Diastereoselective Spirocyclization of Cyclic N-Sulfonyl Ketimines with

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Diastereoselective Spirocyclization of Cyclic N-Sulfonyl Ketimines with Nitroalkenes via Iridium-Catalyzed Redox-Neutral Cascade Reaction Aniket Mishra, Upasana Mukherjee, Writhabrata Sarkar, Sudha Lahari Meduri, Arup Bhowmik, and Indubhusan Deb* Organic and Medicinal Chemistry Division, CSIR-Indian Institute of Chemical Biology, 4-Raja S. C. Mullick Road, Jadavpur, Kolkata 700032, India Org. Lett. Downloaded from pubs.acs.org by MIDWESTERN UNIV on 02/21/19. For personal use only.

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ABSTRACT: An Ir(III)-catalyzed [3 + 2] annulation of weakly coordinating N-sulfonyl ketimines with challenging α, βunsaturated nitro olefins has been achieved via redox-neutral C−H functionalization in the presence of a catalytic amount of silver hexafluoroantimonate. The generation of three consecutive stereogenic centers in a single step via direct C−H functionalization is the prime feature of this methodology. A wide array of pharmaceutically relevant nitro-substituted spirocyclic benzosultams was synthesized with good to excellent diastereoselectivity as well as in high yield starting from easily accessible substrates.

N

itro olefins are versatile synthons employed in synthetic organic chemistry as Michael acceptors as well as dienophiles in Diels−Alder reactions, and the nitro group can be easily transformed into various useful functional groups;1 however, nitro olefins have hardly been explored in the field of transition-metal-catalyzed C−H functionalizations presumably due to the strong affinity of them toward transition metals leading to catalyst deactivation. A major breakthrough was achieved by Ellman’s group very recently when they reported the first rhodium-catalyzed addition of inert C−H bond to α,βunsaturated nitroalkenes via amide assistance.2a Since then, few reports have emerged limited to rhodium catalysis only.2b,c Therefore, there is ample scope for further exploration of nitroalkenes in transition-metal-catalyzed C−H functionalization processes. On the other hand, the directing-group-assisted C−H functionalization followed by annulation has recently emerged as a robust tool for the generation of molecular complexity.3 In this context, [3 + 2] annulations have attracted the interest of organic chemists; however, only alkynes, allenes, acrylates, and maleimides are among the extensively used partners.4 Various imine derivatives have served as ideal substrates for this type of transformation. Cyclic benzosultams are among medicinally privileged heterocycles5 and spirocyclic benzosultams have been identified as potent antidiabatic5a and anticancer5b agents (Figure 1). Cyclic N-sulfonyl ketimines6 could be a good choice as substrates for synthesizing them via C−H functionalization followed by annulation. However, the presence of the sulfonyl group makes the nitrogen weakly coordinating. As a result, these © XXXX American Chemical Society

Figure 1. Representative bioactive benzosultams.

substrates have been less studied in such annulation reactions, and generation of more than one stereogenic center employing cyclic N-sulfonyl ketimines is particularly rare. In 2013, Nishimura reported Ir(I)-catalyzed [3 + 2] annulations between cyclic N-sulfonyl ketimines and 1,3-dienes via direct C−H functionalization for the first time.7a Since then, a few groups have reported annulation reactions employing alkynes, heterocycles, aryl halides, isocyanates, and CF3-substituted enones under Rh(III), Co(III), and Pd(II) catalysis.7 Recently, we have developed a mild and efficient Ir(III)-catalyzed C−H amidation of N-sulfonyl ketimines.6g In continuation of our interest in transition-metal-catalyzed C−H functionalization reactions,8 herein we wish to report an Ir(III)-catalyzed diastereoselective spiroannulation of N-sulfonyl ketimines and α,β-unsaturated nitro olefins under a redox-neutral process. We initiated the study by taking the representative substrate 3-phenylbenzo[d]isothiazole 1,1-dioxide (1a, 0.1 mmol) with (E)-(2-nitrovinyl)benzene as the α,β-unsaturated nitroalkene Received: January 23, 2019

