The conversion of 2-cyano cyanothioformanilides into 3-aminoindole-2- carbonitriles using triphenylphosphine

Article abstract of DOI:10.1016/j.tet.2010.06.020

2-Cyano cyanothioformanilide 3a reacts with triphenylphosphine in the presence of water to give 2-(cyanomethyleneamino)benzonitrile 4a, 2-(cyanomethylamino)benzonitrile 5, 3-aminoindole-2-carbonitrile 2a and (2-cyanoindol-3-yl)iminotriphenylphosphorane 6a. In the presence of p-toluenesulfonic acid in MeOH the reaction between 2-cyano cyanothioformanilide 3a and triphenylphosphine (2 equiv) gives 3-aminoindole-2-carbonitrile 2a in 90% yield. Under the same conditions 2-(cyanomethyleneamino)benzonitrile 4a gives anthranilonitrile 8a, 3-aminoindole-2-carbonitrile 2a and N-(2-cyanophenyl)formamide 9. In addition, substituted 2-cyano cyanothioformanilides 3b-f react with triphenylphosphine and p-toluenesulfonic acid in MeOH to give 3-aminoindole-2-carbonitriles 2b-f in 63-75% yields. Under analogous conditions 2-cyano-4,5-dimethoxyphenyl cyanothioformanilide 2g gives only 4,5-dimethoxyanthranilonitrile 8g and 4,6,7-trimethoxyquinazoline-2- carbonitrile 14g, but in refluxing dry PhMe in the absence of p-toluenesulfonic acid 2-cyano-4,5-dimethoxyphenyl cyanothioformanilide 3g, (2-cyano-5,6- dimethoxyindol-3-yl)iminotriphenylphosphorane 6g and 2-(cyanomethyleneamino)-4, 5-dimethoxybenzonitrile 4g are obtained. The structure of 2- (cyanomethyleneamino)-4,5-dimethoxybenzonitrile 4g is supported unambiguously via independent synthesis and comparison to the isomeric 6,7- dimethoxyquinazoline-2-carbonitrile 15. All new compounds are fully characterised and a tentative mechanism for the transformation of 2-cyano cyanothioformanilides to indoles is proposed.

Full text of DOI:10.1016/j.tet.2010.06.020

Tetrahedron 66 (2010) 6032e6039
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journal homepage: www.elsevier.com/locate/tet
The conversion of 2-cyano cyanothioformanilides into 3-aminoindole-
2-carbonitriles using triphenylphosphine
*
Panayiotis A. Koutentis , Sophia S. Michaelidou
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:
Received 6 April 2010
Received in revised form 21 May 2010
Accepted 7 June 2010
Available online 12 June 2010
2-Cyano cyanothioformanilide 3a reacts with triphenylphosphine in the presence of water to give
2-(cyanomethyleneamino)benzonitrile 4a, 2-(cyanomethylamino)benzonitrile 5, 3-aminoindole-2-car-
bonitrile 2a and (2-cyanoindol-3-yl)iminotriphenylphosphorane 6a. In the presence of p-toluenesulfonic
acid in MeOH the reaction between 2-cyano cyanothioformanilide 3a and triphenylphosphine (2 equiv)
gives 3-aminoindole-2-carbonitrile 2a in 90% yield. Under the same conditions 2-(cyanomethylene-
amino)benzonitrile 4a gives anthranilonitrile 8a, 3-aminoindole-2-carbonitrile 2a and N-(2-cyanophenyl)
formamide 9. In addition, substituted 2-cyano cyanothioformanilides 3bef react with triphenylphos-
phine and p-toluenesulfonic acid in MeOH to give 3-aminoindole-2-carbonitriles 2bef in 63e75% yields.
Under analogous conditions 2-cyano-4,5-dimethoxyphenyl cyanothioformanilide 2g gives only 4,5-di-
methoxyanthranilonitrile 8g and 4,6,7-trimethoxyquinazoline-2-carbonitrile 14g, but in refluxing dry
PhMe in the absence of p-toluenesulfonic acid 2-cyano-4,5-dimethoxyphenyl cyanothioformanilide 3g,
(2-cyano-5,6-dimethoxyindol-3-yl)iminotriphenylphosphorane 6g and 2-(cyanomethyleneamino)-4,5-
dimethoxybenzonitrile 4g are obtained. The structure of 2-(cyanomethyleneamino)-4,5-dimethoxy-
benzonitrile 4g is supported unambiguously via independent synthesis and comparison to the isomeric
6,7-dimethoxyquinazoline-2-carbonitrile 15. All new compounds are fully characterised and a tentative
mechanism for the transformation of 2-cyano cyanothioformanilides to indoles is proposed.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
butylamine,20 tryptamine,21 o-aminophenethylamine and o-phe-
nylenediamine,22 triphenylphosphoraneylidenes,23 triphenylphos-
Cyanothioformanilides (thiooxanilonitriles) demonstrate her-
bicidal activity,1 and have been used extensively for the preparation
of various heterocycles including pyrroles,2a,b imidazoles,3aek
oxazoles,4aec 1,3,4-thiadiazoles,5 quinazolines6aec and other fused
heterocycles.7aeg Furthermore, cyanothioformanilides participate
in DielseAlder8aec and ene9 reactions, can be N aroylated10 and on
addition to the nitrile of H2O, H2S or NH2OH afford amino-
oxothioacetylanilines, aminothioxothioacetylanilines (N-aryldi-
thioxamides)3d,11 or amidinothioformylanilines,4c,12 respectively.
Cyanothioformanilides are traditionally prepared by the
reaction of N-aryl isothiocyanates with cyanide,3j,4c,6a,7f,7g,8c,13aed or
bis(dialkylamino)acetonitriles14 and also via dethiohydration
of N-aryldithiooxamides,13d,15 thionation-dethiohydration of
N‑arylthiooxalamides15 and thionationedehydration of arylox-
alamides.15 More recent methods involve treating 2-(4-chloro-5H-
1,2,3-dithiazol-5-ylideneamino)benzenes with either the oxidising
agent m-CPBA,16 the reducing agent NaBH3CN,17 or with nucleo-
philic (thiophilic) reagents such as aq NaOH,18 NH2OH,19 tert-
phine in moist DCM24aeh and with the use of ethylmagnesium
bromide (1 equiv).24h,25
Recently, we showed that treating 2-(4-chloro-5H-1,2,3-dithi-
azol-5-ylideneamino) benzonitriles 1 with triphenylphosphine
(4 equiv) gave 3-aminoindole-2-carbonitriles
2 and not the
expected 2-cyano cyanothioformanilides 3.26 The latter compounds
could however, be prepared from the dithiazolimines 1 on treat-
ment with DBU in high yield27 (Scheme 1).
