Three-component reaction of an isocyanide and a dialkyl acetylenedicarboxylate with a phenacyl halide in the presence of water: An efficient method for the one-pot synthesis of γ-iminolactone derivatives

Article abstract of DOI:10.1002/hlca.201000057

The zwitterion, formed from the reaction of an alkyl isocyanide and a dialkyl acetylenedicarboxylate, reacts with phenacyl halides in H₂O to produce γ-iminolactone derivatives in high yields. H₂O helps to avoid the use of highly toxic and environmentally unfavorable solvents for this conversion.

Full text of DOI:10.1002/hlca.201000057

Helvetica Chimica Acta – Vol. 93 (2010)
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Three-Component Reaction of an Isocyanide and a Dialkyl
Acetylenedicarboxylate with a Phenacyl Halide in the Presence of Water: An
Efficient Method for the One-Pot Synthesis of g-Iminolactone Derivatives
by Ali Ramazani*, Aram Rezaei, Amir Tofangchi Mahyari, Morteza Rouhani, and Mehdi Khoobi
Chemistry Department, Zanjan University, P.O. Box 45195-313, Zanjan, Iran
(fax: þ 982415283100; e-mail: aliramazani@gmail.com)
The zwitterion, formed from the reaction of an alkyl isocyanide and a dialkyl acetylenedicarboxylate,
reacts with phenacyl halides in H2O to produce g-iminolactone derivatives in high yields. H2O helps to
avoid the use of highly toxic and environmentally unfavorable solvents for this conversion.
Introduction. – Many protocols for the synthesis of iminolactones have been
reported [1 – 8]. The most widely used approach are isocyanide-based reactions [1 – 5].
As early as 1982, Saegusa and his co-workers reported on the Et2AlCl-mediated
reaction of a,b-unsaturated carbonyl compounds with MeNC, leading to unsaturated
N-substituted iminolactones, which can be easily converted to g-butyrolactone [1].
Recently, Chatani et al. re-examined a catalytic [1 þ 4] cycloaddition reaction of
isocyanides and a,b-unsaturated CO compounds in the presence of a catalytic amount
of GaCl3, leading to unsaturated iminolactone derivatives [4]. Moreover, GaCl3
catalyzed the double insertion of aryl isocyanides into terminal and disubstituted
epoxides, which led finally to a,b-unsaturated a-amino iminolactones [5]. Also, the
Pd(Ph3P)4-catalyzed reaction of 4,4-disubstituted allenecarboxamides and organic
iodides in the presence of K2CO3 in toluene afforded iminolactones [6]. Finally, the
haloiminolactonization of 4,4-disubstituted allenecarboxamides with CuX2 (X¼Cl,
Br) or I2 in THF also provided unsaturated iminolactones [7].
Here, we report a simple and practical procedure to prepare highly functionalized
g-iminolactones by a one-pot three-component reaction of isocyanides, acetylenedi-
carboxylates, and phenacyl chloride or bromide in the presence of H2O (Scheme 1).
Results and Discussion. – As part of our ongoing program on the development of
efficient and robust methods for the preparation of heterocyclic compounds [9 – 15], we
describe here a clean and efficient process in H2O at room temperature leading to g-
iminolactone derivatives 4 (Scheme 1 and Table). We also used acetophenone, 1-
benzyl- and 1-(pyridin-2-yl)ethanone instead of phenacyl halides in this reaction, but
the yields of the corresponding products were low and several by-products were
obtained.
As indicated in the Table, the 1:1:1 addition reaction of phenacyl halides with
dimethyl acetylenedicarboxylate and t-BuNC occured in H2O and CH2Cl2 at room
temperature to produce dimethyl 5-(tert-butylimino)-2-(chloromethyl)-2-phenyl-2,5-
dihydrofuran-3,4-dicarboxylate (4a). In the presence of H2O, the yield of 4a (97%) was
ꢀ 2010 Verlag Helvetica Chimica Acta AG, Zꢁrich

