Amino radicals intramolecular cyclization

The extension of the above radical intramolecular cyclization of /V-haloaryl-p-lactams to 2-azetidinones bearing the proradical center at C3 was also explored. The treatment of haloarenes 109a-c under similar conditions for the preparation of benzocarbapenems and benzocarbacephems 104—108 gave the fused tricyclic (1-lactams llOa-c (Scheme 37, Table 2). Compounds 110a and 110b were obtained as mixtures of diastereomers, which are epimers at the newly formed C5 stereocenter, while the amino derivative 110c could be prepared as a single isomer. 

The converse situation in which ring closure is initiated by the attack of a carbon-based radical on the heteroatom has been employed only infrequently (Scheme 18c) (66JA4096). The example in Scheme 18d begins with an intramolecular carbene attack on sulfur followed by rearrangement (75BCJ1490). The formation of pyrrolidines by intramolecular attack of an amino radical on a carbon-carbon double bond is exemplified in Scheme 19. In the third example, where cyclization is catalyzed by a metal ion (Ti, Cu, Fe, Co " ), the stereospecificity of the reaction depends upon the choice of metal ion. 

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>. 

A reaction by Clough et al. comes close to the direct synthesis shown in Scheme 1 (89TL7469). Here amides (62) react in a radical mechanism to 4-methylene compounds (63) that with 03/PPh3 are converted to tetramic acids (64). (See Fig. 29.) Several authors, however, prepared esters of 4-amino-3-oxo-butanoic acid, which served as precursors for intramolecular cyclization to tetramic acids (82JHC883). Koehler and Gerlach in an initial stage of a synthesis of dysidine, contained in marine sponge... 

The primarily formed radical cation can undergo dimerization (path a), which very often is followed by intramolecular cyclization via an amino group to give symmetrically substituted pyrrols [Eq. (23)] [145]. In other cases, cyclization takes place via oxygen functions leading to bischromones [Eq. (24)] [146] or to furans [Eq. (25)] [147]. 

Furthermore, this methodology was developed to afford the synthesis of e t-lycoricidine (248) using photolysis instead of a chemically mediated radical reaction (160). Photolysis of 4-(4/ )-hydroxy-6-[(2-methoxycar-bonyl-4,5-methylenedioxy)phenyl]-25,35-0-isopropylidenehex-5-ynal O-benzyloxime 245 (derived from D-glucose) in the presence of thiophenol under went intramolecular cyclization to produce l-(A-benzyloxy-amino)-5-phenylthiocyclohex-5-ene 246. Cleavage of the N-O bond and reductive elimination of the phenylthio group in 246 with Sml2 in THF... 

The intramolecular cyclization of amino radicals, where the nitrogen is not coordinated by a metal or the proton, has not been studied extensively. Surzur, Stella and Tordo (49) reported the photolysis of N-chloro-N-(4-pentenyl)-N-propyl-amine in various neutral solvents. The data were accounted for by the following scheme. 

The photolysis of donor-acceptor systems provides unique synthetic opportunities. Direct irradiation of the donor-acceptor systems, such as systems containing arene and amine components, leads to intramolecular electron transfer, that is, to amine cation-radical and arene anion-radical moieties. After generation, these moieties undergo cyclization reactions providing efficient synthetic routes to fV-heterocycles with a variety of ring sizes. Thus, direct irradiation of secondary amino-ethyl and aminopropyl stilbenes leads to benzazepines in improved yields (Hintz et al. 1996). As known, benzazepines are used in medicine as antidepressants. Scheme 7.44 illustrates ion-radical cyclization with the formation of benzazepine derivative (65% yield). 

Many methods have been developed for the enantioselective synthesis of unnatural a-amino acids. Jeff Johnston of Indiana University reports (J. Am. Chem. Soc. 125 163,2003) coupling the asymmetric alkylation of O Donnell with intramolecular radical cyclization, leading to what appears to be a general method for the enantioselective construction of indolines. 

In summary, it would appear that the oxidation of a catecholamine probably first involves the formation of a semi-quinone radical (this can be brought about by an one-electron transfer, e.g. from Cu++ ions,14 or by photoactivation 1) which rapidly undergoes further oxidation (e.g. with atmospheric oxygen) to an intermediate open-chain quinone (such as adrenaline-quinone) and then cyclizes by an oxidative nucleophilic intramolecular substitution to the amino-chrome molecule. Whilst the initial formation of a leucoaminochrome by non-oxidative cyclization of the intermediate open-chain quinone in some cases cannot be entirely excluded at the moment (cf. Raper s original scheme for aminochrome formation72), the... 

Under appropriate circumstances, free-radical methods can also be used to prepare macrocyclic systems. For example, Maillard and coworkers prepared the 12-membered macrocyclic ether (102) by Bu3SnH-mediated intramolecular homolytic addition to a remote, but activated (a, / unsaturated) olefin as depicted in equation 77460. Tozer and coworkers employed 7-, 8- and 9-endo cyclization in their preparations of conformationally constrained amino acids (103), an example of which is provided in equation 78448. 

A diastereoselective formal addition of a 7ra i-2-(phenylthio)vmyl moiety to a-hydroxyhydrazones through a radical pathway is shown in Scheme 2.29. To overcome the lack of a viable intermolecular vinyl radical addition to C=N double bonds, not to mention a reaction proceeding with stereocontrol, this procedure employs a temporary silicon tether, which is used to hold the alkyne unit in place so that the vinyl radical addition could proceed intramolecularly. Thus, intermolecular addition of PhS" to the alkyne moiety in the chiral alkyne 161 leads to vinyl radical 163, which cyclizes in a 5-exo fashion, according to the Beckwith-Houk predictions, to give aminyl radical 164 with an a 7z-arrangement between the ether and the amino group. Radical reduction and removal of the silicon tether without prior isolation of the end product of the radical cyclization cascade, 165, yields the a-amino alcohol 162. This strategy, which could also be applied to the diastereoselective synthesis of polyhydroxylated amines (not shown), can be considered as synthetic equivalent of an acetaldehyde Mannich reaction with acyclic stereocontrol. 

Both intermolecular and intramolecular additions of carbon radicals to alkenes and alkynes continue to be a widely investigated method for carbon-carbon bond formation and has been the subject of a number of review articles. In particular, the inter- and intra-molecular additions of vinyl, heteroatomic and metal-centred radicals to alkynes have been reported and also the factors which influence the addition reactions of carbon radicals to unsaturated carbon-carbon bonds. The stereochemical outcome of such additions continues to attract interest. The generation and use of alkoxy radicals in both asymmetric cyclizations and skeletal rearrangements has been reviewed and the use of fi ee radical reactions in the stereoselective synthesis of a-amino acid derivatives has appeared in two reports." The stereochemical features and synthetic potential of the [1,2]-Wittig rearrangement has also been reviewed. In addition, a review of some recent applications of free radical chain reactions in organic and polymer synthesis has appeared. The effect of solvent upon the reactions of neutral fi ee radicals has also recently been reviewed. ... 

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