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

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

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-

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. Current research focuses mainly on safe oxida- metric amounts of the catalyst, and the generation of sub- tion reagents, such as urea–hydrogen peroxide,19 catalytic stantial quantities of hazardous waste. Therefore, a variety systems for milder and faster oxidations20 and solvent-free of more efficient catalysts have been developed throughout systems21 or highly sustainable methods.22 the last decades.25 Special emphasis was placed on more sustainable methods such as reusable solid acids,25e solvent-free25i or ionic-liquid-based25d,f systems and reactions

Syn thesis N.-W. Liu et al. Review with low catalyst loadings.25i The direct sulfonylation of An unusual process is the sulfonylation of arenes with arenes with sulfonic acids in the presence of acid catalysts sulfonamides in the presence of triflic anhydride as activat- has also been reported.25e,26 Activation of the sulfonic acid ing agent.32 This method provides an alternative access to with suitable reagents, such as phosphorus pentoxide or aryl sulfones using a stable primary sulfonamide as sulfo- triflic anhydride, leads to the in situ formation of reactive nylating agent (Scheme 7). mixed anhydrides and an efficient sulfonylation of arenes at O O room temperature.27 Tf2O OO Ar-H + S DCE, 80–120 °C S Sulfones are frequently encountered side-products in R NH2 R Ar the sulfonation of arenes with sulfuric acid.28 They are 42–95% yield formed by the reaction of the intermediate sulfonic acid O O O O Me with an excess of the arene. Removal of water during the re- S S action furnishes the symmetrical diaryl sulfone as the major product (Scheme 5).29 In a similar manner, symmetrical Me Br O2N 89% 42% diaryl sulfones can be prepared by the reaction of an arene Me Me O O O O 30 with dimethyl pyrosulfate in the presence of sulfuric acid. S S S Me

Method A Ph H2SO4 O O Me 86% 58% Ar-H S Method B Ar Ar Scheme 7 MeO-SO2-O-SO2-OMe sulfone H2S2O7 2.3 Alkylation/Arylation of Sulfinates O O O O S S The salts of sulfinic acids are useful precursors for the synthesis of sulfones. Sulfinates are powerful nucleophiles 80% 41% Method A Method A and react with a variety of different electrophiles at the sulfur atom to form sulfones.1,33 Only in the case of hard al- O O O O S S kylating agents, such as dimethyl sulfate or diazomethane, does O-alkylation occur, and the corresponding sulfinate 34 83% 80% Me esters are produced predominantly (Scheme 8). Method B Method B Scheme 5 O O O S S R M R O M 31 Rao and co-workers reported a similar method. Their sulfinate procedure enables the one-pot synthesis of symmetrical as well as unsymmetrical diaryl sulfones starting from arenes, O O O + + S E S sulfone a persulfate salt, trifluoromethanesulfonic acid (TfOH) and R O M R E trifluoroacetic acid anhydride (TFAA) (Scheme 6). The reac- sulfinate electrophile O sulfinate ester tion is presumed to proceed via a sulfonic acid which is ac- S tivated to the corresponding anhydride with TFAA. R O E minor product or not formed at all

K2S2O8 O O

1 2 This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. Ar -H + Ar -H S Scheme 8 TfOH, TFAA Ar1 Ar2 35–98% yield

Me O O Me Me O O Me Typical electrophiles include alkyl halides,34,35 epox- O S N S N O ides,36 Michael acceptors,37 and aryl halides activated to- 38 F C CF wards nucleophilic aromatic substitution (Scheme 9). Al- Me Me 3 3 91% 80% though the reactions are generally high-yielding, simple to O O Me Me O O perform and suitable for a broad scope of alkylating agents, S S S this approach is limited owing to the modest availability of sulfinate salts. F Me 60% Me 47% Scheme 6

Syn thesis N.-W. Liu et al. Review

O O tions, this method is not limited to activated arenes, and S R Alkyl unsymmetrical diaryliodonium salts can transfer one aryl moiety with high degrees of chemoselectivity (Scheme 11). Alkyl-X alkyl hailde X O O Ar-X O EWG O O I S O Ar2 Ar3 O O R Ar S S activated Michael acceptor R EWG S R O M 1 S aryl halide Ar O Na DMF, 90 °C Ar1 Ar2 sulfinate X = Cl, PF6, BF4, 17–96% yield O OTs, OTf

epoxide O O O O S S S O O S R OH 94% 83% Scheme 9 O O Me O O

S S CF3 Recent developments in this field include the sulfonyla- Me Me tion of five- and six-membered heterocycles with sodium 88% 78% sulfinates by way of nucleophilic aromatic substitution Scheme 11 (Scheme 10).39 Both methods enable the transition-metal- free synthesis of heterocyclic sulfones, of particular relevance for medicinal chemistry. Mhaske and Pandya developed a transition-metal-free process for the synthesis of aryl sulfones based on the addi- Y tion of sodium sulfinates to in situ generated arynes X Y 42 Z (Scheme 12). SO2R DMSO, 110 °C Z 1 38–98% yield O TMS TBAF (1.1 equiv) SO2R O S + 1 S X R O Na MeCN, rt R O Na OTf R2 2 N R X = Cl, Br, I, OTf, NO2 TBACl (0.3 equiv) aryne precursor 45–96% yield Y = O, S, NH (HCl) Z = N, CH SO2R DMAc, 100 °C N O O O O 75–98% yield S O S

O O O O O 95% 96% S S S S

N N O O Me O O 84% 89% S S S CN O O Br O O S NO S 2 73% 74% N N Me Me Scheme 12 97%Me 91% This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. Scheme 10 Chen, Yu and co-workers extended the transition- In a similar manner, diaryliodonium salts, powerful ary- metal-free coupling of sodium sulfinates to employ vinyl lating reagents,40 react with sodium sulfinates in the ab- halides (Scheme 13).43 The reaction proceeds in water with 41 sence of any catalyst. In contrast to classical SNAr reac- catalytic amounts of an acid and a phase-transfer catalyst. An addition–elimination mechanism is proposed for this transformation.

Syn thesis N.-W. Liu et al. Review

HCl (30 mol%) 1 1 O X SO2R O Br Br SO2R + TBAB (5 mol%) S S + 1 1 R O Na 2 2 R O Na DMF, 80 °C 2 R H2O, 100 °C R R2 R

65–88% yield X = Br, Cl 40–99% yield

O O2 S Me CN O Ph 2 S NH2 S S S Me O O O O O O OMe Me 80% 80% 65% 99% 40% Pent

O2 O2 Pent S S S S HOOC Me O O O O

Me 66% (5:1)

59% 53% Scheme 15 Scheme 13 Sreedhar and co-workers reported an iron(III) chloride The lithium bromide catalyzed reaction of sodium sulfi- catalyzed direct sulfonylation of activated alcohols with so- nates with terminal epoxides in water provides a sustain- dium sulfinates (Scheme 16).46 The reaction proceeds able approach for the preparation of vinyl sulfones (Scheme through an activation of the alcohol and formation of a sta- 14).44 A mixture of the internal and the terminal regioiso- bilized carbocation. mer is obtained in most cases. The regioselectivity is gov- FeCl3 (15 mol%) 1 O HO SO2R erned by electronic and steric effects of the expoxide sub- TMSCl (1.2 equiv) + R3 2 S R stituent. The reaction is presumed to proceed through ini- 1 2 3 R O Na R CH2Cl2, 45 °C R tial expoxide opening with the sulfinate followed by 2 3 dehydration of the formed β-hydroxy sulfone. R , R = alkyl, aryl, allyl 35–96% yield

1 Me SO2R

O O 2 internal 2 2 R O2S S S vinylsulfone O O LiBr (10 mol%) + S + R1 O Na 2 Me Me R H2O, 80–90 °C 1 R O2S 75% 71% 65% R2 Me combined yield: 71–93% terminal regioselectivity: 100:0 to 9:91 vinylsulfone Me O2S Me Me S Me O2 F Br

O2S O2S O2S 38% 60% O2S This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. O Scheme 16 Me

OMe The Ji group developed a one-pot synthesis of allylic sul- 72% 84% 78% 71% 84:16 91:9 0:100 0:100 fones, β-keto sulfones or triflic alcohols from allylic alcohols and sulfinic acids.47 Substitution of the allylic alcohol Scheme 14 yields the allyl sulfone. Direct treatment of the reaction mixture with phenyliodine(III) diacetate (PIDA) and sulfuric Liang and co-workers developed a synthesis of vinyl sul- acid leads to an oxidative rearrangement of the allyl sulfone fones starting from sodium sulfinates and 1,2-dibromides and formation of β-keto sulfones. For triflated intermedi- in the absence of any catalyst.45 The method provides the ates, no migration is observed and triflic alcohols are ob- (E)-vinyl sulfone as the major stereoisomer or sole product tained instead (Scheme 17). (Scheme 15).

Syn thesis N.-W. Liu et al. Review

1,49 O sponding salt. If unmasking of the sulfinate is performed S in the presence of a suitable electrophile, formation of a R1 OH HO Me Ar sulfone occurs. Exploiting this reactivity, Petrini and co- O2 (balloon) workers reported the synthesis of sulfones from alkyl and Ar DCE, 120 °C R2 SO R1 R2 2 activated aryl halides and p-toluenesulfonyl hydrazide with 33–97% yield sodium acetate as base (Scheme 19).50 R2 = Ar R1 = Ar O Ar Ar O NaOAc O 1 Ar SO2R Me S NHNH2 + RX Me S R 2 1 PIDA, H SO EtOH, reflux R SO2R 2 4 O O Ar OH R = alkyl, benzyl, 80–95% yield allyl, aryl 1 2 1 X = Cl, Br, I R = CF3 R SO2R

O O Me Me O O Me S S Me S Me S O O O O Br O O Me 85% 92%

O2N Me 69% 75% (1:1)

S S OH O CF 3 O O S NO2 O O O F 84% 95% Scheme 19

68% Scheme 17 In a similar manner, sulfonyl hydrazides react with Michael acceptors to yield the corresponding ethyl sulfones.51 The reaction proceeds in water without any catalyst Tian and co-workers reported a catalyst-free alkylation (Scheme 20). of sulfinic acids with allylic and benzylic sulfonamides.48 Cleavage of the C–N bond takes place even at room tem- O O O perature (Scheme 18). H R NaOAc Ar S N NH2 + Ar S R H2O, 65 °C O O O 1 O NHTs SO2R 2 2 70–98% yield S + R R R = OR', NHR' 1 R OH R3 CHCl3, rt R3 56–99% yield OMe NO2 O O