NH
R
R
CN
Ph P
S
NOT
CN
CN
N
CN
N
H
H
R
N
Cl
2
3
S
N
S
R
1
CN
DBU
S
CN
N
H
3
* Corresponding author. Tel.: þ00357 22 892783; fax: þ00357 22 892809; e-mail
Scheme 1.
address: koutenti@ucy.ac.cy (P.A. Koutentis).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.06.020

P.A. Koutentis, S.S. Michaelidou / Tetrahedron 66 (2010) 6032e6039
6033
While a mechanism was not put forward for the formation of
2. Results and discussion
the indoles 2, our initial thoughts focused on the triphenylphos-
phine behaving as a typical thiophile and attacking the dithiazol-
imine S-2 ring sulfur (Scheme 2). This would be expected to lead to
the 2-cyano cyanothioformanilide 3, however, as mentioned above
this was not an observed.
2.1. Reaction of 2-cyano cyanothioformanilides with
triphenylphosphine
Treatment of a solution of the cyanothioformanilide 3a in dry
DCM at ca. 20 ꢀC with triphenylphosphine (2 equiv) rapidly gave
several products: Triphenylphosphine sulfide, 2-(cyanomethyl-
amino)benzonitrile 5, the iminophosphorane 6a and triphenyl-
phosphine oxide (Table 1). Interestingly 3-aminoindole-2-
carbonitrile 2a was not observed, however, as the equivalents of
water added to the reaction mixture were increased the yield of
iminophosphorane 6a decreased while that of the 3-aminoindole
2a increased. The overall yields of indoles (2aþ6a) remained rela-
tively steady. Furthermore, a new compound 4a was isolated in low
yield, which was relatively unstable and identified as 2-(cyano-
methyleneamino)benzonitrile 4a.
2-(Cyanomethyleneamino)benzonitrile 4a was obtained as col-
ourless cotton fibres, mp 75e76 ꢀC (from cyclohexane). Micro-
analysis and mass spectrometry supported the formula C9H5N3
[m/z 155 (Mþ, 28%)]. The presence of a cyano group was supported
by an IR band at 2234 cmꢁ1 and stretching frequencies could not be
observed for any 1ꢀ or 2ꢀ amino functionality. The 13C NMR spec-
trum showed nine separate carbon resonances of which four were
quaternary carbons (DEPT-135 studies). Two of the quaternary
signals (dC 118.3 and 116.2 ppm) were typical of cyano carbons,
tentatively supporting the presence of two nitrile groups. The 1H
NMR spectrum identified five resonances, four of which clearly
belonged to aromatic hydrogens (7.78, 7.68, 7.50 and 7.18 ppm)
of a 1,2-disubstituted benzene ring. The signal at dH 7.63 ppm,
however, was observed as a singlet. Based on the above data
two possible structures could be proposed, which maintained
the carbon and nitrogen connectivity of the starting 2-cyano
R
PPh3
_
R
+
CN
N
CN
N
PPh3
Cl
S
S
S
S
PPh3
N
CN
Cl
1
NH2
R
R
CN
O
H2
PPh3
S
CN
_
_
Ph3P=S
Ph3P=O
N
CN
N
H
H
_
HCl
3
2
Scheme 2.
In light of this a pure sample of 2-cyano cyanothioformanilide
3a (R¼H) was treated with triphenylphosphine to determine
whether it was a possible intermediate in the dithiazole to
indole conversion. Below we report our findings related to
the treatment of 2-cyano cyanothioformanilides
triphenylphosphine.
3
with
Table 1
Reaction of cyanothioformanilide 3a (0.27 mmol) with triphenylphosphine (2 equiv) under a CaCl2 drying tube
S
Ph3P (2 equiv)
PPh3=S, 4a, 5, 2a, 6a, PPh3=O
N
H
CN
CN
3a
NH2
N
CN
CN
PPh3
H
+
CN
CN
N
N
CN
N
H
CN
N
H
H
4a
5
2a
6a
H2O (equiv)
Solvent
Temp (ꢀC)
Time (min)
Yields (%)
PPh3]S
4a
5
2a
6a
PPh3]O
0
1
2
3
0
0
0
0
0
0
0
0
0
0
DCM
DCM
DCM
DCM
PhH
PhH
PhH
PhMe
PhMea
PhMe
MeOH
MeOHb
MeOHa
MeOH
20
20
20
20
20
40
80
20
20
110
20
20
20
60
5
3
1
1
5
5
1
3
10
1
78
80
80
80
84
78
87
86
79
86
45
69
72
52
d
d
7
6
11
5
6
6
d
20
25
30
25
38
d
6
13
21
3
1
9
5
58
7
70
63
50
48
45
69
79
68
7
81
23
23
d
27
54
58
70
71
69
49
34
51
80
32
49
71
80
51
23
traces
17
28
5
63
59
9
61
3
9
4
d
70
60
50
5
d
5
90
1
5
a
PTSA (1 equiv) was added to the reaction mixture.
PTSA (5 mol %) was added to the reaction mixture.
b

6034
P.A. Koutentis, S.S. Michaelidou / Tetrahedron 66 (2010) 6032e6039
cyanothioformanilide 3a; the 2-(cyanomethyleneamino)benzoni-
trile 4a or the quinazoline-2-carbonitrile 7. Fortunately, the latter
compound 7 is known [mp 162e164 ꢀC, 1H NMR (CDCl3) dH-4
9.55 ppm] and had been prepared via an unambiguous route
starting from 2-chloroquinazoline.28
the carbene. Similar thiaphosphiranes, have previously been pro-
posed30 and recently the first single crystal X-ray structure of
a thiaphosphirane was reported.31 Protonation of the zwitterion 10
could generate a new phosphonium species 11 that could then
suffer a second attack by Ph3P on sulfur, followed by protonation, to
release the observed (2-cyanomethylamino)benzonitrile 5. Alter-
natively, the phosphonium species 11 could eliminate triphenyl-
phosphine sulfide to give the observed imine 4a although this could
also form from the carbene 13 via a 1,2-H-shift (Scheme 4).
H
CN
H
N
The formation of the indoles was more speculative. Tenta-
tively the zwitterion 10 could add to the ortho cyano group
either step-wise or via a cycloaddition to yield a heteroarene 12
that could fragment to the iminophosphorane 6a. Hydrolysis of
the iminophosphoranes 6a can give the observed indole 2a and
we have shown previously that these two species can be readily
inter-converted in high yield.26 The proposed cycloadditions
were tentatively supported by the high iminophosphorane
recoveries in PhH and PhMe at reflux, while in MeOH and PTSA
(1 equiv) the possibility that the ortho-cyano group was con-
verted into an imidate prior to a step-wise cyclisation could
explain the high yields of 3-aminoindole-2-carbonitrile 2a.
