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

Article abstract of DOI:10.1515/hc-2017-0034

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.

Full text of DOI:10.1515/hc-2017-0034

Heterocycl. Commun. 2017; 23(2): 125–131
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
1a3nCd AlNfonMs LR. Basumpsetacrkt*roscopy of heterocycles:
1-phenyl-3-aryl/t-butyl-5-arylpyrazoles
DOI 10.1515/hc-2017-0034
Introduction
13C NMR spectroscopy has proven to be useful to investi-
Received February 13, 2017; accepted March 8, 2017; previously
published online March 30, 2017
Abstract: A series of chalcones 1–12 were converted to gate transmission of substituent effects in aromatic and
pyrazolines (1Pi–12Pi) by reaction with phenylhydrazine heteroaromatic systems [1]. Recently, in a 13C NMR study of
followed by DDQ oxidation to produce the corresponding transmission in the 4-bromoisoxazole system it has been
pyrazoles (1Pz–12Pz). Three 1-phenyl-3-t-butyl-5-arylpyra- found that the effect of the 5-aryl group is essentially the
zoles (13Pz–15Pz) were synthesized using an analogous same as that in the planar isoxazole system despite the
approach. Molecular modeling studies predicted the large torsion angle observed in the former [2]. In the isoxa-
5-aryl group of the pyrazoles for both series to have a zole system, the substituent effect from the 5-aryl group
torsion angle of 52°–54° whereas the 1-phenyl group was is readily observed in chemical shift difference at the C4
predicted to have 35°–37° torsion angles. The 3-aryl group of the 3,5-diarylisoxazole ring system where little or no
was predicted to be essentially coplanar (−3°) with the effect is observed from the 3-aryl group [2]. Furthermore,
13
pyrazole system in the first series. C NMR data for both the previous studies have suggested that resonance con-
series, 1Pz–12Pz and 13Pz–15Pz, were collected in DMSO- tributions are of greater importance than inductive con-
d6 at 50°C. A plot of the C4 chemical shifts for 1Pz–12Pz tributions in both the planar isoxazoles and the twisted
versus Hammet constants for 5-aryl substituents yielded a 4-bromoisoxazoles [2, 3]. We were interested in the evalu-
very good linear correlation (R2ꢀ=ꢀ0.96) with a slope of 1.5. ating distal transmission in a different heterocyclic system
The chemical shift data for C4 showed little or no depend- to compare/contrast with the isoxazole results. Herewith,
13
ence on 3-aryl substituents. The result for 13Pz–15Pz, we report the C NMR study of a series of 1-phenyl-3,5-di-
despite only three points, was consistent with the first arylpyrazoles and a series of 1-phenyl-3-t-butyl-5-arylpyra-
series results and yielded a ρ value of 2.0. Distal transmis- zoles in DMSO-d6.
sion of substituent effects (5-aryl groups) to C4 of the pyra-
zole 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. Results and discussion
Keywords: 13C NMR; 1-phenyl-3,5-diarylpyrazoles; 1-phe-
The reaction of chalcones 1–12 with phenylhydrazine pro-
nyl-3-t-butyl-5-arylpyrazoles; substituent effects.
duced 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 pyrazo-
lines 13Pi–15Pi and subsequently pyrazoles 13Pz–15Pz
(Scheme 2) in low isolated yields. The structures of the
recrystallized compounds are fully consistent with spec-
tral and physical data.