MeO EtO S EtO S O O O O O O O O Ph S S Ph Ph 93% 91% Ph Me Me H This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. O O 67% 56% PhO S PhHN S O O O O MeO MeO 99% O O O O 70% S S Me Scheme 20 Me Me OMe 72% 99% Tang and co-workers reported a sulfonylation of allylic Scheme 18 acetates with sulfonyl hydrazides in water.52 The reaction is catalyzed by tetrabutylammonium iodide (TBAI), and tert- Sulfonyl hydrazides can be considered as masked sulfi- butyl hydroperoxide (TBHP) is employed as cooxidant nates, as treatment of a hydrazide with base or with water (Scheme 21). and heating can liberate the free sulfinic acid or the corre-

Syn thesis N.-W. Liu et al. Review

OAc TBAI (20 mol%) O OH i R2 O EWG Pr2NEt 1 TBHP (2.0 equiv) Ph Ar S CN R2 R H EWG + 1 Ar S N NH2 + R CH Cl , rt Ph H2O, 80 °C O 2 2 SO2Ar O SO2Ar 72–95% yield EWG = CO2R, CN 44–72% yield COOMe COOMe Me CO2Me O2N CO2Et SO Ph SO Ph O O 2 2 95% Cl S S 72% O O Me Br 54% 63% Me Z/E = 97:3 Z/E = 99:1 SO2Ph SO2 CO Me 2 CN Br O S O O2N S S 81% 84% O O Me Scheme 23 72% 69% Z/E = 89:11 Z/E = 1:99

Scheme 21 1 O OH SO2R S + R1 Cl R2 R3 R2 R3 Li and co-workers reported an interesting approach CHCl3, 25–60 °C 53–99% yield starting from 1,2-bis(phenylsulfonyl)ethane as sulfinate 53 precursor. In the presence of a palladium catalyst, cleav- SO Ph SO Me 2 COMe 2 age of one C–S bond and formation of a palladium–sulfinate Ph complex occurs. Transfer of the sulfinate to an activated Ph SO2Ph alkyne affords the (E)-vinyl sulfone in good yields (Scheme MeO Ph 77% 22). 75% 78% Scheme 24 Pd-mediated C–S bond cleavage 2.4 Addition to Alkenes and Alkynes Ph O O Pd(OAc)2 (10 mol%) DMEDA (20 mol%) Ph R O S Ph + The addition of sulfonyl radicals to alkenes and alkynes t O Ph S O KO Bu, DMF/MeCN S is an important method for the synthesis of sulfones 120 °C O O R O Ph (Scheme 25).1,56 Since the first reports on addition of sulfo- R = OR, NHR 43–79% yield nyl halides to alkenes in the presence of radical initiators, light or copper(I) chloride,57 various improvements and

O Me modifications of this atom-transfer radical addition (ATRA) O Me O Ph N process have been developed. Sulfonyl radicals can be gen- H11C5 N Ph OMe O erated from sulfonyl haldes, sulfonyl selenides, sulfonyl hy- S O O O S S drazides, sulfonyl azides, or by the oxidation of sulfinates.58 Ph O O Ph Ph OMe O X 64% 54% 43% initiator or catalyst This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. O R2 R1 S X + R2 Scheme 22 R1 S O O O via R1 S radical precursor O Allylic alcohols react with arenesulfonyl cyanides to af- sulfonyl radical ford trisubstituted allyl sulfones (Scheme 23).54 Scheme 25 Tian and co-workers developed a method to convert benzylic and allylic alcohols into the corresponding sulfones using sulfinyl chlorides (Scheme 24).55 The reaction Ruthenium complexes are amongst the most efficient proceeds through in situ formation of a sulfinic acid or a catalysts for the ATRA of sulfonyl chlorides to olefins. Cata- sulfinate ester and is catalyzed by the by-product HCl. lyst loadings as low as 0.1 mol% and high turnover frequen- cies are observed for modified cyclopentadienyl–ruthenium complexes.59,60

Syn thesis N.-W. Liu et al. Review

Addition of sulfonyl halides to alkynes affords haloge- The ATRA of tosyl bromide to bisallenes leads to the for- nated vinyl sulfones. In general, the (E)-β-halovinyl sulfones mation of five-membered rings bearing an exocyclic vinyl are obtained as either the major or the sole diastereomer sulfone via a 5-exo-trig cyclization (Scheme 28).64 (Scheme 26).1,57 Nakamura and co-workers reported an Ts iron-catalyzed regio- and stereoselective addition of sulfo- AIBN nyl chlorides to terminal alkynes (Scheme 26).61 A bromo- O (20 mol%) Tol S X Y Y sulfonylation of terminal alkynes was achieved with a tri- toluene, 90 °C O 62 ethylborane-initiated sulfonyl radical generation. X

X = Br, SePh Y = O, NR, CR2 48–73% yield R2 Fe(acac)3 (10 mol%) O (p-Tol)3P (10 mol%) Cl Ts Ts Ts R1 S H H H O toluene Ph O TsN O 1 R2 R S X Ph O Br O R2 H H H R1 S Br SePh Br Et3B, O2 73% O 55% 63% Scheme 28

O O O O Ph S nBu S 1,6-Diynes react with tosyl bromide in a similar man- Me Cl Cl Me ner, affording bromo-substituted sulfonylated methylcyclo- 65 O pentenes via a 5-endo-dig cyclization (Scheme 29). 83% 67%

R3 R3 Br O R1 R1 O hν O O Tol S Br + Ph S O benzene, rt S O R2 R2 Me R4 R4 Ts Br Me Br 51–72% yield

99% 91% Br Br Me Me Me Br HO O O Scheme 26

HO O O Me Me Me Ts Ts Ts The Kang group developed methods for the synthesis of 68% 72% 51% heterocyclic compounds based on the radical additions of Scheme 29 tosyl bromide or iodide to allenes.63 Treatment of the re- sulting allylic halides with base furnished the corresponding heterocycles (Scheme 27). Generation of sulfonyl radicals from the corresponding azides is also possible. For example, Mantrand and Renaud O developed a radical-mediated azidosulfonylation of alkenes, Tol S X dienes and enynes with phenylsulfonyl azide (Scheme O AIBN Ts 66 + n YH 30). The reaction is limited to 1,6-dienes, 1-en-6-ynes, or toluene, 90 °C YH X alkenes that are able to undergo a rapid radical rearrange- This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. n ment. In the case of simple alkenes, no reaction is observed X = Br, I Y = O, NTs owing to the reversibility of the sulfonyl radical addition Ts and the low reaction rate of the final azidation of secondary Ts (base) n YH n alkyl radicals.

X Y Sulfinic acids and their salts are competent radical pre- Ts cursors and yield the corresponding sulfonyl radicals upon Ts OH O single-electron oxidation. Various methods have been reported for the generation of sulfonyl radicals from sulfi- Br nates or the free acids.1,56,58 Addition to an alkene or alkyne 67% 70% Ts can yield the formal hydrosulfonylation product as well as Ts K2CO3 various other sulfonylated products arising from different n YH DMF HN trapping processes. Two-electron oxidation of sulfinic acids Br 51% 78% can yield a sulfonyl cation, which can undergo similar reac- Scheme 27 tions with double or triple bonds.

Syn thesis N.-W. Liu et al. Review

Jiang and co-workers reported a palladium-catalyzed PhO S X 2 tBuN=NtBu addition of sodium sulfinates to alkynes affording (E)-vinyl O (0.5 equiv) 69 1 3 sulfones (Scheme 32). Ph S N + R R X 2 3 sun lamp R R2 O R3 1 X X = O, NR, CR R 2 N3 O O R2 PdCl2 (5 mol%) 41–89% yield S 1 R1 O Na R S DMSO R2 O PhO S PhO S 2 2 X = H, COOH 65–93% yield

MeO C 2 O Ts N 2 O MeO C Me Me S 2 2 S O Me Me S NO2 N3 N3 OMe 82% 83% 76% 89% X = H X = H

O2 SO2Ph SO2Ph O2 F3C S S Ph O O Ph H H H H 73% 93% Me Me X = COOH X = COOH

N N3 3 Scheme 32 82% 80%

Scheme 30 Kuhakarn and co-workers developed a PIDA and potassium iodide mediated synthesis of vinyl sulfones and β-io- Taniguchi reported a copper-catalyzed addition of sodi- dovinyl sulfones (Scheme 33).70 The reaction of sodium sul- um sulfinates to alkenes and alkynes.67 Addition to alkenes finates with alkenes furnishes β-iodo sulfones, which elimi- affords (E)-vinyl sulfones via an addition–elimination pro- nate to the corresponding vinyl sulfones under the reaction cess. Reaction of alkynes in the presence of potassium ha- conditions or upon treatment with base. In the case of lides furnishes (E)-β-haloalkenyl sulfones (Scheme 31). This alkynes, (E)-β-iodovinyl sulfones are obtained as products. method was later extended to a formal hydrosulfonylation An in situ formation of sulfonyl iodides as reactive species is of alkynes.68 proposed.

