Four-component reaction between aryl aldehydes, ethyl cyanoacetate and dimethyl acetylenedicarboxylate in the presence of cyclohexyl isocyanide

Article abstract of DOI:10.3184/030823410X12875740077344

A four-component reaction between aryl aldehydes, ethyl cyanoacetate and dimethyl acetylenedicarboxylate in the presence of cyclohexyl isocyanide has been developed. The reaction furnishes highly functionalised cyclopentadienes in moderate to good yields

Full text of DOI:10.3184/030823410X12875740077344

JOURNAL OF CHEMICAL RESEARCH 2010
RESEARCH PAPER 613
NOVEMBER, 613–615
Four-component reaction between aryl aldehydes, ethyl cyanoacetate
and dimethyl acetylenedicarboxylate in the presence of cyclohexyl
isocyanide
Mohammad Anary-Abbasinejada, Alireza Hassanabadib* and Farzaneh Aiinparastc
aYoung Researchers Club, Islamic Azad University, Anar Branch, Anar, Iran
bDepartment of Chemistry, Islamic Azad University, Zahedan Branch, PO Box 98135-978, Zahedan, Iran
cDepartment of Chemistry, Islamic Azad University, Yazd Branch, PO Box 89195-155, Yazd, Iran
A four-component reaction between aryl aldehydes, ethyl cyanoacetate and dimethyl acetylenedicarboxylate in
the presence of cyclohexyl isocyanide has been developed. The reaction furnishes highly functionalised cyclopenta-
dienes in moderate to good yields in a one-pot process.
Keywords: cyclohexyl isocyanide, four-component reaction, dimethyl acetylenedicarboxylate, cyclopentadienes
a wide variety of electrophiles have been applied to trap
isocyanide-DMAD intermediates, among them are carbon
electrophiles such as aldehydes, imines, quinonoids,10 1,2-
diketones,11 1,2,3-tricarbonyl compounds,12 isocyanates,13 and
hydrogen electrophiles such as pyrrole,14 amides,15 hydroxy-
coumarin,16 phenols,17 phthalic anhydride,18 and isatoic anhy-
dride.19 Treatment of the isocyanide-DMAD zwitterion with
aromatic carboxylic acids has been reported to produce unsat-
urated amides.20 Reaction of the isocyanide-DMAD adduct
with aromatic-substituted acetic acids has been reported to
afford 2,5-diaminofuran derivatives in the presence of two
equivalents of an isocyanide.21 In the context of our previous
works on IMCRs,14–16,22 we now report the results of our inves-
tigations on the reaction of cyclohexyl isocyanide 1 with
dimethyl acetylenedicarboxylate 2, aryl aldehydes 3, and ethyl
cyanoacetate 4 to afford aminocyclopentadienes 5.
Cyclopentadienes (Cps) or fulvenes are highly useful synthetic
intermediates in the field of organic and organometallic chem-
istry as ligands in coordination chemistry and homogeneous
catalysis for olefin polymerisation.1 They are useful not only
as a reactive diene component in the Diels–Alder reaction2
but also as precursors for the preparation of transition-metal
complexes with Cp-type ligands.3 However, the preparation of
well-defined, highly substituted cyclopentadienes is not neces-
sarily easy owing to the absence of general methods4 and also
to the facile migration of the endocyclic double bonds.5 Among
the MCRs, isocyanide based multi-component reactions
(IMCRs) have gained the most attention byorganic chemists.
Ugi four component reactions (U-4CR)6–8 and Passerini
three component reactions (P-3CR)9 are among the most
important IMCRs. U-4CR and P-3CR describe the reactions of
isocyanides with carboxylic acids in the presence of imines or
aldehydes, respectively.
Results and discussion
Recently, another kind of IMCR has been developed and
extensively investigated. Isocyanides react easily with elec-
tron-deficient acetylenic diesters such as dimethyl acetylenedi-
carboxylate (DMAD) to produce a reactive zwitterionic
intermediate which can be trapped by an electrophile. Recently,
Treatment of the three reactants and cyclohexyl isocyanide in
dichloromethane for 24 h at room temperature, after silica
gel column chromatography afforded highly functionalised
cyclopentadienes 5 in excellent yields (Scheme 1).
Scheme 1 Reaction between aryl aldehydes, ethyl cyanoacetate and dimethyl acetylenedicarboxylate in the presence of
cyclohexyl isocyanide.
* Correspondent. E-mail: ar_hasanabadi@yahoo.com

