Chloro-1-methylpyridinium Iodide

Chloro-l-methylpyridinium iodide (1) reacts with a mixture of a carboxylic acid and an alcohol, in the presence of two equivalents of base, to form an ester (eq 1). The pyridinium salt (2) is formed rapidly by displacement of chloride from (1) by the carboxylate subsequent reaction with the alcohol results in formation of the ester, along with 1 -methyl-2-pyridone (3). A variety of solvents may be employed, but yields are highest in dichloromethane or pyridine. Tri-n-butylamine or Triethylanune are often used as base. The co-product (3) is insoluble in dichloromethane and so precipitates from this solvent. Good results are obtained even for hindered carboxylic acids and alcohols. 

Amide Synthesis. In a similar way, amides can be prepared efficiently by treatment of an equimolar amount of a carboxylic acid and an amine with (1) in the presence of base (eq 2)  

Lactone Formation. The ester formation method has found widespread use in the synthesis of lactones by cyclization of hydroxy acids (eq 3). The cyclization process is believed to be 

Ring size % Yield lactone % Yield dimer 

Cyclization of sensitive /rans-y-hydroxy acids to give strained mons-bicyclic y-lactones of the type (5) is often problematic due to dehydration of the tertiary alcohol. A study showed (1) to be the reagent of choice for this transformation (eq 4). Other reagents, such as 1,3-DicyclohexylcarbodumidelPyridine OT2,2 -Dipyri l Disulfide/Triphenylphosphine, give far lower yields. 

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COOR OTHP THF/DMSO - 78 °C excess allyl chloride 2. PPTS/CH3OH reflux I PR 1 COOEt 6b, Et3NyCH3OH - 2-chloro-1 -methylpyridinium iodide CH3CN reflux... 

Preparative Methods from propionyl chloride and 1,3-thiazo-lidine-2-thione in the presence of triethylamine, or from propionic acid and thiazolidine-2-thione in the presence of triethylamine and 2-chloro- 1-methylpyridinium iodide. Handling, Storage, and Precautions use in a fume hood. 

CMPI, DABCO.cljoxane, 2 h, 20°, 96% yield. co H (CMPI = 2-chloro-l-methylpyridinium iodide)... 

Chloro-l-methylpyridinium iodide [ 14338-32-0] M 255.5, m 203-205°, 205-206°(dec), 207°. Purified by dissolving in EtOH and adding dry Et20. The solid is washed with Me2CO and dried at... 

Levulinic esters. Levulinic esters of sugars can also be prepared by Mukaiyama s method for esterification with 2-chloro-l-methylpyridinium iodide (8, 95-96). Deblocking of the ester group is possible with hydrazine hydrate (1 equivalent, 20°).1... 

Chloro-l-methylpyridinium iodide (683) functions as an important mediator in a variety of different reactions. Esters are formed in high yield from acids and alcohols when reacted with one equivalent of (683) in the presence of two equivalents of triethylamine (Scheme 158) (75CL1045). cv-Hydroxy acids are lactonized under similar conditions (76CL49). The pyridinium salt (683) will also convert thioureas into carbodiimides (77CL575) and pyridine-2-thiones to pyridyl sulfides (75CL1159). 

Treatment of amino acid 156, imine and 2-chloro-l-methylpyridinium iodide (Mukaiyama s reagent) in the presence of triethylamine in refluxing dichloro-methane afforded spiro-(3-lactams 157,158. These were obtained as a 1.8 1 mixture of diastereoisomers and separated by column chromatography. The reaction of 159 and imine under the usual experimental conditions resulted in the formation of a single diastereoisomer 160. The absolute (3 S, 4 S, 7 -configuration was assigned on the basis of mechanistic considerations and XH NMR spectra. The presence of the stereocenter affords complete diastereoselectivity (only trans diastereoisomers 157, 158) and enantioselectivity (160). 

In continuation of the research on solid-phase synthesis of biologically interesting (3-lactam compounds towards the development of combinatorial libraries, Mata et al. [102] investigated use of 2-chloro-l-methylpyridinium iodide (Mukaiyama s reagent) as a key reagent for the construction of the (3-lactam ring in a stereoselective manner. The popular explanation involves the reaction of ketene B with the imine to form a zwitterionic intermediate D (Scheme 13). Alternatively, it is the activated acid A that acylates the imine to form the zwitterion D by abstraction of proton with... 

Reduction of carboxylic acids to aldehydes. 2 3-Acyllhiazolidine-2-thiones (2) can be prepared by reaction of l,3-thiazolidine-2-thione (1) with carboxylic acids directly (using 2-chloro-l-methylpyridinium iodide, 8, 95-96) or with acid chlorides (triethylamine or DCC). They can also be prepared from reaction of the thallium salt of 1 with an acid chloride. Yields by all four methods are 70-95%. The amides are reduced to aldehydes by either DIBAH or, generally in higher yield, by NaBH4 (90-98% yield). 

Kinetic studies of the substitution reaction of 2-chloro-l-methylpyridinium iodide with phenoxides are consistent with the SnAt mechanism, with rate-determining nucleophilic attack.38 The effects of a variety of ring substituents on the reactivities of 2-fluoro- and 2-chloro-pyridines in reactions with sodium ethoxide in ethanol have been examined. The results were discussed in terms of the combination of steric, inductive, and repulsive interactions.39 Substitution in 2,4,6-trihalopyridines normally occurs preferentially at the 4-position. However, the presence of a trialkylsilyl group at the 3-position has been shown to suppress reaction at adjacent positions, allowing substitution at the 6-position.40 Methods have been reported for the introduction and removal of fluorine atoms for polyfluoropyridines. Additional fluorine atoms were introduced by metallation, chlorination, and then fluorodechlorination, while selective removal of fluorine was achieved by reduction with either metals or complex hydrides or alternatively by substitution by hydrazine followed by dehydrogena-tion-dediazotization.41... 

A novel synthesis of a-carboxyl, co-amino heterodifunctional polystyrene and its intramolecular cyclization was reported. Cyclic polystyrene with controlled size was synthesized by the intramolecular cyclization of linear a-carboxyl, co-amino heterodifunctional polystyrene under high dilution in the presence of 2-chloro-l-methylpyridinium iodide [67]. The linear precursor polymer was derived from a-diethyl acetal, co-amino heterodifunc-... 

Lactams. z Carboxylic acids and imines condense to form 9-lactams when treated with 2-chloro-N-methylpyridinium iodide (1 equiv.) and tripropylamine (3 equiv.) in CH2C12. The stereoselectivity depends upon the temperature. Reactions conducted at 25° favor formation of cw-3-lactones. Yields are increased when the reactions are conducted for 12 hours at reflux, but the ris-selectivity decreases. Compared with triethylamine, tributylamine improves the yield and the c/ j-selectiv-... 

A short asymmetric synthesis of the 2-ketocarbacepham (27) involving as the initial step for the preparation of the starting piperidone, a hetero Diels-Alder reaction of the benzylimine derived from the enantiomer of Gamer s aldehyde with Danishesky s diene, has been described <02JOC598>. The key cyclization step to form the bicyclic P-lactam system was achieved from a P-amino acid precursor using the Mukaiyama reagent, 2-chloro-A-methylpyridinium iodide. 

Several other methods to effect ester and lactone formation are now available. Mukaiyama uses 2-chloro-A-methylpyridinium iodide and its derivatives as a condensing agent.12 Staab s imidazole method," sue-... 

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