Process optimization

Dialkylaminodifluorosulfinium Marc-Olivier Turcotte-Savard tetrafluoroborate salts: synthesis and applications

MARC-OLIVIER TURCOTTE-SAVARD1*, OLIVIER MAHÉ2, JEAN-FRANÇOIS PAQUIN2 *Corresponding author 1. OmegaChem, 480, Rue Perreault, Lévis, QC, G6W 7V6, Canada 2. Université Laval, Département de chimie, Canada Research Chair in Organic and Medicinal Chemistry, CCVC, PROTEO, 1045 avenue de la Médecine, Québec, QC, G1V 0A6, Canada

various fluoride ion acceptors (PF , SeF , SbF and AsF ) along KEYWORDS 5 4 5 5 with DAST-type reagents (7 - 10). However, the reactivity of these Organofluorine chemistry; deoxyfluorination; salts has been scarcely studied until 2009. C-F bond; XtalFluor; dialkylaminodifluorosulfinium Recently, a one-pot preparation of diethylaminodifluorosulfinium tetrafluoroborate salts tetrafluoroborate has been developed. Hence, the addition of THF•BF3 adduct to crude DAST, previously formed from SF4 in ABSTRACT CH2Cl2 and N,N-diethyltrimethylsilylamine, resulted in 90% yield of diethylaminodifluorosulfinium tetrafluoroborate 1 (4). The solid The syntheses of dialkylaminodifluorosulfinium obtained was under a different polymorphic form with higher tetrafluoroborate salts are described. These reagents, melting point (89.8°C vs. 74-76°C) and lower moisture sensitivity first used for the deoxyfluorination of alcohols, compared to the first polymorph reported by Markovskii (5). were also shown to fluorinate aldehydes, ketones, carboxylic acids and glycosyl groups. Alternatively, dialkylaminodifluorosulfinium tetrafluoroborate salts were 14 recently shown to act as activating agents for hydroxyl, carbonyl and carboxyl groups in a variety of transformations leading to non-fluorinated products.

Scheme 1.

INTRODUCTION Similarly, addition of boron trifluoride etherate to an ice cold solution of crude morpholinosulfur trifluoride gave an excellent ith 30 to 40% of agrochemicals and 20 to 25% of yield of the corresponding tetrafluoroborate salt 2 (4). pharmaceutical compounds bearing at least one atom Wof fluorine (1), the development of efficient fluorination methods is a highly active field of research within organic synthesis. Deoxyfluorination represents a valuable strategy to insert fluorine atoms on organic compounds (2). However, deoxyfluorination agents are often hygroscopic, unstable, toxic, hazardous and/or non-selective towards fluorination. Dialkylaminodifluorosulfinium Scheme 2. tetrafluoroborate salts (3) were developed as cost effective, safer and more efficient deoxyfluorination reagent when used in DAST was found to react exothermically with tetrafluoroboric conjunction with an appropriate base or fluoride additive (4, 5). acid to form diethylaminodifluorosulfinium tetrafluoroborate Since their first uses, researchers have discovered a number of 1 with elimination of HF. Triflic acid was also reacted with alternate applications for these reagents, such as DAST, thus giving rise to the first dialkylaminodifluorosulfinium cyclodehydration, hydroxyl, carboxyl and glycosyl derivatives triflate salt 3 (5). activation towards substitution, thus broadening the field of action of these practical and inexpensive salts.

Preparation of Dialkylaminodifluorosulfinium Tetrafluoroborate Salts

Markovskii et al. first reported the formation of dialkylaminodifluorosulfinium tetrafluoroborate salts by reacting dialkylaminosulfur trifluoride and its analogues with boron

trifluoride etherate (6). Since then, other Scheme 3. dialkylaminodifluorosulfinium salts have been synthesized using

Chimica Oggi - Chemistry Today - vol. 31(4) July/August 2013 Process optimization

A variety of other dialkylaminodifluorosulfinium salts were also Cyclooctanol was converted in good yield to cyclooctyl prepared, analyzed and their reactivity was studied (11, 12). fluoride with a high fluoro/alkene ratio, using a mixture of However, 1 and 2 were preferred and commercialized. diethylaminodifluorosulfinium tetrafluoroborate and triethylamine dihydrogen fluoride at a low temperature (5).

