Recent Advances in the Synthesis of Sulfones

SYNTHESIS0039-78811437-210X © Georg Thieme Verlag Stuttgart · New York 2016, 48, 1939–1973 1939 review Syn thesis N.-W. Liu et al. Review Recent Advances in the Synthesis of Sulfones Nai-Wei Liu traditional approaches Shuai Liang S 1 2 R1 R2 R -X ++SO2 R -X Georg Manolikakes* O 3-component procedures O O S 1 S Institut für Organische Chemie und Chemische Biologie, R O R1 R2 Goethe-Universität Frankfurt, Max-von-Laue-Str. 7, 60438 R1-H O O Frankfurt, Germany S synthesis by C–H activation [email protected] R1 X Received: 04.03.2016 transformation.1,4 In addition, sulfone groups can stabilize Accepted after revision: 04.04.2016 adjacent carbanions.1,5 Classical reactions of sulfones in or- Published online: 07.06.2016 DOI: 10.1055/s-0035-1560444; Art ID: ss-2016-e0158-r ganic synthesis include the Ramberg–Bäcklund reaction of α-halo sulfones6 or the Julia–Lythgoe as well as the modi- Abstract Sulfones are versatile intermediates in organic synthesis and fied Julia olefination (Scheme 1).7 important building blocks in the construction of biological active molecules or functional materials. This review provides a summary of recent O O developments in the synthesis of sulfones. R1 S 1 Introduction sulfonyl R2 good group 2 Classical Methods and Variants H leaving facilitates group 2.1 Oxidation of Sulfides deprotonation O O 2.2 Aromatic Sulfonylation S 2.3 Alkylation/Arylation of Sulfinates good Michael R2 acceptor 2.4 Addition to Alkenes and Alkynes 1 2.5 Miscellaneous Methods R 3 Metal-Catalyzed Coupling Reactions Ramberg–Bäcklund reaction 4 Sulfone Synthesis by C–H Functionalization O O 1 2 Base 5 Sulfur Dioxide Based Three-Component Approaches R S R – SO2 R1 R2 6 Biological Synthesis of Sulfones X 7 Conclusion Julia–Lythgoe olefination sulfone, addition, coupling, catalysis, medicinal chemistry, 1) base OAc Key words R2 SO2Ph 2 Na(Hg) multicomponent reaction 2) R -CHO R2 R1 R1 3) Ac2O R1 SO2Ph 1 Introduction modified Julia olefination This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. 2 O O O base R Sulfones (R-SO2-R) are versatile synthetic intermediates 1 + S R 2 in organic chemistry, and molecules bearing a sulfone unit Het R H R1 have found various applications in diverse fields such as ag- Het = benzothiazole, 1-phenyl-1H-tetrazole, 1-tert-butyl-1H-tetrazole rochemicals, pharmaceuticals and polymers.1 The sulfone group can be employed as a temporary modulator of chem- Scheme 1 ical reactivity. Therefore a variety of different transformations are feasible with this functional group, leading to the Apart from these classical transformations, sulfones description of sulfones as ‘chemical chameleons’.2 Sulfone have been employed as versatile intermediates for the groups can function as activating, electron-withdrawing preparation of various product classes, for example the substituents in Michael acceptors1,3 or as good leaving van Leusen synthesis of oxazoles and imidazoles8 or the groups producing a sulfinate anion, a reactivity that often synthesis of quinolines (Scheme 2).9 facilitates removal of the sulfone moiety after the desired © Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 1939–1973 1940 Syn thesis N.-W. Liu et al. Review van Leusen synthesis Due to their distinct electronic and structural features, O N sulfones play a prominent role in various fields of applica- Me oxazole X R tions. A large number of biologically active molecules con- base + or tain this functional group.10 The sulfone scaffold is thus of S NC R H R' OO N N imidazole particular relevance in medicinal chemistry. Molecules X = O, NR' R used against diverse medical indications such as eletrip- tan11 (treatment of migraine), bicalutamide12 (treatment of prostate cancer) or the antibacterial dapsone13 feature a sulfone unit (Figure 1). The sulfone group is also embedded NHBoc O O O O O O S in various important agrochemicals, for example mesotri- 3 2 S t-BuLi R R 14 15 16 R3 R2 + one, pyroxasulfone or cafenstrole (Figure 1). Sulfone- R4 CuCN, LiCl R1 containing polymers display interesting properties and bis- R1 R4 17 NHBoc phenol S (Figure 1) is used replacement for bisphenol A. Considering this plethora of possible applications, it is O O O R1 S not surprising that a number of efficient methods for the 3 2 Δ R R TFA, R4 synthesis of sulfones have been developed. Indeed, the first R4 R1 methods were reported in the 19th century. The constant R2 N NHBoc demand for efficient, robust and more sustainable ap- quinoline proaches for the preparation of sulfones has led to a resur- Scheme 2 gence of research activities in this field in recent years. This review highlights advances in the synthesis of sulfones un- til the end of 2015. Biographical Sketches Georg Manolikakes was born ized organometallics and cross- search group leader at the in Ebersberg (Germany) in coupling reactions. From Goethe-Universität Frankfurt. 