- Email: [email protected]
Cu-catalyzed regio- and stereoselective sulfonylation of multi-substituted allenes
Tetrahedron 75 (2019) 1145e1148
Contents lists available at ScienceDirect
Tetrahedron journal homepage: www.elsevier.com/locate/tet
Cu-catalyzed regio- and stereoselective sulfonylation of multisubstituted allenes Shigeru Arai a, b, *, Koki Matsumoto a, Atsushi Nishida a, b a b
Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8675, Japan Molecular Chirality Research Center, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba, 263-8522, Japan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 15 November 2018 Received in revised form 12 December 2018 Accepted 14 December 2018 Available online 14 January 2019
Regio- and stereoselective sulfonylation of allenes under Cu catalysis is described. Allenyl sp carbons exclusively react with TsCN to give the corresponding alkenyl sulfones. The reaction is initiated by addition of tosyl radical to form benzyl radical intermediates, which determines the reaction pathway. The structure of the products is highly dependent on the substituents on allenes. © 2018 Published by Elsevier Ltd.
Keywords: Allenes Cu Catalysis Regioselective Stereoselective
1. Introduction Allenes have been recognized as one of the most versatile precursors to create useful molecules, and it remains the challenging issue to control their unique reactivity in metal catalysis [1]. Recently, we have reported unprecedented catalytic transformation using multi-substituted allenes, for example, 5-exo cyclization [2], cross-coupling reaction [3], chirality-transfer reaction [4] and natural product synthesis [5]. To establish further synthetic application using allenes, we next focused on radical-mediated reactions, which discriminates allenyl carbon-carbon double bonds for regioand stereoselective transformation. A sulfonyl radical species generated under metal catalysis with oxidants is highly reactive towards non-activated carbon-carbon double bonds, and styrene derivatives have been suitable substrates for regioselective oxysulfonylation (Scheme 1-1) [6e9]. On the other hand, arylallenes are not well investigated to be limited in only one example for hydroxysulfonylation even though they are reactive rather than olefins (Scheme 1-2) [10]. This background prompted us to develop a new catalytic sulfonylation of allenes because critical discrimination of allenyl carbon-carbon double
* Corresponding author. Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8675, Japan. E-mail address: [email protected] (S. Arai). https://doi.org/10.1016/j.tet.2018.12.031 0040-4020/© 2018 Published by Elsevier Ltd.
bonds to give highly functionalized molecules in one operation is a challenging issue in synthetic chemistry. Herein we report Cucatalyzed regio- and stereoselective sulfonylative isomerization, oxysulfonylation and [4 þ 2] cycloaddition using multi-substituted allenes. 2. Results and discussion In the beginning, 1a was chosen as a substrate to optimize the reaction condition (Table 1). When the reaction was performed in the presence of Cu(OAc)2 (10 mol%) with TsCN (1.5 eq) under oxygen atmosphere in THF, a tosyl group was selectively installed into sp carbon and the conjugated diene (2a) was isolated in 58% without any trace of oxygenated products (entry 1). Its stereochemistry was determined by X-ray crystallographic analysis to be E-form [11]. The reaction efficacy is dependent on Cu salt, and the reaction without Cu gave 2a only in 5% yield even after 24 h (entry 2e6). Solvent effect revealed that nonprotic polar solvents such as 1,4-dioxane, acetonitrile and DMF gave 2a in the range of 27%e36% yield (entry 7e9) and full conversion was not observed in EtOH (entry 10). The effect of tosyl source did not improve the yield of 2a (entry 13, 14). The reduced amount of TsCN gave slower conversion to give 2a in 52% after 24 h, however higher temperature in DMF was not effective to increase the yield of 2a (entry 15, 16). Under the optimum conditions, the substituent effect was next
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S. Arai et al. / Tetrahedron 75 (2019) 1145e1148
Scheme 1. Reported sulfonylation of CeC double bond.
Table 1 Optimization.
Entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 a b c d
Cu cat. Cu(OAc)2 Cu(TFA)2 Cu(OTf)2 CuBr Cui none Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2
solventa THF THF THF THF THF THF dioxane MeCN DMF EtOH toluene dichloroethane THF THF THF DMF
Ts source TsCN TsCN TsCN TsCN TsCN TsCN TsCN TsCN TsCN TsCN TsCN TsCN TsNHNH2 tolSO2Na TsCNd TsCN
condition
60 C, 4 h 60 C, 8 h 60 C, 24 h 60 C, 24 h 60 C, 24 h 60 C, 24 h 60 C, 2 h 60 C, 3 h 60 C, 2 h 60 C, 24 h 60 C, 4 h 60 C, 4 h 60 C, 4 h 60 C, 24 h 60 C, 24 h 100 C, 1 h
yield of 2ab 58 40 49 49 42 5 30 27 36 17c 8 13 11 7 52 46
All reactions were carried out in 0.4 M. Determined byNMR using 2,2'-bipyridy as an internal standard. Recovery of 1a: 40%. TsCN (1.1 eq) was employed.
examined (Scheme 2). Substituents on benzene ring gave significant influence in the conversion to 2, for example, a 4-MeO group increased the reactivity and furnished the reaction within only 1 h to give 2b in 38% yield. On the other hand, 1c having a 4-CF3 group required 24 h to achieve full conversion to give 2c in 58% yield. The linear alkyl or cycloalkyl groups were also applicable to give the corresponding dienes (TsCN: 3 eq). The reaction of 1d controlled
Scheme 2. Substituent effect.
the stereochemistry of two carbon-carbon double bonds to give 2d in 54% yield, exclusively and its stereochemistry was assigned by NOESY observation between allylic methylenes and a tert-butyl group. When 1e was next employed, the corresponding diene (2e) was obtained in 50% yield. To obtain mechanistic insight, the effect of TEMPO was next investigated (Scheme 3-1). The addition of TEMPO resulted in the recovery of 1a in 88% yield without any trace of 2a, which suggests that radical species to promote the reaction could be involved [6d]. To confirm above speculation, we next examined 1f to investigate cyclopropane cleavage (Scheme 3-2). As expected, a cyclopropane ring was cleaved to give 2f as a sole product [12a]. Its structure was confirmed by X-ray crystallographic analysis to be primary carbonitrile (2f), which suggest CeCN bond formation at the terminal methylene. Based on these observations, the plausible reaction pathway to understand the regio- and stereoselectivity could be proposed in Scheme 4. The first step is the addition of tosyl radical to sp carbon of 1. The observed stereoselectivity in 2 reasonably explains that carbonsulfur bond formation takes place from less-hindered site against a tert-butyl group. The resulting benzyl radical (I) reacts with oxygen to form II. The sequential hydrogen abstraction would prefer the intramolecular process with minimizing the steric repulsion between R and Ar groups. These proposals enable to explain the origin for the exclusive formation of highly stereo-defined products (2a-e). When 1f is employed instead, initial tosylation would give two possible rotamers of benzylic radical species (IIIa,b). The former (IIIa) is sterically disfavored because of the repulsion between cyclopropyl and phenyl groups. The latter species (IIIb) could have the suitable conformation to overlap two orbitals of radical SOMO and a strained CeC sigma bond and its smooth cleavage determines the stereochemistry of later-formed CeC double bonds in 2f. Actually, this step is rapid enough to prevent the oxygen-trapping, and the resulting primary radical (IV) reacts with TsCN to give 2f together with tosyl radical to terminate the catalytic cycle [12,13]. The above mechanism indicates that the property and reactivity of benzyl radical is a key feature to determine the reaction pathway. When 1,3-disubstituted allenes having aromatic ring are employed instead, regio- and stereoselective oxidation of benzylic radical would be expected to give sufonylkentones [6] (Scheme 5). The oxytosylation reaction using 3a with Cu(OAc)2, TsCN and molecular
Scheme 3. TEMPO effect and cyclopropane cleavage.
