Pyruvoyl Chloride1

[5704-66-5]  · C3H3ClO2  · Pyruvoyl Chloride  · (MW 106.51)

(a-ketoacylating agent; selective oxidation of alcohols)

Physical Data: light yellow liquid; bp 53 °C/126 mmHg.

Solubility: sol CCl4, Et2O, THF, etc.

Preparative Methods: most of the conventional reagents for the synthesis of acid chlorides from carboxylic acids are unsatisfactory for the preparation of pyruvoyl chloride. For example, treatment of pyruvic acid with Phosgene or Oxalyl Chloride11 affords the acid chloride in low yield. The method of choice for the preparation of the title compound1 is the reaction of pyruvic acid with Dichloromethyl Methyl Ether12,13 to yield chloromethoxymethyl pyruvate, which readily decomposes into pyruvoyl chloride and methyl formate at 50 °C (eq 1).13 This simple and economical procedure has also been used for the preparation of other a-keto acid chlorides.1

Another facile, but less often used, method for the preparation of pyruvoyl chloride involves the treatment of trimethylsilyl pyruvate, derived from pyruvic acid and Chlorotrimethylsilane, with oxalyl chloride in DMF solution (eq 2).2

Handling, Storage, and Precautions: pyruvoyl chloride reacts vigorously with moisture, giving off fumes of HCl. It should be stored at -20 °C as the pure liquid in a sealed tube or in CCl4 solution. The compound may be characterized as the p-nitroanilide derivative.1a Use in a fume hood.

Reaction of the Acyl Chloride Function.

Of the two functional groups present in pyruvoyl chloride, the acyl chloride function is more reactive than the keto group. The title compound seems to be the reagent of choice for the formation of esters of pyruvic acid.3,4 This method offers the advantage of mild reaction conditions and broad applicability compared to the older procedure starting from pyruvic acid.14 Irradiation of the resulting pyruvate esters furnishes aldehydes, ketones, lactones, enones,3,4 etc., depending on the starting materials employed. Primary alcohols are oxidized to aldehydes without further reaction (eq 3). This procedure is more versatile than Dipyridine Chromium(VI) Oxide or Ruthenium(VIII) Oxide oxidation and it seems to be more consistent than the DMSO-based reactions.

In the presence of the proper base, pyruvoyl chloride reacts with amines,5 phenol,6 and anilines7-9 to furnish the corresponding a-keto-amides, phenyl a-keto acetates, and a-keto anilides. Other nucleophiles employed are hydroxylamine, oxime amine, and amides.10,15 In general, amines are more reactive than alcohols or amides, and anilines react faster than phenols.

Palladium and platinum complexes of pyruvoyl chloride have been prepared by the oxidative addition of the acid chloride to both Pt(PPh3)4 and Tetrakis(triphenylphosphine)palladium(0) in benzene.16 Both classes of compounds are stable as solids and in benzene solution at 25 °C, but slowly decompose to acyl complexes when heated at 65 °C. They can serve as synthetic equivalents of the acetyl moiety, e.g. reaction with Et2NH affords Et2NAc as the major product.16

At rt, pyruvoyl chloride adds to C=N double bonds10 to form chloroacetoamides (Leuch's reaction).17 In an analogous manner, condensation of the acyl chloride with nitriles gives the chloroformamidines.18 Pyruvoyl chloride also adds to C=C double bonds,19 provided an electron-withdrawing group is attached to the alkene.

Reaction of the Keto Function.

Once the acyl chloride function of the title compound has reacted with nucleophiles the a-keto function can manifest its reactivity. With phosphorus ylides it undergoes a Wittig reaction to form the corresponding alkenes.19,20 Asymmetric reduction with B-3-Pinanyl-9-borabicyclo[3.3.1]nonane21 or catalytic hydrogenation22 using chiral rhodium(I) complexes and subsequent hydrolysis furnishes optically active a-hydroxypropanoic acid. Diastereoselective reduction of the keto group in a chiral ester23 or amide24 has also been reported.

The dual reactivity of pyruvoyl chloride has been used to construct both five-membered7 and six-membered8,10,15,25 rings. An example of the latter synthesis is given in eq 4.15b

