Reduction benzylic amines

ANILINES, BENZYL AMINES, AND ANALOGUES An orally active local anesthetic agent that can be used as an (intiarrhythmic agent is meobenti ne (57). Its patented synthesis starts with -hydroxyphenyl nitrile and proceeds by dimethyl sulfate etherification and Raney nickel reduction to Alkylation of -methyl-dimethylthiourea with completes l.he synthesis of meobenti ne (57). ... 

The strategy for the asymmetric reductive acylation of ketones was extended to ketoximes (Scheme 9). The asymmetric reactions of ketoximes were performed with CALB and Pd/C in the presence of hydrogen, diisopropylethylamine, and ethyl acetate in toluene at 60° C for 5 days (Table 20) In comparison to the direct DKR of amines, the yields of chiral amides increased significantly. Diisopropylethylamine was responsible for the increase in yields. However, the major factor would be the slow generation of amines, which maintains the amine concentration low enough to suppress side reactions including the reductive aminafion. Disappointingly, this process is limited to benzylic amines. Additionally, low turnover frequencies also need to be overcome. 

Recently, Borner and coworkers described an efficient Rh-deguphos catalyst for the reductive amination of a-keto acids with benzyl amine. E.e.-values up to 98% were obtained for the reaction of phenyl pyruvic acid and PhCH2COCOOH (entry 4.9), albeit with often incomplete conversion and low TOFs. Similar results were also obtained for several other a-keto acids, and also with ligands such as norphos and chiraphos. An interesting variant for the preparation of a-amino acid derivatives is the one-pot preparation of aromatic a-(N-cyclohexyla-mino) amides from the corresponding aryl iodide, cyclohexylamine under a H2/ CO atmosphere catalyzed by Pd-duphos or Pd-Trost ligands [50]. Yields and ee-values were in the order of 30-50% and 90 >99%, respectively, and a catalyst loading of around 4% was necessary. 

Curtius reaction of ester 196 in benzyl alcohol leads to benzylurethane 197, which by hydrolysis and catalytic reduction gives amine 198 (72JCS(P1)878, 69JCS(C)2235). The primary amino group of compound 198 was converted into dimethylamino using the Eschweiler reaction, and then selectively quaterniz. Hofmann cleavage of this salt then leads to furo[4,3,2-/g]benzazocine 199 (Scheme 54). 

Reductive amination of benzaldehyde with (R)-81 provided the corresponding benzyl amine, which was reductively alkylated with formaldehyde to give 82 (Scheme H) " Compound 82 was debenzylated by hydrogenation in the presence of Pearlman s catalyst to afford frovatriptan ((/J)-6). Alternatively, monomethylation of amine (/ )-81 was affected by treatment with carbon disulfide and dicyclohexylcarbodiimide in pyridine to provide isothiocyanate 83, which was reduced with sodium borohydride to give (l )-6. 

As illustrated by the examples in Table 3.9, resin-bound 4-alkoxybenzylamides often require higher concentrations of TFA and longer reaction times than carboxylic acids esterified to Wang resin. For this reason, the more acid-sensitive di- or (trialkoxy-benzyl)amines [208] are generally preferred as backbone amide linkers. The required resin-bound, secondary benzylamines can readily be prepared by reductive amination of resin-bound benzaldehydes (Section 10.1.4 and Figure 3.17 [209]) or by A-alkyla-tion of primary amines with resin-bound benzyl halides or sulfonates (Section 10.1.1.1). Sufficiently acidic amides can also be A-alkylated by resin-bound benzyl alcohols under Mitsunobu conditions (see, e.g., [210] attachment to Sasrin of Fmoc cycloserine, an O-alkyl hydroxamic acid). 

Phenylethylamine has been made by a number of reactions, many of which are unsuitable for preparative purposes. Only the most important methods, from a preparative point of view, are given here. The present method is adapted from that of Adkins,1 which in turn was based upon those of Mignonac,2 von Braun and coworkers,3 and Mailhe.4 Benzyl cyanide has been converted to the amine by catalytic reduction with palladium on charcoal,5 with palladium on barium sulfate,6 and with Adams catalyst 7 by chemical reduction with sodium and alcohol,8 and with zinc dust and mineral acids.9 Hydrocinnamic acid has been converted to the azide and thence by the Curtius rearrangement to /3-phenyl-ethylamine 10 also the Hofmann degradation of hydrocinnamide has been used successfully.11 /3-Nitrostyrene,12 phenylthioaceta-mide,13 and the benzoyl derivative of mandelonitrile 14 all yield /3-phenylethylamine upon reduction. The amine has also been prepared by cleavage of N- (/3-phenylethyl) -phthalimide 15 with hydrazine by the Delepine synthesis from /3-phenylethyl iodide and hexamethylenetetramine 16 by the hydrolysis of the corre-... 