The 3D-structures of 1,3,5-triphenylpyrazole (5Pz)
and 1-phenyl-3-t-butyl-5-phenylpyrazole (13Pz) were cal-
culated by molecular modeling methods. The calculations
predicted molecule 5Pz to have a torsion angle of 3° for
*Corresponding author: Alfons L. Baumstark, Department of
Chemistry, Center for Biotech and Drug Design, Georgia State
University, Atlanta, GA 30302-4098, USA,
e-mail: abaumstark@gsu.edu
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 and Jianmei Cui:
Department of Chemistry, Georgia State University, Atlanta, GA
30302-4098, USA
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126ꢀ
ꢀA.N. Hockstedler et al.: 13C NMR of 1-phenyl-3-aryl/t-butyl-5-arylpyrazoles
ꢁꢁꢁꢂ
X
Y
Y
Y
X
X
NH2NHPh
DDQ
N
N
N
N
HOAc, ∆
Toluene, ∆
O
1–12
1: X = 4-MeO; Y = H
2: X = 4-MeO; Y = 4-Br
3: X = 4-Me; Y = H
4: X = 4-Et; Y = 4-F
5: X = H; Y = H
1Pi–12Pi
1Pz–12Pz
7: X = H; Y = 4-Cl
8: X = H; Y = 4-Br
9: X = 4-Cl; Y = H
10: X = 4-Br; Y = H
11: X = 3,4-diCl; Y = H
12: X = 4-CF3; Y = H
6: X = H; Y = 4-MeO
Scheme 1ꢁ
X
X
X
NH2NHPh
DDQ
Toluene, ∆
N
N
N
N
HOAc, ∆
O
13: X = H
14: X = 4-Br
15: X = 4-NO2
13Pi–15Pi
13Pz–15Pz
Scheme 2ꢁ
the 3-aryl group, 35° for the N-phenyl group and 54° for are summarized in Table 1 for pyrazoles 1Pz–12Pz and in
the 5-phenyl group (Figure 1). This prediction for the 5-aryl Table 2 for the 3-t-butyl analogs 13Pz–15Pz.
group in the pyrazole is similar to that found for the 5-aryl
The chemical shifts for C4 of the pyrazoles 1Pz–12Pz
group in the 4-bromoisoxazole system and in contrast and 13Pz–15Pz were plotted versus Hammett constants
with the planarity found in the 3,5-diaryl isoxazole system [5] for 5-aryl substituents (Figure 3). The chemical
[2]. Similarly, molecular modeling calculations for 13Pz shift data for C4 show little or no variation with 3-aryl
predicted the torsion angles for the 5-aryl group and the substituents. A very good correlation (R2ꢀ=ꢀ0.96) was
N-phenyl group to be 52° and 37°, respectively, (Figure 2) obtained for series one with sigma values with a slope
which is consistent with predicated values for 5Pz.
of approximately 1.5. The ρ value is roughly 40% of that
The signals for the pyrazoles were assigned from observed (~4.0) for the analogous treatment of the isoxa-
their corresponding 13C NMR spectra taken in DMSO-d6. zole system [3]. The correlation is less significant versus
As expected, the signal for the C4 of the pyrazole ring is sigma plus values, in contrast to the isoxazole and 4-bro-
sensitive to substitution on the 5-aryl group and, despite moisoxazole findings [2]. Despite only three data points,
the limited number (5) of examples, appears insensitive to the results for the second series (t-butyl analogs) also
substitution on the 3-aryl group. The chemical shift data provide a very good correlation with sigma constants
–3°
54°
37°
Figure 1ꢁMolecular modeling predicted structures for 1,3,5-triphenylpyrazole (5Pz).
(Left) Top view. (Right) Side view.
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A.N. Hockstedler et al.: 13C NMR of 1-phenyl-3-aryl/t-butyl-5-arylpyrazolesꢀ
ꢂꢁꢁꢁ
ꢀ127
52°
35°
Figure 2ꢁMolecular modeling predicted structures for 1,5-diphenyl-3-t-butylpyrazole (13Pz). (Left) Top view. (Right) Side view.
Table 1ꢁ13C NMR chemical shifts for pyrazoles 1Pz–12Pz in DMSO-d6 at 50°C.
