Radical cyclization, with amidyl radicals

Cyclizations of amidyl radicals have been studied both synthetically and kinetically. A detailed study on the rates of a variety of amidyl radical reactions was determined by both LFP and indirect competition methods (Table l) In addition, the rate constants for reactions with BusSnH and PhSH were also reported (thus giving a range of simple amidyl radical clocks). The results obtained will be useful in synthetic sequenceplanning involving amidyl radicals. 

In synthetic work, amidyl radicals, prepared by BusSnH/AIBN-mediated homolysis of O-benzoylhydroxamic acid derivatives, have been shown to cyclize in a A-exo fashion to give -lactams (Scheme 10). In addition, radicals generated in this way have also been reported to undergo 5-exo cyclization to give mixtures of cis- and Iranx-pyrrolidinones with the steric nature of the Al-substituent having little effect on the stereochemical outcome (Scheme 11). The major products detected were those predicted by application of the Beckwith rule. ... 

Radical cyclization is an effective approach to the synthesis of isoquinolines (Scheme 8). In some cases these offer an alternative to the palladium-catalyzed reactions with aryl halide intermediates <99EJOC1925, 99TL1125>. For example, the radical cyclization of the iodide 37 onto the vinylsulfide moiety was followed by a cascade cyclization to form the benzo[n]quinolizidine system <99TL1149>. In some cases the radical cyclization can take place without the need for a halo intermediate. The reactive intermediate of 38 was formed on the nitrogen as an amidyl radical, which underwent tandem cyclizations to the lycorane system <99TL2125, 99SL441>. 

In the study of amidyl radicals, obtained from Ar-amidosulfonyl radicals by extmsion of sulfur dioxide, sulfonamide 187 reacted with S -( 1,1 -dimethyl-3-oxobutyl) O-ethyl dithiocarbonate to give, as minor product, the thiazocinone 188 via cyclization of the Ar-amido sulfonyl radical. The major product (55%) was the corresponding seven-membered azepinone from the cyclization of the amidyl radical (Equation 14) <2004CC1848>. 

Self-terminating radical cyclizations have been explored with both aminium and amidyl radicals using the reaction with cyclodecyne (52) as a model system. However, instead of N-containing compounds, the bicyclic ketones 53 and 54 were exclusively obtained. Their formation could be explained by the mechanism that is exemplary shown for reaction of the A-benzyl acetamidyl radical, AcBnN" (Scheme 2.19). ... 

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. 

Recently, Clark and Peacock [27] explored the application of amidyl radical cyclization for the construction of y9-lactams. Reaction of the 0-benzoylhydroxamic acids 100 with BusSnH and AIBN employing a slow addition technique furnished the 4-exo trig cyclized product 101, the uncyclized reduction product amide 102 and the benzoyloxy group migration product 103. 

The jV-chloro-compounds were the first to be employed as radical cyclization precursors in the synthesis of pyrrolidines and piperidines, as well as fused and bridged heterocyclic skeletons [7], Aminyl and amidyl radicals were thus generated and used in intramolecular additions. Higher yields and selectivities are obtained with the metal-complexed species. Some selected examples are reported in Table 4. Generally, a typical radical chain mechanism is involved (with chlorine atom transfer from 7V-chloro-compound). In the particular case of copper-cornplexed aminyl radical cyclization, a redox chain process operates (with fast chlorine ligand transfer from cupric chloride)... 

In Keck s synthesis of 7-deoxypancratistatin, radical precursor 197 was cyclized to the oximine ether unit under radical conditions to give a 3 1 mixture of 198 and 199 in 90% yield. 35 Another very interesting variation was reported by Weinreb involving generation, cyclization, and trapping of amidyl radicals. 36 When hydroxamic acid 200 was cyclized with TEMPO in the presence of diphenyl diselenide, lactam 201 was obtained in 64% yield. 

During their study on 6-exo-trig radical cyclizations of axially chiral a-halo-ortho-alkenyl anihdes, Curran and coworkers [40] prepared the tricyclic amide 93/94 in moderate yield (49-51%) and excellent chirality transfer (98-99%) via a 6-exo-trig/5-exo-trig sequence (Scheme 5.20). The reaction was proposed to be initiated by an attack at the carbon-bromide bond with BujSnH, providing a-amidyl radical 97 (Scheme 5.21). 

Tandem or cascade reactions are arguably the most efficient way of preparing complex synthetic molecules. In radical chemistry this has been remarkably demonstrated by a BusSnH-mediated stereoselective cascade of seven 6-endo cyclizations. ° Thus reaction of (37) with BusSnH and AIBN furnishes the all-trans-anti heptacycle (38) as a single diastereomer in a 20% yield (Scheme 23). Tandem cyclization of nitrogen-centred radicals has also been accomplished. Thus heating either A-chloro derivatives or (9-acyIhydroxamic acid derivatives with BusSnH furnishes aminyl and amidyl radicals, respectively, which can then undergo cascade processes. 

Hydrogen abstraction under conditions similar to those in Section 3.8.1 may occur also from nitrogen compounds, with formation of amidyl free radicals. The results vary, depending on the substrate for example, 6-amino derivatives of steroids were converted into TV-substituted pyrrolidines [127], Medium-sized lactams underwent transannular cyclization to bicyclic lactams [128], and bicyclic carbinolamides afforded mainly -fragmentation products (Table 3.7). 

Fortucine 112, first isolated from the Fortune variety of narcissus by Tokhtabaeva et al. [43] in 1987, is a Lycorine alkaloid. To clarify the structure, Zard and coworkers [44] carried out the first total synthesis of ( )-fortucine using a radical domino process as the key step (Scheme 5.23). It was suggested that an amidyl-nitrogen radical is generated from 110, followed by a 5-exo-trig cyclization in sequence with... 

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