitriles 1 onreactionwith triphenylphosphine,4 while thesecondwas
via a microwave assisted Thorpe–Ziegler cyclisation of the 2-(cya-
nomethylamino)benzonitriles 3.5 During these studies we pursued
Since the tosyl group has been used as an indole N-protecting
group numerous times and a popular method for detosylation
involved treatment with alkali bases or alkoxides,6,7 we found this
migration to be curious and worthy of further study. Below we
describe the difficulties encountered with the detosylation of
3-amino-1-tosylindole-2-carbonitrile 4 and provide a modified,
high yielding process for a clean detosylation of 3-amino-1-tosyl-
indole-2-carbonitrile that involves the use of thiophenol.
* Corresponding author. Tel.: þ357 22 892783; fax: þ357 22 892809.
E-mail address: koutenti@ucy.ac.cy (P.A. Koutentis).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.02.058

S.S. Michaelidou, P.A. Koutentis / Tetrahedron 66 (2010) 3016–3023
3017
2. Results and discussion
2.3. Detosylation
Initially we re-investigated the synthesis of 3-amino-1-tosyl-
indole-2-carbonitrile 4a starting from anthranilonitrile 6a.8 This
synthetic strategy was optimized to provide good yields of the
parent, the 5,6-dimethoxy and the 5-nitro 3-amino-1-tosylindole-
2-carbonitriles 4a–c (Scheme 2).
During the investigation of this route to the 3-amino-1-tosyl-
indole-2-carbonitriles 4a–c some interesting observations were
made:
Rather surprisingly detosylating 3-amino-1-tosylindole-2-car-
bonitrile 4a proved difficult. Acid treatment of the 1-tosylindole 4a
with either sulfuric acid 95%, or conc. HCl, or with HBr (48%) in the
presence of phenol, or even glacial AcOH or p-TSA gave at first no
reaction while prolonged heating led to highly coloured mixtures
from which indigo and isoindigo could be tentatively identified
(TLC). Reductive cleavage using NaBH4 in MeOH, or LiAlH4 in THF, or
treatment with Li dust in THF or Na metal in liquid NH3/THF also
failed to provide the detosylated indole 2a. Heating 3-amino-1-
iv
For Indole 4c (R = 5-O2N)
NH2
R
R
R
R
CN
CN
CN
i
ii
v
CN
or iii
N
NH2
NHTs
N
Ts
CN
Ts
6a R = H
6b R = 4,5-(MeO)2
6c R = 5-O2N
7a R = H
7b R = 4,5-(MeO)2
7c R = 5-O2N
8a R = H
8b R = 4,5-(MeO)2
4a R = H
4b R = 5,6-(MeO)2
4c
R = 5-O2N
Scheme 2. Reagents and conditions: (i) TsCl (1 equiv), C5H5N, 100 ꢀC, 5 h, 7a (5 h, 87%), 7b (7 h, 80%) 7c (36 h, 81%); (ii) ClCH2CN (1 equiv), K2CO3 (1 equiv), dry DMF, 100 ꢀC, 70 min,
(sealed tube) 8a (70 min, 81%) 8b (2 h, 73%); (iii) ClCH2CN (1 equiv), K2CO3 (1 equiv), dry DMF, MW (250 W), 12 PSI, 8a (122 ꢀC, 1 h, 86%) 8b (100 ꢀC, 10 min, 81%); (iv) ClCH2CN
(1 mL), K2CO3 (2 equiv), 100 ꢀC, 4c (24 h, 40%), 6c, (24 h, 46%); (v) K2CO3 (0.01 equiv), EtOH, 4a (ca. 20 ꢀC, 26 h, 96%), 4b (78 ꢀC, 30 h, 93%).
2.1. Cyanomethylation
tosylindole-2-carbonitriles 4a–c (0.06 mmol) in EtOH (1 mL) in the
presence of K2CO3 (1 equiv) at reflux for 24 h gave only recovered
starting materials but at ca. 100 ꢀC (sealed tube), 3-(N-tosylamino)-
indole-2-carbonitriles 5a–c were isolated in good yields. In the ab-
sence of K2CO3, heating the reactions in EtOH at 100 ꢀC (sealed tube)
led to the recovery of unreacted 1-tosylindoles 4a–c.
The direct cyanomethylation of anthranilonitrile 6a using
chloroacetonitrile could not be achieved and a prior N-mono-
tosylation was needed.8,9 Cyanomethylation of either 2-(p-
tosylamino)benzonitrile 7a or 4,5-dimethoxy-2-(p-tosylamino)-
benzonitrile 7b worked relatively well. When only 1 equiv of
chloroacetonitrile was used, the cyanomethylation worked best
in dry DMF and required at least 1 equiv of K2CO3. These re-
actions worked equally well using either conventional or mi-
crowave heating. In neat chloroacetonitrile or in EtOH, THF or
DMF with excess chloroacetonitrile (120 equiv) at ca. 65 ꢀC,
quantitative yields of the cyanomethylated products 8a and 8b
could be obtained with respect to the starting 2-(tosylamino)-
benzonitriles 7a and 7b. Cyanomethylation of 5-nitro-2-(tosyl-
amino)benzonitrile 7c however, could not readily be controlled
and heating 5-nitro-2-(tosylamino)benzonitrile 7c in an excess
of chloroacetonitrile at 100 ꢀC in the presence of K2CO3 (2 equiv)
for one day gave in moderate yield the cyclised 5-nitro-3-
(tosylamino)indole-2-carbonitrile 4c (40%) together with deto-
sylated 2-amino-5-nitrobenzonitrile 6c (46%).
NH2
NHTs
R
R
K2CO3 (1 equiv)
EtOH, 100 oC, X h
sealed tube
CN
CN
N
N
Ts
H
4a, R = H
5a, R = H (65%), X = 5 h
4b, R = 5,6-(MeO)2
4c, R = 5-O2N
5b, R = 5,6-(MeO)2 (79%), X = 3 h
5c, R = 5-O2N (85%), X = 1 h
The isomerisation could also be achieved when 3-amino-1-
tosylindole-2-carbonitrile 4a was treated with DBU (0.2 equiv, 24 h,
to 3 equiv, 1 h) in PhH at 80 ꢀC however, during these reactions the
mixtures became notably green in colour prior to affording 3-(N-
tosylamino)indole-2-carbonitrile 5a in 76–80% yields. The isomer-
isation could not be achieved when DBU was replaced by either
pyridine, Et3N or DMAP (1 equiv).