Attempts to improve the transformation in MeOH by replacing
PTSA by mild Lewis acids such as caesium carbonate or zinc
N
CN
N
CN
4a
7
When dry benzene or toluene was used as solvents, increasing
the reaction temperature significantly raised the yield of the
iminophosphorane 6a to 79 and 81%, respectively, and gave total
indole recoveries (2aþ6a) approaching 90%. In the presence of
p-toluenesulfonic acid (PTSA) (1 equiv) the reaction in toluene at
ca. 20 ꢀC gave mainly 3-aminoindole-2-carbonitrile 2a rather than
the iminophosphorane 6a. It was rationalised that the use of
a protic solvent such as methanol could lead to the formation of
lesser amounts of indole products and greater amounts of the
cyanomethylene 5 and this was indeed the case, although some
indole products were still obtained. In this case, the addition of
a catalytic quantity of PTSA (5 mol %) made little difference to the
product distribution, however the addition of PTSA (1 equiv) gave
rather surprisingly 3-aminoindole-2-carbonitrile 2a in 90% yield.
To better understand this result pure samples of compounds 4a, 5
and 6a were dissolved in methanol and treated with Ph3P (2 equiv)
and PTSA (1 equiv) at ca. 20 ꢀC, respectively. After 24 h reaction,
compounds 5 and 6a proved to be stable. Compound 4a, however,
was consumed after 5 h and chromatography gave unreacted tri-
phenylphosphine (59%), anthranilonitrile 8a (14%), 3-aminoindole-
2-carbonitrile 2a (30%), N-(2-cyanophenyl)formamide 9 (53%) and
triphenylphosphine oxide (35%) (Scheme 3).
chloride gave mainly (2-cyanomethylamino)benzonitrile
5 in
65e67% yields. Further work to understand the scope of this
transformation is now underway.
2.3. Scope of the 2-cyano cyanothioformanilides to
3-aminoindole-2-carbonitrile transformation
Elucidating the reaction mechanisms for the above trans-
formations still requires further work, however, investigating the
effect of aryl substituents can provide useful data as well as iden-
tifying the reaction scope and limitations. As such several aryl
substituted 2-cyano cyanothioformanilides 3aeg were treated with
triphenylphosphine in MeOH in the presence of PTSA (1 equiv) at
ca. 20 ꢀC (Table 2).
NH2
CN
CN
CN
H
i)
O
Ph3P=O
(35%)
+
+
+
CN
N
CN
NH2
N
N
H
H
H
8a (14%)
2a (30%)
9 (53%)
4a
Scheme 3. Reagents and conditions: (i) Ph3P (2 equiv), PTSA (1 equiv) in MeOH at rt, 5 h.
The identity of the latter compound N-(2-cyanophenyl)form-
amide 9 was confirmed via an independent synthesis from
anthranilonitrile 8a, formic acid and zinc oxide according to
a known procedure.29 When the reaction was performed in
the absence of triphenylphosphine, only anthranilonitrile 8a and
N-(2-cyanophenyl)formamide 9 were obtained. This unexpected
transformation of the imine 4a into the indole 2a requires a formal
reduction, and this could have been mediated by the triphenyl-
phosphine. This transformation is now under further study.
In nearly all cases the expected 3-aminoindole-2-carbonitriles
were formed together with triphenylphosphine sulfide,
triphenylphosphine oxide and some recovered substituted
anthranilonitriles 8. Some anomalous results were evident: First,
the 2-cyano-4-nitro substituted cyanothioformanilide 3c gave
2
a
mixture of 3-amino-5-nitroindole-2-cabonitrile 2c (40%)
together with the iminophosphorane 6c (21%) but extending
the reaction time to 6 h led to the latter’s conversion into the
3-amino-5-nitroindole-2-cabonitrile 2c (65%). Secondly, the 4-
chloro-2-cyano cyanothioformanilide 3e gave a moderate yield of
6-chloro-4-methoxyquinazoline-2-carbonitrile 14e (23%). Finally,
and the most notable exception, 2-cyano-4,5-dimethoxyphenyl
cyanothioformanilide 2g gave 4,5-dimethoxyanthranilonitrile
8g (30%) and 4,6,7-trimethoxyquinazoline-2-carbonitrile 14g
(19%) and no indole products in MeOH. Nevertheless, in
anhydrous PhMe at reflux in the absence of PTSA 2-cyano-
4,5-dimethoxyphenyl cyanothioformanilide 3g gave some
2.2. Tentative mechanistic rational for the formation of
compounds 2e6
Thiophilic Ph3P could attack the cyanothioformanilide 3 at sul-
fur then in the absence of water the zwitterion 10 could form,
which would be expected to be in equilibrium with the thiaphos-
phirane, other ring opened zwitterionic forms and even possibly

P.A. Koutentis, S.S. Michaelidou / Tetrahedron 66 (2010) 6032e6039
6035
_ OH
+
CN
CN
PPh3
CN
HO _
H
H2O
H
S
O
+
+
_
_
Ph3P=S
H2O
Ph3P
PPh3
_
_
Ph3P=S
Ph3P=O
N
CN
N
H
CN
N
H
CN
S
H
_
HCl
5
4a
11
H2O
+
PPh3
CN
PPh3
CN
S
CN
CN
+
S
PPh3
CN
S
S
PPh3
CN
_
_
CN
N
H
CN
N
H
N
H
N
H
3a
10
N
PPh3
CN
N
N
PPh3
S +
PPh3
S
CN
PPh3
CN
S
_
_
_
+
Ph3P=S
PPh3
CN
N
H
N
H
CN
N
H
N
H
6a
12
13
Scheme 4.
