Visible-Light-Induced Tertiary C(sp3)−H Sulfonylation: An Approach to Tertiary Sulfones

Sumedha Swarnkar, Mohd Yeshab Ansari, and Atul Kumar*

ABSTRACT:

In seeking to broaden the lexicon of photocatalysis and considering the importance of sulfones as essential pharmaceuticals, herein one-pot visible-light-induced tertiary C(sp3)−H sulfonylation is explored for the first time using indoline-2,3-diones, 4-hydroXy proline, and sulfinic acids as model substrates in the presence of iodine and Na2-Eosin Y as a photocatalyst. In addition, this transformation unlocks a new strategy in the context of the late-stage tertiary C(sp3)−H sulfonylation of Monastrol, a selective Eg5 inhibitor, and its analogue.

Introduction

The functionalization of C−H has become an important and intensive task that has allowed streamlined progress in synthetic organic chemistry. The direct functionalization of sterically hindered tertiary C(sp3)−H bonds is a cutting-edge tool;1−6 in particular, tertiary C(sp3)−H sulfonylation has been found to be an area of high interest in generating complex sulfone molecules. Despite the considerable advancements in the area of sulfonylation reactions of alkynes7−13 and alkenes14−16 as well as the C(sp2)−H sulfonylation of aryl or heteroaryl systems,17−20 C(sp3)−H sulfonylation21−24 at tertiary carbon centers is very rare and underdeveloped and will help to pave the way for new directions for organic chemists. Sulfone functionalities are routinely considered in medicinal chemistry areas searching for antimalarial, anti-cancer, anti-inflammatory, anti-HIV, and antimicrobial activ- ities.25,26 Specifically, scaffolds containing tertiary sulfone funtionalities have found colossal importance in pharmaceut- icals on account of their tremendous effects on the rate of drug metabolism. A wide range of tertiary sulfones used as clinically applied drugs or inhibitors are represented in Figure 1.27−32
Recently, visible-light photocatalysis has been favored as a valuable alternative for sustainable organic synthesis,33−39 and visible-light-induced C(sp3)−H functionalization40−46 has received great attention from chemists, which has enabled an array of direct difficult transformations in a one-pot manner. Many reports have been discussed for remote or direct C(sp3)−H sulfonylation at primary and secondary carbon centers,47−53 but the construction of tertiary sulfones via C(sp3)−H sulfonylation without prefunctionalization remains a formidable challenge for its synthetic approaches. In continuation of the efforts of our laboratory in the develop- ment of novel protocols for medicinally important scaf- folds54−56 and as a first example of our strategy, we sought to disclose a visible-light-induced novel tertiary C(sp3)−H bond sulfonylation approach with the successful application of the cost-effective and simple organic dye Na2-Eosin Y as a photocatalyst for the synthesis of elusive tertiary sulfones. Several reports have been uncovered with this concern (Scheme 1). Kleij et al. in 201957 and Loh et al. in 201858 developed intriguing approaches for the synthesis of tertiary propargylic sulfones. Next, the tertiary allylic sulfones were synthesized by the sulfonylation of either tertiary allylic electrophiles59,60 or vinyl cyclic carbonates61 with sulfinates. The synthesis of hindered tertiary alkylic sulfones was disclosed by Jiang et al. in 202062 and involved the three- component decarboXylative coupling of carboXylate-derived redoXactive esters with sodium dithionite and electrophiles. Significant approaches have found access to sterically hindered sulfones, albeit with the limitation that highly specialized substrates are required. By considering these limits, we uncovered an unexplored visible-light-induced tertiary C- (sp3)−H sulfonylation that provides elusive tertiary sulfones in one pot by the sequential addition of indoline-2,3-diones, 4- hydroXy proline, and sulfinic acids in the presence of iodine and the organic dye Na2-Eosin Y as a photocatalyst. Our protocol involves a sequential route that generates inter- mediate 3-(1H-pyrrol-1-yl)indolin-2-one by the visible-light- induced iodine-catalyzed reaction of 4-hydroXy proline with indoline-2,3-diones followed by novel visible-light-induced tertiary C(sp3)−H sulfonylation. The mechanistic route of this novel approach is outlined in Scheme 1.
