One-step method for the synthesis of aryl olefins from aryl aldehydes and aliphatic aldehydes

Article abstract of DOI:10.1016/j.tetlet.2013.01.008

A conceptually new one-step reaction affording unexpected aryl olefinic product from aromatic aldehyde, aliphatic aldehyde and malononitrile in the presence of acetic acid-ammonium acetate under mild reaction conditions without using any metal catalyst is reported. This novel reaction was used to prepare a number of substituted aryl olefins including new molecules.

Full text of DOI:10.1016/j.tetlet.2013.01.008

Tetrahedron Letters 54 (2013) 1528–1530
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
One-step method for the synthesis of aryl olefins from aryl aldehydes
and aliphatic aldehydes
Hanumant B. Borate a, , Supriya H. Gaikwad b, Ananada S. Kudale a, Subhash P. Chavan a,
⇑
Shrikant G. Pharande a, Vitthal D. Wagh a, Vikram S. Sawant a
a Division of Organic Chemistry, CSIR–National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India
b Center for Material Characterization, CSIR–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:
A conceptually new one-step reaction affording unexpected aryl olefinic product from aromatic aldehyde,
aliphatic aldehyde and malononitrile in the presence of acetic acid-ammonium acetate under mild
reaction conditions without using any metal catalyst is reported. This novel reaction was used to prepare
a number of substituted aryl olefins including new molecules.
Received 21 December 2012
Revised 31 December 2012
Accepted 3 January 2013
Available online 11 January 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Aryl olefin
Aromatic aldehyde
Aliphatic aldehyde
Malononitrile
Dicyanoaniline
We have recently reported1 the synthesis of 4-alkyl-3-aryl-2,6-
dicyanoanilines by a multicomponent reaction of aromatic alde-
hyde, aliphatic aldehyde and malononitrile in the presence of
morpholine. Careful analysis of the reaction mixture obtained
when anisaldehyde was reacted with propionaldehyde and malon-
onitrile in DMF in the presence of morpholine at 80 °C, afforded
3-(4-methoxyphenyl)-4-methyl-2,6-dicyanoaniline (1a) in 77%
yield and 3-ethyl-4-methyl-2,6-dicyanoaniline (2a) in 8% yield
while an olefinic compound, (E)-1-methoxy-4-(prop-1-enyl)ben-
zene (3a), was obtained in 10% yield (Scheme 1).
Literature survey undertaken for writing a review on 2,6-dicy-
anoanilines2 revealed that though there are a number of methods
reported for the synthesis of 2,6-dicyanoanilines, formation of this
type of compounds (3a) during the synthesis of 2,6-dicyanoani-
lines is not reported. Moreover, as per our knowledge, the cross-
condensation of aromatic and aliphatic aldehydes with one-carbon
elimination to afford olefin is not known in the literature. Hence,
the products obtained in reactions of various aliphatic aldehydes
with anisaldehyde and malononitrile in DMF in the presence of
morpholine were analysed and it was observed that in reactions
with anisaldehyde, the corresponding 4-alkyl-3-(4-methoxy-
phenyl)-2,6-dicyanoanilines 1 were obtained as major products
while 3,4-dialkyl-2,6-dicyanoanilines 2 and trans-aryl olefins 3
were obtained as minor products.
Substituted styrenes are known to exhibit biological activities
like hypolipidemic activity3 and antiplatelet activity3c and there
are a number of methods reported to synthesize these compounds
which mainly include Wittig reaction,4 Grignard reaction followed
by dehydration,5 Suzuki cross-coupling,6 isomerization of allyl
benzenes,7 modified Julia olefination,8 Suzuki–Miyaura cross cou-
pling,9 coupling of alkenyl alkyl ethers with aryl Grignard reagent10
etc. Though these methods have their own advantages, some of
these methods require bases like phenyllithium, catalysts which
are either expensive or not easily available, preparation of interme-
diates like Grignard reagent or Wittig salts, less easily available
starting materials like alkenyl- or arylboronic acids or 4-nitro-
phenyl sulfones etc. and some of the methods require multistep
synthesis of starting materials. The present work involves the reac-
tion of easily available aldehydes as such to obtain the substituted
olefins 3 in one step without any need of special catalyst so the ef-
forts were made to increase the yield of olefins 3 and the results
are reported herein.
