The Alkylation of Isatin-Derived Oximes: Spectroscopic and X-Ray Crystallographic Structural Characterization of Oxime and Nitrone Products

• Published in: Journal of heterocyclic chemistry Vol. 46; no. 3; pp. 432 - 442
• Main Authors: Sin, Ny, Venables, Brian L., Liu, Xiaohong, Huang, Stella, Gao, Qi, Ng, Alicia, Dalterio, Richard, Rajamani, Ramkumar, Meanwell, Nicholas A.
• Format: Journal Article
• Language: English
• Published: HOBOKEN Wiley 01.05.2009
• Subjects: Chemistry; Chemistry, Organic; Physical Sciences; Science & Technology; DESIGN; ACID; THIOSEMICARBAZONE; BASIS-SETS; OPTIMIZATION; DERIVATIVES; VIRUS FUSION INHIBITORS
• ISSN: 0022-152X; 1943-5193
• DOI: 10.1002/jhet.84

A series of isatin oximes was alkylated with alkyl halides and under Mitsunobu conditions to generate O-alkylated oxime ether and N-alkylated nitrone products. Alkylation of the sodium salts of oximes 5a and 5b with alkyl iodides produced predominantly the N-alkylated nitrones (E)-7 while alkylation of 5a and 5b with the harder clectrophiles alkyl bromides and alkyl chlorides, gave mostly the O-alkylated products, oxime ethers (E)-6. Interestingly, alkylation of oxime 5b under Mitsunobu conditions with isopropyl alcohol produced the N-alkylated nitrone (E)-7bd as the major product. However, alkylation of oxime 5c, which incorporates a sterically bulky bromine substituent at the C-4 position of the isatin heterocycle, with 2-bromo- and 2-iodo-propane or with isopropyl alcohol under Mitsunobu conditions gave exclusively the O-alkylated product, oxime ether (Z)-6cd. The oxime ether and nitrone products 6 and 7, respectively, were characterized by LC/MS, H-1 NMR, and C-13 NMR. In addition, the structures of oxime ether (E)-6bd and nitrone (E)-7ad were determined by X-ray crystallography.