L-Proline as an efficient enantioinduction organo-catalyst in the solvent-free synthesis of pyrazolo[3,4-b]quinoline derivatives via one-pot multi-component reaction

Abstract

The role of L-proline as an efficient organo-catalyst for the three-component synthesis of pyrazoloquinolinones involving dimedone, 3-methyl-1H-pyrazol-5-amine and various aryl aldehydes under mild solvent-free condition is reported. Besides the several advantages offered by this method such as its generality, simplicity, high yields and environment friendly reaction, the most notable is the ability of the catalyst to influence asymmetric induction in the reaction. Interestingly, it was observed that in addition to being an efficient catalyst, L-proline also imparted enantioselectivity in the synthesised pyrazoloquinolinones derivatives.

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Introduction

One of the most significant approaches to synthetic efficiency in organic synthesis is based on the use of methods that are able to generate several bonds in a single operation¹ which combine three or more substrates, either simultaneously leading to domino processes² or through sequential addition of one or more reactants without isolating the intermediate species or changing the solvent.³ The creation of multiple bonds in a one-pot multi-component coupling reaction guarantees a sustainable synthetic route towards new molecular discovery. The application of microwave (MW) irradiation in organic synthesis has become increasingly important as it facilitates better thermal management of chemical reactions resulting in faster results and increased product yield.⁴

The application of microwave assisted MCRs toward the synthesis of pyrazoloquinolinones constitutes an important and attractive synthetic alternative in organic synthesis since the pyrazole ring constitutes a key structural design in numerous biologically active compounds⁵ of which sildinafil, celebrex, analginum, BAY 41-2272, WYE 354 (Fig. 1) etc. are noteworthy.⁶ Pyrazolo[3,4-b]quinoline derivatives in particular exhibit potential antimalarial,⁷ antiviral,⁸ parasiticidal,⁹ and bactericidal¹⁰ properties. These compounds have been widely studied for their enzyme inhibiting activity¹¹ and are also acknowledged for antitumor, hypotensive, and vasodilation activities.¹²

Fig. 1 Biologically important pyrazoloquinolinone.

A number of methods¹³ have been reported in the literature for the synthesis of pyrazoloquinolinone derivatives. The most commonly used method involves the condensation of 1,3-dicarbonyl compounds with an aldehyde and amino pyrazole and its derivatives in organic solvent such as EtOH.¹⁴ Pyrazoloquinolinones have also been prepared using triethyl amine under MW irradiation,^6b microwave-assisted continuous flow organic synthesis (MACOS) in high boiling solvents.¹⁵ Recently ionic liquids [bmim]Br,¹⁶ polyethylene glycol (PEG-400),^6c cellulose sulfuric acid¹⁷ and nanoparticles¹⁸ have been used for the synthesis of pyrazoloquinolinone derivatives.

Regardless of the many merits reported by these methods however, they are also plagued by limitations like poor yields, difficult work-up and effluent pollution. Moreover according to our literature survey there is no reported method for enantioselective synthesis of pyrazoloquinolinones. L-Proline is considered as a bifunctional catalyst and its high stereoselectivity is well known. It is employed as a chiral modifier in heterogenous catalysis in hydrogenations and as an effective organocatalyst in many asymmetric transformations such as Mannich, Michael and aldol reactions.¹⁹ Polysubstituted heterocyclic ortho-quinones,²⁰ pyridines,²¹ acridine derivatives,²² pyrans and thiopyrans,²³ quinolines²⁴ and pyrano[2,3-c]pyrazole derivatives²⁵ have been successfully synthesised employing L-proline organo-catalyst. Besides being commercially available and inexpensive, L-proline has the added advantage of being highly soluble in water and in many common organic solvents.²⁶

Thus as part of our research aimed at development of synthetic methodologies using environmentally benign catalysts through MCRs, we wish to report herein a metal-free protocol for the synthesis of substituted pyrazoloquinolinones under solvent-free reaction condition via a three-component condensation of dimedone, 3-methyl-1H-pyrazol-5-amine and substituted aldehydes in presence of L-proline as an organo-catalyst to afford the required products in excellent yields, accompanied by moderate to good enantioselectivity (Scheme 1).

Scheme 1 Synthesis of substituted pyrazoloquinolinones catalyzed by L-proline.

