Tandem Rh(II) and Chiral Squaramide Relay Catalysis

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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Tandem Rh(II) and Chiral Squaramide Relay Catalysis: Enantioselective Synthesis of Dihydro-β-carbolines via Insertion to C−H Bond and Aza-Michael Reaction Shanmugam Rajasekar and Pazhamalai Anbarasan* Department of Chemistry, Indian Institute of Technology Madras, Chennai 600036, India

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S Supporting Information *

ABSTRACT: An efficient tandem rhodium(II)/squaramide relay catalysis of readily accessible indole derivatives and Nsulfonyl-1,2,3-triazoles has been developed for the enantioselective synthesis of dihydro-β-carbolines in good yield and enantioselectivity. The developed reaction involves selective insertion of in situ generated azavinyl rhodium carbene onto the C3−H bond of indole derivatives and subsequent squaramide-catalyzed enantioselective intramolecular aza-Michael reaction. Furthermore, the potential of the strategy was demonstrated through the ready conversion to potent tetrahydro-β-carbolines and the tetracyclic alkaloid core structure.

F

Scheme 1. Synthetic Approaches to Complex Frameworks

unctionalized N-heterocycles are the major constituent of various bioactive natural products, pharmaceuticals, and materials.1 In particular, substituted indole and its derivatives such as β-carbolines are the core structures of diverse therapeutically important molecules, which are known to exhibit wide pharmacological properties such as antimalarial, antiviral, antileukemic, antioxidant, anticancer, etc.2 Typically, β-carbolines were synthesized from tryptamine derivatives employing various condensation reactions.3 However, enantioselective synthesis of β-carbolines is rather limited, and most of the known methods utilize the Pictet−Spengler reaction.4 Due to the high potency of the β-carbolines motif, enantioselective construction of these structural units has been an active area of research in contemporary organic synthesis. Traditionally, functionalized complex frameworks were constructed through the multistep process, which requires isolation and purification of intermediates prior to each subsequent reaction; as a consequence, they suffer from poor overall yield and very low atom/step economy. These strategies were subsequently replaced by the cascade/domino reaction, which allows possible access to a number of structurally complex scaffolds in high atom and step economy.5 However, the development of catalytic asymmetric cascade reactions6 involving more than one catalyst, either metal− metal, organo−metal, or organo−organo catalysts, are rather challenging, mostly due to the intrinsic incompatibility of functionally different catalysts and extrinsic conflict of reaction conditions (Scheme 1a). © XXXX American Chemical Society

On the other hand, one-pot relay asymmetric catalysis involving more than one catalytic system gained significant interest due to the possible transformation of intermediate employing a subsequent catalytic system with high compatibility of catalyst and reaction conditions.7 In particular, the combination of transition-metal catalysis and organocatalysis proved to be an efficient relay catalysis for the asymmetric construction of diverse structural motifs.8 Most of these types of relay catalysis have benefited from imine- and enamineReceived: February 21, 2019

A

DOI: 10.1021/acs.orglett.9b00652 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Table 1. Optimizationa

based organocatalysis, and the use of hydrogen-bonding organocatalysis is rather limited.9 Inspired by the importance of β-carbolines and transition metal−organo relay catalysis, we herein disclose the enantioselective synthesis of substituted βcarbolines via rhodium(II)/chiral squaramide relay catalysis of suitably substituted indole and N-sulfonyl-1,2,3-triazoles (Scheme 1b). Recently, Fokin, Murakami, and others have demonstrated N-sulfonyl-1,2,3-triazoles as potential starting point for the synthesis of various carbo- and heterocycles with suitable coupling partners via the in situ generation and functionalization of reactive azavinyl carbenes.10 Keeping in mind the importance of β-carbolines and the reactivity of azavinyl carbenes,11 we envisioned that the rhodium-catalyzed selective insertion of azavinyl carbene onto the C3−H bond of substituted indole 1 would afford the enamide 3,11d,12 which on subsequent asymmetric aza-Michael reaction with organocatalyst,13 particularly hydrogen-bonding catalyst,14 would furnish the dihydro-β-carbolines 4 in excellent selectivity (Scheme 1b).15 The successful development of this transformation in one pot would offer first new transition metal− organo relay catalysis and ready access to potent dihydro-βcarbolines with excellent enantioselectivity. The investigation started with the optimization of initial rhodium(II)-catalyzed insertion of azavinyl carbene, in situ generated from 2a, onto the C3−H bond of indole derivative 1a. After a series of optimizations (see Supporting Information), the inserted product 3a was obtained in 76% yield in the presence of 2 mol % of Rh2(OAc)4 in 1,2dichloroethane (DCE) at 100 °C for 5 h (Scheme 2). It is Scheme 2. One-Pot Relay Approach to (±)-4a

