(4+3) cycloaddition

A (4+3) cycloaddition is a cycloaddition between a four-atom π-system and a three-atom π-system to form a seven-membered ring. Allyl or oxyallyl cations (propenylium-2-olate) are commonly used three-atom π-systems, while a diene (such as butadiene) plays the role of the four-atom π-system. It represents one of the relatively few synthetic methods available to form seven-membered rings stereoselectively in high yield.

Symmetry-allowed (4+3) cycloaddition is an attractive method for the formation of historically difficult-to-access seven-membered rings. Neutral dienes and cationic allyl systems (most commonly oxyallyl cations) may react in a concerted or stepwise fashion to give seven-membered rings. A number of dienes have been employed in the reaction, although cyclic, electron-rich dienes such as those found in the cyclopentadiene and furan ring systems are the best 4π systems for this process. Intramolecular variants are also efficient.

(1)

Recent developments have focused on expanding the scope of enantioselective (4+3) cycloadditions and the range of conditions available for generating the key oxyallyl cation (propenylium-2-olate) intermediate.

Oxyallyl cations (propenyliumolates) may be generated under reductive, mildly basic, or photolytic conditions. Reduction of α,α'-dihalo ketones is a very popular method for generating symmetric oxyallyl cations. After formation of a metal enolate, dissociation of halide generates a positively charged oxyallyl intermediate. This electron-deficient 2π component reacts with electron-rich dienes to give cycloheptenones. Cyclic dienes fare better than the corresponding acyclic dienes because in order to react, the diene must be in the s-cis conformation in the presence of the short-lived oxyallyl cation—cyclic dienes are locked in this reactive conformation.

(2)

Substituents at the 1 and 3 positions are usually required to stabilize the oxyallyl cation and prevent isomerization to cyclopropanones and allene oxides. In most cases, an excess of the diene is employed to prevent isomerization of the oxyallyl cation intermediate. Increasing the covalent character of the metal-oxygen bond (by, for instance, employing iron carbonyl reducing agents instead of sodium) also stabilizes the oxyallyl cation, leading to cleaner reactions. Strongly electrophilic allyl cations tend to give products of electrophilic substitution rather than cycloaddition.

The cycloaddition itself may be either concerted or stepwise, depending on the nature of the oxyallyl intermediate and the reaction conditions. Concerted reactions taking place under reductive conditions usually exhibit low regioselectivity due to somewhat indiscriminate frontier orbital control; however, stepwise (or at least asynchronous) reactions under basic conditions do exhibit moderate regioselectivity (attributed to initial formation of a bond between the less sterically hindered ends of the pi systems).