Synthesis of functionalized iminolactones via an isocyanide-based three-component reaction

Article abstract of DOI:10.1016/j.tet.2011.03.100

A three-component reaction of the zwitterions generated from isocyanides and dialkyl acetylenedicarboxylate with 1-(4-bromophenyl)-2-thiocyanatoethanone or 1-phenyl-2-thiocyanatoethanone is described. The reaction afforded the corresponding special type o

Full text of DOI:10.1016/j.tet.2011.03.100

Tetrahedron 67 (2011) 3624e3630
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Synthesis of functionalized iminolactones via an isocyanide-based
three-component reaction
,
b
Afshin Sarvarya, Shabnam Shaabani a, Ahmad Shaabani a , Seik Weng Ng
*
a Department of Chemistry, Shahid Beheshti University, G.C., PO Box 19396-4716, Tehran, Iran
b Department of Chemistry, University of Malaya, 50603 Kuala Lumpur, Malaysia
a r t i c l e i n f o
a b s t r a c t
Article history:
A three-component reaction of the zwitterions generated from isocyanides and dialkyl acetylenedi-
carboxylate with 1-(4-bromophenyl)-2-thiocyanatoethanone or 1-phenyl-2-thiocyanatoethanone is de-
scribed. The reaction afforded the corresponding special type of functionalized iminolactone derivatives
in good yields at room temperature without using a catalyst.
Received 20 October 2010
Received in revised form 7 March 2011
Accepted 28 March 2011
Available online 2 April 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Iminolactone
Isocyanide
Thiocyanate
Multicomponent reaction
1. Introduction
such as hexachloroacetone,17 2-bromo-1-(4-bromophenyl)-etha-
none,18 benzoyl cyanide,19 ethyl bromopyruvate,20 and alkyl phenyl-
Thiocyanates are versatile synthetic starting materials for the
preparation of a variety of organosulfur and heterocyclic com-
pounds.1e4 These compounds possess a broad range of bioactivities
and applications as anticancer agents, insecticides, antiasthmatic
drugs, and DNA topoisomerase inhibitors.5,6
glyoxylate21 afforded iminolactones. Furthermore, the reaction of
4,4-disubstituted 2,3-allenamides and organic iodides afforded imi-
nolactones.22 Finally the haloiminolactonization of 4,4-disubstituted
2,3-alkadienamides with copper(II) halide or I2 also proceeded to
produce unsaturated iminolactones.23
Iminolactones have been the subject of great consideration be-
cause of their effects as antibacterial agents, aldosterone inhibitors,
and proper precursors for the preparation of a wide spectrum of
natural compounds.7 Iminolactones could be hydrolyzed with
aqueous hydrochloric acid to produce butenolides.8 This core unit is
the key structure to induce a wide range of biological activities like
antimicrobial,9 antifungal,10 anti-inflamatory,11 anticancer,12 and
anti-viral HIV-1.13
2. Results and discussion
As a part of our ongoing research program on the isocyanides
chemistry,24,25 herein we describe an efficient synthesis of fully
substituted iminolactones derivatives 4aes via a three-component
reaction (Scheme 1).
In a model reaction, 1-(4-bromophenyl)-2-thiocyanatoethanone
(1a), dimethyl acetylenedicarboxylate (3a), and cyclohexyl iso-
cyanide (2a) in CH2Cl2 were stirred at room temperature. After
completion of the reaction (after 5 h), the solvent was removed
under vacuum and the residue was crystallized from n-hexane/
ether (2:1) mixture and the product 4a was obtained.
Next, various 1-phenyl-2-thiocyanatoethanone derivatives
(1aed, Scheme 2), alkyl or aryl isocyanides (2aed, Scheme 3) and
different dialkyl acetylenedicarboxylates (3aec, Scheme 4) were
treated under this reaction conditions. All of these reactions work
fine to afford desired iminolactone products (4aeo) in good yields.
In order to investigate the scope and limitations of this reaction
further, we decided to extend it to 1-(4-nitrophenyl)ethanone (1e),
instead of 1-phenyl-2-thiocyanatoethanone derivatives (1aee). In
this regard 1e, 3a, and2a in CH2Cl2 were stirred at room temperature.
Recently, the synthesis of these compounds has been of great in-
terest in literature. A number of the synthetic methods for the syn-
thesis of iminolactones have been developed during the past two
decades. Themostwidelyusedapproachtoiminolactonessynthesis is
the isocyanide-based reactions.14e20 The reactions of
a,b-unsaturated
carbonyl compounds with isocyanide via Et2AlCl14 and GaCl3 ca-
talysis have attracted much attention. Moreover, GaCl3 catalyzes the
double insertion of aryl isocyanides into terminal and disubstituted
15
epoxides leads to a,b-unsaturated a
-amino iminolactones.16 Trapping
of zwitterionsintermediate derived fromelectron deficient acetylenic
compounds and isocyanides with activated carbonyl compounds,
* Corresponding author. Tel.: þ982129902800; fax: þ982122431663; e-mail
address: a-shaabani@cc.sbu.ac.ir (A. Shaabani).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.03.100

A. Sarvary et al. / Tetrahedron 67 (2011) 3624e3630
3625
Scheme 1. Synthesis of fully substituted iminolactone compounds.
Scheme 2. Carbonyl compound starting materials.
intermediate 624,25g,26 by the Michael type addition reaction of
isocyanide 2 with dialkyl acetylenedicarboxylate 3 followed by
a two-step dipolar species 7 formation with carbonyl compound 1
and then intramolecular cyclization reaction (path A) or a one-step
[2þ3] dipolar type cycloaddition reaction with carbonyl compound
1 (path B) to afford iminolactones 4aes (Scheme 5). The efficient
conversion of the carbonyl compounds that involving EW sub-
stituents in the para position of phenyl group and EW groups in
Scheme 3. Isocyanide starting materials.
a
position of carbonyl group (1a and 1c) supported the two-step
mechanism reaction sequence (path A).
As indicated in Table 1, isocyanides 2 react with dialkyl acety-
lenedicarboxylate
3 and 1-phenyl-2-thiocyanatoethanone de-
rivatives 1 to undergo a smooth 1:1:1 addition reaction in CH2Cl2 at
room temperature to produce fully substituted iminolactones 4.
