氧杂蒽与亚磺酸钠的电化学氧...3)—H磺酰化反应（英文）_危斌.pdf

有机化学有机化学 Chinese Journal of Organic Chemistry ARTICLE *Corresponding authors.E-mail:; Received July 5,2022;revised July 29,2022;published online September 15,2022.Project supported by the National Natural Science Foundation of China(Nos.51878326,21861027,22161030,21901100),the Natural Science Foundation of Jiangxi Province(Nos.20212ACB203007,20204BCJ23010,20202ACBL216017,20212AEI91002,20202ACB203002)and the Natural Science Foundation of Jiangxi Provincial Education Department(Nos.GJJ210906,GJJ210909).国家自然科学基金(Nos.51878326,21861027,22161030,21901100)、江西省自然科学基金(Nos.20212ACB203007,20204BCJ23010,20202ACBL216017,20212AEI91002,20202ACB203002)和江西省教育厅自然科学基金(Nos.GJJ210906,GJJ210909)资助项目.共同第一作者(These authors contributed equally to this work).186 http:/sioc- Shanghai Institute of Organic Chemistry,Chinese Academy of Sciences Chin.J.Org.Chem.2023,43,186194 DOI:10.6023/cjoc202207012 研究论文研究论文 氧杂蒽与亚磺酸钠的电化学氧化 C(sp3)H 磺酰化反应 危 斌 周子龙 秦景灏*严泽宇 郭嘉程 雷 澍 谢叶香 欧阳旋慧*宋仁杰*(南昌航空大学 江西省持久性污染物控制与资源回收重点实验室 南昌 330063)摘要摘要 研究了氧杂蒽与亚硫酸钠的 C(sp3)H 键的直接电化学磺酰化反应.在室温下一步合成了多种 9-(芳基磺酰基)-9H 氧杂蒽和 9-(烷基磺酰基)-9H 氧杂蒽.该反应通过自由基途径进行,并在该电化学磺酰化转化下形成新的 CS键.这种策略的显著优点包括无需过渡金属和额外的氧化剂、反应条件温和、操作简单、底物范围广以及优异的官能团耐受性.关键词关键词 电化学氧化;磺酰化;氧杂蒽;亚磺酸钠 Electrochemical Oxidative C(sp3)H Sulfonylation of Xanthenes with Sodium Sulfinates Wei,Bin Zhou,Zilong Qin,Jinghao*Yan,Zeyu Guo,Jiacheng Lei,Shu Xie,Yexiang Ouyang,Xuanhui*Song,Renjie*(Key Laboratory of Jiangxi Province for Persistent Pollutants Control and Resources Recycle,Nanchang Hangkong University,Nanchang 330063)Abstract A direct electrochemical sulfonylation of C(sp3)H bonds of xanthenes with sodium sulfinates was studied.A wide variety of 9-(arylsulfonyl)-9H-xanthenes and 9-(alkylsulfonyl)-9H-xanthenes were constructed in a single step at room temperature.This reaction proceeded through a radical pathway and a new CS bond was formed under this electrochemical sulfonylation transformation.The significant advantages of this strategy include transition metal-and additional oxidant-free,mild reaction conditions,operational simplicity,broad substrate scope and excellent functional group tolerance.Keywords electrooxidation;sulfonylation;xanthene;sodium sulfinate 1 Introduction Organic molecular skeleton bearing a sulfonyl group(RSO2)has gained most interest because sulfone derivatives not only exist in natural products,pharmaceuticals,biolo-gical reagents,agrochemicals and dyes but also act as most commonly synthetic building blocks in organic synthetic field.1-2 In particular,functionalized benzyl sulfones become an ideal molecular for medicinal applications due to the unique pharmaceutical activities.For example,Rigo-sertib as a Ras mimetic that inhibites the phophoinositide 3-kinase and polo-like kinase pathways,has been used to test in patients with higher-risk myelodysplastic syndromes(MDS)following treatment with hypomethylating agents(HMAs)(Figure 1,a).1c Bensulfuron-methyl(BSM)is widely used to control broad-leaf weeds in rice paddies as a kind of sulfonylurea herbicide(Figure 1,c).1a In view of the importance and the wide applications of functionalized benzyl sulfones,some synthetic strategies have been developed for building such architectures.3-4 For instance,the group of Nakata4a reported a sulfonylation of diaryl-methanol diastereomixtures to afford chiral diarylmethyl sulfones in MeNO2 by using SnBr2 as the catalyst and trimethylchlorosilane(TMSCl)as the additive at 15 or 40 (Scheme 1,a).Afterwards,Zhang and co-workers4c have achieved a C(sp3)H sulfonylation of Chinese Journal of Organic Chemistry ARTICLE Chin.J.Org.Chem.2023,43,186194 2023 Shanghai Institute of Organic Chemistry,Chinese Academy of Sciences http:/sioc- isoquinoline-1,3(2H,4H)-diones under