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Received 00th January 20xx, Accepted 00th January 20xx
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Shuai Xu, Yunpeng Gao, Ri Chen, Kang Wang, Yan Zhang, and Jianbo Wang *
DOI: 10.1039/x0xx00000x www.rsc.org/
Cu(I)-catalyzed olefination of N-sulfonylhydrazones with sulfones via metal carbene intermediates is reported. This reaction uses readily available starting materials and is operationally simple, thus representing a practical method for the construction of carbon-carbon double bonds. Mechanistically, Cu(I) carbene formation and subsequent carbene migratory insertion are proposed as the key steps. The construction of C=C double bonds from carbonyl derivatives represents one of the most important transformations in organic 1 synthesis. Among the olefination reactions, the methylenation has attracted particular attention because terminal alkenes are observed as structure units in many natural products and are also frequently used in various transformations such as olefin metathesis. The traditional methods for the methylenation of 2 3 carbonyl compounds include Wittig reaction, Peterson olefination, 4 5 Julia olefination, Johnson olefination, and the use of 6 stoichiometric titanium or zinc reagents. Besides, rhodium(II)catalyzed methylenation of aldehydes using TMSCHN2 has also been 7 developed. Among the various methylenation methods, the one-pot Julia olefination, namely Julia-Kocienski reaction, represents a powerful 8 approach toward terminal olefins. The success of Julia-Kocienski reaction relies on the use of appropriate aryl methyl sulfone reagents. In this context, a series of aryl methyl sulfones have been developed and demonstrated efficient in successful methylenation of aldehydes and ketones. For examples, Ando and coworkers have recently reported a new sulfone reagent, 1-methyl-2(methylsulfonyl)benzimidazole, as an efficient methylenation 9 reagent.
a.
Beijing National Laboratory of Molecular Sciences (BNLMS), Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry, Peking University, Beijing 100871, China. E-mail: [email protected] b. The State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China † Electronic supplementary information (ESI) available: Experimental details, Characterization data. See DOI: 10.1039/x0xx00000x
Scheme 1 Methylenation of aldehydes or ketones
On the other hand, we have recently developed a series of Cu(I)catalyzed cross-coupling reactions with diazo compounds or their 10 precursor N-tosylhydrazones as the coupling partners. These cross-coupling reactions are proposed to follow the common pathway: deprotonation of the relatively acidic C-H bond of the substrates under basic conditions, transmetallation to Cu(I) catalyst, formation of a Cu(I) carbene species with the diazo substrates, migratory insertion of the carbene, and finally protonation to afford the coupling product and regenerate the Cu(I) catalyst. In most of these coupling reactions, C-C single bonds are formed through protonation of the intermediate Cu(I) species, but in one case we have also observed -F elimination to afford olefins as the products. Motivated by our continuous interests in carbene-based coupling 11,12 reactions, we report herein a new methylenation method through Cu(I)-catalyzed reaction of hydrazones with simple dimethyl sulfone. The reaction can also be extended to other sulfones for the construction of C=C double bond in general. During the course of our investigation on Cu(I)-catalyzed cross10 coupling reaction with N-tosylhydrazones, we found that dimethyl sulfone 2 could react with N-tosylhydrazones to afford terminal olefins under similar reaction conditions. Since dimethyl sulfone 2 is cheap and readily available and N-tosylhydrazones are also easily derived from ketones or aldehydes and these crystalline compounds are bench-stable, we decided to further explore the scope of this novel methylenation reaction. As shown in Scheme 2, the reactions worked well with a series of N-tosylhydrazones derived from aldehydes (1a-f) and ketones (1g and 1h) to afford the
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Copper(I)-Catalyzed Olefination of N-Sulfonylhydrazones with Sulfones†
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corresponding terminal alkenes in moderate yields. Notably, halogen substituents are tolerated which is beneficial for further transformation with transition-metal-catalyzed coupling reactions. Besides, the reaction also applicable to the N-tosylhydrazone derived from-unsaturated aldehyde (1f), affording the corresponding 1,3-butadiene derivative (3f).
