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Palladium-catalyzed highly regioselective Heck reaction of aryl nonaflates with electron-rich olefins
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Chinese Chemical Letters 19 (2008) 1017–1020 www.elsevier.com/locate/cclet
Palladium-catalyzed highly regioselective Heck reaction of aryl nonaflates with electron-rich olefins Dan Xu, Zhi Hua Liu, Wei Jun Tang, Jun Mo, Li Jin Xu * Department of Chemistry, Renmin University of China, Beijing 100872, China Received 23 January 2008
Abstract Highly efficient palladium-catalyzed Heck coupling of aryl nonaflates with electron-rich vinyl ethers, and enamides is described. These reactions afforded exclusively the branched products in good yields. The results indicated that aryl nonaflates are effective alternative to the frequently employed aryl triflates. # 2008 Li Jin Xu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved. Keywords: Aryl nonaflates; Electron-rich; Palladium; Heck reaction; Regioselectivity
The palladium-catalyzed Heck reaction has become one of the most powerful tools in organic synthesis [1]. However, a regioselectivity issue exists when electron-rich olefins are used, which produce a mixture of a branched and b linear regioisomers, due to the operation of two reaction pathways (Scheme 1) [2]. This problem can be addressed by employing aryl trifaltes as the arylation reagents [3]. It is believed that the electron-withdrawing ability of the CF3SO2 group makes it an easy-leaving group, thus enabling the reaction to proceed via path A to give the asubstituted olefin. However, the base-sensitivity of aryl triflates could often lead to the cleavage of the triflate moiety and lower the yields of the desired product. The reagents for the preparation of aryl triflates, such as Tf2O or triflimides like Tf2NPh, are relatively expensive and moisture-sensitive, and generally 50% of the triflating reagent is lost as leaving group in the process of producing aryl triflates. An attractive alternative to aryl triflate is aryl nonaflate (ArONf = ArOSO2(CF2)3–CF3), which is easily accessible from the corresponding phenol and commercially cheap nonafluorobutanesulfonic fluoride and is stable to chromatography and storage at room temperature. So far it has successfully demonstrated that aryl nonaflates are efficient coupling reagents in several cross-coupling reactions, such as Suzuki reactions, aminations, Sonogashira reactions, and Negishi reactions, exhibiting similar or better reactivity to aryl triflates [4]. However, to our knowledge no study of the palladium-catalyzed Heck reaction of aryl nonaflates with electron-rich has been reported, and the only report in the literature about the Heck reaction of aryl nonaflates dealt with the arylation of electron-deficient olefins [5]. Herein we wish to show that aryl nonaflates can be used as efficient substrates for regioselective arylation of electron-rich olefins, such as vinyl ethers, and enamides. To determine whether direct, regioselective arylation of electron-rich olefins by aryl nonaflates could take place, we first attempted the coupling reaction of aryl nonaflates with butyl vinyl ether. These aryl nonaflates are
* Corresponding author. E-mail address: [email protected] (L.J. Xu). 1001-8417/$ – see front matter # 2008 Li Jin Xu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved. doi:10.1016/j.cclet.2008.06.004
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D. Xu et al. / Chinese Chemical Letters 19 (2008) 1017–1020
Scheme 1.
