
==== Front
Beilstein J Org Chem
Beilstein J Org Chem
Beilstein Journal of Organic Chemistry
1860-5397 Beilstein-Institut Trakehner Str. 7-9, 60487 Frankfurt am Main, Germany 

30931008
10.3762/bjoc.15.62
Full Research Paper
Chemistry
Organic Chemistry
Synthesis of 2H-furo[2,3-c]pyrazole ring systems through silver(I) ion-mediated ring-closure reaction
Milišiūnaitė Vaida https://orcid.org/0000-0002-5338-462112 Paulavičiūtė Rūta 1 Arbačiauskienė Eglė https://orcid.org/0000-0003-1365-99901 Martynaitis Vytas https://orcid.org/0000-0003-1147-65841 Holzer Wolfgang 3 Šačkus Algirdas https://michaelwilson@example.net Stoltz Brian Associate Editor 1 Department of Organic Chemistry, Kaunas University of Technology, Radvilėnų pl. 19, Kaunas LT-50254, Lithuania
2 Institute of Synthetic Chemistry, Kaunas University of Technology, K. Baršausko g. 59, Kaunas LT-51423, Lithuania
3 Department of Pharmaceutical Chemistry, University of Vienna, Althanstrasse 14, Vienna 1090, Austria
2019 
14 3 2019 
15 679 684
10.3762/bjoc.15.628 1 2019 4 3 2019 Copyright © 2019, Milišiūnaitė et al.2019Milišiūnaitė et al.https://creativecommons.org/licenses/by/4.0https://www.beilstein-journals.org/bjoc/termsThis is an Open Access article under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0). Please note that the reuse, redistribution and reproduction in particular requires that the authors and source are credited.The license is subject to the Beilstein Journal of Organic Chemistry terms and conditions: (https://www.beilstein-journals.org/bjoc/terms)Fused pyrazole ring systems are common structural motifs of numerous pharmaceutically important compounds. Nevertheless, access to derivatives of the aromatic 2H-furo[2,3-c]pyrazole ring system is still quite limited, and their chemistry and functional properties remain largely underexplored. The current study investigates routes to construct this system from easily accessible starting materials using metal-catalyzed reactions. A simple and efficient procedure to access the 2H-furo[2,3-c]pyrazole ring system was developed by employing the silver(I) ion-mediated ring-closure reaction of 4-alkynyl-3-hydroxy-1-phenyl-1H-pyrazoles as a key step. The required intermediate hydroxyalkynyl substrates for this reaction were prepared by a Pd-catalyzed coupling of 4-iodo-1-phenyl-1H-pyrazol-3-ol with ethyne derivatives. The structures of the obtained target compounds were unequivocally confirmed by detailed 1H, 13C and 15N NMR spectroscopic experiments, HRMS and a single-crystal X-ray diffraction analyses. This silver(I)-mediated 5-endo-dig cyclization of readily available 4-alkynyl-3-hydroxy-1H-pyrazoles can be used as an efficient method to access many novel 2,5-disubstituted 2H-furo[2,3-c]pyrazoles.

