Self [3 + 4] Cycloadditions of Isatin N,N′-Cyclic Azomethine Imine 1,3

Article Cite This: J. Org. Chem. 2018, 83, 8410−8416

pubs.acs.org/joc

Self [3 + 4] Cycloadditions of Isatin N,N′‑Cyclic Azomethine Imine 1,3Dipole with N‑(o‑Chloromethyl)aryl Amides Qiaomei Jin,*,†,‡ Jian Zhang,†,‡ Cuihua Jiang,†,‡ Dongjian Zhang,†,‡ Meng Gao,†,‡ and Shihe Hu*,†,‡ †

Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, Jiangsu, China ‡ Laboratories of Translational Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, Jiangsu, China

Downloaded via UNIV OF SOUTH DAKOTA on August 3, 2018 at 17:20:17 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

S Supporting Information *

ABSTRACT: A [3 + 4] annulation of isatin N,N′-cyclic azomethine imine 1,3-dipole 1 with in situ-generated aza-oQMs has been established for the synthesis of spirooxindole seven-membered scaffolds. These highly functionalized scaffolds were assembled in moderate to good yields (up to 96% yield). The novel spirooxindole scaffolds displayed moderate antitumor activities, which represented promising lead compounds for antitumor drug discovery.

■

INTRODUCTION Spirooxindole alkaloids with a spiro ring fusion at the 3position of the oxindole backbone have pronounced and diverse bioactivity.1 C3-modified spirooxindoles with a rigid nitrogen heterocyclic system are effective at inhibiting cancer cell proliferation, such as spirooxindole derivatives bearing fivemembered2 and six-membered3 N-heterocycle moieties. Thus, the development of efficient synthetic approaches to diverse spirooxindole five-membered and six-membered heterocycles is of great importance for drug discovery. Several groups have achieved synthesis of these C3-modified spirooxindoles using the organo- or organometallic-catalytic asymmetric cascade strategies.4 Nevertheless, to the best of our knowledge, methods toward the construction of spirooxindole sevenmembered heterocycles are still challenging and rare. Maybe these nitrogen-containing seven-membered heterocyclic compounds possess anticancer activities like that of spirooxindole five-membered and six-membered heterocycles (Figure 1). In 2003, Fu’s group5 reported the first example of catalytic asymmetric 1,3-dipolar cycloaddition of azomethine imines with alkynes, the azomethine imine molecules are among the most powerful 1,3-dipole for the construction of carbon− carbon and heterocycles over the past decade.6 Among such uses, both transition metal catalysts7 and organocatalysts8 have been introduced to promote 1,3-dipolar [3 + 2] cycloadditions between azomethine imines and various alkynes/alkenes to build a variety of five-membered heterocyclic frameworks (Scheme 1a). In addition to the common [3 + 2] reaction pathway, 1,3-dipolar [3 + 3] cycloadditions of azomethine imines, which are a complement to the concerted Diels−Alder © 2018 American Chemical Society

cycloaddition reaction, offer an advantage for the synthesis of diverse six-membered heterocyclic compounds (Scheme 1a).9 However, the related [3 + 4] cycloadditions of azomethine imines that can form seven-membered heterocyclic derivatives are much less studied. Since the first example of [4 + 2] cycloaddition reported by Corey and Steinhagen, aza-o-quinone methides (aza-oQMs), in situ-generated through the base-mediated elimination of N-(ochloromethyl)aryl amides, have been widely applied as useful synthons in [4 + m] cycloaddition reactions.10 Recently, Xiao’s group established [4 + 1] cycloadditions of sulfur ylides and aza-oQMs,11 and Scheidt’s group developed an efficient approach to dihydroquinolones via an organocatalytic [4 + 1] cycloaddition by combining aza-oQMs with acyl anion.12a They also reported [4 + 2] cycloadditions of enolate equivalents with aza-oQMs in the presence of N-heterocyclic carbenes in 2014.12b Very recently, Shi’s group reported a [4 + 3] cycloaddition of o-hydroxybenzyl alcohols with of N,N′-cyclic azomethine imines under Brønsted acid catalysis.12c Despite those elegant contributions, [4 + 3] cycloadditions of azaoQMs are still appealing and highly desirable. Given our ongoing interest in 1,3-dipolar cycloaddition and spirooxindole alkaloids, we envisioned a direct pathway to access spirooxindole seven-membered heterocycles via a [3 + 4] annulation of a 1,3-dipole (isatin N,N′-cyclic azomethine imine 1,3-dipole 1) with the in situ-formed aza-oQMs (Scheme 1b). These dipoles Received: April 26, 2018 Published: May 30, 2018 8410

DOI: 10.1021/acs.joc.8b01055 J. Org. Chem. 2018, 83, 8410−8416

Article

The Journal of Organic Chemistry

Figure 1. Representative biologically active compounds containing the 3-heterocyclic system substituted oxindole skeleton.

