Isocyanide-based multicomponent reaction: One-pot synthesis of new derivatives of iminofuranone

Article abstract of DOI:10.1002/hlca.201000359

The one-pot multicomponent reaction of alkyl isocyanide, alkylidene-substituted Meldrum's acid, and arylcarboxylic acids affords new derivatives of iminofuranone in fair yields. The structure of the products was deduced from their spectroscopic data. Two

Full text of DOI:10.1002/hlca.201000359

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Isocyanide-Based Multicomponent Reaction: One-Pot Synthesis of New
Derivatives of Iminofuranone
by Azizollah Habibi* and Azadeh Rahmani
Faculty of Chemistry, Tarbiat Moallem University, P. Code 15719-14911, No. 43, Enghelab Avenue,
Tehran, Iran
(phone/fax: þ 98-261-4550702; e-mail: habibi@tmu.ac.ir)
The one-pot multicomponent reaction of alkyl isocyanide, alkylidene-substituted Meldrumꢀs acid,
and arylcarboxylic acids affords new derivatives of iminofuranone in fair yields. The structure of the
products was deduced from their spectroscopic data. Two equivalents of the respective isocyanides
participate in this reaction.
Introduction. – Multicomponent reactions (MCRs) have been used as a versatile
synthetic method in the preparation of complex molecules, in which multiple new
bonds can be created in a single reaction from readily available starting materials.
MCRs have unique features such as high convergence, atom efficiency, simple and short
procedure, and they also reduce the environmental burden [1 – 4]. To accomplish the
synthesis of highly complex molecules, particularly natural products, great efforts have
been made to develop new multicomponent reactions. Among these reactions,
isocyanide-based multicomponent reactions (IMCRs) are very powerful condensations
in organic synthesis [1][2]. The Passerini and Ugi reactions are classical examples. In
the organic synthesis, only a few MCRs are well-known, and each reaction affords
compounds with a similar framework and a few different substituents, whereas, in the
chemistry of the isocyanides, a much greater variation of MCRs is known. In the Ugi
four component reactions (U-4CRs) and related reactions, the skeletons and the
substituents can differ. Thus, IMCRs have achieved an extensive application, because
starting materials and products with a greater variety than in other reactions can
participate. To expand their utility and gaining access also to drug-like heterocyclic
compounds, several research groups are now developing modifications of these
reactions [1 – 8].
Meldrumꢀs acid and its various derivatives have been widely used for heterocycle
and drug synthesis [9 – 11]. We were interested in developing isocyanide-based
multicomponent reaction using these derivatives. We have already studied the
reactions between isocyanides and alkylidene-substituted Meldrumꢀs acid in the
presence of SH-, OH-, and NH-containing compounds [11 – 16]. In this article, we now
describe a facile and convenient one-pot reaction of alkyl isocyanide, alkylidene-
substituted Meldrumꢀs acid, and arylcarboxylic acid.
ꢁ 2011 Verlag Helvetica Chimica Acta AG, Zꢂrich

Helvetica Chimica Acta – Vol. 94 (2011)
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Results and Discussion. – The one-pot reaction of alkyl isocyanide 1, alkylidene-
substituted Meldrumꢀs acid 2, and arylcarboxylic acid 3 in CH2Cl2/DMSO leads to new
derivatives of (2E)-4-{1-[(tert-butyl)amino]-2-methyl-1-oxopropan-2-yl}-2-[(tert-butyl)-
imino]-2,5-dihydro-5-oxofuran-3-yl 4-bromobenzoate (4a; Scheme 1). An interesting
aspect of this reaction is the participation of two molecules of isocyanide in a 2 :1:1
multicomponent reaction. The reaction occurred smoothly at room temperature and
was completed within 48 h. As far as iminofuranones have been of interest for chemists
(the synthesis of new derivatives of iminofuranone and the investigation of their
pharmaceutical activities have been reported recently [17 – 20]), this protocol can be
used as a simple one-pot method to synthesize these derivatives.
