Synthesis and Characterization of Novel 2-(1,2,3-Triazol-4-yl)-4,5-dihydro-1H-pyrazol-1-yl)thiazoles and 2-(4,5-Dihydro-1H-pyrazol-1-yl)-4-(1H-1,2,3-triazol-4-yl)thiazoles

Abstract

Reactions of 1-(5-methyl)-1H-1,2,3-triazol-4-yl)ethan-1-ones and benzaldehydes in ethanol under basic conditions gave the corresponding chalcones. Reactions of the chalcones combined with thiosemicarbazide in dry ethanol containing sodium hydroxide afforded the corresponding pyrazolin-N-thioamides. Reactions of the synthesized pyrazolin-N-thioamides and several ketones (namely, ethyl 2-chloro-3-oxobutanoate, 2-bromoacetylbenzofuran, and hydrazonoyl chloride) gave the corresponding novel 2-(1,2,3-triazol-4-yl)-4,5-dihydro-1H-pyrazol-1-yl)thiazoles in high yields (77–90%). Additionally, 2-(4,5-dihydro-1H-pyrazol-1-yl)-4-(1H-1,2,3-triazol-4-yl)thiazoles were obtained in high yields (84–87%) from reactions with N-pyrazoline-thioamides and 4-bromoacetyl-1,2,3-triazoles under basic conditions. The structures of six of the newly synthesized heterocycles were confirmed by X-ray crystallography.

1. Introduction

Heterocycles containing nitrogen and sulfur have received great attention due to their pharmacological and industrial applications [1,2]. Pyrazoles present antimicrobial, anti-inflammatory, antihypertensive, antipyretic, antioxidant, analgesic, antidepressant, anticancer, and antidiabetic activities [3,4,5]. Naturally occurring thiazole compounds also have antibacterial, anti-inflammatory, antifungal, antihypertensive, neuroleptic, and antimalarial properties [6,7,8,9]. In addition, 1,2,3-triazoles display anti-HIV, antimicrobial, antiviral, and antiproliferative effects [10,11,12,13]. Derivatives of 1,2,3-triazole have been used as insecticides, fungicides, and plant growth regulators [14,15]. The synthesis of heterocycles containing pyrazole, thiazole, and triazole moieties is therefore of interest to both the academic and industrial communities.

Recent synthetic methods used to produce pyrazoles involve, for example, the cycloaddition of N-isocyanoiminotriphenylphosphorane in the presence of silver carbonate [16], oxidative condensations of carbonyl compounds (aldehydes and ketones) and hydrazine monohydrochloride [17], oxidative cyclization of β,γ-unsaturated hydrazones [18], and the reaction of enaminones and hydrazines in the presence of iodine as a catalyst [19]. For the production of thiazoles, the most recent synthetic procedures involve reactions of aldehydes and amines in the presence of sulfur and copper chloride [20], enaminoesters and fluorodibromoamides in the presence of sulfur [21], primary amines and α-nitro epoxides in the presence of potassium thiocyanate [22], and α-oxodithioesters and tosylmethyl isocyanide in the presence of potassium hydroxide [23]. The synthesis of 1,2,4-triazoles includes reactions of N-tosylhydrazones with sodium azide [24], cyclization of 4-toluenesulfonyl hydrazines and methyl ketones in the presence of iodine and 1-aminopyridinium iodide [25], α-ketoacetals and amines [26], and cycloaddition of azides, propiolic acids, and arylboronic acids in the presence of different catalysts [27].

Pyrazolyltriazoles can be synthesized using different procedures. For example, reactions of 2-bromoketones and pyrazole-1-carbothioamides or thiazolyl hydrazines and dicarbonyl or β-ketonitriles led to the production of pyrazolyltriazoles [28]. Triazolylthiazoles can be produced from the cyclization of Schiff bases containing a triazole moiety in the presence of mercaptoacetic acids, or from carbohydrazides containing thiazole units and isothiocyanates or carbon disulfides, followed by cyclization and elimination of hydrogen sulfide [28]. Recently, we have reported the synthesis and crystal structures of novel heterocycles containing thiazole, pyrazoline, and 1,2,4-triazole moieties [29,30,31] as part of our long-term interest in new biologically active heterocycles [32,33,34]. In the current work, we report the synthesis of 2-(1,2,3-triazol-4-yl)-4,5-dihydro-1H-pyrazol-1-yl)thiazoles and 2-(4,5-dihydro-1H-pyrazol-1-yl)-4-(1H-1,2,3-triazol-4-yl)thiazoles using simple procedures and their structure characterization. The synthesized compounds are complex in structure since they contain various heterocyclic rings and substituents. No related heterocycles are reported in the literature and therefore direct comparison is not possible.