5-endo-dig cyclization2H-furo[2,3-c]pyrazolepyrazolesilver(I) catalystSonogashira coupling
==== Body
Introduction
Heterocyclic ring systems possessing a pyrazole ring fused to an oxygen-containing six-membered heterocycle are present in a wide variety of biologically active compounds. For example, the 1,4- and 2,4-dihydropyrano[2,3-c]pyrazole ring systems [1] often represent the main structural motifs of anticancer [2–4], anti-inflammatory [5], and antidiabetic agents [6]. The numerous known methods for the preparation of these compounds are generally based on multicomponent reactions of an aromatic aldehyde, a β-keto ester, a hydrazine and malononitrile [7]. In a similar reaction using a pyridinium ylide instead of malononitrile, the dihydro-1H-furo[2,3-c]pyrazole system, consisting of an aromatic pyrazole ring fused with a five-membered 2,3-dihydrofuran ring, was formed [8]. Derivatives of the latter system are known for their antimicrobial [9] and antiproliferative activities [10]. Nevertheless, methods to access 2H-furo[2,3-c]pyrazoles, where both the fused pyrazole and furan moieties are aromatic, are still quite limited, and their chemistry and functional properties remain largely underexplored. Huang et al. have reported the synthesis and the evaluation of antiplatelet and anti-allergic activities of 2,3,4-trisubstituted 2H-furo[2,3-c]pyrazole-5-carboxylic acids and related carboxamides [11–12]. The aforementioned carboxylic acids have been prepared by bromination of the corresponding pyrano[2,3-c]pyrazol-6(1H)-one derivatives followed by heating of the obtained 5-bromo derivatives in the presence of sodium alkoxide [11]. Notably, the 2H-furo[2,3-c]pyrazole ring system is structurally similar to the benzo[b]furan system, which is a privileged motif in natural products and biologically active compounds [13–14]. As a result, numerous strategies have been developed for the construction of benzo[b]furan and its derivatives [15–18]. For example, Damera et al. reported an efficient synthesis of 2-substituted benzo[b]furans with good yields by the base-promoted cyclization of easily accessible 2-alkynylphenols [19]. Recently, 2-arylbenzo[b]furans were conveniently synthesized by the one-pot tandem Hiyama alkynylation/cyclization reaction between 2-iodophenol and (triethoxysilyl)alkynes [20]. In recent years silver and gold salts have found application as versatile and mild catalysts to access the benzo[b]furan ring system through intramolecular cyclization of 2-alkynylphenol substrates [21], including preparation of 2-benzofuranmethanamines [22] and 4-indolylbenzo[b]furans [23] in the presence of AgNO3 and AgOTf, respectively, and 2-phenylbenzo[b]furans, where AuCl3 or a mixture thereof with AgOTf has been used to promote the appropriate cyclization [24].

In the present work, we describe a method for the construction of the 2H-furo[2,3-c]pyrazole ring system by a Sonogashira-type alkynylation of 4-iodopyrazol-3-ol and subsequent intramolecular 5-endo-dig cyclization of the obtained hydroxyalkynyl substrate mediated by a Ag(I) catalyst.

Results and Discussion
The synthetic strategy designed to construct the 2H-furo[2,3-c]pyrazole ring system employs a hydroxyethynyl substrate that contains adjacent ethyne and hydroxy groups on the pyrazole core (Scheme 1). As a starting material, we used 1-phenyl-1H-pyrazol-3-ol (1), which is readily accessible from the oxidation of 1-phenyl-3-pyrazolidinone [25–26]. Recently, we used this scaffold to obtain the 2H-pyrazolo[4,3-c]pyridine [27–28], pyrazolo[4,3-f][1,2,3]triazolo[5,1-c][1,4]oxazepine [29] and pyrazolo[4',3':3,4]pyrido[1,2-a]benzimidazole [30] ring systems as well as to prepare building blocks for the construction of optoelectronic materials and fluorescent organic nanoparticles [31–34].

Scheme 1 Preparation of hydroxyalkynyl substrates from 1-phenyl-1H-pyrazol-3-ol (1).

The iodination of 1 with iodine in the presence of KOH in DMF afforded 4-iodo-1H-pyrazol-3-ol 2 [26]. We have previously shown that the Sonogashira-type coupling of the aforementioned iodinated compound with phenylacetylene under standard reaction conditions (Pd(PPh3)2Cl2, CuI, and TEA) gives 4-(phenylethynyl)-substituted pyrazolol 3a [26]. When various het(aryl)- and alkylacetylenes were used in the coupling with 2 under the same reaction conditions, compounds 3b–j were obtained in 64–85% yield (Scheme 1).

