Yilin Liu*ab,
Jiaxue Liua,
Yan-Yun Liu*a,
Boxiao Tanga,
Hongwei Lina,
Yuanxiang Lia and
Lin Zhanga
aHunan Engineering Laboratory for Preparation Technology of Polyvinyl Alcohol (PVA) Fiber Material, Institute of Organic Synthesis, Huaihua University, Huaihua 418000, China. E-mail: liuyilinhn@126.com; liuyanyun314@sina.com
bCAS Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China
First published on 13th September 2021
A [3 + 2] cycloaddition of indanone-derived nitrones and alkynes under mild conditions is developed, allowing facile synthesis of spirocyclicindenyl isoxazolines with structural diversity. The sequential protocol of generated in situ ketonitrone from unsaturated ketones and N-alkylhydroxylamines is also achieved successfully, affording the desired products in considerable yield with moderate to good diastereoselectivity. Moreover, the spirocyclic product can be conveniently transformed into indenyl-based allylic alcohol and enamide.
Spiroisoxazolines have been received intensive attention because the incorporation of a rigid spiro-ring can reduce the conformational entropy penalty upon binding with a protein target in modern drug discovery.9 However, the application of cycloaddition reaction of nitrone to construct spiroisoxazolines is largely undeveloped, because methods for the synthesis of cyclic ketonitrone are still not rich and mostly limited to specific substrates scope such as cyclic ketone derived nitrones,10 isatin ketonitrones,11 sugar ketonitrones,12 fluorenone nitrones.13 Therefore, only a few examples using these compounds as substrates to synthesize spirocyclic compounds have been reported. Oxyallyl cations,14 cyclopropanes,11f aza-oxyallyl cations,15 olefins11a,b,d,12,16 gave the expected cycloadducts in high yields, while reactions with acetylenes seldom gave the corresponding spiroisoxazolines. Instead, non spiro products arising from transformations of the initially formed spiroisoxazoline are produced in these cases.13c,17 For example, in 2012, Anderson and co-workers reported that the reaction of alkynes with N-vinyl fluorenone nitrones provides the fluorene-tethered isoxazoles at high temperature via a cyclization and elimination process.13c In contrast, Prathapan and co-workers discovered that the cycloadduct resulting from the reaction of N-phenyl fluorenone nitrones and electron deficient acetylenes was formed predominantly initially and then could undergo rearrangement easily to give 3(2H)-furanone at room temperature.17b Therefore, the continuous development of novel cyclic ketonitrones for the discovery of spirocyclic drug candidates is highly desirable.
Recently, we developed a carbonyl-directed addition of N-alkylhydroxylamines to unactivated alkynes with high stereoselectivity. This strategy enables the facile synthesis of indanone-derived nitrones, which was subjected successfully to [3 + 2] cycloadditions with diethyl acetylenedicarboxylate (DEAD) in dichloromethane (DCM) to give spiro-isoxazoline in 90% yield (Scheme 1c).20 This privilege skeleton prompted us to further expand the substrate scope. Herein, we wish to report our efforts on the [3 + 2] cycloaddition of indanone ketonitrones with alkynes under mild conditions (Scheme 1d).
a All reactions were carried out with 3 (0.20 mmol), 4a (1.5 equiv.), and DCM (3.0 mL), 17–21 h unless otherwise stated; isolated yield based on 3; the dr ratio is given in brackets and determined by 1H NMR analysis (see ESI for details). |
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Next, to further probe the generality of this cycloaddition reaction, a variety of alkynes 4b–j were treated with indanone-derived nitrone 3da. The results are shown in Table 2 (5dab–daj). Although dimethyl acetylenedicarboxylate, ethyl propionate, and 3-butyn-2-one gave the corresponding spiroindenyl isoxazoline in high yields in dichloromethane, the reaction of tert-butyl propionate, methyl phenylpropiolate, ethyl phenylpropiolate, 4-phenyl-3-butyn-2-one, and ethyl 2-butynoate needed to be carried out in chloroform at higher temperature to obtain satisfactory yields (5dab, 5dac, 5dae vs. 5dad, 5daf–dah, 5daj). To our delight, cycloaddition reaction of nitrone 3da with diphenylethyne also went smoothly to give diphenyl-4-isoxazoline (5dai), which may be a potential inhibitor of cyclooxygenase-2 with analgesic and antiinflammatory activity according to the study reported by Knaus.1a It was found that electron deficient olefin was also a good partner in cycloaddition reaction with indanone-derived nitrone, as N-methylmaleimide could afford the spiroindenyl isoxazolidine in moderate yield (5dak).
DCM was used as the solvent in both the preparation of indanone-derived nitrone and the cycloaddition reaction of nitrone with electron deficient alkyne, therefore, we envisioned that cycloaddition of nitrones generated in situ from unsaturated ketone 1, and N-alkylhydroxylamine 2, with alkyne 4 for synthesis of spiroindenyl isoxazoline was possible. Indeed, the cycloaddition of nitrones generated in situ went smoothly to afford the spiroindenyl isoxazoline in good yield, and the results are summarized in Table 3. Of note is that 5dca can be afforded successfully in a yield of 45%. Surprisingly, this cycloaddition gave higher dr value than cycloaddition of pre-prepared nitrone in Table 1. The mechanism is still not clear currently, according to the previous literature17–19 and experimental results, the reaction process may be determined by the attack of nucleophilic oxygen anion in nitrone moiety on the carbon–carbon triple bond in alkynes,19 and the reason is probably that this cycloaddition, at least in part, follows a two-step mechanism, while cycloaddition of pre-prepared nitrone in Table 1 proceeds in a concerted manner.
a All reactions were carried out with 1 (0.50 mmol), 2 (0.50 mmol), EtONa (1.3 equiv.), and DCM (5.0 mL), 12–24 h for step one, then 4 (1.5 equiv.) was added, 17–21 h for step two unless otherwise stated; isolated yield based on 1; the dr ratio is given in brackets and determined by 1H NMR analysis (see ESI for details).b The reactions were carried out with 4 mmol scale of 1d. |
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With the novel spiroisoxazolines in hand, subsequently, transformations of isoxazoline were investigated (Scheme 2). 4-Isoxazoline 5daa underwent reductive cleavage of the N–O bond successfully in the present of zinc powder and NH4Cl at 75 °C, affording allylic alcohol 6 in a yield of 75%.8,21 Besides, it was found that Co2(CO)8 catalyzed rearrangement of 4-isoxazoline 5raa could occur in MeCN, giving enamide 7 in 52% yield, instead of ring contraction product acylaziridines.22 While the mechanism for Co2(CO)8 catalyzed rearrangement is not clear at present, further examination of the rearrangement reaction conditions and mechanism will be carried out in due course.
Diethyl 2′-benzyl-3-(2-oxo-2-phenylethyl)-2-phenyl-2,3-dihydro-2′H-spiro[indene-1,3′-isoxazole]-4′,5′-dicarboxylate (5aaa), 1.8:1 dr. Purified by silica gel column chromatography (10:1 petroleum ether/ethyl acetate): 119.1 mg, 99% yield; light yellow solid, mp 120–122 °C, IR (film) 1739, 1709, 1474, 1303, 1231, 1188 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.93 (d, J = 10.0 Hz, 0.7H), 7.79 (d, J = 10.0 Hz, 1.3H), 7.67 (t, J = 5.0 Hz, 1.3H), 7.57–7.33 (m, 5.7H), 7.32–7.11 (m, 10H), 4.50 (t, J = 10.0 Hz, 0.3H), 4.25–4.07 (m, 5.3H), 4.02 (d, J = 15.0 Hz, 0.7H), 3.87 (dd, J = 15.0, 5.0 Hz, 0.7H), 3.57–3.43 (m, 2.3H), 3.36 (dd, J = 20.0, 10.0 Hz, 0.4H), 3.22 (dd, J = 15.0, 5.0 Hz, 0.3H), 1.29–1.20 (m, 4.1H), 1.13 (d, J = 10.0 Hz, 1.9H); 13C NMR (125 MHz, CDCl3) δ 199.5, 199.1, 162.7, 162.4, 159.2, 155.4, 154.8, 148.0, 147.0, 139.8, 137.8, 137.5, 137.4, 137.4, 137.2, 137.0, 135.5, 133.6, 133.4, 133.1, 131.6, 130.5, 130.0, 129.7, 129.1, 129.0, 128.8, 128.7, 128.6, 128.6, 128.4, 128.3, 128.2, 128.1, 128.0, 127.6, 127.6, 127.4, 127.2, 127.2, 127.1, 126.6, 126.3, 126.0, 124.7, 113.1, 108.7, 100.2, 85.3, 84.0, 62.6, 62.6, 61.4, 60.9, 60.8, 60.6, 60.2, 58.4, 43.9, 42.6, 42.3, 40.4, 14.2,14.1, 14.0, 14.0; HRMS(ESI) calcd for C38H36NO6 [M + H]+ 602.2537, found 602.2543.
Diethyl 2′-benzyl-3-(2-oxo-2-(o-tolyl)ethyl)-2-phenyl-2,3-dihydro-2′H-spiro[indene-1,3′-isoxazole]-4′,5′-dicarboxylate (5baa), 1.1:1 dr. Purified by silica gel column chromatography (20:1 petroleum ether/ethyl acetate): 93.6 mg, 76% yield; light yellow solid, mp 87–89 °C, IR (film) 1747, 1712, 1456, 1371, 1299, 1187 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.64–7.62 (m, 1H), 7.58 (d, J = 8.0 Hz, 0.5H), 7.45–7.43 (m, 2H), 7.39–7.36 (m, 1.5H), 7.34–7.26 (m, 4H), 7.25–7.10 (m, 9H), 4.49–4.43 (m, 0.6H), 4.21–4.12 (m, 4.8H), 4.00 (d, J = 12.0 Hz, 0.5H), 3.86 (d, J = 16.0 Hz, 0.5H), 3.82 (d, J = 12.0 Hz, 0.5H), 3.52 (d, J = 12.0 Hz, 0.5H), 3.50–3.42 (m, 1.3H), 3.32–3.25 (m, 0.6H), 3.16 (dd, J = 16.0, 4.0 Hz, 0.5H), 2.48 (s, 1.6H), 2.36 (s, 1.4H), 1.29–1.18 (m, 4.6H), 1.13 (d, J = 8.0 Hz, 1.4H); 13C NMR (100 MHz, CDCl3) δ 203.3, 202.8, 162.7, 162.4, 159.3, 159.2, 155.5, 154.8, 148.2, 147.0, 138.7, 138.4, 138.3, 137.8, 137.6, 137.5, 137.3, 137.2, 137.0, 135.5, 132.3, 132.1, 131.7, 131.7, 131.4, 130.5, 130.0, 129.7, 129.1, 129.0, 128.7, 128.6, 128.5, 128.3, 128.2, 128.0, 127.6, 127.4, 127.2, 127.2, 127.1, 126.5, 126.4, 126.1, 125.9, 125.7, 124.5, 108.7, 127.2, 85.3, 84.1, 62.6, 61.5, 60.9, 60.8, 60.6, 60.2, 58.4, 45.6, 45.0, 43.9, 40.7, 29.9, 21.7, 21.4, 14.2, 14.1, 14.0, 14.0; HRMS(ESI) calcd for C39H38NO6 [M + H]+ 616.2694, found 616.2690.