2. Results and Discussion

Synthesis of Novel Heterocycles

Reactions of 1-(5-methyl)-1H-1,2,3-triazol-4-yl)ethan-1-ones 1a,b (R¹ = H, F) and benzaldehydes 2a,b (R² = OMe, F) in ethanol (EtOH) under basic conditions gave chalcones 3a,b. The reactions of 3a and 3b and thiosemicarbazide in dry ethanol containing sodium hydroxide (NaOH) afforded the corresponding pyrazolin-N-thioamides 4a and 4b, respectively (Scheme 1).

The chemical structures of 3a and 4a were confirmed by single crystal X-ray diffraction, as shown in Figure 1 and Figure 2, respectively. The CH=CH protons in 3a appeared as two doublets (J = 16.0 Hz) at 7.79 and 7.86 ppm in its ¹H NMR spectrum, while the CH=CH carbons appeared at 120.9 and 143.7 ppm in the ¹³C NMR spectrum. For 4a, the ¹H NMR spectrum showed two doublets at 13.6 (J = 18.2 Hz) and 5.86 (J = 8.1 Hz) that correspond to the CH₂ protons of pyrazoline. The C=S carbon appeared highly down-field (176.5 ppm) in the ¹³C NMR spectrum. For details, see the Supplementary Materials.

For X-ray crystal structure determination, single crystals were obtained following the crystallization of the synthesized heterocycles using dimethylformamide (DMF). The molecule of 3a (Figure 1) is constructed from phenyl A (C1–C6), methyltriazole B (C7–C9, N1–N3), propanal C (C10–C12, O1) and methoxybenzene D (C13–C19, O2) groups. Except for the phenyl group (A), the molecule is nearly planar as shown by the twist angles B/C and C/D of 4.23(19)° and 9.82(18)°, respectively. Regarding the phenyl group, twist angle A/B is 66.96(7)°.

The molecule of 4a (Figure 2) contains phenyl A (C1–C6), methyltriazole B (C7–C9, N1–N3), pyrazole C (C10–C12, N4, N5), methoxybenzene D (C14–C20, O1) and methanethioamide E (C13, S1, N6) groups. In the crystal, the pyrazole ring (C) is distorted from planarity with C12 diverging from the least squares plane of the rest of the atoms by 0.235(5)Å. The methanethioamide (E) and pyrazole (C) groups are roughly coplanar with a C/E twist angle of 10.67(21)°. The methyltriazole (B) and pyrazole (C) groups are also almost coplanar with a B/C twist angle of 15.35(24)°. The phenyl (A) and methoxybenzene (D) groups are significantly twisted from this plane with twist angles A/B and C/D of 78.71(12)° and 87.02(11)°, respectively. Hydrogen bonding of type N–H...N (N6…N4 = 3.117(3)Å, N6-H6B…N4 = 162.1°) and N–H..S (N6…S1 = 3.506(3)Å, N6–H6A…S1= 138.7°) is observed in the crystal structure. For more details, see the Supplementary Materials.

The reaction of thioamide 4a and ethyl 2-chloro-3-oxobutanoate (5) in EtOH and in the presence of triethylamine (Et₃N) gave ethyl 2-(5-(4-methoxyphenyl)-3-(5-methyl-1-phenyl-1H-1,2,3-triazol-4-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-methylthiazole-5-carboxylate (8) in 77% yield (Scheme 2). Similarly, the reaction of 4b and 2-acetylbenzofuran (6) or 1-chloro-1-((4-fluorophenyl)diazenyl)propan-2-one (7) gave 4-(benzofuran-2-yl)-2-(5-(4-fluorophenyl)-3-(1-(4-fluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)-4,5-dihydro-1H-pyrazol-1-yl)thiazole (9) or 2-(5-(4-fluorophenyl)-3-(1-(4-fluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)-4,5-dihydro-1H-pyrazol-1-yl)-5-((4-fluorophenyl)diazenyl)-4-methylthiazole (10) in 90 or 86% yield, respectively (Scheme 2). The structures of 8–10 were confirmed by single crystal X-ray diffraction (Figure 3, Figure 4 and Figure 5).

The ¹H NMR spectrum of compound 8 showed two characteristic double doublets (J = 4.8 Hz) that appeared at 3.37 and 4.42 ppm, corresponding to the CH₂ protons of the pyrazolinyl moiety. In addition, it showed a double doublet (J = 4.8 and 16.4 Hz) that appeared at 5.70 ppm corresponding to the pyrazolinyl proton at position 5. The ¹³C NMR spectrum of 8 showed two high-field signals at 162.3 and 165.3 ppm that correspond to the carbonyl carbon and C2 of the thiazolyl moiety, respectively. For compound 9, the pyrazoline protons appeared as three double doublets of one proton each at 3.43 (J = 6.2 and 18.1 Hz), 4.18 (J = 11.9 and 18.1 Hz), and 5.68 (J = 6.2 and 11.9 Hz). The ¹³C NMR spectra of 9 and 10 showed the coupling between the fluorine atoms and the carbons (C2–C6) of the aryl rings.