easily available by standard nonaflation of the corresponding phenols [4]. In this study, based on the previous results [3,6], DMF was chosen as the solvent and NEt3 as the base, and the reactions were performed at 80 8C under nitrogen with the catalyst generated in situ from Pd(OAc)2 and DPPP (1,3-bis(diphenylphosphino)propane). The a-arylated product was isolated as the aryl methyl ketone following acidification. With phenyl nonafalte 1a as the model compound, we initially carried out the coupling reaction employing a ratio of 1/1.1 of Pd(OAc)2/DPPP as catalyst. The reaction proceeded smoothly to go to completion in 3 h. The exclusive formation of a-arylated product was observed, and no linear product was detected. This indicated that the ionic pathway A is in operative. It has been assumed that DPPP might involve the reduction of Pd(II) to Pd(0) with itself being turned into a monophosphine, DPPP monoxide [7]. Consistent with this assumption, addition of 1 equiv. more of DPPP would enhance the reaction rate. Indeed when the ratio Pd(OAc)2/DPPP was increased to 1/2, the reaction finished in 2 h with 92% yield of the desired product 2a (Table 1, entry 1). Therefore, in our subsequent study, the active catalyst was derived in situ from Pd(OAc) and 2 equiv. DPPP. For comparison, the olefination of phenyl triflate by butyl vinyl ether was examined under otherwise identical conditions. After stirring for 2 h, the reaction went to completion to exclusively give 2a in 90% yield. This outcome indicated that aryl nonaflates possess similar reactivity and efficiency to aryl triflates for the regioselective Heck arylation of electron-rich butyl vinyl ether. The olefination of other aryl nonaflates by butyl vinyl ether was investigated, and the results are summarized in Table 1. As can be seen, excellent regioselectivity and good yields were achieved regardless of the nature of the substituents on the aryl rings. It was observed that shorter reaction time was needed for the olefination of aryl nonafaltes bearing electron-rich groups (entries 3–4), while the presence of electron-withdrawing substituents slowed the coupling process (entries 5–8). It seems to indicate that the rate-determining step of the arylation of butyl vinyl ether by aryl nonaflates might be the migatory insertion of olefins into Pd–Ar bonds. It is the same as that proposed for the arylation of electron-rich olefins by aryl triflates [3]. Noteworthy is also the successful olefination of 4-bromophenyl nonaflate bearing both nonaflate and bromide groups (entry 9), leaving the bromide unaffected. In addition to butyl vinyl ether, other vinyl ethers could also be efficiently arylated by aryl nonaflates with high yields and excellent regioselectivities (entries 10–12). The observed excellent regiocontrol suggest that nonaflates, just like aryl trflates, are an easy-leaving group, which facilitates the formation of anionic Pd(II) species, and allows the exclusive formation of a-substituted product. To further explore the scope of our chemistry, we attempted the regioselective arylation of enamides by aryl nonaflates. Applying the conditions established for the vinyl ethers, excellent regioselectivity of more than 99/1 was observed, but the coupling proceeded very slowly. For instance, it took 24 h to finish the reaction of phenyl nonaflate 1a with N-methyl-N-vinylacetamide. However, when the temperature was increased to 100 8C, the reaction completed within10 h (Table 1, entry 13). With this in mind, the arylation of enamides with different aryl nonaflates were carried out smoothly, affording exclusively the a-arylated enamides in good yields (Table 1, entries 14–17) [8]. In summary, we have proved that aryl nonaflates are efficient coupling substrates for the regioselective Heck arylation of electron-rich olefins. The observed excellent regioselectivity and high yields enables aryl nonaflates effective alternative to frequently employed aryl triflates.
D. Xu et al. / Chinese Chemical Letters 19 (2008) 1017–1020
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Table 1 Heck heteroaryaltion of vinyl ethers in ethylene glycola
a Conditions: aryl nonaflate (1.0 equiv.), olefin (2.0 equiv.), Pd(OAc)2 (0.025 equiv.), DPPP (0.05 equiv.), NEt3 (2.0 equiv.), DMF. Aryl methyl ketones were obtained after acidification with aqueous HCl. All reactions gave >99/1 regioselectivity as determined by 1H NMR. b Isolated yield.