Table 1. Optimization of the Reaction Conditionsa

Scheme 1. (a) Different Reaction Models of Azomethine Imines. (b) Design of the [3 + 4] Cycloaddition

entry

base (equiv)

solvent

temp (°C)

time (h)

yield of 3a (%)b

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

0 K2CO3 (2.0) Na2CO3 (2.0) Cs2CO3 (2.0) t-BuOK (2.0) NaOH (2.0) KOH (2.0) NEt3 (2.0) DIPEA (2.0) DMAP (2.0) Cs2CO3 (2.0) Cs2CO3 (2.0) Cs2CO3 (2.0) Cs2CO3 (2.0) Cs2CO3 (2.0) Cs2CO3 (2.0) Cs2CO3 (4.0)

CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN DMF 1,4-dioxane toluene THF DCE CH3CN CH3CN

reflux 55 55 55 55 55 55 55 55 55 55 55 55 55 55 rt 55

24 10 10 2 10 15 15 1 2 5 2 2 5 2 2 24 1

0 42(35)c 35 73 trace trace trace 29 23 0 62 32 trace trace 100 7.03 N.D. 4.47 >100 5.12 >100 >100 >100 >100 1.08

N.D. 15.50 N.D. 5.141 20.61 N.D. N.D. N.D. N.D. N.D. N.D. N.D. N.D. 1.15

EXPERIMENTAL SECTION

General Information. All reactions were performed in anhydrous solvents under an argon atmosphere and were monitored by thin-layer chromatography carried out on silica gel aluminum sheets (60F-254), and spots were visualized with UV light. All solvents were purchased from commercial suppliers and were purified according to standard procedures. 1,3-Dipoles 114 and N-(o-chloromethyl)aryl amides 215 can be prepared according to known procedures. 1H NMR and 13C NMR spectra were recorded at room temperature on Bruker Avance 400 spectrometers. Chemical shifts were reported in parts per million (ppm, δ units), and tetramethylsilane (TMS) was used as an internal reference. Coupling constants (J) were expressed in hertz. Highresolution mass spectra (HRMS) were recorded on TOF perimer for ESI+. General Procedure for the [3 + 4] Annulation of Isatin N,N′Cyclic Azomethine Imine 1,3-Dipole 1 with the N-(o-Chloromethyl)aryl Amides 2. To the solution of isatin N,N′-cyclic azomethine imine 1,3-dipole 1 (0.2 mmol) and N-(o-chloromethyl)aryl amides 2 (0.25 mmol) in CH3CN (2 mL) was added Cs2CO3 (2.0 equiv). The resulting mixture was stirred and heated at 55 °C under argon atmosphere for the required period of time. After completion of the reaction as monitored by TLC, the solvents were evaporated under reduced pressure and the residue was purified by silica gel chromatography (PE/EtOAc, 2:1) to afford the product 3. Methyl (S)-1′-Benzyl-1,2′-dioxo-2,3-dihydro-1H-spiro[benzo[e]pyrazolo[1,2-a][1,2,4]triazepine-5,3′-indoline]-6(11H)-carboxylate (3a). White solid (68 mg, 73%), mp: 199−200 °C. 1H NMR (400 MHz, CDCl3) δ 7.49−7.44 (m, 3H), 7.41 (s, 2H), 7.38−7.28 (m, 5H), 7.17 (d, J = 7.1 Hz, 1H), 7.04 (t, J = 7.3 Hz, 1H), 6.89 (dd, J = 21.1, 7.7 Hz, 1H), 5.15−4.87 (m, 4H), 3.59 (s, 3H), 2.96−2.89 (m, 1H), 2.69−2.62 (m, 1H), 2.40−2.31 (m, 1H), 2.17−2.11 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 170.8, 169.8, 153.8, 143.7, 138.6, 135.9, 131.7, 130.8, 129.01, 128.9, 128.7, 128.4, 128.4, 127.8, 125.8, 123.7, 123.2, 109.5, 79.2, 53.4, 46.7, 44.6, 44.0, 30.7. HRMS calcd for C27H24N4O4Na [M + Na]+ 491.1695, found 491.1689. Methyl (S)-1′-Methyl-1,2′-dioxo-2,3-dihydro-1H-spiro[benzo[e]pyrazolo[1,2-a][1,2,4]triazepine-5,3′-indoline]-6(11H)-carboxylate (3b). White solid (37 mg, 48%), mp: 239−240 °C. 1H NMR (400 MHz, CDCl3) δ 7.49−7.36 (m, 4H), 7.32 (t, J = 7.3 Hz, 1H), 7.17 (d, J = 7.1 Hz, 1H), 7.07 (t, J = 7.4 Hz, 1H), 6.92−6.85 (m, 1H), 5.03− 4.94 (m, 2H), 3.55 (s, 3H), 3.34 (s, 3H), 2.98−2.91 (m, 1H), 2.71− 2.64 (m, 1H), 2.50−2.46 (m, 1H), 2.29−2.13 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 170.9, 169.7, 153.8, 144.4, 138.4, 131.6, 130.9, 130.4, 129.4, 128.9, 128.6, 128.3, 128.3, 125.8, 123.5, 123.1, 108.5, 79.2, 53.2, 46.6, 44.0, 30.8, 26.6. HRMS calcd for C21H20N4O4Na [M + Na]+ 415.1382, found 415.1375. Methyl (S)-1′-Isopropyl-1,2′-dioxo-2,3-dihydro-1H-spiro[benzo[e]pyrazolo[1,2-a][1,2,4]triazepine-5,3′-indoline]-6(11H)-carboxylate (3c). White solid (64 mg, 76%), mp: 251−252 °C. 1H NMR (400 MHz, CDCl3) δ 7.45−7.42 (m, 1H), 7.42−7.33 (m, 3H), 7.30−7.27 (m, 1H), 7.17−7.13 (m, 1H), 7.13−7.02 (m, 2H), 5.06−4.90 (m, 2H), 4.79−4.62 (m, 1H), 3.54 (s, 3H), 3.00−2.92 (m, 1H), 2.75−2.65 (m, 1H), 2.55−2.51 (m, 1H), 2.29−2.14 (m, 1H), 1.59 (d, J = 7.1 Hz, 3H), 1.56 (d, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 170.4, 169.8, 153.7, 138.6, 131.7, 130.6, 129.3, 128.9, 128.6, 128.4, 128.2, 126.2, 123.8, 122.5, 110.0, 78.7, 53.1, 46.6, 44.3, 43.8, 30.9, 19.4, 18.9. HRMS calcd for C23H24N4O4Na [M + Na]+ 443.1695, found 443.1699. Methyl (S)-1′-Allyl-1,2′-dioxo-2,3-dihydro-1H-spiro[benzo[e]pyrazolo[1,2-a][1,2,4]triazepine-5,3′-indoline]-6(11H)-carboxylate

