Reductive Cycloadditions

Scheme 21 Catalytic [3 + 2] reductive cycloadditions of enals and alkynes...

The mechanism of [3 + 2] reductive cycloadditions clearly is more complex than other aldehyde/alkyne couplings since additional bonds are formed in the process. The catalytic reductive [3 + 2] cycloaddition process likely proceeds via the intermediacy of metallacycle 29, followed by enolate protonation to afford vinyl nickel species 30, alkenyl addition to the aldehyde to afford nickel alkoxide 31, and reduction of the Ni(II) alkoxide 31 back to the catalytically active Ni(0) species by Et3B (Scheme 23). In an intramolecular case, metallacycle 29 was isolated, fully characterized, and illustrated to undergo [3 + 2] reductive cycloaddition upon exposure to methanol [45]. Related pathways have recently been described involving cobalt-catalyzed reductive cyclo additions of enones and allenes [46], suggesting that this novel mechanism may be general for a variety of metals and substrate combinations. 

An unusual reductive cycloaddition leading to a bridged bicyclic 1,3-dioxane was reported by Taylor and coworkers <20030L4441, 20050BC756>. They found that 2-acyl-2 -benzyloxy-substituted (Z)-stilbenes cyclize upon treatment with tin dichloride at room temperature to give the bicyclic product 220 in 94% yield (Equation 85). 

A new synthesis of 2,4,4,6-tetramethyl-4//-l,3-oxazine (155) simply involves a reductive cycloaddition of 4-methylpent-3-en-2-one and acetonitrile in the presence of trimethylsilyl chloride and sodium iodide (Scheme 42) <89TL4741>. Other cycloaddition reactions have been used previously to synthesize 4//-l,3-oxazines and this methodology has been extended to include cycloadditions between alkynes and l-oxa-3-azabuta-1,3-dienes. For example, phenylethyne and the A-benz-oylimine (156) afford 4,4-bis(trifluoromethyl)-2,6-diphenyl-4//-l,3-oxazine (157). The reaction proceeds through a Michael-type addition between the alkyne and the heterodiene giving an adduct which when heated to 80-90°C cyclizes to the oxazine (Scheme 43) <83CC945,89ZN(B)1298>. 

Whereas the preceding processes involving ring openings of cyclopropanes provide useful [3+2] entries to cyclopentanes, the use of simpler substrates in [3+2] cycloadditions is made possible by the development of reductive cycloaddition pathways. Such reactions were initially developed in the context of stoichiometric processes, where metallacycles were prepared by oxidative cyclizations of enones and alkynes, followed by either protonation or alkylation of the nickel 0-enolate functionality. Catalytic protocols involving various intramolecular combinations of 7t-systems include formal [3+2] reductive cycloadditions of bis-enones to form bicyclooctanols (Scheme 3-33), of enones with unsaturated acyl oxazolidinones to form triquinane derivatives, and of enals with alkynes to form bicyclooctenols. ... 

More recent advances in intermolecular [3+2] reductive cycloadditions have involved combinations of enals or enoates with alkynes (Scheme 3-34).l 2 l The initially developed cycloadditions of enals and alkynes likely proceeds by initial formation of a metallacyclic enolate derivative, followed by enolate protonation and addition of the vinyl nickel unit to the resulting carbonyl to produce the boron alkoxide of the observed cyclopentenol product (Scheme 3-35). The analogous transformation with enoates may also proceed by this mechanism, depicted below by the sequence of initial generation of metallacycle 20, followed by enolate protonation to form 21 en route to product generation. Alternatively, the collapse of the metallacycle 20 to a ketene intermediate 22 may occur in the enoate variant. The precise pathway followed likely depends on whether protic or aprotic media are used. 

In 2008, lipshutz reported the first hydrometaUative intramolecular reductive cycloaddition, leading to three new contiguous stereocenters in a one-pot process (Scheme 11.30). The enantioselective domino conjugate reduction/intramolecular... 

Scheme 11.30 First hydrometallative, intramolecular, reductive cycloaddition leading to...

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