Letter Cite This: Org. Lett. 2018, 20, 909−912
pubs.acs.org/OrgLett
Diastereo- and Enantioselective Dearomative [3 + 2] Cycloaddition Reaction of 2‑Nitrobenzofurans with 3‑Isothiocyanato Oxindoles Jian-Qiang Zhao,† Xiao-Jian Zhou,‡,§ Yan Zhou,∥ Xiao-Ying Xu,*,‡ Xiao-Mei Zhang,‡ and Wei-Cheng Yuan*,‡ †
Institute for Advanced Study, Chengdu University, Chengdu 610106, China National Engineering Research Center of Chiral Drugs, Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, China ∥ Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China § University of Chinese Academy of Sciences, Beijing 100049, China ‡
S Supporting Information *
ABSTRACT: Enantioselective dearomative [3 + 2] cycloaddition reaction of 2-nitrobenzofurans with 3-isothiocyanato oxindoles was developed. The reaction employs a chiral bis(oxazoline)/Zn(OTf)2 catalyst, allowing a practical, straightforward access to structurally diverse spirooxindoles containing a 2,3-dihydrobenzofuran motif and three contiguous stereocenters with excellent diastereo- and enantioselectivities. The synthetic potentials of the method have been demonstrated by the scale-up experiment and transformations of the products. The preliminary mechanism was investigated with experimental observations, nonlinear effects studies, and MS experiments.
T
he efficient and selective construction of complex heterocycles is a continuing challenge in synthetic chemistry. The catalytic asymmetric dearomatization processes involving cycloadditions have attracted broad interest due to their potential to rapidly generate chiral polycyclic compounds from readily available arenes and heteroarenes.1 In this area, the vast majority of reported studies typically focus on the dearomative cycloadditions of electron-rich arenes and heteroarenes, including naphthol, phenol, indole, and pyrrole.2 Moreover, these dearomative cycloadditions are generally triggered by a nucleophilic reaction based on the intrinsic nucleophilicity of the electron-rich substrates.3 On the other hand, installing suitable electron-withdrawing groups on the arenes or heteroarenes will change them into electron-deficient compounds, thus having electrophilic character. The involvement of electron-deficient arenes and heteroarenes in dearomative cycloadditions would lead to new synthetic methods and provide creative approaches to access novel heterocyclics.4 However, in contrast, corresponding studies on the catalytic asymmetric version in this area remain underdeveloped.5,6 Exploiting asymmetric dearomative cycloaddition reactions of electrondeficient arenes and heteroarenes for the construction of chiral polycyclic compounds is more attractive. Among the promising asymmetric dearomative cycloadditions based on electron-deficient heteroarenes, we noticed that no examples of 2-nitrobenzofurans for the catalytic asymmetric reaction were reported.7 Moreover, the asymmetric dearomative cycloadditions of 2-nitrobenzofurans will directly construct diverse chiral 2,3-dihydrobenzofuran scaffolds, which are important core structure units found in many biologically active natural products and pharmaceuticals (Figure 1).8 In this © 2018 American Chemical Society
Figure 1. Examples of pharmaceuticals containing 2,3-dihydrobenzofuran scaffold.
