Allyl Trichloroacetimidate1

[51479-73-3]  · C5H6Cl3NO  · Allyl Trichloroacetimidate  · (MW 202.47)

(delivers allyl group under mild conditions;2 used in the preparation of N-containing intermediates1)

Physical Data: bp 74 °C/11 mmHg.

Solubility: sol hexane, ether, dichloromethane.

Preparative Methods: typical procedure:2 Sodium Hydride (0.5 g, 21 mmol) is slurried in anhydrous ether (20 mL) under a nitrogen blanket. Allyl alcohol (210 mmol) is introduced in ether (30 mL) dropwise with stirring to the slurry. After 20 min, the homogeneous solution is cooled to 0 °C and Trichloroacetonitrile (20 mL, 200 mmol) is added over 15 min. The mixture is allowed to warm to 20 °C over 60 min and then concentrated to a syrup. Pentane (20 mL) containing methanol (0.8 mL, 21 mmol) is added followed by vigorous shaking, filtration, and concentration of the filtrate and pentane washings (2 × 20 mL). The product imidate is obtained as a clear liquid (90-97%). No further purification is required. Alternatively, the imidate can be prepared by using sodium methoxide as a catalyst instead of sodium hydride. Other procedures for the preparation of allyl trichloroacetimidate have been reported.3,4

Handling, Storage, and Precautions: allyl trichloroacetimidate can be stored in solutions of hexane for up to 2 months at 0 °C. Preparation of allyl trichloroacetimidate should be performed in a well ventilated hood to avoid exposure to trichloroacetonitrile vapors.

O-Allylation and Protecting Group Delivery.

Protecting groups have become an important part of natural and unnatural product chemistry. In oligosaccharide synthesis, they are vital in obtaining the desired compounds because of the various sites at which reaction can occur if hydroxyl groups, for example, are left unprotected. Allyl groups are one of the many substituents used as a protecting group. This group can be delivered to a free hydroxyl group via a trichloroacetimidate derivative. More importantly, the use of allyl trichloroacetimidate allows the protection of an alcohol to take place in the presence of an ester. This is due, in part, to the fact that this reagent is applied under mildly acidic conditions. For example, a rhamnoside is dissolved in dichloromethane and to it is added allyl trichloroacetimidate in cyclohexane followed by a catalytic amount of triflic acid. After 18 h at 20 °C the allylated product is isolated after neutralization with NaHCO3 and chromatography (eq 1).2,5

Substituted tetrahydrofurans have been prepared by using allyl trichloroacetimidate to generate allyl ether intermediates. For example, the hydroxy ester prepared from Methyl Bromoacetate and isobutyraldehyde reacts with allyl trichloroacetimidate and a catalytic amount of Trifluoromethanesulfonic Acid to give the allylic ether ester in 80% yield (eq 2).6 The resulting tetrahydrofuran-3-one is prepared in four steps with high stereoselection, which is attributed to the use of Copper(II) Acetylacetonate as the cyclization catalyst.

a-Amino acids can be prepared from allylic alcohols using allylic trichloroacetimidates. Thermal 1,3-transposition of the imidate group of allyl trichloroacetimidate is accomplished in refluxing xylene. Oxidation and acidic hydrolysis afford the corresponding a-amino acid (eq 3).7 Other acids prepared by this methodology include imidates derived from benzyl alcohol, 4,4-dimethyl-2-pentenol, and 2-butenol.

Allyl trichloroacetimidate has also been used to deliver an acetaldehyde equivalent in the preparation of b-hydroxy-a-amino acid derivatives. An anti-Phe-Leu mimetic was prepared in four steps from the O-allyl ether of N-phthaloyl-L-phenylalanyl-L-serine. This allyl ether was prepared from allyl trichloroacetimidate and the b-hydroxy-a-amino acid in 60-74% yield (eq 4).8

Benzyl groups can be used to protect alcohols in place of the allyl group with comparable yields. For example, under similar reaction conditions, an isopropylidene protected pyranoside was treated with benzyl trichloroacetimidate at room temperature to give a benzyl ether in 82% yield (eq 5).1,9

N-Containing Compounds from Imidates.