Table 2
Reaction of cyanothioformanilides 3aeg (0.10 mmol) with Ph3P (2 equiv) in the presence of PTSA (1 equiv) in wet MeOH at rt under a CaCl2 drying tube
CN
CN
S
Ph3P (2 equiv)
PTSA (1 equiv)
H
R
Ph3P=S
+
+
R
R
N
CN
NH2
N
CN
H
CN
4a-g
3a-g
8a-g
OMe
R
R
NH2
N
PPh3
N
+
+
Ph3P=O
+
+
R
CN
CN
N
CN
N
N
H
H
2a-g
6a-g
14a-g
3aeg (R)
Time (h)
Yields (%)
Ph3P]S
8
4
14
2
6
Ph3P]O
3a (R¼H)
0.17
1
1
6
1
72
80
77
80
82
68
80
59
52
8a (8)
4a (0)
4b (0)
4c (0)
4c (0)
4d (0)
4e (0)
4f (0)
4g (0)
14a (0)
14b (0)
14c (0)
14c (0)
14d (0)
14e (23)
14f (0)
14g (19)
14g (0)
2a (90)
2b (75)
2c (40)
2c (65)
2d (72)
2e (75)
2f (63)
2g (0)
6a (0)
6b (0)
6c (21)
6c (0)
6d (0)
6e (0)
6f (0)
80
82
78
77
81
76
76
62
50
3b (R¼3-Me)
3c (R¼4-O2N)
3c (R¼4-O2N)
3d (R¼5-Cl)
8b (24)
8c (24)
8c (25)
8d (26)
8e (0)
8f (37)
8g (27)
8g (0)
3e (R¼4-Cl)
1
1
3f (R¼5-MeO)
3g (R¼4,5-(MeO)2)
3g (R¼4,5-(MeO)2)
1
6g (0)
6g (31)
1a
4g (23)
2g (0)
a
The reaction took place in PhMe at reflux.
H
MeO
MeO
CN
N
MeO
MeO
H
N
(2-cyano-5,6-dimethoxyindol-3-yl)iminotriphenylphosphorane 6g
(31%) together with some 2-(cyanomethyleneamino)-4,5-dime-
thoxybenzonitrile 4g (23%). While the 4-methoxy substituted
quinazoline-2-carbonitriles have been previously prepared from
cyanothioformanilides simply on treatment with base in MeOH,6c
2-(cyanomethyleneamino)-4,5-dimethoxybenzonitrile 4g had
previously mistakenly been identified as 6,7-dimethoxyquinazo-
line-2-carbonitrile 1526 and based on the above identification of
2-(cyanomethyleneamino)benzonitrile 4a this tentative assign-
ment was put into doubt (see below).
CN
N
CN
4g
15
Since the by-products from the 2-cyano cyanothioformanilide 3
into indole 2 transformation were in some cases similar or identical
to those isolated from the dithiazolimine 1 to indole 2 trans-
formation it can be postulated that the latter transformation

6036
P.A. Koutentis, S.S. Michaelidou / Tetrahedron 66 (2010) 6032e6039
involved a cyanothioformanilide intermediate or at least a closely
related structure. The overall yields of the cyanothioformanilide to
indole conversion were notably higher (63e90%) than those
reported for the related dithiazolimine reaction (7e75%),26 pre-
sumably owing to a shorter reaction pathway. Despite this, the
dimethoxy substituted cyanothioformanilide 3g gave very low
yields of indoles [2g (0%), 3g (31%)], similar to the analogous
dithiazolimine reaction. Electron donating substituents such as
methoxy groups clearly did not favour the formation of the anti-
cipated indoles.
yield. The reaction in MeOH/PTSA tolerated electron withdrawing
substituents but not the strongly electron releasing dimethoxy
substituents on the arene moiety. Several minor by-products
provided insight into a possible reaction mechanism. Furthermore,
2-(cyanomethyleneamino)benzonitrile treated with triphenyl-
phosphine, PTSA in MeOH also surprisingly gave indole. The
success of this transformation suggested that 2-cyano cyanothio-
formanilide could be an intermediate in the related triphenyl-
phosphine mediated dithiazole to indole transformation.
4. Experimental
2.4. Independent synthesis of 2-(cyanomethyleneamino)-4,5-
dimethoxybenzonitrile 4g and 6,7-dimethoxyquinazoline-2-
carbonitrile 15
4.1. General methods and materials
DCM was freshly distilled fromCaH2 underargon. Reactions were
protected from atmospheric moisture by CaCl2 drying tubes. Anhy-
drous 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 technique of dry flash chromatography was used throughout for
all non-TLC scale chromatographic separations using Merck Silica
Gel 60 (less than 0.063 mm).35 Melting and decomposition points
were determined using either a PolyTherm-A, Wagner & Munz,
Koefler-Hotstage Microscope apparatus or where noted using a TA
Instruments DSC Q1000 with samples hermetically sealed in alu-
minium pans under an argon atmosphere; using heating rates of
5 ꢀC/min. Solvents used for recrystallisation are indicated after the
melting point. UV spectra were obtained using a PerkineElmer
Lambda-25 UV/vis spectrophotometer and inflections are identified
by the abbreviation ‘inf’. IR spectra were recorded on a Shimadzu
FTIReNIR Prestige-21 spectrometer with a Pike Miracle Ge ATR ac-
cessory 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
DEPT-135NMR was used toidentify quaternaryand tertiarycarbons,
respectively. 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. 2-Cyano cyanothioformanilides
3aeg,27 N-(2-cyanophenyl)formamide 929 and 2-chloro-6,7-dime-
thoxyquinazoline 1733 were prepared according to literature pro-
cedures. The isolated reaction by-products, triphenylphosphine
sulfide, triphenylphosphine oxide and the anthranilonitriles 8aeg
were identical to authentic samples.
Unlike 2-(cyanomethyleneamino)benzonitrile 4a the 4,5-dime-
thoxy analogue 4g was considerably more stable and a sample was
prepared independently via the mild oxidation of 2-(cyanomethyl-
amino)-4,5-dimethoxybenzonitrile 16 using either NBS or CaOCl.32
Furthermore, treatment of 2-(cyanomethyleneamino)-4,5-dime-
thoxybenzonitrile 4g with NaBH4 in dry MeOH led to its facile con-
version back to 2-(cyanomethylamino)-4,5-dimethoxybenzonitrile
16 (Scheme 5).
MeO
CN
MeO
CN
i) or ii)
(iii)
MeO
N
H
CN
MeO
N
CN
16
4g
Scheme 5. Reagents and conditions: (i) NBS (1 equiv), CaCl2 (0.5 equiv), Ca(OH)2
(2.1 equiv) in CCl4 at 55 ꢀC,
d, (32%); (ii) CaOCl (1.5 equiv), CaCl2 (0.2 equiv),
2
Ca(OH)2 (2 equiv) in DCM at rt, 4 d (50%); (iii) NaBH4 (1.2 equiv) in dry MeOH, rt,
10 min (91%).
To eliminate any possibility of error a pure sample of 6,7-
dimethoxyquinazoline-2-carbonitrile 15 was also prepared from
2-chloro-6,7-dimethoxyquinazoline 1733 using sodium cyanide
(2 equiv) and DABCO (1 equiv) in DMSO (Scheme 6).34
MeO
MeO
MeO
MeO
i)
N
N
N
Cl
N
CN
17
15
Scheme 6. Reagents and conditions: (i) NaCN (2 equiv), DABCO (1 equiv) in DMSO at
75 ꢀC, 10 h (38%), or at rt, 7 d (40%).