Scheme 7.

(R)-benzyl-3-hydroxypyrrolidine-1-carboxylate 9 was converted to 10 with inversion of configuration and minimal loss of Scheme 4. enantiomeric excess by a combination of diethylaminodifluorosulfinium tetrafluoroborate and DBU (5). Although dialkylaminodifluorosulfinium salts remain Other combinations of reagents gave lower yields, poorer somewhat hygroscopic and moisture sensitive (13), they are fluoro/alkene selectivities, but gave complete inversion and relatively stable solids, as opposed to most of their minimal loss of enantiomeric excess. On the basis of these dialkylaminodifluorosulfur trifluoride counterparts, which are results, both DBU and triethylamine xHF promoted fluorinations fuming liquids that degrade over time and display significant proceeded in an SN2 fashion. moisture sensitivity (14 - 17). Dialkylaminodifluorosulfinium salts are relatively inexpensive and are not subject to the stringent shipping restrictions that apply to DAST and SF4, which makes them a reagent of choice available worldwide, even in remote areas.

DeoxyfluorinatinG AGENT

Dialkylaminodifluorosulfinium tetrafluoroborate salts were initially Scheme 8. developed as a suitable replacement for previous 15 deoxyfluorination reagent. They were found to react appropriately as nucleophilic fluorination reagents with a variety The deoxyfluorination of androstenolone was achieved in 77% of oxygen-containing molecules when used in conjunction with yield using a combination of diethylaminodifluorosulfinium proper additives. tetrafluoroborate and 4 equivalents of triethylamine trihydrogen fluoride (5). No elimination byproducts were observed under Alcohols these conditions. Hydrocinnamyl alcohol 4 was fluorinated in a high yield (93%) using a combination of diethylaminodifluorosulfinium tetrafluoroborate and triethylamine trihydrogen fluoride (5).

Scheme 9.

Diethylaminodifluorosulfinium tetrafluoroborate, with DBU as an additive, were the optimal reagents for the deoxyfluorination of Scheme 5. 2-hydroxy-2-methyl-1-phenylpropan-1-one, giving a moderate fluoro/alkene product ratio of 4.1:1 in high yield (93%) (5). Deoxyfluorination of secondary alcohol 6 using diethylaminodifluorosulfinium tetrafluoroborate and DBU gave a complete conversion of 6, 72% of admixed 7 and 8 in a moderate 6.25:1 ratio (5).

Scheme 10.

Scheme 6. Morpholinodifluorosulfinium tetrafluoroborate enabled the deoxyfluorination of 2-hydroxy-2-methyl-1-phenylpropan-1-one

Chimica Oggi - Chemistry Today - vol. 31(4) July/August 2013 Process optimization

in better yield (72%) and higher selectivity (21:1) than derivatives in generally good to excellent yields (5). diethylaminodifluorosulfinium tetrafluoroborate under the same Monofluoroalkenes were sometime observed as a minor conditions (64%, 12:1) (5). The two previous examples, along with elimination byproduct. this one, demonstrate that alcohols were successfully fluorinated in the presence of a remote carbonyl group in high yields. However, several secondary and tertiary alcohols were shown to form alkenes as minor elimination byproducts when submitted to deoxyfluorination conditions using dialkylaminodifluorosulfinium tetrafluoroborate salts.

Scheme 11.

Deoxyfluorination of geraniol 11, an allylic alcohol, using Scheme 14. morpholinodifluorosulfinium tetrafluoroborate, exclusively

formed the SN2’ type fluorinated product in an 88% yield (5). The same product was obtained (90%) when using A one-pot procedure using dialkylaminodifluorosulfinium diethylaminodifluorosulfinium tetrafluoroborate under similar tetrafluoroborate salts and triethylamine trihydrogen fluoride on reaction conditions. an in situ generated O-trimethylsilyl cyanohydrin afforded α-fluoronitrile 12 in excellent yield (5).