entry

cat.

temp (°C)

time (h)

yieldb (%)

erc

1 2 3 4 5 6 7 8 9 10 11 12d

A B C D E F G H I F F F

rt rt rt rt rt rt rt rt rt 10 0 rt

96 96 36 36 36 24 24 24 24 36 36 24

82 89 57 88 87 87 82 76 69 65 41 75

47.5:52.5 53.5:6.5 78.5:21.5 83:17 82.5:17.5 95.5:4.5 95:5 95.5:4.5 95:5 95.5:4.5 95:5 94.5:5.5

a

Reaction conditions: 3a (30 mg, 0.056 mmol), cat. (20 mol %), DCE, temp, time. bIsolated yield. cThe er was determined by HPLC analysis. d10 mol % of F.

primary amine B (Table 1, entry 2). Next, use of a bifunctional catalyst such as cinchonidine-derived thiourea C, which can activate both enone and enamide through hydrogen bonding, afforded the expected product 4a in good yield with improved er (78.5:21.5) (Table 1, entry 3). Thiourea derivatives D and E were derived from 3,5- cinchonidine and quinine, respectively, and bis(trifluoromethyl)aniline derivative furnished 4a in ∼88% yield with er ∼83:17 (Table 1, entries 4−6). Gratifyingly, replacement of thiourea catalyst with the chiral squaramide derived from cinchonidine and benzyl amine gave the product in 87% yield in 24 h with 95.5:4.5 er (Table 1, entry 7). A similar er was observed observed with other substituted chiral squaramide catalysts G, H, and I in varying yields (Table 1, entries 8−10). To further improve the enantiomeric ratio, the reaction temperature was reduced to 10 and 0 °C. Although similar er was obtained at lower temperatures, the yield of the transformation was drastically reduced (Table 1, entries 9 and 10). Subsequently, various solvents were also tested under the chiral squaramide F catalyzed intramolecular aza-Michael reaction. Among them, chlorinated solvents such as CHCl3, chlorobenzene, and DCE gave the best results. Since the initial rhodium-catalyzed insertion of azavinyl carbenes to the C3−H bond of indole was effective in DCE, the subsequent studies were carried out employing DCE as solvent. Most interestingly, reducing the loading of F to 10 mol % also afforded the product 4a in similar yield and enantiomeric ratio. On the basis of these

important to note that no aza-Michael addition product (±)-4a was observed under the insertion conditions. Interestingly, smooth intramolecular aza-Michael reaction of 3a was achieved on reaction with triethylamine (Et3N) in DCE at rt for 2 h and led to the formation of expected (±)-4a in 88% yield. Subsequently, reaction of 1a and 2a in the presence of Rh2(OAc)4 for 5 h at 100 °C followed by addition of Et3N and continuing the reaction for additional 2 h gave the (±)-βcarboline 4a in 71% yield, which defines the successful one-pot relay approach. Inspired by the successful development of a one-pot approach to the synthesis of (±)-β-carboline 4a involving base-induced aza-Michael reaction, an enantioselective approach to the synthesis of β-carboline 4a was envisaged. At first, enantioselective aza-Michael reaction of 3a was examined employing chiral organocatalysts (see the Supporting Information). Thus, the reaction of 3a in the presence of 20 mol % of cinchonidine at room temperature in DCE afforded the product 4a in 82% yield with recognizable er (Table 1, entry 1). A similar result was observed with the cinchonidine-derived B