NaI/AcOH/dimethyl sulfoxide(DMSO)system at 80.Very recently,the group of Kanyiva and Shibata4b described a silver-cata-lyzed C(sp3)H sulfonylation for the synthesis of benzyl sulfones by the use of-amino acid sulfonamide as the sulfonating agent in the presence of AgF and Na2S2O8 at 100.Throughout these reactions,there may be some limitations,such as single reaction substrate,poor atom economy,reaction temperature limitations,etc.Thus,the development of an environment-friendly,highly-atom-economy and metal-free C(sp3)H sulfonylation method is highly desirable.Recently,much attention has been paid to direct C(sp3)H functionalization5 of xanthenes,which provided 9-substitued-9H-xanthene derivatives.Our team and other groups6 have implemented the construction of these compounds by using electrochemical tool,respectively,in which new CC,CP or CN bond was formed.In addition,organic electrochemical synthesis has proven to be a revolutionary tool in the synthesis of organic molecules.7 However,to the best of our knowledge C(sp3)H sulfonylation of xanthenes with simple sulfonating agent is rare.Very recently,Mo,Ma and coworkers have reportedthe electrochemical direct C(sp3)H sulfonylation of xan-thene derivatives with arylsulfonohydrazide,8 but the re-action was limited to the phenyl sulfonohydrazide and strong bases(MeONa)(Scheme 1,b).Along this line,we report an electrochemically catalyzed C(sp3)H sulfon-ylation of xanthene compounds with sodium sulfinates as the sulfonylation reagents(Scheme 1,c).The reaction proceeds at room temperature under transition metal-and additional oxidant-free condition,featuring with excellent functional group tolerance and broad substrate scope.The most worth pointing out is that sodium alkyl sulfonates,sodium heteroaryl(pyridine,thiophene and isoxazole)sul-fonates are also completely compatible with this reaction system.2 Results and discussion Our study began with screening of the reaction conditions of the electrocatalyzed CH functionalization of 9H-xan-thene(1a)with sodium ethanesulfinate(2a)in an opera-tionally simple undivided cell equipped with a carbon rod anode and a platinum cathode(Table 1).After extensive screening of various conditions,it was found that 71%yield of 9-(ethylsulfonyl)-9H-xanthene(3aa)9 was obtained under constant current of 10 mA with nBu4NBF4 as the electrolyte(Entry 1).Other electrolytes like nBu4NPF6 and OHNOHOSOOOOO(a)RigosertibOOS NHONHNNOOOONNSONNHFSOOONHNFNO2NNNOSOO(b)AZ20(c)Bensulfuron-methyl(d)Centrinone Figure 1 Structures of representative sulfone-based drugs OSOORRSO2NaR1R2OR1R2Inexpensive reagentsMild conditionsHBroad substrate scopeThis work:(c)Electrooxidation sulfonylation of C(sp3)H bonds with sodium sulfinatesCPtL*OHRSO2NaL*SO2RL*=MeOPhOSnBr2/TMSClMeNO2(0.1 mol/L)-15 or-40 oCPrevious work:(a)Sulfonylation of diarylmethanolsMetal-free*+(b)Sulfonylation of C(sp3)H bond with benzene sulfonyl hydrazidesOSOORRSO2NHNH2R1R2OR1R2HCPtRheterocycle,alkylnBu4Nl,MeONa DCE/HFIP,r.t.,4.5 h+R=aryl,heteroaryl,alkyl Scheme 1 Sulfonylation of C(sp3)H bond 有机化学 研究论文 188 http:/sioc- Shanghai Institute of Organic Chemistry,Chinese Academy of Sciences Chin.J.Org.Chem.2023,43,186194 tetrabutylammonium iodide(TBAI)as well as tetrabutyl-ammonium bromide(TBAB)gave lower yield of product 3aa(Entries 24).The yield was reduced to 59%by using a platinum anode and a carbon rod cathode(Entry 5).Basically consistent yield of product 3aa was observed with carbon rod as both anode and cathode(Entry 6).Yields of using reticulated vitreous carbon(RVC),iron,zinc and nickel as cathode are lower than that of platinum(Entries 710).No target product was obtained without adding HOAc(Entry 11).Four acid additives,such as HCOOH,H3PO4,H3BO3 and MsOH,were also tested,and