Diethyl 2′-benzyl-3-(2-oxo-2-(m-tolyl)ethyl)-2-phenyl-2,3-dihydro-2′H-spiro[indene-1,3′-isoxazole]-4′,5′-dicarboxylate (5caa), 1.8:1 dr. Purified by silica gel column chromatography (20:1 petroleum ether/ethyl acetate): 117.0 mg, 95% yield; light yellow oil, IR (film) 1745, 1701, 1496, 1370, 1181, 1108 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.69 (d, J = 10.0 Hz, 2H), 7.59 (s, 0.7H), 7.46–7.40 (m, 2H), 7.36–7.26 (m, 7H), 7.24–7.12 (m, 5H), 6.69 (t, J = 10.0 Hz, 0.5H), 6.79 (d, J = 5.0 Hz, 1H), 4.48 (t, J = 10.0 Hz, 0.6H), 4.26–4.10 (m, 4.5H), 4.02 (d, J = 15.0 Hz, 0.4H), 3.88–3.85 (m, 1.3H), 3.53–3.43 (m, 1.7H), 3.34 (dd, J = 20.0, 10.0 Hz, 0.7H), 3.20 (d, J = 15.0 Hz, 0.6H), 2.38 (s, 1.9H), 2.31 (s, 1.1H), 1.28–1.20 (m, 5H), 1.12 (t, J = 10.0 Hz, 1.3H); 13C NMR (125 MHz, CDCl3) δ 200.0, 199.6, 162.9, 162.4, 159.3, 156.1, 155.6, 154.9, 148.0, 147.0, 138.6, 138.5, 137.5, 137.4, 137.2, 137.1, 137.0, 135.6, 134.2, 133.9, 131.6, 130.5, 130.0, 129.8, 129.7, 128.9, 128.7, 128.6, 128.6, 128.2, 128.2, 128.0, 127.6, 127.5, 127.3, 127.2, 127.2, 127.1, 126.6, 126.3, 126.0, 125.6, 125.4, 124.7, 120.6, 115.5, 107.3, 85.3, 84.0, 62.6, 61.4, 60.9, 60.7, 60.2, 58.4, 44.0, 42.6, 42.3, 40.5, 29.9, 21.5, 14.2, 14.1, 14.0, 14.0; HRMS(ESI) calcd for C39H38NO6 [M + H]+ 616.2694, found 616.2696.
Diethyl 2′-benzyl-3-(2-oxo-2-(p-tolyl)ethyl)-2-phenyl-2,3-dihydro-2′H-spiro[indene-1,3′-isoxazole]-4′,5′-dicarboxylate (5daa), 2.9:1 dr. Purified by silica gel column chromatography (20:1 petroleum ether/ethyl acetate): 118.2 mg, 96% yield; light yellow solid, mp 127–129 °C, IR (film) 1743, 1709, 1474, 1303, 1231, 1181 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.83 (d, J = 10.0 Hz, 1.5H), 7.70–7.66 (m, 1H), 7.47–7.12 (m, 15.5H), 4.50 (t, J = 10.0 Hz, 0.7H), 4.26–4.10 (m, 4.5H), 4.02 (d, J = 15.0 Hz, 0.3H), 3.87 (t, J = 10.0 Hz, 1.5H), 3.57–3.40 (m, 1.4H), 3.33 (dd, J = 20.0, 10.0 Hz, 0.8H), 3.18 (d, J = 20.0 Hz, 0.7H), 2.38 (s, 2.2H), 2.36 (s, 0.8H), 1.28–1.20 (m, 5.2H), 1.12 (t, J = 10.0 Hz, 0.8H); 13C NMR (125 MHz, CDCl3) δ 199.1, 198.8, 162.8, 162.5, 159.2, 155.4, 154.8, 148.0, 147.0, 144.2, 143.8, 137.4, 137.0, 135.6, 135.0, 134.6, 131.6, 130.5, 130.0, 129.6, 129.4, 129.3, 129.0, 128.6, 128.6, 128.5, 128.3, 128.2, 128.2, 128.0, 127.6, 127.5, 127.3, 127.2, 127.1, 127.0, 126.6, 126.3, 125.9, 124.7, 108.8, 107.3, 85.3, 84.0, 62.5, 61.4, 60.8, 60.6, 60.2, 58.4, 43.9, 42.4, 42.1, 40.5, 29.9, 21.8, 14.2, 14.1, 14.0, 14.0; HRMS(ESI) calcd for C39H38NO6 [M + H]+ 616.2694, found 616.2697.
Diethyl 2′-benzyl-3-(2-(4-bromophenyl)-2-oxoethyl)-2-phenyl-2,3-dihydro-2′H-spiro[indene-1,3′-isoxazole]-4′,5′-dicarboxylate (5eaa), 1.4:1 dr. Purified by silica gel column chromatography (20:1 petroleum ether/ethyl acetate): 125.2 mg, 92% yield; white solid, mp 96–98 °C, IR (film) 1735, 1701, 1499, 1373, 1223, 1167 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.77 (d, J = 5.0 Hz, 1H), 7.65–7.60 (m, 2H), 7.56 (d, J = 10.0 Hz, 1H), 7.49–7.38 (m, 4H), 7.33–7.09 (m, 10H), 4.44 (t, J = 10.0 Hz, 0.4H), 4.24–4.10 (m, 5.3H), 4.03 (d, J = 15.0 Hz, 0.6H), 3.86 (q, J = 10.0 Hz, 0.8H), 3.53–3.45 (m, 1.6H), 3.37–3.28 (m, 1H), 3.17 (d, J = 15.0 Hz, 0.4H), 1.28–1.20 (m, 4.3H), 1.13 (t, J = 10.0 Hz, 1.7H); 13C NMR (125 MHz, CDCl3) δ 198.6, 198.1, 162.7, 162.4, 159.2, 159.2, 155.6, 154.8, 147.8, 146.7, 137.9, 137.5, 137.4, 137.1, 136.9, 136.2, 135.7, 135.4, 132.1, 132.0, 131.5, 130.5, 130.0, 129.9, 129.7, 129.7, 128.9, 128.6, 128.6, 128.3, 128.2, 128.0, 127.7, 127.6, 127.4, 127.3, 127.2, 127.2, 126.4, 126.4, 126.1, 124.5, 108.7, 107.2, 85.3, 84.0, 62.6, 62.6, 61.4, 60.9, 60.8, 60.6, 60.2, 58.3, 43.9, 42.4, 42.2, 40.6, 14.2, 14.1, 14.0, 14.0; HRMS(ESI) calcd for C38H35BrNO6 [M + H]+ 680.1642, found 680.1648.
Diethyl 2′-benzyl-3-(2-(furan-2-yl)-2-oxoethyl)-2-phenyl-2,3-dihydro-2′H-spiro[indene-1,3′-isoxazole]-4′,5′-dicarboxylate (5faa), 6.5:1 dr. Purified by silica gel column chromatography (20:1 petroleum ether/ethyl acetate): 99.4 mg, 84% yield; light yellow solid, mp 65–67 °C, IR (film) 1740, 1710, 1467, 1300, 1253, 1189 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.53 (s, 1H), 7.43 (d, J = 10.0 Hz, 2H), 7.38–7.07 (m, 14H), 6.48 (t, J = 5.0 Hz, 1H), 6.42 (s, 0.1H), 4.41 (d, J = 5.0 Hz, 1H), 4.24–4.17 (m, 4H), 3.88–3.82 (m, 2H), 3.46 (d, J = 15.0 Hz, 1H), 3.20 (dd, J = 20.0, 10.0 Hz, 1H), 3.09 (dd, J = 15.0, 5.0 Hz, 1H), 1.28–1.19 (m, 5.7H), 1.12 (t, J = 5.0 Hz, 0.4H); 13C NMR (125 MHz, CDCl3) δ 188.5, 162.7, 159.2, 155.5, 152.8, 146.7, 146.6, 137.4, 136.9, 135.4, 130.4, 130.0, 129.0, 128.6, 128.2, 127.9, 127.5, 127.2, 127.1, 126.0, 124.6, 117.4, 112.4, 107.2, 84.0, 62.6, 61.5, 60.8, 60.2, 41.9, 40.4, 29.9, 14.2, 14.0; HRMS(ESI) calcd for C36H34NO7 [M + H]+ 592.2330, found 592.2333.
Diethyl 2′-benzyl-3-(2-oxopropyl)-2-phenyl-2,3-dihydro-2′H-spiro-[indene-1,3′-is-oxazole]-4′,5′-dicarboxylate (5gaa), 13.0:1 dr. Purified by silica gel column chromatography (30:1 petroleum ether/ethyl acetate): 82.0 mg, 76% yield; Light yellow oil, IR (film) 1712, 1685, 1448, 1370, 1223, 1108 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 4.0 Hz, 2H), 7.45–7.21 (m, 12H), 4.20–4.05 (m, 5H), 4.01–3.84 (m, 2H), 3.52–3.42 (m, 1H), 3.03–2.98 (m, 1H), 2.88–2.81 (m, 1H), 2.75 (d, J = 4.0 Hz, 0.1H), 2.15 (s, 0.2H), 2.02 (s, 2.8H), 1.29–1.19 (m, 3.2H), 1.12 (d, J = 8.0 Hz, 2.8H); 13C NMR (100 MHz, CDCl3) δ 207.7, 162.4, 159.2, 154.7, 147.9, 137.6, 137.2, 137.1, 131.7, 129.7, 129.0, 128.6, 128.1, 127.6, 127.4, 127.2, 126.4, 126.2, 108.7, 85.2, 62.6, 60.9, 60.5, 58.0, 47.4, 43.4, 31.0, 14.1, 13.9. HRMS (ESI) calcd for C33H33NO6Na [M + Na]+ 562.2200, found 562.2199.