A

DOI: 10.1021/acs.orglett.9b00295 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

catalyst gave 2a in 86% isolated yield albeit with less diastereoselectivity (Table 1, entry 12), but [Ru(p-cymene)Cl2]2 proved to be less effective (Table 1, entry 13) and [Cp*Co(CO)I2] completely failed to catalyze the reaction (Table 1, entry 14). Decreasing the loading of the catalyst showed almost similar results (Table 1, entry 15); thus, the combination of 5 mol % of [Cp*IrCl2]2 and 20 mol % of AgSbF6 proved to be the best choice in general (Table S1). Having established the optimized conditions, we set out to explore the scope of the reaction for cyclic N-sulfonyl ketimines with a wide array of substituted nitroalkenes (Scheme 1). At the

partner (1.1 equiv) in the presence of [Cp*IrCl2]2 (5 mol %) as catalyst and AgSbF6 (20 mol %) as halide abstractor in TFE at 80 °C (Table 1, entry 1). To our delight, the desired product 2′Table 1. Optimization of Reaction Conditionsa

entry

deviation from the standard condition

yieldb (%) of 2a (dr)c

1 2 3 4 5 6 7 8 9 10 11 12 13 14d 15

none no [Cp*IrCl2]2 no AgSbF6 AgOTf instead of AgSbF6 AgNTf2 instead of AgSbF6 AgBF4 instead of AgSbF6 DCE instead of TFE HFIP instead of TFE chlorobenzene instead of TFE 1,4-dioxane, MeCN, or toluene instead of TFE 40 °C instead of 80 °C [Cp*RhCl2]2 instead of [Cp*IrCl2]2 [Ru(p-cymene)Cl2]2 instead of [Cp*IrCl2]2 [Cp*Co(CO)I2] instead of [Cp*IrCl2]2 3 mol % of [Cp*IrCl2]2 and 12 mol % of AgSbF6

89 (25:1) nr nr 87 (20:1) 87 (25:1) 87 (20:1) 74 (8:1) 84 (25:1) 31 (4:1) nr 72 (8:1) 86 (8:1) 74 (4:1) nr 89 (14:1)

Scheme 1. Scope of N-Sulfonyl Ketimines 1a

a

Reaction conditions: unless otherwise mentioned all reactions were performed with a mixture of 1a (0.1 mmol), nitroalkene (1.1 equiv), [Cp*IrCl2]2 (5 mol %), and AgSbF6 (20 mol %) in TFE (0.1 M) at 80 °C under N2 for 24 h. bIsolated yield. cdr was calculated by 1H NMR. d10 mol % of catalyst was used. nr: no reaction.

nitro-3′-phenyl-2′,3′-dihydro-2H-spiro[benzo[d]isothiazole3,1′-indene] 1,1-dioxide (2a) was obtained in 89% isolated yield as an inseparable mixture of two diastereomers (dr 25:1). Recrystallization of the diastereomeric mixture from hot ethanol gave the major diastereomer 2a exclusively whose relative stereochemistry was determined using single-crystal X-ray structure analysis (Figure 2). Control experiments performed

a

Reaction conditions: unless otherwise mentioned all reactions were performed with a mixture of 1a (0.2 mmol), nitroalkene (1.1 equiv), [Cp*IrCl2]2 (5 mol %), and AgSbF6 (20 mol %) in TFE (0.1 M) at 80 °C under N2 for 24 h. bIsolated yield. cdr is given within the parentheses calculated by 1H NMR.

0.2 mmol scale, the parent product 2a was isolated in similar yield albeit with relatively lower diastereoselectivity. In general, when the representative substrate 1a was subjected to reaction with various nitro olefins, electron-withdrawing groups on the nitroalkenes proved to be more effective than electron-donating ones (2a−n). Fluoro, chloro, bromo, and methoxy substitution at the ortho position of the aryl group gave the desired products in almost quantitative yield with good to excellent diastereoselectivity (2b−e). In addition, a dihalo-substituted nitro olefin provided the desired product 2f in quantitative yield with high diastereoselectivity. Electron-withdrawing groups like chloro and bromo at the meta position were well tolerated and could be converted into the desired products 2g and 2h in excellent yields and with good diastereoselectivity. However, electron-donating groups like methyl and methoxy at this position showed slightly less conversion (2i,j). Similarly, electron-withdrawing groups like fluoro, chloro and trifluoromethyl and electron-donating groups like methyl at the para position furnished the cyclized products 2k−n in excellent yield, whereas moderate conversion was observed for methoxy (2o). Pleasingly, when aliphatic α,β-unsaturated nitro olefins were

