An efficient protocol for synthesis of novel polyheterocyclic chromeno pyrimido[1,2-b]indazolone derivatives using [Et3NH][HSO4] as a reusable catalyst under solvent-free conditions

Tetrahedron Letters xxx (xxxx) xxx

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An efficient protocol for synthesis of novel polyheterocyclic chromeno pyrimido[1,2-b]indazolone derivatives using [Et3NH][HSO4] as a reusable catalyst under solvent-free conditions Amol Maruti Jadhav, Sandip Gangadhar Balwe, Yeon Tae Jeong ⇑ Department of Image Science and Engineering, Pukyong National University, Busan 608-737, Republic of Korea

a r t i c l e

i n f o

Article history: Received 6 August 2019 Revised 1 October 2019 Accepted 2 October 2019 Available online xxxx Keywords: Multicomponent reaction Chromeno pyrimido[1,2-b]indazolone Polyheterocycles One-pot synthesis

a b s t r a c t A convenient and highly efficient method for the synthesis of novel polyheterocyclic chromeno pyrimido [1,2-b]indazolone derivatives via a three-component condensation of 1H-indazol-3-amine, aldehydes and 4-hydroxycoumarin catalyzed by Bronsted acid ionic liquid [Et3NH][HSO4] under solvent-free reaction conditions is presented. This ionic liquid is air and water stable and easy to prepare from amine and acid. The main advantages of this protocol includes short reaction time, excellent yield, easy work-up, operational simplicity, a wide range of functional group tolerance and column chromatography-free method. The catalyst can be recovered and reused for at least four runs without any significant impact on the product yields. Ó 2019 Published by Elsevier Ltd.

Introduction Multicomponent reactions (MCRs) are well-established methodologies to build a new product, which contains almost all portions of substrates when more than two reactants combine in a sequential manner. MCRs have their inherent advantages of atom economy, short reaction time, operational simplicity, structural diversity to get the goal of an ideal organic synthesis [1,2]. Heterocycles containing nitrogen atom are abundant in nature and exhibit diverse and important biological properties [3]. Nitrogen-bridged poly-heterocycles are frequently found in natural products and pharmaceutical agents. Among them, chromeno pyrimido[1,2-b]indazolone are an important class of nitrogenfused poly-heterocycles and these structural units are found in numerous pharmaceutically important scaffolds with promising biological activities [4]. Pyrimidine fused with an indazole moiety, is an important biologically active nitrogen containing heterocycle [5]. Pyrimido[1,2-b]indazole is an active protein kinase inhibitor [6] that can be used to treat cancer cell proliferation [7], viral infections [8], Alzheimer’s disease [9], neurodegenerative disorders, and auto-immune diseases [7]. Several marketed drugs constitute the fused-pyrimidine fragment in the main core structure, for instance, divaplon, taniplon, and fasiplon which is used as anxiolytic drugs in many clinics [10]. Hence, the development of new and highly

efficient, protocol for the synthesis of novel chromeno pyrimido [1,2-b]indazolone derivatives is still highly desirable. Recently, new one-pot multi-component strategies using ionic liquids (ILs) to access diverse bioactive scaffolds have attracted considerable attention due to the environmentally benign synthesis. ILs have unique chemical and physical properties including low vapor pressure, controlled miscibility, high thermal and chemical stability [11]. Thus, ILs are safer alternatives to organic solvents as they are cheap, stability in water and air, easy separation and reusability [12]. Moreover, ionic liquids and solvent-free combination reactions are well known as environmentally benign methods that also usually provide improved selectively, enhanced reaction rates, cleaner products and manipulative simplicity in organic transformation [13–15]. Our literature investigation revealed that there are no reports for the synthesis of biologically important chromeno pyrimido [1,2-b]indazolone using ILs under one-pot solvent-free reaction conditions. As part of our interest in developing more efficient and environmentally benign methodologies [16], we report herein a simple, rapid and high-yielding one-pot three- component reaction protocol for the synthesis of novel chromeno pyrimido[1,2-b] indazolone derivatives employing environmentally friendly ionic liquid [Et3NH][HSO4] as a catalyst under solvent-free conditions (Scheme 1).

