Diastereoselective synthesis of spiro[cyclopropane-1,3′-indolin]-2′-ones through metal-free cyclopropanation using tosylhydrazone salts

Abstract

Transition metal-free diastereoselective cyclopropanation of 3-methyleneindolin-2-ones using tosylhydrazone salts as a safe alternative to diazo-compounds was achieved in high yields. All the synthesized compounds were evaluated for their biological activity against three different human cancer cell lines DU-145 (prostate cancer), Hela (cervical cancer) and A-549 (lung cancer). Compounds 3b and 3i exhibited promising anticancer activity (IC₅₀ < 10 μM) against the studied cell lines.

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Introduction

Indole is amongst the most prevalent scaffolds found in synthetic and natural products of biological and medicinal importance.¹ Therefore the development of efficient synthetic methods to prepare new types of indole molecules for screening in medicinal and pharmaceutical programmes is gaining enormous interest in both academia and industry. Among indole containing molecules, spiro-oxindoles have attracted much attention due to their interesting anticancer, antiviral, antimicrobial, anti-inflammatory and anti-HIV activities.² Spirotryptostatins I, horsfiline II, elacomine III and compounds of type IV have been recognised as potent anticancer agents (Fig. 1).³

Fig. 1 Chemical structures of some biologically important spiro-oxindole derivatives.

The cyclopropane unit is found as a part of the basic structural scaffold of many synthetic as well as natural products of biological interest.⁴ Cyclopropane containing spiro-oxindoles V have been reported as potent HIV-1 non-nucleoside reverse transcriptase inhibitors whereas naturally occurring hapalindolinone VI are reported as potent antagonists of vasopressin.⁵ As a part of our ongoing interest towards stereoselective construction of new molecular libraries,⁶ we were interested in synthesizing functionalised spiro[cyclopropane-1,3′-indolin]-2′-ones VII.

Due to their significant biological and pharmacological potential, numerous methods have been documented in the literature for the synthesis of spiro[cyclopropane-1,3′-indolin]-2′-ones. 3,3-Di-alkylation of 2-oxindoles with 1,2-dihalo alkanes is a popular strategy for the synthesis of spiroindolines, however it suffers inherently from the view-point of product diversity.⁷ Corey–Chaykovsky cyclopropanation of 3-methyleneindolin-2-ones has been attempted by many researchers but it often suffers with the low yields of the products.⁸ Recently, spiro[cyclopropane-1,3′-indolin]-2′-ones were synthesized by reacting pyridinium salts with 3-phenacylideneoxindoles under basic conditions.⁹ Although this method provides highly diverse spirocyclic cyclopropanes, the competing formation of furan derivatives remains its major drawback.

Among the various methods of stereoselective cyclopropane construction, transition metal catalyzed cyclopropanation of alkenes using diazo-compounds is particularly important.¹⁰ The reaction proceeds through a metal-carbene intermediate derived from catalytic decomposition of diazo-compounds and the selectivity depends largely on the catalyst used.^10,11 Additionally, these methods have the limitation of using explosive diazo compounds. Nevertheless, dirhodium tetraacetate catalyzed cyclopropanations using diazo-compounds have been attempted to synthesize spiro[cyclopropane-1,3′-indolin]-2′-ones by many researchers.^5b,12 However, these methods also suffer from the disadvantages of low yields, limited diversification points in the product and environmental concern.

To address the safety and instability concerns of the diazo-compounds, their in situ generation and subsequent utilization have been preferred by many researchers.¹³ Recently, a metal-free cyclopropanation of 3-methyleneindolin-2-ones via a [3 + 2] cycloaddition/ring contraction sequence using in situ generated 2,2,2-trifluorodiazoethane was reported.¹⁴ Considering the merits and demerits of all these reports, it is obvious that the development of a promising strategy for the synthesis of diverse spiro[cyclopropane-1,3′-indolin]-2′-ones is needed. Presented in this letter are the results of in situ generation of diazo-compounds from corresponding tosylhydrazone salts and their subsequent utilization for metal-free diastereoselective cyclopropanation of 3-methyleneindolin-2-ones (Fig. 2).

Fig. 2 Synthesis of spiro[cyclopropane-1,3′-indolin]-2′-ones through diastereoselective cyclopropanation using in situ generated diazo-compounds.

Results and discussion

At the onset we sought to identify a way to access the diazo compounds of interest from safer and relatively stable starting materials under mild conditions. Of the various available methods for their generation, we were particularly interested in the Bamford–Stevens reaction because of the ease of preparation of tosylhydrazone salt and generation of corresponding diazo-compound under mild conditions.^13c,15 Thus, cyclopropanation of 3-methyleneindolin-2-one 1a was attempted with tosylhydrazone salt 2a under various conditions (Table 1). Among the several solvents attempted, a mixture of THF-acetonitrile (4 : 1, v/v) was found the best for the cyclopropanation of 1a (Table 1, entry 5). However, a better yield of 3a was realized using 10 mol% of benzyltriethylammonium chloride (BTEAC) as an additive to the reaction (Table 1, entry 6). BTEAC improves the reaction possibly by increasing the solubility of tosylhydrazone salt 2a in the reaction medium. The yield of 3a was further improved by taking tosylhydrazone salt in an excess amount (Table 1, entry 7 and 8). The reaction rate was accelerated at elevated temperature and 50 °C found the optimal temperature (Table 1, entry 9). However further increasing the reaction temperature led to a decreased yield of the product (Table 1, entry 10). It should be noted that under all these conditions, the reaction yielded a single diastereomeric product 3a (determined by ¹H NMR spectra of the crude reaction product).

