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Cite this: Chem. Commun., 2014, 50, 936
Copper-catalyzed trifluoromethylation of N-arylacrylamides ‘‘on water’’ at room temperature†
Received 23rd October 2013, Accepted 8th November 2013
Fang Yang,ab Piyatida Klumphu,a Yong-Min Liang*b and Bruce H. Lipshutz*a
DOI: 10.1039/c3cc48131j www.rsc.org/chemcomm
A copper-catalyzed intramolecular trifluoromethylation of arylacrylamides leads to oxindole derivatives, effected with stable and inexpensive Langlois’ reagent (CF3SO2Na). These reactions proceed via a radical process in water at room temperature. The aqueous solution can be recycled.
Trifluoromethyl-containing compounds are very much in vogue, oftentimes due to their unique properties such as increased metabolic stability, increased electronegativity and lipophilicity in pharmaceuticals and agrochemicals.1 Hence, intense research efforts have been directed toward exploration of more practical protocols for incorporating the trifluoromethyl functionality.2 To date, palladium- and copper-catalyzed/mediated trifluoromethylation reactions have proven to be effective strategies to form sp3C–CF3,3 sp2C–CF3,4 and spC–CF35 bonds. In 2012, Liu’s group reported a Pd/Yb-catalyzed oxidative aryltrifluoromethylation of activated alkenes using TMSCF3/CsF as the source of CF3, and PhI(OAc)2 as oxidant (Scheme 1a).6 Meanwhile, Cu and Ru-catalyzed trifluoromethylation of alkenes with Togni’s reagent has also been reported by Sodeoka and Nevado (Scheme 1b),7 and Zhu’s group (Scheme 1c).8 Furthermore, these difunctionalizations of alkenes using ‘CF3+’ or ‘CF3’ equivalents, through cationic or radical pathways, can still require multiple steps, and tend to require expensive catalysts and CF3 reagents, as well as relatively high temperatures, dry organic solvents, and/or an inert atmosphere. Therefore, development of an environmentally innocuous process remains a challenge for the trifluoromethylation arena. Trifluoromethylation based on radical intermediates has been developed as a valuable alternative transformation. Baran,9 Sanford10 and Liu11 reported on trifluoromethylations of heterocycles, aryl boronic acids, and a,b-unsaturated carboxylic acids using the inexpensive and stable solid CF3SO2Na (Langlois’ reagent). These reports indicated that the combination of CF3SO2Na and TBHP could a
Department of Chemistry & Biochemistry, University of California, Santa Barbara, California 93106, USA. E-mail: [email protected]; Fax: +1-805-893-8265; Tel: +1-805-893-2521 b State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China. E-mail: [email protected]; Fax: +86-931-8912582 † Electronic supplementary information (ESI) available. See DOI: 10.1039/c3cc48131j
936 | Chem. Commun., 2014, 50, 936--938
Scheme 1
Transition-metal-catalyzed aryltrifluoromethylation of alkenes.
generate CF3 in the presence of air and moisture. Subsequent addition of the in situ-formed CF3 to heterocycles or electron-rich arenes affords products of trifluoromethylation. Inspired by these reports,12 we hypothesized that CF3 could react with the CQC bond of N-aryl acrylamide 1 to form radical intermediate A, followed by intramolecular radical substitution to produce the corresponding oxindole 2 (Scheme 1). Thus, a Cu-catalyzed sequential difunctionalization/trifluoromethylation of N-arylacrylamides might ensue. This process would offer several important features, such as use of an inexpensive and non-platinoid catalyst in the form of a readily available Cu salt, as well as inexpensive Langlois reagent as the source of CF3 radicals. Perhaps most noteworthy would be the mild reaction conditions using water as the reaction medium, with no investment of energy beyond that provided at ambient temperatures. Moreover, additional advantages include the ease of handing all components in air, the environmentally friendly nature of having eliminated organic solvents from reaction mixtures thereby minimizing organic waste, and the opportunity to recycle the aqueous medium. Owing to the importance of CF3-substituted oxindoles that contain a quaternary carbon in many natural products and
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Table 1
ChemComm
Optimization of reaction conditionsa,b
Entry
Catalyst
1 2 3 4 5 6 7 8 9 10 11
Cu(NO3)22.5H2O Cu(NO3)22.5H2O Cu(NO3)22.5H2O Cu(NO3)22.5H2O Cu(NO3)22.5H2O Cu(NO3)22.5H2O Cu(NO3)22.5H2O Cu(NO3)22.5H2O Cu(NO3)22.5H2O Cu(NO3)22.5H2O Cu(NO3)22.5H2O
(1 equiv.) (1 equiv.) (1 equiv.) (20%) (10%) (10%) (10%) (10%) (10%) (10%) (10%)
Additive
Solvent
Time/temp
Yield (%)
— — NaCl (2 M) TMEDA (20%) TMEDA (10%) TMEDA (10%) TMEDA (10%) TMEDA (10%) TMEDA (10%) TMEDA (10%) TMEDA (10%)
2 wt% TPGS-750-M (0.2 mL) 2 wt% TPGS-750-M (0.2 mL) 2 wt% TPGS-750-M (0.2 mL) 2 wt% TPGS-750-M (0.2 mL) 2 wt% TPGS-750-M (0.2 mL) 2 wt% TPGS-750-M (0.15 mL) 3 wt% TPGS-750-M (0.2 mL) 5 wt% TPGS-750-M (0.2 mL) 2 wt% Nok (0.2 mL) 2 wt% PTS (0.2 mL) H2O (0.2 mL)
20 24 24 24 24 24 24 24 24 24 1
57 55 Trace 64 87/75d 83 68 22 31c Tracec 87/75d
h/50 1C h/RT h/RT h/RT h/RT h/RT h/RT h/RT h/RT h/RT h/RT
a These reactions were carried out by using 1a (0.2 mmol) with CF3SO2Na (1.5 equiv.) and TBHP (70 wt% in H2O, 3.5 equiv.). NMR analysis using 1,3,5-trifluorobenzene as an internal standard. c Incomplete reaction. d Isolated yield.
