An efficient, green synthesis of novel regioselective and stereoselective indan-1,3-dione grafted spirooxindolopyrrolizidine linked 1,2,3-triazoles via a one-pot five-component condensation using PEG-400

Abstract

An efficient synthesis of highly diversified novel functionalized indan-1,3-dione grafted spirooxindolopyrrolizidine linked 1,2,3-triazole conjugates via a one-pot, five-component condensation of indan-1,3-diones, aldehydes, sarcosine, N-propargylated isatin and azides using Cu(I) as a catalyst in PEG-400 as the reaction medium is reported. The reaction proceeds in a highly regio- and stereoselective manner involving a catalyst free Knoevenagel condensation followed by two successive 1,3-dipolar cycloaddition reactions. This protocol is suitable for aromatic, heteroaromatic and aliphatic aldehydes. In situ generation of azomethine ylides and their selectivity towards exocyclic double bonds result in highly functionalized molecular hybrids. All the compounds are obtained in high yield (6a–6s) and were characterized by spectroscopic methods.

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Introduction

Designing highly efficient protocols for accessing biologically active compounds possessing structural diversity from simple starting compounds is one of the major challenges in organic synthesis.¹ Multi-component reaction (MCR) protocols offer remarkable advantages such as high selectivity, operational simplicity, reduction in the number of work-ups, high yields and structural diversity of drug-like compounds.² The 1,3-dipolar cycloaddition reaction of azomethine ylides with olefinic dipolarophiles and the Cu(I) catalyzed [3 + 2] cycloaddition of azides with triple bonds constitute facile approaches for the construction of five-membered nitrogen containing heterocycles.³ Azomethine ylides can be generated in situ for the construction of highly functionalized spirooxindolopyrrolizidines in an efficient manner.⁴ Spirooxindolopyrrolizidines exhibit a wide range of biological activities such as anticonvulsive,⁵ antileukaemic,⁶ anesthetic,⁷ antiviral⁸ and antibacterial activity.⁹ In addition the spirooxindolopyrrolizidine ring system also occurs in alkaloids,¹⁰ for example, (−)-horsfiline^10a and spirotryprostatin A^10b (Fig. 1).

Fig. 1 Some representative compounds containing the spirocyclic oxindole, indanone and 1,2,3-triazole moieties.

1,2,3-Triazoles are privileged structures associated with biological activities such as anti-HIV,¹¹ antimicrobial,¹² antiviral,¹³ antiproliferative,¹⁴ insecticidal,¹⁵ and fungicidal activity.¹⁶ Fluconazole is a well-known antifungal drug consisting of two 1,2,3-triazole moieties (Fig. 1). 1,2,3-Triazoles can be readily constructed from alkynes and azides by a Cu(I) catalyzed 1,3-dipolar addition. Indanone-fused heterocycles (Fig. 1) have also attracted the attention of chemists and pharmacologists¹⁷ due to their role as topoisomerase-I inhibitors.^18,19

Therefore, in continuation of our work on the synthesis of potentially bioactive heterocyclic compounds with diverse applications through hybridization,^20,21 we decided to link spirooxindolopyrrolizidines, indanones and 1,2,3-triazoles in a single matrix through a one-pot five-component reaction using PEG-400 as an efficient and green reaction media.

Results and discussion

The present manuscript reports a new, diversity oriented and highly efficient green protocol for the synthesis of novel functionalized indan-1,3-dione grafted spirooxindolopyrrozolidine linked 1,2,3-triazole conjugates via a one-pot, five-component reaction by using Cu(I) as the catalyst in PEG-400 as an efficient and green reaction medium (Scheme 1).

Scheme 1 Synthesis of 1-N-methyl-spiro[2.3′]-1′-N-((1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)oxindole-spiro[3.2′′]-indan-1,3-dione-(4-chlorophenyl)-pyrrolidine.