Table 1 Optimization of the diastereoselective cyclopropanation of 3-methyleneindolin-2-one 1a with tosylhydrazone salt 2a^a

Entry	Stoichiometry (1a : 2a)	Solvent/additive	Temp. (°C)	Time (h)	Yield^b (%)
a Reaction condition: 1a (0.5 mmol), 2a (stoichiometric or as mentioned above), solvent (2 ml), benzyltriethylammonium chloride (BTEAC) 10 mol%, stir.b Isolated yields which are not optimized.
1	1 : 1	MeOH	30	24	25
2	1 : 1	CH3CN	30	24	40
3	1 : 1	THF	30	24	30
4	1 : 1	DMF	30	24	19
5	1 : 1	THF–CH3CN (4 : 1, v/v)	30	24	50
6	1 : 1	THF–CH3CN (4 : 1, v/v)–BTEAC	30	24	70
7	1 : 1.2	THF–CH3CN (4 : 1, v/v)–BTEAC	30	24	85
8	1 : 1.5	THF–CH3CN (4 : 1, v/v)–BTEAC	30	24	86
9	1 : 1.2	THF–CH3CN (4 : 1, v/v)–BTEAC	50	4	86
10	1 : 1.2	THF–CH3CN (4 : 1, v/v)–BTEAC	70	4	75

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The relative stereochemistry of the product 3a was assigned based on NOESY correlations as pictorially represented in Fig. 3. The NOE cross peak between one of the cyclopropyl H-atom at 4.20 ppm (H11) and ortho-H atoms of 4-methoxybenzoyl residue at 7.90 ppm (H14, H18) helped to identify the cyclopropyl ring H-atoms. The ortho-H atoms of 4-methoxyphenyl residue (H21, H25) at 7.26 ppm showed NOE cross peaks with the cyclopropyl ring H-atoms at 4.08 ppm (H10) and 4.20 ppm (H11). One of the aromatic-H atom from isatin residue (H6) at 7.23 ppm showed NOE cross peak with the cyclopropyl H10-atom at 4.08 ppm. It indicated that the orientation of the isatin aryl residue is syn to the cyclopropyl H-atom (H10) and anti to the 4-methoxyphenyl residue. The observation of NOE cross peaks H10/H6 and H21-/H11 along with ³J_H10–H11 = 8.4 Hz indicated trans orientation of H10 and H11. Thus, the structure of 3a was deduced where the indoline carbonyl is pointing towards p-methoxyphenyl group attached on C10 and the phenyl residue of indoline is pointing towards p-methoxybenzoyl group on C11 as depicted in Fig. 3.

Fig. 3 Characteristic NOE's of compound 3a and chemical shifts of H atoms.

Non-metal catalysed cyclopropanations of alkenes using diazo-compounds have been proposed to proceed through diastereoselective pyrazoline formation and subsequent loss of nitrogen with the retention of configuration.^13c,14,16 Therefore diastereoslective formation of 3a can be explained by a plausible mechanism involving a HOMO (of aryl diazomethane)–LUMO (of alkene) controlled 1,3-dipolar cycloaddition reaction and subsequent nitrogen loss with the retention of configuration as depicted in Fig. 4. The initial five-membered cycloadduct 5a (or 5a′) was never isolated in our experiments even when the reaction was performed at 30 °C. The alternative cis-diastereomer 3a′ was not observed plausibly due to steric crowding between aryl and aroyl groups (transition state A), and between two aromatic rings (transition state C) as depicted in Fig. 4. Moreover, since the alkene 1a can equally approach both faces of the aryl diazomethane 4, the product 3a must be a racemic mixture and indeed it was.

Fig. 4 A plausible mechanism for diastereoselective formation of 3a based on [3 + 2] dipolar cycloaddition reaction/ring contraction sequence.

Having optimized reaction conditions for cyclopropanation at hand, a series of 3-methyleneindolin-2-ones were also subjected to cyclopropanation (Table 2). The reaction worked well with both electron donating and electron withdrawing aromatic aldehydes – tosylhydrazone salts leading to high yields of spiro[cyclopropane-1-3′-indolin]-2′-ones 3a–o (75–88%). The cyclopropanation of 3-methyleneindolin-2-ones was faster with electron donating aromatic aldehyde-tosylhydrazone salts (Table 2; entry 1–3 and 15) compared to those with electron withdrawing aromatic aldehyde-tosylhydrazone salts. The yields were marginally affected by the substituent present in the oxindole or aryl part of alkene 1. It is noteworthy that single diastereomeric products were obtained in all the reactions performed. The stereochemical assignment of the cyclopropane system was proved unambiguously by single crystal X-ray analysis of a typical compound 3g (Fig. 5).