biologically active compounds,13 our initial investigation focused on the stoichiometric Cu-mediated reaction of N-aryl acrylamide (1a) with CF3SO2Na (1.5 equiv.) and TBHP (3.5 equiv.) at 50 1C in DCM/H2O (Table 1). The desired trifluoromethylated product 2a was successfully obtained in up to 50% yield. In this test reaction, copper(II) salts, especially Cu(NO3)22.5H2O were shown to be more efficient than copper(I) salts (see ESI,† Table S1). In the context of our ongoing efforts in developing faster, better, and cheaper surfactants (first-generation species PTS,14 second-generation TPGS-750-M,15 and third-generation ‘‘Nok’’16), we initially examined this reaction with 2 wt% TPGS-750-M/ water, and slightly higher yields of 2a (57%) was obtained (Table 1, entry 1). When the reaction was performed at room temperature, a similar result was obtained after 24 hours (entry 2). Surprisingly, trifluoromethylation was totally suppressed by adding NaCl (2 M) (entry 3), which has been employed previously to increase micellar size looking for increased binding constants to maximize rates. When the catalyst loading was reduced to 20 mol% with 20 mol% TMEDA, the yield of 2a was improved to 64% (entry 4). We next examined the reactant ratio (see ESI,† Table S1), and this further optimization led to an excellent yield (87%) of 2a when Cu(NO3)22.5H2O and TMEDA were used in a 1 : 1 ratio (entry 5). Neither increasing the concentration of the reaction (entry 6) nor the surfactant (entries 7 and 8) improved yields. Other surfactants including PTS and Nok were screened, as was neat H2O (entries 9–11). Remarkably, running the reaction ‘‘on water’’17 (i.e., with pure water as the medium), the same highest yield was obtained, and in much less time (24 h vs. 1 h). This may be a consequence of rapid CF3 generation on water and accelerated trapping due to the hydrophobic effect. The amounts of CF3SO2Na and TBHP were also examined, with the best results obtained with a 1.5 to 3.5 ratio (see ESI,† Table S2). Lastly, the reaction of 1a run in the presence of TEMPO (1.5 equiv.) led to none of the anticipated product 2a. The control reaction between TEMPO and CF3SO2Na led to trifluoromethylated TEMPO (see ESI†). With the optimized reaction conditions, the substrate scope was explored, with examples illustrated in Table 2. Substrates bearing alkyl and aryl N-protecting groups provided good yields of the corresponding oxindoles 2a and 2b, respectively, while a secondary aryl amide failed to give the desired product 2c even after 20 hours.
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b
Determined by 19F
Both electron-withdrawing and electron-donating groups at the p-position on the phenyl ring are well tolerated, and the desired products 2d–2j were obtained in good yields. With substituent groups at the m-position of the aniline ring, a mixture of 2k and 2k 0 was observed in a ratio of 1.3 : 1. The steric effect in substrates having two substituents on the aniline ring, such as Table 2 Representative examples of trifluoromethylation of N-arylacrylamides leading to oxindolesa,b,c
a
The reactions were conducted at 0.3 mmol scale: Cu(NO3)22.5H2O (10 mol%), TMEDA (10 mol%), CF3SO2Na (1.5 equiv.) and TBHP (3.5 equiv.) in H2O (0.5 M). b Conditions: Cu(NO3)22.5H2O (10 mol%), TMEDA (10 mol%) CF3SO2Na (3.0 equiv.) and TBHP (7 equiv.) in H2O (0.5 M). c Isolated yield. d At 40 1C.