The optimized reaction conditions for the above synthesis were identified by attempting the reaction of N-propargylated isatin (1.0 mmol) (1), indane-1,3-dione (1.0 mmol) (2), 4-cholorobenzaldehyde (1.0 mmol) (3), 4-fluorophenyl azide (1.0 mmol) (4) and sarcosine (1.0 mmol) (5) under different conditions. Initially the reaction was attempted in ethanol (10 mL) in the presence of aq. CuSO₄·5H₂O (10 mol%) and sodium ascorbate (20 mol%) (in a 50 mL round-bottomed flask) maintained at 80 °C in an oil-bath. The reaction was incomplete even after 2 h as indicated by TLC (ethyl acetate : petroleum ether, 30 : 70, v/v) (Table 1, entry 1). The reaction was quenched and worked up. After flash chromatography, a solid was obtained which was identified as 1-N-methyl-spiro[2.3′]-1′-N-((1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)oxindole-spiro[3.2′′]-indan-1,3-dione-(4-chlorophenyl)-pyrrolidine (6a) (55% yield) by ¹H NMR and ¹³C NMR spectroscopy, mass spectrometry, IR spectroscopy and X-ray crystallography. Spectroscopic studies revealed the formation of only one isomer though other isomeric products are possible.

Table 1 Optimization of reaction conditions for the synthesis of 1-N-methyl-spiro[2.3′]-1′-N-((1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)oxindole-spiro[3.2′′]-indan-1,3-dione-(4-chlorophenyl)-pyrrolidine

Entry	Solvent	Catalyst^c (mol%)	Temp (°C)	Time (min)	Yield (%)
a Incomplete reaction.b Reaction performed under ultrasonic irradiation.c aq. CuSO4·5H2O (10 mol%) and aq. sodium ascorbate (20 mol%) were added in entries 1–13 after 35–40 min.
1	EtOH	—	80	120	55^a
2	MeOH	—	80	120	60^a
3	CH3CN	—	80	100	65^a
4	THF	—	80	100	60^a
5	CH3COOH	—	80	90	70^a
6	H2O	—	80	120	35^a
7	PEG-400	—	80	45	85
8	PEG-600	—	80	45	82
9	PEG-400	—	100	45	80
10	PEG-400	—	60	70	75
11	PEG-400	—	40^b	120	70
12	PEG-400	p-TSA (20)	80	45	82
13	PEG-400	L-Proline (20)	80	45	80

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The above reaction was then attempted in different reaction media under otherwise identical conditions (Table 1, entries 2–8). Reactions carried out in methanol, acetonitrile, THF, AcOH and water were not complete and gave inferior yields of 6a after work-up (entries 2–6). The same reaction attempted in PEG-400 and PEG-600 at 80 °C was complete in 45 min and yielded 85% and 82% of the desired product (6a) respectively (Table 1, entries 7–8). The five-component reaction was then attempted at different temperatures, under ultrasonic irradiation and in the presence of catalysts in PEG-400 (Table 1, entries 9–13).

It can be inferred from Table 1 that the above one-pot five-component reaction in PEG-400 using aq. CuSO₄·5H₂O (10 mol%) and aq. sodium ascorbate (20 mol%) as catalyst at 80 °C gave the highest yield of 6a (85%) (Table 1, entry 7).

The structure of 6a was elucidated using one and two-dimensional NMR spectroscopy, IR spectroscopy and HRMS. The HMBC and COSY correlations are useful in the signal assignments of 6a, and various characteristic signals are shown in Fig. 2. The ¹H NMR spectrum of 6a revealed one sharp singlet at δ 2.0 due to the N-methyl protons. The benzylic proton on the C₄ carbon of the pyrrolidine ring exhibits a multiplet at δ 5.05–5.01. The two protons on the C₅ carbon of pyrrolidine exhibit multiplets at δ 4.01–3.97 and 3.61–3.56. The two protons on the N–CH₂ carbon appear as a multiplet at δ 4.97–4.91. One proton, on the C₅ carbon of the triazole, appears at δ 8.63 which confirms the formation of the triazole ring. Aromatic protons appeared as a multiplet in the region of δ 7.92–6.71.

Fig. 2 HMBC and COSY correlations useful in the signal assignments of 6a and various characteristic ¹H and ¹³C NMR peaks.

