One-step synthesis of 4-alkyl-3-aryl-2,6-dicyanoanilines and their use in the synthesis of highly functionalized 2,3,5,6,7- and 2,3,4,5,7-substituted indoles

Article abstract of DOI:10.1016/j.tetlet.2011.08.064

A three-component, one-step method for the synthesis of 4-alkyl-3-aryl-2,6-dicyanoanilines involving reaction of alkyl aldehyde, malononitrile and aryl aldehyde in presence of morpholine is reported. Highly functionalized 2,3,5,6,7- and 2,3,4,5,7-substitu

Full text of DOI:10.1016/j.tetlet.2011.08.064

Tetrahedron Letters 52 (2011) 5491–5493
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One-step synthesis of 4-alkyl-3-aryl-2,6-dicyanoanilines and their use in
the synthesis of highly functionalized 2,3,5,6,7- and 2,3,4,5,7-substituted indoles
Sangmeshwer P. Sawargave, Ananada S. Kudale, Jaydeep V. Deore, Dattatry S. Bhosale, Jaisingh M. Divse,
⇑
Subhash P. Chavan, Hanumant B. Borate
Division of Organic Chemistry, National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 June 2011
Revised 9 August 2011
Accepted 10 August 2011
Available online 2 September 2011
A three-component, one-step method for the synthesis of 4-alkyl-3-aryl-2,6-dicyanoanilines involving
reaction of alkyl aldehyde, malononitrile and aryl aldehyde in presence of morpholine is reported. Highly
functionalized 2,3,5,6,7- and 2,3,4,5,7-substituted indoles were prepared from these dicyanoanilines by
reaction with ethyl bromoacetate. These substituted dicyanoanilines and indoles have a potential to be
converted into various other compounds taking advantage of various functional groups present in these
molecules.
Keywords:
Dicyanoanilines
Indoles
Ó 2011 Elsevier Ltd. All rights reserved.
Aldehydes
Malononitrile
2,6-Dicyanoanilines are useful as important substrates for non-
linear optical materials1 and molecular electronic devices.2 They
are strongly fluorescent3 and have been reported to exhibit biolog-
ical activities like antileishmanial activity.4 The amino and cyano
groups can be converted into various other functional groups,
hence these 2,6-dicyanoanilines can be used as starting materials
for a large number of aromatic compounds. There are a number
of methods reported for the synthesis of substituted 2,6-dicyano-
anilines3,5 and conversion of dicyanoanilines into substituted in-
doles is known in the literature.6 During our efforts to develop
new antifungal agents7, we desired to prepare variously substi-
tuted indoles 1 (Fig. 1) and intended to use the dicyanoanilines 2
as intermediates in order to construct the indole skeleton by a
reaction with ethyl bromoacetate.6 Literature survey revealed that
though there are a large number of methods reported for the
synthesis of substituted 2,6-dicyanoanilines, most of the methods
describe the synthesis of 3,5-disubstituted-2,6-dicyanoanilines 3.
There are a very few reports describing synthesis of 3,4-dialkyl-
2,6-dicyanoanilines 48 and there is only one method8c reported
by Khaidem et al. for the synthesis of 4-alkyl-3-aryl-2,6-dic-
yanoaniline 2 wherein 4-methyl-3-phenyl-2,6-dicyanoaniline was
prepared from propiophenone by a three-step reaction sequence
in low yields. We envisioned that a three-component reaction of
alkyl aldehyde, malononitrile and aryl aldehyde in presence of
base would afford 4-alkyl-3-aryl-2,6-dicyanoaniline 2 and the
results are reported herein. The reaction of propionaldehyde,
R1
NH2
R
R
CN
Alkyl
Alkyl
CN
CN
COOR2
Ar
N
Ar
NH2
R2
NH2
CN R1
NH2
CN
2
CN
4
CN
3
1
Figure 1. General structures of pentasubstituted indoles and 2,6-dicyanoanilines.
malononitrile and 4-methoxybenzaldehyde was attempted as a
model reaction in presence of various bases like potassium carbon-
ate, triethylamine, morpholine, basic alumina etc with or without
⇑
Corresponding author. Tel.: +91 2025902546; fax: +91 202590269.
E-mail address: hb.borate@ncl.res.in (H.B. Borate).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.08.064

5492
S. P. Sawargave et al. / Tetrahedron Letters 52 (2011) 5491–5493
R
R
Ar
Morpholine,
DMF, 80 °C
R
O
O
CN
CN
+
R
+
+
H
NC
CN
NC
CN
Ar
H
NH2
2
NH2
4
Minor
Major
Scheme 1. Preparation of 4-alkyl-3-aryl-2,6-dicyanoanilines.
