Borch reductive amination

Reduction (often using NaCNBHs) of the imine formed by an amine and a carbonyl to afford the corresponding amine—basically, reductive amination. 

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 28, Springer-Verlag Berlin Heidelberg 2009 

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FORSTER - DECKER Amine Synthesis Selective monoalkylation of primary amines via imines An altemativa method is the reaction ol 1 and 2 in the preserve of NaCNBH4 or tnaceloxyborohydride (Borch reduction)/... 

Reduction of N-benzylimines.2 Borch reduction of imines (4, 450) to amines is not stereoselective, although reduction to equatorial amines is somewhat favored. Reductions with 1 and a number of dialkylcyanqborohydrides are much more stereoselective. Thus substituted cycloalkanone imines are reduced mainly to axial amines. However, highest selectivities are obtained with lithium tri-sec-butylborohy-dride (4, 312). 

Reductive amination. Conversion of ketones or aldehydes to amines is usually accomplished by reduction of the carbonyl compound with sodium cyanoborohydride in the presence of an amine (Borch reduction, 4, 448-449). However, yields are generally poor in reactions of hindered or acid-sensitive ketones, aromatic amines, or trifluoromethyl ketones. Yields can be improved markedly by treatment of the ketone and amine first with TiCl4 or Ti(0-i -Pr)42 in CH2C12 or benzene to form the imine or enamine and then with NaCNBH3 in CH3OH to effect reduction. Note that primary amines can be obtained by use of hexamethyldisilazane as a substitute for ammonia (last example). 

Several syntheses of 1-hydroxymethylpyrrolizidines have been reported. Borch and Ho1 have utilized a reductive cyclization method for their synthesis of ( )-isoretronecanol (6) and ( )-trachelanthamidine (7). The cycloheptenone ester (1), prepared by a novel route (Scheme 1), was reductively aminated to give a mixture of the diastereoisomeric amino-esters (2) and (3) in 48% yield. These esters could not be separated. Oxidative cleavage of the double bond of the esters, followed by reductive cyclization, gave a 35% yield of the pyrrolizidine esters (4) and (5). Separation of these compounds was achieved by preparative t.l.c., and a final reduction step afforded the racemic alkaloids (6) and (7). The second reductive amination process was stereoselective, because reduction of the unseparated ester mixture (4) and (5) gave a 1 2 ratio (g.l.c.) of the 1-hydroxymethylpyrrolizidines. 

The first reported synthesis of MDMA was from safrole by converting it to its bromo derivative followed by reaction with meth-ylamine (Biniecki et al., 1960). Bailey et al. describe the synthesis of MDMA from 3,4-methylenedioxyphenylacetone using a Leuckart reaction with N-methylformamide and hydrolysis of the N-formyl derivative (Bailey et al., 1975). A third synthesis for MDMA described in the literature starts with peperonal which is reacted with nitroethane, ammonium acetate, and acetic acid to form a nitrostyrene derivative that is reduced to the ketone and then reacted with methylamine to form MDMA (Rabjohns, 1963). Using the method of Borch et al., MDMA can be synthesized by the reductive amination of the appropriate ketone in the presence of sodium cyanoborohydride (Borch et al., 1971). The MDMA syntheses used in clandestine laboratories are analogous. 

LEUCKART - WALLACH Reductive Amnion Reductive amination of cartx>nyl groups with amines and fomifc add or H2-NI (Miquonac) or NaBH4 (see Borch). 

Reductive amination. In a procedure of Borch,3 4 g. of potassium hydroxide (pellets) is added in one portion to a magnetically stirred solution of 21 g. (0.25 mole) of dimethyl-amine. hydrochloride in 150 ml. of methanol in a 500-ml. round-bottomed flask. Precipitation of potassium chloride begins immediately but does not interfere with the reaction. When the pellets are completely dissolved, 20 ml. (0.20 mole) of cyclohexanone is added in one portion. The resulting suspension is stirred at room temperature for... 

Reductive cyclization has been used in a novel, recent synthesis of the alkaloids ( )-isoretronecanol (22) and ( )-trachelanthamidine (23) by Borch and Ho. Condensation of the dianion derived from methyl acetoacetate with Z-l,4-dichlorobut-2-ene, followed by cyclization with sodium meth-oxide yielded the cycloheptenone ester intermediate (32) (Scheme 2). Reductive amination of this ketoester with sodium cyanoborohydride and ammonium nitrate gave a mixture of the diastereoisomeric aminoesters 33 and 34. Oxidation with osmium tetroxide and periodate, followed by reductive cyclization, again using sodium cyanoborohydride, gave the two pyrrolizidine esters 35 and 36 in a ratio of 1 2 [gas-liquid chromatography (GLC) analysis]. The esters were separated by preparative layer chromatography, and lithium aluminum hydride reduction of the individual esters gave the two pyrrolizidine alkaloids 22 and 23. 

The cycloaddition proceeded smoothly, when promoted by acid, to provide ketones 75 and 76. Whereas 76 was surely the kinetic product, acid promoted enolization-isomerization provide 75 as well. Treatment of the mixture with hydroxylamine gave the desired oxime (77) and Borch reduction from the convex face provided 72 The rest of the synthesis proceeded as expected. The intramolecular nitrone cycloaddition gave 70. Methylation of the amine and reduction of the weak N-O bond provided 78. Jones oxidation (Cr in acid) of 78 completed the synthesis of luciduline (55). When a single enantiomer of 74 was used, a single enantiomer of luciduline was obtained. 

Hydrolysis of nitriles.1 N itriles are converted to thioamides by reaction with I (2 equivalents) at 40° overnight. Under these conditions most other functional groups are stable. Kinetic studies indicate that the reaction with nitriles is a two-step process, the first of which is analogous to an enc reaction to give a. Thioamides arc particularly useful precursors to amines by the method of Borch (2, 430 431), reaction with triethyloxonium tetrafluoroborate followed by reduction withNaBHj..- ... 

Reduction of amides. The Borch method for reduction of sec- and t-amides to amines (2, 430-431) is improved by use of NaBH4 and SnCU-2(C2H5)20 in the ratio 4 1. Under these conditions even primary amides are reduced to amines. Examples ... 

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