Lithium 1-Propanethiolate

n-PrSLi

[16203-40-0]  · C3H7LiS  · Lithium 1-Propanethiolate  · (MW 82.11)

(cleavage of the alkyl-oxygen bond of methyl esters under mild conditions;1 lithium thiolates have also been used for selective demethylation of aryl methyl ethers2 and quaternary ammonium salts3)

Preparative Methods: a 5.0 M stock solution in HMPA is typically used. Addition of n-Butyllithium to a stirred solution of freshly distilled 1-propanethiol in dry hexane at 0 °C is followed by stirring for 10 min. The resulting suspension is then concentrated in vacuo to dryness at 0 °C and dissolved in the appropriate amount of HMPA.4

Handling, Storage, and Precautions: the reagent is stored under argon at 0 °C. Contact with oxygen results in rapid oxidation of the thiolate. Propanethiol must be handled with care and used in a hood due to its strong odor. For most applications the reagent is prepared and stored in HMPA, a potent carcinogen; therefore due caution should be exercised when handling this reagent. Note that 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (N,N-Dimethylpropyleneurea; DMPU) has been used as a substitute for the more hazardous HMPA in applications of this reagent.5

Demethylation of Methyl Esters.

Lithium propanethiolate was introduced as a reagent for the mild deprotection of methyl esters in 1970.1 The reagent readily cleaves the alkyl-oxygen bond by an SN2 process.6 Due to this mechanism, the reagent offers advantages over conventional hydrolytic processes, particularly when the substrate carboxylate is sterically hindered or has additional functionality which is sensitive toward acid or base. For example, the sterically hindered ester methyl O-methylpodocarpate is readily cleaved to O-methylpodocarpic acid in quantitative yield at 25 °C in 1.5 h (eq 1). Additionally, methyl 3b-acetoxy-D5-etienate which contains both a hindered ester and a hydrolytically sensitive acetate functionality, is readily cleaved to the etianic acid in high yield without concomitant acetate cleavage (eq 2).1 It should be noted that the lithium thiolate in HMPA is superior to the sodium thiolate in DMF for methyl ester cleavage. Bartlett and Johnson report a rate enhancement for the cleavage of methyl mesitoate by a factor of 57.1

Additional examples include the cleavage of an acid-sensitive methyl gibberellate to afford gibberellic acid in high yield (eq 3),7 and the selective cleavage of a sterically hindered bridgehead ester in the presence of a pyridyl methyl ether to afford a late intermediate in the synthesis of (Z)-huperzine A (eq 4).8 Lithium propanethiolate will also selectively cleave vinylogous methyl esters in the presence of alkyl methyl esters. For example, in work related to the synthesis of chlorothricolide, the selective cleavage of a butenolide ester gave the corresponding ester acid in 79% yield (eq 5).4 This methodology has also been used to prepare tetronic acid analogs of thiolactomycin, and it is reported to be superior to other demethylating agents such as Iodotrimethylsilane9 and dilute acid hydrolysis.10

Demethylation of Aryl Methyl Ethers.

The demethylation of aryl methyl ethers using thiolate ion was also reported in 1970; a variety of anisoles were demethylated using sodium ethanethiolate in hot DMF to afford high yields of the corresponding phenols.2 Lithium propanethiolate has been used for this purpose; however, there appears to be no advantage over the sodium thiolate reagents as is seen with the cleavage of methyl esters. For example, the aryl methyl ether of O-methylpodocarpic acid (see eq 1) can be removed with lithium propanethiolate, but only at elevated temperatures.1 Another example for this class of reagents is the cleavage of a 7-methoxyindole using lithium butanethiolate in HMPA at 110 °C to afford the corresponding phenol in 88% yield (eq 6).11

Demethylation of Quaternary Ammonium Salts.

The selective demethylation of quaternary ammonium salts has also been accomplished using lithium propanethiolate.3 The method has been used to prepare a variety of unsymmetrical tertiary amines and is reported to give superior yields and selectivity over other reagents used for this purpose such as Lithium Aluminum Hydride, Sodium-Ammonia, thiophenoxide anion, or Lithium Iodide. For example, n-dodecyldimethylpropylammonium iodide is readily demethylated using lithium propanethiolate in HMPA at 50 °C after 3 h to afford n-dodecylmethylpropylamine in 99% yield (eq 7).


1. Bartlett, P. A.; Johnson, W. S. TL 1970, 4459.
2. Feutrill, G. I.; Mirrington, R. N. TL 1970, 1327.
3. Hutchins, R. O.; Dux, F. J. JOC 1973, 38, 1961.
4. Ireland, R. E.; Thompson, W. J. JOC 1979, 44, 3041.
5. Roush, W. R.; Madar, D. J. TL 1993, 34, 1553.
6. (a) Vaughan, W. R.; Baumann, J. B. JOC 1962, 27, 739. (b) For a review on ester cleavage via SN2 type dealkylation, see: McMurry, J. OR 1976, 24, 187. (c) For a review on protection of the carboxyl group, see: Haslam, E. T 1980, 36, 2409.
7. Corey, E. J.; Brennan, T. M.; Carney, R. L. JACS 1971, 93, 7316.
8. Kozikowski, A. P.; Yamada, F.; Tang, X.-C.; Hanin, I. TL 1990, 6159.
9. Gedge, D. R.; Pattenden, G. J.; Smith, A. G. JCS(P1) 1986, 2127.
10. Still, I. W. J.; Drewery, M. J. JOC 1989, 54, 290.
11. Toyota, M.; Fukumoto, K. JCS(P1) 1992, 547.

Gregory Merriman

Hoechst-Roussel Pharmaceuticals, Somerville, NJ, USA



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