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Synlett 2008(1): 33-36  
DOI: 10.1055/s-2007-992372
LETTER
© Georg Thieme Verlag Stuttgart · New York

A One-Pot, Ugi Four-Component Synthesis of 2(3H)-Oxazolone 4-Carboxamides

M. García-Valverdea, S. Machoa, S. Marcaccini*b, T. Rodrígueza, J. Rojoa, T. Torroba*a
a Departamento de Química, Facultad de Ciencias, Universidad de Burgos, Pza. Misael Bañuelos s/n 09001 Burgos, Spain
e-Mail: ttorroba@ubu.es;
b Dipartimento di Chimica Organica ‘Ugo Schiff’, Università degli Studi di Firenze, 50019 Sesto Fiorentino (FI), Italy
Fax: +34(947)258831; e-Mail: stefano.marcaccini@unifi.it;
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Publikationsverlauf

Received 28 September 2007
Publikationsdatum:
21. November 2007 (online)

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Abstract

Ugi reaction between arylglyoxals, anilines, cyclohexyl isocyanide and trichloroacetic acid in dichloromethane, in the presence of molecular sieves, afforded 2(3H)-oxazolone 4-carbox­amides in good yields by a one-pot process that involved an in situ spontaneous cyclization of the Ugi product through an intermediate ketone enolate and the chloroacetate carbonyl group. The synthesis is based on the ability of the trichloroacetyl group to function as a masked carbonic acid surrogate.

