13C NMR spectroscopy of heterocycles: 1-phenyl-3-aryl/t-butyl-5-arylpyrazoles

Amy N. Hockstedler; Beatrice A. Edjah; Saajid Z. Azhar; Hadrian Mendoza; Nicole A. Brown; Hayley B. Arrowood; Andrew C. Clay; Anand B. Shah; Glenda M. Duffek; Jianmei Cui; Alfons L. Baumstark

doi:10.1515/hc-2017-0034

Article Open Access

¹³C NMR spectroscopy of heterocycles: 1-phenyl-3-aryl/t-butyl-5-arylpyrazoles

Amy N. Hockstedler , Beatrice A. Edjah , Saajid Z. Azhar , Hadrian Mendoza , Nicole A. Brown , Hayley B. Arrowood , Andrew C. Clay , Anand B. Shah , Glenda M. Duffek , Jianmei Cui and Alfons L. Baumstark

Published/Copyright: March 30, 2017

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From the journal Heterocyclic Communications Volume 23 Issue 2

Abstract

A series of chalcones 1–12 were converted to pyrazolines (1Pi–12Pi) by reaction with phenylhydrazine followed by DDQ oxidation to produce the corresponding pyrazoles (1Pz–12Pz). Three 1-phenyl-3-t-butyl-5-arylpyrazoles (13Pz–15Pz) were synthesized using an analogous approach. Molecular modeling studies predicted the 5-aryl group of the pyrazoles for both series to have a torsion angle of 52°–54° whereas the 1-phenyl group was predicted to have 35°–37° torsion angles. The 3-aryl group was predicted to be essentially coplanar (−3°) with the pyrazole system in the first series. ¹³C NMR data for both series, 1Pz–12Pz and 13Pz–15Pz, were collected in DMSO-d₆ at 50°C. A plot of the C4 chemical shifts for 1Pz–12Pz versus Hammet constants for 5-aryl substituents yielded a very good linear correlation (R²=0.96) with a slope of 1.5. The chemical shift data for C4 showed little or no dependence on 3-aryl substituents. The result for 13Pz–15Pz, despite only three points, was consistent with the first series results and yielded a ρ value of 2.0. Distal transmission of substituent effects (5-aryl groups) to C4 of the pyrazole system was reduced by roughly 50–60% of that of the analogous planar isoxazole system, but are not consistent with results for the similarly twisted 4-bromoisoxazoles.

Keywords: 13C NMR; 1-phenyl-3,5-diarylpyrazoles; 1-phenyl-3-t-butyl-5-arylpyrazoles; substituent effects

Introduction

¹³C NMR spectroscopy has proven to be useful to investigate transmission of substituent effects in aromatic and heteroaromatic systems [1]. Recently, in a ¹³C NMR study of transmission in the 4-bromoisoxazole system it has been found that the effect of the 5-aryl group is essentially the same as that in the planar isoxazole system despite the large torsion angle observed in the former [2]. In the isoxazole system, the substituent effect from the 5-aryl group is readily observed in chemical shift difference at the C4 of the 3,5-diarylisoxazole ring system where little or no effect is observed from the 3-aryl group [2]. Furthermore, the previous studies have suggested that resonance contributions are of greater importance than inductive contributions in both the planar isoxazoles and the twisted 4-bromoisoxazoles [2], [3]. We were interested in the evaluating distal transmission in a different heterocyclic system to compare/contrast with the isoxazole results. Herewith, we report the ¹³C NMR study of a series of 1-phenyl-3,5-diarylpyrazoles and a series of 1-phenyl-3-t-butyl-5-arylpyrazoles in DMSO-d₆.

Results and discussion

The reaction of chalcones 1–12 with phenylhydrazine produced the corresponding pyrazolines 1Pi–12Pi in low to moderate yield. Subsequent oxidation by 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) or singlet oxygen [4] furnished the corresponding pyrazoles 1Pz–12Pz in low to moderate isolated yield (Scheme 1). A similar treatment of 2,2-dimethyl-5-aryl-4-penten-1-ones 13–15 yielded pyrazolines 13Pi–15Pi and subsequently pyrazoles 13Pz–15Pz (Scheme 2) in low isolated yields. The structures of the recrystallized compounds are fully consistent with spectral and physical data.

