INTRODUCTION:

Due to environmental concerns, safety considerations, reduction of costs, and the simplicity of the process, reactions using green solvents have drawn great attention in recent years. Glycerol has been a well-known renewable chemical for centuries, its commercial relevance has increased considerably in the last few years because of its physical and chemical properties, such as polarity, low toxicity, biodegradability, high boiling point and ready availability from renewable feedstocks, prompted us to extend its use as a green solvent in organic synthesis. These include Pd-catalyzed Heck and Suzuki cross-couplings, base and acid-promoted condensations, catalytic hydrogenation, and asymmetrical hydrogenation^1-3. The purpose of this study is to explore the scope of glycerol as an alternative green reaction medium. In this sense and due to our interest on green protocols correlated to the heterocyclic chemistry, we describe herein the use of glycerol as a green solvent for the preparation of quinolines and pyrazoles via multicomponent reaction. Quinolines and Pyrazoles are esteemed as luminescent materials, important scaffold natural products, and medicines. A number of methods have been reported for the synthesis of substituted quinolines.

However, most of the existing means suffer from the limited availability of substrates or require multistep procedures^4-10. The most common method for their preparation relies on the condensation of an aryl amine, aldehyde and alkyne. These routes involved the use of catalyst like Yb(Pfb)₃, AgOTf, molecular iodine, Ce(OTf)₃, Fe(acac)₃, FeCl₃ , Yb(OTf)₃^11-23. Most of these existing methodologies suffer from long reaction times,low yields, tedious work-up, formation of by products, and the use of expensive metal catalysts and toxic organic solvents, which restrict their use under the facet of environmentally benign processes.

MATERIAL AND METHODS:

General Procedure for synthesis of 2,4-diphenyl quinoline (1a-1h):

A mixture of aniline (1.00g, 10mmol), benzaldehyde (1.4g, 10mmol), and phenylacetylene (1.1g, 10mmol) was stirred at room temperature in glycerol (50mL) and 2-3 drops of acetic acid was added. The reaction mixture was heated at 90^oC. The progress of reaction was monitored by TLC, after completion of the reaction, the reaction mixture was diluted with water and further extracted with ethyl acetate (3 X 20mL). Organic layer washed with water and dried over anhydrous NaSO₄ and concentrated under reduced pressure to give crude product. The product was then purified using silica gel column chromatography (EtOAc–Hexane: 1:9)

General procedure for the synthesis of 1, 3, 5-Triphenyl pyrazole derivatives (2a-2d):

Chalcone derivatives (1mmol), phenyl hydrazine (1 mmol), were added to a 25-mL round bottom flaskcontaining 5-6mL of glycerol. Add 2-3 drops of acetic acid in reaction mixture. The mixture was thenstirred at 90°C for a certain period of time to ensure complete reaction (monitored by TLC). Atcompletion, the reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 × 10mL). After drying, the combined ethyl acetate layers were concentrated under reduced pressure and theresulting residue was charged on a silica gel column and eluted with a mixture of ethyl acetate/n-hexane(1:9) to obtain the product.

Table 1: Synthesis of 2, 4-Diphenylquinoline derivatives.^a

Entry

R₁

R₂

Product

% Yield^b

NO₂

OCH₃

NO₂

^aReaction conditions: substituted aniline (1.0 mmol), substituted aldehyde (1.0 mmol), phenylacetylene (1.0 mmol) in glycerol (5.0 mL) in presence of acetic acid (0.01 mmol). ^bIsolated yield after column chromatography and the structure were confirmed by comparison of IR, 1H NMR and M.P with literature value

Table 2: Synthesis of 1,3,5-triphenylpyrazole derivatives.^a

Entry

Product

% Yield^b

NO₂

OCH₃

^a Reaction conditions: Chalcones (1.0 mmol), phenyl hydrazine (1.0 mmol) in Glycerol (5.0 mL) and catalytical acetic acid at 90^oC for 4hrs. ^bIsolated Yield after column chromatography and the structures were confirmed by comparison of IR, ¹H NMR and M.P. with literature value.

Analytical Characterization:

All chemicals were bought from Sigma Aldrich, S. D. Fine Chemicals, Lancaster (Alfa-Aesar), andcommercialsuppliers. Commercially available reagents were used without further purification. Allreaction mixtures were stirred magnetically and were monitored by thin-layer chromatography usingMerck silica gel 60 F-254 aluminum sheets, visualized with UV light, and then developed using iodine.Products were purified by column chromatography on a silica gel (100–200) mesh with distilled solvents.Melting points are uncorrected. 1H NMR (400 MHz) and 13C NMR (125 MHz) spectra were recorded onan NMR spectrometer. Deuterated chloroform and deuterated DMSO were used as the solvent and chemicalshifts are reported in parts per million (δ) relative to tetramethylsilane as an internal standard.