Diethyl 2′-benzyl-3-(2-oxo-2-(p-tolyl)ethyl)-2-(m-tolyl)-2,3-dihydro-2′H-spiro[indene-1,3′-isoxazole]-4′,5′-dicarboxylate (5haa), 1.9:1 dr. Purified by silica gel column chromatography (20:1 petroleum ether/ethyl acetate): 112.1 mg, 89% yield; white yellow solid, mp 50–52 °C, IR (film) 1741, 1712, 1496, 1370, 1300, 1241, 1140 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 8.0 Hz, 0.7H), 7.67 (d, J = 8.0 Hz, 1.3H), 7.55 (d, J = 8.0 Hz, 0.7H), 7.45–7.27 (m, 7.6H), 7.24–7.11 (m, 5.9H), 7.06 (d, J = 8.0 Hz, 0.4H), 7.01 (d, J = 8.0 Hz, 0.7H), 4.48 (t, J = 8.0 Hz, 0.3H), 4.26–4.07 (m, 5.1H), 4.02 (d, J = 16.0 Hz, 0.8H), 3.85 (dd, J = 16.0, 8.0 Hz, 0.7H), 3.55–3.45 (m, 1.6H), 3.34 (dd, J = 20.0, 8.0 Hz, 1H), 3.20 (dd, J = 20.0, 4.0 Hz, 0.4H), 2.39 (s, 0.9H), 2.36 (s, 1.9H), 2.32 (s, 1.1H), 2.21 (s, 2H), 1.30–1.19 (m, 4.1H), 1.12 (t, J = 8.0 Hz, 1.9H); 13C NMR (100 MHz, CDCl3) δ 199.3, 198.8, 162.8, 162.4, 159.4, 159.3, 155.6, 154.8, 148.0, 147.0, 144.2, 143.8, 138.0, 137.6, 137.5, 137.4, 137.2, 137.1, 135.5, 135.0, 134.6, 132.6, 131.3, 129.9, 129.6, 129.4, 129.3, 128.8, 128.5, 128.5, 128.3, 128.2, 128.1, 127.9, 127.9, 127.5, 127.2, 127.1, 127.0, 126.4, 126.2, 125.9, 124.8, 108.8, 107.2, 85.2, 83.9, 62.6, 61.1, 60.8, 60.7, 60.6, 60.2, 58.2, 44.0, 42.4, 42.3, 40.4, 29.9, 21.8, 21.8, 21.7, 21.6, 14.2, 14.1, 14.1, 14.0; HRMS (ESI) calcd for C40H39NO6Na [M + Na]+ 652.2670, found 652.2669.
Diethyl 2′-benzyl-3-(2-oxo-2-(p-tolyl)ethyl)-2-(p-tolyl)-2,3-dihydro-2′H-spiro[indene-1,3′-isoxazole]-4′,5′-dicarboxylate (5iaa), 2.2:1 dr. Purified by silica gel column chromatography (20:1 petroleum ether/ethyl acetate): 117.1 mg, 93% yield; light yellow solid, mp 55–57 °C, IR (film) 1739, 1709, 1497, 1371, 1302, 1241, 1140 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 8.0 Hz, 1.5H), 7.69 (d, J = 8.0 Hz, 0.5H), 7.55 (d, J = 8.0 Hz, 0.6H), 7.44–7.39 (m, 0.7H), 7.37–7.32 (m, 3.3H), 7.29–7.09 (m, 10H), 7.05 (d, J = 8.0 Hz, 0.6H), 4.47 (t, J = 8.0 Hz, 0.8H), 4.25–4.07 (m, 4.5H), 4.01 (d, J = 12.0 Hz, 0.3H), 3.84 (dd, J = 20.0, 12.0 Hz, 1.5H), 3.53–3.38 (m, 1.5H), 3.31 (dd, J = 16.0, 8.0 Hz, 0.8H), 3.20 (dd, J = 16.0, 4.0 Hz, 0.8H), 2.39 (s, 2.1H), 2.36 (s, 0.9H), 2.30 (s, 2.1H), 2.27 (s, 0.9H), 1.29–1.19 (m, 5.1H), 1.12 (t, J = 8.0 Hz, 0.9H); 13C NMR (100 MHz, CDCl3) δ 199.3, 198.9, 162.8, 162.4, 159.3, 155.3, 154.7, 148.1, 147.2, 144.2, 143.8, 137.8, 137.5, 137.1, 137.0, 136.7, 135.1, 134.6, 134.1, 132.5, 131.5, 130.4, 129.9, 129.6, 129.4, 129.3, 129.0, 128.9, 128.8, 128.6, 128.6, 128.5, 128.3, 128.3, 127.6, 127.2, 127.1, 127.0, 126.6, 126.3, 126.0, 124.7, 108.9, 107.5, 85.3, 84.0, 62.5, 61.1, 60.8, 60.6, 60.3, 58.1, 44.0, 42.5, 42.1, 40.5, 29.9, 21.8, 21.4, 21.3, 21.2, 14.2, 14.1, 14.0, 14.0; HRMS(ESI) calcd for C40H40NO6 [M + H]+ 630.2850, found 630.2852.
Diethyl 2′-benzyl-2-(4-chlorophenyl)-3-(2-oxo-2-(p-tolyl)ethyl)-2,3-dihydro-2′H-spiro[indene-1,3′-isoxazole]-4′,5′-dicarboxylate (5jaa), 1.6:1 dr. Purified by silica gel column chromatography (20:1 petroleum ether/ethyl acetate): 127.4 mg, 98% yield; light yellow solid, mp 95–97 °C, IR (film) 1741, 1701, 1476, 1353, 1226, 1156 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 8.0 Hz, 0.7H), 7.70 (d, J = 8.0 Hz, 1.2H), 7.60 (d, J = 8.0 Hz, 1.3H), 7.44–7.37 (m, 2.6H), 7.34–7.28 (m, 5H), 7.25–7.11 (m, 6.4H), 4.44 (t, J = 8.0 Hz, 0.4H), 4.25–4.08 (m, 5.2H), 4.01 (d, J = 12.0 Hz, 0.7H), 3.88 (d, J = 16.0 Hz, 0.4H), 3.79 (d, J = 12.0 Hz, 0.4H), 3.52–3.45 (m, 1.5H), 3.42–3.31 (m, 1.2H), 3.13 (dd, J = 16.0, 4.0 Hz, 0.4H), 2.40 (s, 1.2H), 2.38 (s, 1.8H), 1.30–1.20 (m, 4.2H), 1.13 (t, J = 8.0 Hz, 1.8H); 13C NMR (100 MHz, CDCl3) δ 199.0, 198.5, 162.7, 162.3, 159.1, 155.4, 154.8, 147.9, 146.8, 144.3, 144.0, 137.3, 137.2, 137.1, 136.8, 135.7, 134.9, 134.4, 134.1, 133.3, 133.3, 132.9, 131.8, 130.1, 129.8, 129.5, 129.4, 129.0, 128.6, 128.4, 128.3, 128.3, 128.2, 128.1, 127.7, 127.4, 127.3, 127.2, 126.6, 126.3, 126.0, 124.7, 108.5, 107.2, 100.1, 85.2, 84.0, 62.8, 61.0, 60.6, 60.2, 57.6, 43.8, 42.4, 41.9, 40.7, 21.8, 14.2, 14.1, 14.0, 14.0; HRMS (ESI) calcd for C39H36NO6ClNa [M + Na]+ 672.2123, found 672.2128.
Diethyl 2′-benzyl-2-(4-bromophenyl)-3-(2-oxo-2-(p-tolyl)ethyl)-2,3-dihydro-2′H-spiro[indene-1,3′-isoxazole]-4′,5′-dicarboxylate (5kaa), 1.1:1 dr. Purified by silica gel column chromatography (20:1 petroleum ether/ethyl acetate): 126.4 mg, 91% yield; white solid, mp 82–84 °C, IR (film) 1749, 1712, 1488, 1371, 1299, 1180 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.44–7.27 (m, 8H), 7.25–7.10 (m, 6H), 4.43 (t, J = 8.0 Hz, 0.5H), 4.25–4.15 (m, 3H), 4.13–4.07 (m, 1.8H), 4.00 (d, J = 16.0 Hz, 0.5H), 3.88 (d, J = 12.0 Hz, 0.6H), 3.78 (d, J = 12.0 Hz, 0.6H), 3.52–3.30 (m, 2.5H), 3.12 (dd, J = 16.0, 4.0 Hz, 0.6H), 2.40 (s, 1.5H), 2.38 (s, 1.5H), 1.30–1.19 (m, 4.4H), 1.13 (t, J = 8.0 Hz, 1.6H); 13C NMR (100 MHz, CDCl3) δ 199.0, 198.5, 162.7, 162.3, 159.1, 155.4, 154.8, 147.9, 146.8, 144.3, 144.0, 137.2, 137.1, 136.8, 136.2, 135.0, 134.7, 134.5, 133.3, 132.2, 131.3, 131.1, 130.1, 129.8, 129.5, 129.4, 129.0, 128.7, 128.6, 128.5, 128.3, 128.3, 127.7, 127.4, 127.3, 127.2, 126.6, 126.3, 126.0, 124.7, 121.6, 121.6, 108.5, 107.2, 85.3, 84.0, 62.8, 62.7, 61.1, 61.0, 60.6, 60.3, 57.7, 43.8, 42.4, 41.9, 40.7, 29.9, 21.9, 21.8, 14.2, 14.1, 14.0, 14.0; HRMS(ESI) calcd for C39H37O6BrN [M + H] + 694.1799; found: 694.1799.
