Secondary amines, from reductive alkylation

In 2004 Alexakis independently reported on similar reaction conditions (Ti(OiPr)4/ Pd C/H2) as Nugent [22b, 23], albeit when using chiral amines, for example, phen ylethylamine (PEA), phenylpropylamine, and so on, to reductively aminate skeleton matching achiral ketones [30]. By doing so, he synthesized a set of five C2 symmet rical secondary amines from aryl alkyl ketones (Figure 7.5). The optimal conditions called for neat reaction conditions, equal molar quantities of the achiral ketone and chiral amine, Ti(OiPr)4 (3.0 equiv), Pd C (0.5 mol%), and 1.0 bar (14.5 psi) H2. No reaction times were reported. 

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... 

Reductive alkylation is an efficient method to synthesize secondary amines from primary amines. The aim of this study is to optimize sulfur-promoted platinum catalysts for the reductive alkylation of p-aminodiphenylamine (ADPA) with methyl isobutyl ketone (MIBK) to improve the productivity of N-(l,3-dimethylbutyl)-N-phenyl-p-phenylenediamine (6-PPD). In this study, we focus on Pt loading, the amount of sulfur, and the pH as the variables. The reaction was conducted in the liquid phase under kinetically limited conditions in a continuously stirred tank reactor at a constant hydrogen pressure. Use of the two-factorial design minimized the number of experiments needed to arrive at the optimal solution. The activity and selectivity of the reaction was followed using the hydrogen-uptake and chromatographic analysis of products. The most optimal catalyst was identified to be l%Pt-0.1%S/C prepared at a pH of 6. 

The synthesis of secondary amines from azides is efficient in terms of chemos-electivity [57] and has found valuable applications in the preparation of diamines [58,59], m-alkylaminoboronic esters [60], and in Diels-Alder-based amination reactions [61]. A convenient general route to open-chain polyamines, which play major roles in cellular differentiation and proliferation, has also been developed using the reductive alkylation of aliphatic aminoazides by (co-halogenoalk-yi)dichloroboranes as a key step [62] (Scheme 21). 

Aliphatic and aromatic amines react with nitrous acid to form N-nitroso derivatives. For example, dimethylamine hydrochloride on treatment with sodium nitrite and hydrochloric acid is converted to nitrosodimethyl amine in 90% yield. In like manner, N-nitrosomethylaniline is synthesized from N-methylaniline in 93% yield. The ready formation of these derivatives and the easy reconversion to the amine by reduction affords an advantageous procedure for separating secondary amines from primary and tertiary amines, as shown in the synthesis of N-ethyl-m-toluidine and other N-alkyl derivatives by the alkylation of w-toluidine. ... 

In contrast to the anion of diethyl phosphoramidate or trifluoromethanesulfonamide, which cannot be cleanly monoalkylated, - the anion of trifluoroacetamide (100) was monoalkylated by alkyl halides or alkyl methanesulfonate. The resulting A -alkylamides (101) were converted into primary amines by alkaline hydrolysis or reduction (NuBHa Scheme 42). Various primary amines were prepared from (100) with primary alkyl iodides or methanesulfonate, benzyl and allyl halides, a-bromocarbonyl compounds and 2,4-dinitrochlorobenzene. However, competitive elimination is a serious side reaction for less reactive primary alkyl chlorides and secondary halides or methanesulfonate. The synthesis of secondary amines from (100) has also been reported. ... 

Reductive alkylation is an effective method to synthesize secondary and tertiary amines from primary amines and hence is practiced commercially for the synthesis of a variety of fine and specialty chemicals. These inclnde corrosion inhibitors snch as the derivatives of cyclohexylamine, mbber chemicals such as A-(l,3-dimethylbutyl)-A -phenyl-p-phenylenediamine (6-PPD see Figure 15.13), pharmaceutical intermediates, dye intermediates, and pesticides [66-70]. The reaction starts ont as the condensation of an amine with a carbonyl compound followed by rednction of the intermediate imine (a Schiff base) to the desired amine. If the carbonyl componnd has an a-proton that can be abstracted, this secondary amine can be further reduced to tertiary amine [65]. Dne to the relatively small volume of such chemicals, the production is nsnally achieved in a batch process over a heterogeneous catalyst at pressures of 5 to 35 bar and temperatures of 323 to 423 K. Nishimura [71] provides an excellent overview of the literature for the synthesis of primary, secondary, and tertiary amines via reductive alkylation. 

In general, Hofmann alkylations are carried out with appropriate alkyl halides or dialkyl sulfates. These reagents may have to be prepared from the related alcohols, often by rather troublesome methods. A more convenient conversion of alcohols to amines involves the alkylation of amines with toluenesulfonate esters of alcohols. These tosylates are generally prepared quite easily and may then be used as alkylating agents [1-14]. If the alcohol which is to be converted to an amine has the proper structural features, the Ritter reaction (see below) is another useful approach to the preparation of primary amines (by hydrolysis of the amide formed in the reaction) and of some secondary amines (by reduction of the amides). 

Yields dropped notably, when this procedure was applied to synthesize branched polyamines. This comes from the slow reduction rate of the tertiary amide that leads mainly to only partially reduced side products, even after 5 days at 65 °C. The problem was satisfactorily solved for ahphatic substituents by alkylating the secondary amine by reductive amination with aldehydes using NaBHAcs as an additional hydride source. 

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. 

A -Nitroso derivatives, prepared from secondary amines and nitrous acid, are cleaved by reduction (H2/Raney Ni, EtOH, 28°, 3.5 h CuCl/concd. HCl"). Since many V-nitroso compounds are carcinogens, and because some racemization and cyclodehydration of V-nitroso derivatives of V-alkyl amino acids occur during peptide syntheses, V-nitroso derivatives are of limited value as protective groups. 

Several syntheses of muraghtazar (3) have appeared in patents (Cheng et al.) and journals (Devasthale et al., 2005) (Scheme 8.3). Alkylation of 4-hydroxybenzaldehyde with the phenyloxazolemesylate 23, prepared readily from commercially available alcohol 22, yielded aldehyde 24, which was treated with glycine methyl ester under reductive amination conditions to provide secondary amine 25 in excellent yield. Reaction of amine 25 with 4-methoxyphenyl chloroformate followed by hydrolysis of the methyl ester afforded 3 in 94% yield. 

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 can be prepared from the primary amine and carbonyl compounds by way of the reduction of the derived Schiff bases, with or without the isolation of these intermediates. This procedure represents one aspect of the general method of reductive alkylation discussed in Section 5.16.3, p. 776. With aromatic primary amines and aromatic aldehydes the Schiff bases are usually readily isolable in the crystalline state and can then be subsequently subjected to a suitable reduction procedure, often by hydrogenation over a Raney nickel catalyst at moderate temperatures and pressures. A convenient procedure, which is illustrated in Expt 6.58, uses sodium borohydride in methanol, a reagent which owing to its selective reducing properties (Section 5.4.1, p. 519) does not affect other reducible functional groups (particularly the nitro group) which may be present in the Schiff base contrast the use of sodium borohydride in the presence of palladium-on-carbon, p. 894. 

Starting from TV-o-Fmoc-aspartic acid a-f-butylester, a wide range of 1,3,4,7-tetrasubstituted perhydro-l,4-diazepine-2,5-diones 3 were synthesized (Fig. 2).28 After deprotection of the aspartic acid amino function and reductive alkylation, a second amino acid was coupled and a second reductive alkylation was carried out. Following fBu cleavage, the thermodynamically favorable coupling of the resulting secondary amine to the side chain of aspartic acid was readily accomplished. 

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