4.2. Reaction of 2-cyano cyanothioformanilide 3a with Ph3P
(see Table 1)
Differential scanning calorimetric studies (5 ꢀC/min) of isomers
4g and 15 gave considerably different thermal behaviour; the
cyanomethyleneamino 4g gave no melting point and only a de-
composition peak at 177 ꢀC (onset 175.4 ꢀC) while the quinazoline
15 showed a sharp melting point at 303.4 ꢀC (onset 301.3 ꢀC) and
was followed by an immediate decomposition at 310.3 ꢀC (onset
305.7 ꢀC). Furthermore, unlike the cyanomethyleneamino 4g the
isomeric 6,7-dimethoxyquinazoline-2-carbonitrile 15 was stable to
NaBH4 in dry MeOH. The spectral data of the independently pre-
pared sample of isomer 4g was identical to that isolated from the
reaction of 2-cyano-4,5-dimethoxyphenyl cyanothioformanilide 3g
with triphenylphosphine.
To stirred solution of 2-cyano cyanothioformanilide 3a (50 mg,
0.27 mmol) in dry PhH (2 mL) at ca. 20 ꢀC, was added Ph3P (142 mg,
0.54 mmol). The reaction mixture was then allowed to stir at ca.
20 ꢀC for 5 min, until no starting materials remained (TLC). The re-
action mixture was adsorbed onto silica and chromatography
(hexane/DCM, 5:5) gave triphenylphosphine sulfide (134 mg, 84%)
as colourless needles, mp 161e162 ꢀC (from cyclohexane), Rf (hex-
ane/DCM, 5:5) 0.60, identical to an authentic sample. Further elution
(hexane/DCM, 2:8) gave 2-(cyanomethyleneamino)benzonitrile 4a
(4 mg, 11%) as colourless cotton fibres, mp 75e76 ꢀC (from cyclo-
hexane), Rf (hexane/DCM, 2:8) 0.70; (found: C, 69.7; H, 3.3; N, 27.0.
C9H5N3 requires C, 69.7; H, 3.3; N, 27.1%); lmax(DCM)/nm 229 inf (log
3. Conclusions
3
3.03), 237 inf (3.08), 243 (3.12), 253 inf (2.96), 321 (2.54); vmax/
2-Cyano cyanothioformanilide reacts with triphenylphosphine
(2 equiv) in either MeOH in the presence of PTSA (1 equiv) or in
refluxing toluene to give 3-amino indole-2-carbonitrile in good
cmꢁ1 3096w, 3067w and 3032w (Ar CH), 2926w, 2234m (C^N),
1599w,1587w,1570w,1485m,1447w,1337m,1283w,1213w,1188w,
1045w,1005m, 932m, 874w, 853w, 762s, 733w; dH(300 MHz; CDCl3)

P.A. Koutentis, S.S. Michaelidou / Tetrahedron 66 (2010) 6032e6039
6037
7.78 (1H, dd, J 7.7,1.5, Ph H-2 or 6), 7.68 (1H, ddd, J 7.9, 7.9,1.4, Ph H-4
or 5), 7.62 (1H, s, CH]N), 7.50 (1H, ddd, J 7.7, 7.7, 0.9, Ph H-4 or 5), 7.18
(1H, d, J 8.1, Ph H-2 or 6); dC(75 MHz, CDCl3) 150.6, 137.1 (Ph CH),
134.4 (Ph CH),134.3 (Ph CH),130.05 (CH),118.3 (Ph CH),116.2 (C^N),
114.8 (C^N), 109.25 (CC^N); m/z (EI) 155 (Mþ, 28%), 129 (MþꢁCN,
8), 103 [Mþꢁ2(CN), 100], 102 (26), 76 (C6Hþ4 , 30), 75 (27), 63 (7), 51
(17) and 2-(cyanomethylamino)benzonitrile 5 (16 mg, 38%) as light
yellow needles, mp 95e96 ꢀC (lit.,36 95e96 ꢀC) (from cyclohexane/
EtOH), Rf (hexane/DCM, 2:8) 0.50, identical to an authentic sample.
Further elution (DCM, 100%) gave 3-aminoindole-2-carbonitrile 2a
(1 mg, 3%) as light yellow cotton fibres, mp 172e173 ꢀC (lit.,26
172e173 ꢀC) (from cyclohexane/EtOH), Rf (DCM, 100%) 0.50, identi-
cal toan authentic sample. Furtherelution (DCM/t-BuOMe, 8:2) gave
(2-cyanoindol-3-yl)iminotriphenylphosphorane 6a (51 mg, 45%) as
colourless prisms, mp 183e184 ꢀC (lit.,26 183e183 ꢀC) (from PhH), Rf
(DCM/t-BuOMe, 8:2) 0.50, identical to an authentic sample. Further
elution (DCM/t-BuOMe, 7:3) gave triphenylphosphine oxide
(103 mg, 69%) as colourless needles, mp 154e155 ꢀC (from cyclo-
hexane), Rf (DCM/t-BuOMe, 7:3) 0.50, identical to an authentic
sample.
(indole CH), 119.3 (indole CH), 116.2 (C^N), 111.8 (indole CH), 97.6
(d, JPC 12.8, indole C-2, CC^N); dP(121.5 MHz; DMSO-d6) 6.59; m/z
(EI) 462 (Mþ, 100%), 436 (MþꢁCN, 8), 435 (8), 416 (5), 415 (9), 390
(3), 262 (PPhþ3 , 6), 231 (5), 208 (6), 183 (47), 152 (6), 133 (2), 108 (8).
4.3.4. 3-Amino-5-chloroindole-2-carbonitrile 2d. (37 mg, 72%) light
red powder, mp 190e191 ꢀC (lit.,26 190e191 ꢀC) (from EtOH)
identical to an authentic sample.
4.3.5. 3-Amino-6-chloroindole-2-carbonitrile 2e. (39 mg, 75%) red
powder, mp 210e211 ꢀC (lit.,26 210e211 ꢀC) (from EtOH) identical
to an authentic sample.