Table 2 Scope of the stereoselective cyclopropanation of 3-methyleneindolin-2-ones 1 with tosylhydrazone salt of benzaldehyde 2^a

Entry	R	R^1	R^2	R^3	Reaction time (h)	Product^b (yield %)
a Reaction condition: 1 (0.5 mmol), 2 (0.6 mmol), THF–acetonitrile (2 ml, 4 : 1, v/v), benzyltriethylammonium chloride (BTEAC) 10 mol%, 50 °C, stir.b Isolated yields which are not optimized.
1	H	H	4-MeO-C6H4	4-MeO-C6H4	4	3a (86)
2	H	H	C6H5	4-MeO-C6H4	4	3b (87)
3	H	NO2	OEt	4-MeO-C6H4	4	3c (75)
4	H	Br	4-Me-C6H4	C6H5	12	3d (85)
5	H	H	4-MeO-C6H4	C6H5	12	3e (85)
6	H	F	OEt	C6H5	12	3f (78)
7	H	H	4-MeO-C6H4	4-NO2-C6H4	12	3g (81)
8	H	Cl	2-Naphthyl	4-NO2-C6H4	12	3h (86)
9	H	Br	4-MeO-C6H4	4-NO2C6H4	12	3i (88)
10	H	Br	4-Me-C6H4	4-NO2C6H4	12	3j (81)
11	H	Br	4-Cl-C6H4	4-CN-C6H4	12	3k (81)
12	H	Br	4-MeO-C6H4	4-CN-C6H4	12	3l (84)
13	H	Br	4-Me-C6H4	4-CN-C6H4	12	3m (85)
14	H	H	4-MeO-C6H4	4-CN-C6H4	12	3n (80)
15	Me	H	4-Br-C6H4	4-MeO-C6H4	4	3o (82)
16	H	Cl	4-NO2-C6H4	4-MeO-C6H4	4	3p (79)

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Fig. 5 Stereochemical assignment of the compound 3g by single crystal X-ray analysis.

All the synthesized compounds (3a–o) were evaluated for their anticancer activity against three different human cancer cell lines Hela (cervical cancer), A-549 (Lung cancer), DU-145 (prostate cancer). The MTT assay¹⁷ was used in anticancer activity study and the values obtained were compared to the standard drug doxorubicin as shown in Table 3. Cells were grown in tissue culture flasks in DMEM or MEM supplemented with 10% fetal bovine serum with 1× stabilized antibiotic–antimycotic solution in a CO₂ incubator at 37 °C with 5% CO₂ and 90% relative humidity. The cells at sub confluent stage were harvested with 1× porcine pancreatic trypsin (Hi media) and seeded in required density in tissue culture plates for the assay. Cell viability was determined by MTT assay. The IC₅₀ value of each compound was calculated by the excel curve software. Two compounds of the series (3b and 3i) exhibited promising anticancer activity (IC₅₀ < 10 μM).

Table 3 IC₅₀ values^a (in μM) for compounds 3a–o in human cancer cell lines

Entry	Compounds	Hela^b	A549^c	DU-145^d
a 50% inhibitory concentration and the values are average of three individual experiments after 48 h of drug treatment.b Cervical cancer.c Lung cancer.d Prostate cancer.
1	3a	18.62	25.11	10.71
2	3b	9.332	20.12	8.709
3	3c	52.44	69.18	26.86
4	3d	12.58	30.67	15.84
5	3e	25.11	52.48	20.89
6	3f	20.50	16.48	14.79
7	3g	66.86	83.17	57.54
8	3h	19.65	29.31	17.78
9	3i	9.54	9.332	4.897
10	3j	16.59	19.26	14.79
11	3k	36.92	44.42	22.20
12	3l	69.29	87.09	63.77
13	3m	15.84	25.11	13.81
14	3n	19.95	25.86	16.36
15	3o	45.70	77.52	31.13
16	Doxorubicin	1.77	2.570	1.318

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Conclusions

In conclusion, we have developed a metal-free cyclopropanation of 3-methyleneindolin-2-ones using tosylhydrazone salts as a safe and stable precursor of diazo-compounds. The protocol provides an elegant way to access a series of diastereomerically pure spiro[cyclopropane-1,3′-indolin]-2′-ones. All the synthesized compounds were screened against three different human cancer cell lines and compound 3b as well as 3i showed promising anticancer activity.

Experimental

General information

All the reagents and chemicals were purchased from commercial sources and used without further any purification. Anhydrous solvents were purchased from Sigma-Aldrich Company and used without further any purification. Common laboratory solvents (LR grade) were purchased from domestic suppliers. Analytical thin layer chromatography was performed with E. Merck silica gel 60 F aluminium plates and visualized under UV 254 nm radiation. NMR spectra were measured with Brucker 300, 400, 500, and 600 MHz instruments. Chemical shifts are reported in δ units, parts per million (ppm) downfield from TMS. Coupling constants (J) are in hertz (Hz) and are unadjusted; therefore, due to limits in resolution, in some cases there are small differences (<1 Hz) in the measured J value of the same coupling constant determined from different signals. Splitting patterns are designed as follows: s, singlet; d, doublet; t, triplet; dd, doublet of doublets; dt, doublet of triplets; tt, triplet of triplets; m, multiplet; br, broad. IR spectra were recorded on a Perkin-Elmer FT-IR RXI spectrophotometer and values reported in cm⁻¹. ESI-MS spectra were obtained on a LCQ Advantage Ion trap mass spectrometer (Finnigan thermo Fischer scientific) and high-resolution mass spectra (ESI-HRMS) were recorded on Agilent 6520 ESI-QTOP mass spectrometer. Melting points were determined on a Kofler block and are uncorrected. All the compounds were characterized by ¹H NMR, ¹³C NMR, IR, and ESI-MS/HRMS analysis. The chromatographic solvents are mentioned as v/v ratios. Substituted 3-methyleneindolin-2-ones¹⁸ and tosylhydrazone sodium salts¹⁹ were synthesized by literature procedures.