Diethyl 2′-benzyl-2-(4-methoxyphenyl)-3-(2-oxo-2-(p-tolyl)ethyl)-2,3-dihydro-2′H-spiro[indene-1,3′-isoxazole]-4′,5′-dicarboxylate (5laa), 6.5:1 dr. Purified by silica gel column chromatography (20:1 petroleum ether/ethyl acetate): 127.9 mg, 99% yield; light yellow solid, mp 78–80 °C, IR (film) 1739, 1711, 1491, 1370, 1300, 1107 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 8.0 Hz, 0.2H), 7.71 (d, J = 8.0 Hz, 1.8H), 7.59 (d, J = 8.0 Hz, 2H), 7.44–7.37 (m, 2H), 7.34–7.21 (m, 7H), 7.17 (t, J = 8.0 Hz, 2H), 6.83 (d, J = 8.0 Hz, 0.2H), 6.78 (d, J = 8.0 Hz, 1.8H), 4.22–4.05 (m, 5.9H), 4.01 (d, J = 12.0 Hz, 0.9H), 3.77 (s, 0.4H), 3.75 (s, 2.6H), 3.52–3.38 (m, 2.8H), 2.40 (s, 0.4H), 2.37 (s, 2.6H), 1.30–1.19 (m, 3.4H), 1.13 (t, J = 8.0 Hz, 2.6H); 13C NMR (100 MHz, CDCl3) δ 198.9, 162.4, 159.2, 158.8, 154.6, 148.1, 143.9, 137.7, 137.4, 135.0, 132.7, 131.5, 129.6, 129.3, 129.2, 129.0, 128.6, 128.6, 128.5, 128.3, 127.6, 127.1, 126.6, 126.3, 113.5, 108.9, 85.3, 62.6, 60.9, 60.6, 57.7, 55.3, 44.0, 42.5, 40.8, 21.8, 14.1, 14.0; HRMS (ESI) calcd for C40H39NO7Na [M + Na]+ 668.2619, found 668.2615.
Diethyl 2′-benzyl-2-(cyclohex-1-en-1-yl)-3-(2-oxo-2-(p-tolyl)ethyl)-2,3-dihydro-2′H-spiro[indene-1,3′-isoxazole]-4′,5′-dicarboxylate (5maa), 6.8:1 dr. Purified by silica gel column chromatography (40:1 petroleum ether/ethyl acetate): 114.0 mg, 92% yield; light yellow solid, mp 85–87 °C, IR (film) 1733, 1710, 1372, 1298, 1200, 1175 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.95 (d, J = 10.0 Hz, 0.2H), 7.81 (d, J = 10.0 Hz, 1.7H), 7.39 (d, J = 5.0 Hz, 1H), 7.34–7.23 (m, 8.2H), 7.18 (d, J = 10.0 Hz, 1.8H), 6.22 (s, 0.8H), 4.34–4.28 (m, 2H), 4.16–4.06 (m, 2.8H), 3.99 (d, J = 15.0 Hz, 0.8H), 3.81–3.76 (m, 0.9H), 3.41 (dd, J = 15.0, 10.0 Hz, 0.9H), 3.32–3.20 (m, 1.1H), 3.01 (dd, J = 15.0, 5.0 Hz, 0.8H), 2.43 (s, 0.4H), 2.39 (s, 2.6H), 2.26–2.13 (m, 0.9H), 2.04–1.99 (m, 0.3H), 1.90–1.82 (m, 1.6H), 1.62–1.56 (m, 2.8H), 1.49–1.40 (m, 2.7H), 1.36–1.33 (m, 3H), 1.17 (d, J = 10.0 Hz, 0.4H), 1.13 (d, J = 10.0 Hz, 2.6H); 13C NMR (100 MHz, CDCl3) δ 199.4, 198.6, 162.7, 162.5, 160.0, 159.8, 155.3, 148.1, 147.1, 144.2, 143.7, 137.7, 137.6, 137.4, 135.1, 134.8, 133.2, 132.6, 129.8, 129.5, 129.3, 128.8, 128.6, 128.6, 128.5, 128.4, 128.3, 127.5, 127.3, 126.9, 126.8, 126.1, 126.0, 125.8, 124.6, 108.1, 85.0, 84.4, 62.7, 60.8, 60.6, 59.9, 58.2, 42.6, 42.3, 42.0, 38.4, 31.5, 29.9, 28.5, 27.8, 27.1, 25.9, 25.8, 23.5, 23.4, 22.6, 22.2, 21.9, 21.8, 14.2, 14.1; HRMS (ESI) calcd for C39H41NO6Na [M + Na]+ 642.2826, found 642.2823.
Diethyl 2′-benzyl-5-fluoro-3-(2-oxo-2-(p-tolyl)ethyl)-2-phenyl-2,3-dihydro-2′H-spiro[indene-1,3′-isoxazole]-4′,5′-dicarboxylate (5naa), 4.5:1 dr. Purified by silica gel column chromatography (20:1 petroleum ether/ethyl acetate): 119.1 mg, 94% yield; yellowish white solid, mp 116–118 °C, IR (film) 1743, 1709, 1474, 1303, 1231, 1181 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 8.0 Hz, 0.4H), 7.71 (d, J = 8.0 Hz, 1.6H), 7.65 (d, J = 8.0 Hz, 1.6H), 7.42–7.36 (m, 1.4H), 7.35–7.14 (m, 11H), 7.02–6.97 (m, 1H), 6.82 (d, J = 8.0 Hz, 0.2H), 4.45 (t, J = 8.0 Hz, 0.2H), 4.30–4.07 (m, 5.6H), 3.99 (d, J = 12.0 Hz, 0.8H), 3.87 (d, J = 12.0 Hz, 0.4H), 3.53–3.40 (m, 2.6H), 3.33–3.14 (m, 0.4H), 2.40 (s, 0.5H), 2.38 (s, 2.5H), 1.29–1.22 (m, 3.5H), 1.15 (t, J = 8.0 Hz, 2.5H); 13C NMR (100 MHz, CDCl3) δ 198.8, 198.4, 168.4, 163.7 (d, J = 246.8 Hz), 162.7, 162.3, 159.2, 159.1, 155.7, 155.0, 150.6, 150.5, 149.4, 144.4, 144.1, 141.1, 137.2, 136.8, 136.7, 135.2, 134.8, 134.3, 133.5 (d, J = 2.6 Hz), 131.6, 130.4, 130.2, 129.5, 129.4, 129.0, 128.6, 128.6, 128.5, 128.3, 128.3, 128.1, 127.7, 127.6, 127.5, 127.5, 127.3, 120.5, 114.6 (d, J = 22.9 Hz), 114.0 (d, J = 22.4 Hz), 112.4, 112.2, 108.2, 106.8, 92.9, 84.6, 84.0, 83.3, 62.7, 61.6, 61.0, 60.5, 60.1, 58.8, 43.7, 42.1, 41.9, 40.4, 29.9, 21.8, 14.2, 14.1, 14.0, 14.0; 19F NMR (282 MHz, CDCl3): δ −111.5 (s, 1F); HRMS(ESI) calcd for C39H37FNO6 [M + H]+ 634.2599, found 634.2603.
Diethyl 2′-benzyl-5-chloro-3-(2-oxo-2-(p-tolyl)ethyl)-2-phenyl-2,3-dihydro-2′H-spiro[indene-1,3′-isoxazole]-4′,5′-dicarboxylate (5oaa), 2.5:1 dr. Purified by silica gel column chromatography (20:1 petroleum ether/ethyl acetate): 117.0 mg, 90% yield; light yellow solid, mp 112–114 °C, IR (film) 1740, 1709, 1466, 1304, 1261, 1180 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 8.0 Hz, 1.4H), 7.71 (d, J = 12.0 Hz, 0.5H), 7.64 (d, J = 4.0 Hz, 0.5H), 7.47 (d, J = 1.6 Hz, 0.3H), 7.42 (d, J = 8.0 Hz, 1.5H), 7.39–7.10 (m, 13H), 4.45 (t, J = 8.0 Hz, 0.7H), 4.26–4.09 (m, 4.4H), 3.99 (d, J = 12.0 Hz, 0.3H), 3.89–3.84 (m, 1.5H), 3.52–3.42 (m, 1.5H), 3.33–3.18 (m, 1.6H), 2.40 (s, 2H), 2.38 (s, 1H), 1.29–1.21 (m, 5.1H), 1.16 (t, J = 8.0 Hz, 0.9H); 13C NMR (100 MHz, CDCl3) δ 198.7, 198.3, 162.6, 162.3, 159.1, 155.8, 149.9, 149.0, 144.4, 144.1, 137.1, 136.7, 136.6, 136.5, 136.1, 135.9, 135.7, 135.1, 134.8, 134.3, 131.5, 130.4, 129.5, 129.4, 129.0, 128.6, 128.6, 128.5, 128.3, 128.3, 128.3, 128.1, 127.7, 127.6, 127.5, 127.4, 127.3, 127.0, 125.3, 108.1, 106.6, 84.7, 83.4, 62.7, 61.3, 60.9, 60.6, 60.2, 58.5, 43.6, 42.0, 41.9, 40.3, 29.9, 21.8, 14.2, 14.1, 14.0, 14.0; HRMS(ESI) calcd for C39H37ClNO6 [M + H]+ 650.2304, found 650.2308.
Diethyl 2′-benzyl-7-(2-oxo-2-(p-tolyl)ethyl)-6-phenyl-6,7-dihydro-2′H-spiro[indeno-[5,6-d][1,3]dioxole-5,3′-isoxazole]-4′,5′-dicarboxylate (5paa), 3.2:1 dr. Purified by silica gel column chromatography (10:1 petroleum ether/ethyl acetate): 106.9 mg, 81% yield; yellowish white solid, mp 149–151 °C, IR (film) 1734, 1705, 1497, 1370, 1258, 1143 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 12.0 Hz, 1.6H), 7.71–7.65 (m, 1H), 7.42 (d, J = 8.0 Hz, 1.6H), 7.35 (t, J = 4.0 Hz, 1.3H), 7.31–7.15 (m, 9H), 6.86 (d, J = 8.0 Hz, 0.5H), 6.80 (s, 0.7H), 6.60 (s, 0.7H), 5.97–5.93 (m, 1.9H), 4.40–4.35 (m, 0.9H), 4.27–4.12 (m, 4.2H), 4.03–3.95 (m, 0.5H), 3.91–3.83 (m, 1.4H), 3.57 (dd, J = 20.0, 12.0 Hz, 1H), 3.41 (d, J = 8.0 Hz, 0.4H), 3.27 (dd, J = 16.0, 8.0 Hz, 0.8H), 3.16 (dd, J = 16.0, 4.0 Hz, 0.7H), 2.39 (s, 2.3H), 2.37 (s, 0.7H), 1.29–1.21 (m, 5.3H), 1.18 (t, J = 8.0 Hz, 0.7H); 13C NMR (100 MHz, CDCl3) δ 199.2, 198.9, 162.8, 162.4, 159.3, 155.5, 154.8, 149.4, 149.1, 147.3, 147.2, 144.3, 143.9, 142.0, 140.9, 137.5, 137.2, 137.0, 136.1, 135.7, 135.0, 134.5, 131.6, 130.5, 130.3, 129.5, 129.4, 129.0, 128.9, 128.6, 128.5, 128.5, 128.3, 128.3, 128.2, 128.0, 127.6, 127.5, 127.3, 127.2, 107.0, 106.9, 106.0, 105.9, 105.5, 101.6, 85.2, 83.9, 62.6, 61.5, 60.9, 60.9, 60.6, 60.0, 58.9, 43.7, 42.6, 42.4, 40.2, 21.8, 14.3, 14.2, 14.0, 14.0; HRMS(ESI) calcd for C40H37NO8Na [M + Na]+ 682.2411, found 682.2406.
