Alkylation of Aliphatic Amines

The phosphate method has not been synthetically useful for alkylation of anilines of low basicity such as -nitro- or p-trifluoroaniline. Only monoalkylation occurs in introducing branched-chain alkyl groups such as isopropyl. Use of this method for alkylation of aliphatic amines has not been reported. 

These data give some insight into the sterio effect encountered in alkylations of aliphatic amines with ethylene sulfide. The lack of a... 

Rhenium sulfide was the most active and hydrogenated excess ketone to the corresponding alcohols. The platinum metal sulfides were found to be more active than the base metal sulfides and highly selective for the formation of (V-alkylarylamines. They usually produce a pure product with little or no side reactions, require no excess above the stoichiometric amount of ketone, and are active at relatively low pressures of hydrogen. An example with (V-phenyl-p-phcnylencdiaminc is shown in eq. 6.15.37 Platinum metal sulfides may also be used for the reductive alkylation of aliphatic amines and their nitroalkane precursors with aliphatic ketones. 

Divalent ruthenium complexes are efficient catalysts for A -alkylation of amines by a primary alcohol. RuCl2(PPh3)3 or RuCl3-3H20/P(0Bu)3 effectively catalyze the A -alkylation of aromatic amines (eq (38)) [133-134]. On the other hand, yV-alkylation of aliphatic amines with a primary alcohol is carried out in high yield by the use of RuH2(PPh3>4as catalyst [135]. 

This idea (Fig. 6) was based on an alternative process developed for the racemic product with heterogeneous catalysts in the gas phase [7] and some results of the N-alkylation of aliphatic amines with primary alcohols using homogeneous Ru phosphine catalysts [8],... 

Aldehydes and ketones react with aniline derivatives in the presence of hydrogen and a catalyst to yield N-alkylanilines (Fache et al., 1996 Freifelder, 1971). N-Alkylation of aliphatic amines under microwave irradiation is a well-documented process (Caddick, 1995 Loupy et al., 1998 Varma, 1999 Lidstrom et al., 2001 Wathey et al., 2002). Jiang et al. (1996) reported the N-alkylation of anilines with alcohols over Raney nickel under microwave irradiation. More recently, Khadilkar and Jaizinghani (1999) carried out the direct monobenzylation of aniline with ben-zylchloride on alumina supported potassium carbonate. They reported a fast and efficient metal-free method for the N-alkylation of anilines under microwave irradiation. Romera et al. (2004) reported potassium iodide catalyzed monoalkylation of anilines, where they obtained 54-98% yield. 

Plaiinum was more efficient lhan rhodium in ihese experimenis. These catalysts give excellent yields of tertiary amines in reductive alkylation of aliphatic secondary amines with ketones ( 6). 

Ammonia has always been the starting material for the synthesis of aliphatic amines. Thus, processes have been developed for the condensation of NH3 with alkyl halides (Hoffman reaction) or with alcohols in the presence of various catalysts. The latter reachon, first discovered by Sabatier in 1909 [8, 9] is nowadays the main method of industrial production of light amines (e.g. methylamines 600 000 t/yr) [5]. 

The increase in the values of aliphatic amines (thus making them stronger bases as compared to ammonia) is due to the electron-releasing nature of alkyl groups. This release of electrons pumps electron density back to the nitrogen atom, which stabilizes the positive charge. 

Merrifield resin [33-37] and other support-bound benzyl halides [38] have also been used to alkylate amines (Entries 5-10, Table 10.2). Similarly, resin-bound allyl bromides react cleanly with aliphatic or aromatic amines (Entry 16, Table 10.2). Entry 15 in Table 10.2 is a rare example of the N-alkylation of an amine under the conditions... 

Carbon-13 shift values of aliphatic amines [337-339] collected in Table 4.42 indicate that the y effect is about — 4.5 ppm for primary, secondary, and tertiary amines. The a effect, however, increases while the ft effect decreases with an increasing degree of alkylation at the amino nitrogen. Analogously to alkanols, two increment systems can be used to predict alkyl carbon shifts of amines according to eq. (4.12 a, b), based on the reference shifts of corresponding alkanes (R —H) or the methyl homologs (R —CH3) [337, 338] (Table 4.43). 