Scheme 1

Scheme 2

The 3D-structures of 1,3,5-triphenylpyrazole (5Pz) and 1-phenyl-3-t-butyl-5-phenylpyrazole (13Pz) were calculated by molecular modeling methods. The calculations predicted molecule 5Pz to have a torsion angle of 3° for the 3-aryl group, 35° for the N-phenyl group and 54° for the 5-phenyl group (Figure 1). This prediction for the 5-aryl group in the pyrazole is similar to that found for the 5-aryl group in the 4-bromoisoxazole system and in contrast with the planarity found in the 3,5-diaryl isoxazole system [2]. Similarly, molecular modeling calculations for 13Pz predicted the torsion angles for the 5-aryl group and the N-phenyl group to be 52° and 37°, respectively, (Figure 2) which is consistent with predicated values for 5Pz.

Figure 1

Molecular modeling predicted structures for 1,3,5-triphenylpyrazole (5Pz).

(Left) Top view. (Right) Side view.

Figure 2

Molecular modeling predicted structures for 1,5-diphenyl-3-t-butylpyrazole (13Pz). (Left) Top view. (Right) Side view.

The signals for the pyrazoles were assigned from their corresponding ¹³C NMR spectra taken in DMSO-d₆. As expected, the signal for the C4 of the pyrazole ring is sensitive to substitution on the 5-aryl group and, despite the limited number (5) of examples, appears insensitive to substitution on the 3-aryl group. The chemical shift data are summarized in Table 1 for pyrazoles 1Pz–12Pz and in Table 2 for the 3-t-butyl analogs 13Pz–15Pz.

Table 1

¹³C NMR chemical shifts for pyrazoles 1Pz–12Pz in DMSO-d₆ at 50°C.

Compound	X/Y	Chemical shift (δ)
Compound	X/Y	C3	C4	C5	X/Y	a/a′/a″	b/b′/b″/c/c′/c″/d/d′/d″^a
1Pz	4-MeO/H	139.8	104.7	150.8	55.0	143.8^e 125.2^e 130.0^e	159.1^d/128.7/128.3/128.2/128.1/ 127.3/126.5/124.9/114.0
2Pz	4-MeO/4′-Br	139.7	104.6	149.6	55.0	144.1^e 127.5^e 131.9^e	159.2^d/131.4/129.6/128.8/127.2/ 125.0/122.0^d/120.8/113.9
3Pz	4-Me/H	139.8	104.8	150.8	20.6	144.1^e 127.0^e 132.6^e	137.8^d/129.0/128.9/128.5/128.2/127.8/ 127.5/125.2/125.1
4Pz	4-Et/4′-F	139.9	104.9	150.1	15.0 27.7	144.4^e 126.3^e 129.3^e (d, J=2.7 Hz)	162.0^d (d, J=244.8)/ 44.2^d/129.0/128.3/ 127.9/127.7/127.3 (d, J=8.23 Hz)/125.2/115.5 (d, J=21.5 Hz)
5Pz^b	H/H	139.8	105.1	150.9		144.1^e 129.9^e 132.6^e	128.9/128.6/128.4/128.4/127.9/127.6/ 125.3/125.1
6Pz	H/4-MeO	140.0	104.9	151.2	55.4	144.3^e 125.5^e 130.2^e	159.5^d/129.2/128.7/128.6/128.6/127.8/ 127.0/125.4/114.4
7Pz	H/4-Cl	139.6	105.1	150.0		144.2^e 129.7^e 131.4	132.3^d/128.8/128.5/128.3/128.2/127.6/ 126.9/125.0
8Pz^b	H/4-Br	139.6	105.2	149.8		144.2^e 129.7^e 131.8^e	131.5/128.8/128.3/128.3/127.6/ 127.2/125.0/120.9^d
9Pz	4-Cl/H	139.4	105.3	150.9		142.7^e 128.6^e 132.4^e	133.1^d/130.0/128.6/128.5/128.4/127.8/ 127.6/125.2/125.0
10Pz^b	4-Br/H	139.9	105.5	150.3		128.3^e 132.1^e	132.0/130.0/129.4/128.9/128.7/ 127.7/125.6/121.4^d
11Pz^c	3,4-DiCl/H	139.3	105.9	151.2		141.6^e 130.4^e 132.4^e	131.4^d/131.2^d/130.6/130.1/129.2/128.7/ 128.4/128.1/125.4
12Pz	4-CF₃/H	139.4	105.9	151.2	124.4^d (q, J=272.4 Hz)	142.6^e 133.8^e 132.4^e	129.1/129.0/128.8^d (q, J=32.4 Hz)/ 128.6/128.0/127.9/125.3(q, J=3.7)/ 125.3/125.2

