Benzylamines reduction

In the 2-benzylisoquinoline series, sendaverine (23 R = Me) has been synthesized by the condensation of either 7-benzyloxy-6-methoxyisochromone65,66 or ethyl 4-benzyloxy-2-bromoethyl-5-methoxyphenylacetate67 with 4-methoxy-benzylamine, reduction of the resulting lactams, and debenzylation. Repetition of the second of these syntheses, using 4-benzyloxybenzylamine, gave corgoine (23 R = H).68... 

Morpholiaoglucopyranosides have beea syathesized from sucrose by selective lead tetraacetate oxidatioa of the fmctofuranosyl ring to a dialdehyde (6). This product was subjected to reductive amination with sodium borohydride and a primary amine such as benzylamine to produce the /V-henzy1morpho1ino derivative (7) (99). 

Other secondary amines such as pyrrolidine, di- -butylamine, tetrahydro-quinoline, n-benzylamine, and piperidine were also found to be capable of effecting this reduction. Interestingly, morpholine does not reduce enamines as readily (47) and its acid-catalyzed reaction with norbornanone was reported (45) to give only the corresponding enamine (93), although trace amounts of the reduction product were detected when cyclohexanone was treated with morpholine under these conditions (47a). The yield of morpholine reduction product was increased by using higher temperatures. 

Dihydroquinazolines are stable and a large number have been prepared. They have been synthesized by reductive cyclization of acyl derivatives of o-nitrobenzylamines, and by acylation of o-amino-benzylamines followed by ring closure. The ring closure can be effected by heating with anhydrous zinc chloride ° or by distillation. ... 

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. 

In the discussion of benzylamines, we have met medicinal agents that owe their activity to some particular functionality almost without reference to the structure of the rest of the molecule. The hydrazine group is one such function in that it frequently confers monamine oxidase-inhibiting activity to molecules containing that group. Such agents frequently find use as antidepressants. Thus, reduction of the hydrazone of phenyl-acetaldehyde (84) affords the antidepressant phenelzine (85). Similar treatment of the derivative of phenylacetone (86) gives pheniprazine (87). ... 

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. 

Reductive amination of vanillin with ammonia leads to benzylamine 94. Acylation of that compound with (Z)-9-octadecenoyl chloride affords the analgesic olvanil (95) [23]. 

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]. 

Nickel in the presence of ammonia is often used for reduction of nitriles to primary amines. The reaction is done at elevated temperatures and pressures ( 100 C, 1000 psig) unless massive amounts of nickel are used. Cobalt is used similarly but mainly under even more vigorous conditions. Nitriles containing a benzylamine can be reduced over Raney nickel to an amine without hydrogenolysis of the benzyl group (7). A solution of butoxycarbonyl)-3-aminopropyl]-N-<3-cyanopropyl)benzylamine (13.6 g) in 100 ml of ethanol containing 4 g. NaOH was reduced over 3.0 g Raney nickel at 40 psig for 28 h. The yield of A/ -benzyl-Air -(f-butoxycarbonyl)s >ermidine was 95% (7). 

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... 

If, instead of a palladium catalyst, a nickel catalyst, such as the bipyridylnickel(II) bromide, is used for the arylation of amines (Fig. 7), the reduction of the aryl halide into the corresponding aromatic hydrocarbon is still present for the primary or secondary benzylamines but, the arylation into substituted anilines is the main reaction even most often the only one, for the other types of amines. 

Rather than preforming the a-amino ketimines to be reduced, it is often advantageous to form in situ the more reactive iminium ions from a-aminoketones and primary amines or ammonium salts in the presence of the reducing agent, e.g., sodium cyanoborohydride. Use of this procedure (reductive amination) with the enantiopure a-aminoketone 214 and benzylamine allowed the preparation of the syn diamines 215 with high yields and (almost) complete diastereoselectivities [100] (Scheme 32). Then, the primary diamines 216 were obtained by routine N-debenzylation. Similarly, the diamine 217 was prepared using ammonium acetate. In... 

A comprehensive account of the oxidation of benzylamine by both neutral and alkaline permanganate has been published recently . The neutral amine is the active reductant at all pH values and at pH 9.9 good second-order kinetics were obtained. Under these conditions the stoichiometry is... 

