A simple method for the synthesis of functionalised chromenes via vinylogous Michael addition of α, α-dicyanoalkenes on iminocoumarin derivatives

Article abstract of DOI:10.1055/s-0030-1259509

A one-pot synthesis of 2-amino-4H-chromenes was achieved in good yields from three-component reaction of salicylaldehyde, malononitrile, and α, α-dicyanoalkenes catalysed by triethylamine. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1259509

LETTER
341
A Simple Method for the Synthesis of Functionalised Chromenes via Vinylo-
gous Michael Addition of a,a-Dicyanoalkenes on Iminocoumarin Derivatives
S
ynthesis of Fu
h
nctionalise
d
eChromeneslagathoti Hari Babu, Paramasivan T. Perumal*
Organic Chemistry Division, Central Leather Research Institute (a CSIR Laboratory), Adyar, Chennai 600 020, India
Fax +91(44)24911589; E-mail: ptperumal@gmail.com
Received 30 November 2010
ence of hazardous organic bases like piperidine in organic
Abstract: A one-pot synthesis of 2-amino-4H-chromenes was
achieved in good yields from three-component reaction of salicyl-
aldehyde, malononitrile, and a,a-dicyanoalkenes catalysed by tri-
ethylamine.
solvents, ethanol, and acetonitrile for several hours.9 A lit-
erature survey revealed several modified procedures using
CTACl,10 TEBA,11 g-alumina,12 and K2CO3 in water un-
der microwave irradiation for the synthesis of
chromenes.13 Moreover, enantioselective synthesis of 2-
aminochromenes were also documented in the literature.14
Key words: 2-amino-4H-chromenes, vinylogous Michael addition,
a,a-dicyanoalkenes, multicomponent reactions
As part of our ongoing research on the reactivity of a,a-
dicyanoalkenes15 and the synthesis of 2-amino chromenes
via three-components reaction of salicylaldehyde and ma-
lononitrile with various reagents such as indole, Hantzsch
dihydropyridine,16 indium,17 and triethyl phosphite,18 we
herein wish to report our investigation of a new multicom-
ponent reaction involving salicylaldehyde, malononitrile,
and a,a-dicyanoalkenes. To the best of our knowledge,
this is the first report on a,a-dicyanoalkenes employed as
Michael donors on iminocoumarins to synthesise func-
tionalised chromenes.
The development of novel C–C bond-construction meth-
ods is very important in synthetic organic chemistry. Over
the past century, great advances have been made by em-
ploying nucleophilic carbanions from the deprotonation
of an acidic C–H adjacent to one or more functional
groups.1 Nevertheless, the discovery of new synthons and
synthetic strategies is still essential for the continuing ex-
pansion of synthetic protocols.
a,a-Dicyanoalkenes are materials which are readily avail-
able by the condensation of the corresponding carbonyl
compounds and malononitrile. They were prepared more
than a hundred years ago,2 and inherently act as electron-
deficient electrophiles.3 The self-dimerisation of some
a,a-dicyanoalkenes via intermolecular vinylogous addi-
tion and ring-closing processes by base catalysis has also
been documented.4 However, their potential as successful
vinylogous donors in synthetic chemistry was not recogn-
ised until the independent publications by Jørgensen,
Deng and Chen et al. in 2005.5 In this letter we describe
a,a-dicyanoalkenes as vinylogous donors in 1,4-addition
reaction on iminocoumarin derivatives, thereby identify-
ing a,a-dicyanoalkenes as very versatile synthons for the
construction of multifunctional chromenes.
The reactions were carried out by first mixing salicylalde-
hyde, malononitrile, and vinyl malononitrile (Figure 1) in
ethanol in the presence of triethylamine (Scheme 1). All
the reactions proceeded smoothly at room temperature to
completion within 60 minutes and afforded the corre-
sponding 2-amino-4H-chromenes in good yields. Out of
all bases tested, including triethylamine, potassium car-
bonate, L-proline, urea, and sodium ethoxide, triethyl-
amine was found to be the best catalyst (Table 1). Table 2
summarises our results on the one-pot reaction of various
salicylaldehydes and malononitrile with a,a-dicyanoal-
kene derivatives (Scheme 2). Different salicylaldehydes
either bearing electron-withdrawing groups (such as ha-
lide) or electron-donating groups (such as alkoxy group)
gave expected products in good to high yields under the
same reaction conditions.
2-Aminochromenes are widely employed as pigments,
cosmetics, agrochemicals and represent an important
class of chemical entities being the major constituents of
several natural products.6 Fused chromenes exhibit a wide
spectrum of biological applications as antimicrobial, anti-
viral,7 mutagenicity, antiproliferative, sex pheromone, an-
titumor,8 and central nervous system agents. Due to the
unique pharmacological properties of 2-aminochromenes,
the development of synthetic methods enabling facile ac-
cess to this heterocycle, is desirable.
The structures of compounds 4a–m were characterised by
IR, 1H NMR, and 13C NMR spectroscopy.19 The IR spec-
trum of 4a showed absorptions at 3384, 3326, 2183 cm–1
indicating the presence of NH2 and CN groups, respec-
tively. In the 1H NMR spectroscopy, the benzylic proton
resonated at d = 3.56 ppm with coupling constant 5.35 Hz
and the two diastereotopic methylene protons were ob-
served at d = 3.18 and 3.31 ppm as two doublets of dou-
blets with J1 and J2 values of 7.65, 5.35, 5.35, 8.4 Hz,
respectively. The NH2 protons resonated as sharp singlet
at d = 7.09 ppm which is exchangeable with D2O and in
the 13C NMR spectrum, C-2 resonated at d = 162.7 ppm.
The structure of 4m was additionally confirmed by X-ray
diffraction analysis.20
2-Aminochromenes are generally prepared by refluxing
malononitrile, aldehyde, and activated phenol in the pres-
SYNLETT 2011, No. 3, pp 0341–0344
x
x.
x
x.
2
0
1
1
Advanced online publication: 25.01.2011
DOI: 10.1055/s-0030-1259509; Art ID: G34310ST
© Georg Thieme Verlag Stuttgart · New York