Initially, morpholine was replaced with piperidine, triethyl-
amine, sodium methoxide, potassium hydroxide, pyrrolidine etc.
and DMF was replaced with ethanol, methanol, dioxane, acetoni-
trile, dimethyl sulfoxide, polyethylene glycol etc. but the yields
could not be increased. Further attempts to carry out the reaction
in the presence of various acids or combination of acids–bases
were continued as there are reports11 that the reactions of Knoeve-
nagel condensation products yield different products under differ-
ent conditions. To our delight, it was found that the reaction of
⇑
Corresponding author. Tel.: +91 2025902546; fax: +91 2025902629.
E-mail address: hb.borate@ncl.res.in (H.B. Borate).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.01.008

H. B. Borate et al. / Tetrahedron Letters 54 (2013) 1528–1530
1529
The generality of the reaction was checked13 by the reaction of
various aromatic and aliphatic aldehydes (Table 1). The unoptim-
ized isolated yields obtained in case of some of the aldehydes were
in the range of 40–60% and the corresponding Knoevenagel prod-
ucts and dicyanoanilines were obtained as minor products with
simultaneous formation of unidentified polymeric product.
Me
OMe
MeO
Morpholine,
Me
OMe
CHO
Et
CHO
Me
CN
CN
DMF, 80oC
+
+
+
+
NC
CN
NC
CN
NH2
2a
NH2
1a
3a Me
8%
10%
77%
The desired products can be separated from other side products
very easily by column chromatography as the desired products
elute out in the first few fractions. Though the isolated yields are
lower in some cases, the products are obtained in one step and
reaction conditions are very mild and special catalysts are not
required. A wide variety of olefins can be prepared using this con-
ceptually new reaction. It was observed that the polymeric product
was not formed in the blank reaction run under identical condi-
tions without addition of aldehydes. It was also found out that
the reaction conditions can tolerate different functional groups
and various olefins can be prepared from the corresponding ali-
phatic and aromatic aldehydes (Table 1). The geometry of double
bond formed was assigned based on coupling constants in 1H
NMR spectra (copies given in the Supplementary data) and com-
parison with reported data (References given in Table 1). It is also
worth-mentioning that the products obtained were trans olefins
and the amounts of the cis isomers were negligible to be detected
by 1H NMR spectroscopy. The reaction does not take place in the
absence of malononitrile. The corresponding Knoevenagel products
are the intermediates which are formed within a few minutes after
addition of all reactants. The reaction takes place even in the ab-
sence of solvent by stirring the mixture of all reactants at 80 °C
but the corresponding Knoevenagel product is obtained in substan-
tial amounts and the reaction carried out in solvent is preferred. In
the absence of ammonium acetate, only the corresponding
Scheme 1. Reaction of anisaldehyde with propionaldehyde and malononitrile.
Malononitrile,
AcOH, NH4OAc,
MeCN, 80oC
C4H9
OMe
OMe
CHO
Ar
MeO
OMe
+
NC
Ar
MeO
OMe
+
CHO
C4H9
+
CN
NC
CN
NH2
1b
10%
Ar=3,4,5-trimethoxyphenyl
15%
C4H9
3b
60%
Scheme 2. Preparation of olefin 3b from 3,4,5-trimethoxybenzaldehyde and
hexanal.
3,4,5-trimethoxybenzaldehyde with hexanal and malononitrile
carried out in the presence of acetic acid-ammonium acetate in
acetonitrile afforded the desired olefin 3b as the major product
in 60% yield (Scheme 2). It is worth-mentioning that the reported
procedure for this olefin12 involved preparation of cyclic phospho-
nium salt (for getting trans selectivity) by a 5-step sequence
followed by its Wittig reaction with 3,4,5-trimethoxybenzaldehyde
to afford 3b with trans/cis selectivity as 80:20. It was therefore felt
worthwhile to explore this reaction further.
