Good to excellent yields of aryl trifluoromethyl sulfides, which are an important class of compounds in both the pharmaceutical and agrochemical areas, can be achieved under mild conditions by the Pd-catalyzed reaction of aryl bromides with a trifluoromethylthiolate nucleophile (see scheme).National Institutes of Health (U.S.) (GM-58160)American Society for Engineering Education. National Defense Science and Engineering Graduate Fellowship (32 CFR 168a)National Science Foundation (U.S.) (CHE-980861

Buchwald, Stephen Leffler

Surry, David S.

Teverovskiy, Georgiy

Angewandte Chemie International Edition

PubMed

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Pd-Catalyzed Synthesis of Ar–SCF3 Compounds Under MildConditions**Georgiy Teverovskiy, Dr. David S. Surry, and Prof. Dr. Stephen L. Buchwald**Department of Chemistry, Room 18-490, Massachusetts Institute of Technology, Cambridge,MA, 02139 (USA), Fax: (+1) 617-253-3297, sbuchwal@mit.eduThe unique chemical properties of aryl trifluoromethyl sulfides (ArSCF3) have been knownfor over 60 years.[1] The capacity of SCF3 to act as a lipophilic electron-withdrawing grouphas resulted in the incorporation of ArSCF3 components into a number of pharmaceuticaland agrochemical agents.[2] Unfortunately, direct access to this important class ofcompounds is complicated by a lack of efficient, safe and general methods.[1a, 3]Significant advances in Pd-catalyzed cross-coupling processes have allowed for efficientaccess to a diverse array of functionalized aromatic products, including aryl sulfides.[4]While the coupling of many aromatic or aliphatic thiols with aryl halides has been achievedwith very high efficiency,[5] the analogous transformation to form aryl trifluoromethylsulfides has not been reported. As gaseous CF3SH (b.p. = -36 °C)[6] can be difficult tohandle in a laboratory setting, several SCF3 salts have been developed, however, most ofthese decompose under standard cross-coupling conditions.[3c]It has been postulated that reductive elimination of Ar–SR from a palladium center isinitiated via a nucleophilic attack on the electrophilic hydrocarbyl group by the metal-boundthiolate.[7] Thus, metal-catalyzed Ar–SCF3 coupling might be complicated by the reducednucleophilicity of the SCF3 anion[2b] as compared to a standard thiolate.Recent reports from our group regarding novel ligands including BrettPhos (1), t-BuBrettPhos (2), XPhos (3) and 3,4,5,6-tetramethyl(t-Bu)XPhos (4) (Scheme 1), haveallowed for the successful coupling of weak nucleophiles traditionally thought to bereluctant participants in the transmetalation or reductive elimination steps of a typical Pd(0)/Pd(II) catalytic cycle. Specifically, using these catalyst systems has allowed for the directformation of diaryl ether,[8] aryl fluoride,[9] aryl trifluoromethyl,[10] and aryl nitrocompounds[11] from their corresponding aryl halides or pseudo halides. In light of theseresults, we hypothesized that a similar Pd-based system might allow for the formation of anaromatic C–SCF3 bond.As we suspected that reductive elimination from putative intermediate 11 would be ratelimiting in any catalytic process, we began our investigation by attempting its preparationfrom oxidative addition complex 10 via treatment with AgSCF3 (Scheme 2). We weresurprised when this procedure did not provide the expected transmetalation complex butinstead led directly to the Ar–SCF3 product 12 (presumably via 11).**We thank the National Institutes of Health (NIH) for financial support of this project (GM-58160). We thank BASF for a gift of Pdcompounds, FMC Lithium for a gift of tBu2PCl and Nippon Chemical for a gift of Cy2PCl and unrestricted support. G.T. would alsolike to thank the DoD for the NDSEG Fellowship (32 CFR 168a). The Varian NMR instrument used was supported by the NSF(CHE-980861).Supporting information for this article is available on the WWW under http://www.angewandte.org or from the author.NIH Public AccessAuthor ManuscriptAngew Chem Int Ed Engl. Author manuscript; available in PMC 2012 August 01.Published in final edited form as:Angew Chem Int Ed Engl. 2011 August 1; 50(32): 7312–7314. doi:10.1002/anie.201102543.