View Article Online
DOI: 10.1039/C6CC00444J
Scheme 2 Cu(I)-Catalyzed methylenation with N-tosylhydrazones. Reaction conditions: N-tosylhydrazones 1a-h (0.2 mmol, 1.0 equiv), dimethyl sulfone 2 ( 0.40 mmol, 2.0 equiv), CuI (20 mol%), LiOtBu (3.0 equiv), dioxane (0.5 mL), 110 oC, 3 h. aThese reactions are carried out at 90 oC.
When expanding the substrate scope, we observed that Nmesylhydrazones showed slightly increased reactivity and the o reaction could be carried out at 90 C. Thus, the further expansion of substrate scope was carried out with N-mesylhydrazones and the results were summarized in Scheme 3. Sterically hindered substrate gave the product with slightly diminished yield (5b). The Nmesylhydarzones derived from aryl methyl ketones are good substrates in this transformation, affording the corresponding products in moderate yields (5c-f). Notably, the minor side products due to Shapiro-type elimination were also observed in these 13 cases. Next, we examined the N-mesylhydarzones derived from diaryl ketones. It is worth mentioning that in the previous reports on methylenation with Julia-Kocienski reactions diaryl ketones have not shown as the substrates, presumably due to their low reactivity 8,9 toward carbon anion. Gratifyingly, the current methylenation worked smoothly with a series of N-mesylhydarzones derived from diaryl ketones, affording the corresponding 1,1-diaryl ethylenes in moderate to good yields (5g-s). The reaction tolerated various functional groups and electron-withdrawing substituents such as halogen and cyano group were found beneficial to this transformation (5h, i, l, p and r). The low yield in the case of 5s was presumably due to sterical hindrance. Finally, N-mesylhydarzone of fluorenone could also be methylenated to afford 5t in good yield.
Scheme 3 Cu(I)-Catalyzed methylenation with N-mesylhydrazones. Reaction conditions: N-mesylhydrazones 4a-t (0.2 mmol, 1.0 equiv), dimethyl sulfone 2 (0.40 mmol, 2.0 equiv), CuI (20 mol%), LiOtBu (3.0 equiv), dioxane (0.5 mL), 90 oC, 3 h.
alkenes (7a-c) in good yields under the identical reaction conditions (eq. 1). For the trifluoromethyl butyl sulfone 7, the reaction with Nmesylhydrazone failed to afford the olefination product in satisfactory yield. However, the reaction with diphenyl diazomethane 8 afforded the olefination product 9 in 54% yield (eq. 2). We also examined the reaction of trifluoromethyl benzyl sulfones 6b and 6c with trimethylsilyldiazomethane 10. The corresponding vinyl silanes 11a and 11b could be obtained in moderate yields with good E/Z selectivities (eq. 3). Vinyl silanes are important nucleophiles which find many applications in organic 14,15 chemistry.
Encouraged by the success of methylenation with dimethyl sulfone, we proceeded to explore the construction of general C=C double bond with similar strategy. Upon some experiments, we concluded that trifluoromethyl alkyl sulfones could be employed as appropriate olefination reagents. With trifluoromethyl benzyl sulfone 6a, the reaction of N-mesylhydarzones derived from diaryl ketones (4g, 4k, 4u) afforded the corresponding triaryl substituted
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To gain insights into the reaction mechanism, some control experiments have been carried out. First, for dimethyl sulfone 2 the reaction with diazo compound 8 was also examined. The corresponding methylenation product 5g could be obtained in 78% yield. The results further support the reaction mechanism with diazo compound as the reaction intermediate (vide infra). Since it has been reported that the reaction of N-sulfonylhydrazones and sulfones with strong bases such as LDA and organomagnesium 16 reagents could afford olefination product, we thus carried out the reaction of diazo substrate 8 and sulfone 2 in the absence of Cu(I) catalyst or in the absence of the base. In both cases, the methylenation product 5g could not be observed, indicating that both Cu(I) catalyst and base are required for this transformation. Similar results were obtained from the control experiments with N-tosylhydrazone 1e and N-mesylhydrazone 12.
