Thiolacetic Acid

[507-09-5]  · C2H4OS  · Thiolacetic Acid  · (MW 76.13)

(addition to a,b-unsaturated carbonyl compounds; radical additions to alkenes and alkynes; chiral dithioacetal formation; selective acylating agent; SN2 substitutions to make thiolesters)

Physical Data: bp 88-91.5 °C; d 1.065 g cm-3.

Solubility: sol hot H2O, alcohol.

Form Supplied in: light yellow liquid (impurity: acetic acid).

Purification: fractional distillation.

Handling, Storage, and Precautions: use only in fume hood. Wear protective clothing such as safety goggles and chemical-resistant gloves. Harmful if swallowed, inhaled, or absorbed through the skin. Corrosive. Lachrymator. Flammable. Stench. May develop pressure. Refrigerate. Forms explosive mixtures in air. Vapor may travel considerable distance to source of ignition and flash back. Incompatible with oxidizing agents and strong bases.

Conjugate Addition to a,b-Unsaturated Carbonyl Compounds.

The addition of thiolacetic acid to a,b-unsaturated aldehydes, ketones, and carboxylic acids and their derivatives occurs at the b-position, regardless of whether the mechanism is radical or ionic in nature.1 Stereoselective addition to the less hindered face of the double bond is observed in cases in which there is an inherent facial preference. A representative example is the addition of thiolacetic acid to a D1,2-3-oxo steroid (1) to give the product in which the acylthio substituent is in the a-configuration (eq 1).2

A more recent example by Bartmann3 is the addition of thiolacetic acid to the unsaturated lactone (2) to give exclusively the (R) configuration at the newly formed stereogenic center (eq 2). The enoate double bond undergoes reaction preferentially to the conjugated diene portion of the molecule, but with longer reaction times and an excess of reagent (25 °C, 2 days, 1.7 equiv MeCOSH, 0.2 equiv Et3N), the 1,4-addition products (3) and (4) are also obtained.

Asymmetric induction in the addition of thiolacetic acid to cyclic and acyclic enones and to a,b-unsaturated mono- and diesters has been investigated by Gawronski and co-workers.4 Of the catalysts studied, the cinchona alkaloids are the most effective. The enantiomeric excess in the reaction of thiolacetic acid with cyclohexenone increases from the 50% to the 60% range with variations of catalyst structure and concentration (eq 3).4a,4c It was also found that under standard conditions (1 mol % cinchonine), alteration of the thiolacid structure improves enantiomeric excesses, with cyclohexanethiolcarboxylic acid and t-butyl thiolcarboxylic acid giving the highest ee's (68% and 64%, respectively).

Acyclic enals and enones which differ in conformation due to steric demands of the ketone alkyl group give products with different absolute configurations at the newly formed stereogenic center.4d Thus cinnamaldehyde (5a), which exists predominantly in the s-trans conformation, gives the (S)-product due to si-face attack on the alkene, while benzylideneacetophenone (5b) in the s-cis conformation gives the (R)-product of re-face attack (eqs 4 and 5).

Although absolute configurations can be assigned using circular dichroism, enantiomeric excesses cannot be determined due to product degradation during acetal formation (for a description of this method of determining ee's, see Wynberg.22) The stereochemical outcome of these reactions is rationalized by the transition state complex of enone, thiolacetic acid, and cinchonine in which the cinchonine is in the preferred gauche conformation and is hydrogen-bonded to the enone carbonyl group. Thiolacetate and protonated quinuclidine base form an ion pair, and the si- and re-face attacks of s-trans and s-cis enones, respectively, can be visualized (eq 6).

a,b-Unsaturated mono- and diesters are also subject to asymmetric addition of thiolacetic acid in the presence of cinchona catalysts, but to a lesser degree.4b Derivatives of 2-methylpropenoic acid are used in the monoester cases, and best results are obtained with S-alkyl thiolesters, which give only a 27% enantiomeric excess (eq 7). In the diester cases, the degree of asymmetric induction is difficult to ascertain due to cis/trans isomerization of the substrates. Qualitatively, however, these results indicate that cis-butenedioates enhance the ee's of products and that small alkoxy substituents (such as OEt) result in higher diastereoselectivity of the addition to the cis/trans isomers. It should be noted that asymmetric induction of chirally derivatized a,b-unsaturated mono- and diesters has been attempted by Yoshihara et al.,5 but gives poor results in comparison to Gawronski's work. Using (-)-menthol as a chiral auxiliary, enantiomeric excesses of 15-18% for monoesters and 12% for diesters are obtained in the best cases.