342
T. H. Babu, P. T. Perumal
LETTER
NC
CN
Table 2 Synthesis of 2-Amino-4H-chromenes
NC
CN
NC
CN
NC CN
Entry
Salicylaldehyde Vinyl
Product Time
Yield
(%)a
n
malononitrile
(min)
R1
H
R2
H
3a
3b
3c
3d
1
2
3a
3a
3a
3b
3b
3c
3c
3d
3e
3e
3e
3f
4a
4b
4c
4d
4e
4f
35
50
45
40
38
30
34
55
30
36
40
50
37
78
H
OEt
H
75
NC
CN
NC
CN
NC
CN
3
Br
H
80
4
H
70
5
Br
H
H
74
3e
3f
3g
6
H
80
Figure 1 Structure of vinyl malononitriles
7
Br
H
H
4g
4h
4i
77
NC
CN
8
H
65
9
H
H
88b
85b
80b
75b
85b
Ph
CHO
OH
NC
Ph
CN
Et3N, r.t.
EtOH
+
+
CN
NC CN
10
11
12
13
Br
Br
H
H
4j
Br
H
4k
4l
O
NH2
Scheme 1
Table 1 Screening of Catalysts
H
H
3g
4m
a Isolated yield.
b Obtained as racemic mixture.
Entry
Base
Time (min)
Yield (%)
1
2
3
4
5
K2CO3
NaOEt
NH2CONH2
L-proline
Et3N
60
55
90
60
35
60
65
25
75
78
py. This method offers several advantages like milder re-
action conditions, shorter reaction time, high yield, and
simple experimental and isolation procedures making it
an efficient route to the synthesis of 2-amino-4H-
chromenes. Encouraged by these results, we extended the
protocol replacing salicylaldehyde by 2-hydroxynaphtha-
lene-1-carboxaldehyde (5) in order to synthesise fused
chromene 6 under the same optimised conditions in 70%
yield (Scheme 3).
The chromenes 4a–h were purified by column chroma-
tography, whereas the chromens 4i–m were isolated by
simple filtration as inseparable mixture of diastereomers
with a 50:50 ratio as determined by 1H NMR spectrosco-
We propose the plausible mechanism to account for the
formation of 4a–m. The process represents a typical cas-
R4
CN
R3
NC
CN
CN
R1
CHO
OH
R1
Et3N, r.t.
EtOH
CN
+
+
NC
CN
R3
R4
NH2
O
R2
R2
1
2
3a–g
4a–m
Scheme 2
NC
CN
CHO
OH
NC
CN
CN
Et3N, r.t
EtOH
+
CN CN
+
O
NH2
5
2
3c
6
Scheme 3
Synlett 2011, No. 3, 341–344 © Thieme Stuttgart · New York

