Carbonyl radical cyclization

SCHEME 25.28. a-Carbonyl radical cyclization upon silylalkynes. 

Sha, C.K. and Ho, W.Y. (1998) a-Carbonyl radical cyclization approach toward spiro(4.4)nonene total synthesis of dimethyl gloiosiphone A. Chem. Commun., 2709-2710. 

Entry 21 involves addition to a glyoxylic hydrazone and the cis ring junction is dictated by strain effects. The primary phenylselenyl group is reductively removed under the reaction conditions. Entry 22 involves generation of a stannyloxy radical by addition of the stannyl radical at the carbonyl oxygen. Cyclization then ensues, with the cis-trans ratio being determined by the conformation of the cyclization TS. 

The transformation of2-734 involves an initial generation of an organosamarium species 2-735 with subsequent nucleophilic addition to the lactone carbonyl. Presumably, a tetrahedral intermediate 2-736 is formed that collapses to yield the ketone 2-737. This reacts with Sml2 to give a ketyl radical 2-738, which undergoes an intramolecular S-exo radical cyclization reaction with the alkene moiety. The resultant... 

The Fukuyama indole synthesis involving radical cyclization of 2-alkenylisocyanides was extended by the author to allow preparation of2,3-disubstituted derivatives <00S429>. In this process, radical cyclization of 2-isocyanocinnamate (119) yields the 2-stannylindole 120, which upon treatment with iodine is converted into the 2-iodoindole 121. These N-unprotected 2-iodoindoles can then undergo a variety of palladium-catalyzed coupling reactions such as reaction with terminal acetylenes, terminal olefins, carbonylation and Suzuki coupling with phenyl borate to furnish the corresponding 2,3-disubstituted indoles. 

Two possible mechanisms are proposed. Primarily the enol radical cation is formed. It either undergoes deprotonation because of its intrinsic acidity, producing an a-carbonyl radical, which is oxidized in a further one-electron oxidation step to an a-carbonyl cation. Cyclization leads to an intermediate cyclo-hexadienyl cation. On the other hand, cyclization of the enol radical cation can be faster than deprotonation, producing a distonic radical cation, which, after proton loss and second one-electron oxidation, leads to the same cyclo-hexadienyl cation intermediate as in the first reaction pathway. After a 1,2-methyl shift and further deprotonation, the benzofuran is obtained. Since the oxidation potentials of the enols are about 0.3-0.5 V higher than those of the corresponding a-carbonyl radicals, the author prefers the first reaction pathway via a-carbonyl cations [112]. Under the same reaction conditions, the oxidation of 2-mesityl-2-phenylethenol 74 does not lead to benzofuran but to oxazole 75 in yields of up to 85 %. The oxazole 75 is generated by nucleophilic attack of acetonitrile on the a-carbonyl cation or the proceeding enol radical cation. 

By using either one of these photosystems, one-electron (3-activation of a,(3-unsaturated carbonyl compounds produced carbon-centered radical precursors which cyclize efficiently and stereoselectively to tethered activated olefins or carbonyl groups. The 1,2-anti-stereochemistry observed contrasts with the general trend of syn-stereochemistry expected in 5-hexenyl radical cyclizations. Application of this methodology was successfully demonstrated by the stereoselective synthesis of optically pure C-furanoside, starting from L-tartaric acid (Scheme 38) [57,58]. 

Radical additions to alkenes and aromatic systems are well known reactions. The trapping in this manner of radicals obtained by reduction of the aliphatic carbonyl function has proved to be a versatile electrochemical route for the formation of carbon-carbon bonds. Such reactions are most frequently carried out in protic solvents so that the reactive species is a o-radical formed by protonation of the carbonyl radical-anion. Tlie cyclization step must be fast in order to compete with further reduction of the radical to a carbanion at the electrode surface followed by protonation. Cyclization can be favoured and further reduction disfavoured by a... 