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptGiven this finding, we attempted to convert 4-(4-bromophenyl)morpholine to thecorresponding trifluoromethyl sulfide using AgSCF3 and a catalytic quantity of 1 and(COD)Pd(CH2TMS)2 (Table 1). However, under these conditions, none of 13 was observed.We surmised that failure to observe the coupled product might be due to the inefficienttransfer of ⊖SCF3 to 10 under catalytic conditions. Thus, we elected to examine the use of anumber of alternative previously reported ⊖SCF3 sources (Table 1).[3c, e]Clark’s[3d] work on the use of (Bu)4NI and AgSCF3 for SNAr reactions with aryl halidesindicated to us that the addition of a quaternary ammonium salt might be beneficial.Consistent with this hypothesis, the addition of 1 equivalent of (Bu)4NI to the reactionmixture increased the yield of 13 from 0 % to 55 % (Table 1). Further examination ofdifferent ammonium salts revealed that Ph(Me)3NI was more effective than (Bu)4NI andthat switching to a more soluble ammonium salt, Ph(Et)3NI, provided a nearly quantitativeyield of the desired product (Table 1). Based on work done by Clark, it is presumed that theiodide anion binds to AgSCF3 in order generate an anionic “ate” complex. We hypothesizethat a large diffuse cation further aids in the solubility of this complex. It is worth noting thatwhile the use of quaternary ammonium iodides and bromides allowed for catalytic turnover,the corresponding chloride analogs were ineffective.With the optimal combination of Ph(Et)3NI and AgSCF3 realized, we re-examined variousother previously reported ligands, which have enjoyed a measure of success in Pd-catalyzedcross-coupling reactions.[12] Our survey revealed that only dialkylbiarylphosphine basedligands were successful carrying out this transformation, while other ligands such as 5 or 6did not perform well even with higher catalyst loadings.Accordingly, we were successful in converting electron-rich, -neutral and -deficient arylbromides to their respective aryl trifluoromethyl sulfides in 2 hours at 80 °C using 1.5 - 3.5mol % of Pd and 1.65 – 3.85 mol % of 1. Electron-neutral and electron-rich substrates werecoupled more efficiently than their electron-poor analogs. This effect has previously beennoted in the coupling of aryl halides with NaNO2.[11] Substrates containing acid-sensitivefunctional groups, such as BOC-protected anilines and nitriles, were tolerated and coupledin high yield along with substrates containing ketones, esters, and free NH groups of anilines(Table 3). Aryl bromides containing bulky ortho-groups, e.g., o-cyclohexyl and o-phenylgroups, could also be coupled successfully, although they required the use of the smallerligand XPhos (3) (Table 3).Heteroaryl bromides such as those containing indoles, pyridines, quinolines, thiophenes andfurans, were also viable substrates (Table 4). Unfortunately, attempts to extend thismethodology to the coupling of aryl chlorides or aryl triflates were unsuccessful. We arecurrently working to understand and overcome these limitations.Finally, to demonstrate the utility of this method, we prepared an intermediate in thereported synthesis of Toltrazuril,[13] an antiprotozoal agent. Intermediate 14 can beassembled from readily available starting materials in an overall yield of 88%. The key C–SCF3 bond-forming process proceeded in 95% yield (Scheme 3).In summary, we have developed a general method for the Pd-catalyzed Ar–SCF3 bond-forming reaction. Using this method, a wide range of aryl bromides were converted intotheir corresponding aryl trifluoromethyl sulfides. Additionally, we have been successful ingenerating a variety of heterocyclic aryl trifluoromethyl sulfides from heteroaryl bromideprecursors. Due to the utility of Ar–SCF3 compounds as biologically active agents, and themild reaction conditions employed, we expect this method to be immediately implementedin the discovery of novel compounds with pharmaceutical and agrochemical applications.Teverovskiy et al. Page 2Angew Chem Int Ed Engl. Author manuscript; available in PMC 2012 August 01.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptSupplementary MaterialRefer to Web version on PubMed Central for supplementary material.References1. a) Manteau B, Pazenok S, Vors JP, Leroux FR. J Fluorine Chem. 2010; 131:140.b) Jeschke P. PestManag Sci. 2010; 66:10. [PubMed: 19701961]2. a) Leo A, Hansch C, Elkins D. Chem Rev. 1971; 71:525.b) Yagupolskii LM, Il’chenko AY,Kondratenko NV. Russ Chem Rev. 1974; 43:32.c) Leroux F, Jeschke P, Schlosser M. Chem Rev.2005; 105:827. [PubMed: 15755078]3. a) Kieltsch I, Eisenberger P, Togni A. Angew Chem Int Ed. 2007; 46:754.b) Pooput C, MedebielleM, Dolbier WR. Org Lett. 2004; 6:301. [PubMed: 14723553] c) Tyrra W, Naumann D, Hoge B,Yagupolskii YL. J Fluorine Chem. 2003; 119:101.d) Adams DJ, Clark JH. J Org Chem. 2000;65:1456. [PubMed: 10814109] e) Clark JH, Jones CW, Kybett AP, Mcclinton MA, Miller JM,Bishop D, Blade RJ. J Fluorine Chem. 1990; 48:249.f) Wakselman C, Tordeux M. J Chem SocChem Comm. 1984:793.g) Yagupolskii LM, Kondratenko NV, Sambur VP. Synthesis. 