614 JOURNAL OF CHEMICAL RESEARCH 2010
Scheme 2 Suggested mechanism for formation compound 5.
chromatography using hexane-ethyl acetate (3:1) as eluent. The sol-
vent was removed under reduced pressure to give the product.
1,2-Dimethyl 3-ethyl 3-cyano-5-cyclohexylamino-4-(phenyl)-
cyclopenta-1,4- diene-1,2,3-tricarboxylate (5a): Yellow oil, yield:
90%; IR (KBr) (νmax, cm−1): 3355 (NH), 1744, 1675 (carbonyl groups).
Anal. Calcd for C25H28N2O6: C, 66.36; H, 6.24; N, 6.19. Found:
C, 66.45; H,6.16; N, 6.25%. 1H NMR (500.1 MHz, CDCl3): δ = 1.18
(3H, t, 3JHH = 7 Hz, CH3), 1.23–1.67 (10 H, m, 5 CH2 of cyclohexyl),
3.64 (1 H, m, CH of cyclohexyl), 3.79 and 3.81 (6 H, 2s, 2 OCH3),
4.22 (2 H, q, 3JHH = 7 Hz, OCH2), 7.03–7.68 (4H, m, aromatic), 8.22
(1 H, d, 3JHH = 11 Hz, NH). 13C NMR (125.7 MHz, CDCl3): δ = 14.32
(CH3), 23.12, 24.75, 25.68, 29.68 and 30.21(5CH2 of cyclohexyl),
39.05 (CH of cyclohexyl), 51.86 and 52.94 (2 OCH3), 57.87 (C),
64.40 (OCH2), 99.68 (CN), 113.92, 120.42, 144.38 and 160.22
(4C olefinic), 127.71, 128.80, 130.13 and 134.48 (aromatic), 163.23,
165.42 and 166.29 (3CO).
The structures of compounds 5a–g were deduced from their
1
elemental analyses and IR, H NMR, and 13C NMR spectra.
The 1H NMR spectrum of compound 5a was very simple and
exhibited two sharp signals at 3.79 and 3.81 ppm for methoxy-
carbonyl groups, and one NH group (δ = 8.22 ppm, disap-
peared with addition of D2O). Protons of the ethyl group are
observed as a triplet at δ = 1.18 ppm (3JHH = 7 Hz) and a quartet
at δ = 4.22 (3JHH = 7Hz). Cyclohexyl fragment protons reso-
nated as multiplets at δ = 1.23–1.67 and a multiplet at δ = 3.64
ppm and aromatic protons resonated at δ = 7.03–7.68 ppm.
The 13C NMR spectrum of compound 5a showed 23 distinct
resonances in agreement with the proposed structure. The IR
spectrum showed an absorption bond at 3355 cm−1 for the NH
group. The carbonyl stretching vibrations observed as strong
absorption bands at 1744 and 1675 cm−1. The nitrile stretching
vibrations were observed in an absorption band at 2236 cm−1.
On the basis of the well established chemistry of isocya-
nides6–8,18 it is reasonable to assume that intermediate 7 is pro-
duced by initial Knovenagel condensation of aldehyde 3 with
ethyl cyanoacetate 4. The compound 5 is produced by initial
attack of isocyanide-DMAD zwitterion intermediate 6. The
zwitterions can add to the intermediate of 7 resulting in the
formation of 8. The latter then isomerises to the final product 5
via a [1,5]H shift. (Scheme 2)
1,2-Dimethyl 3-ethyl 3-cyano-5-cyclohexylamino-4-(4-methoxy-
phenyl)- cyclopenta-1,4- diene-1,2,3-tricarboxylate (5b): Yellow oil,
yield: 92%; IR (KBr) (νmax, cm−1): 1743, 1657 (carbonyl groups). Anal.
Calcd for C26H30N2O7: C, 64.72; H, 6.27; N, 5.81. Found: C, 64.85;
1
H, 6.38; N, 5.74%. H NMR (500.1 MHz, CDCl3): δ = 1.24–1.80
(10 H, m, 5 CH2 of cyclohexyl), 1.33 (3 H, t, 3JHH = 7 Hz, CH3), 3.64
and 3.76 (6 H, 2s, 2 OCH3), 3.71 (1 H, m, CH of cyclohexyl), 3.89
(3 H, s, OCH3), 4.33 (2 H, q, 3JHH = 7 Hz, OCH2), 6.88 (2H, d, 3JHH
=
3
7 Hz, aromatic), 7.09 (2H, d, JHH = 7 Hz, aromatic), 8.24 (1 H, d,
3JHH = 11 Hz, NH). 13C NMR (125.7 MHz, CDCl3): δ = 14.34 (CH3),