Thiolacetic acid has also been utilized as an enone protecting group.6 Although few addition products in this study are formed in good yields, an interesting example is the protection of the dienone macrolide (6) (eq 8), which does give a good yield of the (11S)-11-acetylthio derivative (7), along with 3% of the (11R) derivative and 16% of recovered (6). It is interesting to note that in no instance is addition to the terminal position of the dienone observed. Deprotection of (7) with Tetra-n-butylammonium Fluoride to regenerate the dienone presumably occurs smoothly, although no yield is given.

Radical Additions to Alkenes and Alkynes.

Thiolacetic acid typically adds to unsymmetrical alkenes in an anti-Markovnikov sense,7 although exceptions have been noted in cases in which the anti-Markovnikov intermediate C-radical is less stable than the Markovnikov C-radical.8 The addition of thiolacetic acid to cyclic alkenes is stereoselective,7 with trans addition to obtain the cis product preferred over cis addition to obtain the trans product in additions to both cyclohexenes and cyclopentenes (eq 9).9

The addition of thiolacetic acid to acyclic alkenes is generally nonstereoselective, but attempts have been made to induce asymmetry through the use of chiral additives.10 In the presence of (-)-menthol or deoxycholic acid (DCA) and Azobisisobutyronitrile (AIBN), 2-octene gives addition products (8) and (9) (eq 10) with ee's of 28% with (-)-menthol and 7% with DCA for compound (8). Although the absolute configuration of (8) was determined to be (S), no such determination was made for (9), and no ee's for (9) were reported.

Radical addition of thiolacetic acid to alkenes is the key step in a preparation of alkanesulfonic acids developed by Swern and co-workers (eq 11).11 This method is nonideal for complex or sensitive substrates, however, and a much milder method has been reported by Musicki (eq 12)12 which employs a-lithio sulfonates. Subsequent hydrolysis of the sulfonate ester (10) gives the sulfonate (11), which can then be coupled with other ribose units.

Thiolacetic acid adds readily to alkynes to give mono- and bis-adducts. If the alkyne is monosubstituted, anti-Markovnikov regioselectivity is observed in the monoadduct. Varying yields of both the mono- and bis-products are obtained, depending on the structure of the alkynyl substrate and the amount of thiolacetic acid added, and yields are often improved by the addition of initiators, such as peroxide.13,1b Monoadducts can be further transformed into aldehyde equivalents such as semicarbazones (12) (eq 13), which are synthetically useful intermediates.

A more recent method that is much milder and potentially more useful is the conversion of ethynyl carbinols into a,b-unsaturated aldehydes via a two-step Meyer-Schuster rearrangement (eq 14).14 This method employs Thiophenol rather than thiolacetic acid. The (E/Z) ratio of the a,b-unsaturated aldehyde products range from 94/6 to 66/34, depending on the reaction conditions.

Use in the Formation of Chiral Dithioacetals.

Mixed acyl dithioacetals (13) have been prepared in good yield by the reaction of an aldehyde, a thiol, and thiolacetic acid in the presence of an acid catalyst (eq 15).15a These compounds can then be hydrolyzed and alkylated to give chiral dithioacetals (14), which are key functional groups in a series of potent and specific leukotriene D4 antagonists developed by Gauthier et al.15 Highest yields of the acyldithioacetals (13) are obtained with Zinc Iodide as the catalyst in refluxing dichloromethane for 2 h (86-91%). Deacylation with Potassium Carbonate, Sodium Methoxide, or Methyllithium, followed by alkylation at low temperature (-10 to -80 °C), gives chiral dithioacetals (14) in good yield (86-97%). As an extension of this method, optically active dithioacetals can be prepared by use of a chiral thiolacid which renders the intermediate acyl dithioacetals diastereomeric and, thus, separable. Each diastereomer can then be further reacted to yield an optically active dithioacetal (14) with no loss of configurational purity.15b,c

As an Acylating Agent.