16 Scheme 12.

The mechanism for the deoxyfluorination reaction using dialkylaminodifluorosulfinium tetrafluoroborate salts requires an exogenous fluoride source or a base to generate the desired Scheme 15. fluorinated products (2, 4, 5). This clearly contrasts with DAST, which generates a free fluoride upon addition of the oxygen The deoxyfluorination of 13 using diethylaminodifluorosulfinium nucleophile to the sulfur trifluoride moiety. The use of tetrafluoroborate resulted in a rearrangement to bridged triethylamine trihydrogen fluoride as the exogenous fluoride biphenyls 14 and 15. Among the deoxyfluorination reagents and source was preferred to other fluoride sources since it is soluble conditions screened for this transformation leading to in most organic solvents, much less corrosive than free HF and it fluorinated analogues of bioactive bridged biphenyls 14, can be handled in borosilicate glassware without etching at diethylaminodifluorosulfinium tetrafluoroborate, used in

temperatures up to 150°C (18). conjunction with Et3N•HF, was preferred (19). Although 14 and 15 are obtained as a mixture, they were separable by flash chromatography.

Scheme 13. Scheme 16.

Aldehydes, Ketones and Carbonyl Derivatives Methylphenyl sulfoxide was shown to undergo quantitative Dialkylaminodifluorosulfinium salts, when used in conjunction fluoro-Pummerer type rearrangement (20) when reacted with a with triethylamine di-, or trihydrogen fluoride allowed the combination of dialkylaminodifluorosulfinium tetrafluoroborate difluorination of a variety of carbonyl groups or related salts and triethylamine trihydrogen fluoride (5).

Chimica Oggi - Chemistry Today - vol. 31(4) July/August 2013 Process optimization

Scheme 21. Scheme 17.

NBS, as an additive, allowed for a smooth reaction at low Carboxylic acids temperature even if it was not required. The tetrafluoroborate Dialkylaminodifluorosulfinium salts 1 and 2 performed almost anion was shown to act as a fluoride source (22, table 1). equally to form excellent yields of acyl fluorides starting from the corresponding carboxylic acids (5). No trifluoromethylated product could be obtained even under forcing conditions.

Scheme 18. Table 1.

Glycosyl derivatives Indeed, the use of a diethylaminodifluorosulfinium triflate salt Couturier and coworkers reported the quantitative (-OTf) did not achieve the fluorination (entry 3). However, deoxyfluorination of 2,3,4,6-tetra-O-benzyl-D-glucose 16 to form addition of TBA-BF4 allowed similar yields to be obtained glycosyl fluoride 17 as a mixture of anomers (5). (entry 4) when compared to reactions using dialkylaminodifluorosulfinium tetrafluoroborate salts (entries 1-2). 17 ACTIVATING AGENTS

Replacement of the exogenous fluoride source or the base by a nucleophile enabled the use of dialkylaminodifluorosulfinium tetrafluoroborate salts as activating agents for a variety of transformations, thus leading to non-fluorinated products.

Scheme 19. Enantioselective ring expansion of prolinols In 2011, Cossy and coworkers achieved the ring expansion Diethylaminodifluorosulfinium tetrafluoroborate was found of a variety of protected 4-hydroxy, 4-amino, 4-fluoro and to be the reagent of choice for the preparation of 4,4-difluoroprolinols 19 using diethylaminodifluorosulfinium glycosyl fluoride 18, a key fragment of an apoptolidin tetrafluoroborate as an activating agent to form aziridinium total synthesis. An excellent yield was obtained in the intermediates, which were predominantly converted to absence of side products, thus eliminating the need for 3-azidopiperidines 20 in the presence of chromatography (21). tetrabutylammonium azide (23, 24).