generated diazo compound to form Cu(I) carbene intermediate B, View Article Online DOI: 10.1039/C6CC00444J which is followed by carbene migratory insertion to form intermediate C. Subsequently, desulfination occurs from intermediate C to generate the C=C double bond. In conclusion, we have developed an efficient Cu(I)-catalyzed methylenation reaction of N-sulfonylhydrazones using dimethyl sulfone as the methylenation reagent. The reaction, which is considered to follow a pathway involving Cu(I) carbene formation, migratory insertion and finally desulfination, is mechanistically different from the established methylenation reactions. The project is supported by 973 Program (No. 2015CB856600) and NSFC (Grant 21472004 and 21472004).
Notes and references 1 2 3 4
5
6
7 8
9 10 Scheme 4 Control experiments
A mechanistic rationale for this olefination reaction is proposed as shown in Scheme 5. The reaction is initiated by the deportation t of dimethyl sulfone 2 with LiO Bu, followed by transmetallation to generate intermediate A. The intermediate A reacts with the in situ
11
12 13
14 15
16 Scheme 5 The proposed reaction mechanism
Topics in Current Chemistry, Stereoselective Alkene Synthesis, Edited by J. Wang, Springer, 2012, 327. G. Wittig, G. Geissler, Liebigs Ann. Chem., 1953, 580, 44. D. J. Peterson, J. Org. Chem., 1968, 33, 780. (a) M. Julia, J. -M. Paris, Tetrahedron Lett., 1973, 4833; (b) P. J. Kocienski, B. Lythgoe, S. Ruston, J. Chem. Soc., Pekin Trans. 1, 1978, 829; (c) P. J. Kocienski, B. Lythgoe, I. Waterhouse, J. Chem. Soc., Pekin Trans. 1, 1980, 1045. (a) C. R. Johnson, J. R. Shanklin, R. A. Kirchhoff, J. Am. Chem. Soc., 1973, 95, 6462; (b) Johnson, C. R.; Elliott, R. C. J. Am. Chem. Soc., 1982, 104, 7041. (a) F. N. Tebbe, G. W. Parshall, G. S. Reddy, J. Am. Chem. Soc., 1978, 100, 3611; (b) K. Takai, Y. Hotta, K. Oshima, H. Nozaki, Tetrahedron Lett., 1978, 19, 2417; (c) K. Takai, T. Kakiuchi, Y. Kataoka, K. Utimoto, J. Org. Chem., 1994, 59, 2668. H. Lebel, V. Paquet, C. Proulx, Angew. Chem., Int. Ed., 2001, 40, 2887. (a) J. B. Baudin, G. Hareau, S. A. Julia, O. Ruel, Tetrahedron Lett., 1991, 32, 1175; (b) P. A. Blakemore, W. J. Cole, P. J. Kocienski, A. Morley, Synlett, 1998, 26; (c) P. J. Kocienski, A. Bell, P. R. Blakemore, Synlett, 2000, 365; (d) D. Mirk, J. -M. Grassot, Synlett, 2006, 1255; (e) C. Aïssa, J. Org. Chem. 2006, 71, 360. K. Ando, T. Kobayashi, N. Uchida, Org. Lett., 2015, 17, 2554. (a) Q. Xiao, Y. Xia, H. Li, Y. Zhang, J. Wang, Angew. Chem. Int. Ed., 2011, 50, 1114; (b) X. Zhao, G. Wu, Y. Zhang, J. Wang, J. Am. Chem. Soc., 2011, 133, 3296; (c) F. Ye, X. Ma, Q. Xiao, Y. Zhang, J. Wang, J. Am. Chem. Soc., 2012, 134, 5742; (d) Q. Xiao, L. Ling, F. Ye, R. Tan, L. Tian, Y. Zhang, Y. Li, J. Wang, J. Org. Chem., 2013, 78, 3879; (e) S. Xu, G. Wu, F. Ye, X. Wang, H. Li, X. Zhao, Y. Zhang, J. Wang, Angew. Chem. Int. Ed., 2015, 54, 4669; (f) Z. Zhang, Q. Zhou, W. Yu, T. Li, G. Wu, Y. Zhang, J. Wang, Org. Lett., 2015, 17, 2474. For reviews, see: (a) Y. Zhang, J. Wang, Eur. J. Org. Chem., 2011, 1015; (b) J. Barluenga, C. Valdés, Angew. Chem. Int. Ed., 2011, 50, 7486; (c) Z. Shao, H. Zhang, Chem. Soc. Rev., 2012, 41, 560; (d) Q. Xiao, Y. Zhang, J. Wang, Acc. Chem. Res., 2013, 46, 236; (e) Y. Xia, Y. Zhang, J. Wang, ACS Catal. 2013, 3, 2586; (f) Z. Liu, J. Wang, J. Org. Chem., 2013, 78, 10024; (g) F. Hu, Y. Xia, C. Ma, Y. Zhang, J. Wang, Chem. Commun., 2015, 7986. X.-X. Wu, Y. Shen, W.-L. Chen, S. Chen, X-H. Hao, Y. Xia, P.-F. Xu, Y.-M Liang, Chem. Commun., 2015, 8031. (a) Shapiro, R. H. Org. React., 1976, 23, 405; (b) Adlington, R. M.; Barrett, A. G. M. Recent Applications of the Shapiro Reaction. Acc. Chem. Res., 1983, 16, 55. I. Fleming, A. Barbero, D. Walter, Chem. Rev., 1997, 97, 2063. For a recent report on the synthesis of vinyl silanes, see: J. R. McAtee, S. E. S. Martin, D. T. Ahneman, K. A. Johnson, D. A. Watson, Angew. Chem. Int. Ed., 2012, 51, 3663. (a) E. Vedejs, J. M. Dolphin, W. T. Stolle, J. Am. Chem. Soc., 1979, 101, 249; (b) A. Kurek-Tyrlik, S. Marczak, K. Michalak, J. Wicha, A. Zarecki, J. Org. Chem., 2001, 66, 6994.