Assembling different classes of substituents at the C3 position of indoline-2-ones is a long-term aspiration in organic synthesis. Driven by the promising bioactive significance of 3,3-disubstituted indoline-2-ones,63 we started our analysis of the reaction by utilizing indoline-2,3-diones, 4-hydroXy proline, and sulfinic acids as model substrates. Our design reaction seemed to utilize the generation of the intermediate 3-(1H- pyrrol-1-yl)indolin-2-one with the subsequent formation of a C−S bond through the visible-light-induced sulfonylation of the tertiary C(sp3)−H bond. The initial attempt was performed by the treatment of 5-chloroindoline-2,3-dione 1c, proline (0.5 mmol), p-toluenesulfinic acids (1 mmol), molecular- iodine (0.1 mmol), and Na2-Eosin Y (2 mol %) in 2 mL of MeCN/ H2O (2:1) at rt for 9 h under air. n.d. = not detected. bIsolated yields. entry 1. Initial experiments revealed a significant solvent effect, as the intermediate was only obtained in good yields in MeCN, as monitored by TLC (Table 1, entries 2−4). Interestingly, the presence of water facilitated the formation of the intermediate as well as the desired product (Table 1, entry 5) compared with only MeCN due to the increase in the extent of the solubility of the Na2-Eosin Y catalyst in the aqueous MeCN. Different photocatalysts such as Eosin Y, Rose Bengal, and Ru(bpy)3Cl2 were screened (Table 1, entries 6−8), and it was found that Na2-Eosin Y was an appropriate photocatalyst for this transformation. Further optimization studies were also conducted and are represented in the SI. One of the effective parameters of our protocol is the “time economy”. The reaction was completed within 30 min when the intermediate 5-chloro-3-(1H-pyrrol-1-yl)indolin-2-one 5c was isolated and further subjected to the reaction under the optimal conditions (Table 1, entry 5), and the desired product was afforded in good yield. According to all of the above investigations, the optimal reaction system was established as follows: The reaction of 5-chloroindoline-2,3-dione 1c (0.5 mmol) and 4- hydroXy proline 2 (0.5 mmol) with p-toluenesulfinic acid 3a (1.0 mmol) was performed in MeCN/H2O (2:1) (2 mL) with I2 (0.1 mmol) and Na2-Eosin Y (2 mol %) under blue LED irradiation at room temperature for 9 to 10 h. For an unequivocal structure elucidation and confirmation, a single crystal of compound 4n was established, as shown in Scheme 2.
With these novel findings in hand for the visible-light- induced tertiary C(sp3)−H bond sulfonylation, the substrate scopes were investigated. As shown in the results represented in Scheme 2, indoline-2,3-diones with different electronic properties and substitutions at different positions afforded the corresponding tertiary sulfones in good to excellent yields. For instance, halogen substitutions such as 5-F, 5-Cl, 5-Br, 5-I, 7-F, and 7-Cl afforded the desired products 4b, 4c, 4d, 4e, 4f, and 4g, respectively, in excellent yields. The presence of either an electron-withdrawing group, such as 5-NO2, or an electron- donating group, like 5-Me, on the aromatic rings is well tolerated. A variety of N-substitutions at indoline-2,3-diones also acted as suitable reaction partners for this transformation. It is noteworthy that when we explored this strategy with acenaphthylene-1,2-diones, the expected products were obtained in 75−81% (4ag−4ai) yields. Aiming to expand the synthetic applicability of this conversion, the protocol is feasible for a broad range of sulfinic acids. A variety of substitutions at aryl sulfinic acid were successfully carried out and resulted in the corresponding tertiary sulfones in high yields. Alkyl sulfinic acid, due to its low reactivity that posed a great challenge in the synthesis of the desired products, gave products 4ac−4af and 4ai with similar efficiency.
Importantly, late-stage functionalization (LSF) is emerging as an increasingly effective technique that leverages C−H bonds as synthetic handles for the diversification of drug targets. We further disclosed the synthetic application of our protocol by utilizing this concept (LSF) with 3,4-dihydropyrimidine-2(1H)-thione derivatives Monastrol, a selective Eg5 inhibitor, and its analogue and furnished the corresponding tertiary sulfones in good yields, as shown in Scheme 3.