Not determined.

exhibited moderate to good antitumor activities against MCF-7 breast cancer cells at low micromolar concentrations. However, these compounds showed little bioactivity against MDA-MB231 cells. Among all the compounds, 3b (7.26 μM, 15.50 μM) and 3f (7.03 μM, 20.61 μM) showed the best antitumor activities against these two breast cancer lines. These results suggest that seven-membered N-heterocycle-fused spirooxindoles framework could be a new template for the design of novel anticancer molecules.

■

CONCLUSION In summary, we have established an efficient method for the [3 + 4] annulation of isatin N,N′-cyclic azomethine imine 1,3dipole 1 with in situ-generated aza-oQMs, which constructed biologically important spirooxindole seven-membered scaffolds in considerable yields (up to 96% yield). The present methodology is a mild, practical, and one-pot method. The in vitro antitumor activity assay indicated that these scaffolds displayed moderate antitumor activities. Further chemical modification and biological exploration of these compounds are underway in our laboratory. 8413

DOI: 10.1021/acs.joc.8b01055 J. Org. Chem. 2018, 83, 8410−8416

Article

The Journal of Organic Chemistry (3d). White solid (74 mg, 89%), mp: 248−249 °C. 1H NMR (400 MHz, CDCl3) δ 7.49−7.43 (m, 1H), 7.41−7.35 (m, 3H), 7.31 (d, J = 7.7 Hz, 1H), 7.17 (d, J = 7.1 Hz, 1H), 7.06 (t, J = 7.4 Hz, 1H), 6.94 (d, J = 7.8 Hz, 1H), 5.98−5.84 (m, 1H), 5.43 (d, J = 17.2 Hz, 1H), 5.30 (d, J = 10.2 Hz, 1H), 5.08−4.90 (m, 2H), 4.54−4.37 (m, 2H), 3.55 (s, 3H), 3.01−2.94 (m, 1H), 2.75−2.69 (m, 1H), 2.60−2.47 (m, 1H), 2.27−2.14 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 170.5, 169.7, 153.7, 143.5, 138.5, 131.6, 131.3, 130.7, 128.9, 128.6, 128.4, 128.2, 125.8, 123.5, 123.0, 118.7, 118.3, 109.4, 79.1, 53.2, 46.6, 43.9, 42.9, 30.8. HRMS calcd for C23H22N4O4Na [M + Na]+ 441.1539, found 441.1543. Methyl (S)-1′-Benzyl-5′-methyl-1,2′-dioxo-2,3-dihydro-1H-spiro[benzo[e]pyrazolo[1,2-a][1,2,4]triazepine-5,3′-indoline]-6(11H)-carboxylate (3f). White solid (49 mg, 51%), mp: 225−226 °C. 1H NMR (400 MHz, CDCl3) δ 7.50−7.42 (m, 3H), 7.43−7.37 (m, 2H), 7.36− 7.27 (m, 4H), 7.10 (t, J = 9.2 Hz, 1H), 6.98 (s, 1H), 6.79−6.72 (m, 1H), 5.10−4.89 (m, 4H), 3.59 (s, 3H), 2.95−2.88 (m, 1H), 2.71−2.59 (m, 1H), 2.39−2.32 (m, 1H), 2.29 (s, 3H), 2.19−2.06 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 170.7, 169.7, 153.8, 136.0, 132.9, 131.7, 131.1, 129.0, 128.9, 128.6, 128.4, 128.3, 127.8, 124.4, 109.3, 79.4, 53.3, 46.6, 44.6, 44.0, 307, 21.1. HRMS calcd for C28H26N4O4Na [M + Na]+ 505.1852, found 505.1858. Methyl (S)-1′-Benzyl-5′-methoxy-1,2′-dioxo-2,3-dihydro-1Hspiro[benzo[e]pyrazolo[1,2-a][1,2,4]triazepine-5,3′-indoline]-6(11H)-carboxylate (3g). White solid (96 mg, 96%), mp: 198−199 °C. 1 H NMR (400 MHz, CDCl3) δ 7.48−7.43 (m, 3H), 7.42−7.27 (m, 6H), 6.89−6.70 (m, 3H), 