The structures of the products were deduced from their IR, mass, 1H
NMR, and 13C NMR spectra. The mass spectra of these compounds
displayed molecular ion peaks at the appropriate m/z values.
Finally, the structure of the product 4b was confirmed un-
ambiguously by single-crystal X-ray analysis (Fig. 1).
Scheme 4. Dialkyl acetylenedicarboxylate starting materials.
The progress of the reaction was monitored by TLC. After 5 h, the
reaction was completed and (5Z)-dimethyl 5-(cyclohexylimino)-2,5-
dihydro-2-methyl-2-(4-nitrophenyl)furan-3,4-dicarboxylate (4p)
was obtained in 76% yield. To evaluate the use of this approach,
a variety of 1-phenylethanone derivatives (1feh) were used under
similar circumstances; however the reaction did not proceed. These
result, indicate that reactive zwitterionic intermediate has been
trappedbycarbonyl compoundsthatinvolvingelectronwithdrawing
substituent in the para position of phenyl group (1e) or electron
The reaction did not require any optimization, and we explored
the use of various alkyl and aryl isocyanides with 1-phenyl-2-thi-
ocyanatoethanone derivatives in CH2Cl2 at room temperature,
which led to the formation of the corresponding fully substituted
iminolactones derivatives in high yields. The reaction proceeds
under mild reaction conditions and is compatible with a wide range
of functional groups. Owing to the great diversity of substitution
patterns, this reaction may be used in the production of combina-
torial libraries (Table 1).
withdrawing group in
the yields range shown that carbonyl compounds that involving
electronwithdrawing (EW) substituent in the para position of phenyl
group and EWgroup in a position of carbonyl group (1a and 1c) have
highly yields (Table 1, 4aef and 4men). Whereas carbonyl com-
pound that involving electron donating (ED) substituent in the para
position (1d) has low yield (Table 1, 4o). So carbonyl compounds that
involving EW substituent in the para position of phenyl group (1e) or
a
position of carbonyl group (1aed). As well as
The synthetic scope of this new reaction is highly increased by
the potential of the hydrolysis of iminolactones involving imines.
Besides the obvious hydrolysis, more interesting heterocycle for-
mations could be reached using these iminolactones as reactive
intermediates. For instance, hydrolysis of iminolactones with
aqueous hydrochloric acid8 at room temperature provides bute-
nolides in good yields (Table 2). The structures of the products were
deduced from their IR, 1H NMR, and 13C NMR spectra.
EW group in
a
position of carbonyl group (1b) have average yields
In summary we have described a highly efficient approach to the
synthesis of fully substituted iminolactones involving thiocyanate
group from various isocyanides and dialkyl acetylenedicarboxylates
in the presence of 1-phenyl-2-thiocyanatoethanone derivatives in
absence of catalyst. Scope and limitation of the reaction are de-
scribed. The reaction has been shown to display relatively good
(Table 1, 4gek and 4pes). On the other hand electron withdrawing
group moiety has an important role in the reaction pathway and
presence of this moiety is essential for reaction proceeding.
The synthesis of these functionalized iminolactones can be ra-
tionalized by initial formation of a highly reactive 1:1 zwitterionic

3626
A. Sarvary et al. / Tetrahedron 67 (2011) 3624e3630
Table 1
Synthesis of fully substituted iminolactones (4aes)
Scheme 5. Proposed pathway.

A. Sarvary et al. / Tetrahedron 67 (2011) 3624e3630
3627
ionization potential of 70 eV. IR spectra were recorded on a Shi-
madzu IR-470 spectrometer. 1H and 13C NMR spectra were recorded
on a BRUKER DRX-300 AVANCE spectrometer at 300.13 and
75.47 MHz. NMR spectra were obtained on solution in CDCl3 using
TMS as internal standard. The chemicals used in this work were
purchased from Merck and Fluka Chemical Companies. Compounds
(1aed) have previously been described3 and their physical prop-
erties were in agreement with those reported.
3.2. Typical procedure for preparation of (Z)-dimethyl 2-(4-
bromophenyl)-5-(cyclohexylimino)-2-(thiocyanatomethyl)-
2,5-dihydrofuran-3,4-dicarboxylate (4a)
To a magnetically stirred solution of 1-(4-bromophenyl)-2-thi-
ocyanatoethanone (0.26 g, 1.0 mmol) and dimethyl acetylenedi-
carboxylate (0.14 g, 1.0 mmol) in 10 mL CH2Cl2 was added,
dropwise, cyclohexyl isocyanide (0.11 g, 1 mmol) at 0 ꢀC over
10 min. The mixture was allowed to warm up to room temperature
and was finally stirred for 5 h. The solvent was removed under
vacuum and the residue was crystallized from n-hexane/ether (2:1)
mixture and the products were thus obtained as colorless crystals,
yield 0.51 g (81%); mp 123e126 ꢀC; Rf (25% AcOEt/n-hexane) 0.68;
Fig. 1. ORTEP diagram of 4b (CCDC reference number 816044).
functional group tolerance and is high yielding and product iso-
lation is very straightforward. The diversity offered by this process
is further enhanced by hydrolysis of iminolactones with aqueous
hydrochloric acid, which provides butenolide derivatives. We hope
that this approach may be of value to others seeking novel synthetic
fragments with unique properties for medicinal chemistry.
IR (KBr) nmax¼2919, 2841, 2157, 1752, 1729, 1680, 1429, 1296 cmꢁ1
;
1H NMR (300 MHz, CDCl3):
d
¼1.22e2.00 (10H, m, 5CH2 of cyclo-
2
3. Experimental
3.1. General
hexyl), 3.78 (4H, br s, OCH3 and CHeN), 3.86 (1H, d, JAB¼14.2 Hz,
2
CH2SCN), 3.92 (3H, s, OCH3), 4.17 (1H, d, JAB¼14.2 Hz, CH2SCN),
3
3
7.28 (2H, d, JHH¼8.6 Hz, HeAr), 7.52 (2H, d, JHH¼8.6 Hz, HeAr)
ppm; 13C NMR (75 MHz, CDCl3):
d
¼24.6, 24.7, 25.6, 31.0, 33.3, 41.2,
Melting points were measured on an Electrothermal 9100 ap-
paratus and are uncorrected. Mass spectra were recorded on
53.2, 53.3, 57.1, 89.8, 111.3, 123.8, 127.3, 132.5, 135.9, 137.9, 141.7,
153.0, 161.1, 161.7 ppm. Anal. Calcd for C22H23BrN2O5S: C, 52.08; H,
4.57; N, 5.52. Found: C, 51.97; H, 4.60; N, 5.47.