Furthermore, sulfonylation of 3-aminoindoles with TsCl,10
or 4-aminobenzenesulfonyl chlorides11 was reported to occur
regioselectively on the exocyclic 3-amino to afford the 3-(N-sulfo-
nylamino)indoles. Not surprisingly, treating pure samples of 3-ami-
noindole-2-carbonitriles 2a–c with TsCl (1 equiv) and pyridine
(4 equiv) in refluxing EtOH gave the 3-(N-tosylamino)indole-2-car-
bonitriles 5a–c in 85, 86 and 82% yields, respectively while similar
treatment of 3-aminoindole-2-carbonitrile 2a with PhSO2Cl gave the
3-(N-benzenesulfonylamino)indole-2-carbonitrile 5d in 88% yield.
2.2. Thorpe–Ziegler cyclisation
The ring closure of N-(2-cyanophenyl)-N-(p-tosyl)aminoaceto-
nitriles 8a and 8b to afford the 3-amino-1-tosylindole-2-carbon-
itriles 4a and 4b, respectively, worked well in both DCM and EtOH
and was dependent on the nature of the base. Weak amine bases
such as pyridine and Et3N failed to cyclise N-(2-cyanophenyl)-N-(p-
tosyl)aminoacetonitrile 8a, while DBU (0.5 equiv) in EtOH at ca.
20 ꢀC for 1 h gave the indole 4a in high yield (98%). The use of
<0.5 equiv of DBU (0.25 equiv) in EtOH at ca. 20 ꢀC for four days
however, led to incomplete reaction. In EtOH the use of inorganic
bases was superior; alkali metal bicarbonates, carbonates and
hydroxide bases worked well, the stronger the base the faster the
reaction. The use of only a catalytic quantity of K2CO3 (1 mol %) in
EtOH at ca. 20 ꢀC led to a near quantitative cyclisation in 26 h, while
the use of either NaOH or Cs2CO3 (2 equiv) led to a quantitative
conversion in ca. 1 min.
NH2
NHSO2Ar
R
R
ArSO2Cl (1 equiv),
Pyridine (4 equiv)
EtOH, 78 oC, X h
CN
CN
N
N
H
H
2a, R = H
5a, Ar = Tol, R = H (85%), X = 5 h
2b, R = 5,6-(MeO)2
2c, R = 5-O2N
5b, Ar = Tol, R = 5,6-(MeO)2 (86%), X = 2 h
5c, Ar = Tol, R = 5-O2N (82%), X = 48 h
5d, Ar = Ph, R = H (88%), X = 12 h

3018
S.S. Michaelidou, P.A. Koutentis / Tetrahedron 66 (2010) 3016–3023
A pure sample of 3-(N-tosylamino)indole-2-carbonitrile 5a
Furthermore, under the reaction conditions both 3-amino-
indole-2-carbonitrile 2a and 3-(N-tosylamino)indole-2-carbon-
itrile 5a were inert to sodium benzenesulfinate. The reaction
supported that base treatment of 3-amino-1-tosylindole-2-car-
bonitrile 4a released an intermediate, presumed to be the indol-
imine 11, that reacted rapidly via an intermolecular fashion with
the arylsulfinate anion formed.
treated with DBU in PhH at reflux or with K2CO3 in EtOH at reflux
was stable, suffering neither isomerisation nor detosylation. To the
best of our knowledge, only one example of a similar N to N tosyl
migration has been reported on treating N1-methyl-N1-tosylben-
zene-1,2-diamine 9 with BuLi to afford N1-methyl-N2-tosylben-
zene-1,2-diamine 10 in low yield.12
Next we considered the recombination of the p-toluenesulfinate
with the proposed intermediate 2-cyano-3H-indol-3-imine 11. Since
p-toluenesulfinates can be nucleophilic/reactive via oxygen or sul-
fur14 several possibilities needed to be considered: the simplest
(Path A) involved the direct addition of p-toluenesulfinate to the
indolimine 11 in a manner that mimicked the Michael-type addition
of nucleophiles to gramine derived 3-methylene-3H-indoles.15
However, the conflicting local dipole of the exocyclic imine and
lone pair repulsion from the imine nitrogen argued against this path.
Path B, involved the addition of p-toluenesulfinate to the highly
electrophilic indole C-2 position. Isomerization of the sulfinate ester
12 via either a concerted 2,3-sigmatropic rearrangement or via
a stepwise ion pair process could give the 3-(N-tosylamino)indole 5.
Examples of the rearrangement of allylic sulfinate esters to the allylic
sulfones are known,16 tentatively supporting the proposed mecha-
nism, however we were unable to find examples of an analogous
rearrangement of iminoethyl sulfinate esters. Finally, Path C involved
the addition of toluenesulfinate via its sulfur to the indole C-2 po-
sition to afford intermediate 13, followed by a 1,3-shift to the exo-
cyclic imine. Examples of these type of shifts have also been
frequently reported.17 Despite the prevalence of arylsulfinates to
attack via sulfur, we tentatively favour Path B over Path C for two
reasons: First a 2,3-shift would require a five-membered transition
state while a 1,3-shift would required a less favourable four-
membered transition state; and second, adduct B was less steri-
cally crowded at the indole C-2 position than adduct C.
NH2
NHTs
n-BuLi
THF, -68 oC, 2 h
17%
NMeTs
NHMe
9
10
2.3.1. Mechanistic rationale. The indole C-2 nitrile was expected to
activate the C-3 amine towards deprotonation. In the presence of
base, a direct tosyl metathesis could occur between the indole ni-
trogen at N1 and the C-3 amine via presumably an intermolecular
route. However, when the 1-tosyindole 4a was treated with pri-
mary aromatic amines or with the strongly nucleophilic secondary
amine pyrrolidine (2 equiv) in EtOH or benzene at reflux no tosyl
metathesis was observed and the starting 1-tosyindole 4a could be
recovered.
In light of this, we postulated that the migration involved a base
catalyzed elimination of p-toluenesulfinate anion to afford the
2-cyano-3H-indol-3-imine 11, which then trapped the sulfinate
by-product (Scheme 3). DBU is known to promote elimination re-
actions.13 The elimination of toluenesulfinate was partially sup-
ported when the reaction was repeated in the presence of sodium
benzenesulfinate (fivefold excess) since a mixture of 3-(N-tosyl-
amino)- and 3-(N-benzenesulfonylamino)indole-2-carbonitriles 5a
and 5d (ca. 2:1 ratio by 1H NMR) was obtained. Despite the fivefold
excess of sodium benzenesulfinate, the major isomer was clearly
the 3-tosylaminoindole 5a suggesting a possible tight ion pairing.