The crystal structure of 8 also contains water molecules (Figure 3). The molecule of 8 contains ethylformate A (C1–C3, O1, O2), methylthiazole B (C4–C7, N1, S1), pyrazole C (C8–C10, N2, N3), methyltriazole D (C18–C20, N4–N6), phenyl E (C21–C26), and methoxybenzene F (C11–C17, O3) groups. The ethylformate (A) is flat with a maximum deviation from the least squares plane of 0.050(3) Å. The pyrazole (C) ring is slightly deformed from planarity with C8 being 0.356(4)Å from the plane of the other atoms of the ring. Groups A–D are coplanar as indicated by twist angles A/B, B/C, C/D of 4.76(14)°, 1.71(13)°, 0.72(13)°, respectively. Phenyl ring (E) and methoxybenzene (F) groups diverge from the A-D plane with twist angles D/E and C/F of 44.03(7)° and 85.82(7)°, respectively. The water molecule forms two hydrogen bonds with the carbonyl oxygen (O4…O1 = 2.904(3), O4–H41…O1 = 171(4)°) and triazole nitrogen (O4…N4 = 3.128(3)Å, O4–H42…N4 = 162(4)°) of compound 8.

The molecule of 9 is made of two fluorobenzene A (F1, C1–C6), F (F2, C13–C18), methyltriazole B (C7–C9, N1–N3), pyrazole C (C10–C12, N4, N5), thiazole D (C19–C21, N6, S1) and benzofuran E (C22–C29, O1) groups. The pyrazole ring (C) is in envelope conformation with atom C12 located 0.309(4)Å from the plane through the rest of the atoms. The B–E backbone of the molecule is essentially planar with twist angles B/C, C/D, D/E of 2.99(20)°, 10.18(17)° and 2.45(12)°, respectively. The fluorobenzene rings (A and F) are twisted from this plane with A/B and C/F angles of 42.65(8)° and 81.12(7)°, respectively.

The crystal structure of 10 contains two independent molecules (Figure 5). The first molecule consists of three fluorobenzene groups, namely A1 (C1–C6, F1), E1 (C23–C28, F3) and F1 (C13–C18, F2), as well as methyltriazole B1, (C7–C9, N1–N3), pyrazole C1 (C10–C12, N4, N5), methylthiazole D1 (C19–C22, N6, S1) and diazene (N7, N8) groups. The central part of the molecule (B1–E1) is almost planar as indicated by the twist angles B1/C1, C1/D1 and D1/E1 of 3.80(13)°, 3.71(12)° and 9.98(11)°, respectively. Two of the fluorophenyl groups (A1 and F1) are twisted from this plane with A1/B1 and C1/F1 angles of 31.76(10)° and 89.53(10)°, respectively.

The second independent molecule has three fluorobenzene A2, (C29–C34, F3), E2, (C51–C56, F6) and F2, (C41–C46, F5) moieties along with methyltriazole B2, (C35–C37, N9–N11), pyrazole C2 (C38–C40, N12, N13), methylthiazole D2 (C47–C50, N14, S2) and diazene (N15, N16) groups. Similar geometry to that for the first molecule is observed for the second molecule. The middle part of the molecule (B2–E2) is almost planar with twist angles B2/C2, C2/D2 and D2/E2 of 3.38(12)°, 6.48(12)° and 8.18(11)°, respectively. Two of the fluorophenyl groups (A2 and F2) are oriented substantially away from this plane with twist angles A2/B2 and C2/F2 of 31.85(8)° and 82.19(8)°, respectively. In both independent molecules, the pyrazole rings (C1 and C2) are in envelop conformation with C12 deviating from the least squares planes of the rest of the atoms by 0.324(3)Å for the first molecule and C40 deviating by 0.271(3)Å for the second molecule.

2-(4,5-Dihydro-1H-pyrazol-1-yl)-4-(1H-1,2,3-triazol-4-yl)thiazoles 13a–13c were synthesized in excellent yields from reactions of N-pyrazoline-thioamides 11a,b and 4-bromoacetyl-1,2,3-triazole derivatives 12a–12c in anhydrous EtOH and in the presence of Et₃N under reflux conditions to give the corresponding heterocycles 13–15 (Scheme 3). The chemical structure of 14 was confirmed by single crystal X-ray diffraction (Figure 6). The ¹H NMR spectra of 13–15 showed three double doublets for the pyrazoline protons that appeared at the 3.24–3.28, 3.98–3.99, and 5.54–3.54 ppm regions. The ¹³C NMR spectra of 13–15 showed the C2 of the thiazole ring at very low-field in the region of 165.4–165.8 ppm.

The molecule of 14 (Figure 6) comprises methylbenzene A (C1–C7), methyltriazole B (C8–C10, N1–N3), thiazole C (C11–C13, N4, S1), pyrazole D (C14–C16, N5, N6), chlorobenzene E (C23–C28, Cl1), fluorobenzene F (C17–C22, F1). The pyrazole ring is slightly distorted from planarity, with C14 deviating from the plane of the rest of the atoms by 0.186(4)Å. The backbone of the molecule (B–E) is almost planar with twist angles B/C, C/D and D/E of 15.85(12)°, 8.19(18)° and 7.91(17)°, respectively. Rings A and F deviate from the planar segment of the molecule with twist angles A/B and D/F of 48.46(9)° and 74.59(8)°, respectively.