Key words

isocyanide - arylglyoxal - trichloroacetic acid - oxazolone

    References and Notes

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9

Synthesis of 2 (3 H )-Oxazolone 4-Carboxamides 5a-m: A mixture of freshly distilled arylglyoxal (1 mmol), the corresponding arylamine (1.2 mmol) and activated 3 Å MS (1 g) in CH2Cl2 (10 mL) was stirred at r.t. for 10 min. Then cyclohexyl isocyanide (110 mg, 1 mmol) and anhyd tri-chloroacetic acid (162 mg, 1 mmol) were consecutively added and the mixture was stirred at r.t. for 2 d, then filtered and the solvent was evaporated under reduced pressure. The sticky residue was stirred with Et2O (10 mL) until a solid separated. The solid was filtered and recrystallized from the appropriate solvent.
N -Cyclohexyl-2-oxo-3,5-diphenyl-2,3-dihydrooxazole-4-carboxamide (5a): colorless crystals (308 mg, 85%); mp 230-231 °C (i-Pr2O-i-PrOH). 1H NMR (400 MHz, CDCl3): δ = 0.85-0.93 (m, 2 H), 0.98-1.10 (m, 1 H), 1.18-1.29 (m, 2 H), 1.50-1.61 (m, 3 H), 1.64-1.74 (m, 2 H), 3.73-3.81 (m, 1 H), 5.45 (d, J = 8.0 Hz, 1 H), 7.38-7.49 (m, 8 H), 7.76-7.79 (m, 2 H). 13C NMR (100 MHz, CDCl3): δ = 24.4 (CH2), 25.1 (CH2), 32.1 (CH2), 48.6 (CH), 119.1 (Cq), 125.5 (CHAr), 126.1 (Cq), 126.3 (CHAr), 128.5 (CHAr), 128.7 (CHAr), 129.4 (CHAr), 129.6 (CHAr), 133.7 (Cq), 139.1 (Cq), 152.5 (Cq), 157.1 (Cq). IR (KBr): 3254, 1770, 1630 cm-1. MS (EI): m/z (%) = 362 (69) [M+], 279 (100). HRMS (EI): m/z calcd for C22H22N2O3: 362.1630; found: 362.1632. Anal. Calcd for C22H22N2O3: C, 72.91; H, 6.12; N, 7.73. Found: C, 72.97; H, 6.16; N, 7.67.
3-(4-Chlorophenyl)- N -cyclohexyl-2-oxo-5- p -tolyl-2,3-dihydrooxazole-4-carboxamide (5g): colorless crystals (284 mg, 69%); mp 232-233 °C (i-Pr2O-i-PrOH). 1H NMR (400 MHz, CDCl3): δ = 0.93-1.10 (m, 3 H), 1.20-1.34 (m, 2 H), 1.55-1.63 (m, 3 H), 1.75-1.79 (m, 2 H), 2.39 (s, 3 H), 3.75-3.84 (m, 1 H), 5.61 (d, J = 8.2 Hz, 1 H), 7.22-7.25 (m, 2 H), 7.32-7.35 (m, 2 H), 7.40-7.44 (m, 2 H), 7.57-7.59 (m, 2 H). 13C NMR (100 MHz, CDCl3): δ = 21.7 (Me), 24.8 (CH2), 25.4 (CH2), 32.6 (CH2), 49.0 (CH), 118.4 (Cq), 123.3 (Cq), 126.9 (CHAr), 127.1 (CHAr), 129.7 (CHAr), 129.8 (CHAr), 132.8 (Cq), 134.4 (Cq), 140.0 (Cq), 140.7 (Cq), 152.7 (Cq), 157.2 (Cq). IR (KBr): 3282, 1774, 1663, 1635, 1495 cm-1. MS (EI): m/z (%) = 412 (16) [M+ + 2], 410 (57) [M+], 327 (84), 119 (100). HRMS (EI): m/z calcd for C23H23ClN2O3: 410.1397; found: 410.1382. Anal. Calcd for C23H23ClN2O3: C, 67.23; H, 5.64; N, 6.82. Found: C, 67.28; H, 5.67; N, 6.77.
5-(4-Chlorophenyl)- N -cyclohexyl-2-oxo-3-phenyl-2,3-dihydrooxazole-4-carboxamide (5h): colorless crystals (349 mg, 88%); mp 224-226 °C (dec., i-Pr2O-i-PrOH). 1H NMR (400 MHz, CDCl3): δ = 0.78-0.88 (m, 2 H), 0.98-1.08 (m, 1 H), 1.18-1.30 (m, 2 H), 1.51-1.68 (m, 5 H), 3.71-3.79 (m, 1 H), 5.37 (d, J = 8.0 Hz, 1 H), 7.38-7.49 (m, 7 H), 7.75-7.77 (m, 2 H). 13C NMR (100 MHz, CDCl3): δ = 24.6 (CH2), 25.4 (CH2), 32.5 (CH2), 48.9 (CH), 119.5 (Cq), 125.0 (Cq), 125.9 (CHAr), 128.0 (CHAr), 129.0 (CHAr), 129.2 (CHAr), 129.9 (CHAr), 131.7 (Cq), 133.9 (Cq), 135.9 (Cq), 139.2 (Cq), 152.5 (Cq), 157.1 (Cq). IR (KBr): 3305, 1789, 1658, 1632 cm-1. MS (EI): m/z (%) = 398 (24) [M+ + 2], 396 (100) [M+], 313 (59), 315 (19). HRMS (EI): m/z calcd for C22H21ClN2O3: 396.1241; found: 396.1233. Anal. Calcd for C22H21ClN2O3: C, 66.58; H, 5.33; N, 7.06. Found: C, 66.53; H, 5.29; N, 7.01.
3-(3-Chlorophenyl)- N -cyclohexyl-5-(4-methoxyphenyl)-2-oxo-2,3-dihydrooxazole-4-carboxamide (5l): colorless crystals (265 mg, 62%); mp 240-241 °C (dec., i-Pr2O-i-PrOH). 1H NMR (400 MHz, CDCl3): δ = 0.86-1.30 (m, 5 H), 1.53-1.61 (m, 3 H), 1.75-1.79 (m, 2 H), 3.77-3.83 (m, 1 H), 3.85 (s, 3 H), 5.49 (d, J = 8.4 Hz, 1 H), 6.94-6.96 (m, 2 H), 7.32-7.41 (m, 4 H), 7.67-7.69 (m, 2 H). 13C NMR (100 MHz, CDCl3): δ = 24.7 (CH2), 25.4 (CH2), 32.6 (CH2), 48.9 (CH), 55.6 (Me), 114.5 (CHAr), 117.5 (Cq), 118.6 (Cq), 123.9 (CHAr), 126.0 (CHAr), 128.7 (CHAr), 128.8 (CHAr), 130.5 (CHAr), 135.2 (Cq), 152.5 (Cq), 157.2 (Cq), 161.2 (Cq). IR (KBr): 3418, 3247, 1773, 1661, 1632, 1607 cm-1. MS (EI): m/z (%) = 428 (13) [M+ + 2], 426 (47) [M+], 135 (100). HRMS (EI): m/z calcd for C23H23ClN2O4: 426.1346; found: 426.1329. Anal. Calcd for C23H23ClN2O4: C, 64.71; H, 5.43; N, 6.56. Found: C, 64.66; H, 5.38; N, 6.51.

10

Crystal Data for Compound 5b: C23H24N2O3, MW = 376.44, orthorhombic, P212121, a = 9.038(5) Å, b = 10.536 (5) Å, c = 21.916(11) Å, α = 90°, β = 90°, γ = 90°; V = 2087.1(18) Å3, Z = 4, D calc = 1.198 gcm-1, µ(Mo-Kα) = 0.080 mm-1. Colorless prism (0.30 × 0.20 × 0.10 mm3), 19410 measured reflections, 3658 independent (R int = 0.0968), 2247 observed [I > 2σ(I)]. R1 = 0.1434, wR2 = 0.2444 (all data). CCDC 664815 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html or from the Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: +44(1223)336033; email: deposit@ccdc.cam.ac.uk.