While the true nature of this migration requiresfurther study, the
above studies indicated that the base catalysed deprotection would
require reductive conditions. The related 2-aryl-3H-indol-3-oximes
have previously been reduced using Zn/HCl,18 Pd/H2,19 Pt/H2,20
sodium hydrosulfite,21 or ammonium sulfide,22 and there have
been two base catalysed detosylations reported that used
NH2
NHTs
NHSO2Ph
PhSO2Na (5 equiv)
DBU (1 equiv)
PhH, 80 oC, 24 h
+
CN
CN
CN
N
N
N
Ts
H
H
4a
5a
5d
O
NH
NH
S
_ O
Tol
O
O
Path B
Path A
Path C
CN
S
CN
N
N
Tol
H
H
Base
11
11
11
12
5a
13
Isomerization
via 2,3-shift
Base
_
Ts
H
H
N
NH
NHTs
CN
N
CN
CN
N
N
H
O
O
S _
Ts
H
Base
_
S
4a
Tol
O _
Tol
O
Isomerization
via 1,3-shift
O
NH
NH
O
_
Tol
S
S
O
Tol
CN
O
CN
N
N
H
H
Base
Scheme 3.

S.S. Michaelidou, P.A. Koutentis / Tetrahedron 66 (2010) 3016–3023
3019
thiophenol,23 however, despite the known reducing powers of
thiophenol,24 the authors did not mention the role of the mercap-
tans. Thiophenol facilitates the denosylation of 1-(o-, p-nitro
substituted arylsulfonyl)indoles via ipso nucleophilic aromatic
substitution on the nitroarenesulfonamide followed by elimination
of the free indole, sulfur dioxide and a (phenyl)(o-, p-nitro-phe-
nyl)sulfide.25 In addition, thioglycolate has been used to detosylate
indoles26 but no support for a mechanism was presented.
2.3.2. Mechanistic rationale. Under these reaction conditions there
was no trace of the possible diarylsulfide by-product phenyl(p-
tolyl)sulfide. This was not surprising since in the absence of nitro
substitution the tosylamide was not activated towards nucleophilic
aromatic substitution. The possibility that the mercaptan attacked
directly the sulfonamide sulfur to eliminate S-phenyl p-tolylthio-
sulfonate was also unlikely, since no trace of S-phenyl p-tolylthio-
sulfonate could be identified in the reaction mixture. A pure sample
of S-phenyl p-tolylthiosulfonate was stable to the reaction condi-
tions and also inert towards 3-aminoindole-2-carbonitrile 2a. In
light of our inability to detect either phenyl(p-tolyl)sulfide or
S-phenyl p-tolylthiosulfonate in the reaction mixtures we proposed
addition of thiophenol to the 2-cyano-3H-indol-3-imine 11 at the
highly electrophilic indole C-2 position to afford intermediate 14.
Attack of a second mercaptan at the phenyl sulfide could eliminate
the observed diphenyl disulfide and the 3-aminoindole-2-carbon-
itrile 2a that was shown earlier to be inert to the toluenesulfinate
by-product (Scheme 4).
In our hands treating 3-amino-1-tosylindole-2-carbonitrile with
DBU and PhSH (1–5 equiv) in an air atmosphere led to the isolation
of detosylated 3-aminoindole-2-carbonitrile 2a and the 3-(N-
tosylamino)indole-2-carbonitrile 5a together with a large quantity
of diphenyl disulfide. Increasing the equivalents of PhSH (up to
5 equiv) led to formation of detosylated indole 2a in high yield,
however, a pure sample of 3-(N-tosylamino)indole-2-carbonitrile
5a was stable to the reaction conditions suggesting the increased
yield of detosylated indole 2a did not arise from detosylation of the
3-(N-tosylamino)indole-2-carbonitrile 5a. Oxidation of the thio-
phenol could have occurred owing to oxygen in the reaction mix-
ture or in the air atmosphere. When the reaction was repeated
under anaerobic conditions (degassed benzene under an argon
atmosphere) the quantity of diphenyl disulfide recovered became
nearly equimolar with respect to the free indole. This tentatively
supported that thiophenol was reducing the 2-cyano-3H-indol-3-
imine intermediate 11 to afford the desired 3-aminoindole-2-car-
bonitrile 2a. On this basis the reaction was repeated with only
2–2.5 equiv of PhSH under argon and the reaction also came to
completion with only traces of the migrated product. Finally, with
these improved conditions both the dimethoxy and 5-nitro indoles
4b and 4c could be deprotected in high yields (Table 1).
3. Conclusions
3-Amino-1-tosylindole-2-carbonitriles 4a–c supporting both
NO2 and MeO substituents on the benzo fusion on treatment with
either DBU or K2CO3 suffer a tosyl migration to afford 3-(N-tosyl-
amino)indole-2-carbonitriles 5a–c in high yield. This migration can
be thwarted in either anaerobic or aerobic conditions in the pres-
ence of thiophenol (2–2.5 or 5 equiv, respectively), to give the
detosylated indoles 2a–c. Tosylation of 3-aminoindole-2-carbon-
itriles 2a–c gave exclusively the 3-tosylaminoindole-2-carbon-
itriles 5a–c, respectively.
Table 1
Deprotection of the 3-amino-1-tosylindole-2-carbonitriles 4a–c (0.06 mmol) using DBU and PhSH in PhH (2 mL) at 80 ꢀC
NH2
NH2
NHTs
CN
R
R
R
Ph
CN
S
S
+
CN
+
N
Ts
N
H
N
Ph
H
4a-c
2a-c
5a-c
R
DBU (equiv)
PhSH (equiv)
Time (h)
Yields (%)
PhSSPhb
2
5
H
H
H
H
H
H
H
H
1
1
1
1
1
1
1
1
0.5
0.2
1
1
1
1
2
3
4
26
24
18
14
12
24
17
14
24
32
24
1
62
95
2a (27)
2a (40)
2a (60)
2a (85)
2a (92)
2a (88)
2a (89)
2a (88)
2a (80)
2a (90)
2b (88)
2c (90)
2b (86)
2c (89)
5a (71)
5a (57)
5a (39)
5a (8)
d
144
183
248
104
85
5
5a
2a
2.5a
5
d
5a (6–4)
5a (trace)
d
93
H
H
183
243
230
240
91
5
5
d
5,6-(MeO)2
5-O2N
5,6-(MeO)2
5-O2N
d
5
d
2a
2a
25
3
d
1
95
d
a
Dry and degassed PhH was used, and the rxn took place under Argon.
