A convenient synthesis of 1,4-disubstituted imidazoles

Tetrahedron Letters

Volumn 45, Issue 28, 2004, Pages 5529-5532

  He, Yong ^a   Chen, Yingzhong ^a   Du, Hongwang ^a   Schmid, Lesley A ^a   Lovely, Carl J ^a  

^a UNIVERSITY OF TEXAS AT ARLINGTON   (United States)

Author keywords

Imidazoles; Isomerization; Protection; Regioselective

Indexed keywords

IMIDAZOLE DERIVATIVE;

ALKYLATION; ARTICLE; CHEMICAL REACTION KINETICS; HEATING; HYDROLYSIS KINETICS; ISOMERIZATION; ROOM TEMPERATURE; SYNTHESIS;

EID: 2942672496     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.tetlet.2004.05.011     Document Type: Article

References (36)

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8. The use of a trityl group for the selective preparation 1, 5-disubstituted imidazoles via the 4-substituted N-trityl derivative is well known (formally the reverse of Scheme 4, in which 12 R=Tr), for example, see: Shih N.Y., Lupo A.T. Jr., Aslanian R., Orlando S., Piwinski J.J., Green M.J., Ganguly A.K., Clark M.A., Tozzi S., Kreutner W., Hey J.A. J. Med. Chem. 38:1995;1593
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13. It has been reported in the literature that under comparable conditions that the direct selective synthesis of N-alkyl urocanoate derivatives can be achieved, see: Lauth-de Viguerie N., Sergueeva N., Damiot M., Mawlawi H., Riviere M., Lattes A. Heterocycles. 37:1994;1561
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21. It has previously been noted that the 5-isomers with this N-protecting group can isomerize to the 4-isomer, and so it is conceivable that initially a mixture forms and then isomerizes. See Refs. [6b, d]
22. 2: C, 69.41; H, 5.82; N, 11.56. Found: C, 69.57; H, 6.59; N, 11.40
23. 1H NMR spectroscopy by integration of appropriate signals
24. 3: C, 55.09; H, 6.16; N, 14.28. Found: C, 55.12; H, 5.88; N, 14.04
25. General isomerization procedure: The mixture of the two regioisomers (2.5 mmol) was dissolved in DMF (6 mL) and RX (5-10 mol %) was added and the resulting solution heated at 75°C for 24 h. After cooling to room temperature, a small amount of water was added and then the solvent was completely removed under vacuum. The residue was purified by passing through a short pad of silica gel if necessary
26. The spectroscopic data of all the known compounds are consistent with literature reports. 2a: De Esch I.J.P., Vollinga R.C., Goubitz K., Schenk H., Appelberg U., Hacksell U., Lemstra S., Zuiderveld O.P., Hoffmann M., Leurs R., Menge W.M.P.B., Timmerman H. J. Med. Chem. 42:1999;1115. and Ref. [1b]; 2c: Ref. [4a]; 5a: Ref. [1d]; 5b, 6b: Ref. [6a]; 5c, 5d: see Ref. [1e]; 6d: Ref. [4c]
27. 8b, 9b: Iwaoka, K.; Koshio, H.; Ito, H.; Miyata, K.; Ohta, M. PCT Int. Appl. WO 9406791 A1 19940331, 1994
28. 3: Iddon B., Lim B.L. J. Chem. Soc., Perkin Trans. 1. 1983;735
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30. The isomerization was allowed to proceed more than 72 h, but did not result in any further change on the ratio of two methyl isomers
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33. -1): 3144, 3117, 3090, 3067, 3035, 2953, 2252, 1559, 1504, 1456, 1414, 1239, 1153, 1045, 989, 745, 711, 663, 636
34. -1): 2954, 2926, 2896, 2251, 1501, 1416, 1360, 1249, 1149, 1096, 860, 837
35. 1H NMR (500 MHz): 7.58 (s, 1H) 7.09 (s, 1H), 5.28 (s, 2H), 3.77 (s, 2H), 3.27 (s, 3H)
36. In the case of the preparation of N-benzyl 4-urocanoate (2a) and N-methyl-4-iodoimidazole (5d), the corresponding imidazolium salts were obtained in ca. <5% yield, which provides circumstantial support for the proposed mechanism