DOI: 10.1002/chem.201303641
Communication
& Asymmetric Catalysis
Copper–Boxmi Complexes as Highly Enantioselective Catalysts for Electrophilic Trifluoromethylthiolations Qing-Hai Deng,[a] Christoph Rettenmeier,[b] Hubert Wadepohl,[b] and Lutz H. Gade*[a, b] asymmetric trifluoromethylthiolation of b-ketoesters using chiral organocatalysts.[16] Recently, we developed “boxmi” ligands (2),[17] which are chiral pincers that have been used, among others, in the asymmetric Cu-catalyzed trifluoromethylation of b-ketoesters[17c] [Eq. (1 a)] and the Fe-catalyzed azidation of b-ketoesters and oxindoles[17d] [Eq. (1 b)]. In these reactions, the hypervalent iodine compounds 3[18] and 4[19] were used as the group-transfer reagents. These results implied that the boxmi ligands might be efficient as stereodirecting ligands for the asymmetric electrophilic substitution of b-ketoesters with other formally hypervalent iodine compounds. Herein, we report the highly enantioselective Cu-catalyzed trifluoromethylthiolation of b-ketoesters by using Lu and Shen’s reagent 1[15] as SCF3-transfer reagent [Eq. (1 c)], as well as subsequent stereoselective transformations of the reaction products. To test the efficiency of the catalyst system, we studied the model reaction of b-ketoester 5 a with 1 (Table 1). Reacting the substrates at room temperature in CH2Cl2 in the presence of the catalyst prepared in situ from 10 mol % of Cu(OTf)2 and 12 mol % of 2 a gave the corresponding product 6 a in 93 % yield with 95 % enantiomeric excess (ee) after three days (Table 1, entry 1). Other metal salts were also tested in the reaction, but generally gave much poorer enantioselectivities (Table 1, entries 2–4). The presence of ligand 2 a alone did not result in catalytic activity (entry 5). Upon screening the ligands,
Abstract: The enantioselective trifluoromethylthiolation of b-ketoesters using chiral copper–boxmi complexes as catalysts is reported. A number of a-SCF3-substituted b-ketoesters have been obtained with up to > 99 % enantiomeric excess (ee), and the trifluoromethylthiolated products were then transformed diastereoselectively to a-SCF3b-hydroxyesters with two adjacent quaternary stereocenters.
The trifluoromethylthio group (SCF3) plays an important role in a range of pharmaceuticals and agrochemicals, such as Tiflorex, Toltrazuril, and Vaniliprole,[1] mostly because of its extremely high lipophilicity combined with an enhanced stability due the electronegative CF3 substituent.[2] Consequently, considerable efforts have been devoted to the generation of trifluoromethylthiolated compounds. Apart from earlier indirect strategies,[1g, 3–5] a series of SCF3-transfer reagents have been synthesized in the past few years and employed for the direct introduction of (trifluoromethyl)thio moiety into organic molecules.[6–14] Most recently, Shao et al. developed an air- and moisture-stable hypervalent iodine reagent 1, which was successfully applied to the non-asymmetric trifluoromethylathiolation of b-ketoesters.[15] Based on the unique properties of the SCF3 group, enantiopure organic compounds with a chiral SCF3-containing stereocenter would have potential applications in medicinal chemistry and biology. It is notable that despite impressive progress in developing methods for the formation of C SCF3 bonds, the catalytic stereoselective and, in particular, enantioselective introduction of the SCF3 group to organic compounds has not been realized. The development of an efficient enantioselective catalytic trifluoromethylthiolation, therefore, remains a challenge in organic synthesis. During the preparation of this manuscript, Shen and co-workers reported the first catalytic
Table 1. Optimization of the reaction conditions for the trifluoromethylthiolation of 5 a.
H-Lig Solvent n
T [8C] t [days] Yield [%][a] ee [%][b]
1 2 3
2a 2a 2a
CH2Cl2 CH2Cl2 CH2Cl2
2 2 2
RT RT RT
3 3 6
93 91 88
95 21 5
2a 2a 2b 2c 2a 2a 2b 2b
CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 Et2O CH2Cl2 CH2Cl2 CH2Cl2
2 2 2 2 2 2 1.5 2
RT 40 RT RT RT 40 RT RT
6 6 4 3 5 3 3 3
93 NR[c] 92 89 61 53 91 89
0 – 96 93 92 90 92 93
4 5 6 7 8 9 10 11[d]
[a] Dr. Q.-H. Deng, Prof. Dr. L. H. Gade Catalysis Research Laboratory (CaRLa), Im Neuenheimer Feld 270 69120 Heidelberg (Germany) [b] C. Rettenmeier, Prof. Dr. H. Wadepohl, Prof. Dr. L. H. Gade Anorganisch-Chemisches Institut, Universitt Heidelberg Im Neuenheimer Feld 270, 69120 Heidelberg (Germany) Fax: (+ 49) 6221-545-609 E-mail: [email protected]
Cu(OTf)2 Fe(OOCEt)2 Ni(ClO4)2 . 6H2O Zn(NTf2)2 – Cu(OTf)2 Cu(OTf)2 Cu(OTf)2 Cu(OTf)2 Cu(OTf)2 Cu(OTf)2
[a] Isolated yields. [b] Determined by HPLC analysis. [c] NR = no reaction. [d] Addition of 4 MS (50 mg).