Scheme 20.

Williams and coworkers developed an access to α-glycosyl fluorides from thio-, seleno-, and telluroglycosides using dialkylaminodifluorosulfinium tetrafluoroborate salts (22). Generally high yields of α-glycosyl fluorides were obtained within short reaction times. Acetyl, benzyl, benzoyl and Scheme 22. acetals were tolerated as O-protecting groups.

Chimica Oggi - Chemistry Today - vol. 31(4) July/August 2013 Process optimization

2-Azidomethylpyrrolidines 21 were commonly observed as a minor byproduct, 2- and 3-substituted prolinols predominantly gave the corresponding 2-azidomethylpyrrolidines. A Staudinger reaction successfully reduced azides 20 to the free amines.

Amidation of Carboxylic Acids Recently, Cossy and coworkers reported the use of diethylaminodifluorosulfinium tetrafluoroborate as an activator for the amidation of carboxylic acids (25). A wide variety of acid and amine substrates were reacted to give moderate to excellent yields of the corresponding amides 22. When optically active substrates were employed, no epimerization/racemization of substrates was observed. Variations of the amine partner caused the largest impact on the reaction outcome. While anilines Scheme 25. were less reactive, sterically hindered amines tended to form diethylamide 23 as a major byproduct. This could be alleviated by tuning the reaction conditions. Proton sponge, as (TEAX) employed as the source of halide (27). A variety of an additive, avoids deprotonation of the carboxylic acid protected alcohols and amines were tolerated during the substrate by the amine partner and prevents an excessive halogenation of a remote primary alcohol. Iodination of formation of 23, leading to higher yields and better ratios of primary alcohols yielded only modest quantities of desired desired amides. Also, increasing the number of equivalents of iodides. Secondary alcohols also gave modest yields of the amine substrates from 2 to 5 equivalents significantly the corresponding halides, not to mention that secondary increased the yields and 22/23 ratios in most cases. One alkyl fluorides were formed as a major byproduct in every example of peptidic coupling was reported with moderate case. This transformation remains advantageous when yield (52%) albeit excellent diastereomeric excess (> 98/2). compared to the Appel reaction for its atom economy Independently, Paquin and coworkers described the same and its ease of purification, most byproducts being soluble transformation under similar conditions (26). in aqueous media.

Synthesis of N-Containing Paquin and coworkers reported the preparation of 1,3,4-oxadiazoles from 1,2-diacylhydrazines using 18 diethylaminodifluorosulfinium tetrafluoroborate as a cyclodehydrating reagent. Acetic acid was successfully used as an additive for this transformation allowing, in most cases, higher yields to be achieved than without any additive (28). Similarly, Paquin and coworkers also reported the synthesis of 2-oxazolines and related N-containing heterocycles in high yields from the corresponding hydroxylamides, using Scheme 23. diethylaminodifluorosulfinium tetrafluoroborate as a cyclodehydrating agent (29).

Halogenation of primary alcohols The chlorination and bromination of primary alcohols was reported by Paquin and coworkers, using diethylaminodifluorosulfinium tetrafluoroborate as an activating agent, while tetraethylammonium halides

Scheme 24. Scheme 26.

Chimica Oggi - Chemistry Today - vol. 31(4) July/August 2013 Process optimization