Scheme 1. Synthesis of Iminofuranone Derivatives
Alike to our previous work, we expected equimolar amounts of starting materials to
react. But spectroscopic data of the products showed that two equivalents of isocyanide
participated in the reaction. The IR spectrum of 4a clearly exhibited an NH stretching
1
band at 3216 cmꢀ1, and three C¼O bands at 1769, 1744, and 1693 cmꢀ1. The H-NMR
spectrum of 4a exhibited three sharp singlets arising from Me2C (d(H) 1.39) and two
Me3C (d(H) 1.41 and 1.62) groups. An AA’BB’ signal for the aromatic-H-atoms was
indicative for a para-substituted phenyl group, and a signal at 9.59 ppm for the amide
NH. The 13C-NMR spectrum of 4a showed 16 distinct resonances in agreement with the
proposed structure. The signals at d(C) 28.3 and 28.4 relate to two Me3C moieties from
two t-butyl isocyanide molecules. The two signals at d(C) 52.1 and 59.6 belong to Me3C.
All other signals were consistent with the core-structure of compound 4a.
Although the mechanism of the reaction between isocyanide and alkylidene-
substituted Meldrumꢀs acid in the presence of aryl carboxylic acid has not been
established in an experimental manner, a plausible mechanism for the formation of the
product is presented in Scheme 2. The first step of this mechanism involves the formal
[4 þ 1] cycloaddition reaction of the electron-deficient heterodiene moiety of
alkylidene-substituted Meldrumꢀs acid 2 with the isocyanide 1 affording the inter-

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Helvetica Chimica Acta – Vol. 94 (2011)
mediate imino lactone 5. Then, protonation of 5 by the arylcarboxylic acid occurs to
give intermediate 6. Michael addition of the carboxylate anion to the iminium enone
moiety of 6 leads to intermediate 7 and subsequently to compound 8. Then, a second
molecule of 1 attacks the enone in a second Michael addition to give intermediate 9.
Next, ring opening of Meldrumꢀs acid core in intermediate 9 via elimination of acetone
occurs to form intermediate 10. Finally, the latter intermediate undergoes 5-exo-dig
cyclization to form the highly substituted iminofuranone 4 as the product.
In summary, the multicomponent reaction between two molecules of isocyanide,
alkylidene-substituted Meldrumꢀs acid and arylcarboxylic acids provide a simple one-
pot entry to the synthesis of furanones. The advantages of this route are that the
reaction can be performed under neutral conditions at room temperature, and that no
activation or modification of the starting materials is needed. The simplicity of this
protocol makes it a suitable alternative to complex multistep approaches.
Scheme 2. Proposed Mechanism for the Reaction

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Experimental Part
General. Meldrumꢀs acid and isocyanides were obtained from Fluka (Buchs, Switzerland) and used
without further purification. M.p.: Electrothermal 9100 apparatus; uncorrected. IR Spectra: FT-IR
.
102MB BOMEM spectrometer; n˜ in cmꢀ1 1H- and 13C-NMR spectra: Bruker DRX-300 Avance
instrument; in CDCl3 at 300.1 and 75.47 MHz, resp.; d in ppm, J in Hz. MS: Finnigan-MAT-8430 mass
spectrometer at 70 eV; in m/z (rel. %). Elemental analyses (C, H, N): Heraeus CHN-S-O-Rapid
analyzer.
(2E)-4-{1-[(tert-Butyl)amino]-2-methyl-1-oxopropan-2-yl}-2-[(tert-butyl)imino]-2,5-dihydro-5-oxo-
furan-3-yl 4-Bromobenzoate (4a). Typical Procedure. To a magnetically stirred soln. of isopropylidene-
substituted Meldrumꢀs acid 2a (0.18 g, 1 mmol) and 4-bromobenzoic acid (0.20 g, 1 mmol) in CH2Cl2
(10 ml) and a few drops of DMSO was added dropwise a soln. of tert-butyl isocyanide (0.22 ml, 2 mmol)
in CH2Cl2 at r.t. within 5 min. The mixture was kept at r.t. for 48 h. The solvent was removed under
reduced pressure, and the residue was extracted with AcOEt and cold MeOH and filtered. The solvent
was evaporated at reduced pressure, and 4a was obtained. Yield: 320 mg (65%). White powder. M.p.
174 – 1768. IR (KBr): 3216, 3065, 2873, 1769, 1744, 1693, 1670, 1582, 1460, 1346, 1253, 1165, 1138, 1041,
1
t
t
838, 740. H-NMR: 1.39 (s, 2 Me); 1.41 (s, Bu); 1.62 (s, Bu); 7.63, 7.97 (AA’BB’, J ¼ 9, 4 CH); 9.59 (s,
NH). 13C-NMR: 22.8; 28.3; 28.4; 44.5; 52.1; 59.6; 127.0; 128.5; 129.5; 131.9; 132.2; 150.0; 157.3; 164.0;
169.4; 180.0. EI-MS: 495 (4, Mþ), 493 (4, Mþ), 394 (5), 392 (5), 364 (3), 292 (9), 236 (10), 185 (88), 183
(100), 157 (11), 154 (16), 57 (20), 41 (12). Anal. calc. for C23H29BrN2O5 (493.39): C 55.99, H 5.92, N 5.68;
found: C 55.87, H 6.01, N 5.59.
