[4 + 3] Cycloaddition Reactions

Rigby, J. H.; Pigge, F. C.


Cycloaddition in its many manifestations represents one of the most powerful methods in organic chemistry for making cyclic structures. The high levels of convergency and stereoselectivity that frequently characterize these processes are particularly attractive from a preparative point of view. Five- and six-membered rings are typically made by the well-known 1, 3-dipolar and Diels–Alder cycloaddition reactions, respectively, and so-called higher-order cycloaddition processes have emerged recently as useful methodology for the construction of medium-sized carbocycles.

Seven-membered ring systems, owing primarily to their broad occurrence as substructures in many classes of natural products, are particularly important targets for synthesis, but there are relatively few ways currently available for de novo synthesis of these ring systems. As a general solution to this problem, [4 + 3] cycloaddition between a 1, 3-diene and an allyl, or more frequently an oxyallyl, cation offers rapid access to functionalized seven-membered carbocycles with many of the attendant virtues of other cycloaddition processes. Considerable effort has been expended recently to exploit the synthetic utility of these reactions, and several informative reviews of the subject are currently available. Electronically, the process is quite similar to the Diels–Alder reaction and can be viewed as a [4π(4C) + 2π(3C)] combination in which the allyl cation participates as the reactive 2π component. Much of the developmental work associated with [4 + 3] cycloaddition has focused on approaches to the generation of the allyl or oxyallyl cation reaction partner, and a number of useful methods have emerged.

While a wide range of 1, 3-diene partners have been employed in these reactions, π-excessive heterocycles such as furan and pyrrole have been shown to be particularly useful participants and, recently, intramolecular versions of the [4 + 3] process have been effectively applied to natural product synthesis.

This chapter reviews the literature of [4 + 3] cycloadditions that involve allyl and oxyallyl cations and closely related 2π(3C) reactants to mid-1996. Those [4 + 3] cycloadditions previously compiled by Noyori and Hayakawa in their 1983 review of reductive dehalogenations of polyhaloketones are also included in the current review so that all relevant examples are located in one document. Other 4 + 3 annulation processes that afford seven-membered carbocycles but that employ other types of reactive intermediates are not covered in this survey.