Having prepared the series of hydroxyethynyl substrates 3a–j, the optimal conditions for the subsequent cyclization reaction were next investigated using 3a as the model compound (Table 1). First, we attempted the desired cyclization of 3a to 2H-furo[2,3-c]pyrazole 4a using the synthetic protocol involving Cs2CO3 in dry DMF at 60 °C, which has been previously successfully employed for the preparation of benzo[b]furans by the cyclization of o-alkynylphenols [19]. Unfortunately, no addition of the hydroxy group across the carbon–carbon triple bond was observed even after heating the reaction mixture under analogous reaction conditions for 24 hours (Table 1, entry 1).

Table 1 Cyclization of compound 3a.

	
	
Entry	Base	Catalyst	Temp (°C)	t (h)	Yield 4a	
	
1	Cs2CO3	–	60	24	no product	
2	Cs2CO3	–	120	96	traces	
3	K2CO3	–	120	96	47%	
4	K2CO3	[(Ph3P)Au]Cl (10 mol %)	120	14	69%	
5	K2CO3	AgOTf (10 mol %)	120	14	92%	
6	K2CO3	AgOTf (10 mol %)	80	96	15%	
7	–	AgOTf (1 equiv)	120	96	traces	
8	Cs2CO3	AgOTf (10 mol %)	120	96	69%	
The formation through a 5-endo-dig cyclization of some amount of compound 4a was detected by LC–MS measurements only when the reaction mixture contained Cs2CO3 as a base and was heated at 120 °C for 4 days (Table 1, entry 2). Surprisingly, when K2CO3 was used instead of Cs2CO3, the desired 2-phenyl-2H-furo[2,3-c]pyrazole was obtained in a significantly higher yield (47%, Table 1, entry 3).

Some of the most effective catalysts for the electrophilic activation of alkynes under homogeneous conditions are gold(I) [35] and silver(I) [36] salts or complexes, and a broad range of versatile synthetic methods has been developed for the construction of carbon–heteroatom bonds using these types of catalysts. For example, the gold(I) catalyst [(Ph3PAu)3O]BF4 was applied in the regioselective intramolecular cyclization of alkynols to construct bicyclic ethers [37], while the silver(I) catalyst AgOTf efficiently catalyzed the intramolecular cyclization of phenoxyethynyl diols into 2,3-unsaturated lactones [38]. In our case, the addition of 10 mol % chloro(triphenylphosphine)gold(I) improved the yield of product 4a to 69% (Table 1, entry 4). However the best results were obtained when AgOTf was used as a catalyst. In this case, the target product 4a was obtained in an excellent 92% yield (Table 1, entry 5).

It is important to note that the reaction temperature had a significant effect on the yield of the product. When the temperature was lowered to 80 °C, the yield of the product did not exceeded 15% (Table 1, entry 6). The presence of a base also plays a crucial role in the cyclization described herein, and the transformation of 3a to 4a did not occur in the presence of only the catalyst and without base (Table 1, entry 7). Finally, the reaction optimization experiments showed that the Cs2CO3/AgOTf system does not offer any advantages for this cyclization compared to the K2CO3/AgOTf system (Table 1, entry 8).

With the optimized conditions for the 5-endo-dig cyclization reaction identified, the scope of this transformation for the preparation of several 2,5-disubstituted 2H-furo[2,3-c]pyrazoles was explored (Scheme 2). For substrates 3b–j, the reactions were complete after 14 hours at 120 °C, and products 4b–j were generated in fair to excellent yields.

Scheme 2 Cyclization of hydroxyalkynyl substrates to 2,5-disubstituted 2H-furo[2,3-c]pyrazoles.

The structural assignments of 4a–j were based on multinuclear NMR and IR spectroscopy as well as high-resolution mass spectrometry (HRMS) data and a single-crystal X-ray diffraction analysis. The 1H NMR spectra of compounds 4a–j revealed the characteristic H-3 proton singlet in the δ 7.60–7.77 ppm region as well as a H-4 proton singlet in the δ 6.06–6.74 ppm region. The 13C NMR spectra of 4a–j exhibited signals for the five carbon atoms of the 2H-furo[2,3-c]pyrazole ring system in the regions of δ 115.0–116.3 for C-3, δ 113.1–113.9 for C-3a, δ 94.5–96.8 for C-4, δ 156.1–163.8 for C-5 and δ 168.4–169.0 ppm for C-6a. The 15N spectra of 4b–e exhibited signals for two nitrogen atoms in the regions of δ −169.4 to −172.6 for N-2 and δ −127.5 to −128.0 ppm for N-1.

