Direct Trifluoromethylation of the CH Bond

DOI: 10.1002/adsc.201200764

Direct Trifluoromethylation of the C�H Bond

Hui Liu,a Zhenhua Gu,b and Xuefeng Jianga,*a Shanghai Key Laboratory of Green Chemistry and Chemical Process, Department of Chemistry, East China Normal

University, 3663 North Zhongshan Road, Shanghai 200062, People�s Republic of ChinaFax: (+86)-21-5213-3654; phone: (+ 86)-21-5213-3654; e-mail: [email protected]

b Department of Chemistry, University of Science and Technology of China, Hefei 230026, People�s Republic of China

Received: August 26, 2012; Revised: October 30, 2012; Published online: February 22, 2013

Abstract: Trifluoromethylation meets C�H activa-tion: after transition metal-catalyzed trifluoromethy-lation became more and more popular, trifluorome-thylation via C�H activation is now emerging as thelatest attraction. Several pioneering examples andtheir mechanisms are discussed in this review.

1 Introduction

2 Direct Trifluoromethylation of sp2-Hybridized C�H Bonds

3 Direct Trifluoromethylation of sp-Hybridized ACHTUNGTRENNUNGC�H Bonds

4 Direct Trifluoromethylation of sp3-Hybridized ACHTUNGTRENNUNGC�H Bonds

Keywords: catalysis; C�H activation; copper; palla-dium; trifluoromethylation

1 Introduction

Although not more than a dozen of the compoundscreated by nature contain fluorine atom(s),[1] fluorine-containing compounds have found widespread appli-cations in the fields of pharmaceuticals, agrochemi-cals, and materials. Indeed, as many as 20% of phar-maceuticals and 30–40% of agrochemicals on themarket are equipped with fluorine, including 4 of thetop 10 best-selling drugs.[2] Molecules bearing a tri-fluoromethyl group have become of great interestsince the CF3 group can dramatically enhance theirchemical and metabolic stability,[3a] lipophilicity[3b] andbinding selectivity.[3c] Hence, the development of effi-cient methods for the selective introduction of a CF3

group into organic molecules in the search for im-provements in biological activity and other physicalproperties has already became one of the hottestfields in modern organic chemistry.[3]

In recent years, much progress has been made inthe development of transition metal-mediated/-cata-lyzed trifluoromethylation reactions for introducingCF3 groups into organic molecules,[3] which usually re-quire stoichiometric organic halides[4] or organometal-lic reagents.[5] While the direct trifluoromethylation ofthe C�H bond remains challenging, it representsa more straightforward and economic method for thesynthesis of trifluoromethylated compounds. There-fore, developing a catalytic direct C�H trifluorome-thylation is still at the forefront of research. This

review summarizes the recent developments in thedirect trifluoromethylation of the C�H bond.

2 Direct Trifluoromethylation ofsp2-Hybridized C�H Bonds

Great achievements have been achieved in sp2 C�Hbond activation in the past, which make the directfunctionalization of sp2 C�H bonds a facile, green andsustainable method to introduce different functionalgroups.[6] Trifluoromethylation through sp2-hybridizedC�H bond activation is the most straightforwardmethod to synthesize CF3-containing arenes. Yu andco-workers reported a Pd-catalyzed electrophilic tri-fluoromethylation reaction of arenes through C�H ac-tivation by using (trifluoromethyl)dibenzothiopheni-um tetrafluoroborate (Umemoto�s reagent) as theCF3 source and N-heterocycles as the directing group(Scheme 1).[7] This pioneering work on the direct tri-fluoromethylation of C�H bonds provides an easyaccess to trifluoromethylated arenes. Other N-hetero-cycles, such as pyrimidine, imidazole, or thiazole,could also be used as alternative directing groups.However, the reaction needs a stoichiometric amountof Cu ACHTUNGTRENNUNG(OAc)2 as the oxidant and requires heterocyclicring directing groups.

Subsequently, Yu and co-workers developeda Pd(II)-catalyzed trifluoromethylation reaction ofN-[2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl]benz-

Adv. Synth. Catal. 2013, 355, 617 – 626 � 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 617

REVIEW

ACHTUNGTRENNUNGamide (Scheme 2).[8] It is crucial to use of N-methyl-formamide as an additive. The authors also isolateda palladium complex with the C�H insertion of benz-ACHTUNGTRENNUNGamide, which was further characterized by X-ray crys-tallographic analysis. During tests for the possibilityof the palladium complex undergoing trifluoromethy-lation, it was found that both Cu ACHTUNGTRENNUNG(OAc)2 and N-meth-ylformamide are important for the trifluoromethyla-tion of the palladium intermediate.

