Solvent-Controlled, Tunable Domino Reaction of 3-Ylideneoxindoles with in Situ-Generated α-Aryldiazomethanes: A Facile Access to 3-Spirocyclopropyl-2-oxindole and Pyrazoloquinazolinone Scaffolds.

A mild and efficient solvent-controlled, metal-free switchable 1,3-dipolar cycloaddition/ring contraction or ring expansion domino reaction of 3-ylideneoxindoles with in situ-generated α-aryldiazomethanes has been developed. This domino reaction provided a series of aryl-substituted 3-spirocyclopropyl-2-oxindoles and pyrazoloquinazolinones with excellent regio- and diastereoselectivity from common substrates under varying solvent conditions.

Introduction

Structurally complex scaffolds with extensive applications in the pharmaceutical industry have attracted the attention of the synthetic community to design and develop expeditious strategies toward their construction.[1] Among which, spirooxindole represents a ubiquitous skeleton and stands first with regard to its structural complexity and pharmacological utilities.[2,3] Particularly, 3-spirocyclopropyl-2-oxindole is a privileged scaffold, which is found in a plethora of natural products and pharmaceuticals that possess a wide spectrum of biological activities such as antitumor, anti-obesity, and antidiabetic.[4] As these scaffolds also inhibit enzymes such as HIV-1 non-nucleoside reverse transcriptase and kinase and arginine vasopressin hormone, they are useful in the treatment of congestive heart failure, hypertension, edema, and hyponatremia.[5] Considering these biological properties, numerous innovative synthetic approaches have evolved toward the stereoselective construction of spirooxindole scaffolds.[6−15]

3-Spirocyclopropyl-2-oxindoles can be traditionally synthesized in a straightforward, diastereoselective manner by treating oxindoles with bromonitroolefins.[7] They can also be obtained by reacting 3-ylidene-oxindoles with 1,2-dihaloalkanes,[8] diazo compounds under the catalysis of dirhodiumtetraacetate,[9] pyridinium salts in the presence of base,[10] ethyl diazoacetate,[11] or bromonitroalkyl derivatives in a Michael–alkylation cascade manner.[12] Alternatively, they can be constructed by the ring contraction of corresponding spiro[pyrazolin-3,3-oxindoles], which are obtained by 1,3-dipolar cycloaddition of 3-ylidene-oxindoles with active diazo partners such as 2,2,2-trifluorodiazoethane,[13] α-diazocarbonyl compounds,[14] or the Bestmann Ohira reagent (Scheme ).[15] However, the aforementioned strategies suffer from disadvantages such as lower yields; harsh reaction conditions; use of gaseous, toxic, and explosive CF3CHN2; and requirement of transition metal catalysts and active diazo partners. Considering these limitations, investigations for alternate approaches that avoid usage of expensive and explosive diazo compounds for the stereoselective synthesis of these scaffolds are still in great demand. Moreover, in spite of the advances being made, use of inactive α-aryldiazomethanes is rarely exploited in the cyclopropanation of 3-ylidene-oxindoles.

Scheme 1

1,3-Dipolar Cycloadditions of 3-Ylidene-oxindoles and α-Diazo Compounds for the Synthesis of 3-Spirocyclopropyl-2-oxindoles

On the other hand, tremendous advances have been made in the field of switchable intermolecular domino reactions,[16] challenging yet desirable transformations that deliver different products from identical substrates through solvent regiodivergent procedures. Domino reactions have the advantage that minimal purification is required and are step- and atom-economical processes. In continuation of our interest in developing domino strategies toward the synthesis of bioactive scaffolds,[17] we wondered if we could construct 3-spirocyclopropyl-2-oxindole by trapping α-aryldiazomethanes (generated in situ from tosylhydrazide and aldehyde) with 3-ylidene-oxindoles via elimination of N2 in a diastereoselective manner, an approach that has not been described. To realize our goal, initially 3-ylidene-oxindole 1a was treated with tosylhydrazide 3 and aldehyde 2a for the anticipated cyclopropanation, and to our delight, 3-spirocyclopropyl-2-oxindole 4a was obtained with high diastereoselectivity (>95) in 88% yield. Surprisingly, changing the reaction medium from CH3CN to EtOH delivered pyrazoloquinazolinones 5 via the anticipated 1,3-dipolar cycloaddition, followed by an unexpected rearrangement. It is worth mentioning that pyrazoloquinazolinones are also quite interesting fused heterocyclic compounds with vast application in the pharmaceutical industry. They possess AMPA, Gly/NMDA, and KA receptor antagonistic and benzodiazepine receptor agonistic activities and also inhibit phosphodiesterase 10A and vaccinia virus.[17] Herein, we wish to describe our unique observation of solvent-controlled switchable domino reaction between 3-ylidene-oxindoles and α-aryldiazomethanes, which deliver substituted 3-spirocyclopropyl-2-oxindole and pyrazoloquinazolinones.

Results and Discussion

To investigate the envisioned strategy as shown in Table , we commenced our study by treating (E)-ethyl-2-(2-oxoindolin-3-ylidene)acetate with (diazomethyl)benzene, which was generated in situ from benzaldehyde and TsNHNH2 in acetonitrile employing 2.0 equiv of K2CO3 in open air under refluxing temperature. As expected, 1,3-dipolar cycloaddition/ring contraction occurred smoothly and resulted 3-spirocyclopropyl-2-oxindole 4 (Table , entry 1) with excellent regio- and diastereoselectivity. The structure of the compound 4 was unambiguously confirmed by spectroscopic and X-ray crystallographic data. These interesting results encouraged us to investigate various parameters that increase the reaction efficiency. Changing the solvent from acetonitrile to other aprotic solvents such as CH2Cl2, tetrahydrofuran (THF), and toluene offered no improvement in the yield (Table , entries 2–4). Screening of various organic and inorganic bases such as DBU, Et3N, pyridine, Cs2CO3, and K2CO3 revealed that K2CO3 was the best base of choice (Table , entries 5–8).

Table 1

Optimization of Reaction Conditionsa

entry	base	solvent	temp (°C)	yield of 4a (%)b	dr. of 4ac (%)	yield of 5a (%)b
1	K2CO3	CH3CN	80	88	>95
2	K2CO3	CH2Cl2	40	54	>95
3	K2CO3	THF	60	63	>95
4	K2CO3	toluene	100	50	>95
5	DBU	CH3CN	80	76	>95
6	Et3N	CH3CN	80	72	>95
7	Py	CH3CN	80	66	>95
8	Cs2CO3	CH3CN	80	83	>95
9	K2CO3	EtOH	80	<5		76
10	K2CO3	MeOH	65	<5		68
11	Cs2CO3	EtOH	80	<5		70
12	DBU	EtOH	80	<5		55
13	Et3N	EtOH	80	<5		55
14	Py	EtOH	80	<5		50

Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), 3 (0.5 mmol), base (1.0 mmol for entries 1–8 and 1.5 mmol for entries 9–14), and solvent (5 mL).

Isolated yields after column chromatography.

The dr. values were determined by 1H NMR analysis.

To our surprise, use of protic solvents such as EtOH offered an unexpected rearrangement, leading to generation of pyrazoloquinazolinones 5. The structure of the compound was also confirmed by X-ray analysis. This stimulating result forced us to scrutinize the reaction parameters in detail. It is clear that EtOH is superior to MeOH, whereas K2CO3 appeared to be an optimal base even for this transformation (Table , entries 9–14).

With optimized reaction conditions established, the scope and generality of the regio- and diastereoselective 1,3-dipolar cycloaddition/ring contraction reaction to assemble a series of 3-spirocyclopropyl-2-oxindoles were explored first by varying the substitution pattern on both 2,3-oxindole and aldehyde partners. As summarized in Table , the electronic nature of substituents on 2,3-oxindole has only a marginal impact on the reaction efficiency. Accordingly, a series of 3-ylidene-oxindoles bearing electron-neutral, electron-donating (e.g., Me and OMe), and electron-withdrawing substituents (e.g., F, Cl, Br, and NO2) on the aromatic ring reacted well with in situ-generated α-aryldiazomethanes and delivered corresponding products with good regio- and diastereoselectivity (Table , 4a–v). It is pleasing to mention that phenacylidene and arylideneoxindoles were also well compatible with the transformation, providing corresponding products in good yields (Table , 4ab–ae). In the next stage, we have also studied the reactivity of substrates by varying the substitution pattern on the phenacylidene and phenylidine moieties, which delivered corresponding products in moderate to good yields. Notably, the electronic nature of substituents on the aryl moiety of α-aryldiazomethane has discernible impact on the reaction efficacy, where electron-donating (e.g., Me and OMe) groups provided corresponding products in slightly better yields than the electron-withdrawing groups (e.g., Cl and NO2). Furthermore, investigation on the effect of N-protecting groups such as -Me and -Bn revealed that even N-protected 3-ylidene-oxindoles could also be successfully involved in this transformation without altering the reaction efficacy (Table , 4w–z and 4aa).