⇑ Corresponding author. E-mail address: [email protected] (Y. Tae Jeong). https://doi.org/10.1016/j.tetlet.2019.151251 0040-4039/Ó 2019 Published by Elsevier Ltd.

Please cite this article as: A. Maruti Jadhav, S. Gangadhar Balwe and Y. Tae Jeong, An efficient protocol for synthesis of novel polyheterocyclic chromeno pyrimido[1,2-b]indazolone derivatives using [Et3NH][HSO4] as a reusable catalyst under solvent-free conditions, Tetrahedron Letters, https://doi.org/ 10.1016/j.tetlet.2019.151251

2

A. Maruti Jadhav et al. / Tetrahedron Letters xxx (xxxx) xxx

OH

NH2 R1

N H

1a

N

O R

H

O

2a

O

R1

Solvent-free

O

HN

[Et3NH][HSO4], 80 °C 15-40 min

3a

N

O

N

R

(4a-4w)

Scheme 1. Synthesis of novel chromeno pyrimido[1,2-b] indazolone derivatives catalyzed by [Et3NH][HSO4] under solvent-free condition.

Results and discussion For our initial investigation the reaction of 1H-indazole-3amine (1a, 1 mmol), 4-chlorobenzaldehyde (2a, 1 mmol), and 4hydroxycoumarin (3a, 1 mmol) was chosen as a model to optimize the reaction conditions and the results are summarized in (Table 1). The reaction was first carried out under catalyst-free reaction condition in ethanol at 80 °C for 16 h. In this case, the desired product was not observed as the starting materials were unreactive (Table 1, entry 1). Next, the same set of reaction in the presence of 20 mol % of triethylamine (Et3N), the desired product (4a) in 54% product yield after 6 h (Table 1, entry 2). The product 4a was assigned with the help of 1H NMR, 13C NMR, and HRMS data. The above observation was encouraging enough to inspire further optimization studies. Consequently, we evaluated the use of several different catalysts to optimize the reaction conditions. Such as namely, piperidine, DBU, p-TSA, AcOH, and [Et3NH][HSO4], were examined, and the results of these experiments are summarized in (Table 1, entry 3–7). Among all the screened catalysts [Et3NH] [HSO4] was found to be superior with respect to reaction time and product yield (Table 1, entry 12). Next, the model reaction has been studied the effect of different solvents, like CH3CN, CHCl3, THF, and toluene in the presence of 20 mol % of [Et3NH][HSO4] at various temperatures (Table 1, entries 8–11). In our observation at most of the solvent, conditions found that the rate of reaction was lower and desired product was obtained in moderate yield.

Therefore, ethanol is a choice of solvent for this conversion with respect to the reaction rate and the product yield (Table 1, entry 7). Next, we studied the scope of this reaction using solvent-free reaction conditions. The advantage of solvent-free conditions can be explained by the fact that a uniform distribution of the mixture of reactants was in closer proximity, allowing more effective reactions and almost complete conversion of the reactants. To our delight, under solvent-free reaction conditions we observed excellent yields (94%) in shorter reaction time (Table 1, entry 12). Then, the catalyst loading on the model reaction was investigated (Table 1, entries 12–14). We found that, there is no noticeable improvement in the yield of the desired product was observed after increasing the catalyst loading from 20 mol % to 30 mol % (Table 1, entry 13). Notably, decrease in the catalyst loading to 10 mol %, decrease in the yields were observed (Table 1, entry 14). Therefore, 20 mol % [Et3NH][HSO4] was sufficient and optimal quantity for the complete conversion of the reactants in to the desired products. We also carried out reaction at higher temperature, but yields were not improved by increasing the temperature (Table 1, entry 15). From all these establishments, we concluded that the best reaction conditions were obtained by using 20 mol % of [Et3NH][HSO4] as a catalyst under solvent-free condition at 80 °C for 15 min to afford the desired product 4a in (94%) yield (Table 1, entry 12). Initially, we investigated the scope of amines with various aldehydes and 4-hydroxycoumarin. We found that, various aromatic aldehydes take part in this one-pot cascade coupling reaction and provided the corresponding products with good to excellent yields (Table 2, entries 4a-4w). Interestingly, a variety of functional groups substituted at the aromatic ring of the aldehyde substrate, including electron-withdrawing such as, chloro, bromo, fluoro and nitro (Table 2, entries 4a, 4d, 4j, 4l, 4n, 4r, 4s, 4t, and 4v) and electron-donating such as, methoxy, methyl, isopropyl and 4-N,Ndimethylamino (Table 2, entries 4b, 4c, 4e, 4f, 4g, 4h, 4k, 4m, 4p, 4q, 4u, and 4w) groups, were well tolerated. Moreover, substituted amines like plane and bromo also participates in this reaction and

Table 1 Optimization of reaction conditions for the synthesis of novel chromeno pyrimido[1,2-b]indazolone (4a)a.