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D. Xu et al. / Chinese Chemical Letters 19 (2008) 1017–1020
Acknowledgments We thank the Renmin University of China and the National Natural Science Foundation of China (Nos. 20542009 and 20672139) for financial support. References [1] (a) F. Alonso, I.P. Beletskaya, M. Yus, Tetrahedron 61 (2005) 11771; (b) M. Shibasaki, E.M. Vogl, T. Ohshima, Adv. Synth. Catal. 346 (2004) 1533; (c) R.B. Bedford, C.S.J. Cazin, D. Holder, Coord. Chem. Rev. 248 (2004) 2283; (d) M. Larhed, A. Hallberg, in: E.-I. Negishi (Ed.), Handbook of Organopalladium Chemistry for Organic Synthesis, vol. 1, Wiley-Interscience, New York, 2002, p. 1133; (e) I.P. Beletakaya, A.V. Cheprakov, Chem. Rev. 100 (2000) 3009. [2] (a) W. Cabri, I. Candiani, Acc. Chem. Res. 28 (1995) 2; (b) G.T. Crisp, Chem. Soc. Rev. 27 (1998) 427; (c) J.P. Knowles, A. Whiting, Org. Biomol. Chem. 5 (2007) 31. [3] (a) W. Cabri, I. Candiani, A. Bedeschi, J. Org. Chem. 58 (1993) 7421; (b) W. Cabri, I. Candiani, A. Bedeschi, J. Org. Chem. 57 (1992) 3558. [4] (a) R.E. Tundel, K.W. Anderson, S.L. Buchwald, J. Org. Chem. 71 (2006) 430; (b) K.W. Anderson, M. Mendez-Perez, J. Priego, S.L. Buchwald, J. Org. Chem. 68 (2003) 9563; (c) C.G. Blettner, W.A. Konig, W. Stenzel, T. Schotten, J. Org. Chem. 64 (1999) 3885; (d) M. Rottlander, P. Knochel, J. Org. Chem. 63 (1998) 203; (e) X. Han, B.M. Stoltz, E.J. Corey, J. Am. Chem. Soc. 121 (1999) 7600; (f) W.P. Gallagher, R.E. Maleczka Jr., J. Org. Chem. 68 (2003) 6775; (g) L. Neuville, A. Bigot, M.E.T.H. Dau, J. Zhu, J. Org. Chem. 64 (1999) 7638; (h) S.E. Denmark, R.F. Sweis, Org. Lett. 4 (2002) 3771; (i) M. Al-Masum, T. Livinghouse, Tetrahedron Lett. 40 (1999) 7731. [5] Q.Y. Chen, Z.Y. Yang, Tetrahedron Lett. 27 (1986) 1171. [6] (a) L. Xu, W. Chen, J. Xiao, Org. Lett. 3 (2001) 295; (b) J. Mo, L. Xu, J. Xiao, J. Am. Chem. Soc. 127 (2005) 751. [7] (a) C. Amatore, A. Jutand, A. Thuilliez, Organometallics 20 (2001) 3241; (b) F. Oeawa, A. Kubo, T. Hayashi, Chem. Lett. (1992) 2177. [8] Typical procedure for regioselective Heck olefination of aryl nonaflates by olefins: An oven-dried, two-necked round-bottom flask containing a stir bar was charged with aryl halide 1 (1.0 mmol), olefin (2.0 mmol), Pd(OAc)2 (0.025 mmol), DPPP (0.05 mmol), and DMF (2 mL) under nitrogen at room temperature. After degassing three times, NEt3 (2 mmol) was injected. The flask was placed in an oil bath, and the mixture was stirred and heated at desired temperature. The reaction was monitored by TLC. After the reaction went to completion, the reaction mixture for the arylation of vinyl ethers was acidified with aqueous HCl (5%, 5 mL) for 0.5 h, and water (5 mL) was added to the mixture of aryaltion of enamides. The aqueous phase was extracted with dichloromethane 3 times. The combined organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified via flash chromatography on silica gel using a mixture of ethyl acetate and hexane. Selective data for the products. Compound 2g: 1H NMR (400 MHz, CDCl3, dppm): 8.09–8.07 (m, 2H), 7.99–7.96 (m, 2H), 3.88 (s, 3H), 2.57 (s, 3H), 13C NMR (100 MHz, CDCl3, dppm): 147.3, 166.2, 141.1, 136.6, 129.8, 127.9, 51.5, 25.9. HRMS calcd. For C10H10O3: 178.0630. Found: 178.0628. Compound 3l: 1H NMR (400 MHz, CDCl3, dppm): 7.40–7.37 (m, 3H), 7.26–7.25 (m, 2H), 5.69 (s, 1H), 5.23 (s, 1H), 3.10 (s, 3H), 2.08 (s, 3H). 13C NMR (100 MHz, CDCl3, dppm): 171.3, 149.5, 136.0, 129.5, 129.3, 126.1, 112.6, 35.9, 22.2. HRMS calcd. For C11H14NO (M+1)+: 176.1075. Found: 176.1074. Compound 3n: 1H NMR (400 MHz, CDCl3, dppm): 7.85–7.78 (m, 3H), 7.54–7.44 (m, 3H), 7.34–7.32 (m, 1H), 5.51 (s, 1H), 5.39 (s, 1H), 3.59 (t, 2H, J = 7.0 Hz), 2.61 (t, 2H, J = 8.0Hz), 2.29 (tt, 2H, J = 7.0, 8.0 Hz). 13C NMR (100 MHz, CDCl3, dppm): 175.0, 144.1, 134.2, 133.7, 133.6, 128.9, 128.6, 128.4, 128.0, 126.7, 125.9, 124.7, 110.1, 50.0, 32.3, 19.0. HRMS calcd. For C16H16NO (M+1)+: 238.1232. Found: 238.1230. Compound 3p: 1H NMR (400 MHz, CDCl3, dppm): 7.83–7.79 (m, 4H), 7.57–7.54 (m, 1H), 7.49–7.45 (m, 2H), 5.74 (s, 1H), 5.29 (s, 1H), 3.56 (t, J = 5.2 Hz, 2H), 2.73 (t, J = 5.5 Hz, 2H), 1.90–1.78 (m, 6H). HRMS calcd. For C18H20NO (M+1)+: 266.1545. Found: 266.1542.
