Reductive aminations alkylations

Reductive amination of cyclohexanone using primary and secondary aHphatic amines provides A/-alkylated cyclohexylamines. Dehydration to imine for the primary amines, to endocycHc enamine for the secondary amines is usually performed in situ prior to hydrogenation in batch processing. Alternatively, reduction of the /V-a1ky1ani1ines may be performed, as for /V,/V-dimethy1 cyclohexyl amine from /V, /V- di m e th y1 a n i1 i n e [121 -69-7] (12,13). One-step routes from phenol and the alkylamine (14) have also been practiced. 

Aliphatic Alcohols and Alkylene Glycols. Simple aliphatic alcohols, such as methanol [67-56-1], can be used to alkylate alkyleneamines. For example, piperazine reacts with methanol over a reductive amination catalyst to yield a mixture of 1-methyl- [109-01 -3J and 1,4-dimethylpiperazine [106-58-1] (12). 

Reductive amination (Section 22.10) Reaction of ammonia or an amine with an aldehyde or a ketone in the presence of a reducing agent is an effective method for the preparation of primary, secondary, or tertiary amines. The reducing agent may be either hydrogen in the presence of a metal catalyst or sodium cyanoborohy-dride. R, R, and R" may be either alkyl or aryl. 

In a variation on this approach, p-chlorobenzaldehyde is rst condensed with 2-aminopyridine. Reduction of the resulting iff base (62) affords the corresponding secondary amine. Alkyl-ion with the usual side chain affords the antihistamine, chlor-ramine (64). ... 

Reduction of phenylacetone in the presence of methylamine rather than ammonia gives methamphetamine (53), an agent similar in action to the primary amine. Alkylation of 53 with benzyl chloride affords the analog, benzphetamine (54). ... 

Extension of the alkyl group on the carbon bearing the amine changes the pharmacologic profile. Reductive amination of 1-phenylbutanone-2 (60) with pyrrolidine in formic acid gives pro-litane (61), a central nervous system stimulant agent with antidepressant properties. 

Further substitution of benzoic acid leads to a drug with antiemetic activity. Alkylation of the sodium salt of p-hydroxy-benzaldehyde (8) with 2-dimethylaminoethyl chloride affords the so-called basic ether (9). Reductive amination of the aldehyde in the presence of ammonia gives diamine, 10. Acylation of that product with 3,4,5-trimethoxybenzoyl chloride affords trimetho-benzamide (11). ... 

Reductive amination of dihydropyran (which may be regarded as the dehydration product of the cyclic acetal of 5-hydroxy-pentanal) in the presence of isopropylamine and a trace of acid affords the aminoalcohol, 96. Treatment of this compound with thionyl chloride affords the haloamine, 97. Alkylation of the quinoline, 92, with this halide yields pentaquine (98). ... 

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). ... 

Amino acids can be synthesized in racemic form by several methods, including ammonolysis of an a-bromo acid, alkylation of diethyl acetamido-malonate, and reductive amination of an cv-keto acid. Alternatively, an enantio-selective synthesis of amino acids can be carried out using a chiral hydrogenation catalyst. 

The amine could be put in by reductive amination on the secondary side or via an amide on the primary side (Chapter T8) but this crow Jed compound can be made by simple alkylation of (22) with available isopropylamine. Sterlc hindrance prevents a second alkylation. 

The direct reductive amination (DRA) is a useful method for the synthesis of amino derivatives from carbonyl compounds, amines, and H2. Precious-metal (Ru [130-132], Rh [133-137], Ir [138-142], Pd [143]) catalyzed reactions are well known to date. The first Fe-catalyzed DRA reaction was reported by Bhanage and coworkers in 2008 (Scheme 42) [144]. Although the reaction conditions are not mild (high temperature, moderate H2 pressure), the hydrogenation of imines and/or enam-ines, which are generated by reaction of organic carbonyl compounds with amines, produces various substituted aryl and/or alkyl amines. A dihydrogen or dihydride iron complex was proposed as a reactive intermediate within the catalytic cycle. 