Typical experimental procedure of the catalyst-free cyclopropanation of substituted 3-methyleneindolin-2-ones with tosylhydrazone salts

In a 25 ml round bottom flask, substituted 3-methyleneindolin-2-ones (0.5 mmol), tosylhydrazone salt (0.6 mmol), 2 ml of THF–acetonitrile (4 : 1), and benzyltriethyl ammonium chloride (11.5 mg, 0.05 mmol) were taken and the reaction mixture was heated at 50 °C until complete consumption of the substrate. Next the reaction mixture was evaporated to yield a crude reaction product which was further purified by column chromatography.

2-(4-Methoxybenzoyl)-3-(4-methoxyphenyl)spiro[cyclopropane-1,3′-indolin]-2′-one 3a. 172 mg (86%) of 3a was obtained as a pale yellow solid, R_f = 0.37 (ethyl acetate/n-hexane, 1 : 1), Mp. 216–217 °C; IR (KBr, cm⁻¹): 3229, 1709, 1676, 1659, 1598, 1572, 1517, 1471, 1259, ¹H NMR (CDCl₃, 500 MHz) δ: 3.74 (s, 3H, OCH₃), 3.76 (s, 3H, OCH₃), 4.08 (d, J = 8.4 Hz, 1H, CH), 4.20 (d, J = 8.4 Hz, 1H, CH), 6.76 (d, J = 9.0 Hz, 2H, ArH), 6.82 (d, J = 7.6 Hz, 1H, ArH), 6.85 (d, J = 7.8 Hz, 2H, ArH), 6.95 (dt, J = 0.9, 7.6 Hz, 1H, ArH), 7.14 (dt, J = 1.0, 7.6 Hz, 1H, ArH), 7.23 (d, 1H, J = 7.6 Hz, 1H), 7.26 (d, J = 7.8 Hz, 2H, ArH), 7.90 (d, J = 8.9 Hz, 2H, ArH), 8.15 (bs, 1H, NH); ¹³C NMR (CDCl₃, 125 MHz) δ: 39.2, 41.5, 55.1, 55.4, 109.7, 113.5, 113.8, 122.1, 122.2, 125.3, 126.7, 127.3, 129.9, 130.3, 130.6, 140.8, 158.8, 163.8, 174.2, 191.1; HRMS (ESI, Orbitrap): calcd for C₂₄H₂₂NO₄ [M + H]⁺ 400.15488; found 400.15392.

2-Benzoyl-3-(4-methoxyphenyl)spiro[cyclopropane-1,3′-indolin]-2′-one 3b. 161 mg (87%) of 3b was obtained as a yellow solid, R_f = 0.50 (ethyl acetate–n-hexane, 1 : 1), Mp. 99–100 °C; IR (KBr, cm⁻¹): 3251, 1712, 1674, 1615, 1516, 1469, 1248, ¹H NMR (CDCl₃, 500 MHz) δ: 3.78 (s, 3H, OCH₃), 4.07 (d, J = 8.3 Hz, 1H, CH), 4.25 (d, J = 8.3 Hz, 1H, CH), 6.80–6.89 (m, 3H, ArH), 6.95 (t, J = 7.6 Hz, 1H, ArH), 7.13 (t, J = 7.6 Hz, 1H, ArH), 7.23–7.30 (m, 3H, ArH), 7.39 (t, J = 7.6 Hz, 2H, ArH), 7.52 (t, J = 7.3 Hz, 1H, ArH), 7.86 (bs, 1H, NH), 7.95 (d, J = 7.9 Hz, 2H, ArH); ¹³C NMR (CDCl₃, 75 MHz) δ: 39.4, 41.4, 41.8, 55.1, 109.7, 113.5, 122.2, 122.2, 125.1, 126.5, 127.4, 128.4, 128.7, 130.2, 133.6, 136.9, 140.8, 158.8, 173.9, 192.9; HRMS (ESI, Orbitrap): calcd for C₂₄H₂₀NO₃ [M + H]⁺ 370.14432; found 370.14588.

Ethyl 3-(4-methoxyphenyl)-5′-nitro-2′-oxospiro[cyclopropane-1,3′-indoline]-2-carboxylate 3c. 143 mg (75%) of 3c was obtained as a yellow solid, R_f = 0.45 (ethyl acetate–n-hexane, 1 : 1), Mp. 208–209 °C; IR (KBr, cm⁻¹): 3277, 1745, 1701, 1624, 1514, 1478, 1340, ¹H NMR (CDCl₃, 300 MHz) δ: 1.28 (t, J = 7.2 Hz, 3H, CH₃), 3.35 (d, J = 8.3 Hz, 1H, CH), 3.74 (d, J = 8.3 Hz, 1H, CH), 4.17–4.30 (m, 2H, diastereotopic OCH₂), 6.70 (dd, J = 4.3 & 8.5 Hz, 1H, ArH), 6.92 (dt, J = 2.4 & 8.9 Hz, 1H, ArH), 7.19–7.36 (m, 5H, ArH), 8.50 (bs, 1H, NH); ¹³C NMR (CDCl₃ + DMSOd₆, 75 MHz) δ: 13.6, 37.2, 39.2, 40.1, 54.7, 61.3, 109.0, 113.0, 118.0, 123.5, 123.9, 127.0, 129.7, 142.0, 148.0, 158.5, 167.6, 172.8; HRMS (ESI, Orbitrap): calcd for C₂₀H₁₉N₂O₆ [M + H]⁺ 383.12431; found 383.12576.