Sanford and co-workers described the oxidation ofthe cyclometalated Pd dimer [(bzq)Pd ACHTUNGTRENNUNG(OAc)]2 withCF3

+ reagents to form a monomeric Pd(IV) trifluoro-

methyl complex, which underwent highly chemoselec-tive C�CF3 bond formation at 60 8C for 12 h(Scheme 3).[9] Both Brønsted and Lewis acidic addi-tives could significantly enhance the rate and yield ofthis transformation. The monomeric Pd(IV) complexwas shown to be a kinetically competent intermediatefor C�H trifluoromethylation.

Trifluoromethylated heteroarenes are widely appli-cable in the synthesis of pharmaceuticals and agro-chemicals. Liu and co-workers developed a palladi-um-catalyzed oxidative trifluoromethylation of in-doles, in which PhI ACHTUNGTRENNUNG(OAc)2 was used as an oxidant and

Hui Liu received his B.S.degree in chemical engineer-ing and technology at QufuNormal University (China) in2006. In 2012, he received hisPh.D. degree in appliedchemistry from East ChinaUniversity of Science andTechnology under the super-vision of Prof. Limin Wangand Xiaofeng Tong. He isnow pursuing his postdoctor-al studies at East China Normal University withProf. Xuefeng Jiang.

Zhenhua Gu studied chemis-try at Nanjing University(China). In 2002 he pursuedhis Ph.D. studies with Profes-sor Shengming Ma at theShanghai Institute of OrganicChemistry, Chinese Academyof Sciences. After postdoctor-al research with Professor K.Peter C. Vollhardt at theUniversity of California Ber-keley, and with Professor Armen Zakarian at theUniversity of California Santa Barbara in the fieldof natural total synthesis, he joined the University ofScience and Technology of China in 2012. His re-search interests are in the development new trans-formations and their applications in total synthesis.

Xuefeng Jiang received hisB.Sc. degree from NorthwestUniversity (China) in 2003,he pursued his Ph.D. studieswith Professor ShengmingMa at the Shanghai Instituteof Organic Chemistry, Chi-nese Academy of Sciences.From 2008 to 2011 he wasa postdoctoral researcherunder the guidance of Profes-sor K. C. Nicolaou at theScripps Research Institute in the field of total syn-thesis of natural products. He is currently a professorat East China Normal University and his researchinterests are in methodology oriented total synthesis.

Scheme 1. Palladium(II)-catalyzed C�H trifluoromethylation of arenes.

618 asc.wiley-vch.de � 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Adv. Synth. Catal. 2013, 355, 617 – 626

REVIEW Hui Liu et al.

http://asc.wiley-vch.de

TMSCF3 (Ruppert–Prakash reagent) as a trifluorome-thylating reagent.[10] The reaction may involvea palladium ACHTUNGTRENNUNG(II/IV) mechanism for the formation ofthe aryl C�CF3 bond, as was proposed by Sanford�sgroup (Scheme 4).[11] Sodeoka�s group demonstratedthe regioselective C-2 trifluoromethylation of indolederivatives catalyzed by CuOAc (Scheme 5).[12]

Scheme 2. Palladium(II)-catalyzed trifluoromethylation by using N-methylformamide as additive.

Scheme 3. C�H trifluoromethylation with “CF3+” reagents

via a monomeric palladium(IV) complex.

Scheme 4. Palladium-catalyzed oxidative trifluoromethylation of indoles.

Scheme 5. Copper-catalyzed trifluoromethylation of indoles.

Adv. Synth. Catal. 2013, 355, 617 – 626 � 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim asc.wiley-vch.de 619



More recently, Qing and co-workers describeda copper-catalyzed direct C�H oxidative trifluorome-thylation of heteroarenes and highly electron-defi-cient arenes with TMSCF3.

[13] Using this method,a wide range of aromatic compounds, including 1,3,4-oxadiazoles, benzo[d]xazoles, benzo[d]thiazole, ben-zo[d]imidazoles, indoles, and electron-deficient per-fluoroarenes, were converted into their correspondingtrifluoromethylated derivatives in moderate to excel-lent yields (Scheme 6).

