A straightforward synthesis of pyrazolines and pyrazoles: Palladium-catalyzed carbonylative vinylation-cyclocondensation reactions of aryl halides

Article abstract of DOI:10.1002/ejoc.201100654

A novel consecutive one-pot synthesis of pyrazolines and pyrazoles starting from simple aryl halides, styrenes, carbon monoxide, and hydrazines has been established. Palladium-catalyzed carbonylative vinylation of aryl halides gave the corresponding chalcones, which are trapped in situ by addition of hydrazines.

Full text of DOI:10.1002/ejoc.201100654

FULL PAPER
DOI: 10.1002/ejoc.201100654
A Straightforward Synthesis of Pyrazolines and Pyrazoles:
Palladium-Catalyzed Carbonylative Vinylation–Cyclocondensation Reactions of
Aryl Halides
Xiao-Feng Wu,[a] Helfried Neumann,[a] and Matthias Beller*[a]
Keywords: Palladium / Carbonylation / Nitrogen heterocycles / Cyclocondensation
A novel consecutive one-pot synthesis of pyrazolines and
pyrazoles starting from simple aryl halides, styrenes, carbon
monoxide, and hydrazines has been established. Palladium-
catalyzed carbonylative vinylation of aryl halides gave the
corresponding chalcones, which are trapped in situ by ad-
dition of hydrazines.
For example, reactions of 1,3-diketones with hydrazines
are known to proceed in the presence of acid or base at
comparably high temperature.[6] Unfortunately, this reac-
tion often results in mixtures of regioisomers. The use of
α,β-unsaturated ketones with hydrazines presents a modifi-
cation of this common method, wherein pyrazole and pyr-
azoline derivatives can be synthesized in high regioselectiv-
ity.[7]
In 2008, our group demonstrated that it is possible to use
3-butynol as a substitute for 1,3-dicarbonyl compounds and
we reported the regioselective formation of N-aryl-substi-
tuted pyrazolines via Zn-catalyzed hydroamination with ar-
ylhydrazines.[8] Additionally many other methods are avail-
able for the preparation of pyrazolines and pyrazoles.[9]
In the past two decades palladium-catalyzed carbon-
ylation reactions proved to be a versatile tool for the prepa-
ration of (hetero)aromatic carboxylic acid derivatives.[10] As
part of our continuing interest in palladium-catalyzed car-
bonylation reactions,[11] last year we developed a novel
methodology for the synthesis of chalcones. Starting from
either aryl or vinyl triflates,[12] or aryl iodides and bro-
mides,[13] carbonylative coupling reactions with styrenes
proceed smoothly to give various chalcones. Based on this
work, here we present the combination of our carbon-
ylation chemistry with in situ cyclocondensation and oxi-
dation reactions to give 3,5-diarylpyrazolines and 3,5-di-
arylpyrazoles in a straightforward manner.
Introduction
Pyrazoline derivatives are an important class of five-
membered heterocycles that are known to cover a broad
spectrum of biological activities, including antidepressant,
anticancer, antibacterial, antifungal, antiamoebic, and anti-
inflammatory properties.[1] Furthermore, these compounds
serve as valuable precursors to pyrazoles, which are an inte-
gral part of a number of current pharmaceuticals, such as
Celecobix (Celebrex),[2] Sildenafil (Viagra),[3] and Rimonab-
ant (Acomplia).[4] Due to their importance in organic chem-
istry,[5] various methodologies for their synthesis have been
reported. The most general and straightforward approach
makes use of condensation reactions of 1,3-diketones or
α,β-unsaturated ketones with easily available hydrazines
(Scheme 1).[6]
Results and Discussion
Indeed, in situ trapping of chalcones with N-methylhy-
drazine proceeded without any problem in the presence of
our previously optimized catalyst systems[13] for vinylative
carbonylation of aryl iodides and bromobenzene. After the
carbonylation step, simply cooling the reaction mixture to
room temperature and adding hydrazine gave 3,5-diarylpyr-
azolines in moderate to good yields (Table 1). No solvent
Scheme 1. Selected syntheses of pyrazolines.