The synthetic procedure to make allyl trichloroacetimidate has been useful for other allylic imidate systems.1 For example, geraniol trichloroimidate is prepared by reacting geraniol with sodium hydride in ether. The cooled (-10 °C) solution is treated with Trichloroacetonitrile followed by work-up with a methanolic-pentane solution to give the corresponding imidate. Amines and amides are prepared from these intermediates. Thermal rearrangement of the imidate, followed by hydrolysis, gives rise to 1,3-transposition of hydroxyl and amino groups. The amine is produced in 61% yield (eq 6).4,10

Related imidates can undergo [3,3]-sigmatropic rearrangements by using a palladium(II) catalyst instead of heat. For example, an allyl trichloroacetimidate rearranges to the corresponding amide when catalyzed by Bis(benzonitrile)dichloropalladium(II) in THF (eq 7).11 The reaction goes in 8% yield with complete chirality transfer.

Allylic trichloroacetimidates undergo iodocyclization to give the corresponding 4,5-dihydro-1,3-oxazines. The regioselection of the reaction depends on the alkene geometry of the starting allyl imidate (eq 8).12

Imidates have been used in the synthesis of other organic systems, such as coupling reactions in carbohydrate synthesis13 and Claisen-type rearrangements (see also Trichloroacetonitrile).14

1. For a general review of allylic imidic esters in organic synthesis see Overman, L. E. ACR 1980, 13, 218.
2. Wessel, H.-P.; Iversen, T.; Bundle, D. R. JCS(P1) 1985, 2247.
3. (a) Cramer, F.; Pawelzik, K.; Baldauf, H. J. CB 1985, 91, 1049. (b) Cramer, F.; Hennrich, N. CB 1961, 94, 976.
4. (a) Overman, L. E. JACS 1974, 96, 597. (b) Overman, L. E. JACS 1976, 98, 2901.
5. Wessel, H.-P.; Bundle, D. R. JCS(P1) 1985, 2251.
6. Clark, J. S. TL 1992, 33, 6193.
7. Takano, S.; Akiyama, M.; Ogasawara, K. CC 1984, 770.
8. Burkholder, T. P.; Le, T.-B.; Giroux, E. L.; Flynn, G. A. BML 1992, 2, 579.
9. Iversen, T.; Bundle, D. R. CC 1981, 1240.
10. Clizbe, L. A.; Overman, L. E. OS 1978, 58, 4.
11. Metz, P.; Mues, C.; Schoop, A T 1992, 48, 1071.
12. Bongini, A.; Cardillo, G.; Orena, M.; Sandri, S.; Tomasini, C. JOC 1986, 51, 4905.
13. (a) Schmidt, R. R. PAC 1989, 61, 1257. (b) Schmidt, R. R.; Michel, J. AG(E) 1982, 21, 72. (c) Urban, F. J.; Moore, B. S.; Breitenbach, R. TL 1990, 31, 4421. (d) Paulsen, H. AG(E) 1982, 21, 155.
14. (a) Cramer, F.; Baldauf, H.-J. CB 1959, 92, 370. (b) Mumm, O.; Möller, F. CB 1937, 70, 2214. (c) Lauer, W. M.; Lockwood, R. G. JACS 1954, 76, 3974. (d) Lauer, W. M.; Benton, C. S. JOC 1959, 24, 804. (e) Roberts, R. M.; Hussein, F. A. JACS 1960, 82, 1950. (f) Black, D. St.C.; Eastwood, F. W.; Okraglik, R.; Poynton, A. J.; Wade, A. M.; Welker, C. H. AJC 1972, 25, 1483.

Mark R. Sivik

Procter & Gamble, Cincinnati, OH, USA

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