Chem. Commun., 2014, 50, 936--938 | 937
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ChemComm Table 3
Communication
Studies on recycling of the aqueous reaction mixture
Cyclea,b (isolated yield%) 1
2
3
4
5
75
74
70
70
68
Published on 11 November 2013. Downloaded by UTSA Libraries on 11/09/2014 08:25:40.
a
Reaction conditions: substrates 1a (0.5 mmol), Cu(NO3)22.5H2O (10 mol%), TMEDA (10 mol%), CF3SO2Na (1.5 equiv.) and TBHP (3.5 equiv.) in H2O (0.5 M). b 1a (0.5 mmol), 1.5 equiv. CF3SO2Na and 3.5 equiv. TBHP were added per cycle.
that leading to 2l, or an educt bearing an ortho substituent on the phenyl ring as in the precursor to 2m gave modest results. Various olefins with a-substituents, such as phenyl (1n), hydroxyl (1o), ester (1p), ether (1q) and phthalimide (1r) were investigated as well. The corresponding oxindoles 2n–2r were obtained in variable yields. Furthermore, more CF3SO2Na (3.0 equiv.) and TBHP (7.0 equiv.) were required by highly water-insoluble solid substrates (1b, 1m, 1n and 1r), and for substrates bearing electron-withdrawing groups (1g–1j). The potential for recycling of the aqueous medium was studied using 1a as a model system (Table 3). Upon completion of the trifluoromethylation event, a standard in-flask extraction of the product was conducted by employing a single organic solvent (e.g., EtOAc 3). Removal of the EtOAc is followed by product purification, while the aqueous phase retaining the copper catalyst was reused by addition of fresh substrate, CF3 reagent and TBHP. After five cycles, the yield of 2a decreased but only slightly, indicating that the aqueous medium containing the water-soluble copper catalyst remains active. Use of E factors for assessing the extent of waste created in a reaction has become a widely accepted measure of greenness.18 Water is generally excluded from the calculation since it leads to far higher numbers that can overshadow the other components in the mixture (typical E factors range from 5–100). Nonetheless, while an E factor has been calculated based on organic solvent alone, another based on both solvent and water used in these reactions, likewise, illustrate how low the values can be. The potential savings in organic and aqueous waste of our approach in these trifluoromethylation reactions has been documented using 1q as a representative case. As indicated in Scheme 2, E factors of 3.2 based on total organic solvent used, and 10.2 when the water involved is part of the calculation (see ESI†). Considering that the aqueous medium can be recycled several times (vide supra), the E factor of 10.2 should decline dramatically.
Scheme 2
E factors for a model trifluoromethylation reaction.
938 | Chem. Commun., 2014, 50, 936--938
In summary, we have developed a practical and economical copper(II)-catalyzed trifluoromethylation of N-aryl acrylamides for the synthesis of a variety of CF3-containing oxindoles bearing a quaternary carbon center. Compared with existing strategies, this protocol for the introduction of the trifluoromethyl group exhibits several noteworthy features, such as inexpensive and readily available catalyst and trifluoromethylating reagent, and reaction conditions that rely on water and ambient temperatures, in air. Recycling of the aqueous medium has been demonstrated, thereby potentially driving E factors, which are already quite low, down even further.