5′-Bromo-2-(4-methylbenzoyl)-3-phenylspiro[cyclopropane-1,3′-indolin]-2′-one 3d. 184 mg (85%) of 3d was obtained as a yellow solid, R_f = 0.50 (ethyl acetate–n-hexane, 1 : 1), Mp. 216–218 °C; IR (KBr, cm⁻¹): 3188, 3059, 2953, 1706, 1662, 1607, 1475, 1454, 1320, 1260, ¹H NMR (CDCl₃, 500 MHz) δ: 2.39 (s, 3H, CH₃), 4.10 (d, J = 8.4 Hz, 1H, CH), 4.28 (d, J = 8.4 Hz, 1H, CH), 6.70 (d, J = 8.2 Hz, 1H, ArH), 7.22 (d, J = 8.1 Hz, 2H, ArH), 7.27–7.35 (m, 6H, ArH), 7.44 (d, J = 1.5 Hz, 1H, ArH), 7.86 (bs, 1H, NH), 7.88 (d, J = 8.2 Hz, 2H, ArH); ¹³C NMR (CDCl₃ + DMSO-d₆, 75 MHz) δ: 20.9, 39.2, 40.2, 40.9, 110.6, 113.2, 124.1, 126.6, 127.3, 127.7, 127.9, 128.4, 128.7, 129.4, 132.5, 133.7, 140.6, 144.0, 172.0, 191.6; HRMS (ESI, Orbitrap): calcd for C₂₄H₁₉NO₂⁷⁹Br [M + H]⁺ 432.05992; found 432.06163.

2-(4-Methoxybenzoyl)-3-phenylspiro[cyclopropane-1,3′-indolin]-2′-one 3e. 157 mg (85%) of 3e was obtained as a pale yellow solid, R_f = 0.40 (ethyl acetate–n-hexane, 1 : 1), Mp. 203–204 °C; IR (KBr, cm⁻¹): 3145, 3038, 1706, 1662, 1620, 1599, 1582, 1471, 1316, ¹H NMR (CDCl₃, 300 MHz) δ: 3.75 (s, 3H, OCH₃), 4.12 (d, J = 8.3 Hz, 1H, CH), 4.21 (d, J = 8.3 Hz, 1H, CH), 6.70 (d, J = 8.9 Hz, 2H, ArH), 6.80 (d, J = 7.6 Hz, 1H, ArH), 6.93 (t, J = 8.3 Hz, 1H, ArH), 7.12 (dt, J = 0.9 & 7.7 Hz, 1H, ArH), 7.23–7.36 (m, 6H, ArH), 7.87 (d, J = 9.0 Hz, 2H, ArH), 8.63 (bs, 1H, NH); ¹³C NMR (CDCl₃ + DMSO-d₆, 75 MHz) δ: 38.7, 40.2, 40.9, 54.8, 109.2, 113.3, 120.9, 121.1, 125.9, 126.6, 126.7, 127.3, 128.6, 129.4, 130.0, 133.1, 141.4, 163.2, 172.8, 190.6; HRMS (ESI, Orbitrap): calcd for C₂₄H₂₀NO₃ [M + H]⁺ 370.14432; found 370.14352.

Ethyl 5′-fluoro-2′-oxo-3-phenylspiro[cyclopropane-1,3′-indoline]-2-carboxylate 3f. 127 mg (78%) of 3f was obtained as a white solid, R_f = 0.60 (ethyl acetate–n-hexane, 1 : 1), Mp. 163–164 °C; IR (KBr, cm⁻¹): 3203, 1725, 1702, 1481, 1469, 1307, 1219, ¹H NMR (CDCl₃, 300 MHz) δ: 1.28 (t, J = 7.2 Hz, 3H, CH₃), 3.34 (d, J = 8.3 Hz, 1H, CH), 3.74 (d, J = 8.3 Hz, 1H, CH), 4.16–4.31 (m, 2H, diastereotopic OCH₂), 6.69 (dd, J = 4.3, 8.5 Hz, 1H, ArH), 6.89 (dt, J = 2.5, 8.7 Hz, 1H, ArH), 7.25–7.36 (m, 6H, ArH), 8.50 (bs, 1H, NH); ¹³C NMR (CDCl₃, 75 MHz) δ: 14.1, 37.3, 40.1, 40.7, 61.7, 110.3 (110.4 due to C–F coupling: d, J_C–F = 8.8 Hz), 110.6 (110.9 due to C–F coupling: d, J_C–F = 26.3 Hz), 113.8 (114.1 due to C–F coupling: d, J_C–F = 24.1 Hz), 127.6, 128.1, 128.5, 129.1, 132.5, 137.1, 147.5, 157.1 (160.3 due to C–F coupling d, J_C–F = 239.3 Hz), 168.2, 174.0; HRMS (ESI, Orbitrap): calcd for C₁₉H₁₇NO₃F [M + H]⁺ 326.11925; found 326.12038.

