Construction of Unique Eight-or Nine-Membered Polyheterocyclic

Article Cite This: J. Org. Chem. 2019, 84, 622−635

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Construction of Unique Eight- or Nine-Membered Polyheterocyclic Systems via Multicomponent Reaction of L‑Proline, Alkyl Propiolate, and Isatin Jun Cao, Fan Yang, Jing Sun,* Ying Huang, and Chao-Guo Yan* College of Chemistry and Chemical Engineering, Yangzhou University, Yangzhou 225002, China

J. Org. Chem. 2019.84:622-635. Downloaded from pubs.acs.org by IOWA STATE UNIV on 01/18/19. For personal use only.

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ABSTRACT: The multicomponent reaction of L-proline, isatins, and excess of methyl propiolates in methanol unexpectedly afforded 2-(oxoindolin-3-ylidene)propylidene)pyrrolidin-1-yl)acrylates in good yields, and the products subsequently converted to unique nine-membered pyrrolo[1′,2′:1,9]azonino[6,5,4-cd]indoles in the presence of p-TsOH. Furthermore, the multicomponent reaction of L-proline, N-benzylisatins, and excess alkyl propiolates in refluxing chloroform unprecedentedly resulted in eight-membered azocino[1,2-a]benzo[c][1,5]diazocines as the main product. The molecular structures of the polyheterocyclic compounds were confirmed by determination of 19 single crystal structures. The reaction mechanism was believed to contain the sequential 1,3-dipolar cycloaddition, addition of cyclic tertiary amine to excess of propiolate, and fascinating ring opening as well as rearrangement process. The N-substituent on isatins played a critical role in the different reaction patterns.

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INTRODUCTION The spirooxindole system is the core structure of a wide variety of medicinal agents and natural products with broad biological activities, ranging from antitumor, antimicrobial, anti-HIV, and antipyretics agents.1,2 For example, a group of natural products containing spiro[indoline-3,3′-pyrrolizine] is known to possess various bioactivity profiles.3 As a consequence, considerable interest exists in organic and pharmaceutical chemistry for the development of elegant synthetic methodologies for diverse spirooxindole derivatives.4,5 The [3 + 2] cycloaddition of azomethine ylides generated from the addition reaction of isatins with primary amines or α-amino acids has become one of the most convenient synthetic methods for various spirooxindole systems.6−10 In this respect, Singh and coworkers reported that CuI facilitated the three-component reaction of isatin derivatives, L-proline, and terminal alkynes, such as propiolamide and ethyl propiolate, and gave the expected spiro[indoline-3,3′-pyrrolizines] in high yields (Scheme 1, eq 1).11 Recently, we found that a threecomponent reaction of L-proline, isatin, and two molecules of dimethyl acetylenedicarboxylates gave not only the expected spiro[indoline-3,3′-pyrrolizines] through 1,3-dipolar cycloaddition but also the novel seven-membered spiro[indoline3,7′-pyrrolo[1,2-a]azepines] through an annulation reaction (Scheme 1, eq 2).12 We envisioned that a similar sevenmembered product might be produced by using excess methyl propiolate to replace dimethyl acetylenedicarboxylate in the three-component reaction. To continue developing new © 2018 American Chemical Society

multicomponent reactions for the construction of novel spirooxindoles,13 we systematically investigated the threecomponent reaction of L-proline, isatin, and alkyl propiolates and found very interesting results. This three-component reaction afforded not only the unexpected chain 2-(oxoindolin3-ylidene)propylidene)pyrrolidin-1-yl)acrylates (Scheme 1, eq 3) but also unique nine-membered pyrrolo[1′,2′:1,9]azonino[6,5,4-cd]indoles and double eight-membered azocino[1,2a]benzo[c][1,5]diazocines, depending on the molecular structures of the substrates and the reaction conditions.

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RESULTS AND DISCUSSION According to the reaction conditions of the three-component reaction for the formation of spiro[indoline-3,7′-pyrrolo[1,2a]azepines],12 a mixture of L-proline (1.2 mmol), Nbenzylisatin (1.0 mmol), and a large amount of methyl propiolate (3.5 mmol) was stirred in methanol at room temperature for several hours. After work up, instead of formation of the desired seven-membered spirooxindole, the chain product 2-(oxoindolin-3-ylidene)propylidene)pyrrolidin1-yl)acrylate (1a) was obtained in 78% yield. The formation of chain product 1a showed that two molecules of methyl propiolate took part in the reaction and that methyl propiolate played a different role in the reaction than dimethyl acetylenedicarboxylate.14−18 A literature survey indicated that Received: September 24, 2018 Published: December 24, 2018 622

DOI: 10.1021/acs.joc.8b02457 J. Org. Chem. 2019, 84, 622−635

Article

The Journal of Organic Chemistry Scheme 1. Formation of Various Spirooxindoles via Three-Component Reactions

The obtained chain products 1a−1m were fully characterized by IR spectroscopy, HRMS, and 1H and 13C NMR spectroscopy. The 1H NMR spectra clearly indicated that the obtained products 1a−1m contained various proportions of Z/ E isomers with molar ratios in the range of 2:3 to 3:2. Because three CC bonds are present in products 1a−1m, a couple of Z/E isomers might be formed in the reaction. The singlecrystal structures of six compounds 1c (Figure 1), 1d, 1e, 1g,

2-(oxoindolin-3-ylidene)propylidene)pyrrolidin-1-yl)acrylate was prepared from various reactions of methyl propiolate for the first time. Thus, the scope of this reaction was examined by using various N-alkylisatins. The results are summarized in Table 1. Various isatins with N-benzyl, N-n-butyl, and Nmethyl groups reacted smoothly to give the corresponding chain products (1b−1k) in 60−78% yields. Similarly, the reaction with ethyl propiolate in ethanol also gave the chain products (1l−1m) in good yields. These results indicated that the formation of chain products 1a−1m was not an individual event and that this reaction is compatible with a wide variety of substrates. Table 1. Synthesis of 2-(Oxoindolin-3ylidene)propylidene)-pyrrolidin-1-yl)acrylates 1a−1ma

entry

compound

R1

R2

R3

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

1a 1b 1c 1d 1e 1f 1g 1h 1i 1j 1k 1l 1m

H H CH3 CH3 F F Cl Cl H Cl CH3 F Cl

Bn n-Bu Bn n-Bu Bn n-Bu Bn n-Bu CH3 CH3 CH3 Bn Bn

CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 C2H5 C2H5

yield (%, Z/E)b 78 70 72 67 70 62 75 69 70 60 70 70 72

(9:11) (9:11) (9:11) (2:3) (11:9) (11:9) (11:9) (1:1) (3:2) (3:2) (7:4) (11:9) (3:2)

Figure 1. ORTEP drawing (30%) of the crystal structure of 1c.

1h, and 1j ( Figures S1−S5) were successfully determined by X-ray diffraction. The same configuration was observed in all six single-crystal structures. From Figure 1, the two CC bonds connecting the scaffolds of isatin and pyrrolidine have an E configuration, and the terminal N-acrylate unit also has an E configuration. The addition of amines to propiolate or acetylenedicarboxylates is known to usually result in both Z and E isomers of β-enamino esters in varying ratios. Additionally, the Z/E isomers of β-enamino esters exist in equilibrium in solution, which could not be separated by

a

Reaction conditions: isatin (1.0 mmol), L-proline (1.2 mmol), alkyl propiolate (3.5 mmol) in MeOH (15.0 mL), rt, 24 h. bIsolated yield. The ratio of Z/E isomers was determined by 1H NMR spectroscopy. c EtOH was used as the solvent. 623

DOI: 10.1021/acs.joc.8b02457 J. Org. Chem. 2019, 84, 622−635

Article

The Journal of Organic Chemistry Table 2. Three-Component Reaction with Isatins Lacking an N-Substituenta

entry

R1

R2

compound

yield (%)b

compound

yield (%)b

1 2 3 4 5 6 7 8 9 10

5-H 5-CH3 5-OCH3 5-F 5-Cl 6-Cl 6-Br 5-CH3 5-Cl 7-CF3

CH3 CH3 CH3 CH3 CH3 CH3 CH3 C2H5 C2H5 CH3

2a 2b 2c 2d 2e 2f 2g 2h 2i 2j

42 52 38 54 42 38 48 50 46 52

3a 3b 3c 3d 3e 3f 3g 3h 3i

15 20 17 8 12 6 10 9 7

a

Reaction conditions: isatin (1.0 mmol), L-proline (1.2 mmol), alkyl propiolate (3.5 mmol) in MeOH (15.0 mL), rt, 24 h. bIsolated yields.

chromatography.19 Thus, the ratios of Z/E isomers in products 1a−1m might be attributed to the Z/E configuration of the terminal N-acrylate unit. When isatins without an N-substituent were employed in the reaction under the same reaction conditions, the reaction not only gave chain products 2a−2j as the main products but also afforded the unexpected pyrrolo[1′,2′:1,9]azonino[6,5,4-cd]indole-6,13-dicarboxylates 3a−3i in very low yields (Table 2). Because the obtained products 2a−2j and 3a−3i had very similar polarities, it was difficult to separate the two products by column chromatography. However, chain products 2a−2j had a lower solubility in methanol and usually formed precipitates in the reaction mixture, and these precipitates could be directly separated by filtration. The pure cyclized products 3a−3i were obtained from the mother liquor by further chromatography. Various isatins with 5-, 6-, or 7substituents reacted smoothly to give the mixed products, except the corresponding cyclized product 3j was not obtained due to its low yield. The structures of compounds 2a−2j and 3a−3i were fully characterized by IR spectroscopy, HRMS, and 1 H and 13C NMR spectroscopy. The single-crystal structures of compounds 2b (Figure 2), 2d, 2f, 2j (Figures S6−S8), and 3b (Figure 3) were determined by X-ray diffraction. These compounds 2b, 2d, 2f, and 2j had the same configuration as

Figure 3. ORTEP drawing (30%) of the crystal structure of 3b.

the above six compounds 1c, 1d, 1e, 1g, 1h, and 1j. Therefore, we tentatively concluded that all chain compounds 2a−2i had this kind of configuration. From Figure 3, it can be seen that the ring of azonine was formed from two acrylate units connected to the C3 and C4 positions of the oxindole moiety and to the N1 and C2 positions of pyrrolidine. A survey of the literature indicated that aliphatic N-heterocycles containing tertiary amines and propriolates tend to undergo zwitterion formation with subsequent rearrangements and ring opening process,18 and the similar nine-membered azoninones were synthesized from the corresponding vinylpyrrolidines via a zwitterionic aza-Claisen rearrangement.20 Therefore, this is the first example of azonino[6,5,4-cd]indole production in the reactions of isatin and its derivatives, although some reports have described the formation of various heterocyclic systems

Figure 2. ORTEP drawing (30%) of the crystal structure of 2b. 624

DOI: 10.1021/acs.joc.8b02457 J. Org. Chem. 2019, 84, 622−635

Article

The Journal of Organic Chemistry through participation of the reactive C4 position of the oxindole moiety.21 The formation of nine-membered pyrrolo[1′,2′:1,9]azonino[6,5,4-cd]indoles 3a−3i is very interesting. To improve their yields and investigate the reaction mechanism, we carefully examined the reaction conditions and finally found that chain products 2a−2i could be converted to cyclized products 3a−3i in good yields in chloroform in the presence of ptoluenesulfonic acid at room temperature (Table 3). However,

Table 4. Synthesis of Azocino[1,2a]benzo[c][1,5]diazocines 4a−4ea

Table 3. Synthesis of Pyrrolo[1′,2′:1,9]azonino[6,5,4cd]indoles 3a−3ia

entry

compound

R1

R2

yield (%)b

1 2 3 4 5

4a 4b 4c 4d 4e

H CH3 F Cl CH3

CH3 CH3 CH3 CH3 CH2CH3

54 60 51 48 42

a

Reaction conditions: isatin (1.0 mmol), L-proline (1.2 mmol), alkyl propiolate (3.5 mmol) in CHCl3 (15.0 mL), 70−80 °C, 12 h. b Isolated yield.

entry

compound

R1

R2

yield (%)b

1 2 3 4 5 6 7 8 9

3a 3b 3c 3d 3e 3f 3g 3h 3i

H 5-CH3 5-OCH3 5-F 5-Cl 6-Cl 6-Br 5-CH3 5-Cl

CH3 CH3 CH3 CH3 CH3 CH3 CH3 C2H5 C2H5

75 80 77 62 65 53 60 69 42

a

Reaction conditions: 2a−2i (0.5 mmol), p-TsOH (0.5 mmol) in CHCl3(15.0 mL), rt, 12 h. bIsolated yield.

in the p-TsOH/CHCl3 medium, chain products 1a−1m formed a complicated mixture of products, from which no corresponding pyrrolo[1′,2′:1,9]azonino[6,5,4-cd]indole was successfully separated. This fact indicated that the Nsubstituent in isatins played a very important role in the sequential cyclization reaction. To confirm the structures of the pyrrolo[1′,2′:1,9]azonino[6,5,4-cd]indoles, the single-crystal structures of compounds 3d, 3e, and 3g (Figures S9−S11) were successfully determined by X-ray diffraction. When the three-component reaction of L-proline, Nbenzylisatins, and excess methyl or ethyl propiolate was carried out in refluxing chloroform for 12 hours, unique bicyclic azocino[1,2-a]benzo[c][1,5]diazocines 4a−4e were obtained in moderate to good yields (Table 4). However, isatins lacking an N-substituent and those with N-methyl and N-butyl groups gave complicated mixtures of products. The molecular structures of 4a−4e were definitively confirmed by determination of the single-crystal structures of compounds 4b (Figure 4), 4c, and 4d (Figures S12 and S13). In the new bicyclic azocino[1,2-a]benzo[c][1,5]diazocines, the pyrrolidine and isatin rings were both opened and connected with two molecules of the methyl propiolates in an alternative reaction process. These results again indicated that this threecomponent reaction generated diverse products under slightly different reaction conditions. To explain the formation of the different kinds of polycyclic compounds, a plausible reaction mechanism is briefly proposed in Scheme 2 according to the experimental observations and the results of the previously reported works.18,20 First, the expected azomethine ylide (A) was generated by the reaction