Table 1
reaction of propionaldehyde and malononitrile. Therefore, propi-
onaldehyde is required in slightly more amount than anisaldehyde.
The reaction was done with various combinations of aryl and
aliphatic aldehydes to see the generality and the various com-
pounds prepared9 are shown in Table 1.
It was observed that dicyanoanilines with a wide variety of sub-
stituents could be prepared by this method. This protocol provides
easy access to a regiospecific synthesis of unsymmetrical, poly-
functional biaryls, which would be difficult to make by conven-
tional methods. It is also noteworthy that the present method
makes use of easily available starting materials, does not use
expensive catalysts/reagents and the conditions are mild.
Synthesis of 4-alkyl-3-aryl-2,6-dicyanoanilines 2
Entry
Ar
R
Product 2
Yielda (%)
1
2
3
4
5
6
7
8
4-Methoxyphenyl
4-Methoxyphenyl
4-Methoxyphenyl
1-Naphthyl
1-Naphthyl
3,4-(Methylenedioxy)phenyl
2-Thienyl
2-Thienyl
2-Furanyl
2-Furanyl
4-Hydroxyphenyl
4-Nitrophenyl
Me
2a
2b
2c
2d
2e
2f
2g
2h
2i
77
64
69
77
52
75
56
70
10
17
53
62
n-Pr
n-Hex
n-Pr
Me
Me
n-Hex
Me
n-Hex
Me
Me
9
10
11
12
2j
2k
2l
Narsaiah et al. have reported6 that reaction of 2,6-dicyanoani-
lines with ethyl bromoacetate in presence of potassium carbonate
and potassium iodide affords substituted indoles. Accordingly,
reaction of the 3-amino-40-methoxy-6-methyl-[1,10-biphenyl]-
2,4-dicarbonitrile (2a) with ethyl bromoacetate was carried out
in presence of bases like potassium carbonate, potassium hydrox-
ide pellets, sodium hydroxide pellets etc in different solvents like
ethyl acetate, acetonitrile, dimethyl formamide etc at various tem-
peratures and it was observed that the reaction11 in presence of
potassium hydroxide pellets in acetonitrile at room temperature
afforded ethyl 3-amino-7-cyano-1-(2-ethoxy-2-oxoethyl)-6-(4-
methoxyphenyl)-5-methyl-1H-indole-2-carboxylate (1a) as major
product in 69% yield and ethyl 3-amino-7-cyano-1-(2-ethoxy-2-
oxoethyl)-4-(4-methoxyphenyl)-5-methyl-1H-indole-2-carboxyl-
ate (5a) as minor product in 12% yield (Scheme 2). The structures
Me
a
The yields given are for the isolated desired products. In addition, the corre-
sponding products 4 were isolated in 8–18% yields.
solvent (dimethylformamide, ethyl acetate, acetonitrile) at various
temperatures ranging from room temperature to 100 °C and it was
observed that the reaction9,10 in presence of morpholine in DMF at
80 °C afforded the desired 3-amino-40-methoxy-6-methyl-[1,10-
biphenyl]-2,4-dicarbonitrile (2a) as major product in 77% isolated
yield and 2,6-dicyano-5-ethyl-4-methyl-aniline (4, R = Me)8d as a
minor product in 8% yield (Scheme 1). These two products were
easily separated by column chromatography. Product 2a is formed
by a three- component reaction involving anisaldehyde, propional-
dehyde and malononitrile while the side product 4 is formed by
R
NH2
COOEt
COOEt
Ar
NH2
R
Ar
R
KOH, acetonitrile,
Br
rt, 2 h
COOEt
COOEt
N
COOEt
Ar
N
NC
CN
CN
NH2
CN
1
5
Major
Minor
2
Scheme 2. Synthesis of 2,3,5,6,7- and 2,3,4,5,7-substituted indoles 1 and 5.
Table 2
Synthesis of 2,3,5,6,7- and 2,3,4,5,7-substituted indoles 1 and 5
Entry
Ar
R
Substituted aniline 2
Product 1
Compd no.
Product 5
Compd no.
Yielda (%)
Yielda (%)
1
2
3
4
5
6
7
8
9
4-Methoxyphenyl
4-Methoxyphenyl
4-Methoxyphenyl
1-Naphthyl
1-Naphthyl
3,4-(Methylenedioxy)phenyl
2-Thienyl
Me
2a
2b
2c
2d
2e
2f
2g
2h
2j
1a
1b
1c
1d
1e
1f
1g
1h
1i
69
65
85
62
61
69
64
77
69
5a
5b
5c
5d
5e
5f
5g
5h
5i
12
15
9
18
13
23
12
11
15
n-Pr
n-Hex
Me
n-Pr
Me
Me
n-Hex
n-Hex
2-Thienyl
2-Furanyl
a
The yields given are for the isolated products.