a
FINNIGAN-MAT 8430 mass spectrometer operating at an
Table 2
Hydrolysis of iminolactones to butenolides (5aee)

3628
A. Sarvary et al. / Tetrahedron 67 (2011) 3624e3630
3.2.1. (5Z)-Dimethyl 5-(tert-butylimino)-2-(4-bromophenyl)-2,5-di-
hydro-2-(thiocyanatomethyl)furan-3,4-dicarboxylate (4b). Colorless
crystals, yield 0.37 g (78%); mp 120e122 ꢀC; Rf (25% AcOEt/n-hex-
ane) 0.63; IR (KBr) nmax¼2930, 2869, 2146, 1755, 1720, 1672,
yield 0.28 g (65%); Rf (25% AcOEt/n-hexane) 0.71; mp 105e108 ꢀC;
IR (KBr) nmax¼2931, 2852, 2152, 1753, 1728, 1683, 1438 cmꢁ1
;
1H
NMR (300 MHz, CDCl3):
d
¼1.18e2.02 (10H, m, 5CH2 of cyclohexyl),
3.77e4.23 (9H, m, 2OCH3, CHeN and CH2SCN), 7.39 (5H, br s, HeAr)
1650 cmꢁ1; 1H NMR (300 MHz, CDCl3):
d
¼1.36 (9H, s, C(CH3)3), 3.79
ppm; 13C NMR (75 MHz, CDCl3):
d
¼24.6, 24.7, 25.7, 33.3, 33.4, 41.4,
(3H, s, OCH3), 3.87 (1H, d, 2JAB¼14.3 Hz, CH2SCN), 3.92 (3H, s, OCH3),
53.1, 53.2, 56.9, 90.2, 111.5, 125.5, 129.1, 129.4, 136.8, 137.6, 142.3,
153.4, 161.2, 161.8 ppm. Anal. Calcd for C22H24N2O5S: C, 61.67; H,
5.65; N, 6.54. Found: C, 61.87; H, 5.49; N, 6.71.
4.26 (1H, d, 2JAB¼14.3 Hz, CH2SCN), 7.30 (2H, d, 3JHH¼8.3 Hz, HeAr),
3
7.53 (2H, d, JHH¼8.3 Hz, HeAr) ppm; 13C NMR (75 MHz, CDCl3):
d
¼29.7, 41.5, 53.1, 53.3, 55.3, 90.2, 111.2, 123.7, 127.4, 132.2, 135.9,
139.4, 140.5, 150.8, 160.9, 161.8 ppm. Anal. Calcd for C20H21BrN2O5S:
C, 49.90; H, 4.40; N, 5.82. Found: C, 50.03; H, 4.35; N, 5.94; CCDC
reference number 816044.
3.2.7. (5Z)-Dimethyl
5-(tert-butylimino)-2,5-dihydro-2-phenyl-2-
(thiocyanatomethyl)furan-3,4-dicarboxylate (4h). Colorless crystals,
yield 0.25 g (78%); Rf (25% AcOEt/n-hexane) 0.70; mp 102e105 ꢀC;
IR (KBr) nmax¼2968, 2924, 2161, 1752, 1726, 1680, 1432 cmꢁ1
;
1H
3.2.2. (5Z)-Dimethyl 5-(2,6-dimethylphenylimino)-2-(4-bromophe-
nyl)-2,5-dihydro-2-(thiocyanatomethyl)furan-3,4-dicarboxylate
(4c). White crystals, yield 0.45 g (85%); mp 178e182 ꢀC; Rf (25%
AcOEt/n-hexane) 0.64; IR (KBr) nmax¼2952, 2924, 2168, 1733, 1691,
NMR (300 MHz, CDCl3):
d
¼1.38 (9H, s, C(CH3)3), 3.74e3.90 (7H, m,
2OCH3, CH2SCN), 4.31 (1H, d, 2JAB¼14.0 Hz, CH2SCN), 7.38e7.41 (5H,
m, HeAr), ppm; 13C NMR (75 MHz, CDCl3):
55.2, 90.6, 111.5, 125.6, 129.0, 129.4, 136.9, 139.2, 141.1, 151.2, 161.1,
162.0 ppm. Anal. Calcd for C20H22N2O5S: C, 59.69; H, 5.51; N, 6.96.
Found: C, 59.48; H, 5.43; N, 7.12.
d
¼29.7, 41.7, 53.1, 53.2,
1645, 1277 cmꢁ1; 1H NMR (300 MHz, CDCl3):
d
¼2.16 (6H, s, 2CH3),
2
3.68 (1H, d, JAB¼14.1 Hz, CH2SCN), 3.87 (3H, s, OCH3), 4.03 (3H, s,
2
OCH3), 4.32 (1H, d, JAB¼14.1 Hz, CH2SCN), 6.95e7.05 (3H, m,
3
3
HeAr), 7.24 (2H, d, JHH¼7.8 Hz, HeAr), 7.53 (2H, d, JHH¼7.8 Hz,
3.2.8. (5Z)-Dimethyl 5-(2,4,4-trimethylpentan-2-ylimino)-2,5-dihy-
dro-2-phenyl-2-(thiocyanatomethyl)furan-3,4-dicarboxylate
(4i). Colorless crystals, yield 0.29 g (62%); Rf (25% AcOEt/n-hexane)
0.68; mp 80e82 ꢀC; IR (KBr) nmax¼2951, 2866, 2160, 1748, 1727,
HeAr) ppm; 13C NMR (75 MHz, CDCl3):
90.7, 110.8, 124.1, 124.2, 127.0, 127.3, 127.7, 132.3, 135.1, 137.6, 143.0,
143.4, 160.7, 161.3 ppm. Anal. Calcd for C24H21BrN2O5S: C, 54.45; H,
4.00; N, 5.29. Found: C, 54.67; H, 4.07; N, 5.41.