S. Arai et al. / Tetrahedron 75 (2019) 1145e1148
1147
Scheme 4. Proposed reaction pathways.
Scheme 5. Oxysulfonylation of 3.
oxygen in THF at 60 C did proceed regio- and stereoselectively to give 4a in 42% yield. Its structure was assigned to have both a carbonyl group on benzylic position and E-olefin by X-ray crystallographic analysis. This reaction was also applicable to F and CF3 substituents on benzene ring to give the corresponding sulfonylketone (4b,c) in respective yield of 35% and 28%. When a tertbutyl was replaced by a cyclohexyl group such as 3d, the corresponding sunfonylketone (4d) was not obtained at all. This might be caused by undesired cleavage of allenyl Csp3-H bond in 3d to prevent initial regioselective tosylation. In contrast, the different reactivity of the arylallenes under Cu catalysis under argon was observed (Scheme 6). The reaction of 3e with TsCN and CuBr in 1,4-dioxane at 100 C, not 4e but quinoline derivative (5e) was isolated in 25% yield. A CN group was regioselectively incorporated into the [4 þ 2] cycloadduct and its regioisomer was not detected at all [14]. In the case of 1b, the reaction in THF at 60 C was more suitable to give 5b in 34% together with 2b in 22% yield. The tertiary benzyl radical such as I in Scheme
4 might be more reactive to be trapped by the contaminating molecular oxygen to give 2b as a minor product. A methoxy group on benzene ring seems to be essential for increasing the reactivity of substrates, because no any [4 þ 2] cycloadducts were isolated when 1a and 3a were employed under Cu catalysis. Although the detail for this cycloaddition reaction is still unclear, these preliminary results will lead further progress to develop new transformations using multi-substituted allenes.
3. Conclusion In summary, we have developed a new protocol for regio- and stereoselective sulfonylation of multi-substituted allenes under Cu catalysis. The key points are regiocontrol in initial tosylation step and the property and reactivity of benzyl radical intermediates. Based on the above observations, further application under Cu catalysis is currently undergoing.
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S. Arai et al. / Tetrahedron 75 (2019) 1145e1148
Scheme 6. Cu-catalyzed [4 þ 2] cycloaddition.
4. Experimental All reactions were performed with dry solvents and the reagents were purified by the standard methods. Reactions were monitored by thin-layer chromatography carried out on 0.25 mm Merck silica gel plates (60F-254). Column chromatography was performed with silica gel (Fuji Silysia, PSQ-60B) or NH-silica (Fuji Silysia, DM2035). NMR spectra were recorded on spectrometers of JEOL JMN-ECS400, ECP-400, ECZ-400, ECZ-600, and ECA-600 operating at 400 or 600 MHz for 1H NMR and 100 or 150 MHz for 13C NMR with calibration using residual undeuterated solvent as an internal reference. IR spectra were recorded on JASCO FT/IR-4700. High resolution mass spectra were measured by The AccuTOFLC-plus JMS-T100LP (Ionization method: ESI). Typical experimental procedure: Synthesis of 2a: To a solution of 1a (37.3 mg, 0.20 mmol) in THF (0.50 mL, 0.4 M), Cu(OAc)2 (3.6 mg, 0.02 mmol, 10 mol%) and TsCN (54.4 mg, 0.30 mmol, 1.5 eq) were added and the resulting mixture was heated under oxygen atmosphere for 4 h at 60 C. After the completion of the reaction, the mixture was charged onto a silica gel pad and then roughly purified by flash column chromatography (hexane:AcOEt ¼ 10: 1). The chemical yield of 2a was determined by 1H NMR using 2,2'bipyridyl as an internal standard.
