Cyclization, radicals with enamines

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. " ... 

Castedo, Dominguez and coworkers [67] carried out the cyclization of the N-formyl enamines 264. The 1-endo trig radical cyclization of the enamines 264 with Bu3SnH and AIBN using slow addition technique proceeded with excellent stereoselectivity to generate only the trans isomer of the tetracyclic system 265. 

HiroyuM Ishibashi of Kanazawa University showed Organic Lett. 2008, 10, 4129) that the radical cascade cyclization of the enamine 13, derived from diethyl tartrate, proceeded with remarkable diastereocontrol, to give 14. The amide 14 was converted to (-)-Cephalotaxine 15. 

A radical cyclization of a 2-chloroacyl enamine 157 was used to synthesize 2-substituted pyroglutamates 160. Usually, the radical 158 undergoes an initial 5-endo cyclization (path a) and the resulting intermediate 159 attacked electrophiles like methyl acrylate to give the pyroglutamate 160. Unexpectedly, the reaction with methyl methacrylate took another course and a seven-membered... 

Enamine carbaldehyde 76 (Scheme 20) by sequential photochemical cycloaddition and iminium ion-propargylsilane cyclimtion furnishes allenes 77a-c in good yield and with high diastereoselectivity (92X2081). (Gas chromatographic fR values and thin-layer chromatographic Rp values have been reported.) Radical cyclization of ca-iodoalkyl isoquinolone 78a under... 

Cyclopentanones. Enamines (2) react with 1 at 25° to give in high yield the keto nitriles 3, which undergo the expected addition of lithium phenylacetylide to provide 4. On treatment of 4 with (C6H5)3SnH (AIBN) a 5-acetylenic radical is formed, which cyclizes to a benzylidenecyclopentane (5). Ozonolysis of 5 provides cyclopentanone 6. 

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. 

Reversed regioselectivity in aryl radical additions to enamides and enamines can also be observed with aryl substituents on the alkene [86]. This cyclization type has been successfully applied in the synthesis of protoberberines and the pavine alkaloids. Argemonine (39) was obtained from a 6-exo cyclization of 40 passing through a well-stabilized benzylic radical (Scheme 15). 

The photo Diels-Alder reaction of a-acetylnaphthalene 82 with the chiral oc-enaminonitril 83 yielded the cycloadduct 84 with excellent diastereoselec-tivity (Sch. 16) [57]. The intermediary formed biradical Y is particular stable due to delocalization of the radical on the aromatic moiety and to a captodative effect on the enamine part. The chiral induction occurred in two steps [58]. In the first step, a stereogenic center is created in the a-position of the acyl group. In the second step of the diastereoselection, one of the two diasteromeric intermediates undergoes preferentially cyclization to yield the final product 84, while the other one is more readily decomposed to form the starting material. For a more detailed discussion of the mechanism see Ref. [59]. 

Radical reductive alkylation of enamines has also been utilized for the intramolecular cyclization reaction34. Enamine 38 bearing an exo-olefin moiety, on treatment with Bu3SnH in the presence of a radical initiator, generates an aryl radical 39 which undergoes exclusive 1,6-cyclization to give the isoquinoline 40 as the sole product in 51.3% yield (equation 9). 

Anodic oxidation of an A-benzoylated enamine in acetonitrile/methanol/Na2C03 leads not only to the formation of the dimethoxylated starting material but also to a methoxy-substituted oxazoline through intramolecular nucleophilic attack of the benzoyl oxygen [157]. In another case, an electron-rich aromatic system can act as a nucleophile in an intramolecular cyclization with the enamine radical cation or dication [Eq. (29)] [157]. 

Li and colleagues effected the cyclization of A-aryl enamines to indoles with iodine itself (Scheme 5, equation 1) [11]. A suggested mechanism is shown, which involves oxidation of substrate by hyperiodide (generated in situ from Ij and NBS) to give A-iodo 3 and thence radical 4. Cyclization and oxidation of 5 affords the indole. 

The uncyclized enamine 183 was treated in boiling toluene for 5 h. prior to radical cyclization, and then further treated with tri-n-butyltin hydride in boiling toluene. A successful tandem double S-exo-trig, 6-endo-trig cyclization of the aryl radical generated from 184 afforded the tetrahydrolysergate 185 which was obtained as die only isolable product in 75% yield as a 3 1 mixture of two epimers at the 10-position (Scheme 39). 

Chiral amine catalysts have also been used in cascade reactions mediated by SOMO catalysis [143] and Lewis base catalysis [144]. MacMillan s group developed a powerful cascade reaction moderated by SOMO catalysis. The radical cation, generated from an enamine in condensation of imidazolidinone catalyst 208 with aldehyde 207 and subsequent oxidation by Cu oxidant, was expected to engage in a series of 6-endo-trig radical cyclizations terminated by a suitable arene to give a cyclohexadi-enyl radical. After a second oxidation, rearomatization, and liberation of the catalyst, the requisite 209 would be generated (Scheme 1.90). 

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