2,4,6-Trichlorobenzoyl Chloride1

[4136-95-2]  · C7H2Cl4O  · 2,4,6-Trichlorobenzoyl Chloride  · (MW 243.89)

(strong acylating agent; used with DMAP in the formation of esters,1 thioesters,2 amides,3 and, particularly, small- and medium-ring lactones1,4)

Physical Data: bp 107-108 °C/6 mmHg; d 1.561 g cm-3.

Solubility: sol most organic solvents.

Form Supplied in: liquid; commercially available.

Purification: redistill under reduced pressure.5

Preparative Methods: first prepared by Yamaguchi from 2,4,6-trichloroaniline,7 but Seebach has reported a simpler synthesis from 1,3,5-trichlorobenzene (1) (eq 1).8

Handling, Storage, and Precautions: irritant and moisture sensitive. Incompatible with strong bases (see Aldrich safety index for Benzoyl Chloride).6

Carboxylic Acid Derivatives.

2,4,6-Trichlorobenzoyl chloride was designed to react rapidly with carboxylic acids to form mixed anhydrides (2),9 which would then quickly react with alcohols, amines, and thiols to give esters (3), amides (4), and thioesters (5) in high yields (eq 2).

The trichloro-substituted phenyl ring serves two purposes: to prevent any side reaction occurring, due to attack of the alcohol at the carbonyl adjacent to the aromatic ring, and to make the carboxylate anion (6) a good leaving group, enhancing the rate of reaction.

Lactone Formation.

Although many methods exist for lactonizing a,o-hydroxy acids,10 2,4,6-trichlorobenzoyl chloride remains one of the most powerful and has been widely used in the synthesis of naturally occurring macrolides.11 Yamaguchi first showed how 9-, 12-, and 13-membered lactones could be synthesized using high dilution techniques (Table 1)1 and went on to demonstrate the potential of his reagents by using them to synthesize methynolide and (±)-brefeldin A (7) (eq 3), 12- and 13-membered lactones, respectively.7,12

Other groups have also used the Yamaguchi lactonization procedure to synthesize natural products, most notably Seebach in the synthesis of (+)-myscovirescine M2, a 27-membered lactone, in which the seco acid was converted to the lactone in 83% yield.14 Symmetrical diolides (8) have been prepared from unprotected seco acids in fair yields (eq 4)15 when other lactonization procedures failed.9 Unsymmetrical diolides require protected seco acids.16

More recently, treatment of 3-hydroxybutanoic acid (9) under the Yamaguchi lactonization conditions of high dilution gave, in equal proportions, macropentolides, macrohexolides, and macroheptolides in good yields (eq 5).17

The Shanzer lactonization method produces a lower overall yield of macrolides, but an increased ratio of the higher homologs.18

Effect on Stereochemistry.

The Yamaguchi esterification is also often used in preference to other methods because of its lack of racemization of stereogenic centers. Kunz used it to esterify an N-Boc protected aspartate (10)19 when other methods have been known to racemize the chiral center (eq 6).20

The Yamaguchi lactonization also leaves intact any stereochemistry at the carbon bearing the hydroxyl group. This is in contrast to the Mitsunobu lactonization, which inverts that stereochemistry (eq 7).21

Furthermore, when no base is present during esterification, double bonds are also little affected, as Greene showed when converting a variety of alcohols to angelate esters (12) in quantitative yield; standard esterification procedures gave a mixture of angelate and tiglate esters (eq 8).22

Limitations of the Yamaguchi Lactonization Conditions.

The tendency of the Yamaguchi lactonization conditions to form diolides from some seco acids, as shown by Seebach,15 can also pose a problem. Steglich has shown that some a,o-hydroxy acids (13) tend to dimerize under the Yamaguchi lactonization conditions. However, by using a modified Mitsunobu lactonization, the monolide was obtained in 59% yield (eq 9). All other lactonization procedures also gave varying amounts of diolide, including the standard Mitsunobu lactonization procedure.23

1. Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. BCJ 1979, 52, 1989.
2. (a) FF 1984, 11, 552. (b) Kawanami, Y.; Dainobu, Y.; Inanga, J.; Katsuki, T.; Yamaguchi, M. BCJ 1981, 54, 943.
3. Tanaka, T.; Sato, T.; Imura, T. Jpn. Patent 04 99 757 [92 99 757] (CA 1992, 117, 111 155h)
4. FF 1981, 9, 478.
5. Harwood, L. M.; Moody, C. J. Experimental Organic Chemistry; Blackwell: Oxford, 1989; p 147.
6. Sigma-Aldrich Library of Chemical Safety Data, 2nd ed.; Lenga, R. E., Ed.; Sigma-Aldrich: Milwaukee, 1987; Vol. 2, p 371B.
7. Inanaga, J.; Katsuki, T.; Takimoto, S.; Ouchida, S.; Inoue, K.; Nakano, A.; Okukado, N.; Yamaguchi, M. CL 1979, 1021.
8. Sutter, M. A.; Seebach, D. LA 1983, 939.
9. Albertson, N. F. OR 1962, 12, 157.
10. (a) Corey, E. J.; Nicolaou, K. C. JACS 1974, 96, 5614. (b) Corey, E. J.; Brunelle, D. J. TL 1976, 3409. (c) Mukiyama, T.; Usui, M.; Saigo, K. CL 1976, 49. (d) Boden, E. P.; Keck, G. E. JOC 1985, 50, 2394. (e) Mitsunobu, O. S 1981, 1.
11. See, for example: (a) Seebach, D.; Brändli, U.; Müller, H.-M.; Dobler, M.; Egli, M.; Przybylski, M.; Schneider, K. HCA 1989, 72, 1704. (b) Mulzer, J.; Mareski, P. A.; Buschmann, J.; Luger, P. S 1992, 215.
12. Honda, M.; Hirata, K.; Sueoka, H.; Katsuki, T.; Yamaguchi, M. TL 1981, 22, 2679.
13. Inanaga, J.; Kawanami, Y.; Yamaguchi, M. BCJ 1986, 59, 1521.
14. Seebach, D.; Maestro, M. A.; Sefkow, M.; Neidlein, A.; Sternfeld, F.; Adam, G.; Sommerfeld, T. HCA 1991, 74, 2112.
15. Seebach, D.; Chow, H.-F.; Jackson, R. F. W.; Sutter, M. A.; Thaisrivongs, S.; Zimmerman, J. LA 1986, 1281 and references cited therein.
16. Schregenberger, C.; Seebach, D. LA 1986, 2081.
17. (a) Seebach, D.; Brändli, U.; Schnurrenberger, P. HCA 1988, 71, 155. (b) For a review of poly(hydroxyalkanates), see: Müller, H.-M.; Seebach, D. AG(E) 1993, 32, 477.
18. Seebach, D.; Brändli, U.; Müller, H.-M.; Dobler, M.; Egli, M.; Przybylski, M.; Schneider, K. HCA 1989, 72, 1704.
19. Waldmann, H.; Kunz, H. JOC 1988, 53, 4172.
20. Dhaon, M. K.; Olsen, R. K.; Ramasamy, K. JOC 1982, 47, 1962.
21. Tsutsui, H.; Mitsunobu, O. TL 1984, 25, 2163.
22. Hartmann, B.; Kanazawa, A. M.; Deprés, J.-P.; Greene, A. E. TL 1991, 32, 5077.
23. Justus, K.; Steglich, W. TL 1991, 32, 5781.

Richard A. Ewin

King's College London, UK

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