1. (a) Ottenheijm, H. C. J.; de Man, J. H. M. S 1975, 163. (b) Ottenheijm, H. C. J.; Tijhuis, M. W. OS 1983, 61, 1.
2. Häusler, J.; Schmidt, U. CB 1974, 107, 145.
3. (a) Binkley, R. W. SC 1976, 6, 281. (b) Binkley, R. W. JOC 1977, 42, 1216.
4. (a) Binkley, R. W. JOC 1976, 41, 3030. (b) Binkley, R. W.; Hehemann, D. G.; Binkley, W. W. JOC 1978, 43, 2573. (c) Townsend, C. A.; Neese, A. S.; Theis, A. B. CC 1982, 116. (d) Carless, H. A. J.; Fekarurhobo, G. K. TL 1983, 24, 107.
5. (a) Adlington, R. M.; Barrett, A. G. M.; Quayle, P.; Walker, A.; Betts, M. J. JCS(P1) 1983, 605. (b) Kubo, A.; Saito, N.; Yamato, H.; Masubuchi, K.; Nakamura, M. JOC 1988, 53, 4295. (c) Fukuyama, T.; Yang, L.; Ajeck, K. L.; Sachleben, R. A. JACS 1990, 112, 3712.
6. Delaney, E. J.; Massil, S. E.; Shi, G. Y.; Klotz, I. M. Arch. Biochem. Biophys. 1984, 228, 627.
7. Lopatin, W.; Sheppard, C.; Owen, T. C. JOC 1978, 43, 4678.
8. Bashir, M.; Kingston, D. G. I.; Carman, R. J.; Van Tassell, R. L.; Wilkins, T. D. H 1990, 31, 1333.
9. Audin, P.; Sarciron, M. E.; Paris, J.; Petavy, A. F. Eur. J. Med. Chem. 1992, 27, 285.
10. (a) Ottenheijm, H. C. J.; Spande, T. F.; Witkop, B. JACS 1973, 95, 1989. (b) Ottenheijm, H. C. J.; Kerkhoff, G. P. C.; Bijen, J. W. H. A. CC 1975, 768. (c) Ottenheijm, H. C. J.; Herscheid, J. D. M.; Kerkhoff, G. P. C.; Spande, T. F. JOC 1976, 41, 3433.
11. (a) Kharasch, M. S.; Brown, H. C. JACS 1942, 64, 329. (b) Wieland, T.; Köppe, H. LA 1954, 588, 15. (c) Tanner, D. D.; Das, N. C. JOC 1970, 35, 3972.
12. Heslinga, L.; Katerberg, G. J.; Arens, J. F. RTC 1957, 76, 969.
13. Rieche, A.; Gross, H. CB 1959, 92, 83.
14. Examples see: (a) Leermakers, P. A.; Warren, P. C.; Vesley, G. F. JACS 1964, 86, 1768. (b) Derevitskaya, V. A.; Klimov, E. M.; Kochetkov, N. K. TL 1970, 4269.
15. (a) Herscheid, J. D. M.; Nivard, R. J. F.; Tijhuis, M. W.; Scholten, H. P. H.; Ottenheijm, H. C. J. JOC 1980, 45, 1880. (b) Ottenheijm, H. C. J.; Plate, R.; Noordik, J. H.; Herscheid, J. D. M. JOC 1982, 47, 2147. (c) Plate, R.; Nivard, R. J. F.; Ottenheijm, H. C. J. JCS(P1) 1987, 2473. (d) Plate, R.; Akkerman, M. A. J.; Ottenheijm, H. C. J.; Smits, J. M. M. JCS(P1) 1987, 2481.
16. (a) Ozawa, F.; Sugimoto, T.; Yamamoto, T.; Yamamoto, A. OM 1984, 3, 692. (b) Sen, A.; Chen, J. T.; Vetter, W. M.; Whittle, R. R. JACS 1987, 109, 148.
17. Leuchs, H.; Heller, A.; Hoffmann, A. CB 1929, 62, 871.
18. Ried, W.; Schöpke, K. LA 1986, 1997.
19. Capuano, L.; Triesch, T.; Schramm, V.; Hiller, W. CB 1984, 117, 2785.
20. (a) Capuano, L.; Ahlhelm, A.; Hartmann, H. CB 1986, 119, 2069. (b) Himbert, G.; Kosack, S. CB 1988, 121, 2163.
21. Brown, H. C.; Pai, G. G. JOC 1985, 50, 1384.
22. Tani, K.; Suwa, K.; Tanigawa, E.; Ise, T.; Yamagata, T.; Tatsuno, Y.; Otsuka, S. JOM 1989, 370, 203.
23. Solladie-Cavallo, A.; Suffert, J. TL 1984, 25, 1897.
24. Ojima, I.; Yoda, N.; Yatabe, M.; Tanaka, T.; Kogure, T. T 1984, 40, 1255.
25. (a) Shibuya, M.; Sakurai, H.; Maeda, T.; Nishiwaki, E.; Saito, M. TL 1986, 27, 1351. (b) Gaudiano, G.; Sweeney, K.; Haltiwanger, R. C.; Koch, T. H. JACS 1984, 106, 7628.

Harry C. J. Ottenheijm & Ya Fang

Organon, Oss, The Netherlands

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