Yield calculated based on the need for 2ꢁPhSH for the deprotection of 1ꢁtosylindole.
b
NR3
H
+NR3
H
H
_ SPh
_
N
NH
NH
NH2
_ SPh
S
CN
CN
Ph
CN
_
_
CN
PhSSPh
Ts
N
N
N
H
N
H
Ts
H
+NR3
4a
11
14
2a
R3N = DBU
Scheme 4.

3020
S.S. Michaelidou, P.A. Koutentis / Tetrahedron 66 (2010) 3016–3023
4. Experimental
6.80 (1H, s, Ph H-3 or 6), 3.93 (3H, s, CH3O), 3.81 (3H, s, CH3O), 2.39
(3H, s, CH3); dC(75 MHz; CDCl3) 153.5, 147.0, 144.6, 135.2, 134.2,
129.8 (CH), 127.3 (CH), 116.1 (C^N), 112.9 (CH), 107.3 (CH), 96.7
(CC^N), 56.4 (CH3O), 56.2 (CH3O), 21.6 (CH3); m/z (EI) 332 (Mþ,
45%), 177 (C7H7SOþ2 , 100), 150 (19), 135 (8), 120 (4), 107 (3), 104 (3),
91 (C7Hþ7, 27), 77 (7), 68 (9), 65 (23), 53 (1).
4.1. General methods and materials
DMF was freshly distilled from Na2SO4 under argon. Benzene was
freshly distilled from CaH2 under argon. Reactions were protected
from atmospheric moisture by CaCl2 drying tubes. Anhydrous
Na2SO4 was used for drying organic extracts, and all volatiles were
removed under reduced pressure. All reaction mixtures and column
eluents were monitored by TLC using commercial glass backed thin
layer chromatography (TLC) plates (Merck Kieselgel 60 F254). The
plates were observed under UV light at 254 and 365 nm. The tech-
nique of dry flash chromatography27 was used throughout for all
non-TLC scale chromatographic separations using Merck Silica Gel
60 (less than 0.063 mm). A CEM Discover Microwave Reactor was
used for microwave experiments. Chemglass heavy wall cylindrical
pressure vessels (15 mL) with a Teflon bushing as a pressure seal
were used for the sealed tube studies. Melting points were de-
termined using a PolyTherm-A, Wagner & Munz, Koefler-Hotstage
Microscope apparatus or where noted using a TA Instruments DSC
Q1000 with samples hermetically sealed in aluminium pans under
an argon atmosphere; using heating rates of 5 ꢀC/min. Solvents used
for recrystallization are indicated after the melting point. UV spectra
were obtained using a Perkin–Elmer Lambda-25 UV/vis spectro-
photometer and inflections are identified by the abbreviation ‘inf’. IR
spectra were recorded on a Shimadzu FTIR-NIR Prestige-21 spec-
trometer with a Pike Miracle Ge ATR accessory and strong, medium
and weak peaks are represented by s, m and w, respectively. 1H and
13C NMR spectra were recorded on a Bruker Avance 300 machine (at
300 and 75 MHz, respectively). 13C NMR CH assignments were
supported by DEPT-135 NMR experiments. Deuterated solvents were
used for homonuclear lock and the signals are referenced to the
deuterated solvent peaks. Low resolution (EI) mass spectra were
recorded on a Shimadzu Q2010 GC–MS with direct inlet probe.
4.1.3. 5-Nitro-2-(p-tosylamino)benzonitrile 7c. Similar treatment of
2-amino-5-nitrobenzonitrile 6c (1.0 g, 6.17 mmol) with p-TsCl
(1.18 g, 6.17 mmol, 1 equiv) gave after 36 h the title compound 7c
(1.58 g, 81%) as light yellow cotton-like fibres, mp 159–160 ꢀC (lit.,28
165.5–167 ꢀC); lmax(DCM)/nm 229 (log
e 3.31), 237 inf (3.25), 302
(3.10); vmax/cmꢂ1 3217w (NH), 3188w, 3075w, 2239w (C^N),
1585m, 1531m, 1493m, 1416m, 1344s, 1287m, 1169s, 1082m, 924m,
878s, 795m, 745m; dH(300 MHz; CDCl3) 8.39 (1H, d, J 2.4, Ph H-6),
8.36 (1H, d, J 9.2, 2.6, Ph H-4), 7.86 (1H, d, J 9.0, Ph H-3), 7.82 (2H, d, J
8.4, Tos H-2/6), 7.68 (1H, br s, NH), 7.34 (2H, d, J 8.1, Tos H-3/5), 2.42
(3H, s, CH3); dC(75 MHz; CDCl3) 145.8, 144.8, 142.9, 134.8, 130.3
(CH), 129.3 (CH), 128.7 (CH), 127.4 (CH), 118.6 (CH), 113.9 (C^N),
102.3 (CC^N), 21.65 (CH3); m/z (EI)%, 317 (Mþ, 12%), 156 (5), 155
(57), 91 (100), 89 (7), 65 (26).
4.1.4. N-(2-Cyanophenyl)-N-(p-tosyl)aminoacetonitrile 8a. To a stir-
red mixture of 2-(p-tosylamino)benzonitrile 7a (50 mg, 0.18 mmol)
in DMF (2 mL) and K2CO3 (25 mg, 0.18 mmol, 1 equiv) at ca. 20 ꢀC,
chloroacetonitrile was added (11 mL, 0.18 mmol, 1 equiv). The re-
action tube was then sealed and the mixture was heated to ca.100 ꢀC
for 70 min, until no starting material remained (TLC). The mixture
was allowed to cool to ca. 20 ꢀC, diluted with DCM (10 mL) and
washed with water (4ꢁ10 mL). The organic layer was separated and
dried to give the title compound 8a (48 mg, 81%) as colourless
cotton-like fibres, mp 82–83 ꢀC (lit.,8 81–82 ꢀC) (from cyclohexane/
DCM); lmax(DCM)/nm 220 inf (log e 2.91), 231 (3.42), 275 inf (2.34),
282 inf (2.21); vmax/cmꢂ1 2239w (C^N), 1491m, 1449m, 1362s,
1169s, 1117m, 1086m, 856s, 814m, 785m, 766m, 741m; dH(300 MHz;
CDCl3) 7.72 (1H, dd, J 9.0,1.8, Ph H), 7.68–7.62 (3H, m, Ar H), 7.54 (1H,
ddd, J 7.5, 7.5, 1.2, Ph H), 7.44 (1H, dd, J 8.1, 0.6, Ph H), 7.34 (2H, d, J 8.1,
Tos H-3/5), 4.62 (2H, s, CH2), 2.45 (3H, s, CH3); dC(75 MHz; CDCl3)
145.5, 140.0,134.3 (CH),134.0 (CH),134.0,131.0 (CH),130.2 (CH),130.1
(CH), 128.1 (CH), 115.4, 114.5, 114.2, 39.1 (NCH2), 21.7 (CH3); m/z (EI)
311 (Mþ, 12%), 284 (3), 155 (75), 129 (7), 103 (8), 102 (9), 91 (C7Hþ7,
100), 76 (3), 65 (25), 51 (5) identical to an authentic sample.