Table 2

Scope of the 1,3-Dipolar Cycloaddition/Ring Contraction Sequence Domino Reactiona

Reaction conditions: 1 (0.5 mmol), 2 (0.5 mmol), 3 (0.5 mmol), K2CO3 (1.0 mmol), CH3CN (5.0 mL); yields of isolated products.

Encouraged by these fruitful results, to explore our solvent-switchable domino reaction, we next turned to broaden the scope of pyrazoloquinazolinone construction from ethyl-2-(2-oxoindolin-3-ylidene)acetate and α-aryldiazomethane in the presence of protic solvents (Table ). A broad range of 3-ylidene-oxindoles were converted into corresponding pyrazoloquinazolinones in moderate to good yields irrespective of substituents on the aromatic ring of 2,3-oxindole (Table , 5a–e). Oxindole bearing various electron-donating and electron-withdrawing heteroatoms at the fifth position of the 2,3-oxindole ring are equally amenable for this rearrangement and delivered corresponding products in good yields. Comparable variation in the yields of the products was observed by changing the substitution pattern on the aromatic ring of the diazo partner. Similar to cyclopropanation, better yields were obtained with electron-donating substituents (Table , 5h, 5k, and 5l) than with electron-withdrawing substituents (Table , 5b, 5c, 5f, 5i, and 5m). It is worth mentioning that this rearrangement could also be successfully extended to even phenacylidene and phenylidineoxindoles to generate corresponding pyrazoloquinazolinones in moderate to good yields (Table , 5h–m).

Table 3

Scope of the 1,3-Dipolar Cycloaddition/Ring Expansion Sequence Domino Reactiona

Reaction conditions: 1 (0.5 mmol), 2 (0.5 mmol), 3 (0.5 mmol), K2CO3 (1.5 mmol), CH3OH (5.0 mL); yields of isolated products.

To further extend the synthetic feasibility of this reaction, a gram-scale reaction was performed under optimized reaction conditions by changing the solvent that delivered 3-spirocyclopropyl-2-oxindole (4a) and pyrazoloquinazolinone (5a) without affecting the reaction efficacy and diastereoselectivity, showing its potential for bulk-scale utility (Scheme ).

Scheme 2

Gram-Scale Synthesis of Compounds 4a and 5a

On the basis of literature[11−15] and our outcome, a plausible mechanism was proposed (Scheme ). Initially, aldehyde reacts with TsNHNH2 and generates corresponding hydrazone intermediate A, which subsequently converts to aryldiazomethane B in the presence of base by the elimination of tosyl group. A formal 1,3-dipolar cycloaddition of 3-ylideneoxindoles with aryldiazomethane B would afford intermediate C, which undergoes decomposition in an aprotic solvent under elevated temperatures to deliver 3-spirocyclopropyl-2-oxindole 4. Moreover, it is also assumed that in the presence of protic solvent, intermediate C transforms into intermediate D by tautomerism, which may generate spiropyrazole-oxindole E by air oxidation.[15a,15c] Intermediate E after spontaneous rearrangement delivers pyrazoloquinazolinones 5 via a ring-expanded intermediate F.[15d]

Scheme 3

Plausible Reaction Mechanism

Conclusions

In summary, an attractive, switchable solvent-controlled product-selectivity domino reaction between 3-ylideneoxindoles and an in situ-generated α-aryldiazo compound has been developed for the synthesis of 3-spirocyclopropyl-2-oxindole and pyrazoloquinazolinones with high regio- and diastereoselectivity. Two types of domino reactions, i.e., 1,3-dipolar cycloaddition/ring contraction and unprecedented 1,3-dipolar cycloaddition/ring expansion reactions, were demonstrated by employing variable solvent conditions from identical substrates. Broad functional-group tolerance, absence of metals, and atom and step economy are the salient features of the developed protocol. Further investigations toward 1,3-dipolar cycloaddition reactions with methyleneindolinones and evaluation of biological activity for the synthesized scaffolds are currently underway.

Experimental Section

General Procedures

Unless otherwise noted, all reagents were used as received from commercial sources. All air- and moisture-sensitive reactions were conducted under a nitrogen or argon atmosphere using flame-dried or oven-dried glassware with magnetic stirring. Tetrahydrofuran (THF) was dried over Na with benzophenone and distilled prior to use. Reactions were monitored by thin-layer chromatography (TLC) carried out on silica plates (silica gel 60 F254, Merck) using UV-light, iodine, and p-anisaldehyde for visualization. Column chromatography was carried out using silica gel (60–120 mesh or 100–200 mesh) packed in glass columns. Technical-grade EtOAc and petroleum ether were used for column chromatography and were distilled prior to use. Organic solutions were concentrated under reduced pressure using a rotary evaporator. Room temperature (r.t.) is 23–25 °C.

Materials

Commercial reagents were purchased from Merck, Alfa, Spectrochem, or TCI and used as received with the following exceptions. Tetrahydrofuran (THF), ethylene glycol dimethyl ether, toluene, and 1,4-dioxane were dried over Na with the benzophenone-ketyl intermediate as indicator. Dichloroethane and dichloromethane were distilled over CaH2, and acetonitrile (CH3CN) was distilled over P2O5. N,N-Dimethylformamide was distilled under reduced pressure. Other commercially available reagents and solvents were used without further purification.

Instrumentation

1H NMR and 13C NMR spectra were recorded in CDCl3 or dimethyl sulfoxide (DMSO) as solvent on Bruker Avance 400, Inova Instruments, with 400, 300, and 500 MHz frequency spectrometers. The coupling constant J is given in hertz. Chemical shifts (δ) were reported in ppm relative to the residual solvent signal (CDCl3, δ = 7.26 for 1H NMR and δ = 77.0 for 13C NMR) and DMSO (1H NMR: δ = 2.54 and 13C NMR: δ = 39.52 ppm). Chemical shifts (ppm) were recorded with tetramethylsilane (TMS) as the internal reference standard or TMS (δ = 0.0) as the internal standard, and signal patterns are indicated as follows: s = singlet, d = doublet, dd = doublet of doublet, dt = doublet of triplet, t = triplet, q = quartet, qd = quartet of doublet, m = multiplet, br = broad, and tt = triplet of triplet. IR spectra were recorded on a Bruker infrared spectrophotometer and are reported as cm–1. High-resolution mass spectra (HRMS) were recorded on a Waters-TOF spectrometer.

General Procedure for the Preparation of Spirocyclopropyloxindoles (4a–ae)

3-Ylideneoxindole 1 (0.50 mmol), arylaldehyde 2 (0.50 mmol), and TsNHNH23 (0.50 mmol) were stirred in 5.0 mL of CH3CN at room temperature in a 10 mL Schlenk tube for 10 min. Then, to this solution was added K2CO3 (1.0 mmol) at the same temperature and the reaction mixture was stirred at refluxing temperature for 2 h. Upon the completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature and diluted with 10 mL of water and extracted with EtOAc (3 × 10 mL). The organic layers were combined and washed with brine and dried over anhydrous Na2SO4. After the solvent was removed under reduced pressure, the crude product was purified by flash column chromatography on silica gel (petroleum ether/EtOAc) to afford the desired product 4.

Analytical Data for the Compounds 4a–ae

Ethyl-2′-oxo-3-phenylspiro[cyclopropane-1,3′-indoline]-2-carboxylate (4a)

Following the general procedure (80 °C for 2 h), compound 4a was obtained after column chromatography (hexane/EtOAc 8:2) in 88% yield as a white solid. mp 182–183 °C. 1H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.32–7.18 (m, 6H), 7.02 (td, J = 7.6, 0.9 Hz, 1H), 6.78 (d, J = 7.7 Hz, 1H), 4.31–4.11 (m, 2H), 3.79 (d, J = 8.3 Hz, 1H), 3.35 (d, J = 8.3 Hz, 1H), 1.25 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 173.7, 168.2, 141.2, 133.4, 131.4, 130.6, 128.3, 127.8, 126.3, 122.7, 122.3, 109.9, 61.7, 39.6, 39.4, 37.3, 14.2 ppm. HRMS calcd for C19H18O3N [M + H]+: 308.1281; found: 308.1289.