(2E)-4-[1-(tert-Butylamino)-2-methyl-1-oxopropan-2-yl]-2-(tert-butylimino)-2,5-dihydro-5-oxofur-
an-3-yl 4-Chlorobenzoate (4b). Yield: 269 mg (60%). White powder. M.p. 167 – 1698. IR (KBr): 3291,
1
3087, 2932, 1747, 1742, 1707, 1642, 1599, 1488, 1335, 1255, 1160, 1116, 1014, 845, 756. H-NMR: 1.39 (s,
t
t
2 Me); 1.42 (s, Bu); 1.62 (s, Bu); 7.47, 8.05 (AA’BB’, J ¼ 9, 4 CH); 9.58 (s, NH). 13C-NMR: 22.8; 28.3;
28.4; 44.5; 52.1; 59.6; 126.7; 126.8; 129.2; 131.9; 132.0; 150.1; 157.4; 163.9; 169.4; 180.0. EI-MS: 449
(5, Mþ), 376 (2), 350 (3), 348 (3), 320 (3), 292 (4), 236 (5), 155 (6), 141 (29), 139 (100), 113 (4), 111 (15),
57 (16), 41 (9). Anal. calc. for C23H29ClN2O5 (448.94): C 61.53, H 6.51, N 6.24; found: C 61.42, H 6.45, N
6.07.
(2E)-4-{1-[(tert-Butyl)amino]-2-methyl-1-oxopropan-2-yl}-2-[(tert-butyl)imino]-2,5-dihydro-5-oxo-
furan-3-yl 4-Nitrobenzoate (4c). Yield: 363 mg (79%). White powder. M.p. 176 – 1788. IR (KBr): 3216,
3060, 2997, 1777, 1748, 1693, 1667, 1624, 1567, 1531, 1461, 1363, 1347, 1219, 1162, 1136, 1042, 846, 701.
1H-NMR: 1.41 (s, 2 Me); 1.42 (s, tBu); 1.64 (s, tBu); 8.28 – 8.36 (m, 4 CH); 9.87 (s, NH). 13C-NMR: 22.9;
28.3; 28.4; 44.6; 52.2; 59.8; 123.9; 127.0; 128.5; 129.6; 133.8; 151.1; 156.8; 163.0; 169.3; 179.8. EI-MS: 459
(8, Mþ), 387 (4), 361 (2), 359 (20), 331 (21), 303 (40), 292 (6), 236 (12), 155 (13), 150 (100), 104 (24), 92
(12), 76 (15), 57 (39), 56 (15), 41 (22). Anal. calc. for C23H29N3O7 (459.49): C 60.12, H 6.36, N 9.14;
found: C 60.62, H 6.77, N 8.81.
(2E)-4-{1-[(tert-Butyl)carbamoyl]-4-methylcyclohexyl}-2-[(tert-butyl)imino]-2,5-dihydro-5-oxofur-
an-3-yl 4-Nitrobenzoate (4d). Yield: 329 mg (64%). White powder. M.p. 187 – 1898. IR (KBr): 3305, 2956,
2921, 1750, 1744, 1706, 1646, 1605, 1559, 1535, 1524, 1458, 1336, 1260, 1181, 1117, 851, 718. 1H-NMR: 0.88
(d, J ¼ 6.5, Me); 1.42 (s, tBu); 1.61 (s, tBu); 1.10 – 2.09 (m, cyclohexyl); 8.29 – 8.39 (m, 4 CH); 9.48 (s, NH).
13C-NMR: 22.2; 24.7; 28.2; 28.4; 29.9; 31.4; 46.1; 52.2; 59.3; 124.0; 128.7; 131.8; 133.7; 149.5; 151.2; 157.5;
162.9; 169.0; 178.3. EI-MS: 513 (7, Mþ), 414 (3), 385 (5), 357 (12), 290 (5), 234 (7), 208 (12), 150 (100),
104 (19), 92 (11), 76 (7), 57 (29), 41 (8). Anal. calc. for C27H35N3O7 (513.58): C 63.14, H 6.87, N 8.18;
found: C 62.99, H 7.02, N 8.02.
