Isopropenyl Acetate1

[108-22-5]  · C5H8O2  · Isopropenyl Acetate  · (MW 100.13)

(conversion of carbonyl compounds to their enol acetates;5 acetylation of oxygen,12 nitrogen,14 and carbon;12a acetone equivalent in Lewis acid catalyzed aldol reactions;15 conversion of malonic acids to their isopropylidene derivatives17)

Physical Data: bp 97 °C;2 d 0.909 g cm-3; fp 18 °C.

Solubility: sol benzene, acetic acid.

Form Supplied in: 99 and 99+% pure liquid widely available.

Analysis of Reagent Purity: the acetone content may be determined by addition of an excess of Hydroxylamine hydrochloride to an ethanolic solution, followed by back titration against sodium hydroxide.3

Handling, Storage, and Precautions: flammable liquid; mild irritant; narcotic in high concentrations. LD50 orally in rats: 3.0 g kg-1.4

Enol Acetylation.

In the presence of catalytic acid, isopropenyl acetate reacts with enolizable ketones to give the enol acetate plus acetone. This reactivity has been exploited to accomplish selective enolization of ketones, and to provide dienol acetates for Diels-Alder reactions. Each of these reactions is described in more detail in the following sections.

Selective Generation of Kinetic and Thermodynamic Enol Acetates.

While the use of isopropenyl acetate with catalytic acid is considered to provide conditions for the generation of kinetic enols, the ratio of kinetic to thermodynamic isomers obtained for a given enolizable ketone appears to be highly dependent on the individual system being studied. For example, in steroid chemistry, isopropenyl acetate has been used to provide significant yields of the kinetic D2-enol (2) over the thermodynamically favored D3-enol (3) (eq 1).5 For comparison, the results of the corresponding thermodynamically controlled enol acetylation reaction using perchloric acid catalyst and Acetic Anhydride are also given.

As shown in eq 1, introduction of an 11b-hydroxy group causes a 16-18% increase in the amount of the kinetic D2-enol acetate (2) regardless of the reaction conditions. Additionally, enol acetylation proceeds with concomitant acetylation of the 11b-hydroxy group under these same reaction conditions. While these conditions provide only a moderate predilection for formation of the kinetic enol acetate in the cases presented above, other related systems have shown excellent selectivity utilizing this method.6,7

Selective Generation of (E)- or (Z)-Enol Acetates.

The (E)- and (Z)-enol acetates of b-keto esters can be selectively generated by careful choice of acetylation conditions.8 Under acidic conditions isopropenyl acetate gives, almost exclusively, the (Z) isomer (6a) (eq 2). This selectivity is believed to arise because the reactive form of methyl acetoacetate under acidic conditions is the internally hydrogen bound (Z)-enol (5) (eq 2). Alternatively, the corresponding (E)-enol acetate (6b) may be selectively generated under basic conditions utilizing Acetyl Chloride as the acetylating agent (eq 3). The selectivity in this reaction is believed to be due to the solvent-separated ion (7) generated in Hexamethylphosphoric Triamide and Triethylamine. For the anion (7), the (E) conformation places the negatively charged oxygen atoms at a maximum separation.

The use of isopropenyl acetate and catalytic acid for the formation of dienol acetates from a,b-unsaturated aldehydes and ketones is known to favor the formation of the (E) isomer (10a) (eq 4).9 For the enolization of Crotonaldehyde (8) the reaction gives 1-acetoxy-1-propene (10) as an 83:17 (E:Z) mixture. This selectivity is credited to the intermediacy of cation (9) in this process. Cation (9b), which would lead to the (Z) isomer (10b), is disfavored due to an unfavorable steric interaction between the vinyl and acetoxy groups (eq 5).

Dienol Acetates for the Diels-Alder Reaction.

Wolinsky and Login10 found that the methodology described above allows for the in situ generation of reactive dienes for use in Diels-Alder reactions (eqs 6 and 7). The enol acetate of 2-methyl-2-butenone (11) is generated by reaction with isopropenyl acetate and p-Toluenesulfonic Acid. In the presence of Dimethyl Acetylenedicarboxylate (DMAD), the resulting diene undergoes a cycloaddition reaction, giving, after loss of acetic acid, the phthalic acid derivative (12) in 80% yield (eq 6). Similarly, crotonaldehyde (8) is converted to 1-acetoxy-1-propene (10), as shown in eq 4. Diene (10) is then trapped with chloromaleic anhydride (13). Loss of acetic acid and HCl gives phthalic anhydride (14) in 70% yield (eq 7).