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Helvetica Chimica Acta – Vol. 93 (2010)
Scheme 1. Three-Component Synthesis of g-Iminolactone Derivatives 4 in H2O (see the Table)
Table. H2O-Promoted Synthesis of g-Iminolactone Derivatives 4 (cf. Scheme 1)
R’
R
X
Y
Yield [%]a)
Yield [%]b)
4a
4b
4c
4d
4e
4f
4g
4h
4i
Me
Me
Me
Et
Et
Et
Me
Me
Et
t-Bu
Cl
Cl
Cl
Cl
Cl
Cl
Br
Br
Br
Br
H
H
H
H
H
H
Br
Br
Br
Br
77
74
71
74
70
69
90c)
97c)
80c)
83c)
97
92
88
94
90
84
97
97
90
92
Cyclohexyl
1,1,3,3-Tetramethylbutyl
t-Bu
Cyclohexyl
1,1,3,3-Tetramethylbutyl
t-Bu
Cyclohexyl
t-Bu
Cyclohexyl
4j
Et
a) Yields of isolated 4; reaction conditions: CH2Cl2, r.t., 12 h. b) Yields of isolated 4; reaction conditions:
H2O, r.t., 2 h. c) Synthesis of compounds 4g – 4j in CH2Cl2 was reported in [8b].
higher than in CH2Cl2 as solvent (77%), and also the time of product formation was
shorter (2 h) in H2O than in CH2Cl2 (12 h). The structures of the products were
1
deduced from their IR, H- and 13C-NMR, and mass spectra. The mass spectra of 4
1
displayed molecular-ion peaks at the appropriate m/z values. The H-NMR spectrum
(CDCl3) of 4a consisted of a singlet at 1.38 ppm (Me3C), two further singlets at 3.78 and
3.90 ppm (COOMe), an AB system at 4.20 and 4.64 ppm with JAB ¼ 11.8 Hz (CH2Cl),
and a multiplet at 7.26 – 7.40 ppm for the aromatic H-atoms. The 1H-decoupled
13C-NMR spectrum of 4a showed 15 distinct resonances; partial assignment of these
1
resonances is given in the Exper. Part. The H- and 13C-NMR spectra of compounds
4b – 4j were similar to those of 4a, except for the aromatic moiety and the alkyl groups,
which exhibited characteristic signals with appropriate chemical shifts.
Although we have not established experimentally the mechanism of the reaction, a
plausible reaction sequence that accounts for the formation of 4 is depicted in
Scheme 2. It is conceivable that the initial step is the formation of zwitterionic
intermediate 5 from isocyanide 1 and acetylenedicarboxylate 2, which then adds to the
electron-poor CO group of phenacyl halides 3, leading to a dipolar specie 6. Cyclization
of 6 leads then to the g-iminolactone 4.
Conclusions. – In summary, we have established H2O as a novel reaction medium
for the synthesis of highly functionalized g-iminolactone derivatives. This procedure