Chinese Chemical Letters 19 (2008) 1017–1020 www.elsevier.com/locate/cclet
Palladium-catalyzed highly regioselective Heck reaction of aryl nonaflates with electron-rich olefins Dan Xu, Zhi Hua Liu, Wei Jun Tang, Jun Mo, Li Jin Xu * Department of Chemistry, Renmin University of China, Beijing 100872, China Received 23 January 2008
Abstract Highly efficient palladium-catalyzed Heck coupling of aryl nonaflates with electron-rich vinyl ethers, and enamides is described. These reactions afforded exclusively the branched products in good yields. The results indicated that aryl nonaflates are effective alternative to the frequently employed aryl triflates. # 2008 Li Jin Xu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved. Keywords: Aryl nonaflates; Electron-rich; Palladium; Heck reaction; Regioselectivity
The palladium-catalyzed Heck reaction has become one of the most powerful tools in organic synthesis [1]. However, a regioselectivity issue exists when electron-rich olefins are used, which produce a mixture of a branched and b linear regioisomers, due to the operation of two reaction pathways (Scheme 1) [2]. This problem can be addressed by employing aryl trifaltes as the arylation reagents [3]. It is believed that the electron-withdrawing ability of the CF3SO2 group makes it an easy-leaving group, thus enabling the reaction to proceed via path A to give the asubstituted olefin. However, the base-sensitivity of aryl triflates could often lead to the cleavage of the triflate moiety and lower the yields of the desired product. The reagents for the preparation of aryl triflates, such as Tf2O or triflimides like Tf2NPh, are relatively expensive and moisture-sensitive, and generally 50% of the triflating reagent is lost as leaving group in the process of producing aryl triflates. An attractive alternative to aryl triflate is aryl nonaflate (ArONf = ArOSO2(CF2)3–CF3), which is easily accessible from the corresponding phenol and commercially cheap nonafluorobutanesulfonic fluoride and is stable to chromatography and storage at room temperature. So far it has successfully demonstrated that aryl nonaflates are efficient coupling reagents in several cross-coupling reactions, such as Suzuki reactions, aminations, Sonogashira reactions, and Negishi reactions, exhibiting similar or better reactivity to aryl triflates [4]. However, to our knowledge no study of the palladium-catalyzed Heck reaction of aryl nonaflates with electron-rich has been reported, and the only report in the literature about the Heck reaction of aryl nonaflates dealt with the arylation of electron-deficient olefins [5]. Herein we wish to show that aryl nonaflates can be used as efficient substrates for regioselective arylation of electron-rich olefins, such as vinyl ethers, and enamides. To determine whether direct, regioselective arylation of electron-rich olefins by aryl nonaflates could take place, we first attempted the coupling reaction of aryl nonaflates with butyl vinyl ether. These aryl nonaflates are
* Corresponding author. E-mail address: [email protected] (L.J. Xu). 1001-8417/$ – see front matter # 2008 Li Jin Xu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved. doi:10.1016/j.cclet.2008.06.004
1018
D. Xu et al. / Chinese Chemical Letters 19 (2008) 1017–1020
Scheme 1.
