N,N-Diethylaminosulfur Trifluoride1


[38078-09-0]  · C4H10F3NS  · N,N-Diethylaminosulfur Trifluoride  · (MW 161.18)

(mild reagent for converting primary, secondary, tertiary, allylic, and benzylic alcohols to the corresponding fluorides,1 aldehydes and ketones to difluorides,1a,15,19 carboxylic acids to acyl fluorides,22 and sulfoxides to a-fluoro sulfides23)

Alternate Name: DAST.

Physical Data: bp 30-32 °C/3 mmHg; d 1.220 g cm-3.

Solubility: sol ethereal, chlorinated, and hydrocarbon solvents; reacts violently with water and rapidly with hydroxylic solvents.

Form Supplied in: amber yellow oil; widely available.

Purification: discolored (brown) samples give increasingly lower yields of fluorinated products. Freshly distilled oil is satisfactory for use.

Handling, Storage, and Precautions: can be stored for extended periods of time in the freezer under inert atmosphere. Use in a fume hood.

Fluorodehydroxylation of Alcohols.

DAST, like several other variants of dialkylaminotrifluorosulfuranes, converts primary, secondary, tertiary, allylic, and benzylic alcohols to monofluorides.1 The reaction conditions are mild (temperature as low as -78 to 0 °C for reactive substrates), and a variety of functionalities such as acetonides, isolated double/triple bonds, esters, ethers, amides, and unactivated halides are tolerated (eqs 1-3).1b,8-10

The solvents usually employed are dichloromethane, chloroform, carbon tetrachloride, fluorotrichloromethane, ether, THF, benzene, and toluene. Generally, DAST is superior to classical fluorinating agents such as Sulfur Tetrafluoride in that the latter requires much higher temperatures (typically 100 °C) and gives undesired side products. With DAST, rearrangements are sometimes observed, albeit to a lesser extent (eq 4).1a,2,7 Thus b-elimination,1a ether formation,3 Friedel-Crafts alkylation,4 and skeletal rearrangements involving norbornyl cations5 have been reported. The DAST reaction with isobutyl alcohol yields a mixture of 49% isobutyl fluoride and 21% of t-butyl fluoride.1a Other functionalities can interfere with the normal course of reaction. A case in point is a pinacol rearrangement with concomitant ring contraction (eq 5).2a

SN2 rearrangement may occur on reacting DAST with allylic alcohols (eq 6).6

Highly varied stereochemical outcomes have been obtained in the reactions of DAST with secondary alcohols. Thus, although products of partial or complete racemization through ionic or ion-pair mechanisms1a have not been widely observed, the usual steric course is complete inversion or complete retention at the reaction center. An example is the formation of (-)-2-fluorooctane (97.6% optical purity) from (+)-S-2-octanol.30 On the other hand, a mixture of products of inverted and retained stereochemistry are obtained in the reaction of DAST with some protected myo-inositol derivatives (eq 7).11 Interestingly, in unprotected or minimally protected sugars,12a,b and inositols,12c,d where more than two hydroxy groups are present, only one or two hydroxy groups react regio- and stereoselectively (eq 8).12d

Several synthetically useful transformations involving neighboring group participation exist.13 An example is the reaction of DAST with N,N-dibenzyl-L-serine benzyl ester (eq 9).13b

Geminal Difluorination of Aldehydes and Ketones.

The carbonyl group of aldehydes and ketones can be converted to a 1,1-difluoro group in moderate to high yields.1a,8,14 The reaction conditions are mild (rt to 80 °C). The solvents generally used are dichloromethane and chloroform. Functional groups compatible with the fluorination of alcohols are also tolerated in the 1,1-difluorination of aldehydes and ketones (see above). An aldehyde carbonyl reacts much faster than a ketone carbonyl and selective difluorination of keto aldehydes at the aldehyde carbonyl has been reported.14 The general order of reactivity is alcohols > aldehydes > ketones. A variety of aliphatic,15 aromatic,1a and heterocyclic16 aldehydes have been converted to 1,1-difluorinated compounds (eqs 10-12).14b,18,19

While the reactivity of ketones is similar to aldehydes in scope, vinyl fluoride formation is a complication and sometimes DAST, in conjunction with fuming Sulfuric Acid in glyme,17a,b or a mixture of Lithium Chloride and Copper(II) Chloride,17b is used for the preparation of vinyl fluorides (eq 13).

b-Diketones and b-keto esters are oxidatively fluorinated with DAST to furnish a,b-difluoro-a,b-unsaturated ketones and esters, respectively (eq 14).20

Reaction with Epoxides.