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201303641. Chem. Eur. J. 2014, 20, 93 – 97
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Communication The absolute configuration of the optically active product 6 b was established to be (R) by single-crystal X-ray structure analysis (Figure 1).[20] Based on this, we determined the absolute configurations of a-SCF3 b-ketoesters 6. To demonstrate the utility of this synthetic method, we carried out further transformations of the trifluoromethylthiolated products (Table 3). The trifluoromethylthiolated products 6 a, v, and r reacted with methylmagnesium iodide in Et2O at 40 8C to give the a-SCF3 b-ketoesters 7, 8, and 9, respectively, in good yields, as well as excellent diastereoselectivities. Furthermore, reaction of the b-ketoester 6 o with allylmagnesium bromide gave 10 with excellent diastereoselectivity. The relative stereochemistry of Grignard addition products was assigned on the basis of the X-ray structure analysis of rac-8,[20] which demonstrated that the hydroxyl group and SCF3 group are cis disposed, which is consistent with the previous data and stereochemical models for related transformations (Figure 2).[17c, 21] We propose that the copper(II) catalyst acts as a Lewis acid, which stabilizes and orientates the ester-enolate forms of the substrates: as was indicat-
we found slightly improved enantioselectivity for the ligand without substituents in backbone 2 b (Table 1, entries 6 and 7). Use of CH2Cl2 as solvent and ambient temperatures (Table 1, entries 8 and 9), along with an excess of the SCF3-transfer reagent were found to be essential for high enantioselectivities (Table 1, entry 10), whereas addition of 4 molecular sieves did not improve the result (entry 11). With these optimized reaction conditions, we extended the method to other substrates (Table 2) and first investigated the influence of the ester substituent (R3). Upon going from 6 a to d, the bulkier substituent was found to improve the enantioselectivity slightly, with the tert-butyl ester being converted to the product 6 d with > 99 % ee but slightly reduced yield. Although the benzyl ester derivative also generated the product 6 e with high enantioselectivity, the allylic ester derivative was converted to the corresponding product 6 f with only 76 % ee. Although the bulky substituent may often be necessary for the high enantiocontrol, we actually found that the methyl esters gave a very satisfactory combination of reactivities and enantioselectivities in this transformation. Consequently, a series of indanone-derived methyl b-ketoesters were screened, and all of them were converted to the corresponding products 6 g–l in good yields with high enantioselectivities (90–96 % ee). The cyclopentenone-derived tert-butyl esters gave the products 6 m–p with excellent enantioselectivities (> 99 % ee), as did the functionalized tert-butyl ester of cyclohexanone, which was transformed to 6 q with 99 % ee. Finally, the cyclic sixmembered-ring derivatives were also successfully functionalized in the process. Although the methyl ester only gave the product 6 r with 64 % ee, the tert-butyl esters were converted to the products 6 s–v with high enantioselectivities ( 99 % ee). Chem. Eur. J. 2014, 20, 93 – 97
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Figure 1. Molecular structure of trifluoromethylthiolated product 6 b; only one of the two independent molecules is shown, hydrogen atoms are omitted for clarity.
ed above, the control experiments (Table 1, entry 5 and Scheme S1 in the Supporting Information) revealed that the ligand alone does not catalyze the reaction, thus excluding a potential organocatalytic route. The results of in situ EPR experiments of the Cu-ligand complex, in the presence of substrate 5 a (with or without SCF3 reagent 1) are consistent with the presence of a b-ketoester adduct (see the Supporting Information). No direct reaction of the SCF3 reagent 1 with the copper complex was found upon combining stoichiometric amounts of both components as indicated by the absence of significant changes in the EPR spectrum of the Cu complex. 94
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Communication Table 2. Enantioselective trifluoromethylthiolation of b-ketoesters.[a]
[a] Yields refer to isolated products. Enantiomeric excess (ee) was determined by chiral HPLC analysis.
This was further substantiated by monitoring the reaction by 19F NMR spectroscopy in CD2Cl2 at room temperature over a period of three days (see the Supporting Information), precluding the possibility that the copper catalyst reacted with the SCF3 reagent directly. Finally, we noted that the b-ketoester reagents racemize rapidly under the reaction conditions, which renders a potential kinetic resolution caused by the initial interaction of the nonplanarized educt with the chiral catalyst unobservable. The product ee values of 6 a remain constant throughout the conversion, indicating that the selectivity determining step is the attack of the SCF3 transfer reagent on the Cu-bound planarized ester-enolate. Based on these observations along with the absolute configuration of product 6 b, we suggest the mechanistic cycle shown in Scheme 1, which is similar to the one we proposed previously for the corresponding Cu-catalyzed alkylations.[17b] However, further studies are required to elucidate the full mechanistic details. In conclusion, the combination of a boxmi transition-metal catalyst with a benziodoxole-based transfer reagent of an electronegative functional group has enabled the development of an efficient protocol for the enantioselective electrophilic functionalization b-ketoesters. In the case at hand, we employed Lu and Shen’s SCF3-transfer reagent 1, with which both five- and six-membered-ring b-ketoesters were converted to the corresponding products in high yields and with up to > 99 % ee under mild conditions. The way, in which the construction of a chiral CF3S-substituted center may control the stereochemistry of subsequent transformations, was demonstrated in reactions with Grignard reagents, which gave stereochemically pure a-SCF3-b-hydroxyesters containing two adjacent quaternary stereocenters with well-defined absolute configuration.
Experimental Section General procedure: Cu(OTf)2 (10 mol %) and ligand 2 b (12 mol %) were added into a flame-dried Schlenk tube. Dry CH2Cl2 (1 mL) was added under argon atmosphere, and the mixture was stirred for 1 h. Then b-ketoester 5 (0.1 mmol, 1 equiv) was added, and the mixture was stirred at RT for another 30 min. 3,3-Dimethyl-1-(trifluoromethylthio)-1,2-benziodoxole (1; 2.0 equiv) was added into the mixtures directly, and the reaction was initiated and stirred under an atmosphere of argon at RT until the disappearance of b-ketoester (monitored by TLC). After filtering through Celite and removing the solvent in vacuo, the residue was purified by chromatography to obtain the pure product 6.