Besides direct reduction, a one-pot reductive amination of aldehydes and ketones with a-picoline-borane in methanol, in water, and in neat conditions gives the corresponding amine products (Scheme 8.2).40 The synthesis of primary amines can be performed via the reductive amination of the corresponding carbonyl compounds with aqueous ammonia with soluble Rh-catalyst (Eq. 8.17).41 Up to an 86% yield and a 97% selectivity for benzylamines were obtained for the reaction of various benzaldehydes. The use of a bimetallic catalyst based on Rh/Ir is preferable for aliphatic aldehydes. 

A combination of a reductive amination and a Michael addition has been used to synthesize the anticancer alkaloid camptothecin (2-955) via 2-954, starting from the quinoline carbaldehyde 2-953 and benzylamine (Scheme 2.214) [487]. 

Lithium aluminum hydride reduction of 31 in the presence of benzylamine affords a 70% yield of l-benzylamino-2-oxaadamantane.154 This approach is patented as a general method for the preparation of N-substituted 2-oxa-adamantyl-l-amines.155 Transannular cyclization of 31 or 35 in the presence... 

A variety of benzylamines 124 (R1 = Ph, Ar, 2-naphthyl, or 3- or 4-pyridyl etc NR22 = piperidin-l-yl or morpholin-4-yl) was obtained from benzotriazole, an aldehyde R CIIO and an amine HNR22 and subsequent reduction of the products with sodium borohydride (equation 44)125. 

Reductive animation of aromatic aldehydes to give benzylamines is accomplished by heating the aldehyde and tritylamine with molecular sieves, followed by the addition of sodium cyanoborohydride. Catalytic hydrogenolysis of the products with palladium on charcoal yields the benzylamines (equation 56)167. 

Synthesis of a C(8)-C(18) segment of the larger fragment of lb using the same basic strategy is depicted in Scheme 25. Here, hydroxy ketone 176 was subjected to syn-selective (dr of crude product=90 10) reductive amination [42] with sodium cyanoborohydride and benzylamine followed by tetrahydro-oxazine formation using aqueous formaldehyde. The resulting heterocycle 182 was then converted to unsaturated ester 184 by successive desilylation, oxidation, and entirely (Z)-selective Horner-Wadsworth-Emmons olefination. Re-... 

Reductive animation of carbonyl compounds. Method A. N-octylbenzylamine (typical procedure). A THF (30 mL) suspension of benzylamine (1.67 g, 15 mmol), octanal (1.55 g, 15 mmol), EtjN (7.0 mL, 50 mmol) and Al2Te3 (6.1 g, 14 mmol) is refluxed. The reaction is monitorized by GLC and H2O (3 mL, 168 mmol) is added at 15°C after 30 min. The heterogeneous mixture is refluxed for another 30 min. The black solid is removed by fdtra-tion and the filtrate dried (CaCOj) and evaporated. The residue is distilled, giving the product (2.7 g (80%) b.p. 108-112°C/1 torr). 

Aldoximes yielded primary amines by catalytic hydrogenation benzaldehyde gave benzylamine in 77% yield over nickel at 100° and 100 atm [803, with lithium aluminum hydride (yields 47-79%) [809, with sodium in refluxing ethanol (yields 60-73%) [810] and with other reagents. Hydrazones of aldehydes are intermediates in the Wolff-Kizhner reduction of the aldehyde group to a methyl group (p. 97) but are hardly ever reduced to amines. 

The addition of 95 onto 2m-Me in THF at ambient temperature (89% yield) was not stereoselective [53]. All attempts to add the chiral cyclic benzylamine derivative 96 and 97 onto the spirocyclopropanated chloro ester 2c-Me were unsuccessful [21b]. Although it was possible to add heterocycles (S)-4-phenyloxa-zolidine-2-one (98) and its thio analog 99 onto the chloro esters 1-Me and 2j-Me (Scheme 30) [10b, c] and to substitute or reductively remove the chlorine atom in the adducts 101, all attempts to deprotect the amino functions in 101 and the products of their transformations under various conditions were unsuccessful. 

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