5.09−4.89 (m, 4H), 3.73 (s, 3H), 3.59 (s, 3H), 2.98−2.90 (m, 1H), 2.74−2.56 (m, 1H), 2.42−2.34 (m, 1H), 2.22−2.06 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 170.6, 169.7, 156.2, 153.8, 138.6, 137.0, 136.0, 131.7, 129.0, 128.9, 128.7, 128.3, 127.8, 114.8, 111.1, 110.0, 79.4, 55.7, 53.3, 46.7, 44.7, 44.0, 30.7. HRMS calcd for C28H26N4O5Na [M + Na]+ 521.1801, found 521.1803. Methyl (S)-1′-Benzyl-5′-chloro-1,2′-dioxo-2,3-dihydro-1H-spiro[benzo[e]pyrazolo[1,2-a][1,2,4]triazepine-5,3′-indoline]-6(11H)-carboxylate (3h). White solid (48 mg, 48%), mp: 250−251 °C. 1H NMR (400 MHz, CDCl3) δ 7.51−7.43 (m, 3H), 7.40 (d, J = 4.3 Hz, 2H), 7.38−7.26 (m, 5H), 7.14 (d, J = 1.2 Hz, 1H), 6.79 (dd, J = 16.5, 8.3 Hz, 1H), 5.13−4.89 (m, 4H), 3.61 (s, 3H), 3.01−2.93 (m, 1H), 2.71− 2.57 (m, 1H), 2.40−2.31 (m, 1H), 2.22−2.07 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 170.4, 169.6, 153.9, 142.2, 138.2, 135.4, 131.5, 130.7, 129.2, 129.0, 128.7, 128.5, 128.3, 128.0, 127.7, 127.4, 124.1, 110.5, 79.0, 53.4, 46.6, 44.7, 44.0, 30.5. HRMS calcd for C27H23N4O4ClNa [M + Na]+ 525.1306, found 525.1312. Methyl (S)-1′-Benzyl-8-chloro-1,2′-dioxo-2,3-dihydro-1H-spiro[benzo[e]pyrazolo[1,2-a][1,2,4]triazepine-5,3′-indoline]-6(11H)-carboxylate (3i). White solid (51 mg, 51%), mp: 166−167 °C. 1H NMR (400 MHz, CDCl3) δ 7.49 (d, J = 7.4 Hz, 2H), 7.41−7.30 (m, 7H), 7.20 (d, J = 7.2 Hz, 1H), 7.13−7.08 (m, 1H), 6.97−6.82 (m, 1H), 5.15−4.89 (m, 4H), 3.63 (s, 3H), 3.00−2.83 (m, 1H), 2.66−2.57 (m, 1H), 2.31−2.19 (m, 1H), 2.18−2.09 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 170.4, 169.7, 135.8, 134.2, 131.0, 130.2, 129.5, 128.9, 128.6, 128.4, 127.9, 127.8, 123.6, 123.3, 109.6, 79.4, 53.5, 46.0, 44.6, 44.00, 30.6. HRMS calcd for C27H23N4O4ClNa [M + Na]+ 525.1306, found 525.1315. Methyl (S)-1′-Benzyl-8-fluoro-1,2′-dioxo-2,3-dihydro-1H-spiro[benzo[e]pyrazolo[1,2-a][1,2,4]triazepine-5,3′-indoline]-6(11H)-carboxylate (3j). White solid (38 mg, 39%), mp: 175−176 °C. 1H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 7.3 Hz, 2H), 7.38−7.29 (m, 5H), 7.18 (d, J = 7.0 Hz, 1H), 7.13−7.04 (m, 3H), 6.93−6.85 (m, 1H), 5.13−4.87 (m, 4H), 3.60 (s, 3H), 2.94−2.87 (m, 1H), 2.65−2.54 (m, 1H), 2.38−2.90 (m, 1H), 2.21−2.07 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 170.5, 169.6, 163.8, 161.3, 153.4, 135.8, 130.9, 129.6 (d, J = 36.0 Hz), 128.9, 127.9, 127.9, 127.8, 127.7, 123.6, 123.3, 116.1, 115.9, 115.3, 115.1, 109.6, 79.4, 53.5, 45.9, 44.6, 44.0, 30.6. HRMS calcd for C27H23N4O4FNa [M + Na]+ 509.1601, found 509.1607. Methyl (S)-1′-Benzyl-7-methyl-1,2′-dioxo-2,3-dihydro-1H-spiro[benzo[e]pyrazolo[1,2-a][1,2,4]triazepine-5,3′-indoline]-6(11H)-carboxylate (3l). White solid (37 mg, 38%), mp: 201−202 °C. 1H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 7.4 Hz, 2H), 7.37−7.28 (m, 5H), 7.23−7.13 (m, 3H), 7.03 (t, J = 7.4 Hz, 1H), 6.93−6.84 (m, 1H), 5.09