Analytical Data:

2, 4-Diphenylquinoline (1a):

Pale yellow solid, yield 83%, m.p.110°C [Lit.m.p.109-112°C]; ¹H NMR (400 MHz, CDCl₃) δ: 8.28－8.19 (m, 3H), 7.93－7.72 (m, 4H), 7.56－7.50 (m, 8H); ¹³C NMR (125.0 MHz, CDCl₃) δ: 156.9, 153.5, 149.3, 148.8,139.6, 138.4, 130.1, 129.6, 129.4, 128.9, 128.6, 128.4, 127.6, 126.4, 125.7, 119.4, 115.1.

2-(4-Chlorophenyl)-4-phenylquinoline (1b):

White solid, yield 85% m.p.106°C [Lit.m.p.104-105.6°C]^1,3; ¹H NMR (400 MHz, CDCl₃) δ: 8.24－8.15 (m, 3H), 7.89 (s, 2H), 7.79－7.75 (m, 3H), 7.56－7.49 (m, 6H); ¹³C NMR (125.0 MHz, CDCl₃) δ: 155.6, 149.5, 148.8, 138.3, 138.0, 135.6, 130.1, 129.7, 129.6, 129.0, 128.9, 128.7, 128.5, 126.6, 125.8, 125.7.

2-(4-Nitrophenyl)-4-phenylquinoline (1c):

White solid, yield 82%, m.p.162°C [Lit.m.p.160-165°C]^1,4; ¹H NMR (400 MHz, CDCl₃) δ: 8.40(s, 3H), 8.27 (d, J＝7.8 Hz, 2H), 7.95 (d, J＝7.74 Hz, 1H), 7.87 (s, 1H), 7.80 (s, 2H), 7.57 (s, 5H); ¹³C NMR (125.0 MHz, CDCl₃) δ: 154.1, 149.9, 148.8, 148.4, 145.5,137.9, 130.3, 130.1, 129.5, 128.7, 128.4, 127.3, 126.2,

125.8, 124.0, 119.1.

2-(4-Methoxyphenyl)-4-phenylquinoline (1d):

Yellow solid, yield 87%, m.p.76°C [Lit.m.p.75-77°C]; ¹H NMR (400 MHz, CDCl₃) δ: 8.24－8.17 (m, 3H), 7.88 (d, J＝8.25 Hz, 1H), 7.78－7.69 (m, 2H), 7.56－7.39 (m, 5H), 7.20 (d, J＝7.92 Hz, 1H), 7.06 (d, J＝8.37 Hz, 2H), 3.90 (s, 3H); ¹³C NMR (125.0 MHz, CDCl₃) δ: 160.7, 156.5, 149.1, 148.8, 138.5, 132.2, 129.9, 129.6, 129.5, 128.9, 128.6, 128.4, 126.0,125.6, 125.5, 118.9, 114.2, 55.4.

6-Chloro-2, 4-diphenylquinoline (1e):

White solid, yield 82%, m.p. 124°C [lit.m.p. 124.4-125.3 °C]; ¹H NMR (400 MHz, CDCl₃) δ: 8.11–8.15 (m, 3H), 7.82 (d, 1H, J = 2.2 Hz), 7.76 (s, 1H), 7.59–7.60 (m, 2H), and 7.45–7.50 (m, 7H);¹³C NMR (125 MHz, Chloroform-d): δ 157.18, 148.54, 147.31, 139.29, 137.82, 132.29, 131.81, 130.54, 129.69, 129.54, 129.00, 128.91, 128.80, 127.62, 126.57, 124.57, 120.14.

6-Chloro-2-(4-chlorophenyl)-4-phenylquinoline(1f):

Yellow solid, yield 84%, m.p. 158°C [lit.m.p.157.9–159.3°C]; ¹H NMR (400 MHz, CDCl₃) δ: 8.26 (d, 1H, J = 8.4 Hz), 8.15 (d, 2H, J = 8 Hz), 7.87 (d, 1H, J = 2.2 Hz),7.80 (s, 1H), 7.68–7.71 (m, 1H), and 7.50–7.59 (m, 7H);¹³C NMR (125 MHz, Chloroform-d): δ 155.80, 148.78, 147.24, 137.65, 136.04, 131.75, 130.73, 129.49, 129.17, 128.94, 128.86, 126.52, 124.61, 119.69.

