Synthesis of fully substituted iminolactones via a three-component condensation of isocyanides and acetylenic esters with 2-bromo-1-(4-bromophenyl) ethanone

Article abstract of DOI:10.1007/s00706-007-0807-y

A novel three-component condensation reaction between an isocyanide, an electron-deficient acetylenic ester, and 2-bromo-1-(4-bromophenyl)-ethanone efficiently provides fully substituted iminolactones in a one-pot condensation reaction without any activation or modification in high yields.

Full text of DOI:10.1007/s00706-007-0807-y

Monatsh Chem 139, 629–632 (2008)
DOI 10.1007/s00706-007-0807-y
Printed in The Netherlands
Synthesis of fully substituted iminolactones via a three-component
condensation of isocyanides and acetylenic esters with 2-bromo-1-
(4-bromophenyl)ethanone
Ahmad Shaabani, Ebrohim Soleimani, Afshin Sarvary
Department of Chemistry, Shahid Beheshti University, Tehran, Iran
Received 12 September 2007; Accepted 16 September 2007; Published online 19 May 2008
# Springer-Verlag 2008
Abstract A novel three-component condensation re-
action between an isocyanide, an electron-deficient
acetylenic ester, and 2-bromo-1-(4-bromophenyl)-
ethanone efficiently provides fully substituted imino-
lactones in a one-pot condensation reaction without
any activation or modification in high yields.
duce butenolides [4], they are an important class of
natural products that are biologically active com-
pounds which is used in medicine and agriculture
[5].
So far, many synthetic protocols for the synthesis
of iminolactones have been reported [6–12]. The
most widely used approach to iminolactones synthe-
sis is the isocyanide based reactions [6–10]. As early
as 1982, Saegusa and his co-workers reported on
the Et2AlCl-mediated reaction of ꢀ,ꢁ-unsaturated
carbonyl compounds with methyl isocyanide lead-
ing to unsaturated N-substituted iminolactones,
which can be easily converted to ꢂ-butyrolactone
[6]. Recently, Chatani et al. reexamined a catalytic
[1 þ 4] cycloaddition reaction of isocyanides and
ꢀ,ꢁ-unsaturated carbonyl compounds in the pres-
ence of a catalytic amount of GaCl3 leading to the
formation of unsaturated iminolactone derivatives
[9]. Moreover, GaCl3 catalyses the double insertion
of aryl isocyanides into terminal and disubstituted
epoxides leads to ꢀ,ꢁ-unsaturated ꢀ-amino imino-
lactones [10]. Furthermore, the reaction of 4,4-di-
substituted 2,3-allenamides and organic iodides in
toluene afforded iminolactones [11]. Finally, the
haloiminolactonization of 4,4-disubstituted 2,3-alka-
dienamides with copper(II) halide (chloride or
bromide) or I2 in THF also proceeded to produce
unsaturated iminolactones [12].
Keywords Multi-component reaction; Isocyanide; Iminolac-
tones; Acetylenic ester.
Introduction
Multi-component reactions (MCRs), due to their
productivity, simple procedures, convergence, and
facile execution, are one of the best tools in combi-
natorial chemistry [1]. Therefore, the design of novel
MCRs has attracted great attention from research
groups working in areas such as drug discovery, or-
ganic synthesis, and materials science. As a result,
the number of new MCRs has grown rapidly [2].
Recently, iminolactones have been the subject of
great consideration because of their effects as anti-
bacterial agents, aldosterone inhibitors, and proper
precursors for the preparation of a wide spectrum
of natural compounds [3]. Iminolactones could be
hydrolyzed with aqueous hydrochloric acid to pro-
Correspondence: Ahmad Shaabani, Department of Chemistry,
Shahid Beheshti University, P.O. Box 19396-4716, Tehran,
Iran. E-mail: a-shaabani@cc.sbu.ac.ir
As part of an ongoing development of efficient
protocols for the preparation of biologically active

630
A. Shaabani et al.
Scheme 1
heterocycles from common intermediates using iso-
cyanide-based reactions [13] and electron deficient
acetylenic esters [14] we report the synthesis of
iminolactones 4 via the three-component condensa-
tion of isocyanides 1, dialkyl acetylenedicarboxylates
2, and 2-bromo-1-(4-bromophenyl)ethanone (3) in
CH2Cl2 at room temperature in good isolated yields
(Scheme 1).
cyclohexyl ring (ꢃ ¼ 1.21–1.90 ppm), a multiplet for
N–CH of cyclohexyl ring (ꢃ ¼ 3.65–3.75 ppm), two
methoxy groups (ꢃ ¼ 3.79 and 3.92 ppm), two dou-
3
blets for CH2Br (ꢃ ¼ 4.08 ppm, JHH ¼ 11.0 Hz and
3
ꢃ ¼ 4.48 ppm, JHH ¼ 11.0 Hz), and two doublets
3
for phenyl ring (ꢃ ¼ 7.33 ppm, JHH ¼ 8.6 Hz and
3
ꢃ ¼ 7.52 ppm, JHH ¼ 8.6 Hz). The 1H-decoupled
13C NMR spectrum of 4a showed 19 distinct reso-
nances, partial assignment of these resonances is
given in the Experimental section.
Results and discussion
Although the mechanism of the reaction between
the isocyanide and dialkyl acetylenedicarboxylate
in the presence of carbonyl groups has not yet been
established experimentally, a possible pathway is
proposed in Scheme 2. On the basis of the well
established chemistry of isocyanides [15–18], it is
The structures of the products were deduced from
their IR, 1H NMR, and 13C NMR spectra. The mass
spectra of these compounds displayed molecular ion
1
peaks at the appropriate m=z values. The H NMR
spectrum of 4a consisted of a multiplet signals for a
Scheme 2

