2-Bromo-1-methylpyridinium Iodide1

[52693-56-8]  · C6H7BrIN  · 2-Bromo-1-methylpyridinium Iodide  · (MW 299.94)

(dehydrative coupling and activation of alcohols)

Preparative Methods: the title reagent (1a) as well as the chloro analog (1b) can be prepared by adding 1.2 equiv of MeI to an acetone solution of 2-bromo- or 2-chloropyridine at 0 °C. After stirring for 3 days at rt the precipitated pyridinium salt is filtered off and washed with dry ether. Further drying under vacuum results in 80-90% yield of the pyridinium salt as a colorless solid which may be used without further purification.2b,c


The reagent (1a) is a member of the widely used 2-halo-N-alkylpyridinium salts pioneered by Mukaiyama in the mid-1970s. Two general uses have arisen: dehydrative coupling and conversion of alcohols to leaving groups followed by subsequent nucleophilic displacement. Several variants of (1) exhibit analogous reactivity and this discussion will include some of these alternative reagents. The uses of 2-halo-N-alkylpyridinium salts up to 1979 have been reviewed.1

Dehydrative Coupling.

The C-2 bromide of (1a) (as well as the corresponding chloride of 1b) is easily displaced by carboxylates in the presence of an amine base to generate 2-acyloxypyridinium salts (2) which, in turn, can acylate a variety of nucleophiles to provide esters,2 amides,3 thiolesters4 (eq 1), and 3-acylthiazolidine-2-thiones.5 The reactions generally proceed well in a variety of solvents, including diethyl ether, dichloromethane, acetonitrile, pyridine, and toluene. As bases, Triethylamine, Tri-n-butylamine, and 2,6-Lutidine give good results. It was found that less basic pyrimidinone derivatives such as (7) and (8) allow the reaction to be carried out under essentially neutral conditions.6

Ring closure via intramolecular acylation to produce lactones7 (including macrocyclizations8) and b-lactams9 have also been demonstrated with (1b). These dehydrative processes have two outstanding characteristics: a number of functional groups can tolerate the mild reaction conditions, and even hindered nucleophiles may be acylated. For example, pivalic acid (10) may be converted to its t-butyl ester (12) in 54% yield (eq 2). However, the steroidal alcohol (9) was acylated in only 10-15% yield using 2-bromo-1-ethylpyridinium iodide after 5 days at 100 °C.10 The mildness of the conditions was demonstrated in the macrolactamization which produced (13) in 81% yield using (1b) with Et3N in CH2Cl2 at 20 °C.11

Activation of Alcohols.

This aspect of the Mukaiyama reagents has not been studied as intensely as dehydrative coupling. In many respects the activation of alcohols by 2-halo-1-methylpyridinium salts mirrors that of the Triphenylphosphine-Diethyl Azodicarboxylate (Mitsunobu reagent). That is, alcohols are converted to good leaving groups and can then undergo invertive substitution with nucleophiles (eq 3). Thus activated, both primary and secondary alcohols have been displaced with Grignard reagents,12 trichloroacetic acid/Et3N13 (to eventually induce the equivalent of the Mitsunobu process), iodide (-> R-I) and chloride ion (-> R-Cl),14 sulfides (-> R-SR),15 sodium N,N-dimethyldithiocarbamate (-> R-SH),16 and azide ion (-> R-NH2).17 With secondary alcohols, complete inversion normally occurs. The 2-chlorobenzoxazolium salt (17) plays the same role as (14) in several of the processes.

Other Uses.

These reagents also promote the following: reductive elimination of b-hydroxy sulfides to give alkenes,18 preparation of nucleosides,19 phosphorylation,20 carbocation formation as a prelude to cationic cyclizations,21 Beckmann and pinacol rearrangements,22 preparation of isothiocyanates,23 carbodiimides,24 and isocyanates from amines,25 and dehydration of amides to give nitrile and isocyanides.26 None of these latter processes have been utilized beyond their original descriptions.