Figure 4. ORTEP drawing (30%) of the crystal structure of 4b.

of proline with isatin according to the known condensation and elimination process.11,12 Then, the [3 + 2]cycloaddition reaction of azomethine ylide (A) with the first molecule of alkyl propiolate results in the spiro[indoline-3,3′-pyrrolizine] 5. In the presence of excess of alkyl propiolate, the cyclic tertiary amine reacted with the second molecule of alkyl propiolate to give the adduct (B). Then, the ring of middle pyrroline was opened to give the product 1 or 2 with a proton transferring process in the protic solvent.18 In the acidic medium, the protonation of carbonyl group afforded an intermediate (C) with its resonance hybrid (D). Then, the intramolecular electrophilic reaction resulted in the nine-membered cyclic intermediate (E), which in turn transferred to pyrrolo[1′,2′:1,9]azonino[6,5,4-cd]indole 3 by sequential deprotonation and aromatization process. On the other hand, when the reaction was carried out in aprotic chloroform, the intramolecular nucleophilic addition of the terminal β-enamino ester to the carbonyl group at the C2 position of the isatin scaffold gave the polycyclic intermediate (F). Then, the regain of carbonyl group caused the ring opening of the isatin to give the intermediate (G), which has a resonance form (H). At last, fragmentation of the intermediate (H) with the ring expansion process afforded the eight-membered azocino[1,2-a]benzo[c]625

DOI: 10.1021/acs.joc.8b02457 J. Org. Chem. 2019, 84, 622−635

Article

The Journal of Organic Chemistry Scheme 2. Proposed Reaction Mechanism for Three-Component Reaction

good yields. Various isatins having N-methyl and N-benzyl groups and without N-substituent reacted smoothly in the reaction to give the expected [3 + 2]cycloaddition product (Table 5). The single crystal structures of the spiro[indoline3,3′-pyrrolizines] 5a and 5j were also successfully determined (Figures S12 and S13). The two single crystal structures showed that the carbonyl group of oxindole scaffold exists on the cis-position to the proton in the newly formed pyrrolidyl ring. Apparently, the formation of spiro[indoline-3,3′-pyrrolizines] was accomplished by the initial generation of azomethine ylide from reaction of L-proline with isatin and sequential 1,3-dipolar cycloaddition reaction of azomethine ylide with dienophilic alkyl propiolate.6,11 Third, the further reaction of the previously prepared spiro[indoline-3,3′pyrrolizines] with excess methyl propiolate was carried out in methanol to give the chain product 1 or 2 in good yields (Scheme 3). Therefore, these control experiments successfully

[1,5]diazocine 4. Here, the N-substituents on the isatins played a critical role in the reaction and result in the formation of different kinds of products. Although the exact reason for the different reactivity is not very clear at present, many examples of the different reactivity of various isatins with Nalkyl groups and those without N-alkyl groups have been reported in the literature.22 To probe the credibility of our proposed mechanistic scheme and shed more light on the formation of the different polycyclic compounds, some control experiments were carried out. At first, the transformation of chain products 2a−2i to the cyclized products 3a−3i in chloroform in the presence of pTsOH showed that the proposed intermediates C, D, and E might exist in the reaction process. Second, the threecomponent reaction of proline and isatins with nearly equivalent alkyl propiolate in methanol reacted smoothly to give spiro[indoline-3,3′-pyrrolizines] 5a−5j in moderate to 626

DOI: 10.1021/acs.joc.8b02457 J. Org. Chem. 2019, 84, 622−635

The Journal of Organic Chemistry

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Table 5. Synthesis of Spiro[indoline-3,3′-pyrrolizines] 5a− 5ja

entry

compound

R1

R2

R3

yield (%)b

1 2 3 4 5 6 7 8 9 10

5a 5b 5c 5d 5e 5f 5g 5h 5i 5j

5-CH3 5-Cl 6-Cl 7-F 7-CF3 H 5-Cl 5-Cl H 7-CF3

H H H H H CH3 CH3 Bn Bn H

CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 C2H5 C2H5

76 82 74 77 68 74 82 83 66 72

EXPERIMENTAL SECTION

1. General Procedure for the Preparation of 2-(Oxoindolin3-ylidene)propylidene)-pyrrolidin-1-yl)acrylates 1a−1m. A mixture of isatin (1.0 mmol), L-proline (1.2 mmol), and methyl (ethyl) propiolate (3.5 mmol) in MeOH (EtOH) (15.0 mL) was stirred at room temperature for 24 h. The resulting precipitates were collected by filtration to give the crude product, which was recrystallized in a mixed methylene dichloride and methanol (v/v = 1:3 to 1:5) to give the pure product 1a−1m. Methyl 3-(2-(2-(1-Benzyl-2-oxoindolin-3-ylidene)-3-methoxy-3oxopropylidene)pyrrolidin-1-yl)acrylate (1a). Red solid, 0.357 g, 78%, mp 166−168 °C; 1H NMR (400 MHz, CDCl3) δ: Z-isomer: 8.13 (d, J = 13.6 Hz, 1H), 7.97 (s, 1H), 7.30−7.23 (m, 5H), 7.15− 7.03 (m, 2H), 6.90 (t, J = 7.6 Hz, 1H), 6.68 (d, J = 2.8 Hz, 1H), 5.17 (d, J = 13.6 Hz, 1H), 4.99 (s, 2H), 4.00 (s, 3H), 3.75 (s, 3H), 3.60− 3.53 (m, 2H), 2.80 (t, J = 7.6 Hz, 2H), 2.16−2.06 (m, 2H); E-isomer: 8.04 (d, J = 13.6 Hz, 1H), 7.57 (d, J = 7.6 Hz, 1H), 6.70 (d, J = 2.8 Hz, 1H), 6.39 (s, 1H), 5.24 (d, J = 13.2 Hz, 1H), 4.95 (s, 2H), 3.99 (s, 3H), 3.77 (s, 3H), 2.90 (t, J = 7.2 Hz, 2H); ratio of Z/E isomer = 9:11; 13C{1H} NMR (100 MHz, CDCl3) δ: 169.7, 169.3, 167.8, 167.7, 167.6, 166.9, 153.7, 152.9, 142.2, 140.9, 139.4, 139.2, 139.1, 138.6, 136.3, 136.1, 128.7, 128.6, 128.3, 127.8, 127.4, 127.1, 123.3, 122.4, 122.1, 121.7, 121.6, 120.3, 118.8, 115.6, 109.1, 108.8, 98.9, 98.8, 96.0, 95.5, 53.0, 52.8, 51.4, 51.3, 49.6, 49.3, 43.4, 43.2, 29.4, 29.1, 21.0, 20.9; IR(KBr) υ: 3091, 3030, 2948, 2884, 1695, 1613, 1587, 1553, 1497, 1463, 1383, 1321, 1268, 1247, 1173, 1107, 1076, 1052, 974, 948, 891, 820, 782, 735 cm−1; MS (m/z): HRMS (ESITOF) calcd for C27H26N2NaO5 ([M + Na]+): 481.1734, found: 481.1742. Methyl 3-(2-(2-(1-Butyl-2-oxoindolin-3-ylidene)-3-methoxy-3oxopropylidene)pyrrolidin-1-yl)acrylate (1b). Red solid, 0.297 g, 70%, mp 132−134 °C; 1H NMR (400 MHz, CDCl3) δ: Z-isomer: 8.10 (d, J = 13.6 Hz, 1H), 7.91 (s, 1H), 7.18 (t, J = 8.0 Hz, 1H), 7.06 (d, J = 6.0 Hz, 1H), 6.92 (t, J = 7.6 Hz, 1H), 6.82 (t, J = 8.0 Hz, 1H), 5.15 (d, J = 13.6 Hz, 1H), 3.99 (s, 3H), 3.76 (s, 3H), 3.75 (t, J = 7.2 Hz, 2H), 3.58−3.51 (m, 2H), 2.78 (t, J = 7.2 Hz, 2H), 2.14−2.05 (m, 2H), 1.70−1.61 (m, 2H), 1.45−1.34 (m, 2H), 0.97−0.92 (m, 3H); Eisomer: 8.03 (d, J = 13.6 Hz, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 6.35 (s, 1H), 5.22 (d, J = 13.2 Hz, 1H), 3.97 (s, 3H), 3.77 (s, 3H), 3.70 (t, J = 7.6 Hz, 2H), 2.87 (t, J = 7.2 Hz, 2H); ratio of Z/E isomer = 9:11; 13C{1H} NMR (100 MHz, CDCl3) δ: 169.7, 169.4, 167.8, 167.7, 167.5, 153.4, 152.6, 142.6, 141.2, 139.2, 139.0, 138.7, 138.6, 128.3, 127.8, 123.4, 122.3, 121.8, 121.6, 121.3, 120.3, 119.2, 116.0, 108.2, 108.0, 98.6, 98.5, 95.9, 95.5, 52.9, 52.4, 51.4, 51.3, 49.6, 49.3, 39.6, 39.4, 29.8, 29.7, 29.3, 29.1, 21.0, 20.9, 20.3, 13.9, 13.7; IR(KBr) υ: 3091, 3054, 2955, 2870, 1713, 1692, 1617, 1585, 1551, 1465, 1414, 1382, 1314, 1240, 1201, 1179, 1107, 973, 946, 889, 840, 781, 733 cm−1; MS (m/z): HRMS (ESI-TOF) calcd for C24H28N2NaO5 ([M + Na]+): 447.1890, found: 447.1901. Methyl 3-(2-(2-(1-Benzyl-5-methyl-2-oxoindolin-3-ylidene)-3methoxy-3-oxopropylidene)-pyrrolidin-1-yl)acrylate (1c). Red solid, 0.340 g, 72%, mp 182−184 °C; 1H NMR (400 MHz, CDCl3) δ: Z-isomer: 8.12 (d, J = 13.6 Hz, 1H), 7.96 (s, 1H), 7.29− 7.22 (m, 5H), 6.89 (d, J = 8.0 Hz, 1H), 6.86 (s, 1H), 6.56 (s, 1H), 5.16 (d, J = 13.2 Hz, 1H), 4.97 (s, 2H), 4.00 (s, 3H), 3.75 (s, 3H),

a Reaction conditions: isatin (1.0 mmol), L-proline (1.2 mmol) and alkyl propiolate (1.2 mmol) in MeOH (15.0 mL), rt, 12 h. bIsolated yields.

provided reliable evidence for the above proposed reaction mechanism.

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Article

CONCLUSIONS

In summary, we investigated the multicomponent reaction of L-proline, isatins, and alkyl propiolates and found that the reaction exhibits interesting molecular diversity. The unprecedented chain 2-(oxoindolin-3-ylidene)propylidene)pyrrolidin1-yl)acrylate derivatives, nine-membered pyrrolo[1′,2′:1,9]azonino[6,5,4-cd]indole derivatives, and double eight-membered azocino[1,2-a]benzo[c][1,5]diazocine derivatives were selectively formed through domino cyclization reactions depending on the substrates and the reaction conditions. The chemical structures, stereochemistry, and reaction mechanism were carefully elucidated through analysis of 19 single-crystal structures and the transformations of the different products. This reaction not only showed the versatile reactivity of alkyl propiolates in cycloaddition reactions but also provided convenient synthetic protocols for complex polycyclic systems. Prominent among the advantages of this reaction are its novelty, molecular diversity, operational simplicity, and good yields. Further expansion of the reaction scope and synthetic applications of this methodology are in progress in our laboratory. Scheme 3. Control Experiments

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DOI: 10.1021/acs.joc.8b02457 J. Org. Chem. 2019, 84, 622−635