c′′
c′
b′
a′
b′′
a′′
d′′
d′
Y
X
4
3
5
N N
b
a
c
d
Compoundꢁ X/Y
ꢁ
ꢁ
Chemical shift (δ)
b/b′/b″/c/c′/c″/d/d′/d″a
C3ꢁ
C4ꢁ
C5ꢁ X/Y
ꢁ
a/a′/a″
ꢁ
1Pz
2Pz
3Pz
4Pz
ꢃ
ꢃ
ꢃ
ꢃ
4-MeO/H
ꢃ
139.8ꢃ
104.7ꢃ
150.8ꢃ 55.0
149.6ꢃ 55.0
150.8ꢃ 20.6
ꢃ
143.8e
125.2e
130.0e
144.1e
127.5e
131.9e
144.1e
127.0e
132.6e
144.4e
126.3e
129.3e
ꢃ
159.1d/128.7/128.3/128.2/128.1/
127.3/126.5/124.9/114.0
4-MeO/4′-Brꢃ
139.7ꢃ
139.8ꢃ
139.9ꢃ
104.6ꢃ
104.8ꢃ
104.9ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
159.2d/131.4/129.6/128.8/127.2/
125.0/122.0d/120.8/113.9
4-Me/H
ꢃ
ꢃ
137.8d/129.0/128.9/128.5/128.2/127.8/
127.5/125.2/125.1
4-Et/4′-F
150.1ꢃ 15.0
27.7
162.0d (d, Jꢂ=ꢂ244.8)/ 44.2d/129.0/128.3/
127.9/127.7/127.3 (d,
Jꢂ=ꢂ8.23 Hz)/125.2/115.5 (d, Jꢂ=ꢂ21.5 Hz)
(d, Jꢂ=ꢂ2.7 Hz)
144.1e
129.9e
132.6e
144.3e
125.5e
130.2e
144.2e
129.7e
131.4
b
5Pz
6Pz
7Pz
8Pz
9Pz
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
H/H
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
139.8ꢃ
140.0ꢃ
139.6ꢃ
139.6ꢃ
139.4ꢃ
139.9ꢃ
105.1ꢃ
104.9ꢃ
105.1ꢃ
105.2ꢃ
105.3ꢃ
105.5ꢃ
150.9ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
128.9/128.6/128.4/128.4/127.9/127.6/
125.3/125.1
H/4-MeO
H/4-Cl
H/4-Br
4-Cl/H
4-Br/H
151.2ꢃ 55.4
150.0ꢃ
159.5d/129.2/128.7/128.6/128.6/127.8/
127.0/125.4/114.4
132.3d/128.8/128.5/128.3/128.2/127.6/
126.9/125.0
b
149.8ꢃ
144.2e
129.7e
131.8e
142.7e
128.6e
132.4e
128.3e
132.1e
131.5/128.8/128.3/128.3/127.6/
127.2/125.0/120.9d
150.9ꢃ
133.1d/130.0/128.6/128.5/128.4/127.8/
127.6/125.2/125.0
b
10Pz
150.3ꢃ
132.0/130.0/129.4/128.9/128.7/
127.7/125.6/121.4d
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128ꢀ
ꢀA.N. Hockstedler et al.: 13C NMR of 1-phenyl-3-aryl/t-butyl-5-arylpyrazoles
ꢁꢁꢁꢂ
Table 1ꢁ(continued)
Compoundꢁ X/Y
ꢁ
ꢁ
Chemical shift (δ)
b/b′/b″/c/c′/c″/d/d′/d″a
131.4d/131.2d/130.6/130.1/129.2/128.7/
128.4/128.1/125.4
C3ꢁ
C4ꢁ
C5ꢁ X/Y
151.2ꢃ
ꢁ
a/a′/a″
ꢁ
c
11Pz
ꢃ
ꢃ
3,4-DiCl/H
4-CF3/H
ꢃ
139.3ꢃ
105.9ꢃ
ꢃ
141.6e
130.4e
132.4e
142.6e
133.8e
132.4e
ꢃ
12Pz
ꢃ
139.4ꢃ
105.9ꢃ
151.2ꢃ 124.4d
(q, Jꢂ=ꢂ272.4 Hz)
ꢃ
ꢃ
129.1/129.0/128.8d (q, Jꢂ=ꢂ32.4 Hz)/
128.6/128.0/127.9/125.3(q, Jꢂ=ꢂ3.7)/
125.3/125.2
aNot assigned specifically, listed in descending order; b1 aryl signal not resolved; c2 aryl signals not resolved; dipso; equaternary.
Table 2ꢁ13C NMR chemical shifts for pyrazoles 13Pz–15Pz in DMSO-d6 at 50°C.
c′
b′
d′
X
4
a′
3
5
N N
b
a
c
d
Compoundꢁ
X
ꢁ
ꢁ
Chemical shift (δ)
C3 C4
ꢁ
ꢁ
C5
ꢁ
C6
ꢁ
C7
ꢁ
a/a′
ꢁ
b/b′/c/c′/d/d′a
13Pz
14Pz
15Pz
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
H
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
140.0ꢃ
104.5ꢃ
161.4ꢃ
31.7ꢃ
30.2ꢃ
130.4ꢃ
128.7/128.6
128.2/128.1
127.8/126.8
131.3/130.2
128.9/127.2
124.9/121.4b
150.8b/129.1
129.0/127.6
125.1/123.4
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
142.6ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
129.6ꢃ
141.5ꢃ
ꢃ
136.6ꢃ
140.6ꢃ
ꢃ
4-Br
139.7ꢃ
104.8ꢃ
161.7ꢃ
31.8ꢃ
30.2ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
4-NO2 ꢃ
139.5ꢃ
106.0ꢃ
162.0ꢃ
31.6ꢃ
30.1ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
aNot assigned specifically, listed in descending order; bipso.