The regiochemistry of 6a formed in the reaction was confirmed by ¹H NMR. The regioisomer 6a should exhibit a multiplet for the benzylic proton on the C₄ carbon of the pyrrolidine ring, whereas the other possible regioisomer 8 (see Fig. 4) would show a singlet. The ¹H NMR of the product showed a multiplet at δ 5.05–5.01 rather than a singlet thus suggesting the formation of regioisomer 6a. Furthermore, the off-resonance decoupled ¹³C NMR of the product exhibited signals at δ 76.8 and 69.6 which correspond to the C₃ spiro carbon and the C₂ carbon of the pyrrolidine ring of 6a. The signals at δ 197.3 and 196.3 for the product 6a correspond to the keto carbonyls of indan-1,3-dione. The resonance at δ 173.4 is due to the oxindole carbonyl carbon. The signal at δ 34.6 is due to N–CH₃ carbon and peaks at δ 45.3 and 55.9 are due to the C₄ and C₅ carbons of the pyrrolidine ring. The mass spectrum of 6a showed a molecular ion peak at m/z 618.1705 (M⁺ + 1). The formation of only one regioisomer i.e. 6a was also confirmed by single crystal X-ray structural analysis (Fig. 3).

Fig. 3 Single crystal X-ray structure of 6a.

The generality of the above protocol was confirmed by carrying out the reactions of N-propargylated isatin (1), indane-1,3-dione (2) and sarcosine (5) with aromatic/aliphatic azides and aromatic/aliphatic aldehydes. All the reactions proceeded smoothly to yield a diverse library of 1-N-methyl-spiro[2.3′]-1′-N-((1-(aryl/alkyl)-1H-1,2,3-triazol-4-yl)methyl)oxindole-spiro[3.2′′]-indan-1,3-dione-(aryl/alkyl)-pyrrolidines (6a–6s) in high yields under the optimized protocol (Scheme 2). The results are summarized in Table 2.

Scheme 2 Synthesis of 1-N-methyl-spiro[2.3′]-1′-N-((1-(aryl/alkyl)-1H-1,2,3-triazol-4-yl)methyl)oxindole-spiro[3.2′′]-indan-1,3-dione-(aryl/alkyl)-pyrrolidine.

Table 2 Synthesis of 1-N-methyl-spiro[2.3′]-1′-N-((1-(aryl/alkyl)-1H-1,2,3-triazol-4-yl)methyl)oxindole-spiro[3.2′′]-indan-1,3-dione-(aryl/alkyl)-pyrrolidine

Product code	R^1	R^2	Time (min)	Yield (%)
6a	4-ClC6H4	4-FC6H4	45	85
6b	4-ClC6H4	4-(CH3)C6H4	50	80
6c	4-BrC6H4	4-FC6H4	50	83
6d	4-FC6H4	4-(CH3)C6H4	40	82
6e	4-BrC6H4	4-(CH3)C6H4	50	81
6f	4-FC6H4	4-FC6H4	45	84
6g	4-ClC6H4	4-(NO2)C6H4	50	82
6h	4-BrC6H4	4-(NO2)C6H4	45	86
6i	4-(CH3)C6H4	4-(NO2)C6H4	40	79
6j	4-(NO2)C6H4	4-(OCH3)C6H4	45	84
6k	4-FC6H4	4-(NO2)C6H4	40	82
6l	4-(CF3)C6H4	4-(NO2)C6H4	40	87
6m	4-(CF3)C6H4	7-Chloroquinoline	50	80
6n	4-(CF3)C6H4	4-FC6H4	45	85
6o	4-(CH3)C6H4	7-Chloroquinoline	50	74
6p	Furfuraldehyde	n-Butyl	50	80
6q	Piperonal	4-FC6H4	50	86
6r	Isobutyl	7-Chloroquinoline	60	78
6s	Isobutyl	4-(OCH3)C6H4	65	74

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The proposed pathway for the formation of 6 is given in Fig. 4. The pathway consists of two sequential steps. The first step involves formation of intermediate 7 by Cu(I) catalyzed [3 + 2] azide-alkyne cycloaddition. The Cu(I) is generated in situ by the reduction of Cu(II) to Cu(I) by sodium ascorbate.²¹ In the second part, the azomethine ylide, generated in situ via decarboxylative condensation of sarcosine with intermediate 7, undergoes a [3 + 2] cycloaddition reaction with the Knoevenagel condensation product of indan-1,3-dione and aldehyde, resulting in the formation of product 6. The [3 + 2] dipolar cycloaddition reaction between the azomethine ylide and the exocyclic double bond can proceed through two paths i.e. path (a) and path (b). However, in the case of path (b), there are secondary orbital interactions between the carbonyl group of indan-1,3-dione with the carbonyl group of isatin in the transition state, which results in the formation of only 6. The formation of intermediate 7 was confirmed by CO-TLC with an authentic sample of 7. The intermediacy of 7 was confirmed by an independent reaction of preformed 7 with the Knoevenagel product of indan-1,3-dione and sarcosine in PEG-400 which led to the formation of 6.