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ChemComm Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: J. Wang, S. Xu, Y. Gao, R. Chen, K. Wang and Y. Zhang, Chem. Commun., 2016, DOI: 10.1039/C6CC00444J.
This is an Accepted Manuscript, which has been through the Royal Society of Chemistry peer review process and has been accepted for publication. Accepted Manuscripts are published online shortly after acceptance, before technical editing, formatting and proof reading. Using this free service, authors can make their results available to the community, in citable form, before we publish the edited article. We will replace this Accepted Manuscript with the edited and formatted Advance Article as soon as it is available. You can find more information about Accepted Manuscripts in the Information for Authors. Please note that technical editing may introduce minor changes to the text and/or graphics, which may alter content. The journal’s standard Terms & Conditions and the Ethical guidelines still apply. In no event shall the Royal Society of Chemistry be held responsible for any errors or omissions in this Accepted Manuscript or any consequences arising from the use of any information it contains.
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a
a
ab
Shuai Xu, Yunpeng Gao, Ri Chen, Kang Wang, Yan Zhang, and Jianbo Wang *
DOI: 10.1039/x0xx00000x www.rsc.org/
Cu(I)-catalyzed olefination of N-sulfonylhydrazones with sulfones via metal carbene intermediates is reported. This reaction uses readily available starting materials and is operationally simple, thus representing a practical method for the construction of carbon-carbon double bonds. Mechanistically, Cu(I) carbene formation and subsequent carbene migratory insertion are proposed as the key steps. The construction of C=C double bonds from carbonyl derivatives represents one of the most important transformations in organic 1 synthesis. Among the olefination reactions, the methylenation has attracted particular attention because terminal alkenes are observed as structure units in many natural products and are also frequently used in various transformations such as olefin metathesis. The traditional methods for the methylenation of 2 3 carbonyl compounds include Wittig reaction, Peterson olefination, 4 5 Julia olefination, Johnson olefination, and the use of 6 stoichiometric titanium or zinc reagents. Besides, rhodium(II)catalyzed methylenation of aldehydes using TMSCHN2 has also been 7 developed. Among the various methylenation methods, the one-pot Julia olefination, namely Julia-Kocienski reaction, represents a powerful 8 approach toward terminal olefins. The success of Julia-Kocienski reaction relies on the use of appropriate aryl methyl sulfone reagents. In this context, a series of aryl methyl sulfones have been developed and demonstrated efficient in successful methylenation of aldehydes and ketones. For examples, Ando and coworkers have recently reported a new sulfone reagent, 1-methyl-2(methylsulfonyl)benzimidazole, as an efficient methylenation 9 reagent.
a.