DOI: 10.1021/acs.orglett.9b00652 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

Scheme 4. Substrates Scope: N-Sulfonyl-1,2,3-triazole

studies, entry 12 was chosen as suitable conditions for the enantioselective aza-Michael reaction. To further demonstrate the practical applicability of the developed enantioselective aza-Michael reaction, one-pot recycling of chiral squaramide was envisaged. The reaction of 3a with 10 mol % of F in DCE followed by addition of 3a after the completion of reaction was continued for four cycles (Scheme 3a). HPLC analysis of reaction mixture after each cycle suggested that the catalyst is highly efficient to give comparable enantiomeric ratio and yield even after the fourth cycle. Scheme 3. (a) One-Pot Catalyst Recycling Experiment; (b) One-Pot Rh(II)/Squaramide Relay Catalysis

Having achieved the practical approach to enantioselective intramolecular aza-Michael reaction, one-pot rhodium(II) and chiral squaramide relay catalysis was envisaged. Thus, following the conditions mentioned in the Scheme 2, indole derivative 1a was treated with 2a in the presence of 2 mol % of rhodium acetate in DCE at 100 °C for 5 h followed by cooling of the reaction mixture to room temperature, 10 mol % of squaramide F was added, and the reaction was continued for 24 h to furnish the product 4a in 69% yield with a loss of enantiomeric ratio (Scheme 3b). This successful development offers a new relay catalysis comprising of rhodium(II)catalyzed insertion of azavinyl carbenes to the C3−H bond of indole followed by chiral squaramide-catalyzed aza-Michael reaction. After the successful development of one-pot relay catalysis for the enantioselective synthesis of dihydro-β-carbolines, we next examined the scope and generality of the transformation. As can be seen in Scheme 4, various substituted N-sulfonyl1,2,3-triazoles were subjected under the optimized conditions to afford the corresponding dihydro-β-carbolines in good yield and er. For instance, phenylsulfonyl- and mesyl-derived triazoles afforded the products 4b and 4c in good yield and er. Similarly, p-tolyl-, m-tolyl-, and p-ethylphenyl-substituted triazole also gave the products 4d−f in ∼70% yield with 95:5 er. Formation of halo- and trifluoromethyl-substituted aryl containing dihydro-β-carbolines 4g−i, 4k, and 4m were also achieved with a high level of efficiency employing the optimized relay catalysis. Among them, the structure and stereochemistry of 4h were unambiguously confirmed by single-crystal X-ray analysis (Flack parameter: 0.02). Interestingly, electron-donating p-methoxyphenyl-substituted and sterically challenging 1-naphthyl-substituted triazoles gave the product in moderate yield without losing any er. The optimized conditions tolerate various highly electron-deficient aryl-substituted triazoles and led to the synthesis of 4n−p in moderate to good yield with good er. Furthermore, the

synthesis of vinyl- and thiophene-substituted dihydro-βcarbolines was also efficiently obtained employing the present protocol. Subsequently, substituents on the indole moiety were varied to understand the scope and limitation of this transformation. Changing phenyl ketone to methyl ketone led to the formation of products 4s and 4t in good yield, but with relatively less er. On the other hand, alkyl- and halo-substituted aryl ketones containing indole derivative underwent smooth reaction to afford 4u−z in good yield and er (Scheme 5). Interestingly, an electron-donating group on aryl ketone, which can reduce the electrophilicity of enone toward Michael addition, also gave the products 4aa−ac. Sterically hindered ortho-, electronwithdrawing nitro-substituted aryl ketones and heteroaryl ketone were also tolerated to provide 4ad−ag with good yield and moderate er. The structure and stereochemistry of 4x and 4ae (Flack parameter: 0.004 and −0.02) was confirmed by single-crystal X-ray analysis. Next, substituents on the aryl moiety of indole were examined, and importantly, all of them led to the formation of substituted dihydro-β-carbolines 4ah− ak in good yield and er. Similar results were also observed with N-benzyl- and N-allyl-substituted indole derivatives. To demonstrate the synthetic utility of the developed method, subsequent conversion of the dihydro-β-carbolines to potential molecules was envisaged. Selective hydrogenation of enamide in 4na over Pd/C with 250 psi of hydrogen pressure at 60 °C afforded 5 with excellent anti-diastereoselectivity (Scheme 6). The structure and stereochemistry of 5 were confirmed by single-crystal X-ray analysis. On the other hand, selective reduction of ketone in 4a with NaBH4 and CeCl3 in methanol gave the alcohol 6 in 84% with a 3:1 mixture of diastereomers. Next, treatment of 4an with MePPh3Br and n BuLi afforded the diene 7 with no loss in er, which on subsequent ring-closing metathesis with Grubbs’ secondgeneration catalyst in DCM furnished the product 8, a core C