2-(4-Methoxybenzoyl)-3-(4-nitrophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one 3g. 168 mg (81%) of 3g was obtained as a pale yellow solid, R_f = 0.50 (ethyl acetate–n-hexane, 1 : 1), Mp. 200–201 °C; IR (KBr, cm⁻¹): 3383, 1713, 1699, 1667, 1595, 1515, 1350, 1324, 1310, ¹H NMR (CDCl₃, 300 MHz) δ: 3.83 (s, 3H, OCH₃), 4.14 (d, J = 8.3 Hz, 1H, CH), 4.23 (d, J = 8.3 Hz, 1H, CH), 6.82–6.90 (m, 3H, ArH), 6.97 (t, J = 7.6 Hz, 1H, ArH), 7.17 (dt, J = 0.9 & 7.7 Hz, 1H, ArH), 7.23 (d, J = 7.9 Hz, 1H, ArH), 7.51 (d, J = 8.7 Hz, 2H, ArH), 7.92 (d, J = 8.9 Hz, 3H, 2ArH + NH), 8.17 (d, J = 8.7 Hz, 2H, ArH); ¹³C NMR (CDCl₃, 125 MHz) δ: 38.4, 40.9, 41.5, 55.5, 109.9, 114.0, 122.3, 122.6, 123.3, 125.7, 128.0, 129.6, 130.2, 130.8, 140.8, 141.2, 147.1, 164.2, 173.7, 190.1; HRMS (ESI, Orbitrap): calcd for C₂₄H₁₉N₂O₅ [M + H]⁺ 415.12940; found 415.12821.

2-(2-Naphthoyl)-5′-chloro-3-(4-nitrophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one 3h. 202 mg (86%) of 3h was obtained as a pale yellow solid, R_f = 0.50 (ethyl acetate–n-hexane, 1 : 1), Mp. 268–270 °C; IR (KBr, cm⁻¹): 3264, 1713, 1665, 1621, 1516, 1343, ¹H NMR (CDCl₃, 300 MHz) δ: 4.20 (d, J = 8.2 Hz, 1H, CH), 4.47 (d, J = 8.2 Hz, 1H, CH), 6.81 (d, J = 8.4 Hz, 1H, ArH), 7.15 (dd, J = 2.1 & 8.4 Hz, 1H, ArH), 7.34 (d, J = 2.0 Hz, 1H, ArH), 7.55–7.58 (m, 3H, ArH), 7.61–7.64 (m, 1H, ArH), 7.86 (d, J = 8.2 Hz, 1H, ArH), 7.90 (d, J = 8.7 Hz, 1H, ArH), 7.96 (d, J = 8.1 Hz, 1H, ArH), 8.04 (dd, J = 1.7 & 8.5 Hz, 1H, ArH), 8.19 (d, J = 8.9 Hz, 2H, ArH), 8.40 (bs, 1H, NH), 8.51 (d, J = 1.2 Hz, 1H, ArH); ¹³C NMR (CDCl₃ + DMSO-d₆, 125 MHz) δ: 37.2, 39.4, 40.5, 109.9, 120.9, 121.7, 122.2, 125.1, 125.9, 126.2, 126.4, 126.5, 127.5, 127.8, 128.4, 129.1, 129.2, 129.3, 130.9, 132.6, 134.4, 139.9, 145.6, 171.1, 190.6; HRMS (ESI, Orbitrap): calcd for C₂₇H₁₈N₂O₄Cl [M + H]⁺ 469.09551; found 469.09439.

5′-Bromo-2-(4-methoxybenzoyl)-3-(4-nitrophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one 3i. 217 mg (88%) of 3i was obtained as a orange solid, R_f = 0.38 (ethyl acetate–n-hexane, 1 : 1), Mp. 235–236 °C; IR (KBr, cm⁻¹): 3282, 2924, 1714, 1652, 1600, 1573, 1517, 1347, ¹H NMR (CDCl₃, 500 MHz) δ: 3.85 (s, 3H, OCH₃), 4.12 (d, J = 8.3 Hz, 1H, CH), 4.26 (d, J = 8.3 Hz, 1H, CH), 6.75 (d, J = 8.3 Hz, 1H, ArH), 6.91 (d, J = 9.0 Hz, 2H, ArH), 7.31 (dd, J = 1.9 & 8.1 Hz, 1H, ArH), 7.42 (d, J = 1.7 Hz, 1H, ArH), 7.50 (d, J = 8.5 Hz, 2H, ArH), 7.79 (bs, 1H, NH), 7.96 (d, J = 8.9 Hz, 2H, ArH), 8.17 (d, J = 8.7 Hz, 2H, ArH); ¹³C NMR (CDCl₃ + DMSO-d₆, 75 MHz) δ: 37.31, 39.57, 40.33, 54.54, 110.52, 112.94, 113.10, 121.97, 123.88, 126.98, 128.59, 129.41, 129.70, 140.31, 145.95, 140.59, 163.15, 171.35, 189.15; HRMS (ESI, Orbitrap): calcd for C₂₄H₁₈N₂O₅⁷⁹Br [M + H]⁺ 493.03991; found 493.03919.

5′-Bromo-2-(4-methylbenzoyl)-3-(4-nitrophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one 3j. 193 mg (81%) of 3j was obtained as a yellow solid, R_f = 0.58 (ethyl acetate–n-hexane, 1 : 1), Mp. 271–272 °C; IR (KBr, cm⁻¹): 3345, 1712, 1670, 1601, 1512, 1476, 1443, 1347, ¹H NMR (CDCl₃, 300 MHz) δ: 2.40 (s, 3H, CH₃), 4.12 (d, J = 8.5 Hz, 1H, CH), 4.28 (d, J = 8.5 Hz, 1H, CH), 6.74 (d, J = 8.3 Hz, 1H, ArH), 7.24–7.27 (m, 2H, ArH), 7.31 (dd, J = 1.9 & 8.3 Hz, 1H, ArH), 7.42 (d, J = 1.9 Hz, 1H, ArH), 7.50 (d, J = 8.5 Hz, 2H, ArH), 7.87 (d, J = 8.1 Hz, 2H, ArH), 7.99 (bs, 1H, NH), 8.17 (d, J = 8.7 Hz, 2H, ArH); ¹³C NMR (CDCl₃ + DMSO-d₆, 75 MHz) δ: 21.1, 37.9, 38.3, 41.0, 111.1, 122.6, 124.5, 127.3, 128.0, 129.0, 129.7, 129.8, 130.1, 131.2, 133.6, 140.6, 140.9, 144.5, 172.0, 191.1; HRMS (ESI, Orbitrap): calcd for C₂₄H₁₈N₂O₄⁷⁹Br [M + H]⁺ 477.04499; found 477.04380.

