Roy A. Olofson

New Synthetic Methods and Reagents

Professor Olofson and his co-workers are primarily interested in the invention of new synthetic reagents and preparative methods.

In collaboration with SNPE of France, they have invented an efficient, economical synthesis of 1-chloroalkyl chloroformates by reaction of phosgene with aldehydes in the presence of a naked chloride catalyst. Useful reactions of several compounds in the series have been developed. For example, a-chloroethyl chloroformate (ACE-Cl) is the best reagent yet described for the N-dealkylation of tertiary amines and has been used in the practical conversion of oxycodone into two important narcotic antagonists, naloxone and naltrexone, and a potent analgesic, nalbuphine. 1,2,2,2-Tetrachloroethyl chloroformate (4CE-Cl) is a useful protecting reagent for alcohols, while the COCl2 adducts of acrolein and crotonaldehyde are of value as synthons.

This group has developed the only economical routes to O-vinyl urethanes and O-vinyl carbonates. As a consequence, interesting polyurethane and polycarbonate polymers now are easily available by polyvinyl polymerizations. In the O-vinyl carbonate synthesis, they have been the first to take advantage of the donor properties of an aldehyde enolate without complications from the normally dominant acceptor properties of the aldehyde. Previously unknown 2,2-dihalovinyl chloroformates have been made economically and used both in polymer chemistry and in routes to selective biocidal materials. They also have invented a simple uphill synthesis of fluoroformates, including tBuOCOF, from carbonates. Because fluoroformates, unlike chloroformates, do not react exothermically with DMSO, high-yield carboalkoxylations of sugars with fluoroformates in DMSO have been achieved.

Dr. Olofson and co-workers introduced H+arpoons (a special class of proton-specific, strong bases) to the arsenal of synthetic chemists. One of these reagents, LTMP, has been widely used to perform previously impossible or low-yield transformations in his laboratories and elsewhere.

New preparative methods in heterocyclic chemistry (one of the group's main interests) are exemplified by a recent regiospecific synthesis of isoxazoles the most versatile known heteroaromatic synthon. Their studies of aromaticity, homoaromaticity, and antiaromaticity in heterocycles have proven that benzoazetinones violate Huckel's Rule and that 1-thia-4-azanaphthalenes are not what their name implies. Recently they observed simple azetinones for the first time. Dr. Olofson's group also investigates the mechanisms of organic and biological reactions and is particularly interested in attaining a predictive understanding of heteroaromatic C-H acidities.