6-Chloro-2-(4-nitrophenyl)-4-phenylquinoline (1g):

White solid, yield 80%, m.p.218°C [lit.m.p.218–220°C]; ¹H NMR (400 MHz, CDCl₃) δ: 8.34–8.38 (m, 4H), 8.20 (d, 1H,J = 8.0 Hz), 7.90 (d, 1H, J = 2.4 Hz), 7.88 (s, 1H), 7.23 (dd,1H, J1 = 9.2 Hz, J2 = 2.4 Hz), and 7.54–7.60 (m, 5H).

1, 3, 5-Triphenyl pyrazole (2a):

Light yellow solid, yield 84%; m.p.138°C [Lit.⁷m.p.139-140°C]; ¹H-NMR(400 MHz, CDCl₃, δ ppm): 6.84(1H, s),7.26-7.44(13H, m, Ar. H), 7.94 (2H, d, J=6.8Hz); ¹³C NMR (CDCl3, 125 MHz, δ ppm): 152.7, 144.4, 139.8, 133.2, 130.4, 129.4, 127.7, 128.5, 127.9, 127.6, 128.4, 122.7, 120.1, 105.8.

5-(4^’-chlorophenyl)-1, 3-diphenyl pyrazole (2b):

Pale yellow solid, Yield 84%; m.p.114°C[Lit.m.p.114-115°C]; ¹H-NMR (400 MHz, CDCl3, δ ppm): 6.82 (1H, s), 7.21-7.50(12H, m), 7.92 (2H, d, J=6.0Hz); ¹³C NMR (CDCl₃, 125MHz, δ ppm): 152.2, 144.2, 139.7, 133.3, 132.6, 129.8, 129.3, 128.7, 128.6, 128.1, 127.5, 126.8, 125.3, 120.4, 106.2.

5-(-4’-nitrophenyl)-1, 3-diphenyl pyrazole (2c):

Yellow solid,Yield 85%; m.p.142°C [Lit.⁷m.p.142-144°C]; ¹H-NMR (400 MHz, CDCl3, δ ppm): 6.97 (1H, s), 7.15 (2H, d, J=9.0Hz), 7.28-7.74 (10H, m), 8.10 (2H, d, J=6.0Hz);¹³C NMR (CDCl₃, 125 MHz, δ ppm): 153.7, 148.5,144.7, 139.7, 133.8, 131.7, 129.8, 129.4, 128.6, 128.1, 127.5, 126.7, 124.3, 121.6, 106.5.

5-(-4’-methoxyphenyl)-1, 3-diphenyl pyrazole (2d):

White Solid, Yield 89%; m.p. 78°C[Lit.⁷m.p.79-80°C]; ¹H-NMR (400 MHz, CDCl₃, δ ppm): 3.85(3H, s, -OCH₃), 6.65 (1H, s), 6.88 (2H, d, J=9.0Hz), 7.20-7.46(10H, m), 8.03 (2H, d, J=6.0Hz);¹³C NMR (CDCl3, 125 MHz, δ ppm): 160.5, 153.1, 143.1, 139.4, 133.8, 131.7, 130.2, 129.4, 128.8, 128.5, 127.1, 126.6, 125.6, 120.3, 114.6, 106.2, 55.8.

RESULT AND DISCUSSION:

During the course of our efforts directed toward the development of glycerol as a green solvent in organictransformations, ²⁴ we found that treatment of benzaldehyde, aniline, with phenylacetylene in the presence of glycerol at room temperature gave 2, 4-diphenylquinoline in lower yields. This reaction would proceed apparently through a tandem condensation reaction with only water as the waste product (Scheme 1).

Scheme 1: Synthesis of 2, 4-diphenylquinoline

There was no increase in yield of desired product was observed even after long reaction time as well as at higher temperature. The efforts were put to increase the yield of the reaction and it was observed that the used of catalytic amount of acid increases the yield of product. Thus, to optimize the reaction conditions, reactions were carried out in different acid as catalyst and results are summarized in Table 3.