4-(5′-Bromo-2-(4-chlorobenzoyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-3-yl)benzonitrile 3k. 194 mg (81%) of 3k was obtained as a pale yellow solid, R_f = 0.61 (ethyl acetate–n-hexane, 1 : 1), Mp. 277–278 °C; IR (KBr, cm⁻¹): 3251, 2242, 1712, 1676, 1608, 1588, 1477, 1443, 1212, ¹H NMR (CDCl₃ +DMSO-d₆, 300 MHz) δ: 4.03 (d, J = 8.1 Hz, 1H, CH), 4.18 (d, J = 8.1 Hz, 1H, CH), 6.80 (d, J = 8.1 Hz, 1H, ArH), 7.25–7.29 (m, 2H, ArH), 7.43–7.49 (m, 4H, ArH), 7.60 (d, J = 8.3 Hz, 2H, ArH), 7.90 (d, J = 8.5 Hz, 2H, ArH), 10.40 (bs, 1H, NH); ¹³C NMR (CDCl₃ + DMSO-d₆, 75 MHz) δ: 37.5, 39.4, 40.4, 109.7, 110.5, 112.8, 117.5, 123.7, 126.5, 128.0, 128.7, 129.1, 129.4, 130.5, 133.8, 137.6, 138.9, 140.5, 171.0, 189.9; HRMS (ESI, Orbitrap): calcd for C₂₄H₁₅N₂O₂⁷⁹BrCl [M + H]⁺ 477.00054; found 476.99872.

4-(5′-Bromo-2-(4-methoxybenzoyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-3-yl)benzonitrile 3l. 199 mg (84%) of 3l was obtained as a orange solid, R_f = 0.66 (ethyl acetate–n-hexane, 1 : 1), Mp. 220–221 °C; IR (KBr, cm⁻¹): 3281, 2228, 1715, 1667, 1599, 1574, 1476, 1323, 1263, ¹H NMR (CDCl₃, 300 MHz) δ: 3.85 (s, 3H, OCH₃), 4.09 (d, J = 8.2 Hz, 1H, CH), 4.23 (d, J = 8.2 Hz, 1H, CH), 6.76 (d, J = 8.2 Hz, 1H, ArH), 6.89 (d, J = 8.7 Hz, 2H, ArH), 7.31 (d, J = 8.2 Hz, 1H, ArH), 7.41 (s, 1H, ArH), 7.45 (d, J = 8.1 Hz, 2H, ArH), 7.60 (d, J = 8.1 Hz, 2H, ArH), 7.95 (d, J = 8.7 Hz, 2H, ArH), 8.26 (bs, 1H, NH); ¹³C NMR (CDCl₃, 75 MHz) δ: 39.1, 40.7, 41.2, 55.5, 111.3, 114.0, 115.3, 118.6, 125.5, 127.9, 129.4, 129.8, 130.0, 130.8, 131.8, 134.0, 138.5, 139.9, 164.3, 173.3, 189.8; HRMS (ESI, Orbitrap): calcd for C₂₅H₁₈N₂O₃⁷⁹Br [M + H]⁺ 473.05008; found 473.04895.

4-(5′-Bromo-2-(4-methylbenzoyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-3-yl)benzonitrile 3m. 194 mg (85%) of 3m was obtained as a pale yellow solid, R_f = 0.51 (ethyl acetate–n-hexane, 1 : 1), Mp. 254–256 °C; IR (KBr, cm⁻¹): 3266, 2243, 1713, 1670, 1607, 1477, 1444, 1209, ¹H NMR (CDCl₃, 300 MHz) δ: 2.40 (s, 3H, CH₃), 4.09 (d, J = 8.2 Hz, 1H, CH), 4.26 (d, J = 8.2 Hz, 1H, CH), 6.72 (d, J = 8.2 Hz, 1H, ArH), 7.23 (d, J = 8.1 Hz, 2H, ArH), 7.31 (dd, J = 2.0 & 8.4 Hz, 1H, ArH), 7.41 (d, J = 1.8 Hz, 1H, ArH), 7.45 (d, J = 8.1 Hz, 2H, ArH), 7.60 (d, J = 8.2 Hz, 2H, ArH), 7.86 (d, J = 8.2 Hz, 2H, ArH), 8.17 (bs, 1H, NH); ¹³C NMR (CDCl₃ + DMSOd₆, 75 MHz) δ: 21.1, 38.2, 40.0, 41.0, 110.4, 111.0, 113.6, 118.1, 124.4, 127.4, 127.9, 128.9, 129.6, 129.9, 131.2, 133.5, 138.4, 140.8, 144.5, 171.9, 191.1; HRMS (ESI, Orbitrap): calcd for C₂₅H₁₈N₂O₂⁷⁹Br [M + H]⁺ 457.05517; found 457.05736.