easily available by standard nonaflation of the corresponding phenols [4]. In this study, based on the previous results [3,6], DMF was chosen as the solvent and NEt3 as the base, and the reactions were performed at 80 8C under nitrogen with the catalyst generated in situ from Pd(OAc)2 and DPPP (1,3-bis(diphenylphosphino)propane). The a-arylated product was isolated as the aryl methyl ketone following acidification. With phenyl nonafalte 1a as the model compound, we initially carried out the coupling reaction employing a ratio of 1/1.1 of Pd(OAc)2/DPPP as catalyst. The reaction proceeded smoothly to go to completion in 3 h. The exclusive formation of a-arylated product was observed, and no linear product was detected. This indicated that the ionic pathway A is in operative. It has been assumed that DPPP might involve the reduction of Pd(II) to Pd(0) with itself being turned into a monophosphine, DPPP monoxide [7]. Consistent with this assumption, addition of 1 equiv. more of DPPP would enhance the reaction rate. Indeed when the ratio Pd(OAc)2/DPPP was increased to 1/2, the reaction finished in 2 h with 92% yield of the desired product 2a (Table 1, entry 1). Therefore, in our subsequent study, the active catalyst was derived in situ from Pd(OAc) and 2 equiv. DPPP. For comparison, the olefination of phenyl triflate by butyl vinyl ether was examined under otherwise identical conditions. After stirring for 2 h, the reaction went to completion to exclusively give 2a in 90% yield. This outcome indicated that aryl nonaflates possess similar reactivity and efficiency to aryl triflates for the regioselective Heck arylation of electron-rich butyl vinyl ether. The olefination of other aryl nonaflates by butyl vinyl ether was investigated, and the results are summarized in Table 1. As can be seen, excellent regioselectivity and good yields were achieved regardless of the nature of the substituents on the aryl rings. It was observed that shorter reaction time was needed for the olefination of aryl nonafaltes bearing electron-rich groups (entries 3–4), while the presence of electron-withdrawing substituents slowed the coupling process (entries 5–8). It seems to indicate that the rate-determining step of the arylation of butyl vinyl ether by aryl nonaflates might be the migatory insertion of olefins into Pd–Ar bonds. It is the same as that proposed for the arylation of electron-rich olefins by aryl triflates [3]. Noteworthy is also the successful olefination of 4-bromophenyl nonaflate bearing both nonaflate and bromide groups (entry 9), leaving the bromide unaffected. In addition to butyl vinyl ether, other vinyl ethers could also be efficiently arylated by aryl nonaflates with high yields and excellent regioselectivities (entries 10–12). The observed excellent regiocontrol suggest that nonaflates, just like aryl trflates, are an easy-leaving group, which facilitates the formation of anionic Pd(II) species, and allows the exclusive formation of a-substituted product. To further explore the scope of our chemistry, we attempted the regioselective arylation of enamides by aryl nonaflates. Applying the conditions established for the vinyl ethers, excellent regioselectivity of more than 99/1 was observed, but the coupling proceeded very slowly. For instance, it took 24 h to finish the reaction of phenyl nonaflate 1a with N-methyl-N-vinylacetamide. However, when the temperature was increased to 100 8C, the reaction completed within10 h (Table 1, entry 13). With this in mind, the arylation of enamides with different aryl nonaflates were carried out smoothly, affording exclusively the a-arylated enamides in good yields (Table 1, entries 14–17) [8]. In summary, we have proved that aryl nonaflates are efficient coupling substrates for the regioselective Heck arylation of electron-rich olefins. The observed excellent regioselectivity and high yields enables aryl nonaflates effective alternative to frequently employed aryl triflates.
