Boron Trifluoride-Dimethyl Sulfide1

BF3.SMe2

[353-43-5]  · C2H6BF3S  · Boron Trifluoride-Dimethyl Sulfide  · (MW 129.93)

(reagent for the cleavage of benzyl ethers and carbamates)

Physical Data: solid at -78 °C, liquid at rt; Psatn(25 °C) 217 mmHg.2a

Solubility: sol most organic solvents such as pentane.

Form Supplied in: liquid complex sealed under nitrogen; commercially available.

Preparative Methods: made by the addition of equimolar amounts of the two components at -78 °C.2a Dissociation of the complex reported as 96.2% at 12 °C and 97.4% at 34 °C.2a Also formed when crystalline bromodimethylsulfonium tetrafluoroborate is aspirated at rt to give a colorless product without change in crystal form.2b The reagent system is normally assembled by adding a large excess of dimethyl sulfide to an excess of boron trifluoride etherate.2c

Handling, Storage, and Precautions: moisture-sensitive; use with carefully dried apparatus. All work must be carried out in an efficient fume hood.

Introduction.

A number of boron trifluoride-type reagents have been used for the cleavage of ethers and related compounds, and a review of the earlier work on ether cleavage exists.3 Carbon-oxygen bond cleavage using boron trifluoride combined with a sulfide or a thiol is based on the principle that a hard acid will interact with the oxygen and that the sulfur, being a soft nucleophile, will attack carbon. Small variations in the balance between the electrophilic and nucleophilic components can result in important changes in reactivity. Although the boron trifluoride-dimethyl sulfide complex is commercially available, the majority of the work reported has used Boron Trifluoride Etherate in combination with Dimethyl Sulfide.2c A number of related reagent systems are compared in this entry. It will be seen that, although boron trifluoride together with a thiol can cause ether cleavage, there are certain functionalities, notably the carbonyl group in aldehydes and ketones and the alkene residue in a,b-unsaturated esters, that are themselves reactive to the system. The reagent system Aluminum Chloride-Ethanethiol (or dialkyl sulfide) is much more reactive than the boron-based systems and is thereby less selective.4 For example, aluminum chloride in the presence of ethanethiol demethylates methyl ethers and cleaves methylenedioxy derivatives,4b but it also dehalogenates o- and p-bromoanisole in addition to cleaving the ether.4e Ethyl 4-bromobenzoate gives the acid in 92.5% yield using aluminum chloride-dimethyl sulfide.4d On the other hand, the system which uses aluminum chloride and Sodium Iodide in acetonitrile has been used to demethylate aliphatic methyl ethers selectively in the presence of phenolic methyl ethers.5 The use of aluminum chloride in the presence of N,N-dimethylaniline has been recommended recently as a reagent for the cleavage of benzyl and allyl ethers.6 The regioselective debenzylation of poly-O-benzylated monosaccharides has been achieved using Tin(IV) Chloride and Titanium(IV) Chloride. Three appropriately located metal chelating groups are necessary for selective debenzylation to proceed.7 Recent general reviews on the cleavage of ethers8 and on the chemical deprotection of esters9 have been published.

Dealkylation of Ethers.

The combination of an aliphatic thiol such as ethanethiol and boron trifluoride etherate has been used to remove benzyl groups. However, although that method works well it does suffer from an incompatibility with certain functional groups.2c The presence of an a,b-unsaturated ester in the same molecule can result in Michael addition as well as debenzylation (eq 1).10 Boron trifluoride in the presence of dimethyl sulfide, being a milder reagent, does not cause this type of complication, as shown in eq 2.11

It is clear that boron trifluoride in the presence of a thiol will convert an aldehyde or ketone into the related thioacetal. For example, 4-benzyloxyacetophenone is converted into the ethyl thioacetal of 4-hydroxyacetophenone in 84% yield by BF3.OEt2-EtSH, whereas using BF3.OEt2-Me2S gives 4-hydroxyacetophenone in 97% yield.2c The conversion of an acetal to a dithioacetal has also been reported using, for example 1,3-propanedithiol in the presence of BF3; also known is the conversion of a dithiane into the related acyclic dithioacetal by using an excess of Methanethiol and BF3.12 It has also been found that the double bond in substituted styrenes is cleaved by boron trifluoride etherate-ethanethiol when an electron-withdrawing group is present at the b-position (eq 3).13 It is of interest to note that, although the system using a thiol does not result in benzyl ester cleavage, the removal of an acetyl group from a highly functionalized pyrrole has been reported (eq 4).14

In a series of papers on the synthesis of benzopyrone derivatives, benzyl protection-deprotection of phenolic hydroxy groups has been a standard protocol.15 It should be noted that in this series the yields of the debenzylated products are poor unless the boron difluoride complex is preformed. The example (eq 5) shown is part of a fulvic acid synthesis.15c

In the example shown in eq 6, the benzylic ether is part of a ring.16 A number of other examples are recorded,17 including cases where complex functionality and stereochemistry are unaffected by the procedure, as illustrated in eq 7.18

The method has also been used successfully to remove the methoxymethyl (MOM) group (eqs 8 and 9),19,20 and should be compared once again with the use of boron trifluoride etherate-ethanedithiol (eq 10), which was used in a total synthesis of bruceantin.21

Cleavage of Benzyl Carbamates.