4.3.6. 6-Chloro-4-methoxyquinazoline-2-carbonitrile 14e. (12 mg,
23%) as colourless fibres, mp 139e140 ꢀC (from cyclohexane);
(found: C, 54.7; H, 2.8; N, 19.2. C10H6ClN3O requires C, 54.7; H, 2.8;
N, 19.1%); lmax(DCM)/nm 237 (log
3 4.46), 309 inf (3.80), 322 inf
(3.40); vmax/cmꢁ1 3092w (Ar CH), 2963w, 2241w (C^N), 1609w,
1570s, 1553m, 1499s, 1460m, 1499s, 1346w, 1294m, 1221w, 1190m,
1146w, 1130m, 1074m, 988m, 951s, 891m, 835s, 814m, 791m;
dH(300 MHz; CDCl3) 8.14 (1H, d, J 2.1, H-5), 7.93 (1H, d, J 9.0, H-8),
7.85 (1H, dd, J 8.9, 2.3, H-7), 4.23 (3H, br s, CH3O); dC(75 MHz;
CDCl3) one peak missing 166.8, 148.8, 139.7, 135.7 (Ar CH), 129.9 (Ar
CH), 122.9 (Ar CH), 117.5, 115.9, 55.7 (CH3O); m/z (EI) 221 (Mþþ2,
35%), 219 (Mþ, 100), 190 (41), 184 (83), 162 (15), 149 (16), 139 (32),
137 (80), 126 (18), 124 (28), 111 (23), 100 (29), 97 (31), 85 (41), 75
(27), 71 (53), 57 (94).
4.3. Reaction of 2-cyano cyanothioformanilides with
triphenylphosphine and PTSA in MeOH. (Typical procedure)
Table 2
To stirred solution of 2-cyano cyanothioformanilide 3a (50 mg,
0.27 mmol) in MeOH (2 mL) at ca. 20 ꢀC, was added PTSA (46.4 mg,
0.27 mmol) and the mixture was left to stir ca. 20 ꢀC for 5 min. Then
Ph3P (142 mg, 0.54 mmol) was added and the mixture was then
allowed to stir at ca. 20 ꢀC for 50 min, until no starting materials
remained (TLC). The reaction mixture was adsorbed onto silica and
chromatography (hexane/DCM, 5:5) gave triphenylphosphine sul-
fide (114 mg, 72%) as colourless needles, mp 161e162 ꢀC (from cy-
clohexane), Rf (hexane/DCM, 5:5) 0.60, identical to an authentic
sample. Further elution (hexane/DCM, 3:7) gave anthranilonitrile
(2.5 mg, 8%) 8a as yellow prisms, mp 50e51 ꢀC (from cyclohexane/
EtOH), Rf (hexane/DCM, 3:7) 0.60, identical to an authentic sample.
Further elution (DCM, 100%) gave 3-aminoindole-2-carbonitrile 2a
(38 mg, 90%) as light yellow cotton fibres, mp 172e173 ꢀC (lit.,26
172e173 ꢀC) (from cyclohexane/EtOH), Rf (DCM, 100%) 0.50, iden-
tical to an authentic sample. Further elution (DCM/t-BuOMe, 7:3)
gave triphenylphosphine oxide (120 mg, 80%) as colourless needles,
mp 154e155 ꢀC (from cyclohexane), Rf (DCM/t-BuOMe, 7:3) 0.50,
identical to an authentic sample.
4.3.7. 3-Amino-6-methoxyindole-2-carbonitrile 2f. (32 mg, 63%) red
prisms, mp 179e180 ꢀC (lit.,26 179e180 ꢀC) (from cyclohexane/
EtOH) identical to an authentic sample.
4.3.8. 4,6,7-Trimethoxyquinazoline-2-carbonitrile 14g. (9 mg, 19%)
yellow needles, mp 228e229 ꢀC (lit.,6c 238 ꢀC) (from cyclohexane/
EtOH); (found: C, 58.8; H, 4.6; N, 17.1. C12H11N3O3 requires C, 58.8;
H, 4.5; N, 17.1%); lmax(DCM)/nm 248 (log 3 4.65), 263 inf (4.32), 303
inf (4.05), 313 (4.12), 328 (4.05); vmax/cmꢁ1 3011w (Ar CH), 2986w
and 2943w, 2237w (C^N), 1611m, 1578m, 1558w, 1504m, 1481s,
1454w, 1433m, 1420m, 1410m, 1375m, 1315w, 1267s, 1250s, 1223m,
1213m, 1182m, 1167m, 1105m, 1022m, 999s, 947m, 862m, 847m,
789m, 764w; dH(300 MHz; CDCl3) 7.37 (1H, s, H-5 or 8), 7.29 (1H, s,
H-5 or 8), 4.19 (3H, s, CH3O), 4.04 (3H, s, CH3O), 4.03 (3H, s, CH3O);
dC(75 MHz; CDCl3) 165.7, 156.1, 151.7, 147.9, 138.1, 116.5, 111.6, 107.0
(Ar CH), 101.1 (Ar CH), 56.5 (CH3O), 56.4 (CH3O), 55.0 (CH3O); m/z
(EI) 245 (Mþ, 100%), 230 (MþꢁCH3, 21), 216 (23), 202 (7), 174 (6),
159 (6), 145 (6), 131 (6), 97 (8), 77 (9), 67 (17), 57 (12).
4.3.1. 3-Amino-4-methylindole-2-carbonitrile 2b. (35 mg, 75%) yel-
low cotton fibres, mp 156e157 ꢀC (lit.,26 156e157 ꢀC) (from cyclo-
hexane/EtOH) identical to an authentic sample.
4.4. Reaction of 2-(cyanothioformamido)-4,5-
dimethoxybenzonitrile 3f with triphenylphosphine in dry
toluene (see Table 2)
4.3.2. 3-Amino-5-nitroindole-2-carbonitrile 2c. (35.5 mg, 65%) red
cotton fibres, mp 310e311 ꢀC (lit.,26 310e311 ꢀC) (from PhH) iden-
tical to an authentic sample.
To a stirred solution of 2-(cyanothioformamido)-4,5-dime-
thoxybenzonitrile 3f (67 mg, 0.27 mmol) in toluene (2 mL) at ca.
