Reduction with benzylamine

Bicyclic isothiazole dioxides 81 (99JHC(36)161), on treatment with Ai-nucleo-philes such as benzylamine, afforded isothiazole dioxides 82a,b together with a minor amount of compounds 83. Alternatively, 82b could be obtained from 84 by reduction with 1,2-dimethylhydrazine and DBU. By using r-butylamine as the A-nucleophile, due to steric reasons, the formation of the isothiazole dioxide 85 could also be observed followed by transformation in the bicyclic system 86. 

Thus, condensation of isoniazide with acetone at the basic nitrogen gives the corresponding Shiff base (8). Catalytic reduction affords the antidepressant, iproniazid (9). Addition of the same basic nitrogen to methyl acrylate by Michael condensation leads to the 3-amino ester (10). This is converted to the amide, nialamide (11), on heating with benzylamine. 

The majority of analgesics can be classified as either central or peripheral on the basis of their mode of action. Structural characteristics usually follow the same divisions the former show some relation to the opioids while the latter can be recognized as NSAlD s. The triamino pyridine 17 is an analgesic which does not seem to belong stmcturally to either class. Reaction of substituted pyridine 13 (obtainable from 12 by nitration ) with benzylamine 14 leads to the product from replacement of the methoxyl group (15). The reaction probably proceeds by the addition elimination sequence characteristic of heterocyclic nucleophilic displacements. Reduction of the nitro group with Raney nickel gives triamine 16. Acylation of the product with ethyl chlorofor-mate produces flupirtine (17) [4]. 

The procedure described is a modification of the general procedure of Angyal2 for the preparation of aldehydes from benzylamines by the Sommelet reaction. Isophthalaldehyde has been prepared from w-xylene by preparation of the tetrachloro derivative and hydrolysis,3 from isophthaloyl chloride by the Rosenmund reaction,4 from a,a -dibromo-m-xylene by the Sommelet reaction,5 and from isophthaloyl chloride by reduction with lithium tri-Cbutoxyaluminumhydride.6... 

A structurally unusual 3-blocker that uses a second molecule of itself as the substituent on nitrogen is included here in spite of the ubiquity of this class of compounds. Exhaustive hydrogenation of the chromone (13-1) leads to a reduction of both the double bond and the carbonyl group, as in the case of (11-2). The car-boxyhc acid is then reduced to an aldehyde (13-2) by means of diisobutylaluminum hydride. Reaction of that intermediate with the ylide from trimethylsulfonium iodide gives the oxirane (13-3) via the addition-displacement process discussed earlier (see Chapters 3 and 8). Treatment of an excess of that epoxide with benzylamine leads to the addition of two equivalents of that compound with each basic nitrogen (13-4). The product is then debenzylated by catalytic reduction over palladium to afford nebivolol (13-5) [16]. The presence of four chiral centers in the product predicts the existence of 16 chiral pairs. 

An alternative synthesis of ( )-a- and ( )--y-lycoranes (57 and 93) commenced with the 2-oxocyclohexyl acetic acid derivative 114 obtained by the alkylation of the enamine derived from 113 (Scheme 10) (116). Refluxing the oxime of 114 with zinc dust in glacial acetic acid afforded a mixture of the lactams 115, 116, and 117 in an approximate ratio of 4 6 3. The structure of 115 was verified by catalytic hydrogenation to give the lactam 118, which had previously been converted to ( )-a-lycorane (57). When the lactam 116 was subjected to sequential catalytic hydrogenation, hydride reduction, and Pictet-Spengler cyclization, ( )-y-lycorane (93) was obtained. A more efficient route to ( )-a-lycorane (57) involved refluxing the ketone 114 first with benzylamine in xylene and then with 87% formic acid to furnish the unsaturated lactam 119. 

They offer an even more surprising alternative in which reductive amination with benzylamine with reduction of the other ketone and cleavage of the A-benzyl bond followed by dehydration gives the simple amine 40. Now reaction with 1,3-dibromopropane gives 31, presumably again via 32 X = Br. 

Derivatives of 14-hydroxydihydrocodeinone have been converted into 6a- and 6/ff-amino-compounds by condensation with benzylamine and then reduction and hydrogenolysis of the resulting Schiff-bases,195 and also into their hydrazones.196 Codeine and ethylmorphine have been nitrated and sulphonated at position 1197 and fluoro-compounds of structures (103 R = H), (103 R = OH), (104 R = H), and (104 R = OH) have been prepared from dihydrocodeinone and 14-hydroxy-dihydrocodeinone by treatment with diethylaminosulphur trifluoride.198... 

The synthesis is interesting because, after the acylation of the enamine, the amino group is introduced by a clever reductive animation with benzylamine (PI1CH2NH2) that forms the C-N bond, reduces the ketone, and hydrogenolyses the N-benzyl bond (Chapter 24). Dehydration and double alkylation then give tazadolene. 

An interesting reaction has been described by Simonov and his colleagues [371], Studying the reaction of some aromatic rnt/zo-dinitro- and trinitrocompounds with benzylamine they have discovered that under special conditions the reaction of substitution of the nitro group with the benzylamine group is accompanied by reduction of the second nitro group and cyclization into 2-phenylbenzimidazole derivatives. In this case benzyl alcohol forming from benzylamine serves as a reducer. By the way it was obtained 4,5-dimethoxy-7-nitro-2-phenylbenzimidazole in 89% yield from 3,4,5-trinitroveratrole [371],... 

Among other similar reports, Bray et al. (122) optimized the SP reductive amination of a model ketone with three primary amines using a 56-member reaction library with simultaneous variation of amines, reducing agent concentrations, pH, and solvents. Gayo and Suto (123) optimized the coupling of an acyl chloride with benzylamine in solution using a 30-member reaction library with simultaneous variation of the... 

This transient intermediate decarboxylates under reaction conditions to afford the bis(enone) 154. Hydrogenation over platinum proceeds to give the saturated ketone (155). Treatment of 155 with benzylamine in the presence of cyanoborohydride leads to the product from reductive amination (156). Acylation with hydrocinnamoyl chloride affords the amide 157. ... 

Chiral polymer-supported thiiranes 401 were prepared by free radical copolymerization of TMA ((3)-thiiranylmethyl-methacrylate) and ethylene glycol dimethacrylate (EDMA) (Equation 60) <2006TA1944>. These chiral thiiranes were transformed into polymer-supported aminothiols by the facile ring opening of the thiirane group with benzylamine and methylamine. These derivatives, complexed with [RuCl2(p-cymene)]2, were used in assymmetric reduction of acetophenone to gave (A)-l-phenylethanol (39% ee from methylamine and 50% ee from benzylamine derivatives). 

Such hydroxyimidazoles or oxides are capable of complete reduction to the unoxygenated imidazoles, while the 1-hydroxyimidazole 3-oxides can also be partically reduced with, for example, NaBUi [53], or completely deoxygenated with Raney nickel [52, 54], Although most cyclizations of a-ketooximes lead to A -oxygenated imidazoles, there are exceptions. When an o(-oximino-)6-dicarbonyl compound is refluxed with benzylamine in a suitable solvent (c.g. DMSO, acetonitrile, toluene), 4-acylimidazoles (11) are formed in moderate to good yields. The reaction is readily adapted to the synthesis of imidazole-4-carboxylates and -amides (Scheme 4.1.7)... 

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... 

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