NH2 N H

1a

CHO

OH

Catalyst, Temperature

N

Solvent-free, Cl

2a

O

O

HN

N

15-40 min

N

(4a)

3a

O O

Cl

Entry

Catalyst (mol %)

Solvent

Temp (°C)

Time

Yield (%)b

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

– Et3N (20%) Piperidine (20%) DBU (20%) p-TSA(20%) AcOH(20%) [Et3NH]HSO4](20%) [Et3NH]HSO4](20%) [Et3NH]HSO4](20%) [Et3NH]HSO4](20%) [Et3NH]HSO4](20%) [Et3NH]HSO4](20%) [Et3NH]HSO4](30%) [Et3NH]HSO4](10%) [Et3NH]HSO4](20%)

EtOH EtOH EtOH EtOH EtOH EtOH EtOH CH3CN CHCl3 THF Toluene Solvent-free Solvent-free Solvent-free Solvent-free

80 80 80 80 80 80 80 Reflux Reflux Reflux Reflux 80 80 80 100

16 6 8 8 6 6 4 8 8 6 6 15 min 15 min 40 min 15 min

– 54 38 34 50 52 84 50 45 42 38 94 93 74 94

a Reaction of 1H-indazole-3-amine (1a, 1 mmol), 4-chloro benzaldehyde (2a, 1 mmol) and 4-hydroxycoumarin (3a, 1 mmol), [Et3NH][HSO4] (20 mol %) with solvent (5 mL) or solvent-free conditions. b Isolated yield.

Please cite this article as: A. Maruti Jadhav, S. Gangadhar Balwe and Y. Tae Jeong, An efficient protocol for synthesis of novel polyheterocyclic chromeno pyrimido[1,2-b]indazolone derivatives using [Et3NH][HSO4] as a reusable catalyst under solvent-free conditions, Tetrahedron Letters, https://doi.org/ 10.1016/j.tetlet.2019.151251

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A. Maruti Jadhav et al. / Tetrahedron Letters xxx (xxxx) xxx Table 2 Substrate scope.a,b

OH

NH2 R1

N H

O

N

R

O

HN

O

N

O

N

O

HN

O

N

O

N

OMe MeO (4e), 90%, 35 min

HN

O

N

O

N

O

N

O

Me

O

N

O

O

N

O

N

O O OMe

HN

O

N

O

N

O

N

O

O

N

O

(4u), 92%, 40 min OMe

O

N

O

Br

O

N

O

N

HN

O

N

O

N

O

(4v), 92%, 24 min

Br

O O OMe

N

O

N

O Cl

HN

O

N

O

Me

(4p), 88%, 35 min

Br

HN

O

N

O

N

(4t), 94%, 21 min Cl

HN

O

N

O

N

Br

Br

HN N

F

O

O R

MeO (4h), 88%, 32 min

(4s), 90%, 30 min

N

O

N

HN

N

(4l), 91%, 28 min

HN

N

N

HN

(4o), 92%, 34 min

Br

O

(4d), 94%, 24 min

OMe

N

(4r), 94%, 19 min

(4q), 89%, 26 min

Br

HN N

HN

HN

O

N

HN N

(4k), 89%, 26 min

(4m), 92%, 38 min N CH3 H3C (4n), 92%, 40 min NO2

N

O

N

O

HN N

HN

N

(4g), 89%, 28 min OC2H5

Br

(4j), 91%, 22 min

HN

O

N

(4a-4w)

Me (4c), 91%, 22 min

Me

HN N

HN

N

(4f), 82%, 36 min

(4i), 94%, 15 min

N

HN N

OMe

3a

N

OMe (4b), 92%, 25 min

Cl (4a), 94%, 15 min

R1

Solvent-free

O

15-40 min

HN

N

O

2a

1a

N

H

O

HN

[Et3NH][HSO4], 80 °C

(4w), 90%, 36 min Me

a Reactions were performed with 1H-indazole-3-amine (1 mmol), aldehydes (1 mmol) and 4-hydroxycoumarin (1 mmol), in the presence of 20 mol % [Et3NH][HSO4] under solvent-free conditions at 80 °C. b Isolated yields.