Article

The Journal of Organic Chemistry

C{1H} NMR (100 MHz, CDCl3) δ: 169.3, 169.0, 167.5, 167.4, 166.5, 158.4 (d, J = 236.8 Hz), 158.3 (d, J = 235.8 Hz), 157.3, 157.2, 154.5, 153.7, 140.2, 140.0, 139.0, 138.6 (d, J = 1.6 Hz), 138.3, 137.2 (d, J = 1.4 Hz), 123.2 (d, J = 8.7 Hz), 122.6 (d, J = 8.8 Hz), 118.3 (d, J = 3.0 Hz), 115.1 (d, J = 3.1 Hz), 114.1 (d, J = 23.6 Hz), 113.8 (d, J = 23.9 Hz), 110.8 (d, J = 26.0 Hz), 108.3 (d, J = 8.3 Hz), 108.1 (d, J = 8.3 Hz), 107.8 (d, J = 26.3 Hz), 99.6, 99.3, 95.7, 94.9, 53.0, 52.9, 51.4, 51.3, 49.6, 49.4, 39.7, 39.5, 29.7, 29.6, 29.4, 29.2, 20.9, 20.8, 20.3, 13.8, 13.7; IR(KBr) υ: 3068, 3032, 2953, 2882, 1729, 1703, 1679, 1619, 1582, 1547, 1474, 1452, 1378, 1313, 1252, 1199, 1154, 1103, 986, 939, 843, 821, 801, 725 cm−1; MS (m/z): HRMS (ESI-TOF) calcd for C24H27FN2NaO5 ([M + Na]+): 465.1796, found: 465.1800. Methyl 3-(2-(2-(1-Benzyl-5-chloro-2-oxoindolin-3-ylidene)-3-methoxy-3-oxopropylidene)-pyrrolidin-1-yl)acrylate (1g). Red solid, 0.369 g, 75%, mp 188−190 °C; 1H NMR (400 MHz, CDCl3) δ: Zisomer: 8.12 (d, J = 13.2 Hz, 1H), 7.97 (s, 1H), 7.32−7.23 (m, 5H), 7.03 (d, J = 8.0 Hz, 1H), 6.99 (s, 1H), 6.60 (s, 1H), 5.21 (d, J = 13.6 Hz, 1H), 4.98 (s, 2H), 4.03 (s, 3H), 3.76 (s, 3H), 3.62−3.55 (m, 2H), 2.82 (t, J = 7.6 Hz, 2H), 2.17−2.08 (m, 2H); E-isomer: 8.04 (d, J = 13.6 Hz, 1H), 7.54 (s, 1H), 7.09 (d, J = 8.4 Hz, 1H), 6.58 (s, 1H), 6.30 (s, 1H), 5.27 (d, J = 13.6 Hz, 1H), 4.93 (s, 2H), 3.99 (s, 3H), 3.79 (s, 3H), 2.91 (t, J = 7.6 Hz, 2H); ratio of Z/E isomer = 11:9; 13 C{1H} NMR (100 MHz, CDCl3) δ: 169.3, 169.0, 167.5, 167.4, 167.3, 166.6, 155.0, 154.2, 140.9, 140.8, 140.5, 139.1, 138.9, 138.1, 135.9, 135.7, 128.8, 128.7, 127.5, 127.4, 127.3, 127.2, 127.1, 126.9, 123.8, 123.3, 123.2, 120.4, 117.0, 114.1, 109.8, 109.5, 100.1, 99.7, 95.8, 95.0, 53.1, 53.0, 51.5, 51.4, 49.7, 49.5, 43.5, 43.3, 29.6, 29.3, 20.9, 20.8; IR(KBr) υ: 3091, 3031, 2947, 2883, 1717, 1699, 1670, 1613, 1582, 1541, 1474, 1433, 1382, 1322, 1281, 1154, 1117, 1081, 1041, 992, 961, 894, 815, 730 cm−1; MS (m/z): HRMS (ESI-TOF) calcd for C27H25ClN2NaO5 ([M + Na]+): 515.1344, found: 515.1347. Methyl 3-(2-(2-(1-Butyl-5-chloro-2-oxoindolin-3-ylidene)-3-methoxy-3-oxopropylidene)-pyrrolidin-1-yl)acrylate (1h). Red solid, 0.316 g, 69%, mp 147−149 °C; 1H NMR (400 MHz, CDCl3) δ: Zisomer: 8.10 (d, J = 13.6 Hz, 1H), 7.91 (s, 1H), 7.15−7.12 (m, 1H), 6.98 (d, J = 2.0 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 5.19 (d, J = 13.6 Hz, 1H), 4.01 (s, 3H), 3.76 (s, 3H), 3.69 (t, J = 7.6 Hz, 2H), 3.59 (t, J = 7.2 Hz, 2H), 2.89 (t, J = 7.6 Hz, 2H), 2.16−2.06 (m, 2H), 1.67− 1.59 (m, 2H), 1.43−1.32 (m, 2H), 0.97−0.91 (m, 3H); E-isomer: 8.04 (d, J = 13.6 Hz, 1H), 7.52 (d, J = 2.0 Hz, 1H), 7.22−7.19 (m, 1H), 6.72 (d, J = 8.4 Hz, 1H), 6.26 (s, 1H), 5.26 (d, J = 13.6 Hz, 1H), 3.97 (s, 3H), 3.79 (s, 3H), 3.74 (t, J = 7.6 Hz, 2H), 3.55 (t, J = 7.2 Hz, 2H), 2.80 (t, J = 7.6 Hz, 2H); ratio of Z/E isomer = 1:1; 13C{1H} NMR (100 MHz, CDCl3) δ: 169.3, 169.0, 167.5, 167.3, 167.2, 166.3, 154.6, 153.9, 140.9, 140.4, 140.3, 139.5, 139.0, 138.1, 127.5, 127.1, 126.9, 126.6, 123.8, 123.3, 123.1, 120.5, 117.4, 114.5, 108.9, 108.7, 99.9, 99.4, 95.8, 94.9, 53.0, 52.9, 51.5, 51.4, 49.7, 49.5, 39.7, 39.5, 29.7, 29.7, 29.5, 29.3, 20.9, 20.8, 20.3, 13.8, 13.7; IR(KBr) υ: 3067, 2954, 2879, 1728, 1704, 1687, 1619, 1604, 1580, 1543, 1475, 1416, 1380, 1313, 1246, 1196, 1110, 1082, 1044, 985, 961, 866, 827, 752, cm−1; MS (m/z): HRMS (ESI-TOF) calcd For C24H27ClN2NaO5([M + Na]+): 481.1501, found: 481.1501. Methyl 3-(2-(2-(1-Methyl-2-oxoindolin-3-ylidene)-3-methoxy-3oxopropylidene)-pyrrolidin-1-yl)acrylate (1i). Red solid, 0.267 g, 70%, mp 201−202 °C; 1H NMR (600 MHz, CDCl3) δ: Z-isomer: 8.11 (d, J = 13.4 Hz, 1H), 7.94 (s, 1H), 7.56 (d, J = 7.8 Hz, 1H), 7.26 (t, J = 7.8 Hz, 1H), 7.09 (t, J = 7.8 Hz, 1H), 6.82 (t, J = 7.8 Hz, 1H), 5.23 (d, J = 13.4 Hz, 1H), 4.00 (s, 3H), 3.77 (s, 3H), 3.59 (t, J = 7.2 Hz, 2H), 3.27 (s, 3H), 2.88 (t, J = 7.2 Hz, 2H), 2.12−2.08 (m, 2H); E-isomer: 8.04 (d, J = 13.4 Hz, 1H), 6.35 (s, 1H), 7.06 (d, J = 7.8 Hz, 1H), 7.20 (t, J = 7.8 Hz, 1H), 6.94 (t, J = 7.8 Hz, 1H), 6.75 (t, J = 7.8 Hz, 1H), 5.17 (d, J = 13.4 Hz, 1H), 3.98 (s, 3H), 3.76 (s, 3H), 3.54 (t, J = 7.2 Hz, 2H), 3.23 (s, 3H), 2.78 (t, J = 7.2 Hz, 2H); ratio of Z/E isomers = 3:2; 13C{1H} NMR (150 MHz, CDCl3) δ: 169.7, 169.4, 167.9, 167.8, 167.0, 153.5, 152.6, 143.2, 141.8, 139.2, 139.0, 138.7, 128.4, 128.0, 123.3, 122.3, 122.1, 121.6, 120.3, 119.1, 116.0, 108.0, 107.8, 98.8, 96.0, 95.9, 95.4, 52.9, 52.8, 51.4, 51.3, 49.6, 49.3, 29.4, 29.1, 25.9. 25.8, 21.0, 20.9; IR(KBr) υ: 2994, 2949, 2893, 1732, 1688, 1625, 1573, 1529, 1480, 1415, 1375, 1336, 1240, 1202, 1154, 1130, 1102, 1046, 963, 936, 891, 840, 808, 774, 735 cm−1; MS (m/z): 13

3.53 (t, J = 7.6 Hz, 2H), 2.80 (t, J = 8.0 Hz, 2H), 2.26 (s, 3H), 2.15− 2.05 (m, 2H); E-isomer: 8.07 (d, J = 13.2 Hz, 1H), 7.41 (s, 1H), 6.94 (d, J = 8.0 Hz, 1H), 6.58 (s, 1H), 6.43 (s, 1H), 5.23 (d, J = 13.2 Hz, 1H), 4.92 (s, 2H), 3.99 (s, 3H,), 3.77 (s, 3H), 3.57 (t, J = 7.2 Hz, 2H), 2.89 (t, J = 8.0 Hz, 2H), 2.37 (s, 3H); ratio of Z/E isomer = 9:11; 13C{1H} NMR (100 MHz, CDCl3) δ: 169.7, 169.4, 167.7, 167.6, 167.5, 166.9, 153.3, 152.6, 140.1, 139.2, 139.1, 138.9, 138.8, 138.5, 136.3, 136.2, 131.3, 130.7, 128.7, 128.6, 128.5, 128.4, 127.3, 127.1, 124.1, 122.4, 121.7, 121.1, 118.9, 115.9, 108.8, 108.5, 98.9, 98.7, 96.0, 95.5, 52.9, 52.8, 51.4, 51.3, 49.5, 49.3, 43.4, 43.2, 29.3, 29.1, 21.4, 21.3, 21.0, 20.9; IR(KBr) υ: 3090, 3030, 2948, 2923, 2885, 1734, 1693, 1620, 1578, 1541, 1484, 1452, 1430, 1418, 1382, 1334, 1302, 1279, 1243, 1200, 1186, 1166, 1122, 1091, 1062, 1028, 979, 951, 860, 827, 805, 782, 738 cm−1; MS (m/z): HRMS (ESI-TOF) calcd for C28H28N2NaO5([M + Na]+): 495.1890, found: 495.1892. Methyl 3-(2-(2-(1-Butyl-5-methyl-2-oxoindolin-3-ylidene)-3-methoxy-3-oxopropylidene)-pyrrolidin-1-yl)acrylate (1d). Red solid, 0.293 g, 67%, mp 144−146 °C; 1H NMR (400 MHz, CDCl3) δ: Zisomer: 8.10 (d, J = 14.4 Hz, 1H), 7.90 (s, 1H), 7.00 (d, J = 7.6 Hz, 1H), 6.85 (s, 1H), 6.73−6.69 (m, 1H), 5.14 (d, J = 13.6 Hz, 1H), 3.99 (s, 3H), 3.75 (s, 3H), 3.74 (t, J = 7.6 Hz, 2H), 3.52 (t, J = 7.6 Hz, 2H), 2.77 (t, J = 8.0 Hz, 2H), 2.30 (s, 3H), 2.14−2.05 (m, 2H), 1.68−1.60 (m, 2H), 1.44−1.33 (m, 2H), 0.96−0.91 (m, 3H); Eisomer: 8.06 (d, J = 14.4 Hz, 1H), 7.39 (s, 1H), 7.05 (d, J = 8.0 Hz, 1H), 6.39 (s, 1H), 5.22 (d, J = 13.6 Hz, 1H), 3.97 (s, 3H), 3.77 (s, 3H), 3.68 (t, J = 7.2 Hz, 2H), 3.56 (t, J = 7.2 Hz, 2H), 2.87 (t, J = 8.0 Hz, 2H), 2.40 (s, 3H); ratio of Z/E iosmer = 2:3; 13C{1H} NMR (100 MHz, CDCl3) δ: 169.7, 169.4, 167.6, 167.5, 166.6, 152.9, 152.3, 140.5, 139.3, 139.2, 138.6, 138.5, 138.4, 130.9, 130.4, 128.6, 128.4, 124.4, 121.7, 121.2, 119.3, 119.2, 116.3, 116.2, 108.0, 107.8, 98.6, 98.5, 96.0, 95.4, 52.9, 52.7, 51.3, 51.2, 49.5, 49.2, 39.6, 39.4, 29.8, 29.7, 29.2, 29.0, 21.4, 21.3, 21.0, 20.9, 20.3, 13.8, 13.7; IR(KBr) υ: 3078, 3041, 2953, 2871, 1733, 1696, 1618, 1592, 1558, 1484, 1436, 1414, 1378, 1343, 1318, 1291, 1247, 1197, 1174, 1151, 1121, 1080, 1049, 980, 945, 852, 821, 806, 734 cm−1; MS (m/z): HRMS (ESITOF) calcd for C25H30N2NaO5 ([M + Na]+): 461.2047, found: 461.2056. Methyl 3-(2-(2-(1-Benzyl-5-fluoro-2-oxoindolin-3-ylidene)-3-methoxy-3-oxopropylidene)-pyrrolidin-1-yl)acrylate (1e). Red solid, 0.333 g, 70%, mp 178−180 °C; 1H NMR (400 MHz, CDCl3) δ: Zisomer: 8.12 (d, J = 13.2 Hz, 1H), 7.99 (s, 1H), 7.29−7.22 (m, 5H), 6.86−6.78 (m, 1H), 6.77−6.76 (m, 1H), 6.58 (d, J = 4.4 Hz, 1H), 5.20 (d, J = 13.2 Hz, 1H), 4.98 (s, 2H), 4.02 (s, 3H), 3.75 (s, 3H), 3.62−3.55 (m, 2H), 2.82 (t, J = 7.6 Hz, 2H), 2.17−2.08 (m, 2H); Eisomer: 8.03 (d, J = 13.6 Hz, 1H), 7.33−7.32 (m, 1H), 6.56 (d, J = 4.4 Hz, 1H), 6.26 (s, 1H), 5.27 (d, J = 13.2 Hz, 1H), 4.93 (s, 2H), 3.99 (s, 3H), 3.79 (s, 3H), 2.90 (t, J = 7.6 Hz, 2H); ratio of Z/E iosmer = 11:9; 13C{1H} NMR (100 MHz, CDCl3) δ: 169.3, 169.0, 167.6, 167.5, 167.4, 166.8, 158.6 (d, J = 237.3 Hz), 158.5 (d, J = 236.2 Hz), 154.9, 154.0, 140.7, 140.6, 138.9, 138.3, 138.2 (d, J = 1.6 Hz), 136.8 (d, J = 1.5 Hz), 136.0, 135.8, 128.7, 128.7, 127.5, 127.1, 127.1, 123.3 (d, J = 8.7 Hz), 122.8 (d, J = 8.8 Hz), 117.9 (d, J = 3.0 Hz), 114.7 (d, J = 3.1 Hz), 114.3, 114.1, 114.0, 113.7, 110.8 (d, J = 26.1 Hz), 109.2 (d, J = 8.3 Hz), 108.9 (d, J = 8.5 Hz), 107.8 (d, J = 26.3 Hz), 99.9, 99.5, 95.8, 95.0, 53.0, 52.9, 51.5, 51.4, 49.7, 49.5, 43.5, 43.3, 29.6, 29.3, 20.9, 20.8; IR(KBr) υ: 3095, 3031, 2948, 1728, 1700, 1663, 1617, 1584, 1538, 1479, 1430, 1385, 1324, 1286, 1207, 1148, 1081, 1039, 995, 955, 893, 846, 758 cm−1; MS (m/z): HRMS (ESI-TOF) calcd for C27H25FN2NaO5 ([M + Na]+): 499.1640, found: 499.1641. Methyl 3-(2-(2-(1-Butyl-5-fluoro-2-oxoindolin-3-ylidene)-3-methoxy-3-oxopropylidene)-pyrrolidin-1-yl)acrylate (1f). Red solid, 0.274g, 62%, mp 139−141 °C; 1H NMR (400 MHz, CDCl3) δ: Zisomer: 8.08 (d, J = 13.6 Hz, 1H), 7.90 (s, 1H), 6.89−6.84 (m, 1H), 6.76−6.73 (m, 1H), 6.72−6.67 (m, 1H), 5.16 (d, J = 13.2 Hz, 1H), 3.99 (s, 3H), 3.74 (s, 3H), 3.72 (t, J = 7.6 Hz, 2H), 3.58−3.51 (m, 2H), 2.77 (t, J = 7.6 Hz, 2H), 2.13−2.04 (m, 2H), 1.66−1.57 (m, 2H), 1.42−1.31 (m, 2H), 0.95−0.90 (m, 3H); E-isomer: 8.00 (d, J = 13.6 Hz, 1H), 7.26−7.23 (m, 1H), 6.95−6.90 (m, 1H), 6.20 (s, 1H), 5.23 (d, J = 13.6 Hz, 1H), 3.95 (s, 3H), 3.76 (s, 3H), 3.66 (t, J = 7.6 Hz, 2H), 2.86 (t, J = 7.6 Hz, 2H); ratio of Z/E isomer = 11:9; 628

