Formation and reactions of alkoxy alkyl radicals
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Introduction
Radicals can be defined as electrophilic or nucleophilic.[Giese, 1989] Alkoxy alkyl radicals are nucleophilic, because the oxygen at the radical carbon increases the SOMO energy.[Giese, 1983] In reaction with alkenes nucleophilic radicals add preferentially to alkenes with electron- withdrawing substituents, because the electron-withdrawing substituent lowers the LUMO of the alkene and thus reduces the SOMO-LUMO difference. [Giese, 1986]
(1) Reaction of a-halo ethers with tributylstannane in the presence of a radical initiator
Alkoxy alkyl radicals are conveniently prepared by reaction of a-halo ethers with tributylstannane in the presence of a radical initiator (e.g. AIBN) as illustrated in the reaction of the glucosyl bromide 1with acrylonitrile. The C-glucoside 2 is obtained with high diastereoselectivity (49:1) for the a-isomer.[Giese, 1983b]
The high preference for the a-isomer is probably due to overlapping between the non-bonding electrons on the ring oxygen and the unpaired electron on C-1. An effective overlap is only possible when the radical is axially attacked.
The outcome of an axial attack with respect of a- or b-product, is dependent on the structure of the glycosyl radical. ESR-studies have shown that the radical from 1 has the twisted boat-structure 3 while the mannosyl radical 4 has a chair-conformation. The preference for these conformations is explained by effective overlap of orbitals. In both conformations the carbon-oxygen bond of the substituent in the 2-position is periplanar with the radical orbital. This ensures a maximum overlap between the SOMO of the radical and the LUMO of the carbon-oxygen bond. An electron-withdrawing substituent (e.g. acetoxy) at C-2 lowers the LUMO energy and increases thus the stabilizing effect of the SOMO-LUMO interactions.[Giese, 1989b] These conformations also ensures an effective overlap of the unpaired electron at the radical center with one of the lone pairs on the ring oxygen. Radical 3 will for the same reasons as 3 (vide supra) be attacked from an axial position.
If other conformers of the glycosyl radical are preferred, the a-selectivity may drop or can even be reversed. For instance in the reaction of 2,3,4,-tri-O-acetyl-a-D-xylosyl bromide with acrylonitrile the b-isomer is the major product.[Giese, 1987] This is attributed to the occurence of the radical conformers 5 and 6, which both will give the b-isomer.[Giese, 1989b]
The radical reaction described above has also been used in the synthesis of the C-glycopeptides [Kessler, 1992] and C-disaccharides.[Giese, 1988]
(2) Reductive cylization of a-chloro ethers
Reductive cylization of a-chloro ethers can be effected by tributylstannane using AIBN as radical initiator as illustrated in the synthesis of the vinylsilane 3, an intermediate in the synthesis of b-Agarofuran.[Büchi, 1979] The a-chloro ether 2 was prepared by treatment of the hemiacetal 1 with PCl5.
The cyclization reaction was accompanied by 13 % of an uncyclized reduction product. The vinylsilane 3 was produced in a 4:1 mixture of the geometric isomers, showing that this radical cyclization is not stereospecific. When the TMS group in 2 was replaced by hydrogen, reductive cyclization failed.
(3) Allylation of a-chloro ethers
Allylation of a-chloro ethers can be achieved by trialkylallylstannane under conditions where the halide is transformed into a carbon-centered radical. Thus reaction of the mannose derivative 1 with of tributylstannane in the presence of AIBN, gives the allylated sugar-derivative 2 in 79 % yield.[Keck, 1982] What concerns the stereochemistry of this reaction, complete retention of configuration was observed. This is also expected since it implies attack of the allylstannane from the least hindered side of the intermediate radical.
See also:[Boto, 2002]
(4) Rearrangement of pyranosyl radicals
In the absence of radical traps, glycosyl radicals can of course dimerize;[Giese, 1988b] but if the radical has an acyloxy group in 2-position, a 1,2-migration of the acyloxy group may take place.[Giese, 1987b]In the presence of a low concentration of tributylstannane, the benzoyl group in the glycosyl radical 1 undergoes a 1,2-migration. The rearranged pyranosan-2-yl radical 2 abstracts a hydrogen from the tributylstannane to give the 2-desoxysugar 3.[Korth, 1988] The rearrangement only takes place if the radical center is at the anomeric carbon atom. Halogens in other positions are simply replaced by hydrogen (2 to 3)
The radical center in 1 is more stable than in 2, due to a-oxygen radical stabilization. The seemingly unfavorable rearrangement of radical 1 to 2, is explained by 2 being a more stable molecule than 1. The greater stability of 2 compared to 1, comes from a relatively large anomeric stabilization of C-1 in 2, which now is connected to two oxygen atoms.
(5) Glycosyl radicals from alkylcobaltiooximes.
The cobalt-carbon bond in alkylcobaltiooximes can be cleaved homolytically to give an alkyl radical and a Co(II) complex. [Maillard, 1982],[Rao, 1984] This procedure has been utilized in the synthesis of glycosyl radicals from glycosyl bromides.[Ghosez, 1988]
(6) a,b-Unsaturated diesters: radical acceptors in dialkylzinc mediated tandem radical/aldol condensation
Methoxy methyl radical is formed from (iodomethoxy)methane and dimethyl zinc at - 70 oC. [Bazin, 2007]
(7) Formation and addition of a-alkoxy radicals to a,b-unsaturated compounds
a-Alkoxy radicals can be prepared from a-bromo ethers by reaction with mixture of triethyl borane, oxygen and tributylstannane. The triethylborane in the presence of oxygen functions as a radical initiator while the tin hydride is chain carrier. The a-alkoxy radicals have been used in conjugate addition to a,b-unsaturated systems.[Sibi, 2002] Moderate diastereoselectivity was found for addition of a-alkoxy radicals to the a,b-unsaturated system below.