4.1.1. 2-(p-Tosylamino)benzonitrile 7a. To
a stirred solution of
2-aminobenzonitrile 6a (1.0 g, 8.47 mmol) in pyridine (10 mL) at ca.
20 ꢀC and protected with CaCl2 drying tube, was added p-TsCl
(1.61 g, 8.47 mmol, 1 equiv). The mixture then was heated to ca.
100 ꢀC for 5 h until no starting material remained (TLC). The mix-
ture was allowed to cool to ca. 20 ꢀC, diluted with DCM (20 mL) and
washed with 5% HCl (4ꢁ20 mL). The organic layer was separated
and dried to give the title compound 7a (2.0 g, 87%) as colourless
plates, mp (DSC) onset: 133 ꢀC, peak max: 135 ꢀC (lit.,8 133–134 ꢀC)
4.1.5. N-(2-Cyano-4,5-dimethoxyphenyl)-N-(p-tosyl)aminoaceto-
nitrile 8b. Similar treatment of 4,5-dimethoxy-2-[(p-tosylami-
no)]benzonitrile 7b (50 mg, 0.15 mmol) with chloroacetonitrile
gave after 2 h the title compound 8b (43 mg, 73%) as colourless
needles, mp 191–192 ꢀC (from cyclohexane/DCM); (Found: C, 58.3;
H, 4.6; N, 11.3. C18H17N3O4S requires C, 58.2; H, 4.6; N, 11.3%);
(from cyclohexane/EtOH); lmax(DCM)/nm 231 (log e 4.21), 241 inf
(4.07), 275 inf (3.21), 294 (3.39); vmax/cmꢂ1 3472w, 3364w, 3212w
(NH), 2230m (C^N), 1597m, 1578m, 1495s, 1431m, 1335s, 1298m,
1290m, 1159s, 1094s, 916s, 822m, 806s, 762s, 719m; dH(300 MHz;
CDCl3) 7.73–7.69 (3H, m, Ar H), 7.55 (1H, dd, J 7.9, 7.9, 1.5, Ph H), 7.47
(1H, dd, J 7.8, 1.5, Ph H), 7.26 (2H, d, J 8.1, Tos H-3/5), 7.17 (1H, ddd, J
7.6, 7.6, 1.0, Ph H), 7.11 (1H, br s, NH), 2.39 (3H, s, CH3); dC(75 MHz;
CDCl3) 144.6, 139.2, 135.4, 134.1 (CH), 132.8 (CH), 129.9 (CH), 127.3
(CH), 125.1 (CH), 121.8 (CH), 115.7 (C^N), 104.3 (CC^N), 21.5 (CH3);
m/z (EI) 272 (Mþ, 32%), 207 (2), 155 (56), 139 (2), 91 (C7Hþ7, 100), 77
(2), 65 (24), 51 (3) identical to an authentic sample.
lmax(DCM)/nm 242 (log
e 2.93), 261 (2.87), 269 (2.86), 274 inf
(2.83), 297 inf (2.51); vmax/cmꢂ1 2272w (C^N), 1599m, 1522m,
1360s, 1275m, 1225m, 1164s, 1134m, 1090m, 1076m, 1015m, 968m,
876m, 860m, 816m, 781m; dH(300 MHz; CDCl3) 7.68 (2H, d, J 8.4,
Tos H-2/6), 7.34 (2H, d, J 8.1, Tos H-3/5), 7.02 (1H, s, Ph H-3 or 6), 6.90
(1H, s, Ph H-3 or 6), 4.61 (2H, s, CH2), 3.91 (3H, s, CH3O), 3.84 (3H, s,
CH3O) 2.45 (3H, s, CH3); dC(75 MHz; CDCl3) 153.0, 149.9, 145.4,
134.2, 134.1, 130.0 (CH), 128.2 (CH), 115.7 (C^N), 114.6 (C^N), 114.3
(CH), 113.8 (CH), 105.5 (CC^N), 56.4 (CH3O), 39.3 (CH2), 21.7 (CH3);
m/z (EI) 371 (Mþ, 18%), 216 (C7H7SOþ2 , 100), 200 (1), 189 (41), 174 (3),
155 (5), 147 (3), 119 (2), 104 (3), 91 (C7Hþ7, 28), 77 (2), 65 (12).
4.1.2. 4,5-Dimethoxy-2-(p-tosylamino)benzonitrile 7b. Similar treat-
ment of 2-amino-4,5-dimethoxybenzonitrile 6b (1.0 g, 5.62 mmol)
with p-TsCl gave after 7 h the title compound 7b (1.49 g, 80%) as
colourless prisms, mp 192–193 ꢀC (from cyclohexane/EtOH);
(Found: C, 57.9; H, 4.9; N, 8.4. C16H16N2O4S requires C, 57.8; H, 4.85;
N, 8.4%); lmax(DCM)/nm 242 (log
e
2.87), 268 inf (2.80), 301 (2.57);
4.1.6. 3-Amino-1-(p-tosyl)indole-2-carbonitrile 4a. To
a
stirred
vmax/cmꢂ1 3254m (NH), 2224w (C^N), 1514s, 1396m, 1354s,
1333m, 1275s, 1223s, 1202m, 1169s, 1110m, 1090m, 999s, 893s,
862s, 816s; dH(300 MHz; CDCl3) 7.64 (2H, d, J 8.4, Tos H-2/6), 7.24
(2H, d, J 9.0, Tos H-3/5), 7.23 (1H, s, Ph H-3 or 6), 6.98 (1H, br s, NH),
solution of N-(2-cyanophenyl)-N-(p-tosyl)aminoacetonitrile 8a
(100 mg, 0.32 mmol) in EtOH (2 mL) at ca. 20 ꢀC, was added K2CO3
(0.4 mg, 3.2ꢁ10ꢂ3 mmol, 0.01 equiv). The reaction mixture was left
to stir for 26 h until no starting material remained (TLC). The

S.S. Michaelidou, P.A. Koutentis / Tetrahedron 66 (2010) 3016–3023
3021
mixture was then diluted with DCM (15 mL) and washed with
water (4ꢁ20 mL). The organic layer was separated and dried to give
the title compound 4a (96 mg, 96%) as light orange needles, mp
(DSC) onset: 203 ꢀC, peak max: 205 ꢀC (lit.,8 195.5–196.5 ꢀC) (from
1 equiv). The reaction vessel was sealed, and heated at 100 ꢀC (bath
temperature). The reaction mixture was left to stir for 5 h until no
startingmaterial remained (TLC). Themixturewas diluted with DCM
(15 mL) andwashedwith water(4ꢁ20 mL) toremovetheK2CO3. The
organic layer was separated and dried to give the title compound 5a
(25.7 mg, 65%) as a colourless cotton-like fibres, mp 234–235 ꢀC
(from cyclohexane/EtOH); (Found: C, 61.7; H, 4.2; N, 13.4.
