Multi-component reaction between cyclohexyl isocyanide, cyanoacetic acid and aldehyde: Synthesis of methyl 2-cyano-3-(aryl)-cyclohexylcarbamoyl-(aryl)- acrylate

Article abstract of DOI:10.3184/030823410X12828274077263

An improved multi-component reaction of cyclohexyl isocyanide is described. The reaction between two equivalents of an aldehydes, cyclohexyl isocyanide and cyanoacetic acid at room temperature leads to methyl 2-cyano-3-(aryl)- cyclohexylcarbamoyl-(aryl)-a

Full text of DOI:10.3184/030823410X12828274077263

506 RESEARCH PAPER
SEPTEMBER, 506–507
JOURNAL OF CHEMICAL RESEARCH 2010
Multi-component reaction between cyclohexyl isocyanide,
cyanoacetic acid and aldehyde: synthesis of methyl
2-cyano-3-(aryl)-cyclohexylcarbamoyl-(aryl)-acrylate
Mohammad Anary-Abbasinejada, Alireza Hassanabadib* and Mahdiye Foroughi Kaldarehc
aYoung Researchers Club, Islamic Azad University, Anar Branch, Anar, Iran
bDepartment of Chemistry, Islamic Azad University, Zahedan Branch, P.O. Box 98135-978, Zahedan, Iran
cDepartment of Chemistry, Islamic Azad University, Yazd Branch, P.O. Box 89195-155, Yazd, Iran
An improved multi-component reaction of cyclohexyl isocyanide is described. The reaction between two equivalents
of an aldehydes, cyclohexyl isocyanide and cyanoacetic acid at room temperature leads to methyl 2-cyano-3-(aryl)-
cyclohexylcarbamoyl-(aryl)-acrylate in good yields.
Keywords: cyclohexyl isocyanide, multi-component reaction, aldehydes, cyanoacetic acid
Modern synthetic design demands high efficiency in terms of
minimisation of synthetic steps together with maximisation
of complexity.1 One way to fulfill these goals is the use of mul-
ticomponent reactions (MCRs) that consist of several simulta-
neous bond-forming reactions which allow the high efficient
synthesis of complex molecules starting from simple substrates
in a one-pot manner.2–4 New strategies for the synthesis of
complex molecular structures from easily available substrates
by short and effective routes have been investigated. The most
important of these strategies has been the developing of MCRs,
a reaction in which three or more compounds connect together
by covalent bonds to produce a complex molecule containing
the main structure of all the starting materials. As MCRs are
one-pot reactions, they are easier to carry out than multistep
syntheses. Coupled with high-throughput library screening,
this strategy has been important for the rapid identification
and optimisation of biologically active lead compounds.5–13
Among the MCRs, isocyanide based multi-component reac-
tions (IMCRs) have gained the most attention by organic
chemists. Ugi four component reaction(U-4CR)10–12 and Pas-
serini three component reaction (P-3CR)14 are among the most
important IMCRs. U-4CR and P-3CR describe the reaction of
isocyanides with carboxylic acids in the presence of imines or
aldehydes, respectively.
aromatic carboxylic acids has been reported to produce unsat-
urated amides.25 Reaction of isocyanide-DMAD adduct with
aromatic-substituted acetic acids has been reported to afford
2,5-diaminofuran derivatives in the presence of two equiva-
lents of an isocyanide.26 In the context of our previous works
on IMCRs19–21,27, we report here the results of our investigations
on the reaction of cyclohexyl isocyanide, cyanoacetic acid and
aromatic aldehydes.
Results and discussion
Treatment of aldehyde (2 equiv.) with cyanoacetic acid
(1 equiv.) and cyclohexyl isocyanide (1equiv.) in methanol for
24 h at room temperature, after silica gel column chromatogra-
phy afforded methyl 2-cyano-3-(aryl)-cyclohexylcarbamoyl-
(aryl)-acrylate (4) in excellent yields (Scheme1).
The structures of compounds 4a-d were deduced from
their elemental analyses and IR, 1H NMR, 13C NMR. The mass
spectra of these compounds displayed molecular ion peaks at
appropriate m/z values.
1
The H NMR spectrum of compound 4a was simple and
exhibited two sharp single lines, which are respectively due
to olefinic and methine protons (δ = 8.63 and 6.16 ppm) and
one NH group (δ = 7.81 ppm, disappeared with addition of
D2O). Cyclohexyl fragment protons resonated as multiplets at
δ = 1.06–1.74 and a multiplet at δ = 3.47 ppm and aromatic
protons resonated at δ = 7.42–8.81 ppm. The 13C NMR spec-
trum of compound 4a showed 20 distinct resonances in agree-
ment with the proposed structure. The IR spectrum showed an
absorption bond at 3230 cm−1 for the NH group. The carbonyl
stretching vibrations were observed as strong absorption bonds
at 1743 and 1658 cm−1. The nitrile stretching vibrations were
A wide variety of electrophiles have been used to trap
isocyanide-DMAD intermediates, among them are carbon
electrophiles such as aldehydes, imines, quinonoids,15 1,2-
diketones,16 1,2,3-tricarbonyl compounds,17 isocyanates,18 and
hydrogen electrophiles such as pyrrole,19 amides,20 hydroxy
coumarine,21 phenoles,22 phthalic anhydride,23 and isatoic
anhydride.24 Treatment of isocyanide-DMAD zwitterion with
Scheme 1 Reaction between aldehydes, cyanoacetic acid and cyclohexyl isocyanide.
* Correspondent: E-mail: ar_hasanabadi@yahoo.com

