UPDATES DOI:10.1002/adsc.201501028 Direct DecarboxylativeAlkynylation of a,a-Difluoroarylacetic Acids under Transition Metal-Free Conditions Xiang Li,a Siyu Li,a Suyan Sun,a FanYang,a,*Weiguo Zhu,a Yu Zhu,a Yusheng Wu,b,c,*and Yangjie Wua,* a TheCollege of Chemistry and Molecular Engineering, Henan Key Laboratory of Chemical Biology and Organic Chemistry Key LaboratoryofApplied Chemistry of HenanUniversities Zhengzhou University,Zhengzhou 450052, Peoples Republic of China E-mail:[email protected] or [email protected] b Tetranov Biopharm, LLC.75Daxue Road, Zhengzhou 450052, Peoples Republic of China E-mail:[email protected] c Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province,Peoples Republic of China Received:November 8, 2015;Revised: February 23, 2016; Published online:April 15, 2016 Supporting information for this article is availableonthe WWW under http://dx.doi.org/10.1002/adsc.201501028. Abstract: An efficient andgenerally applicable pro- Due to the their uniquestructure and properties, tocol for decarboxylative coupling of a,a-difluoro- developing asimple and facile routetoa,a-difluoro- arylacetic acids with ethynylbenziodoxolone(EBX) methylated alkynesishighly desirable.Traditional reagents has been developed, affording a,a- procedures for the preparation of a,a-difluoromethy- difluoromethylated alkynes bearing various func- lated alkynes mainly rely on twosynthetic ap- tional groups in moderate to excellent yields.Re- proaches.[5–7] One is the direct difluoropropargylation markably, this potassium persulfate (K2S2O8)-pro- of electrophiles (aldehydes or imines) with diverse moted reactionemploys water as solvent under gem-difluoropropargylsynthons,such as gem-difluoro- transitionmetal-free conditions,thus providing propargylmetal or difluoropropargylindium com- agreensynthetic approachtoa,a-difluoromethylat- plexes, but this approach is still suffering from the ed alkynes. harsh reaction conditions and narrow substrate scope.[5] Anotherroute to a,a-difluoromethylated al- Keywords: alkynylation;decarboxylation; a,a-di- kynesisthe direct transformation from gem-difluoro- fluoroarylacetic acids; a,a-difluoromethylated al- propargyl bromideorg-bromodifluoroallenes and nu- kynes;transition metal-free conditions cleophiles,affording the corresponding a,a-difluoro- methylated alkynes in good yields.However, the mul- tistep preparation andthe unstable character of g-bro- modifluoroallenes restrict the wide application of these synthetic routes.[6] To resolve these limitations, Fluorine-containing compoundsare of great impor- just recently,Zhang andco-workers developed apalla- tance in pharmaceuticals,agrochemicals andmaterial dium-catalyzed Suzuki-type reactionofgem-difluoro- science.[1] Specifically,the difluoromethylene group propargyl bromidewith organoboron compounds, (CF2)plays an important role in medicinalchemistry generating a,a-difluoromethylated alkynes as the because the incorporation of adifluoromethylene productsinhigh yields (Scheme 1a).[8] However, this group into an organic molecule not only leads to pro- pioneering work employed awater-and air-sensitive found changes of the compounds physical, chemical, reagent, gem-difluoropropargylbromide, as adifluoro- and biological properties,[2] but also acts as abioisos- methyland alkyne source. tere of an oxygenatomorcarbonylgroup.[3] In partic- a,a-Difluoroarylacetic acids are easy to prepare, ular, a,a-difluoromethylated alkyneshavewide appli- usuallystable,and insensitive to moisture or air, and cations in organic synthesis,especially for the prepa- should serve as promising difluoromethylating re- ration of CF2-containing compounds because the agents.Recently,Gouverneur and co-workersreport- alkyne moiety could be easily functionalized by oxida- ed the preparation of difluoromethylarenes via tion, reduction, addition or click reactions,[4] thus pro- asilver-catalyzed decarboxylative fluorination of a- viding potentialopportunities for new discoveries in fluoroarylacetic acid under mild conditions.[9] On the medicinalchemistry. other hand, the reagent ethynylbenziodoxolone Adv.Synth. Catal. 2016, 358,1699 –1704 2016 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim 1699 Xiang Li et al. UPDATES Table 1. Optimizing the reaction conditions.[a] Scheme 1. Synthesis of a,a-difluoromethylated alkynes. Entry Catalyst Oxidant Solvent Yield [%][b] (EBX), which is preparedfrom commerciallyavail- [c] able 2-iodobenzoic acid andcorresponding alkynylsi- 1 AgNO3 K2S2O8 CH3CN/H2O47 lane,[10] is asafe and air-stable alkyne source that has 2AgNO3 K2S2O8 CH3CN/H2O91 found wide applications in decarboxylation,CH 3AgNO3 K2S2O8 CH2Cl2/H2Otrace À 4AgNO3 K2S2O8 acetone/H2O65 bond activation andmany other types of reactions in 5AgNO K S O H Otrace recent years.