Liu and co-workers recently developed a tandemPd-catalyzed oxidative aryltrifluoromethylation of ac-tivated alkenes using TMSCF3/CsF as trifluoromethylgroup source and PhIACHTUNGTRENNUNG(OAc)2 as oxidant(Scheme 7).[14]

Yamakawa and co-workers recently reported thetrifluoromethylation of various aromatic and hetero-aromatic compounds by CF3I in the presence ofFe(II) compound, H2O2 and DMSO (Scheme 8).[15]

Benzene derivatives, six-membered nitrogen-contain-ing aromatic compounds and five-membered hetero-aromatic compounds can be smoothly trifluoromethy-lated under mild conditions. The regioselectivity isoriented by the general trend of electrophilic substitu-tion of aromatic compounds with some exceptions.

Sanford�s group described a silver-mediated C�Htrifluoromethylation of aromatic substrates withTMSCF3 (Scheme 9).[16] The reaction was proposed toproceed via an AgCF3 intermediate, and preliminarystudies suggest against the existence of free CF3C as anintermediate.

Br�se and co-workers reported the trifluoromethy-lation of aromatic triazenes by means of in situ gener-ated AgCF3 in high ortho selectivity and good yieldsvia C�H activation (Scheme 10).[17] Since triazenescould undergo further transformation easily, a varietyof CF3-substituted building blocks is thus accessible.

The “innate trifuoromethylation” of heterocycleswas recently developed by Baran�s group(Scheme 11).[18] CF3SO2Na (Langlois reagent) wasused as the trifluoromethylating reagent, and a variety

Scheme 6. Copper-catalyzed direct C�H oxidative trifluoro-methylation of heteroarenes.

Scheme 7. Palladium-catalyzed oxidative aryltrifluoromethy-lation of activated alkenes.

Scheme 8. Iron(II)-catalyzed trifluoromethylation of aromat-ic and heteroaromatic compounds.

Scheme 9. Silver-mediated trifluoromethylation of arenes.

Scheme 10. ortho-Trifluoromethylation of functionalized ar-omatic triazenes.

Scheme 11. Baran�s direct C�H trifluoromethylation of het-erocycles and a putative mechanism.




of electron-deficient and electron-rich heteroaromaticsystems could be conveniently trifluoromethylated.This protocol demonstrates high functional group tol-erance, proceeds at ambient temperature under air at-mosphere, and shows the major advantage proceedingwithout a directing group. Although the regioselectiv-ity is moderate, the different regioisomers obtainedare advantageous for new drug discovery in medicinalchemistry. Based on the characteristics of the Langloisreagent and experimental results, a putative mecha-nism was proposed (Scheme 11). The CF3 transientradical intermediate may be involved, and the EPRstudies of CF3SO2Na and t-BuOOH in aqueous solu-tion indicate the presence of radical intermediates.The position selectivity with more than one functiona-lizable C�H bond can also be predicted in this reac-tion system.

Taking the advantage of photoredox catalysis,Nagib and MacMillan developed a RuACHTUNGTRENNUNG(phen)3Cl2-cata-lyzed trifluoromethylation reaction of arenes and het-eroarenes by the use of trifluoromethanesulfonylchloride (TfCl) as trifluoromethyl group source(Scheme 12).[19] The relatively low cost and ease ofhanding of TfCl as well as the mild reaction condi-tions led this method to become particular interesting.The absorption of one photon by the photocatalystRu ACHTUNGTRENNUNG(phen)3

2+ will generate a high energy excited spe-cies *Ru ACHTUNGTRENNUNG(phen)3

2+. The reaction is initiated by the re-duction of triflyl chloride with *Ru ACHTUNGTRENNUNG(phen)3

2+ (calledoxidative quench) via one-electron transfer. The trifl-yl chloride rapidly collapses to trifluoromethyl radicalwhen it ensues an electron from *RuACHTUNGTRENNUNG(phen)3

2+. The

addition of the trifluoromethyl radical to areneswould form a new cyclohexadienyl radical species,which would give trifluoromethylate aryl compoundsby the oxidation of Ru ACHTUNGTRENNUNG(phen)3

3+ followed by deproto-nation.