DOI: 10.1021/acs.orglett.9b00652 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

proposed the possible transition state for the enantioselective aza-Michael addition. Thus, a hydrogen-bonding interaction of squaramide with ketone would bring a substrate in contact with catalyst (Figure 1). Next, preferential Re-face approach of

Scheme 5. Substrates Scope: Substituted Indole

Figure 1. Plausible transition-state model.

nitrogen would afford the observed enantioselectivity. The preference for the Re-face attack over the Si-face attack can be readily realized through the potential hydrogen bonding interaction with quinuclidine nitrogen with the sulfonamide, which is above the plane of squaramide. In conclusion, an efficient one-pot rhodium(II)/squaramide relay catalysis have been developed for the enantioselective construction of dihydro-β-carbolines from readily accessible suitably substituted indole derivatives and N-sulfonyl-1,2,3triazoles. The developed reaction involves the selective insertion of in situ generated azavinyl rhodium carbene onto the C3−H bond of the substituted indole derivative followed by squaramide-catalyzed enantioselective intramolecular azaMichael reaction. The one-pot relay catalysis tolerates various steric and electronic effects and allows the synthesis of dihydro-β-carbolines in excellent yield and enantiomeric ratio. Furthermore, the potential of the strategy was demonstrated through the ready conversion to potent tetrahydro-β-carbolines and tetracyclic alkaloid core structures.

Scheme 6. Synthetic Application

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b00652. Experimental details, characterization data, 1H and 13C NMR spectra of isolated compounds (PDF) Accession Codes

CCDC 1874780−1874783 contain 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 [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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structure of various alkaloids such as arborescidine, akagerine, etc.16 To demonstrate the potential interaction of catalyst F and substrate 3a, equimolar mixtures of both in DCE were analyzed in ESI-MS. Interestingly, the peak at 1011.4266 was observed, which corresponds to the catalyst + substrate adduct (F + 3a + H). This observation suggested that there is a strong interaction between the catalyst F and 3a. Based on the observed stereochemistry and literature precedents,14f we

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Pazhamalai Anbarasan: 0000-0001-6049-5023 Notes

