Cyclization reactions, ring size effect

This example illustrates the synthesis of cyclic compounds by intramolecular alkylation reactions. The relative rates of cyclization for ca-haloalkyl malonate esters are 650,000 1 6500 5 for formation of three-, four-, five-, and six-membered rings, respectively.28 (See Section 3.9 of Part A to review the effect of ring size on Sn2 reactions.)... 

A few scattered examples of hexahydro- and octahydro-l,3-diazocines have been reported, mainly in the context of studies on the effect of chain length on the cyclization of diamines. Reaction of the N- aryl-iV - aroyldiamines (194) with polyphosphoric ester gives the cyclic amidines (195) (77JCS(P2)2068). Yields of the diazocines (195 n =5) were about 40%, compared to 90% for the 1,3-diazepine (195 n =4). The basicities of the products decrease in the order of ring size 6 7>8 5, lower basicity reflecting non-planarity of the amidine system. 

Cyclic compounds are mainly prepared from non-cyclic starting materials either by cycloaddition reactions or by cyclization. Whereas in cycloadditions the ring size of the product is determined by the reaction mechanism of a given cycloaddition, cyclizations enable the use of most bond-forming reactions and, in principle, enable access to any ring size. Certain rings, however, are more difficult to prepare than others, and because oligomerization competes with all cyclizations, slow cyclizations will have a detrimental effect on the yield of cyclic products. In this section some of the critical structural considerations for successful cyclizations will be presented and examples of difficult cyclizations will be discussed. 

The regioselectivity in diene addition reactions can also be influenced by ring strain effects in cyclization reactions. The regioselectivity is highly predictable in those cases, in which addition to the preferred diene center forms the preferred ring size. Thus, the cyclization of radical 15 proceeds readily to form the ct s-disubstituted cyclopentyhnethyl radical 16 with high selectivity. Similarly, cyclization of 17 affords exclusively bicyclic radical 18, in which the additional cyclopentane ring has been formed by addition to the terminal position of the butadiene subunit. This preference for 5-exo cyclizations onto dienes is not even dismpted by substiments at the C1 or C4 positions of the diene system, as seen for radical 19, which cyclizes to 20 (equation lO). This is in contrast to alkyl radical cyclizations to alkenes, in which major amounts of 6-endo cyclization is observed for 5-substituted systems. ... 

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