The reaction has wide substrate scope. Numerousdifferent types of arenes gave good to excellent yieldsof trifluoromethylated products (Scheme 13). Themethod could be potentially used in drug discoveryprograms. Trifluoromethylation under the standardphotoredox catalysis conditions of Lipitor, a cholester-ol-lowering drug, gave three products with a 1:1:1ratio (74% total yield) (Scheme 14).

A visible light-induced trifluoromethylation of elec-tron-rich heterocycles was developed by Cho and co-workers, providing a direct method to access trifluoro-methylated heteroaromatic compounds without pre-functionalization (Scheme 15).[20] This method couldbe used for the synthesis a variety of trifluoromethy-lated heterocycles under mild reaction conditions ingood to excellent yields.

Togni�s group developed a novel methodology forthe direct trifluoromethylation of both activated andinactivated arenes and heteroarenes using an easilyaccessible, shelf-stable, hypervalent iodine trifluoro-methylating reagent and methyltrioxorhenium (MTO)as catalyst (Scheme 16).[21] While low yields were ob-tained in the case of substrates bearing electron-with-drawing substituents, it exhibited a broad substratescope in direct aromatic trifluoromethylation reac-tions.

The [(phen)CuCF3]-mediated trifluoromethylationof arenes through arylboronate esters was developedby Hartwig and co-workers (Scheme 17).[22] An arylboronate ester could be obtained in situ from substi-tuted arenes, which readily underwent trifluoromethy-lation in air with [(phen)CuCF3] in a one-pot process.

A sequential iridium-catalyzed borylation andcopper-catalyzed trifluoromethylation of arenes was

Scheme 12. RuACHTUNGTRENNUNG(phen)3Cl2-catalyzed trifluoromethylation re-action of arenes and heteroarenes.

Scheme 13. Examples of trifluoromethylated arenes.




described by Shen and co-workers (Scheme 18).[23]

The reaction was carried out under mild reaction con-ditions and a variety of functional groups could be

tolerated, which might lead to a number of biological-ly active molecules.

3 Direct Trifluoromethylation ofsp-Hybridized ACHTUNGTRENNUNGC�H Bonds

Qing and co-workers have reported a copper-mediat-ed oxidative trifluoromethylation of terminalalkynes with a nucleophilic trifluoromethylatingreagent (TMSCF3, the Ruppert–Prakash reagent)(Scheme 19a).[24a] This reaction provides a general,straightforward, and practically useful method to pre-pare trifluoromethylated acetylenes. However, stoi-chiometric amounts of CuI and a 5-fold excess of tri-fluoromethylating reagent are required. In 2012, anefficient copper-catalyzed oxidative trifluoromethyla-tion of terminal alkynes was developed by the samegroup (Scheme 19b).[24b] The catalytic protocol is suc-cessfully achieved by adding both the substrate anda portion of TMSCF3 slowly via a syringe pump.

Scheme 14. Application in the synthesis of Lipitor.

Scheme 15. Visible light-induced trifluoromethylation.

Scheme 16. Trifluoromethylation of arenes and heteroarenesusing MTO as catalyst.

Scheme 17. Trifluoromethylation of arenes conducted by[(phen)CuCF3] and arylboronate esters.

Scheme 18. Sequential iridium-catalyzed borylation andcopper-catalyzed trifluoromethylation of arenes.

Scheme 19. Copper-mediated trifluoromethylation of termi-nal alkynes.




Subsequently, Qing�s group reported an improvedprocedure for the Cu-mediated oxidative trifluorome-thylation of terminal alkynes, using (phen)Cu ACHTUNGTRENNUNG(CF3)generated in situ from TMSCF3. This oxidative tri-fluoromethylation could proceed smoothly at roomtemperature with a smaller amount of TMSCF3

(Scheme 20).[25]

4 Direct Trifluoromethylation ofsp3-Hybridized ACHTUNGTRENNUNGC�H Bonds

The benzoyl peroxide (BPO)-promoted oxidativefunctionalization of tertiary amines under transitionmetal-free reaction conditions has been developed(Scheme 21).26 Various 1-trifluoromethylated tetrahy-droisoquinoline derivatives were prepared by employ-ing this method. It constitutes the first example ofa direct trifluoromethylation of tertiary amines.