3. Materials and Methods

3.1. General

Sodium hydroxide (98%), 4-fluorobenzaldehyde (99%), 4-methoxybenzaldehyde (98%), thiosemicarbazide (98%), triethylamine (99%), and solvents were obtained from different sources, including Merck (Gillingham, UK) and Thermo Fisher Scientific (Waltham, MA, USA). Melting points were determined using an Electrothermal melting point apparatus (Cole-Parmer, Illinois, IL, USA. The NMR spectra (δ in ppm and J in Hz) were recorded in dimethyl sulfoxide (DMSO-d₆) using a JEOL NMR 500 MHz spectrometer (Tokyo, Japan) at 500 MHz for the ¹H and 25 MHz for the ¹³C NMR measurements. Microanalyses of carbon, hydrogen, and nitrogen were carried out using a CHNS-932 (LECO) Vario elemental analyzer. Compounds 1 [35], 3b [36], 4b [29], 6 [36], 7 [37], 11 [38,39], and 12 [40] were prepared based on procedures in the literature.

3.2. Synthesis of Chalcones 3a,b

A mixture of 1a or 1b (12 mmol) and 2a or 2b (12 mmol) in EtOH (50 mL) was added slowly to a solution of NaOH (0.5 g, 12.2 mmol) in water (10 mL). The mixture was stirred at 25 °C for 4 h and the solid obtained was filtrated, washed with cold water, dried, and recrystallized from EtOH to give pure 3a or 3b.

3.2.1. (E)-3-(4-Methoxyphenyl)-1-(5-methyl-1-phenyl-1H-1,2,3-Triazol-4-yl)prop-2-en-1-one (3a)

Yield: 89%, mp 144–145 °C. ¹H NMR (ppm): 2.59 (s, 3H, Me), 3.79 (s, 3H, OMe), 7.00 (d, 8.6 Hz, 2H, Ar), 7.61–7.63 (m, 5H, Ph), 7.71 (d, 8.6 Hz, 2H, Ar), 7.79 (d, 16.0 Hz, 1H, CH), 7.86 (d, 16.0 Hz, 1H, CH). ¹³C NMR (ppm): 10.4 (Me), 55.9 (OMe), 115.1 (C3/C5 of Ar), 120.9 (CH), 126.0 (C2/C6 of Ph), 127.6 (C1 of Ar), 130.2 (C2/C6 of Ar), 130.6 (C4 of Ph), 131.1 (C3/C5 of Ph), 135.6 (C5 of triazolyl), 139.01 (C1 of Ph), 143.5 (C4 of triazolyl), 143.7 (CH), 162.0 (C4 of Ar), 183.8 (C=O). Anal. Calcd. for C₁₉H₁₇N₃O₂ (319.13): C, 71.46; H, 5.37; N, 13.16. Found: C, 71.53, H, 5.66, N, 13.23%.

3.2.2. (E)-3-(4-Fluorophenyl)-1-(1-(4-fluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)prop-2-en-1-one (3b)

Yield: 90%, mp 170–172 °C (lit. 168–170 [36]). The spectroscopic data of 3b agreed with those reported.

3.3. Synthesis of Pyrazolin-N-Thioamides 4a,b

To a suspension of chalcone 3a or 3b (10 mmol) and NaOH (1.0 g, 25 mmol) in EtOH (50 mL), thiosemicarbazide (1.1 g, 12 mmol) was added. The mixture was refluxed for 6 h and the solid obtained on cooling was filtered, washed with EtOH, and dried to give 4a or 4b.

3.3.1. 5-(4-Methoxyphenyl)-3-(5-methyl-1-phenyl-1H-1,2,3-triazol-4-yl)-4,5-dihydro-1H-pyrazole-1-carbothioamide (4a)

Yield: 82%, mp 183–185 °C. ¹H NMR (ppm) 2.96 (s, 3H, Me), 3.16 (d, 18.2 Hz, 1H, 1H of CH₂ of pyrazoline), 3.95 (s, 3H, OMe), 3.98 (dd, 8.1 and 18.2 Hz, 1H, pyrazolinyl), 5.86 (d, 8.1 Hz, 1H, 1H of CH₂ of pyrazoline), 6.85 (d, 8.6 Hz, 2H, Ar), 7.06 (d, 8.6 Hz, 2H, Ar), 7.57–7.59 (m, 5H, Ph), 8.03 (s, 1H, exch., NH). ¹³C NMR (ppm): 10.7 (Me), 40.5 (C4 of pyrazolinyl), 55.6 (OMe), 61.8 (C5 of pyrazolinyl), 114.4 (C3/C5 of Ar), 125.9 (C2/C6 of Ph), 127.2 (C2/C6 of Ar), 130.3 (C3/C5 of Ph), 130.5 (C4 of Ph), 135.1 (C1 of Ar), 135.3 (C1 of Ph), 135.9 (C5 of triazolyl), 137.5 (C4 of triazolyl), 150.8 (C3 of pyrazolinyl), 158.8 (C4 of Ar), 176.5 (C=S). Anal. Calcd. for C₂₀H₂₀N₆OS (392.14): C, 61.21; H, 5.14; N, 21.41. Found: C, 61.47, H, 5.42, N, 21.66%.