Diethyl 2′-benzyl-3-(2-oxo-2-(p-tolyl)ethyl)-2-phenyl-2,3-dihydro-2′H-spiro[cyclopenta[a]naphthalene-1,3′-isoxazole]-4′,5′-dicarboxylate (5qaa), 21.0:1 dr. Purified by silica gel column chromatography (40:1 petroleum ether/ethyl acetate): 115.8 mg, 87% yield; yellowish white solid, mp 158–160 °C, IR (film) 1747, 1711, 1370, 1300, 1181, 1094 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.34 (d, J = 8.0 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.70 (t, J = 8.0 Hz, 4H), 7.55 (t, J = 8.0 Hz, 2H), 7.45 (t, J = 8.0 Hz, 1H),7.32–7.20 (m, 8H), 7.15 (d, J = 8.0 Hz, 2H), 4.30–4.24 (m, 3H), 4.20 (d, J = 8.0 Hz, 2H), 4.05–3.90 (m, 2H), 3.75–3.55 (m, 3H), 2.37 (s, 3H), 1.23 (t, J = 8.0 Hz, 3H), 0.98 (d, J = 8.0 Hz, 0.1H), 0.85 (d, J = 8.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 198.9, 162.4, 159.4, 154.9, 148.1, 143.9, 137.7, 137.2, 135.0, 133.6, 132.0, 132.0, 130.8, 129.4, 129.3, 128.8, 128.6, 128.3, 128.1, 127.5, 127.4, 127.1, 125.4, 124.4, 124.1, 108.7, 85.8, 62.7, 60.6, 60.6, 59.1, 44.0, 43.1, 21.8, 14.0, 13.9; HRMS(ESI) calcd for C43H40NO6 [M + H]+ 666.2850, found 666.2855.
Diethyl 2′-cyclohexyl-3-(2-oxo-2-(p-tolyl)ethyl)-2-phenyl-2,3-dihydro-2′H-spiro[indene-1,3′-isoxazole]-4′,5′-dicarboxylate (5dba), 1.2:1 dr. Purified by silica gel column chromatography (10:1 petroleum ether/ethyl acetate): 94.8 mg, 78% yield; light yellow solid, mp 142–144 °C, IR (film) 1746, 1703, 1455, 1353, 1278, 1171 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H),7.68–7.65 (m, 1H), 7.42–7.11 (m, 10H), 4.47 (d, J = 8.0 Hz, 0.4H), 4.26–3.99 (m, 4H), 3.94 (d, J = 8.0 Hz, 0.5H), 3.57 (d, J = 12.0 Hz, 0.4H), 3.52–3.39 (m, 0.9H), 3.29 (dd, J = 16.0, 8.0 Hz, 0.4H), 3.12 (dd, J = 16.0, 4.0 Hz, 0.4H), 2.40 (s, 1.6H), 2.38 (s, 1.4H), 2.30–2.25 (m, 0.5H), 2.13 (d, J = 12.0 Hz, 0.5H), 1.97 (d, J = 12.0 Hz, 0.5H), 1.82–1.69 (m, 1.7H), 1.65–1.51 (m, 3H), 1.31–1.18 (m, 6H), 1.11 (t, J = 8.0 Hz, 2H), 1.02–0.86 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 199.4, 199.4, 162.7, 162.4, 159.3, 159.2, 156.3, 155.7, 148.5, 147.9, 144.2, 143.8, 137.6, 137.5, 137.4, 135.7, 135.3, 134.6, 132.0, 130.7, 129.6, 129.4, 129.4, 129.4, 128.5, 128.2, 127.9, 127.6, 127.4, 127.3, 126.9, 126.7, 126.5, 125.7, 125.7, 124.5, 110.3, 108.8, 85.0, 83.7, 63.8, 63.7, 63.2, 62.4, 62.4, 60.7, 59.3, 44.0, 42.1, 41.8, 40.0, 33.8, 32.7, 29.9, 27.7, 27.6, 26.2, 25.9, 25.7, 25.2, 25.1, 21.8, 21.8, 14.2, 14.2, 14.1, 14.1, 14.0; HRMS (ESI) calcd for C38H42NO6 [M + H]+ 608.3007, found 608.3012.
Dimethyl 2′-benzyl-3-(2-oxo-2-(p-tolyl)ethyl)-2-phenyl-2,3-dihydro-2′H-spiro[indene-1,3′-isoxazole]-4′,5′-dicarboxylate (5dab), 3.2:1 dr. Purified by silica gel column chromatography (20:1 petroleum ether/ethyl acetate): 111.7 mg, 95% yield; light yellow solid, mp 123–125 °C, IR (film) 1763, 1754, 1443, 1352, 1296, 1142 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 8.0 Hz, 0.5H), 7.70–7.67 (m, 3H), 7.47–7.40 (m, 2.5H), 7.36–7.15 (m, 10H), 7.13 (d, J = 4.0 Hz, 2H), 4.50 (t, J = 8.0 Hz, 0.2H), 4.19–4.10 (m, 1.8H), 4.00 (d, J = 16.0 Hz, 0.9H), 3.91–3.81 (m, 0.7H), 3.75 (d, J = 4.0 Hz, 1.2H), 3.73 (s, 2.2H), 3.66 (s, 2.2H), 3.54–3.32 (m, 2.7H), 3.18 (dd, J = 4.0, 16.0 Hz, 0.2H), 2.39 (s, 0.7H), 2.36 (s, 2.2H); 13C NMR (100 MHz, CDCl3) δ 199.1, 198.8, 163.3, 162.9, 159.5, 154.9, 154.4, 148.0, 147.0, 144.2, 143.9, 137.6, 137.3, 137.1, 136.9, 135.5, 135.4, 135.0, 134.6, 131.6, 130.5, 130.1, 129.7, 129.4, 129.3, 128.9, 128.6, 128.5, 128.3, 128.2, 128.0, 127.6, 127.4, 127.3, 127.2, 126.7, 126.1, 125.8, 124.8, 109.2, 107.9, 100.2, 85.4, 84.1, 61.3, 60.7, 60.2, 58.4, 53.2, 52.1, 44.0, 42.4, 42.1, 40.5, 29.9, 21.8; HRMS (ESI) calcd for C37H34NO6 [M + H]+ 588.2381, found 588.2379.
Ethyl 2′-benzyl-3-(2-oxo-2-(p-tolyl)ethyl)-2-phenyl-2,3-dihydro-2′H-spiro[indene-1,3′-isoxazole]-4′-carboxylate (5dac), 1.5:1 dr. Purified by silica gel column chromatography (20:1 petroleum ether/ethyl acetate): 87.0 mg, 80% yield; light yellow oil, IR (film) 1704, 1682, 1454, 1372, 1278, 1106 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 8.0 Hz, 1H),7.73–7.71 (m, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.46–7.39 (m, 2H), 7.37 (d, J = 4.0 Hz, 2H), 7.34–7.27 (m, 4H), 7.26–7.21 (m, 4H), 7.19–7.12 (m, 3H), 4.45 (t, J = 8.0 Hz, 0.6H), 4.23–4.16 (m, 1.5H), 4.14–4.07 (m, 1.3H), 3.95–3.88 (m, 1H), 3.73 (d, J = 16.0 Hz, 0.6H), 3.50–3.33 (m, 2.4H), 3.17 (dd, J = 16.0, 4.0 Hz, 0.6H), 2.39 (s, 1.8H), 2.35 (s, 1.2H), 1.26–1.23 (m, 1.8H), 1.15 (d, J = 8.0 Hz, 1.2H), 13C NMR (100 MHz, CDCl3) δ 199.3, 198.8, 163.8, 163.3, 156.4, 156.2, 147.8, 146.6, 144.2, 143.8, 138.3, 138.3, 138.0, 137.9, 137.5, 136.3, 135.1, 134.6, 131.6, 130.7, 129.7, 129.4, 129.4, 129.3, 128.7, 128.5, 128.4, 128.3, 128.3, 128.2, 127.9, 127.6, 127.4, 127.3, 127.0, 126.6, 126.0, 125.7, 124.7, 108.3, 127.7, 83.3, 82.1, 61.1, 60.6, 60.6, 60.1, 57.9, 43.9, 42.4, 42.3, 40.8, 29.9, 21.8, 21.8, 14.5, 14.4; HRMS (ESI) calcd for C36H34NO4 [M + H]+ 544.2482, found 544.2479.
tert-Butyl 2′-benzyl-3-(2-oxo-2-(p-tolyl)ethyl)-2-phenyl-2,3-dihydro-2′H-spiro[indene-1,3′-isoxazole]-4′-carboxylate (5dad), 1.3:1 dr. Purified by silica gel column chromatography (20:1 petroleum ether/ethyl acetate): 85.8 mg, 75% yield; reddish brown solid, mp 85–87 °C, IR (film) 1699, 1624, 1455, 1364, 1228, 1134 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.83 (d, J = 5.0 Hz, 1H), 7.12 (d, J = 5.0 Hz, 1H), 7.68 (d, J = 10.0 Hz, 1H), 7.47–7.36 (m, 4H), 7.34–7.21 (m, 8H), 7.18–7.11 (m, 3H), 4.43 (t, J = 10.0 Hz, 0.5H), 4.13 (d, J = 5.0 Hz, 0.4H), 4.10–4.05 (m, 0.5H), 3.93–3.85 (m, 0.9H), 3.75 (d, J = 20.0 Hz, 0.5H), 3.51–3.37 (m, 1.8H), 3.31 (dd, J = 20.0, 10.0 Hz, 0.6H), 3.17 (dd, J = 15.0, 5.0 Hz, 0.5H), 2.40 (s, 1.7H), 2.36 (s, 1.3H), 1.40 (s, 5H), 1.30 (s, 4H); 13C NMR (125 MHz, CDCl3) δ 199.3, 198.9, 163.3, 162.8, 156.0, 155.9, 147.9, 146.6, 144.2, 143.8, 138.6, 138.6, 138.1, 138.0, 137.7, 136.4, 135.1, 134.6, 131.7, 130.7, 129.6, 129.4, 129.4, 129.3, 129.2, 128.6, 128.5, 128.4, 128.3, 128.2, 128.2, 127.9, 127.5, 127.4, 127.2, 127.2, 126.9, 126.9, 126.5, 126.2, 125.8, 124.6, 109.9, 109.1, 83.3, 82.1, 80.6, 80.5, 61.1, 60.9, 60.7, 58.0, 43.9, 42.5, 42.4, 40.7, 28.4, 28.2, 21.8, 21.8; HRMS (ESI) calcd for C38H37NO6Na [M + Na]+ 594.2615, found 594.2615.