^aNot assigned specifically, listed in descending order; ^b1 aryl signal not resolved; ^c2 aryl signals not resolved; ^dipso; ^equaternary.

Table 2

¹³C NMR chemical shifts for pyrazoles 13Pz–15Pz in DMSO-d₆ at 50°C.

Compound	X	Chemical shift (δ)
Compound	X	C3	C4	C5	C6	C7	a/a′	b/b′/c/c′/d/d′^a
13Pz	H	140.0	104.5	161.4	31.7	30.2	130.4	128.7/128.6
							142.6	128.2/128.1
								127.8/126.8
14Pz	4-Br	139.7	104.8	161.7	31.8	30.2	129.6	131.3/130.2
							141.5	128.9/127.2
								124.9/121.4^b
15Pz	4-NO₂	139.5	106.0	162.0	31.6	30.1	136.6	150.8^b/129.1
							140.6	129.0/127.6
								125.1/123.4

^aNot assigned specifically, listed in descending order; ^bipso.

The chemical shifts for C4 of the pyrazoles 1Pz–12Pz and 13Pz–15Pz were plotted versus Hammett constants [5] for 5-aryl substituents (Figure 3). The chemical shift data for C4 show little or no variation with 3-aryl substituents. A very good correlation (R²=0.96) was obtained for series one with sigma values with a slope of approximately 1.5. The ρ value is roughly 40% of that observed (~4.0) for the analogous treatment of the isoxazole system [3]. The correlation is less significant versus sigma plus values, in contrast to the isoxazole and 4-bromoisoxazole findings [2]. Despite only three data points, the results for the second series (t-butyl analogs) also provide a very good correlation with sigma constants with a ρ value of ~2.0, consistent with the results found for series one.

Figure 3

Plot of chemical shift data for C4 vs sigma constants for 5-aryl substituents only (3-aryl Hammett constants excluded) of 1,3-diphenyl-5-arylpyrazoles, 1-phenyl-3,5-diarylpyrazoles (■, 1Pz–12Pz) and 1-phenyl-3-t-butyl-5-arylpyrazoles (▲, 13Pz–15Pz).

Conclusion

The overall reduction in transmission of substituent effects for the 5-aryl group to C4 of the pyrazole compared to the planar isoxazole system is consistent with expectations based on the predicted torsion angle difference of 52°–54° between the 5-aryl group and the central pyrazole ring. Interestingly, the present results contrast with those obtained for the 4-bromoisoxazole twisted system [2] in which essentially no reduction of transmission is observed despite the apparent similarity of the 5-aryl-central ring torsional angles. Additional research on other related heterocyclic systems will be necessary to address the fundamental reasons for this discrepancy.

Experimental

Chemicals were purchased from commercial sources and were used without additional purification. All compounds were purified by crystallization from ethanol and characterized by spectral and physical methods. Melting points were determined using a Stuart SMP10 apparatus and are uncorrected. ¹H NMR spectra were obtained at 23°C in CDCl₃ on a 60 MHz FT spectrometer. ¹³C NMR spectra were obtained at 50°C in DMSO-d₆ at 500 MHz on a Bruker 500 UltraShield™ NMR instrument and referenced to the solvent at 39.50 ppm. ¹³C Decoupled and ¹³C DEPT 135 methods were used to assign the chemical shifts of compounds 12Pi and 12Pz (see Figure S1 in Supplementary Material). Molecular modeling studies were conducted using the Spartan ’10. The initial structure was generated using MMFF force field and minimized using the ab initio method (Hartree-Fock with a 3-21G basis set). Exact mass data (ESI, M⁺+1) were obtained at Georgia State University.