4-(2-(4-Methoxybenzoyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-3-yl)benzonitrile 3n. 158 mg (80%) of 3n was obtained as a pale yellow solid, R_f = 0.37 (ethyl acetate–n-hexane, 1 : 1), Mp. 140–141 °C; IR (KBr, cm⁻¹): 3284, 2228, 1714, 1667, 1599, 1574, 1511, 1470, 1348, 1264, ¹H NMR (CDCl₃, 500 MHz) δ: 3.82 (s, 3H, OCH₃), 4.11 (d, J = 8.1 Hz, 1H, CH), 4.21 (d, J = 8.1 Hz, 1H, CH), 6.81–6.86 (m, 3H, ArH), 6.97 (dt, J = 0.9 & 7.6 Hz, 1H, ArH), 7.18 (dt, J = 1.1 & 7.7 Hz, 1H, ArH), 7.23 (d, J = 7.7 Hz, 1H, ArH), 7.46 (d, J = 8.1 Hz, 2H, ArH), 7.60 (d, J = 8.4 Hz, 2H, ArH), 7.91 (d, J = 9.0 Hz, 2H, ArH), 8.05 (bs, 1H, NH); ¹³C NMR (CDCl₃, 125 MHz) δ: 38.6, 40.8, 41.4, 55.5, 109.9, 111.2, 114.0, 118.7, 122.3, 122.6, 125.8, 127.9, 129.6, 130.1, 130.8, 131.8, 139.1, 140.8, 164.1, 173.7, 190.2; HRMS (ESI, Orbitrap): calcd for C₂₅H₁₉N₂O₃ [M + H]⁺ 395.13957; found 395.13852.

2-(4-Bromobenzoyl)-3-(4-methoxyphenyl)-1′-methylspiro[cyclopropane-1,3′-indolin]-2′-one 3o. 189 mg (82%) of 3o was obtained as a pale yellow solid, R_f = 0.60 (ethyl acetate–n-hexane, 2 : 3), Mp. 206–207 °C; IR (KBr, cm⁻¹): 3054, 2930, 1705, 1673, 1613, 1584, 1492, 1469, 1347, ¹H NMR (CDCl₃, 300 MHz) δ: 3.24 (s, 3H, NCH₃), 3.79 (s, 3H, OCH₃), 4.06 (d, J = 8.3 Hz, 1H, CH), 4.21 (d, J = 8.3 Hz, 1H, CH), 6.80–6.90 (m, 3H, ArH), 6.98 (t, J = 7.6 Hz, 1H, ArH), 7.22–7.30 (m, 4H, ArH), 7.55 (d, J = 8.3 Hz, 2H, ArH), 7.81 (d, J = 8.3 Hz, 2H, ArH); ¹³C NMR (CDCl₃, 125 MHz) δ: 26.7, 39.3, 41.0, 41.8, 55.1, 108.0, 113.5, 121.8, 122.4, 124.8, 125.8, 127.5, 128.9, 129.9, 130.2, 132.0, 135.7, 143.7, 158.9, 171.8, 192.1; HRMS (ESI, Orbitrap): calcd for C₂₅H₂₁NO₃⁷⁹Br [M + H]⁺ 462.07048; found 462.07266.

5′-Chloro-2-(4-methoxyphenyl)-3-(4-nitrobenzoyl)spiro[cyclopropane-1,3′-indolin]-2′-one 3p. 177 mg (79%) of 3p was obtained as a pale yellow solid, R_f = 0.45 (ethyl acetate–n-hexane, 1 : 2), Mp. 116–117 °C; IR (KBr, cm⁻¹): 3253, 2924, 2852, 1715, 1638, 1526, 1469, 1318, 1250, ¹H NMR (DMSO-d₆, 300 MHz) δ: 3.74 (s, 3H, OCH₃), 4.00 (d, J = 8.3 Hz, 1H, CH), 4.40 (d, J = 8.3 Hz, 1H, CH), 6.83–6.89 (m, 3H, ArH), 7.01 (d, J = 1.9 Hz, 1H, ArH), 7.18 (dd, J = 2.0, 8.3 Hz, 1H, ArH), 7.33 (d, J = 8.5 Hz, 2H, ArH), 8.10 (d, J = 8.9 Hz, 2H, ArH), 8.33 (d, J = 8.7 Hz, 2H, ArH), 10.80 (bs, 1H, NH); ¹³C NMR (CDCl₃, 75 MHz) δ: 39.7 & 40.2 (buried in DMSO-d₆), 41.2, 55.9, 110.8, 113.1, 113.8, 121.2, 124.1, 124.6, 125.1, 127.2, 127.9, 129.4, 130.5, 141.0, 150.1, 158.4, 171.8, 192.2; HRMS (ESI, Orbitrap): calcd for C₂₄H₁₈N₂O₅Cl [M + H]⁺ 449.09042; found 449.09062.

Acknowledgements

R.A.M. is thankful to DST-India for financial support (GAP 0378) in the form of INSPIRE Faculty Award. Financial support in part from 12^th Five Year Plan Project “Affordable Cancer Therapeutics (ACT-CSC-0301)” is also acknowledged. C.N.R. and P.R.A. acknowledge CSIR-New Delhi for their fellowships. R. N. acknowledges DST India for financial support in the form of INSPIRE Fellowship.

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Footnote

† Electronic supplementary information (ESI) available: Copies of ¹H NMR, ¹³C NMR and HRMS spectra are available. CCDC 1016218. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4ra05755d

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