23.01, 24.23, 25.84, 29.75 and 30.07 (5 CH2 of cyclohexyl), 39.16
(CH of cyclohexyl), 53.10 and 53.19 (2 OCH3), 56.92 (OCH3), 63.45
(C), 64.60 (OCH2), 114.50 (CN), 115.00, 127.81, 129.65 and 144.31
(aromatic), 114.27, 129.79, 144.58 and 160.49 (4C olefinic), 162.75,
163.82 and 165.49 (3CO).
In conclusion, we report here the four-component reaction
between aryl aldehydes, ethyl cyanoacetate and dimethyl acet-
ylenedicarboxylate with cyclohexyl isocyanide as a simple and
efficient route for the synthesis of functionalised cyclopentadi-
ene derivatives. The advantages of the reported method are
that it is inexpensive with easily available starting materials, it
has simple and neutral reaction conditions, gives high yields, is
a single-product reaction and is a simple work-up process.
1,2-Dimethyl 3-ethyl 3-cyano-5-cyclohexylamino-4-(4-clorophe-
nyl)- cyclopenta-1,4- diene-1,2,3-tricarboxylate (5c): Yellow oil,
yield: 90%; IR (KBr) (νmax, cm−1): 1746, 1666 (carbonyl groups). Anal.
Calcd for C25H27ClN2O6: C, 61.66; H, 5.59; N, 5.75. Found: C, 61.79;
1
H, 5.43; N, 5.68%. H NMR (500.1 MHz, CDCl3): δ = 1.25–2.02
(10 H, m, 5 CH2 of cyclohexyl), 1.37 (3 H, t, 3JHH = 7 Hz, CH3), 3.66
and 3.91 (6 H, 2s, 2 OCH3), 3.76 (1 H, m, CH of cyclohexyl), 4.35
(2 H, q, 3JHH = 7 Hz, OCH2), 7.28 (2H, d, 3JHH = 7 Hz, aromatic), 7.38
Experimental
Melting points were determined with an Electrothermal 9100 appara-
tus. Elemental analyses were performed using a Costech ECS 4010
CHNS-O analyzer at analytical laboratory of Islamic Azad University
Yazd branch. 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.
3
3
(2H, d, JHH = 7 Hz, aromatic), 8.28 (1 H, d, JHH = 11 Hz, NH). 13C
NMR (125.7 MHz, CDCl3): δ = 14.44 (CH3), 23.09, 24.82, 25.84,
29.76 and 30.09 (5CH2 of cyclohexyl), 39.15 (CH of cyclohexyl),
51.73 and 52.83 (2 OCH3), 58.37 (C), 64.66 (OCH2), 99.87 (CN),
113.92, 120.42, 129.33 and 160.92 (4C olefinic), 129.44, 130.07,
134.69 and 139.37 (aromatic), 163.35, 165.50 and 166.38 (3CO).
1,2-Dimethyl 3-ethyl 3-cyano-5-cyclohexylamino-4-(4-nitrophe-
nyl)- cyclopenta-1,4- diene-1,2,3-tricarboxylate(5d): Yellow oil,
yield: 89%; IR (KBr) (νmax, cm−1): 3320 (NH), 1741, 1643 (carbonyl
groups). Anal.Calcd for C25H27N3O8: C, 60.36; H, 5.47; N, 8.45.
Found: C, 60.19; H, 5.63; N, 8.33%. 1H NMR (500.1 MHz, CDCl3):
δ = 1.20 (3H, t, 3JHH = 7 Hz, CH3), 1.25-2.16 (10 H, m, 5 CH2 of cyclo-
hexyl), 3.74 and 3.76 (6 H, 2s, 2 OCH3), 3.58 (1 H, m, CH of cyclo-
General procedure
To a magnetically stirred solution of ethyl cyanoacetate (1 mmol)
and aryl aldehydes (1 mmol) in dichloromethane (10 mL) was added
a mixture of dimethyl acetylenedicarboxylate (1 mmol) in dichloro-
methane (2 mL) at room temperature. The reaction mixture was
then stirred for 1 min. Cyclohexyl isocyanide (1 mmol) was added
and the reaction mixture was stirred for more than 24 h. The solvent
was removed and the residue was purified by silica gel column
3
3
hexyl), 4.18 (2 H, q, JHH = 7 Hz, OCH2), 7.31 (2H, d, JHH = 7 Hz,
aromatic), 7.44 (2H, d, 3JHH = 7 Hz, aromatic), 8.29 (1 H, d, 3JHH = 11
Hz, NH). 13C NMR (125.7 MHz, CDCl3): δ = 14.02 (CH3), 23.17,