To elucidate the reaction mechanism adequately, some mechanistic investigations were performed to shed light on the reaction parameters, as shown in Scheme 4. When the reaction was carried out without iodine, it was unable to furnish the desired product (Scheme 4A), suggesting that this trans- formation might involve the intermediate 5-chloro-3-(1H- pyrrol-1-yl) indolin-2-one 5c, generated by the visible-light- induced iodine-catalyzed condensation of 5-chloroindoline- 2,3-dione and 4-hydroXy proline. Furthermore, with the addition of p-toluenesulfinic acid and Na2-Eosin Y, after 4 h, the disproportionate coupling product thiosulfonate 6 was observed as a side product64 in the presence of blue LED. Next, in the absence of light, the intermediate was formed in low yield, and the conversion into desired product was then completely halted (Scheme 4B). The presence of light facilitated the formation of intermediate 5c and is indis- pensable for the generation of the sulfonyl radical. When the reaction was conducted without a photocatalyst, the efficient conversion into its intermediate 5c was observed, followed by the addition of p-toluenesulfinic acid 3a. The next reaction was absent (Scheme 4C). This result suggested that the photo- catalyst initiated the generation of a sulfonyl radical under blue-LED irradiation. Subsequently, when TEMPO (2.0 equiv) or BHT (2.0 equiv) was purposefully introduced as a radical scavenger under the standard reaction conditions, a trace amount of the desired product was found (Scheme 4D), demonstrating the involvement of radical intermediates in this reaction. Furthermore, the presence of 1,1-diphenylethene (2 equiv) as an additive under the standard reaction conditions resulted in the radical adduct (2-tosylethene-1,1-diyl)- dibenzene 7 (detected by HRMS) and the desired tertiary sulfone product 4c in 16% yield. Finally, with the simultaneous addition of all model substrates in the presence of I2 (20 mol %) and the photocatalyst Na2-Eosin Y (2 mol %) in the MeCN/H2O (2:1) miXed-solvent system, only a 10% yield of the desired product with thiosulfonate as a side product (42% yield) was observed after 10 h, indicating that the sequential addition was a key step for the completion of the reaction (Scheme 4E). In addition, on/off visible-light irradiation experiments were conducted to prove the necessity of the continuous irradiation of visible light. (See the SI.) A detailed kinetic profile of this sequential protocol was then studied (Scheme 4F), and a description is given in the SI.
To account for observed reactivities coupled to the above investigations and based on literature precedents,64−71 a plausible mechanistic network is outlined in Scheme 5. First, azomethine ylide A is generated by the condensation of 5- chloroindoline-2,3-diones 1c with 4-hydroXyproline 2, folradical G via homolysis of the corresponding homocoupling dimer 5c′, formed by the transient homocoupling dimer strategy under the oXidative conditions.65,69−71 This radical G couples to the sulfur-centered sulfonyl radical F to deliver the expected tertiary sulfone products 4. Furthermore, the sulfurcentered sulfonyl radical F undergoes self-coupling and generates the intermediate disulfone H. This intermediate H may be reduced in the presence of p-toluenesulfinic acid to give the corresponding disulfoXide I. The homolytic cleavage of unstable intermediate I takes place and disproportionates into radical Ia and radical Ib. Finally, these radicals combine and form thiosulfonate 6 as a side product.64 Importantly, the formation of the side product thiosulfonate 6 is observed only under certain conditions, as shown in Scheme 4.
In summary, we present herein the first visible-light-induced novel one-pot tertiary C(sp3)−H sulfonylation using indoline- 2,3-diones, 4-hydroXy proline, and sulfinic acids as model substrates to construct sterically congested tertiary sulfones that could further broaden the potential of sulfone-based drug ingredients. This approach is characterized by good to excellent yields, the sequential addition of reacting partners with its appreciable scope, and excellent product selectivity. Mechanistic studies further explained that 3-(1H-pyrrol-1- yl)indolin-2-one was the key intermediate, followed by the novel visible-light-induced tertiary C(sp3)−H sulfonylation approach. Furthermore, the synthetic utility of our protocol is lowed by decarboXylation, which is facilitated in the presence of I2/blue LED.65,66 Spontaneously, dehydration leads to azomethine ylide B, and the more stable zwitterion intermediate C is formed by 1,5 proton transfer and will change to intermediate 5c.66,67 Next, the sequential addition of p-toluenesulfinic acid and 2 mol % Na2-Eosin Y is accomplished. Under the irradiation of blue LED, Na2-Eosin Y is converted to Na2-Eosin Y*, followed by single-electron transfer (SET) to Na2-Eosin Y* from sulfinic acid 3a. applicable to the tertiary C(sp3)−H sulfonylation of 3,4- dihydropyrimidine-2(1H)-thione derivatives Monastrol, a selective Eg5 inhibitor, and its analogue.