2-(4′-Acetyl-2′-benzyl-2-phenyl-2,3-dihydro-2′H-spiro[indene-1,3′-isoxazol]-3-yl)-1-(p-tolyl)ethan-1-one (5dae), 4.0:1 dr. Purified by silica gel column chromatography (30:1 petroleum ether/ethyl acetate): 98.6 mg, 96% yield; white solid, mp 71–73 °C, IR (film) 1679, 1653, 1457, 1374, 1228, 1140 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 8.0 Hz, 1.5H),7.70–7.65 (m, 0.6H), 7.45–7.34 (m, 3H), 7.31–7.17 (m, 12H), 7.13 (d, J = 4.0 Hz, 1H), 4.44 (d, J = 8.0 Hz, 0.8H), 4.20 (d, J = 8.0 Hz, 0.2H), 4.13–4.07 (m, 0.2H), 4.03 (d, J = 12.0 Hz, 0.8H), 3.86 (d, J = 16.0 Hz, 0.2H), 3.70 (d, J = 16.0 Hz, 0.8H), 3.48–3.36 (m, 2H), 3.13 (dd, J = 16.0, 4.0 Hz, 0.8H), 2.38 (s, 2.4H), 2.35 (s, 0.6H), 2.32 (s, 2.3H), 2.22 (s, 0.5H); 13C NMR (100 MHz, CDCl3) δ 199.4, 198.8, 191.7, 191.3, 157.7, 157.6, 147.6, 146.5, 144.1, 143.8, 138.2, 137.9, 137.9, 137.8, 137.4, 136.5, 135.0, 134.6, 131.6, 130.7, 129.6, 129.4, 129.3, 128.7, 128.5, 128.3, 128.2, 128.2, 127.9, 127.6, 127.3, 127.3, 127.2, 127.0, 126.7, 125.9, 125.4, 124.8, 118.1, 117.9, 83.6, 82.3, 61.2, 60.7, 59.8, 57.2, 43.9, 42.4, 42.2, 40.8, 29.9, 28.1, 28.0, 21.8, 21.8; HRMS (ESI) calcd for C35H32NO3 [M + H]+ 514.2377, found 514.2380.
Methyl 2′-benzyl-3-(2-oxo-2-(p-tolyl)ethyl)-2,5′-diphenyl-2,3-dihydro-2′H-spiro-[indene-1,3′-isoxazole]-4′-carboxylate (5daf), 2.2:1 dr. Purified by silica gel column chromatography (10:1 petroleum ether/ethyl acetate): 93.2 mg, 77% yield; yellow white solid, mp 73–75 °C, IR (film) 1738, 1697, 1495, 1350, 1241, 1092 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 8.0 Hz, 1.5H), 7.74 (t, J = 8.0 Hz, 1H), 7.53 (d, J = 4.0 Hz, 1.5H), 7.43–7.13 (m, 19H), 4.59 (t, J = 8.0 Hz, 0.7H), 4.25 (d, J = 8.0 Hz, 0.3H), 4.17–4.12 (m, 0.3H), 4.05 (d, J = 16.0 Hz, 0.3H), 3.93–3.85 (m, 1.3H), 3.59 (s, 2.7H), 3.55–3.45 (m, 1.5H), 3.41–3.34 (m, 0.8H), 3.22–3.17 (m, 0.8H), 2.39 (s, 2.1H), 2.37 (s, 0.9H); 13C NMR (100 MHz, CDCl3) δ 199.4, 199.2, 166.7, 164.9, 148.1, 147.1, 144.1, 143.8, 138.6, 138.1, 138.0, 137.8, 136.4, 134.7, 131.9, 130.6, 130.5, 129.6, 129.4, 129.4, 129.3, 129.2, 128.6, 128.6, 128.5, 128.4, 128.3, 128.3, 128.2, 128.0, 127.9, 127.9, 127.8, 127.4, 127.3, 127.0, 127.0, 126.8, 126.7, 126.2, 125.8, 124.7, 101.7, 86.1, 84.8, 62.2, 60.5, 60.2, 58.8, 51.2, 3.9, 42.9, 42.2, 40.5, 29.9, 21.8, 21.8; HRMS (ESI) calcd for C41H36NO4 [M + H]+ 606.2639, found 606.2646.
Ethyl 2′-benzyl-3-(2-oxo-2-(p-tolyl)ethyl)-2,5′-diphenyl-2,3-dihydro-2′H-spiro[indene-1,3′-isoxazole]-4′-carboxylate (5dag), 1.5:1 dr. Purified by silica gel column chromatography (10:1 petroleum ether/ethyl acetate): 99.2 mg, 80% yield; yellow white solid, mp 81–83 °C, IR (film) 1695, 1646, 1454, 1372, 1336, 1091 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 8.0 Hz, 1.3H), 7.74 (t, J = 8.0 Hz, 1.4H), 7.53 (d, J = 8.0 Hz, 1.4H), 7.44–7.13 (m, 19H), 4.58 (t, J = 8.0 Hz, 0.6H), 4.26 (d, J = 8.0 Hz, 0.4H), 4.17–3.96 (m, 2.3H), 3.94–3.86 (m, 1.5H), 3.66–3.59 (m, 1.1H), 3.53 (d, J = 12.0 Hz, 0.7H), 3.35 (dd, J = 20.0, 8.0 Hz, 0.7H), 3.20 (dd, J = 16.0, 4.0 Hz, 0.6H), 2.40 (s, 1.8H), 2.37 (s, 1.2H), 0.99 (d, J = 8.0 Hz, 1.8H), 0.90 (d, J = 8.0 Hz, 1.2H); 13C NMR (100 MHz, CDCl3) δ 199.4, 199.2, 166.5, 166.4, 166.0, 148.2, 147.1, 144.1, 143.8, 141.3, 138.9, 138.8, 138.2, 138.0, 137.9, 136.5, 135.2, 134.7, 131.9, 130.6, 130.6, 129.5, 129.4, 129.4, 129.3, 129.2, 128.6, 128.6, 128.5, 128.4, 128.3, 128.3, 128.2, 128.0, 127.9, 127.8, 127.8, 127.4, 127.2, 127.0, 126.9, 126.8, 126.6, 126.3, 125.9, 124.6, 102.7, 102.0, 86.0, 84.8, 62.2, 60.5, 60.2, 60.0, 59.9, 58.8, 43.9, 42.9, 42.2, 40.6, 32.1, 29.9, 21.8, 21.8, 14.0, 13.9; HRMS (ESI) calcd for C42H37NO4Na [M + Na]+ 642.2615, found 642.2610.
2-(4′-Acetyl-2′-benzyl-2,5′-diphenyl-2,3-dihydro-2′H-spiro[indene-1,3′-isoxazol]-3-yl)-1-(p-tolyl)ethan-1-one (5dah), 5.0:1 dr. Purified by silica gel column chromatography (20:1 petroleum ether/ethyl acetate): 96.7 mg, 82% yield; light yellow solid, mp 70–72 °C, IR (film) 1736, 1680, 1454, 1371, 1241, 1118 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 8.0 Hz, 1.5H), 7.75–7.72 (m, 0.6H), 7.53 (d, J = 8.0 Hz, 1.5H), 7.42–7.13 (m, 19H), 6.97 (d, J = 8.0 Hz, 0.6H), 4.59 (t, J = 8.0 Hz, 0.8H), 4.32–4.26 (m, 0.2H), 4.17–4.09 (m, 0.2H), 4.05 (d, J = 12.0 Hz, 0.1H), 3.95–3.88 (m, 1.7H), 3.64 (t, J = 8.0 Hz, 0.5H), 3.52–3.39 (m, 1.8H), 3.16 (dd, J = 16.0, 4.0 Hz,1H), 2.39 (s, 2.4H), 2.37 (s, 0.6H), 1.97 (s, 2.5H), 1.83 (s, 0.5H); 13C NMR (100 MHz, CDCl3) δ 199.5, 199.2, 194.0, 167.9, 148.2, 147.1, 144.1, 143.7, 138.3, 138.1, 137.8, 136.6, 135.3, 134.7, 132.0, 131.0, 130.9, 130.7, 129.5, 129.4, 129.4, 129.3, 129.2, 128.9, 128.8, 128.7, 128.6, 128.5, 128.3, 128.0, 127.8, 127.5, 127.3, 127.1, 126.9, 126.8, 126.2, 125.7, 124.8, 113.4, 85.5, 61.7, 60.3, 58.5, 43.8, 43.0, 42.1, 40.7, 30.2, 30.0, 29.9, 21.8; HRMS (ESI) calcd for C41H36NO3 [M + H]+ 590.2690, found 590.2692.
2-(2′-Benzyl-4'-(2,4-dinitrophenyl)-2,5′-diphenyl-2,3-dihydro-2′H-spiro[indene-1,3′-isoxazol]-3-yl)-1-(p-tolyl)ethan-1-one (5dai), 1.8:1 dr. Purified by silica gel column chromatography (20:1 petroleum ether/ethyl acetate): 121.3 mg, 85% yield; brownish red solid, mp 135–137 °C, IR (film) 1721, 1680, 1536, 1453, 1345, 1180 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.42 (s, 1H), 8.31 (d, J = 8.0 Hz, 1H), 7.87 (d, J = 8.0 Hz, 2H), 7.53–7.14 (m, 20H), 6.97 (d, J = 8.0 Hz, 2H), 4.70 (s, 0.7H), 4.25–4.03 (m, 1.6H), 3.90 (d, J = 8.0 Hz, 1H), 3.63 (d, J = 12.0 Hz, 1H), 3.41 (d, J = 4.0 Hz, 1.7H), 2.42 (s, 1.9H), 2.37 (s, 1.1H), 3.71 (d, J = 16.0 Hz, 0.6H), 3.49–3.28 (m, 2.4H), 3.17 (dd, J = 16.0, 4.0 Hz, 0.5H), 2.39 (s, 1.6H), 2.35 (s, 1.4H), 2.06 (s, 1.5H), 2.00 (s, 1.4H), 1.14 (t, J = 8.0 Hz, 1.6H), 1.05 (d, J = 8.0 Hz, 1.4H); 13C NMR (100 MHz, CDCl3) δ 198.7, 150.5, 145.5, 144.4, 144.0, 138.1, 137.8, 135.7, 135.6, 135.4, 134.7, 131.1, 131.0, 130.1, 129.5, 129.3, 129.0, 128.8, 128.7, 128.6, 128.5, 128.4, 128.1, 128.0, 127.8, 127.6, 127.4, 127.2, 126.8, 126.6, 124.6, 121.0, 117.9, 88.8, 86.9, 59.6, 41.3, 34.6, 29.8, 21.9; HRMS (ESI) calcd for C45H35N3O6Na [M + Na]+ 736.2418, found 736.2425.