3.3.2. 5-(4-Fluorophenyl)-3-(1-(4-fluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)-4,5-dihydro-1H-pyrazole-1-carbothioamide (4b)

Yield: 87%, mp 230–232 °C (lit. 229–231 [29]). The spectroscopic data of 4b agreed with those reported.

3.4. Synthesis of Compounds 8–10

To a suspension of 4a or 4b (2 mmol) in EtOH (15 mL) and Et₃N (0.2 mL, 5 (0.16 g, 1 mmol), 6 (0.24 g, 1 mmol) or 7 (0.22 g, 1 mmol) was added. The mixture was heated under reflux for 2 h and the solid obtained on cooling was collected by suction filtration, washed with EtOH, and recrystallized from DMF to give the corresponding heterocycle 8, 9, or 10, respectively.

3.4.1. Ethyl 2-(5-(4-Methoxyphenyl)-3-(5-methyl-1-phenyl-1H-1,2,3-triazol-4-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-methylthiazole-5-carboxylate (8)

Yield: 77%, mp 145–146 °C. ¹H NMR (ppm, Hz): 1.33 (t, 7.0 Hz, 3H, MeCH₂), 2.38 (s, 3H, Me), 2.63 (s, 3H, Me), 3.37 (d, 4.8 Hz, 1H, 1H of CH₂ of pyrazoline), 3.42 (d, 4.8 Hz, 1H, 1H of CH₂ of pyrazolinyl), 3.73 (s, 3H, OMe), 4.21 (q, 7.0 Hz, 2H, MeCH₂), 5.70 (dd, 4.8 and 16.4 Hz, 1H, pyrazolinyl), 6.92 (d, 8.8 Hz, 2H, Ar), 7.22 (d, 8.8 Hz, 2H, Ar), 7.65–7.68 (m, 5H, Ar). ¹³C NMR (ppm): 10.6 (Me), 14.8 (Me), 18.0 (Me), 45.2 (C4 of pyrazolinyl), 55.5 (OMe), 60.4 (C5 of pyrazolinyl), 62.1 (MeCH₂), 110.8 (C3/C5 of Ar), 114.6 (C5 of thiazolyl), 125.7 (C2/C6 of Ph), 127.7 (C2/C6 of Ar), 130.2 (C3/C5 of Ph), 130.5 (C4 of Ph), 133.4 (C3 of pyrazolinyl), 134.8 (C1 of Ar), 135.8 (C1 of Ph), 137.2 (C5 of triazolyl), 150.5 (C4 of triazolyl), 159.2 (C4 of thiazolyl), 159.7 (C4 of Ar), 162.3 (C=O), 165.3 (C2 of thiazolyl). Anal. Calcd. for C₂₆H₂₆N₆O₃S (502.17): C, 62.13; H, 5.21; N, 16.72. Found: C, 62.29, H, 5.33, N, 16.85%.

3.4.2. 4-(Benzofuran-2-yl)-2-(5-(4-fluorophenyl)-3-(1-(4-fluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)-4,5-dihydro-1H-pyrazol-1-yl)thiazole (9)

Yield: 90%, mp 215–216 °C. ¹H NMR (ppm): 2.59 (s, 3H, Me), 3.43 (dd, 6.2 and 18.1 Hz, 1H, 1H of CH₂ of pyrazoline), 4.18 (dd, 11.9 and 18.1 Hz, 1H, 1H of CH₂ of pyrazoline), 5.68 (dd, 6.2 and 11.9 Hz, 1H, pyrazolinyl), 6.88 (s, 1H, thiazolyl), 7.18–7.22 (m, 3H, Ar), 7.26 (t, 7.6 Hz, 1H, benzofuranyl), 7.30 (s, 1H, benzofuranyl), 7.46–7.53 (m, 5H, Ar), 7.61 (d, 7.6 Hz, 1H, Ar), 7.71–7.73 (m, 2H, Ar). ¹³C NMR (ppm): 10.5 (Me), 45.0 (C4 of pyrazolinyl), 63.0 (C5 of pyrazolinyl), 103.1 (C3 of benzofuranyl), 107.4 (C5 of thiazolyl), 114.5 (C7 of benzofuranyl), 116.0 (d, 21.5 Hz, C3/C5 of Ar), 117.3 (d, 23.9 Hz, C3/C5 of Ar), 121.9 (C4 of benzofuranyl), 123.8 (C5 of benzofuranyl), 125.2 (C6 of benzofuranyl), 128.3 (d, 9.6 Hz, C2/C6 of Ar), 128.9 (C4a of benzofuranyl), 129.4 (d, 8.4 Hz, C2/C6 of Ar), 132.3 (C5 of triazolyl), 134.7 (C4 of triazolyl), 137.5 (C1 of Ar), 138.0 (C1 of Ar), 142.6 (C4 of thiazolyl), 148.7 (C2 of benzofuranyl), 152.4 (C7a of benzofuranyl), 154.6 (C3 of pyrazolinyl), 161.6 (d, 115.7 Hz, C-4 of Ar), 163.4 (d, 130.0 Hz, C4 of Ar), 165.7 (C2 of thiazolyl). Anal. Calcd. for C₂₉H₂₀F₂N₆OS (538.13): C, 64.67; H, 3.74; N, 15.60. Found: C, 64.77, H, 3.89, N, 15.88%.