TERTIARY AMINE PREPARATION BY REDUCTIVE ALKYLATION OF ALIPHATIC SECONDARY AMINES WITH KETONES... 

We developed a process of preparative and potential commercial utility for the production of tertiary aliphatic amines by the reductive alkylation of dialkyl amines and of alicyclic secondary amines with ketones in the presence of hydrogen and a catalyst3. Such tertiary amines have at least one secondary alkyl group. 

Yoshida et al. were the first to report the synthesis of carbamate esters by the direct reaction of aliphatic amines, C02 and alkyl halides [47]. The process involved the O-alkylation of intermediate alkylammonium carbamate salt, and required relatively, severe conditions (333-393 K 4MPa C02), long reaction times (1-2 days) and an excess of amine (2.5 equiv.) with respect to the alkylating agent. The method was shown to be effective only with secondary aliphatic amines which, however, were converted into organic carbamates in low to moderate yield and with modest selectivity because of significant side-formation of N-alkylation products. 

The most conspicuous property of aliphatic amines, apart from their fishy smell, is their high basicity, which usually precludes N-alkylations under acidic reaction conditions (last reaction, Scheme 6.3). Hence, alkylation of amines with tertiary alkyl groups is not usually possible without the use of highly stabilized carbocations which can be formed under basic reaction conditions. Rare exceptions are N-alkyla-tions of amines via radicals (Scheme 4.2), copper-catalyzed propargylations (Scheme 6.3), and the addition of amines to some Michael acceptors and allyl palladium or iridium complexes. Better strategies for the preparation of tert-alkylamines include the addition of Grignard reagents to ketone-derived imines [13] or the reduction of tert-alkyl nitro compounds. 

Boric acid (10 mol%) efficiently catalyses the conjugate addition of aliphatic amines RNH2 and R2NH to a,/9-unsaturated compounds R1CH=C(R2)X (R1 and R2 = alkyl, H X = COMe, C02Me, CONH2) in water at room temperature to produce /3-amino derivatives. Aromatic amines do not participate effectively in the reaction.141... 

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). 

Malz, Jr. and Greenfield studied the preparation of tertiary amines by reductive alkylation of aliphatic secondary amines with ketones, using platinum metals and their sulfides as catalysts.40 Excellent yields of tertiary amines were obtained with unhindered ketones, such as cyclohexanone and acetone, and relatively unhindered secondary amines. In this study, 5% Pd-C and various transition metal sulfides were compared in the reductive alkylation of dibutylamine with cyclohexanone. By using the reaction conditions suitable to each catalyst, excellent yields of tertiary amines were obtained, as shown in Table 6.5. Approximately 5-15% of the excess cyclohex-... 

Incorporation of triethylamine into the reaction medium produced more reduction product presumably due to electron transfer from the triethylamine to the excited alkyl halide. This results in a weakly-bound amine-alkyl halide pair [57]. The alkyl halide radical anion releases X- (Scheme 17). In a related example, it is known that solutions of aliphatic amines in CC14 are unstable to light quickly forming white crystalline precipitates [60]. The initial reaction is formation of a singlet radical pair via excitation of a ground state charge-transfer complex. 

Several iV, iV -alkylaled derivatives of purine-2,6-diamine have been prepared by the stepwise reaction of aliphatic amines with 2,6-dichloropurine, e.g. formation of 16."... 

The reaction is especially suited to the generation of optically active diazonium ions with specifically oriented counter-ions. In this respect it has possibilities which are absent for the reaction of diazoalkanes with acids and the deamination of aliphatic amines. However, in carrying out stereochemical studies, great care must be exercised to avoid spurious results, since the transient formation of a diazoalkane, either by loss of a proton from the diazonium ion or by what is probably a concerted elimination reaction of the diazoester, can lead to racemisation of the alkyl function and loss of asymmetry in the anion. Moreover, the diazoester is liable to nucleophilic displacement, for example by an acid molecule formed from already rearranged nitrosoamide, and this can lead to inverted product. 

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