context, the development of a new method to realize this potentially useful transformation of 2-nitrobenzofurans should be a significant advancement. As a continuation of our recent research on the asymmetric dearomative cycloaddition reactions of 3-nitroindoles,6 we envisaged that 2-nitrobenzofurans should undergo dearomative cycloaddition reaction, wherein the nucleophilic addition to the C3-position of 2-nitrobenzofurans acts as a trigger and sequentially attacks electrophiles at the C2position (Scheme 1A). Herein, we present the first Zn-catalyzed dearomative [3 + 2] cycloaddition reaction of 2-nitrobenzofurans with 3-isothiocyanato oxindoles for generating structurally diverse spirooxindoles, containing a 2,3-dihydrobenzofuran motif and three contiguous stereocenters, with excellent diastereo- and enantioselectivities (Scheme 1B). Our initial investigation began with the optimization of reaction between 2-nitrobenzofuran 1a9 and 3-isothiocyanato oxindole 2a.10 As shown in Table 1, using Zn(OTf)2/ Received: November 28, 2017 Published: January 31, 2018 909
DOI: 10.1021/acs.orglett.7b03667 Org. Lett. 2018, 20, 909−912
Letter
Organic Letters
explored. As shown in Table 2, the reactions are generally unbiased toward 2-nitrobenzofurans with either electron-with-
Scheme 1. Strategy for the Dearomative Cycloaddition Reactions of 2-Nitrobenzofurans (A), and the Catalytic Asymmetric Dearomative [3 + 2] Cycloaddition Reaction with 3-Isothiocyanato Oxindoles Reported Herein (B)
Table 2. Asymmetric Dearomative [3 + 2] Cycloaddition Reaction of 2-Nitrobenzofurans with 3-Isothiocyanato Oxindolesa
Table 1. Optimization of Reaction Conditionsa
entry
L1−4
solvent
t (h)
yield (%)b
drc
ee (%)c
1 2 3 4 5 6 7 8 9d 10d,e
L1 L2 L3 L4 L3 L3 L3 L3 L3 L3
toluene toluene toluene toluene DCE CHCl3 xylene MTBE xylene xylene
45 48 48 45 48 48 45 48 45 24
90 90 92 83 91 93 97 90 99 99
81:19 63:37 97:3 69:31 96:4 99:1 99:1 94:6 >99:1 >99:1
91 37 99 4 95 99 99 96 >99 >99
a Unless otherwise noted, the reactions were carried out with 1 (0.1 mmol), 2 (0.1 mmol), Zn(OTf)2 (10 mol %), and L3 (11 mol %) in 1.0 mL of xylene with 50 mg of 5 Å MS at 50 °C for 24 h; see the Supporting Information for experimental details. bThe reported yields are of the isolated yields of the sum of the diastereoisomers for two steps. cDetermined by chiral HPLC.
a
Unless otherwise noted, the reactions were carried out with 1a (0.1 mmol), 2a (0.1 mmol), Zn(OTf)2 (10 mo l%), and ligand (11 mol %) in 1.0 mL of solvent at room temperature for the indicated time; see the Supporting Information for experimental details. bThe reported yields are of the isolated yields of the sum of the diastereoisomers for two steps. cDetermined by chiral HPLC. d50 mg of 5 Å MS was used. e Run at 50 °C. DCE = dichloroethane; MTBE = methyl tert-butyl ether.
drawing or -donating groups, regardless of the bulkiness, or positions on the aryl ring, providing the corresponding adducts 3b−m in excellent yields (93−99%) with virtually pure stereoisomers (≥99:1 dr and >99% ee, entries 1−12). The more sterically hindered 2-nitronaphtho[2,1-b]furan 1n also proved to be amenable to this catalytic system, furnishing 3n with 93% yield and excellent dr and ee values (entry 13). On the other hand, for the 3-isothiocyanato oxindoles, bearing different substituents such as ethyl-, propyl-, and benzyl- at the N1 position, they were well compatible with the conditions and gave the respective products 3o−q in excellent yields and ee values (entries 14−16). These results suggested that increasing the size of the N-alkyl group had no detrimental effect on the reactivity and stereoselectivity. Nevertheless, the presence of either electron-withdrawing or -donating group on the 5-position of the aromatic ring also provided the desired product 3r−t in very high yield with excellent dr and ee (entries 17−19). In addition, similar outcome was also observed with substrates 2h and 2i having substitution at 7-position (entries 20 and 21). Ultimately,
