Abstract

Higher-order cycloaddition reactions possess many of the attributes that have made the Diels–Alder reaction so useful in synthesis, including high stereoselectivity, rapid increase in molecular complexity, and the ability to accommodate substantial functionalization in both reaction partners. The limiting feature of many higher-order processes, however, is a lack of periselectivity that translates directly into relatively low chemical yields of the desired cycloadducts.

[6π + 4π] Cycloaddition reactions are typical higher-order transformations in that they exhibit many of the attractive features delineated above, but afford only modest yields of adducts in many instances. The engagement of the 6π and 4π components in these reactions often results in multiple, competitive pericyclic events that yield numerous cycloaddition products. The obvious synthetic potential offered by this class of reactions has prompted recent developments, such as metal mediation, that have successfully addressed the periselectivity issue and, as a result, have considerably broadened the synthetic scope and utility of the reaction.¹

The thermally allowed [6 + 4] cycloaddition of 2,4,6-cycloheptatrien-1-one (tropone) (1) has been well studied and offers substantial opportunities for assembling functionally rich and stereochemically homogeneous bicyclic systems (Eq. 1). Typically, the triene partner is heated at 80–140° in the presence of excess diene (trienophile) to afford a bicyclo[4.4.1]undecene ring system that is sufficiently functionalized to permit subsequent manipulations. The scope of this transformation for preparative purposes is somewhat restricted, however, since only a limited set of diene partners will effectively participate. For example, electron-rich dienes constitute the majority of reactants that afford meaningful yields of bicyclo[4.4.1]undecane products upon reaction with 1.

A variety of substituted fulvene species also participate as effective 6π partners in a closely related set of [6 + 4] cycloaddition reactions (Eq. 2). The range of useful 4π partners is reasonably broad and rapid access to functionalized polycycles of considerable synthetic interest can be achieved with these transformations.

More recently, transition metal promoted versions of the [6 + 4] cycloaddition have been developed.^2,3 Group VI metals (Cr and Mo) have been identified as capable promoters for this transformation, with chromium(0) emerging as the metal of choice for most applications (Eq. 3). The ring-forming event in this case can be achieved through either thermal or photochemical activation, and the metal-promoted process has proven to accommodate a much wider range of triene and trienophilic participants than the thermal metal-free reaction. Unlike the cycloaddition reactions of tropone, the metal-mediated reactions are relatively insensitive to the electronic nature of the diene partner, and high chemical yields of stereochemically homogeneous products are typical for these reactions. It is noteworthy that, in certain instances, reactions employing sub-stoichiometric quantities of metal have been reported.⁴

This chapter covers the thermal, metal-free [6 + 4] cycloaddition chemistry of tropone and related trienes, fulvenes, and metal-promoted reactions through mid-1995. Aspects of both the metal-mediated and metal-free versions of the [6 + 4] cycloaddition reaction have been reviewed.^1–3