Carbonyl compounds reductive amination

The zwitterion (6) can react with protic solvents to produce a variety of products. Reaction with water yields a transient hydroperoxy alcohol (10) that can dehydrate to a carboxyUc acid or spHt out H2O2 to form a carbonyl compound (aldehyde or ketone, R2CO). In alcohoHc media, the product is an isolable hydroperoxy ether (11) that can be hydrolyzed or reduced (with (CH O) or (CH2)2S) to a carbonyl compound. Reductive amination of (11) over Raney nickel produces amides and amines (64). Reaction of the zwitterion with a carboxyUc acid to form a hydroperoxy ester (12) is commercially important because it can be oxidized to other acids, RCOOH and R COOH. Reaction of zwitterion with HCN produces a-hydroxy nitriles that can be hydrolyzed to a-hydroxy carboxyUc acids. Carboxylates are obtained with H2O2/OH (65). The zwitterion can be reduced during the course of the reaction by tetracyanoethylene to produce its epoxide (66). 

Oxaziridines are powerful oxidizing agents. Free halogen is formed from hydrobromic acid (B-67MI50800). Reduction by iodide in acidic media generally yields a carbonyl compound, an amine and two equivalents of iodine from an oxaziridine (1). With 2-alkyl-, 2-acyl and with N-unsubstituted oxaziridines the reaction proceeds practically quantitatively and has been used in characterization. Owing to fast competing reactions, iodide reduction of 2-aryloxaziridines does not proceed quantitatively but may serve as a hint to their presence. 

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. 

A useful way of making amines is by reduction of imines (or iminium ions). This overall process, from carbonyl compound to amine, is called reductive amination. This is, in fact, one of the few successful ways, and the best way, of making secondary amineLs. This should be your first choice in amine synthesis. 

We ve talked about reduction of iminium ions formed from carbonyl compounds plus amines. Iminium ions can also be formed by reducing amides with lithium aluminium hydride. A tetrahedral intermediate is formed that collapses to the iminium ion. 

Principally, the same ring closure reactions as for tetraazacycles (Section 14.11.5.3) can be applied for preparation of larger polyazamacrocycles however, mostly tosylamide and peptide-like syntheses are employed. In addition, metal template or cyclization reactions between carbonyl compounds and amines (and reduction of intermediate Schiff base) are often utilized. 

Cyclopropylimines are usually generated by reduction of nitriles or condensation of carbonyl compounds with amines. An alternative to this process involves the generation of cyclopropylinunoni-um salts such as (209) at room temperature from cyanohydrin equivalent (208 Scheme 49). ... 

Mild reduction converts azines and hydrazines into disubstituted hydrazines, but under vigorous conditions reductive cleavage of the N-N bond affords amines. Reduction of oximes thus affords a further but seldom used method of converting carbonyl compounds into amines. 

Reductive amination. A method for the conversion of carbonyl compounds to amines is by reaction with Bu SnH and ammonium salts (derived from primary or secondary amines) in DMF at room temperature. 

Aldehydes and ketones react with primary amines to form imines and with secondary amines to form enamines. The mechanisms are the same, except for the site from which a proton is lost in the last step of the reaction. Imine and enamine formation are reversible imines and enamines are hydrolyzed under acidic conditions back to the carbonyl compound and amine. A pH-rate profile is a plot of the observed rate constant as a function of the pH of the reaction mixture. Hydroxide ion and heat differentiate the Wolff-Kishner reduction from ordinary hydrazone formation. 

Carbonyl Compounds Multiple Bond Reduction Nitrile Group Nitro Compounds Reductive Amination Wolff-Kishner Reduction... 

SchifT s bases A -Arylimides, Ar-N = CR2, prepared by reaction of aromatic amines with aliphatic or aromatic aldehydes and ketones. They are crystalline, weakly basic compounds which give hydrochlorides in non-aqueous solvents. With dilute aqueous acids the parent amine and carbonyl compounds are regenerated. Reduction with sodium and alcohol gives... 

Aldehydes and ketones may be converted into the corresponding primary amines by reduction of their oximes or hydrazones (p. 93). A method of more limited application, known as the Leuckart Reaction, consists of heating the carbonyl compound with ammonium formate, whereby the formyLamino derivative is formed, and can be readily hydrolysed by acids to the amine. Thus acetophenone gives the i-phenylethylformamide, which without isolation can be hydrolysed to i-phenylethylamine. 

Reductive amination has been successfully applied to the preparation of tertiary amines from carbonyl compounds and secondary amines even though a neutral mine is not possible m this case... 

A variation of the classical reductive amination procedure uses sodium cyanoboro hydride (NaBH3CN) instead of hydrogen as the reducing agent and is better suited to amine syntheses m which only a few grams of material are needed All that is required IS to add sodium cyanoborohydride to an alcohol solution of the carbonyl compound and an amine... 

The Knorr pyrrole synthesis involves the reaction between an a-amino ketone 1 and a second carbonyl compound 2, having a reactive a-methylene group, to give a pyrrole 3. The amine 1 is often generated in situ by reduction of an oximino group. 

The mechanism of the original Knorr pyrrole synthesis entails in situ reduction of the oxime moiety to an amine, condensation with the second carbonyl compound, and cyclization with loss of a second molecule of water to give a pyrrole for example, 10 + 11 to 12. Several studies have demonstrated that different pathways and pyrrole products obtain depending on the substrates. 

By application of the Leuckart-Wallach reaction,amines 2 can be alkylated with a carbonyl compound 1 formic acid is used as reductive agent, and is in turn oxidized to give carbon dioxide. 

Some workers allow the amine and carbonyl compound to stand together some time before hydrogenation (i,59), but this procedure is not always necessary nor even desirable (ii). The delay technique is illustrated by reductive alkylation of ethyl-4-aminocyclohexane carboxylate (4) with benzaldehyde to S, a route that permitted an important improvement in the production of isoquinuclidine (8) (59). 

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