106.2
106.0
4-NO2/t-butyl
y = 1.5287x + 105.03
4-CF3/H
R² = 0.9645
105.8
3,4-DiCl/H
105.6
4-Br/H
H/4-Cl
105.4
H/4-Br
H/H
105.2
105.0
104.8
104.6
104.4
104.2
4-Cl/H
4-Et/4-F
4-Me/H
4-Br/t-butyl
H/4-MeO
4-MeO/4-Br
y = 1.9703x + 104.44
R² = 0.9899
4-MeO/H
–0.20
H/t-butyl
1.00
–0.40
0.00
0.20
0.40
0.60
0.80
σ
Figure 3ꢁPlot of chemical shift data for C4 vs sigma constants for 5-aryl substituents only (3-aryl Hammett constants excluded) of 1,3-diphe-
nyl-5-arylpyrazoles, 1-phenyl-3,5-diarylpyrazoles (■, 1Pz–12Pz) and 1-phenyl-3-t-butyl-5-arylpyrazoles (▲, 13Pz–15Pz).
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A.N. Hockstedler et al.: 13C NMR of 1-phenyl-3-aryl/t-butyl-5-arylpyrazolesꢀ
ꢂꢁꢁꢁ
ꢀ129
127.1, 130.1, 130.5, 131.5, 136.7, 144.2, 161.3, 188.0. ESI-MS. Calcd for
with a ρ value of ~2.0, consistent with the results found
for series one.
+
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, Jꢀ=ꢀ21.9 Hz), 120.9, 128.2, 128.8, 131.2 (d, Jꢀ=ꢀ9.4 Hz), 132.1, 134.4,
144.2, 146.9, 164.9 (d, Jꢀ=ꢀ251.9 Hz), 187.8 (s). ESI-MS. Calcd for C17H16OF
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 expec-
tations based on the predicted torsion angle difference
of 52°–54° between the 5-aryl group and the central pyra-
zole 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.
+
(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 method-
ology [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 phenyl-
hydrazine 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 atmos-
1
phere for 24 h. The crude crystals were filtered and analyzed by H
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 (gener-
ally 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, 11–14].
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.
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 physi-
cal 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 mini-
mized using the ab initio method (Hartree-Fock with a 3-21G basis
1,3-Diphenyl-5-(4-methoxyphenyl)pyrazoline (1Pi)ꢁMp 123–
1
124°C (lit [4] mp 119–121°C); H 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
1
(2Pi)ꢁYellow crystals; mp 174–175°C; yield 72%; H 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):
+
set). Exact mass data (ESI, M ꢀ+ꢀ1) were obtained at Georgia State
University.
m/z 407.0754. Found: m/z 407.0750.
1,3-Diphenyl-5-(4-methylphenyl)pyrazoline (3Pi)ꢁMp 133–134°C
1
(lit [15] mp 133–135°C); H 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).
Chalcones 1–12 and (E)-4,4-dimethyl-1-aryl-1-penten-
3-ones 13–15
5-(4-Ethylphenyl)-3-(4-fluorophenyl)-phenyl-2-pyrazoline
The α,β-unsaturated ketones were prepared by the cross-aldol reac- (4Pi)ꢁYellow crystals; mp 83–85°C; yield 73%; 1H NMR: δ 1.3 (t, 3H),
tion of the appropriately substituted benzaldehyde (0.08 mol) with 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,
the appropriate acetophenone (0.08 mol) or pinacolone (0.16 mol) in 13H); 13C NMR: δ 15.0, 27.5, 42.9, 63.1, 112.9, 115.5 (d, Jꢀ=ꢀ21.9 Hz), 118.4,
ethanol with sodium hydroxide. Use of an additional equivalent of 125.6, 127.6 (d, Jꢀ=ꢀ250 Hz), 128.1, 128.6 (d, Jꢀ=ꢀ3.2 Hz), 139.6, 142.7, 144.3,
+
pinacolone increased the yields of 13–15. The reaction mixture was 146.2, 161.2, 163.1. ESI-MS. Calcd for C23H22N2F (M +H): m/z 345.1762.
shaken for approximately 2 h and stored overnight at −20°C. The Found: m/z 345.1749.
resulting solid was filtered, washed with water and crystallized from
ethanol. The physical and spectra data for 1, 3, 5–15 were in good 1,3,5-Triphenylpyrazoline (5Pi)ꢁMp 135–137°C (lit [13] mp 135–
1
agreement with the literature values [6–10]. Chalcones 2 and 4 have 137°C); H NMR: δ 2.9–3.2 (m, 1H), 3.5–4.1 (m, 1H), 5.1–5.4 (m, 1H),
not been previously reported.