[a] Leibniz-Institut für Katalyse e.V. an der Universität Rostock
Albert-Einstein-Strasse 29a, 18059 Rostock, Germany
Fax: +49-381-1281-5000
E-mail: matthias.beller@catalysis.de
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100654.
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X.-F. Wu, H. Neumann, M. Beller
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change, addition of acid or base, or removal of the palla-
Apart from simple alkyl-substituted aryl halides, meth-
dium metal or ligands is necessary for the subsequent cy- oxy- and halo-substituted aryl iodides yielded the corre-
clocondensation step. As expected from our previous work, sponding pyrazolines in moderate to good yields. Both elec-
the carbonylative coupling proceeded with excellent regiose- tron-donating and electron-withdrawing functional groups
lectivity.
are well tolerated under our reaction conditions. 3-Iodo-
Table 1. One-pot synthesis of pyrazolines.[a]
[a] Reaction conditions: 1. Aryl iodide (1 mmol), styrene (6 mmol), NEt3 (2 equiv.), [(cinnamyl)PdCl]2 (1 mol-%), L1 (4 mol-%), CO
(5 bar), dioxane (0.5 mL), 100 °C, 20 h. 2. Methylhydrazine (1 mmol), r.t., 1 h. [b] Isolated yield based on aryl halide. [c] 1. [(Cinnamyl)-
PdCl]2 (2 mol-%), L2 (8 mol-%), CO (10 bar), DMF (0.5 mL), 120 °C, 20 h. 2. Methylhydrazine (1 mmol), r.t., 1 h.
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Straightforward Synthesis of Pyrazolines and Pyrazoles
thiophene as a representative sample of a heterocycle also quential palladium-catalyzed carbonylative vinylation, cy-
successfully gave the corresponding pyrazoline in 68% yield clocondensation, and oxidation sequence. Notably, no sol-
(Table 1, Entry 8). Besides styrene, fluoride-, chloride-, vent change or purification of intermediates has to be done,
methoxy-, and tert-butyl-substituted styrenes were trans- which makes the process convenient to perform, syntheti-
formed into the desired pyrazolines in 38–79% yield cally attractive, and efficient.
(Table 1, Entries 11–14).
In addition to N-methylhydrazine, also N-benzylhydraz-
ine and N-(1,1,1-trifluoroethyl)hydrazine were employed
Experimental Section
and gave similar yields of the corresponding products (40–
General Comments: All reactions were carried out under an argon
45%). More interestingly, instead of aryl iodides, less ex-
atmosphere. Dioxane, triethylamine, and THF were distilled from
pensive aryl bromides can also be applied as substrates
sodium ketyl or CaH and stored in Aldrich Sure/Stor flasks under
(Table 1, Entries 15 & 16). Obviously, this enlarges the sub-
an atmosphere of argon. Aryl iodides and styrenes were purchased
strate scope of our methodology to a significant extent.
Furthermore, aryl triflates as another family of electro-
philes can also be used as substrates for this one-pot synthe-
sis of pyrazolines. However, the described different reaction
conditions for the first step have to be used.[12]
from Aldrich or ABCR and used as received. 2-(Di-1-adamantyl-
phosphanyl)-1-(2,6-diisopropylphenyl)-1H-imidazole[15] and [(cinn-
[16]
amyl)PdCl]2 were synthesized according to reported procedures.