Results and discussion

To develop L-proline catalyse stereoselective MCR protocol, we selected the model reaction of 4-chloro benzaldehyde 1 (2.1 mmol), dimedone 2 (2.0 mmol), 3-methyl-1H-pyrazol-5-amine 3 (2.0 mmol) in the presence of a catalytic amount of L-proline. It was observed that only trace amount of the product was formed under prolonged stirring at room temperature. Even at elevated temperature, the desired product was obtained in low yield along with unreacted starting materials. This result prompted us to explore the ideal reaction condition to get maximum product yield. Thus, when the same reaction was carried out under microwave irradiation for 5 min at 110 °C in presence of 5 mol% L-proline, pyrazoloquinolinone (4a) was formed at a much enhanced yield (76%). When the reaction time and amount of L-proline was increased to 15 min and 10 mol% respectively, it led to a significant improvement in the yield of the compound 4a (92% isolated yield) (Table 1). During further optimization study, it was observed that 100–110 °C is the ideal temperature for the reaction and beyond 130 °C the reaction resulted in undesired byproducts. TLC of a test reaction carried out in the absence of the catalyst did not indicate any product formation. The structure of the desired product was confirmed by ¹H, ¹³C NMR, LC-MS, and IR analyses. The enantioselectivity was confirmed by HPLC analysis of the product using chiral ADV column with 20% isopropanol in hexane at a flow rate of 0.5 mL min⁻¹ which showed two peaks of unequal intensity at retention time t_R = 5.722, t_R = 6.353 with area 7.58% and 92.42% respectively, indicating excellent enantioselectivity having 85% enantiomeric excess (% ee). Evidently, an efficient external asymmetric induction promoted by L-proline resulted in the enantioselective formation of the products.

Table 1 Optimization of the reaction conditions for product 4a

Product	Reaction conditions (MW)	Yield^a (%)
a Isolated yields.
4a	No catalyst, 15 min	0
4a	L-Proline (5 mol%), 5 min, 75 °C	52
4a	L-Proline (5 mol%), 5 min, 110 °C	76
4a	L-Proline (10 mol%), 10 min, 110 °C	80
4a	L-Proline (10 mol%), 15 min, 110 °C	92

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To check the generality of the method, the reaction was carried out using a number of substituted aromatic aldehydes having diverse substituents. In each case the reaction proceeded smoothly to give the desired product in moderate to excellent yields, while the presence of electron withdrawing or releasing substituent in the ortho-, meta- and para-positions does not appear to have any effect on the product yield. All the pyrazoloquinolinone compounds (4a–4u) summarized in Table 2, obtained after simple work-up and purification by column chromatography were characterised by ¹H, ¹³C NMR, LC-MS, and IR analyses.

Table 2 L-Proline catalyzed multi-component reaction for the preparation of pyrazoloquinolinones compound

Entry	Substrate (R)	Product (4)^b	Time (min)	Yield^a/(%)	er^c
a Isolated yields.b Products were characterized by ^1H & ^13C NMR mass and IR analyses, absolute configuration is not determined.c Enantiomeric ratio (er) was determined by chiral HPLC analysis.
a			15	92	08 : 92
b			15	85	29 : 71
c			15	90	07 : 93
d			15	60	15 : 85
e			15	90	28 : 72
f			15	85	0.70 : 99.30
g			15	80	02 : 98
h			15	80	01 : 99
i			15	75	01 : 99
j			15	80	01 : 99
k			15	80	09 : 91
l			15	75	01 : 99
m			15	70	01 : 99
n			15	70	04 : 96
o			15	80	0.71 : 99.29
p			15	85	2 : 98
q			15	80	09 : 91
r			15	90	0.57 : 99.43
s			15	80	02 : 98
t			15	82	02 : 98
u			15	87	0.78 : 99.22

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The HPLC analysis of the compounds synthesized employing Chiral ADV column with isopropanol and hexane as mobile phase with a flow rate of 0.5 mL min⁻¹ provided excellent result showing the enantioselectivity upto 99% ee (compounds 4f, 4o, 4r, 4u (Table 2)). For the rest of the compounds enantiomeric excess was found to be in the range of to 42% ee to 98% ee. Ironically, 2-Cl and 4-F (4b and 4e) substituted compounds showed only 42% ee and 44% ee, respectively, inspite of giving excellent yield. It is important to note that the previous methods reported in the literature do not show any asymmetric induction (Table 3).

Table 3 Comparison of the syntheses of various pyrazolo pyrido[2,3-d]pyrimidine derivatives in the literature with present methodology

Sl. no.	Solvent	Condition/temperature	Reaction time	ee^a	Reference
a ee – enantiomeric excess.
1	EtOH	Et3N MW/150 °C	15 min	—	6b
2	Solvent-free	PEG-400 heat/100–110 °C	240 min	—	6c
3	Water	Et3N MW/170 °C	10 min	—	13a
4	DMF	Reflux	15–20 min	—	13b
5	Water	SDS heat/90 °C	360–1020 min	—	13c
6	EtOH	Et3N heat/150 °C	30 min	—	13d
7	EtOH	Reflux	20–30 min	—	14
8	DMSO	MACOS	29 min	—	15
9	Solvent-free	[bmim]Br heat/90 °C	90–150 min	—	16
10	Solvent-free	Cellulose–OSO3 heat/110 °C	30–45 min	—	17
11	ACN	Ni Nps reflux	10 min	—	18
12	Solvent-free	L-Proline MW/110 °C	15 min	>98%	Our method