Ethyl-5′-methyl-2′-oxo-3-phenylspiro[cyclopropane-1,3′-indoline]-2-carboxylate (4b)

Following the general procedure (80 °C for 2 h), compound 4b was obtained after column chromatography (hexane/EtOAc 8:2) in 90% yield as a creamy white solid. mp 230–232 °C. 1H NMR (400 MHz, CDCl3) δ 8.75 (s, 1H), 7.36–7.16 (m, 6H), 7.00 (dd, J = 7.9, 0.7 Hz, 1H), 6.65 (d, J = 7.9 Hz, 1H), 4.33–4.05 (m, 2H), 3.75 (d, J = 8.3 Hz, 1H), 3.33 (d, J = 8.3 Hz, 1H), 2.34 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 173.9, 168.6, 138.9, 133.0, 131.6, 129.2, 128.1, 128.0, 127.5, 126.8, 123.4, 109.6, 61.6, 40.3, 40.0, 37.3, 21.4, 14.2 ppm. HRMS calcd for C20H20O3N [M + H]+: 322.1437; found: 322.1435.

Ethyl-5′-bromo-2′-oxo-3-phenylspiro[cyclopropane-1,3′-indoline]-2-carboxylate (4c)

Following the general procedure (80 °C for 2 h), compound 4c was obtained after column chromatography (hexane/EtOAc 8:2) in 82% yield as a white solid. mp 183–183 °C. 1H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 7.64 (d, J = 1.8 Hz, 1H), 7.37–7.21 (m, 6H), 6.64 (d, J = 8.3 Hz, 1H), 4.32–4.17 (m, 2H), 3.77 (d, J = 8.4 Hz, 1H), 3.35 (d, J = 8.4 Hz, 1H), 1.29 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 173.33, 168.2, 140.2, 132.4, 130.4, 129.2, 128.8, 128.2, 127.7, 125.9, 114.9, 111.6, 61.8, 40.9, 39.8, 37.5, 14.2 ppm. HRMS calcd for C19H17O3NBr [M + H]+: 386.0386; found: 386.0391.

Ethyl-5′-chloro-2′-oxo-3-phenylspiro[cyclopropane-1,3′-indoline]-2-carboxylate (4d)

Following the general procedure (80 °C for 2 h), compound 4d was obtained after column chromatography (hexane/EtOAc 8:2) in 80% yield as a creamy white solid. mp 222–224 °C. 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 7.51 (d, J = 2.1 Hz, 1H), 7.31–7.24 (m, 5H), 7.19 (dd, J = 8.3, 2.1 Hz, 1H), 6.70 (d, J = 8.3 Hz, 1H), 4.31–4.16 (m, 2H), 3.77 (d, J = 8.4 Hz, 1H), 3.35 (d, J = 8.4 Hz, 1H), 1.29 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 173.4, 168.22, 139.7, 132.4, 129.2, 128.4, 128.2, 127.7, 127.6, 127.6, 123.2, 110.7, 61.8, 40.9, 39.9, 37.5, 14.2 ppm. HRMS calcd for C19H17O3NCl [M + H]+: 342.0891; found: 342.0890.

Ethyl-5′-fluoro-2′-oxo-3-phenylspiro[cyclopropane-1,3′-indoline]-2-carboxylate (4e)

Following the general procedure (80 °C for 2 h), compound 4e was obtained after column chromatography (hexane/EtOAc 8:2) in 79% yield as a white solid. mp 186–189 °C. 1H NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 7.32–7.24 (m, 6H), 6.94–6.87 (m, 1H), 6.68 (dd, J = 8.5, 4.3 Hz, 1H), 4.31–4.15 (m, 2H), 3.75 (d, J = 8.3 Hz, 1H), 3.36 (d, J = 8.3 Hz, 1H), 1.28 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 173.9, 168.3, 158.8 (d, J = 239.1 Hz), 137.2, 132.5, 129.2, 128.2, 127.7, 114.0 (d, J = 23.8 Hz), 110.9 (d, J = 26.6 Hz), 110.3 (d, J = 8.2 Hz), 61.8, 40.9, 40.2, 37.4, 14.2 ppm. 19F NMR (376 MHz, CDCl3) δ −120.37 ppm. HRMS calcd for C19H17O3NF [M + H]+: 326.1187; found: 326.1184.

Ethyl-5′-nitro-2′-oxo-3-phenylspiro[cyclopropane-1,3′-indoline]-2-carboxylate (4f)

Following the general procedure (80 °C for 2 h), compound 4f was obtained after column chromatography (hexane/EtOAc 8:2) in 77% yield as a light yellow solid. mp 168–170 °C. 1H NMR (400 MHz, CDCl3) δ 9.10 (s, 1H), 8.45 (d, J = 2.1 Hz, 1H), 8.20 (dd, J = 8.6, 2.2 Hz, 1H), 7.35–7.24 (m, 5H), 6.85 (d, J = 8.6 Hz, 1H), 4.26 (qq, J = 10.9, 7.2 Hz, 2H), 3.94 (d, J = 8.5 Hz, 1H), 3.42 (d, J = 8.5 Hz, 1H), 1.31 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 174.2, 167.8, 146.8, 143.3, 131.9, 129.2, 128.3, 128.0, 127.4, 124.6, 119.1, 109.7, 62.2, 41.4, 39.7, 38.0, 14.2 ppm. HRMS calcd for C19H17O5N2 [M + H]+: 353.1132; found: 353.1137.

Ethyl-3-(4-methoxyphenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-2-carboxylate (4g)

Following the general procedure (80 °C for 2 h), compound 4g was obtained after column chromatography (hexane/EtOAc 8:2) in 91% yield as a white solid. mp 210–212 °C. 1H NMR (400 MHz, CDCl3) δ 8.10 (s, 1H), 7.48 (d, J = 7.7 Hz, 1H), 7.22 (d, J = 8.5 Hz, 3H), 7.02 (dd, J = 15.2, 7.6 Hz, 1H), 6.87–6.79 (m, 3H), 4.28–4.12 (m, 2H), 3.77 (s, 3H), 3.73 (d, J = 8.4 Hz, 1H), 3.32 (d, J = 8.3 Hz, 1H), 1.26 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 174.0, 168.6, 158.9, 141.2, 130.3, 127.5, 126.8, 124.8, 122.6, 122.1, 113.5, 109.8, 61.5, 55.2, 40.0, 37.5, 14.2 ppm. HRMS calcd for C20H20O4N [M + H]+: 338.1387; found: 338.1388.

Ethyl-5′-methoxy-3-(4-methoxyphenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-2-carboxylate (4h)

Following the general procedure (80 °C for 2 h), compound 4h was obtained after column chromatography (hexane/EtOAc 8:2) in 93% yield as a light brown solid. mp 178–181 °C. 1H NMR (500 MHz, CDCl3) δ 8.18 (s, 1H), 7.22 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 2.4 Hz, 1H), 6.84–6.81 (m, 2H), 6.78–6.71 (m, 2H), 4.27–4.14 (m, 2H), 3.80 (s, 3H), 3.77 (s, 3H), 3.69 (d, J = 8.3 Hz, 1H), 3.32 (d, J = 8.3 Hz, 1H), 1.27 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 174.0, 168.5, 158.9, 155.5, 134.8, 130.3, 128.1, 124.8, 113.5, 112.8, 110.2, 109.3, 61.6, 55.9, 55.2, 40.4, 40.3, 37.5, 14.2 ppm. HRMS calcd for C21H22O5N [M + H]+: 368.1492; found: 368.1490.

Ethyl-5′-chloro-3-(4-methoxyphenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-2-carboxylate (4i)

Following the general procedure (80 °C for 2 h), compound 4i was obtained after column chromatography (hexane/EtOAc 8:2) in 86% yield as a brown solid. mp 180–182 °C. 1H NMR (500 MHz, CDCl3) δ 8.72 (s, 1H), 7.50 (d, J = 2.1 Hz, 1H), 7.22–7.16 (m, 3H), 6.81 (d, J = 8.7 Hz, 2H), 6.70 (d, J = 8.3 Hz, 1H), 4.30–4.17 (m, 2H), 3.76 (s, 3H), 3.72 (d, J = 8.4 Hz, 1H), 3.32 (d, J = 8.4 Hz, 1H),1.28 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 173.8, 168.3, 159.1, 139.8, 130.3, 128.5, 127.6, 127.4, 124.4, 123.1, 113.6, 110.8, 61.8, 55.2, 40.6, 40.0, 37.7, 14.2 ppm. HRMS calcd for C20H19O4NCl [M + H]+: 372.0997; found: 372.1000.

