From a three-component synthesis to multistep cascade reactions. Twenty years in the chemistry of N -(1-haloalkyl)azinium halides

N -(1-Haloalkyl)azinium halides are readily available through a three-component reaction of an azine, an aldehyde, and a thionyl halide. Those salts represent activated forms of the starting aldehydes and can be used advantageously for the preparation of other azinium salts, imines, 1,1-diamines, and a wide range of nitrogen (fused) heterocycles. Recently it has also been demonstrated that N -(1-haloalkyl)azinium halides can be transformed into bis(1,3,4-thiadiazolo)- 1,3,5-triazinium halides, a novel class of versatile tricyclic systems that exhibits many useful synthetic potentialities.


Introduction
The chemistry of N-(1-haloalkyl)heteroarylium salts (1, Figure 1), one of the leading activities of E. Anders and his group, was reviewed comprehensively in 2000 in the series "Advances in Heterocyclic Chemistry". 1 The aim of the present paper is to summarize that review and to highlight recent developments in the field.

Preparation of N-(1-haloalkyl)pyridinium Halides
The first N-(1-haloalkyl)pyridinium halides (3, Scheme 1) described in the literature were obtained by bromination of phenacyl pyridinium derivatives 2. The experiments were performed by Kroehnke in the 1930s. 2 Since that time only a few scattered reports have mentioned such salts.Among them (see ref 1 for an exhaustive list), let us mention (Scheme 1) that (chloromethyl)pyridinium salts 4 and 5 have been prepared 3 from pyridine and chloroiodomethane or from 2-pyridyl platinium (II) complexes and dichloromethane.N-(Trifluoromethyl)-and N-(difluoromethyl)-4-(dimethylamino)pyridinium bromides (6, 7) have been synthesized 4 by a two-step sequence as illustrated in Scheme 1. Two decades ago, 5 Anders developed a procedure that has the advantage of a much wider scope of applicability. 6This three-component reaction involves an azine, an aldehyde, and a thionyl halide (Scheme 2) in an inert solvent, generally at room temperature and without any particular experimental precaution.Numerous nitrogen heterocycles have been used in those reactions, including pyridine, 3-bromopyridine, 3-methylpyridine, pyridine-3-carbonitrile, methyl pyridine-3-carboxylate, 4-tert-butylpyridine, 4-(dimethylamino)pyridine, pyridine-4-carbonitrile, pyrimidine, pyrazine, quinoline, isoquinoline, and even 1-methylimidazole.Aromatic, heteroaromatic, or aliphatic aldehydes can be used in the presence of thionyl chloride or bromide indifferently.The highly branched trimethylacetaldehyde 6c and gaseous formaldehyde, 6d generated from paraformaldehyde, have also been successfully employed.Yields are nearly quantitative.Most of the salts, although sometimes hygroscopic, are stable at room temperature for several years and soluble in many organic solvents.

Scheme 2
More recently polymer-bound N-(1-chloroalkyl)quinolinium (8) and isoquinolinium (9) chlorides (Scheme 3) have been described. 7Based on exploratory experiments and a kinetic study 6c of the rate of formation of N-(1-haloalkyl)azinium halides, Merrifield's resin linked through an ether bound to position 6 of quinoline or position 5 of isoquinoline emerged as highly attractive insoluble auxiliaries.Such solid reagents were readily available by coupling Merrifield's resin with 6-hydroxyquinoline or 5-hydroxyisoquinoline in a hot mixture of aqueous sodium hydroxide and N,N-dimethylformamide for 6 hours.Noteworthy reaction time could be decreased to five minutes when performing the experiment under microwave irradiation (Biotage Initiator TM ).Conversion of the aldehydes was effected at room temperature and the so-obtained polymer-bound salts could be kept for months without any degradation.The mechanism suggested (Scheme 4) to explain the formation of N-(1haloalkyl)heteroarylium halides (1) by the three-component reaction discovered by Anders is based on a 1 H-NMR study of the rates of formation of 1. 6c Kinetic data ruled out the presence of a preequilibrium between the aldehyde and the thionyl halide or between the heterocycle and the thionyl halide.It was therefore suggested 6c that the azine could add to the aldehyde to form a betaine prior to interact with the thionyl halide.subsequent O-sulfinylation and elimination of sulfur dioxide would afford the salts.

Reactivity of the salts
In N-(1-haloalkyl)heteroarylium halides both the halogen atom and the heterocyclic moiety can be displaced by nucleophiles.Theoretical 1 calculations and experimental 6b data revealed that substitution of the halogen atom is the rate-determining step.
In order to evaluate the synthetic potential of the polymer-bound fused N-(1chloroalkyl)azinium halides 8 and 9 towards nucleophiles, they were reacted with N,N'-dimethyl ethane-1,2-diamine in dichloromethane at room temperature.The experiments 7 afforded the expected 2-substituted 1,3-dimethylimidazolidines 46 in good to excellent yields (50-80 %, not optimized).After washing with an aqueous solution of sodium hydroxide, the starting neutral heterocycle-containing resin (identified by IR) was recovered and it could be recycled several times without a significant loss of activity.The sequence is illustrated in Scheme 11 in the case of the quinoline auxiliary 8.

Scheme 13
Interestingly bis(1,3,4-thiadiazolo)-1,3,5-triazinium halides (47) appeared to be highly sensitive to nitrogen nucleophiles.When they were treated with primary or secondary aliphatic amines, guanidines like those represented in Scheme 14 could be isolated in good yields. 21,22 is procedure therefore represents an original route to access novel heterocycles-containing highly substituted guanidines.Some of the compounds described in Scheme 14 have been used as tailor-made ligands for complexation of Cu(II) and Zn(II). 23he mechanism suggested 21,24 to explain the transformation of 47 into guanidines (52) is depicted in Scheme 15.It is a cascade reaction in which the most important steps are (i) the deprotonation of intermediate 53 by the amine or an added base to give 55 and (ii) the cleavage of both the S(5)-C(4a) bond in the thiadiazole and then the C(9)-N(10) bond in the triazinium ring.This rearrangement gives rise to a novel chiral center at the 2,3-dihydrothiadiazole ring in 52.Mention should be made that in species 55 the S(5)-C(4a) is an unusually long bond (193.6 pm 24 ) due to a negative hyperconjugation effect. 25The fission of this bond needs only 7.9 kcal/mol and gives the zwitterionic compound 56, the key intermediate determining the consecutive steps.Several zwitterions of structure 56 have been successfully prepared, isolated, and characterized. 24When heated above their melting point, they reacted intramolecularly and were completely transformed into the corresponding guanidines 52.auxiliaries for the preparation of diverse neutral or compounds that are readily available in high yields through simple experimental procedures.Their impact in organic synthesis has now found a novel niche because they are starting materials for the preparation of bis(1,3,4thiazolo)-1,3,5-triazinum halides, from which various highly substituted guanidines, aminals, and triazinium halides can be accessed.