Thiolacetic acid is not generally used as an acylating agent. It has been employed to acylate aromatic amines16 and thiols,17a,b but in these cases there is no distinct advantage of thiolacetic acid over more commonly used acylating agents such as acid chlorides and anhydrides. Thiolacetic acid has the capability, however, of selectively acylating certain functional groups in the presence of others. For example, van Montagu et al.18 selectively acylated the primary amino group of a cytidine moiety in the presence of a primary alcohol (eq 16). Acylation of alcohols will occur but typically requires forcing conditions. This is a common side reaction when thiolacetic acid is employed in 1,4-addition to enones containing alcohol groups.2,5 Chemoselective reductive acylation of azides has also been observed with thiolacetic acid (eq 17).19

SN2 Substitutions of Halides and Activated Alcohols.

Just as in the case of carboxylic acids, thiolacetic acid can be successfully used to effect Mitsunobu-type substitutions of secondary alcohols to give thioesters with inversion of configuration at the carbinol center (eq 18).20 SN2 substitution by thiolacetic acid of a-glycosides, activated at the anomeric position, has been observed by several groups (eqs 19 and 20).21 In all cases, the b-thioglycoside product predominates.

1. (a) Brown, R.; Jones, W. E.; Pinder, A. R. JCS 1951, 2123. (b) Stacy, F. W.; Harris, J. F., Jr. OR 1963, 13, 165.
2. Dodson, R. M.; Tweit, R. C. JACS 1959, 81, 1224.
3. Bartmann, W.; Beck, G.; Granzer, E.; Jendralla, H.; v. Kerekjarto, B.; Wess, G. TL 1986, 27, 4709.
4. (a) Gawronski, J.; Gawronska, K.; Wynberg, H. CC 1981, 307. (b) Gawronski, J.; Gawronska, K.; Kolbon, H. RTC 1983, 102, 479. (c) Brzostowska, M.; Gawronski, J. M 1984, 115, 1373. (d) Gawronski, J.; Brzostowska, M.; Radocki, D. Pol. J. Chem. 1992, 66, 457.
5. (a) Yoshihara, M.; Fujihara, H.; Maeshima, T. CL 1980, 195. (b) Nozaki, K.; Yoshihara, M.; Matsubara, Y.; Maeshima, T. PS 1985, 22, 1.
6. Fishman, A.; Mallams, A.; Mohindar, S.; Rossman, R.; Stephens, R. JCS(P1) 1987, 1189.
7. Stacy, F. W.; Harris, J. F., Jr. OR 1963, 13, 165, and references cited therein.
8. Schierhorn, A.; Adam, G.; Kutschabsky, L.; Leibnitz, P. JCS(P1) 1987, 2111.
9. Bordwell, F. G.; Hewett, W. A. JACS 1957, 79, 3493.
10. Yoshihara, M.; Fujihara, H.; Yoneda, A.; Maeshima, T. CL 1980, 39.
11. Showell, J. S.; Russell, J. R.; Swern, D. JOC 1962, 27, 2853.
12. Musicki, B.; Widlanski, T. JOC 1990, 55, 4231.
13. Bader, H.; Cross, L. C.; Heilbron, Sir I.; Jones, E. R. H. JCS 1949, 619.
14. Julià, M.; Lefebvre, C. TL 1984, 25, 189.
15. (a) Gauthier, J. Y.; Henien, T.; Lo, L.; Thérien, M.; Young, R. N. TL 1988, 29, 6729. (b) Thérien, M.; Gauthier, J. Y.; Young, R. N. TL 1988, 29, 6733. (c) Young, R. N.; Gauthier, J. Y.; Thérien, M.; Zamboni, R. H 1989, 28, 967.
16. Blodinger, J. JACS 1952, 74, 5514.
17. (a) Wilson, I. B. JACS 1952, 74, 3205. (b) Walton, E.; Wilson, A. N.; Holly, F. W.; Folkers, K. JACS 1954, 76, 1146.
18. van Montagu, M.; Molemans, F.; Stockx, J. BSB 1968, 77, 171.
19. Rosen, T.; Lico, I.; Chu, D. JOC 1988, 53, 1581.
20. (a) Volante, R. P. TL 1981, 22, 3119. (b) Corey, E. J.; Cimprich, K. A. TL 1992, 33, 4099.
21. (a) Bonner, W. JACS 1951, 73, 2659. (b) Priebe, W.; Grynkiewicz, G.; Neamati, N. TL 1991, 32, 2079. (c) Li, Z.-J.; Liu, P.-L.; Li, Z.-J.; Qiu, D.-X.; Cai, M.-S. SC 1990, 20, 2169.
22. Wynberg, H. JACS 1981, 103, 417.

Jeannie R. Phillips

University of Wisconsin, Madison, WI, USA

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