3.4.3. 2-(5-(4-Fluorophenyl)-3-(1-(4-fluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)-4,5-dihydro-1H-pyrazol-1-yl)-5-((4-fluorophenyl)diazenyl)-4-methylthiazole (10)

Yield: 86%, mp 222–223 °C. ¹H NMR (ppm): 2.44 (s, 3H, Me), 2.58 (s, 3H, Me), 3.40 (dd, 4.3 and 18.1 Hz, 1H, 1H of CH₂ of pyrazoline), 4.20 (dd, 11.4 and 18.6 Hz, 1H, 1H of CH₂ of pyrazoline), 5.83 (dd, 4.3 and 11.4 Hz 1H, pyrazolinyl), 7.18 (app. t, 8.6 Hz, 2H, Ar), 7.24 (app. t, 8.6 Hz, 2H, Ar), 7.33 (m, 2H, Ar), 7.48 (app. t, 8.6 Hz, 2H, Ar), 7.67–7.71 (m, 4H, Ar). ¹³C NMR (ppm): 10.6 (Me), 16.5 (Me), 45.2 (C4 of pyrazolinyl), 61.8 (C5 of pyrazolinyl), 116.3 (d, 23.8 Hz, C3/C5 of Ar), 117.2 (d, 23.0 Hz, C3/C5 of Ar), 117.4 (d, 23.2 Hz, C3/C5 of Ar), 124.0 (d, 8.4 Hz, C2/C6 of Ar), 128.3 (d, 8.4 Hz, C2/C6 of Ar), 128.4 (d, 8.4 Hz, C2/C6 of Ar), 132.2 (C3 of pyrazolinyl), 135.5 (C5 of thiazolyl), 137.1 (C5 of triazolyl), 137.5 (C4 of thiazolyl), 140.9 (C1 of Ar), 149.5 (C1 of Ar), 151.6 (C1 of Ar), 158.7 (C4 of triazolyl), 161.3 (d, 83.5 Hz, C4 of Ar), 162.6 (d, 124.0 Hz, C4 of Ar), 163.8 (C2 of thiazolyl), 164.5 (d, 112.1 Hz, C4 of Ar). Anal. calcd. for C₂₈H₂₁F₃N₈S (558.15): C, 60.21; H, 3.79; N, 20.06. Found: C, 60.38, H, 3.91, N, 20.21%.

3.5. Synthesis of Compounds 13–15

To a suspension of compound 11a or 11b (2 mmol) in EtOH (15 mL) and Et₃N (0.2 mL), appropriate bromoketones 12a–12c (2 mmol) were added. The mixture was heated under reflux for 2 h and the solid obtained on cooling was collected by filtration, washed with EtOH, and recrystallized from DMF to give the corresponding compound 13–15.

3.5.1. 2-(3-(4-Chlorophenyl)-5-(4-fluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)-4-(5-methyl-1-phenyl-1H-1,2,3-triazol-4-yl)thiazole (13)