Column chromatography was performed using Merck Silicagel 60
(0.043–0.06 mm). NMR spectroscopic data were recorded with
1
Bruker ARX 300 and Bruker ARX 400 spectrometers. 13C and H
Next, we were interested in the further extension of this
uncomplicated reaction sequence towards the synthesis of
pyrazoles. Oxidation of pyrazolines towards pyrazoles is
well established and sometimes takes place simply in air.[14]
However, in our case for smooth transformation at room
temperature it was necessary to add DDQ (1 equiv.) and to
stir the mixture for another 2 h. As shown in Scheme 2, the
synthesis of five different pyrazoles is easily achieved in a
one-pot process directly from bromobenzene and styrenes.
Notably, some of the substrates gave overall higher yields
for pyrazoles compared to the corresponding pyrazolines
shown in Table 1 (Entries 10, 15, 16). This increase in the
product yield is explained by partial oxidation of the pyr-
azolines during their purification process, which gave rise
to lower yield.
NMR spectra were referenced to signals of deutero solvents and
residual protiated solvents, respectively. Gas chromatography
analysis was performed with an Agilent HP-5890 instrument with
an FID detector and HP-5 capillary column (polydimethylsiloxane
with 5% phenyl groups, 30 m, 0.32 mm i.d., 0.25 μm film thickness)
using argon as carrier gas. Gas chromatography–mass analysis was
carried out with an Agilent HP-5890 instrument with an Agilent
HP-5973 Mass Selective Detector (EI) and HP-5 capillary column
(polydimethylsiloxane with 5% phenyl groups, 30 m, 0.25 mm i.d.,
0.25 μm film thickness) using helium carrier gas. HRMS (ESI)
measurements were performed with an Agilent 1969A TOF mass
spectrometer.
General Procedure for the Synthesis of Pyrazolines: A 10-mL
Schlenk flask was charged with [(cinnamyl)PdCl]2 (26 mg, 1 mol-
%), 2-(di-1-adamantylphosphanyl)-1-(2,6-diisopropylphenyl)-1H-
imidazole (105.8 mg, 4 mol-%), NEt3 (1.4 mL, 2 equiv.), and diox-
ane (2.5 mL). Then, 0.78 mL of this clear brown stock solution
were transferred into 4 vials (12 mL reaction volume) equipped
with a septum, a small cannula, a stirring bar, the corresponding
aryl iodides (1 mmol) and styrenes (6 mmol). The vials were placed
in an alloy plate, which was transferred into a 300 mL autoclave of
the 4560 series from Parr Instruments under an argon atmosphere.
After flushing the autoclave three times with CO and adjusting the
pressure to 5 bar, the reaction was performed for 20 h at 100 °C.
After the reaction was cooled down to room temperature, the pres-
sure was carefully released. The mixture was then injected into
methylhydrazine (1 mmol) and stirred at room temperature for 1 h.
The mixture was washed with water, extracted with ethyl acetate
(3ϫ2 mL), and concentrated under reduced pressure. The product
was purified by silica gel chromatography (n-heptane/AcOEt, 40:1).
Synthesis of Pyrazoles: The pyrazoline was synthesized as described
above and added to DDQ (1 mmol). The mixture was stirred at
room temperature for 2 h, and then washed with water and ex-
tracted with ethyl acetate (3ϫ2 mL). The solution was concen-
trated under reduced pressure, and the product was purified by
silica gel chromatography (n-heptane/AcOEt, 40:1).
Scheme 2. One-pot synthesis of pyrazoles. Reaction conditions:
1. Bromobenzene (1 mmol), styrene (6 mmol), NEt3 (2 equiv.),
[(cinnamyl)PdCl]2 (2 mol-%), L2 (8 mol-%), CO (10 bar), DMF
(0.5 mL), 120 °C, 20 h. 2. Hydrazine (1 mmol), r.t., 1 h. 3. DDQ
(1 mmol), r.t., 2 h.