Table 1
Synthesis of olefins 3
Entry
1
Aromatic aldehyde
Aliphatic aldehyde
CH3(CH2)4CHO
Product 3 (Refs.)b
Yielda
H3CO
H3CO
n-C4H9
A: 60
B: 57
C: 58
H3CO
H3CO
CHO
H3CO
3b (12)
n-C10H21
H3CO
3c
2
3
3,4,5-Trimethoxybenzaldehyde
CH3(CH2)10CHO
CH3CH2CHO
A: 51
A: 49
Ar
Ar=3,4,5-trimethoxyphenyl
CH3
3a
H3CO
H3CO
CHO
CHO
(7b)
H3CO
n-C4H9
4
5
6
CH3(CH2)4CHO
CH3CH2CHO
A: 46
A: 51
A: 39
H3CO
Ar
3d
(14)
3e
Ar =1-naphthyl
1-Naphthaldehyde
CH3
n-C10H21
CH3(CH2)10CHO
3f (15)
CHO
S
S
n-C4H9
(16)
A: 37
B: 48
CHO
CHO
O2N
7
CH3(CH2)4CHO
CH3(CH2)10CHO
CH3(CH2)4CHO
CH3CH2CHO
O2N
3g
n-C10H21
3h
O2N
NC
8
A: 52
A: 56
A: 39
O2N
NC
n-C4H9
CHO
9
3i (17)
CH3
3j
10
CHO
CHO
O
O
(18)
CH3
O
11
12
CH3CH2CHO
CH3CH2CHO
O
A: 38
A: 42
3k
3l
CH3
CHO
PMBO
Cl
PMBO
Cl
n-C5H11
CHO
13
CH3(CH2)5CHO
A: 21
3m
Cl
Cl
a
Acid-base used: A—Acetic acid, ammonium acetate; B—Alanine, ammonium acetate; C—Proline, ammonium acetate. The yields given are unoptimized yields for the
isolated desired products. In addition, the corresponding Knoevenagel products and dicyanoanilines were isolated in minor amounts in varying yields.
b
The numbers in parentheses indicate the literature reference numbers for the corresponding products used for comparison of spectral data.

1530
H. B. Borate et al. / Tetrahedron Letters 54 (2013) 1528–1530
2. Borate, H. B.; Kudale, A. S.; Agalave, S. G. Org. Prep. Proced. Int. 2012, 44, 467–
Ar
H
O
O
CN
CN
+
+
Acid or base
Acid or base
521.
R
Ar
H
3. (a) Chamorro, G.; Garduño, L.; Sánchez, A.; Labarrios, F.; Salazar, M.; Martínez,
E.; Diaz, F.; Tamariz, J. Drug Dev. Res. 1998, 43, 105–108; (b) Labarrios, F.;
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Chamorro, G.; Tamariz, J. J. Pharm. Pharmacol. 1999, 51, 1–7; (c) Popławski, J.;
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4. (a) Tuntiwachwuttikul, P.; Pancharoen, O.; Jaipetch, T.; Reutrakul, V.
Phytochemistry 1981, 20, 1164–1165; (b) Mangold, B. L. K.; Hanna, P. E. J.
Med. Chem. 1982, 25, 630–638.
NC
R
CN
Ar
H
H
Base
+
NC
CN
NC
CN
CN
CN
H
I
II
R
H
NC
CN
Ar
R
Ar
R
NC
NC
Ar
NC
CN
R
CN
NC
3
CN
CN
5. (a) Sharma, A.; Joshi, B. P.; Sinha, A. K. Bull. Chem. Soc. Jpn. 2004, 77, 2231–2235;
(b) Kumar, R.; Sharma, A.; Sharma, N.; Kumar, V.; Sinha, A. K. Eur. J. Org. Chem.
2008, 5577–5582.
III
IV
6. Peyroux, E.; Berthiol, F.; Doucet, H.; Santelli, M. Eur. J. Org. Chem. 2004, 1075–
1082.
Scheme 3. The proposed mechanism for formation of olefin 3.
7. (a) Shulgin, A. T. Can. J. Chem. 1965, 43, 3437–3440; (b) Mayer, M.; Welther, A.;
von Wangelin, A. J. ChemCatChem 2011, 3, 1567–1571.
8. Mirk, D.; Grassot, J.-M.; Zhu, J. Synlett 2006, 1255–1259.
9. Zhang, H.-P.; Dai, Y.-Z.; Zhou, X.; Yu, H. Synlett 2012, 1221–1224.
10. Xie, L.-G.; Wang, Z.-X. Chem. Eur. J. 2011, 17, 4972–4975.
11. (a) Green, B.; Khaidem, I. S.; Crane, R. I.; Newaz, S. S. Tetrahedron 1976, 32,
2997–3001; (b) Khaidem, I. S.; Singh, S. L.; Singh, L. R.; Khan, M. Z. R. Indian J.
Chem. 1996, 35B, 911–914; (c) Helmy, N. M.; El-Baih, F. E. M.; Al-Alshaikh, M.
A.; Moustafa, M. S. Molecules 2011, 16, 298–306.