Synthesis of fully substituted iminolactones
631
24.80, 25.71, 32.88, 33.47 (5CH2 of cyclohexyl), 38.26
(CH2Br), 53.06, 53.16 (2OCH3), 56.96 (CH–N), 89.54 (C–
CH2Br), 123.53, 127.57, 132.06, 135.80, 137.65, 142.47,
154.00 (C–Ar, C¼C, C¼N), 160.93, 161.94 (2C¼O) ppm.
reasonable to assume that initial formation of a
highly reactive 1:1 zwitterionic intermediate 5 by
the Michael-type addition reaction of the isocya-
nide 1 with the dialkyl acetylenedicarboxylate 2
which adds to the carbonyl group of 2-bromo-1-
(4-bromophenyl)ethanone (3) leading to a dipolar
species 6. Cyclization of the latter leads to the imi-
nolactones 4.
In conclusion, we developed a new and general
method for the preparation of the fully substituted
iminolactones from the readily available dialkyl
acetylenedicarboxylate, 2-bromo-1-(4-bromophenyl)-
ethanone and isocyanides under neutral conditions
without using any catalyst and activation. The reac-
tion was shown to display good functional group
tolerance, in high yielding, and product isolation is
very straightforward.
(5Z)-Diethyl 2-(bromomethyl)-2-(4-bromophenyl)-5-(cyclo-
hexylimino)-2,5-dihydrofuran-3,4-dicarboxylate
(4b, C23H27Br2NO5)
Colorless crystals, yield 0.46 g (83%); mp 113–115ꢁC; IR
(KBr): ꢄꢀ¼ 2929, 2855, 1745, 1715, 1684, 1280 cmꢀ1
;
1H NMR (300MHz, CDCl3): ꢃ ¼ 1.22–1.90 (m, 5CH2 of
3
cyclohexyl), 1.27 (t, JHH ¼ 7.1 Hz, OCH2CH3), 1.37 (t,
3JHH ¼ 7.1 Hz, OCH2CH3), 3.70–3.76 (m, CH–N), 4.09
3
(d, JHH ¼ 11.0 Hz, CH2Br), 4.18–4.43 (m, 2OCH2-
3
3
CH3), 4.46 (d, JHH ¼ 11.0Hz, CH2Br), 7.35 (d, JHH
¼
8.6 Hz, H–Ar), 7.53 (d, JHH ¼ 8.6 Hz, H–Ar) ppm; 13C
NMR (75 MHz, CDCl3): ꢃ ¼ 13.80, 14.07 (2OCH2CH3),
24.72, 24.75, 25.74, 32.90, 33.47 (5CH2 of cyclohexyl),
36.39 (CH2Br), 56.78 (CH–N), 62.23, 62.30 (2OCH2CH3),
89.50 (C–CH2Br), 123.41, 127.65, 131.97, 136.00, 137.65,
142.20, 154.03 (C–Ar, C¼C, C¼N), 160.60, 161.56
(2C¼O) ppm.
3
Experimental
Melting points were measured on an Electrothermal 9200 ap-
paratus. IR spectra were recorded on FT-IR 102MB BOMEM
apparatus. Mass spectra were recorded on a FINNIGAN-MAT
8430 mass spectrometer operating at an ionization potential of
70eV. 1H and 13C NMR spectra were recorded on a BRUKER
DRX-300 AVANCE spectrometer at 300.13 and 75.47 MHz.
1H and 13C NMR spectra were obtained on solutions in
CDCl3. Dialkyl acetylenedicarboxylate, isocyanides, and 2-
bromo-1-(4-bromophenyl)ethanone (3) were purchased from
Fluka and Merck and used without purification. All the pro-
ducts are new compounds, which were characterized by IR,
1H, and 13C NMR spectral data.
(5Z)-Dimethyl 5-(tert-butylimino)-2-(bromomethyl)-2-(4-
bromophenyl)-2,5-dihydrofuran-3,4-dicarboxylate