Li and Mitsudera also reported a copper-catalyzedtrifluoromethylation of sp3 C�H bonds adjacent toa nitrogen atom (Scheme 22).[27] The reactions of vari-ous tetrahydroisoquinoline derivatives gave the corre-sponding trifluoromethylated products in 15–90%yields under very mild conditions.

Visible light-induced oxidative C�H functionaliza-tion of tertiary amines catalyzed by the combinationof graphene oxide and Rose Bengal was developed by

Tan�s group (Scheme 23).[28] This reaction could pro-vide trifluoromethylated tertiary amines avoiding theuse of stoichiometric amounts of peroxy reagents asterminal oxidants.

Recently, Buchwald�s[29a] and Wang�s group[29b] haveindependently developed a catalytic allylic trifluoro-methylation of olefins by employing copper as thecatalyst and Togni�s reagent as CF3 source(Scheme 24). [(MeCN)4Cu]PF6 was used as the metalcatalyst in Buchwald�s system, while CuCl was em-ployed in Wang�s work. Both methods tolerate a widerange of functional groups, including unprotected al-cohols, protected amines, esters, amides, alkyl bro-mides, terminal epoxides and so on. Branched termi-

Scheme 20. Oxidative trifluoromethylation of terminal alk-ACHTUNGTRENNUNGynes.

Scheme 21. Oxidative trifluoromethylation of tetrahydroiso-quinoline.

Scheme 22. Copper-catalyzed trifluoromethylation ofamines.

Scheme 23. Oxidative C�H functionalisation of tertiaryamines.

Scheme 24. Copper-catalyzed trifluoromethylation of olefins.




nal olefins, 1,2-disubstituted olefins, and cyclic alkeneswere found to be unsuitable substrates in Buchwald�smethod, however, these substrates worked well inWang�s system, affording the corresponding allyl-CF3

products in moderate to good yields, albeit at a highertemperature.

In regard to the reaction mechanism, Wang pro-posed that the CF3 radical was likely involved as a re-active species in the reaction.[29a] To validate this pro-posal, TEMPO (2,2,6,6-tetramethylpiperidinyl-1-oxy),a well-known radical scavenger, was subjected to thestandard reaction conditions with or without alkenes(Scheme 25). The experimental results showed thatthe TEMPO-trapped complex 3 was formed in 44%yield without alkenes, while a 79% yield was obtainedwith n-dodecene under the standard reaction condi-tions, under which the trifluoromethylation was total-ly shut down. It is worth noting that the allyl-TEMPOadduct was not detected in their system. Based onthese observations, a mechanistic rationale was pro-posed by them (Scheme 26). Meanwhile Buchwald

probed whether this transformation proceeded via anallylic radical intermediate through a cyclopropane“radical probe”, but the corresponding product in-volving the formation of an allylic radical could notbe obtained.[29b] However, when diethyl diallylmalo-nate was used as a cyclization radical probe to exam-ine the reaction mechanism, 5-exo-trig cyclizationcompounds were obtained as the major product,which proceeded after the C�CF3 bond-forming event(Scheme 27). It is suggested that a CF3 free-radical in-termediate was generated during the reaction, as wasassumed by Wang. However, no evidence for the pro-duction of either an allylic radical or a trifluoromethyl-metal species was observed. The reaction mechanismis still unclear and needs to be further investigated.

Meanwhile, Fu and Liu also reported a copper-cata-lyzed trifluoromethylation of terminal alkenesthrough allylic C�H bond activation, but using Ume-moto�s reagent as CF3 source (Scheme 28).[30] The re-action also exhibits good functional group tolerance,although 2-substituted terminal alkenes or internal(including cyclic) alkenes cannot undergo the

Scheme 25. Radical scavenger control experiment.

Scheme 26. Wang�s mechanistic rationale.

Scheme 27. 5-exo-trig cyclization after the C�CF3 bond for-mation.




trifluoroACHTUNGTRENNUNGmethylation reaction under the same reactionconditions or even with elevated reaction tempera-tures, which could be explained by the theoreticalprediction. By both experimental tests and theoreticalanalysis, the authors excluded the involvement of anallylic radical intermediate and the Cu-allyl mecha-nism, instead suggesting that the reaction may pro-ceed through a Heck-like four-membered-ring transi-tion state TS1 (the rate-limiting step of the reaction).TfO� may assist the C�H activating step and acceler-ate the elimination reaction. The theoretical calcula-tions indicate that the generation of 6b (from 5 toTS2b, ~H= ++5.6 kcal mol�1) is more favorable thanthat of 6a (from 5 to TS2a, ~H= ++9.0 kcal mol�1).This prediction is consistent with the regioselectivityobserved in DMAc (Scheme 28).