DOI: 10.1021/acs.joc.8b02457 J. Org. Chem. 2019, 84, 622−635

Article

The Journal of Organic Chemistry HRMS (ESI-TOF) calcd for C21H22N2NaO5 ([M + Na]+): 405.1421, found: 405.1417. Methyl 3-(2-(2-(1-Methyl-5-chloro-2-oxoindolin-3-ylidene)-3methoxy-3-oxopropylidene)-pyrrolidin-1-yl)acrylate (1j). Red solid, 0.250 g, 60%, mp 203−205 °C; 1H NMR (600 MHz, CDCl3) δ: Z-isomer: 8.10 (d, J = 13.5 Hz, 1H), 7.94 (s, 1H), 7.23 (d, J = 8.4 Hz, 1H), 6.98 (s, 1H), 6.74 (d, J = 7.8 Hz, 1H), 5.27 (d, J = 13.5 Hz, 1H), 4.02 (s, 3H), 3.80 (s, 3H), 3.60 (t, J = 7.2 Hz, 2H), 3.25 (s, 3H), 2.90 (t, J = 7.2 Hz, 2H), 2.14−2.10 (m, 2H); E-isomer: 8.05 (d, J = 13.5 Hz, 1H), 7.53 (s, 1H), 7.16 (d, J = 8.4 Hz, 1H), 6.27 (s, 1H), 6.71 (d, J = 7.8 Hz, 1H), 5.21 (d, J = 13.5 Hz, 1H), 3.98 (s, 3H), 3.77 (s, 3H), 3.56 (t, J = 7.2 Hz, 2H), 3.21 (s, 3H), 2.80 (t, J = 7.2 Hz, 2H); ratio of Z/E isomer = 11:9; 13C{1H} NMR (150 MHz, CDCl3) δ: 169.3, 169.0, 167.6, 167.5, 166.7, 154.8, 154.0, 141.4, 140.6, 140.0, 138.9, 138.2, 127.7, 127.3, 126.9, 123.7, 123.3, 123.1, 120.5, 117.4, 114.5, 108.7, 108.5, 100.1, 99.6, 95.7, 94.9, 53.0, 52.9, 51.6, 51.5, 49.7, 49.5, 29.5, 29.3, 26.0, 25.9, 21.0, 20.9; IR(KBr) υ: 2989, 2948, 1737, 1698, 1621, 1577, 1544, 1480, 1462, 1417, 1381, 1319, 1254, 1200, 1158, 1137, 1117, 1072, 1045, 964, 933, 844, 825, 794 cm−1; MS (m/z): HRMS (ESI-TOF) calcd for C21H21ClN2NaO5 ([M + Na]+): 439.1031, found: 439.1023. Methyl 3-(2-(2-(1,5-Dimethyl-2-oxoindolin-3-ylidene)-3-methoxy-3-oxopropylidene)-pyrrolidin-1-yl)acrylate (1k). Red solid, 0.277 g, 70%, mp 222−224 °C; 1H NMR (600 MHz, CDCl3) δ: Zisomer: 8.11 (d, J = 13.5 Hz, 1H), 7.93 (s, 1H), 7.07 (d, J = 7.8 Hz, 1H), 6.85 (s, 1H), 6.71 (d, J = 7.8 Hz, 1H), 5.23 (d, J = 13.4 Hz, 1H), 4.00 (s, 3H), 3.78 (s, 3H), 3.57 (t, J = 7.2 Hz, 2H), 3.24 (s, 3H), 2.87 (t, J = 7.5 Hz, 2H), 2.41 (s, 3H), 2.12−2.09 (m, 2H); E-isomer: 8.07 (d, J = 13.5 Hz, 1H), 7.40 (s, 1H), 7.01 (d, J = 7.8 Hz, 1H), 6.40 (s, 1H), 6.69 (d, J = 7.8 Hz, 1H), 5.16 (d, J = 13.4 Hz, 1H), 3.97 (s, 3H), 3.76 (s, 3H), 3.53 (t, J = 7.2 Hz, 2H), 3.20 (s, 3H), 2.78 (t, J = 7.5 Hz, 2H), 2.30 (s, 3H); ratio of Z/E isomers = 7:4; 13C{1H} NMR (150 MHz, CDCl3) δ: 169.8, 169.5, 167.9, 167.9, 167.8, 167.0, 153.2, 152.4, 141.1, 139.7, 139.3 138.9, 138.7, 138.6, 131.3, 130.8, 128.8, 128.5, 124.4, 122.3, 121.6, 121.2, 119.2, 116.3, 107.8, 107.6, 98.8, 98.6, 96.0, 95.5, 53.0, 52.8, 51.4, 49.6, 49.3, 29.2, 29.1, 25.9, 25.8, 21.5, 21.4, 21.0, 20.9; IR(KBr) υ: 2992, 2951, 2890, 1733, 1710, 1688, 1624, 1561, 1537, 1491, 1450, 1418, 1388, 1332, 1244, 1204, 1151, 1113, 1074, 1045, 961, 848, 807, 765, 732 cm−1; MS (m/z): HRMS (ESI-TOF) calcd for C22H24N2NaO5 ([M + Na]+): 419.1577, found: 419.1575. Ethyl 3-(2-(2-(1-Benzyl-5-fluoro-2-oxoindolin-3-ylidene)-3ethoxy-3-oxopropylidene)-pyrrolidin-1-yl)acrylate (1l). Red solid, 0.353 g, 70%, mp 176−178 °C; 1H NMR (400 MHz, CDCl3) δ: Zisomer 8.15 (d, J = 13.2 Hz, 1H),8.02 (s, 1H), 7.29−7.26 (m, 4H), 7.26−7.22 (m, 1H), 6.84−6.80 (s, 2H), 6.58 (s, 1H), 5.20 (d, J = 13.6 Hz, 1H), 4.97 (s, 2H), 4.52−4.45 (m, 2H), 4.27−4.19 (m, 2H), 3.62−3.55 (m, 2H), 2.84 (t, J = 8.0 Hz, 2H), 2.17−2.08 (m, 2H), 1.46−1.41 (m, 3H), 1.34−1.30 (m, 3H); E-isomer: 8.04 (d, J = 13.6 Hz, 1H), 7.32−7.29 (m, 2H), 6.80−6.76 (s, 1H), 6.27 (s, 1H), 5.27 (d, J = 13.6 Hz, 1H), 4.93 (s, 2H), 2.94 (t, J = 8.0 Hz, 2H); ratio of Z/E isomer = 11:9; 13C{1H} NMR (100 MHz, CDCl3) δ: 169.0, 168.7, 167.6, 167.2, 167.0, 166.7, 158.6 (d, J = 233.3 Hz), 158.5 (d, J = 236.0 Hz), 157.4, 154.8, 154.0, 141.1, 141.0, 139.0, 138.2 (d, J = 1.3 Hz), 138.0, 136.8 (d, J = 1.0 Hz), 136.1, 135.9, 128.7, 128.7, 127.5, 127.2, 127.1, 123.4 (d, J = 8.7 Hz), 122.8 (d, J = 8.8 Hz), 117.8 (d, J = 3.2 Hz), 114.7 (d, J = 3.2 Hz), 114.0 (d, J = 23.6 Hz), 113.7 (d, J = 23.8 Hz), 110.7 (d, J = 26.2 Hz), 109.2 (d, J = 8.3 Hz), 108.9 (d, J = 8.5 Hz), 107.9 (d, J = 26.4 Hz), 100.4, 99.8, 95.9, 94.9, 62.4, 62.3, 60.3, 60.1, 49.7, 49.4, 43.5, 43.4, 29.7, 29.4, 21.0, 20.9, 14.4, 14.3, 13.9; IR(KBr) υ: 3092, 2974, 2923, 1729, 1678, 1621, 1584, 1540, 1483, 1454, 1424, 1368, 1334, 1296, 1247, 1223, 1157, 1112, 1072, 1037, 963, 839, 806, 736 cm−1; MS (m/z): HRMS (ESI-TOF) calcd for C29H29FN2NaO5 ([M + Na]+): 527.1953, found: 527.1955. Ethyl 3-(2-(2-(1-Benzyl-5-chloro-2-oxoindolin-3-ylidene)-3ethoxy-3-oxopropylidene)-pyrrolidin-1-yl)acrylate (1m). Red solid, 0.374 g, 72%, mp 192−194 °C; 1H NMR (400 MHz, CDCl3) δ: Zisomer: 8.14 (d, J = 13.6 Hz, 1H),8.00 (s, 1H), 7.32−7.24 (m, 5H), 7.09−7.02 (m, 1H), 7.07 (s, 1H), 6.61−6.58 (m, 1H), 5.21 (d, J = 13.2 Hz, 1H), 4.97 (s, 2H), 4.53−4.44 (m, 2H), 4.28−4.19 (m, 2H),