Chalcones 1–12 and (E)-4,4-dimethyl-1-aryl-1-penten-3-ones 13–15

The α,β-unsaturated ketones were prepared by the cross-aldol reaction of the appropriately substituted benzaldehyde (0.08 mol) with the appropriate acetophenone (0.08 mol) or pinacolone (0.16 mol) in ethanol with sodium hydroxide. Use of an additional equivalent of pinacolone increased the yields of 13–15. The reaction mixture was shaken for approximately 2 h and stored overnight at −20°C. The resulting solid was filtered, washed with water and crystallized from ethanol. The physical and spectra data for 1, 3, 5–15 were in good agreement with the literature values [6], [7], [8], [9], [10]. Chalcones 2 and 4 have not been previously reported.

(E)-1-(4-Bromophenyl)-3-(methoxyphenyl)-prop-2-en-1-one (2)

Yellow crystals; mp 145–47°C; yield 45%; ¹H NMR: δ 3.8 (s, 3H), 7.6 (s, 1H), 7.9(s, 1H), 7.4–7.9 (m, 8H); ¹³C NMR: δ 55.2, 114.2, 119.2, 126.6, 127.1, 130.1, 130.5, 131.5, 136.7, 144.2, 161.3, 188.0. ESI-MS. Calcd for C₁₆H₁₄O₂Br (M⁺ +H): m/z 317.0172. Found: m/z 317.0177.

(E)-3-(4-Ethylphenyl)-1-(4-fluorophenyl)-prop-2-en-1-one (4)

Yellow crystals: mp 94–96°C; yield 73%; ¹H NMR: δ 1.2 (t, 3H); 2.7 (q, 2H), 7.3(s, 1H), 7.5(s, 1H), 7–8.2 (m, 8H); ¹³C NMR: δ 15.0, 28.0, 115.6 (d, J=21.9 Hz), 120.9, 128.2, 128.8, 131.2 (d, J=9.4 Hz), 132.1, 134.4, 144.2, 146.9, 164.9 (d, J=251.9 Hz), 187.8 (s). ESI-MS. Calcd for C₁₇H₁₆OF (M⁺ +H): m/z 255.1180. Found: m/z 255.1169.

1-Phenyl-3-aryl/t-butyl-5-arylpyrazolines 1Pi–15Pi

Compounds 1Pi–15Pi were prepared by using the standard methodology [4]. To a solution of 0.01 mol of the appropriate chalcone in a minimum amount of acetic acid (~20–50 mL), 0.015 mol of phenylhydrazine was added at room temperature. The solution was heated to 80–90°C for 1 h, then allowed to cool and sit open to the atmosphere for 24 h. The crude crystals were filtered and analyzed by ¹H NMR. Heating of the post-reaction mixture is necessary to reduce or eliminate the isolation of hydrazone intermediates (generally colored material). Crystallization from ethanol yielded pure samples (generally white crystals). Isolated yields ranged up to 70% and were not optimized. Physical and spectra data were in good agreement with the published values for 1Pi, 3Pi, 5Pi–7Pi, 9Pi, and 10Pi [4], [11], [12], [13], [14]. Compound 8Pi is known [15] as is 13Pi [16] but the ¹³C data have not been reported. Compounds 2Pi, 4Pi, 11Pi, 12Pi, 14Pi and 15Pi have not been previously reported.

1,3-Diphenyl-5-(4-methoxyphenyl)pyrazoline (1Pi)

Mp 123–124°C (lit [4] mp 119–121°C); ¹H NMR: δ 2.9–3.2 (m, 1H), 3.8 (s, 3H), 3.5–4.1 (m, 1H), 5.0–5.3 (m, 1H), 6.5–7.8 (m, 14H).