6.8–7.8 (m, 15H).
(E)-1-(4-Bromophenyl)-3-(methoxyphenyl)-prop-2-en-1-one 1,5-Diphenyl-3-(4-methoxyphenyl)pyrazoline (6Pi)ꢁMp 140–
1
(2)ꢁYellow crystals; mp 145–47°C; yield 45%; H NMR: δ 3.8 (s, 3H), 142°C (lit [13] mp 139.5–141°C); 1H NMR: δ 2.9–3.2 (m, 1H), 3.5–4.1 (m,
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, 1H), 3.9 (s, 3H) 5.0–5.4 (m, 1H), 6.9–7.7 (m, 14H).
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ꢀA.N. Hockstedler et al.: 13C NMR of 1-phenyl-3-aryl/t-butyl-5-arylpyrazoles
ꢁꢁꢁꢂ
Compounds with strong withdrawing groups required heating
3-(4-Chlorophenyl)-1,5-diphenylpyrazoline (7Pi)ꢁMp 149–151°C
1
under reflux for up to 24 h; the reactions of compounds with donat-
ing 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 val-
ues [4, 18–22]. 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.
(lit [13] mp 148–149°C); H 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 crys-
tals; 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
1
(lit [13] mp 135–137°C); H 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
1
(lit [15] mp 128–130°C); H NMR: δ 2.9–3.2 (m, 1H), 3.5–4.1 (m, 1H),
1,3-Diphenyl-5-(4-methoxyphenyl)-pyrazole (1Pz)ꢁMp 77–79°C
5.1–5.4 (m, 1H), 6.8–7.8 (m, 15H).
1
(lit [18] mp 77–78°C); yield 27%; H NMR: δ 3.8 (s, 3H), 6.8 (s, 1H),
7.1–7.5 (m, 9H), 7.8–8.0 (m, 5H).
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-
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):
MS. Calcd for C21H17N2Cl (M +H): m/z 367.0738. Found: m/z 367.0756.
m/z 405.0602. Found: m/z 405.0581.
1,3-Diphenyl-5-(4-trifluorophenyl)pyrazoline (12Pi)ꢁYellow crys-
tals; 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-
1,3-Diphenyl-5-(4-methylphenyl)pyrazole (3Pz)ꢁMp 114–116°C
(lit [13] mp 115–116°C); yield 11%; 1
H 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.
MS. Calcd for C21H18N2F3 (M +H): m/z 367.1420. Found: m/z 367.1422.
5-(4-Ethylphenyl)-3-(4-fluorophenyl)-1-phenylpyrazole
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,
1
(4Pz)ꢁYellow crystals; mp 44–46°C; yield 18%; H NMR: δ 1.3 (t,
Jꢀ=ꢀ7 Hz, 3H), 2.8 (q, Jꢀ=ꢀ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.
+
158.6. ESI-MS. Calcd for C19H23N2 (M +H): m/z 279.1856. Found: m/z
279.1844.
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).
5-(4-Bromophenyl)-3-(tert-butyl)-1-phenylpyrazolineꢀ(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,
1,5-Diphenyl-3-(4-methoxyphenyl)pyrazole (6Pz)ꢁMp 137–139°C
1
(lit [13] mp 137–139°C) [13]; yield 52%; H NMR: δ 3.8 (s, 3H), 6.8 (s,
1H), 7.0–7.3 (m, 4H), 7.8–8.0 (m, 10H).
+
158.8. ESI-MS. Calcd for C19H22N2Br (M +H): m/z 357.0966. Found: m/z
357.0952.
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).
5-(4-Nitrophenyl)-3-(tert-butyl)-1-phenylpyrazolineꢀ(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.
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),
+
Calcd for C19H22N3O2F3 (M +H): m/z 324.1711. Found: m/z 324.1705.
+
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.