(2E)-4-{1-[(tert-Butyl)carbamoyl]cyclohexyl}-2-[(tert-butyl)imino]-2,5-dihydro-5-oxofuran-3-yl 4-
Nitrobenzoate (4e). Yield: 364 mg (73%). White powder. M.p. 173 – 1758. IR (KBr): 3218, 3063, 2975,
2935, 1761, 1742, 1694, 1668, 1619, 1566, 1529, 1459, 1362, 1260, 1183, 1118, 1050, 1010, 865, 847, 708.
t
t
1H-NMR: 1.42 (s, Bu); 1.63 (s, Bu); 1.56 – 1.95 (m, cyclohexyl); 8.30 – 8.39 (m, 4 CH); 9.48 (s, NH).
13C-NMR: 21.4; 24.8; 29.6; 28.4; 28.6; 46.5; 52.1; 59.3; 123.9; 128.8; 131.6; 133.7; 149.5; 151.1; 157.5; 162.8;
169.0; 178.3. EI-MS: 499 (5, Mþ), 427 (8), 399 (8), 371 (5), 343 (18), 276 (7), 220 (7), 194 (14), 150 (100),
120 (5), 104 (19), 92 (6), 76 (6), 57 (29), 41 (13). Anal. calc. for C26H33N3O7 (499.56): C 62.51, H 6.66, N
8.41; found: C 63.07, H 7.00, N 8.09.

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Helvetica Chimica Acta – Vol. 94 (2011)
(2E)-4-{1-[(tert-Butyl)carbamoyl]cyclopentyl}-2-[(tert-butyl)imino]-2,5-dihydro-5-oxofuran-3-yl 4-
Bromobenzoate (4f). Yield: 390 mg (75%). White powder. M.p. 201 – 2038. IR (KBr): 3222, 3060, 2974,
1759, 1741 1690, 1667, 1589, 1579, 1485, 1361, 1261, 1219, 1167, 1124, 1068, 997, 848, 739. 1H-NMR: 1.42 (s,
t
tBu); 1.65 (s, Bu); 1.46 – 2.06 (m, cyclopentyl); 7.64, 7.97 (AA’BB’, J ¼ 9.2, 4 CH), 9.78 (s, NH).
13C-NMR: 28.0; 28.3; 28.4; 28.7; 37.4; 53.0; 59.4; 127.3; 129.5; 129.7; 132.0; 132.2; 149.2; 157.3; 164.1;
169.9; 181.6. EI-MS: 520 (2, Mþ), 518 (2, Mþ), 518 (2), 420 (8), 418 (8), 318 (10), 262 (16), 206 (10), 185
(100), 183 (97), 180 (15), 157 (11), 153 (10), 76 (7), 57 (18), 41 (10). Anal. calc. for C25H31BrN2O5
(519.43): C 57.81, H 6.02, N 5.39; found: C 57.73, H 6.05, N 5.33.
(2E)-4-[1-(Cyclohexylamino)-2-methyl-1-oxopropan-2-yl]-2-(cyclohexylimino)-2,5-dihydro-5-oxo-
furan-3-yl 4-Chlorobenzoate (4g). Yield: 375 mg (75%). White powder. M.p. 196 – 1988. IR (KBr): 3270,
3092, 2956, 2936, 1746, 1711, 1669, 1639, 1592, 1569, 1451, 1402, 1368, 1257, 1230, 1163, 1099, 863, 755.
1H-NMR: 1.22 – 2.24 (m, 2 cyclohexyl); 1.43 (s, Me); 1.53 (s, Me); 3.85 (br., CH); 4.12 (tt, Jaa ¼ 12.0, Jae
¼
3.7, CH), 7.05, 7.94 (AA’BB’, J ¼ 9.2, 4 CH); 9.95 (d, J ¼ 6, NH). 13C-NMR: 22.7; 24.7; 25.8; 28.6; 32.4;
44.6; 49.5; 52.4; 126.7; 126.8; 129.2; 131.8; 132.0; 157.3; 159.2; 164.0; 168.4; 179.2. EI-MS: 501 (4, Mþ), 376
(16), 363 (19), 344 (33), 140 (24), 139 (100). Anal. calc. for C27H33ClN2O5 (501.01): C 64.73, H 6.64, N
5.59; found: C 64.64, H 6.74, N 5.57.