JOURNAL OF CHEMICAL RESEARCH 2010 615
24.87, 25.79, 29.64 and 30.13 (5CH2 of cyclohexyl), 39.19 (CH of
cyclohexyl), 51.90 and 52.75 (2 OCH3), 58.46 (C), 64.39 (OCH2),
99.77 (CN), 114.08, 120.63, 129.42 and 160.87 (4C olefinic), 129.21,
130.19, 133.98 and 139.12 (aromatic), 163.17, 165.43 and 166.52
(3CO).
of cyclohexyl), 39.19 (CH of cyclohexyl), 51.65 and 52.73 (2 OCH3),
55.62 (C), 64.59 (OCH2), 99.92 (CN), 113.88, 122.90, 139.41 and
160.98 (4C olefinic), 120.43, 128.50, 129.18, 129.65, 132.26 and
149.45 (aromatic), 163.34, 165.48 and 166.34 (3CO).
1,2-Dimethyl 3-ethyl 3-cyano-5-cyclohexylamino-4-(2-nitrophe-
nyl)- cyclopenta-1,4- diene-1,2,3-tricarboxylate (5e): Yellow oil,
yield: 88%; IR (KBr) (νmax, cm−1): 3380 (NH), 1734, 1671 (carbonyl
groups). Anal.Calcd for C25H27N3O8: C, 60.36; H, 5.47; N, 8.45.
Found: C, 60.19; H, 5.63; N, 8.33%. 1H NMR (500.1 MHz, CDCl3):
δ = 1.21 (3H, t, 3JHH = 7 Hz, CH3), 1.25–2.19 (10 H, m, 5 CH2 of cyclo-
hexyl), 3.32 (1 H, m, CH of cyclohexyl), 3.57 and 3.71 (6 H, 2s,
We gratefully acknowledge financial support from the Research
Council of Islamic Azad University of Yazd and The Islamic
Azad University of Zahedan of Iran.
Received 27 July 2010; accepted 6 September 2010
Paper 1000266 doi: 10.3184/030823410X12875740077344
Published online: 24 November 2010
3
2 OCH3), 4.24 (2 H, q, JHH = 7 Hz, OCH2), 7.53–7.99 (4H, m, aro-
3
matic), 8.44 (1 H, d, JHH = 11 Hz, NH). 13C NMR (125.7 MHz,
CDCl3): δ = 14.14 (CH3), 24.10, 24.77, 25.44, 32.76 and 34.23 (5CH2
of cyclohexyl), 39.15 (CH of cyclohexyl), 51.60 and 53.36 (2 OCH3),
55.52 (C), 65.11 (OCH2), 98.57 (CN), 114.05, 125.18, 140.87 and
160.95 (4C olefinic), 126.29, 129.69, 130.52, 133.34, 134.67 and
149.08 (aromatic), 163.49, 164.85 and 165.62 (3CO).
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3
OCH3), 4.25 (2 H, q, JHH = 7 Hz, OCH2), 7.50–8.26 (4H, m, aro-
3
matic), 8.39 (1 H, d, JHH = 11 Hz, NH). 13C NMR (125.7 MHz,
CDCl3): δ = 14.51 (CH3), 23.09, 25.35, 29.76, 33.05 and 34.61 (5CH2
of cyclohexyl), 39.22 (CH of cyclohexyl), 51.90 and 53.15 (2 OCH3),
55.89 (C), 65.10 (OCH2), 99.96 (CN), 113.63, 125.61, 135.68 and
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hexyl), 3.60 (1 H, m, CH of cyclohexyl), 3.74 and 3.76 (6 H, 2s,
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3
2 OCH3), 4.18 (2 H, q, JHH = 7 Hz, OCH2), 7.32–7.70 (4H, m, aro-
3
matic), 8.33 (1 H, d, JHH = 11 Hz, NH). 13C NMR (125.7 MHz,
CDCl3): δ = 14.42 (CH3), 23.15, 25.40, 29.85, 34.83 and 35.25 (5CH2

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