Alkylation of secondary amines

Tertiary amines may be obtained from alkaline alkylation of secondary amines (46), but mixtures are obtained (see Section III.l.B) hence heterocyclization and ammonolysis of 2-halothiazoles are to be preferred. 

The N-alkylation of secondary amines was also examined under the same catalytic conditions. Reactions of N-methylaniline and N-methylbenzylamine with benzyl alcohol gave the corresponding tertiary amines in good yields (Scheme 5.20). 

Another type of N-alkylation was achieved by the [IrCl(cod)]2-catalyzed reductive alkylation of secondary amine with aldehyde and silane (Equation 10.29) [53], For example, the treatment of dibutylamine 117 with butyraldehyde 118 and EtsSiH 119 (a 1 1 1 molar ratio amine, aldehyde and silane) or polymethyUiydrosiloxane (PMHS) in 1,4-dioxane at 75 °C under the influence of a catalytic amount of [lrCl(cod)]2, gave tributylamine 120. 

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. 

The preparation of tertiary amines with the aid of insoluble supports has mostly been performed by 3-elimination of support-bound quaternary ammonium salts or by N-alkylation of secondary amines with support-bound alkylating agents (Figure 3.28). 

Tertiary amines do not react with nitrous acid, acetyl chloride, benzoyl chloride, benzenesulfonyl chloride, but react with alkyl halides to form quaternary ammonium halides, which are converted by silver hydroxide to quaternary ammonium hydroxides. Quaternary ammonium hydroxides upon heating yield (1) tertiary amine pins alcohol (or, for higher members, olefin plus water). Tertiary amines may also be formed (2) by alkylation of secondary amines, e.g., by dimethyl sulfate, (3) from amino acids by living organisms, e g, decomposition of fish in the case of trimethylamine. 

Since ketimine formation is not possible in the reductive alkylation of secondary amines, this reaction must involve the hydrogenolysis of an alcoholamine. However, if either carbon a to the starting carbonyl has a hydrogen available, the enamine formation is possible. 

N. Narsimhachari and R. O. Friedel, N.-Alkylation of secondary amine tricyclic antidepressants by GC-MS-MS technique, Anal. Lett., 725 77(1979). 

Two complementary procedures have been developed for alkylation of secondary amines [11] - both of which involve the use an excess of amine to drive the reaction to completion. The remaining amine was removed from the required tertiary amine using a polymer supported isocyanate 5 as a nucleophilic scavenger (under thermodynamic control) (Table 1 entry 2). The use of this amine scavenger has subsequently been applied in the purification of urea-based libraries prepared by solid-phase organic synthesis [12],... 

F]FBI, 17, has been prepared in three steps (equation 15) and applied for [18F]-labelling of the pharmacologically active spiperone38 18. Model alkylation study using [I8F]FBI has been carried out also. N-alkylation of secondary amines took place under mild (RT) conditions, alkylation of A-methylaniline in a sealed vial required 100 °C and alkylation of amides required the use of TEOH as the base catalyst. 

TABLE 6.4 Reductive Alkylation of Secondary Amines with Aldehydes and Ketones over Platinum Catalyst4 ... 

Method E-5 is useful for the preparation of functionalized diaza-crown ethers. As mentioned in previous chapters, alkylation of secondary amine groups in the presence of hydroxy groups is possible when weak bases are used in the reaction. A bis(2-hydroxyethyl)-substituted diaza-18-crown-6 was prepared by this procedure (method E-6) (Bradshaw et al., 1990b Krakowiak et al., 1990). This procedure also allows the preparation of diaza-crowns with... 

Kahn, N.M., Arumugam, V. and Balasubramanian, S. (1996) Solid phase reductive alkylation of secondary amines. Tetrahedron Lett. 37 4819-4822. 

A -alkylation of secondary amines. The presence of EtjN apparently prevents quatemization of the products. 

N-Alkylation of secondary amine takes place under sonication in the presence of a PTC reagent, polyethylene glycol monomethyl ether. SimilarlyN-alkylation of diphenyl amine is accomplished under sonication (Scheme 10). 

Cation and solvent hydrogen bonding to the hydrophilic phosphate group of the anion BNPPA (l,l-binaphthyl-2-diyl phosphate) (71) leads to bilayers with an interior hydrophilic region and with hydrophobic binaphthyl groups on both exterior sides.A simple thiophosphate-based method for 2-alkylidenation of lactones has been described. Phosphorus-derived chiral auxiliaries for a-alkylation of secondary amines by anodic oxidation has been elaborated. lodotrimethyl-sUane, which is routinely used for the dealkylation of ethers and esters, may be used to iodinate allyl or benzyl diethyl phosphates. ... 

Clerici MG, Maspero F (1980) Catalytic C-alkylation of secondary amines with alkenes. Synthesis 305-306... 

For many groups of compounds of pharmacological interest, a wide variety of labelling procedures are available and indeed two of the earliest compounds to be labelled with carbon-14 were meperidine [5] and morphine [6]. This procedure which involves the reductive alkylation of secondary amines with labelled formaldehyde is still the most widely used method for preparing N-methyl tertiary amines and it has also been used for the synthesis of nicotine [7] and chlorpromazine [8, 9] and, with slight modification, for the preparation of erythromycin [10] and acetylmethadol [11], The reaction of C-methyl iodide has also been used to prepare tertiary amines as in the case of codeine [6] and mepivacaine [12], as well as the tranquillisers, thioridazine [13] and methixene [14]. These examples illustrate that labelling of... 

Secondary amines are also the products of the catalytic C-alkylation of secondary amines with alkenes, the ring-opening of cyclopropanimines, the Michael addition of primary amines to a,unsaturated ketones, and the phase-transfer catalysed reaction of 1,2-diamines with ketones to give hindered cyclic secondary amines. ... 

Tertiary Amines.—A new approach to the direct alkylation of secondary amines leading to tertiary amines is based on the oxidative coupling of lithium alkyl copper amides (Scheme 16). The method is also applicable to the synthesis of secondary amines. 

With secondary acyclic alkylamines (Scheme 6) the alkylation was performed without CO, as under the previous experimental conditions, the reaction preferentially led to the carbonylation of the N-H bond and the formation of formamide. The alkylation of secondary amines with ethylene in isopropanol led to monoalkylation of the benzylic sp C-H bond. Alkylation of the tertiary dialkylamine 26 took place under carbon monoxide but was not selective leading to a mixture of mono- and dialkylated products 27-29 (Scheme 6). 

Heil997 Heinonen, P. and Lonnberg, H., A Novel Support for Derivatisation and Subsequent N-Alkylation of Secondary Amines Preparation of N-Alkylated 5- and 6-Alkoxy-l,2,3,4-tetrahydroisoquinolines via Mitsunobu Reaction, Tetrahedron Lett., 38 (1997) 8569-8572. 

Mesylates found an apphcation in the solid phase synthesis of polyamine-imidazole conjugates and usnic acid, both described by Uriac et al. [164,246] (Scheme 17). They showed that the use of longer reaction times (32 h) and higher temperatures (70 °C) gave good yields for the alkylation of secondary amines. Primary amines are sufficiently alkylated in much shorter time (6 h) and at lower temperatures (50 °C). 

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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