An efficient CACHTUNGTRENNUNG(sp3)�CF3 bond-forming reaction viathe Cu-catalyzed oxidative trifluoromethylation ofterminal alkenes was developed by Qing�s group,which was conducted under mild conditions usingreadily available, comparably inexpensive TMSCF3 asthe source of the CF3 group (Scheme 24).[31] A newera is opening in the field of trifluoromethylation.Going from trasition metal-catalyzed to direct C�Hactivation of trifluoromethylation, this syntheticmethod is becoming more and more efficient. It canbe predicted that the new reagents will be emergingwith improvements in both chemo- and regioselectivi-ty in the near future.

Acknowledgements

Financial support was provided by the NSFC (21272075), the“Yingcai Program” of ECNU, the “Shanghai Pujiang Pro-gram” (12PJ402500), “Shanghai Talent Development Sup-port” (2011022) and China Postdoctoral Science Foundation(2012M520858).

References

[1] a) A. M. Thayer, Chem. Eng. News 2006, 84, 15;b) V. V. Grushin, Acc. Chem. Res. 2010, 43, 160; c) D.Cahard, X. Xu, S. Couve-Bonnaire, X. Pannecoucke,Chem. Soc. Rev. 2010, 39, 558.

[2] a) K. M�ller, C. Faeh, F. Diederich, Science 2007, 317,1881; b) M. Schlosser, Angew. Chem. 2006, 118, 5558;Angew. Chem. Int. Ed. 2006, 45, 5432.

[3] For reviews, see: a) T. Furuya, A. S. Kamlet, T. Ritter,Nature 2011, 473, 470; b) O. A. Tomashenko, V. V.Grushin, Chem. Rev. 2011, 111, 4475; c) J.-A. Ma, D.Cahard, J. Fluorine Chem. 2007, 128, 975; d) T. Ume-moto, Chem. Rev. 1996, 96, 1757; e) R. J. Lundgren, M.Stradiotto, Angew. Chem. 2010, 122, 9510; Angew.Chem. Int. Ed. 2010, 49, 9322; f) T. Besset, C. Schneid-er, D. Cahard, Angew. Chem. 2012, 124, 5134; Angew.Chem. Int. Ed. 2012, 51, 5048; g) F. Pan, Z. Shi, ActaChim. Sinica 2012, 70, 1679; h) A. Studer, Angew.Chem. 2012, 124, 9082; Angew. Chem. Int. Ed. 2012, 51,8950. For reviews on asymmetric trifluoromethylation,see: i) J. Nie, H.-C. Guo, D. Cahard, J.-A. Ma, Chem.Rev. 2011, 111, 455; j) J.-A. Ma, D. Cahard, Chem. Rev.2004, 104, 6119, for an update, see: Chem. Rev. 2008,108, PR1-PR43. For recent examples on catalytic asym-metric trifluoromethylation, see: k) A. E. Allen,

Scheme 28. Fu and Liu�s proposed mechanism for copper-catalyzed trifluoromethylation of alkenes.




D. W. C. MacMillan, J. Am. Chem. Soc. 2010, 132,4986; l) D. A. Nagib, M. E. Scott, D. W. C. MacMillan,J. Am. Chem. Soc. 2009, 131, 10875; m) Y. Zheng, J.-A.Ma, Adv. Synth. Catal. 2010, 352, 2745.