Method A R2 O R2 CuI/bpy (8 mol%) PIDA, KI O X R1 S KX (1.1 equiv) 1 MeCN, rt R S H O O AcOH, air 3 O (then DBU) O R for alkenes S 100 °C S R1 O Na 1 for alkynes R O Na R2 2 Method A PIDA, KI R CuI/bpy (8 mol%) O 2 O R3 R2 R I KI (50 mol%) R1 S MeCN, rt R1 S AcOH, air R3 100 °C O O for alkenes for alkynes

X/H Method B O2N O 2 CuCl/ligand (5 mol%) R

R1 S This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. AcOH, DMI 3 O R C6H13 H2O or MX, 60 °C O O I for alkynes I Me S Me S O Br SO2Tol O 77% 64%

Ph SO2Me

74% 68% Method A Method A O OMe O O Me S O SO2Tol Br Me S O O N SO2Tol 75% 62% 91% 35% Method B Method B Scheme 33 Scheme 31 DMI = 1,3-Dimethyl-2-imidazolidinone

Syn thesis N.-W. Liu et al. Review

The potassium persulfate promoted direct sulfonylation Visible-light-photocatalyzed oxidation of sulfinates or of N-phenylmethacrylamides with sulfinic acids leads to sulfinic acids provides an attractive alternative for the gen- the formation of sulfonylated oxindoles (Scheme 34).71 eration of sulfonyl radicals. König and co-workers developed a visible-light-mediated addition of sodium sulfinates 1 73 SO2R to alkenes. This method provides a general and simple Me R3 procedure for the synthesis of vinyl sulfones (Scheme 36). O N O K2S2O8 R2 O S + R2 1 MeCN, H2O R OH N 1 R3 80 °C R Eosin Y (10 mol%) R1 Me O PhNO2 (1.0 equiv) 2 ArO S 54–93% yield R green LED 2 2 S + R Ar O Na EtOH, 40 °C

SO2Ph 51–99% yield SO Ph Me O 2 Me O O O O O Me S S O N N F Me Me 79% 74% 70% 76%

F3C O O O O OH S S SO2Ph Me O2 S

O OMe O N N 88% 90% Me Me Scheme 36 92% 81%

Scheme 34 Visible-light-initiated addition of sulfinic acids to N- arylacrylamides furnishes sulfonylated oxindoles via an ad- In general, the addition of sulfinic acids or sulfinates to dition/cyclization cascade (Scheme 37).74 alkynes leads to the regioselective formation of the anti- 1 Markovnikov-type products. Shi and co-workers reported a Me SO2R Na2-Eosin Y R3 gold-catalyzed synthesis of α-substituted vinyl sulfones.72 O N O (2 mol%) white LED S + R2 R2 O In the presence of a suitable gold catalyst and gallium(III) R1 OH R3 TBHP (1 equiv) N triflate, regioselective Markovnikov addition to terminal H O, rt 2 Me alkynes takes place (Scheme 35). 60–91% yield

[BrettPhosAu(TA)]OTf Me Me O2 SO Ph S (5 mol%) 2 n O O Bu Ga(OTf)3 (10 mol%) S + R2 R1 S O O 1 R OH 2 N N DCE, rt to 45 °C O R Me Me 50–91% yield 85% 65% O Me Me Cl Me O SO2Tol This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. Ph S O2N N SO2Tol S O O Cl O S N O Me tBu Ph 70% 70% 80% 82% Scheme 37 O

H Under similar reaction conditions, sulfinic acids react H H with phenyl propiolates to afford coumarins (Scheme 38).75

S O Ph O 86%

Scheme 35

Syn thesis N.-W. Liu et al. Review

O The oxidative addition of sodium sulfinates to terminal S alkenes can be catalyzed by molecular iodine in the pres- R1 OH 3 R 77 + Eosin Y (1 mol%) 1 ence of air. Oxygen acts as terminal oxidant, while iodine visible light SO2R O O R2 serves as radical initiator and reducing agent for the initial- 2 TBHP (1 equiv) R O O ly formed β-hydroperoxo sulfone (Scheme 40). MeCN/H2O, rt

55–77% yield O I2 (10 mol%) OH R3 O (air) 2 1 S + 2 SO2R R1 O Na R R2 Ph Ph MeCN, AcOH O2 O2 61–93% yield S I S OH OH HO Me

O O Me O O Me SO2Ph SO2Ph SO2Ph 71% 65% Me Br 93% 72% 79% Ph O2 O2 Scheme 40 S CF3 S

O O Cl O O Me Interestingly, addition of sulfinic acids to alkenes can be 78 58% 77% mediated by oxygen alone. A basic additive, such as pyridine, enhances the reaction rate considerably (Scheme 41). Scheme 38 The reaction proceeds through the initial formation of a β- hydroperoxo sulfone, which is reduced to the correspond- In the presence of oxygen or another oxidant as radical ing hydroxysulfone upon workup with triphenylphospine. trapping reagent, the addition of sulfonyl radicals to 3 alkenes and alkynes yields the corresponding hydroxy or O R R3 pyridine, O2 (air) HO R4 4 keto sulfones. Taniguchi reported a nickel-catalyzed hy- S + 2 R R1 OH R R2 CHCl3, 45 °C droxysulfonylation of alkenes with sodium sulfinates in the 1 then Ph3P SO2R 76 presence of air. Addition to disubstituted alkenes leads to 60–98% yield the formation of trans-substituted β-hydroxy sulfones in- Me OH Me dependent of the olefin configuration (Scheme 39). O2 HO O2 Me S S Ph NiBr2-TEEDA (5 mol%) OMe Me NH4PF6 OH O 83% 66% Ar2 (30 mol%) R S R Ar2 OH Ar1 O Na O AcOH, DMF 1 2 SO2Ar S Me H2O, air, 60 °C OH O2 62–88% yield EtO S F Me OH OH O O2 O2 Me S S 95% 82%

OMe Br Me Scheme 41 80% 74% HO Me OH O2 O2

S S Yadav and co-workers reported a silver nitrate and po- This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. tassium persulfate promoted synthesis of β-keto sulfones Me Me starting from alkenes and sodium sulfinates.79 The same 73% 67% keto sulfones can be also prepared by the oxygen-initiated Scheme 39 addition of sulfinic acids to alkynes (Scheme 42).80

Syn thesis N.-W. Liu et al. Review

Method A Interestingly, in the presence of stoichiometric amounts O O AgNO3 Method B of iodine, the TBHP-mediated reaction of sulfonyl hydra- S K2S2O8 pyridine S 1 O R1 OH R ONa O2 O (air) zides with alkenes yields the corresponding β-iodo sulfones SO R1 2 + 2 2 + 83 H2O R CHCl3 (Scheme 44). Performing the same reaction with alkynes 2 25 °C 2 R 45 °C R furnishes (E)-β-vinyl sulfones (Scheme 45).84

OMe O O O O O I S S H I2, TBHP 1 2 SO R1 R S N NH2 + R 2 2 O O 0–20 °C R O F 71–95% yield 71% 75% Method A Method A O O O O I I O S S 2 O2 S S Me O O S Me 76% 67% MeO Method B Method B 89% 88%

Scheme 42 I I O2 O2 S S Br O Me Sulfonyl hydrazides can be employed as stable and easi- Me ly accessible starting materials for the sulfonylation of 72% 84% double and triple bonds. Jiang and co-workers reported a Scheme 44 copper-catalyzed synthesis of vinyl sulfones based on the oxidative cleavage of a hydrazide, followed by reaction of a O R2 H I2, TBHP 1 2 1 81 R S N NH2 + R SO2R reactive sulfonyl species with the alkene (Scheme 43). Lei I O 0–20 °C and co-workers were able to achieve the generation of sul- 22–94% yield fonyl radicals from sulfonyl hydrazides with catalytic I I amounts of potassium iodide and TBHP (Scheme 43).82

O2S O2S Me Method A S CuCl (10 mol%) O LiBr (30 mol%) H DMSO, 100 °C, air SO R1 1 2 2 2 94% 83% R S N NH2 + R R Method B O KI (20 mol%) I I TBHP DMSO/AcOH, 25–30 °C Pent O2S Me F3C O2S

O2 F N S O2 CF3 Me S Br 22% S 94% Me Me Scheme 45 88% 76% Method A Method B

O2 O2 In the presence of catalytic amounts of copper acrylate This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. S S NC and iron(II) chloride, the reaction of sulfonyl hydrazides Me 85 Me Me with alkynes affords (E)-vinyl sulfones (Scheme 46). The iron-catalyzed reaction of sulfonyl hydrazides with alkenes 54% 79% Method A Method B in the presence of air yields β-hydroxy sulfones (Scheme 86 Scheme 43 47). With Cu(OAc)2 as catalyst, the reaction of sulfonyl hydrazides with alkenes affords the corresponding β-keto sulfones (Scheme 48).87

Syn thesis N.-W. Liu et al. Review

O [Rh(COD)Cl]2 (2.5 mol%) H Fe/Cu catalyst 1 R1 DPEphos (10 mol%) 1 + 2 SO2R 1 R S N NH2 R X R2 SO2R DTBP, DMSO O S O PhCO2H (50 mol%) O + 100 °C 2 X = H, COOH 30–84% yield NHNH2 DCE, 80 °C R R2 79–98% yield

O2 O2 SO2Tol S S SO2Tol SO2Bz

Ph Pent Me OMe 82% 87% 90% 81% 72% Scheme 49 X = COOH X = COOH

O2 S O2 S Another approach to allylic sulfones is the TBAI/TBHP- Br Me N Me mediated reaction of sulfonyl hydrazides with α-substituted styrenes (Scheme 50).89 Generation of a sulfonyl radical, 75% 80% X = H X = H followed by addition to the double bond and elimination Scheme 46 leads to the formation of nonconjugated sulfones.

OH TBAI (20 mol%) Ts R1 TBHP (2.0 equiv) FeCl3, air 1 SO2Tol TsNHNH + TsNHNH2 + R 2 R R R2 THF, 80 °C R2 Ar MeCN, 80 °C Ar 21–90% yield 21–95% yield SO Tol SO Tol 2 2 SO2Tol OH OH OH Me SO2Tol Ph SO2Tol Ph SO2Tol Me F3C MeO 21% 60% 90% N 95% 54% 48% Scheme 50 Scheme 47 Qu, Chen and co-workers developed a copper-catalyzed 1 Cu(OAc)2 (5 mol%) O R SO2NHNH2 O2 1 sulfonylation of alkynes with tert-butylsulfinamide SO2R + Ar 90 EtOH, 70 °C (Scheme 51). Phosphorous acid serves as terminal reduc- 2 R2 R Ar ing agent and the oxidation of the sulfinyl (SO) to the sulfo- 50–72% yield nyl (SO2) moiety takes place under the reaction conditions.

