A domino green method for the rapid synthesis of novel fused isoquinoline derivatives via Knoevenagel/Michael/cyclization reactions on aqueous media and their photophysical properties

Abstract

An expedient, eco-friendly and green-protocol has been developed for the synthesis of novel 4-imino-2-aryl-4H-pyrido[2,1-a]isoquinoline-3-carbonitrile derivatives via Knoevenagel/Michael/cyclisation reactions in one pot under catalyst-free conditions on aqueous media. These products exhibited UV-Vis absorption and photoluminescence properties.

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As popular fused-ring nitrogen heterocycles, isoquinolines are important scaffolds that exist in synthetic drugs and natural products.¹ Several fused-isoquinolines as core structures are found in many pharmacological motifs because of their outstanding biological activities, as depicted in Fig. 1.² Substituted fused-isoquinolines also have been used in material science for their fascinating luminescent properties (Fig. 1).³ Therefore, functionalized isoquinolines and related azaarenes play increasingly essential roles in natural products synthesis and drug discovery. Significant efforts have been made for the synthesis of this class of compounds, in which stepwise making of the desired ring system is usually required.⁴ In the past few decades, enormous progress in the synthesis of substituted fused-isoquinolines had been accomplished. However, most of those methods have many drawbacks, such as the use of complex substrates, harsh reaction conditions and toxic metal catalysts.⁵

Fig. 1 Some of the fused isoquinoline compounds which shows biological activities and photophysical properties.

On the other hand, C–H bond activation has considered as an important-tool for modern synthetic organic chemistry.^6–9 Because C–H bond activation generally engage synthetic protocols that build use of toxic metal or transitional metal catalyzed activation and consecutive functionalization of sp² and sp³ C–H bonds which directly install significant functional groups to synthesize complex structures.¹⁰ By considering ecological concerns and waste management, particularly in the area of pharmaceutical industries, identification of protocols that do not require toxic metal catalysts and hazardous organic solvents are very essential since the removal of waste and impurities from final pharmaceutical entities enhance the cost considerably. The development of an eco-efficient and catalyst-free protocol will remarkably change synthetic applications of direct C–H functionalization.

Furthermore, the replacement of hazardous solvents in chemical processes with environmentally more benign reaction media is highly desirable in view of point of “green chemistry”.¹¹ Water has examined as an eco-friendly medium and is non-toxic, non-flammable, non-volatile and inexpensive solvent. In addition to economical and environmental advantages, the choice of water as the reaction medium enhances the rate and selectivity's of many organic transformations.¹² The ability of water as a medium for developing novel reactions has also been established by recent observations of a few multi-component domino reactions.¹³

In recent times, sp³ C–H bond functionalization of alkyl azaarenes catalyzed by metal catalysts,¹² Brønsted acids,¹³ Lewis acids,¹⁴ or even without using catalyst,¹⁵ has been broadly used to synthesize azaarene derivatives. Literature reports reveal that, alkylazarenes displays different reactivity with the difference in their structure.^12–15 Mao and his co-workers demonstrates the reactivity of alkylazaarenes are changed with the change in position or number of alkyl substituents and the azaarenes ring system.¹⁶ For example, 2-picoline, 2,6-lutidene, 2-methyl quinoline reactions with aldehydes, gave corresponding products with difference in yield or structure or gave different products with the change in catalysts.¹⁶ Similarly, as depicted in Scheme 1, 2-methylquinoline reacted with methylenemalononitriles gave 2-(1-aryl-2-(azaaryl)ethyl)malononitrile derivatives with and without use of catalyst.^14a,15b Recently, we reported the catalyst-free one-pot three-component synthesis of 2-(1-aryl-2-(azaaryl)ethyl)malononitriles (Scheme 1).^17d Therefore, to explore the difference in the reactivity of alkylazaarenes with malononitrile, aldehydes and also as a part of our ongoing research program in establishing new, eco-friendly, on water protocols, multi-component reactions¹⁷ and developing process for sp³ C–H bond functionalization of azaarenes,¹⁷ here we would like to report a simple strategy to synthesize novel 4-imino-2-aryl-4H-pyrido[2,1-a]isoquinoline-3-carbonitrile derivatives (Scheme 1).

Scheme 1

As an extension of our investigation on the sp³ C–H bond activation of alkyl azaarenes in water,^17a,17d we conduct a reaction of 1-methylisoquinoline 1 (1.0 mmol), malononitrile 2 (1.0 mmol) and benzaldehyde 3a (1.0 mmol) in water (3 mL) at various temperatures and times without use of catalyst, which resulted in the formation of compound 4a (Scheme 2, Table 1). The structure of compound 4a was confirmed by ¹H NMR, ¹³C NMR, MS and IR spectral data analysis and unambiguously confirmed by single X-ray analysis of its analogous 4i (Fig. 2).²⁰ In order to optimize the best reaction conditions, we also screen the organic solvents as shown in Table 1. We have observed that the reaction is sluggish in toluene (entry 5) but proceeded smoothly and the product was obtained in very good yield in water compared to polar organic solvents such as DMF, DMSO, methanol and ethanol (entries 6–10). Further attempt to prepare the compound 4a in neat condition gave poor yield (entries 11 and 12, Table 1).