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¹H NMR and XRD analysis of the isolated products indicated the formation of only one isomer in all cases rather than pyrazoloquinolinones and isomeric pyrazoloquinolinones as reported elsewhere in the literature.^6a In a typical example, the ¹H NMR data of compound 4j are consistent with the given structure showing two singlet peaks at 0.93 ppm and 0.99 ppm which indicates the presence of two methyl groups in the cyclohexenone ring of the product. The methylene group in the cyclohexenone also shows the presence of diastereotopic protons. A sharp singlet was also observed at 9.27 ppm which can be correlated with the pyrimidine –NH group. No peak was observed for pyrazole methine group (–CH) indicating the absence of the isomeric product 4j′ (Fig. 2), thus showing the formation of only one major product 4j. Furthermore, the crystal of 4j was obtained by careful recrystallization from a solution of EtOH. The structure of compound was unambiguously confirmed by X-ray diffraction analysis. Fig. 3 shows the ORTEP diagram of compound 4j with probability ellipsoids representation. Thus, the crystal structure 4j suggests that the product is a tautomer of the one found in literature.²⁷

Fig. 2 Confirmation of regioselectivity.

Fig. 3 ORTEP image of 4j. (CCDC 1410800†).

The plausible mechanism is depicted in Scheme 2. The reaction presumably proceeds through the initial activation of the aldehyde by L-proline to form an iminium complex.^21b Nucleophilic attack of the enolized dimedone at the electrophilic carbon centre of the iminium complex followed by intermolecular cyclization with 3-methyl-1H-pyrazol-5-amine, dehydration and tautomerisation afforded the final product 4.²⁸

Scheme 2 Plausible mechanism for the formation of substituted pyrazolo derivatives catalyzed by L-proline.

Experimental

Materials and methods

All commercially available chemicals and reagents were purchased from Sigma Aldrich, Merck and were used without further purification. Purity of the products were confirmed by infrared (IR), ¹H NMR, ¹³C NMR and mass spectra. IR spectra were recorded in KBr pellets on a Perkin Elmer Spectrum 400 FTIR instrument, and the frequencies are expressed in cm⁻¹. ¹H NMR and ¹³C NMR spectra were recorded on Bruker Avance II-400 spectrometer in DMSO-d₆ (chemical shifts in δ with TMS as internal standard). Mass spectral data were obtained with a JEOL D-300 (ESI) mass spectrometer. All reactions were monitored by thin layer chromatography (TLC) using precoated aluminum sheets (silica gel 60 F₂₅₄ 0.2 mm thickness). HPLC analyses were performed on Waters M515 series equipped with a Agela chiral ADV analytical column (5 μm, 1000 Å, 4.6 × 250 mm). UV-detection at 254 nm was used to analyse the data. The analytical separation was carried out at 25 °C using a mobile phase (A) of isopropanol and (B) of n-hexane as eluent, the all solvents were HPLC-grade. TFA was of analytical grade. The flow rate applied was 0.5 mL min⁻¹.

X-ray crystallography

The X-ray data of 4j was collected at 293 K with a Agilent Xcalibur (Eos, Gemini) diffractometer using graphite-monochromated Mo-Kα radiation (λ = 0.71073 Å). The data was collected and reduced in CrysAlis PRO (Agilent, 2011) software and cell refinement was done in CrysAlis PRO software. The absorption was corrected by SCALE3 ABSPACK multi-scan method in CrysAlis Pro. The structures were solved by direct methods using the program SHELXS-2013 and refined by full matrix least-squares calculations (F²) by using the SHELXL-2013 software. All non-H atoms were refined anisotropically against F² for all reflections. All hydrogen atoms were placed at their calculated positions and refined isotropically. ORTEP image of 4j is shown in Fig. 2.

General procedure for the synthesis of pyrazoloquinolinones

A pre-stirred mixture of aldehyde 1 (1.1 eq.), dimedone 2 (1.1 eq.) and 3-methyl-1H-pyrazol-5-amine 3 (1 eq.) was irradiated in a Chem Discover microwave reactor at 110 °C, for 15 min, in the presence of L-proline (0.5 eq.). The completion of the reaction was monitored by TLC. After the completion of the reaction, it was worked up using ethyl acetate, washed with brine. The organic layer was dried over anhydrous Na₂SO₄ and concentrated in vacuo to give the crude mass. The crude compound was then purified by silica gel column chromatography to afford the pyrazoloquinolinones 4 in pure form.

Conclusions

In summary, we have established a hitherto unreported enantioselective method for the synthesis of pyrazoloquinolinones following an environmentally friendly protocol using L-proline as a catalyst. The method is simple involving short reaction time, simple aqueous work-up and purification while affording excellent yields with good to excellent asymmetric induction in the products. Due to its operational simplicity, this facile method is expected to have wider application for the preparation of pyrazoloquinolinone derivatives.

Acknowledgements

The authors thank DST-PURSE and Dr Snehadrinarayan Khatua for the Crystallographic analysis. The authors also thank SAIF, NEHU for providing analytical facilities. D. B. thanks the UGC and for the financial assistance and B. M. acknowledged financial assistance from SERB, DST (SB/EMEQ-006/2013).

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1410800. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra22429f

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