Fig. 4 Plausible mechanism for the regio- and stereo-selective formation of 1-N-methyl-spiro[2.3′]-1′-N-((1-(aryl/alkyl)-1H-1,2,3-triazol-4-yl)methyl)oxindole-spiro[3.2′′]-indan-1,3-dione-(aryl/alkyl)-pyrrolidines.

The role of Cu(I) in catalyzing only the first part of the pathway was also confirmed by an independent reaction of 7 with the Knoevenagel product and sarcosine. The reaction was attempted both in the presence and absence of CuSO₄·5H₂O (10 mol%) and sodium ascorbate (20 mol%). The reactions resulted in the formation of 6a in 85 and 82% yield, respectively, in 45 min, which suggests that Cu(I) has no effect on the dipolar cycloaddition reaction of the azomethine ylide and the double bond. The formation of regioisomer 8, as shown in Fig. 4, has already been ruled out based on ¹H and 2D NMR spectroscopy and X-ray crystallography.

Conclusion

In conclusion, we have reported an efficient multicomponent methodology for the synthesis of indan-1,3-dione grafted spirooxindolopyrrolizidine linked 1,2,3-triazole hybrids, namely 1-N-methyl-spiro[2.3′]-1′-N-((1-(aryl/alkyl)-1H-1,2,3-triazol-4-yl)methyl)oxindole-spiro[3.2′′]-indan-1,3-dione-(aryl/alkyl)-pyrrolidines (6a–6s), by the reaction of N-propargylated isatin (1), indane-1,3-dione (2), aldehydes (3), azides (4) and sarcosine (5) using Cu(I) as the catalyst in PEG-400 at 80 °C. The products could be obtained in high yields using a simple work-up.

Experimental

Chemistry

Silica gel 60 F₂₅₄ (precoated aluminium plates) from Merck was used to monitor reaction progress. Melting points were determined on Buchi melting point 545 apparatus and are uncorrected. IR (KBr) spectra were recorded on a Perkin Elmer FTIR spectrophotometer, and the values are expressed as ν_max cm⁻¹. The ¹H and ¹³C spectra were recorded on Jeol JNM ECX-400P at 400 MHz and 100 MHz, respectively. Chemical shift values are recorded on a δ scale, and the coupling constants (J) are in Hertz. Mass spectra were recorded on a Bruker Micro TOF Q – II. The aryl azides and propargylated isatin were prepared from aromatic amines and isatin respectively by a reported procedure.²²

General procedure for the synthesis of 1-N-methyl-spiro[2.3′]-1′-N-((1-(aryl/alkyl)-1H-1,2,3-triazol-4-yl)methyl)oxindole-spiro[3.2′′]-indan-1,3-dione-(aryl/alkyl)-pyrrolidine (6a–6s)

An equimolar mixture of N-propargylated isatin (1) (1.0 mmol), indan-1,3-dione (2) (1.0 mmol), aldehydes (3) (1.0 mmol), azides (4) (1.0 mmol) and sarcosine (5) (1.0 mmol) was dissolved in PEG-400 (10 mL) in a 50 mL round-bottomed flask. An aqueous solution of CuSO₄·5H₂O (10 mol%) followed by an aqueous solution of sodium ascorbate (20 mol%) were then added to the reaction mixture. The reaction contents were stirred magnetically in a pre-heated oil-bath maintained at 80 °C for 45–70 min (Table 2). The progress of the reaction was monitored by TLC (eluent: ethyl acetate : petroleum ether, 30 : 70 v/v). After completion of the reaction, the reaction mixture was allowed to cool to room temperature and was quenched with water (∼5 mL). The precipitate formed was collected by filtration at the pump and washed with water. The crude material was purified by flash chromatography over silica gel (230–400 mesh) to afford pure products. The products were characterized by IR spectroscopy, ¹H NMR and ¹³C NMR spectroscopy and mass spectrometry.

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Footnote

† Electronic supplementary information (ESI) available. CCDC 996871. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5ra03505h

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