diphenylamine-linked bis(oxazoline) ligand L1 complex11 as the catalyst in toluene, the reaction furnished the expected dearomative [3 + 2] cycloaddition product 3a in 90% yield with 81:19 dr and 91% ee (entry 1). Some other bis(oxazoline) ligands L2−4 were examined; it was observed that L3 provided good yield and the best dr and ee values (entry 3). Afterward, the screening of solvents showed that xylene was better than other solvents and gave 3a in 97% yield with 99:1 dr and 99% ee (entry 7). When 50 mg of 5 Å molecular sieves (MS) were added into the reaction mixture, the dr and ee values could be further improved (entry 9). When the reaction was performed at 50 °C, the reaction was complete within 24 h and afforded 3a in 99% yield without sacrificing the diastereo- and enantioselectivity (entry 10). Under the optimized reaction conditions, the scope of the asymmetric dearomative [3 + 2] cycloaddition reaction was 910
DOI: 10.1021/acs.orglett.7b03667 Org. Lett. 2018, 20, 909−912
Letter
Organic Letters
loss of diastereo- and enantioselectivity. Treating 3e with DBU in CH2Cl2, after loss of nitrous acid, led to the efficient formation of compound 8 in 99% yield with >99% ee. The reduction of the nitro moiety in 3e into amine group with concomitant opening of the dihydrofuran cycle in a single step delivered compound 9 in 78% yield with excellent stereocontrol. Ultimately, the Suzuki coupling reaction between 3e and phenylboronic acid proceeded well, along with the elimination of nitro group, affording 10 in 87% yield. To gain insight into the reaction mechanism, the nonliear effect for the present system was investigated by varying the ee value of ligand L3.12 The relationship between the ee value of L3 and the product 3a showed that the ee correlated linearly, which suggested that the monomeric complex might function as the most active and effective catalyst.13 The absolute configurations of 3a were determined to be (7S,9S,16S) by single-crystal X-ray analysis. In addition, the catalytic composition was also examined by using ESI-MS experiments. The spectrum of a mixture of ligand L3 and Zn(OTf)2 in a ratio 1.1:1 in toluene displayed an ion at m/z 843.9955 (m/z calcd for [L3+Zn(OTf)2+Na]+ 844.0171). This result suggested that ligand L3 is coordinated with Zn(OTf)2 in a 1:1 ratio.12 Based on these results and relevant reports,11 a possible transition state was tentatively proposed for the asymmetric dearomative [3 + 2] cycloaddition reaction (Figure 2). Ligand L3
the reaction for the disubstituted substrate 2j proceeded smoothly and gave 3w with excellent results similar to the other monosubstituted substrates (entry 22). We also examined some other substrates under the standard conditions. As shown in Scheme 2, when we conducted reactions Scheme 2. Investigation of Some Other Substrates
of 3-methyl-2-nitrobenzofuran 1o and 3-benzyl-2-nitrobenzofuran 1p with 2a, the reactions did not proceed. However, reaction of methyl 5-nitrofuran-2-carboxylate 1q with 2a gave the desired product 3x in only 41% yield with 62:38 dr and with poor enantioselectivity. In order to demonstrate the synthetic potential of the method, we explored a scale-up experiment of the preparation of 3e. Under the standard conditions, 3e could be obtained without any influence on the reactivity and without loss in the diastereo- and enantioselectivity (90% yield, >99:1 dr, and >99% ee), with only 3 mol % catalyst loading at 1 mmol scale of the reactants.12 This experiment reflects the good scalability of the reaction and the potential value of the catalyst system. To further prove the synthetic value and versatility of this work, we explored various transformations of the products to give some key heterocyclic compounds (Scheme 3).12 The γScheme 3. Different Transformations of the Dearomative [3 + 2] Cycloaddition Reaction Products
Figure 2. Proposed transition state for the asymmetric dearomative [3 + 2] cycloaddition reaction.