[4] For recent examples of trifluoromethylation of aryl/vinyl halides, see: a) E. J. Cho, T. D. Senecal, T. Kinzel,Y. Zhang, D. A. Watson, S. L. Buchwald, Science 2010,328, 1679; b) H. Morimoto, T. Tsubogo, N. D. Litvinas,J. F. Hartwig, Angew. Chem. 2011, 123, 3877; Angew.Chem. Int. Ed. 2011, 50, 3793; c) C.-P. Zhang, Z.-L.Wang, Q.-Y. Chen, C.-T. Zhang, Y.-C. Gu, J.-C. Xiao,Angew. Chem. 2011, 123, 1936; Angew. Chem. Int. Ed.2011, 50, 1896; d) O. A. Tomashenko, E. C. Escudero-Ad�n, M. M. Belmonte, V. V. Grushin, Angew. Chem.2011, 123, 7797; Angew. Chem. Int. Ed. 2011, 50, 7655;e) T. Knauber, F. Arikan, G.-V. Rçschenthaler, L. J.Gooßen, Chem. Eur. J. 2011, 17, 2689; f) H. Kondo, M.Oishi, K. Fujikawa, H. Amii, Adv. Synth. Catal. 2011,353, 1247; g) A. Hafner, S. Br�se, Adv. Synth. Catal.2011, 353, 3044; h) T. Kino, Y. Nagase, Y. Ohtsuka, K.Yamamoto, D. Uraguchi, K. Tokuhisa, T. Yamakawa, J.Fluorine Chem. 2010, 131, 98; i) M. Oishi, H. Kondo,H. Amii, Chem. Commun. 2009, 1909; j) G. G. Dubini-na, H. Furutachi, D. A. Vicic, J. Am. Chem. Soc. 2008,130, 8600; k) G. G. Dubinina, J. Ogikubo, D. A. Vicic,Organometallics 2008, 27, 6233. For a highlight on tran-sition metal-catalyzed trifluoromethylation of aryl hal-ides, see: l) R. J. Lundgren, M. Stradiotto, Angew.Chem. 2010, 122, 9510; Angew. Chem. Int. Ed. 2010, 49,9322.

[5] For recent examples of the trifluoromethylation ofaryl- and vinylboronic acids, see: a) T. D. Senecal, A. T.Parsons, S. L. Buchwald, J. Org. Chem. 2011, 76, 1174;b) T.-F. Liu, Q.-L. Shen, Org. Lett. 2011, 13, 2342; c) J.Xu, D. F. Luo, B. Xiao, Z.-J. Liu, T.-J. Gong, Y. Fu, L.Liu, Chem. Commun. 2011, 47, 4300; d) L.-L. Chu, F.-L. Qing, Org. Lett. 2010, 12, 5060.

[6] a) C. Jia, T. Kitamura, Y. Fujiwara, Acc. Chem. Res.2001, 34, 633; b) M. Miura, M. Nomura, Top. Curr.Chem. 2002, 219, 211; c) V. Ritleng, C. Sirlin, M. Pfeff-er, Chem. Rev. 2002, 102, 1731; d) F. Kakiuchi, N. Cha-tani, Adv. Synth. Catal. 2003, 345, 1077; e) K. Godula,D. Sames, Science 2006, 312, 67; f) I. V. Seregin, V. Ge-vorgyan, Chem. Soc. Rev. 2007, 36, 1173; g) M. E.Scott, M. Lautens, Chem. Rev. 2007, 107, 174; h) M. S.Chen, M. C. White, Science 2007, 318, 783; i) O. Daugu-lis, H.-Q. Do, D. Shabashov, Acc. Chem. Res. 2009, 42,1074; j) C.-J. Li, Acc. Chem. Res. 2009, 42, 335; k) T.Satoh, M. Miura, Chem. Eur. J. 2010, 16, 11212;l) D. A. Colby, R. G. Bergman, J. A. Ellman, Chem.Rev. 2010, 110, 624; m) T. W. Lyons, M. S. Sanford,Chem. Rev. 2010, 110, 1147; n) I. A. I. Mkhalid, J. H.Barnard, T. B. Marder, J. M. Murphy, J. F. Hartwig,Chem. Rev. 2010, 110, 890; o) W. R. Gutekunst, P. S.Baran, Chem. Soc. Rev. 2011, 40, 1976; p) J. Wencel-Delord, T. Drçge, F. Liu, F. Glorius, Chem. Soc. Rev.2011, 40, 4740; q) C. S. Yeung, V. M. Dong, Chem. Rev.

2011, 111, 1215; r) S. H. Cho, J. Y. Kim, J. Kwak, S.Chang, Chem. Soc. Rev. 2011, 40, 5068; s) L. Acker-mann, Chem. Rev. 2011, 111, 1315; t) J. C. Lewis, P. S.Coelho, F. H. Arnold, Chem. Soc. Rev. 2011, 40, 2003.