3-(4-Bromophenyl)-5-(4-methoxyphenyl)-phenyl-2-pyrazoline (2Pi)

Yellow crystals; mp 174–175°C; yield 72%; ¹H NMR: δ 2.8–3.3 (m, 1H), 3.8 (s, 3H), 3.5–4.1 (m, 1H), 5.1–5.4 (m, 1H), 6.7–7.7 (m, 13H); ¹³C NMR: δ 42.6, 54.9, 62.9, 113.0, 114.2, 118.6, 121.4, 126.9, 127.3, 128.5, 131.3, 131.5, 134.1, 144.0, 145.9, 158.4. ESI-MS. Calcd for C₂₂H₂₀N₂OBr (M⁺ +H): m/z 407.0754. Found: m/z 407.0750.

1,3-Diphenyl-5-(4-methylphenyl)pyrazoline (3Pi)

Mp 133–134°C (lit [15] mp 133–135°C); ¹H NMR: δ 2.3 (s, 3H), 2.9–3.2 (m, 1H), 3.5–4.1 (m, 1H), 5.0–5.4 (m, 1H), 6.8–7.8 (m, 14H).

5-(4-Ethylphenyl)-3-(4-fluorophenyl)-phenyl-2-pyrazoline (4Pi)

Yellow crystals; mp 83–85°C; yield 73%; ¹H NMR: δ 1.3 (t, 3H), 2.8 (q, 2H), 2.9–3.2 (m, 1H), 3.5–4.1 (m, 1H), 5.1–5.4 (m, 1H), 7.3–7.9 (m, 13H); ¹³C NMR: δ 15.0, 27.5, 42.9, 63.1, 112.9, 115.5 (d, J=21.9 Hz), 118.4, 125.6, 127.6 (d, J=250 Hz), 128.1, 128.6 (d, J=3.2 Hz), 139.6, 142.7, 144.3, 146.2, 161.2, 163.1. ESI-MS. Calcd for C₂₃H₂₂N₂F (M⁺ +H): m/z 345.1762. Found: m/z 345.1749.

1,3,5-Triphenylpyrazoline (5Pi)

Mp 135–137°C (lit [13] mp 135–137°C); ¹H NMR: δ 2.9–3.2 (m, 1H), 3.5–4.1 (m, 1H), 5.1–5.4 (m, 1H), 6.8–7.8 (m, 15H).

1,5-Diphenyl-3-(4-methoxyphenyl)pyrazoline (6Pi)

Mp 140–142°C (lit [13] mp 139.5–141°C); ¹H NMR: δ 2.9–3.2 (m, 1H), 3.5–4.1 (m, 1H), 3.9 (s, 3H) 5.0–5.4 (m, 1H), 6.9–7.7 (m, 14H).

3-(4-Chlorophenyl)-1,5-diphenylpyrazoline (7Pi)

Mp 149–151°C (lit [13] mp 148–149°C); ¹H NMR: δ 2.8–3.2 (m, 1H), 3.5–4.1 (m, 1H), 5.1–5.4 (m, 1H), 6.8–7.8 (m, 14H).

3-(4-Bromophenyl)-1,5-diphenyl-2-pyrazoline (8Pi)

Yellow crystals; mp 156–157°C (lit [15] mp 156–157°C); yield 18% ¹H NMR: δ 2.9–3.2 (m, 1H), 3.5–4.1 (m, 1H), 5.0–5.4 (m, 1H), 6.8–7.6 (m, 14H); ¹³C NMR: δ 42.6, 63.3, 113.0, 118.7, 121.5, 125.6, 127.3, 128.2, 128.6, 128.7, 131.3, 131.4, 142.1, 143.9, 146.0. ESI-MS. Calcd for C₂₁H₁₆N₂Br (M⁺ +H): m/z 377.0491. Found: m/z 377.0469.

5-(4-Chlorophenyl)-1,3-diphenylpyrazoline (9Pi)

Mp 133–135°C (lit [13] mp 135–137°C); ¹H NMR: δ 2.8–3.2 (m, 1H), 3.5–4.1 (m, 1H), 5.1–5.4 (m, 1H), 6.8–7.8 (m, 14H).