Please cite this article as: A. Maruti Jadhav, S. Gangadhar Balwe and Y. Tae Jeong, An efficient protocol for synthesis of novel polyheterocyclic chromeno pyrimido[1,2-b]indazolone derivatives using [Et3NH][HSO4] as a reusable catalyst under solvent-free conditions, Tetrahedron Letters, https://doi.org/ 10.1016/j.tetlet.2019.151251

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A. Maruti Jadhav et al. / Tetrahedron Letters xxx (xxxx) xxx

Et Et Et O H

H

Et

O

Et

O

HO

NH2

Knoevenagel condensation O

R

N H

S O

S O O

O

N H

Et

N

-H2O

H

N H

O

2

R

O

1

3

5

Et Et

O

Et

N H

Et

N H

Et O

Et O

O

O

S H O

O

Michael addition

S H

NH2

N

R

6

O

Et

O

[Et3N][HSO4] = Et

N

O

7

HN

N

H R

N

O

N

O

HN

Cyclization

N

-H2O

HO

O

O

N Et

H HO

S O O

R

4 Scheme 2. Possible mechanism for the synthesis of novel chromeno pyrimido[1,2-b]indazolone derivatives.

afforded good to excellent yields (Table 2, entries 4a-4w). In addition, bulky a-naphthaldehyde provided the desired products in good yields (Table 2, entry 4o). Most of the tried substrates showed reasonable reactivity profiles, giving to a heterocyclization sequence that readily afforded the novel chromeno pyrimido[1,2b]indazolone. In all cases, the reactions proceeded efficiently at 80 °C under solvent-free conditions and with 20 mol % of the [Et3NH][HSO4] catalyst, and the pure products can be obtained by recrystallization of the crude products in ethanol to avoid tedious work-up and column-chromatography-free method. Therefore, the present protocol has general applicability and accommodates a variety of substitution patterns. The structure of all the synthesized novel compounds (4a-4w) were determined based on 1H NMR, 13C NMR, 19F NMR and HRMS data. The reusability of the catalyst is a significant advantage particularly for commercial applications. Thus, the recovery and reusability of [Et3NH][HSO4] were also investigated (Table 3). After the completion of the reaction, cold water was added to the reac-

tion mixture, and the products were isolated by filtration. The ionic liquid was recovered by removing the water under reduced pressure and was reused at least four times without any appreciable decrease in yield. A plausible reaction mechanism for the synthesis of novel chromeno pyrimido[1,2-b]indazolone derivatives (4) is shown in (Scheme 2). The first step is the Knoevenagel condensation between aldehyde 2 and 4-hydroxycoumarin 3 in the presence of [Et3NH][HSO4] as a catalyst afforded intermediate 5, which acts as Michael acceptor. The adduct 5 immediately undergoes Michael type addition with 1H-indazol-3-amine 1 to affords the adduct 6. Subsequently, adduct 6 undergoes intramolecular ring-closure followed by elimination of water to afford the novel chromeno pyrimido[1,2-b]indazolone 4. We believe that the catalyst enhances the electrophilicity of the carbonyl groups in all three steps, i.e., Knoevenagel condensation, Michael addition, and intramolecular ring closure.

Conclusion

Table 3 A study of the reusability of [Et3NH][HSO4] in the model reaction.a Entry

Reaction cycle

Yield (%)b

1 2 3 4

First (fresh run) Second cycle Third cycle Fourth cycle

94 92 91 89

a Model reaction run with 1H-indazole-3-amine (1a, 1 mmol), 4-chlorobenzaldehyde (2a, 1 mmol) and 4-hydroxycoumarin (3, 1 mmol), [Et3NH][HSO4] (20 mol %) under solvent-free conditions. b Isolated yield.

