Trimethylacetyl Chloride

[3282-30-2]  · C5H9ClO  · Trimethylacetyl Chloride  · (MW 120.59)

(ether cleavage;1 synthesis of ketones from carboxylic acids;2 peptide synthesis;3 selective protection of polyols4)

Alternate Names: pivaloyl chloride; 2,2-dimethylpropanoyl chloride.

Physical Data: bp 105-106 °C; d 0.979 g cm-3.

Form Supplied in: colorless liquid; widely available.

Handling, Storage, and Precautions: flammable; can cause severe burns and is irritating to the eyes and respiratory system; toxic by contact with the skin, by inhalation, and if swallowed. It should be used in a fume hood. During use, avoid sources of ignition and any contact. Avoid exposure to moisture.5

Ether Cleavage.

Ethers can be cleaved by the action of trimethylacetyl chloride (t-BuCOCl) and Sodium Iodide to give the corresponding trimethylacetate and alkyl iodide.1 The reaction is regioselective, the cleavage occurring at the less substituted a-carbon-oxygen bond.1,6 Other acyl chlorides can be used, but the reaction is more regioselective with trimethylacetyl chloride.1 The reaction is particularly useful for cleaving methyl ethers (eq 1).1

Ketone Synthesis.

Carboxylic acids can be converted to ketones by first forming the mixed anhydride with trimethylacetyl chloride and then treating it with a Grignard reagent (eq 2).2 In addition to trimethylacetyl chloride, ortho-substituted benzoyl chlorides such as o-anisoyl chloride can be used to form the mixed anhydride. Yields were found to be slightly higher than when trimethylacetyl chloride was used.2

The carboxylic acid (1) has been converted to the ketone (2) via the mixed anhydride with trimethylacetyl chloride (eq 3).7

A g-keto aldehyde synthesis has been developed using similar methodology. The ethoxy lactam (3) was converted to its N-trimethylacetyl derivative (4), which was then treated with a Grignard reagent. Acid workup gave the g-keto aldehyde (5) (eq 4).8

Peptide Synthesis.

Trimethylacetyl chloride has been used to synthesize peptidic bonds by the mixed anhydride method (eq 5).

A comparison of a range of carboxylic acid chlorides showed trimethylacetyl chloride to be one of the most effective for peptide synthesis, though slightly inferior to diethylacetyl chloride.3 The extent of racemization that occurred using various acyl chlorides has been studied and trimethylacetyl chloride was shown to give only a very small amount of racemization.9 Trimethylacetyl chloride has been used in the synthesis of adrenocorticotrophic hormone.10,11

Selective Protection of Polyols.

The protection (as the trimethylacetate) of a primary alcohol in the presence of two secondary alcohols has been achieved in high yield using 1 equiv of trimethylacetyl chloride (eq 6).4

The selective protection of a less hindered primary alcohol in the presence of another more hindered one has also been achieved (eq 7).12

Sucrose has been selectively protected using trimethylacetyl chloride. By varying the conditions a variety of penta-, hexa-, and heptatrimethylacetates was obtained.13

1. Oku, A.; Harada, T.; Kita, K. TL 1982, 23, 681.
2. Araki, M.; Mukaiyama, T. CL 1974, 663.
3. Vaughan, J. R.; Osato, R. L. JACS 1951, 73, 5553.
4. Nicolaou, K. C.; Webber, S. E. S 1986, 453.
5. For further information, see: The Sigma-Aldrich Library of Chemical Safety Data, 2nd ed.; Leng, R. E., Ed.; Sigma-Aldrich: Milwaukee, 1987; Vol. 2, p 3479.
6. Rodriguez, J.; Dulcere, J.-P.; Bertrand, M. TL 1984, 25, 527.
7. Bakuzis, P.; Bakuzis, M. L. F. JOC 1977, 42, 2362.
8. Savoia, D.; Concialini, V.; Roffia, S.; Tarsi, L. JOC 1991, 56, 1822.
9. Taschner, E.; Smulkowski, M.; Lubiewska-Nakonieczna, L. LA 1970, 739, 228.
10. Schwyzer, R.; Sieber, P. Nature 1963, 199, 172.
11. Schwyzer, R.; Sieber, P. HCA 1965, 49, 134.
12. Schuda, P. F.; Heimann, M. R. TL 1983, 24, 4267.
13. Hough, L.; Chowdhary, M. S.; Richardson, A. C. CC 1978, 664.

Christopher J. Urch

Zeneca Agrochemicals, Bracknell, UK

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