Ethyl-5′-fluoro-3-(4-methoxyphenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-2-carboxylate (4j)

Following the general procedure (80 °C for 2 h), compound 4j was obtained after column chromatography (hexane/EtOAc 8:2) in 85% yield as a brown solid. mp 168–171 °C. 1H NMR (400 MHz, CDCl3) δ 8.92 (s, 1H), 7.27 (dd, J = 8.9, 2.3 Hz, 1H), 7.20 (d, J = 8.6 Hz, 2H), 6.89 (td, J = 8.9, 2.3 Hz, 1H), 6.81 (d, J = 8.7 Hz, 2H), 6.66 (d, J = 4.1 Hz, 1H), 4.22 (qq, J = 10.9, 7.1 Hz, 2H), 3.75 (s, 3H), 3.70 (d, J = 8.3 Hz, 1H), 3.32 (d, J = 8.3 Hz, 1H), 1.27 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 173.8, 168.4, 159.1 158.8 (d, J = 239.1 Hz), 137.1, 130.3, 128.4 (d, J = 9.5 Hz), 124.4, 113.8 (d, J = 23.5 Hz), 113.6, 110.8 (d, J = 26.4 Hz), 110.1 (d, J = 8.1 Hz), 61.7, 55.2, 40.6, 40.3, 37.6, 14.2 ppm. 19F NMR (376 MHz, CDCl3) δ −120.26 ppm. HRMS calcd for C20H19O4NF [M + H]+: 356.1293; found: 356.1292.

Ethyl-3-(4-chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-2-carboxylate (4k)

Following the general procedure (80 °C for 2 h), compound 4k was obtained after column chromatography (hexane/EtOAc 8:2) in 84% yield as a white solid. mp 159–161 °C. 1H NMR (400 MHz, CDCl3) δ 8.16 (s, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.29–7.21 (m, 5H), 7.04 (td, J = 7.7, 1.0 Hz, 1H), 6.84 (d, J = 7.7 Hz, 1H), 4.28–4.12 (m, 2H), 3.73 (d, J = 8.2 Hz, 1H), 3.31 (d, J = 8.2 Hz, 1H), 1.26 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 173.6, 168.2, 141.2, 133.4, 131.4, 130.6, 128.3, 127.8, 126.3, 122.8, 122.3, 109.9, 61.7, 39.8, 39.4, 37.3, 14.2 ppm. HRMS calcd for C19H17O3NCl [M + H]+: 342.0892; found: 342.0893

Ethyl-3-(4-chlorophenyl)-5′-methyl-2′-oxospiro[cyclopropane-1,3′-indoline]-2-carboxylate (4l)

Following the general procedure (80 °C for 2 h), compound 4l was obtained after column chromatography (hexane/EtOAc 8:2) in 85% yield as a light brown solid. mp 208–209 °C. 1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 7.29–7.20 (m, 5H), 7.03 (dd, J = 7.9, 0.8 Hz, 1H), 6.67 (d, J = 7.9 Hz, 1H), 4.29–4.13 (m, 2H), 3.69 (d, J = 8.2 Hz, 1H), 3.28 (d, J = 8.2 Hz, 1H), 2.34 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (125 MHz, CDCl3) δ 173.9, 168.3, 138.9, 133.3, 131.8, 131.6, 130.6, 128.3, 128.2, 126.4, 123.3, 109.7, 61.7, 39.9, 39.4, 37.2, 21.3, 14.2 ppm. HRMS calcd for C20H19O3NCl [M + H]+: 356.1048; found: 356.1051.

Ethyl-5′-bromo-3-(4-chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-2-carboxylate (4m)

Following the general procedure (80 °C for 2 h), compound 4m was obtained after column chromatography (hexane/EtOAc 8:2) in 80% yield as a creamy white solid. mp 214–215 °C. 1H NMR (400 MHz, CDCl3) δ 8.95 (s, 1H), 7.62 (d, J = 1.8 Hz, 1H), 7.36 (dd, J = 8.3, 2.0 Hz, 1H), 7.28–7.18 (m, 4H), 6.62 (d, J = 8.3 Hz, 1H), 4.31–4.17 (m, 2H), 3.72 (d, J = 8.3 Hz, 1H), 3.30 (d, J = 8.3 Hz, 1H), 1.29 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 173.4, 167.9, 140.2, 133.6, 140.0, 130.7, 130.6, 128.4, 126.0, 115.1, 111.4, 62.0, 39.9, 39.7, 37.5, 14.2 ppm. HRMS calcd for C19H16O3NBrCl [M + H]+: 419.9997; found: 419.9999.

Ethyl-5′-chloro-3-(4-chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-2-carboxylate (4n)

Following the general procedure (80 °C for 2 h), compound 4n was obtained after column chromatography (hexane/EtOAc 8:2) in 77% yield as a creamy white solid. mp 206–208 °C. 1H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 7.49 (d, J = 2.0 Hz, 1H), 7.29–7.19 (m, 5H), 6.70 (d, J = 8.3 Hz, 1H), 4.32–4.16 (m, 2H), 3.72 (d, J = 8.3 Hz, 1H), 3.31 (d, J = 8.3 Hz, 1H), 1.31 (s, 3H) ppm. 13C NMR (125 MHz, CDCl3) δ 173.5, 168.0, 139.7, 133.6, 131.0, 130.6, 128.4, 128.0, 127.8, 123.3, 110.9, 62.0, 39.9, 39.8, 37.4, 14.2 ppm. HRMS calcd for C19H16O3NCl 2 [M + H]+: 376.0502; found: 376.0507.

Ethyl-3-(4-chlorophenyl)-5′-fluoro-2′-oxospiro[cyclopropane-1,3′-indoline]-2-carboxylate (4o)

Following the general procedure (80 °C for 2 h), compound 4o was obtained after column chromatography (hexane/EtOAc 8:2) in 76% yield as a creamy white solid. mp 149–151 °C. 1H NMR (400 MHz, CDCl3) δ 8.80 (s, 1H), 7.28–7.20 (m, 5H), 6.94 (td, J = 8.9, 2.6 Hz, 1H), 6.68 (dd, J = 8.5, 4.3 Hz, 1H), 4.31–4.15 (m, 2H), 3.70 (d, J = 8.3 Hz, 1H), 3.31 (d, J = 8.3 Hz, 1H), 1.28 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (125 MHz, CDCl3) δ 173.9, 168.0, 158.9 (d, J = 239.5 Hz), 137.2, 133.6, 131.1, 130.6, 128.3, 127.9 (d, J = 9.3 Hz), 114.3 (d, J = 23.8 Hz), 110.9 (d, J = 26.7 Hz), 110.4 (d, J = 8.2 Hz), 61.9, 40.1, 39.9, 37.3, 14.2 ppm. 19F NMR (376 MHz, CDCl3) δ −120.06 ppm. HRMS calcd for C19H16O3NClF [M + H]+: 360.0797; found: 360.0800.

Ethyl-5′-methoxy-3-(4-nitrophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-2-carboxylate (4p)

Following the general procedure (80 °C for 2 h), compound 4p was obtained after column chromatography (hexane/EtOAc 7:3) in 82% yield as a brown solid. mp 192–195 °C. 1H NMR (500 MHz, CDCl3) δ 8.16 (d, J = 8.7 Hz, 2H), 7.98 (s, 1H), 7.48 (d, J = 8.6 Hz, 2H), 7.14 (d, J = 2.1 Hz, 1H), 6.79 (dt, J = 16.2, 5.4 Hz, 2H), 4.30–4.17 (m, 2H), 3.81 (s, 3H), 3.78 (d, J = 8.2 Hz, 1H), 3.37 (d, J = 8.2 Hz, 1H), 1.28 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 173.4, 167.8, 155.8, 147.3, 140.6, 134.6, 130.2, 127.0, 123.3, 113.3, 110.4, 109.7, 62.0, 55.9, 40.3, 39.2, 37.1, 14.2 ppm. HRMS calcd for C20H19O6N2 [M + H]+: 383.1238; found: 383.1241.

Ethyl-5′-methyl-3-(4-nitrophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-2-carboxylate (4q)

Following the general procedure (80 °C for 2 h), compound 4q was obtained after column chromatography (hexane/EtOAc 7:3) in 80% yield as a brown solid. mp 215–218 °C. 1H NMR (400 MHz, CDCl3) δ 8.35 (bs, 1H), 8.14 (d, J = 8.8 Hz, 2H), 7.47 (d, J = 8.5 Hz, 2H), 7.28 (s, 1H), 7.05 (d, J = 7.9 Hz, 1H), 6.72 (d, J = 7.9 Hz, 1H), 4.31–4.16 (m, 2H), 3.78 (d, J = 8.2 Hz, 1H), 3.36 (d, J = 8.2 Hz, 1H), 2.35 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (125 MHz, CDCl3) δ 173.4, 167.8, 147.2, 140.7, 138.8, 132.1, 130.2, 128.6, 125.8, 123.5, 123.3, 109.8, 61.9, 40.1, 38.9, 37.1, 21.3, 14.2. HRMS calcd for C20H19O5N2 [M + H]+: 367.1289; found: 367.1291.