12

Synthesis of Deacylated Ugi Products 7a-c; General Procedure: A mixture of p-chlorophenylglyoxal (169 mg, 1 mmol) and the corresponding arylamine (1 mmol) in i-Pr2O (10 mL) was stirred at r.t. for 10 min. Then cyclo-hexyl isocyanide (110 mg, 1 mmol) and anhyd trichloro-acetic acid (163 mg, 1 mmol) were consecutively added and the mixture was stirred at r.t. for 2 d. The solid residue was filtered and then recrystallized from the i-Pr2O-i-PrOH mixture.
3-(4-Chlorophenyl)- N -cyclohexyl-3-oxo-2-(phenyl-amino)propionamide (7a): colorless crystals (130 mg, 35%); mp 164-165 °C (i-Pr2O-i-PrOH). 1H NMR (400 MHz, CDCl3): δ = 0.89-1.13 (m, 3 H), 1.20-1.32 (m, 2 H), 1.48-1.83 (m, 5 H), 3.57-3.68 (m, 1 H), 5.31 (d, J = 3.0 Hz, 1 H), 5.43 (d, J = 3.0 Hz, 1 H), 6.68-6.71 (m, 2 H), 6.80-6.85 (m, 2 H), 7.21-7.24 (m, 2 H), 7.44-7.46 (m, 2 H), 8.21-8.23 (m, 2 H). 13C NMR (100 MHz, CDCl3): δ = 24.5 (CH2), 24.6 (CH2), 25.2 (CH2), 32.4 (CH2), 32.5 (CH2), 48.6 (CH), 66.6 (CH), 113.8 (CHAr), 119.4 (CHAr), 128.7 (CHAr), 129.5 (CHAr), 131.8 (CHAr), 132.3 (Cq), 140.9 (Cq), 145.5 (Cq), 165.8 (Cq), 193.0 (Cq). IR (KBr): 3390, 3298, 1695, 1654 cm-1. MS (EI): m/z (%) = 372 (7) [M+ + 2], 370 (24) [M+], 245 (100), 231 (99), 104 (69). HRMS (EI): m/z calcd for C21H23ClN2O2: 370.1448; found: 370.1443. Anal. Calcd for C21H23ClN2O2: C, 68.01; H, 6.25; N, 7.55. Found: C, 67.94; H, 5.95; N, 7.48.

14

Synthesis of N -Cyclohexyl-3-oxo-3- p -tolyl-2-(2,2,2-trichloro- N - p -tolylacetamido)propionamide (6e): A mixture of p-tolylglyoxal (148 mg, 1 mmol) and p-toluidine (107 mg, 1 mmol) in MeOH (10 mL) was stirred for 10 min, and then cyclohexyl isocyanide (110 mg, 1 mmol) and anhyd trichloroacetic acid (327 mg, 2 mmol) were consecutively added. The mixture was stirred at r.t. for 3 d, cooled at 0 °C overnight, then filtered, and the collected solid was recrys-tallized from MeOH, from which product 6e was obtained as colorless crystals (347 mg, 68%); mp 210-212 °C (MeOH). 1H NMR (400 MHz, CDCl3): δ = 0.73-1.28 (m, 5 H), 1.65-1.41 (m, 5 H), 2.34 (s, 3 H), 2.42 (s, 3 H), 3.50-3.61 (m, 1 H), 6.10 (d, J = 7.8 Hz, 1 H), 6.27 (s, 1 H), 7.10 (d, J = 8.5 Hz, 2 H), 7.28 (d, J = 8.1 Hz, 2 H), 7.39 (d, J = 8.5 Hz, 2 H), 7.86 (d, J = 8.1 Hz, 2 H). 13C NMR (100 MHz, CDCl3): δ = 21.2 (Me), 21.8 (Me), 24.4 (CH2), 24.5 (CH2), 25.3 (CH2), 32.0 (CH2), 32.3 (CH2), 48.6 (CH), 71.1 (CH), 93.0 (Cq), 127.8 (Cq), 128.5 (CHAr), 129.0 (CHAr), 129.6 (CHAr), 131.2 (CHAr), 132.9 (Cq), 135.8 (Cq), 139.7 (Cq), 145.2 (Cq), 161.1 (Cq), 162.8 (Cq), 194.1 (Cq). IR (KBr): 3242, 1771, 1631, 744 cm-1. MS (EI): m/z (%) = 512 (0.7) [M+ + 4], 510 (3.4) [M+ + 2], 508 (2.5) [M+], 391 (27), 390 (100), 307 (45), 119 (92). HRMS (EI): m/z calcd for C25H27Cl3N2O3: 508.1056; found: 508.1087. Anal. Calcd for C25H27Cl3N2O3: C, 58.89; H, 5.34; N, 5.49. Found: C, 58.83; H, 5.28; N, 5.43.