Practical and scalable synthesis of N-Alkyl-N,N'Diacylhydrazines

The work presented in this thesis is concerned with the evaluation of potential synthetic routes for the diacylhydrazine group of compounds, and particularly, unsymmetrical diacylhydrazines. Diacylhydrazines form the basis for a relatively new group of insecticides that have molt accelerating properties, and which are considered to offer substantial advantages over other insecticides used for the control of certain insects. The overall objective for this study is to evaluate different potential synthetic routes for a model diacylhydrazine with the view to define potentially scaleable routes. The compound selected for this study was the unsymmetrical diacylhydrazine, N-[N-(tertbutyl) phenylcarbonylamino](4-methylphenyl)-carboxamide since it offers the same range of challenges that would be expected for the synthesis of other similar unsymmetrical diacylhydrazines. Thus, the synthesis of unsymmetrical diacylhydrazines require two reaction steps: The first step is the synthesis of the intermediate mono-acylhydrazine, while the second step is the synthesis of the desired diacylhydrazine from the intermediate mono-acylhydrazine. The most important factor in the two-step reaction sequence is to obtain a high degree of selectivity for the desired mono-acylhydrazine isomer. Acylation of t-butylhydrazine using 4-methylbenzoyl chloride can produce the desired product N-[(tert-butyl)amino](4-methylphenyl)carboxamide in yields above 90 percent, but this reaction produces a variety of by-products, including the “wrong” isomer (N-amino-N- (tert-butyl)(4-methylphenyl)carboximide). Unexpected byproducts for this particular acylation reaction, not previously reported in the literature have also been identified during this investigation. This includes a de-butylated diacylhydrazine, (4-methylphenyl)- N-[(4-methylphenyl)carbonylamino] carboxamide. Although the reaction between tert-butylhydrazine and 4-methylbenzaldehyde is very selective giving near quantitative yields of the desired hydrazone, the subsequent conversion of the hydrazone into the desired mono-acylhydrazine is problematic. The most promising route appears via bromination to form the hydrazidic bromide, followed by hydrolysis of the hydrazidic bromide. Yields for the bromination reaction during this investigation were somewhat higher than that reported previously in literature. Hydrolysis of the hydrazidic bromide, apparently also results in the hydrolysis of the reaction product to give an ester of the free acid (when an ester solvent is used). The synthesis of N-[N-(tert-butyl)phenylcarbonylamino](4-methyl phenyl)carboxamide was only briefly considered to evaluate essentially two approaches, namely: · The conversion of the monoacylhydrazine, N-[(tert-butyl)amino](4- methylphenyl)carboxamide, by acylating with either benzoyl chloride or methylbenzoate (gave 86 percent N-[N-(tert-butyl)phenylcarbonylamino](4-methyl phenyl)carboxamide when benzoyl chloride was used as acylating agent); and · The one-pot conversion of the hydrazone, [(1E)-2-(4-methylphenyl)-1- azavinyl](tert-butyl)]amine, by bromination/hydrolysis and acylation. In this case, benzoyl chloride (2 percent N-[N-(tert-butyl)phenylcarbonylamino](4-methyl phenyl)carboxamide), benzoic acid (80.67 percent N-[N-(tertbutyl) phenylcarbonylamino](4-methylphenyl)carboxamide) were evaluated as potential acylating agent