Alkylation of amines. General exhaustive alkylation method for the synthesis of quaternary ammonium compounds

Abstract

A method, whereby primary and secondary amines are exhaustively alkylated to their quaternary stage in a one-step procedure, has been extended to a broad spectrum of amines. The study synthetically utilizes the fact that protonation of sterically hindered amines is affected only slightly by steric hindrance, whereas nucleophilicity as measured by the rate of alkylation is considerably decreased. A sterically hindered organic base of greater base strength than the reactant amines is employed to bind the acid that is generated in alkylation reactions. Selection of an appropriate organic base as the proton acceptor enables complete alkylation of primary and secondary aromatic amines with pKa values as low as 2.36 and alicyclic and strong aliphatic amines with pKa values as high as 11.1. The mild and homogeneous reaction conditions result in good yields with minimal laboratory manipulations and effort. The method is of particular importance for reactions in which the amines and the alkylating agents possess labile functions.

Benzyllithium from methylated benzylamine and its ammonium salt via naphthalene-catalyzed carbon-nitrogen bond reductive cleavage

“…Benzyltrimethylammonium iodide (3). 20 General procedure for synthesis of ammonium salts 4-8 n-Butyllithium (10.0 mmol, 6.25 mL of a 1.6M solution in hexane) was dropwise added to a solution of the corresponding benzylic primary amine (10.0 mmol) in anhydrous THF (10 mL), under Ar, at 0ºC. After stirring for 10 min.…”

A new method of quaternizing amines and its use in amino acid and peptide chemistry

“…We found the use of methyl iodide and the highly basic, sterically hindered and weakly nucleophiiic amine 1,2,2,6,6-pentamethyipiperidine as hydrohalide acceptor (8) to be quite satisfactory for the quaternization of protected derivatives such as Bz-Lys-NHPh, Bz-Phe-LysOMe, and Boc-Ala-Lys-OMe; however, we were unable to separate the product from the hydroiodide of the base in the latter case. Furthermore, application of this method to zwitter-ionic compounds was impractical, since the reaction was 2Abbreviations are in compliance with IUPAC-IUB recommendations (2).…”

Utilization of the Sterically Hindered Base, 4-Hydroxy-2,2,6,6-tetramethylpiperidine, as a Hydrogen Halide Acceptor

“…Dehydrohalogenation of Alkyl Bromides [8] Recently, considerable interest has been shown in the utilization of sterically hindered bases in the synthesis of alkenes via the corresponding alkyl halides [1,2,5,6,20]. The bicyclic bases, 1,5-diazabicyclo[4,3,0]non-5-ene (DBN) and 1,8-diazabicyclo(5,4,0)undec-7-ene (DBU) [21,22] initially became known as dehydrohalogenating agents, i. e., hydrogen halide acceptors, in the syntheses of [20].…”

“…propylaniline [6], and 1,2,2,6,6-pentamethylpiperidine (PMP) [1,2,6] have been utilized in the exhaustive alkylation reactions of primary amines. The organic bases are superior to inorganic bases, such as, sodium hydroxide due to the ease of separation of by-products and lack of complicated side reactions under the milder reaction conditions.…”

“…The organic bases are superior to inorganic bases, such as, sodium hydroxide due to the ease of separation of by-products and lack of complicated side reactions under the milder reaction conditions. Sommer et al [6] have shown that, in order to be an effective hydrogen halide acceptor, the base which is utilized should fulfill four criteria. 1) In order to attain homogeneous reaction conditions, the organic base should have solubility characteristics similar to those of the primary amines and the alkylating agents.…”