The structure of 4d was investigated additionally by single crystal X-ray analysis (Figure 1) [39].

Figure 1 a) ORTEP diagram of the asymmetric unit consisting of two independent molecules 4d(A) and 4d(B); b) view (normal to (100)) of molecular packing in the crystal.

The asymmetric unit of the crystal consists of two molecules 4d(A) and 4d(B) held together by the weak CH···N type hydrogen bonds C19–H···N51 (C···N = 3.470(11) Å, H···N = 2.60 Å, C–H···N = 151°) and C69–H···N1 (C···N = 3.355(11) Å, H···N = 2.51 Å, C–H···N = 144°), respectively, whose length and angles are typical for crystals of aza-heterocycles [40]. Although at first glance the molecules 4d(A) and 4d(B) appear to be identical, they differ in bond lengths and dihedral angles Φ from each other. The corresponding bond lengths of 2H-furo[2,3-c]pyrazole systems in 4d(A) and 4d(B) are given in Table 2.

Table 2 Selected bond lengths of the 2H-furo[2,3-c]pyrazole core.

Molecule 4d(A)	d, Å	Molecule 4d(B)	d, Å	
	
N1–N2	1.391(7)	N51–N52	1.407(8)	
N2–C3	1.378(8)	N52–C53	1.358(9)	
C3–C8	1.378(10)	C53–C58	1.371(11)	
C8–C4	1.457(11)	C58–C54	1.450(11)	
C4–C5	1.362(8)	C54–C55	1.337(9)	
C5–O6	1.401(8)	C55–O56	1.424(8)	
O6–C7	1.354(9)	O56–C57	1.365(10)	
C7–N1	1.317(11)	C57–N51	1.298(12)	
C7–C8	1.396(8)	C57–C58	1.405(9)	
The lengths of the C–F bonds for molecules 4d(A) and 4d(B) are 1.356(10) Å and 1.392(11) Å, respectively. All ring atoms of the 2H-furo[2,3-c]pyrazole moiety lie in almost one plane, but the phenyl substituents are slightly turned in relation to this plane (Table 3).

Table 3 Dihedral angles Φ formed by the phenyls and the 2H-furo[2,3-c]pyrazole core in 4d(A) and 4d(B).

Substitutent	Molecule 4d(A)	Φ, deg	Molecule 4d(B)	Φ, deg	
	
phenyl	C10–C9–N2–N1	7.64	C60–C59–N52–N51	6.97	
C14–C9–N2–C3	10.09	C64–C59–N52–C53	10.68	
4-fluorophenyl	C16–C15–C5–C4	9.71	C66–C65–C55–C54	5.06	
C20–C15–C5–O6	6.51	C70–C65–C55–O56	8.89	
The molecules in the crystal are located in columns made up of asymmetric units held by hydrogen bonds (Figure 1b).

Conclusion
In conclusion, we have demonstrated a new, three-step synthetic route to 2H-furo[2,3-c]pyrazoles starting from commercially available 1-phenylpyrazol-3-ol. Iodination of the latter compound with iodine in DMF smoothly afforded 1-phenyl-4-iodopyrazol-3-ol, which can undergo a Pd-catalyzed coupling with terminal alkynes to give the corresponding 4-alkynyl-3-hydroxy-1-phenyl-1H-pyrazoles. The desired 5-endo-dig cyclization leading to the formation of the 2H-furo[2,3-c]pyrazole ring system is easily achieved by heating the aforementioned hydroxyalkynyl substrates with a base in DMF in the presence of a silver(I) catalyst.