Notes and references 1 (a) T. Furuya, A. S. Kamlet and T. Ritter, Nature, 2011, 473, 470; (b) O. A. Tomashenko and V. V. Grushin, Chem. Rev., 2011, 111, 4475; (c) A. Studer, Angew. Chem., Int. Ed., 2012, 51, 8950; (d) X. F. Wu, H. Neumann and M. Beller, Chem.–Asian J., 2012, 7, 1199. 2 (a) X. G. Zhang, H. X. Dai, M. Wasa and J. Q. Yu, J. Am. Chem. Soc., 2012, 134, 11948; (b) T. S. N. Zhao and K. J. Szabo, Org. Lett., 2012, 14, 3966; (c) R. Zhu and S. L. Buchwald, J. Am. Chem. Soc., 2012, 134, 12462; (d) E. Pair, N. Monteiro, D. Bouyssi and O. Baudoin, Angew. Chem., Int. Ed., 2013, 52, 5346. 3 (a) P. V. Pham, D. A. Nagib and D. W. C. MacMillan, Angew. Chem., Int. Ed., 2011, 50, 6119; (b) L. L. Chu and F. L. Qing, Org. Lett., 2012, 14, 2106; (c) Q. H. Deng, H. Wadepohl and L. H. Gade, J. Am. Chem. Soc., 2012, 134, 10769; (d) P. Novak, A. Lishchynskyi and V. V. Grushin, J. Am. Chem. Soc., 2012, 134, 16167. 4 (a) L. L. Chu and F. L. Qing, J. Am. Chem. Soc., 2012, 134, 1298; (b) A. T. Parsons, T. D. Senecal and S. L. Buchwald, Angew. Chem., Int. Ed., 2012, 51, 2947; (c) Y. D. Ye and M. S. Sanford, J. Am. Chem. Soc., 2012, 134, 9034; (d) Y. T. He, L. H. Li, Y. F. Yang, Y. Q. Wang, J. Y. Luo, X. Y. Liu and Y. M. Liang, Chem. Commun., 2013, 49, 5687; (e) Y. Li, L. P. Wu, H. Neumann and M. Beller, Chem. Commun., 2013, 49, 2628. 5 (a) X. L. Jiang, L. L. Chu and F. L. Qing, J. Org. Chem., 2012, 77, 1251; (b) K. Zhang, X. L. Qiu, Y. G. Huang and F. L. Qing, Eur. J. Org. Chem., 2012, 58. 6 X. Mu, T. Wu, H. Y. Wang, Y. L. Guo and G. S. Liu, J. Am. Chem. Soc., 2012, 134, 878. 7 (a) H. Egami, R. Shimizu, S. Kawamura and M. Sodeoka, Angew. Chem., Int. Ed., 2013, 52, 4000; (b) H. Egami, R. Shimizu and M. Sodeoka, J. Fluorine Chem., 2013, 152, 51; (c) W. Kong, M. Casimiro, E. Merino and C. Nevado, J. Am. Chem. Soc., 2013, 135, 14480; (d) W. Kong, M. Casimiro, N. Fuentes, E. Merino and C. Nevado, Angew. Chem., Int. Ed., 2013, DOI: 10.1002/anie.201307377. 8 P. Xu, J. Xie, Q. C. Xue, C. D. Pan, Y. X. Cheng and C. J. Zhu, Chem.–Eur. J., 2013, 19, 14039. 9 Y. N. Ji, T. Brueckl, R. D. Baxter, Y. Fujiwara, I. B. Seiple, S. Su, D. G. Blackmond and P. S. Baran, Proc. Natl. Acad. Sci. U. S. A., 2011, 108, 14411. 10 Y. D. Ye, S. A. Kuenzi and M. S. Sanford, Org. Lett., 2012, 14, 4979. 11 Z. J. Li, Z. L. Cui and Z. Q. Liu, Org. Lett., 2013, 15, 406. 12 (a) Y. M. Li, M. Sun, H. L. Wang, Q. P. Tian and S. D. Yang, Angew. Chem., Int. Ed., 2013, 52, 3972; (b) Y. Meng, L. N. Guo, H. Wang and X. H. Duan, Chem. Commun., 2013, 49, 7540; (c) W. T. Wei, M. B. Zhou, J. H. Fan, W. Liu, R. J. Song, Y. Liu, M. Hu, P. Xie and J. H. Li, Angew. Chem., Int. Ed., 2013, 52, 3638. 13 (a) C. V. Galliford and K. A. Scheidt, Angew. Chem., Int. Ed., 2007, 46, 8748; (b) F. Zhou, Y. L. Liu and J. A. Zhou, Adv. Synth. Catal., 2010, 352, 1381; (c) H. L. Wei, T. Piou, J. Dufour, L. Neuville and J. P. Zhu, Org. Lett., 2011, 13, 2244. 14 B. H. Lipshutz, S. Ghorai, W. W. Y. Leong, B. R. Taft and D. V. Krogstad, J. Org. Chem., 2011, 76, 5061. 15 B. H. Lipshutz, S. Ghorai, A. R. Abela, R. Moser, T. Nishikata, C. Duplais, A. Krasovskiy, R. D. Gaston and R. C. Gadwood, J. Org. Chem., 2011, 76, 4379. 16 P. Klumphu and B. H. Lipshutz, ‘‘Nok’’. A New Phytosterol-Based Amphiphile Enabling Transition Metal-Catalyzed Couplings in Water at Room Temperature, J. Org. Chem., in press. 17 S. Narayan, J. Muldoon, M. G. Finn, V. V. Fokin, H. C. Kolib and K. B. Sharpless, Angew. Chem., Int. Ed., 2005, 44, 3275. 18 (a) R. A. Sheldon, Chem. Commun., 2008, 3352; (b) S. Bonollo, D. Lanari, J. M. Longo and L. Vaccaro, Green Chem., 2012, 14, 164; (c) T. Angelini, S. Bonollo, D. Lanari, F. Pizzo and L. Vaccaro, Org. Biomol. Chem., 2013, 11, 5042; (d) E. Ballerini, P. Crotti, I. Frau, D. Lanari, F. Pizzo and L. Vaccaro, Green Chem., 2013, 15, 2394.