1-Methyl-5-phenyl-3-p-tolyl-4,5-dihydro-1H-pyrazole: 1H NMR
(300 MHz, CDCl3): δ = 7.46 (d, J = 8.23 Hz, 2 H), 7.35–7.42 (m,
2 H), 7.19–7.33 (m, 3 H), 7.08 (d, J = 7.98 Hz, 2 H), 4.01 (dd, J =
14.15, 9.86 Hz, 1 H), 3.37 (dd, J = 16.07, 9.87 Hz, 1 H), 2.89 (dd,
J = 16.02, 14.37 Hz, 1 H), 2.74 (s, 3 H), 2.27 (s, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 150.2, 140.3, 138.7, 130.0, 129.2,
Conclusions
In conclusion, we have developed a straightforward syn-
thesis of 3,5-diarylpyrazolines and similar pyrazoles via se- 128.6, 127.8, 127.5, 125.7, 73.6, 43.3, 41.6, 21.4 ppm. GC–MS (EI,
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70eV): m/z (%) = 250 (90) [M]+, 173 (100), 118 (15), 91 (15). HRMS
7.33–7.37 (m, 2 H), 7.23–7.29 (m, 2 H), 7.15–7.23 (m, 3 H), 3.96
(dd, J = 14.43, 9.89 Hz, 1 H), 3.27 (dd, J = 15.86, 9.81 Hz, 1 H),
2.88 (dd, J = 16.04, 14.38 Hz, 1 H), 2.70 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 146.5, 140.1, 135.4, 128.6, 127.7, 127.4,
126.1, 125.4, 122.8, 73.3, 44.1, 41.5 ppm. GC–MS (EI, 70eV): m/z
(%) = 242 (100) [M]+, 165 (85). HRMS (ESI): calcd. for C14H15N2S
[M + H]+ 243.0950; found 243.0953.
(EI): calcd. for C17H18N2 [M]+ 250.1465; found 250.1466.
3-(4-Methoxyphenyl)-1-methyl-5-phenyl-4,5-dihydro-1H-pyrazole:
1H NMR (300 MHz, CDCl3): δ = 7.50 (d, J = 9.03 Hz, 2 H), 7.34–
7.41 (m, 2 H), 7.18–7.32 (m, 3 H), 6.79 (d, J = 9.03 Hz, 2 H), 3.96
(dd, J = 14.33, 9.91 Hz, 1 H), 3.71 (s, 3 H), 3.33 (dd, J = 16.05,
9.84 Hz, 1 H), 2.86 (dd, J = 16.10, 14.40 Hz, 1 H), 2.71 (s, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 160.0, 149.9, 140.3,
128.6, 127.7, 127.4, 127.2, 125.5, 113.8, 73.5, 55.2, 43.4, 41.7 ppm.
GC–MS (EI, 70eV): m/z (%) = 266 (100) [M]+, 189 (90), 174 (10),
133 (15). HRMS (EI): calcd. for C17H18N2O [M]+ 266.1414; found
266.1412.
3-(4-Bromophenyl)-1-methyl-5-phenyl-4,5-dihydro-1H-pyrazole: 1H
NMR (400 MHz, CDCl3): δ = 7.33–7.43 (m, 6 H), 7.19–7.31 (m, 3
H), 4.04 (dd, J = 14.50, 10.28 Hz, 1 H), 3.31 (dd, J = 16.18,
10.01 Hz, 1 H), 2.86 (dd, J = 16.00, 14.40 Hz, 1 H), 2.74 (s, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 148.3, 140.0, 131.8,
131.5, 128.6, 127.8, 127.4, 127.1, 122.4, 73.5, 43.0, 41.3 ppm. GC–
MS (EI, 70eV): m/z (%) = 317 (20) [M]+, 316 (80), 315 (40), 314
(100), 239 (80), 237 (80), 192 (20), 158 (30), 118 (10), 91 (10), 77
(10). HRMS (ESI): calcd. for C16H16BrN2 [M + H]+ 315.0491,
317.0472; found 315.0485, 317.0479.