O O O CuSO4 (20 mol%) SO2Ph H PO (2.0 equiv) SO2Ph O 3 3 t SO2Ph Ph TFA (2.0 equiv) SO2 Bu Ph S Me t + MeO Bu NH2 R2 DMF, 100 °C R2 70% 70% 52% 51–81% yield

Scheme 48 t t SO2 Bu SO2 Bu

81%MeO 66% This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. Breit and co-workers reported a rhodium-catalyzed t t S SO2 Bu synthesis of branched allylic sulfones starting from termi- SO2 Bu nal alkynes and sulfonyl hydrazides (Scheme 49).88 The reaction proceeds via a benzoic acid mediated formation of a 53% 69% rhodium–allyl species, which undergoes nucleophilic dis- Scheme 51 placement with a sulfinic acid generated in situ from the sulfonyl hydrazide. Widely available dimethyl sulfoxide (DMSO) is a suitable starting material for the methylsulfonylation of alkenes and alkynes. The ammonium iodide induced addition of DMSO to alkenes yields (E)-vinyl methyl sulfones (Scheme

Syn thesis N.-W. Liu et al. Review

52).91 The authors propose that the reaction proceeds via any catalyst at high temperatures in DMSO97 (Scheme 55). A the generation of thiomethyl radicals and water serves as mechanism consisting of sulfonyl radical formation fol- the source of the second sulfonyl oxygen. lowed by addition to the alkene and decarboxylation is proposed for all transformations. SO Me O NH4I (4.0 equiv) 2 + S O HO C Me Me R DMSO/H2O R 2 conditions SO2R 130 °C S 46–99% yield + R O Na – CO Ar 2 Ar

SO2Me Ph conditions: yield (for R, Ar = Ph) SO2Me MeO Ph 75% 68% PIDA (2.0 equiv), DMF, 100 °C 73% Me SO Me CuCl (20 mol%), KI (1.5 equiv), DMSO, air, 100 °C 74% SO2Me 2 Ph N I (2.0 equiv), TBHP (2.0 equiv), toluene, 90 °C 92% S 2 46% 87% I2 (1.0 equiv), K2CO3 (1.0 equiv), H2O, 60 °C 78% Scheme 52 K2CO3 (0.50 equiv), DMSO, 100 °C 82% The groups of Chen and Qu and the group of Loh report- Scheme 55 ed two procedures for the copper-catalyzed synthesis of (E)-vinyl methyl sulfones from alkynes in DMSO.92 Diethyl Liu and Li reported a copper/silver-mediated domino H-phosphonate acts as terminal reducing agent (Scheme reaction for the synthesis of 2-sulfonylbenzofurans based 53). Loh showed that under identical conditions, the reac- on a cyclization–decarboxylation sequence (Scheme 56).98 tion of alkenes affords β-keto sulfones (Scheme 54).92b 1 HO2C SO2R CuCl2 (0.5 equiv) Method A O AgTFA (2.5 equiv) CuSO (25 mol%) O 4 OH Cs2CO3 (2.0 equiv) (EtO) P(O)H (1.1 equiv) S 2 1 + R1 TFA (2.0 equiv) R O Na DMF, 80–100 °C O 120 °C SO2Me 2 – CO2 R2 + R S Me Me Method B R1 R2 20–79% yield R2 CuBr (10 mol%), O2 (EtO)2P(O)H (3.0 equiv) O O O O 120 °C S S O SO2Me SO2Me Ph O O Ph Me N Me Me H 79% 72% 89% Method A 68% Method A 85% Method B 70% Method B O O O O SO Me SO Me S MeO S 2 2 Tol Et O O MeO F 60% Method A 55% Method A 81% 31% 80% Method B 82% Method B Scheme 53 Scheme 56

CuBr (10 mol%) O R O (EtO)2P(O)H (3.0 equiv) 69

SO2Me Interestingly, palladium-catalyzed as well as phos- This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. S + Ar Me Me O2, 90 °C 99 Ar R phoric acid mediated decarboxylative coupling reactions 43–84% yield of sodium sulfinates with aryl propiolic acids affords (E)-vi- O O O nyl sulfones (Scheme 57).

SO2Me SO2Me S SO2Me Ph Ph As mentioned previously, sulfonyl hydrazides are at- Me tractive alternatives to sulfinates in various transforma- 82% 71% 75% tions. Accordingly, the iodine-mediated reaction of sulfonyl Scheme 54 hydrazides with cinnamic acids yields (E)-vinyl sulfones via a radical addition and carbon dioxide extrusion (Scheme Several groups have developed decarboxylative cou- 58).100 The copper-101 or copper/iron-catalyzed86 decarbox- plings of sodium sulfinates and cinnamic acids for the syn- ylative hydrosulfonylation of phenyl propiolic acids with thesis of vinyl sulfones. These reactions can be mediated by sulfonyl hydrazides furnishes the corresponding vinyl sul- PIDA,93 catalytic ammounts of copper(I) chloride,94 iodine fones (Scheme 59). and TBHP,95 or iodine96 and even proceed in the absence of

Syn thesis N.-W. Liu et al. Review

Method A Lei and co-workers developed a copper-catalyzed decar- O CO2H PdCl2 (5 mol%) boxylative oxosulfonylation of arylacrylic acids with sulfin- DMSO, 100 °C SO2R S + ic acids (Scheme 60).102 Evidence for a single-electron- R O Na Method B Ar transfer process between copper and the sulfinic acid was Ar H3PO4 DMSO, 80 °C provided by extensive spectroscopic studies.

CO2H CuBr2 (10 mol%) O PhO S MeO S O air 1 2 2 + SO2R Ph Ph S Ar Ar R1 OH DMF, rt 83% Method A 91% Method A R2 R2 92% Method B 82% Method B 38–92% yield

O O O O O O O S S SO2Ph SO2Ph SO2Me Ph Ph Ph Ph Ph Me F C 3 92%38% 61% 73% Method A 73% 87% Method A 64% Method B 64% 80% Method B O O Scheme 57 SO2Ph MeO SO2Ph

F MeO I (40 mol%) HO C 2 81% 63% O O 2 DBU, TBHP SO2R S + Scheme 60 R NHNH MeCN, H O, rt 2 Ar 2 Ar 57–88% yield Vinyl acetates are suitable olefins for the synthesis of β-

SO2Tol S SO2Tol Ph keto sulfones. Sulfonylation of vinyl acetates with sulfonyl 87% 78% hydrazides mediated by either iron(III) chloride in the presence of air103 or TBAI and TBHP104 affords the oxidative cou- SO2Ph Ph SO Tol Ph 2 pling products via a radical addition (Scheme 61). 68% 61% Scheme 58 Method A FeCl3 (10 mol%), air O O OAc THF, 70 °C O Method A S + SO R1 1 2 2 2 CO2H CuI/bpy (10 mol%) R NHNH2 R Method B R DMF, air, 100 °C TBAI (20 mol%) O O SO2R TBHP (2.0 equiv) S + R NHNH Method B MeCN, 80 °C 2 Ar Ar copper acrylate (20 mol%) FeCl2 (15 mol%) DTBP DMSO,100 °C O O

SO2Tol SO2Tol Ph Ph SO2Tol SO2Tol Ph Tol Me 91% Method A 53% Method A 85% Method A 60% Method A 70% Method B 40% Method B 81% Method B 73% Method B O O O O SO Tol 2 O O S SO2Tol S S Ph Ph This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. F F OMe 40% Method A 80% Method A 43% Method A 71% Method A 45% Method B 51% Method B 72% Method B 72% Method B Scheme 61 Scheme 59 A photoredox-catalyzed addition of sulfonyl chlorides to vinyl acetates for the synthesis of β-keto sulfones was developed by Zhang, Yu and co-workers (Scheme 62).105

Syn thesis N.-W. Liu et al. Review

AcO 1 Katritzky reported on N-sulfonylbenzotriazoles as ad- O SO2R III O O fac-Ir (ppy)3 (1 mol%) vantageous reagents for the sulfonylation of lithiated het- + S 110 R1 Cl CH2Cl2, white LED erocycles or lithium enolates (Scheme 65). N2, rt 2 R R2 46–98% yield R3 O O O O S N O O O O O O R1 N R2O OLi S R3 N R1 S S R2O O

F3C 69% 98% O O O S N O O O SO Tol R N Het-Li O O 2 N S S R Het

N 71% 46% O O O O Scheme 62 S Ph S Bn

O The TBAI-mediated oxidative coupling of enamides with Me Et O Et O sulfonyl hydrazides yields β-keto sulfones in a similar fash- 60% 71% 106 ion (Scheme 63). O O O O S S S Me TBAI (20 mol%) NHAc O O O O THBP (2.0 equiv) Me SO R1 73% 47% S + 2 2 2 1 R R R NHNH2 MeCN, 80 °C R3 R3 Scheme 65 13–80% yield

O O O O O

SO2Tol S In the presence of Lewis or Brønsted acid, aryl sulfon- Ph Ph ates and aryl sulfonamides will rearrange to the corre- SO2Tol Cl sponding hydroxyaryl and aminoaryl sulfones, respectively 80% 27% 63% (Scheme 66).24a,111 This exetension of the classical Fries re- Scheme 63 arrangement affords a mixture of ortho and para isomers. Solvents and substituents on the aromatic ring can affect the ortho/para ratio. 2.5 Miscellaneous Methods O O XH S Lewis or XH R1 X Brønsted acid Apart from these first four important approaches for the SO R1 2 + preparation of sulfones, several other synthetic routes exist. Δ R2 The reaction of sulfonic acid derivatives, such as sulfonate 2 1 2 R SO2R esters, or sulfonyl chlorides, with organometallic reagents R produces sulfones (Scheme 64).1,107 Generally, these reac- X = O, NR

tions are low-yielding and limited to certain substrate com- Scheme 66 This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. binations. For example, reactions with sulfonyl chlorides frequently afford the corresponding sulfoxides as the major Wang and co-workers reported a copper-catalyzed rear- products.108 It has been shown that sulfonyl fluorides are rangement of N-tosylhydrazones to (E)-vinyl sulfones.112 superior electrophiles for reactions with organomagnesium Prabhu and Ojha developed a similar reaction mediated by or organolithium reagents.109 cyanogen bromide and a phase-transfer catalyst (Scheme 67).113 O O O O O 2 S ++R M S S R1 X R1 R2 R1 R2 X = OR, Cl, F M = Li, Mg, Hg Scheme 64

Syn thesis N.-W. Liu et al. Review

R1 Method A Dienediones react with sulfonamides in an acid-mediat- Cu(OAc) (15 mol%) 1 O S O 2 SO2R ed cascade process furnishing sulfonated cyclopentanes xylene, 90–140 °C 116 NH R2 with three contiguous stereocenters (Scheme 70). N Method B 3 R3 CNBr (1.1 equiv), TBAB (2.5 equiv) R 2 2 R K2CO3 (3.0 equiv), dioxane, 100 °C R O O 1 SO2R R2 TolSO2 TolSO2 TolSO2 O HBF4 (1.0 equiv) S + 1 R NH2 MeCN/CH2Cl2, rt Ph Ph Ph SO2(p-Tol) Me Ph 2 O R 93% Method A 87% Method A 81% Method A 93% Method B 69% Method B 84% Method B O 64–83% yield R2 1,2-syn/2,3-anti major Scheme 67 1,2-anti/2,3-anti minor

O t O t SO Bu SO2 Bu In the presence of a copper catalyst, sulfonyl hydrazones 2 Ph Me can undergo nitrogen extrusion to yield sulfones (Scheme 68).114

