Synthesis of new 6-halogeno-imidazo[1,2-a ]pyridines by S RN 1 reactions

New 2-chloromethyl-6-halogeno-imidazo[1,2-a ]pyridines and 2-chloromethyl-6-halogeno-3-nitroimidazo[1,2-a ]pyridines were prepared and reacted under experimental conditions of S RN 1 reactions with different sulfur and carbon centered nucleophiles to give new 6-halogeno-2-substituted-imidazo[1,2-a ]pyridines and 6-halogeno-3-nitro-2-substituted-imidazo[1,2-a ] pyridines in good yields. Only the chloromethyl group was found to be reactive under these experimental conditions.


Introduction
Substitution reactions at an sp 3 carbon atom of the reductive alkylating agents, p-nitrobenzyl chloride or 2-halogeno-2-nitropropane, which proceed via a chain multi-stage sequence involving radical anions and free radicals as intermediates were first proposed independently by Kornblum 1 and Russell 2 in 1966.This pathway has been applied in 1970 to rationalize the substitution of unactivated aromatic halides and named S RN 1 by Bunnett. 3 The process has a considerably wide scope and synthetic capabilities.Recently, all the aspects of nucleophilic substitution reactions by electron transfer have been magnificently reviewed by Rossi, Pierini and Peñéñory. 4Among the heterocyclic analogues of o-nitrobenzyl derivatives which react by S RN 1 reactions, our group has reported the S RN 1 reactions of nitronate anions with a series of imidazoles fused to a heterocyclic ring bearing the chloromethyl group ortho to the nitro group.
This system constitue a powerful synthetic tool to obtain nitro heterocycles with potential pharmaceutical properties. 5midazo [1,2-a]pyridine derivatives are important compounds which are known for their useful pharmacological activities. 6For example, gastric antisecretory, 7 local anesthetic, 8 antiviral, 9 hypnotic 10 and antianxiety 11 properties have been described.The nature and the position of the substituent on the pyridinic moiety influence these activities. 9Zolpidem (Stilnox®, Ambien®, Myslee®) saled by Sanofi-Synthélabo, is a non-benzodiazepine hypnotic of the imidazopyridine class, leader of the international market with a blockbuster status for the treatment of sleep disorders.
As part of our current interest on the synthesis by S RN 1 reactions of new imidazo [1,2a]pyridines, which can be used in different coupling reactions for the preparation of more complex structures of pharmacological interest, we have prepared new 2-chloromethyl-6halogeno-imidazo[1,2-a]pyridines 3a-b and 2-chloromethyl-6-halogeno-3-nitroimidazo[1,2a]pyridines 4a-b (Figure 1) and studied their reactivity with different nucleophiles under S RN 1 experimental conditions.

Results and Discussion
Herein we describe the synthesis of 3a and 3b (Scheme 1) starting respectively from the commercially available 2-amino-5-chloropyridine (1a) or 2-amino-5-bromopyridine (1b) by condensation with 1,3-dichloroacetone (2) and nitration to give 4a and 4b (Scheme 2) and their conversion to new 6-halogeno-2-substituted-imidazo[1,2-a]pyridines 3c-d by reaction with sodium benzenesulfinate (Scheme 1) and 6-halogeno-3-nitro-2-substituted-imidazo [1,2-a]  pyridines by S RN 1 reactions with lithium salt of 2-nitropropane 5a-b (Scheme 2), sodium phenylthiolate 6a-b, sodium benzenesulfinate 7a-b and sodium salt of diethylmalonate 8a-b (Scheme 3).Although S RN 1 displacements of aromatic substrates by sulfur nucleophiles can be achieved in DMSO with different types of initiation, 3 the PhSO 2anion has not been reported to react.With photostimulation in DMSO in presence of 2 equivalents of the sodium salt of benzenesulfinic acid, 3a and 3b react probably following an S N 2 mechanism only at the chloromethyl group with good yield, respectively 69 and 80%, to give the corresponding sulfones 3c and 3d.No substitution of chloride or bromide in position 6 has been observed under these experimental conditions.The sulfones 3c and 3d were also obtained with similar yields without photostimulation.The S RN 1 displacements on the pyridine moiety of the imidazo[1,2-a]pyridine being more difficult than an S N 2 on the chloromethyl group, we have prepared, new reductive alkylating agents, the nitro derivatives 4a and 4b and studied their conversion with different nucleophiles to the corresponding derivatives by S RN 1 reactions at the sp 3 carbon atom of the chloromethyl group.The C-alkylation of 2-nitropropane anion, which is a classical example of an S RN 1 reaction at sp 3 carbon atom of an o-or p-nitrobenzyl chloride, gives with 4a and 4b (Scheme 2) the ethylenic derivatives 5a and 5b in 70% yields.5a and 5b result of the consecutive C-alkylation of the 2-nitropropane anion and nitrous acid elimination from the C-alkylation product (Scheme 2).These reactions are strongly inhibited in presence of TEMPO, a classical free scavenger used in the mechanism studies of S RN 1 reactions. 12ith the phenylthiolate anion, 4a and 4b react to give the corresponding sulfides 6a and 6b in 80% yields.(Scheme 3).These reactions also are inhibited in presence of TEMPO.
With the phenylsulfinate anion, 4a and 4b react to give the corresponding sulfones 7a and 7b in 80% yields.These sulfones could be used for further S RN 1 reactions with different electrophiles as recently shown in nitroimidazole series. 13inally, 4a and 4b react with diethyl malonate anion to give the corresponding diethyl malonates in 85% yields.Further functional group transformations could give lactams of pharmaceutical interest. 14

Experimental Section
General Procedures.Melting points were determined with a B-540 Büchi melting point apparatus.300 MHz 1 H NMR and 75.4 MHz 13 C NMR spectra were recorded on a Bruker Avance DPX 300 in CDCl 3 or DMSO-d 6 solution at the Centre Régional de RMN de la Faculté des Sciences et Techniques de Saint-Jérôme. 1 H and 13 C NMR chemical shifts (δ) are reported in ppm with respect to CHCl 3 7.26 ppm ( 1 H) and 77.16 ppm ( 13 C) or DMSO 2.62 ppm ( 1 H) and 40.6 ppm ( 13 C).The multiplicity of the signals is: s, singulet; d, doublet; t, triplet; q, quadruplet; m, multiplet.Elemental analyses were carried out at the Centre de Microanalyses de la Faculté des Sciences et Techniques de Saint-Jérôme.