ORGANIC SYNTHESIS
Reactions in Formic Acid
Our efforts in the area of organic synthesis were initially spurred by efforts to develop a new strategy for the synthesis of the C19 norditerpenoid alkaloids, e.g. cardiopetaline.
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Our approach, which envisaged a key intramolecular phenoxy radical coupling of acyclic precursors such as those below, has led to discoveries about reactions in formic acid that have led, in turn, to a new direction in our current research efforts.
In our attempt to prepare a precursor for the preparation of these synthons, we had occasion to attempt the alkylation of benzhydrol with a variety of active methylene compounds in refluxing formic acid. In the course of this work, we have developed a new, mild method for the Ritter reaction between benzylic alcohols and nitriles in refluxing formic acid ((Synthesis, 2003, 681-684), and for the alkylation of benzhydrol itself with enols in refluxing formic acid (Aust. J. Chem. 2003, 56, 385-388). The reaction occurs through benzhydryl formate, which undergoes a rate-limiting solvolysis in formic acid to give the benzhydryl cation. There is a minimum cation stability required for this reaction to proceed at a reasonable rate: saturated secondary alcohols are converted to their formate esters under these reaction conditions, but no further.
We are continuing our work in this area to encompass intramolecular reactions, including intramolecular Friedel-Crafts syntheses of ketones and lactams (especially tetrahydroquinolones).
Anion Chemistry
Our forays into anion chemistry have resulted in the first complete study of the stereochemistry of the aldol addition of the dilithio derivative of propionanilide with aldehydes. The deprotonation of propionanilide by butyllithium at 0oC gives an approximately 20:1 mixture of the Z and E enolates, which then react with the aldehyde to give mixtures of the syn and anti aldols in close to equal proportions (Synthesis 2005, 2906-2912). The addition is invariably accompanied by recovery of some unreacted propionanilide.
In the course of other work, we have developed a convenient synthesis of homoallylic alcohols by means of the Barbier-Grignard reaction between allyl bromide, magnesium, and the carbonyl compound that circumvents problems associated with the synthesis of allylmagnesium bromide (Synth. Commun. 2004 34, 3473-3480).
Fluorescent Compounds
For many years, we have had an interest in the synthesis and uses of highly fluorescent 4-amino-1,8-naphthalimide derivatives. We have now extended this work, and have recently reported the first synthesis of a naphthalimide-based Troeger's base derivative (Tetrahedron Lett. 2005, 46, 2149-2153). The fluorescence quantum yield of these compounds is remarkably sensitive to the medium in which it is measured, with quantum yields measured in ethanol being less than 1% the value of the fluorescence quantum yield of the same compound in cyclohexane solution. These observations may have some bearing on the mechanism of stereochemical inversion of these chiral diamines, and we are investigating the photophysics of these compounds in detail.