Knoevenagel product is formed and the olefinic product is not ob-
tained. Ammonium acetate can be replaced with ammonium
formate while acetic acid can be replaced with proline or alanine
affording similar yields. Although the exact mechanism has not
been ascertained, the proposed plausible mechanism for the pres-
ent reaction is depicted in Scheme 3.
In conclusion, the present manuscript reports preliminary
results19 about a conceptually new method for the synthesis of
various aryl olefins using easily available starting materials. The
products obtained can be studied for various biological activities
as aryl olefins are known to exhibit hypolipidemic activity3 and
antiplatelet activity3c or they can be used as intermediates for
the synthesis of new molecules taking advantage of various func-
tional groups as depicted in Table 1. Due to the easy availability
of starting materials and potential to prepare aryl olefins with a
variety of substituents, this method would be useful in organic
synthesis as well as medicinal chemistry.
12. Lawrence, N. J.; Beynek, H. Synlett 1998, 497–498.
13. Spectral data for all olefins prepared by this method are given in the
Supplementary data.
Preparation of (E)-5-(hex-1-en-1-yl)-1,2,3-trimethoxybenzene: To a mixture of
3,4,5-trimethoxybenzaldehyde (0.784 g, 0.004 mol), hexanal (0.5 g, 0.005 mol)
and malononitrile (0.66 g, 0.01 mol), was added 30 ml of acetonitrile followed
by the addition of glacial acetic acid (0.42 ml 0.0075 mol). The reaction mixture
was stirred for 10 min and then ammonium acetate (0.385 g, 0.005 mol) was
added. The reaction was stirred at 80 °C for 8 h. The mixture was then allowed
to come to room temperature, filtered through Whatmann filter paper and the
filtrate was concentrated on rotavapor. The residual oil was then partitioned
between water and ethyl acetate and the organic extract was dried over
sodium sulfate, concentrated and purified over silica gel using ethyl acetate-
pet ether (3% ethyl acetate in pet ether) as an eluent to give (E)-5-(hex-1-en-1-
yl)-1,2,3-trimethoxybenzene as
a
colourless liquid (0.6 g, 60%); IR
(chloroform): 810, 925, 1377, 1506, 1582, 1651, 2929, 2989 cmÀ1
.
1H NMR
Acknowledgment
(200 MHz, CDCl3): d 0.93 (t, J = 7 Hz, 3H), 1.30–1.56 (m, 4H), 2.27 (q, J = 7 Hz,
2H), 3.84 (s, 3H), 3.88 (s, 6H), 6.14 (dt, J = 16, 7 Hz, 1H), 6.32 (d, J = 16 Hz, 1H),
6.58 (s, 2H); 13C NMR (50 MHz, CDCl3): d 13.7, 22.0, 31.3, 32.4, 55.7 (2C), 60.6,
102.6 (2C), 129.4, 130.5, 133.5, 136.9, 153.0 (2C); HRMS (ESI) m/z calcd for
[C15H22O3 + Na]+: 273.1461, found 273.1462; [C15H22O3 + H]+: 251.1642, found
251.1642.
We thank DST, New Delhi and FDC Ltd, Mumbai for partial
financial support.
14. Han, L.-B.; Kambe, N.; Ogawa, A.; Ryu, I.; Sonoda, N. Organometallics 1993, 12,
473–477.
Supplementary data
15. Hodgson, D. M.; Fleming, M. J.; Stanway, S. J. J. Org. Chem. 2007, 72, 4763–4773.
16. Hadebe, S. W.; Sithebe, S.; Robinson, R. S. Tetrahedron 2011, 67, 4277–4282.
17. Negishi, E.; Takahashi, T.; Baba, S.; Van Horn, D. E.; Okukado, N. J. Am. Chem.
Soc. 1987, 109, 2393–2401.
18. Bauld, N. L.; Yang, J. J. Phys. Org. Chem. 2000, 13, 518–522.
19. Provisional Indian patent filed; Provisional Filing Number: 3486/DEL/2012 dt
Nov 9, 2012.
Supplementary data (experimental procedures and spectral
data) associated with this article can be found, in the online ver-
sion, at http://dx.doi.org/10.1016/j.tetlet.2013.01.008.
References and notes
1. Sawargave, S. P.; Kudale, A. S.; Deore, J. V.; Bhosale, D. S.; Divse, J. M.; Chavan, S.
P.; Borate, H. B. Tetrahedron Lett. 2011, 52, 5491–5493.