In conclusion, we successfully developed a simple and efficient method for the synthesis of novel chromeno pyrimido[1,2-b]indazolone derivatives via one-pot three-component coupling reaction from 1H-indazol-3-amine, aldehydes and 4-hydroxycoumarin catalyzed by [Et3NH][HSO4] ionic liquid under solvent-free conditions. This protocol is environmental-friendly and transition-metal-free, with advantages, including good yields, high catalytic activity, catalyst reusability, convenient operation, a wide range of functional group tolerance and column chromatography-free method. The

Please cite this article as: A. Maruti Jadhav, S. Gangadhar Balwe and Y. Tae Jeong, An efficient protocol for synthesis of novel polyheterocyclic chromeno pyrimido[1,2-b]indazolone derivatives using [Et3NH][HSO4] as a reusable catalyst under solvent-free conditions, Tetrahedron Letters, https://doi.org/ 10.1016/j.tetlet.2019.151251

A. Maruti Jadhav et al. / Tetrahedron Letters xxx (xxxx) xxx

procedure provides access to compounds that are useful in heterocyclic synthesis. Experimental Material and methods Chemicals were purchased from Sigma-Aldrich and Alfa Aesar Chemical Companies and used without further purification. NMR spectra were recorded in parts per million (ppm) in DMSO-d6 on a Jeol JNM ECP 600 NMR instrument using TMS as internal standard. Standard abbreviations were used to denote signal multiplicities (s = singlet, d = doublet, t = triplet, q = quartet and m = multiplet) and the coupling constants are given in hertz (Hz). Mass spectra were recorded on a Jeol JMS-700 mass spectrometer. All melting points were determined using open capillaries on an Electrothermal-9100 (Japan) instrument and are uncorrected. General procedure for the synthesis of 7-(4-chlorophenyl)-7,14dihydro-6H-chromeno [40 ,30 :4,5]pyrimido[1,2-b]indazol-6-one (4a) A mixture of 1H-indazole-3-amine (1a, 1 mmol), 4-chlorobenzaldehyde (2a, 1 mmol) and 4-hydroxycoumarine (3a, 1 mmol) and 20 mol % [Et3NH][HSO4] was added, and the mixture was stirred at 80 °C under solvent-free conditions. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, water was added, and the mixture was stirred for 5 min. The solid obtained was removed by filtration and recrystallized from ethanol to afford the pure white product 4a. The water was removed from filtrate under reduced pressure to recover [Et3NH][HSO4], which was then reused in subsequent cycles. Compounds 4a-4w were also synthesized by adopting this procedure. Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Appendix A. Supplementary data