1975:721.h)Adams DJ, Goddard A, Clark JH, Macquarrie DJ. Chem Commun. 2000:987.i) Boiko VN,Shchupak GM, Yagupolskii LM. Zh Org Khim. 1977; 13:1057.4. a) Surry DS, Buchwald SL. Chemical Science. 2011; 2:27. [PubMed: 22432049] b) Cacchi S,Fabrizi G. Chem Rev. 2005; 105:2873. [PubMed: 16011327] c) Miyaura, N. Metal-CatalyzedCross-Coupling Reactions. Second ed. de Meijere, A.; Diedrech, F., editors. Wiley-VCH;Weinheim: 2004.5. Fernández-Rodríguez MA, Shen Q, Hartwig JF. J Am Chem Soc. 2006; 128:2180. [PubMed:16478149]6. Zack NR, Shreeve JM. Synthetic Commun. 1974; 4:233.7. Mann G, Baranano D, Hartwig JF, Rheingold AL, Guzei IA. J Am Chem Soc. 1998; 120:9205.8. Burgos CH, Barder TE, Huang X, Buchwald SL. Angew Chem Int Ed. 2006; 45:4321.9. Watson DA, Su MJ, Teverovskiy G, Zhang G, Garcia-Fortanet J, Kinzel T, Buchwald SL. Science.2009; 325:1661. [PubMed: 19679769]10. Cho EJ, Senecal TD, Kinzel T, Zhang Y, Watson DA, Buchwald SL. Science. 2010; 328:1679.[PubMed: 20576888]11. Fors BP, Buchwald SL. J Am Chem Soc. 2009; 131:12898. [PubMed: 19737014]12. a) Barder TE, Walker SD, Martinelli JR, Buchwald SL. J Am Chem Soc. 2005; 127:4685.[PubMed: 15796535] b) Milne JE, Buchwald SL. J Am Chem Soc. 2004; 126:13028. [PubMed:15469301] c) Wolfe JP, Buchwald SL. J Am Chem Soc. 1996; 118:7215.d) Hartwig JF,Kawatsura M, Hauck SI, Shaughnessay KH, Alcazar-Roman LM. J Org Chem. 1999; 64:5575.[PubMed: 11674624] e) Reddy NP, Tanaka M. Tetrahedron Lett. 1997; 38:4807.13. Günther A, Mohrmann K-H, Stubbe M, Ziemann H, Bayer AG. 1986 DE3516630.Teverovskiy et al. Page 3Angew Chem Int Ed Engl. Author manuscript; available in PMC 2012 August 01.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptScheme 1.Various ligands used in Pd-catalyzed cross-coupling reactions.Teverovskiy et al. Page 4Angew Chem Int Ed Engl. Author manuscript; available in PMC 2012 August 01.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptScheme 2.Formation of ArSCF3 via transmetalation and reductive elimination from an isolatedLPdAr(Br) complex.Teverovskiy et al. Page 5Angew Chem Int Ed Engl. Author manuscript; available in PMC 2012 August 01.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptScheme 3.Synthesis of Toltrazuril intermediate.Teverovskiy et al. Page 6Angew Chem Int Ed Engl. Author manuscript; available in PMC 2012 August 01.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptTeverovskiy et al. Page 7Table 1Examination of different SCF3 sources.[a]Entry SCF3 Source Additive Yield [%]1 CsSCF3 none 102 AgSCF3 none 03 (Me)4NSCF3 None 204 AgSCF3 (Me)4NI 05 AgSCF3 (Bu)4NCl 06 AgSCF3 (Bu)4NBr 567 AgSCF3 (Bu)4NI 558 AgSCF3 Ph(Me)3NI 809 AgSCF3 Ph(Et)3NI >99[a](COD)Pd(CH2TMS)2 (2.5 mol %), PhMe (4 mL); all reactions are run on 0.2 mmol scale and all reported yields are based on GC dataAngew Chem Int Ed Engl. Author manuscript; available in PMC 2012 August 01.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptTeverovskiy et al. Page 8Table 2Examination of various ligands commonly employed in Pd-catalyzed reactions.[a]Entry Ligand Time (h) Yield (%)1 1 1 >99[b]2 2 1.5 60[b]3 3 1 84[b]4 7 2 36[c]5 8 2 3[c]6 5 2 29[d]7 6 2 0[d]8 9 2 0[d]9 4 2 <1[c][a]PhMe (4 mL); all reactions are run on 0.2 mmol scale and all reported yields are based on GC data.[b]1.15 mol % Pd, 1.27 mol % L.[c]1.5 mol % Pd, 1.65 mol % L.[d]2.5 mol % Pd, 2.75 mol % LAngew Chem Int Ed Engl. Author manuscript; available in PMC 2012 August 01.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptTeverovskiy et al. Page 9Table 3Pd-catalyzed coupling of aryl bromides.[a]Angew Chem Int Ed Engl. Author manuscript; available in PMC 2012 August 01.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptTeverovskiy et al. Page 10Table 4Pd-catalyzed formation of heteroaryl–SCF3 compounds.[a]Angew Chem Int Ed Engl. Author manuscript; available in PMC 2012 August 01.

Pd-Catalyzed Synthesis of Ar-SCF3 Compounds under Mild Conditions

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