[7] X. Wang, L. Truesdale, J.-Q. Yu, J. Am. Chem. Soc.2010, 132, 3648.

[8] X. Zhang, H. Dai, M. Wasa, J.-Q. Yu, J. Am. Chem.Soc. 2012, 134, 11948.

[9] Y. Ye, N. D. Ball, J. W. Kampf, M. S. Sanford, J. Am.Chem. Soc. 2010, 132, 14682.

[10] X. Mu, S. Chen, X. Zhen, G. Liu, Chem. Eur. J. 2011,17, 6039.

[11] a) N. D. Ball, J. B. Gary, Y. Ye, M. S. Sanford, J. Am.Chem. Soc. 2011, 133, 7577; b) see ref.[9] ; c) N. D. Ball,J. W. Kampf, M. S. Sanford, J. Am. Chem. Soc. 2010,132, 2878.

[12] R. Shimizu, H. Egami, T. Nagi, J. Chae, Y. Hamashima,M. Sodeoka, Tetrahedron Lett. 2010, 51, 5947.

[13] L. Chu, F.-L. Qing, J. Am. Chem. Soc. 2012, 134, 1298.[14] X. Mu, T. Wu, H.-Y. Wang, Y.-L. Guo, G. Liu, J. Am.

Chem. Soc. 2012, 134, 878.[15] T. Kino, Y. Nagase, Y. Ohtsuka, K. Yamamoto, D. Ura-

guchi, K. Tokuhisa, T. Yamakawa, J. Fluorine Chem.2010, 131, 98.

[16] a) Y. Ye, S. H. Lee, M. S. Sanford, Org. Lett. 2011, 13,5464; b) R. N. Loy, M. S. Sanford, Org. Lett. 2011, 13,2548.

[17] A. Hafner, S. Br�se, Angew. Chem. 2012, 124, 3773;Angew. Chem. Int. Ed. 2012, 51, 3713.

[18] Y. Ji, T. Brueckl, R. D. Baxter, Y. Fujiwara, I. B. Seiple,S. Su, D. G. Blackmond, P. S. Baran, Proc. Natl. Acad.Sci. USA 2011, 108, 14411.

[19] D. A. Nagib, D. W. C. MacMillan, Nature 2011, 480,224.

[20] N. Iqbal, S. Choi, E. Ko, E. J. Cho, Tetrahedron Lett.2012, 53, 2005.

[21] E. Mej�a, A. Togni, ACS Catal. 2012, 2, 521.[22] N. D. Litvinas, P. S. Fier, J. F. Hartwig, Angew. Chem.

2012, 124, 551; Angew. Chem. Int. Ed. 2012, 51, 536.[23] T. Liu, X. Shao, Y. Wu, Q. Shen, Angew. Chem. 2012,

124, 555; Angew. Chem. Int. Ed. 2012, 51, 540.[24] a) L.-L. Chu, F.-L. Qing, J. Am. Chem. Soc. 2010, 132,

7262; b) X. Jiang, L. Chu, F.-L. Qing, J. Org. Chem.2012, 77, 1251.

[25] K. Zhang, X.-L. Qiu, Y. Huang, F.-L. Qing, Eur. J. Org.Chem. 2012, 58.

[26] L. Chu, F.-L. Qing, Chem. Commun. 2010, 46, 6285.[27] H. Mitsudera, C.-J. Li, Tetrahedron Lett. 2011, 52 1898.[28] Y. Pan, S. Wang, C. W. Kee, E. Dubuisson, Y. Yang,

K. P. Loh, C-H. Tan, Green Chem. 2011, 13, 3341.[29] a) A. T. Parsons, S. L. Buchwald, Angew. Chem. 2011,

123, 9286; Angew. Chem. Int. Ed. 2011, 50, 9120; b) X.Wang, Y. Ye, S. Zhang, J. Feng, Y. Xu, Y. Zhang, J.Wang, J. Am. Chem. Soc. 2011, 133, 16410.

[30] J. Xu, Y. Fu, D.-F. Luo, Y.-Y. Jiang, B. Xiao, Z.-J. Liu,T.-J. Gong, L. Liu, J. Am. Chem. Soc. 2011, 133, 15300.

[31] L. Chu, F.-L. Qing, Org. Lett. 2012, 14, 2106.




Documents

Direct Trifluoromethylation of the CH Bond