3.63−3.55 (m, 2H), 2.85 (t, J = 7.6 Hz, 2H), 2.17−2.08 (m, 2H), 1.47−1.41 (m, 3H), 1.34−1.29 (m, 3H); E-isomer: 8.03 (d, J = 13.6 Hz, 1H), 7.52 (s, 1H), 6.28 (s, 1H), 5.27 (d, J = 13.6 Hz, 1H), 4.93 (s, 2H), 2.95 (t, J = 7.6 Hz, 2H); ratio of Z/E isomer = 3:2; 13C{1H} NMR (100 MHz, CDCl3) δ: 168.9, 168.6, 167.4, 167.1, 166.9, 166.5, 155.1, 154.2, 141.3, 141.3, 140.4, 139.0, 138.9, 137.9, 136.0, 135.8, 128.7, 128.7, 127.5, 127.2, 127.1, 127.0, 126.9, 123.9, 123.2, 123.1, 120.6, 117.0, 113.9, 109.7, 109.4, 100.6, 99.9, 95.8, 95.0, 62.4, 62.3, 60.3, 60.1, 49.8, 49.5, 43.4, 43.3, 29.8, 29.5, 20.9, 20.9, 14.4, 14.4, 13.9; IR(KBr) υ: 3089, 3031, 2975, 2931, 1724, 1696, 1614, 1582, 1540, 1472, 1385, 1330, 1240, 1203, 1148, 1116, 1090, 1038, 954, 857, 812, 731 cm−1; MS (m/z): HRMS (ESI-TOF) calcd for C29H29ClN2NaO5 ([M + Na]+): 543.1657, found: 543.1663. 2. General Procedure for the Multicomponent Reaction of Isatin without N-Substituent, L-Proline, and Methyl Propiolate. A mixture of isatin (1.0 mmol), L-proline (1.2 mmol), and methyl propiolate (3.5 mmol) in MeOH (15.0 mL) was stirred at room temperature for 24 h. The resulting precipitates were collected by filtration and washed with cold methanol to give the pure product 2a−2j. The mother liquid was subjected to column chromatography with a mixture of petroleum ether and ethyl acetate (v/v = 2:1) as eluent to give the pure product 3a−3i. Methyl (3-(2-(3-Methoxy-3-oxo-2-((E)-2-oxoindolin-3-ylidene)propylidene)pyrrolidin-1-yl)-acrylate (2a). Red solid, 0.155 g, 42%, mp 234−236 °C; 1H NMR (600 MHz, DMSO-d6) δ: 10.59 (s, 1H), 7.92 (d, J = 13.2 Hz, 1H), 7.87 (s, 1H), 7.13 (t, J = 6.6 Hz, 1H), 6.94 (d, J = 7.2 Hz, 1H), 6.90−6.88 (m, 1H), 6.82 (d, J = 7.2 Hz, 1H), 5.37 (d, J = 13.2 Hz, 1H), 3.98 (s, 3H), 3.67 (s, 3H), 3.59 (t, J = 6.0 Hz, 2H), 2.72 (t, J = 6.0 Hz, 2H), 2.02 (t, J = 6.0 Hz, 2H); 13C{1H} NMR (150 MHz, DMSO-d6) δ: 168.7, 168.6, 167.2, 153.8, 139.9, 139.2, 138.2, 127.9, 121.6, 121.0, 120.0, 114.6, 109.5, 98.5, 93.8, 53.1, 51.0, 49.5, 28.9, 20.5; IR(KBr) υ: 3015, 2884, 1735, 1702, 1667, 1619, 1586, 1530, 1427, 1371, 1300, 1239, 1164, 1099, 1032, 945, 867, 789, 749 cm−1; MS (m/z): HRMS (ESI-TOF) calcd for C20H20N2NaO5 ([M + Na]+): 391.1264, found: 391.1258. Methyl 3-(2-(3-Methoxy-2-((E)-5-methyl-2-oxoindolin-3-ylidene)-3-oxopropylidene)-pyrrolidin-1-yl)acrylate (2b). Red solid, 0.198 g, 52%, mp 234−236 °C; 1H NMR (600 MHz, DMSO-d6) δ: 10.48 (s, 1H), 7.91 (d, J = 13.2 Hz, 1H), 7.87 (s, 1H), 6.95 (d, J = 7.8 Hz, 1H), 6.72−6.70 (m, 2H), 5.35 (d, J = 13.8 Hz, 1H), 3.98 (s, 3H), 3.67 (s, 3H), 3.58 (t, J = 6.0 Hz, 2H), 2.72 (t, J = 6.0 Hz, 2H), 2.23 (s, 3H), 2.02 (t, J = 6.0 Hz, 2H); 13C{1H} NMR (150 MHz, DMSO-d6) δ: 168.8, 168.6, 167.2, 153.5, 138.9, 138.2, 137.8, 129.4, 128.4, 121.7, 120.4, 114.8, 109.3, 98.3, 93.8, 54.9, 53.0, 51.0, 49.4, 28.8, 20.5; IR (KBr) υ: 3013, 1728, 1667, 1618, 1585, 1535, 1428, 1305, 1245, 1203, 1155, 1041, 959, 820, 733 cm−1; MS (m/z): HRMS (ESI) calcd for C21H22N2NaO5 ([M + Na]+): 405.1421, found: 405.1409. Methyl 3-(2-(3-Methoxy-2-((E)-5-methoxy-2-oxoindolin-3-ylidene)-3-oxopropylidene) pyrrolidin-1-yl)acrylate (2c). Red solid, 0.151 g, 38%, mp 237−239 °C; 1H NMR (600 MHz, DMSO-d6) δ: 10.40 (s, 1H), 7.91 (d, J = 13.2 Hz, 1H), 7.88 (s, 1H), 6.75 (s, 2H), 6.48 (s, 1H), 5.37 (d, J = 13.2 Hz, 1H), 3.97 (s, 3H), 3.68 (s, 3H), 3.67 (s, 3H), 3.59 (t, J = 6.0 Hz, 2H), 2.72 (t, J = 6.0 Hz, 2H), 2.02 (t, J = 6.0 Hz, 2H); 13C{1H} NMR (150 MHz, DMSO-d6) δ: 168.7, 168.5, 167.1, 154.0, 153.9, 139.3, 138.1, 133.8, 122.4, 114.8, 113.3, 109.8, 106.1, 98.5, 93.7, 55.3, 52.9, 51.0, 49.4, 28.8, 20.4; IR(KBr) υ: 3139, 1716, 1664, 1618, 1582, 1532, 1479, 1428, 1306, 1198, 1154, 1039, 964, 821 cm−1; MS (m/z): HRMS (ESI-TOF) calcd for C21H22N2NaO6 ([M + Na]+): 421.1370, found: 421.1367. Methyl 3-(2-(2-(5-Fluoro-2-oxoindolin-3-ylidene)-3-methoxy-3oxopropylidene)pyrrolidine-1-yl)acrylate (2d). Red solid, 0.208 g, 54%, mp 246−248 °C; 1H NMR (600 MHz, DMSO-d6) δ: 10.62 (s, 1H), 7.92 (d, J = 13.2 Hz, 1H), 7.88 (s, 1H), 6.98 (t, J = 9.0 Hz, 1H), 6.82−6.80 (m, 1H), 6.61 (d, J = 9.6 Hz, 1H), 5.42 (d, J = 13.2 Hz, 1H), 3.99 (s, 3H), 3.68 (s, 3H), 3.61 (t, J = 7.2 Hz, 2H), 2.74 (t, J = 7.2 Hz, 2H), 2.03 (t, J = 7.2 Hz, 2H); 13C{1H} NMR (150 MHz, DMSO-d6) δ: 168.7, 168.3, 167.0, 157.3 (d, J = 232.8 Hz), 155.2, 140.6, 138.0, 136.1, 122.6, 114.0 (d, J = 23.4 Hz), 113.5, 110.1 (d, J = 8.6 Hz), 106.5 (d, J = 26.3 Hz), 99.3, 93.5, 53.1, 51.0, 49.6, 29.1, 20.4; IR(KBr) υ: 3149, 3083, 1736, 1668, 1625, 1583, 1528, 1474, 1358, 629

DOI: 10.1021/acs.joc.8b02457 J. Org. Chem. 2019, 84, 622−635

Article

The Journal of Organic Chemistry 1299, 1244, 1162, 1042, 985, 822 cm−1; MS (m/z): HRMS (ESITOF) calcd for C20H19FN2NaO5 ([M + Na]+): 409.1170, found: 409.1164. Methyl 3-(2-(2-(5-Chloro-2-oxoindolin-3-ylidene)-3-methoxy-3oxopropylidene)pyrrolidine-1-yl)acrylate (2e). Red solid, 0.169 g, 42%, mp 242−244 °C; 1H NMR (600 MHz, DMSO-d6) δ: 10.74 (s, 1H), 7.92 (d, J = 13.2 Hz, 1H), 7.87 (s, 1H), 7.18 (d, J = 7.8 Hz, 1H), 6.84 (d, J = 7.2 Hz, 1H), 6.81 (s, 1H), 5.43 (d, J = 13.2 Hz, 1H), 3.98 (s, 3H), 3.68 (s, 3H), 3.62 (t, J = 6.0 Hz, 2H), 2.75 (t, J = 6.0 Hz, 2H), 2.03 (t, J = 6.0 Hz, 2H); 13C{1H} NMR (150 MHz, DMSO-d6) δ: 168.4, 168.4, 167.1, 155.6, 140.9, 138.9, 137.9, 127.0, 124.8, 123.4, 119.1, 112.8, 110.8, 99.6, 93.5, 53.2, 51.1, 49.8, 29.2, 20.4; IR(KBr) υ: 3734, 3149, 1718, 1666, 1619, 1579, 1527, 1430, 1353, 1298, 1238, 1159, 1109, 956, 865, 818, 701 cm−1; MS (m/z): HRMS (ESI-TOF) calcd for C20H19ClN2NaO5 ([M + Na]+): 425.0875, found: 425.0874. Methyl 3-(2-(2-(6-Chloro-2-oxoindolin-3-ylidene)-3-methoxy-3oxopropylidene)-pyrrolidin-1-yl)acrylate (2f). Red solid, 0.153 g, 38%, mp 226−228 °C; 1H NMR (600 MHz, DMSO-d6) δ: 10.74 (s, 1H), 7.92 (d, J = 13.2 Hz, 1H), 7.84 (s, 1H), 6.94−6.90 (m, 2H), 6.84 (s, 1H), 5.40 (d, J = 13.2 Hz, 1H), 3.98 (s, 3H), 3.68 (s, 3H), 3.60 (t, J = 6.0 Hz, 2H), 2.73 (t, J = 6.0 Hz, 2H), 2.03 (t, J = 6.0 Hz, 2H); 13C{1H} NMR (150 MHz, DMSO-d6) δ: 168.5, 168.4, 167.1, 154.7, 140.9, 140.0, 138.0, 131.6, 121.0, 120.7, 120.6, 113.1, 109.3, 99.0, 93.6, 53.1, 51.0, 49.6, 29.0, 20.4; IR(KBr) υ: 3167, 1727, 1673, 1612, 1523, 1448, 1367, 1313, 1240, 1159, 1065, 944, 816 cm−1; MS (m/z): HRMS (ESI-TOF) calcd for C20H19ClN2NaO5 ([M + Na]+): 425.0875, found: 425.0869. Methyl 3-(2-(2-((E)-6-Bromo-2-oxoindolin-3-ylidene)-3-methoxy3-oxopropylidene)-pyrrolidin-1-yl)acrylate (2g). Red solid, 0.214 g, 48%, mp 227−229 °C; 1H NMR (600 MHz, DMSO-d6) δ: 10.74 (s, 1H), 7.92 (d, J = 13.2 Hz, 1H), 7.85 (s, 1H), 7.07 (d, J = 7.2 Hz, 1H), 6.98 (s, 1H), 6.85 (d, J = 7.2 Hz, 1H), 5.39 (d, J = 13.2 Hz, 1H), 3.99 (s, 3H), 3.68 (s, 3H), 3.60 (brs, 2H), 2.73 (brs, 2H), 2.03 (brs, 2H); 13 C{1H} NMR (150 MHz, DMSO-d6) δ: 168.4, 167.0, 154.8, 141.0, 140.1, 138.0, 123.5, 121.3, 120.9, 120.0, 113.1, 112.0, 99.1, 93.6, 53.1, 51.0, 49.6, 29.0, 20.3; IR(KBr) υ: 3736, 3162, 1727, 1663, 1622, 1533, 1432, 1357, 1302, 1240, 1149, 1105, 952, 816 cm−1; MS (m/z): HRMS (ESI-TOF) calcd for C20H19BrN2NaO5 ([M + Na]+): 469.0370, found: 469.0377. Ethyl 3-(2-(3-Ethoxy-2-(5-methyl-2-oxoindolin-3-ylidene)-3-oxopropylidene)-pyrrolidin-1-yl)-acrylate (2h). Red solid, 0.205 g, 50%, mp 222−224 °C; 1H NMR (600 MHz, DMSO-d6) δ: 10.48 (s, 1H), 7.93 (d, J = 13.2 Hz, 1H), 7.89 (s, 1H), 6.95 (d, J = 7.2 Hz, 1H), 6.78 (s, 1H), 6.71 (d, J = 7.2 Hz, 1H), 5.35 (d, J = 7.2 Hz, 1H), 4.46 (d, J = 7.2 Hz, 2H), 4.14 (d, J = 7.2 Hz, 2H), 3.58 (t, J = 6.6 Hz, 2H), 2.75 (t, J = 6.6 Hz, 2H), 2.23 (s, 3H), 2.03 (t, J = 6.0 Hz, 2H), 1.36 (t, J = 6.6 Hz, 3H), 1.23 (t, J = 6.6 Hz, 3H); 13C{1H} NMR (150 MHz, DMSO-d6) δ: 168.8, 168.1, 166.7, 153.4, 139.2, 138.1, 137.7, 129.3, 128.3, 121.8, 120.5, 114.6, 109.2, 98.6, 93.7, 62.0, 59.3, 49.4, 28.9, 20.9, 20.5, 14.3, 13.6; IR(KBr) υ: 3695, 3154, 2985, 1717, 1671, 1616, 1580, 1535, 1476, 1378, 1301, 1243, 1146, 1051, 960, 814 cm−1; MS (m/z): HRMS (ESI-TOF) calcd for C23H26N2NaO5 ([M + Na]+): 433.1734, found: 433.1734. Ethyl 3-(2-(2-(5-Chloro-2-oxoindolin-3-ylidene)-3-ethoxy-3-oxopropylidene)-pyrrolidin-1-yl)acrylate (2i). Red solid, 0.198 g, 46%, mp 229−231 °C; 1H NMR (600 MHz, DMSO-d6) δ: 10.74 (s, 1H), 7.93 (d, J = 13.8 Hz, 1H), 7.89 (s, 1H), 7.17 (d, J = 7.8 Hz, 1H), 6.90 (s, 1H),6.84 (d, J = 8.4 Hz, 1H), 5.42 (d, J = 7.2 Hz, 1H), 4.46 (q, J = 6.6 Hz, 2H), 4.14 (q, J = 6.6 Hz, 2H), 3.62 (q, J = 6.6 Hz, 2H), 2.78 (t, J = 6.6 Hz, 2H), 2.04 (t, J = 6.6 Hz, 2H), 1.37 (t, J = 6.6 Hz, 3H), 1.23 (t, J = 6.6 Hz, 3H); 13C{1H} NMR (150 MHz, DMSO-d6) δ: 168.5, 167.9, 166.6, 155.6, 141.2, 138.4, 137.9, 126.9, 124.7, 123.4, 119.3, 112.6, 110.8, 99.8, 93.5, 62.3, 59.5, 49.7, 29.3, 20.4, 14.3, 13.6; IR(KBr) υ: 3458, 2981, 1740, 1704, 1665, 1622, 1579, 1523, 1458, 1359, 1296, 1240, 1162, 1109, 1033, 954, 813 cm−1; MS (m/z): HRMS (ESI-TOF) calcd for C22H23ClN2NaO5 ([M + Na]+): 453.1188, found: 453.1179. Methyl 3-(2-(3-Methoxy-3-oxo-2-((E)-2-oxo-7-(trifluoromethyl)indolin-3-ylidene)-propylidene)pyrrolidin-1-yl)acrylate (2j). Red solid, 0.227 g, 52%, mp 229−231 °C; 1H NMR (400 MHz,