The removal of the benzyloxycarbonyl (Cbz) group from nitrogen can be achieved successfully using boron trifluoride etherate in the presence of either a thiol or dimethyl sulfide. The carbamates derived from secondary amines are cleaved more rapidly than those from primary amines using the ethanethiol method, even when using BF3.OEt2 as the solvent. The procedure allows reasonable selectivity, as shown in eq 11.10

In another interesting example, the removal of the Cbz protecting group and concomitant intramolecular 1,4-addition of the resulting amine to the spiroenone gave racemic dihydrooxocrinine in a single operation (eq 12).22

Related Reagents.

Boron Trifluoride-Acetic Acid; Boron Trifluoride-Acetic Anhydride; Boron Trifluoride Etherate; Boron Trifluoride; Dimethyl Sulfide; Tetrafluoroboric Acid.


1. For a general review of the boron trihalides and their addition complexes, see: Greenwood, N. N., Thomas, B. S. In Comprehensive Inorganic Chemistry; Trotman-Dickenson, A. F., Ed.; Pergamon: New York, 1973; Vol. 1, pp 956-973.
2. (a) Graham, W. A. G.; Stone, F. G. A. J. Inorg. Nucl. Chem. 1956, 3, 164; for a preliminary report, see: CI(L) 1956, 319. (b) Böhme, H.; Boll, E. Z. Anorg. Allg. Chem. 1957, 290, 17. (c) Fuji, K.; Kawabata, T.; Fujita, E. CPB 1980, 28, 3662.
3. Meerwein, H. MOC 1965, 6/3, 143.
4. (a) Node, M.; Nishide, K.; Sai, M.; Fujita, E. TL 1978, 5211. (b) Node, M.; Nishide, K.; Sai, M.; Ichikawa, K.; Fuji, K.; Fujita, E. CL 1979, 97. (c) Node, M.; Nishide, K.; Fuji, K.; Fujita, E. JOC 1980, 45, 4275. (d) Node, M.; Nishide, K.; Sai, M.; Fuji, K.; Fujita, E. JOC 1981, 46, 1991. (e) Node, M.; Kawabata, T.; Ohta, K.; Fujimoto, M.; Fujita, E.; Fuji, K. JOC 1984, 49, 3641.
5. Node, M.; Ohta, K.; Kajimoto, T.; Nishide, K.; Fujita, E.; Fuji, K. CPB 1983, 31, 4178.
6. Akiyama, T.; Hirofuji, H.; Ozaki, S. BCJ 1992, 65, 1932.
7. Hori, H.; Nishida, Y.; Ohrui, H.; Meguro, H. JOC 1989, 54, 1346.
8. Bhatt, M. V.; Kulkarni, S. U. S 1983, 249.
9. Salomon, C. J.; Mata, E. G.; Mascaretti, O. A. T 1993, 49, 3691.
10. Fuji, K.; Ichikawa, K.; Node, M.; Fujita, E. JOC 1979, 44, 1661.
11. Danishefsky, S. J.; Pearson, W. H.; Harvey, D. F. JACS 1984, 106, 2455.
12. Sánchez, I. H.; Soria, J. J.; López, F. J.; Larraza, M. I.; Flores, H. J. JOC 1984, 49, 157.
13. (a) Fuji, K.; Kawabata, T.; Node, M.; Fujita, E. TL 1981, 22, 875. (b) JOC 1984, 49, 3214.
14. Smith, K. M.; Langry, K. C. CC 1981, 283.
15. (a) Yamauchi, M.; Katayama, S.; Nakashita, Y.; Watanabe, T. CC 1983, 335. (b) Yamauchi, M.; Katayama, S.; Nakashita, Y.; Watanabe, T. JCS(P1) 1985, 183. (c) Yamauchi, M.; Katayama, S.; Todoroki, T.; Watanabe, T. JCS(P1) 1987, 389. (d) Yamauchi, M.; Katayama, S.; Watanabe, T. JCS(P1) 1987, 395.
16. Hashigaki, K.; Yoshioka, S.; Yamoto, M. S 1986, 1004.
17. (a) Bonjoch, J.; Casamitjana, N.; Quirante, J.; Rodríguez, M.; Bosch, J. JOC 1987, 52, 267. (b) Engler, T. A.; Combrink, K. D.; Ray, J. E. JACS 1988, 110, 7931. (c) Yadav, J. S.; Sreenivasa Rao, E.; Sreenivasa Rao, V. SC 1989, 19, 705. (d) Engler, T. A.; Reddy, J. P.; Combrink, K. D.; Vander Velde, D. JOC 1990, 55, 1248. (e) Diez, A.; Vila, C.; Sinibaldi, M.-E.; Troin, Y.; Rubiralta, M. TL 1993, 34, 733.
18. Ohtsuka, Y.; Niitsuma, S.; Tadokoro, H.; Hayashi, T.; Oishi, T. JOC 1984, 49, 2326.
19. Kawabata, T.; Kimura, Y.; Ito, Y.; Terashima, S.; Sasaki, A.; Sunagawa, M. T 1988, 44, 2149.
20. Sugiyama, S.; Honda, M.; Higuchi, R.; Komori, T. LA 1991, 349.
21. Sasaki, M.; Murae, T.; Takahashi, T. JOC 1990, 55, 528.
22. Sánchez, I. H.; López, F. J.; Soria, J. J.; Larraza, M. I.; Flores, H. J. JACS 1983, 105, 7640.

Harry Heaney

Loughborough University of Technology, UK



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