Amidyl radicals cyclizations

Amidyl Radical Cyclizations from A-Halo- and A-Nitrosoamides. 35... 

Kinetics of Amidyl Radical Cyclizations and H-Atom Abstractions.. . 35... 

Amidyl Radical Cyclizations from N-Halo- and N-Nitrosamides... 

A variety of methods are available for the synthesis of heterocyclic carbonyl compounds by radical cyclization. For example, the cyclization of alkoxycarbonyl radicals is particularly useful for the synthesis of five- and six-membered ring lactones [80]. Recent applications of this cyclization method include Zard s photoly-tical transformation of an alkoxycarbonyl dithiocarbonate having a double bond which can serve as a key step in the synthesis of ( )-cinnamolide and RA. Evans s enantioselective synthesis of 4-hydroxy butenolide terminus, which is applicable to the synthesis of mucocin [81J. Amidyl radical cyclizations are frequently utilized for the synthesis of five- and six-membered ring lactams [82]. However, this section only focuses on recent methods for heterocyclic carbonyl compounds by an n-i-1 type strategy based on radical carbonylations. 

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. 

An unprecedented domino radical cyclization/Smiles rearrangement process of 175 to give 3-(2-aryl-N-methylacetamido)indolin-2-ones 178 or 180 was reported by Gerard, Sapi, et al. [63] (Scheme 5.38). The reaction proceeds via a 5-exo-trig cyclization followed by radical substitution. The radical intermediate 177, formed via the radicals A and 176, could undergo either a normal termination of a radical to form product 178 in 11-66% yields or an additional amidyl radical cyclization, giving the product 180 in up to 40% yield depending on the reaction conditions. 

The attacking radical need not always be at carbon. Amidyl radical are known and give cyclization reactions. Aminyl radical cyclizations have been reported. Oxygen radical can be generated under photochemical conditions, and they add to alkenes in a normal manner. ... 

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>. 

To facilitate the cyclizations of nitrogen-centered radicals, one need only increase the electronegativity at nitrogen. This makes the radical more electrophilic (which accelerates the cyclization), and strengthens the forming bonds (which shifts the equilibrium to the cyclic product). Amminium radical cations are more well-behaved in cyclizations than aminyl radicals, and these radical cations can either be formed directly from ammonium salts, or by protonation of aminyl radicals (which are relatively weak bases and require strong acids for protonation). Metal-complexed aminyl radicals are highly reactive, and amidyl radicals are also useful.178... 

The electronic nature of a nitrogen centered radical, dictated by reaction conditions and/or the radical precursor employed, is crucial to the mode of reaction, to the ability to undergo efficient intramolecular cyclizations or intermolecular additions, and to the products isolated from the radical reaction. The types of radicals discussed in this review include neutral aminyl radicals, protonated aminyl radicals (aminium cation radicals), metal complexed aminyl radicals, and amidyl radicals. Sulfonamidyl and urethanyl radicals are known (71S1 78T3241), but they are not within the scope of this chapter. 

Exposure of unsaturated anilides to o-iodoxybenzoic acid in THF-DMSO at 90°C results in cyclization to give y-lactams [Eq. (88)] [163]. A mechanism involving an intermediacy of amidyl radical 95, produced by SET and then deprotonation, was proposed for the formation of y-lactams. 

Radical cyclization of suitably substituted benzamides yields the reduced 1-isoquinolinone (Equation 124) <1999TL2125>. In the illustrated example, the reactive intermediate was formed on the nitrogen as an amidyl radical, and this was followed by tandem cyclization. 

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). ... 

Zard has developed the use of N-amidyl radicals. The precursors of the radical intermediates are 0-benzoyl hydroxyamines such as 37. Addition of a tributylstannyl radical to the carbonyl group of the benzoate moiety is followed by the cleavage of the weak N - O bond. A subsequent 5-exol6-endo tandem cyclization takes place to yield the skeleton of the natural product deoxyserratine (Scheme 12) [49]. Later, the same group disclosed a tin-free source of amidyl radicals that relies on the use of M-(0-ethyl thiocarbonyl-sulfanyl) amides and lauryl peroxide as initiator. Examples of polycyclization were also given [50]. On the occasion of a model study toward the synthesis of kirkine, the use of thiosemicarbazide precursors gave access to the tetracyclic structure of the natural product [51]. 

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. 

More recently 2,3-dihydro-4-methyl-2-thioxo-3-thiazolyl alkenylcarbamates were shown to be useful precursors of monoalkylaminium radicals23, and amidyl radicals were generated from 1,2-dihydro-2-thioxo-l-pyridinyl imidates24. Both radicals, which contain <5,e-unsaturation, cyclize in a 5-exo fashion, but examples of stereoselective cyclization have not yet been reported. 

Similarly, amidyl radicals can be produced by visible light irradiation of unsaturated A -PTOC imidate esters which can be cyclized to prepare lactams127 138, e g., 4 and 5 (tandem cycloaddition)138. The configuration of the prevalent diastereomer of 5 was not determined, but a tram orientation of the substituents on the pyrrolidine ring would be expected. 

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)... 

The iV-hydroxypyridine-2(///)thione derivatives (PTOC carbamates and PTOC imidates) permit facile generation of neutral, protonated, Lewis acid-complexed aminyl radicals and amidyl radicals. For cyclization reactions, the PTOC protocol was comparable or superior in yield to those involving Af-chloro or Al-thioaryl compounds. The thioxothiazolyloxycarbonyl (TTOC) carbamates containing a primary amine group would appear to be the most useful precursors now available for generating monoalkylaminium cation radicals [55]. Some representative examples are collected in Table 6. 

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. 

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