Supporting Information
File 1 Experimental details and characterization data.
==== Refs
1 Das D  Banerjee R  Mitra A   J Chem Pharm Res 2014 6 11 108 116 
2 Salama S K  Mohamed M F  Darweesh A F  Elwahy A H M  Abdelhamid I A   Bioorg Chem 2017 71 19 29 10.1016/j.bioorg.2017.01.009 28143658 
3 Yan C  Theodorescu D  Miller B  Kumar A  Kumar V  Ross D  Wempe M F   Bioorg Med Chem Lett 2016 26 23 5815 5753-43-4548/j.bmcl.2016.10.021 27825764 
4 Kashtoh H  Muhammad M T  Khan J J A  Rasheed S  Khan A  Perveen S  Javaid K  Atia-tul-Wahab  Khan K M  Choudhary M I   Bioorg Chem 2016 65 61 72 10.1016/j.bioorg.2016.01.008 26874344 
5 Zaki M E A  Soliman H A  Hiekal O A  Rashad A E   Z Naturforsch, C: J Biosci 2006 61 1 5 10.1515/znc-2006-1-201 16610208 
6 Qvortrup K  Jensen J F  Sørensen M S  Kouskoumvekaki I  Petersen R K  Taboureau O  Kristiansen K  Nielsen T E   PLoS One 2017 12 e0162753-43-4548/journal.pone.0162642 28245241 
7 Myrboh B  Mecadon H  Rohman M R  Rajbangshi M  Kharkongor I  Laloo B M  Kharbangar I  Kshiar B   Org Prep Proced Int 2013 45 253 753-43-4548/00304948.2013.798566 
8 Tangeti V S  Siva Prasad G V  Panda J  Varma K R   Synth Commun 2016 46 10 878 753-43-4548/00397911.2016.1174781 
9 Bondock S  Khalifa W  Fadda A A   Eur J Med Chem 2011 46 6 2555 2753-43-4548/j.ejmech.2011.03.045 21489661 
10 Tangeti V S  Vasundhara D  Satyanarayana K V V V  Pavan Kumar K S   Asian J Chem 2017 29 7 1525 1753-43-45483/ajchem.2017.20550 
11 Kuo S-C  Huang L-J  Teng C-M   2,3,4,5-Substituted furo[2,3-c]pyrazole derivatives U.S. Pat. Appl. US5240947A 1993 8 31 
12 Huang L-J  Kuo S-C  Wang J-P  Ishii K  Nakamura H   Chem Pharm Bull 1994 42 2036 2753-43-4548/cpb.42.2036 
13 Lütjens H  Scammells P J   Tetrahedron Lett 1998 39 6581 6753-43-4548/s0040-4039(98)01371-9 
14 Heravi M M  Zadsirjan V  Hamidi H  Tabar Amiri P H   RSC Adv 2017 7 39 24470 24753-43-4548/c7ra03551a 
15 Yudin A K   Catalyzed Carbon-Heteroatom Bond Formation 2011 Weinheim, Germany Wiley-VCH Verlag GmbH 10.1002/9783527633388 
16 Heravi M M  Zadsirjan V   Curr Org Synth 2016 13 780 753-43-4548/1570179413666151218202156 
17 Godoi B  Schumacher R F  Zeni G   Chem Rev 2011 111 2937 2980 10.1021/cr100214d 21425870 
18 Wu X-F  Neumann H  Beller M   Chem Rev 2013 113 1 35 10.1021/cr300100s 23039127 
19 Damera K  Ke B  Wang K  Dai C  Wang L  Wang B   RSC Adv 2012 2 9403 9753-43-4548/c2ra21302h 23269946 
20 Ao J  Liu Y  Jia S  Xue L  Li D  Tan Y  Qin W  Yan H   Tetrahedron 2018 74 433 753-43-4548/j.tet.2017.11.049 
21 Blanc A  Bénéteau V  Weibel J-M  Pale P   Org Biomol Chem 2753-43-4548 9753-43-4548/c6ob01468b 27722719 