Scheme 2

Table 1 Optimization of the reaction conditions^a

Entry	Solvent	Temp (°C)	Time (min)	Yield^c (%)
a All reactions were carried out with 1 (1 mmol), 2 (1 mmol), 3a (1 mmol) and solvent (3 mL).b Reaction was carried out in neat condition.c Isolated yields of the product 4a.
1	Water	100	60	95
2	Water	100	40	95
3	Water	100	30	95
4	Water	100	20	80
5	Toluene	100	60	Trace
6	Methanol	70	60	30
7	Ethanol	80	60	20
8	DMSO	100	60	60
9	DMF	100	60	60
10	PEG-400	100	60	70
11	—	100	60	20^b
12	—	120	60	20^b

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Fig. 2 X-ray crystal structure of 4i·2CF₃COOH (ORTEP diagram).²⁰

We optimized the reaction condition as temperature 100 °C in 30 min and water is used as a medium (entry 3). With the optimum reaction conditions in hand, we investigated the scope of various aromatic aldehydes and the results were summarized in Table 2. To our delight, the reaction of different aromatic aldehydes bearing electron-donating methyl and methoxy groups or electron-withdrawing fluoro, chloro, bromo and nitro groups underwent reactions with 1-methyl isoquinoline and malononitrile in excellent yield (Table 2, compounds 4b–4i). Additionally, the scope of this method was extended to heterocyclic aldehydes such as 2-furanyl, 2-thiophenyl and 1,3-diaryl-1H-pyrazole-4-carbaldehydes (Table 2).

Table 2 Catalyst-free one-pot three-component synthesis of 4-imino-2-aryl-4H-pyrido[2,1-a]isoquinoline-3-carbonitrile derivatives^a,b

a All reactions were carried out with 1 (1 mmol), 2 (1 mmol), 3a–q (1 mmol) and water 3 (mL).b Isolated yields of the product 4a–q.

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A plausible mechanism for the formation of product 4 was shown in Scheme 3. Presumably, 2-benzylidenemalononitrile 5a could arise via Knoevenagel condensation of malononitrile 2 with the benzaldehyde 3a. Then Michael addition of enamine intermediate 6 (generated in situ from 1)¹⁸ to 5a affords 7a, which cyclizes to form 8a, which subsequently undergoes thermal dehydrogenation to give 4a. Overall, this domino green protocol leads to the generation of one C–C, one C–N and one N–H bonds.

Scheme 3 The plausible mechanism for the formation of 4-imino-2-aryl-4H-pyrido[2,1-a]isoquinoline-3-carbonitrile.

We presume that, minerals present in the tap water may help the formation of desire product (4). In order to identify the role of tap water, we perform the reaction with HPLC grade water and distilled water. But, there is no difference in the product formation in terms of yield and time. Similar results were obtained like tap water. Therefore, minerals present the tap water may not influence the reaction. However, we also analyzed the water purity by ICP-OES method, to find the content and amount of minerals present in the water (see ESI†).

All the newly synthesized products were screened for their photo physical studies. The photophysical properties of the products (4a–4q) such as absorption spectra (λ_max) and emission spectra (λ_em) were measured in chloroform/trifluoroacetic acid (99 : 1) and these results are summarized in Table 3. Fig. 3 and 4 show the absorption and fluorescence spectra of all the products (4a–4q), respectively (see ESI†).

Table 3 UV-Vis absorption data and fluorescence data of compounds 4a–4q in CF₃COOH/CHCl₃ (1 : 99)

