Reductive alkylation of thioureas: A highly practical synthesis of unsymmetrical N,N′-disubstituted thioureas

Tetrahedron Letters

Volumn 45, Issue 43, 2004, Pages 8091-8093

  Ciszewski, Lech ^a   Xu, Daquiang ^a   Repič, Oljan ^a   Blacklock, Thomas J ^a  

^a Novartis Inst Biomed Res E H   (Switzerland)

Author keywords

[No Author keywords available]

Indexed keywords

ALDEHYDE; CARBAMIC ACID DERIVATIVE; THIOUREA DERIVATIVE;

ALKYLATION; AMINATION; ARTICLE; DRUG SYNTHESIS; REDUCTION; SUBSTITUTION REACTION;

EID: 4644316300     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.tetlet.2004.08.182     Document Type: Article

References (12)

1. R.J. Herr, L.L. Kuhler, H. Meckler, and C.J. Opalka Synthesis 2000 1569 1574
2. M. Ballabeni, R. Ballini, F. Bigi, R. Maggi, M. Parrini, G. Predieri, and G. Sartori J. Org. Chem. 64 1999 1029 1032
3. K. Ramadas, N. Janarthanan, and S. Velmathi Synth. Commun. 27 1997 2255 2260
4. U. Boas, and H. Jakobsen J. Chem. Soc., Chem. Commun. 1995 1995 1996
5. J.S. Duceppe, and J. Gauthier J. Heterocycl. Chem. 21 1984 1685 1687
6. K. Ramadas, N. Srinivasa, and N. Janarthanan Tetrahedron Lett. 34 1993 6447 6450
7. D. Xu, L. Ciszewski, T. Li, O. Repič, and T.J. Blacklock Tetrahedron Lett. 39 1998 1107 1110
8. Typical procedure for N-monoalkylated thioureas: To a suspension of thiourea (15.25 g, 0.2 mol) in acetic acid (150 mL) was added an aldehyde (0.02 mol) at room temperature. The suspension was warmed to 60-65°C to obtain a solution. The resulting solution was cooled to 45°C, and trimethylsilyl chloride (7.61 mL, 0.06 mol) was added during 3 min. The reaction mixture was cooled to room temperature and stirred overnight. To the resulting suspension was added sodium borohydride (1.51 g, 0.04 mol) over 30 min at 23-30°C. Completion of the reaction was monitored by HPLC. Water (70 mL) was added to the reaction mixture at room temperature and concentrated (150 mbar, 45-50°C) to collect 150 mL of a mixture of acetic acid and water. To the suspension was added 6 N NaOH (80 mL) over 10 min at 24-30°C to adjust the pH to 10. After stirring the mixture at room temperature for 30 min the crude product was collected by filtration, washed with water (2 x 50 mL). The crude product was recrystallized from a mixture of heptane and ethyl acetate
9. Use of sodium triacetoxyborohydride in this reaction gave similar results as obtained with sodium borohydride suggesting that the actual reducing agent is sodium triacetoxyborohydride
10. Typical procedure for unsymmetrical N,N′-disubstituted thioureas: The procedure was essentially the same as described above in Ref. 3 using N-alkyl thiourea (0.017 mol), and aldehyde (0.02 mol), followed by trimethylsilyl chloride (0.051 mol) and sodium borohydride (0.034 mol)
11. All the compounds gave satisfactory spectral data
12. Typical procedure for N-alkylated carbamates: The procedure was essentially the same as described above in Ref. 3 using carbamate (0.01 mol) and aldehyde (0.015 mol), followed by trimethylsilyl chloride (0.03 mol) and sodium borohydride (0.03 mol)