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2.6 Metal-Catalyzed (2 + 2 + 2) Cycloadditions

DOI: 10.1055/sos-SD-222-00161

Tanaka, K.; Shibata, Y.Science of Synthesis: Metal-Catalyzed Cyclization Reactions, (20162265.

General Introduction

The transition-metal-catalyzed (2 + 2 + 2) cycloaddition is a useful and atom-economical method for the synthesis of substituted six-membered-ring molecules. The reaction has been extensively investigated and this research topic has been thoroughly reviewed.[‌1‌‌13‌] Compared with the well-established transition-metal-catalyzed cross-coupling approach, the transition-metal-catalyzed (2 + 2 + 2)-cycloaddition approach is advantageous for the synthesis of densely substituted six-membered carbocycles and heterocycles. In the (2 + 2 + 2) cycloaddition, many different substituents can be introduced through the formation of the six-membered ring. This chapter discusses the metal-catalyzed (2 + 2 + 2) cycloaddition of not only alkynes but also heterocumulenes, alkenes, and carbonyl compounds for the synthesis of six-membered carbocycles and heterocycles. Asymmetric variants of these reactions will also be discussed. Although this chapter focuses on catalytic reactions, (2 + 2 + 2) cycloadditions mediated by stoichiometric amounts of metal complexes have also been reported.[‌1‌‌13‌]

Reppe reported the first transition-metal-catalyzed (2 + 2 + 2) cycloaddition of alkynes using a nickel complex.[‌14‌] Vollhardt smartly utilized the cobalt-mediated (2 + 2 + 2) cycloaddition in organic synthesis[‌15‌,‌16‌] and Yamazaki examined the general reactivity of cobaltacycles in detail.[‌17‌] After these pioneering works, many transition-metal complexes were utilized as catalysts for the (2 + 2 + 2) cycloaddition.[‌1‌‌13‌] Among them, the most common catalysts are cobalt [CoCpL2, CoCp(alkene)(L), and CoX2/M/L], nickel [Ni(0)/phosphine], ruthenium [Ru(Cp*)Cl(cod)], rhodium [RhCl(PPh3)3 and Rh(I)+/diphosphine], and iridium [Ir(I)/diphosphine] complexes.[‌1‌‌13‌]

General mechanisms of the transition-metal-catalyzed (2 + 2 + 2) cycloaddition of alkynes are shown in Schemes 1 and 2. Two alkynes react with the transition-metal complex to generate metallacyclopentadiene 1. The subsequent (4 + 2) cycloaddition of 1 with the alkyne affords metallabicyclo[2.2.0]heptadiene 2. Reductive elimination affords the desired benzene (Scheme 1). Alternatively, insertion of the alkyne into 1 leading to metallacycloheptatriene 3 followed by reductive elimination also affords the desired benzene (Scheme 1).[‌18‌] On the other hand, a mechanism through metallacyclopentatriene 4 is proposed in the (2 + 2 + 2) cycloaddition of alkynes catalyzed by Ru(Cp*)Cl(cod).[‌19‌] The (2 + 2) cycloaddition of metallacyclopentatriene 4 with the alkyne affords metallabicyclo[3.2.0]heptatriene 5. Skeletal rearrangement leading to metallacycloheptatetraene 6 followed by reductive elimination affords the desired benzene (Scheme 2).[‌19‌]

Scheme 1 Mechanism of Transition-Metal-Catalyzed (2 + 2 + 2) Cycloaddition through a Metallacyclopentadiene Intermediate

Scheme 2 Mechanism of Transition-Metal-Catalyzed (2 + 2 + 2) Cycloaddition through a Metallacyclopentatriene Intermediate

References