Modified Bucherer-Bergs Reaction for the One-Pot Synthesis of 5,5′-Disubstituted Hydantoins from Nitriles and Organometallic Reagents

Abstract

Diverse sets of 5,5′-disubstituted hydantoins can conveniently be made in moderate to good yields (40-92%) by a one-pot process involving treatment of aromatic, heteroaromatic or aliphatic nitriles with an organometallic reagent (RLi or RMgX) followed by KCN/(NH₄)₂CO₃.

Key words

heterocycles - multicomponent reactions - combinatorial chemistry

References and Notes

• 1a Ware E. Chem. Rev.  1950,  46:  403 
• 1b López CA. Trigo GG. Adv. Heterocycl. Chem.  1985,  38:  177 
• 1c Meusel M. Gütschow M. Org. Prep. Proced. Int.  2004,  36:  391 
• 2 Nakabayashi M. Regan MM. Lifsey D. Kantoff PW. Taplin M.-E. Sartor O. Oh WK. Br. J. Urol. Int.  2005,  96:  783 
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• 4 Nakajima M. Itoi K. Takamatsu Y. Kinoshita T. Okazaki T. Kawakubo K. Shindo M. Honma T. Tohjigamori M. Haneishi T. J. Antibiot.  1991,  44:  293 
• 5 Burton SG. Dorrington RA. Tetrahedron: Asymmetry  2004,  15:  2737 
• For recent illustrative examples, see:
• 6a Zhang D. Xing XC. Cuny GD. J. Org. Chem.  2006,  71:  1750 
• 6b Ignacio JM. Macho S. Marcaccini S. Pepino R. Torroba T. Synlett  2005,  3051 
• 6c Patel VM. Desai KR. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem.  2005,  44:  1084 
• 6d Manku S. Curran DP. J. Org. Chem.  2005,  70:  4470 
• 6e Alsina J. Scott WL. O’Donnell MJ. Tetrahedron Lett.  2005,  46:  3131 
• 6f Volonterio A. de Arellano CR. Zanda M. J. Org. Chem.  2005,  70:  2161 
• 7a Bergs H. inventors; DRP  566094. 
• 7b Bucherer HT. Brandt W. J. Prakt. Chem.  1934,  140:  129 
• 7c Bucherer HT. Steiner W. J. Prakt. Chem.  1934,  140:  291 
• 7d Bucherer HT. Lieb VA. J. Prakt. Chem.  1934,  141:  5 ; see also ref. 1a
• For recent applications, see:
• 8a Wermuth UD. Jenkins ID. Bott RC. Byriel KA. Smith G. Aust. J. Chem.  2004,  57:  461 
• 8b Micová J. Steiner B. Koós M. Langer V. Gyepesová D. Carbohydr. Res.  2003,  338:  1917 
• 8c Micová J. Steiner B. Koós M. Langer V. Gyepesová D. Synlett  2002,  1715 
• A similar approach has been used to improve and extend other multicomponent reactions, see:
• 9a Simoneau CA. Ganem B. Tetrahedron  2005,  61:  11374 
• 9b Simoneau CA. George EA. Ganem B. Tetrahedron Lett.  2006,  47:  1205 
• 10 Weiberth FJ. Hall SS. J. Org. Chem.  1987,  52:  3901 ; and references cited therein
• 11 Wakefield BJ. The Chemistry of Organolithium Compounds   Pergamon; Oxford: 1974. 
• 16 Shipman M, and Montagne C. inventors; GB  0603239.5. 

12

Lower conversion was observed when the quantities of KCN and (NH₄)₂CO₃ were reduced.

13

Experimental Method (Using RLi).
In a flame dried ACE thick-walled pressure tube under nitrogen, are successively added THF (1 mL) and the organolithium reagent (1.2 mmol). The solution is cooled to 0 °C whereupon the nitrile (1.0 mmol) is added. The reaction mixture is stirred for 30 min at 0 °C then carefully quenched with EtOH (4 mL). Then, (NH₄)₂CO₃ (576 mg, 6 mmol), KCN (197 mg, 3 mmol; CAUTION) and H₂O (4 mL) are successively added and the tube is sealed. The hetero-geneous solution is heated at 75 °C (preheated bath) for 24 h then allowed to cool to r.t. The mixture is poured into H₂O (50 mL) and extracted with EtOAc (2 × 25 mL). The combined organic extract is washed with brine (25 mL), dried over MgSO₄ and evaporated to dryness. The resulting solid is washed with n-pentane (2 × 10 mL) and dried under high vacuum to yield the hydantoin in a high state of purity as judged by NMR analysis and microanalytical data.