Figure 2. Molecular structure of trifluoromethylated product rac-8; hydrogen atoms are omitted for clarity. Chem. Eur. J. 2014, 20, 93 – 97
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2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Communication
[2]
[3] [4]
[5]
Scheme 1. Proposed mechanism of the Cu-catalyzed trifluoromethylthiolation of cyclic b-ketoesters.
Table 3. Highly diastereoselective Grignard reaction of a-SCF3-b-ketoesters.[a]
[6] [7]
[8]
[9]
[a] Yields refer to isolated products; ee values were determined by HPLC analysis. [b] Determined by 1H and 19F NMR analyses. [10]
Acknowledgements CaRLa is co-financed by the University of Heidelberg, the State of Baden-Wrttemberg, and BASF SE. Support from these institutions is gratefully acknowledged.
[11]
[12]
Keywords: b-ketoesters · asymmetric catalysis · copper · pincer ligands · trifluoromethylthiolation [13] [1] For recent monographs and reviews of catalytic asymmetric synthesis of quaternary carbon centers, see: a) Bioorganic and Medicinal Chemistry of Fluorine (Eds.: J.-P. Bgu, D. Bonnet-Delpon), Wiley-VCH, Hoboken, Chem. Eur. J. 2014, 20, 93 – 97
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2008; b) Organofluorine Chemistry (Ed.: K. Uneyama), Blackwell, Oxford, 2006; c) Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Applications (Ed.: P. Kirsch), Wiley-VCH, Weinheim, 2004; d) Organofluorine Compounds: Chemistry and Properties (Ed.: T. Hiyama), Springer, Berlin, 2000; e) Fluorinated Bio-active Compounds (Eds.: B. R. Langlois, T. Billard, S. Large, N. Roques), Fluorine Technology Lyd., Cheshire, 1999; f) Inventory of Industrial Fluoro-Biochemicals (Ed.: A. Becker), Eyrolles, Paris, 1996; g) F. Leroux, P. Jeschke, M. Schlosser, Chem. Rev. 2005, 105, 827; h) J. Stetter, F. Lieb, Angew. Chem. 2000, 112, 1792; Angew. Chem. Int. Ed. 2000, 39, 1724. a) C. Hansch, A. Leo, R. W. Taft, Chem. Rev. 1991, 91, 165; b) C. Hansch, A. Leo, S. H. Unger, K. H. Kim, D. Nikaitani, E. J. Lien, J. Med. Chem. 1973, 16, 1207; c) A. Leo, C. Hansch, D. Elkins, Chem. Rev. 1971, 71, 525. Reviews: a) V. N. Boiko, Beilstein J. Org. Chem. 2010, 6, 880; b) B. Manteau, S. Pazenok, J.-P. Vors, F. R. Leroux, J. Fluorine Chem. 2010, 131, 140. For selected examples on the formation of SCF3 group through halogen/fluorine exchange, see: a) J. M. Kremsner, M. Rack, C. Pilger, C. Oliver Kappe, Tetrahedron Lett. 2009, 50, 3665; b) L. Saint-Jalmes, J. Fluorine Chem. 2006, 127, 85; c) E. A. Nodiff, S. Lipschutz, P. N. Craig, M. Gordon, J. Org. Chem. 1960, 25, 60. For selected examples on the formation of SCF3 group through trifluoromethylation of sulfur compounds, see: a) A. Harsnyi, . Dork, . Csap, T. Bak, C. Peltz, J. Rbai, J. Fluorine Chem. 2011, 132, 1241; b) I. Kieltsch, P. Eisenberger, A. Togni, Angew. Chem. 2007, 119, 768; Angew. Chem. Int. Ed. 2007, 46, 754; c) C. Pooput, M. Medebielle, W. R. Dolbier, Org. Lett. 2004, 6, 301; d) S. Large, N. Roques, B. R. Langlois, J. Org. Chem. 2000, 65, 8848; e) B. Quiclet-Sire, R. N. Saicic, S. Z. Zars, Tetrahedron Lett. 1996, 37, 9057; f) T. Umemoto, S. Ishihara, J. Am. Chem. Soc. 1993, 115, 2156; g) V. G. Koshechko, L. A. Kiprianova, L. I. Fileleeva, Tetrahedron Lett. 1992, 33, 6677; h) V. Soloshonok, V. Kukhar, Y. Pastrait, V. Nazaretian, Synlett 1992, 657. Review: A. Tlili, T. Billard, Angew. Chem. 2013, 125, 6952; Angew. Chem. Int. Ed. 2013, 52, 6818. For selected examples on SCF3Cl as CF3S-transfer reagent, see: a) S. Braverman, E. V. K. Suresh Kumar, M. Cherkinsky, M. Sprecher, I. Goldberg, Tetrahedron 2005, 61, 3547; b) S. Munavalli, D. K. Rohrbaugh, D. I. Rossman, F. J. Berg, G. W. Wagner, H. D. Durst, Synth. Commun. 2000, 30, 2847; c) A. Haas, U. Niemann, Chem. Ber. 1977, 110, 67; d) A. Haas, V. Hellwig, J. Fluorine Chem. 1975, 6, 521; e) S. Andreades, J. F. Harris, W. A. Sheppard, J. Org. Chem. 1964, 29, 898; f) J. F. Harris, J. Am. Chem. Soc. 1962, 84, 3148. For selected examples on CuSCF3 as CF3S-transfer reagent, see: a) J. H. Clark, C. W. Jones, A. P. Kybett, M. A. McClinton, J. M. Miller, D. Bishop, R. J. Blade, J. Fluorine Chem. 1990, 48, 249; b) A. Haas, H.