1-Phenyl-3-aryl/t-butyl-5-arylpyrazoles 1Pz–15Pz
5-(4-Chlorophenyl)-1,3-diphenylpyrazole (9Pz)ꢁMp 105–107°C
1
(lit [22] mp 106–108°C); yield 30%; H NMR: δ 6.8 (s, 1H), 7.2–7.6 (m,
Compounds 1Pz–15Pz were synthesized from the appropriate pyra-
zolines by treatment with DDQ [17]. Pure pyrazoline (0.5–1.0 g)
was dissolved in 5 mL of toluene. Three equivalents of DDQ were
10H), 7.8–8.1 (m, 5H).
added and the mixture was heated under reflux. Reaction progress 5-(4-Bromophenyl)-1,3-diphenylpyrazole (10Pz)ꢁ1H NMR: δ 6.8
was monitored by TLC (silica gel; eluent dichloromethane/hex- (s, 1H), 7.1–7.6 (m, 10H), 7.8–8.1 (m, 5H). ESI-MS. Calcd for C21H16N2Br
+
anes). Reaction time was found to be dependent on substituents. (M +H): m/z 375.0491. Found: m/z 375.0485.
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A.N. Hockstedler et al.: 13C NMR of 1-phenyl-3-aryl/t-butyl-5-arylpyrazolesꢀ
ꢂꢁꢁꢁ
ꢀ131
5-(3,4-Dichlorophenyl)-1,3-diphenylpyrazole
(11Pz)ꢁYellow
[7] Baumstark, A. L.;. Harden Jr, D. B. Epoxidation of α,β-
1
crystals; mp 82°C (lit [22] mp 83–84°C); yield 32%; H NMR: δ 6.8 (s,
unsaturated carbonyl compounds by dimethyldioxirane. J. Org.
Chem. 1993, 58, 7615–7618.
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.
[8] Jiang, Q.; Jia, J.; Xu, B.; Zhao, A.; Guo, C. C. Iron-facilitated
oxidative radical decarboxylative cross-coupling between
alpha-oxocarboxylic acids and acrylic acids: an approach to
alpha,beta-unsaturated carbonyls. J. Org. Chem. 2015, 80,
3586–3596.
1,3-Diphenyl-5-(4-trifluorophenyl)pyrazole (12Pz)ꢁmp 140–142°C
1
(lit [18] mp 154–156°C); yield 59%; H 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):
[9] Sinisterra, J. V.; Garcia-Raso, A.; Cabello, J. A.; Marinas, J. M. An
improved procedure for the Claisen-Schmidt reaction. Synthe-
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[10] Peach, P.; Cross, D. J.; Kenny, J. A.; Mann, I.; Houston, I.;
Campbell, L.; Wills, M. Asymmetric transfer hydrogenation of
α,β-unsaturated, α-tosyloxy and α-substituted ketones. Tetra-
hedron 2006, 62, 1864–1876.
m/z 365.1260. Found: m/z 365.1254.
1,5-Diphenyl-3-tert-butylpyrazole (13Pz)ꢁWhite crystals; mp
1
109–110°C; yield 72%; H 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.
[11] Azarifar, D.; Shaebanzadeh, M. Synthesis and characteriza-
tion of new 3,5-dinaphthyl substituted 2-pyrazolines and
study of their antimicrobial activity. Molecules 2002, 7,
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[12] Anam, F.; Abbas, A.; Lo, K. M.; Zia ur, R.; Hameed, S.; Naseer,
M. M. Homologous 1,3,5-triarylpyrazolines: synthesis, CH
center dot center dot center dot pi interactions guided self-
assembly and effect of alkyloxy chain length on DNA binding
properties. New J. Chem. 2014, 38, 5617–5625.
[13] Movassagh, B.; Rooh, H.; Bijanzadeh, H. R. A mild and highly
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[15] Raiford, L. C., Peterson, W. J. Identification of phenylhydra-
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5-(4-Bromophenyl)-3-(tert-butyl)-1-phenylpyrazole (14Pz)ꢁYel-
1
low crystals; mp 139–139°C; yield 33%; H 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
1
crystals; mp 154–155°C; yield 27%; H 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 acknowl-
edge GSU Research Foundation and Department of
Chemistry for partial support of this research. Amy N.
Hockstedler and Beatrice A. Edjah are GA-AL LSAMP fel-
lows funded by NSF grant #1305041. We thank Dr. Markus
Germann for providing access to the Bruker 500 UltraSh-
ield™ NMR spectrometer and molecular modeling pro-
grams in his labs.
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