d
¼18.2, 40.7, 53.5, 53.6,
1690, 1648 cmꢁ1; 1H NMR (300 MHz, CDCl3):
d
¼1.05(9H, s, (CH3)3),
1.43 (6H, s, (CH3)2), 1.63 (2H, br s, CH2), 3.79 (3H, s, OCH3), 3.89 (3H,
2
3.2.3. (5Z)-Diethyl 2-(4-bromophenyl)-5-(cyclohexylimino)-2,5-dihy
s, OCH3), 3.94 (1H, d, JAB¼13.9 Hz, CH2SCN), 4.28 (1H, d,
dro-2-(thiocyanatomethyl)furan-3,4-dicarboxylate
(4d). Colorless
2JAB¼13.9 Hz, CH2SCN),7.39e7.43 (5H, br s, HeAr) ppm; 13C NMR
crystals, yield 0.43 g (80%); Rf (25% AcOEt/n-hexane) 0.67; mp
(75 MHz, CDCl3):
d
¼29.6, 31.0, 31.6, 32.0, 41.9, 52.9, 53.1, 55.8, 58.8,
102e105 ꢀC; IR (KBr) nmax¼2928, 2847, 2152, 1750, 1722, 1681,
90.6, 111.5, 125.7, 128.9, 129.3, 137.0, 139.6, 140.3, 149.8, 161.2,
162.1 ppm. Anal. Calcd for C24H30N2O5S: C, 62.86; H, 6.59; N, 6.11.
Found: C, 63.04; H, 6.60; N, 6.14.
1485 cmꢁ1
;
1H NMR (300 MHz, CDCl3):
d
¼1.22e1.77 (16H, m,
2OCH2CH3, 5CH2 of cyclohexyl), 3.80e4.43 (7H, m, 2OCH2CH3, CH2SCN
and CHeN), 7.31 (2H, d, 3JHH¼8.5 Hz, HeAr), 7.54 (2H, d, 3JHH¼8.5 Hz,
HeAr) ppm; 13C NMR (75 MHz, CDCl3):
d¼13.9, 14.0, 24.5, 24.6, 25.7,
3.2.9. (5Z)-Diethyl 5-(cyclohexylimino)-2,5-dihydro-2-phenyl-2-(thi
ocyanatomethyl)furan-3,4-dicarboxylate (4j). Colorless crystals,
yield 0.27 g (60%); Rf (25% AcOEt/n-hexane) 0.72; mp 100e102 ꢀC;
33.3, 41.3, 56.9, 62.5, 62.6, 89.7, 111.3, 123.7, 127.3, 132.2, 136.0, 137.9,
141.4,153.0,160.8,161.3 ppm. Anal. Calcd for C24H27BrN2O5S: C, 53.83;
H, 5.08; N, 5.23. Found: C, 53.70; H, 4.89; N, 5.35.
IR (KBr) nmax¼2930, 2847, 2152, 1746, 1718, 1687, 1650, 1446 cmꢁ1
;
1H NMR (300 MHz, CDCl3):
d
¼1.24e1.83 (16H, m, 5CH2 of cyclo-
3.2.4. (5Z)-Diethyl 5-(2,4,4-trimethylpentan-2-ylimino)-2-(4-bromo
phenyl)-2,5-dihydro-2-(thiocyanatomethyl)furan-3,4-dicarboxylate
(4e). Yellow oil, yield 0.43 g (81%); Rf (25% AcOEt/n-hexane) 0.65; IR
hexyl and 2OCH2CH3), 3.89e4.40 (7H, m, 2OCH2CH3, CHeN and
CH2SCN), 7.41 (5H, br s, HeAr) ppm; 13C NMR (75 MHz, CDCl3):
d
¼13.8, 14.0, 24.5, 24.7, 25.7, 33.4, 41.6, 56.8, 62.4, 62.5, 90.1, 111.5,
(KBr) nmax¼2983, 2926, 2146,1755,1735,1663,1658,1585 cmꢁ1;1HNMR
125.5, 129.0, 129.3, 136.9, 137.5, 142.1, 153.3, 160.9, 161.4 ppm. Anal.
Calcd for C24H28N2O5S: C, 63.14; H, 6.18; N, 6.14. Found: C, 63.05; H,
6.19; N, 6.21.
3
(300 MHz, CDCl3):
d
¼0.99 (9H, s, C(CH3)3) 1.24 (3H, t, JHH¼7.1 Hz,
OCH2CH3), 1.33 (3H, t, 3JHH¼7.1 Hz, OCH2CH3), 1.40 (6H, s, C(CH3)2), 1.61
2
(2H, br s, CH2), 3.87 (1H, d, JAB¼14.0 Hz, CH2SCN) 4.11e4.36 (5H,
2OCH2CH3 and CH2SCN), 7.34 (2H, d, 3JHH¼8.5 Hz, HeAr), 7.50 (2H, d,
3.2.10. (5Z)-Diethyl 5-(tert-butylimino)-2,5-dihydro-2-phenyl-2-(thi
ocyanatomethyl)furan-3,4-dicarboxylate (4k). Yellowoil, yield 0.24 g
(57%); Rf (25% AcOEt/n-hexane) 0.69; IR (KBr) nmax¼2968, 2897,
3JHH¼8.5 Hz, HeAr) ppm; 13C NMR (75 MHz, CDCl3):
¼13.7, 14.1, 29.7,
d
29.8, 31.7, 31.9, 41.7, 55.7, 58.7, 62.2, 62.5, 90.1, 111.2, 123.5, 127.6, 132.1,
136.2,139.7,139.8,149.6,160.6,161.5ppm. Anal. CalcdforC26H33BrN2O5S:
C, 55.22; H, 5.88; N, 4.95. Found: C, 55.38; H, 5.76; N, 5.03.
2152, 1744, 1719, 16891651 cmꢁ1 1H NMR (300 MHz, CDCl3):
;
d
¼1.23e1.42 (15H, 3, (CH3)3 and 2OCH2CH3), 3.91e476 (6H,
2OCH2CH3, CH2SCN), 7.37e7.45 (5H, br s, HeAr) ppm; 13C NMR
(75 MHz, CDCl3):
3.2.5. (5Z)-Di-tert-butyl 2-(4-bromophenyl)-5-(cyclohexylimino)-2,
5-dihydro-2-(thiocyanatomethyl)furan-3,4-dicarboxylate
(4f). White crystals, yield 0.44 g (75%); mp 123e126 ꢀC; Rf (25%
AcOEt/n-hexane) 0.65; IR (KBr) nmax¼2930, 2863, 2157, 1744, 1722,
d
¼13.8, 14.1, 29.7, 41.9, 55.1, 62.2, 62.4, 90.5, 111.5,
125.7, 129.1, 129.3, 137.0, 139.1, 140.8, 151.2, 160.7, 161.4 ppm. Anal.