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Cite this: Chem. Commun., 2014, 50, 936
Copper-catalyzed trifluoromethylation of N-arylacrylamides ‘‘on water’’ at room temperature†
Received 23rd October 2013, Accepted 8th November 2013
Fang Yang,ab Piyatida Klumphu,a Yong-Min Liang*b and Bruce H. Lipshutz*a
DOI: 10.1039/c3cc48131j www.rsc.org/chemcomm
A copper-catalyzed intramolecular trifluoromethylation of arylacrylamides leads to oxindole derivatives, effected with stable and inexpensive Langlois’ reagent (CF3SO2Na). These reactions proceed via a radical process in water at room temperature. The aqueous solution can be recycled.
Trifluoromethyl-containing compounds are very much in vogue, oftentimes due to their unique properties such as increased metabolic stability, increased electronegativity and lipophilicity in pharmaceuticals and agrochemicals.1 Hence, intense research efforts have been directed toward exploration of more practical protocols for incorporating the trifluoromethyl functionality.2 To date, palladium- and copper-catalyzed/mediated trifluoromethylation reactions have proven to be effective strategies to form sp3C–CF3,3 sp2C–CF3,4 and spC–CF35 bonds. In 2012, Liu’s group reported a Pd/Yb-catalyzed oxidative aryltrifluoromethylation of activated alkenes using TMSCF3/CsF as the source of CF3, and PhI(OAc)2 as oxidant (Scheme 1a).6 Meanwhile, Cu and Ru-catalyzed trifluoromethylation of alkenes with Togni’s reagent has also been reported by Sodeoka and Nevado (Scheme 1b),7 and Zhu’s group (Scheme 1c).8 Furthermore, these difunctionalizations of alkenes using ‘CF3+’ or ‘CF3’ equivalents, through cationic or radical pathways, can still require multiple steps, and tend to require expensive catalysts and CF3 reagents, as well as relatively high temperatures, dry organic solvents, and/or an inert atmosphere. Therefore, development of an environmentally innocuous process remains a challenge for the trifluoromethylation arena. Trifluoromethylation based on radical intermediates has been developed as a valuable alternative transformation. Baran,9 Sanford10 and Liu11 reported on trifluoromethylations of heterocycles, aryl boronic acids, and a,b-unsaturated carboxylic acids using the inexpensive and stable solid CF3SO2Na (Langlois’ reagent). These reports indicated that the combination of CF3SO2Na and TBHP could a
Department of Chemistry & Biochemistry, University of California, Santa Barbara, California 93106, USA. E-mail: [email protected]; Fax: +1-805-893-8265; Tel: +1-805-893-2521 b State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China. E-mail: [email protected]; Fax: +86-931-8912582 † Electronic supplementary information (ESI) available. See DOI: 10.1039/c3cc48131j
936 | Chem. Commun., 2014, 50, 936--938
Scheme 1
Transition-metal-catalyzed aryltrifluoromethylation of alkenes.
generate CF3 in the presence of air and moisture. Subsequent addition of the in situ-formed CF3 to heterocycles or electron-rich arenes affords products of trifluoromethylation. Inspired by these reports,12 we hypothesized that CF3 could react with the CQC bond of N-aryl acrylamide 1 to form radical intermediate A, followed by intramolecular radical substitution to produce the corresponding oxindole 2 (Scheme 1). Thus, a Cu-catalyzed sequential difunctionalization/trifluoromethylation of N-arylacrylamides might ensue. This process would offer several important features, such as use of an inexpensive and non-platinoid catalyst in the form of a readily available Cu salt, as well as inexpensive Langlois reagent as the source of CF3 radicals. Perhaps most noteworthy would be the mild reaction conditions using water as the reaction medium, with no investment of energy beyond that provided at ambient temperatures. Moreover, additional advantages include the ease of handing all components in air, the environmentally friendly nature of having eliminated organic solvents from reaction mixtures thereby minimizing organic waste, and the opportunity to recycle the aqueous medium. Owing to the importance of CF3-substituted oxindoles that contain a quaternary carbon in many natural products and
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Table 1
ChemComm
Optimization of reaction conditionsa,b
Entry
Catalyst
1 2 3 4 5 6 7 8 9 10 11
Cu(NO3)22.5H2O Cu(NO3)22.5H2O Cu(NO3)22.5H2O Cu(NO3)22.5H2O Cu(NO3)22.5H2O Cu(NO3)22.5H2O Cu(NO3)22.5H2O Cu(NO3)22.5H2O Cu(NO3)22.5H2O Cu(NO3)22.5H2O Cu(NO3)22.5H2O
(1 equiv.) (1 equiv.) (1 equiv.) (20%) (10%) (10%) (10%) (10%) (10%) (10%) (10%)
Additive
Solvent
Time/temp
Yield (%)
— — NaCl (2 M) TMEDA (20%) TMEDA (10%) TMEDA (10%) TMEDA (10%) TMEDA (10%) TMEDA (10%) TMEDA (10%) TMEDA (10%)
2 wt% TPGS-750-M (0.2 mL) 2 wt% TPGS-750-M (0.2 mL) 2 wt% TPGS-750-M (0.2 mL) 2 wt% TPGS-750-M (0.2 mL) 2 wt% TPGS-750-M (0.2 mL) 2 wt% TPGS-750-M (0.15 mL) 3 wt% TPGS-750-M (0.2 mL) 5 wt% TPGS-750-M (0.2 mL) 2 wt% Nok (0.2 mL) 2 wt% PTS (0.2 mL) H2O (0.2 mL)
20 24 24 24 24 24 24 24 24 24 1
57 55 Trace 64 87/75d 83 68 22 31c Tracec 87/75d
h/50 1C h/RT h/RT h/RT h/RT h/RT h/RT h/RT h/RT h/RT h/RT
a These reactions were carried out by using 1a (0.2 mmol) with CF3SO2Na (1.5 equiv.) and TBHP (70 wt% in H2O, 3.5 equiv.). NMR analysis using 1,3,5-trifluorobenzene as an internal standard. c Incomplete reaction. d Isolated yield.