Figure 2. Single-crystal X-ray structure of 2a and 2r′ (ellipsoid contour at 50% probability level).

under the optimized conditions revealed that both [Cp*IrCl2]2 and AgSbF6 are essential for the reaction (Table 1, entries 2 and 3). Various silver additives were tested (Table 1, entries 4−6), and all gave similar results. To increase the efficiency of the reaction, various solvents were screened (Table 1, entries 7− 10). This showed that HFIP has reactivity similar to that of TFE but DCE and chlorobenzene were inferior and 1,4-dioxane, toluene, or acetonitrile were completely ineffective. Decreasing the temperature of the reaction diminished the yield of 2a (Table 1, entry 11). Use of [Cp*RhCl2]2 as the B

DOI: 10.1021/acs.orglett.9b00295 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

To illustrate the practicality of the method, a scale up experiment was conducted with 4.1 mmol of 1a and (E)-(2nitrovinyl)benzene, and the product 2a was obtained in 80% yield (SI). To determine a possible reaction mechanism, various preliminary mechanistic experiments were conducted (Scheme 3 and SI). Rapid ortho H−D exchange of 1a in the presence of an

used under the standard conditions, the desired products 2p, 2q, and 2r + 2r′ were obtained in 49%, 62%, and 41% yields, respectively. The minor diastereomer 2r′ was isolated successfully, and the relative stereochemistry was determined using single-crystal X-ray diffraction (Figure 2). However, the reaction remained unsuccessful in case of more substituted nitroalkenes or with furan in place of phenyl as depicted in Scheme 1. Next, we subjected various substituted cyclic N-sulfonyl ketimines for cyclization (Scheme 2). It was observed that when

Scheme 3. Mechanistic Experiments

Scheme 2. Scope of N-Sulfonyl Ketimines 1a

excess amount of CD3OD clearly suggested that a reversible cleavage of C−H bond may be involved in the reaction (Scheme 3a). Kinetic isotope effect (KIE) values of 2.0 and 2.3 were found in both parallel and competitive experiments between 1a and 1a-d5, implying that the cleavage of the C−H bond may be involved in the rate−limiting step of the reaction (Scheme 3b,c). The electronic effect on substituted nitroalkenes was minimal (Scheme 3d). Based on our findings and previous reports,2,7 we consider that a monomeric and more reactive cationic complex A may form in situ from [Cp*IrCl2]2 in the presence of AgSbF6, followed by a reversible C−H activation of 1a via concerted metalation deprotonation resulting in the formation of iridacycle B (Scheme 4). Next, the α, β-unsaturated nitroalkene may undergo coordination followed by insertion, producing an intermediate like C. Finally proto-demetalation may regenerate the active catalyst A along with the formation of the desired product 2a. The secondary interaction of nitro and sulfonyl groups with either Ir(III) or Ag+ in the 1,2-addition step (from C to D) is likely to account for the high degree of diastereoselectivity. In conclusion, we have achieved an iridium(III)-catalyzed diastereoselective redox-neutral cascade annulation reaction between weakly coordinating N-sulfonyl ketimines and challenging α, β-unsaturated nitroalkenes in the presence of a catalytic amount of AgSbF6. The methodology provides an easy access to a broad spectrum of nitro-functionalized valuable spirocyclic benzosultams which may find potential applications in the field of medicinal chemistry. The development of asymmetric version of the same reaction is underway in our laboratory.

a

Reaction conditions: unless otherwise mentioned, all reactions were performed with a mixture of 1a (0.2 mmol), nitroalkene (1.1 equiv), [Cp*IrCl2]2 (5 mol %), and AgSbF6 (20 mol %) in TFE (0.1 M) at 80 °C under N2 for 24 h. bIsolated yield. cdr is given within the parentheses calculated by 1H NMR.