D. Xu et al. / Chinese Chemical Letters 19 (2008) 1017–1020
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Table 1 Heck heteroaryaltion of vinyl ethers in ethylene glycola
a Conditions: aryl nonaflate (1.0 equiv.), olefin (2.0 equiv.), Pd(OAc)2 (0.025 equiv.), DPPP (0.05 equiv.), NEt3 (2.0 equiv.), DMF. Aryl methyl ketones were obtained after acidification with aqueous HCl. All reactions gave >99/1 regioselectivity as determined by 1H NMR. b Isolated yield.
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D. Xu et al. / Chinese Chemical Letters 19 (2008) 1017–1020
Acknowledgments We thank the Renmin University of China and the National Natural Science Foundation of China (Nos. 20542009 and 20672139) for financial support. References [1] (a) F. Alonso, I.P. Beletskaya, M. Yus, Tetrahedron 61 (2005) 11771; (b) M. Shibasaki, E.M. Vogl, T. Ohshima, Adv. Synth. Catal. 346 (2004) 1533; (c) R.B. Bedford, C.S.J. Cazin, D. Holder, Coord. Chem. Rev. 248 (2004) 2283; (d) M. Larhed, A. Hallberg, in: E.-I. Negishi (Ed.), Handbook of Organopalladium Chemistry for Organic Synthesis, vol. 1, Wiley-Interscience, New York, 2002, p. 1133; (e) I.P. Beletakaya, A.V. Cheprakov, Chem. Rev. 100 (2000) 3009. [2] (a) W. Cabri, I. Candiani, Acc. Chem. Res. 28 (1995) 2; (b) G.T. Crisp, Chem. Soc. Rev. 27 (1998) 427; (c) J.P. Knowles, A. Whiting, Org. Biomol. Chem. 5 (2007) 31. [3] (a) W. Cabri, I. Candiani, A. Bedeschi, J. Org. Chem. 58 (1993) 7421; (b) W. Cabri, I. Candiani, A. Bedeschi, J. Org. Chem. 57 (1992) 3558. [4] (a) R.E. Tundel, K.W. Anderson, S.L. Buchwald, J. Org. Chem. 71 (2006) 430; (b) K.W. Anderson, M. Mendez-Perez, J. Priego, S.L. Buchwald, J. Org. Chem. 68 (2003) 9563; (c) C.G. Blettner, W.A. Konig, W. Stenzel, T. Schotten, J. Org. Chem. 64 (1999) 3885; (d) M. Rottlander, P. Knochel, J. Org. Chem. 63 (1998) 203; (e) X. Han, B.M. Stoltz, E.J. Corey, J. Am. Chem. Soc. 121 (1999) 7600; (f) W.P. Gallagher, R.E. Maleczka Jr., J. Org. Chem. 68 (2003) 6775; (g) L. Neuville, A. Bigot, M.E.T.H. Dau, J. Zhu, J. Org. Chem. 64 (1999) 7638; (h) S.E. Denmark, R.F. Sweis, Org. Lett. 4 (2002) 3771; (i) M. Al-Masum, T. Livinghouse, Tetrahedron Lett. 40 (1999) 7731. [5] Q.Y. Chen, Z.Y. Yang, Tetrahedron Lett. 27 (1986) 1171. [6] (a) L. Xu, W. Chen, J. Xiao, Org. Lett. 3 (2001) 295; (b) J. Mo, L. Xu, J. Xiao, J. Am. Chem. Soc. 