CONCLUSIONS 10. Pashinnik V. E., Martynyuk E. G., Shermolovich Y. G. Ukr. Khim. Zh. 68(11-12), 83-87 (2002). Dialkylaminodifluorosulfinium tetrafluoroborate salts 11. Couturier M., L’Heureux A. WO 2010/145037. 12. Mahé, O.; L’Heureux, A.; Couturier, M.; Bennett, C.; Clayton, S.; were shown to perform adequately in a range Tovell, D.; Beaulieu, F.; Paquin, J.-F. J. Fluorine Chem. (2013), In press of deoxyfluorination reactions when used with the (DOI: 10.1016/j.jfluchem.2013.05.019). appropriate additives. Thus, they represent an efficient, 13. Wang Z., Hunter L., J. Fluorine Chem.143, 143-147 (2012). safe and inexpensive alternative to sulfur trifluoride 14. Wang C.-L. J. Sulfur Tetrafluoride, in electronic-Encyclopedia of based reagents. Reagents for Organic Synthesis, Edited by John Wiley & Sons, Ltd, In addition, a variety of alternate transformations using online (2001). dialkylaminodifluorosulfinium tetrafluoroborate salts as 15. Middleton W. J., Bingham E. M., Organic Syntheses, Coll. Vol. 6, activating agents were presented, furnishing a new range 440-442 (1988). of potent methodologies to access structurally important 16. Singh R. P., Shreeve J. M. Synthesis, 2002(17), 2561-2578 (2002). motifs. These novel activations illustrate the potential 17. Xu W., Martinez H., Dolbier Jr. W. R. J. Fluorine Chem. 132(7), 482–488 (2011). for the development of new applications using 18. McClinton M. A. Aldrichimica Acta 28(2), 31-35 (1995). dialkylaminodifluorosulfinium tetrafluoroborate salts. 19. Nemoto H., Takubo K., Shimizu K., Akai S. Synlett 23(13), 1978-1984 (2012). 20. Umemoto T., Tomizawa G. Bull. Chem. Soc. Jpn. 59(11), 3625-3629 REFERENCES (1990). 21. Srinivasarao M., Park T., Chen Y., Fuchs P. L. Chem. Commun. 47(20), 5858-5860 (2011). 1. Thayer A. M. Chem. Eng. News, 84(23), 15-24 (2006). 22. Tsegay S., Williams R. J., Williams S. J. Carbohydr. Res. 357, 16-22 2. Al-Maharik N., O’Hagan D. Aldrichimica Acta, 44(3), 65-75 (2011). (2012). 3. A mini-review has been published: Franconetti A., Synlett, 24(7), 23. Cochi A., Pardo D. G., Cossy J. Org. Lett. 13(16), 4442-4445 (2011). 891-892 (2013). 24. Cochi A., Pardo D. G., Cossy J. Eur. J. Org. Chem. 2012(10), 2023 4. Beaulieu F., Beauregard L.-P., Courchesne G., Couturier M., (2012). LaFlamme F., L’Heureux A. Org. Lett. 11(21), 5050-5053 (2009). 5. L’Heureux A., Beaulieu F., Bennett C., Bill D. R., Clayton S., LaFlamme 25. Orliac A., Gomez P. D., Bombrun A., Cossy J. Org. Lett. 15(4), F., Mirmehrabi, M., Tadayon, S., Tovell, D., Couturier, M. J. Org. 902-905 (2013). Chem. 75(10), 3401-3411 (2010). 26. Mahé O., Desroches J., Paquin J.-F. Eur. J. Org. Chem. 2013(20), 6. Markovskii L. N., Pashinnik V. E., Saenko E. P. Zh. Org. Khim. 13(5), 4325-4331 (2013). 1116-1117 (1977). 27. Pouliot M.-F., Mahe O., Hamel J.-D., Desroches J., Paquin J.-F. 7. Cowley A. H., Pagel D. J., Walker M. L. J. Am. Chem. Soc. 100(22), Org. Lett. 14(21), 5428-5431 (2012). 7065-7066 (1978). 28. Pouliot M.-F., Angers L., Hamel J.-D., Paquin J.-F. Org. Biomol. 8. Mews R., Henle H. J. Fluorine Chem. 14(6), 495-510 (1979). Chem. 10(5), 988-993 (2012). 9. Pauer F., Erhart M., Mews R., Stalke D. Z. Naturforsch., B: Chem. Sci. 29. Pouliot M.-F., Angers L., Hamel J.-D., Paquin J.-F. Tetrahedron Lett. 45(3), 271-276 (1990). 53(32), 4121-4123 (2012). 19

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