parent (E)-(2-nitrovinyl)benzene was used as nitro olefin partner methyl- and chloro-substituted products 2s and 2t were obtained with moderate selectivity in 85% and 45% yields, respectively. While exploring the scope of the reaction with electron-withdrawing Cl-substituted nitro olefin, it was found that the yield, as well as selectivity, improved. It was found that substrates bearing electron-donating groups like methyl and tert-butyl at the para position of the aryl ring were well tolerated and furnished the desired products 2u and 2v in good yield with excellent diastereoselectivity. However, a methoxy group at this position showed moderate conversion (2w). Products 2x−z carrying electron-withdrawing groups like chloro, fluoro, and trifluoromethyl were obtained in good to excellent yields. Methyl and methoxy groups at the ortho position showed moderate conversion to the products 2aa and 2ab, most probably due to steric factors, though with excellent diastereoselectivity. The naphthyl-substituted substrate provided the desired product 2ac in 93% yield along with good selectivity. A methyl group at the less sterically hindered meta position gave the desired product 2ad exclusively in quantitative yield. However, the fluoro-substituted substrate gave rise to both of the regioisomers 2ae and 2ae′ in an almost 1:1 ratio. C

DOI: 10.1021/acs.orglett.9b00295 Org. Lett. XXXX, XXX, XXX−XXX

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(2) (a) Potter, T. J.; Kamber, D. N.; Mercado, B. Q.; Ellman, J. A. ACS Catal. 2017, 7, 150. (b) Bai, D.; Jia, Q.; Xu, T.; Zhang, Q.; Wu, F.; Ma, C.; Liu, B.; Chang, J.; Li, X. J. Org. Chem. 2017, 82, 9877. (c) Potter, T. J.; Li, Y.; Ward, M. D.; Ellman, J. A. Eur. J. Org. Chem. 2018, 2018, 4381. (3) For recent reviews, see: (a) Gulías, M.; Mascareňas, J. L. Angew. Chem., Int. Ed. 2016, 55, 11000. (b) Hummel, J. R.; Boerth, J. A.; Ellman, J. A. Chem. Rev. 2017, 117, 9163. (4) For representative examples, see: (a) Kuninobu, Y.; Kawata, A.; Takai, K. J. Am. Chem. Soc. 2005, 127, 13498. (b) Kuninobu, Y.; Nishina, Y.; Shouho, M.; Takai, K. Angew. Chem., Int. Ed. 2006, 45, 2766. (c) Kuninobu, Y.; Yu, P.; Takai, K. Org. Lett. 2010, 12, 4274. (d) Tran, D. N.; Cramer, N. Angew. Chem., Int. Ed. 2010, 49, 8181. (e) Nishimura, T.; Nagamoto, M.; Ebe, Y.; Hayashi, T. Chem. Sci. 2013, 4, 4499. (f) Zhang, J.; Ugrinov, A.; Zhao, P. Angew. Chem., Int. Ed. 2013, 52, 6681. (g) Qi, Z.; Wang, M.; Li, X. Org. Lett. 2013, 15, 5440. (h) Huang, J.-R.; Qin, L.; Zhu, Y.-Q.; Song, Q.; Dong, L. Chem. Commun. 2015, 51, 2844. (i) Liu, W.; Zell, D.; John, M.; Ackermann, L. Angew. Chem., Int. Ed. 2015, 54, 4092. (j) Sharma, S.; Oh, Y.; Mishra, N. K.; De, U.; Jo, H.; Sachan, R.; Kim, H. S.; Jung, Y. H.; Kim, I. S. J. Org. Chem. 2017, 82, 3359. (k) Zhu, C.; Luan, J.; Fang, J.; Zhao, X.; Wu, X.; Li, Y.; Luo, Y. Org. Lett. 2018, 20, 5960. (5) For representative examples of bioactive benzosultams, see: (a) Wrobel, J.; Dietrich, A.; Woolson, S. A.; Millen, A.; McCaleb, M.; Harrison, M. C.; Hohman, T. C.; Sredy, J.; Sullivan, D. J. Med. Chem. 1992, 35, 4613. (b) Pineiro, J. L. C.; Collins, I. J.; Harrison, T. Patent US 20050143369 A1, June 30, 