-U. Kr chter, Chem. Ber. 1988, 121, 1833; c) L. M. Yagupolskii, N. V. Kondratenko, V. P. Sambur, Synthesis 1975, 721. For references on (PhNR)SCF3 as CF3S-transfer reagent, see: a) J. Liu, L. Chu, F.-L. Qing, Org. Lett. 2013, 15, 894; b) Y. Yang, X. Jiang, F.-L. Qing, J. Org. Chem. 2012, 77, 7538; c) A. Ferry, T. Billard, E. Bacqu, B. R. Langlois, J. Fluorine Chem. 2012, 134, 160; d) F. Baert, J. Colomb, T. Billard, Angew. Chem. 2012, 124, 10528; Angew. Chem. Int. Ed. 2012, 51, 10382; e) A. Ferry, T. Billard, B. R. Langlois, E. Bacqu, Angew. Chem. 2009, 121, 8703; Angew. Chem. Int. Ed. 2009, 48, 8551. For references on AgSCF3 as CF3S-transfer reagent, see: a) K.-P. Wang, S. Y. Yun, P. Mamidipalli, D. Lee, Chem. Sci. 2013, 4, 3205; b) G. Teverovskiy, D. S. Surry, S. L. Buchwald, Angew. Chem. 2011, 123, 7450; Angew. Chem. Int. Ed. 2011, 50, 7312; c) D. J. Adams, J. H. Clark, J. Org. Chem. 2000, 65, 1456. For references on (NMe4)SCF3 as CF3S-transfer reagent, see: a) C.-P. Zhang, D. A. Vicic, Chem. Asian J. 2012, 7, 1756; b) C.-P. Zhang, D. A. Vicic, J. Am. Chem. Soc. 2012, 134, 183. For references on CF3S SCF3 as CF3S-transfer reagent, see: a) L. D. Tran, I. Popov, O. Daugulis, J. Am. Chem. Soc. 2012, 134, 18237; b) A. A. Kolomeitsev, K. Yu. Chabanenko, G.-V. Rçschenthaler, Y. L. Yagupolskii, Synthesis 1994, 145. For references on Cu(bpy)SCF3 as CF3S-transfer reagent, see: a) D. Kong, Z. Jiang, S. Xin, Z. Bai, Y. Yuan, Z. Weng, Tetrahedron 2013, 69, 6046; b) Z. Weng, W. He, C. Chen, R. Lee, D. Tan, Z. Lai, D. Kong, Y. Yuan, K.-W. Huang, Angew. Chem. 2013, 125, 1588; Angew. Chem. Int. Ed. 2013, 52, 1548. 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Communication [14] For references on the generation of CF3S moiety in situ, see: a) Y.-D. Yang, A. Azuma, E. Tokunaga, M. Yamasaki, M. Shiro, N. Shibata, J. Am. Chem. Soc. 2013, 135, 8782; b) C. Chen, Y. Xie, L. Chu, R.-W. Wang, X. Zhang, F.-L. Qing, Angew. Chem. 2012, 124, 2542; Angew. Chem. Int. Ed. 2012, 51, 2492; c) C. Chen, L. Chu, F.-L. Qing, J. Am. Chem. Soc. 2012, 134, 12454; d) Q.-Y. Chen, J.-X. Duan, J. Chem. Soc. Chem. Commun. 1993, 918. [15] X. Shao, X. Wang, T. Yang, L. Lu, Q. Shen, Angew. Chem. 2013, 125, 3541; Angew. Chem. Int. Ed. 2013, 52, 3457. [16] X. Wang, T. Yang, X. Cheng, Q. Shen, Angew. Chem. 2013, 125, 13098; Angew. Chem. Int. Ed. 2013, 52, 12860. Another organocatalytic method has since been published by T. Bootwicha, X. Liu, R. Pluta, I. Atodiresei, M. Rueping, Angew. Chem. 2013, 125, 13093; Angew. Chem. Int. Ed. 2013, 52, 12856. [17] a) Q.-H. Deng, H. Wadepohl, L. H. Gade, Chem. Eur. J. 2011, 17, 14922; b) Q.-H. Deng, H. Wadepohl, L. H. Gade, J. Am. Chem. Soc. 2012, 134, 2946; c) Q.-H. Deng, H. Wadepohl, L. H. Gade, J. Am. Chem. Soc. 2012, 134, 10769; d) Q.-H. Deng, T. Bleith, H. Wadepohl, L. H. Gade, J. Am. Chem. Soc. 2013, 135, 5356.
Chem. Eur. J. 2014, 20, 93 – 97
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[18] P. Eisenberger, S. Gischig, A. Togni, Chem. Eur. J. 2006, 12, 2579. [19] a) V. V. Zhdankin, A. P. Krasutsky, C. J. Kuehl, A. J. Simonsen, J. K. Woodward, B. Mismash, J. T. Bolz, J. Am. Chem. Soc. 1996, 118, 5192; b) S. Akai, T. Okuno, T. Takada, H. Tohma, Y. Kita, Heterocycles 1996, 42, 47. [20] Details of the crystal structure determinations are given in the Supporting Information. CCDC- < 960246 (6 b) and CCDC-960247 (8) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. [21] a) V. Justrib, S. C. Pellegrinet, M. I. Colombo, J. Org. Chem. 2007, 72, 3702; b) A. Ivkovic, R. Matovic, R. N. Saicic, Org. Lett. 2004, 6, 1221; c) K. V. Emelen, T. D. Wit, G. J. Hoornaert, F. Compernolle, Org. Lett. 2000, 2, 3083; d) G. A. Molander, C. R. Harris, J. Am. Chem. Soc. 1995, 117, 3705.
