Nitrogen reductive alkylation

Two synthetic bridged nitrogen heterocycles are also prepared on a commercial scale. The pentazocine synthesis consists of a reductive alkylation of a pyridinium ring, a remarkable and puzzling addition to the most hindered position, hydrogenation of an enamine, and acid-catalyzed substitution of a phenol derivative. The synthesis is an application of the reactivity rules discussed in the alkaloid section. The same applies for clidinium bromide. 

A phenyl ethanol amine in which the nitrogen is alkylated by a long chain alphatic group departs in activity from the prototypes. This agent, suloctidil (43) is described as a peripheral vasodilator endowed with platelet antiaggregatory activity. As with the more classical compounds, preparation proceeds through bromination of the substituted propiophen-one ( ) and displacement of halogen with octyl amine. Reduction, in this case by means of sodium borohydride affords suloctidil (43). ... 

Reaction No. 5 (Table 11) is part of a synthetically useful method for the alkylation of aromatic compounds. At first the aromatic carboxylic acid is reductively alkylated by way of a Birch reduction in the presence of alkyl halides, this is then followed by an eliminative decarboxylation. In reaction No. 9 decarboxylation occurs probably by oxidation at the nitrogen to the radical cation that undergoes decarboxylation (see... 

Amphetamine (53) is the prototype drug in this group. One significant objective of molecular manipulation in this group is to retain the appetite depressant activity without significant central stimulation. This is as yet unrealized. Some of the drugs prepared with this purpose in mind are discussed in this section. Reductive alkylation of the nitrogen... 

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. 

In aprotic media, quinoxalines may be reductively acylated297 or car-boxylated16 [Eq. (115)] and probably also reductively alkylated at the two nitrogen atoms to stable 1,4-dihydroderivatives. 

In solid-phase synthesis the standard conditions used in solution resulted in an incomplete reaction probably due to a swelling problem of the resin in MeOH. In this case the use of DMF in place of MeOH results in an approximately complete reaction. 7 It has been shown that the introduction of a reduced amide linkage between Phe and Pro residues, by reductive alkylation of the Pro nitrogen with Boc-Phe-H in the presence of NaBH3CN under acidic conditions leads to epimerization of the Phe residue. 57 This problem of racemization is... 

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