2-Methoxycarbonylbenzoyl Chloride1

[4397-55-1]  · C9H7ClO3  · 2-Methoxycarbonylbenzoyl Chloride  · (MW 198.61)

(N-phthaloylation of a-amino acids; preparation of isocoumarins)

Physical Data: mp 48-52 °C; bp 107-110 °C/0.1 mmHg; fp >110 °C.

Solubility: sol most organic solvents.

Form Supplied in: pale yellow oil.1

Preparative Method: heat o-methoxycarbonylbenzoic acid (methyl hydrogen phthalate) with Thionyl Chloride for 1 h on a steam bath (eq 1).1

Handling, Storage, and Precautions: corrosive and moisture sensitive; reacts with protic solvents; use in a fume hood; do not breathe vapors and avoid contact with skin, eyes, and clothing; causes burns and irritation of the respiratory system; lachrymator; use immediately after preparation.

Phthaloyl Amino Acids.

2-Methoxycarbonylbenzoyl chloride is used in the N-phthaloylation of a-amino acids.2 N-Phthaloyl-a-amino acids may be obtained by heating mixtures of phthalic anhydride3 and the appropriate a-amino acids. In a number of cases, racemization occurs and the experimental conditions are too drastic for the preparation of N-phthaloyl-a-amino acids containing additional functional groups. In addition, when a-amino acid esters are used, 2,5-diketopiperazines may result as the major product. On the other hand, the reagent reacts with a-amino acid esters at 0 °C (2 h) in THF or 1,4-dioxane in the presence of Et3N to give N-phthaloyl-a-amino acid esters2 in high yields (90-85%) and without racemization (eq 2). Under these mild conditions the formation of 2,5-diketopiperazines and anhydrides is also suppressed. The reagent forms an intermediate N-(o-methoxycarbonylbenzoyl)amino acid ester with the amino acid ester (eq 2), which eliminates MeOH to gave the N-phthaloyl-a-amino acid ester. The corresponding N-phthaloyl-a-amino acids are obtained by selective removal of the ester group (i.e. Me, Et, Bn, t-Bu). The preferred ester is benzyl, since this group is easily removed by hydrogenolysis without racemization; the yields for (1) are consistently high (Tables 1 and 2).4,5


Some isochroman-1,4-diones (R = H, OMe) were prepared in good yield using o-methoxycarbonylbenzoyl chloride and appropriate diazoethyl ketones.6-8 They were reduced with Sodium Borohydride to the related 4-hydroxy-3-methyl-3,4-dihydroisocoumarins (eq 3)

1. Eliel, E. L.; Burgstahler, A. W. JACS 1949, 71, 2251.
2. (a) Hoogwater, D. A.; Reinhoudt, D. N.; Lie, T. S.; Gunneweg, J. J.; Beyerman, H. C. RTC 1973, 92, 819. (b) Proceedings of the 10th European Peptide Symposium, Italy; Reinhoudt, D. N.; Hoogwater, D. A.; Beyerman, H. C. Scoffone, E., Eds.; North-Holland: Amsterdam, 1971; p. 7. (c) Rubottom, G. M.; Pichardo, J. L. SC 1973, 3, 185.
3. (a) Billman, J. H.; Harting, W. F. JACS 1948, 70, 1473. (b) Sheehan, J. C.; Frank, JACS 1949, 71, 1856.
4. Taub, B.; Leipold, H. A.; Hino, J. B. JOC 1959, 42, 2062.
5. Losse, G. CB 1965, 98, 1522.
6. (a) Chatterjea, J. N.; Bhakta, C.; Mukherjee, IJC(B) 1974, 12, 1259. (b) Chatterjea, J. N.; Sinha, N. D.; Bhakta, C. IJC 1979, 56, 515.
7. Bhatt, M. V.; Ashry, S. H.; Somayaji, V. IJC(B) 1980, 19, 473.
8. Hepworth, J. D. In Comprehensive Heterocyclic Chemistry; Katritzky, A. R.; Rees, C. W., Eds.; Pergamon: Oxford, 1984; Vol. 3, p 832.

Jerry W. Skiles

Ciba-Geigy Corp., Summit, NJ, USA

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