Yield: 85%, mp 237–238 °C. ¹H NMR (ppm): 2.18 (s, 3H, Me), 3.28 (dd, 7.7 and 17.8 Hz, 1H, 1H of CH₂ of pyrazoline), 3.99 (dd, 11.8 and 17.8 Hz, 1H, 1H of CH₂ of pyrazoline), 5.59 (dd, 7.7 and 11.8 Hz, 1H, pyrazolinyl), 7.13 (app. t, 9.0 Hz, 2H, Ar), 7.25 (s, 1H, 1H, thiazolyl), 7.38 (app. t, 9.0 Hz, 2H, Ar), 7.50–7.58 (m, 7H, Ph and Ar), 7.76 (d, 2H, 8.1 Hz, H2/H6 of Ph). ¹³C NMR (ppm): 9.7 (Me), 43.8 (C4 of pyrazolinyl), 64.8 (C5 of pyrazolinyl), 105.8 (C5 of thiazolyl), 115.9 (d, 21.5 Hz, C3/C5 of Ar), 125.8 (C2/C6 of Ph), 128.7 (C2/C6 of Ar), 129.1 (d, 8.4 Hz, C2/C6 of Ar), 129.4 (C3/C5 of Ph), 130.0 (C3/C5 of Ar), 130.1 (C4 of Ph), 130.3 (C5 of triazolyl), 131.1 (C3 of pyrazolinyl), 135.1 (C1 of Ar), 136.4 (C4 of Ar), 138.5 (C1 of Ph), 140.2 (C4 of triazolyl), 143.9 1 (C4 of thiazolyl), 152.5 (C1 of Ar), 161.9 (d, 240.8 Hz, C4 of Ar), 165.5 (C2 of thiazolyl). Anal. Calcd. for C₂₇H₂₀ClFN₆S (514.11): C, 62.97; H, 3.91; N, 16.32. Found: C, 63.11, H, 4.08, N, 16.49%.

3.5.2. 2-(3-(4-Chlorophenyl)-5-(4-fluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)-4-(5-methyl-1-(4-tolyl)-1H-1,2,3-triazol-4-yl)thiazole (14)

Yield: 84%, mp 252–253 °C. ¹H NMR (ppm): 2.15 (s, 3H, Me), 2.37 (s, 3H, Me), 3.28 (dd, 7.7 and 17.7 Hz, 1H, 1H of CH₂ of pyrazoline), 3.98 (dd, 11.9 and 17.7 Hz, 1H, 1H of CH₂ of pyrazoline), 5.58 (dd, 7.7 and 11.7 Hz, 1H, pyrazolinyl), 7.12 (app. t, 8.6 Hz, 2H, Ar), 7.24 (s, 1H, thiazolyl), 7.35–7.41 (m, 6H, Ar and Ph), 7.50 (d, 8.6 Hz, 2H, Ar), 7.75 (d, 8.6 Hz, 2H, Ar). ¹³C NMR (ppm): 9.7 (Me), 21.3 (Me), 43.8 (C4 of pyrazolinyl), 64.8 (C5 of pyrazolinyl), 105.7 (C5 of thiazolyl), 115.9 (d, 21.5 Hz, C3/C5 of Ar), 125.6 (C2/C6 of Ar), 128.6 (C2/C6 of Ar), 129.1 (d, 8.4 Hz, C2/C6 of Ar), 129.4 (C3/C5 of Ar), 130.4 (C5 of triazolyl), 130.5 (C3/C5 of Ar), 131.1 (C4 of triazolyl), 133.9 (C3 of pyrazolinyl), 134.0 (C1 of Ar), 135.1 (C4 of Ar), 139.8 (C1 of Ar), 140.1 (C4 of thiazolyl), 144.0 (C4 of Ar), 152.5 (C1 of Ar), 162.0 (d, 243.2 Hz, C4 of Ar), 165.4 (C2 of thiazolyl). Anal. Calcd. for C₂₈H₂₂ClFN₆S (528.13): C, 63.57; H, 4.19; N, 15.89. Found: C, 63.70, H, 4.14, N, 15.99.

3.5.3. 2-(5-(4-Fluorophenyl)-3-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl)-4-(5-methyl-1-(4-nitrophenyl)-1H-1,2,3-triazol-4-yl)thiazole (15)

Yield: 87%, mp 287–288 °C. ¹H NMR (ppm): 2.28 (s, 3H, Me), 3.24 (dd, 7.6 and 17.6 Hz, 1H, 1H of CH₂ of pyrazoline), 3.77 (s, 3H, OMe), 3.98 (dd, 11.4 and 17.7 Hz, 1H, 1H of CH₂ of pyrazoline), 5.54 (dd, 7.6 and 11.4 Hz, 1H, pyrazolinyl), 7.00 (d, 8.7 Hz, 2H, Ar), 7.13 (app. t, 8.6 Hz, 2H, Ar), 7.25 (s, 1H, thiazolyl), 7.37 (m, 2H, Ar), 7.69 (d, 8.6 Hz, 2H, Ar), 7.89 (d, 9.0 Hz, 2H, Ar), 7.39 (d, 8.6 Hz, 2H, Ar). ¹³C NMR (ppm): 9.9 (Me), 44.2 (C4 of pyrazolinyl), 55.9 (OMe), 64.5 (C5 of pyrazolinyl), 105.9 (C5 of thiazolyl), 114.8 (C3/C5 of Ar), 115.9 (d, 21.5 Hz, C3/C5 of Ar), 123.9 (C3/C5 of Ar), 125.5 (C2/C6 of Ar), 126.4 (C2/C6 of Ar), 127.6 (C3 of pyrazolinyl), 128.7 (C2/C6 of Ar), 129.0 (d, 8.3 Hz, C2/C6 of Ar), 131.4 (C5 of triazolyl), 138.7 (C4 of thiazolyl), 140.8 (C1 of Ar), 141.2 (C4 of triazolyl), 143.4 (C1 of Ar), 147.9 (C4 of Ar), 153.5 (C1 of Ar), 160.1.2 (d, 46.5 Hz, C4 of Ar), 165.8 (C2 of thiazolyl). Anal. Calcd. for C₂₈H₂₂FN₇O₃S (555.15): C, 60.53; H, 3.99; N, 17.65. Found: C, 60.69, H, 3.89, N, 17.81%.