thiolactam moiety of product 4 could be oxidized to γ-lactam by 30% H2O2 and formic acid, giving compound 5 in 76% yield with excellent dr and ee values. Nevertheless, 4 also could be readily converted into benzylated thiolactam 6 with excellent results. The same excellent results could also be obtained in the conversion of compound 4 to the methylated thiolactam 3e. Treating 3e with tributyltin hydrogen and AIBN, the radical denitration process provided compound 7 in 91% yield without
coordinates with ZnII to form a Zn(OTf)2/L3 complex serving as Lewis acid to activate 2-nitrobenzofurans through the coordination between ZnII and the nitro group. Synchronously, the 3isothiocyanato oxindole is directed by the NH group acting as a Lewis base. Thus, under the bifunctional activation of the Zn(OTf)2/L3 complex, the C3-position of 2-nitrobenzofurans undergoes nucleophilic attack at the Re face by the activated 3isothiocyanato oxindoles from the Re face. The subsequent intramolecular annulation process from C2-position of 2nitrobenzofurans to the −NCS group generates the expected products with stereospecific configurations. We have presented Zn(OTf)2-catalyzed dearomative cycloaddition of 2-nitrobenzofurans. The enantioselective dearomative [3 + 2] cycloaddition between 2-nitrobenzofurans and 3isothiocyanato oxindoles employs a chiral Zn(OTf)2/diphenylamine-linked bis(oxazoline) catalyst, operates under mild conditions, and displays broad scope, allowing for a practical, straightforward access to structurally diverse spirooxindole compounds containing a 2,3-dihydrobenzofuran motif and three contiguous stereocenters in quantitative yields with excellent diastereo- and enantioselectivities. Further investigations employing other heteroarenes such as 2-nitroindoles and 2nitrobenzothiophenes in catalytic asymmetric reactions are currently being pursued in our laboratory.14 911
DOI: 10.1021/acs.orglett.7b03667 Org. Lett. 2018, 20, 909−912
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Organic Letters
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R. Org. Lett. 2007, 9, 4159. (d) Lee, S.; Chataigner, I.; Piettre, S. R. Angew. Chem., Int. Ed. 2011, 50, 472. (e) Lee, S.; Diab, S.; Queval, P.; Sebban, M.; Chataigner, I.; Piettre, S. R. Chem. - Eur. J. 2013, 19, 7181. (f) Beemelmanns, C.; Gross, S.; Reissig, H.-U. Chem. - Eur. J. 2013, 19, 17801. (g) Wang, K.-K.; Du, W.; Zhu, J.; Chen, Y.-C. Chin. Chem. Lett. 2017, 28, 512. (h) Laugeois, M.; Ling, J.; Férard, C.; Michelet, V.; Ratovelomanana-Vidal, V.; Vitale, M. R. Org. Lett. 2017, 19, 2266. (i) Santhini, P. V.; Babu, S. A.; Krishnan R, A.; Suresh, E.; John, J. Org. Lett. 2017, 19, 2458. (j) Santhini, P. V.; Krishnan R, A.; Babu, S. A.; Simethy, B. S.; Das, G.; Praveen, V. K.; Varughese, S.; John, J. J. Org. Chem. 2017, 82, 10537. (5) (a) Trost, B. M.; Ehmke, V.; O’Keefe, B. M.; Bringley, D. A. J. Am. Chem. Soc. 2014, 136, 8213. (b) Awata, A.; Arai, T. Angew. Chem., Int. Ed. 2014, 53, 10462. (c) Andreini, M.; De Paolis, M.; Chataigner, I. Catal. Commun. 2015, 63, 15. (d) Gerten, A. L.; Stanley, L. M. Org. Chem. Front. 