Calcd for C22H26N2O5S: C, 61.38; H, 6.09; N, 6.51. Found: C, 61.36; H,
6.13; N, 6.46.
1683, 1479 cmꢁ1; 1H NMR (300 MHz, CDCl3):
5CH2 of cyclohexyl and 2OC(CH3)3), 3.82 (1H, br s, CHeN), 3.85 (1H,
d
¼1.35e2.17 (28H, m,
3.2.11. (5Z)-Dimethyl 2-(4-phenylophenyl)-5-(cyclohexylimino)-2-(th
2
2
d, JAB¼14.0 Hz, CH2SCN), 4.13 (1H, d, JAB¼14.0 Hz, CH2SCN), 7.29
iocyanatomethyl)-2,5-dihydrofuran-3,4-dicarboxylate
(4l). White
3
3
(2H, d, JHH¼8.4 Hz, HeAr), 7.53 (2H, d, JHH¼8.4 Hz, HeAr) ppm;
crystals, yield 0.42 g (83%); mp 165e167 ꢀC; Rf (25% AcOEt/n-hexane)
0.58; IR (KBr) nmax¼2930, 2849, 2156, 1751, 1724, 1679, 1642,
13C NMR (75 MHz, CDCl3):
d
¼24.1, 24.2, 25.9, 27.9, 28.2, 30.9, 33.4,
41.9, 55.9, 84.0, 84.6, 89.4, 111.4, 123.4, 127.3, 132.0, 136.5, 137.4,
141.6, 152.8, 160.4, 160.5 ppm. Anal. Calcd for C28H35BrN2O5S: C,
56.85; H, 5.96; N, 4.74. Found: C, 56.97; H, 5.84; N, 4.90.
1440 cmꢁ1; 1H NMR (300 MHz, CDCl3):
d
¼1.23e1.88 (10H, m, 5CH2 of
cyclohexyl), 3.83 (4H, br s, OCH3 and CHeN), 3.92 (3H, s, OCH3), 3.96
2
2
(1H, d, JAB¼14.2 Hz, CH2SCN), 4.27 (1H, d, JAB¼14.2 Hz, CH2SCN),
7.28e7.66 (9H, m, HeAr) ppm; 13C NMR (75 MHz, CDCl3):
d¼24.6,
3.2.6. (5Z)-Dimethyl 5-(cyclohexylimino)-2,5-dihydro-2-phenyl-2-
(thiocyanatomethyl)furan-3,4-dicarboxylate (4g). Colorless crystals,
24.8, 25.7, 33.4, 33.5, 41.4, 53.2, 57.1, 90.1, 111.5, 127.1, 127.7, 127.9,
128.9, 129.1, 135.7, 137.7, 142.2, 142.3, 153.3, 161.3, 161.8 ppm. Anal.

A. Sarvary et al. / Tetrahedron 67 (2011) 3624e3630
3629
Calcd for C28H28N2O5S: C, 66.65; H, 5.59; N, 5.55. Found: C, 66.91; H,
5.73; N, 5.51.
(69%); Rf (25% AcOEt/n-hexane) 0.43; IR (KBr) nmax¼2980, 2865,
1745, 1724, 1678, 1528 cmꢁ1 1H NMR (300 MHz, CDCl3):
;
d
¼1.13e1.44 (15H, m, C(CH3)3 and 2OCH2CH3), 2.03 (3H, s, CH3),
2
2
3.2.12. (5Z)-Diethyl 2-(4-phenylophenyl)-5-(cyclohexylimino)-2,5-di
hydro-2-(thiocyanatomethyl)furan-3,4-dicarboxylate (4m). White
crystals, yield 0.45 g (85%); mp 149e151 ꢀC; Rf (25% AcOEt/n-hex-
ane) 0.57; IR (KBr) nmax¼2931, 2829, 2161, 1745, 1740, 1666,
4.09 (2H, q, JAB¼7.0 Hz, OCH2CH3), 4.29 (2H, q, JAB¼7.1 Hz,
OCH2CH3), 7.57 (2H, d, 3JHH¼8.8 Hz, HeAr), 8.13 (2H, d, 3JHH¼8.8 Hz,
HeAr)ppm; 13C NMR (75 MHz, CDCl3):
d¼13.6, 13.8, 24.2, 29.4, 54.6,
61.9, 62.0, 89.5, 123.5, 127.1, 129.3, 137.3, 144.2, 146.8, 147.6, 152.3,
160.3, 162.0 ppm. Anal. Calcd for C21H26N2O7: C, 60.28; H, 6.26; N,
6.69. Found: C, 60.46; H, 6.19; N, 6.81.
1598 cmꢁ1
;
1H NMR (300 MHz, CDCl3):
d
¼1.20e1.79 (16H, m,
2OCH2CH3 and 5CH2 of cyclohexyl), 3.98e4.43 (7H, m, 2OCH2CH3,
CH2SCN and CHeN), 7.39e7.66 (9H, m, HeAr) ppm; 13C NMR
(75 MHz, CDCl3):
d
¼13.8, 14.1, 24.6, 24.7, 25.7, 33.4, 41.5, 56.9, 62.4,
3.2.18. (5Z)-Di-tert-butyl
5-(cyclohexylimino)-2,5-dihydro-2-
62.5, 90.1, 111.5, 126.1, 127.1, 127.7, 128.9, 129.1, 135.8, 137.6, 139.9,
142.2,153.4,161.0,161.4 ppm. Anal. Calcd for C30H32N2O5S: C, 67.65;
H, 6.06; N, 5.26. Found: C, 67.63; H, 5.98; N, 5.35.
