NOVEL SYNTHESIS & APPLICATIONS OF DIAZOMETHANE

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Since 1894, diazomethane has proven to be one of the most valuable and powerful reagents available to the synthetic chemist. It is easily the most common methylating reagent for carboxylic acids, and has found wide application in the methylation of phenols, alcohols, enols, and heteroatoms such as nitrogen and sulfur. Most importantly, it has been the major electrophilic species responsible for post DNA-methylation when a variety of different N-nitroso precursors were used to generate diazomethane as the methylating reagent. There are several review articles concerning diazomethane applications in organic and organometallic chemistry. Some of the many applications of diazomethane are as follows: a. Ring expansion of ketones. b. Chain extension or methylene insertion: conversion of acid halides to a-diazoketones which are valuable synthetic intermediates with three primary uses (the preparation of a-haloketones, Wolf rearrangement, carbene precursors). c. Cyclopropanation: diazomethane acts as a powerful 1,3-dipole in many cycloaddition reactions with unsaturated systems. d. Pyrazoline ring formation from olefinic and acetylenic precursors. e. Thiadiazole ring formation from the isothiocyanate precursors. f. Epoxidation: addition of diazomethane to ketones and esters. g. Synthesis of ketones from aldehyde: simple aldehydes react with diazomethane to form the homologous ketones. h. Synthesis of methylene diiodide: diazomethane can react with iodine under mild conditions to form methylene diiodide, an essential reagent in the Simmons-Smith reaction. TITLE: Novel Synthesis and Applications of Diazomethane (Continued) The reagent has been synthesized from base-catalyzed decomposition of N-methyl-N-nitro-N-nitrosoguanidine (MNNG) using a variety of different methods. Deuteriated diazomethane has also recently become available in kit form from the Aldrich Chemical Company. Although quite safe when handled as a dilute solution and in small scale synthesis in an inert solvent, diazomethane is toxic and explosive and highly irritating if inhaled in high concentrations. The only commercially available precursor for in situ generation of tritiated diazomethane is [3H-methyl]-N-nitrosourea (MNU) at a specific activity of 0.5 to 2 Ci/mmole. This compound is also known as a highly carcinogenic and toxic material. Over the next year we propose to develop a simple, efficient and novel synthesis for high specific activity tritiated diazomethane, depending on a fluoride-induced reaction in the presence of fully tritiated water. The procedure will be performed in a well designed and safe apparatus, at very small scale. We expect this approach to further extend chemistry and equipment previously developed at the NTLF.