O Ph O Me R1 80% (75:25) 66% (68:32) O S O CuI (20 mol%) 1 NH SO2R N K2CO3 O SO Ph O 2 3 2 SO Tol dioxane, 110 °C R R 2 R2 R3 Ph 46–90% yield Me

SO2Tol SO2Tol SO2Tol O Ph O Me Ph Me 73% (70:30) 64% (83:17)

Br OMe Scheme 70

88% 46 % 76% Scheme 68 The reaction of sulfur dioxide with dienes yields sulfo- lenes in a chelotropic reaction. Although this [4+1] cycload- Jiang and Tu reported a THBP/TBAI-mediated synthesis dition is one of the classical textbook examples for a ste- of allenyl sulfones starting from propargylic alcohols and reospecific, pericyclic reaction, it is rarely used in organic sulfonyl hydrazides (Scheme 69).115 The authors propose synthesis.1,117,118 Vogel and Sordo showed that the reaction the formation of a sulfonyl hydrazone followed by a radical of dienes with sulfur dioxide can indeed produce not only fragmentation/coupling process to afford the final product. one but two products.119 Under kinetic control (< –60 °C), a hetero-Diels–Alder reaction takes place and the corre- Ar 3 sponding sultine is formed. Under thermodynamic control TBAI (20 mol%) Ar SO2R O O TBHP (2.0 equiv) (> –40 °C), the sulfolene is formed (Scheme 71). + S 3 C R NHNH2 AcOH, MeCN HO R2 60 °C 2 1 1 R R [4+2] O R This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. SO2 + 42–84% yield S < –60 °C O sultine Ph SO2Tol Ph SO2(2-Np)

C C [4+1] O SO2 + S Ph Ph Ph Ph > –40 °C O 84% 69% Me sulfolene Cl Scheme 71 SO2C6H4-4-Cl SO2Ph C C 3 Metal-Catalyzed Coupling Reactions Ph Ph F F 73% 63% In the last 15 years, transition-metal-catalyzed coupling Scheme 69 reactions of either sulfinates as nucleophilic or sulfonyl halides as electrophilic coupling partners have emerged as at-

Syn thesis N.-W. Liu et al. Review

tractive alternatives to the traditional procedures. They al- CuI (15 mol%) + – DMEDA (15 mol%) low the synthesis of sulfones in a regiospecific manner, of- Ar N2 BF4 TBAI (1.3 equiv) O O ten under milder reaction conditions compared to those + K2CO3 S Tol Ar used in sulfide oxidation or electrophilic sulfonylation reac- O DMSO, N2, 100 °C 72–91% yield tions. Therefore metal-catalyzed coupling reactions can ex- S Tol O Na pand the functional group compatibility considerably. Since the first report by Suzuki and Abe on the copper- O O O O S assisted coupling of sodium sulfinates with non-activated S Tol iodoarenes,120 various improvements have been developed. Tol Ph OMe The introduction of ligands such as proline,121 N,N-di- 91% 89% methyethylenediamine (DMEDA),122 D-glucosamine,123 O O O O Me 124 125 S functionalized ionic liquids or 1,10-phenanthroline Tol S enables the copper-catalyzed coupling of sulfinic acid sodi- Tol NO2 um salts with aryl iodides or bromides (Scheme 72). How- 84% 72% Me ever, there is only one report for copper-catalyzed cross- Scheme 73 couplings with aryl chlorides,126 and this procedure is limited to activated, electron-poor (hetereo)aromatic chlorides, which should undergo a direct, uncatalyzed nucleophilic Xu and Qing employed arenediazonium salts as starting aromatic substitution.1,38 materials in a copper-catalyzed coupling with sodium tri- fluoromethylsulfinate.128 This method allows the mild syn- O conditions O thesis of trifluoromethanesulfonyl-substituted arenes, of S + Ar X RSAr R O Na particular interest for medicinal chemistry, in good yields X = Br, I O (Scheme 74).

O O N +BF – Cu2O (10 mol%) conditions yield 2 4 S + F3CSAr F C O Ar DMSO, N , rt (for R = Ph, Ar = Tol, X = I) 3 Na 2 O 45–90% yield CuI (10 mol%), L-proline sodium salt (20 mol%) 77% DMSO, 90 °C O O O O

. S S (CuOTf)2 PhH (5 mol%), DMEDA (10 mol%) 70% CF3 CF3 DMSO, 110 °C HO2C NO2 52% 85% CuI (10 mol%), D-glucosamine (20 mol%) 94% O O KOAc, DMSO/H2O, 100 °C O O S CF3 S CuI (10 mol%), [enim][Val] (20 mol%) 81% H CF N 3 DMSO, 95 °C Tol S N O O 59% 45% CuFe2O4 (10 mol%), 1,10-phenanthroline (10 mol%) 78% DMF, 110 °C Scheme 74 Scheme 72 Cacchi and co-workers developed a palladium-catalyzed

Nagarkar and co-workers developed a copper-catalyzed coupling of sodium sulfinates with aryl and vinyl halides This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. cross-coupling of sodium p-toluenesulfinate with arenedi- for the synthesis of diaryl and aryl vinyl sulfones.129 The 127 azonium salts as an alternative to aryl halides. The best yields were obtained with Pd2(dba)3–Xantphos as the authors propose a TBAI-mediated in situ formation of aryl catalyst system. The reaction is strongly influenced by the iodides as coupling partners by way of a Sandmeyer-type addition of tetraalkylammonium salts, such as tetrabu- reaction (Scheme 73). tylammonium chloride (Scheme 75). The palladium-catalyzed coupling of vinyl tosylates with aryl sulfonate salts gives aryl vinyl sulfones in a similar manner (Scheme 76).130

Syn thesis N.-W. Liu et al. Review

Pd2(dba)3 (2.5 mol%) The groups of Beaulieu and Evans developed a copper- Xantphos (5 mol%) 1 mediated cross-coupling of boronic acids and sodium sulfi- X TBACl (0 or 1.2 equiv) SO2R 132 O Cs2CO3 (1.5 equiv) nates (Scheme 78). This oxidative coupling reaction pro- + S R1 O Na toluene, argon vides a useful and mild alternative to the just-described 60–120 °C coupling reactions. X = I, Br, OTf 20–96% yield

O O NO2 O O Cu(OAc)2 (1.1 equiv) O K CO (2.0 equiv) O O S S B(OH)2 2 3 + S S R2 1 2 R1 O Na DMSO, 4 Å MS R R rt to 60 °C Me Me 96% 89% Me 19–97% yield

O O O O Me O O O O Me O O S S S S Me S Me Me Me

Me N Ph Me N Me Me Me 80% 52% 97% 63% 19% Scheme 75 Scheme 78

Pd2(dba)3 (2.5 mol%) Xantphos (5 mol%) 1 OTs SO2R O K3PO4 (1.5 equiv) + 3 3 Later, several catalytic versions of these Chan–Evans– S R R R3 R3 R1 O Na toluene, N2,100 °C Lam-type couplings were reported (Scheme 79), including methods with imidazole133 or phenanthroline134 ligands, in 40–75% yield ionic liquids135 or water136 and utilizing magnetically sepa- 125 SO2Tol SO2Tol rable copper ferrite nanoparticles.

BocN O O O B(OH)2 conditions 69% 75% + S S R2 1 2 R1 O Na R R O O conditions yield S Ph 1 2 (for R = Me , R = 4-MeOC6H4) SO2Tol Ph

Cu(OAc)2 (20 mol%) 68% 40% 74% 1-benzylimidazole (40 mol%) Scheme 76 4 Å MS, DMSO, air, 60 °C

Cu(OAc)2 (10 mol%) 60% Yu and Wu reported an interesting palladium-catalyzed 1,10-phenanthroline (20 mol%) synthesis of sulfones by a denitrative coupling of ni- 4 Å MS, CH2Cl2/DMSO, O2, 40 °C 131 troarenes with sulfinic acid salts (Scheme 77). Cu2O (10 mol%), NH3, H2O, air, rt 76% Scheme 79 palladacycle (0.75 mol%) O NO2 K2CO3 (1.0 equiv) + Ar SO2R S Ar R O Na DMSO, N2, 110 °C 48–90% Xu, Liang and co-workers developed a palladium-catalyzed coupling of sulfonyl hydrazones with aryl iodides for N 137

the synthesis of allylic sulfones. Base-mediated decom- This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. Fe Pd Cl 2 position of the hydrazine leads to the simultaneous forma- palladacycle tion of a diazo compound and a sulfinate as nucleophilic coupling partners (Scheme 80).

O O O O SO2R Pd2dba3 (2.5 mol%) S Ph P (15 mol%) 1 Me S NH 3 Ar N BnNEt3Cl (1.0 equiv) I + Na2CO3 (2.5 equiv) N Ar1 SO2R O2N Me Me MeCN, 50 °C 85% 90% Ar2 2 O O O O Ar 40–93% yield O S S S Me 2-Tol Ph Ph O O O Me SO2Tol SO2Ph S S 68% 48% 2-Tol Ph Ph Scheme 77 40% 93% 78% Scheme 80

Syn thesis N.-W. Liu et al. Review

A common method for the regio- and stereoselective more recent example is the iridium-catalyzed regio- and preparation of allylic sulfones is the transition-metal-cata- enantioselective allylic substitution with sodium sulfi- lyzed coupling of allylic electrophiles with sulfinate salts or nates.146 Branched allylic sulfones are obtained in high sulfininic acids.138 Allylic carboxylates,139 carbonates,140 al- regio- and enantioselectivities (Scheme 85). cohols141 or nitro compounds142 can undergo substitution Pd catalyst O OAc SO R1 reactions with sulfinic acids and their salts (Scheme 81). chiral ligand 2 S + Reactivities and regioselectivities can differ significantly R1 O Na R2 R2 R2 R2 depending on the structure of the allyl electrophile and the Scheme 84 catalyst system.

