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

M. García-Valverde; S. Macho; S. Marcaccini; T. Rodríguez; J. Rojo; T. Torroba

doi:10.1055/s-2007-992372

LETTER

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

M. García-Valverde^a, S. Macho^a, S. Marcaccini*^b, T. Rodríguez^a, J. Rojo^a, 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;

Abstract

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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

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References

References and Notes

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2 Matsunaga H. Ishizuka T. Kunieda T. Tetrahedron 2005, 61: 8073

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4a Fraunhoffer KJ. White MC. J. Am. Chem. Soc. 2007, 129: 7274

4b Luppi G. Lanci D. Trigari V. Garavelli M. Garelli A. Tomasini C. J. Org. Chem. 2003, 68: 1982

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4d Falb E. Nudelman A. Gottlieb HE. Hassner A. Eur. J. Org. Chem. 2000, 645

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4f Evans DA. Wood MR. Trotter BW. Richardson TI. Barrow JC. Katz JL. Angew. Chem. Int. Ed. 1998, 37: 2700

5a Marcaccini S. Torroba T. In Multicomponent Reactions Zhu J. Bienaymé H. Wiley-VCH; Weinheim Germany: 2005. Chap. 2. p.33-75

5b Ignacio JM. Macho S. Marcaccini S. Pepino R. Torroba T. Synlett 2005, 3051

5c Sañudo M. Marcaccini S. Basurto S. Torroba T. J. Org. Chem. 2006, 71: 4578

Phenylglyoxal:

6a Riley HA. Gray AR. Org. Synth., Coll. Vol. II Wiley; New York: 1943. p.509

6b Riley HA. Gray AR. Org. Synth. 1935, 15: 67

6c p-Chlorophenyl-glyoxal: Muccioli GG. Wouters J. Charlier C. Scriba GKE. Pizza T. Di Pace P. De Martino P. Poppitz W. Poupaert JH. Lambert DM. J. Med. Chem. 2006, 49: 872

6d p-Methoxyphenylglyoxal: Fodor G. Kovacs O.
J. Am. Chem. Soc. 1949, 71: 1045

6e p-Methylphenyl-glyoxal: De Meester JWG. van der Plas HC. Middelhoven WJ. J. Heterocycl. Chem. 1987, 24: 441

6f p-Fluorophenylglyoxal: Joshi KC. Dubey K. Dandia A. Heterocycles 1981, 16: 1545

7 Arnold RT. Fuson RC. J. Am. Chem. Soc. 1936, 58: 1295

8a Gokel W. Widera RP. Weber WP. Org. Synth., Coll. Vol. VI Wiley; New York: 1988. p.232

8b Gokel W. Widera RP. Weber WP. Org. Synth. 1976, 55: 96

Alternative procedure:

8c Ugi I. Meyr R. Lipinski M. Bodesheim F. Rosendahl F. Org. Synth., Coll. Vol. V Wiley; New York: 1973. p.300

8d Ugi I. Meyr R. Lipinski M. Bodesheim F. Rosendahl F. Org. Synth. 1961, 41: 13

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 (C_q), 125.5 (CH_Ar), 126.1 (C_q), 126.3 (CH_Ar), 128.5 (CH_Ar), 128.7 (CH_Ar), 129.4 (CH_Ar), 129.6 (CH_Ar), 133.7 (C_q), 139.1 (C_q), 152.5 (C_q), 157.1 (C_q). 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 (C_q), 123.3 (C_q), 126.9 (CH_Ar), 127.1 (CH_Ar), 129.7 (CH_Ar), 129.8 (CH_Ar), 132.8 (C_q), 134.4 (C_q), 140.0 (C_q), 140.7 (C_q), 152.7 (C_q), 157.2 (C_q). 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 (C_q), 125.0 (C_q), 125.9 (CH_Ar), 128.0 (CH_Ar), 129.0 (CH_Ar), 129.2 (CH_Ar), 129.9 (CH_Ar), 131.7 (C_q), 133.9 (C_q), 135.9 (C_q), 139.2 (C_q), 152.5 (C_q), 157.1 (C_q). 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 (CH_Ar), 117.5 (C_q), 118.6 (C_q), 123.9 (CH_Ar), 126.0 (CH_Ar), 128.7 (CH_Ar), 128.8 (CH_Ar), 130.5 (CH_Ar), 135.2 (C_q), 152.5 (C_q), 157.2 (C_q), 161.2 (C_q). 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-K_α) = 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.

11a Pirrung MC. Das Sarma K. J. Am. Chem. Soc. 2004, 126: 444

11b See also: Mironov MA. Ivantsova MN. Mokrushin VS. Mol. Divers. 2003, 6: 193

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 (CH_Ar), 119.4 (CH_Ar), 128.7 (CH_Ar), 129.5 (CH_Ar), 131.8 (CH_Ar), 132.3 (C_q), 140.9 (C_q), 145.5 (C_q), 165.8 (C_q), 193.0 (C_q). 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.

13 For a complete discussion about the effect of reagents and solvents in the Ugi reaction, see: Marcaccini S. Torroba T. Nature Prot. 2007, 2: 632

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 (C_q), 127.8 (C_q), 128.5 (CH_Ar), 129.0 (CH_Ar), 129.6 (CH_Ar), 131.2 (CH_Ar), 132.9 (C_q), 135.8 (C_q), 139.7 (C_q), 145.2 (C_q), 161.1 (C_q), 162.8 (C_q), 194.1 (C_q). 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.