C16H13N3O2S requires C, 61.7; H, 4.2; N, 13.5%); lmax(DCM)/nm 231
cyclohexane/EtOH); lmax(DCM)/nm 231 (log e 4.35), 247 inf (4.25),
270 inf (3.95), 277 inf (3.93), 297 (4.04), 319 (4.10); vmax/cmꢂ1
3447m (NH2), 3348m (NH), 3260w, 3240w, 2208s (C^N), 1653s,
1597m, 1568m, 1364s, 1184m, 1169s, 1153m, 1115m, 1086s, 974m,
810m, 770s, 752s; dH(300 MHz; CDCl3) 8.18 (1H, d, J 8.7, indole H-4),
7.72 (2H, d, J 8.4, Tos H-2/6), 7.54 (1H, ddd, J 7.8, 7.8, 1.2, indole H-5),
7.40 (1H, d, J 7.5, indole H-7), 7.31 (1H, ddd, J 7.5, 7.5, 0.9, indole H-
6), 7.18 (2H, d, J 8.1, Tos H-3/5), 4.49 (2H, br s, NH2), 2.33 (3H, s, CH3);
dC(75 MHz; DMSO-d6) one peak overlapping 148.1, 145.5, 137.2,
131.4, 129.9 (CH), 126.7 (CH), 124.7 (indole CH), 123.7, 120.8 (indole
CH), 115.9 (indole CH), 114.4 (C^N), 84.3 (CC^N), 20.95 (CH3); m/z
(EI) 311 (Mþ, 11%), 156 (100), 129 (21), 102 (13), 91 (C7Hþ7, 15), 76 (5),
65 (9), 51 (5) identical to an authentic sample.
(log e
4.50), 289 (4.23), 313 inf (3.75); vmax/cmꢂ1 3358m and 3310m
(NH), 2228m (C^N), 1366m, 1346s, 1310s, 1250m, 1182m, 1157s,
1090m, 893m, 814s, 748s; dH(300 MHz; DMSO-d6) 12.33 (1H, br s,
NHTs), 10.19 (1H, br s, NH), 7.52 (2H, d, J 8.1, Tos H-2/6), 7.35 (1H, d, J
8.4, indole H-4), 7.29–7.22 (3H, m, Ar H), 7.12 (1H, d, J 8.1, indole H-7),
6.96 (1H, dd, J 7.5, 7.5, indole H-6), 2.33 (3H, s, CH3); dC(75 MHz;
DMSO-d6) 143.2, 136.8, 135.3, 129.5 (CH), 126.8 (CH), 125.8 (indole
CH), 122.4, 121.6, 120.7 (indole CH), 119.4 (indole CH), 112.9 (C^N),
112.4 (indole CH), 103.9 (CC^N), 20.9 (CH3); m/z (EI) 311 (Mþ, 23%),
156 (100), 129 (20), 102 (11), 91 (C7Hþ7, 7), 76 (4), 65 (5).
4.1.7. 3-Amino-5,6-dimethoxy-1-(p-tosyl)indole-2-carbonitrile
4b. Similar treatment of N-(2-cyano-4,5-dimethoxyphenyl)-N-(p-
tosyl)aminoacetonitrile 8b (100 mg, 0.27 mmol) gave after 30 h the
title compound 4b (93 mg, 93%) as light yellow needles, mp 209–
210 ꢀC (from cyclohexane/EtOH); (Found C, 58.3; H, 4.6; N, 11.2.
C18H17N3O4S requires C, 58.2; H, 4.6; N, 11.3%); lmax(DCM)/nm 230
4.1.10. 5,6-Dimethoxy-3-(p-tosylamino)indole-2-carbonitrile
5b. Similar treatment of 3-amino-5,6-dimethoxy-1-(p-tosyl)indole-
2-carbonitrile 4b (20 mg, 0.05 mmol) gave after 3 h the title
compound 5b (29 mg, 79%) as a colourless cotton-like fibres, mp
214–215 ꢀC (from cyclohexane/EtOH); (Found: C, 58.3; H, 4.6; N,11.3.
C18H17N3O4S requires C, 58.2; H, 4.6; N, 11.3%); lmax(DCM)/nm 230
(log e 2.34), 269 (2.23), 277 (2.23), 312 (2.28), 324 inf (2.22); vmax/
cmꢂ1 3466w (NH2), 3372w, 3352m (NH), 3265w, 2185m (C^N),
1649m, 1570m, 1485s, 1437m, 1364s, 1298s, 1229s, 1188m, 1176m,
1171m, 1159s, 1090m, 1013s, 918m, 849m, 816m, 770m;
dH(300 MHz; DMSO-d6) 7.58 (2H, d, J 8.1, Tos H-2/6), 7.51 (1H, s,
indole H-4), 7.37 (1H, s, indole H-7), 7.32 (2H, d, J 8.1, Tos H-3/5),
6.79 (2H, br s, NH2), 3.92 (3H, s, CH3O), 3.73 (3H, s, CH3O) 2.29 (3H,
s, CH3); dC(75 MHz; DMSO-d6) 151.3, 148.7, 147.5, 145.3, 132.1, 131.2,
129.8 (CH), 126.9 (CH), 116.1, 114.9, 101.8 (CH), 99.0 (CH), 83.3
(CC^N), 55.8 (CH3O), 55.6 (CH3O), 21.0 (CH3); m/z (EI) 371 (Mþ, 8%),
216 (C7H8SOþ2 , 100), 200 (2), 189 (2), 172 (6), 158 (4), 143 (2), 121 (3),
116 (3), 103 (3), 91 (C7H7þ, 14), 78 (3), 65 (13), 51 (4).