JOURNAL OF CHEMICAL RESEARCH 2010 507
Scheme 2 Suggested mechanism for formation of compound 4.
observed as an absorption bond at 2241 cm−1. The molecular
ion peak at 478 in the mass spectrum of compound 4a sup-
ported the 2:1:1 adduct of aldehydes, cyanoacetic acid and
cyclohexyl isocyanide.
On the basis of the well established chemistry of isocya-
nides6–8,22 it is reasonable to assume that intermediate 5 is pro-
duced by initial Knoevenagel condensation of aldehyde with
cyanoacetic acid which is then converted to product 4 during a
Passerini reaction with isocyanide and another molecule of
aldehyde (Scheme 2).
In conclusion, we report here the multicomponent reaction
between aldehydes, cyanoacetic acid and cyclohexyl isocya-
nide as a simple and efficient route for the synthesis of
methyl 2-cyano-3-(aryl)-cyclohexylcarbamoyl-(aryl)-acrylate.
The advantages of this method are that it is inexpensive, has
easily available starting materials, simple and neutral reaction
conditions, high yields, single-product reaction and simple
work-up processes.
Methyl 2-cyano-3-(2-methoxyphenyl)-cyclohexylcarbamoyl-(2-meth-
oxyphenyl)-acrylate: (4c): Yield (90%); white powder, m.p. 207–
o
209 C, IR (KBr) (νmax, cm−1): 3405 (NH), 2245 (C=N), 1747, 1673
(C=O). Anal.Calcd for C26H28N2O5: C, 69.63; H, 6.29; N, 6.25. Found:
1
C, 69.80; H, 6.14; N, 6.31%. MS (m/z,%): 448 (M+, 6). H NMR
(500.1 MHz, CDCl3): δ = 1.18–1.93 (10 H, m, 5 CH2 of cyclohexyl),
3.87 (1 H, m, CH of cyclohexyl), 3.33, 3.84 (6H, 2s, 2OCH3), 4.97
3
(1 H, s, CH), 6.71 (1 H, d, JHH = 7.5 Hz, NH), 6.89–7.58 (8H, m,
aromatic), 8.21 (1 H, s, C=CH) ppm. 13C NMR (125.7MHz, CDCl3):
δ 25.24, 25.27, 26.01, 33.48, 33.65 and 47.99 (5 CH2 and CH of cyclo-
hexyl), 56.14 and 57.61 (2OCH3) 111.68, 115.03, 116.67, 119.94,
121.20, 126.32, 129.27, 130.19, 131.31, 156.73, 156.88 and 158.39
(12C aromatic), 79.08 (CH), 115.87 (CN), 102.26 and 135.05 (C=CH),
160.53 and 170.19 (2CO) ppm.
Methyl 2-cyano-3-(4-chlorophenyl)-cyclohexylcarbamoyl-(4-chlo-
rophenyl)- acrylate: (4d): Yield (89%); White powder, m.p. 201–
o
203 C, IR (KBr) (νmax, cm−1): 3285 (NH), 2225 (C=N), 1728, 1658
(C=O). Anal.Calcd for C24H22Cl2N2O3: C, 63.03; H, 4.85; N, 6.13.
1
Found: C, 62.89; H, 4.99; N, 6.01%. MS (m/z,%): 456 (M+, 11). H
NMR (500.1 MHz, CDCl3): δ = 1.06–1.72 (10 H, m, 5 CH2 of cyclo-
hexyl), 3.45 (1 H, m, CH of cyclohexyl), 5.98 (1 H, s, CH), 7.88 (1 H,
3
d, JHH = 7.5 Hz, NH), 7.47–8.25 (8H, m, aromatic), 8.44 (1 H, s,