methyl-2-(4-nitrophenyl)furan-3,4-dicarboxylate (4s). White crys-
tals, yield 0.39 g (78%); mp 124e126 ꢀC; Rf (25% AcOEt/n-hexane)
0.45;IR (KBr)nmax¼2989, 2933, 2863,1725,1682,1521 cmꢁ1; 1H NMR
(300 MHz, CDCl3):
d
¼093e2.04 (28H, m, 5CH2 of cyclohexyl and
3.2.13. (5Z)-Diethyl 5-(tert-butylimino)-2-(4-phenylophenyl)-2,5-di-
2OC(CH3)3), 3.63 (1H, br s, CHeN), 7.58 (2H, d, 3JHH¼8.3 Hz, HeAr),
3
hydro-2-(thiocyanatomethyl)furan-3,4-dicarboxylate
(4n). White
8.20 (2H, d, JHH¼8.4 Hz, HeAr) ppm; 13C NMR (75 MHz, CDCl3):
crystals, yield 0.4 g (80%); mp 120e121 ꢀC; Rf (25% AcOEt/n-hexane)
d
¼24.3, 25.8, 27.1, 27.8, 28.2, 33.3, 55.6, 83.7, 83.8, 88.7, 123.3, 123.5,
0.60; IR (KBr) nmax¼2967, 2931, 2156, 1752, 1721, 1685, 1637 cmꢁ1
;
125.8, 127.0, 129.2, 147.1, 147.6, 159.9, 160.9 ppm. Anal. Calcd for
C27H36N2O7: C, 64.78; H, 7.25; N, 5.60. Found: C, 64.97; H, 7.41; N,
1H NMR (300 MHz, CDCl3):
d
¼1.21e1.42 (15H, m, C(CH3)3 and
2
2OCH2CH3), 3.98 (1H, d, JAB¼13.9 Hz, CH2SCN), 4.17e4.45 (5H, m,
5.78.
2OCH2CH3 and CH2SCN), 7.28e7.77 (9H, m, HeAr) ppm; 13C NMR
(75 MHz, CDCl3):
d
¼13.8, 14.1, 29.8, 41.9, 55.2, 62.3, 62.4, 90.5, 111.5,
3.3. Typical procedure for preparation of diethyl 2-(4-
bromophenyl)-2,5-dihydro-5-oxo-2-(thiocyanatomethyl)
furan-3,4-dicarboxylate (5a)
126.2, 127.1, 127.6, 127.8, 128.9, 135.8, 139.2, 139.9, 140.7, 142.1, 151.2,
160.8, 161.7 ppm. Anal. Calcd for C28H30N2O5S: C, 66.38; H, 5.97; N,
5.53. Found: C, 66.52; H, 5.92; N, 5.50.
To a solution of hydrochloric acid (18%, 10 mL) was added pow-
dered iminolactone 4d (0.53 g, 1.0 mmol) and stirred at room tem-
perature for 12 h. Aftercompletion of the reaction (monitoredbyTLC
method), thereaction mixturewasextractedwithCH2Cl2 (2ꢂ10 mL).
The combined extract solvent was removed under vacuum and the
residue was crystallized from 1:3 CH2Cl2/n-hexane mixture to yield
5a as a white crystals, yield 0.39 g (86%); mp 69e71 ꢀC; Rf (25%
3.2.14. (5Z)-Diethyl 5-(cyclohexylimino)-2,5-dihydro-2-(4-methox-
yphenyl)-2-(thiocyanatomethyl)furan-3,4-dicarboxylate
(4o). Yellow oil, yield 0.29 g (60%); Rf (25% AcOEt/n-hexane) 0.62; IR
(KBr) nmax¼2933, 2844, 2151, 1748, 1724, 1678, 1601, 1513 cmꢁ1; 1H
NMR (300 MHz, CDCl3):
d¼1.1.18e1.75 (16H, m, 2OCH2CH3 and 5CH2
of cyclohexyl), 3.71e4.31 (10H, m, OCH3, 2OCH2CH3, CH2SCN and
3
3
CHeN), 6.84 (2H, d, JHH¼7.9 Hz, HeAr), 7.26 (2H, d, JHH¼7.9 Hz,
AcOEt/n-hexane) 0.38; IR (KBr) nmax¼2162, 1749, 1729, 1656 cmꢁ1
;
3
HeAr) ppm; 13C NMR (75 MHz, CDCl3):
33.3, 41.4, 55.2, 56.6, 62.2, 62.3, 90.0, 111.5, 114.2, 126.9, 128.7, 137.3,
142.2, 153.5, 160.1, 160.7, 161.4 ppm. Anal. Calcd for C25H30N2O6S: C,
61.71; H, 6.21; N, 5.76. Found: C, 61.90; H, 6.17; N, 5.84.
d
¼13.7, 13.9, 24.5, 24.6, 25.7,
1H NMR (300 MHz, CDCl3):
d
¼1.31 (3H, t, JHH¼7.1 Hz, OCH2CH3),
3
2
1.39 (3H, t, JHH¼7.1 Hz, OCH2CH3), 3.89 (1H, d, JAB¼14.4 Hz,
2
CH2SCN), 4.21 (1H, d, JAB¼14.4 Hz, CH2SCN),4.27e4.44 (4H, m,
2OCH2CH3), 7.32 (2H, d, 3JHH¼8.7 Hz, HeAr), 7.58 (2H, d, 3JHH¼8.7 Hz,
HeAr) ppm; 13C NMR (75 MHz, CDCl3):
d
¼13.7, 14.0, 41.0, 63.0, 63.5,
3.2.15. (5Z)-Dimethyl 5-(cyclohexylimino)-2,5-dihydro-2-methyl-2-
(4-nitrophenyl)furan-3,4-dicarboxylate (4p). White crystals, yield
0.32 g (76%); Rf (25% AcOEt/n-hexane) 0.40; mp 167e170 ꢀC; IR
87.2, 110.5, 124.5, 127.2, 130.4, 132.6, 133.0, 153.2, 159.5, 160.2,
164.7 ppm. Anal. Calcd for C18H16BrNO6S: C, 47.59; H, 3.55; N, 3.08.
Found: C, 47.71; H, 3.49; N, 3.00.
(KBr) nmax¼2929, 2849, 1753, 1731, 1676, 1521 cmꢁ1
;
1H NMR
(300 MHz, CDCl3):
d
¼1.19e1.85 (10H, m, 5CH2 of cyclohexyl), 2.09
3.3.1. Dimethyl 2-(4-bromophenyl)-2,5-dihydro-5-oxo-2-(thiocyana
tomethyl)furan-3,4-dicarboxylate (5b). Colorless oil, yield 0.34 g
(81%); Rf (25% AcOEt/n-hexane) 0.27; IR (KBr) nmax¼2168, 1793,
(3H, s, CH3), 3.61 (1H, br s, CHeN), 3.73 (3H, s, OCH3), 3.92 (3H, s,
3
3
OCH3), 7.61 (2H, d, JHH¼8.6 Hz, HeAr), 8.23 (2H, d, JHH¼8.6 Hz,
HeAr) ppm; 13C NMR (75 MHz, CDCl3):
53.1, 56.8, 88.9, 123.7, 127.1, 135.9, 145.5, 146.4, 147.8, 154.2, 160.8,
162.3 ppm. Anal. Calcd for C21H24N2O7: C, 60.57; H, 5.81; N, 6.73.