3-(4-Ethylphenyl)-1-methyl-5-phenyl-4,5-dihydro-1H-pyrazole: 1H
NMR (300 MHz, CDCl3): δ = 7.46 (d, J = 8.30 Hz, 2 H), 7.32–
7.37 (m, 2 H), 7.15–7.28 (m, 3 H), 7.07 (d, J = 8.27 Hz, 2 H), 3.94
(dd, J = 14.50, 9.90 Hz, 1 H), 3.31 (dd, J = 16.13, 9.90 Hz, 1 H),
2.83 (dd, J = 16.01, 14.52 Hz, 1 H), 2.70 (s, 3 H), 2.52 (q, J =
7.59 Hz, 2 H), 1.11 (t, J = 7.60 Hz, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 149.7, 144.8, 140.3, 130.2, 128.5, 127.9, 127.6, 127.3,
125.7, 73.4, 43.2, 41.5, 28.6, 15.3 ppm. GC–MS (EI, 70eV): m/z (%)
= 264 (100) [M]+, 187 (100). HRMS (ESI): calcd. for C18H21N2 [M
+ H]+ 265.1699; found 265.1704.
3-(4-Chlorophenyl)-1-methyl-5-phenyl-4,5-dihydro-1H-pyrazole: 1H
NMR (300 MHz, CDCl3): δ = 7.46 (d, J = 8.63 Hz, 2 H), 7.33–
7.38 (m, 2 H), 7.17–7.31 (m, 5 H), 4.02 (dd, J = 14.47, 10.15 Hz, 1
H), 3.30 (dd, J = 16.09, 10.09 Hz, 1 H), 2.84 (dd, J = 16.17,
14.54 Hz, 1 H), 2.73 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 148.3, 140.0, 134.2, 131.4, 128.6, 128.5, 127.8, 127.4, 126.8, 73.5,
43.0, 41.3 ppm. GC–MS (EI, 70eV): m/z (%) = 270 (100) [M]+, 193
(100). HRMS (ESI): calcd. for C16H16ClN2 [M + H]+ 271.0997;
found 271.0995.
1
3-(4-Fluorophenyl)-1-methyl-5-phenyl-4,5-dihydro-1H-pyrazole: H
NMR (400 MHz, CDCl3): δ = 7.48–7.54 (m, 2 H), 7.33–7.38 (m, 2
H), 7.18–7.29 (m, 3 H), 6.89–6.96 (m, 2 H), 3.99 (dd, J = 14.40,
10.01 Hz, 1 H), 3.30 (dd, J = 16.12, 10.03 Hz, 1 H), 2.85 (dd, J =
16.05, 14.42 Hz, 1 H), 2.72 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 162.9 (d, J = 249.38 Hz), 148.7, 140.1, 129.1 (d, J =
2.99 Hz), 128.6, 127.8, 127.5, 127.4, 115.4 (d, J = 21.89 Hz), 73.6,
43.2, 41.4 ppm. GC–MS (EI, 70eV): m/z (%) = 254 (80) [M]+, 177
(100). HRMS (ESI): calcd. for C16H16FN2 [M + H]+ 255.1292;
found 255.1295.
1-Methyl-3,5-diphenyl-4,5-dihydro-1H-pyrazole: 1H NMR
(300 MHz, CDCl3): δ = 7.50–7.57 (m, 2 H), 7.32–7.38 (m, 2 H),
7.14–7.29 (m, 6 H), 3.99 (dd, J = 14.56, 10.02 Hz, 1 H), 3.33 (dd,
J = 16.04, 9.97 Hz, 1 H), 2.86 (dd, J = 16.13, 14.40 Hz, 1 H), 2.72
(s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 149.6, 140.2, 132.8,
128.6, 128.5, 128.4, 127.7, 127.4, 125.6, 73.4, 43.1, 41.4 ppm. GC–
MS (EI, 70eV): m/z (%) = 236 (80) [M]+, 159 (100), 131 (10), 115
(10), 104 (10), 91 (10), 77 (10). HRMS (ESI): calcd. for C16H17N2
[M + H]+ 237.1386; found 237.1385.