R2 O Pd catalyst O 2 1 2 Ir catalyst (2 mol%) R SO2R + LG SO2R S S + 1 1 R O Y R O Na dioxane, N2, 50 °C

Y = metal or H LG = OAc, OCO2Et, OCO2Me 77–99% yield OH, NO2, etc. 86–98% ee Scheme 81

Tian, Gu and co-workers reported a stereospecific substitution of enantioenriched allylic alcohols with sodium sulfinates that proceeds with complete retention of configuration (Scheme 82).141b Palladium-catalyzed direct substi- O Ir P O tution of allylic amines with sulfinate salts is also possible, N furnishing allyl sulfones with almost complete retention of 143 Ph Ph configuration (Scheme 83). Ir catalyst

Pd(OAc)2 (5 mol%) 1 HO rac-BINAP (5 mol%) R O2S SO Ph SO2Tol O 2 R3 B(OH)3 (4 equiv) 3 + R S n 1 Ph Pr R O Na dioxane, N2, 100 °C R2 R2 92%, 94% ee 92%, 94% ee 51–97% yield i SO2Me SO2 Pr PhO2S PhO2S Me PhO2S Me Me O MeO MeO Ph Cy 95%, 92% ee 99%, 93% ee Scheme 85 90%, 97% ee 72%, 97% ee 51%, 97% ee Scheme 82 Plietker and Jegelka showed that low-valent iron(II) complexes can catalyze the allylation of sodium sulfi-

[Pd(allyl)Cl]2 (0.1 mol%) 147 1 nates. The sulfonylation of allylic carbonates proceeds H2N rac-BINOL (0.4 mol%) R O2S O 3 3 R B(OH)3 (4.0 equiv) R with excellent retention of configuration (Scheme 86). They S + R1 O Na dioxane, N2, 100 °C later extended their work to include α-sulfonyl succinimid- 2 4 2 4 R R R R 148

es as sulfonyl donors. This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. 86–93% yield

OR2 TBAFe (5 mol%) TolO2S TolO2S BnO2S O (4-MeOAr)3P SO R1 Me Me Me O O (6 mol%) 2 S 3 R1 O Na R3 R 4 Ph H Cy H Ph H R4 DMF/MeOC2H4OH R 80 °C 93% 82% 88% 31–86% yield

Scheme 83 Me Me SO2Ph SO2Ph N SO2Ph In addition, various efficient chiral catalyst systems for Me Me O MeO2C the asymmetric allylic sulfonylation were developed in the Me Me Me 1980s and 1990s (Scheme 84).144 In general, these methods 83% 62% 77% enable the highly enantioselective synthesis of allylic sul- Scheme 86 fones, which are useful asymmetric building blocks.145 A

Syn thesis N.-W. Liu et al. Review

The transition-metal-catalyzed coupling of sulfonyl The copper-catalyzed reaction of silyl dienol ethers chlorides with various organometallic reagents is another with sulfonyl chlorides affords γ-sulfonylated α,β-unsatu- approach for the synthesis of sulfones. Crucial for the suc- rated carbonyl compounds (Scheme 89).154 cess of these transformations is the reaction temperature. OTMS O Vogel and co-workers showed that, at higher temperatures, O CuCl (10 mol%) MeCN, 80 °C desulfinylative carbon–carbon bond formation via sulfur RSCl + 149 dioxide extrusion takes place. Palladium-catalyzed reac- O 150 151 tion of organostannes or organoboronic acids with sul- SO2R fonyl chlorides at low temperatures yields the desired sul- 38–87% yield fones (Scheme 87). O2 O2 S S Method A (M = SnR ): O 3 O Pd(PPh3)4, THF, 65–70 °C O 1 R2 M R1 S R2 O Me R S Cl + 87% 70% Method B (M = B(OH)2): O O PdCl2, K2CO3 O acetone/H O, 0–25 °C O2 2 2 S M = SnR3, B(OH)2 S

Me O Me O N Me

O2 CO2Me S 75% Me S dr = 15:1 56% O2 MeO Scheme 89 90% 57% Method A Method A 4 Sulfone Synthesis by C–H Functionaliza- O2 O2 S S tion

MeO N Me The selective functionalization of C–H bonds plays a key 98% 82% Method B Method B role in the development of efficient and sustainable meth- 155 Scheme 87 ods for organic synthesis. Regioselective metal-catalyzed as well as metal-free activations of C–H bonds have emerged as valuable tools for the preparation of carbon– Hu and Lei reported copper-catalyzed coupling reac- carbon and carbon–heteroatom bonds. In recent years, syn- tions of sulfonyl chlorides with arylboronic acids152 or or- thesis of sulfones by selective functionalization of C–H ganozinc reagents,153 respectively (Scheme 88). bonds has become an important area of research. Although the established Friedel–Crafts-type sulfonylation can be Method A (M = ZnX): considered as C–H functionalization, recent research efforts O CuI (5 mol%), TMEDA (2.0 equiv) O THF, rt focus on different reactivity profiles. R1 S Cl + R2 M R1 S R2 Method B (M = B(OH)2): O Dong and co-workers reported the first palladium-cata- (phen)CuBr (10 mol%), K CO O 2 3 lyzed C–H bond sulfonylation of phenylpyridines with sul- CH2Cl2/H2O, rt 156 M = ZnX, B(OH)2 fonyl chlorides (Scheme 90). Mechanistic studies indicate a Pd(II)/Pd(IV) catalytic cycle.157 O O2 2 S O2 This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. S S Me Pd(MeCN)2Cl2 (10 mol%) N Br S N O K2CO3 + RSCl SO R H 4 Å MS 2 O 86% 74% 76% dioxane, 120 °C Method A Method A Method A 41–88% yield O2 O2 S S OMe Ph N N O N N Me SO Tol SO2Tol OMe SO2Tol 2 88% 73% Method B Method B

Scheme 88 82% 78% 42%

Scheme 90

Syn thesis N.-W. Liu et al. Review

Palladium-catalyzed sulfonylation of 2-aryloxypyridines DG O Pd(PhCN)2Cl2 (10 mol%) DG K2CO3, 4 Å MS 1 SO R1 with sulfonyl chlorides proceeds in the ortho-position rela- 2 + R S Cl 2 2 R dioxane, 120 °C R 158 O tive to the directing group. Removal of the pyridyl group R3 R3 thus gives access to ortho-sulfonylated phenols, which are 25–70% yield difficult to synthesize otherwise (Scheme 91). Me Me Cl O2 O2 S S

N N Pd(OAc) (8 mol%) O N O O N Cl Cl K2CO3 + 67% Me 61% H RSCl SO2R 4 Å MS O O dioxane, 120 °C O Me NH NH O 29–67% yield Me O2 2 S S

N N O Me O O 61% 33% O2 O2 S S Scheme 93

Me Cl 62% Cl 46% Palladium-catalyzed coupling of quinones with arylsulfonyl chlorides gives rise to arylsulfonyl quinones via a N N Heck-type coupling (Scheme 94).161 O O O2 O2 S S O O

O O Pd(OAc) (5 mol%) Me 2 + RSCl Me K2CO3 H O DCE, 90 °C SO2R 47% 57% O O 52–91% yield Scheme 91 O Two independent reports describe the ortho-sulfonyla- O O OMe Me tion of azobenzenes with arylsulfonyl chlorides via palladi- 159 um-catalyzed C–H activation (Scheme 92). Loh and co- S S S O O2 O2 2 workers developed a palladium-catalyzed alkenyl C–H bond O O OMe O sulfonylation of vinyl pyridines and enamides with sulfonyl 89% 81% 63% chlorides (Scheme 93).160 Scheme 94 Ph N N Method A: Ph N Regioselective ortho-sulfonylation of quinolone N-ox- Pd(OAc)2 (5 mol%) K2S2O5 (1.1 equiv) N ides was achieved via copper-catalyzed C–H bond activa- H DCE, air, 110 °C 162 + tion (Scheme 95). Method B: O SO2R Pd(MeCN)2Cl2 (10 mol%) RSCl K CO , 4 Å MS O 2 3 CuI (10 mol%) O dioxane, 130 °C + RSCl

N H N SO R This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. O K2CO3 2 Ph Ph O DCE, 100 °C N N O N Me N F 28–91% yield

Me S S OMe O2 O2

90% 86% N S N S Method A Method B O2 O2 O O Ph Ph 80% 84% N N Me N N Me Me Me F N S S N S N S O2 O2 O O2 O2 CN O O Me 71% 90% 53% 65% Method A Method B Scheme 95 Scheme 92

Syn thesis N.-W. Liu et al. Review

Kambe and co-workers reported a nickel-mediated C–H bond sulfonylation of benzamides enabled by the 8-amino- [Ru(p-cymene)Cl ] N O 2 2 N 163 (2.5 mol%) quinoline (AQ) directing group (Scheme 96). + RSCl K2CO3 O MeCN, 115 °C H H O N O N H SO2R AQ O AQ NiCl2 (50 mol%) 1 23–74% yield H + R1 S Cl SO2R Na CO R2 2 3 R2 O dioxane, 140 °C

N N N AQ = 33–57% yield N Br Me AQ AQ O NH SO2Ph S S O NH O2 O2 O O 2 2 S Me S 70% 74% 40%

OMe 42%Cl 38% Scheme 98 Scheme 96 Several groups reported copper-mediated ortho-sulfo- Interestingly, the copper-catalyzed reaction of benz- nylations of benzoic acid derivatives with sodium sulfinates amides bearing the 8-aminoquinoline moiety with sulfonyl employing the 8-aminoquinoline (AQ),166 the 2-pyridinyl chlorides leads to a remote functionalization of the quino- isopropyl (PIP),167 or the amide-oxazoline (Oxa)168 directing line (Scheme 97).164 groups (Scheme 99). These oxidative coupling reactions utilize sulfinates as the coupling partner. H O N H H 2 O N O N R DG DG N H H O N O H conditions SO2R CuCl (10 mol) S R2 + 2 R O Na Na2CO3 N SO2R O toluene, 110 °C R1 S Cl 27–89% yield Me O Me O N 2 N SO2Ph S S H NH O O O H N N N

Ph N Ph N AQ PIP Oxa H H N N

86% 86% Ts Ts conditions: O O yield (for R = Ph)

DG = AQ Cu(OAc) (1.0 equiv), K CO N N 2 2 3 76% H H DMF, 80 °C S N N 78% 70% DG = PIP Cu(OAc)2 (10 mol%), Ag2CO3 73% DCE, 120 °C Scheme 97 DG = Oxa Cu(OAc)2 (2.0 equiv), K2CO3 69% This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. TFE, 80 °C Scheme 99 A ruthenium-catalyzed regioselective meta-sulfonylation of 2-phenylpyridines with sulfonyl chlorides was developed by Frost and co-workers.165 The observed switch in Shi and co-workers described a palladium-catalyzed di- regioselectivity is attributed to a change in the mechanistic rect sulfonylation of non-activated C(sp3)–H bonds with so- pathway via a para-directing Ru–C bond (Scheme 98). dium sulfinates enabled by the 8-aminoquinoline moiety (Scheme 100).169 Late-stage sulfonylation of complex molecules can be achieved with this method.