1979. He studied chemistry at 2009–2010 he worked as a His research interests are multi- the LMU Munich (Germany) postdoctoral fellow with Prof. component and one-pot reac- where he received his Diploma Phil S. Baran at the Scripps Re- tions, synthesis of sulfonyl- in 2005. In 2009 he obtained his search Institute (La Jolla, USA) group-containing molecules PhD from the same university on synthesis of cortistatin A. At and asymmetric synthesis. under the guidance of Prof. Paul the end of 2010 he took up his Knochel working on functional- current position as junior re- Shuai Liang was born in Qing- versity under the supervision of research interest focuses on dao (P. R. of China) in 1988. He Prof. Xiaoqi Yu. Since November novel methods for the synthesis earned his BS degree in 2011 2014 he is a PhD student at the of sulfones via selective C–H from Sichuan University. In Goethe-Universität Frankfurt, functionalization. 2014 he received his MS degree under the supervision of Dr. This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. in chemistry from Sichuan Uni- Georg Manolikakes. His current Nai-Wei Liu was born in Taipei Universität Frankfurt (Germa- veloping new methods for the (Taiwan R.O.C.) in 1987. He ob- ny). He is currently working on fixation of sulfur dioxide into tained his B.Sc. and M.Sc. de- his PhD thesis in the group of small molecules. grees from the Goethe- Dr. Georg Manolikakes and de- © Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 1939–1973 1941 Syn thesis N.-W. Liu et al. Review O O General reaction: HO Me O O S H H N S O Ph oxidizing conditions O O S via N R1 R2 S S O R1 R2 R1 R2 Me NC F sulfide sulfone sulfoxide N CF3 H Recent examples eletriptan bicalutamide O O NO O O O O 2 S oxidant Ph Me S S Ph Me Me O S H2N NH2 O O Oxidant: dapsone mesotrione urea-H O , neat, 85 °C 87% N O 2 2 Me O O S Me H O , NbC (4 mol%), 92% Me CHF2 N 2 2 O O N S O EtOH, 60 °C O Me N NEt N 2 KMnO4/MnO2, neat, rt 83–93% N Me pyroxasulfone cafenstrole Me 30% aq H2O2, 75 °C 68% O O NaOCl, cyanuric acid (10 mol%) 96% S toluene, rt Scheme 3 HO OH bisphenol S Figure 1 2.2 Aromatic Sulfonylation Another widely used strategy for the synthesis of sul- 2 Classical Methods and Variants fones involves the reaction between a (hetero)arene and a sulfonyl halide or sulfonic acid in the presence of a suitable The four traditional and still most common approaches Lewis or Brønsted acid catalyst (Scheme 4).1 Sulfonyl chlo- for the synthesis of sulfones are the oxidation of the corre- rides are most commonly employed in these Friedel–Crafts- sponding sulfides or sulfoxides, alkylation of sulfinate salts, type reactions and substituents on the (hetero)arene exert Friedel–Crafts-type sulfonylation of arenes, and addition activating/deactivating as well as directing effects as ex- reactions to alkenes and alkynes.1 Although all four reac- pected for electrophilic aromatic substitutions.23 Typically, tion types were discovered several decades ago, new vari- these reactions are performed in the presence of stoichio- ants with improved substrate scope, functional group toler- metric amounts of conventional Lewis or Brønsted acid, ance and efficiency, as well as new reagents, are constantly such as aluminum trichloride, iron(III) chloride or phos- being developed. Other methods, such as rearrangements, phoric acid.24 reactions of sulfonic acid derivatives with nucleophiles, or cycloaddition reactions, although known for decades, are O O catalyst O O S S rarely used. R X Ar-H R Ar sulfonyl halide sulfone (X = Cl, F, Br) 2.1 Oxidation of Sulfides catalyst and/or The oxidation of sulfides is perhaps still the most fa- O O activating agent O O This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. vored method for the synthesis of sulfones. While a variety S S R OH Ar-H R Ar of oxidants can be used for this transformations,1 peracids sulfonic acid sulfone or hydrogen peroxide in combination with acetic acid are most frequently employed (Scheme 3).18 In general, excess Scheme 4 oxidizing agent, high temperatures and/or long reaction times are necessary to achieve complete conversion of the In general, these reactions suffer from the typical draw- intermediate sulfoxide to the sulfone. In most cases, exist- backs of Friedel–Crafts-type processes, such as harsh reac- ing procedures will furnish the desired sulfones in accept- tion conditions, low regioselectivity, the need for stoichio- able yields.

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