(d, J = 15.4 Hz, 1H), 5.01−4.89 (m, 3H), 3.58 (s, 3H), 3.01−2.85 (m, 1H), 2.72−2.58 (m, 1H), 2.42 (s, 3H), 2.40−2.30 (m, 1H), 2.17−2.08 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 170.9, 169.7, 153.9, 143.7, 138.4, 135.9, 131.4, 130.8, 129.6, 129.4, 128.9, 128.1, 127.8, 123.7, 123.1, 109.5, 79.1, 53.3, 46.7, 44.6, 43.9, 30.7, 21.2. HRMS calcd for C28H26N4O4Na [M + Na]+ 505.1852, found 505.1855. Methyl (S)-1′-Benzyl-9-bromo-1,2′-dioxo-2,3-dihydro-1H-spiro[benzo[e]pyrazolo[1,2-a][1,2,4]triazepine-5,3′-indoline]-6(11H)-carboxylate (3m). White solid (48 mg, 44%), mp: 199−200 °C. 1H NMR (400 MHz, CDCl3) δ 7.62−7.51 (m, 2H), 7.47 (d, J = 7.3 Hz, 2H), 7.39−7.28 (m, 4H), 7.19−7.12 (m, 2H), 7.04 (t, J = 7.4 Hz, 1H), 6.95−6.80 (m, 1H), 5.15−4.88 (m, 4H), 3.58 (s, 3H), 2.92−2.87 (m, 1H), 2.72−2.55 (m, 1H), 2.46−2.28 (m, 1H), 2.16−2.07 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 170.5, 169.8, 153.5, 135.8, 133.6, 132.1, 131.6, 130.9, 130.0, 128.9, 127.9, 127.7, 123.5, 123.3, 121.6, 109.6, 79.2, 53.4, 46.2, 44.6, 44.0, 30.6. HRMS calcd for C27H23N4O4BrNa [M + Na]+ 569.0800, found 569.0810. Benzyl (S)-1′-Benzyl-1,2′-dioxo-2,3-dihydro-1H-spiro[benzo[e]pyrazolo[1,2-a][1,2,4]triazepine-5,3′-indoline]-6(11H)-carboxylate (3n). White solid (25 mg, 23%), mp: 169−170 °C. 1H NMR (400 MHz, CDCl3) δ 7.52−7.48 (m, 2H), 7.40−7.27 (m, 9H), 7.25−7.14 (m, 3H), 7.10−7.04 (m, 3H), 6.87−6.80 (m, 1H), 5.14−4.90 (m, 5H), 4.89−4.61 (m, 1H), 2.98−2.74 (m, 1H), 2.70−2.45 (m, 1H), 2.42− 2.26 (m, 1H), 2.23−2.04 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 170.9, 169.7, 135.9, 131.6, 131.5, 130.8, 128.9, 128.6, 128.5, 128.4, 128.4, 128.3, 127.8, 127.2, 123.7, 123.2, 109.5, 100.0, 79.2, 46.7, 44.0, 30.7, 14.2. HRMS calcd for C33H28N4O4Na [M + Na]+ 567.2008, found 567.2012. tert-Butyl (S)-1′-Benzyl-1,2′-dioxo-2,3-dihydro-1H-spiro[benzo[e]pyrazolo[1,2-a][1,2,4]triazepine-5,3′-indoline]-6(11H)-carboxylate (3p). White solid (58 mg, 57%), mp: 199−201 °C. 1H NMR (400 MHz, CDCl3) δ 7.52−7.43 (m, 3H), 7.38−7.27 (m, 7H), 7.136−7.10 (m, 1H), 7.05−6.96 (m, 1H), 6.98−6.81 (m, 1H), 5.16−4.72 (m, 4H), 2.90−2.71 (m, 1H), 2.68−2.48 (m, 1H), 2.44−2.13 (m, 1H), 2.05− 1.91 (m, 1H), 1.26 (s, 9H). 13C NMR (100 MHz, CDCl3) δ 171.0, 170.8, 153.2, 140.6, 139.5, 136.1, 135.5, 131.5, 130.4, 129.0, 128.7, 128.4, 128.2, 127.7, 127.3, 123.5, 109.4, 81.2, 47.9, 46.7, 44.5, 43.8, 30.8, 28.1, 27.8. HRMS calcd for C30H30N4O4Na [M + Na]+ 533.2165, found 533.2168. Methyl 1-Oxo-5-phenyl-2,3-dihydro-1H,5H-benzo[e]pyrazolo[1,2-a][1,2,4]triazepine-6(11H)-carboxylate (5). White solid (53 mg, 78%), mp: 193−194 °C. 1H NMR (400 MHz, CDCl3) δ 7.41−7.30 (m, 5H), 7.21 (s, 2H), 6.73 (d, J = 7.6 Hz, 1H), 6.14 (s, 1H), 4.92 (d, J = 14.5 Hz, 1H), 4.70−4.50 (m, 1H), 3.90−3.75 (m, 1H), 3.63 (s, 3H), 3.33 (d, J = 8.5 Hz, 1H), 3.10−2.90 (m, 2H), 2.39−2.21 (m, 1H).13C NMR (100 MHz, CDCl3) δ 171.4, 155.5, 133.1, 130.5, 129.0, 128.5, 128.3, 128.3, 128.2, 128.1, 78.8, 53.2, 48.5, 47.3, 30.0. HRMS calcd for C19H19N3O3Na [M + Na]+ 360.1324, found 360.1329.

■

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b01055. X-ray data of 3a (CIF) H and 13C NMR spectra of final products (PDF)

1

■

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Qiaomei Jin: 0000-0002-8559-9125 Jian Zhang: 0000-0002-8402-9753 Notes