LETTER
Synthesis of Functionalised Chromenes
343
R1
CHO
OH
CN
CN
+
R2
2
1
Et3N, EtOH
r.t.
N
CN
NC
CN
–
NC
CN
R3
R3
Et3N
–
R1
CN
R4
R3
R4
R4
3a–g
O
NH
R2
R4
CN
CN
R3
R1
CN
O
NH2
R2
4a–m
Scheme 4 Plausible mechanism
(4) Weir, M. R. S.; Hyne, J. B. Can. J. Chem. 1964, 42, 1440.
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1395.
cade reaction in which salicylaldehyde first condenses
with malononitrile to form the Knoevenagel product21 fol-
lowed by cyclisation as a result of nucleophilic attack of
the hydroxy group on the cyano group to form imino cou-
marin. The second step involves regioselective nucleo-
philic attack of vinyl malononitrile to produce 2-amino-
4H-chromenes 4a–m (Scheme 4).
In summary, we have demonstrated a new, one-pot, three-
component reaction that offers a simple method for the
synthesis of new 2-amino-4H-chromenes from salicylal-
dehyde, malononitrile, and a,a-dicyanoalkenes catalysed
by triethylamine. Investigation of the reaction using chiral
bases is under investigation.
(11) Shi, D. Q.; Zhang, S.; Zhuang, Q. Y.; Tu, S. J.; Hu, H. W.
Youji Huaxue 2003, 23, 809.
(12) Maggi, R.; Ballini, R.; Sartori, G.; Sartorio, R. Tetrahedron
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Lett. 2004, 45, 2297.
(13) Kidwai, M.; Saxena, S.; Khan, M. K. R.; Thukral, S. S.
Bioorg. Med. Chem. Lett. 2005, 15, 4295.
(14) (a) Gogoi, S.; Zhao, C. G. Tetrahedron Lett. 2009, 50, 2252.
(b) Ding, D.; Zhao, C. G. Tetrahedron Lett. 2010, 51, 1322.
(c) Wang, X. S.; Yang, G. S.; Zhao, G. Tetrahedron:
Asymmetry 2008, 19, 709. (d) Dong, Z. H.; Liu, X. H.; Feng,
J. H.; Wang, M.; Lin, L. L.; Feng, X. M. Eur. J. Org. Chem.
2011, 137.
(15) (a) Babu, T. H.; Joseph, A. A.; Muralidharan, D.; Perumal,
P. T. Tetrahedron Lett. 2010, 51, 994. (b) Babu, T. H.;
Karthik, K.; Perumal, P. T. Synlett 2010, 1128. (c) Babu,
T. H.; Pawar, S.; Muralidharan, D.; Perumal, P. T. Synlett
2010, 2125.
Acknowledgment
The authors thank the Council of Scientific and Industrial Research,
New Delhi, India for the financial assistance.
References and Notes
(1) Advanced Organic Chemistry, 4th ed.; Carey, F. A.;
Sundberg, R. J., Eds.; Kluwer: New York, 2000, 57.
(2) Hueck, W. Chem. Ber. 1895, 28, 2251.
(3) For selected examples, see: (a) Kojima, S.; Suzuki, M.;
Watanabe, A.; Ohkata, K. Tetrahedron Lett. 2006, 47, 9061.
(b) Fernández, I.; Araújo, C. S.; Romero, M. J.; Alcudia, F.;
Khiar, N. Tetrahedron 2000, 56, 3749. (c) Marco, J. L.
J. Org. Chem. 1997, 62, 6575. (d) Yue, L.; Du, W.; Liu,
Y.-K.; Chen, Y.-C. Tetrahedron Lett. 2008, 49, 3881.
(16) Shanthi, G.; Perumal, P. T. Tetrahedron Lett. 2007, 48,
6785.
(17) Shanthi, G.; Perumal, P. T. Synlett 2008, 2791.
(18) Jayashree, P.; Shanthi, G.; Perumal, P. T. Synlett 2009, 917.
Synlett 2011, No. 3, 341–344 © Thieme Stuttgart · New York