Reductive alkylation of ammonia has been proved an effective and highly versatile method for obtaining primary amines. The most satisfactory conditions have been catalytic hydrogenation (Raney nickel) of the carbonyl compound in an ethanolic solution of ammonia under pressure ranging from 20 to 150 atm. and at temperatures in the range of 40° to 150°. Typical amines prepared in this manner include benzyl-amine and 2-aminoheptane (80%). With liquid ammonia and no... 

The starting materials are readily available by dialkylation of benzyl-amine or by the monoalkylation of alkylbenzylamines, which in turn are prepared by the reduction of Schiff bases (method 429). The method has been extended to the formation of hydroxy amines, amino esters, and amino acids. ... 

Benzylic amines are resistant to hydrogenolysis under Birch reduction conditions, unless the amine is quaternary, as in the Emde reaction. A means of preserving an aryl carbonyl group is therefore to protect it as an aminal derivative. An illustration is provided by the preparation of aldehyde (213), an important flavor constituent of cumin, as outlined in Scheme 47." ... 

Benzylic amines are particularly susceptible to hydrogenolysis by catalytic hydrogenation or dissolving metal reduction. " Note that the Wolff-Kishner reduction in 19-61 involved formation of a hydrazone and deprotonation by base led to loss of nitrogen and reduction. Ceric ammonium nitrate in aqueous acetonitrile has also been shown to reductively cleave the V-benzyl group. Primary amines have been reduced to RH with hydroxylamine-O-sulfonic acid and... 

Reductive Methods. The following table shows that substituents have a significant effect on the rate of hydrogenolysis of benzyl amines. 

Some years ago, Malmstrom etal. synthesized water-soluble metal phosphine complexes based on water-soluble polymers [41], In order to have solubility in both an acidic and a basic medium, they prepared two different water-soluble polymers. For the first, they made methyl [4-(diphenylphosphino)benzyl]amine (PNH) react with poly(acrylic acid) (PAA) using dicydocarbodiimide (DCC) as the coupling agent, under strict exclusion of oxygen (25). For the second, they reacted (4-carboxy-phenyl)diphenylphosphine with polyethylene imine (PEI) at room temperature (26). The reduction by sodium borohydride was made in situ, followed by the addition of methanesulfonic add and diethyl ether. Then, the methanesulfonic salt of phosphinated polyethylenimine was predpitated. 

Likewise, the preparation of phenethyl amines is well precedented. The benzylic amine functionality can be introduced by either displacement of the phenethyl alcohol (Mitsunobu), Grignard addition to an aldimine derivative, or reduction of an enamine and ketimine precursors (see Scheme... 

Primary amines are not usually made by reduction of amides (15) but by other reductive processes which are minor variations on this scheme. For unbranched amines (16) we can reduce cyanides. This method is especially suitable for benzylic amines since aryl cyanides (17) can be made from diazonium salts (see Chapter 2), and for the homologous amines (18) since cyanide ion reacts easily with benzyl halides. 

Friedel-Craft acetylation of385 followed by bromination yields 5-(2-bromoacetyl)-1,3-dibenzyl-1H, 3H-2,1,3,-benzothiadiazole-2,2-dioxide (387). Reaction of 387 with N-benzylated amines followed by reduction with hydrogen produces (388). No significant increase in heart rate, blood pressure, left ventricular pressure and bronchodilator activity was observed when the thiadiazoles 388 were tested in dogs. 

The reaction between 2-hydroxy-5-nitro-benzyl chloride with diethylamine yields 2-hydroxy-5-nitro-N, N, diethyl benzyl amine, which on reduction gives 5-amino-2-diethylamino ethyl phenol. 

Pli2P(=0)-assisted asymmetric deprotonation of benzylic amines using BuLi/(—)-sparteine allows the synthesis of a series of phos-phinamides with good to excellent enantioinduction (eq 43). The cleavage of these derivatives to the corresponding amines is effected by cone HCl in THF or under reductive conditions, for example, L1A1H4 in THF. ... 

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