biologically active compounds,13 our initial investigation focused on the stoichiometric Cu-mediated reaction of N-aryl acrylamide (1a) with CF3SO2Na (1.5 equiv.) and TBHP (3.5 equiv.) at 50 1C in DCM/H2O (Table 1). The desired trifluoromethylated product 2a was successfully obtained in up to 50% yield. In this test reaction, copper(II) salts, especially Cu(NO3)22.5H2O were shown to be more efficient than copper(I) salts (see ESI,† Table S1). In the context of our ongoing efforts in developing faster, better, and cheaper surfactants (first-generation species PTS,14 second-generation TPGS-750-M,15 and third-generation ‘‘Nok’’16), we initially examined this reaction with 2 wt% TPGS-750-M/ water, and slightly higher yields of 2a (57%) was obtained (Table 1, entry 1). When the reaction was performed at room temperature, a similar result was obtained after 24 hours (entry 2). Surprisingly, trifluoromethylation was totally suppressed by adding NaCl (2 M) (entry 3), which has been employed previously to increase micellar size looking for increased binding constants to maximize rates. When the catalyst loading was reduced to 20 mol% with 20 mol% TMEDA, the yield of 2a was improved to 64% (entry 4). We next examined the reactant ratio (see ESI,† Table S1), and this further optimization led to an excellent yield (87%) of 2a when Cu(NO3)22.5H2O and TMEDA were used in a 1 : 1 ratio (entry 5). Neither increasing the concentration of the reaction (entry 6) nor the surfactant (entries 7 and 8) improved yields. Other surfactants including PTS and Nok were screened, as was neat H2O (entries 9–11). Remarkably, running the reaction ‘‘on water’’17 (i.e., with pure water as the medium), the same highest yield was obtained, and in much less time (24 h vs. 1 h). This may be a consequence of rapid CF3 generation on water and accelerated trapping due to the hydrophobic effect. The amounts of CF3SO2Na and TBHP were also examined, with the best results obtained with a 1.5 to 3.5 ratio (see ESI,† Table S2). Lastly, the reaction of 1a run in the presence of TEMPO (1.5 equiv.) led to none of the anticipated product 2a. The control reaction between TEMPO and CF3SO2Na led to trifluoromethylated TEMPO (see ESI†). With the optimized reaction conditions, the substrate scope was explored, with examples illustrated in Table 2. Substrates bearing alkyl and aryl N-protecting groups provided good yields of the corresponding oxindoles 2a and 2b, respectively, while a secondary aryl amide failed to give the desired product 2c even after 20 hours.
This journal is © The Royal Society of Chemistry 2014
b
Determined by 19F
Both electron-withdrawing and electron-donating groups at the p-position on the phenyl ring are well tolerated, and the desired products 2d–2j were obtained in good yields. With substituent groups at the m-position of the aniline ring, a mixture of 2k and 2k 0 was observed in a ratio of 1.3 : 1. The steric effect in substrates having two substituents on the aniline ring, such as Table 2 Representative examples of trifluoromethylation of N-arylacrylamides leading to oxindolesa,b,c
a
The reactions were conducted at 0.3 mmol scale: Cu(NO3)22.5H2O (10 mol%), TMEDA (10 mol%), CF3SO2Na (1.5 equiv.) and TBHP (3.5 equiv.) in H2O (0.5 M). b Conditions: Cu(NO3)22.5H2O (10 mol%), TMEDA (10 mol%) CF3SO2Na (3.0 equiv.) and TBHP (7 equiv.) in H2O (0.5 M). c Isolated yield. d At 40 1C.