Found: C, 60.60; H, 5.81; N, 6.92.
d
¼4.2, 24.7, 25.7, 33.3, 52.8,
1734, 1663 cmꢁ1; 1H NMR (300 MHz, CDCl3):
d
¼3.87 (4H, br s, OCH3
2
and CH2SCN), 3.94 (3H, s, OCH3), 4.20 (1H, d, JAB¼14.3 Hz,
CH2SCN), 7.28 (2H, d, 3JHH¼7.8 Hz, HeAr), 7.56 (2H, d, 3JHH¼7.8 Hz,
HeAr) ppm; 13C NMR (75 MHz, CDCl3):
110.7, 124.6, 127.1, 129.9, 132.6, 132.8, 154.0, 159.8, 160.6, 164.6 ppm.
Anal. Calcd for C16H12BrNO6S: C, 45.09; H, 2.84; N, 3.29. Found: C,
44.87; H, 2.76; N, 3.35.
d
¼40.8, 53.6, 54.0, 87.3,
3.2.16. (5Z)-Diethyl 5-(cyclohexylimino)-2,5-dihydro-2-methyl-2-(4-
nitrophenyl)furan-3,4-dicarboxylate (4q). White crystals, yield
0.33 g (74%); mp 138e140 ꢀC; Rf (25% AcOEt/n-hexane) 0.48; IR
(KBr) nmax¼2936, 2839, 1745, 1723, 1676, 1519 cmꢁ1
;
1H NMR
3.3.2. Diethyl 2-(bromomethyl)-2-(4-bromophenyl)-2,5-dihydro-5-
oxofuran-3,4-dicarboxylate (5c). Colorless oil, yield 0.38 g (80%); Rf
(25% AcOEt/n-hexane) 0.30; IR (KBr) nmax¼1795, 1731, 1663,
(300 MHz, CDCl3):
d
¼1.21e1.76 (16H, m, 2OCH2CH3 and 5CH2 of
cyclohexyl), 2.10 (3H, s, CH3), 3.65 (1H, m, CHeN), 4.16 (2H, q,
3JHH¼6.9 Hz, OCH2CH3), 4.39 (2H, q, JHH¼7.0 Hz, OCH2CH3), 7.62
1486 cmꢁ1
;
1H NMR (300 MHz, CDCl3):
d
¼1.23e1.36 (6H, m,
3
3
3
(2H, d, JHH¼8.6 Hz, HeAr), 8.23 (2H, d, JHH¼8.6 Hz, HeAr) ppm;
2OCH2CH3), 4.06e4.44 (6H, m, CH2Br and 2OCH2CH3), 7.31 (2H, d,
13C NMR (75 MHz, CDCl3):
62.1, 62.3, 89.0, 123.6, 127.1, 135.9, 145.3, 146.7, 147.8, 154.3, 160.4,
161.9 ppm. Anal. Calcd for C23H28N2O7: C, 62.15; H, 6.35; N, 6.30.
Found: C, 62.32; H, 6.21; N, 6.39.
d
¼13.8, 14.1, 24.3, 24.7, 25.7, 33.4, 56.6,
3JHH¼7.4 Hz, HeAr), 7.51 (2H, d, 3JHH¼7.4 Hz, HeAr) ppm; 13C NMR
(75 MHz, CDCl3):
d
¼13.8, 14.1, 35.1, 62.8, 63.2, 87.0, 124.2, 127.4,
130.1, 132.4, 133.1, 154.2, 159.8, 160.0, 165.1 ppm. Anal. Calcd for
17H16Br2O6: C, 42.89; H, 3.39. Found: C, 42.70; H, 3.45.
C
3.2.17. (5Z)-Diethyl 5-(tert-butylimino)-2,5-dihydro-2-methyl-2-(4-
3.3.3. Dimethyl 2,5-dihydro-2-methyl-2-(4-nitrophenyl)-5-oxofuran-
nitrophenyl)furan-3,4-dicarboxylate (4r). Yellow oil, yield 0.29 g
3,4-dicarboxylate (5d). White crystals, yield 0.30 g (91%); mp

3630
A. Sarvary et al. / Tetrahedron 67 (2011) 3624e3630
97e100 ꢀC; Rf (25% AcOEt/n-hexane) 0.25; IR (KBr) nmax¼1762,1732,
1600, 1517 cmꢁ1; MS, m/z (%): 336 (Mþþ1, 1), 320 (3), 293 (5), 277
(10), 261 (10), 218 (5),150 (20),100 (5), 56 (100); 1H NMR (300 MHz,
4. Loksha, Y.; el Barbary, A.; el-Badawi, M.; Nielsen, C.; Pedersen, E. Bioorg. Med.
Chem. 2005, 13, 4209e4920.
5. Rudolph, J.; Theis, H.; Hanke, R.; Endermann, R.; Johannsen, L.; Geschke, F. U. J.
Med. Chem. 2001, 44, 619e626.
6. Linares, G. G.; Gismondi, S.; Codesido, N. O.; Moreno, S. N. J.; Docampob, R.;
Rodrigueza, J. B. Bioorg. Med. Chem. Lett. 2007, 17, 5068e5071.
7. Oliaruso, M. A.; Wolf, J. F. In Synthesis of Lactones and Lactams; Wiley: New York,
NY, 1993.
8. (a) Villemin, D.; Liao, L. Synth. Commun. 2003, 33, 1575e1585; (b) Tang, Y.; Li, C.
Tetrahedron Lett. 2006, 47, 3823e3825.
CDCl3):
d
¼2.14 (3H, s, CH3), 3.81 (3H, s, OCH3), 3.91 (3H, s, OCH3), 7.58
(2H, d, 3JHH¼7.9 Hz, HeAr), 8.22 (2H, d, 3JHH¼7.9 Hz, HeAr) ppm; 13
C
NMR (75 MHz, CDCl3):
d¼24.4, 53.4, 53.6, 86.6, 124.1, 126.8, 127.2,
143.1, 148.2, 159.2, 160.3, 160.6, 165.4 ppm. Anal. Calcd for
15H13NO8: C, 53.74; H, 3.91; N, 4.18. Found: C, 53.47; H, 4.00; N, 4.27.