Ethyl-5′-chloro-3-(4-nitrophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-2-carboxylate (4r)

Following the general procedure (80 °C for 2 h), compound 4r was obtained after column chromatography (hexane/EtOAc 7:3) in 75% yield as a brick red solid. mp 186–188 °C. 1H NMR (500 MHz, CDCl3) δ 8.17–8.13 (m, 3H), 7.52 (d, J = 1.6 Hz, 1H), 7.47 (d, J = 8.6 Hz, 2H), 7.27–7.23 (m, 1H), 6.82 (d, J = 8.3 Hz, 1H), 4.34–4.20 (m, 2H), 3.81 (d, J = 8.3 Hz, 1H), 3.39 (d, J = 8.3 Hz, 1H), 1.30 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 173.0, 167.5, 147.4, 140.0, 139.7, 130.2, 128.2, 128.1, 127.4, 123.4, 123.3, 110.9, 62.2, 39.9, 39.4, 37.3, 14.2 ppm. HRMS calcd for C19H16O5N2Cl [M + H]+: 387.0742; found: 387.0747.

Ethyl-5′-fluoro-3-(4-nitrophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-2-carboxylate (4s)

Following the general procedure (80 °C for 2 h), compound 4s was obtained after column chromatography (hexane/EtOAc 7:3) in 74% yield as a brown solid. mp 164–168 °C. 1H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 8.16 (d, J = 8.7 Hz, 2H), 7.47 (d, J = 8.7 Hz, 2H), 7.29 (dd, J = 8.8, 2.5 Hz, 1H), 6.97 (td, J = 8.8, 2.6 Hz, 1H), 6.78 (dd, J = 8.5, 4.3 Hz, 1H), 4.32–4.18 (m, 2H), 3.79 (d, J = 8.3 Hz, 1H), 3.38 (d, J = 8.2 Hz, 1H), 1.29 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (75 MHz, CDCl3) δ 173.0, 167.5, 147.4, 139.8 (d, J = 29.0 Hz), 130.2, 129.9, 128.2, 128.1, 127.4, 123.4, 123.3, 110.9, 62.1, 40.2, 39.4, 37.2, 14.2 ppm. 19F NMR (376 MHz, CDCl3) δ −119.49 ppm. HRMS calcd for C19H16O5N2F [M + H]+: 371.1038; found: 371.1041.

Ethyl-5′-nitro-3-(4-nitrophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-2-carboxylate (4t)

Following the general procedure (80 °C for 2 h), compound 4t was obtained after column chromatography (hexane/EtOAc 7:3) in 72% yield as a brown solid. mp 255–258 °C. 1H NMR (500 MHz, CDCl3) δ 8.48 (d, J = 2.1 Hz, 1H), 8.26 (dd, J = 8.7, 2.2 Hz, 2H), 8.19 (d, J = 8.7 Hz, 2H), 7.49 (d, J = 8.6 Hz, 2H), 7.02 (d, J = 8.6 Hz, 1H), 4.36–4.20 (m, 2H), 3.96 (d, J = 8.4 Hz, 1H), 3.47 (s, 1H), 1.32 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 172.5, 167.2, 147.6, 146.5, 143.6, 139.2, 130.2, 126.6, 125.1, 123.5, 119.4, 109.6, 62.5, 40.0, 39.6, 37.8, 14.2 ppm. HRMS calcd for C19H16O7N3 [M + H]+: 398.0983; found: 398.0984.

Ethyl-2′-oxo-3-(p-tolyl)spiro[cyclopropane-1,3′-indoline]-2-carboxylate (4u)

Following the general procedure (80 °C for 2 h), compound 4u was obtained after column chromatography (hexane/EtOAc 8:2) in 89% yield as a white solid. mp 188–191 °C. 1H NMR (400 MHz, CDCl3) δ 8.19 (bs, 1H), 7.41 (d, J = 7.6 Hz, 1H), 7.17–7.09 (m, 3H), 7.02 (d, J = 8.0 Hz, 2H), 6.96 (t, J = 7.6 Hz, 1H), 6.74 (d, J = 7.6 Hz, 1H), 4.22–4.03 (m, 2H), 3.68 (d, J = 8.3 Hz, 1H), 3.26 (d, J = 8.3 Hz, 1H), 2.23 (s, 3H), 1.18 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (100 MHz, DMSO) δ 172.9, 168.3, 142.7, 136.8, 130.3, 129.5, 129.0, 128.1, 126.8, 122.2, 121.7, 110.1, 61.7, 40.5, 39.3, 37.0, 21.2, 14.5 ppm. HRMS calcd for C20H20O3N [M + H]+: 322.1438; found: 322.1436.

Ethyl-5′,7′-dimethyl-2′-oxo-3-phenylspiro[cyclopropane-1,3′-indoline]-2-carboxylate (4v)

Following the general procedure (80 °C for 2 h), compound 4v was obtained after column chromatography (hexane/EtOAc 8:2) in 88% yield as a white solid. mp 225–228 °C. 1H NMR (400 MHz, CDCl3) δ 9.60 (s, 1H), 7.32–7.19 (m, 6H), 6.83 (d, J = 0.6 Hz, 1H), 4.26–4.11 (m, 2H), 3.73 (d, J = 8.3 Hz, 1H), 3.34 (d, J = 8.3 Hz, 1H), 2.31 (s, 3H), 2.04 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 174.7, 168.5, 138.0, 133.0, 131.4, 129.5, 129.2, 127.9, 127.4, 126.3, 120.6, 119.1, 61.5, 40.5, 40.2, 37.2, 21.3, 16.1, 14.2 ppm. HRMS calcd for C21H22O3N [M + H]+: 336.1594; found: 336.1593.

Ethyl-1′-benzyl-3-(4-methoxyphenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-2-carboxylate (4w)

Following the general procedure (80 °C for 2 h), compound 4w was obtained after column chromatography (hexane/EtOAc 9:1) in 93% yield as a creamy white solid. mp 149–151 °C. 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 7.6 Hz, 1H), 7.31–7.14 (m, 8H), 7.02 (t, J = 7.6 Hz, 1H), 6.84 (d, J = 8.6 Hz, 2H), 6.79 (d, J = 7.8 Hz, 1H), 4.91 (d, J = 15.6 Hz, 1H), 4.82 (d, J = 15.6 Hz, 1H), 4.28–4.11 (m, 2H), 3.78 (s, 3H), 3.77 (d, J = 7.3 Hz, 1H), 3.42 (d, J = 8.3 Hz, 1H), 1.26 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 171.9, 168.7, 159.0, 143.1, 136.0, 130.3, 128.7, 127.6, 127.4, 126.4, 124.8, 122.5, 122.2, 113.5, 108.9, 61.5, 55.2, 44.1, 40.1, 39.8, 37.4, 14.2 ppm. HRMS calcd for C27H26NO4 [M + H]+: 428.1856; found: 428.1860.

Ethyl-1′-benzyl-5′-methoxy-2′-oxo-3-phenylspiro[cyclopropane-1,3′-indoline]-2-carboxylate (4x)

Following the general procedure (80 °C for 2 h), compound 4x was obtained after column chromatography (hexane/EtOAc 9:1) in 90% yield as a creamy white solid. mp 148–149 °C. 1H NMR (500 MHz, CDCl3) δ 7.32 (d, J = 4.3 Hz, 4H), 7.30–7.23 (m, 4H), 7.22–7.19 (m, 3H), 6.72 (dd, J = 8.5, 2.5 Hz, 1H), 6.67 (s, 1H), 4.89 (d, J = 15.6 Hz, 1H), 4.78 (d, J = 15.6 Hz, 1H), 4.29–4.16 (m, 2H), 3.79 (d, J = 8.3 Hz, 1H), 3.78 (s, 3H), 3.46 (d, J = 8.3 Hz, 1H), 1.28 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (125 MHz, CDCl3) δ 171.6, 168.6, 155.7, 136.7, 136.1, 132.9, 129.2, 128.7, 128.1, 127.7, 127.6, 127.4, 112.5, 109.7, 109.3, 61.6, 55.9, 44.2, 40.7, 34.0, 37.1, 14.2 ppm. HRMS calcd for C27H25NNaO4 [M + H]+: 450.1681; found: 450.1673.