5-(4-Bromophenyl)-1,3-diphenylpyrazoline (10Pi)

Mp 126–128°C (lit [15] mp 128–130°C); ¹H NMR: δ 2.9–3.2 (m, 1H), 3.5–4.1 (m, 1H), 5.1–5.4 (m, 1H), 6.8–7.8 (m, 15H).

5-(3,4-Dichlorophenyl)-1,3-diphenylpyrazoline (11Pi)

Yellow crystals; mp 107–108°C; yield 17%; ¹H NMR: δ 3.0–3.3 (m, 1H), 3.5–4.2 (m, 1H), 5.1–5.4 (m, 1H), 6.5–7.1 (m, 13H); ¹³C NMR: δ 42.5, 62.0, 113.0, 121.5, 125.7, 127.2, 127.4, 128.6, 128.8, 131.4, 131.4 142.2, 114.0, 146.0. ESI-MS. Calcd for C₂₁H₁₇N₂Cl (M⁺ +H): m/z 367.0738. Found: m/z 367.0756.

1,3-Diphenyl-5-(4-trifluorophenyl)pyrazoline (12Pi)

Yellow crystals; mp 148–149°C; yield 21%; ¹H NMR: δ 2.9–3.3 (m, 1H), 3.5–4.1 (m, 1H), 5.2–5.5 (m, 1H), 6.9–7.8 (m, 14H); ¹³C NMR: δ 42.7, 62.7, 113, 118.8, 125.6, 125.8, 125.8, 126.7, 128.5, 128.7, 128.8, 132.0, 114.1, 147.0, 147.3. ESI-MS. Calcd for C₂₁H₁₈N₂F₃ (M⁺ +H): m/z 367.1420. Found: m/z 367.1422.

1,5-Diphenyl-3-tert-butylpyrazoline (13Pi)

White crystals; mp 109–110°C (lit [15] mp 108–108.5°C); ¹HNMR: δ 1.2 (s, 9H), 2.4–2.9 (m, 1H), 3.2–3.7 (m, 1H), 4.8–5.2 (m, 1H), 6.8–8.3 (m, 10H); ¹³C NMR: δ 27.8, 33.1, 42.4, 63.4, 112.5, 117.6, 125.6, 126.9, 128.3, 128.6, 142.8, 145.5, 158.6. ESI-MS. Calcd for C₁₉H₂₃N₂ (M⁺ +H): m/z 279.1856. Found: m/z 279.1844.

5-(4-Bromophenyl)-3-(tert-butyl)-1-phenylpyrazoline (14Pi)

Yellow crystals; mp 136–139°C; yield 33%; ¹H NMR: δ 1.2 (s, 9H), 2.6–2.9 (m, 1H), 3.3–3.8 (m, 1H), 4.8–5.2 (m, 1H), 6.9–7.8 (m, 9H); ¹³C NMR: δ 27.7, 33.2, 42.2, 62.7, 112.6, 117.9, 120.0, 127.9, 128.5, 131.5, 142.2, 145.3, 158.8. ESI-MS. Calcd for C₁₉H₂₂N₂Br (M⁺ +H): m/z 357.0966. Found: m/z 357.0952.

5-(4-Nitrophenyl)-3-(tert-butyl)-1-phenylpyrazoline (15Pi)

Yellow crystals: mp 154–155°C; yield 27%; ¹H NMR: δ 1.2 (s, 9H), 2.4–2.9 (m, 1H), 3.3–3.8 (m, 1H), 4.9–5.2 (m, 1H), 6.8–8.3 (m, 9H). ESI-MS. Calcd for C₁₉H₂₂N₃O₂F₃ (M⁺ +H): m/z 324.1711. Found: m/z 324.1705.