The authors declare no competing financial interest. 8414

DOI: 10.1021/acs.joc.8b01055 J. Org. Chem. 2018, 83, 8410−8416

Article

The Journal of Organic Chemistry

■

10962. (f) Shi, F.; Xing, G. J.; Zhu, R. Y.; Tan, W.; Tu, S. A catalytic asymmetric isatin-involved Povarov reaction: Diastereo- and enantioselective construction of spiro[indolin-3,2′-quinoline] scaffold. Org. Lett. 2013, 15, 128−131. (g) Zhu, Y.; Li, Y.; Meng, Q.; Li, X. An organocatalytic enantioselective vinylogous Mannich reaction of α,αdicyanoolefins with isatin N-Boc ketimines. Org. Chem. Front. 2016, 3, 709−713. (h) Xie, D.; Yang, L.; Lin, Y.; Zhang, Z.; Chen, D.; Zeng, X.; Zhong, G. Rapid access to spirocylic oxindoles: application of asymmetric N-heterocyclic carbene-catalyzed [3 + 3] cycloaddition of imines to oxindole-derived enals. Org. Lett. 2015, 17, 2318−2321. (5) (a) Shintani, R.; Fu, G. C. A new copper-catalyzed [3 + 2] cycloaddition: Enantioselective coupling of terminal alkynes with azomethine imines to generate five-membered nitrogen heterocycles. J. Am. Chem. Soc. 2003, 125, 10778−10779. (b) Suarez, A.; Downey, C. W.; Fu, G. C. Kinetic resolutions of azomethine imines via coppercatalyzed [3 + 2] cycloadditions. J. Am. Chem. Soc. 2005, 127, 11244− 11245. (6) For selected 1,3-dipolar cycloaddition reviews, see: (a) Gothelf, K. V.; Jørgensen, K. A. Asymmetric 1,3-Dipolar cycloaddition reactions. Chem. Rev. 1998, 98, 863−910. (b) Stanley, L. M.; Sibi, M. P. Enantioselective copper-catalyzed 1,3-dipolar cycloadditions. Chem. Rev. 2008, 108, 2887−2902. (c) Hashimoto, T.; Maruoka, K. Recent advances of catalytic asymmetric 1,3-dipolar cycloadditions. Chem. Rev. 2015, 115, 5366−5412. (7) (a) Suga, H.; Funyu, A.; Kakehi, A. Highly enantioselective and diastereoselective 1,3-dipolar cycloaddition reactions between azomethine imines and 3-acryloyl-2-oxazolidinone catalyzed by binaphthyldiimine−Ni(II) complexes. Org. Lett. 2007, 9, 97−100. (b) Sibi, M. P.; Rane, D.; Stanley, L. M.; Soeta, T. Copper(II)-catalyzed exo and enantioselective cycloadditions of azomethine imines. Org. Lett. 2008, 10, 2971−2974. (c) Yoshimura, K.; Oishi, T.; Yamaguchi, K.; Mizuno, N. An efficient, ligand-free, heterogeneous supported copper hydroxide catalyst for the synthesis of n,n-bicyclic pyrazolidinone derivatives. Chem. - Eur. J. 2011, 17, 3827−3831. (d) Imaizumi, T.; Yamashita, Y.; Kobayashi, S. Group 11 metal amide-catalyzed asymmetric cycloaddition reactions of azomethine imines with terminal alkynes. J. Am. Chem. Soc. 2012, 134, 20049−20052. (e) Li, J.; Lian, X.; Liu, X.; Lin, L.; Feng, X. Nickel(II)-catalyzed enantioselective 1,3-dipolar cycloaddition of azomethine imines with alkylidene malonates. Chem. - Eur. J. 2013, 19, 5134−5140. (f) Yin, C. K.; Lin, L. L.; Zhang, D.; Feng, J. H.; Liu, X. H.; Feng, X. M. Asymmetric [3 + 2] Cycloaddition of Methyleneindolinones with N,N′-Cyclic Azomethine Imines Catalyzed by a N,N′-DioxideMg(OTf)2 Complex. J. Org. Chem. 2015, 80, 9691−9699. (8) (a) Chen, W.; Du, W.; Duan, Y. Z.; Wu, Y.; Yang, S. Y.; Chen, Y. C. Enantioselective 1,3-dipolar cycloaddition of cyclic enones catalyzed by multifunctional primary amines: Beneficial effects of hydrogen bonding. Angew. Chem., Int. Ed. 2007, 46, 7667−7670. (b) Na, R.; Jing, C.; Xu, Q.; Jiang, H.; Wu, X.; Shi, J.; Zhong, J.; Wang, M.; Benitez, D.; Tkatchouk, E.; Goddard, W. A.; Guo, H.; Kwon, O. Phosphinecatalyzed annulations of azomethine imines: Allene-dependent [3 + 2], [3 + 3], [4 + 3], and [3 + 2 + 3] pathways. J. Am. Chem. Soc. 2011, 133, 13337−13348. (c) Hong, L.; Kai, M.; Wu, C.; Sun, W.; Zhu, G.; Li, G.; Yao, X.; Wang, R. Enantioselective 1,3-dipolar cycloaddition of methyleneindolinones and N,N′-cyclic azomethine imines. Chem. Commun. 2013, 49, 6713−6715. (d) Pair, E.; Berini, C.; Noel, R.; Sanselme, M.; Levacher, V.; Briere, J. F. Organocatalysed multicomponent synthesis of pyrazolidinones: Meldrum’s acid approach. Chem. Commun. 2014, 50, 10218−10221. (9) For [3 + 2], [3 + 3], and [3 + 4] cycloadditions of azomethine imines: (a) Shintani, R.; Hayashi, T. Palladium-catalyzed [3 + 3] cycloaddition of trimethylenemethane with azomethine imines. J. Am. Chem. Soc. 2006, 128, 6330−6331. (b) Chan, A.; Scheidt, K. A. Highly stereoselective formal [3 + 3] cycloaddition of enals and azomethine imines catalyzed by N-heterocyclic carbenes. J. Am. Chem. Soc. 2007, 129, 5334−5335. (c) Shapiro, N. D.; Shi, Y.; Toste, F. D. Goldcatalyzed [3 + 3]-annulation of azomethine imines with propargyl esters. J. Am. Chem. Soc. 2009, 131, 11654−11655. (d) Xu, X.; Qian, Y.; Zavalij, P. Y.; Doyle, M. P. Highly selective catalyst-dependent

ACKNOWLEDGMENTS We sincerely thank the China Pharmaceutical University for providing spectra.