Ethyl 2′-benzyl-5′-methyl-3-(2-oxo-2-(p-tolyl)ethyl)-2-phenyl-2,3-dihydro-2′H-spiro[indene-1,3′-isoxazole]-4′-carboxylate (5daj), 1.1:1 dr. Purified by silica gel column chromatography (20:1 petroleum ether/ethyl acetate): 50.2 mg, 45% yield; brown solid, mp 39–41 °C, IR (film) 1734, 1696, 1473, 1374, 1258, 1107 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 8.0 Hz, 1H), 7.69 (t, J = 8.0 Hz, 2H), 7.41–7.33 (m, 4H), 7.31–7.09 (m, 11H), 4.48 (t, J = 8.0 Hz, 0.5H), 4.23–3.98 (m, 3H), 3.87–3.78 (m, 1H), 3.71 (d, J = 16.0 Hz, 0.6H), 3.49–3.28 (m, 2.4H), 3.17 (dd, J = 16.0, 4.0 Hz, 0.5H), 2.39 (s, 1.6H), 2.35 (s, 1.4H), 2.06 (s, 1.5H), 2.00 (s, 1.4H), 1.14 (t, J = 8.0 Hz, 1.6H), 1.05 (d, J = 8.0 Hz, 1.4H); 13C NMR (100 MHz, CDCl3) δ 199.4, 199.1, 168.5, 168.3, 164.9, 164.6, 147.7, 146.7, 144.1, 143.7, 139.4, 139.1, 138.3, 137.9, 136.6, 135.1, 134.7, 131.6, 130.5, 129.4, 129.3, 129.3, 129.0, 128.6, 128.5, 128.5, 128.3, 128.2, 128.1, 127.7, 127.4, 127.3, 127.0, 126.7, 126.7, 126.4, 126.2, 125.9, 124.5, 102.1, 101.6, 84.7, 83.5, 61.4, 60.8, 60.3, 59.7, 59.6, 58.1, 43.9, 42.6, 42.3, 40.3, 29.9, 21.8, 21.8, 14.4, 14.3, 13.2, 13.1; HRMS (ESI) calcd for C37H35NO4Na [M + Na]+ 580.2458, found 580.2460.
2′-Benzyl-5′-methyl-3-(2-oxo-2-(p-tolyl)ethyl)-2-phenyl-2,3,3a′,6a′-tetrahydro-2′H,4′H-spiro[indene-1,3′-pyrrolo[3,4-d]isoxazole]-4′,6′(5′H)-dione (5dak), 2.0:1 dr. Purified by silica gel column chromatography (10:1 petroleum ether/ethyl acetate): 76.8 mg, 69% yield; yellowish white solid, mp 110–112 °C, IR (film) 1709, 1677, 1453, 1377, 1281, 1181 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 8.0 Hz, 0.7H), 7.54 (d, J = 8.0 Hz, 1.2H), 7.41–7.17 (m, 15H), 7.10 (d, J = 4.0 Hz, 0.8H), 7.00 (d, J = 8.0 Hz, 0.5H), 4.94 (d, J = 8.0 Hz, 0.6H), 4.66 (d, J = 8.0 Hz, 0.3H), 4.56–4.51 (m, 0.1H), 4.37–4.29 (m, 0.5H), 4.11–3.95 (m, 2.1H), 3.90–3.78 (m, 1H), 3.73–3.67 (m, 0.4H), 3.51–3.44 (m, 0.4H), 3.36–3.29 (m, 1.2H), 3.21–3.15 (m, 1.3H), 3.00 (s, 1H), 2.50 (s, 2H), 2.39 (s, 1H), 2.38 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 198.8, 175.2, 173.9, 172.7, 146.5, 145.0, 144.3, 141.3, 137.4, 137.2, 136.8, 134.9, 134.7, 134.4, 134.4, 132.1, 130.7, 129.8, 129.6, 129.5, 128.8, 128.5, 128.4, 128.4, 128.3, 128.2, 128.2, 128.1, 128.0, 127.7, 127.6, 127.2, 127.1, 125.3, 124.9, 124.7, 124.7, 79.8, 78.8, 75.4, 60.3, 58.7, 58.1, 56.8, 56.4, 56.0, 46.5, 43.4, 43.0, 42.6, 29.9, 24.9, 24.4, 21.8. HRMS (ESI) calcd for C36H32N2O4Na [M + Na]+ 579.2254, found 579.2259.
Diethyl 2′-benzyl-3-(2-oxo-2-phenylethyl)-2-phenyl-2,3-dihydro-2′H-spiro[indene-1,3′-isoxazole]-4′,5′-dicarboxylate (5aaa), 9:1 dr. Purified by silica gel column chromatography (petroleum ether/ethyl acetate from 50:1 to 10:1): 228.6 mg, 76% yield; light yellow solid, mp 127–129 °C, IR (film) 1740, 1706, 1454, 1393, 1239, 1106 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 8.0 Hz, 2H), 7.67 (d, J = 8.0 Hz, 2H), 7.52–7.42 (m, 3H), 7.39–7.20 (m, 12H), 4.21–4.08 (m, 6H), 4.02 (d, J = 16.0 Hz, 1H), 3.56–3.42 (m, 3H), 1.31–1.19 (m, 3.3H), 1.13 (t, J = 8.0 Hz, 2.7H); 13C NMR (100 MHz, CDCl3) δ 199.2, 162.4, 159.2, 154.8, 148.0, 137.8, 137.5, 137.4, 137.2, 133.1, 131.6, 129.7, 129.0, 128.7, 128.6, 128.2, 128.1, 127.6, 127.3, 127.2, 126.6, 126.3, 108.7, 85.3, 62.6, 60.9, 60.6, 58.4, 43.9, 42.6, 14.1, 14.0.
Diethyl 2′-benzyl-3-(2-oxo-2-(o-tolyl)ethyl)-2-phenyl-2,3-dihydro-2′H-spiro[indene-1,3′-isoxazole]-4′,5′-dicarboxylate (5baa), 23.0:1 dr. Purified by silica gel column chromatography (petroleum ether/ethyl acetate from 50:1 to 10:1): 200.1 mg, 65% yield; light yellow solid, mp 96–97 °C, IR (film) 1743, 1719, 1495, 1393, 1300, 1176 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.64–7.62 (m, 2H), 7.46–7.43 (m, 2H), 7.39 (d, J = 8.0 Hz, 1H), 7.34–7.31 (m, 3H), 7.29–7.18 (m, 9H), 7.16–7.12 (m, 1H), 4.19–4.08 (m, 6H), 3.99 (d, J = 12.0 Hz, 1H), 3.52 (d, J = 12.0 Hz, 1H), 3.48–3.41 (m, 2H), 2.49 (s, 0.1H), 2.36 (s, 3H), 1.22 (t, J = 8.0 Hz, 3H), 1.13 (t, J = 8.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 202.8, 162.4, 159.2, 154.8, 148.2, 138.4, 138.3, 137.8, 137.3, 137.2, 132.1, 131.7, 131.4, 129.7, 129.0, 128.7, 128.5, 128.2, 127.6, 127.4, 127.2, 126.4, 126.3, 125.7, 108.7, 85.3, 62.6, 60.9, 60.6, 58.4, 45.6, 43.9, 21.4, 14.1, 14.0.
Diethyl 2′-benzyl-3-(2-oxo-2-(p-tolyl)ethyl)-2-phenyl-2,3-dihydro-2′H-spiro[indene-1,3′-isoxazole]-4′,5′-dicarboxylate (5daa), 14.0:1 dr. Purified by silica gel column chromatography (petroleum ether/ethyl acetate from 50:1 to 10:1): 243.2 mg, 79% yield; 112.1 mg, 89% yield; light yellow solid, mp 140–142 °C, IR (film) 1740, 1713, 1474, 1370, 1241, 1140 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 8.0 Hz, 4H), 7.43–7.39 (m, 2H), 7.32–7.15 (m, 12H), 4.21–4.10 (m, 6H), 4.02 (d, J = 12.0 Hz, 1H), 3.54–3.39 (m, 3H), 2.40 (s, 0.2H), 2.37 (s, 2.8H), 1.23 (t, J = 8.0 Hz, 3.2H), 1.13 (t, J = 8.0 Hz, 2.8H); 13C NMR (100 MHz, CDCl3) δ 198.8, 162.4, 159.2, 154.8, 148.1, 143.9, 137.8, 137.5, 137.2, 135.1, 131.6, 129.7, 129.4, 129.0, 128.6, 128.3, 128.2, 127.6, 127.3, 127.1, 126.6, 126.3, 108.8, 85.3, 62.6, 60.9, 60.6, 58.4, 44.0, 42.5, 21.8, 14.1, 14.0.
Diethyl 2′-benzyl-3-(2-(4-bromophenyl)-2-oxoethyl)-2-phenyl-2,3-dihydro-2′H-spiro[indene-1,3′-isoxazole]-4′,5′-dicarboxylate (5eaa), 5.5:1 dr. Purified by silica gel column chromatography (petroleum ether/ethyl acetate from 50:1 to 10:1): 251.8 mg, 74% yield; light yellow solid, mp115–117 °C, IR (film) 1735, 1707, 1499, 1370, 1242, 1169 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.0 Hz, 0.4H), 7.66–7.56 (m, 3.5H), 7.50–7.37 (m, 4H), 7.35–7.14 (m, 10H), 4.22–4.08 (m, 5.2H), 4.03 (d, J = 12.0 Hz, 0.9H), 3.89–3.76 (m, 0.4H), 3.54–3.48 (m, 1.8H), 3.38–3.28 (m, 1H), 3.20–3.14 (m, 0.2H), 1.29–1.20 (m, 3.6H), 1.13 (t, J = 8.0 Hz, 2.5H); 13C NMR (100 MHz, CDCl3) δ 198.1, 162.4, 159.2, 154.8, 147.7, 137.8, 137.4, 137.1, 136.1, 132.1, 131.9, 131.5, 130.5, 129.9, 129.7, 129.7, 128.9, 128.6, 128.6, 128.3, 128.2, 128.0, 127.7, 127.4, 127.3, 126.4, 126.4, 108.6, 85.3, 62.7, 60.9, 60.6, 58.3, 43.9, 42.4, 14.1, 14.0.
