Synthesis of Amines by Reductive Amination

Many methods are available for making amines. Most of these methods derive from the reactions of amines covered in the preceding sections. The most common amine syntheses start with ammonia or an amine and add another alkyl group. Such a process converts ammonia to a primary amine, or a primary amine to a secondary amine, or a secondary amine to a tertiary amine. 

Primary Amines Primary amines result from condensation of hydroxylamine (zero alkyl groups) with a ketone or an aldehyde, followed by reduction of the oxime. Hydroxylamine is used in place of ammonia because most oximes are stable, easily isolated compounds. The oxime is reduced using catalytic reduction, lithium aluminum hydride, or zinc and HCl. 

Secondary Amines Condensation of a primary amine with a ketone or aldehyde forms an -substituted imine (a Schiff base). Reduction of the imine gives a secondary amine. 

Reductive amination is the most useful amine synthesis It adds a 1° or 2° alkyl group to nitrogen. Use an aldehyde to add a 1° group, and a ketone to add a 2° group. 

Show how to synthesize the following amines from the indicated starting materials. 

A more general method of amine synthesis, called reductive amination of aldehydes and ketones, allows the construction of primary, secondary, and tertiary amines. In this process, the carbonyl compound is exposed to an amine containing at least one N-H bond (NH3, primary, secondary amines) and a reducing agent to furnish a new alkylated amine directly (a primary, secondary, or tertiary amine, respectively). The new C-N bond is formed to the carbonyl carbon of the aldehyde or ketone. 

The sequence begins by the initial condensation of the amine with the carbonyl component (Section 17-9) to produce the corresponding imine (for NH3 and primary amines) or iminium ion (secondary amines). Similar to the carbon-oxygen double bond in aldehydes and ketones, the carbon-nitrogen double bond in these intermediates is then reduced by simultaneous catalytic hydrogenation or by added special hydride reagents. 

Reductive Amination of a Ketone with a Primary Amine 

Dbninished ability of H to leave as H, hence reagent is less sensitive to H  

Similarly, reductive aminations with secondary amines give tertiary amines. 

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A valuable application of sodium cyanoborohydride is in the synthesis of amines by reductive amination. What combination of carbonyl and amine components would give the following amines by this method ... 

Mechanism 19-6 Diazotization of an Amine 910 19-17 Reactions of Arenediazonium Salts 911 Summary Reactions of Amines 915 19-18 Synthesis of Amines by Reductive Amination 918 19-19 Synthesis of Amines by Acylation-Reduction 920... 

Reduction of amides by LiAlH4 is an important method for the synthesis of amines. 

The synthesis of amines by the in-situ reductive amination of ketones is termed the Leuckart-Wallach reaction. Recently, an asymmetric transfer hydrogenation version of this reaction has been realized [85]. Whilst many catalysts tested give significant amounts of the alcohol, a few produced almost quantitative levels of the chiral amine, in high enantiomeric excess. 

Aqueous organometalHc catalysis allows the use of NH3-solutions in water for the direct synthesis of amines from olefins in a combined hydroformylation/reductive amination procedure (Scheme 4.19). The hydroformylation step was catalyzed by the proven Rh/TPPTS or Rh/BINAS (44) catalysts, while the iridium complexes formed from the same phosphine ligands and [ IrCl(COD) 2] were found suitable for the hydrogenation of the intermediate imines. With sufficiently high NH3/olefin ratios (8/1) high selectivity towards the formation of primary amines (up to 90 %) could be achieved, while in an excess of olefin the corresponding... 

The synthesis of amines from oximes is exemplified by the reduction of oxime 332 to 333 (99W032453) and of bicyclic oximes (derived from ketones 3 and 23a), for instance, of oxime 387 (Scheme 87) to amine 388 that is acylated to yield potential pharmaceutical agent 390 (92BML1147). Nucleophilic substitution of chloropyridine 384 generates morpholino derivative 385 (76IJB400). 

The third group of reactions relies on the fact that amides usually can be converted to amines, either by reduction, hydrolysis, or rearrangement, so that any viable synthesis of amides usually is also a synthesis of amines ... 