■

REFERENCES

(1) (a) Galliford, C. V.; Scheidt, K. A. Pyrrolidinyl-spirooxindole natural products as inspirations for the development of potential therapeutic agents. Angew. Chem., Int. Ed. 2007, 46, 8748−8758. (b) Xia, M.; Ma, R. Z. Recent progress on routes to spirooxindole systems derived from isatin. J. Heterocycl Chem. 2014, 51, 539−554. (c) Santos, M. M. M. Recent advances in the synthesis of biologically active spirooxindoles. Tetrahedron 2014, 70, 9735−9757. (d) Ye, N.; Chen, H.; Wold, E. A.; Shi, P. Y.; Zhou, J. Therapeutic potential of spirooxindoles as antiviral agents. ACS Infect. Dis. 2016, 2, 382−392. (e) Cheng, D. J.; Ishihara, Y.; Tan, B.; Barbas, C. F. Organocatalytic asymmetric assembly reactions: Synthesis of spirooxindoles via organocascade strategies. ACS Catal. 2014, 4, 743−762. (f) Mei, G. J.; Shi, F. Catalytic asymmetric synthesis of spirooxindoles: Recent developments. Chem. Commun. 2018, DOI: 10.1039/C8CC02364F. (g) Zhang, Y.; Panek, J. S. Stereocontrolled synthesis of spirooxindoles through Lewis acid-promoted [5 + 2]-annulation of chiral silyl alcohols. Org. Lett. 2009, 11, 3366−3369. (h) Chen, H.; Shi, D. Q. Efficient one-pot synthesis of spiro[indoline-3,4′-pyrazolo[3,4-e][1,4]thiazepine]dione via three-component reaction. Tetrahedron 2011, 67, 5686−5692. (i) Wang, Y.; Shi, F.; Yao, X. X.; Sun, M.; Dong, L.; Tu, S. J. Catalytic asymmetric construction of 3,3′-spirooxindoles fused with seven-membered rings by enantioselective tandem reactions. Chem. Eur. J. 2014, 20, 15047−15052. (2) (a) Zhao, Y.; Yu, S.; Sun, W.; Liu, L.; Lu, J.; McEachern, D.; Shargary, S.; Bernard, D.; Li, X.; Zhao, T.; Zou, P.; Sun, D.; Wang, S. A potent small-molecule inhibitor of the MDM2-p53 interaction (MI888) achieved complete and durable tumor regression in mice. J. Med. Chem. 2013, 56, 5553−5561. (b) Aguilar, A.; Lu, J.; Liu, L.; Du, D.; Bernard, D.; McEachern, D.; Przybranowski, S.; Li, X.; Luo, R.; Wen, B.; Sun, D.; Wang, H.; Wen, J.; Wang, G.; Zhai, Y.; Guo, M.; Yang, D.; Wang, S. Discovery of 4-((3′R,4′S,5′R)-6″-Chloro-4′-(3-chloro-2fluorophenyl)-1′-ethyl-2″-oxodispiro[cyclohexane-1,2′-pyrrolidine3′,3″-indoline]-5′-carboxamido)bicyclo[2.2.2]octane-1-carboxylic Acid (AA-115/APG-115): A Potent and Orally Active Murine Double Minute 2 (MDM2) Inhibitor in Clinical Development. J. Med. Chem. 2017, 60, 2819−2839. (c) Ribeiro, C. J. A.; Amaral, J. D.; Rodrigues, C. M. P.; Moreira, R.; Santos, M. M. M. Spirooxadiazoline oxindoles with promising in vitro antitumor activities. MedChemComm 2016, 7, 420−425. (d) Bertamino, A.; Soprano, M.; Musella, S.; Rusciano, M. R.; Sala, M.; Vernieri, E.; Di Sarno, V.; Limatola, A.; Carotenuto, A.; Cosconati, S.; Grieco, P.; Novellino, E.; Illario, M.; Campiglia, P.; Gomez-Monterrey, I. Synthesis, in vitro, and in cell studies of a new series of [indoline-3,2′-thiazolidine]-based p53 modulators. J. Med. Chem. 2013, 56, 5407−5421. (3) Ding, Q.; Liu, J. J.; Zhang, Z. Spiroindolinone derivatives. Patent Appl. WO2007104714A1, 2007. (4) (a) Zhao, S.; Lin, J. B.; Zhao, Y. Y.; Liang, Y. M.; Xu, P. F. Hydrogen-bond-directed formal [5 + 1] annulations of oxindoles with ester-linked bisenones: Facile access to chiral spirooxindole δ-lactones. Org. Lett. 2014, 16, 1802−1805. (b) Chen, W. B.; Wu, Z. J.; Pei, Q. L.; Cun, L. F.; Zhang, X. M.; Yuan, W. C. Highly enantioselective construction of spiro[4H-pyran-3,3′-oxindoles] through a domino Knoevenagel/Michael/cyclization sequence catalyzed by cupreine. Org. Lett. 2010, 12, 3132−3135. (c) MacDonald, J. P.; Badillo, J. J.; Arevalo, G. E.; Silva-Garcia, A.; Franz, A. K. Catalytic stereoselective synthesis of diverse oxindoles and spirooxindoles from isatins. ACS Comb. Sci. 2012, 14, 285−293. (d) Holmquist, M.; Blay, G.; Munoz, M. C.; Pedro, J. R. Aza-Henry reaction of isatin ketimines with methyl 4-nitrobutyrate en route to spiro[piperidine-3,3′-oxindoles]. Adv. Synth. Catal. 2015, 357, 3857−3862. (e) Zheng, H.; Liu, X.; Xu, C.; Xia, Y.; Lin, L.; Feng, X. Regio- and enantioselective aza-Diels-Alder reactions of 3-vinylindoles: A concise synthesis of the antimalarial spiroindolone NITD609. Angew. Chem., Int. Ed. 2015, 54, 10958− 8415