Chem. Commun., 2014, 50, 936--938 | 937
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Studies on recycling of the aqueous reaction mixture
Cyclea,b (isolated yield%) 1
2
3
4
5
75
74
70
70
68
Published on 11 November 2013. Downloaded by UTSA Libraries on 11/09/2014 08:25:40.
a
Reaction conditions: substrates 1a (0.5 mmol), Cu(NO3)22.5H2O (10 mol%), TMEDA (10 mol%), CF3SO2Na (1.5 equiv.) and TBHP (3.5 equiv.) in H2O (0.5 M). b 1a (0.5 mmol), 1.5 equiv. CF3SO2Na and 3.5 equiv. TBHP were added per cycle.
that leading to 2l, or an educt bearing an ortho substituent on the phenyl ring as in the precursor to 2m gave modest results. Various olefins with a-substituents, such as phenyl (1n), hydroxyl (1o), ester (1p), ether (1q) and phthalimide (1r) were investigated as well. The corresponding oxindoles 2n–2r were obtained in variable yields. Furthermore, more CF3SO2Na (3.0 equiv.) and TBHP (7.0 equiv.) were required by highly water-insoluble solid substrates (1b, 1m, 1n and 1r), and for substrates bearing electron-withdrawing groups (1g–1j). The potential for recycling of the aqueous medium was studied using 1a as a model system (Table 3). Upon completion of the trifluoromethylation event, a standard in-flask extraction of the product was conducted by employing a single organic solvent (e.g., EtOAc 3). Removal of the EtOAc is followed by product purification, while the aqueous phase retaining the copper catalyst was reused by addition of fresh substrate, CF3 reagent and TBHP. After five cycles, the yield of 2a decreased but only slightly, indicating that the aqueous medium containing the water-soluble copper catalyst remains active. Use of E factors for assessing the extent of waste created in a reaction has become a widely accepted measure of greenness.18 Water is generally excluded from the calculation since it leads to far higher numbers that can overshadow the other components in the mixture (typical E factors range from 5–100). Nonetheless, while an E factor has been calculated based on organic solvent alone, another based on both solvent and water used in these reactions, likewise, illustrate how low the values can be. The potential savings in organic and aqueous waste of our approach in these trifluoromethylation reactions has been documented using 1q as a representative case. As indicated in Scheme 2, E factors of 3.2 based on total organic solvent used, and 10.2 when the water involved is part of the calculation (see ESI†). Considering that the aqueous medium can be recycled several times (vide supra), the E factor of 10.2 should decline dramatically.
Scheme 2
E factors for a model trifluoromethylation reaction.
938 | Chem. Commun., 2014, 50, 936--938
In summary, we have developed a practical and economical copper(II)-catalyzed trifluoromethylation of N-aryl acrylamides for the synthesis of a variety of CF3-containing oxindoles bearing a quaternary carbon center. Compared with existing strategies, this protocol for the introduction of the trifluoromethyl group exhibits several noteworthy features, such as inexpensive and readily available catalyst and trifluoromethylating reagent, and reaction conditions that rely on water and ambient temperatures, in air. Recycling of the aqueous medium has been demonstrated, thereby potentially driving E factors, which are already quite low, down even further.