[2]
[3] [4]
[5] [6]
[7]
[8] [9] [10] [11] [12]
Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.tet.2018.12.031. References [1] (a) S. Yu, D. Ma, Angew. Chem. Int. Ed. 51 (2012) 3074e3112; (b) C. Aubert, L. Fensterbank, P. Garcia, M. Malacria, A. Simonneau, Chem. Rev.
[13] [14]
111 (2011) 1954e1993; (c) D. Ma, Chem. Rev. 105 (2005) 2871e2898. (a) S. Arai, Y. Amako, X. Yang, A. Nishida, Angew. Chem. Int. Ed. 52 (2013) 8147e8150; (b) Y. Amako, H. Hori, S. Arai, A. Nishida, J. Org. Chem. 78 (2013) 10763e10775; (c) H. Hori, S. Arai, A. Nishida, Adv. Synth. Catal. 359 (2017) 1170e1176. X. Yang, S. Arai, A. Nishida, Adv. Synth. Catal. 355 (2013) 2974e2981. (a) Y. Amako, S. Arai, A. Nishida, Org. Biomol. Chem. 15 (2017) 1612e1617; (b) S. Arai, H. Hori, Y. Amako, A. Nishida, Chem. Commun. 51 (2015) 7493e7496. K. Matsumoto, S. Arai, A. Nishida, Tetrahedron 74 (2018) 2865e2870. For Cu Catalysis; (a) S. Huang, N. Thirupathi, C.-H. Tung, Z. Xu, J. Org. Chem. 83 (2018) 9449e9455; (b) A.O. Terent’ev, O.M. Mulina, D.M. Pirgach, D.V. Demchuk, M.A. Syroeshkin, G.I. Nikishin, RSC Adv. 6 (2016) 93476e93485; (c) Y. Jian, T.-P. Loh, Chem. Sci. 5 (2014) 4939e4943; (d) W. Wei, C. Liu, D. Yang, J. Wen, J. You, Y. Suo, H. Wang, Chem. Commun. 49 (2013) 10239e10241. For Fe Catalysis; (a) X. Shi, X. Rem, Z. Ren, J. Li, Y. Wang, S. Yang, J. Gu, Q. Gao, G. Huang, Eur. J. Org. Chem. (2014) 5083e5088; (b) W. Weo, W. Jingwei, D. Yang, M. Wu, J. You, H. Wang, Org. Biomol. Chem. 12 (2014) 7678e7681. For Ag catalysis A.K. Singh, R. Chawla, L.D.S. Yadav, Tetrahedron Lett. 55 (2014) 4742e4746. For photocatalysis D. Yang, B. Huang, W. Wei, J. Li, G. Lin, Y. Liu, J. Ding, P. Sun, H. Wang, Green Chem. 18 (2016) 5630e5634. Z. Huang, Q. Lu, Y. Liu, D. Liu, J. Zhang, A. Leo, Org. Lett. 18 (2016) 3940e3943. CCDC 1872488 (2a), 1872637 (2f), 1872902 (4a), 1872903 (5e) and 1872904 (5b) contain the supplementary crystallographic data for this paper. Recent reports for Cu-catalyzed radical cyanation: (a) F. Wang, D. Wang, Y. Zhou, L. Liang, R. Lu, P. Chen, Z. Lin, G. Liu, Angew. Chem. Int. Ed. 57 (2018) 7140e7145; (b) D. Wang, F. Wang, P. Chen, Z. Lin, G. Liu, Angew. Chem. Int. Ed. 56 (2017) 2054e2058; (c) Z. Wu, R. Ren, C. Zhu, Angew. Chem. Int. Ed. 55 (2016) 108210e110824; (d) F. Wang, D. Wang, X. Wan, L. Wu, P. Chen, G. Liu, J. Am. Chem. Soc. 138 (2016) 15547e15550. Radical cyanation using TsCN B. Gasper, E.M. Carreira, Angew. Chem. Int. Ed. 46 (2007) 4519e4522. M.L. Conner, M.K. Brown, Tetrahedron 72 (2016) 3759e3765.