2016, 3, 339. (e) Li, Y.; Tur, F.; Nielsen, R. P.; Jiang, H.; Jensen, F.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2016, 55, 1020. (6) For the studies of our group, see: (a) Zhao, J.-Q.; Zhou, M.-Q.; Wu, Z.-J.; Wang, Z.-H.; Yue, D.-F.; Xu, X.-Y.; Zhang, X.-M.; Yuan, W.-C. Org. Lett. 2015, 17, 2238. (b) Zhao, J.-Q.; Wu, Z.-J.; Zhou, M.-Q.; Xu, X.-Y.; Zhang, X.-M.; Yuan, W.-C. Org. Lett. 2015, 17, 5020. (c) Yue, D.-F.; Zhao, J.-Q.; Chen, X.-Z.; Zhou, Y.; Zhang, X.-M.; Xu, X.-Y.; Yuan, W.-C. Org. Lett. 2017, 19, 4508. (7) During the preparation of this manuscript, You reported a dearomative cycloaddition of nitrobenzofurans, see: Cheng, Q.; Zhang, H.-J.; Yue, W.-J.; You, S.-L. Chem. 2017, 3, 428. (8) (a) Santavy, F. Alkaloids 1979, 17, 385. (b) Lu King, M.; Chiang, C.-C.; Ling, H.-C.; Fujita, E.; Ochiai, M.; McPhail, A. T. J. Chem. Soc., Chem. Commun. 1982, 1150. (c) Han, S.; Sweeney, J. E.; Bachman, E. S.; Schweiger, E. J.; Forloni, G.; Coyle, J. T.; Davis, B. M.; Joullié, M. M. Eur. J. Med. Chem. 1992, 27, 673. (d) Melian, E. B.; Goa, K. L. Drugs 2002, 62, 107. (e) Blakemore, P. R.; White, J. D. Chem. Commun. 2002, 1159. (f) Mubarak, K. K. Respir. Med. 2010, 104, 9. (9) For the preparation of 2-nitrobenzofurans, see: (a) Ohishi, Y.; Doi, T.; Nakanishi, T. Chem. Pharm. Bull. 1984, 32, 4260. (b) Lu, S.-C.; Zheng, P.-R.; Liu, G. J. Org. Chem. 2012, 77, 7711. (c) Osyanin, V. A.; Osipov, D. V.; Demidov, M. R.; Klimochkin, Y. N. J. Org. Chem. 2014, 79, 1192. (10) For a review about the use of 3-isothiocyanato oxindoles in various reactions, see: (a) Han, W.-Y.; Zhao, J.-Q.; Zuo, J.; Xu, X.-Y.; Zhang, X.-M.; Yuan, W.-C. Adv. Synth. Catal. 2015, 357, 3007. For selected examples, see: (b) Wang, L.; Yang, D.; Li, D.; Wang, R. Org. Lett. 2015, 17, 3004. (c) Wang, L.; Yang, D.; Li, D.; Liu, X.; Zhao, Q.; Zhu, R.; Zhang, B.; Wang, R. Org. Lett. 2015, 17, 4260. (d) Zhao, H.-W.; Tian, T.; Pang, H.-L.; Li, B.; Chen, X.-Q.; Yang, Z.; Meng, W.; Song, X.Q.; Zhao, Y.-D.; Liu, Y.-Y. Adv. Synth. Catal. 2016, 358, 2619. (e) Chowdhury, R.; Kumar, M.; Ghosh, S. K. Org. Biomol. Chem. 2016, 14, 11250. (f) Lin, Y.; Liu, L.; Du, D.-M. Org. Chem. Front. 2017, 4, 1229. (11) For selected examples on the Zn(OTf)2/bis(oxazoline) complexes for the asymmetric reactions, see: (a) Lu, S.-F.; Du, D.-M.; Xu, J.-X. Org. Lett. 2006, 8, 2115. (b) Peng, J.; Du, D.-M. Eur. J. Org. Chem. 2012, 2012, 4042. (c) Tan, F.; Xiao, C.; Cheng, H.-G.; Wu, W.; Ding, K.-R.; Xiao, W.-J. Chem. - Asian J. 2012, 7, 493. (d) Tan, F.; Lu, L.Q.; Yang, Q.-Q.; Guo, W.; Bian, Q.; Chen, J.-R.; Xiao, W.-J. Chem. - Eur. J. 2014, 20, 3415. (e) Chu, J. C. K.; Dalton, D. M.; Rovis, T. J. Am. Chem. Soc. 2015, 137, 4445. (12) See the Supporting Information for more details. (13) (a) Guillaneux, D.; Zhao, S. H.; Samuel, O.; Rainford, D.; Kagan, H. B. J. Am. Chem. Soc. 1994, 116, 9430. (b) Girard, C.; Kagan, H. B. Angew. Chem., Int. Ed. 1998, 37, 2922. (c) Satyanarayana, T.; Abraham, S.; Kagan, H. B. Angew. Chem., Int. Ed. 2009, 48, 456. (14) Preliminary reaction with 2-nitroindole and 2-nitrobenzothiopene showed promising results, which will be disclosed in a separate paper.
