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44412-GB1
New Synthetic Methods Using Oxime Ethers

Debra D. Dolliver, Southeastern Louisiana University

            This PRF grant has afforded the PI the opportunity to establish an active undergraduate research program which has resulted in numerous presentations by students (five at national ACS meetings, three at regional ACS meetings, and one at a Louisiana Academy of Sciences meeting with an additional two scheduled for the Southwest Regional meeting in October, 2008) and by the PI (three at national ACS meetings).  This work has resulted in one publication in the Canadian Journal of Chemistry¹ on nucleophilic substitution of N-alkoxyimidoyl fluorides by carbon nucleophiles which was primiarly performed by undergraduate researchers.  In addition, one manuscript is currently being completed for publication on work performed by undergraduates involving the synthesis of O-alkylazidoximes and an investigation of their reactions in electrophilic media.

Under the term of this grant the research group has investigated using N-alkoxyimidoyl halides as starting materials in the synthesis of oxime ethers of pure E or Z isomeric configuration, even in cases where there is little difference in the thermodynamic stability of the two geometric isomers.¹  This type of control of the geometric configuration is of importance as oxime ethers in a single isomeric form are useful starting materials for the formation of chiral amines.^2-6

Work has been published by the PI and her undergraduate researchers showing that a single geometric configuration of an oxime ether is formed from nucleophilic substitution of a (Z)-N-alkoxyimidoyl fluoride by a Grignard reagent in moderate to good yields (Scheme 1).  

Scheme 1:  Nucleophilic Substitution of a (Z)-N-alkoxyimidoyl fluoride by a Grignard Reagent

Additionally, nucleophilic substitution of N-alkoxyimidoyl fluorides by enolate-type ions was also included in the previously-mentioned paper.  These substitutions result in novel carbon acids which display varying degrees of imine-enamine tautomerism (Scheme 2). 

Scheme 2:  Nucleophilic substitution reactions of N-alkoxyimidoyl fluorides by enolate-type ions.

            Work has been completed on the synthesis of O-alkylazidoximes (1, Scheme 3).   X-ray crystallography on 1e revealed it to be only in the Z configuration,⁷ so it is assumed that the others are also in this configuration.  Reaction of 1 with an electrophile results in two different products produced by two different pathways:  a Schmidt-type rearrangement pathway to form a N-alkoxyurea (2) and an isomerization-cyclization pathway to form an N-alkoxytetrazole (3).   These two pathways have been recognized for related compounds,^8,9 but no work has been performed to better understand the factors that influence the path chosen.  Our group has now completed studies on the impact of the solvent and the electrophile on the pathway preference.  Our results indicate that the type of electrophile is responsible for the reaction pathway chosen.  To better understand the energetic parameters of both pathways, the PI has successfully collaborated with a computational chemist (Dr. Thomas Sommerfeld) who has mapped out the features of both mechanistic pathways, and a manuscript is being currently prepared for publication on the work.

Scheme 3:  Synthesis of an azidoxime ether and competing reaction pathways in electrophilic media.