Contents lists available at ScienceDirect
Tetrahedron journal homepage: www.elsevier.com/locate/tet
Cu-catalyzed regio- and stereoselective sulfonylation of multisubstituted allenes Shigeru Arai a, b, *, Koki Matsumoto a, Atsushi Nishida a, b a b
Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8675, Japan Molecular Chirality Research Center, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba, 263-8522, Japan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 15 November 2018 Received in revised form 12 December 2018 Accepted 14 December 2018 Available online 14 January 2019
Regio- and stereoselective sulfonylation of allenes under Cu catalysis is described. Allenyl sp carbons exclusively react with TsCN to give the corresponding alkenyl sulfones. The reaction is initiated by addition of tosyl radical to form benzyl radical intermediates, which determines the reaction pathway. The structure of the products is highly dependent on the substituents on allenes. © 2018 Published by Elsevier Ltd.
Keywords: Allenes Cu Catalysis Regioselective Stereoselective
1. Introduction Allenes have been recognized as one of the most versatile precursors to create useful molecules, and it remains the challenging issue to control their unique reactivity in metal catalysis [1]. Recently, we have reported unprecedented catalytic transformation using multi-substituted allenes, for example, 5-exo cyclization [2], cross-coupling reaction [3], chirality-transfer reaction [4] and natural product synthesis [5]. To establish further synthetic application using allenes, we next focused on radical-mediated reactions, which discriminates allenyl carbon-carbon double bonds for regioand stereoselective transformation. A sulfonyl radical species generated under metal catalysis with oxidants is highly reactive towards non-activated carbon-carbon double bonds, and styrene derivatives have been suitable substrates for regioselective oxysulfonylation (Scheme 1-1) [6e9]. On the other hand, arylallenes are not well investigated to be limited in only one example for hydroxysulfonylation even though they are reactive rather than olefins (Scheme 1-2) [10]. This background prompted us to develop a new catalytic sulfonylation of allenes because critical discrimination of allenyl carbon-carbon double
* Corresponding author. Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8675, Japan. E-mail address: [email protected] (S. Arai). https://doi.org/10.1016/j.tet.2018.12.031 0040-4020/© 2018 Published by Elsevier Ltd.
bonds to give highly functionalized molecules in one operation is a challenging issue in synthetic chemistry. Herein we report Cucatalyzed regio- and stereoselective sulfonylative isomerization, oxysulfonylation and [4 þ 2] cycloaddition using multi-substituted allenes. 2. Results and discussion In the beginning, 1a was chosen as a substrate to optimize the reaction condition (Table 1). When the reaction was performed in the presence of Cu(OAc)2 (10 mol%) with TsCN (1.5 eq) under oxygen atmosphere in THF, a tosyl group was selectively installed into sp carbon and the conjugated diene (2a) was isolated in 58% without any trace of oxygenated products (entry 1). Its stereochemistry was determined by X-ray crystallographic analysis to be E-form [11]. The reaction efficacy is dependent on Cu salt, and the reaction without Cu gave 2a only in 5% yield even after 24 h (entry 2e6). Solvent effect revealed that nonprotic polar solvents such as 1,4-dioxane, acetonitrile and DMF gave 2a in the range of 27%e36% yield (entry 7e9) and full conversion was not observed in EtOH (entry 10). The effect of tosyl source did not improve the yield of 2a (entry 13, 14). The reduced amount of TsCN gave slower conversion to give 2a in 52% after 24 h, however higher temperature in DMF was not effective to increase the yield of 2a (entry 15, 16). Under the optimum conditions, the substituent effect was next
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S. Arai et al. / Tetrahedron 75 (2019) 1145e1148
Scheme 1. Reported sulfonylation of CeC double bond.
Table 1 Optimization.
Entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 a b c d
Cu cat. Cu(OAc)2 Cu(TFA)2 Cu(OTf)2 CuBr Cui none Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2
solventa THF THF THF THF THF THF dioxane MeCN DMF EtOH toluene dichloroethane THF THF THF DMF
Ts source TsCN TsCN TsCN TsCN TsCN TsCN TsCN TsCN TsCN TsCN TsCN TsCN TsNHNH2 tolSO2Na TsCNd TsCN
condition
60 C, 4 h 60 C, 8 h 60 C, 24 h 60 C, 24 h 60 C, 24 h 60 C, 24 h 60 C, 2 h 60 C, 3 h 60 C, 2 h 60 C, 24 h 60 C, 4 h 60 C, 4 h 60 C, 4 h 60 C, 24 h 60 C, 24 h 100 C, 1 h
yield of 2ab 58 40 49 49 42 5 30 27 36 17c 8 13 11 7 52 46
All reactions were carried out in 0.4 M. Determined byNMR using 2,2'-bipyridy as an internal standard. Recovery of 1a: 40%. TsCN (1.1 eq) was employed.
examined (Scheme 2). Substituents on benzene ring gave significant influence in the conversion to 2, for example, a 4-MeO group increased the reactivity and furnished the reaction within only 1 h to give 2b in 38% yield. On the other hand, 1c having a 4-CF3 group required 24 h to achieve full conversion to give 2c in 58% yield. The linear alkyl or cycloalkyl groups were also applicable to give the corresponding dienes (TsCN: 3 eq). The reaction of 1d controlled
Scheme 2. Substituent effect.
the stereochemistry of two carbon-carbon double bonds to give 2d in 54% yield, exclusively and its stereochemistry was assigned by NOESY observation between allylic methylenes and a tert-butyl group. When 1e was next employed, the corresponding diene (2e) was obtained in 50% yield. To obtain mechanistic insight, the effect of TEMPO was next investigated (Scheme 3-1). The addition of TEMPO resulted in the recovery of 1a in 88% yield without any trace of 2a, which suggests that radical species to promote the reaction could be involved [6d]. To confirm above speculation, we next examined 1f to investigate cyclopropane cleavage (Scheme 3-2). As expected, a cyclopropane ring was cleaved to give 2f as a sole product [12a]. Its structure was confirmed by X-ray crystallographic analysis to be primary carbonitrile (2f), which suggest CeCN bond formation at the terminal methylene. Based on these observations, the plausible reaction pathway to understand the regio- and stereoselectivity could be proposed in Scheme 4. The first step is the addition of tosyl radical to sp carbon of 1. The observed stereoselectivity in 2 reasonably explains that carbonsulfur bond formation takes place from less-hindered site against a tert-butyl group. The resulting benzyl radical (I) reacts with oxygen to form II. The sequential hydrogen abstraction would prefer the intramolecular process with minimizing the steric repulsion between R and Ar groups. These proposals enable to explain the origin for the exclusive formation of highly stereo-defined products (2a-e). When 1f is employed instead, initial tosylation would give two possible rotamers of benzylic radical species (IIIa,b). The former (IIIa) is sterically disfavored because of the repulsion between cyclopropyl and phenyl groups. The latter species (IIIb) could have the suitable conformation to overlap two orbitals of radical SOMO and a strained CeC sigma bond and its smooth cleavage determines the stereochemistry of later-formed CeC double bonds in 2f. Actually, this step is rapid enough to prevent the oxygen-trapping, and the resulting primary radical (IV) reacts with TsCN to give 2f together with tosyl radical to terminate the catalytic cycle [12,13]. The above mechanism indicates that the property and reactivity of benzyl radical is a key feature to determine the reaction pathway. When 1,3-disubstituted allenes having aromatic ring are employed instead, regio- and stereoselective oxidation of benzylic radical would be expected to give sufonylkentones [6] (Scheme 5). The oxytosylation reaction using 3a with Cu(OAc)2, TsCN and molecular
Scheme 3. TEMPO effect and cyclopropane cleavage.