The transition metal catalyzed synthesis of arylamines by the reaction of aryl halides or tri-flates with primary or secondary amines has become a valuable synthetic tool for many applications. This process forms monoalkyl or dialkyl anilines, mixed diarylamines or mixed triarylamines, as well as N-arylimines, carbamates, hydrazones, amides, and tosylamides. The mechanism of the process involves several new organometallic reactions. For example, the C-N bond is formed by reductive elimination of amine, and the metal amido complexes that undergo reductive elimination are formed in the catalytic cycle in some cases by N-H activation. Side products are formed by / -hydrogen elimination from amides, examples of which have recently been observed directly. An overview that covers the development of synthetic methods to form arylamines by this palladium-catalyzed chemistry is presented. In addition to the synthetic information, a description of the pertinent mechanistic data on the overall catalytic cycle, on each elementary reaction that comprises the catalytic cycle, and on competing side reactions is presented. The review covers manuscripts that appeared in press before June 1, 2001. This chapter is based on a review covering the literature up to September 1, 1999. However, roughly one-hundred papers on this topic have appeared since that time, requiring an updated review. 

Baxter, E W, Reitz, A B, Expeditious synthesis of azasugars by the double reductive amination of dicarbonyl sugars, J. Org. Chem., 59, 3175-3185, 1994. 

The preparative use of nitrile reduction has been primarily for the synthesis of amines [1,2,152-157]. This is done in acidic medium and gives fair to good yields. Electrocatalytic hydrogenation of nitriles is also sometimes efficient [158] in these cases, nickel or palladium black, deposited on the cathode, promotes reduction by electrolyti-cally generated hydrogen atoms. 

Methods for preparation of hydroxylamine derivatives have been reviewed in detail recently. Here, mainly new developments concerning the synthesis of hydroxylamines by substitution processes with heterobond formation are presented. Reduction of nitro, nitroso, oxime and nitrone derivatives as well as direct oxidation of amines leading to hydroxylamine compounds will not be considered. 

Alkylations, A stepwise synthesis of amines via I-aminomethylbenzotriazoles involves reductive alkylation with Zn in DME. Stereoselective synthesis of 1,2-amino alcohols is attained by Zn-mediated allylation of a-amino aldehydes. Change of regioselectivity is observed in the reactions of fluorinated prenylzinc species with aldehydes (aliphatic vs. aromatic)."... 

In another application, PEG-bound a-aminoaldehydes served as a starting point for the combinatorial synthesis of polyamines [154], Reductive amination with an amine of type 5, followed by alkylation of the formed secondary amine (via reductive amination) and cleavage of the cyclic aminal yielded the starting aldehyde for the next cycle. 

The hydroxyimino group attached to carbon (C=NOH) may be converted into an amino group by way of the intermediate hydroxyamino or imino group. The reduction of oximes can be conducted so as to yield (1) a synthesis of amines from carbonyl compounds, (2) introduction of amino groups into a compound containing active methylene groups (by way of the isonitroso compounds obtained by nitrosation), or (3) production of amines from the adducts of nitrogen oxides or nitrosyl chloride to olefins. 

Finally, the strategy should be of interest because it only requires two reactions steps. This is possible because ketimine isolation is not required, and while rarely discussed can be time consuming, may provide mediocre yield, and unnecessarily lengthens the synthesis of amines. Furthermore, all the reagents are already in use by the pharmaceutical industry, a broad range of ketone substrates are suitable (even aliphatic ketones), either enantiomeric form of the a-chiral amine product can be produced, and the process has been demonstrated on a 20 g scale. The method is compatible with acetonides, ethers, silyl ethers, bulky esters, secondary amides, tertiary amides, carbamates, urethanes, etc. With these beneficial qualities noted, the method suffers when non-branched 2-alkanones are used (product des <75%). In these cases, HCl salt formation allows further enrichment via crystallization, alternatively stoichiometric Yb(OAc)3 can be used during the reductive amination to allow enhanced de. Both of these solutions require additional processing time and/or cost and require consideration before scale-up. 

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