(2E)-4-{1-[(tert-Butyl)carbamoyl]-4-methylcyclohexyl}-2-[(tert-butyl)imino]-2,5-dihydro-5-oxofur-
an-3-yl 4-Chlorobenzoate (4h). Yield: 392 mg (78%). White powder. M.p. 192 – 1948. IR (KBr): 3304,
3086, 2956, 2927, 1748, 1742, 1707, 1646, 1592, 1560, 1486, 1444, 1365, 1336, 1258, 1202, 1170, 1047, 1013,
844, 749. 1H-NMR: 0.89 (d, J ¼ 6.4, Me); 1.4 – 2.02 (m, cyclohexyl); 1.43 (s, tBu); 1.65 (s, tBu); 7.49, 8.06
(AA’BB’, J ¼ 9.2, 4 CH); 9.03 (s, NH). 13C-NMR: 22.3; 24.9; 28.3; 28.4; 30.3; 31.3; 45.9; 52.0; 59.1; 126.7;
127.9; 129.1; 131.9; 149.5; 151.2; 158.2; 163.7; 168.9; 178.6. EI-MS: 503 (3, Mþ), 402 (3), 346 (3), 290 (7),
234 (5), 207 (8), 141 (35), 139 (100), 113 (4), 111 (12), 57 (13), 41 (6). Anal. calc. for C27H35ClN2O5
(503.03): C 64.47, H 7.01, N 5.57; found: C 64.36, H 6.96, N 5.46.
(2E)-4-[1-(Cyclohexylcarbamoyl)cyclopentyl]-2-(cyclohexylimino)-2,5-dihydro-5-oxofuran-3-yl 4-
Nitrobenzoate (4i). Yield: 402 mg (75%). White powder. M.p. 166 – 1688. IR (KBr): 3269, 3062, 2932,
2856, 1761, 1740, 1691, 1664, 1634, 1529, 1450, 1409, 1373, 1354, 1247, 1182, 1149, 1019, 1052, 1010, 847,
709. 1H-NMR: 1.29 – 2.12 (m, 2 cyclohexyl, cyclopentyl); 3.81 (br., CH); 4.10 (br., CH); 8.28 – 8.37 (m,
4 CH); 10.43 (d, J ¼ 6, NH). 13C-NMR: 24.6; 24.9; 25.8; 28.0; 28.6; 32.3; 35.6; 49.6; 52.4; 123.9; 131.7;
133.7; 149.0; 151.1; 156.8; 163.2; 168.8; 180.4. EI-MS: 537 (5, Mþ), 413 (14), 411 (57), 370 (32), 288 (13),
262 (11), 235 (13), 180 (41), 152 (12), 150 (100), 104 (11). Anal. calc. for C29H35N3O7 (537.60): C 64.79, H
6.56, N 7.82; found: C 64.71, H 6.68, N 7.65.
(2E)-4-{1-[(tert-Butyl)carbamoyl]cyclohexyl}-2-[(tert-butyl)imino]-5-oxo-2,5-dihydrofuran-3-yl 4-
Bromobenzoate (4j). Yield: 299 mg (56%). White powder. M.p. 184 – 1858. IR (KBr): 3434, 3066,
2967, 2927, 2853, 1745, 1701, 1675, 1587, 1532, 1459, 1366, 1260, 1229, 1150, 1121, 1043, 1005, 845, 751.
1H-NMR: 1.43 (s, tBu); 1.62 (s, tBu); 1.42 – 1.95 (m, cyclohexyl); 7.68, 8.02 (AA’BB’, J ¼ 9.2, 4 CH); 9.04
(s, NH). 13C-NMR: 21.4; 24.8; 30.0; 28.3; 28.4; 46.3; 52.0; 59.0; 127.1; 128.6; 129.7; 131.9; 132.4; 149.6;
158.2; 164.8; 168.9; 179.6. EI-MS: 535 (4, Mþ), 533 (4, Mþ), 435 (2), 433 (2), 332 (4), 276 (7), 220 (6), 194
(12), 184 (78), 182 (100), 157 (12), 155 (12), 104 (5), 76 (5), 57 (17), 41 (8). Anal. calc. for C26H33BrN2O5
(533.45): C 58.54, H 6.24, N 5.25; found: C 58.42, H 6.10, N 5.19.
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Received September 20, 2010