3-(4-Ethylphenyl)-5-(4-fluorophenyl)-1-methyl-4,5-dihydro-1H-pyr-
azole: 1H NMR (300 MHz, CDCl3): δ = 7.48 (d, J = 8.31 Hz, 2
H), 7.31–7.39 (m, 2 H), 7.11 (d, J = 8.31 Hz, 2 H), 6.97 (t, J =
8.70 Hz, 2 H), 3.98 (dd, J = 14.24, 9.98 Hz, 1 H), 3.35 (dd, J =
16.09, 9.87 Hz, 1 H), 2.84 (dd, J = 16.13, 14.35 Hz, 1 H), 2.71 (s,
3 H), 2.56 (q, J = 7.58 Hz, 2 H), 1.45 (t, J = 7.58 Hz, 3 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 162.3 (d, J = 245.65 Hz), 150.1,
145.0, 136.1, 130.1, 129.0 (d, J = 8.34 Hz), 128.0, 125.8, 115.4 (d,
J = 21.57 Hz), 72.8, 43.4, 41.5, 28.7, 15.4 ppm. GC–MS (EI, 70eV):
m/z (%) = 282 (100) [M]+, 265 (20), 187 (70). HRMS (ESI): calcd.
for C18H20FN2 [M + H]+ 283.1605; found 283.1610.
5-(4-Chlorophenyl)-3-(4-ethylphenyl)-1-methyl-4,5-dihydro-1H-pyr-
azole: 1H NMR (300 MHz, CDCl3): δ = 7.46 (d, J = 8.27 Hz, 2
H), 7.29 (d, J = 8.58 Hz, 2 H), 7.22 (d, J = 8.58 Hz, 2 H), 7.08 (d,
J = 8.43 Hz, 2 H), 3.93 (dd, J = 14.43, 10.08 Hz, 1 H), 3.32 (dd, J
= 16.11, 9.91 Hz, 1 H), 2.79 (dd, J = 16.09, 14.38 Hz, 1 H), 2.69
(s, 3 H), 2.54 (q, J = 7.58 Hz, 2 H), 1.13 (t, J = 7.65 Hz, 3 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 149.8, 145.0, 138.9, 133.3, 130.0,
128.7, 128.6, 127.9, 125.8, 72.8, 43.3, 41.5, 28.6, 15.4 ppm. GC–MS
(EI, 70eV): m/z (%) = 298 (90) [M]+, 187 (100). HRMS (ESI): calcd.
for C18H20ClN2 [M + H]+ 299.1310; found 299.1316.
3-(3,5-Dimethylphenyl)-1-methyl-5-phenyl-4,5-dihydro-1H-pyrazole:
1H NMR (300 MHz, CDCl3): δ = 7.33–7.39 (m, 2 H), 7.16–7.30
(m, 5 H), 6.86 (s, 1 H), 7.67 (dd, J = 14.42, 9.96 Hz, 1 H), 3.33
(dd, J = 16.16, 9.99 Hz, 1 H), 2.86 (dd, J = 16.19, 14.48 Hz, 1 H),
2.72 (s, 3 H), 2.21 (s, 6 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
150.1, 140.3, 137.9, 132.6, 130.4, 128.5, 127.7, 127.4, 123.6, 73.4,
43.3, 41.5, 21.2 ppm. GC–MS (EI, 70eV): m/z (%) = 264 (100) [M]
+, 187 (100). HRMS (ESI): calcd. for C18H21N2 [M + H]+ 265.1699;
found 265.1702.