Received: September 15, 2013 Published online on December 11, 2013
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Communication
& Asymmetric Catalysis
Copper–Boxmi Complexes as Highly Enantioselective Catalysts for Electrophilic Trifluoromethylthiolations Qing-Hai Deng,[a] Christoph Rettenmeier,[b] Hubert Wadepohl,[b] and Lutz H. Gade*[a, b] asymmetric trifluoromethylthiolation of b-ketoesters using chiral organocatalysts.[16] Recently, we developed “boxmi” ligands (2),[17] which are chiral pincers that have been used, among others, in the asymmetric Cu-catalyzed trifluoromethylation of b-ketoesters[17c] [Eq. (1 a)] and the Fe-catalyzed azidation of b-ketoesters and oxindoles[17d] [Eq. (1 b)]. In these reactions, the hypervalent iodine compounds 3[18] and 4[19] were used as the group-transfer reagents. These results implied that the boxmi ligands might be efficient as stereodirecting ligands for the asymmetric electrophilic substitution of b-ketoesters with other formally hypervalent iodine compounds. Herein, we report the highly enantioselective Cu-catalyzed trifluoromethylthiolation of b-ketoesters by using Lu and Shen’s reagent 1[15] as SCF3-transfer reagent [Eq. (1 c)], as well as subsequent stereoselective transformations of the reaction products. To test the efficiency of the catalyst system, we studied the model reaction of b-ketoester 5 a with 1 (Table 1). Reacting the substrates at room temperature in CH2Cl2 in the presence of the catalyst prepared in situ from 10 mol % of Cu(OTf)2 and 12 mol % of 2 a gave the corresponding product 6 a in 93 % yield with 95 % enantiomeric excess (ee) after three days (Table 1, entry 1). Other metal salts were also tested in the reaction, but generally gave much poorer enantioselectivities (Table 1, entries 2–4). The presence of ligand 2 a alone did not result in catalytic activity (entry 5). Upon screening the ligands,
Abstract: The enantioselective trifluoromethylthiolation of b-ketoesters using chiral copper–boxmi complexes as catalysts is reported. A number of a-SCF3-substituted b-ketoesters have been obtained with up to > 99 % enantiomeric excess (ee), and the trifluoromethylthiolated products were then transformed diastereoselectively to a-SCF3b-hydroxyesters with two adjacent quaternary stereocenters.
The trifluoromethylthio group (SCF3) plays an important role in a range of pharmaceuticals and agrochemicals, such as Tiflorex, Toltrazuril, and Vaniliprole,[1] mostly because of its extremely high lipophilicity combined with an enhanced stability due the electronegative CF3 substituent.[2] Consequently, considerable efforts have been devoted to the generation of trifluoromethylthiolated compounds. Apart from earlier indirect strategies,[1g, 3–5] a series of SCF3-transfer reagents have been synthesized in the past few years and employed for the direct introduction of (trifluoromethyl)thio moiety into organic molecules.[6–14] Most recently, Shao et al. developed an air- and moisture-stable hypervalent iodine reagent 1, which was successfully applied to the non-asymmetric trifluoromethylathiolation of b-ketoesters.[15] Based on the unique properties of the SCF3 group, enantiopure organic compounds with a chiral SCF3-containing stereocenter would have potential applications in medicinal chemistry and biology. It is notable that despite impressive progress in developing methods for the formation of C SCF3 bonds, the catalytic stereoselective and, in particular, enantioselective introduction of the SCF3 group to organic compounds has not been realized. The development of an efficient enantioselective catalytic trifluoromethylthiolation, therefore, remains a challenge in organic synthesis. During the preparation of this manuscript, Shen and co-workers reported the first catalytic
Table 1. Optimization of the reaction conditions for the trifluoromethylthiolation of 5 a.
H-Lig Solvent n
T [8C] t [days] Yield [%][a] ee [%][b]
1 2 3
2a 2a 2a
CH2Cl2 CH2Cl2 CH2Cl2
2 2 2
RT RT RT
3 3 6
93 91 88
95 21 5
2a 2a 2b 2c 2a 2a 2b 2b
CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 Et2O CH2Cl2 CH2Cl2 CH2Cl2
2 2 2 2 2 2 1.5 2
RT 40 RT RT RT 40 RT RT
6 6 4 3 5 3 3 3
93 NR[c] 92 89 61 53 91 89
0 – 96 93 92 90 92 93
4 5 6 7 8 9 10 11[d]
[a] Dr. Q.-H. Deng, Prof. Dr. L. H. Gade Catalysis Research Laboratory (CaRLa), Im Neuenheimer Feld 270 69120 Heidelberg (Germany) [b] C. Rettenmeier, Prof. Dr. H. Wadepohl, Prof. Dr. L. H. Gade Anorganisch-Chemisches Institut, Universitt Heidelberg Im Neuenheimer Feld 270, 69120 Heidelberg (Germany) Fax: (+ 49) 6221-545-609 E-mail: [email protected]
Cu(OTf)2 Fe(OOCEt)2 Ni(ClO4)2 . 6H2O Zn(NTf2)2 – Cu(OTf)2 Cu(OTf)2 Cu(OTf)2 Cu(OTf)2 Cu(OTf)2 Cu(OTf)2
[a] Isolated yields. [b] Determined by HPLC analysis. [c] NR = no reaction. [d] Addition of 4 MS (50 mg).