DMSO-d6) δ: 10.86 (s, 1H),8.02 (d, J = 13.2 Hz, 1H), 7.83 (d, J = 7.6 Hz, 1H), 7.45 (d, J = 7.6 Hz, 1H), 7.18 (t, J = 7.6 Hz, 1H), 6.34 (s, 1H),5.45 (d, J = 13.2 Hz, 1H), 3.82 (s, 3H), 3.68 (t, J = 6.4 Hz, 3H), 3.64 (t, J = 6.4 Hz, 2H), 2.78 (t, J = 6.8 Hz, 2H), 2.03 (t, J = 6.4 Hz, 2H); 13C{1H} NMR (100 MHz, DMSO-d6) δ: 168.8, 168.0, 167.5, 157.2, 141.5, 139.2, 138.4 (q, J = 19 Hz), 126.7, 124.7, 124.1 (q, J = 270.4 Hz), 124.1 (q, J = 4.3 Hz), 121.4, 115.4, 110.5 (d, J = 32.1 Hz), 100.2, 94.8, 53.0, 51.5, 50.4, 30.1, 20.8; IR(KBr) υ: 3200, 3089, 2955, 1708, 1618, 1541, 1447, 1417, 1319, 1250, 1167, 1111, 985, 947, 808, 727 cm−1; MS (m/z): HRMS (ESI-TOF) calcd for C21H20F3N2O5 ([M + H]+): 437.1319, found: 437.1342. 3. General Procedure for the Conversion of Chain Products 2a−2i to the Cyclized Products 3a−3i. The chain product 2a−2i (0.5 mmol) was dissolved in chloroform (15.0 mL). The ptoluenesulfonic acid (0.5 mmol) was added. The solution was stirred at room temperature overnight. The solvent was removed by rotatory evaporation at reduced pressure. The residue was subjected to column chromatography with a mixture of petroleum ether and ethyl acetate (v/v = 2:1) as eluent to give the pure product 3a−3i. Dimethyl 1-Oxo-2,9,10,11,11a,13a-hexahydropyrrolo[1′,2′:1,9]azonino[6,5,4-cd]indole-6,13-dicarboxylate (3a). Light yellow solid, 0.276 g, 75%, mp 236−238 °C; 1H NMR (400 MHz, DMSO-d6) δ: 10.62 (s, 1H), 7.47 (s, 1H), 7.37 (td, J1 = 7.6 Hz, J2 = 0.8 Hz, 1H), 6.79 (d, J = 7.6 Hz, 1H), 6.59 (d, J = 8.0 Hz, 1H), 6.09 (dd, J1 = 10.4 Hz, J2 = 1.2 Hz, 1H), 4.82 (s, 1H), 4.05−4.00 (m, 1H), 3.75 (s, 3H), 3.61−3.54 (m, 1H), 3.51 (s, 3H), 3.39−3.32 (m, 1H), 2.04−1.91 (m, 1H), 1.83−1.67 (m, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ: 174.9, 168.2, 168.1, 146.2, 142.5, 134.8, 134.3, 129.2, 128.4, 127.2, 126.4, 109.1, 100.3, 52.9, 52.8, 52.3, 51.2, 46.7, 30.9, 21.6; IR(KBr) υ: 3426, 3345, 2929, 2884, 1725, 1663, 1600, 1533, 1499, 1450, 1425, 1371, 1293, 1247, 1163, 1126, 1073, 1011, 964, 939, 858, 825, 788, 750, 728 cm−1; MS (m/z): HRMS (ESI-TOF) calcd for C20H20N2NaO5 ([M + Na]+): 391.1264, found: 391.1266. Dimethyl 5-Methyl-1-oxo-2,9,10,11,11a,13a-hexahydropyrrolo[1′,2′:1,9]azonino[6,5,4-cd]-indole-6,13-dicarboxylate (3b). Light yellow solid, 0.306 g, 80%, mp 254−256 °C; 1H NMR (400 MHz, DMSO-d6) δ:10.50 (s, 1H), 7.51 (s, 1H), 7.13 (d, J = 7.6 Hz, 1H), 6.72 (d, J = 8.0 Hz, 1H), 6.05 (d, J = 10.4 Hz, 1H), 4.77 (s, 1H), 3.99−3.95 (m, 1H), 3.74 (s, 3H), 3.57−3.52 (m, 1H), 3.52 (s, 3H), 2.50 (S, 1H), 1.97 (s, 3H), 1.97−1.90 (m, 1H), 1.80−1.65 (m, 3H); 13 C{1H} NMR (100 MHz, DMSO-d6) δ: 174.9, 168.2, 167.8, 146.4, 140.4, 134.6, 133.9, 131.5, 130.2, 128.9, 127.5, 109.0, 99.2, 52.9, 52.7, 52.5, 51.1, 47.1, 30.9, 21.6, 19.4; IR(KBr) υ: 3360, 2988, 2951, 2910, 2880, 1722, 1665, 1598, 1460, 1431, 1403, 1370, 1281, 1246, 1187, 1168, 1122, 1074, 1028, 1000, 936, 915, 867, 832, 805, 762, 719 cm−1; MS (m/z): HRMS (ESI-TOF) calcd For C21H22N2NaO5 ([M + Na]+): 405.1421, found: 405.1426. Dimethyl 5-Methoxy-1-oxo-2,9,10,11,11a,13ahexahydropyrrolo[1′,2′:1,9]azonino[6,5,4-cd]indole-6,13-dicarboxylate (3c). Light yellow solid, 0.306 g, 77%, mp 222−224 °C; 1H NMR (400 MHz, DMSO-d6) δ:10.43 (s, 1H), 7.45 (s, 1H), 6.87 (brs, 1H), 6.76 (d, J = 8.0 Hz, 1H), 6.08 (d, J = 9.6 Hz, 1H), 4.79 (s, 1H), 4.14 (brs, 1H), 3.74 (s, 3H), 3.68−3.64 (m, 1H), 3.61 (s, 3H), 3.55− 3.51 (m, 1H), 3.48 (s, 3H), 2.01−1.90 (m, 1H), 1.82−1.68 (m, 3H); 13 C{1H} NMR (100 MHz, DMSO-d6) δ: 174.7, 168.2, 168.1, 153.8, 146.5, 135.7, 134.6, 128.6, 128.3, 124.2, 112.1, 109.3, 95.9, 56.6, 52.8, 52.7, 52.4, 51.1, 47.3, 30.8, 21.4; IR(KBr) υ: 3342, 3010, 2952, 2876, 2837, 1720, 1669, 1605, 1533, 1462, 1377, 1288, 1239, 1180, 1011, 982, 928, 865, 828, 794, 767, 718 cm−1; MS (m/z): HRMS (ESITOF) calcd for C21H22N2NaO6 ([M + Na]+): 421.1370, found: 421.1384. Dimethyl 5-Fluoro-1-oxo-2,9,10,11,11a,13a-hexahydropyrrolo[1′,2′:1,9]azonino[6,5,4-cd]-indole-6,13-dicarboxylate (3d). Light yellow solid, 0.240 g, 62%, mp 242−244 °C; 1H NMR (400 MHz, DMSO-d6) δ: 10.58 (s, 1H), 7.54 (s, 1H), 7.05 (t, J = 8.8 Hz, 1H), 6.77 (dd, J1 = 8.0 Hz, J2 = 4.0 Hz, 1H), 6.09 (d, J = 10.4 Hz, 1H), 4.85 (s, 1H), 4.12−4.08 (m, 1H), 3.72 (s, 3H), 3.59−3.55 (m, 1H), 3.49 (s, 3H), 3.41−3.35 (m, 1H), 2.00−1.88 (m, 1H), 1.85−1.79 (m, 1H), 1.85−1.79 (m, 2H); 13C{1H} NMR (100 MHz, DMSO-d6) δ: 174.8, 168.0, 167.6, 156.6 (d, J = 234.4 Hz), 147.3, 138.4 (d, J = 2.2 Hz), 630

DOI: 10.1021/acs.joc.8b02457 J. Org. Chem. 2019, 84, 622−635

Article

The Journal of Organic Chemistry 134.7, 128.9 (d, J = 2.7 Hz), 128.0, 122.6 (d, J = 19.9 Hz), 115.5 (d, J = 25.5 Hz), 110.0 (d, J = 8.5 Hz), 92.3, 53.1, 52.9, 52.4, 51.3, 47.3, 30.9, 21.5; IR(KBr) υ: 3421, 2950, 2886, 1730, 1717, 1665, 1624, 1602, 1533, 1487, 1460, 1425, 1371, 1303, 1287, 1251, 1228, 1179, 1141, 1072, 1018, 994, 948, 925, 869, 811, 785, 762 cm−1; MS (m/z): HRMS (ESI-TOF) calcd for C20H19FN2NaO5 ([M + Na]+): 409.1170, found: 409.1170. Dimethyl 5-Chloro-1-oxo-2,9,10,11,11a,13a-hexahydropyrrolo[1′,2′:1,9]-azonino[6,5,4-cd]indole-6,13-dicarboxylate (3e). White solid, 0.262 g, 65%, mp 247−249 °C; 1H NMR (400 MHz, DMSOd6) δ:10.73 (s, 1H), 7.55 (s, 1H), 7.39 (d, J = 8.0 Hz, 1H), 6.83 (d, J = 8.0 Hz, 1H), 6.10 (d, J = 9.6 Hz, 1H), 4.88 (s, 1H), 4.05−4.00 (m, 1H), 3.75 (s, 3H), 3.61−3.57 (m, 1H), 3.52 (s, 3H), 3.40−3.38 (m, 1H), 1.96−1.92 (m, 1H), 1.90−1.83 (m, 1H), 1.80−1.69 (m, 2H); 13 C{1H} NMR (100 MHz, DMSO-d6) δ: 174.6, 168.0, 167.4, 146.9, 141.4, 134.7, 133.0, 129.8, 129.4, 128.7, 128.2, 110.6, 97.6, 53.1, 52.9, 52.7, 51.2, 47.4, 30.9, 21.5; IR(KBr) υ: 3397, 2945, 1717, 1664, 1600, 1444, 1371, 1287, 1226, 1148, 1111, 1052, 1024, 917, 839, 812, 775 cm−1; MS (m/z): HRMS (ESI-TOF) calcd For C20H19ClN2NaO5 ([M + Na]+): 425.0875, found: 425.0888. Dimethyl 4-Chloro-1-oxo-2,9,10,11,11a,13a-hexahydropyrrolo[1′,2′:1,9]-azonino[6,5,4-cd]indole-6,13-dicarboxylate (3f). White solid, 0.213 g, 53%, mp 252−254 °C; 1H NMR (600 MHz, CDCl3) δ:8.84 (s, 1H), 7.53 (s, 1H), 6.87 (s, 1H), 6.74 (s, 1H), 6.24 (d, J = 10.2 Hz, 1H), 5.12 (s, 1H), 4.20−4.17 (m, 1H), 3.88 (s, 3H), 3.65 (s, 3H), 3.53−3.44 (m, 2H), 2.06−2.02 (m, 1H), 1.95−1.85 (m, 2H), 1.80−1.77 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ: 175.9, 168.7, 167.7, 146.0, 141.9, 135.5, 135.2, 134.1, 127.4, 126.7, 125.6, 109.8, 99.8, 53.1, 52.8, 52.5, 51.5, 46.2, 31.0, 21.6; IR(KBr) υ: 3383, 2949, 1728, 1666, 1604, 1430, 1380, 1298, 1248, 1181, 1133, 1081, 1013, 932, 836, 768 cm−1; MS (m/z): HRMS (ESI-TOF) calcd for C20H19ClN2NaO5 ([M + Na]+): 425.0875, found: 425.0875. Dimethyl 4-Bromo-1-oxo-2,9,10,11,11a,13a-hexahydropyrrolo[1′,2′:1,9]azonino[6,5,4-cd]-indole-6,13-dicarboxylate (3g). Light yellow solid, 0.268 g, 60%, mp 236−238 °C; 1H NMR (400 MHz, DMSO-d6) δ:10.77 (s, 1H), 7.47 (s, 1H), 6.93 (s, 1H), 6.76 (s, 1H), 6.11 (d, J = 10.0 Hz, 1H), 4.80 (s, 1H), 4.11−4.07 (m, 1H), 3.74 (s, 3H), 3.62−3.56 (m, 1H), 3.52 (s, 3H), 3.41−3.35 (m, 1H), 2.02− 1.84 (m, 2H), 1.71 (brs, 2H); 13C{1H} NMR (100 MHz, DMSO-d6) δ: 174.3, 167.6, 167.5, 146.2, 143.8, 135.9, 134.6, 128.1, 127.4, 126.5, 120.9, 111.6, 98.5, 52.8, 52.5, 52.1, 51.0, 46.1, 30.7, 21.2; IR(KBr) υ: 3382, 3025, 2947, 2880, 2829, 1726, 1668, 1603, 1526, 1428, 1381, 1298, 1245, 1174, 1133, 1080, 1013, 954, 915, 848, 815, 766, 725 cm−1; MS (m/z): HRMS (ESI-TOF) calcd for C20H19BrN2NaO5 ([M + Na]+): 469.0370, found: 469.0369. Diethyl 5-Methyl-1-oxo-2,9,10,11,11a,13a-hexahydropyrrolo[1′,2′:1,9]azonino[6,5,4-cd]-indole-6,13-dicarboxylate (3h). Light yellow solid, 0.283 g, 69%, mp 260−262 °C; 1H NMR (400 MHz, DMSO-d6) δ:10.50 (s, 1H), 7.50 (s, 1H), 7.13 (d, J = 7.6 Hz, 1H), 6.72 (d, J = 7.6 Hz, 1H), 6.03 (d, J = 10.4 Hz, 1H), 4.78 (s, 1H), 4.24−4.16 (m, 2H), 4.07−3.94 (m, 3H), 3.57−3.52 (m, 1H), 3.37− 3.31 (m, 1H), 1.98 (s, 3H), 1.96−1.87 (m, 1H), 1.80−1.65 (m, 3H), 1.25 (t, J = 7.2 Hz, 3H), 1.09 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ: 174.9, 167.7, 167.3, 146.7, 140.4, 134.3, 134.0, 131.4, 130.4, 129.2, 127.5, 109.2, 99.5, 61.4, 59.2, 52.6, 47.2, 46.9, 30.9, 21.6, 19.4, 15.1, 14.6; IR(KBr) υ: 3272, 2972, 2881, 1721, 1650, 1591, 1464, 1365, 1290, 1254, 1171, 1067, 1029, 947, 861, 816, 763 cm−1; MS (m/z): HRMS (ESI-TOF) calcd for C23H26N2NaO5 ([M + Na]+): 433.1734, found: 433.1730. Diethyl 5-Chloro-1-oxo-2,9,10,11,11a,13a-hexahydropyrrolo[1′,2′:1,9]azonino-[6,5,4-cd]-indole-6,13-dicarboxylate (3i). Light yellow solid, 0.181 g, 42%, mp 211−213 °C; 1H NMR (400 MHz, CDCl3) δ:8.52 (s, 1H), 7.61 (s, 1H), 7.35 (d, J = 8.4 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H), 6.21 (d, J = 10.4 Hz, 1H), 5.19 (s, 1H), 4.34 (q, J = 7.2 Hz, 2H), 3.55−3.47 (m, 2H), 2.06−1.76 (m, 5H), 1.64 (s, 2H), 1.37 (t, J = 7.2 Hz, 3H), 1.19 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ: 175.7, 167.8, 167.3, 146.3, 139.4, 134.7, 133.4, 130.3, 129.4, 129.1, 127.9, 110.0, 98.7, 61.7, 59.8, 53.1, 52.6, 47.3, 31.0, 21.6, 14.5, 14.1; IR(KBr) υ: 3255, 2945, 1715, 1650, 1595, 1445, 1362, 1293, 1245, 1188, 1168, 1118, 1061, 1024, 955, 814, 775 cm−1;

