Alkylation of primary amines

Secondary amines synthesized by catalytic reductive alkylation of primary amines are used in a variety of fine and specialty chemical indnstries. For example, derivatives of cyclohexylamine are used as corrosion inhibitors, N-(l,3-dimethylbntyl)-N -phenyl-p-phenylenediamine (6-PPD) is nsed as an anti-oxidant in rabber indnstiy, several dialkylated diamines are used in the coatings indnstiy, while they are nsed in the pharmacentical industry as pharmacophores (1-7). Harold Greenfield and co-workers have examined the ability of platinum group metals (PGM), base metals, and their snlfides to catalyze rednctive alkylation of primary and secotrdary amines (8-11). They found that different catalysts are optimal for the... 

Figure 17.1. General schematic for the reductive alkylation of primary amines and diamines...

The current work indicates that sulfided platinum catalysts are, in general, more active and selective than Pt, Pd, or sulfided Pd catalysts for reductive alkylation of primary amines with ketones. The choice of the catalyst preparation parameters, especially the support, plays a major role in determining the performance of the catalyst. Diamines, especially of lower molecular weight, tend to react with ketones even at room temperature to form heterocycles such as imidazolidine, diazepanes, and pyrimidines. Hence, a continuous reactor configuration that minimizes the contact between the amine and the ketone, along with a highly active catalyst is desired to obtain the dialkylated product. In general, sulfided Pt appears to be more suited for the reductive alkylation of ethylenediamine while unsulfided Pd or Pt may also be used if 1,3-diaminopropane is the amine. 

A possible mechanism for the N-alkylation of primary amines is shown in Scheme 5.21. The first step of the reaction involves the oxidation of an alcohol to a carbonyl intermediate, accompanied by the generation of an iridium hydride. 

Table 5.10 N-Alkylation of primary amines with various primary and secondary alcohols catalyzed by [Cp lrCl2]2 (1)- ...

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. 

REDUCTIVE ALKYLATION OF PRIMARY AMINES WITH CARBONYL COMPOUNDS... 

Dovell and Greenfield have shown that base metal sulfides as well as noble metal sulfides are excellent catalysts for the preparation of secondary amines by the reductive alkylation of primary amines (or their nitro precursors) with ketones.36,37 There was little or no hydrogenation of aromatic rings for arylamines, an important side re-... 

Alkylation of primary amines can be accomplished with Raney nickel (W-2) in the presence of ethanol, as in the preparation of N,N -diethylbenzidine. The mixture is stirred vigorously during the reflux period. 

The same nucleophilic substitution chemistry can be manipulated by means of microwave irradiation to afford a variety of cyclic amines as building blocks in natural product syntheses via double V -alkylation of primary amines (Scheme 11). The protocol circumvents the difficulty associated with running multi-step reactions to assemble Y -aryl azacycloalkanes and avoids the use of expensive metal catalysts in building aryl C-N bonds. Further, reactive functional groups, such as carbonyl, ester, and hydroxyl, remain unaffected under these mild reaction conditions. The V-alkylation reaction is now extended to hydrazines as well. ... 

In many literature procedures for reductive alkylations (of primary amines), concerns over the bis-alkylation side reaction to give the tertiary amine are evident It is claimed that this type of problem does not affect the procedures described above [30]. For reactions with isocyanates, the best results are obtained with a chlorinated solvent (CH2CI2). Isothiocyanates give optimum yields when heated to reflux in acetonitrile. 

Methylalkylammonium salts, obtained by alkylation of primary amines with dimethyl H-phosphonate, are thermally unstable and easily yield the corresponding alkylammonium salts [292,295,296]. 

Potassium fluoride in combination with alumina has been shown to be a good catalyst for the iV-alkylation of carboxamides, lactams and other N-heterocycles using alkyl halides or dialkyl sulfates under mild conditions [47]. The system was also used to AT-alkylate secondary amides and N,N-dialkylate primary amides. Potassium hydroxide and alumina make a useful combination for the catalysis of the selective mono-AT-alkylation of primary amines (e.g. equation 4.6) [48]. 

In 2013, Gao, Hou, and co-workers reported a mesoporous silica (SBA-15) supported iridium complex-catalyzed A/-alkylation of primary amines with benzyl alcohols (Eq. 38) [141]. The catalyst could be recovered easily and reused at least 12 times without notable decrease in catalytic efficiency (1st, 93 % 12th, 83 %). 

The aforementioned Pt-Sn/y-AlaOs catalyst developed by Yu and co-workers in 2011 was also effective for self-coupling of aliphatic primary amines with catalyst loading as low as 0.25 mol% (Eq. 80) [142]. In 2012, Shimizu and co-workers found nano-NaPt/Si02 and nano-SPt/Si02 are both effective catalysts for the N-alkylation of anilines, secondary and branched primary amines [223, 224]. In 2013, Shi and co-workers accidentally found that NiCuFeOx complex could catalyze the self-A-alkylation of primary amines [157]. 

Lazier WA, Adkins H (1924) The alkylation of primary amines with aluminum alkoxides to give secondary amines free from tertiary amines. J Am Chem Soc 46(3) 741-746... 

Reductive alkylation of primary amines to secondary amines has also been carried out using iridium and rhodium complexes supported on solid montmorillonites. ... 

A new method for the facile a-alkylation of primary amines utilizes the easily prepared and little exploited N-sulphinylamines (6). Successive treatment of (6) with base and an allylic halide provides a new sulphinylamine, e.g. (7), which is hydrolysed to the free primary amine during aqueous work-up (Scheme 6). It is suggested that alkylation occurs on sulphur, and that a subsequent 3,3-sig-matropic shift provides (7). 

Tertiary amines may also be synthesised by the alleviation of secondaiy amines with alcohols. Whereas the alkylation of primary amines involves formation of an imine intermediate, the alleviation of secondaiy amines requires the more challenging formation of an iminium ion intermediate prior to the return of hydrogen to the substrate. The pharmaceutical agents piribedil, tripelennamine, and chlorpheniramine were all prepared on milligram scale by [Ru(p-cymene)Cl2]2-catalysed iV-alkylation of secondary amines (Scheme 12.5). ... 

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