The authors declare no competing financial interest. D

DOI: 10.1021/acs.orglett.9b00652 Org. Lett. XXXX, XXX, XXX−XXX

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X.-Y.; Shi, M. Org. Chem. Front. 2015, 2, 1516−1520. (d) Fu, L.; Davies, H. M. L. Org. Lett. 2017, 19, 1504−1507. (13) (a) Sánchez-Roselló, M.; Aceña, J. L.; Simón-Fuentes, A.; del Pozo, C. Chem. Soc. Rev. 2014, 43, 7430−7453. (b) Enders, D.; Wang, C.; Liebich, J. X. Chem. - Eur. J. 2009, 15, 11058−11076. (14) (a) Miyaji, R.; Asano, K.; Matsubara, S. Org. Lett. 2013, 15, 3658−3661. (b) Du, J.-Y.; Zeng, C.; Han, X.-J.; Qu, H.; Zhao, X.-H.; An, X.-T.; Fan, C.-A. J. Am. Chem. Soc. 2015, 137, 4267−4273. (c) Xiao, X.; Liu, X.; Dong, S.; Cai, Y.; Lin, L.; Feng, X. Chem. - Eur. J. 2012, 18, 15922−15926. (d) Gu, Q.; You, S.-L. Chem. Sci. 2011, 2, 1519−1522. (e) Liu, X.; Lu, Y. Org. Lett. 2010, 12, 5592−5595. (f) Roy, T. K.; Parhi, B.; Ghorai, P. Angew. Chem., Int. Ed. 2018, 57, 9397−9401. (15) (a) Sydorenko, N.; Zificsak, C. A.; Gerasyuto, A. I.; Hsung, R. P. Org. Biomol. Chem. 2005, 3, 2140−2144. (b) Itoh, T.; Yokoya, M.; Miyauchi, K.; Nagata, K.; Ohsawa, A. Org. Lett. 2003, 5, 4301−4304. (c) Itoh, T.; Yokoya, M.; Miyauchi, K.; Nagata, K.; Ohsawa, A. Org. Lett. 2006, 8, 1533−1535. (16) (a) Angenot, L.; Diberg, O.; Dupont, L. Tetrahedron Lett. 1975, 16, 1357−1358. (b) Verpoorte, R. J. Nat. Prod. 1986, 49, 1−25. (c) Chbani, M.; Païs, M.; Delauneux, J.-M.; Debitus, C. J. Nat. Prod. 1993, 56, 99−104.

ACKNOWLEDGMENTS We thank DST-SERB (EMR/2016/003677) for the financial support. S.R. thanks CSIR, New Delhi, for the fellowship. We also thank DST-FIST for the ESI-MS facility and Mr. Ramkumar, IIT Madras, for single-crystal X-ray analysis.