S. Arai et al. / Tetrahedron 75 (2019) 1145e1148
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Scheme 4. Proposed reaction pathways.
Scheme 5. Oxysulfonylation of 3.
oxygen in THF at 60 C did proceed regio- and stereoselectively to give 4a in 42% yield. Its structure was assigned to have both a carbonyl group on benzylic position and E-olefin by X-ray crystallographic analysis. This reaction was also applicable to F and CF3 substituents on benzene ring to give the corresponding sulfonylketone (4b,c) in respective yield of 35% and 28%. When a tertbutyl was replaced by a cyclohexyl group such as 3d, the corresponding sunfonylketone (4d) was not obtained at all. This might be caused by undesired cleavage of allenyl Csp3-H bond in 3d to prevent initial regioselective tosylation. In contrast, the different reactivity of the arylallenes under Cu catalysis under argon was observed (Scheme 6). The reaction of 3e with TsCN and CuBr in 1,4-dioxane at 100 C, not 4e but quinoline derivative (5e) was isolated in 25% yield. A CN group was regioselectively incorporated into the [4 þ 2] cycloadduct and its regioisomer was not detected at all [14]. In the case of 1b, the reaction in THF at 60 C was more suitable to give 5b in 34% together with 2b in 22% yield. The tertiary benzyl radical such as I in Scheme
4 might be more reactive to be trapped by the contaminating molecular oxygen to give 2b as a minor product. A methoxy group on benzene ring seems to be essential for increasing the reactivity of substrates, because no any [4 þ 2] cycloadducts were isolated when 1a and 3a were employed under Cu catalysis. Although the detail for this cycloaddition reaction is still unclear, these preliminary results will lead further progress to develop new transformations using multi-substituted allenes.
3. Conclusion In summary, we have developed a new protocol for regio- and stereoselective sulfonylation of multi-substituted allenes under Cu catalysis. The key points are regiocontrol in initial tosylation step and the property and reactivity of benzyl radical intermediates. Based on the above observations, further application under Cu catalysis is currently undergoing.
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Scheme 6. Cu-catalyzed [4 þ 2] cycloaddition.
4. Experimental All reactions were performed with dry solvents and the reagents were purified by the standard methods. Reactions were monitored by thin-layer chromatography carried out on 0.25 mm Merck silica gel plates (60F-254). Column chromatography was performed with silica gel (Fuji Silysia, PSQ-60B) or NH-silica (Fuji Silysia, DM2035). NMR spectra were recorded on spectrometers of JEOL JMN-ECS400, ECP-400, ECZ-400, ECZ-600, and ECA-600 operating at 400 or 600 MHz for 1H NMR and 100 or 150 MHz for 13C NMR with calibration using residual undeuterated solvent as an internal reference. IR spectra were recorded on JASCO FT/IR-4700. High resolution mass spectra were measured by The AccuTOFLC-plus JMS-T100LP (Ionization method: ESI). Typical experimental procedure: Synthesis of 2a: To a solution of 1a (37.3 mg, 0.20 mmol) in THF (0.50 mL, 0.4 M), Cu(OAc)2 (3.6 mg, 0.02 mmol, 10 mol%) and TsCN (54.4 mg, 0.30 mmol, 1.5 eq) were added and the resulting mixture was heated under oxygen atmosphere for 4 h at 60 C. After the completion of the reaction, the mixture was charged onto a silica gel pad and then roughly purified by flash column chromatography (hexane:AcOEt ¼ 10: 1). The chemical yield of 2a was determined by 1H NMR using 2,2'bipyridyl as an internal standard.
[2]
[3] [4]
[5] [6]
[7]
[8] [9] [10] [11] [12]
Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.tet.2018.12.031. References [1] (a) S. Yu, D. Ma, Angew. Chem. Int. Ed. 51 (2012) 3074e3112; (b) C. Aubert, L. Fensterbank, P. Garcia, M. Malacria, A. Simonneau, Chem. Rev.
[13] [14]
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