Nitrones, addition organometallics

Nitrones have a more reactive C=N bond toward nucleophilic addition compared to imines. In spite of this fact, there have been only a limited number of studies on the nucleophilic addition reactions of nitrones, particularly organometallic reagents.352-355 During the last decade, research related to reactions of nitrones with zinc-containing reagents was essentially focused on (i) dialkylzinc-assisted alkynylations356-358 and vinylations359 of nitrones, (ii) catalytic asymmetric nucleophilic additions to the C=N bond,360-364 and (iii) nitrone allylations by allylzinc halides.365,366... 

Table 6. Addition of Organometallic Reagents to Racemic Nitrones S8-9...

Michael addition of alkyl organometallic reagents to a,/ -disubstituted nitroalkenes followed by protonation of the intermediate nitronate anion generally gives mixtures of syn- and anti-diastereomers with poor diastereoselectivity19. 

Nucleophilic addition of organometalic reagents occurs when the nitrone form is in equilibrium with the hydroxylamine form, for instance, in the case of N -benzyl-/V-glycosyl hydroxylamines (Scheme 2.130) (213). 

Addition of organometalic compounds to nitrones is known as an efficient method of enantioselective synthesis of primary amines that can be easily obtained by the reduction of hydroxylamines which are the products of nucleophilic addition. 

Diastereoselective addition of a wide range of Grignard reagents to C -alkyl and C-aryl-A-[a.-phenyl- or u-methyl-j3-(benzyloxy)ethyl nitrones is determined by the presence of a stereogenic A -substituent (136, 137). High diastereoselectiv-ity in the addition of organometalic compounds to A-(( i-methoxyalkyl) nitrones can be explained by a simple chelation model (Scheme 2.132) (136). 

Addition of various organometalic reagents to chiral nitrones, derived from L-erythrulose, proceeds with variable diastereoselectivity, depending on Lewis acids as additives. ZnBr2 facilitates the attack at the Si face of the C=N bond, whereas Et2AlCl makes the attack at the Re face more preferable. The obtained adducts can be transformed into derivatives of /V - h y d r o x y - u. u - d i s u b s t i t u t e d -a-amino acids, with their further conversion into a,a-disubstituted a-amino acids (193, 202). 

O - P h e n y 1 - /V - e r y t h r o s y 1 nitrone (336), as a Ci,C i-bis-electrophile, when subjected to the double addition of Grignard reagents (in a domino style), leads to acyclic hydroxylamine (338) via the formation of open-chain nitrone (337 ). The reaction proceeds at 0°C with variable diastereoselectivity ranging from medium to good, depending on the organometalic reagent used (Scheme 2.140) (564). 

Recently, semiempirical PM3 computational analysis (568) and first ab initio study (569) of the nucleophilic addition to chiral nitrones of Grignard reagents have been carried out. The data revealed that all reactions are exothermic and proceed through /w-complexation of nitrones with the organometalic reagent. 

Additions of organometallics to the C=N bond of imines, oximes, hydrazones, and nitrones have been reviewed, with emphasis on the issues of reactivity and selectivity. Recent advances in enantioselective addition to imines of ketones are highlighted. 

The acid-catalyzed isomerization to nitrones has been used as a route to precursors of doxyl spin labels. This method provides a route whereby imines can be converted to nitrones, a route not generally available previously. Lewis acids seem to be best for catalyzing the isomerization. " Indirectly this route also leads to hydroxylamines by addition of organometallics to the nitrone. 

Z. Y. Chang and R. M. Coates, Diastereoselectivity of organometallic additions to nitrones bearing stereogenic Al-substituents, J. Org. Chem. 55 3464 (1990) R. Huber and A. Vasella,... 

The absolute configuration of the major products (213) or (214) can be predicted by the chelation model shown in Scheme 40, as the resident stereogenic substituent controls the facial selectivity in the organometallic additions. The diastereoselectivity is affected by the 3-alkoxy functionality. The methoxy substituent is preferred, as the selectivity erodes with benzyloxy substitution (entries 1 and 2, Table 16) and is reversed with the bulky f-butyldimethylsiloxy group (entries 6 and 7, Table 16). As expected, selectivity is poor for nitrones devoid of (3-alkoxy substituents (entry 3, Table 16). By appropriate nitrone/organometallic substitution, both diastereomeric products can be preferentially generated (entries 1 and 6, Table 16). 

Table 17 Additions of Organometallic Reagents to Cyclic Nitrones...

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