2-Chloro-1-methylpyridinium Iodide1

[14338-32-0]  · C6H7ClIN  · 2-Chloro-1-methylpyridinium Iodide  · (MW 255.49)

(activation of carboxylic acids;1 formation of esters2 and amides;3 lactonization;4 ketene formation;5 b-lactam synthesis;6,7 carbodiimide synthesis8)

Alternate Name: Mukaiyama's reagent.

Physical Data: mp 204-206 °C.

Form Supplied in: commercially available yellow solid.

Preparative Method: by reaction between 2-chloropyridine and Iodomethane in acetone at reflux.9

Purification: recrystallization from acetone.

Handling, Storage, and Precautions: hygroscopic.

Activation of Carboxylic Acids: Ester Formation.

2-Chloro-1-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).2 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 Triethylamine 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).3

Lactone Formation.

The ester formation method has found widespread use in the synthesis of lactones by cyclization of hydroxy acids (eq 3).4 The cyclization process is believed to be entropically favored because of the close proximity of all reactants to a central pyridinium salt (4). Optimum conditions for the process involve addition over 8 h of a solution of the hydroxy acid (0.0125 M) and triethylamine (8 equiv) in dichloromethane or acetonitrile to a solution of (1) (4 equiv; 0.04 M) in the same solvent at reflux. After a further 30 min at reflux, evaporation of the solvent and chromatography affords the lactone. Results of a study of the formation of lactones of various ring sizes are shown in Table 1. Good results are obtained for ring sizes 7 and &egt;12, but attempts to form 8- or 9-membered lactones result in substantial dimerization.

Cyclization of sensitive trans-g-hydroxy acids to give strained trans-bicyclic g-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).10 Other reagents, such as 1,3-Dicyclohexylcarbodiimide/Pyridine or 2,2-Dipyridyl Disulfide/Triphenylphosphine, give far lower yields.

Ketene Formation.

There is evidence that the above esterification procedure may occur at least partly via formation of the ketene from the carboxylic acid.5 If a carboxylic acid contains a suitably placed alkene, the resulting ketene can undergo intramolecular [2 + 2] cycloaddition (eq 5).5 Benzene is the best solvent for this reaction, giving yields comparable to those obtained by ketene formation from the corresponding acid chloride.

b-Lactam Synthesis.

Dehydration of b-amino acids to give b-lactams can be effected in high yield using (1) in CH2Cl2 or MeCN (eq 6).6

b-Lactams can also be prepared by the reaction of carboxylic acids, activated by (1), with imines; best results are obtained with Tripropylamine as base in CH2Cl2 at reflux (eq 7).7

Carbodiimides from Thioureas.

Conversion of N,N-disubstituted thioureas into carbodiimides can be effected by treatment with (1) and 2 equiv of base (eq 8).8

1. Mukaiyama, T. AG(E) 1979, 18, 707.
2. Mukaiyama, T.; Usui, M.; Shimada, E.; Saigo, K. CL 1975, 1045.
3. Bald, E.; Saigo, K.; Mukaiyama, T. CL 1975, 1163.
4. Mukaiyama, T.; Usui, M.; Saigo, K. CL 1976, 49.
5. Funk, R. L.; Abelman, M. M.; Jellison, K. M. SL 1989, 36.
6. Huang, H.; Iwasawa, N.; Mukaiyama, T. CL 1984, 1465.
7. Georg, G. I.; Mashava, P. M.; Guan, X. TL 1991, 32, 581.
8. Shibanuma, T.; Shiono, M.; Mukaiyama, T. CL 1977, 575.
9. Amin, S. G.; Glazer, R. D.; Manhas, M. S. S 1979, 210.
10. Strekowski, L.; Visnick, M.; Battiste, M. A. S 1983, 493.

Alan Armstrong

University of Bath, UK

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