Syn thesis N.-W. Liu et al. Review

Pd(OAc)2 Qu, Zhao and co-workers developed a metal-free, H- (10 mol%) O O phosphonate-mediated direct sulfonylation of heteroaro- MesCO2H O 2 R2 AQ (20 mol%) R AQ matic N-oxides with sulfonyl chlorides,172 wherein 2-sulfo- S N N R1 O Na H H Ag2CO3 nyl-N-heterocycles are obtained as products (Scheme 103). 1 H CH2Cl2, 90 °C SO2R

26–72% yield i O HP(O)(O Pr)2 (1 equiv) KOH O + RSCl O O N SO2R N H O THF, rt N N N O 35–87% yield H H O N N SO2Ph SO2Ph Me N 72% 53% O2 Me Me S O H N S O N O2 H Me OMe N 86% SO2Ph 65% 44% N Me

Scheme 100 N S O N S 2 O2

60% 35% The copper-catalyzed oxidative coupling of oxime acetates with sodium sulfinates provides access to sulfonylvi- Scheme 103 nylamines and keto sulfones via a formal C(sp3)–H bond activation (Scheme 101).170 The groups of Deng and Kuhakarn described methods for the regioselective C2-sulfonylation of indoles with sodi- NH2 um sulfinates catalyzed or mediated by iodine (Scheme 1 SO2R O R2 104).173 Both authors propose an addition–elimination S 1 direct product R O Na Cu(OAc)2 (10 mol%) mechanism for this transformation. Later, an extension to toluene, 100 °C or the coupling of azetidine and oxetane sulfinate salts was re- 174 HO (hydrolysis with SiO2) O ported. N SO R1 2 2 H R R2 O after hydrolysis Method A: S R1 O Na I2 (10 mol%), TBHP AcOH, rt R2 SO R1 O O 2 NH2 O2 Method B: N SO Tol H 2 S I2 (1.5 equiv), MeOH, rt SO2Tol Ph 2 Ph R H S N H 92% 78% 97% Me Scheme 101

SO2Ph SO2Me N N Kamijo and co-workers reported a photoinduced sulfo- H H 171 84% nylation of ethereal C–H bonds with sulfonyl chlorides. 90% This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. Method A The C–H bond activation is achieved by hydrogen abstrac- Method A tion with photoexcited benzophenone (Scheme 102). SO2 N SO2 ν O O Ph2C=O, h O Me N 1 1 H H + R S Cl SO2R acetone, rt NBoc n O n Cl 44–100% yield 75% 94% Method B Method B Ts Scheme 104 H Ts O O O2 O S Oct TBHP/TBAI-mediated oxidative coupling of C2/C3-un- substituted indoles with sulfonyl hydrazides leads to the H formation of 3-sulfonyl-2-sulfonyldiazenyl-1H-indoles 44% 100% 74% (Scheme 105).175 Scheme 102

Syn thesis N.-W. Liu et al. Review

O Of course, sulfur dioxide (SO2) would be an obvious H R1 S N NH 1 2 SO2R choice as reagent for the installation of a sulfonyl (-SO2-) O TBAI (30 mol%) TBHP moiety. Sulfur dioxide is produced on an enormous scale 2 H R N 1 and has been utilized by mankind since ancient times. MeCN, 40 °C N N SO2R H However, it is a toxic and corrosive gas. The associated safe- R2 H N 42–87% yield ty considerations and the difficult handling can limit the H use of sulfur dioxide in the laboratory-scale synthesis of fine chemicals. Despite this, sulfur dioxide has found vari- SO2Tol SO2Tol Cl ous applications in organic synthesis.178 Important exam- N N ples include the sulfur dioxide ene reaction and the associ- N N SO Tol N N SO2Tol 179 H 2 H ated sulfur dioxide induced alkene isomerization, as well 87% 72% as copolymerizations with alkenes to produce polysul- 180 Scheme 105 fones. Vogel and co-workers were among the first to investi- gate the potential of sulfur dioxide as a reagent in the syn- Xiao, Deng and co-workers reported a metal-free direct thesis of complex molecules.177d They reported a Lewis acid sulfonylation of 2-methylquinolines with sodium sulfinates promoted ene reaction of enoxysilanes and allylsilanes or mediated by potassium iodide and TBHP (Scheme 106).176 allylstannanes.181 The formed sulfinates can be trapped in situ with a variety of electrophiles, enabling a one-pot, O three-componenet synthesis of polyfunctional sulfones S KI (1.0 equiv) R O Na X TBHP (1.0 equiv) (Scheme 107).

DMSO/AcOH SO2R N SO X air, 80 °C 2 1 R O R1 O OSiMe3 TBSOTf (cat.) 3 H 37–94% yield R -X 1 O N R R2 S TBAF 2 3 R SO2R 2 R OSiMe3 N Ph SO2 R1 1 SO Ph TBSOTf R R1 2 SO2Ph 3 F N N (cat.) R -X O 2 2 (TBAF) R M R S R2 SO R3 94% 69% 2 OM M = SiMe3, SnBu3 O2 S O2 50–88% yield N S N

Me O O 51% 56% O O S CO2Et S Scheme 106 60% 65%

5 Sulfur Dioxide Based Three-Component O O O O O O S CO2Et Approaches MeO S Ph Me Me

Almost all hitherto-described methods for the synthesis This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. of sulfones utilize starting materials that already contain a 50% 70% sulfur functionality. Only a few of these sulfur-containing Scheme 107 starting materials are commercially available, and their synthesis can be quite cumbersome. Therefore, efficient methods for the incorporation of the sulfonyl moiety from Unfunctionalized alkenes can react with sulfur dioxide simple, readily available sources offer a very attractive ap- in the presence of stoichiometric amounts of boron trichlo- proach for the preparation of sulfones. In the last 10 to 15 ride to form sulfinic acid–boron trichloride adducts, which years, the development of new one-pot and multicompo- can be hydrolyzed with base to generate sulfinates.182 Reac- nent processes for the synthesis of sulfones from two tion of the latter with alkyl halides yields α,β-unsaturated sulfur-free starting materials and a simple sulfonyl source sulfones in a one-pot transformation (Scheme 108). has become a very active area of research.177

Syn thesis N.-W. Liu et al. Review

The reaction of organometallic compounds with sulfur R1 R1 R3 SO 3 dioxide gas for the preparation of sulfinates is well docu- 2 R 4 3 BCl R2 R -X R 1,178a R1 3 R2 mented. Direct trapping of these salts without prior O CH2Cl2 NaOH 2 S 4 isolation provides a convenient one-pot approach for the R –20 °C SO2R OH.BCl 3 80–91% yield synthesis of sulfones. Since various efficient procedures for the preparation of a plethora of highly functionalized organometallic reactions are known,185 this process offers an O O O O O Me S attractive approach for the synthesis of complex sulfones. S Ph Ph A group from Boehringer Ingelheim developed a practi- Me 83% 87% cal three-step protocol for the transformation of (hetero)aromatic halides into sulfones (Scheme 110).186 Their proce-

O O O O O dure consists of (1) generation of a Grignard reagent via S S Ph magnesium–halide exchange; (2) reaction of the Grignard Ph Me reagent with sulfur dioxide to afford the corresponding magnesium sulfinate; and (3) trapping of the sulfinate with 80% 85% an alkylating agent. Scheme 108 1) cPentMgBr O O O THF, –40 °C R-X Vogel and co-workers pioneered the use of sulfur diox- Ar X S S 2) SO Ar OMgBr Ar R ide in Lewis acid mediated hetero-Diels–Alder processes as 2 60–91% yield a novel method to construct C–C bonds via an umpolung of electron-rich 1,3-dienes.183 A typical example is depicted in Scheme 109. Reaction of a mixture of an electron-rich diene O O O O with sulfur dioxide and a silyl enol ether in the presence of S S (CH ) OAc a Lewis acid affords a silyl sulfinate. The Lewis acid catalyz- 2 4 es the initial formation and heterolysis of the hetero-Diels– EtO2C EtO2C Alder adduct to from a zwitterionic sulfinate, which is 91% 65% trapped by the enoxy silane as terminal nucleophile. Treat- O O O O ment of the sulfinate with tetrabutylammonium fluoride S S (CH2)4OAc (TBAF) and methyl iodide affords the corresponding sulfone N (CH2)4OAc in 63% yield and high stereoselectivity. This method allows S the one-pot, four-component synthesis of polyfunctional Me sulfones and sulfonamides and has found application in the 60% 94% total synthesis of complex molecules and natural prod- Scheme 110 ucts.183,184 A similar one-pot sequence has been reported with a di- OSiMe3 aryliodonium salt as terminal electrophile (Scheme 111).187 Me SO2 OMe OMe Et This procedure allows the efficient synthesis of aryl sul- TBSOTf LA (cat.) O O + fones starting from (hetero)aromatic or aliphatic halides as S S O O well as non-prefunctionalized (hetero)arenes. The lithium, OMe

magnesium and zinc reagents were prepared via metal in- This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. sertion, exchange or deprotonation. OSiMe3 It has been shown that lithium sulfinates, prepared in Me Et situ from the reaction of organolithium compounds with sulfur dioxide, can undergo oxidative coupling with benzoic acids bearing the amide-oxazoline (Oxa) directing group O via copper-mediated C–H bond activation (Scheme 112).168 SO2Me TBAF S O OMe MeI O OMe OSiMe3

Et Et Me Me

63%, dr = 81:19 100% Z

Scheme 109

Syn thesis N.-W. Liu et al. Review

RX + – O O Pd(OAc)2 1) metalation Ar2I Y O O O or RSOM S Ph3P, 1,10-phenanthroline R-X 2 S 2) SO2 R Ar Ar X S Ar O Ar R RH K S O , NaO CH 17–97% yield 2 2 5 2 X = Br, I TBAB 31–79% yield M = Li, MgX, ZnX DMSO, 70 °C

O O O O O O O O S t S S S CO2 Bu NC N Me

EtO2C MeO MeO 85% 64% 58% 56% O O O O Me O O O O S S N Ph S S Me MeO2C Me Me Me N 51% 80% 68% 57% Scheme 111 Scheme 113