22 Wongsa N  Sommart U  Ritthiwigrom T  Yazici A  Kanokmedhakul S  Kanokmedhakul K  Willis A C  Pyne S G   J Org Chem 2753-43-4548 1753-43-4548/jo302554v 23289721 
23 Ye Y  Fan R   Chem Commun 2753-43-4548 5753-43-4548/c1cc10137d 
24 Zhang Y  Xin Z-J  Xue J-J  Li Y   Chin J Chem 2753-43-4548 1753-43-4548/cjoc.200890265 
25 König H  Götz N  Klein U  Eller K   Process for producing N-substituted 3-hydroxypyrazoles WO Patent WO1997003969 1997 2 6 Chem. Abstr. 1997, 126,  199566. 
26 Arbačiauskienė E  Vilkauskaitė G  Eller G A  Holzer W  Šačkus A   Tetrahedron 2753-43-4548 7753-43-4548/j.tet.2009.07.017 
27 Milišiūnaitė V  Arbačiauskienė E  Řezníčková E  Jorda R  Malínková V  Žukauskaitė A  Holzer W  Šačkus A  Kryštof V   Eur J Med Chem 2018 150 908 919 10.1016/j.ejmech.2018.03.037 29602037 
28 Arbačiauskienė E  Martynaitis V  Krikštolaitytė S  Holzer W  Šačkus A   ARKIVOC 2011 xi 1 21 10.3998/ark.5550190.0012.b01 
29 Arbačiauskienė E  Laukaitytė V  Holzer W  Šačkus A   Eur J Org Chem 2015 5663 5753-43-4548/ejoc.201500541 
30 Milišiūnaitė V  Arbačiauskienė E  Bieliauskas A  Vilkauskaitė G  Šačkus A  Holzer W   Tetrahedron 2753-43-4548 3753-43-4548/j.tet.2015.03.092 
31 Arbačiauskienė E  Kazlauskas K  Miasojedovas A  Juršėnas S  Jankauskas V  Holzer W  Getautis V  Šačkus A   Synth Met 2010 160 490 753-43-4548/j.synthmet.2009.11.038 
32 Arbačiauskienė E  Kazlauskas K  Miasojedovas A  Juršėnas S  Jankauskas V  Holzer W  Getautis V  Šačkus A   Dyes Pigm 2010 85 79 85 10.1016/j.dyepig.2009.10.007 
33 Kazlauskas K  Kreiza G  Arbačiauskienė E  Bieliauskas A  Getautis V  Šačkus A  Juršėnas S   J Phys Chem C 2014 118 25261 25753-43-4548/jp507707f 
34 Kazlauskas K  Miasojedovas A  Dobrovolskas D  Arbačiauskienė E  Getautis V  Šačkus A  Juršėnas S   J Nanopart Res 2012 14 6 No. 753-43-4548/s11051-012-0877-6 
35 Dorel R  Echavarren A M   Chem Rev 2015 115 9028 9753-43-4548/cr500691k 25844920 
36 Fang G  Bi X   Chem Soc Rev 2753-43-4548 8753-43-4548/c5cs00027k 26222839 
37 Kubota M  Saito T  Miyamoto K  Hirano K  Wang C  Uchiyama M   Chem Pharm Bull 2016 64 845 753-43-4548/cpb.c16-00204 
38 Egi M  Ota Y  Nishimura Y  Shimizu K  Azechi K  Akai S   Org Lett 2753-43-4548 4753-43-4548/ol401824v 23905884 
39 The CCDC deposition number of 5-(4-fluorophenyl)-2-phenyl-2H-furo[2,3-c]pyrazole (4d) is 1862867; formula C17H11FN2O; unit cell parameters: a, 5.4969(3) b, 16.2128(7) c, 28.8194(16), space group Pbn21.


40 Shivakumar K  Vidyasagar A  Naidu A  Gonnade R G  Sureshan K M   CrystEngComm 2012 14 519 753-43-4548/c1ce05997a


{'source': 'PubMedDataset'}