Reaction between alkyl isocyanides and dialkyl acetylenedicarboxylates in the presence of 1-aryl-2-thiocyanatoethanone yields highly functionalised iminolactones

Article abstract of DOI:10.3184/174751912X13518651809556

The reactive intermediate produced in the reaction between alkyl isocyanides and dialkyl acetylenedicarboxylates was trapped by 1-aryl-2-thiocyanatoethanone to yield highly functionalised iminolactones derivatives in good yields.

Full text of DOI:10.3184/174751912X13518651809556

706 RESEARCH PAPER
DECEMBER, 706–708
JOURNAL OF CHEMICAL RESEARCH 2012
Reaction between alkyl isocyanides and dialkyl acetylenedicarboxylates
in the presence of 1-aryl-2-thiocyanatoethanone yields highly
functionalised iminolactones
Alireza Hassanabadia* and Mohammad R. Hosseini-Tabatabaeia
aDepartment of Chemistry, Islamic Azad University, Zahedan Branch, PO Box 98135-978, Zahedan, Iran
The reactive intermediate produced in the reaction between alkyl isocyanides and dialkyl acetylenedicarboxylates
was trapped by 1-aryl-2-thiocyanatoethanone to yield highly functionalised iminolactones derivatives in good
yields.
Keywords: three-component reactions, dialkyl acetylenedicarboxylates, alkyl isocyanides, 1-aryl-2-thiocyanatoethanone
Multi-component reactions (MCRs) are powerful tools in
modern drug discovery processes and allow fast, automated
and high throughput generation of organic compounds.1,2 The
reactivity of nucleophilic carbenes, such as isocyanides,
towards dimethyl acetylenedicarboxylate (DMAD) is well
documented.3,4 The reaction of isocyanides with carbon–carbon
triple bonds occurs in a stepwise manner through a zwitter-
ionic intermediate, the ultimate fate of which appears to be
dictated by the nature of the original triple-bonded substrate.4–6
many synthetic protocols for the synthesis of iminolactones
have been reported.7–19 The most widely used approach to
iminolactones synthesis is the isocyanide-based reactions.7–10
As early as 1982, Saegusa and his co-workers reported on
the Et2AlCl-mediated reaction of α,β-unsaturated carbonyl
compounds with methyl isocyanide leading to unsaturated
N-substituted iminolactones, which can be easily converted
to γ-butyrolactone.7 Recently, Chatani et al. reexamined a
catalytic [1+4] cycloaddition reaction of isocyanides and α,β-
unsaturated carbonyl compounds in the presence of a catalytic
amount of GaCl3 leading to the formation of unsaturated
iminolactone derivatives.10 Moreover, gallium(III) chloride-
catalysed double insertion of aryl isocyanides into terminal
and disubstituted epoxides leading to α,β-unsaturated α-amino
iminolactones was reported.11 Furthermore, the reaction of
4,4-disubstituted allenecarboxamides and organic iodides
in toluene afforded iminolactones.12 Finally, the haloimino-
lactonisation of 4,4-disubstituted alka-2,3dienamides with
copper(II) halide (chloride or bromide) or I2 in THF also
produces unsaturated iminolactones.13 As part of an ongoing
development of efficient protocols for the preparation of
biologically active heterocycles from common intermediates
using isocyanide-based reactions and electron deficient acety-
lenic esters,14–29 we report here the results of our study on the
reaction between alkyl isocyanides and dialkyl acetylenedicar-
boxylates in the presence of 1-aryl-2-thiocyanatoethanone.
Results and discussion
The reaction of alkyl isocyanides 1 with dialkyl acetylenedi-
carboxylates 2 in the presence of 1-aryl-2-thiocyanatoethanone
3 produces highly functionalised iminolactones derivatives
4a–f in excellent yields (Scheme 1).
The structures of compounds 4a–f were deduced from their
1
elemental analyses and their IR, H NMR, 13C NMR spectra.
The mass spectra of these compounds displayed molecular ion
peaks at appropriate m/z values.