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201303641. Chem. Eur. J. 2014, 20, 93 – 97
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Communication The absolute configuration of the optically active product 6 b was established to be (R) by single-crystal X-ray structure analysis (Figure 1).[20] Based on this, we determined the absolute configurations of a-SCF3 b-ketoesters 6. To demonstrate the utility of this synthetic method, we carried out further transformations of the trifluoromethylthiolated products (Table 3). The trifluoromethylthiolated products 6 a, v, and r reacted with methylmagnesium iodide in Et2O at 40 8C to give the a-SCF3 b-ketoesters 7, 8, and 9, respectively, in good yields, as well as excellent diastereoselectivities. Furthermore, reaction of the b-ketoester 6 o with allylmagnesium bromide gave 10 with excellent diastereoselectivity. The relative stereochemistry of Grignard addition products was assigned on the basis of the X-ray structure analysis of rac-8,[20] which demonstrated that the hydroxyl group and SCF3 group are cis disposed, which is consistent with the previous data and stereochemical models for related transformations (Figure 2).[17c, 21] We propose that the copper(II) catalyst acts as a Lewis acid, which stabilizes and orientates the ester-enolate forms of the substrates: as was indicat-
we found slightly improved enantioselectivity for the ligand without substituents in backbone 2 b (Table 1, entries 6 and 7). Use of CH2Cl2 as solvent and ambient temperatures (Table 1, entries 8 and 9), along with an excess of the SCF3-transfer reagent were found to be essential for high enantioselectivities (Table 1, entry 10), whereas addition of 4 molecular sieves did not improve the result (entry 11). With these optimized reaction conditions, we extended the method to other substrates (Table 2) and first investigated the influence of the ester substituent (R3). Upon going from 6 a to d, the bulkier substituent was found to improve the enantioselectivity slightly, with the tert-butyl ester being converted to the product 6 d with > 99 % ee but slightly reduced yield. Although the benzyl ester derivative also generated the product 6 e with high enantioselectivity, the allylic ester derivative was converted to the corresponding product 6 f with only 76 % ee. Although the bulky substituent may often be necessary for the high enantiocontrol, we actually found that the methyl esters gave a very satisfactory combination of reactivities and enantioselectivities in this transformation. Consequently, a series of indanone-derived methyl b-ketoesters were screened, and all of them were converted to the corresponding products 6 g–l in good yields with high enantioselectivities (90–96 % ee). The cyclopentenone-derived tert-butyl esters gave the products 6 m–p with excellent enantioselectivities (> 99 % ee), as did the functionalized tert-butyl ester of cyclohexanone, which was transformed to 6 q with 99 % ee. Finally, the cyclic sixmembered-ring derivatives were also successfully functionalized in the process. Although the methyl ester only gave the product 6 r with 64 % ee, the tert-butyl esters were converted to the products 6 s–v with high enantioselectivities ( 99 % ee). Chem. Eur. J. 2014, 20, 93 – 97
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Figure 1. Molecular structure of trifluoromethylthiolated product 6 b; only one of the two independent molecules is shown, hydrogen atoms are omitted for clarity.
ed above, the control experiments (Table 1, entry 5 and Scheme S1 in the Supporting Information) revealed that the ligand alone does not catalyze the reaction, thus excluding a potential organocatalytic route. The results of in situ EPR experiments of the Cu-ligand complex, in the presence of substrate 5 a (with or without SCF3 reagent 1) are consistent with the presence of a b-ketoester adduct (see the Supporting Information). No direct reaction of the SCF3 reagent 1 with the copper complex was found upon combining stoichiometric amounts of both components as indicated by the absence of significant changes in the EPR spectrum of the Cu complex. 94
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Communication Table 2. Enantioselective trifluoromethylthiolation of b-ketoesters.[a]
[a] Yields refer to isolated products. Enantiomeric excess (ee) was determined by chiral HPLC analysis.
This was further substantiated by monitoring the reaction by 19F NMR spectroscopy in CD2Cl2 at room temperature over a period of three days (see the Supporting Information), precluding the possibility that the copper catalyst reacted with the SCF3 reagent directly. Finally, we noted that the b-ketoester reagents racemize rapidly under the reaction conditions, which renders a potential kinetic resolution caused by the initial interaction of the nonplanarized educt with the chiral catalyst unobservable. The product ee values of 6 a remain constant throughout the conversion, indicating that the selectivity determining step is the attack of the SCF3 transfer reagent on the Cu-bound planarized ester-enolate. Based on these observations along with the absolute configuration of product 6 b, we suggest the mechanistic cycle shown in Scheme 1, which is similar to the one we proposed previously for the corresponding Cu-catalyzed alkylations.[17b] However, further studies are required to elucidate the full mechanistic details. In conclusion, the combination of a boxmi transition-metal catalyst with a benziodoxole-based transfer reagent of an electronegative functional group has enabled the development of an efficient protocol for the enantioselective electrophilic functionalization b-ketoesters. In the case at hand, we employed Lu and Shen’s SCF3-transfer reagent 1, with which both five- and six-membered-ring b-ketoesters were converted to the corresponding products in high yields and with up to > 99 % ee under mild conditions. The way, in which the construction of a chiral CF3S-substituted center may control the stereochemistry of subsequent transformations, was demonstrated in reactions with Grignard reagents, which gave stereochemically pure a-SCF3-b-hydroxyesters containing two adjacent quaternary stereocenters with well-defined absolute configuration.
Experimental Section General procedure: Cu(OTf)2 (10 mol %) and ligand 2 b (12 mol %) were added into a flame-dried Schlenk tube. Dry CH2Cl2 (1 mL) was added under argon atmosphere, and the mixture was stirred for 1 h. Then b-ketoester 5 (0.1 mmol, 1 equiv) was added, and the mixture was stirred at RT for another 30 min. 3,3-Dimethyl-1-(trifluoromethylthio)-1,2-benziodoxole (1; 2.0 equiv) was added into the mixtures directly, and the reaction was initiated and stirred under an atmosphere of argon at RT until the disappearance of b-ketoester (monitored by TLC). After filtering through Celite and removing the solvent in vacuo, the residue was purified by chromatography to obtain the pure product 6.