DOI: 10.1021/acs.joc.8b01055 J. Org. Chem. 2018, 83, 8410−8416

Article

The Journal of Organic Chemistry competitive 1,2-C→C, -O→C, and -N→C migrations from βmethylene-β-silyloxy-β-amido-α-diazoacetates. J. Am. Chem. Soc. 2013, 135, 1244−1247. (e) Zhu, G.; Sun, W.; Wu, C.; Li, G.; Hong, L.; Wang, R. Base-catalyzed diastereoselective [3 + 3] annulation of 3isothiocyanatooxindoles and azomethine imines. Org. Lett. 2013, 15, 4988−4991. (f) Tong, M. C.; Chen, X.; Tao, H. Y.; Wang, C. J. Catalytic asymmetric 1,3-dipolar cycloaddition of two different ylides: facile access to chiral 1,2,4-triazinane frameworks. Angew. Chem., Int. Ed. 2013, 52, 12377−12380. (g) Wang, M.; Huang, Z.; Xu, J.; Chi, Y. R. N-heterocyclic carbene-catalyzed [3 + 4] cycloaddition and kinetic resolution of azomethine imines. J. Am. Chem. Soc. 2014, 136, 1214− 1217. (h) Wei, l.; Wang, Z. F.; Yao, L.; Qiu, G. F.; Tao, H. Y.; Li, H.; Wang, C. J. Copper(II)-catalyzed asymmetric 1,3-Dipolar [3 + 4] cycloaddition and kinetic resolution of azomethine imines with azoalkenes. Adv. Synth. Catal. 2016, 358, 3955−3959. (i) Zhu, R. Y.; Wang, C. S.; Zheng, J.; Shi, F.; Tu, S. J. Organocatalytic asymmetric inverse-electron-demand 1,3-dipolar cycloaddition of N,N′-cyclic azomethine imines. J. Org. Chem. 2014, 79, 9305−9312. (10) (a) Steinhagen, H.; Corey, E. J. A convenient and versatile route to hydroquinolines by inter- and intramolecular Aza-Diels-Alder pathways. Angew. Chem., Int. Ed. 1999, 38, 1928−1931. (b) Avemaria, F.; Vanderheiden, S.; Brase, S. The aza-xylylene Diels−Alder approach for the synthesis of naturally occurring 2-alkyl tetrahydroquinolines. Tetrahedron 2003, 59, 6785−6796. (11) (a) Yang, Q. Q.; Xiao, C.; Lu, L. Q.; An, J.; Tan, F.; Li, B. J.; Xiao, W. J. Synthesis of indoles through highly efficient cascade reactions of sulfur ylides and N-(ortho-chloromethyl)aryl amides. Angew. Chem., Int. Ed. 2012, 51, 9137−9140. (b) Yang, Q. Q.; Wang, Q.; An, J.; Chen, J. R.; Lu, L. Q.; Xiao, W. J. Construction of optically active indolines by formal [4 + 1] annulation of sulfur ylides and N(ortho-chloromethyl)aryl amides. Chem. - Eur. J. 2013, 19, 8401− 8404. (12) (a) Lee, A.; Younai, A.; Price, C. K.; Izquierdo, J.; Mishra, R. K.; Scheidt, K. A. Enantioselective annulations for dihydroquinolones by in situ generation of azolium enolates. J. Am. Chem. Soc. 2014, 136, 10589−10592. (b) Hovey, M. T.; Check, C. T.; Sipher, A. F.; Scheidt, K. A. N-heterocyclic-carbene-catalyzed synthesis of 2-aryl indoles. Angew. Chem., Int. Ed. 2014, 53, 9603−9607. (c) Mei, G. J.; Zhu, Z. Q.; Zhao, J. J.; Bian, C. Y.; Chen, J.; Chen, R. W.; Shi, F. Brønsted acidcatalyzed stereoselective [4 + 3] cycloadditions of ortho-hydroxybenzyl alcohols with N,N′-cyclic azomethine imines. Chem. Commun. 2017, 53, 2768−2771. (13) CCDC 1818995 contains the supplementary crystallographic data for compound 3a. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/ data_request/cif. (14) For selected examples, see: (a) Wang, X.; Yang, P.; Zhang, Y.; Tang, C. Z.; Tian, F.; Peng, L.; Wang, L. X. Isatin N,N′-cyclic azomethine imine 1,3-dipole and abnormal [3 + 2]-cycloaddition with maleimide in the presence of 1,4-diazabicyclo[2.2.2]octane. Org. Lett. 2017, 19, 646−649. (b) Wang, X.; Wu, L.; Yang, P.; Song, X. J.; Ren, H. X.; Peng, L.; Wang, L. X. Isatin N,N′-cyclic azomethine imine 1,3dipole and base catalyzed Michael addition with β-nitrostyrene via C3 umpolung of oxindole. Org. Lett. 2017, 19, 3051−3054. (15) For selected examples, see: (a) Lee, A.; Younai, A.; Price, C. K.; Izquierdo, J.; Mishra, R. K.; Scheidt, K. A. Enantioselective annulations for dihydroquinolones by in situ generation of azolium enolates. J. Am. Chem. Soc. 2014, 136, 10589−10592. (b) Kim, S.; Kang, K. T.; Kim, S. G. Asymmetric domino aza-Michael−Michael reaction of o-Nprotected aminophenyl α,β-unsaturated ketones: Construction of chiral functionalized tetrahydroquinolines. Tetrahedron 2014, 70, 5114−5121.

8416

DOI: 10.1021/acs.joc.8b01055 J. Org. Chem. 2018, 83, 8410−8416