The reactivity of DAST with epoxides varies with structure. Thus cyclopentene oxide and cyclohexene oxide give a mixture of 1,1-difluoro and bis(a-fluoro) ethers (eq 15).21 A stereospecific synthesis of meso- or (±)-difluorides has been accomplished in two steps using, respectively, cis- or trans-epoxides as starting materials (eq 16).22

Reaction with Organic Acids.

Acyl fluorides can be prepared by the reaction of DAST with carboxylic acids in good to excellent yields.23 a-Hydroxy acids give a-fluoroacyl fluorides which hydrolyze on workup to form a-fluoro acids.24 Sulfur tetrafluoride, on the other hand, converts the carboxylic group into a trifluoromethyl group.21

Reaction with Halides and Sulfonates.

Reactive halides such as iodides, allylic, and benzylic halides, and chlorides of organic acids (sulfinic, sulfonic, and phosphonic) react with DAST to form the corresponding fluorides.1a

Reaction with Sulfoxides.

DAST reacts with a-hydrogen containing dialkyl and aralkyl sulfoxides to form a-fluoroalkyl sulfides in high yields (eq 17).25 This reaction can be extended to less reactive sulfoxides by catalysis with certain Lewis acids, e.g. Antimony(III) Chloride (eq 18)26 and Zinc Iodide.27

Miscellaneous Reactions.

Lactones containing a-hydrogen or fluorine do not react with DAST. However, a-hydroxy lactones undergo normal fluorodehydroxylation along with geminal difluorination at the lactone carbonyl.28 Glycosyl fluorides can be obtained in high yield, and in a stereospecific manner, either by reacting DAST with hemithioacetals in the presence of N-Bromosuccinimide or, more simply, hemiacetals.29b An interesting fluorination of a phenyl ring of N-benzylphenylhydroxylamine has been reported (eq 19).30

An attempt to convert the C-7 hydroxy group of 7-epi-taxol to a fluoride failed. Instead, a high yield of a cyclopropanated product with A-ring contraction was obtained (eq 20). A cyclopropane intermediate corner-protonated at C-19 was postulated to explain this anomalous transformation.31

Related Reagents.

Pyridinium Poly(hydrogen fluoride); Sulfur Tetrafluoride.

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3. Gai, S.; Hakomori, S.; Toyokuni, T. JOC 1992, 57, 3431.
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11. Moyer, J. D.; Reizes, O.; Malinowski, N.; Jiang, C.; Baker, D. C. ACS Symp. Ser. 1988, 374, 43.
12. (a) Card, P. J.; Reddy, G. S. JOC 1983, 48, 4734. (b) Somawardhana, C. W.; Brunngraber, E. G. Carbohydr. Res. 1981, 94, C14. (c) Kozikowski, A. P.; Fauq, A. H.; Powis, G.; Melder, D. C. JACS 1990, 112, 4528. (d) Kozikowski, A. P.; Fauq, A. H.; Rusnak, J. M. TL 1989, 30, 3365.
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14. (a) Biollaz, M.; Kalvoda, J. Swiss Patent 616 433, 1980 (CA 1980, 93, 168 491e). (b) Campbell, J. A. U.S. Patent 4 416 822, 1983.
15. Markovskij, L. N.; Pashinnik, V. E.; Kirsanov, A. V. S 1973, 787.
16. (a) Kotick, M. P.; Polazzi, J. O. JHC 1981, 18, 1029. (b) Boswell, G. A., Jr.; Brittelli, D. R. U.S. Patent 3 919 204, 1975.
17. (a) Boswell, G. A., Jr. U.S. Patent 4 212 815, 1980 (CA 1980, 93, 239 789w). (b) Daub, W.; Zuckermann, R. N.; Johnson, W. S. JOC 1985, 50, 1599.
18. Boehm, M. F.; Prestwich, G. D. TL 1988, 29, 5217.
19. Ando, K.; Kondo, F.; Koike, F.; Takayama, H. CPB 1992, 40, 1662.
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22. Hamatani, T.; Matsubara, S.; Matsuda, H.; Schlosser, M. T 1988, 44, 2875.
23. Middleton, W. J. U.S. Patent 3 914 265, 1975.
24. Cantrell, G. L.; Filler, R. JFC 1985, 27, 35.
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26. Wnuk, S. F.; Robins, M. J. JOC 1990, 55, 4757.
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Abdul H. Fauq

Mayo Foundation, Jacksonville, FL, USA

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