C
9. Grossmann, G.; Poncioni, M.; Bornand, M.; Jolivet, B.; Neuburger, M.; Sequin, U.
Tetrahedron 2003, 59, 3237e3251.
3.3.4. Diethyl 2,5-dihydro-2-methyl-2-(4-nitrophenyl)-5-oxofuran-
3,4-dicarboxylate (5e). White crystals, yield 0.32 g (87%); Rf (25%
AcOEt/n-hexane) 0.30; IR (KBr) nmax¼1788, 1734, 1656, 1527,
10. (a) Hein, S. M.; Gloer, J. B.; Koster, B.; Malloch, D. J. Nat. Prod. 2001, 64, 809e812;
(b) Pour, M.; Spulak, M.; Balsanek, V.; Kunes, J.; Kubanova, P.; Butcha, V. Bioorg.
Med. Chem. 2003, 11, 2843e2866.
11. Padakanti, S.; Pal, M.; Yeleswarapu, K. R. Tetrahedron 2003, 59, 7915e7920.
12. (a) Takahashi, S.; Kubota, A.; Nakata, T. Tetrahedron Lett. 2002, 43, 8661e8664;
(b) Bellina, F.; Falchi, E.; Rossi, R. Tetrahedron 2003, 59, 9091e9100.
13. (a) Hanessian, S.; Park, R. Y.; Yang, R. Y. Synlett 1997, 351e352; (b) Hanessian, S.;
Park, R. Y.; Yang, R. Y. Synlett 1997, 353e354; (c) Choudhury, A.; Jin, F.; Wang, D.;
Wang, Z.; Xu, G.; Nguyen, D.; Castoro, J.; Pierce, M. E.; Confalone, P. N. Tetra-
hedron Lett. 2003, 44, 247e250.
1346 cmꢁ1
;
1H NMR (300 MHz, CDCl3):
d¼1.24e1.38 (6H, m,
2OCH2CH3), 2.15 (3H, s, CH3), 4.24e4.42 (4H, m, 2OCH2CH3), 7.61 (2H,
d, 3JHH¼8.9 Hz, HeAr), 8.24 (2H, d, 3JHH¼8.9 Hz, HeAr)ppm; 13C NMR
(75 MHz, CDCl3):
d
¼13.7,14.1, 24.4, 62.8, 63.0, 86.6,124.0,126.9,127.6,
143.3,148.2,158.4,159.9,160.0,165.7 ppm. Anal. Calcd for C17H17NO8:
C, 56.20; H, 4.72; N, 3.86. Found: C, 56.52; H, 4.90; N, 3.80.
14. Ito, Y.; Kato, H.; Saegusa, T. J. Org. Chem. 1982, 47, 741e743.
15. Chatani, N.; Oshita, M.; Tobisu, M.; Ishii, Y.; Murai, S. J. Am. Chem. Soc. 2003, 125,
7812e7813.
Acknowledgements
16. Bez, B.; Zhao, C. G. Org. Lett. 2003, 5, 4991e4993.
17. Yavari, I.; Sabbaghan, M.; Hossaini, Z. Monatsh. Chem. 2008, 139, 625e628.
18. Shaabani, A.; Soleimani, E.; Sarvary, A. Monatsh. Chem. 2008, 139, 629e632.
19. Teimouri, M. B.; Shaabani, A.; Bazhrang, R. Tetrahedron 2006, 62, 1845e1848.
20. Esmaeili, A. A.; Zendegani, H. Tetrahedron 2005, 61, 4031e4034.
21. Yavari, I.; Hossaini, Z.; Sabbaghan, M. Mol. Diversity 2006, 10, 479e482.
22. Ma, S.; Xie, H. J. Org. Chem. 2002, 67, 6575e6578.
We gratefully acknowledge financial support from the Research
Council of Shahid Beheshti University.
Supplementary data
23. Ma, S.; Xie, H. Tetrahedron 2005, 61, 251e258.
24. Shaabani, A.; Maleki, A.; Rezayan, A. H.; Sarvary, A. Mol. Diversity 10.1007/
Experimental procedures, spectra of products, IR, mass, 1H and
13C NMR for 4aes and 5eed, and crystallographic data for com-
pound 4b. Supplementary data associated with this article can be
found in online version at doi:10.1016/j.tet.2011.03.100.
s11030-010-9258-1.
25. (a) Shaabani, A.; Rezayan, A. H.; Kishipour, S.; Sarvary, A.; Ng, S. W. Org. Lett.
2009, 11, 3342e3345; (b) Shaabani, A.; Soleimani, E.; Rezayan, A. H.; Sarvary, A.;
Khavasi, H. R. Org. Lett. 2008, 10, 2581e2584; (c) Shaabani, A.; Rezayan, A. H.;
Sarvary, A.; Heidary, M.; Ng, S. W. Tetrahedron 2009, 65, 6063e6068; (d)
Shaabani, A.; Sarvary, A.; Rezayan, A. H.; Keshipour, S. Tetrahedron 2009, 65,
3492e3495; (e) Shaabani, A.; Ghadari, R.; Sarvary, A.; Rezayan, A. H. J. Org.
Chem. 2009, 74, 4372e4374; (f) Shaabani, A.; Rezayan, A. H.; Ghasemi, S.;
Sarvary, A. Tetrahedron Lett. 2009, 50, 1456e1458; (g) Shaabani, A.; Rezayan, A.
H.; Rahmati, A.; Sarvary, A. Synlett 2007, 1458e1460.
References and notes
1. Patai, S. In Syntheses and Preparative Application of Thiocyanates Chemistry of
Cyanates and their Derivatives; John Wiley: New York, NY, 1977; Vol. 2.
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2005, 39, 405e408.
26. Nair, V.; Rajesh, C.; Vinod, A. U.; Bindu, S.; Speekanth, A. R.; Mathen, J. S.;
Balagopal, L. Acc. Chem. Res. 2003, 36, 899e907.
3. Bisogno, F. R.; Cuetos, A.; Lavandera, I.; Gotor, V. Green Chem. 2009, 11, 452e454.