1. Mukaiyama, T. AG(E) 1979, 18, 707.
2. (a) Mukaiyama, T.; Usui, M.; Shimada, E.; Saigo, K. CL 1975, 1045. (b) Saigo, K.; Usui, M.; Kikuchi, K.; Shimada, E.; Mukaiyama, T. BCJ 1977, 50, 1863. (c) Lingeman, H.; Hulshoff, A.; Underberg, W. J. M.; Offerman, F. B. J. M. J. Chromatogr. 1984, 290, 215.
3. Bald, E.; Saigo, K.; Mukaiyama, T. CL 1975, 1163.
4. Watanabe, Y.; Shoda, S.; Mukaiyama, T. CL 1976, 741.
5. Izawa, T.; Mukaiyama, T. CL 1977, 1443.
6. (a) Mukaiyama, T.; Toda, H.; Kobayashi, S. CL 1976, 13. (b) Mukaiyama, T.; Aikawa, Y.; Kobayashi, S. CL 1976, 57. (c) Bald, E.; Kobayashi, S.; Mukaiyama, T. H 1976, 1707. (d) Bald, E. CS 1978, 13, 108.
7. Strekowski, L.; Visnick, M.; Battiste, M. S 1983, 493.
8. (a) Mukaiyama, T.; Usui, M.; Saigo, K. CL 1976, 49. (b) Mukaiyama, T.; Narasaka, K.; Kikuchi, K. CL 1977, 441. (c) Narasaka, K.; Yamaguchi, T.; Mukaiyama, T. CL 1977, 959. (d) Shiono, M.; Shibanuma, T.; Mukaiyama, T. CL 1976, 1041. (e) Narasaka, K.; Maruyama, K.; Mukaiyama, T. CL 1978, 885.
9. (a) Huang, H.; Iwasawa, N.; Mukaiyama, T. CL 1984, 1465. (b) Georg, G.; Mashava, P. M.; Guan, X. TL 1991, 32, 581.
10. Muller, J.; Herz, J. E. Steroids 1979, 34, 793.
11. Jones, T. K.; Mills, S. G.; Reamer, R. A.; Aspin, D.; Desmond, R.; Volante, R. P.; Shinkai, I. JACS 1989, 111, 1157.
12. (a) Mukaiyama, T.; Imaoka, M.; Izawa, T. CL 1977, 1257. (b) Mukaiyama, T.; Yamaguchi, M.; Narasaka, K. CL 1978, 689. (c) Mukaiyama, T.; Kawata, K. CL 1978, 785.
13. Mukaiyama, T.; Hojo, K. CL 1976, 893.
14. Hojo, K.; Mukaiyama, T. CL 1976, 619.
15. Mukaiyama, T.; Ikeda, S.; Kobayashi, S. CL 1975, 1159.
16. Hojo, K.; Yoshino, H.; Mukaiyama, T. CL 1977, 437.
17. Hojo, K.; Kobayashi, S.; Soai, K.; Ikeda, S.; Mukaiyama, T. CL 1977, 635.
18. Mukaiyama, T.; Imaoka, M. CL 1978, 413.
19. Mukaiyama, T.; Shoda, S.; Nakatsuka, K.; Narasaka, K. CL 1978, 605.
20. Watanabe, Y.; Mukaiyama, T. CL 1978, 349.
21. (a) Kobayashi, S.; Tsutsui, T.; Mukaiyama, T. CL 1976, 1137. (b) Kobayashi, S.; Tsutsui, T.; Mukaiyama, T. CL 1976, 1169.
22. (a) Shiono, M.; Echigo, Y.; Mukaiyama, T. CL 1976, 1397. (b) Mukaiyama, T.; Echigo, Y.; Shiono, M. CL 1977, 179.
23. Shibanuma, T.; Shiono, M.; Mukaiyama, T. CL 1977, 573.
24. Shibanuma, T.; Shiono, M.; Mukaiyama, T. CL 1977, 575.
25. Echigo, Y.; Watanabe, Y.; Mukaiyama, T. CL 1977, 1345.
26. Echigo, Y.; Watanabe, Y.; Mukaiyama, T. CL 1977, 697.

Kim F. Albizati

University of California, San Diego, CA, USA

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