5

References [1] (a) C.V. Kavitha, S. Basappa, N. Swamy, K. Mantelingu, S. Doreswamy, M.A. Sridhar, J.S. Prasad, K.S. Rangappa, Bioorg. Med. Chem. Lett. 14 (2006) 2290– 2299. [2] K.S. Mani, W. Kaminsky, S.P. Rajendran, New J. Chem. 42 (2018) 301–310. [3] (a) R. Sakhuja, K. Pericherla, K. Bajaj, B. Khungar, A. Kumar, Synthesis 48 (2016) 4305–4346; (b) B. Banerjee, Ultrason. Sonochem. 35 (2017) 15–35; (c) R. Tohme, N. Darwiche, H. Gali-Muhtasib, Molecules 16 (2011) 9665–9696; (d) D. Anand, P.K. Yadav, O.P.S. Patel, N. Parmar, R.K. Maurya, P. Vishwakarma, K.S.R. Raju, I. Taneja, M. Wahajuddin, S. Kar, P.P. Yadav, J. Med. Chem. 60 (2017) 1041–1059. [4] (a) M. Thangadurai, S. Minu, S. Wakode, S. Agrawal, B. Narasimhan, Med. Chem. Res. 21 (2012) 1509–1523; (b) M.C. Venuti, R. Jones, J.J. Bruno, J. Med. Chem. 30 (1987) 303–318; (c) S.G. Balwe, Y.T. Jeong, Org. Chem. Front. 5 (2018) 1628–1632; (d) S.G. Balwe, Y.T. Jeong, Org. Biomol. Chem. 16 (2018) 1287–1296; (e) S. Dey, C.H. Wong, Chem. Sci. 9 (2018) 6685–6691; (f) C.W. Cheng, Y. Zhou, W.H. Pan, S. Dey, C.Y. Wu, W.L. Hsu, C.H. Wong, Nat. Commun. 9 (2018) 5202; (g) S. Dey, H.J. Lo, C.H. Wong, J. Am. Chem. Soc. 141 (2019) 10309–10314; (h) H.J. Lo, L. Krasnova, S. Dey, T. Cheng, H. Liu, T.I. Tsai, K.B. Wu, C.Y. Wu, C.H. Wong, J. Am. Chem. Soc. 141 (2019) 6484–6488. [5] T. Yakaiah, B.P.V. Lingaiah, B. Narsaiah, K.P. Kumar, U.S.N. Murthy, J. Eur, Med. Chem. 43 (2008) 341–347. [6] R.D. Amici, A.K.M. Matteo, S.B.A. Vetti, PCT Int. Appl. WO 0328, 720 (2003) 132 pp. (Eng) (C.A.138: 304278t). [7] N. Conception, M. Patrick, F. Thompson, M.T. Fabienne, B. Eric, W. Sylvie, C. Cecile, PCT Int. Appl. WO 0311, 833 (2003) 188 pp. (Fr) (C.A. 138: 153529x). [8] (a) R.J. Griffin, P.R. Lowe, J. Chem. Soc. Perkin Trans. 1 (1992) 1811–1819; (b) B.J. Whilock, S.H. Lipton, F.M. Strong, J. Org. Chem. 30 (1965) 115–118. [9] M. Pedro, A. Antonio, V. Maria, V. Vinader, Tetrahedron Lett. 30 (1989) 6237– 6240. [10] W.R. Tully, C.R. Gardner, R.J. Gillespie, R. Westwood, J. Med. Chem. 34 (1991) 2060–2067. [11] J.K. Rajput, P. Arora, G. Kaur, M. Kaur, Ultrason. Sonochem. 26 (2015) 229–240. [12] F. Shirini, M. Abedini, S. Zarrabzadeh, M. Seddighi, J. Iran. Chem. Soc. 12 (12) (2015) 2105–2115. [13] Z.N. Siddiqui, K. Khan, ACS Sustainable Chem. Eng. 2 (2014) 1187–1194. [14] D.J. Tao, X.M. Lu, J.F. Lu, K. Huang, Z. Zhou, Y.T. Wu, Chem. Eng. J. 171 (2011) 1333–1339. [15] A.M. Malla, M. Parveen, F. Ahmad, S. Azaza, M. Alamb, RSC Adv. 5 (2015) 19552. [16] (a) S.G. Balwe, Y.T. Jeong, RSC Adv. 6 (2016) 107225–107232; (b) S.G. Balwe, K.T. Lim, B.G. Cho, Y.T. Jeong, Tetrahedron 73 (2017) 3564– 3570; (c) S.G. Balwe, V.V. Shinde, Y.T. Jeong, Tetrahedron Lett. 57 (2016) 5074–5078; (d) S.G. Balwe, V.V. Shinde, A.A. Rokade, S.S. Park, Y.T. Jeong, Catal. Commun. 99 (2017) 121–126; (e) S.G. Balwe, J.S. Kim, Y.I. Kim, Y.T. Jeong, Tetrahedron 75 (2019) 797–807; (f) A.M. Jadhav, S.G. Balwe, J.S. Kim, K.T. Lim, Y.T. Jeong, Tetrahedron Lett. 60 (2019) 560–565; (g) S.G. Balwe, A.A. Rokade, S.S. Park, Y.T. Jeong, Catal. Commun. 128 (2019) 105703.

Supplementary data to this article can be found online at https://doi.org/10.1016/j.tetlet.2019.151251.

Please cite this article as: A. Maruti Jadhav, S. Gangadhar Balwe and Y. Tae Jeong, An efficient protocol for synthesis of novel polyheterocyclic chromeno pyrimido[1,2-b]indazolone derivatives using [Et3NH][HSO4] as a reusable catalyst under solvent-free conditions, Tetrahedron Letters, https://doi.org/ 10.1016/j.tetlet.2019.151251