REFERENCES

(1) Liao, K.; Pickel, T. C.; Boyarskikh, V.; Bacsa, J.; Musaev, D. G.; Davies, H. M. L. Nature 2017, 551, 609−613.
(2) Yang, C.-J.; Zhang, C.; Gu, Q.-S.; Fang, J.-H.; Su, X.-L.; Ye, L.; Sun, Y.; Tian, Y.; Li, Z.-L.; Liu, X.-Y. Nat. Catal. 2020, 3, 539−546.
(3) Michaudel, Q.; Thevenet, D.; Baran, P. S. J. Am. Chem. Soc.2012, 134, 2547−2550.
(4) Li, K.; Wu, Q.; Lan, J.; You, J. Nat. Commun. 2015, 6, 1−9.
(5) Hong, G.; Nahide, P. D.; Neelam, U. K.; Amadeo, P.; Vijeta, A.; Curto, J. M.; Hendrick, C. E.; Van Gelder, K. F.; Kozlowski, M. C. ACS Catal. 2019, 9, 3716−3724.
(6) Vasu, D.; Fuentes de Arriba, A. L.; Leitch, J. A.; de Gombert, A.; DiXon, D. J. Chem. Sci. 2019, 10, 3401−3407.
(7) Zeng, X.; Ilies, L.; Nakamura, E. Org. Lett. 2012, 14, 954−956.
(8) Zhu, C.; Yue, H.; Maity, B.; Atodiresei, I.; Cavallo, L.; Rueping, M. Nat. Catal. 2019, 2, 678−687.
(9) Ning, Y.; Ji, Q.; Liao, P.; Anderson, E. A.; Bi, X. Angew. Chem., Int. Ed. 2017, 56, 13805−13808.
(10) García-Domínguez, A.; Müller, S.; Nevado, C. Angew. Chem., Int. Ed. 2017, 56, 9949−9952.
(11) Ansari, M. Y.; Kumar, N.; Kumar, A. Org. Lett. 2019, 21, 3931−3936.
(12) Ansari, M. Y.; Swarnkar, S.; Kumar, A. Chem. Commun. 2020, 56, 9561−9564.
(13) Wang, H.; Lu, Q.; Chiang, C.-W.; Luo, Y.; Zhou, J.; Wang, G.; Lei, A. Angew. Chem., Int. Ed. 2017, 56, 595−599.
(14) Hell, S. M.; Meyer, C. F.; Misale, A.; Sap, J. B. I.; Christensen, K. E.; Willis, M. C.; Trabanco, A. A.; Gouverneur, V. Angew. Chem.020, 132, 11717−11723.
(15) Hossain, A.; Engl, S.; Lutsker, E.; Reiser, O. ACS Catal. 2019, 9, 1103−1109.
(16) Zeng, D.; Wang, M.; Deng, W.-P.; Jiang, X. Org. Chem. Front.2020, 7, 3956−3966.
(17) Mahanty, K.; Maiti, D.; De Sarkar, S. J. Org. Chem. 2020, 85, 3699−3708.
(18) Du, B.; Qian, P.; Wang, Y.; Mei, H.; Han, J.; Pan, Y. Org. Lett.2016, 18, 4144−4147.
(19) Guo, Y.-J.; Lu, S.; Tian, L.-L.; Huang, E.-L.; Hao, X.-Q.; Zhu, X.; Shao, T.; Song, M.-P. J. Org. Chem. 2018, 83, 338−349.
(20) Rao, W. H.; Shi, B. F. Org. Lett. 2015, 17, 2784−2787.
(21) Tang, X.; Huang, L.; Xu, Y.; Yang, J.; Wu, W.; Jiang, H. Angew. Chem., Int. Ed. 2014, 53, 4205−4208.
(22) Lan, X.-W.; Wang, N.-X.; Bai, C.-B.; Zhang, W.; Xing, Y.; Wen, J.-L.; Wang, Y.-J.; Li, Y.-H. Sci. Rep. 2015, 5, 1−8.