Compound^a	λabs (nm)	ε × 10^5 (L mol^−1 cm^−1)	λfluo (nm)	Quantum yield^b
a All the compounds were measured in 1.0 × 10^−5 M concentration, at room temperature.b Luminescence quantum yields for selected compounds.
4a	327, 478, 505	0.35, 0.44, 0.41	541	—
4b	329, 478, 507	0.39, 0.41, 0.39	538	0.20
4c	340, 476, 504	0.49, 0.44, 0.41	535	0.18
4d	321, 485, 512	0.33, 0.32, 0.32	552	—
4e	326, 480, 509	0.28, 0.42, 0.39	544	0.20
4f	325, 479, 509	0.28, 0.45, 0.41	538	—
4g	328, 479, 508	0.32, 0.43, 0.41	540	—
4h	321, 481, 508	0.42, 0.38, 0.37	543	0.21
4i	327, 481, 509	0.33, 0.43, 0.41	541	—
4j	322, 476, 505	0.31, 0.47, 0.43	535	—
4k	350, 490, 521	0.25, 0.33, 0.37	550	0.18
4l	346, 488, 518	0.56, 0.46, 0.47	551	—
4m	323, 478, 508	0.32, 0.41, 0.38	538	—
4n	345, 479, 509	0.36, 0.36, 0.36	535	0.24
4o	348, 479, 509	0.34, 0.36, 0.36	540	—
4p	345, 480, 510	0.36, 0.41, 0.40	538	—
4q	350, 480, 510	0.25, 0.37, 0.37	538	0.20
Rhodamine B (standard)	—	—	—	0.31

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Fig. 3 UV-Vis spectra of compounds 4j, 4l–4p in chloroform/trifluoroacetic acid solution (1.0 × 10⁻⁵ M).

Fig. 4 Fluorescence spectra of compounds 4j, 4l–4p in chloroform/trifluoroacetic acid solution (1.0 × 10⁻⁵ M).

All the synthesized compounds showed strong absorptions, with the positions of maxima ranging from 504 to 521 nm. All the products displayed three absorption maxima, band I in the region of 321–350 nm, band II in the region of 476–490 nm and band III in the region of 504–521 nm.

From Fig. 4, it can be inferred that the products are fluorescent in solution. All of the compounds displayed almost similar fluorescence spectra with the positions of maxima in the range of 535–551 nm (see ESI Fig. 5 and 6†). A fluorescence excitation wavelength (λ_ext) of 505 nm was used for all the compounds (4a–4q). Since the steric and electronic effects of the substituted groups on the aromatic aldehydes have slight influence on the fluorescence properties, it can be inferred that the luminescence of the products is a direct result of their framework. Luminescence quantum yields for selected compounds are determined by using rhodamine B as a standard and the results are shown in Table 3.¹⁹

Conclusions

In summary, we have developed a domino one-pot three-component and catalyst-free protocol for the synthesis of novel 4-imino-2-aryl-4H-pyrido[2,1-a]isoquinoline-3-carbonitrile derivatives via Knoevenagel/Michael/cyclisation reactions of 1-methyl isoquinoline with malononitrile, aromatic aldehydes. UV-Vis and fluorescence spectra of these compounds 4a–4q were also examined. Further investigations on the biological activities of these compounds are currently underway in our laboratory.

Experimental section

General information

1-methyl isoquinoline, malononitrile, aromatic aldehyde and all solvents were purchased from Sigma Aldrich and Alpha Aesar company and used without further purification as received. All ¹H and ¹³C NMR spectra were recorded in CDCl₃ on Avance 300 or Avance 500 spectrometers. Chemical shifts (δ) are reported in parts per million (ppm) relative to residual CHCl₃ (¹H: δ 7.26 ppm, ¹³C: δ 77.00 ppm) as an internal reference. Coupling constants (J) are reported in Hertz (Hz). Peak multiplicity is indicated as follows: s-singlet, d-doublet, t-triplet, q-quartet, m-multiplet and dd-doublet of doublet. Melting points were measured on a BUCHI melting point machine. IR spectra were recorded on Thermo Nicolet FT/IR-5700 spectrometer. Mass spectra were recorded using Waters mass spectrometer. High resolution mass spectrums (HRMS) were recorded using Applied Bio-Sciences HRMS spectrometer at national center for mass spectroscopy-IICT. A 99 : 1 mixture of chloroform/trifluoroacetic acid was used for all experiments. All UV/Vis spectra were recorded using a Hitachi U-2910 spectrophotometer. All steady-state fluorescence spectra were recorded at room temperature by a Fluorolog-3 spectrofluorimeter (Horiba Jobin Yvon, USA).

General experimental procedure

A 5 mL RB flask containing 1-methyl isoquinoline (1) (1 mmol), malononitrile (2) (1 mmol), aromatic aldehyde (3) (1 mmol) water (2 mL) was placed in oil bath and refluxed for the appropriate time, at 100 °C (temperature monitored by a thermometer). The progress of reaction was monitored by TLC. After completion of the reaction, the flask was removed from the oil bath and cooled to room temperature. The solid was filtered and then washed with pet-ether (2 × 3 mL). The products were dried.

Acknowledgements

N. S. K and L. C. R thank the CSIR-India for award of a fellowship and Dr A. Kamal, Outstanding scientist and Head of MCP Division, for his support and encouragement. The authors thank CSIR-India for financial support as part of XII five year plan programme under title ACT (CSC-0301).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1063210. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5ra15948b

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