S. P. Sawargave et al. / Tetrahedron Letters 52 (2011) 5491–5493
5493
of the isomers were assigned based on spectral data11 and litera-
ture precedent.6 The various novel 2,6-dicyanoanilines 2 synthe-
sized above were subjected to the above reaction conditions and
the results are shown in Table 2.
Jiang, H.; Tu, S. Synth. Commun. 2007, 37, 3767–3772; (i) Singh, F. V.; Kumar, V.;
Kumar, B.; Goel, A. Tetrahedron 2007, 63, 10971–10978; (j) Yi, C.; Blum, C.; Liu,
S.-X.; Frei, G.; Neels, A.; Renaud, P.; Leutwyler, S.; Decurtins, S. J. Org. Chem.
2008, 73, 3596–3599; (k) Shaterian, H. R.; Honarmand, M.; Oveisi, A. R.
Monatsh. Chem. 2010, 141, 557–560.
6. Maitraie, D.; Reddy, G. V.; Rao, V. V. V. N. S. R.; Ravikanth, S.; Narsaiah, B.; Rao,
P. S.; Ravikumar, K.; Sridhar, B. Tetrahedron 2005, 61, 3999–4008.
7. Borate, H. B.; Sawargave, S. P.; Maujan, S. R. Tetrahedron Lett. 2009, 50, 6562–
6566.
8. (a) Klaus, K. Ger. Offen. 1975, DE2340569 A1.; (b) Klaus, K. Ger. Offen. 1976,
DE2448911 A1.; (c) Khaidem, I. S.; Singh, S. L.; Singh, L. R.; Khan, M. Z. R. Ind. J.
Chem. 1996, 35B, 911–914; (d) Dyachenko, V. D. Russ. J. Gen. Chem. 2004, 74,
1135–1136.
It is interesting to note that all the substituents on indoles 1
prepared in the present work are different and they can act as
intermediates in the preparation of a large number of substituted
indoles, and compounds derived from indoles, taking advantage
of different reactivities of various groups present in these mole-
cules. The same is true with the compounds 5. In conclusion, the
present manuscript describes a three-component, one-step meth-
od for the synthesis of 4-alkyl-3-aryl-2,6-dicyanoanilines 2 using
easily available starting materials. The dicyanoanilines prepared
above were utilized for the preparation of highly functionalized
2,3,5,6,7- and 2,3,4,5,7-substituted indoles 1 and 5 in one step un-
der mild conditions. The present method has a potential to gener-
ate a large number of new compounds for structure-property
studies in order to explore their utility as new substrates for
non-linear optical materials or molecular electronic devices. Also,
these molecules exhibit strong fluorescence in UV light (except
2l) and may have utility as fluorescent materials. We are using
these molecules as intermediates for the synthesis of new mole-
cules being studied for their antifungal activity and the results will
be published elsewhere.
9. Spectral data for all compounds prepared in the present work are available as
Supplementary data for this Letter.
Representative procedure for preparing 3-aryl-4-alkyl-2,6-dicyanoanilines 2
Preparation of 3-amino-40-methoxy-6-methyl-[1,10-biphenyl]-2,4-dicarbonitrile
(2a): To
a
mixture of propionaldehyde (2.00 g, 34.48 mmol), 4-
methoxybenzaldehyde (3.75 g, 27.58 mmol) and malononitrile (4.55 g,
68.96 mmol) in dry DMF (20 mL) taken in a round bottom flask equipped
with reflux condenser and guard tube, was added morpholine (6.60 g,
75.85 mmol) at 0 °C. The mixture was allowed to come to rt and then stirred
at 80 °C for 12 h. It was then cooled to room temperature, diluted with ice-cold
water (100 mL), extracted with ethyl acetate (3 ꢀ 75 mL), dried over Na2SO4,
concentrated and purified by column chromatography on silica gel using pet
ether–ethyl acetate (3–20% ethyl acetate in pet ether) as eluent to give 3-ethyl-
4-methyl-2,6-dicyanoaniline (4, R = Me)8d as a white solid in initial fractions
(0.255 g, 8%). Further elution afforded pure 3-amino-40-methoxy-6-methyl-
[1,10-biphenyl]-2,4-dicarbonitrile 2a as white solid (5.58 g, 77%), mp: 199 °C. IR
(chloroform):1270, 1477, 1514, 1606, 1644, 2218, 2915, 3247, 3349,
3434 cmꢁ1 1H NMR (200 MHz, CDCl3): d 2.05 (s, 3H), 3.87 (s, 3H), 5.07 (br s,
.