(log e 4.45), 296 inf (4.23), 307 inf (4.27), 318 (4.31), 330 inf (4.22);
vmax/cmꢂ1 3362m and 3271m (NH), 2833, 2218m (C^N), 1487m,
1379m, 1339s, 1319s, 1260s, 1246m, 1227m, 1204m, 1161s, 1117m,
1092s, 1016m, 947w, 887m, 849m, 816s, 758m, 750m; dH(300 MHz;
DMSO-d6) 12.02 (1H, br s, NHTs), 9.97 (1H, br s, NH), 7.54 (2H, d, J 8.1,
Tos H-2/6), 7.30 (2H, d, J 8.1, Tos H-3/5), 6.75 (1H, s, indole H-4 or 7),
6.20 (1H, s, indole H-4 or 7), 3.76 (3H, s, CH3O), 3.46 (3H, s, CH3O),
2.33 (3H, s, CH3); dC(75 MHz; DMSO-d6) 150.0, 145.8, 143.1, 137.1,
130.4, 129.5 (CH),126.9 (CH), 121.4, 115.3, 113.5 (C^N),102.1 (CC^N),
99.0 (indole CH), 94.1 (indole CH), 55.4 (OCH3), 55.0 (OCH3), 20.9
(CH3); m/z (EI) 371 (Mþ, 21%), 216 (MþꢂC7H7O2S, 100), 200 (3), 189
(7), 173 (4), 163 (4), 155 (4), 144 (3), 130 (2), 104 (3), 91 (14), 77 (4),
65 (9).
4.1.8. 3-Amino-5-nitro-1-(p-tosyl)indole-2-carbonitrile 4c. To a stir-
red mixture of 5-nitro-2-(p-tosylamino)benzonitrile 7c (100 mg,
0.315 mmol)inchloroacetonitrile(1 mL)atca. 20 ꢀCwas addedK2CO3
(87 mg,0.63 mmol,2 equiv). Themixtureheatedtoca.100 ꢀCfor24 h,
until no starting material remained (TLC). The mixture was allowed to
cool to ca. 20 ꢀC, diluted with DCM (10 mL) and washed with water
(4ꢁ10 mL). The organic layer was separated, dried, adsorbed onto
silica and chromatography (hexane/DCM, 2:8) gave 2-amino-5-
nitrobenzo-carbonitrile 6c (23.1 mg, 45%) as light yellow dust, mp
(DSC) onset: 207 ꢀC, peak max: 208 ꢀC (lit.,29 210–211 ꢀC), Rf (hexane/
DCM, 2:1) 0.66; identical to an authentic sample. Further elution
(DCM 100%) gave the title compound 4c (45 mg, 40%) as yellow fibres,
mp 236–237 ꢀC (from cyclohexane/EtOH); Rf (DCM) 0.30; (Found C,
53.8; H, 3.2; N, 15.65. C16H12N4O4S requires C, 53.9; H, 3.4; N, 15.7%);
4.1.11. 5-Nitro-3-(p-tosyl)aminoindole-2-carbonitrile 5c. Similar treat-
ment of 3-amino-5-nitro-1-(p-tosyl)indole-2-carbonitrile 4c (20 mg,
0.056 mmol) gave after 1 h the title compound 5c (17 mg, 85%) as
colourless plates, mp 264–265 ꢀC (from cyclohexane/EtOH); (Found
C, 54.0; H, 3.4; N, 15.7. C16H12N4O4S requires C, 53.9; H, 3.4; N,
15.72%); lmax(DCM)/nm 226 (log e 4.06), 263 inf (4.13), 265 (4.14),
268 (4.11), 272 (4.09); vmax/cmꢂ1 3375m (NH), 3258, 2232 (C^N),
1533m, 1485m, 1404m, 1339s, 1157s, 1088m, 897m, 814m, 777m,
735s; dH(300 MHz; DMSO-d6) 13.13 (1H, br s, NHTs), 10.42 (1H, br s,
NH), 8.08 (1H, dd, J 6.6, 2.3, indole H-6), 7.86 (1H, d, J 2.1, indole H-4),
7.57 (1H, d, J 9.0, indole H-7), 7.51 (2H, d, J 8.4, Tos H-2/6), 7.28 (2H, d,
J 8.1 Tos H-3/5), 2.29 (3H, s, CH3); dC(75 MHz; DMSO-d6) 143.7, 141.8,
137.6, 136.0, 129.6 (CH), 126.8 (CH), 123.9, 121.4, 120.3 (indole CH),
116.8 (indole CH), 113.7 (indole CH), 111.8 (C^N), 107.5 (CC^N), 20.8
(CH3); m/z (EI) 356 (Mþ, 28%), 201 (80),155 (64),148 (3),128 (13),116
(4), 101 (17), 91 (100), 75 (13), 65 (40), 51 (8).
lmax(DCM)/nm 233 (log
e 3.43), 287 (3.50), 326 inf (3.04), 338 inf
(2.91);vmax/cmꢂ13458m(NH2), 3375s, 3102w, 2207m(C^N),1632m,
1612m, 1593m, 1524s, 1477m, 1383s, 1342s, 1285m, 1256s, 1192s,
1175s, 1088m, 1070m, 982m, 903m, 891m, 837m, 822m, 810s, 739m,
702s; dH(300 MHz; CDCl3) 8.41 (1H, s, indole H-4), 8.37 (1H, d, J 2.1,
indole H-7), 8.30 (1H, dd, J 8.7,1.2, indole H-6), 7.77 (2H, d, J 8.4, Tos H-
2/6), 7.28 (2H, d, J 7.8, Tos H-3/5), 2.36 (3H, s, CH3); dC(75 MHz; CDCl3)
147.0, 144.4, 139.7, 136.2, 133.5, 130.6 (CH), 127.5 (CH), 124.4 (CH),
123.7, 122.6, 116.5 (CH), 116.2 (CH), 112.4 (C^N), 21.8 (CH3); m/z (EI)
356 (Mþ, 21%), 202 (13), 201 (C7H8SOþ2 ,100),156(7),155(55),128(16),
116 (3),102 (8),101 (14), 92 (19), 91 (87), 77 (5), 76 (6), 75 (7), 65 (33).