(23) Rao, W.-H.; Zhan, B.-B.; Chen, K.; Ling, P.-X.; Zhang, Z.-Z.; Shi, B.-F. Org. Lett. 2015, 17, 3552−3555.
(24) Yavari, I.; Shaabanzadeh, S. Org. Lett. 2020, 22, 464−467.
(25) Scott, K. A.; Njardarson, J. T. Top. Curr. Chem. 2018, 376, 376.
(26) Feng, M.; Tang, B.; Liang, S. H.; Jiang, X. Curr. Top. Med. Chem. 2016, 16, 1200−1216.
(27) Ichikawa, Y. Tetrahedron Lett. 1988, 29, 4957−4958.
(28) Kobayashi, M.; Nakamura, H.; Wu, H.; Kobayashi, J.; Ohizumi, Y. Arch. Biochem. Biophys. 1987, 259, 179−184.
(29) Foote, K. M.; Blades, K.; Cronin, A.; Fillery, S.; Guichard, S. S.; Hassall, L.; Hickson, I.; Jacq, X.; Jewsbury, P. J.; McGuire, T. M.; Nissink, J. W. M.; Odedra, R.; Page, K.; Perkins, P.; Suleman, A.; Tam, K.; Thommes, P.; Broadhurst, R.; Wood, C. J. Med. Chem. 2013, 56, 2125−2138.
(30) Eto, H.; Kaneko, Y.; Takeda, S.; Tokizawa, M.; Sato, S.;Yoshida, K.; Namiki, S.; Ogawa, M.; Maebashi, K.; Ishida, K.; Matsumoto, M.; Asaoka, T. Chem. Pharm. Bull. 2001, 49, 173−182.
(31) Weber, C.; Birnbock, H.; Leube, J.; Kobrin, I.; Kleinbloesem, C.H.; Brummelen, P. V. Br. J. Clin. Pharmacol. 1993, 36, 547−554.
(32) Fischli, W.; Clozel, J.-P.; Breu, V.; Buchmann, S.; Mathews, S.; Stadler, H.; Vieira, E.; Wostl, W. Hypertension 1994, 24, 163−169.
(33) Shaw, M. H.; Twilton, J.; MacMillan, D. W. C. J. Org. Chem.2016, 81, 6898−6926.
(34) Milligan, J. A.; Phelan, J. P.; Badir, S. O.; Molander, G. A.Angew. Chem., Int. Ed. 2019, 58, 6152−6163.
(35) Le, C.; Chen, T. Q.; Liang, T.; Zhang, P.; MacMillan, D. W. C.Science 2018, 360, 1010−1014.
(36) Romero, N. A.; Nicewicz, D. A. Chem. Rev. 2016, 116, 10075− 10166.
(37) Crisenza, G. E. M.; Melchiorre, P. Nat. Commun. 2020, 11, 8− 11.
(38) Marzo, L.; Pagire, S. K.; Reiser, O.; König, B. Angew. Chem., Int. Ed. 2018, 57, 10034−10072.
(39) Garbarino, S.; Ravelli, D.; Protti, S.; Basso, A. Angew. Chem., Int.Ed. 2016, 55, 15476−15484.
(40) Revathi, L.; Ravindar, L.; Fang, W. Y.; Rakesh, K. P.; Qin, H. L.Adv. Synth. Catal. 2018, 360, 4652−4698.
(41) Chu, J. C. K.; Rovis, T. Nature 2016, 539, 272−275.
(42) Li, G.-X.; Morales-Rivera, C. A.; Gao, F.; Wang, Y.; He, G.; Liu, P.; Chen, G. Chem. Sci. 2017, 8, 7180−7185.
(43) Guo, Q.; Peng, Q.; Chai, H.; Huo, Y.; Wang, S.; Xu, Z. Nat.Commun. 2020, 11, 1−10.
(44) Kumar, Y.; Jaiswal, Y.; Kumar, A. Org. Lett. 2018, 20, 4964− 4969.
(45) Li, F.; Tian, D.; Fan, Y.; Lee, R.; Lu, G.; Yin, Y.; Qiao, B.; Zhao, X.; Xiao, Z.; Jiang, Z. Nat. Commun. 2019, 10, 1−9.
(46) Liang, X. A.; Niu, L.; Wang, S.; Liu, J.; Lei, A. Org. Lett. 2019, 21, 2441−2444.