5-(4-tert-Butylphenyl)-3-(4-ethylphenyl)-1-methyl-4,5-dihydro-1H-pyr-
azole: 1H NMR (300 MHz, CDCl3): δ = 7.48 (d, J = 8.27 Hz, 2
H), 7.31 (s, 4 H), 7.10 (d, J = 8.44 Hz, 2 H), 3.96 (dd, J = 14.51,
9.95 Hz, 1 H), 3.33 (dd, J = 16.06, 9.84 Hz, 1 H), 2.88 (dd, J =
16.06, 14.49 Hz, 1 H), 2.73 (s, 3 H), 2.56 (q, J = 7.62 Hz, 2 H),
1.25 (s, 9 H), 1.15 (t, J = 7.56 Hz, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 150.7, 150.0, 144.9, 137.2, 130.4, 127.9, 127.1, 125.8,
125.5, 73.2, 43.3, 41.6, 34.5, 31.4, 28.6, 15.5 ppm. GC–MS (EI,
70eV): m/z (%) = 320 (100) [M]+, 187 (50), 160 (10). HRMS (ESI):
calcd. for C22H29N2 [M + H]+ 321.2325; found 321.2333.
3-(4-tert-Butylphenyl)-1-methyl-5-phenyl-4,5-dihydro-1H-pyrazole:
1H NMR (300 MHz, CDCl3): δ = 7.51 (d, J = 8.62 Hz, 2 H), 7.35–
7.41 (m, 2 H), 7.18–7.34 (m, 5 H), 3.99 (dd, J = 14.41, 9.94 Hz, 1
H), 3.37 (dd, J = 16.05, 9.93 Hz, 1 H), 2.88 (dd, J = 16.07,
14.21 Hz, 1 H), 2.70 (s, 3 H), 1.24 (s, 9 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 151.8, 149.8, 140.4, 130.0, 128.6, 127.7,
127.4, 125.5, 125.4, 73.5, 43.3, 41.6, 34.7, 31.2 ppm. GC–MS (EI,
70eV): m/z (%) = 292 (100) [M]+, 277 (50), 215 (30), 159 (10).
HRMS (ESI): calcd. for C20H25N2 [M + H]+ 293.2012; found
293.2017.
3-(4-Ethylphenyl)-5-(4-methoxyphenyl)-1-methyl-4,5-dihydro-1H-pyr-
azole: 1H NMR (300 MHz, CDCl3): δ = 7.46 (d, J = 8.28 Hz, 2
1
1-Methyl-5-phenyl-3-(thiophen-3-yl)-4,5-dihydro-1H-pyrazole: H H), 7.26 (d, J = 8.64 Hz, 2 H), 7.07 (d, J = 8.35 Hz, 2 H), 6.78 (d,
NMR (400 MHz, CDCl3): δ = 7.40 (dd, J = 5.14, 1.48 Hz, 1 H), J = 8.71 Hz, 2 H), 3.90 (dd, J = 14.41, 9.76 Hz, 1 H), 3.67 (s, 3 H),
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Straightforward Synthesis of Pyrazolines and Pyrazoles
3.27 (dd, J = 16.11, 9.82 Hz, 1 H), 2.82 (dd, J = 16.02, 14.33 Hz,
1 H), 2.69 (s, 3 H), 2.53 (q, J = 7.61 Hz, 2 H), 1.12 (t, J = 7.57 Hz,
3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 159.1, 149.9, 144.8,
132.0, 130.3, 128.5, 127.9, 125.7, 113.9, 72.9, 55.1, 43.1, 41.3, 28.6,
15.3 ppm. GC–MS (EI, 70eV): m/z (%) = 294 (100) [M]+, 293 (40),
277 (10), 187 (50), 121 (10). HRMS (ESI): calcd. for C19H23N2O
[M + H]+ 295.1805; found 295.1808.
Acknowledgments
The authors thank the state of Mecklenburg-Vorpommern and the
Bundesministerium für Bildung und Forschung (BMBF) for finan-
cial support. We also thank Mrs. S. Leiminger, Dr W. Baumann,
and Dr. C. Fischer (all LIKAT) for analytical support.