Helvetica Chimica Acta – Vol. 93 (2010)
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Scheme 2. Proposed Mechanism for the Formation of g-Iminolactone Derivatives 4
offers significant advantages such as operational simplicity, mild reaction conditions,
enhanced rates, ease of isolation of products, cleaner reaction profiles, and H2O as
solvent, which makes it a useful and an attractive alternative for the synthesis of g-
iminolactone derivatives.
Experimental Part
General. Freshly distilled solvents were used throughout, and anh. solvents were dried according to
the procedure of Perrin and Armarego [16]. IR Spectra (KBr): Mattson-1000 FT-IR spectrophotometer.
1H- and 13C-NMR spectra: Bruker 250 spectrometer in CDCl3 with TMS as internal standard. MS:
FINNIGAN-MAT 8430 mass spectrometer operating at an ionization potential of 20 eV. Elemental
analyses: Heraeus CHN-O-Rapid analyzer.
General Procedure. To a magnetically stirred soln. of 2-chloroacetophenone (1 mmol) and dimethyl
acetylenedicarboxylate (1 mmol) in H2O (3 ml) was added dropwise of a soln. of t-BuNC (1 mmol) in
H2O (1 ml) at r.t. over 5 min. The mixture was stirred for 2 h. The solvent was removed under reduced
pressure, and the viscous residue was purified by flash column chromatography (CC; SiO2; petroleum
ether/AcOEt). The solvent was removed under reduced pressure, and product 4a was obtained as
colorless oil (for yields, see the Table).
Dimethyl 5-(tert-Butylimino)-2-(chloromethyl)-2,5-dihydro-2-phenylfuran-3,4-dicarboxylate (4a).
1
IR: 2937, 2870, 1748, 1715, 1680, 1452, 1244. H-NMR: 1.38 (s, t-Bu); 3.78, 3.90 (2s, 2 MeO); 4.20, 4.64
(AB, J ¼ 11.8, CH2Cl); 7.26 – 7.40 (m, 5 arom. H). 13C-NMR: 29.54 (Me3C); 48.08 (CH2Cl); 52.84, 52.95
(2 MeO); 54.96 (Me3C); 91.35 (C(2)); 125.75, 128.82, 129.07 (5 arom. CH); 136.73, 139.04, 141.20 (3 C);
152.31 (C¼N); 161.13, 162.37 (2 C¼O). EI-MS: 380 (6), 356 (100), 302 (83), 250 (38), 236 (41), 157 (9),
105 (23), 57 (23), 41 (15). Anal. calc. for C19H22ClNO5: C 60.08, H 5.84, N 3.69; found: C 60.00, H 5.78, N
3.58.
Dimethyl 2-(Chloromethyl)-5-(cyclohexylimino)-2,5-dihydro-2-phenylfuran-3,4-dicarboxylate (4b).
IR: 2940, 2857, 1751, 1720, 1686, 1473, 1254. 1H-NMR: 1.15 – 1.90 (m, 5 CH2 of cyclohexyl); 3.69 – 3.76 (m,
CHꢀN); 3.77, 3.90 (2s, 2 MeO); 4.20, 4.64 (AB, J ¼ 11.8, CH2Cl); 7.26 – 7.40 (m, 5 arom. H). 13C-NMR:
24.82 (2 CH2(b) of cyclohexyl); 25.72 (1 CH2(g) of cyclohexyl); 33.47 (2 CH2(a) of cyclohexyl); 47.98
(CH2Cl); 52.87, 53.04 (2 MeO); 56.83 (CHꢀN); 90.62 (C(2)); 125.67, 128.88, 129.18 (5 arom. CH);
136.61, 137.69, 142.30 (3 C); 154.36 (C¼N); 161.12, 162.13 (2 C¼O). EI-MS: 406 (25), 398 (30), 378 (48),
352 (36), 332 (100), 290 (60), 250 (33), 105 (50), 98 (12), 55 (33), 41 (19). Anal. calc. for C21H24ClNO5: C
62.14, H 5.96, N 3.45; found: C 62.09, H 5.88, N 3.39.
Dimethyl 2-(Chloromethyl)-2,5-dihydro-2-phenyl-5-[(1,1,3,3-tetramethylbutyl)imino]furan-3,4-di-
carboxylate (4c). IR: 2960, 2878, 1751, 1720, 1680, 1474, 1246. 1H-NMR: 1.00 (s, Me3C); 1.42 (s,
Me2CN); 1.66 (s, CH2CMe3); 3.76, 3.86 (2s, 2 MeO); 4.20, 4.61 (AB, J ¼ 11.8, CH2Cl); 7.36 – 7.44 (m, 5
arom. H). 13C-NMR: 29.68 (Me2C); 31.63 (Me3C); 31.94 (Me3C); 52.76, 52.80 (2 MeO); 55.32
(CH2CMe3); 56.50 (Me2C); 91.44 (C(2)); 125.81, 128.77, 129.03 (5 arom. CH); 137.32, 139.59, 140.42
(3 C); 150.99 (C¼N); 161.19, 162.45 (2 C¼O). EI-MS: 436 (30), 394 (100), 362 (30), 282 (28), 250 (90),
233 (35), 91 (5), 57 (30), 41 (10). Anal. calc. for C23H30ClNO5: C 63.37, H 6.94, N 3.21; found: C 63.28, H
6.88, N 3.18.

