Reductive Alkylation of Ammonia with Carbonyl Compounds

1 REDUCTIVE ALKYLATION OF AMMONIA WITH CARBONYL COMPOUNDS 

The reaction of nonanal with 0.5 equiv of ammonia gave dinonylamine in 81 % yield (GC) along with small amounts of nonylamine, trinonylamine, and 1-nonanol over Raney Ni in heptane/methanol at 75°C and 6.9 MPa H2, while substitution of Pd-C for the nickel catalyst and omission of solvent resulted in the formation of trinonylamine as the predominant product (eq. 6.4). It is noted that hydrogenation of the stoichiometric 3 1 aldehyde-ammonia mixture resulted in decreased yield of trinonylamine (73.2%) accompanied by the formation of 1-nonanol in an amount of 20.0%. 

TABLE 6.1 Reductive Alkylation of Ammonia with Nonanala,i 

The yields of primary amines over platinum oxide were improved in the presence of an excess molar equivalent of ammonium chloride in low pressure reductive alkylation of ammonia with ketones in methanol saturated with ammonia.10 With acetophenone and 4-methyl-2-pentanone, the yields of primary amine increased from 37 and 49% in the absence of ammonium chloride to 69 and 57-65%, respectively, in the presence of ammonium chloride. Moller obtained a much higher yield ( 90%) of 1-phenethylamine from acetophenone by adding a small amount of acetic acid to methanol-ammonia with Raney Ni (eq. 6.6).15 The reductive amination of benzophenone in the presence of Raney Co and some ammonium acetate gave 70% yield ofbenzohy-drylamine, compared to only 19% under usual conditions with Raney Ni.3 

Gobolos et al. studied reductive amination of acetone with ammonia in a flow system at 169-210°C and 0.8 MPa H2 (H2/NH3 = 0.5) on Raney Ni that had been modified by organic tin compounds with general formula of SnR l (R = Et, Bu, or benzyl) in order to suppress the formation of isopropyl alcohol.16 By introducing tin from tetraalkyl tin, the selectivity to the formation of secondary amine significantly increased at the expense of the primary amine (isopropylamine/diisopropylamine ratio = 68.2/24.1 at 192°C, compared to 83.6/8.6 at 190°C with unmodified catalyst). By modifying the catalyst with SnBzl2Cl2, the lowest selectivity ( 1%) for the formation of isopropyl alcohol was obtained at temperatures of 171-202°C. The isopropy-lamine/diisopropylamine ratio was close to the values obtained on the unmodified catalyst (7.3% selectivity to isopropyl alcohol at 190°C). 

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Reductive alkylation of ammonia may proceed under mild conditions over nickel catalysts. In examples using Raney Ni, temperatures ranging from 40 to 150°C and hydrogen pressures of 2-15 MPa have been used to obtain satisfactory results.3,4 In general, the reductive alkylation of ammonia with carbonyl compounds may produce primary, secondary, and tertiary amines, as well as an alcohol, a simple hydrogenation product of the carbonyl compound (Scheme 6.1). The selectivity to respective amine depends primarily on the molar ratio of the carbonyl compound to ammonia, although the nature of catalyst and structure of the carbonyl compound are also important factors for the selectivity. As an example, the reaction of benzaldehyde in the presence of 1 equiv of ammonia in ethanol over Raney Ni gave benzylamine in an 89.4% yield while with 0.5 molar equivalent of ammonia dibenzylamine was obtained in an 80.8% yield (eq. 6.1).4... 

Reductive alkylation of ammonia should give primary amines, reductive alkylation of primary amines secondary amines, and reductive alkylation of secondary amines tertiary amines. In reality, secondary and even tertiary amines are almost always present to varying extents since the primary amines formed in the reaction of the carbonyl compounds with ammonia react with the carbonyl compounds to give secondary amines, and the secondary amines similarly afford tertiary amines according to Scheme 128. In addition, secondary amines may be formed, especially at higher temperatures, by additional reactions shown in Scheme 129. Depending on the ratios of the carbonyl compounds to ammonia or amines, different classes of amines predominate. 

When an aldehyde or a ketone is treated with ammonia or a primary or secondary amine in the presence of hydrogen and a hydrogenation catalyst (heterogeneous or homogeneous), reductive alkylation of ammonia or the amine (or reductive amination of the carbonyl compound) takes place.165 The reaction can formally be regarded as occurring in the following manner (shown for a primary amine), which probably does correspond to the actual sequence of steps 166... 

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... 

Leuckart-Wallach reaction. Reductive alkylation of ammonia or of primary or secondary amines with carbonyl compounds and formic acid or formamides as reducing agents. 