Notes and references 1 (a) T. Furuya, A. S. Kamlet and T. Ritter, Nature, 2011, 473, 470; (b) O. A. Tomashenko and V. V. Grushin, Chem. Rev., 2011, 111, 4475; (c) A. Studer, Angew. Chem., Int. Ed., 2012, 51, 8950; (d) X. F. Wu, H. Neumann and M. Beller, Chem.–Asian J., 2012, 7, 1199. 2 (a) X. G. Zhang, H. X. Dai, M. Wasa and J. Q. Yu, J. Am. Chem. Soc., 2012, 134, 11948; (b) T. S. N. Zhao and K. J. Szabo, Org. Lett., 2012, 14, 3966; (c) R. Zhu and S. L. Buchwald, J. Am. Chem. Soc., 2012, 134, 12462; (d) E. Pair, N. Monteiro, D. Bouyssi and O. Baudoin, Angew. Chem., Int. Ed., 2013, 52, 5346. 3 (a) P. V. Pham, D. A. Nagib and D. W. C. MacMillan, Angew. Chem., Int. Ed., 2011, 50, 6119; (b) L. L. Chu and F. L. Qing, Org. Lett., 2012, 14, 2106; (c) Q. H. Deng, H. Wadepohl and L. H. Gade, J. Am. Chem. Soc., 2012, 134, 10769; (d) P. Novak, A. Lishchynskyi and V. V. Grushin, J. Am. Chem. Soc., 2012, 134, 16167. 4 (a) L. L. Chu and F. L. Qing, J. Am. Chem. Soc., 2012, 134, 1298; (b) A. T. Parsons, T. D. Senecal and S. L. Buchwald, Angew. Chem., Int. Ed., 2012, 51, 2947; (c) Y. D. Ye and M. S. Sanford, J. Am. Chem. Soc., 2012, 134, 9034; (d) Y. T. He, L. H. Li, Y. F. Yang, Y. Q. Wang, J. Y. Luo, X. Y. Liu and Y. M. Liang, Chem. Commun., 2013, 49, 5687; (e) Y. Li, L. P. Wu, H. Neumann and M. Beller, Chem. Commun., 2013, 49, 2628. 5 (a) X. L. Jiang, L. L. Chu and F. L. Qing, J. Org. Chem., 2012, 77, 1251; (b) K. Zhang, X. L. Qiu, Y. G. Huang and F. L. Qing, Eur. J. Org. Chem., 2012, 58. 6 X. Mu, T. Wu, H. Y. Wang, Y. L. Guo and G. S. Liu, J. Am. Chem. Soc., 2012, 134, 878. 7 (a) H. Egami, R. Shimizu, S. Kawamura and M. Sodeoka, Angew. Chem., Int. Ed., 2013, 52, 4000; (b) H. Egami, R. Shimizu and M. Sodeoka, J. Fluorine Chem., 2013, 152, 51; (c) W. Kong, M. Casimiro, E. Merino and C. Nevado, J. Am. Chem. Soc., 2013, 135, 14480; (d) W. Kong, M. Casimiro, N. Fuentes, E. Merino and C. Nevado, Angew. Chem., Int. Ed., 2013, DOI: 10.1002/anie.201307377. 8 P. Xu, J. Xie, Q. C. Xue, C. D. Pan, Y. X. Cheng and C. J. Zhu, Chem.–Eur. J., 2013, 19, 14039. 9 Y. N. Ji, T. Brueckl, R. D. Baxter, Y. Fujiwara, I. B. Seiple, S. Su, D. G. Blackmond and P. S. Baran, Proc. Natl. Acad. Sci. U. S. A., 2011, 108, 14411. 10 Y. D. Ye, S. A. Kuenzi and M. S. Sanford, Org. Lett., 2012, 14, 4979. 11 Z. J. Li, Z. L. Cui and Z. Q. Liu, Org. Lett., 2013, 15, 406. 12 (a) Y. M. Li, M. Sun, H. L. Wang, Q. P. Tian and S. D. Yang, Angew. Chem., Int. Ed., 2013, 52, 3972; (b) Y. Meng, L. N. Guo, H. Wang and X. H. Duan, Chem. Commun., 2013, 49, 7540; (c) W. T. Wei, M. B. Zhou, J. H. Fan, W. Liu, R. J. Song, Y. Liu, M. Hu, P. Xie and J. H. Li, Angew. Chem., Int. Ed., 2013, 52, 3638. 13 (a) C. V. Galliford and K. A. Scheidt, Angew. Chem., Int. Ed., 2007, 46, 8748; (b) F. Zhou, Y. L. Liu and J. A. Zhou, Adv. Synth. Catal., 2010, 352, 1381; (c) H. L. Wei, T. Piou, J. Dufour, L. Neuville and J. P. Zhu, Org. Lett., 2011, 13, 2244. 14 B. H. Lipshutz, S. Ghorai, W. W. Y. Leong, B. R. Taft and D. V. Krogstad, J. Org. Chem., 2011, 76, 5061. 15 B. H. Lipshutz, S. Ghorai, A. R. Abela, R. Moser, T. Nishikata, C. Duplais, A. Krasovskiy, R. D. Gaston and R. C. Gadwood, J. Org. Chem., 2011, 76, 4379. 16 P. Klumphu and B. H. Lipshutz, ‘‘Nok’’. A New Phytosterol-Based Amphiphile Enabling Transition Metal-Catalyzed Couplings in Water at Room Temperature, J. Org. Chem., in press. 17 S. Narayan, J. Muldoon, M. G. Finn, V. V. Fokin, H. C. Kolib and K. B. Sharpless, Angew. Chem., Int. Ed., 2005, 44, 3275. 18 (a) R. A. Sheldon, Chem. Commun., 2008, 3352; (b) S. Bonollo, D. Lanari, J. M. Longo and L. Vaccaro, Green Chem., 2012, 14, 164; (c) T. Angelini, S. Bonollo, D. Lanari, F. Pizzo and L. Vaccaro, Org. Biomol. Chem., 2013, 11, 5042; (d) E. Ballerini, P. Crotti, I. Frau, D. Lanari, F. Pizzo and L. Vaccaro, Green Chem., 2013, 15, 2394.
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