Uses of Morpholinylsulfur trifluoride as a synthetic Intermediate

Morpholinylsulfur trifluoride (MORPHOLINOSULPHUR TRIFLUORIDE (MORPHO DAST); Morph-DAST, Morpho-DAST; 4-Morpholinylsulfur trifluoride, 95%; Morpholin-4-ylsulphur trifluoride;Morpho-DAST, 4-(Trifluorothio)morpholine;4-(trifluoro-4-sulfanyl)morpholine; MORPHOLINOSULFUR TRIFLUORIDE; MORPHOLINOSULPHUR TRIFLUORIDE, C4H8F3NOS) is an important intermediate of organic synthesis for preparing organic fluorine compounds[1]. 

Morpholinylsulfur trifluoride (Morph-DAST) can involve in deoxofluorination with ketone group , hydroxyl group and active methylene for obtaining specific organic fluoride. A wide variety of substrates such as β-keto esters, malonates, 1,3-diketones, and dicyanoalkylidenes could be transformed toα-fluoro-α-sulfenamide derivatives in good to high yields by using morpholinylsulfur trifluoride as fluorinating agent[2]. In addition,  3-(tert-butoxy)cyclobutanone would react with morpholinylsulfur trifluoride in dichloromethane for producing 3,3-difluorocyclobutane-1-tert-butoxy. Simirlarly, by reacting with morpholinylsulfur trifluoride, 3-(benzyloxy)cyclobutanone can be transformed to 3,3-difluorocyclobutane-1-benzyloxy. These obtained substituted 3,3-difluorocyclobutane would be transformed to 3,3-difluorocyclobutanone, which could be further applied to synthesize some biologically active 3,3-difluorocyclopropane derivatives[2]. In the some deoxofluorination of ketones, rearrangement of neighboring groups would be occurred. De Kimpe and coworkers found that by using morpholinylsulfur trifluoride as fluorinating agent, the rearrangement of cyclic α,α-dialkoxy ketones into 1,2-dialkoxy-1,2-difluorinated compounds would be accomplished[3]. This rearrangement could be occurred in moderate and the products was the mixture of cis and trans diastereoisomers.

Morpholinylsulfur trifluoride also could induce the fluoridation of alcohols. For example, after treated with morpholinylsulfur trifluoride, N-Boc protected amino alcohol could be transformed one fluoromethylated pyrrolidine. However, after oxidation of alcohol with Py•SO3, then treated with morpholinylsulfur trifluoride, N-Boc protected amino alcohol would be transformed to difluoromethylated pyrrolidine[5]. Moreover, morpholinylsulfur trifluoride could mediate ring-expansion of substituted N-containing heterocyclic alcohols compound in fluoridation process. For instant, after reacting with morpholinylsulfur trifluoride, rel-(2S,5S)-5-(hydroxymethyl) -1-(phenylmethyl)-2- pyrrolidinecarbo-xylic acid would give the mixture of direct substituted product of rel-(2S,5S)-5-(fluoromethyl)-1-(phenylmethyl)-proline, methyl ester and rearrangement  product of rel-(2S,5R)-5-fluoro-1-(phenylmethyl)-2-piperidinecarboxylic acid, methyl ester. In this reaction process, the cationic aziridine intermediate would be produced and underwent ring-opening by a fluorine-anion to give either 2-fluoromethylpyrrolidine derivative or the corresponding 3-fluoropiperidine[6].

In conclusion, morpholinylsulfur trifluoride is a common fluorinating agent for preparing organic fluorine compounds.

References

[1] https://www.chemicalbook.com/ProductChemicalPropertiesCB7691865.htm.
[2] Saidalimu, I., Guo, M., Tokunaga, E., Shibata, N. (2016). Direct Fluoro‐aminosulfenylation of Active Methylenes by Dialkylaminosulfur Trifluorides under Catalyst‐Free Conditions. Asian Journal of Organic Chemistry, 5(10), 1208-1212.
[3] Melnykov, K. P., Granat, D. S., Volochnyuk, D. M., Ryabukhin, S. V., Grygorenko, O. O. (2018). Multigram Synthesis of C4/C5 3, 3-Difluorocyclobutyl-Substituted Building Blocks. Synthesis, 50(24), 4949-4957.
[4] Surmont, R., Verniest, G., De Groot, A., Thuring, J. W., De Kimpe, N. (2010). Morpholinosulfur Trifluoride (Morph‐DAST)‐Mediated Rearrangement in the Fluorination of Cyclic α, α‐Dialkoxy Ketones toward 1, 2‐Dialkoxy‐1, 2‐difluorinated Compounds. Advanced Synthesis & Catalysis, 352(16), 2751-2756.

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