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Synlett 2005(20): 3051-3054  
DOI: 10.1055/s-2005-922745
LETTER
© Georg Thieme Verlag Stuttgart · New York

A Facile Synthesis of 1,3,5-Trisubstituted Hydantoins via Ugi Four-Component Condensation

José Miguel Ignacioa, Sonia Machoa, Stefano Marcaccini*a, Roberto Pepinoa, Tomás Torrobab
a Dipartimento di Chimica Organica ‘Ugo Schiff’, Università di Firenze, via della Lastruccia 13, 50019 Sesto Fiorentino (FI), Italy
Fax: +39(055)4573531; e-Mail: stefano.marcaccini@unifi.it;
b Departamento de Química, Facultad de Ciencias, Universidad de Burgos, Plaza Misael Bañuelos s/n, 09001 Burgos, Spain
Further Information

Publication History

Received 5 September 2005
Publication Date:
28 November 2005 (online)

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Abstract

A facile access to 1,3,5-trisubstituted hydantoins is achieved by combining an Ugi four-component condensation with a base-induced cyclization. This two-step sequence, which differs from any other method, is experimentally simple and allows a wide variety in the substitution pattern. In this synthesis the acid component, namely trichloroacetic acid, acts as a carbonic acid equivalent.

Key words

Ugi four-component condensation (U-4CC) - isocyan­ides - heterocycles - cyclizations - multicomponent reactions

1

Present address: Departamento de Química, Facultad de Ciencias, Universidad de Burgos, Spain.

9

Synthesis of Ugi Adducts 8a-f,h,j. General Procedure.
A solution of the amine 4 (12 mmol) in MeOH (10 mL) was treated with aldehyde 5 (finely powdered if solid; 12 mmol), a solution of isocyanide 7 (12 mmol) in MeOH (5 mL), and trichloroacetic acid (6, 1.96 g, 12 mmol) in the order given. The reaction mixture was stirred for 2 d at r.t. and then cooled at 0 °C and filtered. The collected solid was washed with a little cold i-Pr2O and then with pentane and dried to give almost pure 8. Analytical samples were obtained from i-PrOH.
2-( N -Phenyl- N -trichloroacetyl)amino-2-phenylacetic Acid N -Cyclohexyl Amide (8a).
IR (KBr): ν = 3275, 3062, 2930, 1688, 1651, 697 cm-1. 1H NMR (200 MHz, CDCl3): δ = 7.25-7.10 (m, 10 H), 5.81 (s, 1 H), 5.41 (d, J = 8.00 Hz, 1 H), 3.94-3.77 (m, 1 H), 1.98-0.89 (m, 10 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 167.46, 160.66, 138.20, 133.28, 132.40, 130.46, 128.70, 128.44, 128.34, 127.53, 93.01, 69.87, 48.76, 32.60, 32.55, 25.28, 24.69, 24.57 ppm.

10

Improved Procedure for the Synthesis of Ugi Adducts 8c,d. A mixture of 4-chloroaniline (4b, 549 mg, 4.3 mmol), benzaldehyde (5a, 456 mg, 4.3 mmol), CHCl3 (10 mL) and anhyd Na2SO4 (900 mg) was stirred for 4 h at r.t. and then filtered. The collected solid was washed with CHCl3 (5 mL). The filtrate was evaporated to dryness and the residue dissolved in Et2O (10 mL). The above solution was cooled at 10 °C and treated under stirring with a solution of isocyanide 7 (4.3 mmol) in Et2O (5 mL) and then with trichloroacetic acid (6, 703 mg, 4.3 mmol). The solution turned violet and the precipitation of the reaction product began within 1 h. After 24 h stirring the reaction mixture was filtered to give almost pure 8. Another crop was obtained by evaporating the filtrate and stirring the residue with i-PrOH (3-4 mL).
2-[ N -(4-Chlorophenyl)- N -trichloroacetyl]amino-2-phenylacetic Acid N -Cyclohexyl Amide (8c).
IR (KBr): ν = 3268, 3064, 2927, 1691, 1651, 748 cm-1; 1H NMR (200 MHz, CDCl3): δ = 7.26-6.94 (m, 9 H), 5.88 (s, 1 H), 5.39 (d, J = 8.40 Hz, 1 H), 3.85-3.76 (m, 1 H), 1.97-0.96 (m, 10 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 167.29, 160.61, 136.38, 134.45, 134.06, 132.98, 130.51, 128.99, 128.52, 127.67, 92.84, 69.26, 48.87, 32.60, 25.28, 24.69 ppm.

11

Synthesis of Hydantoins 9a-f,h,i. General Procedure.
A 1.0 M ethanolic solution of NaOEt was dropped into a well-stirred suspension of 8 (1.0 mmol) in EtOH (4-5 mL) until a clear solution was obtained. Within a few minutes the precipitation of a solid product commenced. The suspension was cooled at 0 °C and filtered to give almost pure 9. Analytical samples were obtained from i-PrOH.
1-(4-Chlorophenyl)-3-cyclohexyl-5-phenylhydantoin (9a).
IR (KBr): ν = 3031, 2928, 1773, 1704 cm-1. 1H NMR (200 MHz, CDCl3): δ = 7.49-7.03 (m, 10 H), 5.36 (s, 1 H), 4.09-3.97 (m, 1 H), 2.26-1.17 (m, 10 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 169.85, 154.51, 136.51, 133.33, 129.14, 128.94, 128.90, 126.58, 124.45, 120.17, 63.52, 52.05, 29.26, 29.11, 25.75, 25.72, 24.92 ppm. Anal. Calcd for C21H22N2O2 (334.41): C, 75.42; H, 6.63; N, 8.38. Found: C, 75.71; H, 6.81; N, 8.12.

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Synthesis of Hydantoins 9g,i. General Procedure. Supporting Ugi reagents were allowed to react as described in ref. 11, general procedure. The clear reaction mixture was treated with 1.0 M ethanolic NaOEt and stirred for 15 min at r.t. The resulting suspension was cooled at 0 °C and filtered to give almost pure 9g,i. Analytical samples were obtained from i-PrOH.
1-Benzyl-3-hexyl-5-(4-methylphenyl)hydantoin (9g).
IR (KBr): ν = 3033, 2929, 1766, 1698 cm-1. 1H NMR (200 MHz, CDCl3): δ = 7.32-7.02 (m, 9 H), 5.11 (d, J = 14.7 Hz, 1 H), 4.53 (s, 1 H), 4.03-3.94 (m, 1 H), 3.68 (d, J = 14.7 Hz, 1 H), 2.37 (s, 3 H), 2.25-1.15 (m, 10 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 171.25, 156.33, 138.92, 135.50, 129.79, 128.65, 128.21, 127.77, 127.24, 62.02, 44.14, 29.32, 29.15, 25.72, 25.68, 24.82, 21.00 ppm. Anal. Calcd for C23H28N2O2 (364.48): C, 75.79; H, 7.74; N, 7.69. Found: C, 75.88; H, 7.41; N, 7.95.