20 ꢀC, was added Ph3P (142 mg, 0.54 mmol) in one portion. The
mixture was then heated to 110 ꢀC for 1 h, until no starting material
remained (TLC) and adsorbed onto silica. Chromatography (hexane/
DCM, 5:5) gave triphenylphosphine sulfide (61 mg, 52%) as col-
ourless needles, mp 161e162 ꢀC (from cyclohexane), Rf (hexane/
DCM, 2:8) 0.60, identical to an authentic sample. Further elution
(DCM, 100%) gave 2-(cyanomethyleneamino)-4,5-dimethoxy-
benzonitrile 4g (10 mg, 23%) as yellow cotton fibres, mp 170e171 ꢀC
(from cyclohexane) (DSC: onset 175.4 ꢀC, peak 177.0 ꢀC), Rf (DCM,
100%) 0.50 (found: C, 61.4; H, 4.2; N, 19.5. C11H9N3O2 requires C,
4.3.3. N-(2-Cyano-5-nitroindol-3-yl)iminotriphenylphosphorane
6c. (21 mg, 21%) red powder, mp>300 ꢀC (from PhH); (found: C,
70.1; H, 4.1; N, 12.2. C27H19N4O2P requires C, 70.1; H, 4.1; N, 12.1%);
lmax(DCM)/nm 231 (log
3 4.31), 294 (4.51), 332 inf (4.07); vmax/
cmꢁ1 3248w (NH), 2210m (C^N), 1612w, 1576m, 1537s, 1468s,
1437m, 1396w, 1329s, 1310s, 1258m, 1180w, 1134w, 1109s, 1070m,
1016m, 997m, 897w, 870w, 854w, 841w, 818m, 756m, 741m, 733m,
719s; dH(300 MHz; CD2Cl2) 8.29 (1H, d, J 2.1, indole H-4), 8.07 (1H,
br s, NH), 8.05 (1H, dd, J 9.2, 2.3, indole H-6), 7.84e7.77 (6H, m, PPh3
H), 7.62e7.57 (3H, m, PPh3 H), 7.54e7.48 (6H, m, PPh3 H), 7.20 (1H,
d, J 9.3, indole H-7); dC(75 MHz; CD2Cl2) 143.5, 141.3, 139.2, 133.0 (d,
JPC 9.8, Ph3P C-3), 132.6 (d, JPC 3.0, Ph3P C-4), 131.0 (d, JPC 101.3, Ph3P
C-1), 129.2 (d, JPC 12.7, Ph3P C-2), 124.7 (d, JPC 12.8, indole C-3), 121.2
61.4; H, 4.2; N, 19.5%); lmax(DCM)/nm 228 (log
3 3.02), 235 (3.21),
261 (3.35), 285 inf (2.88), 363 (3.02); nmax/cmꢁ1 2920w, 2230m
(C^N), 1597m, 1547m, 1537m, 1516s, 1464m, 1368m, 1287s, 1231s,

6038
P.A. Koutentis, S.S. Michaelidou / Tetrahedron 66 (2010) 6032e6039
1198m, 1109s, 1026m, 993s, 908w, 876m, 837m; dH(300 MHz;
DMSO-d6) 8.17 (1H, s, N]CH), 7.51 (1H, s, Ph H), 7.31 (1H, s, Ph H)
3.87 (3H, s, CH3O), 3.86 (3H, s, CH3O); dC(75 MHz; DMSO-d6) 152.9,
150.2, 143.9, 137.4 (Ar CH),116.8,116.0,114.5 (Ar CH),102.2, 101.8 (Ar
CH), 56.4 (CH3O), 56.3 (CH3O); m/z (EI) 215 (Mþ,100%), 200 (72),172
(33), 157 (5), 145 (74), 129 (11), 117 (25), 104 (29), 102 (49), 90 (39),
88 (23), 78 (57), 76 (58), 64 (33), 53 (30). Further elution (DCM/
t-BuOMe, 8:2) gave triphenylphosphine oxide (55 mg, 50%) as
colourless needles, mp 154e155 ꢀC (from cyclohexane), Rf (DCM/
t-BuOMe, 8:2) 0.50, identical to an authentic sample. Further elu-
tion (hexane/EtOH, 7:3) gave (2-cyano-5,6-dimethoxyindol-3-yl)
iminotriphenylphosphorane 6g (30 mg, 31%) as red prisms, mp
157e158 ꢀC (from cyclohexane/EtOH), Rf (hexane/EtOH, 7:3) 0.60;
(found: C, 73.0; H, 5.1; N, 8.8. C29H24N3O2P requires C, 73.0; H, 5.1;
(TLC). The mixture was then extracted with DCM (20 mL). The
combined organic layers were dried (Na2SO4) and filtered to afford
the title compound 16 (18 mg, 91%) as colourless cotton fibres, mp
143e144 ꢀC (lit.,36 143e144 ꢀC) (from cyclohexane/EtOH) identical
to an authentic sample.
4.7. 6,7-Dimethoxyquinazoline-2-carbonitrile 15
To a stirred solution of 2-chloro-6,7-dimethoxyquinazoline 17
(30 mg, 0.134 mmol) in DMSO (2 mL) at ca. 20 ꢀC, were added
DABCO (15 mg, 0.134 mmol) and NaCN (13 mg, 0.268 mmol). The
mixture was left to warm at 80 ꢀC for 10 h until no starting material
remained (TLC). On cooling to rt the mixture was diluted with
water (20 mL) and extracted with DCM (3ꢂ20 mL). The combined
organic layers were dried (Na2SO4), filtered and concentrated in
vacuo to give a pale yellow solid reside. Chromatography (DCM,
100%) gave the title compound 15 (11 mg, 38%) as a colourless
powder, mp 300e301 ꢀC (from EtOH) (DSC: onset 301.3 ꢀC, peak
303.4 ꢀC), Rf (DCM, 100%) 0.60; (found: C, 61.3; H, 4.1; N, 19.5.
C11H9N3O2 requires C, 61.4; H, 4.2; N, 19.5%); lmax(DCM)/nm 230
N, 8.8%); lmax(DCM)/nm 230 (log
3 3.47), 256 (3.22), 318 (3.22),
351.5 inf (2.79); vmax/cmꢁ1 3057w, 3015w, 2926w, 2193m (C^N),
1630w, 1518s, 1477s, 1450w, 1437s, 1329m, 1294s, 1250m, 1227m,
1204w, 1194s, 1173m, 1144m, 1111s, 1016m, 993m, 988m, 932m,
841m, 802m, 750m, 745m, 718s; dH(300 MHz; CD2Cl2) 7.80e7.73
(6H, m, Ph3P H), 7.65 (1H, br s, NH), 7.60e7.54 (3H, m, Ph3P H),
7.50e7.45 (6H, m, Ph3P H), 6.63 (1H, s, indole H-4 or 7), 6.54 (1H, s,
indole H-4 or 7), 3.78 (3H, s, CH3O), 3.45 (3H, s, CH3O); dC(75 MHz;
CD2Cl2) 150.7,145.3,141.5,133.0 (d, JPC 9.8, Ph3P C-3),132.7,132.3 (d,
JPC 3.0, Ph3P C-4), 132.0 (d, JPC 100.5, Ph3P C-1), 129.0 (d, JPC 12.0,
Ph3P C-2), 117.7 (d, JPC 2.3, indole C^N), 117.3 (d, JPC 9.0 indole C-3),
102.3 (indole CH), 95.7 (d, JPC 15.8, indole C-2, CC^N), 94.5 (indole
CH), 56.1 (CH3O), 56.0 (CH3O); dP(121.5 MHz; CD2Cl2) 4.0; m/z (EI)
477 (Mþ, 100%), 462 (4), 435 (8), 292 (6), 265 (17), 262 (8), 239 (7.5),
183 (37), 108 (14), 77 (3).