Beijing National Laboratory of Molecular Sciences (BNLMS), Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry, Peking University, Beijing 100871, China. E-mail: [email protected] b. The State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China † Electronic supplementary information (ESI) available: Experimental details, Characterization data. See DOI: 10.1039/x0xx00000x
Scheme 1 Methylenation of aldehydes or ketones
On the other hand, we have recently developed a series of Cu(I)catalyzed cross-coupling reactions with diazo compounds or their 10 precursor N-tosylhydrazones as the coupling partners. These cross-coupling reactions are proposed to follow the common pathway: deprotonation of the relatively acidic C-H bond of the substrates under basic conditions, transmetallation to Cu(I) catalyst, formation of a Cu(I) carbene species with the diazo substrates, migratory insertion of the carbene, and finally protonation to afford the coupling product and regenerate the Cu(I) catalyst. In most of these coupling reactions, C-C single bonds are formed through protonation of the intermediate Cu(I) species, but in one case we have also observed -F elimination to afford olefins as the products. Motivated by our continuous interests in carbene-based coupling 11,12 reactions, we report herein a new methylenation method through Cu(I)-catalyzed reaction of hydrazones with simple dimethyl sulfone. The reaction can also be extended to other sulfones for the construction of C=C double bond in general. During the course of our investigation on Cu(I)-catalyzed cross10 coupling reaction with N-tosylhydrazones, we found that dimethyl sulfone 2 could react with N-tosylhydrazones to afford terminal olefins under similar reaction conditions. Since dimethyl sulfone 2 is cheap and readily available and N-tosylhydrazones are also easily derived from ketones or aldehydes and these crystalline compounds are bench-stable, we decided to further explore the scope of this novel methylenation reaction. As shown in Scheme 2, the reactions worked well with a series of N-tosylhydrazones derived from aldehydes (1a-f) and ketones (1g and 1h) to afford the
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ChemComm Accepted Manuscript
Published on 25 February 2016. Downloaded by University College London on 25/02/2016 15:47:12.
Copper(I)-Catalyzed Olefination of N-Sulfonylhydrazones with Sulfones†
Please do not adjust margins ChemComm COMMUNICATION
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corresponding terminal alkenes in moderate yields. Notably, halogen substituents are tolerated which is beneficial for further transformation with transition-metal-catalyzed coupling reactions. Besides, the reaction also applicable to the N-tosylhydrazone derived from-unsaturated aldehyde (1f), affording the corresponding 1,3-butadiene derivative (3f).
View Article Online
DOI: 10.1039/C6CC00444J
Scheme 2 Cu(I)-Catalyzed methylenation with N-tosylhydrazones. Reaction conditions: N-tosylhydrazones 1a-h (0.2 mmol, 1.0 equiv), dimethyl sulfone 2 ( 0.40 mmol, 2.0 equiv), CuI (20 mol%), LiOtBu (3.0 equiv), dioxane (0.5 mL), 110 oC, 3 h. aThese reactions are carried out at 90 oC.