The 1H NMR spectrum of compound 4a exhibited two single
sharp lines readily recognised as arising from methoxy
(δ = 3.79 and 3.98 ppm). The methylene protons resonate at
4.12 ppm as an AB-quartet (2JHH = 11 Hz). Cyclohexyl frag-
ment protons resonated as multiplets at δ = 1.22–1.85 and a
Scheme 1 Reaction of alkyl isocyanides and dialkyl acetylenedicarboxylates in the presence of 1-aryl-2-thiocyanatoethanone.
* Correspondent. E-mail: ar_hasanabadi@yahoo.com

JOURNAL OF CHEMICAL RESEARCH 2012 707
Diethyl
5-(tert-butylimino)-2-(4-chlorophenyl)-2-(thiocyanato-
methyl)-2,5-dihydrofuran-3,4-dicarboxylate (4b): Yellow powder;
yield 86%; m.p. 102–104 °C, IR (KBr) (νmax/cm−1): 2290 (C≡N), 1748
and 1735 (C=O), 1684 (C=N), 1646 (C=C). Anal. Calcd for
C22H25ClN2O5S, C, 56.83; H, 5.42; N, 6.02. Found: C, 56.70 H, 5.50
N, 6.15%. MS (m/z, %): 464 (4).1H NMR (500 MHz, CDCl3): δ 1.19
and 1.39 (6H, 2t, 3JHH = 7.1 Hz, 2CH3), 1.33 (9H, s, CMe3), 4.07 (2H,
AB quartet, 2JHH = 11 Hz, CH2), 4.15–4.38 (4H, m, 2OCH2), 7.41 (2 H,
multiplet at δ = 3.62 ppm and aromatic protons resonated at
δ = 7.40–7.63 ppm. The 13C NMR spectrum of compound 4a
showed 20 distinct signals in agreement with the proposed
structure. The characteristic signal due to the cyano group
carbon was discernible at δ 113.76 ppm. Carbons of imino and
two carbonyl groups were resonated at δ 151.85, 159.43 and
161.27 ppm, respectively. The mass spectrum of 4a displayed
the molecular ion peak at m/z= 462. The IR spectrum of 4a
showed strong absorptions at 1736 and 1754 cm−1 due to the
ester carbonyls, at 1682 cm−1 due to the C=N and the cyano
group at 2294 cm−1 as a weak sharp band.
The formation of compounds 4 can be rationalised as shown
in Scheme 2. The reaction starts with initial formation of a
highly reactive 1:1 zwitterionic intermediate 5 by the Michael-
type addition reaction30,31 of the alkyl isocyanide 1 with the
dialkyl acetylenedicarboxylate 2, which adds to the carbonyl
group of 1-aryl-2-thiocyanatoethanone 3 leading to a dipolar
species 6. Cyclisation of the latter leads to the iminolactones 4.
3
3
d, JHH = 8 Hz, 2CH of C6H4Cl), 7.69 (2H, d, JHH = 8 Hz, 2CH of
C6H4Cl) ppm. 13C NMR (125.8 MHz, CDCl3): δ 13.85, 14.21 (2CH3),
29.52 (CMe3), 36.77 (CH2), 56.49 (NCMe3), 62.53, 62.74 (2OCH2),
83.25 (C), 113.92 (C≡N), 128.07, 128.50, 129.13, 133.19, 135.72 and
143,90 (aromatic and C=C), 151.88 (C=N), 159.35 and 161.37 (2CO)
ppm.
Dimethyl 5-(tert-butylimino)-2-(4-chlorophenyl)-2-(thiocyanato-
methyl)-2,5-dihydrofuran-3,4-dicarboxylate (4c): Yellow powder;
yield 88%; m.p. 98–100 °C, IR (KBr) (νmax/cm−1): 2311 (C≡N), 1762
and 1730 (C=O), 1693 (C=N), 1648 (C=C). Anal. Calcd for
C20H21ClN2O5S, C, 54.98; H, 4.84; N, 6.41. Found: C, 54.85 H, 4.70
N, 6.50%. MS (m/z, %): 436 (8). 1H NMR (500 MHz, CDCl3): δ 1.43
(9H, s, CMe3), 3.71 and 3.96 (6H, 2s, 2OCH3), 4.19 (2H, AB quartet,
2JHH = 11Hz, CH2), 7.52 (2H, d, 3JHH = 8Hz, 2CH of C6H4Cl), 7.74 (2H,
d, 3JHH = 8 Hz, 2CH of C6H4Cl) ppm. 13C NMR (125.8 MHz, CDCl3):
δ 29.74 (CMe3), 36.62 (CH2), 53.21 and 53.77 (2OCH3), 56.62
(NCMe3), 83.27 (C), 113.59 (C≡N), 128.18, 128.66, 129.13, 133.26,
135.72 and 143,84 (aromatic and C=C), 151.96 (C=N), 159.63 and
161.35 (2CO) ppm.