Ethyl-1′-benzyl-5′-chloro-2′-oxo-3-phenylspiro[cyclopropane-1,3′-indoline]-2-carboxylate (4y)

Following the general procedure (80 °C for 2 h), compound 4y was obtained after column chromatography (hexane/EtOAc 9:1) in 86% yield as a light yellow solid. mp 150–152 °C. 1H NMR (500 MHz, CDCl3) δ 7.57 (s, 1H), 7.35–7.22 (m, 8H), 7.15 (dd, J = 13.6, 4.8 Hz, 3H), 6.68 (d, J = 8.4 Hz, 1H), 4.89 (d, J = 15.7 Hz, 1H), 4.78 (d, J = 15.7 Hz, 1H), 4.34–4.15 (m, 2H), 3.81 (d, J = 8.3 Hz, 1H), 3.48 (d, J = 8.3 Hz, 1H), 1.30 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (125 MHz, CDCl3) δ 171.4, 168.4, 141.7, 135.6, 132.5, 129.2, 128.8, 128.2, 128.0, 127.9, 127.8, 127.8, 127.5, 127.4, 123.2, 109.8, 61.8, 44.2, 41.0, 39.6, 37.3, 14.2 ppm. HRMS calcd for C26H23O3NCl [M + H]+: 432.1361; found: 432.1371.

Ethyl-3-(4-methoxyphenyl)-1′-methyl-2′-oxospiro[cyclopropane-1,3′-indoline]-2-carboxylate (4z)

Following the general procedure (80 °C for 2 h), compound 4z was obtained after column chromatography (hexane/EtOAc 9:1) in 90% yield as a white solid. mp 156–157 °C. 1H NMR (400 MHz, CDCl3) δ 7.51 (d, J = 7.4 Hz, 1H), 7.30 (td, J = 7.7, 0.9 Hz, 1H), 7.24 (d, J = 8.6 Hz, 2H), 7.07 (t, J = 7.3 Hz, 1H), 6.88 (d, J = 7.8 Hz, 1H), 6.83 (d, J = 8.7 Hz, 2H), 4.26–4.10 (m, 2H), 3.78 (s, 3H), 3.74 (d, J = 8.3 Hz, 1H), 3.35 (d, J = 8.3 Hz, 1H), 3.18 (s, 3H), 1.24 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 171.9, 168.6, 158.9, 144.1, 130.2, 127.6, 126.3, 124.7 122.4, 122.2, 113.5, 108.0, 61.5, 55.2, 39.8, 39.7, 37.5, 26.6, 14.2 ppm. HRMS calcd for C21H22O4N [M + H]+: 352.1543; found: 352.1542.

Ethyl-5′-methoxy-3-(4-methoxyphenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-2-carboxylate (4aa)

Following the general procedure (80 °C for 2 h), compound 4aa was obtained after column chromatography (hexane/EtOAc 9:1) in 92% yield as a white solid. mp 145–147 °C. 1H NMR (500 MHz, CDCl3) δ 7.23 (d, J = 8.7 Hz, 2H), 7.18 (d, J = 2.4 Hz, 1H), 6.85–6.81 (m, 3H), 6.77 (d, J = 8.5 Hz, 1H), 4.26–4.12 (m, 2H), 3.82 (s, 3H), 3.78 (s, 3H), 3.70 (d, J = 8.3 Hz, 1H), 3.35 (d, J = 8.3 Hz, 1H), 3.16 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (125 MHz, CDCl3) δ 171.6, 168.6, 158.9, 155.7, 137.7, 130.2, 127.6, 124.7, 113.5, 112.4, 109.6, 108.2, 61.5, 55.9, 55.2, 40.1, 39.9, 37.4, 26.7, 14.2 ppm. HRMS calcd for C22H24O5N [M + H]+: 382.1649; found: 382.1666.

2-Benzoyl-3-phenylspiro[cyclopropane-1,3′-indolin]-2′-one (4ab)

Following the general procedure (80 °C for 2 h), compound 4ab was obtained after column chromatography (hexane/EtOAc 8:2) in 78% yield as a light yellow solid. mp 212–213 °C. 1H NMR (500 MHz, CDCl3) δ 8.00–7.95 (m, 2H), 7.79 (s, 1H), 7.57–7.52 (m, 1H), 7.43 (t, J = 7.8 Hz, 2H), 7.37–7.26 (m, 6H), 7.17 (td, J = 7.7, 1.1 Hz, 1H), 6.98 (td, J = 7.7, 0.9 Hz, 1H), 6.85 (d, J = 7.7 Hz, 1H), 4.29 (d, J = 8.3 Hz, 1H), 4.15 (d, J = 8.3 Hz, 1H) ppm. 13C NMR (101 MHz, CDCl3) δ 193.0, 173.9, 140.9, 137.0, 133.7, 133.3, 129.3, 128.8, 128.5, 128.2, 127.6, 126.5, 122.4, 122.4, 109.8, 41.9, 41.3, 39.9 ppm. HRMS calcd for C23H18O2N [M + H]+: 340.1332; found: 340.1344.

2,3-Diphenylspiro[cyclopropane-1,3′-indolin]-2′-one (4ac)

Following the general procedure (80 °C for 2 h), compound 4ac was obtained after column chromatography (hexane/EtOAc 8:2) in 78% yield as a creamy white solid. mp 213–218 °C. 1H NMR (500 MHz, CDCl3) δ 8.46 (s, 1H), 7.41 (d, J = 7.4 Hz, 2H), 7.37–7.27 (m, 8H), 7.09 (td, J = 7.7, 1.0 Hz, 1H), 6.79 (d, J = 7.7 Hz, 1H), 6.72 (dd, J = 7.6, 0.8 Hz, 1H), 6.06 (d, J = 7.5 Hz, 1H), 3.98 (d, J = 8.7 Hz, 1H), 3.59 (d, J = 8.7 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3) δ 175.4, 141.0, 135.0, 134.6, 129.9, 129.4, 128.6, 128.2, 128.1, 127.7, 127.4, 126.6, 121.4, 120.9, 109.6, 42.6, 39.9, 39.8 ppm. HRMS calcd for C22H18ON [M + H]+: 312.1383; found: 312.1381.

2-(4-Methoxyphenyl)-3-phenylspiro[cyclopropane-1,3′-indolin]-2′-one (4ad)

Following the general procedure (80 °C for 2 h), compound 4ad was obtained after column chromatography (hexane/EtOAc 8:2) in 82% yield as a creamy white solid. mp 188–191 °C. 1H NMR (500 MHz, CDCl3) δ 8.46 (s, 1H), 7.36–7.27 (m, 7H), 7.08 (t, J = 7.5 Hz, 1H), 6.87 (d, J = 8.6 Hz, 2H), 6.81–6.76 (m, 1H), 6.70 (t, J = 7.6 Hz, 1H), 6.04 (d, J = 7.5 Hz, 1H), 3.94 (d, J = 8.7 Hz, 1H), 3.78 (s, 3H), 3.54 (d, J = 8.7 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3) δ 175.6, 158.9, 140.9, 135.1, 130.4, 130.0, 128.6, 128.2, 127.6, 126.6, 126.5, 121.4, 120.8, 113.6, 109.6, 55.2, 42.3, 39.9, 39.9 ppm. HRMS calcd for C23H20O2N [M + H]+: 342.1489; found: 342.1495.

2-(4-Chlorophenyl)-3-(4-methoxyphenyl)spiro[cyclopropane-1,3′-indolin]-2′-one (4ae)

Following the general procedure (80 °C for 2 h), compound 4ae was obtained after column chromatography (hexane/EtOAc 8:2) in 81% yield as a creamy white solid. mp 200–202 °C. 1H NMR (400 MHz, CDCl3) δ 8.27 (s, 1H), 7.30 (d, J = 6.4 Hz, 4H), 7.21 (d, J = 8.0 Hz, 2H), 7.11 (t, J = 7.5 Hz, 1H), 6.84 (dd, J = 15.7, 8.0 Hz, 3H), 6.76 (d, J = 7.5 Hz, 1H), 6.06 (d, J = 7.4 Hz, 1H), 3.87 (d, J = 8.5 Hz, 1H), 3.79 (s, 3H), 3.48 (d, J = 8.5 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3) δ 175.1, 159.0, 140.8, 133.6, 133.5, 131.3, 130.3, 128.8, 127.8, 126.7, 126.1, 121.6, 120.8, 113.6, 109.6, 55.2, 42.4, 39.8, 39.0 ppm. HRMS calcd for C23H19O2NCl [M + H]+: 376.1099; found: 376.1111.