2H), 7.01 (d, J = 8 Hz, 2H), 7.21 (d, J = 10 Hz, 2H), 7.47 (s, 1H). 13C NMR (50 MHz,
DMSO-d6): d 18.8, 55.3, 96.1, 98.0, 114.1 (2C), 116.1, 116.7, 124.7, 129.4, 130.1
(2C), 138.9, 150.5, 151.1, 159.6. MS (ESI) m/z: 262.14 (M-1).
Acknowledgments
10. Part of this work was presented as a poster during the CRSI zonal meeting held
at NCL, Pune during May 13–14, 2011.
11. Representative procedure for preparing 2,3,5,6,7- and 2,3,4,5,7-substituted indoles
S.P.S. thanks CSIR, New Delhi for grant of SRF. We thank DST,
New Delhi and FDC Ltd, Mumbai for partial financial support.
1
and 5 Preparation of ethyl 3-amino-7-cyano-1-(2-ethoxy-2-oxoethyl)-6-(4-
methoxyphenyl)-5-methyl-1H-indole-2-carboxylate (1a) and ethyl 3-amino-7-
cyano-1-(2-ethoxy-2-oxoethyl)-4-(4-methoxyphenyl)-5-methyl-1H-indole-2-
carboxylate (5a): The 3-amino-40-methoxy-6-methyl-[1,10-biphenyl]-2,4-
dicarbonitrile (2a) (263 mg, 1 mmol) and ethyl bromoacetate (0.34 mL,
Supplementary data
3 mmol) were dissolved in acetonitrile (5 mL) in
a 2-necked RB flask
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.08.064.
equipped with guard tube at rt and the pellets of potassium hydroxide
(336 mg, 6 mmol) were added. The reaction mixture was stirred at room
temperature for 2 h. It was then diluted with excess of cold water and
extracted with ethyl acetate (3 ꢀ 10 mL), dried over Na2SO4, concentrated and
purified by column chromatography on silica gel using pet ether-ethyl acetate
(5–7% ethyl acetate in pet ether) as eluent. Ethyl 3-amino-7-cyano-1-(2-
ethoxy-2-oxoethyl)-4-(4-methoxyphenyl)-5-methyl-1H-indole-2-carboxylate
(5a) was obtained as yellow solid (53 mg, 12.15%); mp: 167 °C. IR
(chloroform): 1274, 1330 1515, 1609, 1672, 1751, 2219, 2912, 2982, 3374,
References and notes
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3476 cmꢁ1 1H NMR (200 MHz, CDCl3): d 1.33 (t, J = 6 Hz, 6H), 2.09 (s, 3H), 3.90
.
(s, 3H), 4.23–4.37 (m, 4H), 4.49 (bs, 2H), 5.57 (s, 2H), 7.05 (d, J = 8 Hz, 2H), 7.23
(d, J = 8 Hz, 2H), 7.56 (s, 1H). 13C NMR (50 MHz, CDCl3): d 14.1, 14.2, 46.9, 55.2,
60.1, 61.4, 92.7, 109.5, 114.1 (2C), 118.1, 118.5, 127.0, 129.1, 129.6 (2C), 135.4,
135.9, 137.9, 141.2, 159.5, 162.4, 169.3. MS (ESI) m/z: 458.20 (M+1). Further
elution provided ethyl 3-amino-7-cyano-1-(2-ethoxy-2-oxoethyl)-6-(4-
methoxyphenyl)-5-methyl-1H-indole-2-carboxylate (1a) as yellow solid
(301 mg, 69.2%); mp: 188 °C. IR (chloroform): 1270, 1621 1682, 1733, 2215,
3370, 3476 cmꢁ1 1H NMR (200 MHz, CDCl3): d 1.28 (t, J = 6Hz, 3H), 1.41 (t,
.
J = 6 Hz, 3H), 2.18 (s, 3H), 3.87 (s, 3H), 4.28 (q, J = 8 Hz, 2H), 4.39 (q, J = 6 Hz,
2H), 4.97 (bs, 2H), 5.60 (s, 2H), 7.00 (d, J = 10 Hz, 2H), 7.22 (d, J = 10 Hz, 2H),
7.62 (s, 1H). 13C NMR (50 MHz, CDCl3): d 14.0, 14.3, 20.6, 46.7, 55.1, 60.3, 61.4,
95.0, 110.2, 113.8 (2C), 117.3, 119.5, 124.9, 127.5, 130.2 (2C), 130.4, 136.2 (2C),
147.4, 159.4, 162.4, 169.6. MS (ESI) m/z: 458.14 (M+1). 1H–13C HMBCNMR
spectroscopy supported the assigned structures.