Radical cyclization, with amides

Radical cyclization is compatible with the presence of other functional groups. Treatment of XCH2CON(R)-C(R )=CH2 derivatives (X = Cl, Br, 1) with Ph3SnH and AIBN led to formation of a lactam via radical cyclization. " Cyclization of N-iodoethyl-5-vinyl-2-pyrrolidinone led to the corresponding bicyclic lactam, " and there are other examples of radical cyclization with molecules containing a lactam unit " or an amide unit. Radical cyclization occurs with enamines as well. Photochemical irradiation of A,A-dialIyl acrylamide leads to formation of a lactam ring, and in this case thiophenol was added to generate the phenylthio derivative. Phenylseleno N-allylamines lead to cyclic amines. co-Iodo acrylate esters cyclize to form lactones. " ... 

The electrochemical cyclization reaction is less successful with the N-(3-phenylallyl)acetanilide 60 which has two potential bond cleavage sites from the radical-anion [173]. Carbon-nitrogen bond cleavage with loss of a 3-phenylallyl radical, leaving an amide nitrogen anion, is favoured over carbon-chlorine bond cleavage. 

Radical cyclizations are often used in ring formations and are an effective methodology in the synthesis of piperidines. The intramolecular cyclization of an oxime ether, such as 63 onto an aldehyde or ketone gives a new entry into cyclic amino alcohols <99JOC2003, 99H(51)2711>. Similarly, reaction of a terminal acetylene with BujSnH generates a vinyl radical, which will cyclize with an imine moiety to give 3-methylenepiperidine <99TL1515>. The indolizidine alkaloid ipalbidine was prepared by a sulfur-controlled 6-exo-selective radical cyclization of an a/p/ia-phenylthio amide <99H(50)31>. 

Marcus treatment does not exclude a radical pathway in lithium dialkyl-amide reduction of benzophenone. It does, however, seem to be excluded (Newcomb and Burchill 1984a,b) by observations on the reductions of benzophenone by N-lithio-N-butyl-5-methyl-l-hex-4-enamine in THF containing HMPA. Benzophenone is reduced to diphenylmethanol in good yield, and the amine yields a mixture of the acyclic imines no cyclic amines, expected from radical cyclization of a putative aminyl radical, were detected. An alternative scheme (17) shown for the lithium diethylamide reduction, accounts for rapid formation of diphenylmethoxide, and for formation of benzophenone ketyl under these conditions. Its key features are retention of the fast hydride transfer, presumably via the six-centre cyclic array, for the formation of diphenylmethoxide (Kowaski et al., 1978) and the slow deprotonation of lithium benzhydrolate to a dianion which disproportion-ates rapidly with benzophenone yielding the ketyl. The mechanism demands that rates for ketyl formation are twice that for deprotonation of the lithium diphenylmethoxide, and, within experimental uncertainty, this is the case. 

The generation of amidyl radicals from N-allylsulfonamides and their subsequent cyclization was probed by Moutrille and Zard [130]. This strategy allowed the preparation of lactams such as 140 by treatment of acylsulfon-amide 138 with lauryl peroxide and a xanthate in DCE (Scheme 44). However, when the stability of the generated amidyl radical (as with 137) was not high enough, the extrusion of sulfur dioxide turned to be too slow, and premature cyclization of the N-amidosulfonyl radical intermediate took place, leading to 139. 

Chiral auxiliaries are capable of controlling the absolute steric course of radical reactions. 8-Phenylmenthyl ester or an amide derived from Oppolzer s camphor sultam can be utilized for enantioselective ring closure to cyclopentane, the chiral auxiliary directing the addition to the alkene. The reductive radical cyclization of 8-phenylmenthyl 2-phenylthio-6-heplenoale at 80 °C gives four isomeric cyclopentane derivatives in an overall yield of 90 % 3. The reaction proceeds with modest cis irons ratio, but a considerably higher RiS selectivity of 80 20. 

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