Figure 2. Molecular structure of trifluoromethylated product rac-8; hydrogen atoms are omitted for clarity. Chem. Eur. J. 2014, 20, 93 – 97
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Communication
[2]
[3] [4]
[5]
Scheme 1. Proposed mechanism of the Cu-catalyzed trifluoromethylthiolation of cyclic b-ketoesters.
Table 3. Highly diastereoselective Grignard reaction of a-SCF3-b-ketoesters.[a]
[6] [7]
[8]
[9]
[a] Yields refer to isolated products; ee values were determined by HPLC analysis. [b] Determined by 1H and 19F NMR analyses. [10]
Acknowledgements CaRLa is co-financed by the University of Heidelberg, the State of Baden-Wrttemberg, and BASF SE. Support from these institutions is gratefully acknowledged.
[11]
[12]
Keywords: b-ketoesters · asymmetric catalysis · copper · pincer ligands · trifluoromethylthiolation [13] [1] For recent monographs and reviews of catalytic asymmetric synthesis of quaternary carbon centers, see: a) Bioorganic and Medicinal Chemistry of Fluorine (Eds.: J.-P. Bgu, D. Bonnet-Delpon), Wiley-VCH, Hoboken, Chem. Eur. J. 2014, 20, 93 – 97
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2008; b) Organofluorine Chemistry (Ed.: K. Uneyama), Blackwell, Oxford, 2006; c) Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Applications (Ed.: P. Kirsch), Wiley-VCH, Weinheim, 2004; d) Organofluorine Compounds: Chemistry and Properties (Ed.: T. Hiyama), Springer, Berlin, 2000; e) Fluorinated Bio-active Compounds (Eds.: B. R. Langlois, T. Billard, S. Large, N. Roques), Fluorine Technology Lyd., Cheshire, 1999; f) Inventory of Industrial Fluoro-Biochemicals (Ed.: A. Becker), Eyrolles, Paris, 1996; g) F. Leroux, P. Jeschke, M. Schlosser, Chem. Rev. 2005, 105, 827; h) J. Stetter, F. Lieb, Angew. Chem. 2000, 112, 1792; Angew. Chem. Int. Ed. 2000, 39, 1724. a) C. Hansch, A. Leo, R. W. Taft, Chem. Rev. 1991, 91, 165; b) C. Hansch, A. Leo, S. H. Unger, K. H. Kim, D. Nikaitani, E. J. Lien, J. Med. Chem. 1973, 16, 1207; c) A. Leo, C. Hansch, D. Elkins, Chem. Rev. 1971, 71, 525. Reviews: a) V. N. Boiko, Beilstein J. Org. Chem. 2010, 6, 880; b) B. Manteau, S. Pazenok, J.-P. Vors, F. R. Leroux, J. Fluorine Chem. 2010, 131, 140. For selected examples on the formation of SCF3 group through halogen/fluorine exchange, see: a) J. M. Kremsner, M. Rack, C. Pilger, C. Oliver Kappe, Tetrahedron Lett. 2009, 50, 3665; b) L. Saint-Jalmes, J. Fluorine Chem. 2006, 127, 85; c) E. A. Nodiff, S. Lipschutz, P. N. Craig, M. Gordon, J. Org. Chem. 1960, 25, 60. For selected examples on the formation of SCF3 group through trifluoromethylation of sulfur compounds, see: a) A. Harsnyi, . Dork, . Csap, T. Bak, C. Peltz, J. Rbai, J. Fluorine Chem. 2011, 132, 1241; b) I. Kieltsch, P. Eisenberger, A. Togni, Angew. Chem. 2007, 119, 768; Angew. Chem. Int. Ed. 2007, 46, 754; c) C. Pooput, M. Medebielle, W. R. Dolbier, Org. Lett. 2004, 6, 301; d) S. Large, N. Roques, B. R. Langlois, J. Org. Chem. 2000, 65, 8848; e) B. Quiclet-Sire, R. N. Saicic, S. Z. Zars, Tetrahedron Lett. 1996, 37, 9057; f) T. Umemoto, S. Ishihara, J. Am. Chem. Soc. 1993, 115, 2156; g) V. G. Koshechko, L. A. Kiprianova, L. I. Fileleeva, Tetrahedron Lett. 1992, 33, 6677; h) V. Soloshonok, V. Kukhar, Y. Pastrait, V. Nazaretian, Synlett 1992, 657. Review: A. Tlili, T. Billard, Angew. Chem. 2013, 125, 6952; Angew. Chem. Int. Ed. 2013, 52, 6818. For selected examples on SCF3Cl as CF3S-transfer reagent, see: a) S. Braverman, E. V. K. Suresh Kumar, M. Cherkinsky, M. Sprecher, I. Goldberg, Tetrahedron 2005, 61, 3547; b) S. Munavalli, D. K. Rohrbaugh, D. I. Rossman, F. J. Berg, G. W. Wagner, H. D. Durst, Synth. Commun. 2000, 30, 2847; c) A. Haas, U. Niemann, Chem. Ber. 1977, 110, 67; d) A. Haas, V. Hellwig, J. Fluorine Chem. 1975, 6, 521; e) S. Andreades, J. F. Harris, W. A. Sheppard, J. Org. Chem. 1964, 29, 898; f) J. F. Harris, J. Am. Chem. Soc. 1962, 84, 3148. For selected examples on CuSCF3 as CF3S-transfer reagent, see: a) J. H. Clark, C. W. Jones, A. P. Kybett, M. A. McClinton, J. M. Miller, D. Bishop, R. J. Blade, J. Fluorine Chem. 1990, 48, 249; b) A. Haas, H.