(47) Lan, X.-W.; Wang, N.-X.; Bai, C.-B.; Zhang, W.; Xing, Y.; Wen, J.-L.; Wang, Y.-J.; Li, Y.-H. Sci. Rep. 2015, 5, 18391.
(48) Yavari, I.; Shaabanzadeh, S. Org. Lett. 2020, 22, 464−467.
(49) Rao, W.-H.; Zhan, B.-B.; Chen, K.; Ling, P.-X.; Zhang, Z.-Z.; Shi, B.-F. Org. Lett. 2015, 17, 3552−3555.
(50) Zhang, G.; Zhang, L.; Yi, H.; Luo, Y.; Qi, X.; Tung, C.-H.; Wu, L.-Z.; Lei, A. Chem. Commun. 2016, 52, 10407−10410.
(51) Gong, X.; Chen, J.; Lai, L.; Cheng, J.; Sun, J.; Wu, J. Chem. Commun. 2018, 54, 11172−11175.
(52) Chang, M. Y.; Chen, H. Y.; Wang, H. S. J. Org. Chem. 2017, 82, 10601−10610.
(53) Yang, W. C.; Dai, P.; Luo, K.; Wu, L. Adv. Synth. Catal. 2016,358, 3184−3190.
(54) Pratap, K.; Kumar, A. Org. Lett. 2018, 20 (23), 7451−7454.
(55) Maurya, S.; Yadav, D.; Pratap, K.; Kumar, A. Green Chem. 2017,19, 629−633.
(56) Swarnkar, S.; Ansari, M. Y.; Kumar, A. Eur. J. Org. Chem. 2020,30, 4787−4791.
(57) Gómez, J. E.; Cristof̀ol, À.; Kleij, A. W. Angew. Chem., Int. Ed.2019, 58, 3903−3907.
(58) Liu, Y.; Xie, P.; Sun, Z.; Wo, X.; Gao, C.; Fu, W.; Loh, T.-P.Org. Lett. 2018, 20, 5353−5356.
(59) Cai, A.; Kleij, A. W. Angew. Chem., Int. Ed. 2019, 58, 14944− 14949.
(60) Salman, M.; Xu, Y.; Khan, S.; Zhang, J.; Khan, A. Chem. Sci.2020, 11, 5481−5486.
(61) Khan, A.; Zhao, H.; Zhang, M.; Khan, S.; Zhao, D. Angew. Chem., Int. Ed. 2020, 59, 1340−1345.
(62) Li, Y.; Chen, S.; Wang, M.; Jiang, X. Angew. Chem., Int. Ed.2020, 59, 8907−8911.
(63) Zhou, F.; Liu, Y. L.; Zhou, J. Adv. Synth. Catal. 2010, 352, 1381−1407.
(64) Cao, L.; Luo, S.-H.; Jiang, K.; Hao, Z.-F.; Wang, B.-W.; Pang, C.-M.; Wang, Z.-Y. Org. Lett. 2018, 20, 4754−4758.
(65) Kumar Reddy, N. N.; Rawat, D.; Adimurthy, S. J. Org. Chem.2018, 83, 9412−9421.
(66) Yadav, J. S.; Reddy, B. V. S.; Jain, R.; Reddy, U. V. S. J. Mol. Catal. A: Chem. 2007, 278, 38−41.
(67) Azizian, J.; Karimi, A. R.; Kazemizadeh, Z.; Mohammadi, A. A.; Mohammadizadeh, M. R. J. Org. Chem. 2005, 70, 1471−1473.
(68) Xie, L.-Y.; Fang, T.-G.; Tan, J.-X.; Zhang, B.; Cao, Z.; Yang, L.- H.; He, W.-M. Green Chem. 2019, 21, 3858−3863.
(69) Huang, H.-Y.; Wu, H.-R.; Wei, F.; Wang, D.; Liu, L. Org. Lett. 2015, 17, 3702−3705.
(70) Tsuji, T.; Tanaka, T.; Tanaka, T.; Yazaki, R.; Ohshima, T. Org. Lett. 2020, 22, 4164−4170.
(71) Tanaka, T.; Tanaka, T.; Tsuji, T.; Yazaki, R.; Ohshima, T. Org. Lett. 2018, 20, 3541−3544.