the results showed that AcOH was the best choice for this electro-catalyzed CH functionalization(Entry 1 vs Entries Table 1 Optimization of reaction conditionsa Entry Variation from the standard conditions Yieldb/%1 None 71 2 nBu4NPF6 instead of nBu4NBF4 52 3 TBAI instead of nBu4NBF4 41 4 TBAB instead of nBu4NBF4 57 5 Pt()/C()instead of C()/Pt()59 6 C()/C()instead of C()/Pt()64 7 C()/RVC()instead of C()/Pt()56 8 C()/Fe()instead of C()/Pt()33 9 C()/Zn()instead of C()/Pt()58 10 C()/Ni()instead of C()/Pt()49 11 Without AcOH Trace 12 HCOOH instead of AcOH 55 13 H3PO4 instead of AcOH 42 14 H3BO3 instead of AcOH 53 15 MsOH instead of AcOH 45 16 AcOH(1 equiv.)56 17 AcOH(3 equiv.)61 18 No electric current 0 19 5 mA instead of 10 mA,3.5 h 60 20 15 mA instead of 10 mA,2 h 51 21 CF3CH2OH instead of HFIP 38 22 CH3CH2OH instead of HFIP Trace 23 MeOH instead of HFIP 42 24 MeCN instead of HFIP 52 25 ClCH2CH2Cl instead of HFIP 44 26 MeCN/HFIP(VV11,5 mL)40 27 ClCH2CH2Cl/HFIP(VV11,5 mL)45 a Reaction conditions:carbon rod anode,platinum plate cathode,constant current10 mA,1a(0.2 mmol),2a(2 equiv.),nBu4NBF4(0.25 mmol),HFIP hexafluoroisopropanol(5.0 mL),room temperature under air atmosphere for 2 h.b Isolated yield.1215).The effect of the amount of AcOH was also explored.The yield was decreased to 56%when 1 equiv.of AcOH was used(Entry 16),while 3 equiv.of AcOH gave the similar yield of product 3aa(Entry 17).No reaction was carried out without electric current(Entry 18).Reducing or increasing the current will reduce the yield(Entries 19,20).In addition,when the reaction took place in other solvents,such as CF3CH2OH(TFE),CH3CH2OH,MeOH,MeCN and ClCH2CH2Cl,the yields decreased and even no target product was detected(Entries 2125).The use of mixed solvents,such as MeCN/HFIP(VV11)and dichlo-roethane(DCE)/HFIP(VV11)did not improve the reaction yield(Entries 26,27).With the optimal conditions in hand,the scope of the sodium sulfonates component in this electrocatalyzed CH functionalization reaction was next explored.As shown in Table 2,many sodium alkylsulfinates were attempted,which afforded the corresponding 9-(alkylsulfonyl)-9H-xanthenes 3aaag in 41%71%yields.Moreover,the reaction worked well for two complex sodium sulfonates 2f and 2g,delivering the corresponding products 3ax and 3ay in 39%and 48%yields.To our delight,other sodium het-eroaromatic sulfonates 2h2j were well compatible under current conditions.For instance,sodium 3,5-dimethyl-isoxazole-4-sulfinate performed well,affording 4-(9H-xanthen-9-yl)sulfonyl)-3,5-dimethylisoxazole(3ai)in 65%yield.It was noted that sodium 2,3-dihydrobenzofuran-5-sulfinate(2k),bearing a heterocycle,could also provide the desired product 3ak in 63%yield.Gratifyingly,di-or tri-substitution sodium sulfonates reacted with 9H-xanthene(1a)to afford the desired products 3al and 3am in 64%and 79%yields,respectively.Substituent groups(e.g.,Cl,CN,Me)at the meta-position of the aromatic ring were also proved to be suitable for the transformation,furnishing the corresponding products 3an3ap in 40%72%yields.A variety of sodium benzenesulfonates bearing various elec-tron-withdrawing(e.g.,I,Br,Cl,F),electron-donating(e.g.,OMe,Ph,t-Bu,Me),or neutral(H)groups at the para-position of the aromatic ring were effective partners in this protocol.Desired products 3aq3ay were obtained in 51%78%yields.Notably,the halogen atoms(F,Cl,Br,I)well all tolerated to give the corresponding products 3aq3at,which could further couple with other reagents.In addition,the reaction of 9H-xanthene(1a)with sodium 1,1-biphenyl-4-sulfinate(2v)proceeded smoothly to afford the expected product 3av in 78%yield.Subsequently,we shifted our attention to explore the substrate scope of 9H-xanthenes 1 for this electrocatalyzed CH