1-Phenyl-3-aryl/t-butyl-5-arylpyrazoles 1Pz–15Pz

Compounds 1Pz–15Pz were synthesized from the appropriate pyrazolines by treatment with DDQ [17]. Pure pyrazoline (0.5–1.0 g) was dissolved in 5 mL of toluene. Three equivalents of DDQ were added and the mixture was heated under reflux. Reaction progress was monitored by TLC (silica gel; eluent dichloromethane/hexanes). Reaction time was found to be dependent on substituents. Compounds with strong withdrawing groups required heating under reflux for up to 24 h; the reactions of compounds with donating groups were completed in 3 h. Upon completion, approximately 10 mL NaOH was added to the mixture followed by 10–25 mL of aqueous saturated NaCl solution and 25–50 mL of dichloromethane. The organic layer was separated and the solid material removed by filtration. The organic layer was placed on a rotary evaporator and the solvents removed. The residue was crystallized from ethanol to remove traces of starting material and any residual hydroquinone. In general, the pyrazoles were slow to crystallize and the isolated yields generally ranged from 20% to 60% and were not optimized. Physical and spectra data for recrystallized samples of 1Pz, 3Pz, 5Pz–10Pz, and 12Pz were in good agreement to the published values [4], [18], [19], [20], [21], [22]. Compounds 2Pz and 11Pz have been reported [19], [22] without ¹³C NMR data. Compounds 4Pz and 13Pz, 14Pz, and 15Pz have not been previously reported.

1,3-Diphenyl-5-(4-methoxyphenyl)-pyrazole (1Pz)

Mp 77–79°C (lit [18] mp 77–78°C); yield 27%; ¹H NMR: δ 3.8 (s, 3H), 6.8 (s, 1H), 7.1–7.5 (m, 9H), 7.8–8.0 (m, 5H).

3-(4-Bromophenyl)-5-(4-methoxyphenyl)-1-phenylpyrazole (2Pz)

Mp 136–138°C (lit [19] mp 139°C); yield 45%; ¹H NMR: δ 3.8 (s, 3H), 6.8 (s, 1H), 7.1–7.9 (m, 13H). ESI-MS. Calcd for C₂₂H₁₈OBr (M⁺ +H): m/z 405.0602. Found: m/z 405.0581.

1,3-Diphenyl-5-(4-methylphenyl)pyrazole (3Pz)

Mp 114–116°C (lit [13] mp 115–116°C); yield 11%; ¹H NMR: δ 3.8 (s, 3H), 6.8 (s, 1H), 7.1 (m, 4H), 7.2–7.5 (m, 5H), 7.9–8 (m, 5H). ESI-MS. Calcd for C₂₁H₁₉N₂ (M⁺ +H): m/z 311.1543. Found: m/z 311.1533.

5-(4-Ethylphenyl)-3-(4-fluorophenyl)-1-phenylpyrazole (4Pz)

Yellow crystals; mp 44–46°C; yield 18%; ¹H NMR: δ 1.3 (t, J=7 Hz, 3H), 2.8 (q, J=7 Hz, 2H), 6.8 (s, 1H), 7.0–7.4 (m, 8H), 7.8–8.1 (m, 5H). ESI-MS. Calcd for C₂₃H₂₀N₂F (M⁺ +H): m/z 343.1605. Found: m/z 343.1590.

1,3,5-Triphenylpyrazole (5Pz)

mp 135–138°C (lit [20] mp 136–137°C); yield 67%. ¹H NMR: δ 6.8 (s, 1H), 7.2–7.6 (m, 13H), 7.9 (d, 2H).

1,5-Diphenyl-3-(4-methoxyphenyl)pyrazole (6Pz)

Mp 137–139°C (lit [13] mp 137–139°C) [13]; yield 52%; ¹H NMR: δ 3.8 (s, 3H), 6.8 (s, 1H), 7.0–7.3 (m, 4H), 7.8–8.0 (m, 10H).

3-(4-Chlorophenyl)-1,5-diphenylpyrazole (7Pz)

mp 134–135°C (lit [21] mp 135–136°C); yield 35%; ¹H NMR: δ 6.8 (s, 1H), 7.1–7.5 (m, 10H), 7.7–7.9 (m, 5H).

3-(4-Bromophenyl)-1,5-diphenylpyrazole (8Pz)

Mp 154–155°C (lit [18] mp 152–154°C); yield 97%; ¹H NMR: δ 6.8 (s, 1H), 7.1–7.5 (m, 10H), 7.5–7.8 (d, 2H), 7.8–7.9 (d, 2H). ESI-MS. Calcd for C₂₁H₁₆N₂Br (M⁺ +H): m/z 375.0491. Found: m/z 375.0490.