Preparation of secondary amines by reductive alkylation of ammonia is not such a general reaction as that of primary amines. In the aliphatic series treating ammonia with 2 moles of a carbonyl compound usually affords a mixture of mono-, di-, and tri-alkylamines. However, 80-90% yields of the corresponding dibenzylamine are obtained from benzaldehyde or its o-chloro or o-methyl derivative.996... 

The Leuckart-Wallach reaction992 consists of the reductive alkylation of ammonia or an amine by a carbonyl compound with formic acid or a derivative thereof as reducing agent ... 

Even if the imine may not be isolated, the transient species may sometimes be trapped by reaction with a suitable nucleophile. This is the basis of the reductive amination reaction in which an amine is formed from the reaction of ammonia with a carbonyl compound in the presence of a reducing agent such as sodium borohydride or formate. Use of a primary or secondary amine results in the specific formation of secondary or tertiary amines respectively (Fig. 5-45). This synthetic method allows the preparation of high yields of amines, in contrast to the unselective and uncontrollable reaction of alkylating agents with amines. A specific example involving the preparation of a-phenylethylamine from acetophenone is presented in Fig. 5-46. 

Reductive alkylation of amines proceeds by the hydrogenation of the imine or enamine formed, in situ, by the condensation of the amine with a carbonyl compound. This reaction can give a mixture of products if the amine produced initially competes with the reactant amine in the carbonyl condensation step. The proper selection of reagent concentrations avoids this difficulty and leads to the formation of good yields of the desired product. 50 jhe use of a large excess of ammonia gives the primary amine as the predominant product (Eqn. 19.50). 51 An excess of a primary amine as the reactant leads to the preferential formation of the secondary amine product. An excess of the carbonyl compound gives the symmetrical secondary or tertiary amines (Eqn. 19.51). 50... 

The reaction of formic acid or a variety of formic acid derivatives, such as formate salts and formamides, with ammonia or a variety of amines, as well as various amine derivatives and salts such as ammonium formate salts, and carbonyl compounds, results in the reductive alkylation of the amine in which the entering alkyl group is derived from the carbonyl compound. This reaction is known as the Leuckart reaction [30]. By proper selection of reagents, primary, secondary, and tertiary amines may be prepared. In general this reaction is carried out at elevated temperatures without further solvents. More recent work indicates that magnesium chloride and ammonium sulfate are particularly useful catalysts in the preparation of tertiary amines by the Leuckart reaction [31]. 

Miscellaneous Compounds. A saturated spirocychc pyrrohdine serves as the nucleus for a diamine that has been described as a hypohpemic agent. Treatment of the carbanion of the substituted cylcohexane carboxyhc ester (20-1) with methyl bromoacetate leads to the alkylation and formation of the diester (20-2). Saponification of the ester groups followed by reaction with acetic anhydride leads to ring closure of the succinic anhydride (20-3). Condensation with ammonia leads to the succinimide (20-4). The side chain is then added by alkylation of the anion on nitrogen with l-bromo-4-dimethylaminobutane (20-5). Reaction of this last intermediate with lithium aluminum hydride leads to the reduction of the carbonyl groups to methylene. This affords the pyrrolidine (20-6) atiprimod [22]. 

The reduction is usually effected catalytically in ethanol solution using hydrogen under pressure in the presence of Raney nickel. As in the reduction of nitriles (Section 5.16.1, p. 771), which also involves the intermediate imine, ammonia or the amines should be present in considerable excess to minimise the occurrence of undesirable side reactions leading to the formation of secondary and tertiary amines. These arise from the further reaction of the carbonyl compound with the initially formed amine product. Selected experimental conditions for these reductive alkylation procedures have been well reviewed.210 Sodium borohydride has also been used as an in situ reducing agent and is particularly effective with mixtures of primary amines and aliphatic aldehydes and ketones.211... 

Secondary amines are prepared by several procedures of reductive alkylation. A procedure similar to that described for primary amines may be employed the ratio of reactants must be changed to at least two moles of the carbonyl compound to one of ammonia. The procedure leads to symmetrical secondary amines and is most successful starting with aromatic aldehydes, as in the formation of dibenzylamine (67%). ... 

Reductions of aldehydes and ketones to alcohols proceed at slower rates with AERs in BH4 form than with NaBH4 in ethanol.a,j8-Unsaturated carbonyl compounds are reduced by BH4 in a gel AER to the allylic alcohols. Cyanoborohydride ion in a macroporous AER effects reductive aminations of ketones and ammonia to primary amines, reductive methylations of primary amines to the N,iV-dimethyl tertiary amines with aqueous formaldehyde, reductions of N-alkyl- and AT-acyl-pyridinium ions to tetrahydropyridines, and reductions of primary alkyl halides to alkanes. Nitroarenes are reduced to amines, the bromide of a-bromocarbonyl compounds is replaced by hydride, and 1,2-dibromoalkanes give alkenes by treatment with HFe(CO)4 in a macroporous AER. 

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