Synthesis of tri- and tetrasubstituted imidazoles

Tetrahedron Letters

Volumn 49, Issue 42, 2008, Pages 6155-6159

  Paone, Daniel V ^a   Shaw, Anthony W ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

Amino alcohol; Imidazole; Intramolecular cyclization; Thioamide

Indexed keywords

AMINOALCOHOL; IMIDAZOLE DERIVATIVE; THIOAMIDE;

ARTICLE; CHEMICAL STRUCTURE; CYCLIZATION; GEL CHROMATOGRAPHY; OXIDATION; SUBSTITUTION REACTION; SYNTHESIS;

EID: 50649110469     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.tetlet.2008.08.036     Document Type: Article

References (30)

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24. The aqueous workup of the PDC reaction is greatly facilitated by first quenching with a reducing agent such as sodium sulfite, then adjusting the mixture to mildly acidic pH (∼5). This allows for complete dissolution of chromium salts and separation of two homogeneous layers.
25. Major byproducts of the sequence include reversion back to the amide precursor of 3 and oxazoline formation resulting from nucleophilic attack of the hydroxyl group prior to oxidation.
26. Typical procedure for the synthesis of substituted aminomethyl alcohols (Table 1, entry 3): Trimethylsilyl cyanide (920 mg, 9.28 mmol) was added dropwise to a solution of 2,2-dimethylpropanal (400 mg, 4.64 mmol) and zinc iodide (15 mg, 0.046 mmol) in dichloromethane (10 mL) at 0 °C, and the solution was allowed to warm to ambient temperature. After 16 h the solution was recooled to 0 °C, lithium aluminum hydride (1.0 M in ether; 11.6 mL, 11.6 mmol) was added, and the solution was allowed to warm to ambient temperature.
27. Typical procedure for the synthesis of substituted imidazoles (Table 2, entry 5): To a solution of 3-(4-fluorophenyl)-N-(3-phenylpropyl)propanethioamide (50.0 mg, 0.17 mmol) and 1-amino-3,3-dimethyl-butan-2-ol (38.9 mg, 0.33 mmol) in acetonitrile (1.7 mL) was added mercury(II) chloride (90.1 mg, 0.33 mmol). After 10 min the mixture was filtered and washed with a total of 6 mL acetonitrile. Pyridinium dichromate (312 mg, 0.83 mmol) was added to the filtrate and the mixture was heated to 60 °C. After 2 h the mixture was allowed to cool to ambient temperature and quenched with saturated aqueous sodium sulfite (4 mL) and water (4 mL).
28. For the trifluoroethyl analog in entry 3 of Table 2, the HCl salt of the amino alcohol was used along with equimolar triethylamine, and the yields were comparable to those when the free base was used.
29. The corresponding cyclopentane-fused imidazole was not obtained under the standard conditions, presumably due to increased ring strain versus the 6,5-fused system.
30. The amino alcohol in entry 16 was obtained from hydrogenation of the commercially available aryl derivative.