Formaldehyde reductive amination

The principal side reaction to epoxide coupling is hydrolysis. Particularly at acid pH values, the epoxide ring can hydrolyze to form adjacent hydroxyls. This diol can be oxidized with periodate to create a terminal aldehyde residue with loss of one molecule of formaldehyde (Chapter 1, Section 4.4). The aldehyde then can be used in reductive amination reactions. The reaction of an epoxide group with an ammonium ion generates a terminal primary amine group that also can be used for further derivatization. 

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-... 

Amine synthesis from reductive amination of a ketone and an amine in the presence of excess formic acid, which serves as the reducing reagent by delivering a hydride. When the ketone is replaced by formaldehyde, it becomes Eschweiler-Clarke reductive alkylation of amines. 

Treatment of aldehydes or ketones with ammonia, primary or secondary amines in reducing media is called reductive alkylation (of ammonia or amines) or reductive amination (of aldehydes or ketones). Reducing agents are most frequently hydrogen in the presence of catalysts such as platinum, nickel or Raney nickel [955], complex borohydrides [705, 954, 955], formaldehyde or formic acid [522]. 

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. 

This reaction allows the preparation of tertiary methylamines from secondary amines via treatment with formaldehyde in the presence of formic acid. The formate anion acts as hydride donor to reduce the imine or iminium salt, so that the overall process is a reductive amination. The formation of quaternary amines is not possible. 

The reduction of enamine unit occurs much more rapidly than that of the carbonyl group. Therefore, this reagent can be used to perform reductive amination of aldehydes and ketones, by simply reacting the carbonyl compound with a fourfold excess of the amine. In a similar manner, reductive methylation of amines could be accomplished by addition of formaldehyde to the amine119. 

Certain aliphatic diamines have been prepared by reduction of nitro amines with hydrogen or aluminum amalgam. The starting materials are readily obtained by the reaction of nitroparaffins with formaldehyde and amines (method 444). 

The usefulness of reductive amination is augmented by the facile methylation of amines with formaldehyde (usually in MeCN), which provides a convenient, mild alternative to Clark-Eschweiler and other methylation procedures. Table 8 presents a selection of successful methylation applications with various amines, and further illustrates the chemoselectivity and versatility of the process. 

Formic acid is commonly used for reductive amination in what is called the Wallach reaction. Secondary amines react with formaldehyde and NaH2P03 to give the A-methylated tertiary amine and microwave irradiation has also been used. Conjugated aldehydes are converted to alkenyl-amines with the amine/sili-ca gel followed by reduction with zinc borohydride.In the particular case where primary or secondary amines are reductively methylated with formaldehyde and formic acid, the method is called the Eschweiler-Clarke procedure. Heating with paraformaldehyde and oxalyl chloride has been used to give the same result. It is... 

Reductive amination with formaldehyde and sodium cyanoborohydride provides a convenient method for methylation of a secondary amine (or dimethylation of a primary amine). An alternative procedure uses formaldehyde together with formic acid (HCOOH) as the source of hydride in what is termed the Eschweiler-Clark reaction. Deprotonation of formic acid provides the formate anion, which delivers hydride to the iminium ion with concomitant formation of carbon dioxide. 

All that remains is to introduce the dimethylamino group. The nitrile is reduced by hydrogenation and the two methyl groups added by reductive amination with formaldehyde. The reducing agent is formic acid, and the reaction works by sequential formation... 

This reaction was initially reported by Eschweiler in 1905, and subsequently by Clarke and co-workers in 1933. It is the preparation of tertiary methylamines from primary or secondary amines by means of the treatment of those amines with an excess amount of aqueous formaldehyde and formic acid. Therefore, it is generally known as the Eschweiler-Clarke methylation. In addition, this reaction is also referred to as the Eschweiler-Clarke condition," Eschweiler-Clarke A -methylation, Eschweiler-Clarke procedure, -) Eschweiler-Clarke reaction, s.3j,7 Eschweiler-Clarke reductive methylation, Eschweiler-Clarke reductive -methylation, Clarke-Eschweiler methylation, Clarke-Eschweiler reaction,or Clarke-Eschweiler procedure. In this reaction, the formate anion donates its proton to reduce the imine or iminium salt, so that carbon dioxide is evolved. Thus the whole process is a reductive amination of formaldehyde. This reaction is very useful for the reductive amination, without the application of hydrogen gas, catalyst (e.g., Pd/C), and high-pressure apparatus and has been widely applied to alkaloid chemistry. A special case of such reductive amination that occurs on phenylethylamine and results in the formation of tetrahydroisoquinolines is also referred to as the Clarke-Eschweiler cyclization. In a few cases, the methylation also occurs on an aromatic ring during the reductive amination. J... 

In the presence of formaldehyde the initially formed primary amine further underwent a double reductive amination reaction to give the A, A -dimethylamine product (Scheme 36). 

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