General Procedure for the Preparation of Dihydropyrazoloquinazolones (5a–m)

3-Ylideneoxindole 1 (0.50 mmol), arylaldehyde 2 (0.50 mmol), and TsNHNH23 (93 mg, 0.50 mmol) were stirred in 5.0 mL of C2H5OH at room temperature in a 10 mL Schlenk tube for 10 min. Then, to this solution was added K2CO3 (1.50 mmol) at the same temperature and the reaction mixture was stirred at refluxing temperature for 2 h. Upon the completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, diluted with 10 mL of water, and extracted with EtOAc (3 × 10 mL). The organic layers were combined and washed with brine and dried over anhydrous Na2SO4. After the solvent was removed under reduced pressure, the crude product was purified by flash column chromatography on silica gel (petroleum ether/EtOAc) to afford the desired product 5.

Analytical Data for the Compounds 5a–m

Ethyl-5-oxo-2-phenyl-5,6-dihydropyrazolo[1,5-c]quinazoline-1-carboxylate (5a)

Following the general procedure (80 °C for 2 h), compound 5a was obtained after column chromatography (hexane/EtOAc 5:5) in 75% yield as a creamy white solid. mp 342–344 °C. 1H NMR (400 MHz, CDCl3) δ 11.27 (s, 1H), 8.79 (d, J = 8.2 Hz, 1H), 7.71–7.64 (m, 2H), 7.56–7.50 (m, 2H), 7.45 (dd, J = 6.4, 3.6 Hz, 3H), 7.34 (t, J = 7.3 Hz, 1H), 4.30 (q, J = 7.1 Hz, 2H), 1.13 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (101 MHz, CDCl3) δ 164.4, 157.4, 146.1, 141.8, 134.4, 132.1, 131.7, 129.2, 129.1, 128.0, 126.3, 124.3, 116.6, 112.3, 109.9, 61.5, 13.7 ppm. HRMS calcd for C19H16O3N3 [M + H]+: 334.1192; found: 334.1199.

Ethyl-2-(4-nitrophenyl)-5-oxo-5,6-dihydropyrazolo[1,5-c]quinazoline-1-carboxylate (5b)

Following the general procedure (80 °C for 2 h), compound 5b was obtained after column chromatography (hexane/EtOAc 5:5) in 70% yield as a creamy white solid. mp 336–338 °C. 1H NMR (500 MHz, CDCl3) δ 10.56 (s, 1H), 8.93 (d, J = 7.9 Hz, 1H), 8.33 (d, J = 8.0 Hz, 2H), 7.87 (d, J = 8.1 Hz, 2H), 7.62 (t, J = 7.6 Hz, 1H), 7.51–7.36 (m, 2H), 4.32 (q, 6.8 Hz, 2H), 1.15 (t, J = 6.9 Hz, 3H) ppm. 13C NMR (75 MHz, CDCl3 + DMSO) δ 168.3, 159.0, 152.7, 149.2, 147.0, 144.0, 140.5, 136.6, 135.1, 131.0, 128.2, 127.8, 121.2, 116.5, 114.0, 66.2, 18.6 ppm. HRMS calcd for C19H15O5N4 [M + H]+: 379.1037; found: 379.1039.

Ethyl-9-fluoro-2-(4-nitrophenyl)-5-oxo-5,6-dihydropyrazolo[1,5-c]quinazoline-1-carboxylate (5c)

Following the general procedure (80 °C for 2 h), compound 5c was obtained after column chromatography (hexane/EtOAc 5:5) in 68% yield as a creamy white solid. mp 230–235 °C. 1H NMR (300 MHz, DMSO) δ 12.42 (s, 1H), 8.65 (dd, J = 10.5, 2.7 Hz, 1H), 8.37 (d, J = 8.8 Hz, 2H), 7.90 (d, J = 8.8 Hz, 2H), 7.63–7.49 (m, 1H), 7.44 (dd, J = 9.0, 5.1 Hz, 1H), 4.26 (q, J = 7.1 Hz, 2H), 1.05 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (100 MHz, DMSO) δ 162.4, 157.9, 155.5, 153.0, 147.1, 142.8, 140.7, 138.2, 131.9, 129.9, 122.7, 119.3, 119.0, 117.5, 117.4, 111.6, 111.5, 111.0, 110.7, 108.2, 60.8, 12.8 ppm. 19F NMR (376 MHz, CDCl3) δ -115.0 ppm. HRMS calcd for C19H14O5N4F [M + H]+: 397.0943; found: 397.0968.

Ethyl-9-chloro-5-oxo-2-phenyl-5,6-dihydropyrazolo[1,5-c]quinazoline-1-carboxylate (5d)

Following the general procedure (80 °C for 2 h), compound 5d was obtained after column chromatography (hexane/EtOAc 5:5) in 71% yield as a creamy white solid. mp 345–348 °C. 1H NMR (300 MHz, DMSO) δ 12.27 (bs, 1H), 8.61 (d, J = 7.4 Hz, 1H), 7.68–7.54 (m, 5H), 7.45–7.31 (m, 2H), 4.29 (q, J = 7.1 Hz, 2H), 1.10 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (100 MHz, DMSO) δ 164.2, 154.3, 144.2, 141.7, 136.0, 134.4, 132.2, 131.4, 131.0, 128.8, 125.8, 123.7, 116.6, 111.72, 108.7, 61.8, 14.0 ppm. HRMS calcd for C19H15O3N3Cl [M + H]+: 368.0797; found: 368.0798.

Ethyl-9-nitro-5-oxo-2-phenyl-5,6-dihydropyrazolo[1,5-c]quinazoline-1-carboxylate (5e)

Following the general procedure (80 °C for 2 h), compound 5e was obtained after column chromatography (hexane/EtOAc 5:5) in 70% yield as a creamy white solid. mp 190–195 °C. 1H NMR (300 MHz, DMSO) δ 12.48 (s, 1H), 9.03 (d, J = 2.1 Hz, 1H), 8.37 (d, J = 8.8 Hz, 2H), 7.90 (d, J = 8.8 Hz, 2H), 7.81 (dd, J = 8.8, 2.1 Hz, 1H), 7.36 (d, J = 8.8 Hz, 2H), 4.28 (tt, J = 11.7, 5.8 Hz, 2H), 1.08 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (75 MHz, DMSO) δ 162.9, 153.7, 147.7, 143.3, 140.7, 138.7, 135.0, 134.4, 130.4, 130.2, 127.9, 123.3, 123.2, 118.2, 114.7, 61.4, 13.4 ppm. HRMS calcd for C19H15N4O5 [M + H]+: 379.1037; found: 379.1025.

Ethyl-6-methyl-2-(4-nitrophenyl)-5-oxo-5,6-dihydropyrazolo[1,5-c]quinazoline-1-carboxylate (5f)

Following the general procedure (80 °C for 2 h), compound 5f was obtained after column chromatography (hexane/EtOAc 5:5) in 72% yield as a light yellow solid. mp 268–272 °C. 1H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 8.31 (d, J = 8.6 Hz, 2H), 7.89 (d, J = 8.6 Hz, 2H), 7.40–7.30 (m, 3H), 4.33 (q, J = 7.0 Hz, 2H), 2.45 (s, 3H), 1.18 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (75 MHz, CDCl3 + DMSO) δ 168.3, 158.8, 152.7, 149.2, 146.9, 144.1, 138.3, 137.7, 135.1, 130.6, 127.8, 121.1, 116.3, 113.7, 66.2, 26.0, 18.6 ppm. HRMS calcd for C20H17O5N4 [M + H]+: 393.1194; found: 393.1193.

Methyl-2-(4-chlorophenyl)-5-oxo-5,6-dihydropyrazolo[1,5-c]quinazoline-1-carboxylate (5g)

Following the general procedure using MeOH as solvent instead of EtOH (65 °C for 2 h), compound 5g was obtained after column chromatography (hexane/EtOAc 5:5) in 71% yield as a light brown solid. mp 324–326 °C. 1H NMR (300 MHz, DMSO) δ 12.28 (s, 1H), 8.53 (d, J = 8.0 Hz, 1H), 7.69–7.54 (m, 5H), 7.44–7.31 (m, 2H), 3.81 (s, 3H) ppm. 13C NMR (75 MHz, DMSO) δ 164.2, 153.45, 143.6, 141.2, 135.5, 133.9, 131.6, 130.8, 130.3, 128.4, 125.2, 123.2, 116.1, 111.2, 107.8, 52.2 ppm. HRMS calcd for C18H13O3N3Cl [M + H]+: 354.0640; found: 354.0655.