5-(4-Chlorophenyl)-1,3-diphenylpyrazole (9Pz)

Mp 105–107°C (lit [22] mp 106–108°C); yield 30%; ¹H NMR: δ 6.8 (s, 1H), 7.2–7.6 (m, 10H), 7.8–8.1 (m, 5H).

5-(4-Bromophenyl)-1,3-diphenylpyrazole (10Pz)

¹H NMR: δ 6.8 (s, 1H), 7.1–7.6 (m, 10H), 7.8–8.1 (m, 5H). ESI-MS. Calcd for C₂₁H₁₆N₂Br (M⁺ +H): m/z 375.0491. Found: m/z 375.0485.

5-(3,4-Dichlorophenyl)-1,3-diphenylpyrazole (11Pz)

Yellow crystals; mp 82°C (lit [22] mp 83–84°C); yield 32%; ¹H NMR: δ 6.8 (s, 1H), 6.9–7.1 (m, 3H), 7.2–7.5 (m, 5H), 7.8–7.9 (m, 5H). ESI-MS. Calcd for C₂₁H₁₅Cl₂N₂ (M⁺ +H): m/z 365.0607. Found: m/z 365.0595.

1,3-Diphenyl-5-(4-trifluorophenyl)pyrazole (12Pz)

mp 140–142°C (lit [18] mp 154–156°C); yield 59%; ¹H NMR: δ 6.9 (s, 1H), 7.1 (d, 2H) 7.6–7.6 (m, 8H), 7.8–8.0 (m 4H). ESI-MS. Calcd for C₂₂H₁₆N₂F₃ (M⁺ +H): m/z 365.1260. Found: m/z 365.1254.

1,5-Diphenyl-3-tert-butylpyrazole (13Pz)

White crystals; mp 109–110°C; yield 72%; ¹H NMR: δ 1.4 (s, 9H), 6.3 (s, 1H), 6.7–7.4 (m, 10H). ESI-MS. Calcd for C₁₉H₂₃N₂ (M⁺ +H): m/z 279.1856. Found: m/z 279.1844.

5-(4-Bromophenyl)-3-(tert-butyl)-1-phenylpyrazole (14Pz)

Yellow crystals; mp 139–139°C; yield 33%; ¹H NMR: δ 1.4 (s, 9H), 6.4 (s, 1H), 6.9–7.5 (m, 9H); ESI-MS. Calcd for C₁₉H₂₀N₂Br (M⁺ +H): m/z: 355.0804. Found: m/z: 355.0795.

5-(4-Nitrophenyl)-3-(tert-butyl)-1-phenylpyrazole (15Pz)

Yellow crystals; mp 154–155°C; yield 27%; ¹H NMR: δ 1.4 (s, 9H), 6.4 (s, 1H), 7.2–7.4 (m, 4H), 7.9–8.2 (m, 5H). ESI-MS. Calcd for C₁₉H₂₀O₂N₂ (M⁺ +H): m/z 322.1550. Found: m/z 322.1538.

Acknowledgments

Dr. Al Baumstark wishes to acknowledge GSU Research Foundation and Department of Chemistry for partial support of this research. Amy N. Hockstedler and Beatrice A. Edjah are GA-AL LSAMP fellows funded by NSF grant #1305041. We thank Dr. Markus Germann for providing access to the Bruker 500 UltraShield™ NMR spectrometer and molecular modeling programs in his labs.

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Supplemental Material:

The online version of this article (DOI: 10.1515/hc-2017-0034) offers supplementary material, available to authorized users.

Received: 2017-2-13

Accepted: 2017-3-8

Published Online: 2017-3-30

Published in Print: 2017-4-1

This article is distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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https://doi.org/10.1515/hc-2017-0034

Keywords for this article

13C NMR; 1-phenyl-3,5-diarylpyrazoles; 1-phenyl-3-t-butyl-5-arylpyrazoles; substituent effects

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