-U. Kr chter, Chem. Ber. 1988, 121, 1833; c) L. M. Yagupolskii, N. V. Kondratenko, V. P. Sambur, Synthesis 1975, 721. For references on (PhNR)SCF3 as CF3S-transfer reagent, see: a) J. Liu, L. Chu, F.-L. Qing, Org. Lett. 2013, 15, 894; b) Y. Yang, X. Jiang, F.-L. Qing, J. Org. Chem. 2012, 77, 7538; c) A. Ferry, T. Billard, E. Bacqu, B. R. Langlois, J. Fluorine Chem. 2012, 134, 160; d) F. Baert, J. Colomb, T. Billard, Angew. Chem. 2012, 124, 10528; Angew. Chem. Int. Ed. 2012, 51, 10382; e) A. Ferry, T. Billard, B. R. Langlois, E. Bacqu, Angew. Chem. 2009, 121, 8703; Angew. Chem. Int. Ed. 2009, 48, 8551. For references on AgSCF3 as CF3S-transfer reagent, see: a) K.-P. Wang, S. Y. Yun, P. Mamidipalli, D. Lee, Chem. Sci. 2013, 4, 3205; b) G. Teverovskiy, D. S. Surry, S. L. Buchwald, Angew. Chem. 2011, 123, 7450; Angew. Chem. Int. Ed. 2011, 50, 7312; c) D. J. Adams, J. H. Clark, J. Org. Chem. 2000, 65, 1456. For references on (NMe4)SCF3 as CF3S-transfer reagent, see: a) C.-P. Zhang, D. A. Vicic, Chem. Asian J. 2012, 7, 1756; b) C.-P. Zhang, D. A. Vicic, J. Am. Chem. Soc. 2012, 134, 183. For references on CF3S SCF3 as CF3S-transfer reagent, see: a) L. D. Tran, I. Popov, O. Daugulis, J. Am. Chem. Soc. 2012, 134, 18237; b) A. A. Kolomeitsev, K. Yu. Chabanenko, G.-V. Rçschenthaler, Y. L. Yagupolskii, Synthesis 1994, 145. For references on Cu(bpy)SCF3 as CF3S-transfer reagent, see: a) D. Kong, Z. Jiang, S. Xin, Z. Bai, Y. Yuan, Z. Weng, Tetrahedron 2013, 69, 6046; b) Z. Weng, W. He, C. Chen, R. Lee, D. Tan, Z. Lai, D. Kong, Y. Yuan, K.-W. Huang, Angew. Chem. 2013, 125, 1588; Angew. Chem. Int. Ed. 2013, 52, 1548. 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Communication [14] For references on the generation of CF3S moiety in situ, see: a) Y.-D. Yang, A. Azuma, E. Tokunaga, M. Yamasaki, M. Shiro, N. Shibata, J. Am. Chem. Soc. 2013, 135, 8782; b) C. Chen, Y. Xie, L. Chu, R.-W. Wang, X. Zhang, F.-L. Qing, Angew. Chem. 2012, 124, 2542; Angew. Chem. Int. Ed. 2012, 51, 2492; c) C. Chen, L. Chu, F.-L. Qing, J. Am. Chem. Soc. 2012, 134, 12454; d) Q.-Y. Chen, J.-X. Duan, J. Chem. Soc. Chem. Commun. 1993, 918. [15] X. Shao, X. Wang, T. Yang, L. Lu, Q. Shen, Angew. Chem. 2013, 125, 3541; Angew. Chem. Int. Ed. 2013, 52, 3457. [16] X. Wang, T. Yang, X. Cheng, Q. Shen, Angew. Chem. 2013, 125, 13098; Angew. Chem. Int. Ed. 2013, 52, 12860. Another organocatalytic method has since been published by T. Bootwicha, X. Liu, R. Pluta, I. Atodiresei, M. Rueping, Angew. Chem. 2013, 125, 13093; Angew. Chem. Int. Ed. 2013, 52, 12856. [17] a) Q.-H. Deng, H. Wadepohl, L. H. Gade, Chem. Eur. J. 2011, 17, 14922; b) Q.-H. Deng, H. Wadepohl, L. H. Gade, J. Am. Chem. Soc. 2012, 134, 2946; c) Q.-H. Deng, H. Wadepohl, L. H. Gade, J. Am. Chem. Soc. 2012, 134, 10769; d) Q.-H. Deng, T. Bleith, H. Wadepohl, L. H. Gade, J. Am. Chem. Soc. 2013, 135, 5356.
Chem. Eur. J. 2014, 20, 93 – 97
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[18] P. Eisenberger, S. Gischig, A. Togni, Chem. Eur. J. 2006, 12, 2579. [19] a) V. V. Zhdankin, A. P. Krasutsky, C. J. Kuehl, A. J. Simonsen, J. K. Woodward, B. Mismash, J. T. Bolz, J. Am. Chem. Soc. 1996, 118, 5192; b) S. Akai, T. Okuno, T. Takada, H. Tohma, Y. Kita, Heterocycles 1996, 42, 47. [20] Details of the crystal structure determinations are given in the Supporting Information. CCDC- < 960246 (6 b) and CCDC-960247 (8) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. [21] a) V. Justrib, S. C. Pellegrinet, M. I. Colombo, J. Org. Chem. 2007, 72, 3702; b) A. Ivkovic, R. Matovic, R. N. Saicic, Org. Lett. 2004, 6, 1221; c) K. V. Emelen, T. D. Wit, G. J. Hoornaert, F. Compernolle, Org. Lett. 2000, 2, 3083; d) G. A. Molander, C. R. Harris, J. Am. Chem. Soc. 1995, 117, 3705.
Received: September 15, 2013 Published online on December 11, 2013
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