1-Benzoyl-2-(4-methoxyphenyl)pyrazolo[1,5-c]quinazolin-5(6H)-one (5h)

Following the general procedure (80 °C for 2 h), compound 5h was obtained after column chromatography (hexane/EtOAc 5:5) in 70% yield as a creamy white solid. mp 380–382 °C. 1H NMR (300 MHz, CDCl3 + DMSO) δ 12.36 (s, 1H), 10.15 (d, J = 7.9 Hz, 1H), 8.09 (d, J = 8.6 Hz, 1H), 7.87–7.73 (m, 3H), 7.58 (s, 1H), 7.51–7.36 (m, 5H), 7.24 (d, J = 7.0 Hz, 1H), 7.02 (t, J = 7.5 Hz, 1H), 3.82 (s, 3H) ppm. 13C NMR (75 MHz, CDCl3 + DMSO) δ 199.27, 166.1, 164.9, 160.0, 149.5, 142.7, 141.6, 135.3, 135.1, 134.5, 134.4, 132.3, 131.3, 129.9, 128.6, 127.1, 125.7, 121.4, 119.3, 60.5 ppm. HRMS calcd for C24H18O3N3 [M + H]+: 396.1348; found: 396.1362.

1-Benzoyl-2-(4-nitrophenyl)pyrazolo[1,5-c]quinazolin-5(6H)-one (5i)

Following the general procedure (80 °C for 2 h), compound 5i was obtained after column chromatography (hexane/EtOAc 5:5) in 68% yield as a creamy white solid. mp 370–372 °C. 1H NMR (300 MHz, CDCl3 + DMSO) δ 12.07 (s, 1H), 8.03 (d, J = 8.8 Hz, 2H), 7.78 (t, J = 7.5 Hz, 3H), 7.62 (d, J = 8.2 Hz, 1H), 7.46 (t, J = 7.3 Hz, 1H), 7.39–7.25 (m, 5H), 7.01 (t, J = 7.4 Hz, 1H) ppm. 13C NMR (75 MHz, CDCl3 + DMSO) δ 192.6, 152.4, 147.9, 144.9, 140.6, 137.7, 137.1, 135.2, 134.5, 131.3, 129.8, 129.4, 129.0, 124.7, 123.6, 123.5, 116.6, 115.3, 111.7 ppm. HRMS calcd for C23H15N4O4 [M + H]+: 411.1088; found: 411.1093.

1,2-Diphenylpyrazolo[1,5-c]quinazolin-5(6H)-one (5j)

Following the general procedure (80 °C for 2 h), compound 5j was obtained after column chromatography (hexane/EtOAc 5:5) in 66% yield as a creamy white solid. mp 340–342 °C. 1H NMR (400 MHz, CDCl3) δ 11.03 (s, 1H), 7.59 (dd, J = 7.9, 1.5 Hz, 2H), 7.54–7.48 (m, 4H), 7.45–7.38 (m, 3H), 7.35 (d, J = 8.0 Hz, 1H), 7.31–7.25 (m, 3H), 7.01 (t, J = 7.7 Hz, 1H) ppm. 13C NMR (75 MHz, CDCl3 + DMSO) δ 158.4, 150.0, 142.3, 139.7, 137.5, 136.9, 135.5, 134.8, 134.2, 133.4, 133.4, 133.2, 133.0, 127.8, 127.7, 121.8, 121.1, 117.9 ppm. HRMS calcd for C22H16ON3 [M + H]+: 338.1288; found: 338.1307.

1-(4-Chlorophenyl)-2-(4-methoxyphenyl)pyrazolo[1,5-c]quinazolin-5(6H)-one (5k)

Following the general procedure (80 °C for 2 h), compound 5k was obtained after column chromatography (hexane/EtOAc 5:5) in 68% yield as a creamy white solid. mp 360–362 °C. 1H NMR (400 MHz, DMSO) δ 11.94 (s, 1H), 7.63 (d, J = 8.2 Hz, 2H), 7.47 (d, J = 8.3 Hz, 3H), 7.37 (t, J = 8.8 Hz, 3H), 7.14 (d, J = 7.8 Hz, 1H), 7.07 (d, J = 7.3 Hz, 1H), 6.92 (d, J = 8.7 Hz, 2H), 3.75 (s, 3H) ppm. 13C NMR (125 MHz, DMSO) δ 160.1, 153.1, 144.8, 137.7, 135.3, 133.8, 133.1, 132.0, 130.6, 130.0, 129.8, 124.5, 123.4, 122.8, 116.5, 115.4, 114.4, 112.9, 55.6 ppm. HRMS calcd for C23H17O2N3Cl [M + H]+: 402.1004; found: 402.1015.

2-(4-Methoxyphenyl)-1-phenylpyrazolo[1,5-c]quinazolin-5(6H)-one (5l)

Following the general procedure (80 °C for 2 h), compound 5l was obtained after column chromatography (hexane/EtOAc 5:5) in 69% yield as a creamy white solid. mp 310–312 °C. 1H NMR (300 MHz, CDCl3 + DMSO) δ 11.61 (s, 1H), 7.53–7.48 (m, 2H), 7.27–7.16 (m, 8H), 6.94 (d, J = 8.6 Hz, 2H), 6.91–6.84 (m, 1H), 3.82 (s, 3H) ppm. 13C NMR (75 MHz, CDCl3 + DMSO) δ 164.3, 158.8, 150.3, 142.3, 139.5, 136.9, 136.6, 134.4, 133.3, 133.2, 132.8, 129.3, 127.9, 127.6, 121.5, 120.91, 119.5, 118.1, 60.0 ppm. HRMS calcd for C23H18O2N3 [M + H]+: 368.1394; found: 368.1409.

2-(4-Nitrophenyl)-1-phenylpyrazolo[1,5-c]quinazolin-5(6H)-one (5m)

Following the general procedure (80 °C for 2 h), compound 5m was obtained after column chromatography (hexane/EtOAc 5:5) in 65% yield as a brown solid. mp 315–318 °C. 1H NMR (300 MHz, DMSO) δ 12.08 (s, 1H), 8.19 (d, J = 8.5 Hz, 2H), 7.71 (d, J = 8.6 Hz, 2H), 7.59 (s, 2H), 7.54–7.41 (m, 3H), 7.37 (d, J = 7.9 Hz, 2H), 7.14 (d, J = 7.8 Hz, 1H), 7.04 (t, J = 7.5 Hz, 1H) ppm. 13C NMR (100 MHz, DMSO) δ 151.1, 147.7, 144.6, 138.9, 138.2, 135.3, 132.2, 131.0, 130.8, 130.2, 129.4, 124.2, 123.4, 122.9, 117.5, 116.6, 113.0 ppm. HRMS calcd for C22H15O3N4 [M + H]+: 383.1139; found: 383.1142.

5′-(4-Methoxyphenyl)-4′-(p-tolyl)-2′,4′-dihydrospiro[indoline-3,3′-pyrazol]-2-one (D)

1H NMR (400 MHz, DMSO) δ 10.31 (s, 1H), 7.90 (s, 1H), 7.46 (d, J = 8.7 Hz, 2H), 7.07–6.99 (m, 3H), 6.87 (dd, J = 15.2, 8.3 Hz, 4H), 6.73 (d, J = 7.7 Hz, 1H), 6.53 (t, J = 7.5 Hz, 1H), 6.18 (d, J = 7.4 Hz, 1H), 4.76 (s, 1H), 3.72 (s, 3H), 2.21 (s, 3H) ppm. 13C NMR (101 MHz, DMSO) δ 179.8, 159.7, 151.5, 142.9, 136.8, 133.0, 129.5, 129.4, 129.2, 128.1, 127.2, 126.4, 125.5, 121.2, 114.3, 109.6, 73.7, 58.6, 55.6, 21.2 ppm. HRMS calcd for C24H22O2N3 [M + H]+: 384.1707; found: 384.5140.

4'-(4-Chlorophenyl)-5'-(4-methoxyphenyl)-2',4'-dihydrospiro[indoline-3,3'-pyrazol]-2-one (D1)

1H NMR (300 MHz, CDCl3 + DMSO) δ 10.04 (s, 1H), 7.72 (s, 1H), 7.48–7.41 (m, 3H), 7.14 (d, J = 8.6 Hz, 2H), 6.96 (t, J = 7.2 Hz, 1H), 6.80 (d, J = 8.5 Hz, 2H), 6.65 (dd, J = 11.5, 8.3 Hz, 2H), 6.50 (t, J = 7.5 Hz, 1H), 6.23 (d, J = 7.4 Hz, 1H), 4.63 (s, 1H), 3.64 (s, 3H) ppm. 13C NMR (75 MHz, CDCl3 + DMSO) δ 184.6, 163.7, 155.2, 147.1, 138.3, 135.9, 135.1, 133.7, 133.21, 132.6, 131.5, 131.3, 131.1, 126.1, 118.7, 114.4, 79.2, 63.3, 59.9. ppm. HRMS calcd for C23H19ClN3O2 [M + H]+: 404.1160; found: 404.5130.