In summary, we have observed
a three-component
condensation reaction that offers an easy and effective one-pot
synthesis of iminolactones derivatives, which are potentially
amenable to a number of synthetic transformations.32
The present method has the advantage that the reaction is
performed under neutral conditions and the substances can be
mixed without any activation or modification.
Dimethyl 5-(cyclohexylimino)-2-(4-bromophenyl)-2-(thiocyanato-
methyl)-2,5-dihydrofuran-3,4-dicarboxylate (4d): Yellow powder;
yield 90%; m.p. 114–126 °C, IR (KBr) (νmax/cm−1): 2302 (C≡N), 1750
and 1737 (C=O), 1680 (C=N), 1643 (C=C). Anal. Calcd for
C22H23BrN2O5S, C, 52.08; H, 4.57; N, 5.52. Found: C, 52.15 H, 4.40
N, 5.60%. MS (m/z, %): 507 (8).1H NMR (500 MHz, CDCl3): δ 1.25–
1.83 (10H, m, 5CH2), 3.60 (1H, m, NCH), 3.72 and 3.95 (6 H, 2 s,
Experimental
Melting points were determined with an Electrothermal 9100 appara-
tus and are uncorrected. Elemental analyses were performed using a
Heraeus CHN-O-Rapid analyser. 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.
2OCH3), 4.18 (2H, AB quartet, 2JHH = 11 Hz, CH2), 7.46 (2H, d, 3JHH
=
8 Hz, 2CH of C6H4Cl), 7.68 (2H, d, 3JHH = 8 Hz, 2CH of C6H4Cl) ppm.
13C NMR (125.8 MHz, CDCl3): δ 24.58, 25.11, 25.57, 33.21 and
33.45 (5 CH2 of cyclohexyl), 36.61 (CH2), 53.38 and 53.64 (2OCH3),
57.17 (CHN), 83.22 (C), 113.88 (C≡N), 128.13, 128.62, 129.17,
133.19, 135.93 and 143,92 (aromatic and C=C), 151.74 (C=N), 159.55
and 161.38 (2CO) ppm.
Diethyl
5-(tert-butylimino)-2-(4-bromophenyl)-2-(thiocyanato-
General procedure
methyl)-2,5-dihydrofuran-3,4-dicarboxylate (4e): Yellow powder;
yield 84%; m.p. 112–114 °C, IR (KBr) (νmax/cm−1): 2304 (C≡N), 1755
and 1732 (C=O), 1681 (C=N), 1649 (C=C). Anal. Calcd for
C22H25BrN2O5S, C, 51.87; H, 4.95; N, 5.50. Found: C, 51.95 H, 4.80
N, 5.42%. MS (m/z, %): 509 (11).1H NMR (500 MHz, CDCl3): δ 1.17
and 1.43 (6H, 2t, 3JHH = 7.1 Hz, 2CH3), 1.37 (9H, s, CMe3), 4.10 (2H,
AB quartet, 2JHH = 11Hz, CH2), 4.11–4.35 (4H, m, 2OCH2), 7.45 (2 H,
d, JHH = 8 Hz, 2CH of C6H4Cl), 7.63 (2 H, d, JHH = 8 Hz, 2CH of
C6H4Cl) ppm. 13C NMR (125.8 MHz, CDCl3): δ 13.94, 14.37 (2CH3),
29.57 (CMe3), 36.92 (CH2), 56.37 (NCMe3), 62.50, 62.86 (2OCH2),
83.21 (C), 113.88 (C≡N), 128.05, 128.62, 129.26, 133.14, 135.77 and
143,97 (aromatic and C=C), 151.83 (C=N), 159.42 and 161.49 (2CO)
ppm.