MS (m/z): HRMS (ESI-TOF) calcd For C22H23ClN2NaO5 ([M + Na]+): 453.1188, found: 453.1205. 4. General Procedure for the Preparation of Azocino[1,2a]benzo[c][1,5]diazocines 4a−4e. A mixture of N-benzylisatin (1.0 mmol), L-proline (1.2 mmol), and propiolate (3.5 mmol) in dry chloroform (15.0 mL) was refluxed overnight. The solvent was removed by rotary evaporation under reduced pressure. The resulting oily residue was subjected to preparative thin-layer chromatography with light petroleum and ethyl acetate (v/v = 1:1) as developing agent to give the pure product 4a−4e. Dimethyl 5-Benzyl-6-oxo-5,10,11,12-tetrahydroazocino[1,2-a]benzo[c][1,5]diazocine-7,14-dicarboxylate (4a). Light yellow solid, 0.247 g, 54%, mp 196−198 °C; 1H NMR (400 MHz, CDCl3) δ: 7.34 (t, J = 7.2 Hz, 1H), 7.24 (t, J = 7.6 Hz, 1H), 7.20−7.17 (m, 3H), 7.13−7.09 (m, 3H), 7.02 (d, 1H), 6.83 (t, J = 8.8 Hz, 1H), 6.80 (s, 1H), 5.38 (d, J = 14.0 Hz, 1H), 4.68 (d, J = 14.4 Hz, 1H), 4.44 (s, 1H), 4.04−3.96 (m, 1H), 3.72 (s, 3H), 3.70 (s, 3H), 3.57−3.52 (m, 1H), 2.74−2.64 (m, 1H), 2.37−2.31 (m, 1H), 1.86−1.78 (m, 1H), 1.55−1.48 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ: 166.9, 165.8, 164.6, 143.6, 141.7, 139.9, 139.4, 135.7, 135.4, 130.2, 130.1, 129.5, 129.4, 128.3, 127.8, 127.2, 123.8, 112.1, 110.1, 52.7, 52.0, 51.8, 51.5, 24.2, 23.5; IR(KBr) υ: 3221, 2952, 2871, 1730, 7698, 1617, 1475, 1437, 1388, 1330, 1249, 1198, 1121, 1014, 965, 919, 887, 819, 770, 741, 701 cm−1; MS (m/z): HRMS (ESI-TOF) calcd for C27H26N2NaO5 ([M + Na]+): 481.1734, found: 481.1742. Dimethyl 5-Benzyl-2-methyl-6-oxo-5,10,11,12tetrahydroazocino[1,2-a]benzo[c][1,5]diazocine-7,14-dicarboxylate (4b). Light yellow solid, 0.283 g, 60%, mp 210−212 °C; 1H NMR (400 MHz, CDCl3) δ: 7.16 (d, J = 6.8 Hz, 2H), 7.10−7.02 (m, 5H), 6.82−6.77 (m, 3H), 5.32 (d, J = 14.0 Hz, 1H), 4.64 (d, J = 14.0 Hz, 1H), 4.44 (s, 1H), 4.01−3.94 (m, 1H), 3.71 (s, 3H), 3.68 (s, 3H), 3.55−3.50 (m, 1H), 2.72−2.62 (m, 1H), 2.34−2.31 (m, 1H), 2.28 (s, 3H), 1.84−1.76 (m, 1H), 1.52−1.45 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ: 166.9, 166.0, 164.6, 143.5, 139.8, 139.7, 139.1, 137.7, 135.5, 135.4, 130.5, 130.3, 130.1, 129.5, 128.2, 127.2, 123.5, 112.1, 109.8, 52.7, 52.0, 51.8, 51.5, 24.2, 23.4, 20.9; IR(KBr) υ: 3027, 2948, 2871, 1720, 1693, 1643, 1590, 1498, 1424, 1354, 1280, 1241, 1201, 1174, 1127, 1096, 1057, 962, 925, 871, 818, 773, 748, 705 cm−1; MS (m/z): HRMS (ESI-TOF) calcd for C28H29N2O5 ([M + H]+): 473.2071, found: 473.2075. Dimethyl 5-Benzyl-2-fluoro-6-oxo-5,10,11,12tetrahydroazocino[1,2-a]-benzo[c][1,5]diazocine-7,14-dicarboxylate (4c). Light yellow solid, 0.243 g, 51%, mp 226−228 °C; 1H NMR (400 MHz, CDCl3) δ: 7.18−7.10 (m, 6H), 7.04 (td, J1 = 8.4 Hz, J2 = 2.8 Hz, 1H), 6.85 (t, J = 8.8 Hz, 1H), 6.80 (s, 1H), 6.75 (dd, J1 = 8.4 Hz, J2 = 2.8 Hz, 1H), 5.36 (d, J = 14.0 Hz, 1H), 4.63 (d, J = 14.0 Hz, 1H), 4.42 (s, 1H), 4.01−3.93 (m, 1H), 3.73 (s, 3H), 3.70 (s, 3H), 3.57−3.52 (m, 1H), 2.71−2.61 (m, 1H), 2.37−2.32 (m, 1H), 1.85− 1.77 (m, 1H), 1.55−1.48 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ: 166.7, 165.7, 164.5, 161.3 (d, J = 247.7 Hz), 143.3, 140.3, 138.2, 137.8 (d, J = 2.6 Hz), 137.2 (d, J = 8.2 Hz) 135.1, 130.0, 129.5, 128.3, 127.4, 125.5 (d, J = 8.9 Hz), 116.8 (d, J = 22.5 Hz), 116.6 (d, J = 22.6 Hz), 112.2, 110.3, 52.8, 52.1, 51.9, 51.5, 24.2, 23.3; IR(KBr) υ: 3032, 2994, 2950, 2871, 1720, 1698, 1642, 1591, 1494, 1431, 1355, 1278, 1245, 1174, 1144, 1099, 1084, 1054, 969, 929, 882, 816, 775, 742, 702 cm −1 ; MS (m/z): HRMS (ESI-TOF) calcd for C27H25FN2NaO5 ([M + Na]+): 499.1640, found: 499.1641. Dimethyl 5-Benzyl-2-chloro-6-oxo-5,10,11,12tetrahydroazocino[1,2-a]benzo[c][1,5]diazocine-7,14-dicarboxylate (4d). Light yellow solid, 0.236 g, 48%, mp 226−228 °C; 1H NMR (400 MHz, CDCl3) δ: 7.32−7.30 (m, 1H), 7.18−7.10 (m, 6H), 7.03 (d, J = 2.4 Hz, 1H), 6.85 (t, J = 8.8 Hz, 1H), 6.80 (s, 1H), 5.36 (d, J = 14.0 Hz, 1H), 4.64 (d, J = 14.0 Hz, 1H), 4.42 (s, 1H), 4.01−3.94 (m, 1H), 3.73 (s, 3H), 3.70 (s, 3H), 3.57−3.52 (m, 1H), 2.70−2.60 (m, 1H), 2.37−2.32 (m, 1H), 1.85−1.78 (m, 1H), 1.55−1.48 (m, 1H); 13 C{1H} NMR (100 MHz, CDCl3) δ: 166.6, 165.5, 164.3, 143.4, 140.3, 140.3, 137.9, 136.8, 135.0, 133.0, 130.0, 130.0, 129.6, 129.4, 128.3, 127.4, 125.1, 112.1, 110.4, 52.6, 52.0, 51.8, 51.4, 24.1, 23.2; IR(KBr) υ: 3040, 2992, 2952, 2876, 1728, 1700, 1646, 1592, 1494, 1436, 1358, 1272, 1246, 1176, 1145, 1100, 1090, 1055, 970, 928, 886, 631

DOI: 10.1021/acs.joc.8b02457 J. Org. Chem. 2019, 84, 622−635

Article

The Journal of Organic Chemistry 822, 781, 746, 705 cm−1; MS (m/z): HRMS (ESI-TOF) calcd for C27H26ClN2O5 ([M + H]+): 493.1525, found: 493.1545. Dimethyl 5-Benzyl-2-methyl-6-oxo-5,10,11,12tetrahydroazocino[1,2-a]benzo[c][1,5]diazocine-7,14-dicarboxylate (4e). Light yellow solid, 0.210 g, 42%, mp 216−218 °C; 1H NMR (400 MHz, CDCl3) δ: 7.23−7.20 (m, 2H), 7.16−7.10 (m, 3H), 7.06 (dd, J1 = 8.4 Hz, J2 = 1.6 Hz, 1H), 6.96 (d, J = 20.0 Hz, 1H), 6.83− 6.78 (m, 2H), 6.76 (s, 1H), 5.09 (d, J = 14.4 Hz, 1H), 4.82 (d, J = 14.4 Hz, 1H), 4.62 (s, 1H), 4.20−4.09 (m, 4H), 4.04−3.96 (m, 1H), 3.53 (dd, J1 = 14.4 Hz, J2 = 5.6 Hz, 1H), 2.75−2.65 (m, 1H), 2.35− 2.30 (m, 1H), 2.28 (s, 3H), 1.86−1.76 (m, 1H), 1.54−1.46 (m, 1H), 1.29 (t, J = 7.2 Hz, 3H), 1.25 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ: 166.5, 165.4, 164.8, 143.1, 139.8, 139.5, 139.4, 137.6, 135.9, 135.4, 130.4, 129.9, 129.2, 128.2, 127.2, 123.3, 112.6, 109.8, 60.9, 60.4, 52.6, 51.4, 24.2, 23.3, 20.8, 14.3, 14.2; IR(KBr) υ: 3443, 2939, 1644, 1596, 1503, 1460, 1399, 1321, 1211, 1042, 930, 845, 775 cm−1; MS (m/z): HRMS (ESI-TOF) calcd for C30H33N2O5 ([M + H]+): 501.2384, found: 501.2401. 5. General Procedure for the Preparation of Spiro[indoline3,3′-pyrrolizines] 5a−5m. A mixture of isatin (1.0 mmol), L-proline (1.2 mmol), and alkyl propiolate (1.2 mmol) in MeOH (EtOH) (15.0 mL) was stirred at room temperature for twelve hours. After the solvent was removed by rotary evaporation at reduced pressure, the residue was subjected to column chromatography with light petroleum and ethyl acetate (v/v = 2:1) to give the pure products 5a−5j. Methyl 5-Methyl-2-oxo-5′,6′,7′,7a′-tetrahydrospiro[indoline3,3′-pyrrolizine]-2′-carboxylate (5a). White solid, 0.226 g, 76%, mp 174−176 °C; 1H NMR (400 MHz, CDCl3) δ: 8.59 (s, 1H), 7.21 (s, 1H), 7.05 (d, J = 8.0 Hz, 1H), 6.82 (d, J = 7.6 Hz, 1H), 6.74 (s, 1H), 4.75−4.71 (m, 1H), 3.56 (s, 3H), 2.74 (t, J = 6.0 Hz, 2H), 2.29 (s, 3H), 2.17−2.10 (m, 1H), 1.94−1.87 (m, 2H), 1.65−1.55 (m, 1H); 13 C{1H} NMR (100 MHz, DMSO) δ: 178.5, 162.5, 147.4, 141.1, 133.8, 130.1, 126.8, 126.7, 109.9, 76.9, 72.0, 51.8, 48.3, 30.8, 27.2, 21.0. IR(KBr) υ: 3168, 2955, 2879, 1736, 1621, 1486, 1436, 1391, 1308, 1244, 1197, 1118, 828, 782 cm−1; MS (m/z): HRMS (ESITOF) calcd For C17H19N2O3 ([M + H]+): 299.1390, found:299.1410. Methyl 5-Chloro-2-oxo-5′,6′,7′,7a′-tetrahydrospiro[indoline3,3′-pyrrolizine]-2′-carboxylate (5b). White solid, 0.261 g, 82%, mp 188−190 °C; 1H NMR (400 MHz, CDCl3) δ: 9.47 (s, 1H), 7.24 (d, J = 2.0 Hz, 1H), 7.22 (dd, J1 = 8.4 Hz, J2 = 2.0 Hz, 1H), 6.90 (d, J = 2.4 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 4.74−4.70 (m, 1H), 3.58 (s, 3H), 2.79−2.66 (m, 2H), 2.18−2.11 (m, 1H), 1.98−1.86 (m, 2H), 1.62−1.52 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ: 180.2, 162.4, 147.0, 140.9, 133.6, 129.8, 128.3, 127.3, 126.0, 111.9, 77.6, 72.5, 51.9, 48.3, 31.3, 27.6; IR(KBr) υ: 3540, 3420, 3224, 2952, 2870, 2720, 1730, 1617, 1475, 1437, 1388, 1330, 1249, 1197, 1121, 1013, 919, 887, 818, 770, 741, 701 cm−1; MS (m/z): HRMS (ESI-TOF) calcd for C16H16ClN2O3 ([M + H]+): 319.0844, found: 319.0854. Methyl 6-Chloro-2-oxo-5′,6′,7′,7a′-tetrahydrospiro[indoline3,3′-pyrrolizine]-2′-carboxylate (5c). White solid, 0.235 g, 74%, mp 182−184 °C; 1H NMR (400 MHz, CDCl3) δ: 9.34 (s, 1H), 7.23 (d, J = 1.6 Hz, 1H), 6.97−6.95 (m, 2H), 6.86 (d, J = 7.6 Hz, 1H), 4.74− 4.70 (m, 1H), 3.57 (s, 3H), 2.77−2.65 (m, 2H), 2.16−2.12 (m, 1H), 1.92−1.86 (m, 2H), 1.59−1.54 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ: 180.1, 162.4, 146.9, 143.3, 135.4, 133.6, 126.6, 124.8, 121.8, 111.4, 72.2, 51.8, 48.3, 31.2, 27.4; 13C{1H} NMR (100 MHz, DMSO) δ: 178.4, 162.5, 147.9, 145.0, 134.1, 133.2, 127.7, 125.7, 121.1, 110.2, 76.4, 72.1, 51.9, 48.4, 30.7, 27.2; IR(KBr) υ: 3083, 2963, 2892, 1717, 1614, 1445, 1321, 1244, 1191, 1086, 918, 866, 792, 709 cm−1; MS (m/z): HRMS (ESI-TOF) calcd For C16H16ClN2O3 ([M + H]+): 319.0844, found:319.0869. Methyl 7-Fluoro-2-oxo-5′,6′,7′,7a′-tetrahydrospiro[indoline3,3′-pyrrolizine]-2′-carboxylate (5d). White solid, 0.233 g, 77%, mp 172−174 °C; 1H NMR (400 MHz, CDCl3) δ: 8.07 (s, 1H), 7.22 (d, J = 1.6 Hz, 1H), 7.07−7.03 (m, 1H), 6.98−6.93 (m, 1H), 6.76 (d, J = 7.2 Hz, 1H), 4.75−4.71 (m, 1H), 3.57 (s, 3H), 2.77−2.66 (m, 2H), 2.17−2.10 (m, 1H), 1.93−1.83 (m, 2H), 1.63−1.53 (m, 1H); 13 C{1H} NMR (100 MHz, CDCl3) δ: 178.7, 162.5, 147.3 (d, J = 243.4 Hz), 147.0, 133.7, 129.4 (d, J = 12.5 Hz), 129.2 (d, J = 3.2 Hz),