functionalization(Table 3).When sodium 4-methyl-benzenesulfinate(2x)was employed as sulfonic acid source,a broad range of 9H-xanthenes were compatible with the reaction conditions,leading to the corresponding products 3bx3gx in 31%61%yields.Both the electron-withdrawing and electron-donating groups of 9H-xanthenes were tolerated.Me-substituted substrate 1b was success-fully converted to the corresponding product 3bx in 61%yield,whereas the F-substituted substrate 1f afforded the Chinese Journal of Organic Chemistry ARTICLE Chin.J.Org.Chem.2023,43,186194 2023 Shanghai Institute of Organic Chemistry,Chinese Academy of Sciences http:/sioc- Table 2 Variation of the sodium sulfonates 2a 3ai,65%OSOO3am,79%OMeOMeOSOO3al,64%OSOO3ak,63%OOSOON3aj,45%OSOO3ah,68%SOSOO3ab,61%OSOO3ac,42%OSOO3ad,66%OSOO3ae,41%COOMeOSOO3af,39%3ag,48%NOOHOSOOOS OOOR1N OSOOOOSOO3ax,72%R2=I,3aq,57%R2=Br,3ar,66%R2=Cl,3as,51%R2=F,3at,63%R2=OMe,3au,60%R2=Ph,3av,78%R2=t-Bu,3aw,58%OSOOR2R1=Cl,3an,70%R1=CN,3ao,40%R1=Me,3ap,72%OSOO3ay,60%a Reaction conditions:carbon rod anode,platinum plate cathode,constant current 10 mA,1a(0.2 mmol),2(2 equiv.),nBu4NBF4(0.25 mmol),HFIP(5.0 mL),room temperature under air atmosphere for 2 h.Table 3 Variation of the 9H-xanthenes 1a a Reaction conditions:carbon rod anode,platinum plate cathode,constant current 10 mA,1a(0.2 mmol),2(2 equiv.),nBu4NBF4(0.25 mmol),HFIP(5.0 mL),room temperature under air atmosphere for 2 h.有机化学 研究论文 190 http:/sioc- Shanghai Institute of Organic Chemistry,Chinese Academy of Sciences Chin.J.Org.Chem.2023,43,186194 product 3fx in 31%yield,which showed that the electron-donating groups had higher reactivities than electron-deficient ones.Two benzoaxanthene substrates,for instance,reacted smoothly to deliver the desired 9-tosyl-9H-xanthenes 3hx and 3ix in 59%and 57%yields.However,substrates with oxygen of substrate 1a replaced by C,N and S were failed in this transformation.To study the reaction pathway of this method,some control experiments were performed.Interestingly,the desired product 3ax could also be obtained in 28%yield when 4-methylbenzenesulfonohydrazide was applied as a sulfonic source.However,no desired product could be observed by using thiophene-2-sulfonohydrazide or me-thanesulfonohydr-azide as coupling partner.The most common radical-trapping reagents,such as 2,2,6,6-tetra-methylpiperidine-1-oxyl(TEMPO)and 2,6-di-tert-butyl-4-methylphenol(BHT),were added into the system of the transformation.The results showed that only trace of product 3ax was detected when TEMPO was used,while the yield significantly decreased to 13%when BHT was added.The radical clock experiment also captured the rad-ical intermediate to provide the product 4c in 41%yield,which suggested that a radical process might be involved in current CH functionalization.Based on previous works,6c-6d,10 control experiments and cyclic voltammogram(CV)results,the possible reaction mechanism of the electrochemical C(sp3)H bond sul-fonylation is proposed in Scheme 3.Firstly,a sin-gle-electron-transfer(SET)oxidation of 1a took place to generate the xanthene radical I.At the same time,2x could be oxidized to form radical intermediate II or intermediate III.Cross-coupling between xanthene radical I and inter-mediate III afforded the desired product 3ax.3 Conclusions In summary,a novel electrochemical strategy for the C(sp3)H bond sulfonylation of xanthenes with sodium sulfinates has been developed.This transformation provides a directly and powerful synthetic tool for the formation of sulfone-substituted xanthenes.Importantly,not only sodium benzenesulfonates but also sodium alkylsulfonates worked well with excellent functional-group tolerance.Furthermore,a radical pathway involving the sulfonyl radical and xant