Table 3: Optimization of the reaction conditions ^a

Entry	Catalyst	Temp ^oC	Time (hr)	Yield (%)^b
1	Acetic acid	rt	4	30
2	Acetic acid	rt	8	40
3	Acetic acid	70	8	60
4	Acetic acid	90	8	82
5	Acetic acid	100	8	80
6	Acetic acid	90	4	83
7	Acetic acid	90	3	70
8	HCl	90	4	40
9	H₂SO₄	90	4	42
10	Molecular Sives	90	4	41
11	Molecular Sives	90	8	58

^aReaction conditions: Aniline (1.0 mmol), benzaldehyde (1.0 mmol), phenylacetylene (1.0 mmol) in glycerol (5.0 ml), catalytic amount of acid. ^bIsolated yield.

The desired 2,4-diphenylquinoline was obtained in good yield within 4h in presence of acetic acid at 90^oC (Table 1, entry 6). Under this reaction condition, verities of benzaldehydes and anilines were condensed with phenylacetylene and the results are summarised in Table 1.As can be seen from Table 1 most of the substrates afforded good yields of the corresponding Quinolines. In general, the aromatic aldehydes containing an electron-donating substituent react faster giving better yield as compared to the aromatic aldehydes containing an electron-withdrawing substituent. It was further observed that under this reaction condition, Chalcone and phenylhydrazine successfully condense and provide a new route for the synthesis of the corresponding triphenyl pyrazole. To evaluate the use of this procedure, a variety of substituted chalcone were condensed with phenylhydrazine and results are reported in Table 2.Based on the literature and experimental details, we proposed a plausible reaction pathway (Scheme 2). When aniline reacts with the benzaldehyde in the presence of base it forms the imine intermediate A (Schiff's base). Hydroxyl group of glycerol act as a base and takes the proton of the acetylene group of phenylacetylene to form intermediate B. Intermediate B act as a nucleophile and attack on imine group of intermediate A to form intermediate C in the presence of acid. Further intermediate C undergoes intramolecular cyclization by removal of the water molecule, and which further undergoes aromatization to give 2, 4-biphenylquinoline.

Scheme 2: Plausible mechanism

CONCLUSION:

In summary, we have described an efficient protocol for preparing quinoline and pyrazole derivatives using glycerol as a solvent. The advantages of the present method lie in using economic and environmentally benevolent glycerol as a solvent, no use of a costly catalyst, mild reaction conditions and good yields.

ACKNOWLEDGEMENT:

ARP and PKB thank BARTI and DST Inspire, for providing financial support.

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

REFERENCES:

1. Gu Y. Jérôme F. Glycerol as a sustainable solvent for green chemistry. 2010; Green Chemistry, 12(7), 1127–1138. https://doi.org/10.1039/C001628D

2. PagliaroM.Rossi M. The Future of Glycerol. The Royal Society of Chemistry. 2010.https://doi.org/10.1039/9781849731089

3. Díaz-Álvarez AE. Francos J. Lastra-Barreira B. Crochet P.Cadierno V. Glycerol and derived solvents: new sustainable reaction media for organic synthesis. 2011; Chemical Communications,47(22), 6208–6227. https://doi.org/10.1039/C1CC10620A

4. Kuninobu Y. Inoue Y.Takai K. Copper(I)- And gold(I)-catalyzed synthesis of 2,4-disubstituted quinoline derivatives from N-Aryl-2-propylamine. 2007; Chemistry Letters, 36(12), 1422–1423. https://doi.org/10.1246/cl.2007.1422

5. Ghorai J. Reddy ACS.Anbarasan P.Divergent Functionalization of N-Alkyl-2-alkenylanilines: Efficient Synthesis of Substituted Indoles and Quinolines. 2018; Chemistry - An Asian Journal, 13(17), 2499–2504. https://doi.org/10.1002/asia.201800441

6. ZhangX. Liu B. Shu X. Gao Y. Lv H. Zhu J. Silver-mediated C-H activation: Oxidative coupling/cyclization of N -arylimines and alkynes for the synthesis of quinolines. 2012; Journal of Organic Chemistry, 77(1), 501–510. https://doi.org/10.1021/jo202087j

7. Ou W.Huang PQ. Amides as surrogates of aldehydes for C-C bond formation: amide-based direct Knoevenagel-type condensation reaction and related reactions. 2020; Science China Chemistry, 63(1), 11–15. https://doi.org/10.1007/s11426-019-9586-3