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REFERENCES

(1) Fattorusso, E.; Taglialatela-Scafati, O. Modern Alkaloids: Structure, Isolation, Synthesis, and Biology; Wiley, 2008. (2) (a) Antkiewicz-Michaluk, L.; Rommelspacher, H. Current Topics In Neurotoxicity: Isoquinolines and Beta-Carbolines As Neurotoxins and Neuroprotectants: New Vistas In Parkinson’s Disease Therapy; Springer, 2012. (b) Cao, R.; Peng, W.; Wang, Z.; Xu, A. Curr. Med. Chem. 2007, 14, 479−500. (c) Laine, E. A.; Lood, C.; Koskinen, M. A. Molecules 2014, 19, 1544−1567. (d) Cain, M.; Weber, R. W.; Guzman, F.; Cook, J. M.; Barker, S. A.; Rice, K. C.; Crawley, J. N.; Paul, S. M.; Skolnick, P. J. Med. Chem. 1982, 25, 1081−1091. (3) (a) Cox, E. D.; Cook, J. M. Chem. Rev. 1995, 95, 1797−1842. (b) Milen, M.; Á brányi-Balogh, P. Chem. Heterocycl. Compd. 2016, 52, 996−998. (4) (a) Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 10558−10559. (b) Raheem, I. T.; Thiara, P. S.; Peterson, E. A.; Jacobsen, E. N. J. Am. Chem. Soc. 2007, 129, 13404−13405. (c) Larghi, E. L.; Amongero, M.; Bracca, A. B. J.; Kaufman, T. S. ARKIVOC 2005, 98−153. (d) Stöckigt, J.; Antonchick, A. P.; Wu, F.; Waldmann, H. Angew. Chem., Int. Ed. 2011, 50, 8538−8564. (e) Dalpozzo, R. Molecules 2016, 21, 699. (5) (a) Tietze, L. F. Chem. Rev. 1996, 96, 115−136. (b) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45, 7134−7186. (c) Shindoh, N.; Takemoto, Y.; Takasu, K. Chem. - Eur. J. 2009, 15, 12168−12179. (6) (a) Grondal, C.; Jeanty, M.; Enders, D. Nat. Chem. 2010, 2, 167. (b) Volla, C. M. R.; Atodiresei, I.; Rueping, M. Chem. Rev. 2014, 114, 2390−2431. (c) Zhou, J. Chem. - Asian J. 2010, 5, 422−434. (7) Albrecht, Ł.; Jiang, H.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2011, 50, 8492−8509. (8) (a) Du, Z.; Shao, Z. Chem. Soc. Rev. 2013, 42, 1337−1378. (b) Deng, Y.; Kumar, S.; Wang, H. Chem. Commun. 2014, 50, 4272− 4284. (c) Inamdar, S. M.; Shinde, V. S.; Patil, N. T. Org. Biomol. Chem. 2015, 13, 8116−8162. (d) Rueping, M.; Koenigs, R. M.; Atodiresei, I. Chem. - Eur. J. 2010, 16, 9350−9365. (e) Zhong, C.; Shi, X. Eur. J. Org. Chem. 2010, 2010, 2999−3025. (9) (a) Qiu, H.; Li, M.; Jiang, L.-Q.; Lv, F.-P.; Zan, L.; Zhai, C.-W.; Doyle, M. P.; Hu, W.-H. Nat. Chem. 2012, 4, 733−738. (b) Jiang, J.; Xu, H.-D.; Xi, J.-B.; Ren, B.-Y.; Lv, F.-P.; Guo, X.; Jiang, L.-Q.; Zhang, Z.-Y.; Hu, W.-H. J. Am. Chem. Soc. 2011, 133, 8428−8431. (c) Chen, D.-F.; Zhao, F.; Hu, Y.; Gong, L.-Z. Angew. Chem., Int. Ed. 2014, 53, 10763−10767. (d) Jia, S.; Xing, D.; Zhang, D.; Hu, W. Angew. Chem., Int. Ed. 2014, 53, 13098−13101. (e) Zhang, D.; Zhou, J.; Xia, F.; Kang, Z.; Hu, W. Nat. Commun. 2015, 6, 5801. (10) (a) Chattopadhyay, B.; Gevorgyan, V. Angew. Chem., Int. Ed. 2012, 51, 862−872. (b) Davies, H. M. L.; Alford, J. S. Chem. Soc. Rev. 2014, 43, 5151−5162. (c) Anbarasan, P.; Yadagiri, D.; Rajasekar, S. Synthesis 2014, 46, 3004−3023. (d) Wang, Y.; Lei, X.; Tang, Y. Synlett 2015, 26, 2051−2059. (e) Jiang, Y.; Sun, R.; Tang, X.-Y.; Shi, M. Chem. - Eur. J. 2016, 22, 17910−17924. (f) Li, Y.; Yang, H.; Zhai, H. Chem. − Eur. J. 2018, 24, 12757−12766. (11) (a) Yadagiri, D.; Chaitanya, M.; Reddy, A. C. S.; Anbarasan, P. Org. Lett. 2018, 20, 3762−3765. (b) Yadagiri, D.; Reddy, A. C. S.; Anbarasan, P. Chem. Sci. 2016, 7, 5934−5938. (c) Yadagiri, D.; Anbarasan, P. Chem. Sci. 2015, 6, 5847−5852. (d) Rajasekar, S.; Yadagiri, D.; Anbarasan, P. Chem. - Eur. J. 2015, 21, 17079−17084. (e) Yadagiri, D.; Anbarasan, P. Chem. - Eur. J. 2013, 19, 15115− 15119. (f) Rajasekar, S.; Anbarasan, P. J. Org. Chem. 2014, 79, 8428− 8434. (g) Yadagiri, D.; Anbarasan, P. Org. Lett. 2014, 16, 2510−2513. (12) (a) Alford, J. S.; Davies, H. M. L. J. Am. Chem. Soc. 2014, 136, 10266−10269. (b) Yang, J.-M.; Zhu, C.-Z.; Tang, X.-Y.; Shi, M. Angew. Chem., Int. Ed. 2014, 53, 5142−5146. (c) Zhang, Y.-S.; Tang, E

DOI: 10.1021/acs.orglett.9b00652 Org. Lett. XXXX, XXX, XXX−XXX