When expanding the substrate scope, we observed that Nmesylhydrazones showed slightly increased reactivity and the o reaction could be carried out at 90 C. Thus, the further expansion of substrate scope was carried out with N-mesylhydrazones and the results were summarized in Scheme 3. Sterically hindered substrate gave the product with slightly diminished yield (5b). The Nmesylhydarzones derived from aryl methyl ketones are good substrates in this transformation, affording the corresponding products in moderate yields (5c-f). Notably, the minor side products due to Shapiro-type elimination were also observed in these 13 cases. Next, we examined the N-mesylhydarzones derived from diaryl ketones. It is worth mentioning that in the previous reports on methylenation with Julia-Kocienski reactions diaryl ketones have not shown as the substrates, presumably due to their low reactivity 8,9 toward carbon anion. Gratifyingly, the current methylenation worked smoothly with a series of N-mesylhydarzones derived from diaryl ketones, affording the corresponding 1,1-diaryl ethylenes in moderate to good yields (5g-s). The reaction tolerated various functional groups and electron-withdrawing substituents such as halogen and cyano group were found beneficial to this transformation (5h, i, l, p and r). The low yield in the case of 5s was presumably due to sterical hindrance. Finally, N-mesylhydarzone of fluorenone could also be methylenated to afford 5t in good yield.
Scheme 3 Cu(I)-Catalyzed methylenation with N-mesylhydrazones. Reaction conditions: N-mesylhydrazones 4a-t (0.2 mmol, 1.0 equiv), dimethyl sulfone 2 (0.40 mmol, 2.0 equiv), CuI (20 mol%), LiOtBu (3.0 equiv), dioxane (0.5 mL), 90 oC, 3 h.
alkenes (7a-c) in good yields under the identical reaction conditions (eq. 1). For the trifluoromethyl butyl sulfone 7, the reaction with Nmesylhydrazone failed to afford the olefination product in satisfactory yield. However, the reaction with diphenyl diazomethane 8 afforded the olefination product 9 in 54% yield (eq. 2). We also examined the reaction of trifluoromethyl benzyl sulfones 6b and 6c with trimethylsilyldiazomethane 10. The corresponding vinyl silanes 11a and 11b could be obtained in moderate yields with good E/Z selectivities (eq. 3). Vinyl silanes are important nucleophiles which find many applications in organic 14,15 chemistry.
Encouraged by the success of methylenation with dimethyl sulfone, we proceeded to explore the construction of general C=C double bond with similar strategy. Upon some experiments, we concluded that trifluoromethyl alkyl sulfones could be employed as appropriate olefination reagents. With trifluoromethyl benzyl sulfone 6a, the reaction of N-mesylhydarzones derived from diaryl ketones (4g, 4k, 4u) afforded the corresponding triaryl substituted
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To gain insights into the reaction mechanism, some control experiments have been carried out. First, for dimethyl sulfone 2 the reaction with diazo compound 8 was also examined. The corresponding methylenation product 5g could be obtained in 78% yield. The results further support the reaction mechanism with diazo compound as the reaction intermediate (vide infra). Since it has been reported that the reaction of N-sulfonylhydrazones and sulfones with strong bases such as LDA and organomagnesium 16 reagents could afford olefination product, we thus carried out the reaction of diazo substrate 8 and sulfone 2 in the absence of Cu(I) catalyst or in the absence of the base. In both cases, the methylenation product 5g could not be observed, indicating that both Cu(I) catalyst and base are required for this transformation. Similar results were obtained from the control experiments with N-tosylhydrazone 1e and N-mesylhydrazone 12.
generated diazo compound to form Cu(I) carbene intermediate B, View Article Online DOI: 10.1039/C6CC00444J which is followed by carbene migratory insertion to form intermediate C. Subsequently, desulfination occurs from intermediate C to generate the C=C double bond. In conclusion, we have developed an efficient Cu(I)-catalyzed methylenation reaction of N-sulfonylhydrazones using dimethyl sulfone as the methylenation reagent. The reaction, which is considered to follow a pathway involving Cu(I) carbene formation, migratory insertion and finally desulfination, is mechanistically different from the established methylenation reactions. The project is supported by 973 Program (No. 2015CB856600) and NSFC (Grant 21472004 and 21472004).
Notes and references 1 2 3 4
5
6
7 8
9 10 Scheme 4 Control experiments
A mechanistic rationale for this olefination reaction is proposed as shown in Scheme 5. The reaction is initiated by the deportation t of dimethyl sulfone 2 with LiO Bu, followed by transmetallation to generate intermediate A. The intermediate A reacts with the in situ
11
12 13
14 15
16 Scheme 5 The proposed reaction mechanism
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