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Helvetica Chimica Acta – Vol. 93 (2010)
Diethyl 5-(tert-Butylimino)-2-(chloromethyl)-2,5-dihydro-2-phenylfuran-3,4-dicarboxylate (4d). IR:
2938, 2876, 1743, 1722, 1680, 1448, 1243. 1H-NMR: 1.24, 1.35 (2t, J ¼ 7.3, 2 MeCH2); 1.37 (s, t-Bu); 4.36,
4.20 (2q, J ¼ 7.3, 2 MeCH2); 4.21, 4.61 (AB, J ¼ 11.8, CH2Cl); 7.26 – 7.40 (m, 5 arom. H). 13C-NMR: 13.74,
14.06 (2 MeCH2); 29.55 (Me3C); 48.15 (CH2Cl); 54.89 (Me3C); 62.00, 62.09 (2 MeCH2); 91.33 (C(2));
125.83, 128.74, 128.98 (5 arom. CH); 136.85, 138.94, 141.06 (3 C); 152.51 (C¼N); 160.76, 162.00
(2 C¼O). EI-MS: 408 (12), 380 (5), 352 (100), 306 (95), 250 (50), 233 (39), 156 (15), 105 (20), 57 (25),
41 (13). Anal. calc. for C21H26ClNO5: C 61.84, H 6.42, N 3.69; found: C 61.30, H 5.78, N 3.58.
Data of Diethyl 2-(Chloromethyl)-5-(cyclohexylimino)-2,5-dihydro-2-phenylfuran-3,4-dicarboxylate
(4e). IR: 2944, 2857, 1751, 1718 1685, 1435, 1258. 1H-NMR: 1.24, 1.35 (2t, J ¼ 7.3, 2 MeCH2); 1.21 – 1.89
(m, 5 CH2 of cyclohexyl); 3.69 – 3.74 (m, CHꢀN); 4.20, 4.62 (AB, JAB ¼ 11.8, CH2Cl); 4.21, 4.33 (2q, J ¼
7.3, 2 MeCH2); 7.26 – 7.42 (m, 5 arom. H). 13C-NMR: 13.76, 14.04 (2 MeCH2); 24.75 (2 CH2(b) of
cyclohexyl); 25.76 (CH2(g) of cyclohexyl); 33.46 (2 CH2(a) of cyclohexyl); 48.05 (CH2Cl); 56.66
(CHꢀN); 62.03, 62.18 (2 MeCH2); 90.61 (C(2)); 125.76, 128.81, 129.09 (5 arom. CH); 136.77, 137.56,
142.13 (3 C); 154.47 (C¼N); 160.76, 161.71 (2 C¼O). EI-MS: 434 (10), 408 (25), 395 (30), 378 (48), 352
(36), 332 (100), 290 (60), 250 (33), 233 (35), 98 (12), 105 (50), 55 (33), 41 (19). Anal. calc. for
C23H28ClNO5: C 63.66, H 6.50 N 3.23; found: C 63.09, H 5.88, N 3.39.
Diethyl 2-(Chloromethyl)-2-phenyl-5-[(1,1,3,3-tetramethylbutyl)imino]-2,5-dihydrofuran-3,4-dicarb-
oxylate (4f). IR: 2967, 2878, 1746, 1715, 1685, 1457, 1222. 1H-NMR: 1.00 (s, Me3C); 1.27, 1.36 (2t, J ¼ 7.3,
2 MeCH2); 1.42 (s, Me2C); 1.66 (s, CH2CMe3); 4.20, 4.59 (AB, JAB ¼ 11.8, CH2Cl); 4.22, 4.33 (2q, J ¼ 7.3,
2 MeCH2); 7.26 – 7.49 (m, 5 arom. H). 13C-NMR: 13.74, 14.08 (2 MeCH2); 29.75 (Me2CN); 31.68 (Me3C);
31.93 (Me3C); 48.18 (CH2Cl); 55.27 (CH2CMe3); 58.41 (Me2CN); 61.96, 62.03 (2 MeCH2); 91.39 (C(2));
125.90, 128.70, 128.93 (5 arom. CH); 137.11, 139.62, 140.95 (3 C); 153.86 (C¼N); 160.84, 162.10
(2 C¼O). EI-MS: 464 (13), 428 (38), 408 (100), 392 (90), 362 (36), 296 (32), 250 (80), 233 (40), 105
(37), 57 (45), 41 (20). Anal. calc. for C25H34ClNO5: C 64.71, H 7.39, N 3.02; found: C 64.09, H 7.22, N 2.99.
This work was supported by the Iran National Science Foundation: INSF.
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Received February 9, 2010