127 (2005) 751. [7] (a) C. Amatore, A. Jutand, A. Thuilliez, Organometallics 20 (2001) 3241; (b) F. Oeawa, A. Kubo, T. Hayashi, Chem. Lett. (1992) 2177. [8] Typical procedure for regioselective Heck olefination of aryl nonaflates by olefins: An oven-dried, two-necked round-bottom flask containing a stir bar was charged with aryl halide 1 (1.0 mmol), olefin (2.0 mmol), Pd(OAc)2 (0.025 mmol), DPPP (0.05 mmol), and DMF (2 mL) under nitrogen at room temperature. After degassing three times, NEt3 (2 mmol) was injected. The flask was placed in an oil bath, and the mixture was stirred and heated at desired temperature. The reaction was monitored by TLC. After the reaction went to completion, the reaction mixture for the arylation of vinyl ethers was acidified with aqueous HCl (5%, 5 mL) for 0.5 h, and water (5 mL) was added to the mixture of aryaltion of enamides. The aqueous phase was extracted with dichloromethane 3 times. The combined organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified via flash chromatography on silica gel using a mixture of ethyl acetate and hexane. Selective data for the products. Compound 2g: 1H NMR (400 MHz, CDCl3, dppm): 8.09–8.07 (m, 2H), 7.99–7.96 (m, 2H), 3.88 (s, 3H), 2.57 (s, 3H), 13C NMR (100 MHz, CDCl3, dppm): 147.3, 166.2, 141.1, 136.6, 129.8, 127.9, 51.5, 25.9. HRMS calcd. For C10H10O3: 178.0630. Found: 178.0628. Compound 3l: 1H NMR (400 MHz, CDCl3, dppm): 7.40–7.37 (m, 3H), 7.26–7.25 (m, 2H), 5.69 (s, 1H), 5.23 (s, 1H), 3.10 (s, 3H), 2.08 (s, 3H). 13C NMR (100 MHz, CDCl3, dppm): 171.3, 149.5, 136.0, 129.5, 129.3, 126.1, 112.6, 35.9, 22.2. HRMS calcd. For C11H14NO (M+1)+: 176.1075. Found: 176.1074. Compound 3n: 1H NMR (400 MHz, CDCl3, dppm): 7.85–7.78 (m, 3H), 7.54–7.44 (m, 3H), 7.34–7.32 (m, 1H), 5.51 (s, 1H), 5.39 (s, 1H), 3.59 (t, 2H, J = 7.0 Hz), 2.61 (t, 2H, J = 8.0Hz), 2.29 (tt, 2H, J = 7.0, 8.0 Hz). 13C NMR (100 MHz, CDCl3, dppm): 175.0, 144.1, 134.2, 133.7, 133.6, 128.9, 128.6, 128.4, 128.0, 126.7, 125.9, 124.7, 110.1, 50.0, 32.3, 19.0. HRMS calcd. For C16H16NO (M+1)+: 238.1232. Found: 238.1230. Compound 3p: 1H NMR (400 MHz, CDCl3, dppm): 7.83–7.79 (m, 4H), 7.57–7.54 (m, 1H), 7.49–7.45 (m, 2H), 5.74 (s, 1H), 5.29 (s, 1H), 3.56 (t, J = 5.2 Hz, 2H), 2.73 (t, J = 5.5 Hz, 2H), 1.90–1.78 (m, 6H). HRMS calcd. For C18H20NO (M+1)+: 266.1545. Found: 266.1542.