344
T. H. Babu, P. T. Perumal
LETTER
(19) General Procedure for the Synthesis of 2-Amino
Chromenes 4a–h from Salicylaldehyde, Malononitrile,
and a,a-Dicyanoalkenes 3a–h – Representative
Procedure for 2-Amino-4-(3,3-dicyano-2-phenylallyl)-
4H-chromene-3-carbonitrile (4a)
1]. Anal. Calcd (%) for C21H14N4O: C, 74.54; H, 4.17; N,
16.56. Found: C, 75.97; H, 4.11; N, 15.71.
Spectral Data of 3-Amino-1-[2-(dicyanomethylene)-4-
methylpentyl]-1H-benzo[f]chromene-2-carbonitrile (6)
Pale brown solid; yield 70%. 1H NMR (500 MHz, CDCl3):
d = 0.86 (d, J = 6.1 Hz, 3 H), 1.01 (d, J = 6.15 Hz, 3 H), 1.91
(m, 1 H), 2.42 (dd, J1 = 8.4 Hz, J2 = 4.6 Hz, 1 H) 2.59 (dd,
J1 = 6.85 Hz, J2 = 6.15 Hz, 1 H), 2.85 (dd, J1 = 9.2 Hz,
J2 = 3.8 Hz, 1 H), 3.00 (dd, J1 = 3.8 Hz, J2 = 8.45 Hz, 1 H),
4.55 (dd, J1 = 4.6 Hz, J2 = 4.6 Hz, 1 H), 5.00 (s, 2 H, D2O
exchangeable), 7.20 (d, J = 9.15 Hz, 1 H), 7.52 (t, J = 6.9
Hz, 1 H), 7.64 (t, J = 7.65 Hz, 1 H), 7.85 (m, 3 H). 13C NMR
(125 MHz, CDCl3): d = 22.2, 22.8, 29.2, 32.6, 43.2, 45.1,
56.5, 89.5, 111.7, 112.0, 115.1, 116.9, 119.6, 121.5, 125.7,
128.0, 129.3, 129.7, 130.0, 131.5, 147.7, 161.9, 180.1. IR
(KBr): nmax = 3434, 3327, 2959, 2183, 1643 cm–1. ESI-MS:
369 [M + 1]. Anal. Calcd (%) for C23H20N4O: C, 74.98; H,
5.47; N, 15.21%. Found: C, 74.87; H, 5.11; N, 15.11.
(20) Crystallographic data for compound 4m in this paper have
been deposited with the Cambridge Crystallographic Data
Centre as supplemental publication No. CCDC-796193.
Copies of the data can be obtained, free of charge on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK [fax: +44 (1223)336033 or email:
To a stirred mixture of salicylaldehyde (1 mmol) and
malononitrile (1 mmol) in EtOH, vinyl malononitrile 3a (1.5
mmol), and Et3N (0.5 mmol) were added. The reaction
mixture was stirred at r.t. for the appropriate time (Table 2).
After complete conversion as indicated by TLC, the mixture
was concentrated under vacuo and subjected to
chromatographic purification over silica gel (Merck; 100–
200 mesh; EtOAc–hexane, 3:7) to obtain chromene 4a
(78%).
Spectral Data of 2-Amino-4-(3,3-dicyano-2-phenylallyl)-
4H-chromene-3-carbonitrile (4a, Table 2, Entry 1)
Pale pink solid; yield 78%. 1H NMR (500 MHz, DMSO-d6):
d = 3.18 (dd, J1 = 7.65 Hz, J2 = 5.35 Hz, 1 H), 3.31 (dd,
J1 = 5.35 Hz, J2 = 8.4 Hz, 1H), 3.56 (t, J = 5.35 Hz, 1 H),
6.93 (d, J = 7.6 Hz, 1 H), 7.09 (s, 2 H, D2O exchangeable),
7.13 (t, J = 6.1 Hz, 4 H), 7.28 (t, J = 8.4 Hz, 1 H) 7.53 (m, 3
H) 7.65 (d, J = 7.6 Hz, 1 H). 13C NMR (125 MHz, DMSO-
d6): d = 35.6, 48.1, 52.7, 86.1, 113.2, 113.7, 116.5, 121.0,
122.8, 125.2, 128.8, 128.9, 128.9, 129.2, 129.4, 129.4,
132.6, 134.5, 149.6, 162.7, 177.0. IR (KBr): nmax = 3384,
3326, 2183, 1653, 1423, 1050, 757 cm–1. ESI-MS: 339 [M +
deposit@ccdc.cam.ac.uk].
(21) Bhuyan, P. J.; Deb, M. L. Tetrahedron Lett. 2005, 46, 6453.
Synlett 2011, No. 3, 341–344 © Thieme Stuttgart · New York

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