8. XuX. Yang Y. Zhang X. Yi W.Direct Synthesis of Quinolines via Co(III)-Catalyzed and DMSO-Involved C–H Activation/Cyclization of Anilines with Alkynes. 2018; Organic Letters, 20(3), 566–569. https://doi.org/10.1021/acs.orglett.7b03673

9. LiY. ZhangQ. Xu X. ZhangX. YangY.YiW. One-pot synthesis of 2,4-disubstituted quinolines via silver-catalyzed three-component cascade annulation of amines, alkyne esters, and terminal alkynes. 2019; Tetrahedron Letters, 60(14), 965–970. https://doi.org/https://doi.org/10.1016/j.tetlet.2019.03.003

10. Wang XS. Zhou J. YinMY.Yang K. Tu SJ. Efficient and Highly Selective Method for the Synthesis of Benzo(naphtho)quinoline Derivatives Catalyzed by Iodine. 2010; Journal of Combinatorial Chemistry, 12(2), 266–269. https://doi.org/10.1021/cc900165j

11. ChenS. Li L. Zhao H. Li, B.Ce(OTf)3-catalyzed multicomponent domino cyclization–aromatization of ferrocenylacetylene, aldehydes, and amines: a straightforward synthesis of ferrocene-containing quinolines. 2013; Tetrahedron, 69(30), 6223–6229. https://doi.org/https://doi.org/10.1016/j.tet.2013.05.026

12. Rao DK. Tiwari R. Chhikara B. Shirazi A. Parang K. Kumar A. Copper Triflate-Mediated Synthesis of 1,3,5-triarylpyrazoles in [bmim][PF6] Ionic Liquid and Evaluation of Their Anticancer Activities. 2013; RSC Advances, 3, 15396–15403. https://doi.org/10.1039/C3RA41830H

13. Patil SS. PatilSV. Bobade VD. Synthesis of aminoindolizine and quinoline derivatives via Fe(acac)TBAOH-catalyzed sequential cross-coupling-cycloisomerization reactions. 2011;Synlett, (16), 2379–2383. https://doi.org/10.1055/s-0030-1260305

14. BachhavHM. Bhagat, SB.TelvekarVN. An efficient protocol for the synthesis of quinoxaline, benzoxazole and benzimidazole derivatives using glycerol as a green solvent. 2011; Tetrahedron Letters, 52(43), 5697–5701. https://doi.org/https://doi.org/10.1016/j.tetlet.2011.08.105

15. ZhangX. Fan X. Wang J. LiY.A Novel Preparation of 4-Phenylquinoline Derivatives in Ionic Liquids. 2004; Journal of the Chinese Chemical Society, 51(6), 1339–1342. https://doi.org/https://doi.org/10.1002/jccs.200400194

16. Das S. Maiti D. De SarkarS. Synthesis of PolysubstitutedQuinolines from α-2-Aminoaryl Alcohols Via Nickel-CatalyzedDehydrogenative Coupling. 2018; Journal of Organic Chemistry, 83(4), 2309–2316. https://doi.org/10.1021/acs.joc.7b03198

17. Tufail F. Saquib M. Singh S. Tiwari J. Singh M. Singh J. Bioorganopromoted green Friedländer synthesis: a versatile new malic acid promoted a solvent free approach to multisubstitutedquinolines. 2017; New Journal of Chemistry, 41(4), 1618–1624. https://doi.org/10.1039/C6NJ03907C

18. SteinAL. RosárioAR.ZeniG. Synthesis of 3-Organoseleno-Substituted Quinolines through Cyclization of 2--Amino¬phenylprop-1-yn-3-ols Promoted by Iron(III) Chloride with DiorganylDiselenides. 2015;European Journal of Organic Chemistry, 2015(25), 5640–5648. https://doi.org/https://doi.org/10.1002/ejoc.201500766

19. WangJ. Fan X. Zhang X. Han L. Green preparation of quinoline derivatives through FeCl3•6H2O catalyzed Friedlander reaction in ionic liquids. 2004; Canadian Journal of Chemistry, 82(7), 1192–1196. https://doi.org/10.1139/v04-066

20. KumarA. Rao VK. Microwave-Assisted and Yb(OTf)3-Promoted One-Pot Multicomponent Synthesis of Substituted Quinolines in Ionic Liquid. 2011; Synlett, 15, 2157-2162.http://dx.doi.org/10.1055/s-0030-1261200.

Received on 19.03.2021 Modified on 23.04.2022

Research J. Pharm. and Tech 2023; 16(4):1622-1626.

DOI: 10.52711/0974-360X.2023.00265