Acetylation of Other O, N, and C Centers.

In addition to the preparation of enol acetates from ketones, isopropenyl acetate has also seen use in the acetylation of other O, N, and C centers. Hydroxy acetylation was first noted11 as a simultaneous reaction occurring during the enol acetylation of steroids bearing unprotected hydroxy groups (eq 1). The reagent has since been used more deliberately for the protection of alcohols.12 More recently the reagent has been used in conjunction with enzymes to afford chiral acylated material.13 Kaupp and Matthies14 were surprised to observe N-acetylation of the benzothiazepine derivative (15) with no formation of the isomer (17) (eq 8). Attempts by the authors to generate the expected isomer (17) were unsuccessful.

The 5-position of some N-methylpyrrole derivatives (18) were successfully acetylated using isopropenyl acetate in the presence of catalytic acid under refluxing conditions (eq 9).12a

Aldol Reactions.

Isopropenyl acetate participates in some aldol-type reactions. This enol ester, like enol ethers, can react with various acetals (20) in the presence of a Lewis acid to afford the aldol-type addition products (21 and 22) (eq 10).15 This same reactivity is observed in the condensation of Succinic Anhydride with isopropenyl acetate.16

Isopropenyl Acetate as a Source of Acetone.

Under certain reaction conditions, isopropenyl acetate reacts to deliver an equivalent of acetone for acetonide formation or for oxidative addition to an enol. Under acidic conditions, isopropenyl acetate has been used to generate isopropylidene derivatives of malonic acids.17 Isopropenyl acetate also undergoes an oxidative addition reaction with ketones in the presence of Manganese(III) Acetate.18 An acetone subunit is added to the a-position of a ketone to give a 1,4-diketone.

Related Reagents.

Acetic Anhydride.

1. Hagemeyer, H. J., Jr.; Hull, D. C. Ind. Eng. Chem. 1949, 41, 2920.
2. The Merck Index, 11th ed.; Budavari, S., Ed.; Merck: Rahway, NJ, 1989; p 5092.
3. Jeffery, E. A.; Satchell, D. P. N. JCS 1962, 1876.
4. Smyth, H. F., Jr.; Carpenter, C. P.; Weil, C. S. J. Ind. Hyg. Toxicol. 1949, 31, 60.
5. Liston, A. J.; Howarth, M. JOC 1967, 32, 1034.
6. Nemoto, H.; Kurobe, H.; Fukumoto, K.; Kametani, T. JOC 1986, 51, 5311.
7. Bold, G; Chao, S.; Bhide, R.; Wu, S.-H.; Patel, D. V.; Sih, C. J.; Chidester, C. TL 1987, 28, 1973.
8. Casey, C. P.; Marten, D. F. TL 1974, 925.
9. Fukuda, W.; Sato, H.; Kakiuchi, H. BCJ 1986, 59, 751.
10. Wolinsky, J; Login, R. B. JOC 1970, 35, 3205.
11. Villotti, R.; Ringold, H. J.; Djerassi, C. JACS 1960, 82, 5693. The experimental data are cited by Djerassi, C. Steroid Reactions; Holden-Day: San Francisco, CA, 1963; p 41.
12. (a) Gizur, T.; Harsanyi, K. SC 1990, 20, 2365. (b) Shiao, M.-J.; Lin, J. L.; Kuo, Y.-H.; Shih, K.-S. TL 1986, 27, 4059. (c) Alarcon, P.; Pardo, M.; Soto, J. L. JHC 1985, 273. (d) Pauluth, D.; Hoffmann, H. M. R. LA 1985, 403.
13. Asensio, G.; Andreu, C.; Marco, J. A. CB 1992, 2233.
14. Kaupp, G.; Matthies, D. CB 1987, 1741.
15. Mukaiyama, T.; Izawa, T.; Saigo, K. CL 1974, 323.
16. (a) Merenyi, F.; Nilsson, M. ACS 1963, 17, 1801; 1964, 18, 1368; Nilsson, M. ACS 1964, 18, 441. (b) Merenyi, F.; Nilsson, M. OS 1972, 52, 1.
17. (a) Davidson, D.; Bernhard, S. A. JACS 1948, 70, 3426. (b) Singh, R. K.; Danishefsky, S. OS 1981, 60, 66. (c) Maier, G.; Wolf, B. S 1985, 871.
18. Dessau, R. M.; Heiba, E. I. JOC 1974, 39, 3457.

Michael A. Walters & Melissa D. Lee

Dartmouth College, Hanover, NH, USA

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