Dimethyl 5-(tert-butylimino)-2-(4-bromophenyl)-2-(thiocyanato-
methyl)-2,5-dihydrofuran-3,4-dicarboxylate (4f): Yellow powder;
yield 85%; m.p. 92–94 °C, IR (KBr) (νmax/cm−1): 2308 (C≡N), 1768
and 1736 (C=O), 1698 (C=N), 1642 (C=C). Anal. Calcd for
C20H21BrN2O5S, C, 49.90; H, 4.40; N, 5.82. Found: C, 49.82 H, 4.45
N, 5.90%. MS (m/z, %): 481 (5). 1H NMR (500 MHz, CDCl3): δ 1.46
(9H, s, CMe3), 3.68 and 3.93 (6H, 2s, 2OCH3), 4.24 (2H, AB quartet,
2JHH = 11Hz, CH2), 7.48 (2H, d, 3JHH = 8Hz, 2CH of C6H4Cl), 7.79 (2H,
A mixture of alkyl isocyanide (1 mmol) was added dropwise to a mag-
netically stirred solution of 1-aryl-2-thiocyanatoethanone (1 mmol)
and dialkyl acetylenedicarboxylate (1.1 mmol) in 20 mL dry benzene
via a syringe, and refluxing was continued for 12 h. The solvent was
removed under reduced pressure and the residue was purified by silica
gel column chromatography using hexane-ethyl acetate as eluent. The
solvent was removed under reduced pressure to afford the product.
Dimethyl 5-(cyclohexylimino)-2-(4-chlorophenyl)-2-(thiocyanato-
methyl)-2,5-dihydrofuran-3,4-dicarboxylate (4a): Yellow powder;
yield 91%; m.p. 108–110 °C, IR (KBr) (νmax/cm−1): 2294 (C≡N), 1754
and 1736 (C=O), 1682 (C=N), 1640 (C=C). Anal. Calcd for
C22H23ClN2O5S, C, 57.08; H, 5.01; N, 6.05. Found: C, 57.19; H, 4.84
N, 6.20%. MS (m/z, %): 462 (5). 1H NMR (500 MHz, CDCl3): δ 1.22–
1.85 (10H, m, 5CH2 of cyclohexyl), 3.62 (1H, m, NCH), 3.79 and 3.98
(6H, 2s, 2OCH3), 4.12 (2H, AB quartet, 2JHH = 11Hz, CH2), 7.40 (2H,
3
3
3
3
d, JHH = 8Hz, 2CH of C6H4Cl), 7.63 (2H, d, JHH = 8 Hz, 2CH of
C6H4Cl) ppm. 13C NMR (125.8 MHz, CDCl3): δ 24.58, 25.18, 25.49,
33.14 and 33.36 (5CH2 of cyclohexyl), 36.74 (CH2), 53.32 and 53.60
(2OCH3), 57.28 (CHN), 83.12 (C), 113.76 (C≡N), 128.02, 128.56,
129.05, 133.14, 135.81 and 143,96 (aromatic and C=C), 151.85
(C=N), 159.43 and 161.27 (2CO) ppm.
Scheme 2 Suggested mechanism for formation of compound 4.

708 JOURNAL OF CHEMICAL RESEARCH 2012
d, 3JHH = 8 Hz, 2CH of C6H4Cl) ppm. 13C NMR (125.8 MHz, CDCl3):
δ 29.63 (CMe3), 36.74 (CH2), 53.26 and 53.71 (2OCH3), 56.69
(NCMe3), 83.20 (C), 113.51 (C≡N), 128.28, 128.78, 129.15, 133.22,
135.79 and 143,80 (aromatic and C=C), 151.91 (C=N), 159.60 and
161.42 (2CO) ppm.
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We gratefully acknowledge financial support from the Research
Council of Islamic Azad University of Zahedan of Iran.
Received 28 August 2012; accepted 10 October 2012
Paper 1201485 doi: 10.3184/174751912X13518651809556
Published online: 5 December 2012
23 A. Hassanabadi, M.H. Mosslemin, M.Anary-Abbasinejad and S. Koocheki,
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