Intramolecular radical-induced

Our Total Synthesis (Part I) Construction of the A/B Ring System Highlighted by an Intramolecular Radical-Induced Carbocyclization Approach... 

An experimental probe for the presence of radical intermediates resulting from thermally induced homolytic cleavage of the N-0 bond was derived by incorporating an alkene into a model substrate to act as a potential intramolecular radical trap (Scheme 6.25) [11]. In a control experimental, thermal reaction of 73 gave the desired product 74 in 66% isolated yield. On the other hand, thermal rearrangement of the unsaturated compound 75 under our typical conditions gave the desired hydroxypyrimidinone 76 in only 38% isolated yield. When the vinyl ami-doxime mixture 75Z/E was heated in o-xylene at 125 °C in the presence of a... 

Other light-induced ring closures to benzazepines include the intramolecular radical arylation of A-substituted enaminones (224) to hydrodibenz[6,[Pg.536]

In the series of hydroxycyclohexadienylperoxyl radicals, one encounters the competition between the H02-/02- elimination leading to phenol [reactions (9) and (14)/(15)] and fragmentation of the ring (Pan et al. 1993). That latter has been attributed to an intramolecular addition of the peroxyl radical function to a diene double bond [reaction (24)]. This reaction is reversible [reaction (-24)], but when 02 adds to the newly created carbon-centered radical the endoperoxidic function is locked in [reaction (25)]. In analogy to reaction (24), the first step of the trichloromethylperoxyl-radical-induced oxidation of indole is its addition to the indole C(2)-C(3) double bond (Shen et al. 1989). 

An intramolecular 2-alkylation was also observed in a sulfonyl free radical induced addition-cyclization <95SL763>. A key intermediate in a new synthesis of pallescensin A (a biologically active labdane diterpene) was prepared by a cationic cyclization reaction with a furan <95SYN1141>. The sonochemical Barbier reaction was extended to carboxylate salts. 2-Furanylketones 10 can be obtained by sonication of a mixture of furan, lithium carboxylate, an alkylchloride, and lithium in THF <95JOC8>. 

Spirocycles can be obtained from intramolecular radical biaryl coupling reactions when suitable substituents are present for an alternative stabilization of the cyclohexadienyl intermediate (c.f. 69, Scheme 25). Otherwise, rearomatization can occur by cleavage of one substituent from the quaternary center of the spirocycle, such as the C-P bond in 69. First examples for an alternative reaction course have been reported in studies on the photochemically induced cyclization of iodoarenes [134]. Recently, ferf-butyldimethylsilyl ethers [135] and azides [136] were identified as well-suited substituents to lead the ipso substitution into the pathway towards spirocycles (Scheme 27). 

Other applications of nitrite photolysis include the functionalisation of the i4a-methyl group of the lanosterol skeleton by irradiation of the nitrite of a, y a-alcohol [20], attack on C(i9> by irradiation of 5a-halo-6ji mtrito derivatives [2X,22] or nitrites of 2/ alcohols [23], intramolecular addition of a 20 alkoxy radical to a Ai -double bond [24], and some reactions involving radical-induced fragmentation of adjacent C-C bonds [23]. A comprehensive review by Nussbaum and Robinson [26] surveys the wide variety of reaction paths open to alkoxy radicals generated by photolysis of nitrites. 

Intramolecular pinacol coupling reactions are known, giving cyclic 1,2-diols. Dialdehydes have been cyclized by reaction with TiCls to give cyclic 1,2-diols in good yield. ° A radical-induced coupling of an a,03-dialdehyde led to cw-l,2-cyclo-pentanediol when treated with BuaSnH and AIBN. or induced photochemically. ... 

A slightly different approach has been utilized for the three-carbon expansion in a system which does not contain a carboalkoxy group. The initial intramolecular addition step is carried out separately with butyllithium or samarium diiodide to give a bicyclic alcohol (Scheme 78). The radical-induced fiag-mentation step is carried out photochemically in the presence of mercury(II) oxide and iodine to provide the expanded iodo ketone. 

By Addition o/P—H to Unsaturated Compounds. There has been a marked reduction in the number of papers concerned with this route in the past year, but nevertheless a number of interesting studies have been reported. Thus, for example, the primary phosphine (21) undergoes free-radical-induced intramolecular cyclization to form the bicyclic phosphine l-phosphabicyclo[3,3,l]nonane (22). ... 

Intramolecular carbon carbon bond formation is more efficient as demonstrated by Kim and Rawal, who reported the radical-induced fragmentation of epoxides followed by hydrogen abstraction and cyclization (Scheme 11). Kim s approach... 

Radically induced coupling of two t-systems also provides a synthetically useful route to cyclohexanes. The 6-endo-tng cyclization of the vinyl radical generated by Bu3Sn radical addition to the carbohydrate alkyne 147 provided a novel route to carbasugar 148 [93]. The intramolecular pinacol coupling of 1,6-dicarbonyl compounds such as 149 provides a direct synthesis of the inositol 150 [94] (Scheme 24). 

On irradiation in MeOH, (3 R = Me or Et) undergoes y-hydrogen abstraction followed by intramolecular radical reaction to give a jS-lactam. However, excitation in the nn region of the thiocarbonyl group does not induce this transformation, suggesting that photocyclization of the thioxoacetamides proceeds from upper excited states as in the case of thiones. ... 

Some further examples involving radiation chemical studies deal with an intramolecular RS -induced hydrogen atom abstraction from a-amino activated C-H bonds. Thus Zhao et report on the formation of C-centered reducing radicals... 

A new approach to construction of 3-aminosugar moieties by stereospecific intramolecular addition of a carbon-free radical to hydrazone 125 derived from crotonaldehyde was recently demonstrated by Friestad. This synthesis, comprising asymmetric dihydroxylation, PhS radical-induced C = N bond alkylation (C-vinylation) and subsequent Wacker oxidation [88] of terminal olefin 128, which afforded L-daunosaminide derivative 129, in overall 32% yield, is outlined in Scheme 23 [89]. 

The Fukuyama indole synthesis involves the intramolecular radical cyclization of 2-alkenylisocyanides, the availability of which often limits the utility of this process. In order to access a wider variety of such substrates, the author prepared the versatile Horner-Wadsworth-Emmons reagent 131 using the Pudovik reaction <01SL1403>. Reaction of 131 with a variety of aldehydes thus provides a convenient and general route to diverse alkenyl precursors 132. Additionally, instead of the standard radical conditions using tri-n-butyltin hydride, Fukuyama now finds that excess thiols arc quite effective for inducing cycliz.ation, whereupon desulfurization of the indoles 133 can be effected with Raney-Ni if desired. 

Although, consequently, a dimer diradical was assumed instead to be the relevant initiating species, the constitution of this species remained undetermined. The above-described NMR analysis of the [2.2]paracyclophane side products proved to be highly valuable in answering this question, with l,2-dihalo-[2.2]paracyclophanes 13a appearing exclusively, and systems such as 13c and 13d never being observed [62]. Since it is reasonable to assume that these side products are the result of an intramolecular radical recombination of the same dimer diradicals, which alternatively induce chain propagation, it was concluded that a dimerization of 11 must lead to either 14 or 15, but never to systems such as 16 (Scheme 29.4). When, in addition, the relative stabilities of the radical centers of 14 and 15 are taken into account, it was concluded that 14 with CHX-localized radicals would be the relevant species. These conclusions have been fuUy corroborated by computational studies, which have confirmed the process 11 14 within this... 

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