(log 3 2.96), 255 (3.35), 299 inf (2.44), 324 (2.58), 338 (2.71); vmax/
cmꢁ1 3059w, 2986w, 2955w, 2239w (C^N), 1611m, 1568m, 1560w,
1501s, 1476w, 1445m, 1427s, 1412m, 1389w, 1342m, 1288m, 1256s,
1240m, 1219m, 1167s, 1096w, 1022m, 997s, 951m, 870s, 841m,
789m; dH(300 MHz; DMSO-d6) 9.43 (1H, s, H-4), 7.65 (1H, s, H-5 or
8), 7.53 (1H, s, H-5 or 8), 4.02 (3H, s, CH3O), 3.99 (3H, s, CH3O);
dC(75 MHz; DMSO-d6) 157.9 (C-4), 157.4, 152.5, 147.4, 138.5, 121.7,
117.1 (C^N), 106.2 (Ar C-5 or 8), 105.1 (Ar C-5 or 8), 56.7 (CH3O),
56.4 (CH3O); m/z (EI) 215 (Mþ, 100%), 200 (19), 172 (19), 145 (13),
120 (23), 117 (8), 102 (6), 92 (13), 90 (11), 77 (10), 65 (12).
4.5. 2-(Cyanomethyleneamino)-4,5-dimethoxybenzonitrile
4g via oxidation of 2-(cyanomethylamino)-4,5-
dimethoxybenzonitrile 16
4.8. Reaction of 2-(cyanomethyleneamino)benzonitrile 4a
with Ph3P, PTSA in MeOH
4.5.1. Using NBS. To a stirred solution of NBS (27 mg, 0.20 mmol) in
CCl4 (1 mL) at ca. 55 ꢀC, was added a solution of 2-(cyanomethyl-
amino)-4,5-dimethoxybenzonitrile 16 (36 mg, 0.20 mmol) in CCl4
(1 mL). The mixture was left to stir at ca. 55 ꢀC for 5 min and then
Ca(OH)2 (31 mg, 0.42 mmol) and CaCl2 (11 mg, 0.1 mmol) were
added to the solution. The mixture was left to stir at this temper-
ature for 2 d until no starting material remained (TLC) and the
mixture was then adsorbed onto silica. Chromatography (DCM,
100%) gave 2-(cyanomethyleneamino)-4,5-dimethoxybenzonitrile
4g (14 mg, 32%) as yellow cotton fibres, mp 170e171 ꢀC (from cy-
clohexane), Rf (DCM, 100%) 0.50, identical that described above.
To a stirred solution of 2-(cyanomethyleneamino)benzonitrile
4a (20 mg, 0.13 mmol) and PTSA (24.5 mg, 0.13 mmol) in MeOH
(2 mL) at ca. 20 ꢀC, was added in one portion Ph3P (68 mg,
0.26 mmol). The mixture was left to stir at this temperature for 5 h,
until no starting material remained (TLC) and then adsorbed onto
silica. Chromatography (hexane/DCM, 5:5) gave unreacted Ph3P
(40 mg, 59%) as colourless flakes, mp 80e81 ꢀC (from cyclohexane),
Rf (hexane/DCM, 5:5) 0.70, identical to an authentic sample. Further
elution (hexane/DCM, 2:8) gave anthranilonitrile 8a (2 mg, 13%) as
yellow prisms, identical to an authentic sample. Further elution
(DCM, 100%) gave 3-aminoindole-2-carbonitrile 2a (6 mg, 30%) as
light yellow cotton fibres, mp 172e173 ꢀC (lit.,26 172e173 ꢀC) (from
cyclohexane/EtOH), Rf (DCM, 100%) 0.50, identical to an authentic
sample. Further elution (DCM/t-BuOMe, 9:1) gave N-(2-cyano-
phenyl)formamide 9 (10 mg, 53%) as yellow fibres, mp 121e122 ꢀC
4.5.2. Using calcium hypochlorite. To a stirred solution of 2-(cya-
nomethylamino)-4,5-dimethoxybenzonitrile
16
(36 mg,
0.20 mmol) in DCM (2 mL) was added CaOCl (43 mg, 0.30 mmol)
and CaCl2 (11 mg, 0.10 mmol). The mixture was left to stir at ca.
20 ꢀC for 5 min and then Ca(OH)2 (30 mg, 0.40 mmol) was added to
the solution. The mixture was left to stir at this temperature for 4
d until no starting material remained (TLC) and then adsorbed onto
silica. Chromatography (DCM, 100%) gave 2-(cyanomethylenea-
mino)-4,5-dimethoxybenzonitrile 4g (21.5 mg, 50%) as yellow cot-
ton fibres, mp 170e171 ꢀC (from cyclohexane), Rf (DCM, 100%) 0.50,
identical to that described above.
(lit.,37 125e127 ꢀC) (from Et2O), Rf (DCM/t-BuOMe, 9:1) 0.45; vmax
/
cmꢁ1 3260w (NH), 2220m (C^N), 1711m, 1668s, 1585s, 1537s,
1450s, 1404s, 1358w, 1302s, 1258w, 1165m, 1038w, 947w, 864m;
dH(300 MHz; DMSO-d6) 10.39 (1H, br s, NH), 8.35 (1H, s, CHO), 7.91
(1H, d, J 8.1, Ph H-3 or 6), 7.82 (1H, d, J 7.5, Ph H-3 or 6), 7.69 (1H, dd,
J 7.8, 7.7, Ph H-4 or 5), 7.33 (1H, dd, J 7.8, 7.7, Ph H-4 or 5); m/z (EI)
146 (Mþ, 24%), 118 (100), 91 (50), 64 (19), 57 (13), identical to an
authentic sample. Further elution (DCM/t-BuOMe, 8:2) gave tri-
phenylphosphine oxide (13 mg, 35%) as colourless needles, mp
154e155 ꢀC (from cyclohexane), Rf (DCM/t-BuOMe, 8:2) 0.50,
identical to an authentic sample.
4.6. 2-(Cyanomethylamino)-4,5-dimethoxybenzonitrile 16 via
reduction of 2‑(cyanomethyleneamino)-4,5-
dimethoxybenzonitrile 4g
Acknowledgements
To a stirred solution of 2-(cyanomethyleneamino)-4,5-dime-
thoxybenzonitrile 4g (20 mg, 0.09 mmol) in dry MeOH (2 mL) at ca.
20 ꢀC, was added NaBH4 (4 mg, 0.11 mmol). The mixture was then
left to stir at ca. 20 ꢀC for 10 min until no starting material remained
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

P.A. Koutentis, S.S. Michaelidou / Tetrahedron 66 (2010) 6032e6039
6039
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