The cyclization process can be promoted by using a single electron transfer mediator. Electron transfer from the mediator generates the carbonyl radical-ion away from the electrode surface so that cyclization can occur before there is opportunity for a second electron transfer. Thus reduction of 16, R = Me, in dimethyl-forraaraide at mercury in the presence of tetraethylammonium fluoroborate leads only to conversion of the ketone function to the secondaiy alcohol. However addition of a low concentration of N,N-dimethyl pyrrolidinium fluoroborate alters the course of reaction and the cyclized tertiary alcohol is now formed. This pyrrolidinium salt is reduced at -2.7 V vs. see at mercuiy to yield a complex DMP(Hg5) which is thought to act as a single electron transfer mediator [94]. Cyclization can... 

Scheme 24 illustrates how this notation can be combined with that of Seebach.73 Clive has formed a new ring by sequencing a Michael reaction, a carbonyl addition, and a radical cyclization.79 Phenylsele-noacrylonitrile is the actual reagent that accomplishes the transformation implied by synthon (7). 

Even though radicals can be nucleophilic or electrophilic, the chemistry of radicals is not naturally intertwined with the carbonyl group and related functionalites in the same way that the chemistry of ionic reactions is. This notation does not now account for the frequent need for radicals and alkenes to be electronically paired for a successful reaction. This is in part because I could not envision a simple, unambiguous notation device and more importantly because such a device could be artificial and misleading in the realm of radical cyclizations where arrangement of the double bond and the radical site in the molecule is often much more important than any electronic pairing. 

Among the oxidants that have been used to generate radicals, manganese (HI) acetate has emerged as a powerful reagent to mediate radical cyclizations.147 The manganese(III) acetate-mediated oxidation of enolizable carbonyl compounds is one of the best methods available for the cyclization of electrophilic radicals. The substrates are vety easily prepared by standard alkylation and acylation reactions. Radicals are formed with high selectivity by oxidation of acidic C—H bonds, and, because the reaction is an oxi-... 

Below are shown a few examples of the types of complex structures that can be assembled by intramolecular free-radical cyclization. Note the presence of a great many polar functional groups present in the cyclization substrates which are compatible with the process. While the examples shown do not need protecting groups, a great number of other free-radical cyclizations are known which have unprotected alcohols, carbonyl groups, and carboxylic acids in the cyclization precursor. 

Intermolecular coupling of ketones and alkenes, promoted by SmH, occurs with excellent stereochemical control. In one such reaction, samarium(II) iodide has been used to prepare cyclobutanones and cyclobutanols from chiral, 6-oxohex-2-enoates (equation 137)520. The reaction is performed in THF in the presence of HMPT and occurs in good yield with excellent stereocontrol. If appropriately located carbonyl and alkene moieties are present in a molecule, then Sml2-HMPT can be used to form cyclooctanols by a radical cyclization process in some cases there is a reasonable degree of diastereoselectivity (equation 138)521,522. 

Radical carbonylation can also be conducted in a zinc-induced reduction system. A similar three-component transformation reaction to that illustrated in the second equation of Scheme 6.14 can be attained using zinc and protic solvents (Scheme 6.38) [59]. The observed stereochemical outcome is identical to that for the tin hydride-mediated reaction, providing a additional evidence for free-radical generation, radical carbonylation, and acyl radical cyclization taking place simultaneously, even in the zinc-induced system. In this system, however, the final step is reduction to form a carbanion and protonation. 

The above described total synthesis shows the application of the (7-carbonyl radical-initiated tandem cyclization reaction for the first generation of (+)-paniculatine. With this method starting from 2-substituted-5-(R)-cyclohexenone 5 Sha and co-workers obtained 15 (=1) in 21 steps. Furthermore the HBr-salt of this alkaloid was prepared and subjected to a single X-ray analysis, which unambiguously confirmed the structure and stereochemistry of this synthetic (+)-paniculatine. 

Aryl radical cyclization.10 Sml2 in HMPA/THF at 25° can effect cyclization of l-allyloxy-2-iodobenzene to a Sm(III) intermediate (a) that can be trapped by electrophiles, including aldehydes or ketones. The report suggests that a similar mechanism operates in the Barbier-type coupling generation of an alkyl radical followed by formation of RSml2, which adds to a carbonyl compound to form an adduct that is hydrolyzed to an alcohol. 

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