Synthesis of pyrrolidines and tetrahydro-1H-azepines from 4-aryl-1-benzoyl(ethoxycarbonyl)methyl-1-methyl-1,2,3,6-tetrahydropyridinium halides

Abstract

6-tetrahydropyridinium quaternary salts which have a benzoylmethyl or ethoxycarbonylmethyl group on atom N-1 generate N-ylides when heated in the presence of NaH and they can rearrange in situ with contraction or expansion of the six-membered heterocycle to give substituted pyrrolidines (as a result of a [2,3]-sigmatropic rearrangement) or 1H-tetrahydroazepine derivatives (via Stevens rearrangement). The presence of an aryl substituent at position C-4 in the tetrahydropyridine ring allows to avoid the formation of elimination products and changes the direction of the reaction towards the preparation of the tetrahydroazepines.In the presence of base, N-methyl-N-phenacyl-1,2,3,6-tetrahydropyridinium halides are converted to N-ylide systems which can rearrange with contraction of the six-membered heterocycle to five-membered forming N-alkyl-2-benzoyl-3-vinylpyrrolidines [1, 2]. Exchange of the N-phenacyl fragment in the starting quaternary tetrahydropyridinium salts for N-(alkoxycarbonyl)methyl also stabilizes the intermediate ylides and leads to derivatives of the natural α-amino acid proline [3][4][5][6][7] which may be important from the viewpoint of biological activity. Key features in the studies [1-7] are as follows: firstly only C-unsubstituted tetrahydropyridines were used as the basic starting materials; secondly a high diastereoselectivity (95%) was found in the substituted pyrrolidines formed; and finally the basic electrophilic [2,3]-sigmatropic rearrangement was accompanied by up to 45% β-elimination with opening of the heterocycle and the formation of dialkylaminopenta-2,4-dienes.In connection with our systematic investigation of the chemistry of 4-aryl-substituted tetrahydropyridines and related compounds [8,9] we decided to study the effect of an aryl substituent in the quaternary tetrahydropyridinium salts on the route of their reaction in the presence of base.

Synthesis of 2‐Aryl‐N‐(EWG‐methyl)‐N‐methylpyrrolidinium Salts as Precursors of Ylides Entering the [1,2] Stevens Rearrangement

“…[59] Therefore, the formation of oily salts 3 with predominating cis isomer was unexpected and inconsistent with most of the literature data, referring to the synthesis of quaternary derivatives of 2-substituted pyrrolidines [13,[15][16][17][18][24][25][26][27][28][29][30] and other cyclic ammonium salts mentioned above. [1][2][3][4][8][9][40][41][42][43][44][45][46][47][48][49][50][51][52][53] The salts 3 a-d were formed as mixtures of diastereoisomers, with cis isomer usually predominating. At first, the configurations of both isomers of salts 3 a-d were assigned based on the similarity of their 1 H NMR spectra to Ncyanomethyl-N-methyl-2-arylpyrrolidinum salts spectra.…”

“…[37][38][39] Many other cyclic ammonium salts, including pyrrolidinium ones, containing EWG group in the α position to the quaternary nitrogen atom, are crystalline compounds. N-(Alkoxycarbonylmethyl)-N-(alkyl)methyl five-or six-membered cyclic ammonium salts were synthesized by quaternization of respective N-methyl(alkyl)amines by bromoacetates [40][41][42][43][44][45] and chloroacetates [42,[46][47][48][49] while the more sterically crowded derivatives were treated with ethoxycarbonylmethyl trifluoromethanesulfonate. [27,[50][51] The substituents attached to a quaternary nitrogen atom might be introduced in the reverse order.…”

“…[27,[50][51] The substituents attached to a quaternary nitrogen atom might be introduced in the reverse order. [52] Much less is known about the synthesis of cyclic ammonium salts with other EWG groups like carbonyl [41,46] or carbamoyl groups. [52,53] Scheme 3.…”