Even with a limited amount of the alkylating agent, the equilibria between protonated product and the neutral starting amine are sufficiently fast that a mixture of products may be obtained. For this reason, when monoalkylation of an amine is desired, the reaction is usually best carried out by reductive amination, a reaction that is discussed in Chapter 5. If complete alkylation to the quaternary salt is desired, use of excess alkylating agent and a base to neutralize the liberated acid normally results in complete reaction. 

Sodium triacetoxyborohydride is an alternative to NaBH3CN for reductive amination. This reagent can be used with a wide variety of aldehydes or ketones with primary and secondary amines, including aniline derivatives.93 This reagent has been used successfully to alkylate amino acid esters.94... 

Next, reductive amination (step 4 in scheme 1) was exchanged with copper catalyzed palladium coupling (step 2 in scheme 1). Atomic absorption analysis for palladium in RWJ-26240 samples prepared by scheme 2 indicated that the level of palladium was reduced to an acceptable level. This improvement may be due to the two reduction steps subsequent to the use of palladium in scheme 2.177 The final major modification to the reaction scheme was the substitution of NaBH4 for NaBH3CN. The yield of product (60%) was determined by HPLC (Method 2). Reductive alkylation with formalin/NaBH4 afforded a pharmaceutically acceptable drug substance. 

Perhaps the advantage of the medicinal chemistry route lies in the flexibility of introducing different alkyl groups on the primary amine through reductive amination on 2-aminoethyl indole 10 and hence allows access to various N, N-dialkyl tryptamine derivatives for structure-activity relationship (SAR) studies. 

Brown EG, Nuss JM. Alkylation of Rink s amide linker on polystyrene resin a reductive amination approach to modified amine-linkers for the solid phase synthesis of /Y-substiuited amide derivatives. Tetrahedron Lett 1997 38 8457-8460. 

With these solid supports in hand, we turned our attention to a new route to the synthesis of our target molecule 23 (Scheme 8). The tricky reductive amination should be replaced by an N-alkylation. To that end, bromoacetic acid is attached to 24c using DIC and Hiinig s base followed by the nucleophilic substitution with the corresponding benzy-lamine in DMSO/toluene (1 1), which can be easily monitored by the Beilstein test, followed by sulfonamide formation in DCM using N-methylmorpholine as base. For the final cleavage, 2% TFA in DCM is used and the resulting solution is filtered in a saturated NaHCC>3 solution to neutralise the acid before evaporation of the solvent. The crude product was then crystallised from ethyl acetate/heptane to yield the desired product in 27% yield overall and 99A% HPLC purity (see Table 4). 

The method gives better yields, utilizes more readily available starting materials, and is much less laborious than the hydrolysis of N-methyl-N-alkylarenesulfonamides and -nitroso-N, N-di-alkylanilines, or the lithium aluminum hydride reduction of alkyl isocyanates. Compared to the closely related procedure of Lucier, Harris, and Korosec,12 in which the N-benzylidenealkyl-amine is treated with dialkyl sulfate at atmospheric pressure, the present procedure tends to give higher yields and purer products, but it is less convenient because of the need for a pressure vessel. 

Catalytic reduction (Raney-Ni, H2) of the nitroso acetal-mesylate 243 resulted in reductive cleavage of both N-O bonds followed by intramolecular reductive amination and finally intramolecular iV-alkylation providing the masked 7-epiaustraline alkaloid 244 (Scheme 65) <1998JA7357>. 

REDUCTION OF ALKYL HALIDES AND TOSYLATES WITH SODIUM CYANOBOROHYDRIDE IN HEXAMETHYL-PHOSPHORAMIDE (HMPA) A. 1-IODODECANE TO n—DECANE B. 1-DODECYL TOSYLATE TO n-DODECANE, 53, 107 REDUCTION OF KETONES BY USE OF TOSYLHYDRAZONE DERIVATIVES ANDROSTAN-17 0—OL, 52, 122 REDUCTIVE AMINATION WITH SO-... 

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