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b03667. Experimental details, characterization data for new compounds, nonlinear effect experiment, and X-ray crystal structure of 3a (PDF) Accession Codes
CCDC 1569592 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
[email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected] ORCID
Yan Zhou: 0000-0002-3015-724X Wei-Cheng Yuan: 0000-0003-4850-8981 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We are grateful for financial support from the National NSFC (Nos. 21372217, 21572223, 21572224), Sichuan Youth Science and Technology Foundation (2015JQ0041 and 2016JQ0024), and the Start-up Fund of Chengdu University (2081916044)
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REFERENCES
(1) For reviews, see: (a) Pape, A. R.; Kaliappan, K. P.; Kündig, E. P. Chem. Rev. 2000, 100, 2917. (b) Keane, J. M.; Harman, W. D. Organometallics 2005, 24, 1786. (c) Bandini, M.; Eichholzer, A. Angew. Chem., Int. Ed. 2009, 48, 9608. (d) Bartoli, G.; Bencivenni, G.; Dalpozzo, R. Chem. Soc. Rev. 2010, 39, 4449. (e) Roche, S. P.; Porco, J. A., Jr. Angew. Chem., Int. Ed. 2011, 50, 4068. (f) You, S.-L. Asymmetric Dearomatization Reactions; Wiley-VCH: Weinheim, Germany, 2016. (2) For selected reviews, see: (a) Zhuo, C.-X.; Zhang, W.; You, S.-L. Angew. Chem., Int. Ed. 2012, 51, 12662. (b) Zhuo, C.-X.; Zheng, C.; You, S.-L. Acc. Chem. Res. 2014, 47, 2558. (c) Ding, Q.; Zhou, X.; Fan, R. Org. Biomol. Chem. 2014, 12, 4807. (d) Zheng, C.; You, S.-L. Chem. 2016, 1, 830. (e) Wu, W.-T.; Zhang, L.; You, S.-L. Chem. Soc. Rev. 2016, 45, 1570. (3) For selected examples, see: (a) Cera, G.; Chiarucci, M.; Mazzanti, A.; Mancinelli, M.; Bandini, M. Org. Lett. 2012, 14, 1350. (b) Zhu, S.; MacMillan, D. W. C. J. Am. Chem. Soc. 2012, 134, 10815. (c) Xiong, H.; Xu, H.; Liao, S.; Xie, Z.; Tang, Y. J. Am. Chem. Soc. 2013, 135, 7851. (d) Nan, J.; Zuo, Z.; Luo, L.; Bai, L.; Zheng, H.; Yuan, Y.; Liu, J.; Luan, X.; Wang, Y. J. Am. Chem. Soc. 2013, 135, 17306. (e) Tong, M.-C.; Chen, X.; Li, J.; Huang, R.; Tao, H.; Wang, C.-J. Angew. Chem., Int. Ed. 2014, 53, 4680. (f) Xu, R.-Q.; Gu, Q.; Wu, W.-T.; Zhao, Z.-A.; You, S.-L. J. Am. Chem. Soc. 2014, 136, 15469. (g) Yang, D.; Wang, L.; Han, F.; Li, D.; Zhao, D.; Wang, R. Angew. Chem., Int. Ed. 2015, 54, 2185. (h) Zheng, J.; Wang, S.-B.; Zheng, C.; You, S.-L. J. Am. Chem. Soc. 2015, 137, 4880. (i) Shao, W.; Li, H.; Liu, C.; Liu, C.-J.; You, S.-L. Angew. Chem., Int. Ed. 2015, 54, 7684. (j) Lian, X.; Lin, L.; Wang, G.; Liu, X.; Feng, X. Chem. Eur. J. 2015, 21, 17453. (k) Tu, H.-F.; Zheng, C.; Xu, R.-Q.; Liu, X.-J.; You, S.-L. Angew. Chem., Int. Ed. 2017, 56, 3237. (4) (a) Biolatto, B.; Kneeteman, M.; Paredes, E.; Mancini, P. M. E. J. Org. Chem. 2001, 66, 3906. (b) Chataigner, I.; Panel, C.; Gérard, H.; Piettre, S. R. Chem. Commun. 2007, 3288. (c) Chataigner, I.; Piettre, S. 912
DOI: 10.1021/acs.orglett.7b03667 Org. Lett. 2018, 20, 909−912
