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

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.

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

References

<A NAME="RG27105ST-1">1</A>

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

<A NAME="RG27105ST-2">2</A> Ugi I. Offermann K. Chem. Ber.  1964,  97:  2276 

<A NAME="RG27105ST-3">3</A> Ugi I. Rosendahl FK. Bodesheim F. Liebigs Ann. Chem.  1963,  666:  61 

For two excellent reviews on the isocyanide multicomponent reactions see:

<A NAME="RG27105ST-4A">4a</A> Dömling A. Ugi I. Angew. Chem. Int. Ed.  2000,  39:  3168 

<A NAME="RG27105ST-4B">4b</A> Ugi I. Werner B. Dömling A. Molecules  2003,  8:  53 

See for example:

<A NAME="RG27105ST-5A">5a</A> Short KM. Ching BW. Mjalli AMM. Tetrahedron  1997,  53:  6653 

<A NAME="RG27105ST-5B">5b</A> Hanusch-Kompa C. Ugi I. Tetrahedron Lett.  1998,  39:  2725 

<A NAME="RG27105ST-5C">5c</A> Zhang J. Jacobson A. Rusche JR. Herlihy W. J. Org. Chem.  1999,  64:  1074 

<A NAME="RG27105ST-5D">5d</A> Marcaccini S. Miguel D. Torroba T. García-Valverde M. J. Org. Chem.  2003,  68:  3315 

See for example:

<A NAME="RG27105ST-6A">6a</A> Lee D. Sello JK. Schreiber SL. Org. Lett.  2000,  2:  709 

<A NAME="RG27105ST-6B">6b</A> Nixey T. Tempest P. Hulme C. Tetrahedron Lett.  2002,  43:  1637 

<A NAME="RG27105ST-6C">6c</A> Tempest P. Pettus L. Gore V. Hulme C. Tetrahedron Lett.  2003,  44:  1947 

<A NAME="RG27105ST-6D">6d</A> Faggi C. García-Valverde M. Marcaccini S. Pepino R. Pozo MC. Synthesis  2003,  1553 

<A NAME="RG27105ST-6E">6e</A> Marcaccini S. Pepino R. Pozo MC. Basurto S. García-Valverde M. Torroba T. Tetrahedron Lett.  2003,  44:  3999 

<A NAME="RG27105ST-6F">6f</A> Beck B. Picard A. Herdtweck E. Dömling A. Org. Lett.  2004,  6:  39 

<A NAME="RG27105ST-6G">6g</A> For a recent review see: Marcaccini S. Torroba T. In Multicomponent Reactions   Zhu J. Bienaymé H. Wiley-VCH; Weinheim: 2005.  p.33 

<A NAME="RG27105ST-7A">7a</A> Hulme C. Ma L. Romano JJ. Morton G. Tang S.-Y. Cherrier M.-P. Choi S. Salvino J. Labaudiniere R. Tetrahedron Lett.  2000,  41:  1889 

<A NAME="RG27105ST-7B">7b</A>

The conversion of iminohydantoins into hydantoins was accomplished by hydrolysis in harsh conditions, whereas the conversion of iminothiohydantoins into hydantoins was achieved via KMnO₄ oxidation and alkaline hydrolysis. These transformations were used by Ugi and co-workers (see ref. 1 and 2) as structural proof of the Ugi-4CC adducts.

<A NAME="RG27105ST-8">8</A> Marcaccini S. Pepino R. Pozo MC. Tetrahedron Lett.  2001,  42:  2727 

<A NAME="RG27105ST-9">9</A>

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.

<A NAME="RG27105ST-10">10</A>

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.

<A NAME="RG27105ST-11">11</A>

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.

<A NAME="RG27105ST-12">12</A>

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.

<A NAME="RG27105ST-13A">13a</A> Martin D. J. Prakt. Chem.  1991,  333:  261 

<A NAME="RG27105ST-13B">13b</A> Atay E. Blogoeva IB. Jirby AJ. Pojarieff IG. J. Chem. Soc., Perkin Trans. 2  1998,  2289 

<A NAME="RG27105ST-13C">13c</A> Blogoeva IB. Toteva MM. Ouarti N. Ruasse M.-F. J. Org. Chem.  2001,  66:  2123 

<A NAME="RG27105ST-14A">14a</A> Matthews J. Rivero RA. J. Org. Chem.  1997,  62:  6090 

<A NAME="RG27105ST-14B">14b</A> Lee S.-H. Chung S.-H. Lee Y.-S. Tetrahedron Lett.  1998,  39:  9469 

<A NAME="RG27105ST-15A">15a</A> Saettone MF. Nuti V. J. Pharm. Sci.  1968,  57:  1798 

<A NAME="RG27105ST-15B">15b</A> Fujiwara H. Bose AK. Manhas MS. van der Veen JM. J. Chem. Soc., Perkin Trans. 2  1980,  1573 

<A NAME="RG27105ST-15C">15c</A> Otter BA. Sasson IM. Gagnier RP. J. Org. Chem.  1982,  47:  508 

<A NAME="RG27105ST-16">16</A> Hepner B. Frenkenberg S. J. Prakt. Chem.  1932,  134:  249 

<A NAME="RG27105ST-17">17</A> Seguchi K. Tanaka S. Heterocycles  1997,  45:  707 

<A NAME="RG27105ST-18">18</A> Milcent R. Akhnazarian A. Lensen N. J. Heterocycl. Chem.  1996,  33:  1829 

<A NAME="RG27105ST-19">19</A> Marciniec B. Pharmazie  1985,  40:  180 

<A NAME="RG27105ST-20">20</A> Moskal J. Bronowski J. Rogowski A. Monatsh. Chem.  1981,  112:  1405 

<A NAME="RG27105ST-21">21</A> Beller M. Eckert M. Moradi WA. Neumann H. Angew. Chem. Int. Ed.  1999,  38:  1454