2005. (c) Tumey, L. N.; Robarge, M. J.; Gleason, E.; Song, J.; Murphy, S. M.; Ekema, G.; Doucette, C.; Hanniford, D.; Palmer, M.; Pawlowski, G.; Danzig, J.; Loftus, M.; Hunady, K.; Sherf, B.; Mays, R. W.; Stricker-Krongrad, A.; Brunden, K. R.; Bennani, Y. L.; Harrington, J. J. Bioorg. Med. Chem. Lett. 2010, 20, 3287. (d) Azevedo, C. M. G.; Watterson, K. R.; Wargent, E. T.; Hansen, S. V. F.; Hudson, B. D.; Kępczyńska, M. A.; Dunlop, J.; Shimpukade, B.; Christiansen, E.; Milligan, G.; Stocker, C. J.; Ulven, T. J. Med. Chem. 2016, 59, 8868. (6) For examples of cyclic N-sulfonyl ketimines as DG, see: (a) Wang, N.-J.; Mei, S.-T.; Shuai, L.; Yuan, Y.; Wei, Y. Org. Lett. 2014, 16, 3040. (b) Zhang, Q.-R.; Huang, J.-R.; Zhang, W.; Dong, L. Org. Lett. 2014, 16, 1684. (c) Mei, S.-T.; Wang, N.-J.; Ouyang, Q.; Wei, Y. Chem. Commun. 2015, 51, 2980. (d) Mei, S.-T.; Jiang, K.; Wang, N.-J.; Shuai, L.; Yuan, Y.; Wei, Y. Eur. J. Org. Chem. 2015, 2015, 6135. (e) Manoharan, M.; Jeganmohan, M. Eur. J. Org. Chem. 2016, 2016, 4013. (f) Maraswami, M.; Chen, G.; Loh, T.-P. Adv. Synth. Catal. 2018, 360, 416. (g) Mishra, A.; Mukherjee, U.; Vats, T. K.; Deb, I. J. Org. Chem. 2018, 83, 3756. (7) (a) Nishimura, T.; Ebe, Y.; Hayashi, T. J. Am. Chem. Soc. 2013, 135, 2092. (b) Dong, L.; Qu, C.-H.; Huang, J.-R.; Zhang, W.; Zhang, Q.-R.; Deng, J.-G. Chem. - Eur. J. 2013, 19, 16537. (c) Pham, M. V.; Cramer, N. Chem. - Eur. J. 2016, 22, 2270. (d) Mei, S.-T.; Jiang, K.; Wang, N.-J.; Shuai, L.; Yuan, Y.; Wei, Y. Org. Lett. 2016, 18, 1088. (e) Liu, H.; Li, J.; Xiong, M.; Jiang, J.; Wang, J. J. Org. Chem. 2016, 81, 6093. (f) Reddy, K. N.; Rao, M. V. K.; Sridhar, B.; Reddy, B. V. S. Eur. J. Org. Chem. 2017, 2017, 4085. (g) Liu, B.; Hu, P.; Zhang, Y.; Li, Y.; Bai, D.; Li, X. Org. Lett. 2017, 19, 5402. (h) Reddy, K. N.; Subhadra, U.; Sridhar, B.; Reddy, B. V. S. Org. Biomol. Chem. 2018, 16, 2522. (8) (a) Mishra, A.; Deb, I. Adv. Synth. Catal. 2016, 358, 2267. (b) Mishra, A.; Vats, T. K.; Deb, I. J. Org. Chem. 2016, 81, 6525. (c) Mishra, A.; Vats, T. K.; Nair, M. P.; Das, A.; Deb, I. J. Org. Chem. 2017, 82, 12406. (d) Vats, T. K.; Mishra, A.; Deb, I. Adv. Synth. Catal. 2018, 360, 2291. (e) Sarkar, W.; Bhowmik, A.; Mishra, A.; Vats, T. K.; Deb, I. Adv. Synth. Catal. 2018, 360, 3228.

Scheme 4. Plausible Mechanism

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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.9b00295. Experimental procedure, characterization data, mechanistic studies, 1H and 13C NMR spectra (PDF) Accession Codes

CCDC 1890322 and 1890324−1890327 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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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected], indubhusandeb@gmail. com. ORCID

Aniket Mishra: 0000-0003-3961-159X Indubhusan Deb: 0000-0002-9007-1042 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS A.M. and W.S. thank CSIR and U.M. and A.B. thank UGC for their fellowships, and I.D. thanks CSIR-IICB and Bristol-Myers Squibb (U.S.A.) for research funds. We thank Mr. Sandip Kundu (CSIR-IICB) for recording X-ray.

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REFERENCES

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DOI: 10.1021/acs.orglett.9b00295 Org. Lett. XXXX, XXX, XXX−XXX