Azides reductive alkylation

Reductive alkylations have been carried out successfully with compounds that are not carbonyls or amines, but which are transformed during the hydrogenation to suitable functions. Azides, azo, hydrazo, nitro and nitroso compounds, oximes, pyridines, and hydroxylamines serve as amines phenols, acetals, ketals, or hydrazones serve as carbonyls 6,7,8,9,12,17,24,41,42,58). Alkylations using masked functions have been successful at times when use of unmasked functions have failed (2). In a synthesis leading to methoxatin, a key... 

The use of reductive alkylation conditions has been employed to access tricycles from the azide 353 <2002S242> (Equation 95). Hydroboration of the alkene double bond with dicyclohexylborane followed by reaction with the azide and subsequent elimination of nitrogen and cyclization gave the linear tricyclic diketopiperazine 354 and 355 as a mixture of diastereoisomers. 

The diastereomerically related keto esters 53 and 55, activated for removal of the chiral auxiliary, were obtained from 5 and 9. The requisite nitrogen atom was introduced by an azide displacement of chloride and at an opportune stage of the synthesis an intramolecular aminolysis of the carboxylic ester provided the enantiomerically related keto lactams 54 and 56. Although shorter routes to these popular synthetic targets have been reported in recent years, the conversion of 9 to (—)-iso-nitramine (ten steps, 50% overall yield) clearly illustrates the efficiency of the asymmetric Birch reduction-alkylation strategy for construction of the azaspiroundecane ring system. 

The synthesis of a triptan with a chiral side chain begins by reduction of the carboxylic acid in chiral 4-nitrophenylalanine (15-1). The two-step procedure involves conversion of the acid to its ester by the acid chloride by successive reaction with thionyl chloride and then methanol. Treatment of the ester with sodium borohy-dride then afford the alanilol (15-2). Reaction of this last intermediate with phosgene closes the ring to afford the oxazolidone (15-3) the nitro group is then reduced to the aniline (15-4). The newly obtained amine is then converted to the hydrazine (15-5). Reaction of this product with the acetal from 3-chloropropionaldehyde followed by treatment of the hydrazone with acid affords the indole (15-6). The terminal halogen on the side chain is then replaced by an amine by successive displacement by means of sodium azide followed by catalytic reduction of the azide. The newly formed amine is then methylated by reductive alkylation with formaldehyde in the presence of sodium cyanoborohydride to afford zolmitriptan (15-7) [15]. 

The synthesis of secondary amines from azides is efficient in terms of chemos-electivity [57] and has found valuable applications in the preparation of diamines [58,59], m-alkylaminoboronic esters [60], and in Diels-Alder-based amination reactions [61]. A convenient general route to open-chain polyamines, which play major roles in cellular differentiation and proliferation, has also been developed using the reductive alkylation of aliphatic aminoazides by (co-halogenoalk-yi)dichloroboranes as a key step [62] (Scheme 21). 

The synthesis shown in Scheme 60 exemplifies the first approach <20010L2575, 2004JOC2831>. A rather lengthy series of transformations provides epoxide 311. The epoxide is opened with azide and the resulting alcohol converted to the mesylate. A few additional functional group modifications are then necessary for the synthesis of 312. A standard azide reduction followed by an intramolecular alkylation provides the aziridine 313. This aziridine is then carried on to FR900482 in three additional steps. 

Gurtius and co-workers studied the acid-catalysed decomposition of alkyl azides such as benzyl azide. This was decomposed in either warm 1 1 (v/v) sulphuric acid-water or with concentrated hydrochloric acid to give a mixture of products corresponding to hydrogen migration [benzaldiinine (1)], phenyl migration [formaldehyde anil (2)], the azide reduction product [benzylamine (3)], and the solvolysis product [benzyl alcohol (4)]. The first two were obtained as the... 

In the other synthetic route (119), Birch reduction-alkylation and transformation of functionalized hexahydroindoline derivatives constitute key reactions (Schemes 4 and 5). Birch reduction of A-(2-methoxybenzoyl)-(25)-methoxymethylpyrrolidine, followed by alkylation with 2-acetoxyethyl bromide, produced a key compound 76, azidation of which, followed by hydrolysis with acid, gave the azide 77 in 69% yield (two steps). lodolactoni-... 

The azide moiety, which can be reduced to a primary amine, can be used to prepare secondary amines by means of a reductive alkylation using an... 

Reduction. Alkyl azides are reduced to primary amines with CeCl3 7H2O - Nal in hot MeCN. ... 

Reduction of Azides. Reduction of alkyl, aryl, and aroyl-azides to the corresponding primary amine or amide occurs... 

Later, Armstrong, et al. reported a similar methodology. Cinchona alkaloid-catalyzed reaction of ethyl glyoxylate 169 with substituted ketenes, formed in situ, gave P-lactones, which was underwent ring opening by sodium azide, reduction and ester hydrolysis to afford P-alkyl aspartates 172, Schane 3.54 [70]. Noteworthy in... 

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