122.3 (d, J = 5.7 Hz), 121.5 (d, J = 3.3 Hz), 116.8 (d, J = 17.2 Hz), 77.4, 72.3, 51.8, 48.3, 31.2, 27.5; IR(KBr) υ: 3415, 3230, 2967, 2894, 2821, 1735, 1623, 1466, 1419, 1369, 1318, 1261, 1183, 1101, 1062, 1001, 925, 874, 812, 781, 737 cm−1; MS (m/z): HRMS (ESI-TOF) calcd for C16H16FN2O3 ([M + H]+): 303.1139, found: 303.1151. Methyl 2-Oxo-7-(trifluoromethyl)-5′,6′,7′,7a′-tetrahydrospiro[indoline-3,3′-pyrrolizine]-2′-carboxylate (5e). White solid, 68%, mp 192−194 °C; 1H NMR (400 MHz, CDCl3) δ: 7.76 (s, 1H), 0.240 g, 7.48 (d, J = 7.2 Hz, 1H), 7.24 (d, J = 2.0 Hz, 1H), 7.14−7.08 (m, 2H), 4.76−4.72 (m, 1H), 3.55 (s, 3H), 2.77−2.64 (m, 2H), 2.20− 2.12 (m, 1H), 1.94−1.88 (m, 2H), 1.64−1.55 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ: 178.0, 162.2, 147.3, 139.3 (q, J = 1.9 Hz), 133.5, 129.3, 128.0, 126.5 (q, J = 4.1 Hz), 123.8 (q, J = 270.4 Hz), 121.7, 112.4 (q, J = 32.9 Hz), 75.8, 72.2, 51.7, 48.4, 31.0, 27.3; IR(KBr) υ: 3188, 3116, 2961, 2866, 1731, 1617, 1452, 1342, 1248, 1180, 1125, 966, 926, 878, 810, 754 cm−1; MS (m/z): HRMS (ESITOF) calcd For C 17 H 16 F 3 N 2 O 3 ([M + H] + ): 353.1108, found:353.1140. Methyl 1-Methyl-2-oxo-5′,6′,7′,7a′-tetrahydrospiro[indoline3,3′-pyrrolizine]-2′-carboxylate (5f). White solid, 0.220 g, 74%, mp 114−116 °C; 1H NMR (400 MHz, CDCl3) δ: 7.31 (td, J1 = 7.6 Hz, J2 = 1.6 Hz, 1H), 7.16 (d, J = 1.6 Hz, 1H), 7.02−6.95 (m, 2H), 6.84 (d, J = 7.6 Hz, 1H), 4.73−4.69 (m, 1H), 3.50 (s, 3H), 3.22 (s, 3H), 2.74−2.64 (m, 2H), 2.15−2.07 (m, 1H), 1.92−1.79 (m, 2H), 1.63− 1.54 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ: 177.5, 162.5, 146.7, 144.8, 134.1, 129.8, 125.9, 125.6, 121.9, 108.4, 76.8, 72.1, 51.6, 48.5, 31.1, 27.4, 26.5; IR(KBr) υ: 3071, 3029, 2953, 2868, 1719, 1634, 1606, 1468, 1434, 1345, 1252, 1184, 1118, 1086, 991, 953, 905, 843, 766 cm−1; MS (m/z): HRMS (ESI-TOF) calcd For C17H19N2O3 ([M + H]+): 299.1390, found:299.1399. Methyl 5-Chloro-1-methyl-2-oxo-5′,6′,7′,7a′-tetrahydrospiro[indoline-3,3′-pyrrolizine]-2′-carboxylate (5g). White solid, 0.272 g, 82%, mp 190−192 °C; 1H NMR (400 MHz, CDCl3) δ: 7.32−7.30 (m, 1H), 7.18 (d, J = 1.6 Hz, 1H), 6.94 (d, J = 2.0 Hz, 1H), 6.78 (d, J = 8.4 Hz, 1H), 4.76−4.73 (m, 1H), 3.56 (s, 3H), 3.22 (s, 3H), 2.73− 2.70 (m, 2H), 2.19−2.11 (m, 1H), 1.96−1.88 (m, 2H), 1.64−1.55 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ: 176.9, 162.3, 146.9, 143.5, 133.7, 129.7, 127.6, 127.3, 125.9, 109.3, 76.7, 72.2, 51.7, 48.5, 31.0, 27.4, 26.5; IR(KBr) υ: 3438, 3074, 2956, 2869, 1725, 1604, 1484, 1435, 1334, 1243, 1113, 997, 916, 826, 773 cm−1; MS (m/z): HRMS (ESI-TOF) calcd For C17H18ClN2O3 ([M + H]+): 333.1000, found:333.1026. Methyl 1-Benzyl-5-chloro-2-oxo-5′,6′,7′,7a′-tetrahydrospiro[indoline-3,3′-pyrrolizine]-2′-carboxylate (5h). Light yellow solid, 0.338 g, 83%, mp 130−132 °C; 1H NMR (400 MHz, CDCl3) δ: 7.36−7.25 (m, 6H), 7.15 (dd, J1 = 8.0 Hz, J2 = 1.6 Hz, 1H), 6.94 (brs, 1H), 6.61 (d, J = 8.4 Hz, 1H), 5.02 (d, J = 16.0 Hz, 1H), 4.85 (d, J = 16.0 Hz, 1H), 4.76 (t, J = 7.6 Hz, 1H), 3.53 (s, 3H), 2.77−2.66 (m, 2H), 2.19−2.12 (m, 1H), 1.96−1.87 (m, 2H), 1.64−1.54 (m, 1H); 13 C{1H} NMR (100 MHz, CDCl3) δ: 177.3, 162.4, 147.4, 142.4, 135.4, 133.7, 129.6, 128.7, 127.9, 127.6, 127.4, 127.2, 125.9, 110.5, 76.7, 72.3, 51.8, 48.4, 44.1, 31.1, 27.5; IR(KBr) υ: 3066, 3032, 2975, 2931, 2872, 1709, 1609, 1489, 1461, 1356, 1326, 1246, 1179, 1119, 1072, 1017, 966, 935, 859, 806, 747 cm−1; MS (m/z): HRMS (ESITOF) calcd for C 23 H 22 ClN 2 O 3 ([M + H] + ): 409.1313, found:409.1325. Ethyl 1-Benzyl-2-oxo-5′,6′,7′,7a′-tetrahydrospiro[indoline-3,3′pyrrolizine]-2′-carboxylate (5i). Light yellow solid, 0.256 g, 66%, mp 126−128 °C; 1H NMR (400 MHz, CDCl3) δ: 7.37 (d, J = 7.2 Hz, 2H), 7.30 (d, J = 7.6 Hz, 2H), 7.26−7.16 (m, 3H), 6.99−6.94 (m, 2H), 6.69 (d, J = 8.0 Hz, 1H), 4.97−4.89 (m, 2H), 4.77 (t, J = 6.8 Hz, 1H), 4.05−3.97 (m, 1H), 3.85−3.76 (m, 1H), 2.78−2.72 (m, 2H), 2.17−2.09 (m, 1H), 1.91−1.84 (m, 2H), 1.66−1.57 (m, 1H), 0.87 (t, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ: 177.7, 162.1, 146.9, 143.9, 135.9, 134.4, 129.6, 128.6, 127.5, 127.4, 126.3, 125.8, 121.9, 109.5, 76.8, 72.1, 60.4, 48.6, 44.0, 31.1, 27.4, 13.7; IR(KBr) υ: 3067, 2956, 2899, 2858, 1728, 1634, 1604, 1482, 1430, 1333, 1251, 1176, 1126, 1067, 1031, 993, 946, 914, 874, 819, 775, 741, 701 cm−1; MS (m/z): HRMS (ESI-TOF) calcd for C24H25N2O3 ([M + H]+): 389.1860, found: 389.1872. 632

DOI: 10.1021/acs.joc.8b02457 J. Org. Chem. 2019, 84, 622−635

Article

The Journal of Organic Chemistry Ethyl 2-Oxo-7-(trifluoromethyl)-5′,6′,7′,7a′-tetrahydrospiro[indoline-3,3′-pyrrolizine]-2′-carboxylate (5j). White solid, 0.264 g, 72%, mp 154−156 °C; 1H NMR (400 MHz, CDCl3) δ: 7.69 (s, 1H), 7.48 (d, J = 7.2 Hz, 1H), 7.27 (d, J = 2.0 Hz, 1H), 7.15−7.08 (m, 2H), 4.74−4.70 (m, 1H), 4.04−3.88 (m, 2H), 2.76−2.64 (m, 2H), 2.18−2.11 (m, 1H), 1.93−1.84 (m, 2H), 1.64−1.54 (m, 1H), 0.98 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ: 178.3, 161.8, 147.4, 139.3 (q, J = 2.0 Hz), 133.8, 129.4, 128.3, 126.4 (q, J = 4.0 Hz), 123.8 (q, J = 270.4 Hz), 121.7, 112.3 (q, J = 33.1 Hz), 75.8, 72.1, 60.7, 48.5, 31.0, 27.4, 13.4; IR(KBr) υ: 3205, 3120, 2915, 1739, 1708, 1620, 1456, 1409, 1331, 1253, 1169, 1123, 963, 809, 754, 710 cm−1; MS (m/z): HRMS (ESI-TOF) calcd For C18H18F3N2O3 ([M + H]+): 367.1264, found: 367.1292. Crystallographic data of the compounds 1c (CCDC 1853138), 1d (CCDC 1853139), 1e (CCDC 1853140), 1g (CCDC 1422021), 1h (CCDC 1857271), 1j (CCDC 18572722), 2b (CCDC 1853141), 2d (CCDC 1853142), 2f (CCDC 1853143), 2j (CCDC 1853144), 3b (CCDC 1422022), 3d (CCDC 1853145), 3e (CCDC1853146), 3g (CCDC 1853147), 4b (CCDC 1853148), 4c (CCDC 1853149), 4d (CCDC 1853150), 5a (CCDC 1853151), and 5j (CCDC 1853152) have been deposited at the Cambridge Crystallographic Database Center (http//www.ccdc.cam.ac.uk).

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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.joc.8b02457.

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copies of the 1H and 13C NMR spectra for all new products (PDF) Crystallographic information for 1c−2j (CIF) Crystallographic information for 3b−5j (CIF)

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]; Fax: (+86) 514-87975531. ORCID

Chao-Guo Yan: 0000-0002-2777-9582 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful to the National Natural Science Foundation of China (Grant 21572196) and the Priority Academic Program Development of Jiangsu Higher Education Institutions (Grant BK2013016) for financial support. We also wish to thank one anonymous reviewer for his helpful proposal on the reaction mechanisms.

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REFERENCES

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DOI: 10.1021/acs.joc.8b02457 J. Org. Chem. 2019, 84, 622−635

Article

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DOI: 10.1021/acs.joc.8b02457 J. Org. Chem. 2019, 84, 622−635