4.2. Preparation of 3-(p-tosylamino)indole-2-carbonitrile 5a
from 3-amino-1-(p-tosyl)indole-2-carbonitrile 4a using DBU:
(typical procedure)
To a stirred solution of DBU (3 mL, 0.019 mmol, 0.2 equiv) in dry
PhH at ca. 20 ꢀC, was added 3-amino-1-tosylindole-2-carbonitrile
4a (30 mg, 0.096 mmol). The reaction mixture was left to stir for
24 h at reflux until no starting material remained (TLC). The re-
action mixture was then allowed to cool to ca. 20 ꢀC, adsorbed onto
silica and chromatography (hexane/tert-butyl ether, 50:50) gave 3-
4.1.9. 3-(p-Tosylamino)indole-2-carbonitrile 5a. To a stirred solution
of 3-amino-1-(p-tosyl)indole-2-carbonitrile 4a (20 mg, 0.06 mmol)
in EtOH (1 mL) at ca. 20 ꢀC was added K2CO3 (9 mg, 0.06 mmol,

3022
S.S. Michaelidou, P.A. Koutentis / Tetrahedron 66 (2010) 3016–3023
(p-tosylamino)indole-2-carbonitrile 5a in (30 mg, 76%) as a colour-
less cotton-like fibres, mp 234–235 ꢀC (from cyclohexane/EtOH)
identical to that described above.
4b (20 mg, 0.05 mmol) gave after 24 h the title compound 2b
(10 mg, 88%) as yellow needles, mp 194–195 ꢀC (lit.,5 194–195 ꢀC)
(from cyclohexane/EtOH) identical to an authentic sample.
4.3. Preparation of 3-(p-tosylamino)indole-2-carbonitrile 5a
from 3-aminoindole-2-carbonitrile 2a and p-TsCl: (typical
procedure)
4.4.3. 3-Amino-5-nitroindole-2-carbonitrile 2c. Similar treatment
of 3-amino-5-nitro-1-(p-tosyl)indole-2-carbonitrile 4c (20 mg,
0.056 mmol) gave after 1 h the title compound 2c (10 mg, 90%) as
red cotton-like fibres, mp 310–311 ꢀC (lit.,4 310–311 ꢀC) (from
benzene) identical to an authentic sample.
To a stirred solution of 3-aminoindole-2-carbonitrile 2a (20 mg,
0.06 mmol) and pyridine (21 mL, 0.24 mmol, 4 equiv) in EtOH
(2 mL) at ca. 20 ꢀC, was added p-TsCl (11 mg, 0.06 mmol, 1 equiv).
The reaction mixture was heated at reflux for 5 h until no starting
material remained (TLC). The mixture was diluted with DCM
(15 mL) and washed with 5% HCl (4ꢁ20 mL) to remove pyridine.
The organic layer was separated and dried to give 3-(p-tosyla-
mino)indole-2-carbonitrile 5a (34 mg, 85%) identical to that de-
scribed above.
4.4.4. 3-Aminoindole-2-carbonitrile 2a (Anaerobic conditions, see
Table 1). To a stirred solution of DBU (10
mL, 0.06 mmol, 1 equiv)
and thiophenol (31 L, 0.30 mmol, 5 equiv) in distilled and
m
degassed benzene (2 mL) at ca. 20 ꢀC under argon atmosphere,
3-amino-1-(p-tosyl)indole-2-carbonitrile 4a (20 mg, 0.06 mmol)
was added. The reaction mixture was then heated to ca. 80 ꢀC for
24 h, until no starting material remained (TLC). The reaction mix-
ture was then allowed to cool to ca. 20 ꢀC, adsorbed onto silica and
chromatography (hexane) gave diphenyl disulfide (14 mg, 104%) as
colourless needles, mp 60–61 ꢀC (from cyclohexane). Further
elution (hexane/tert-butyl methyl ether, 50:50) gave the title
compound 2a (8 mg, 88%) as light yellow cotton-like fibres, mp
172–173 ꢀC (lit.,4 172–173 ꢀC) (from cyclohexane/EtOH) identical to
an authentic sample.
4.3.1. 3-(Benzesulfonylamino)indole-2-carbonitrile 5d. Similar treat-
ment of 3-aminoindole-2-carbonitrile 2a (20 mg, 0.06 mmol) gave
after12 h the title compound 5d (16 mg, 88%) as a light yellowcotton-
like fibres, mp 230–231 ꢀC (from cyclohexane/EtOH);(Found C, 60.6;
H, 3.7; N, 14.1. C15H11N3O2S requires C, 60.6; H, 3.7; N, 14.1%);
lmax(DCM)/nm 208 (log e 3.50), 223 (3.61), 289 (3.29), 305 inf (3.02),
317 inf (2.76); vmax/cmꢂ1 3360m and 3306m (NH), 2228m (C^N),
1450m, 1366m, 1344m, 1308m, 1167s, 1159s, 1094m, 895m, 745s,
721m; dH(300 MHz; DMSO-d6) 12.36 (1H, br s, NHSO2Ph),10.27 (1H,
br s, NH), 7.66–7.58 (3H, m, Ph H), 7.51–7.45 (2H, m, Ph H), 7.36 (1H, d,
J 8.4, indole H-4 or 7), 7.25 (1H, dd, J 7.5, 7.4, indole H-5 or 6), 7.07 (1H,
d, J 8.1, indole H-4 or 7), 6.95 (1H, dd, J 7.7, 7.35, indole H-5 or 6);
dC(75 MHz; DMSO-d6) 139.5, 135.3, 132.9 (CH), 129.1 (CH), 126.7
(CH), 125.8 (CH), 122.5, 121.4, 120.8 (CH), 119.3 (CH), 112.8 (C^N),
112.4 (CH), 104.1 (CC^N); m/z (EI) 297 (Mþ, 16%), 287 (4), 156
(PhSO2Nþ, 100), 129 (30), 103 (25), 77 (19), 76 (14), 51 (17).
Acknowledgements
The authors wish to thank the Cyprus Research Promotion
Foundation [Grant No. TEXNOLOGIA/QEPIS/0308(BE)/08] and the
following organisations in Cyprus for generous donations of
chemicals and glassware: the State General Laboratory, the Agri-
cultural Research Institute and the Ministry of Agriculture. Fur-
thermore, we thank the A.G. Leventis Foundation for helping to
establish the NMR facility in the University of Cyprus.
4.4. Reaction of 3-amino-1-(p-tosyl)indole-2-carbonitrile
References and notes
4a with sodium phenylsulfinate
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was added. The reaction mixture was then heated to ca. 80 ꢀC for
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Table 1). To a stirred solution of DBU (10
mL, 0.06 mmol, 1 equiv)
and thiophenol (31 L, 0.30 mmol, 5 equiv) in distilled benzene
m
(2 mL) at ca. 20 ꢀC and protected with CaCl2 drying tube, 3-amino-
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to an authentic sample.
4.4.2. 3-Amino-5,6-dimethoxyindole-2-carbonitrile 2b. Similar treat-
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