3.6. Crystal Structure Determination

Single-crystal X-ray diffraction data were collected at room temperature on an Agilent SuperNova Dual Atlas diffractometer with mirror-monochromated Cu or Mo radiation. SHELXS [41] and SHELXL [42] were used for crystal structure solution and refinement. Anisotropic displacement parameters were used in the refinement for non-hydrogen atoms. A riding model with idealized geometry was used for the hydrogen atoms and Uiso(H) were set at 1.2 of 1.5 the values for the atom to which the hydrogen atoms are bonded. Crystal data, data collection and structure refinement details are summarized in

Table 1. Data collection and refinement data for compounds 3a, 4a, 8–10, and 14.

	3a	4a	8	9	10	14
MF	C19H17N3O2	C20H20N6OS	C26H28N6O4S	C29H20F2N6OS	C28H21F3N8S	C28H22ClFN6S
FW	319.35	392.48	520.60	538.57	558.59	529.02
T (K)	296 (2)	296 (2)	296 (2)	298 (2)	296 (2)	293 (2)
λ (Å)	0.71073	1.54184	0.71073	0.71073	0.71073	0.71073
System	Triclinic	Orthorhombic	Monoclinic	Triclinic	Triclinic	Monoclinic
Space group	$\mathrm{P}\overline{1}$	Pca21	P21/n	$\mathrm{P}\overline{1}$	$\mathrm{P}\overline{1}$	P21/c
A (Å)	8.7987 (7)	23.0527 (11)	17.7187 (7)	6.5793 (4)	11.4945 (5)	12.7331 (8)
b (Å)	9.4342 (11)	11.8887 (5)	7.6878 (4)	13.1589 (8)	14.8707 (6)	21.2977 (9)
c (Å)	10.6006 (13)	7.2229 (3)	19.1203 (9)	16.0368 (12)	16.2570 (6)	9.7424 (5)
α (°)	85.681 (10)	90	90	65.959 (6)	96.807 (3)	90
β (°)	72.823 (9)	90	94.160 (4)	82.697 (5)	95.999 (4)	105.329 (6)
γ (°)	79.304 (9)	90	90	87.701 (5)	106.731 (4)	90
Volume (Å3)	825.89 (16)	1979.56 (15)	2597.7 (2)	1257.58 (15)	2614.20 (19)	2548.0 (2)
Z	2	4	4	2	4	4
D (Mg/m−3)	1.284	1.317	1.331	1.422	1.419	1.379
μ/(mm−1)	0.085	1.641	0.169	0.180	0.180	0.269
F (000)	336	824	1096	556	1152	1096
Crystal size (mm3)	0.480 × 0.170 × 0.120	0.326 × 0.092 × 0.045	0.329 × 0.144 × 0.062	0.275 × 0.142 × 0.091	0.434 × 0.156 × 0.065	0.278 × 0.122 × 0.119
Reflections collected	6864	9173	24844	11051	25295	24815
Independent reflections	3935	3397	6550	5939	11910	6378
R (int)	0.0369	0.0222	0.0616	0.0341	0.0327	0.0282
Goodness-of-fit on F2	1.057	1.050	1.030	1.031	1.012	1.036
R1 [I > 2sigma(I)]	0.0627	0.0369	0.0573	0.0538	0.0508	0.0487
wR2 [I > 2sigma(I)]	0.1639	0.0955	0.1380	0.1156	0.1233	0.1194
R1 (all data)	0.0928	0.0400	0.1006	0.0868	0.0945,	0.0834
wR2 (all data)	0.1935	0.0989	0.1640	0.1386	0.1523	0.1395
Largest diff. peak and hole (e.Å−3)	0.231/−0.196	0.137/−0.170	0.275/−0.245	0.197/−0.283	0.221/−0.265	0.234/−0.316

MF: molecular formula, FW: formula weight, T: temperature, λ: wavelength, D: calculated density, and μ: absorption coefficient.

. The crystal structures have been deposited in the Cambridge Structural Database under reference CCDC Numbers 2220613–2220618.

4. Conclusions

Novel 2-(1,2,3-triazol-4-yl)-4,5-dihydro-1H-pyrazol-1-yl)thiazoles and 2-(4,5-dihydro-1H-pyrazol-1-yl)-4-(1H-1,2,3-triazol-4-yl)thiazoles were synthesized in high yields using facile methods and their chemical structures were established using spectral data and the single crystal X-ray diffraction.