Diethyl 2′-benzyl-3-(2-(furan-2-yl)-2-oxoethyl)-2-phenyl-2,3-dihydro-2′H-spiro[indene-1,3′-isoxazole]-4′,5′-dicarboxylate (5faa), 33.0:1 dr. Purified by silica gel column chromatography (petroleum ether/ethyl acetate from 50:1 to 10:1): 210.1 mg, 71% yield; light yellow solid, mp 141–143 °C, IR (film) 1739, 1710, 1465, 1371, 1189, 1140 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.68 (d, J = 10.0 Hz, 2H), 7.45–7.42 (m, 2H), 7.40 (d, J = 5.0 Hz, 2H), 7.36–7.33 (m, 3H), 7.30–7.20 (m, 6H), 7.00 (d, J = 5.0 Hz, 1H), 6.50–6.49 (m, 0.03H), 6.44–6.43 (m, 1H), 4.20–4.15 (m, 3H), 4.14–4.06 (m, 3H), 4.01 (d, J = 15.0 Hz, 1H), 3.54 (d, J = 15.0 Hz, 1H), 3.47 (dd, J = 20.0, 10.0 Hz, 1H), 3.21 (dd, J = 20.0, 5.0 Hz, 1H), 1.23 (t, J = 10.0 Hz, 3H), 1.12 (t, J = 10.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 188.7, 162.4, 159.2, 154.9, 153.3, 147.5, 146.2, 137.8, 137.5, 137.0, 131.6, 129.6, 129.1, 128.6, 128.1, 127.6, 127.4, 127.2, 126.4, 126.3, 116.8, 112.5, 108.5, 85.2, 62.7, 60.9, 60.7, 58.3, 44.0, 42.3, 14.1, 14.0.
Diethyl 2′-benzyl-2-(4-methoxyphenyl)-3-(2-oxo-2-(p-tolyl)ethyl)-2,3-dihydro-2′H-spiro[indene-1,3′-isoxazole]-4′,5′-dicarboxylate (5laa), 29.0:1 dr. Purified by silica gel column chromatography (petroleum ether/ethyl acetate from 50:1 to 10:1): 222.8 mg, 69% yield; light yellow solid, mp 85–86 °C, IR (film) 1738, 1712, 1496, 1393, 1305, 1140 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.71 (d, J = 5.0 Hz, 2H), 7.59 (d, J = 10.0 Hz, 2H), 7.44–7.39 (m, 2H), 7.36–7.32 (m, 4H), 7.30–7.27 (m, 3H), 7.17 (d, J = 10.0 Hz, 2H), 6.78 (d, J = 10.0 Hz, 2H), 4.21–4.16 (m, 2H), 4.15–4.05 (m, 4H), 4.01 (d, J = 15.0 Hz, 1H), 3.75 (s, 3H), 3.52–3.48 (m, 2H), 3.44–3.38 (m, 1H), 2.37 (s, 2.9H), 1.25 (t, J = 10.0 Hz, 3.1H), 1.13 (t, J = 10.0 Hz, 2.9H); 13C NMR (125 MHz, CDCl3) δ 198.9, 162.5, 159.2, 158.9, 154.6, 148.1, 143.9, 137.7, 137.5, 135.1, 132.7, 129.6, 129.3, 129.2, 129.0, 128.6, 128.3, 127.6, 127.1, 126.6, 126.3, 113.6, 108.9, 85.3, 62.6, 60.9, 60.6, 57.7, 55.3, 44.1, 42.5, 21.8, 14.1, 14.0.
Diethyl 2′-benzyl-5-chloro-3-(2-oxo-2-(p-tolyl)ethyl)-2-phenyl-2,3-dihydro-2′H-spiro[indene-1,3′-isoxazole]-4′,5′-dicarboxylate (5oaa), 12.0:1 dr. Purified by silica gel column chromatography (petroleum ether/ethyl acetate from 50:1 to 10:1): 211.3 mg, 65% yield; light yellow solid, mp 118–120 °C, IR (film) 1740, 1710, 1454, 1394, 1304, 1143 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 8.0 Hz, 0.2H), 7.71 (d, J = 8.0 Hz, 2H), 7.65–7.62 (m, 2H), 7.48 (d, J = 4.0 Hz, 1H), 7.38–7.16 (m, 12H), 4.21–4.09 (m, 6H), 3.99 (d, J = 12.0 Hz, 1H), 3.52–3.38 (m, 3H), 2.40 (s, 0.2H), 2.38 (s, 2.7H), 1.23 (t, J = 8.0 Hz, 3H), 1.16 (t, J = 8.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 198.3, 162.3, 159.1, 155.1, 149.9, 144.1, 137.1, 136.7, 136.5, 135.6, 134.8, 131.5, 129.4, 129.0, 128.6, 128.3, 128.2, 127.7, 127.6, 127.5, 127.3, 127.1, 108.1, 84.7, 62.7, 61.0, 60.6, 58.5, 43.6, 42.0, 21.8, 14.1, 14.0.
Diethyl 2′-benzyl-6-methyl-3-(2-oxo-2-(p-tolyl)ethyl)-2-phenyl-2,3-dihydrospiro[indene-1,3′-isoxazolidine]-4′,5′-dicarboxylate (5raa), 14.8:1 dr. Purified by silica gel column chromatography (petroleum ether/ethyl acetate from 50:1 to 10:1): 198.4 mg, 63% yield; yellowish white solid, mp 145–147 °C, IR (film) 1749, 1712, 1453, 1305, 1200, 1178 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.70–7.65 (m, 4H), 7.34 (t, J = 4.0 Hz, 4H), 7.30–7.20 (m, 6H), 7.16 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 8.0 Hz, 1H), 4.21–4.05 (m, 6H), 4.00 (d, J = 16.0 Hz, 1H), 3.53 (d, J = 12.0 Hz, 1H), 3.49–3.37 (m, 2H), 2.37 (s, 3H), 2.36 (s, 3H), 1.25 (t, J = 8.0 Hz, 3.2H), 1.13 (t, J = 8.0 Hz, 2.8H); 13C NMR (100 MHz, CDCl3) δ 199.0, 162.5, 159.2, 154.5, 145.0, 143.8, 137.8, 137.5, 137.3, 136.8, 135.1, 131.6, 130.6, 129.3, 129.1, 128.6, 128.3, 128.2, 127.6, 127.3, 126.6, 126.2, 123.0, 109.0, 100.1, 93.3, 85.3, 62.6, 60.8, 60.6, 58.6, 43.7, 42.6, 21.8, 21.6, 14.1, 14.0.
Dimethyl 2′-benzyl-3-(2-oxo-2-(p-tolyl)ethyl)-2-phenyl-2,3-dihydro-2′H-spiro[indene-1,3′-isoxazole]-4′,5′-dicarboxylate (5dab), 11.0:1 dr. Purified by silica gel column chromatography (petroleum ether/ethyl acetate from 50:1 to 10:1): 241.0 mg, 82% yield; light yellow solid, mp 132–134 °C, IR (film) 1765, 1750, 1448, 1352, 1307, 1140 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.68 (t, J = 8.0 Hz, 4H), 7.47–7.41 (m, 2H), 7.36–7.20 (m, 10H), 7.16 (d, J = 8.0 Hz, 2H), 4.19–4.10 (m, 2H), 4.00 (d, J = 16.0 Hz, 1H), 3.73 (s, 3H), 3.66 (s, 3H), 3.52–3.39 (m, 3H), 2.39 (s, 0.3H), 2.37 (s, 2.7H); 13C NMR (100 MHz, CDCl3) δ 198.8, 162.9, 159.5, 154.4, 148.0, 143.9, 137.6, 137.3, 137.1, 135.0, 131.6, 129.7, 129.3, 128.9, 128.6, 128.3, 128.2, 127.6, 127.4, 127.3, 126.7, 126.1, 109.2, 85.3, 60.7, 58.4, 53.3, 52.1, 44.0, 42.4, 21.8.
Diethyl 2′-methyl-3-(2-oxo-2-(p-tolyl)ethyl)-2-phenyl-2,3-dihydro-spiro[indene-1,3′-isoxazolidine]-4′,5′-dicarboxylate (5dca), 7.3:1 dr. Purified by silica gel column chromatography (petroleum ether/ethyl acetate from 50:1 to 10:1): 121.4 mg, 45% yield; brown solid, mp 74–76 °C, IR (film) 1737, 1702, 1460, 1370, 1291, 1186 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.84 (d, J = 10.0 Hz, 0.3H), 7.72 (d, J = 10.0 Hz, 1.7H), 7.68 (d, J = 5.0 Hz, 1.7H), 7.44 (d, J = 5.0 Hz, 0.3H), 7.37 (d, J = 10.0 Hz, 1H), 7.32 (t, J = 5.0 Hz, 1H), 7.29–7.19 (m, 7H), 7.14 (d, J = 10.0 Hz, 0.2H), 4.26–4.14 (m, 2.3H), 4.13–4.04 (m, 3.5H), 3.43 (dd, J = 15.0, 5.0 Hz, 0.9H), 3.32 (dd, J = 15.0, 10.0 Hz, 1H), 2.62 (s, 2.6H), 2.45 (s, 0.4H), 2.40 (s, 0.4H), 2.38 (s, 2.6H), 1.31–1.19 (m, 3.4H), 1.11 (t, J = 10.0 Hz, 2.6H); 13C NMR (125 MHz, CDCl3) δ 199.0, 162.6, 159.1, 153.8, 148.0, 143.8, 137.3, 137.2, 135.1, 131.8, 130.4, 129.9, 129.5, 129.4, 129.4, 128.5, 128.3, 128.0, 127.9, 127.4, 126.9, 126.5, 126.5, 108.9, 85.6, 62.6, 60.9, 58.1, 43.9, 43.7, 42.5, 21.8, 14.1, 14.0. HRMS (ESI) calcd for C33H34NO6 [M + H]+ 540.2381, found 540.2386.
Footnote |
† Electronic supplementary information (ESI) available: Experimental procedures, X-ray crystal structures of compounds 6 and 7. CCDC 2068718 and 2068719. Copies of NMR spectra. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/d1ra06063e |
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