(4c, C19H21Br2NO5)
Colorless crystals, yield 0.45 g (90%); mp 112–115ꢁC; IR
(KBr): ꢄꢀ¼ 2967, 1751, 1725, 1680, 1351, 1213 cmꢀ1
;
1H
NMR (300MHz, CDCl3): ꢃ ¼ 1.38 (s, C(CH3)3), 3.78, 3.91
3
(2s, 2OCH3), 4.10 (d, JHH ¼ 11.0Hz, CH2Br), 4.46 (d,
3
3JHH ¼ 11.0Hz, CH2Br), 7.33 (d, JHH ¼ 8.2 Hz, H–Ar), 7.52
3
(d, JHH ¼ 8.2 Hz, H–Ar) ppm; 13C NMR (75 MHz, CDCl3):
ꢃ ¼ 29.56 (C(CH3)3), 36.32 (CH2Br), 53.01, 53.06 (2OCH3),
55.12 (C(CH3)3), 90.27 (C–CH2Br), 123.40, 127.65, 131.98,
135.94, 138.98, 141.34, 151.82 (C–Ar, C¼C, C¼N), 160.93,
162.21 (2C¼O) ppm.
General prodedure
To a magnetically stirred solution of 0.28 g 2-bromo-1-(4-
bromophenyl)ethanone (3, 1 mmol) and 1 mmol dialkyl
acetylenedicarboxylate in 10 cm3 CH2Cl2 was added, drop-
wise, a solution of 1 mmol isocyanide in 2 cm3 CH2Cl2 at
ꢀ10ꢁC over 10 min. The mixture was allowed to warm up
to room temperature and was finally stirred for 12 h. The
solvent was removed under vacuum and the residue was
crystallized from an n-hexane=ether (1=2) mixture and
washed with ether (3ꢂ5 cm3) and the products were thus
obtained.
(5Z)-Diethyl 5-(tert-butylimino)-2-(bromomethyl)-2-(4-bromo-
phenyl)-2,5-dihydrofuran-3,4-dicarboxylate
(4d, C21H25Br2NO5)
Colorless crystals, yield 0.42 g (80%); mp 95–97ꢁC; IR (KBr):
ꢄꢀ¼ 2971, 1740, 1721, 1682, 1395, 1286cmꢀ1
;
1H NMR
3
(300MHz, CDCl3): ꢃ ¼ 1.26 (t, JHH ¼ 7.1 Hz, OCH2CH3),
3
1.36 (t, JHH ¼ 7.1Hz, OCH2CH3), 1.38 (s, C(CH3)3),
3
4.12 (d, JHH ¼ 11.1Hz, CH2Br), 4.16–4.41 (m, 2OCH2-
3
3
CH3), 4.44 (d, JHH ¼ 11.1Hz, CH2Br), 7.35 (d, JHH
¼
3
8.6 Hz, H–Ar), 7.52 (d, JHH ¼ 8.6 Hz, H–Ar) ppm; 13C
NMR (75 MHz, CDCl3): ꢃ ¼ 13.78, 14.10 (2OCH2CH3),
29.58 (C(CH3)3), 36.37 (CH2Br), 55.06 (C(CH3)3),
62.18, 62.31 (2OCH2CH3), 90.30 (C–CH2Br), 123.30,
127.73, 131.90, 136.09, 139.00, 141.30, 151.80 (C–Ar,
C¼C, C¼N), 160.58, 161.77 (2C¼O) ppm.
(5Z)-Dimethyl 2-(bromomethyl)-2-(4-bromophenyl)-5-(cyclo-
hexylimino)-2,5-dihydrofuran-3,4-dicarboxylate
(4a, C21H23Br2NO5)
Colorless crystals, yield 0.51 g (97%); mp 132–134ꢁC; IR
(KBr): ꢄꢀ¼ 2924, 2849, 1750, 1720, 1680, 1440, 1294 cmꢀ1
;
1H NMR (300MHz, CDCl3): ꢃ ¼ 1.21–1.90 (m, 5CH2 of
cyclohexyl), 3.65–3.75 (m, CH–N), 3.79, 3.92 (2s, 2OCH3),
Acknowledgement
3
3
4.08 (d, JHH ¼ 11.0Hz, CH2Br), 4.48 (d, JHH ¼ 11.0 Hz,
3
3
CH2Br), 7.33 (d, JHH ¼ 8.6 Hz, H–Ar), 7.52 (d, JHH
¼
We gratefully acknowledge the financial support from the
Research Council of Shahid Beheshti University.
8.6 Hz, H–Ar) ppm; 13C NMR (75 MHz, CDCl3): ꢃ ¼ 24.77,

632
A. Shaabani et al.
9. Chatani N, Oshita M, Tobisu M, Ishii Y, Murai S (2003) J
Am Chem Soc 125:7812
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