14

Selected Data.
Compound 5f: mp 228-229 °C. IR (neat): 3169, 2961, 1750, 1717, 1430, 1370, 1108, 764 cm^-1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 0.92 (s, 9 H), 1.24 (s, 3 H), 7.95 (s, 1 H), 10.50 (s, 1 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 18.8, 24.5, 36.1, 66.8, 156.7, 178.2. MS (ES): m/z = 169 [M - H]^-. HRMS (EI): m/z calcd for C₈H₁₂N₂O₂: 171.1134; found: 171.1128. Anal. Calcd for C₈H₁₄N₂O₂ (%): C, 56.45; H, 8.29; N, 16.46. Found: C, 56.52; H, 8.35; N, 16.35.
Compound 5h: mp 181-182 °C. IR (neat): 3180, 3052, 2927, 1774, 1709, 1432, 1232, 813, 756 cm^-1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 0.89 (t, J = 7.0 Hz, 3 H), 1.09-1.20 (m, 1 H), 1.24-1.41 (m, 3 H), 2.00-2.09 (m, 2 H), 7.21 (dt, J = 1.0, 7.0 Hz, 1 H), 7.23 (d, J = 7.5 Hz, 1 H), 7.38-7.45 (m, 1 H), 7.53 (dt, J = 1.5, 8.2 Hz, 1 H), 8.31 (s, 1 H), 10.87 (s, 1 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 13.9, 22.0, 24.8, 34.7, 64.9, 116.3 (d, J = 22 Hz), 124.4 (d, J = 3 Hz), 126.3 (d, J = 11 Hz), 128.1 (d, J = 3 Hz), 130.4 (d, J = 9 Hz), 156.7, 160.4 (d, J = 247 Hz), 176.1. MS (ES): m/z = 249 [M - H]^-. HRMS (EI): m/z calcd for C₁₃H₁₅FN₂O₂: 250.1118; found: 250.1114. Anal. Calcd for C₁₃H₁₅FN₂O₂ (%): C, 62.39; H, 6.04; N, 11.19. Found: C, 62.50; H, 6.11; N, 11.01.
Compound 5j: mp 244-245 °C. IR (neat): 3304, 3191, 1775, 1759, 1728, 1710, 1411, 1023, 747, 693 cm^-1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 2.88 (s, 6 H), 6.70 (d, J = 8.8 Hz, 2 H), 7.11 (d, J = 8.8 Hz, 2 H), 7.29-7.40 (m, 5 H), 9.12 (s, 1 H), 10.9 (s, 1 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 40.0, 69.8, 111.9, 126.6, 127.1, 127.2, 127.7, 128.3, 140.4, 149.8, 156.0, 175.4. MS (ES): m/z = 294 [M - H]^-. HRMS (EI): m/z calcd for C₁₇H₁₇N₃O₂: 295.1321; found: 295.1317. Anal. Calcd for C₁₇H₁₇N₃O₂ (%): C, 69.14; H, 5.80; N, 14.23. Found: C, 68.80; H, 5.88; N, 13.96.
Compound 5m: mp 199 °C (decomp.). IR (neat): 3227, 2958, 1767, 1736, 1713, 1396, 1232, 1006, 763, 710 cm^-1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 1.14-1.32 (m, 2 H), 1.44-1.66 (m, 6 H), 2.63-2.73 (m, 1 H), 7.02 (dd, J = 3.8, 5.0 Hz, 1 H), 7.09 (dd, J = 1.3, 3.8 Hz, 1 H), 7.48 (dd, J = 1.3, 5.0 Hz, 1 H), 8.83 (s, 1 H), 10.83 (s, 1 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 25.0, 25.4, 26.2, 26.8, 46.6, 68.5, 124.5, 125.8, 127.0, 143.1, 156.9, 175.1. MS (ES): m/z = 249 [M - H]^-. HRMS (EI): m/z calcd for C₁₂H₁₄N₂O₂S: 250.0776; found: 250.0767. Anal. Calcd for C₁₂H₁₄N₂O₂S (%): C, 57.58; H, 5.64; N, 11.19. Found: C, 57.91; H, 5.80; N, 11.04.
Compound 5q: mp 244-245 °C. IR (neat): 3250, 3042, 1760, 1712, 1598, 1450, 1255, 758 cm^-1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 0.92 (s, 9 H), 3.74 (s, 3 H), 6.88-6.92 (m, 1 H), 7.22-7.30 (m, 3 H), 8.91 (s, 1 H), 10.80 (s, 1 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 24.8, 37.8, 55.1, 71.9, 112.5, 113.8, 119.6, 128.3, 137.6, 156.3, 158.4, 175.3. MS (ES): m/z = 261 [M - H]^-. HRMS (EI): m/z calcd for C₁₄H₁₉N₂O₃: 263.1396; found: 263.1384. Anal. Calcd for C₁₄H₁₈N₂O₃ (%): C, 64.10; H, 6.92; N, 10.68. Found: C, 64.00; H, 6.95; N, 10.59.

15

Experimental Method (Using RMgX).
In a flame-dried ACE pressure tube under nitrogen, are successively added copper iodide (9.5 mg, 0.05 mmol), THF (1 mL) and the organomagnesium reagent (1.2 mmol) immediately followed by the nitrile [1 mmol; either as liquid or in THF (1 mL) if solid]. The vessel is quickly heated to 70 °C (preheated bath) and maintained at this temperature for 24 h. Upon cooling to r.t., the reaction is carefully quenched with EtOH (4 mL). Then, (NH₄)₂CO₃ (576 mg, 6 mmol), KCN (197 mg, 3 mmol; CAUTION) and H₂O (4 mL) are successively added and the tube is sealed. The heterogeneous solution is heated at 75 °C (preheated bath) for 24 h then allowed to cool to r.t. The hydantoin is isolated using the same work-up and crystallisation protocol described in ref. 12.