H O N DG DG Ar B(OH) [Pd(MeCN)2Cl2] (10 mol%) 2 O O H O NH tBuXPhos (10 mol%) + S Ar R O K2S2O5, TBAB SO2R RX SO2 DMF, 85 °C RLi S 39–96% yield R OLi Cu(OAc) 2 O O K2CO3 O O TFE, 80 °C 81% (R = Ph) S S n n n Pr O Pr O 44% (R = Bu) N N DG = Me N N Me H 58% 96%

Scheme 112 O O O O NHBoc S CO2Et S CO2Me

Despite its potential utility, there are some drawbacks MeO MeO associated with the toxic, corrosive and gaseous nature of 94% 51% sulfur dioxide. A popular strategy to overcome this limita- Scheme 114 tion is the use of solid, easy-to-handle surrogates.10c,177 Sim- ple, commercially available metal sulfites (MSO3) or meta- bisulfites (M2S2O5) can release sulfur dioxide upon the addi- The gold-catalyzed reaction of (hetero)arylboronic acids tion of Brønsted acids or upon heating to high with K2S2O5 and alkyl halides yields the corresponding sul- temperatures. Researchers from Pfizer described a palladi- fones in a similar fashion (Scheme 115).190 um-catalyzed sulfonylation of (hetero)aryl halides with potassium metabisulfite (K2S2O5) and sodium formate t BuP3AuCl 188

(Scheme 113). Direct reaction of the generated sulfinates (10 mol%) This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. O O with alkyl halides enables the one-pot synthesis of sul- K2S2O5 Ar B(OH)2 + RX S fones. DIPEA Ar R MeOH/toluene They later reported a palladium-catalyzed three-com- 100 °C 46–66% yield ponent synthesis of sulfones from (hetero)arylboronic O O O O Me O O acids, alkyl halides and potassium metabisulfite (Scheme S Ph S Ph S Ph 114).189 The authors propose an in situ formation of a palla- N dium sulfinate, which then reacts with the alkyl halide. N Me Me

56% 49% 53% Scheme 115

Syn thesis N.-W. Liu et al. Review

Willis and co-workers pioneered the use of the 1,4-di- t Pd(OAc)2 O O 1) BuLi Ar1 SO ligand 1 2 S azabicyclo[2.2.2]octane–bis(sulfur dioxide) adduct DABSO Ar Br 1 2 2) DABSO 2 Ar Ar as very useful, solid and bench-stable sulfur dioxide surro- Li Ar -Br, Cs2CO3 dioxane, 110 °C 35–98% yield gate.191 The addition of organolithium or organomagnesium reagents to DABSO generates the corresponding sulfinates, Me Me which can be directly trapped with a variety of different electrophiles, such as alkyl halides, epoxides or diaryliodo- ligand [R = 3,5-(F3C)2C6H3)] O nium salts (Scheme 116).192 This method enables the one- PR2 PR2 pot synthesis of a diverse set of sulfones. Organozinc reagents react with DABSO in a similar manner, and the gen- O O O O erated zinc sulfinates can be alkylated to form sulfones S S (Scheme 117).193 CO2Me N OMe Me Me O O O 81% 95% DABSO E+ RM RS S THF, –40 °C R E OM O O O O 46–94% yield M = Li, MgX F3C S Me S O O O O S Ph Cl S S Ph OMe Me OMe 92% MeO2C 93%

83% 46% Scheme 118 O O OH O O O S S nBu Ph O Pd(OAc)2 Me + O O PAd2Bu Ar SO E 90% 56% Ar I 2 S Ar E DABSO, Et3N HNEt3 Scheme 116 iPrOH, 75 °C 38–90% yield

O O O O DABSO O 2 O O t R -X S CO2 Bu S CO tBu R1 ZnX R1 S S 2 DMSO R1 R2 THF, 21 °C OZnx 70 °C S 25–90% yield MeO2C O O O O 74% 64% O O t t S Ph S CO2 Bu S S CO2 Bu O O O O OH N CO2Et BocHN CO2Me Me S Ph Me S 58% 89 % 77% Scheme 117 Me Me 85% 76% Reaction of organolithium reagents with DABSO, fol- Scheme 119 lowed by palladium-catalyzed cross-coupling of the formed

lithium sulfinate with (hetero)aryl halides allows the three- This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. component synthesis of aryl sulfones (Scheme 118).194 The Waser and Chen reported a one-pot, three-component lithium reagents can be prepared in situ through halogen– synthesis of aryl alkynyl sulfones through the reaction of in lithium exchange. situ generated sulfinates with ethynyl-benziodoxolone Palladium-catalyzed coupling of aryl halides with (EBX).196 The sulfinates were prepared from DABSO and an DABSO in the presence of triethylamine yields ammonium organomagnesium reagent or aryl iodide and a palladium sulfinates. These salts can be directly converted into a vari- catalyst (Scheme 120). ety of sulfones by trapping with different electrophiles (Scheme 119).195

Syn thesis N.-W. Liu et al. Review

Ar-Br + Mg O O Wu and co-workers extended this approach to the syn- DABSO R-EBX S thesis of diaryl sulfones utilizing diaryliodonium salts as or Ar-SO2 Ar electrophiles.199 In this study, the intermediate sulfonyl hy- Ar-I + cat. Pd(0) R 39–85% yield drazines were prepared by reaction of diazonium salts with DABSO and hydrazines (Scheme 122).200 R I O 1 + – Ar N2 BF4 O 1) DABSO, MeCN, rt O O S + 2 + – Ar1 Ar2 2) (Ar )2I BF4 O 2-methylbutan-2-ol R-EBX 42–88% yield N 90 °C H2N O O O O S S

i O O Si Pr3 i O Si Pr3 O O O O MeO2C S Ph S S 56% 70% Ph Ph

Cl OMe O O O O CO2Me S S 74% 88% 42% tBu i Si Pr3 Me Scheme 122

79% 46% Scheme 120 Feng and co-workers reported an iodide-catalyzed three-component synthesis of vinyl sulfones from aryldi- Building on their previous results with the palladium- azonium salts, DABSO and alkenes (Scheme 123).201 catalyzed aminosulfonylation of aryl halides,197 the Willis + – (Het)Ar N2 BF4 TBAI (10 mol%) O group developed a different approach for the one-pot syn- TBHP O (Het)Ar S + thesis of aryl sulfones based on in situ generated sulfonyl DABSO 198 MeCN, 80 °C 1 hydrazines. Key steps in this transformation are the pal- R1 R ladium-catalyzed aminosulfonylation of the aryl halide 58–88% yield with DABSO and the hydrazine, degradation of the generat- O O O O ed sulfonyl hydrazine to the corresponding sulfinate, and Cl S S sulfinate alkylation to yield the desired sulfone (Scheme S Ph Ph 121). 82% 75% O O O O Ph S S N O O Ph Pd(OAc)2 (10mol%) I S NR2 tBu P.HBF (20 mol%) 2 3 4 N CO2Me R1 R1 H 2 71% 83% DABSO, H2N-NR 2 Scheme 123

K2CO3 BnBr

O O O 6 Biological Synthesis of Sulfones 3 S R -X S This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. R3 1 O K R R1 Considering the biological activity profile of sulfones, 36–91% yield and especially their antibacterial activities, it is very sur- O O O O prising that there are only three known examples of natu- S Ph S Ph rally occurring sulfones (Figure 2). The diaryl sulfone echi-

N nosulfone A, a bromoindole derivative, was isolated from H MeS 202 36% 89% the marine sponge Echinodictyum sp. So far nothing is known about the biosynthesis of echinosulfone A. Only as O O O O recently as 2015 did Hertweck and co-workers report the S S CO2Et Me isolation of two more diaryl sulfones, sulfadixiamycins B Me Me EtO EtO and C, from recombinant Streptomyces species harboring the entire xiamycin biosynthesis gene cluster.203 The au- 55% 57% thors propose a flavoprotein-mediated incorporation of Scheme 121 sulfur dioxide, via a radical copolymerization of two carba-

Syn thesis N.-W. Liu et al. Review zoles with sulfur dioxide. This report might provide useful References insights for biomimetic synthesis of sulfones in organic lab- oratories. (1) (a) Whitham, G. H. Organosulfur Chemistry; Oxford University Press: Oxford/New York, 1995. (b) Oae, S. Organic Chemistry of Sulfur; Plenium Press: New York, 1977. (c) Stirling, C. J. M. O O Organic sulphur chemistry: Structure, mechanism, and synthesis; Br Br S Butterworths: London/Boston, 1975. (d) Patai, S.; Rappoport, Z.; HO C 2 H Me Stirling, C. J. M. The Chemistry of Sulphones and Sulphoxides; HO N NH Wiley: New York, 1988. HO2C (2) Trost, B. M.; Chadiri, M. R. J. Am. Chem. Soc. 1984, 106, 7260. echinosulfone A Me NH (3) (a) Simpkins, N. S. Tetrahedron 1990, 46, 6951. (b) Forristal, I. J. Sulfur Chem. 2005, 26, 163. (4) (a) Alonso, D. A.; Ájera, C. N. Org. React. 2009, 72, 367. (b) Gui, J.; OH Zhou, Q.; Pan, C.-M.; Yabe, Y.; Burns, A. C.; Collins, M. R.; Me O S Me Ornelas, M. 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S.-S.; Zhou, Y.; You, J.-B.; Yang, Q.; Wang, C.; Chu, T.-S.; Liu, D.- C.; Yu, X.-L.; Sun, Y.-H.; Ning, Y.; Wei, Z.-H.; Chen, S.-L.; Chen, X.-C.; Zhang, Z.-X.; Liu, Y.-X.; Pulit, S. L.; Wu, W.-B.; Zheng, Z.-Y.; Acknowledgment Yang, R.-D.; Long, H.; Liu, Z.-S.; Wang, J.-Q.; Li, M.; Zhang, L.-H.; Wang, H.; Wang, L.-M.; Xiao, P.; Li, J.-L.; Huang, Z.-M.; Huang, J.- We thank Prof. Michael Göbel for his support. Funding by the Fonds X.; Li, Z.; Xiong, L.; Yang, J.; Wang, X.-D.; Yu, D.-B.; Lu, X.-M.; der Chemischen Industrie (Liebig Fellowship to G.M.), the Deutsche Zhou, G.-Z.; Yan, L.-B.; Shen, J.-P.; Zhang, G.-C.; Zeng, Y.-X.; de Forschungsgemeinschaft (DFG), and the Chinese Scholarship Council Bakker, P.; Chen, S.-M.; Liu, J.-J. N. Engl. J. Med. 2013, 369, 1620. (PhD fellowship to S.L.) is gratefully acknowledged.

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