[11–14] Inspired by these reports,weenvi- 3 2 2 8 2 6AgNO3 –CH3CN/H2Otrace sioned asimple and facile construction of the 7– K2S2O8 CH3CN/H2O93 difluoropropargyl moiety under transitionmetal-free 8– Na2S2O8 CH3CN/H2O55 conditions by using the above-mentioned a,a- 9– (NH4)2S2O8 CH3CN/H2O28 difluoroarylacetic acids and ethynylbenziodoxolone 10 –PhI(OAc)2 CH3CN/H2Otrace (EBX) reagents as difluoromethyl and alkyne source, 11 –TBHP CH3CN/H2Otrace respectively,which would establish anew synthetic 12 –BQCH3CN/H2Otrace [d] 13 –K2S2O8 CH3CN/H2O30 strategyfor difluoropropargyl derivatives [e] (Scheme 1b). 14 –K2S2O8 CH3CN/H2Otrace Initially,biphenyl-4-yl(difluoro)acetic acid (1a)and [a] Reaction conditions: 1a (0.2 mmol), 2a (0.22 mmol),cata- 1-[(triisopropylsilyl)-ethynyl]-1,2-benziodoxol-3(1H)- lyst (20 mol), oxidant(2.0 equiv.), and solvent (2 mL) at one (TIPS-EBX, 2a)were used as model substrates to 558Cunder anitrogen atmosphere for 12 h. optimize the reactionconditions.Using the typical [b] Yield of isolated product. [15] [c] Under air. AgNO3/K2S2O8 catalytic decarboxylative system, [d] the desired product 3a could be obtained in 47% 1.0 equiv.ofoxidant was used. [e] At room temperature. yield in aqueous media CH3CN/H2O(1mL/1 mL) at 558Cunder air (Table 1, entry 1). To our delight, when the reactionwas conducted under anitrogen at- fluoroarylacetic acids was examined, andthe sub- mosphere,the yield wasimprovedto91% (Table 1, strates bearing either electron-donating groups[16] or entry 2). Subsequently,other solvents such as CH2Cl2/ electron-withdrawing groups could be efficiently H2O(1mL/1 mL), acetone/H2O(1mL/1mL) or neat transformed into the corresponding gem-difluorome- water were tested, and the CH3CN/H2O(1mL/1 mL) thylatedalkynesingoodtohigh yields (Table 2, 3a– was the best choice (Table 1, entries3–5). Surprising- 3n). To our delight,the desired product 3f could be ly,the reactionproceeded smoothly in the absence of obtained in 65% yield even if the reaction was per- silver catalyst, affording the desired product in formed on a2.0 mmol scale (Table 2, 3f). The gem-di- ahigher yield of 93%, while the reactiondid not fluoroarylacetic acids with ahalogen atom at the occur without the oxidant, indicating that the oxidant para-position, which could be easily further function- was essential for this reaction(Table1,entries6 and alized,were also well tolerated in this reactionafford- 7). Then,some other oxidants were checked, and ing the desired productsingood yields (Table 2, 3h among them, only Na2S2O8 and (NH4)2S2O8 gave and 3i). It was noteworthy that substrates bearing lower yields (Table 1, entries 8–12). Finally,some con- asynthetically valuablealkyne moiety were also suc- trol experiments were also performed (Table 1, en- cessfullyconverted into the corresponding products in tries 13 and14). Forexample,when the amount of ox- yields of 67% and 63%, respectively (Table 2, 3j and idant was changed to 1.0 equiv., the yield decreased 3k). Moreover, the scope of electron-withdrawing sharply to 30%, and the reactiondid not occur at all groups could be successfully extended to at room temperature. NHCOCHC(CH3)3,COCH3 andCF3 (Table 2, 3l–3n). With the optimized conditions in hand, we next ex- Furthermore,N-heteroaromatic gem-difluoroarylace- plored the substrate scope and the result was summar- tic acids were also tolerated in this reaction, affording ized in Table 2. First, the electronic effect of gem-di- the desired product in 49% yield (Table 2, 3o). Next, 1700 asc.wiley-vch.de 2016 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim Adv.Synth. Catal. 2016, 358,1699 –1704 UPDATES Direct Decarboxylative Alkynylationofa,a-Difluoroarylacetic Acids Table 2. Decarboxylative coupling of gem-difluoroarylacetic acids with R-EBX.[a,b] [a] Reaction conditions: 1 (0.20 mmol), 2 (0.22 mmol), K2S2O8 (2.0 equiv.), CH3CN (1.0 mL), and H2O(1.0 mL) at 558C under anitrogen atmosphere. [b] Yield of isolated product. [c] Reactionwas performed on a2.0 mmol scale. different hypervalentalkynyl iodine reagents were also tested, and aryl-substituted EBXs worked well in this process (Table 2, 3p–3x). Forexample,phenyl- EBX could be coupled with various gem-difluoroaryl- acetic acids efficiently,affording the products in good yields (Table 2, 3p–3u). Thereactioncouldbecom- patible with the reagents possessing ahalogen atom (Cl or Br), thusproviding an opportunity for further functionalization (Table 2, 3w–3x). In addition, an alkyl-substituted EBX was also examined, and the de- sired product couldbeobtained in 53% yield (Table 2, 3y). To further establish the scope of this reaction, we next performed the reactionof2,2’-([1,1’-biphenyl]- 4,4’-diyl)bis(2,2-difluoroacetic acid) (4a)with TIP- EBX (2a)orPh-EBX(2b)inthe presence of