4-Nitrobenzyl bromide reduction

Previous syntheses An example of this point can be recognized by examination of one known synthesis of thienobenzazepines (Scheme 6.1). This synthetic route involves a key palladinm-catalyzed cross-conpling of stannyl intermediate 3, prepared by method of Gronowitz et al., with 2-nitrobenzyl bromide. Acetal deprotection and reductive cyclization afforded the desired thienobenzazepine tricycle 4. In support of structure activity relationship studies, this intermediate was conveniently acylated with varions acyl chlorides to yield several biologically active componnds of structure type 5. While this synthetic approach does access intermediate 4 in relatively few synthetic transformations for stractnre activity relationship studies, this route is seemingly nnattractive for preparative scale requiring stoichiometric amounts of potentially toxic metals that are generally difficult to remove and present costly purification problems at the end of the synthesis. 

A molecular dissection of the alkaloid vasicine (52) ultimately resulted in the expectorant and mucolytic agent bromhexine (54). The synthesis starts with displacement of halogen on 2-nitrobenzyl-bromide (53) by N-methyl cyclohexylamine, followed by Raney nickel and hydrazine reduction of the nitro group. Bromination in acetic acid then affords bromhexine. 

Bromoadamantane and 1-bromoadamantane are reduced to adamantane in yields of 84% and 79%, respectively, when treated with triethylsilane and catalytic amounts of aluminum chloride.186 Similar treatment of benzhydryl chloride and exo-2-bromonorbomane gives the related hydrocarbons in yields of 100% and 96%, respectively.186 In contrast, 2-bromo-l-phenylpropane gives only a 43% yield of 1-phenylpropane the remainder consists of Friedel-Crafts alkylation products.186 Some alkyl halides resist reduction by this method, even when forcing conditions are employed. These include p-nitrobenzyl bromide, 3-bromopropanenitrile, and 5-bromopentanenitrile.186... 

Construction of the azepine ring by C-N bond formation. Aranapakam et al. synthesized 5,10-dihydro-4H-benzo[l7]thieno[2,3-e]azepine 111 and 4H-benzo[ 7]thieno[3,2-e]azepin-10(9H)-one 113 (X = CO) starting from the corresponding tributylstannyl derivatives 110 and 112, which react with 2-nitrobenzyl bromide and [(Ph)3P]4Pd. Sequential deprotection and reductive cyclization were carried out in one step with zinc and aqueous acetic acid (Scheme 22 (1999BMCL1733)). 

Amino-l,2,4-triazole was alkylated with 4-nitrobenzyl bromide by simply refluxing the mixture in isopropanol to give SO in excellent yield. The aminotriazole SO was deaminated with NaNOa in aqueous HCI and the nitro group was reduced with ammonium formate catalyzed by 10% Pd/C to deliver 47 in an improved yield over the route shown in Scheme 17. Diazotization of 47, reduction of the diazonium salt with sodium sulphite and Fischer indolization of the resulting hydrazine with 4-( /, /-dimethylamino)butanol dimethyl acetal was performed in a single step to afford rizatriptan (4) in 45% yield. 

Nitrobenzyl halides are reduced in a 1 e-process to radical anions, which rapidly lose halide ion to form the neutral nitrobenzyl radical. The rates for this dissociation were calculated from cyclic voltammetry data to be k = 2,5 for m-nitrobenzyl chloride and k = 2 109 secfor o-nitrobenzyl bromide. The nitrobenzyl radicals predominantly dimerize (90%), whereas a small amount yields nitrotoluenes (< 10%) by hydrogen abstraction 4541. From a series of substituted benzyl bromides those with the more positive reduction potential form bibenzyl in 25—74% yield, whereas from the less easily reducible ones dibenzyl-mercury derivatives are obtained (50—60%) 485). Reduction of benzyl chloride at the plateau of the first wave yields dibenzylmercury 4 By reduction of diphenyliodonium hydroxide at -1,6 V 51% diphenylmercury is obtained 488 ... 

Compound 37 was condensed with tryptamine perchlorate in the presence of sodium cyanoborohydride to provide the secondary amine 38. On the other hand, the aldehyde 37 was stirred with silica gel in methylene chloride to afford the epimer, which on reductive condensation with tryptamine perchlorate gave 39. Lactamization of 38 and 39 gave the lactams 40 and 41, respectively. Reaction of 40 and 41 with Lawesson s reagent gave the corresponding thio-lactams 42 and 43, which were treated with p-nitrobenzyl bromide to afford the crude salts 44 and 45. Reduction of 44 and 45 with sodium borohydride afforded (-)-tetrahydroalstonine (3) and (-)-ajmalicine (1), respectively. 

A detailed study of reactions between dialkyl phosphite anions and nitrobenzyl bromides has been described. In reactions between the halides and the phosphites (RO)2PONa in a solvent (THF, PriOH, or MeOD) the observed products (Z = 2-, 3-, or 4-nitro), apart from phosphonic diester (104), are those of reduction, (105) or (106), coupling (107), and ether formation (108). Phosphonate formation was moderate for Z = 2-nitro (R = Me), rather higher (51-97% isolated yields) for Z = 3-nitro (R = Me or Pr ), but extremely low for Z = 4-nitro (R = Me) and absent for R = Pr . In all cases when R = Me, ether formation also occurred. In cases where the yields of phosphonate were low, the yields of (107) were correspondingly high, and vice versa. Reactions performed in darkness, daylight or UV, produced little variation in the yields of phosphonate ester (R = Me) for Z = 3-nitro, but for Z = 2-nitro- or 4-nitro-, no diisopropyl phosphonates were obtained under various conditions. Probable mechanisms of reaction were discussed. ... 

The electrochemical method also serves as an effective means of reducing organic compoimds. For example, the electrochemical reduction of 4-nitrobenzyl bromide in N,N-dimethylformamide in the presence and absence of intentionally added... 

Phytohaemagglutinins.—Abrin, ricin, and their isolated A and B chains have been subjected to various chemical treatments and the effect of these on the biological activity of the lectins assessed. Reductive methylation, periodate oxidation, or succinylation of abrin or ricin reduced the toxicity and haemagglutinating ability of the former but not the latter. Treatment with A-acetylimidazole or A-bromosuccinimide resulted in strongly reduced toxicity of abrin and ricin, while 2-hydroxy-5-nitrobenzyl bromide had much less effect. 

Scheme 6.10 Electrochemical reduction of 4-nitrobenzyl bromide in a microreactor.

Hughes exploited a polymer-bound phosphonium-salt as a traceless linker for the synthesis of alkyl, alkenyl and heteroaryl products [263]. The linker system 383 was prepared from commercially available resin-bound triph-enylphosphine and nitrobenzyl bromide with following reduction of the nitro group and acylation. 

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