Experimental
C=CH) ppm. 13C NMR (125.7MHz, CDCl3): δ 25.15, 25.24, 25.97,
32.82, 32.07 and 48.65(5 CH2 and CH of cyclohexyl), 76.83
(CH),116.09 (CN), 103.57 and 135.05 (C=CH) 129.44, 129.80,
130.45, 132.04, 133.47, 134.36, 139.17, 155.28 (8C aromatic), 161.77
and 166.7 5 (2CO) ppm.
Melting points were determined with an Electrothermal 9100 appara-
tus. Elemental analyses were performed using a Costech ECS 4010
CHNS-O analyser at the analytical laboratory of Islamic Azad Univer-
sity Yazd branch. Mass spectra were recorded on a FINNIGAN-MAT
8430 mass spectrometer operating at an ionisation potential of 70 eV.
IR spectra were recorded on a Shimadzu IR-470 spectrometer.1H
and 13C NMR spectra were recorded on Bruker DRX-500 Avance
spectrometer at solution in CDCl3 using TMS as internal standard.
The chemicals used in this work were purchased from Fluka (Buchs,
Switzerland) and were used without further purification.
Received 11 June 2010; accepted 24 July 2010
Paper 1000191 doi: 10.3184/030823410X12828274077263
Published online: 7 October 2010
References
General procedure:
To a magnetically stirred solution of aldehyde (2mmol) and cyanoace-
tic acid (1 mmol) in 15 ml methanol was added a mixture of cyclo-
hexyl isocyanide (1 mmol) in 1 mL methanol at room temperature.
The reaction mixture was then stirred for 24 h. The solvent was
removed and the residue was purified by silica gel column chromatog-
raphy using hexane–ethyl acetate as eluent. The solvent was removed
under reduced pressure to afford the product.
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C, 60.38; H, 4.52; N,11.63%. MS (m/z,%): 478 (M+,12). H NMR
1
(500.1 MHz, CDCl3): δ = 1.06–1.74 (10 H, m, 5 CH2 of cyclohexyl),
3.47 (1 H, m, CH of cyclohexyl), 6.16 (1 H, s, CH), 7.81 (1 H, d, 3JHH
= 7.5 Hz, NH), 7.42–8.81 (8H, m, aromatic), 8.63 (1 H, s, C=CH)
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33.05 and 48.80 (5 CH2 and CH of cyclohexyl), 76.80 (CH),115.58
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oxyphenyl)-acrylate: (4b): Yield (89%); white powder, m.p. 189–
o
191 C, IR (KBr) (νmax, cm−1): 3270 (NH), 2238 (C=N), 1736, 1655
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1
(500.1 MHz, CDCl3): δ = 1.25–1.94 (10 H, m, 5 CH2 of cyclohexyl),
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3
(1 H, s, CH), 6.39 (1 H, d, JHH = 7.5 Hz, NH), 6.89–7.60 (8H, m,
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