1-Benzyl-3,5-diphenyl-4,5-dihydro-1H-pyrazole: 1H NMR
(300 MHz, CDCl3): δ = 7.35–7.79 (m, 15 H), 4.67 (d, J = 14.38 Hz,
1 H), 4.38 (dd, J = 14.32, 10.39 Hz, 1 H), 4.09 (d, J = 14.38 Hz, 1
H), 3.45 (d, J = 16.05, 10.56 Hz, 1 H), 3.07 (dd, J = 16.05,
10.56 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 162.0, 148.9,
140.5, 136.7, 133.0, 129.5, 128.6, 128.3, 128.0, 127.7, 127.6, 127.1,
125.6, 68.9, 56.5, 42.8 ppm. GC–MS (EI, 70eV): m/z (%) = 312
(100) [M]+, 235 (20), 221 (25), 191 (10), 115 (10), 91 (80).
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3,5-Diphenyl-1-(2,2,2-trifluoroethyl)-4,5-dihydro-1H-pyrazole: H
NMR (300 MHz, CDCl3): δ = 7.49–7.58 (m, 2 H), 7.11–7.39 (m, 8
H), 4.46 (dd, J = 12.25, 10.24 Hz, 1 H), 3.49 (qd, J = 9.45, 3.86 Hz,
2 H), 3.35 (dd, J = 16.20, 10.17 Hz, 1 H), 2.91 (dd, J = 16.20,
12.28 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 150.2, 139.3,
132.3, 128.9, 128.8, 128.5, 128.3, 127.5, 125.9, 124.81 (q, J =
281.22 Hz), 70.3, 53.21 (q, J = 31.70 Hz), 40.9 ppm. GC–MS (EI,
70eV): m/z (%) = 304 (100) [M]+, 235 (75), 206 (10), 104 (15), 77
(10).
1-Benzyl-3,5-diphenyl-1H-pyrazole: 1H NMR (300 MHz, CDCl3): δ
= 7.75–7.82 (m, 2 H), 7.09–7.37 (m, 11 H), 6.97–7.06 (m, 2 H),
6.58 (s, 1 H), 5.31 (s, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
151.0, 145.6, 137.8, 133.5, 130.7, 128.9, 128.7 (br. s), 128.69, 128.67,
127.8, 127.5, 126.8, 125.8, 103.8, 53.3 ppm. GC–MS (EI, 70eV):
m/z (%) = 310 (90) [M]+, 309 (100), 233 (40), 191 (10), 189 (10), 91
(50).
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3,5-Diphenyl-1-(2,2,2-trifluoroethyl)-1H-pyrazole: 1H NMR
(300 MHz, CDCl3): δ = 7.74–7.79 (m, 2 H), 7.27–7.41 (m, 8 H),
6.57 (s, 1 H), 4.61 (q, J = 8.13 Hz, 2 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 152.5, 146.9, 132.8, 129.8, 129.3, 129.1, 129.0, 128.7,
128.3, 126.8 (q, J = 283.23 Hz), 125.9, 104.9, 50.3 (q, J =
34.84 Hz) ppm. GC–MS (EI, 70eV): m/z (%) = 302 (100) [M]+, 233
(40), 130 (10), 77 (10).
3-(3,5-Diphenyl-1H-pyrazol-1-yl)propanenitrile: 1H NMR
(300 MHz, CDCl3): δ = 7.70–7.77 (m, 2 H), 7.22–7.43 (m, 8 H),
6.51 (s, 1 H), 4.28 (t, J = 6.91 Hz, 2 H), 2.88 (t, J = 6.96 Hz, 2
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 151.7, 145.7, 132.9,
129.7, 129.1, 128.99, 128.91, 128.6, 127.9, 125.6, 117.0, 103.9, 44.6,
18.7 ppm. GC–MS (EI, 70eV): m/z (%) = 273 (90) [M]+, 233 (100),
220 (80), 130 (20), 77 (35).
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1-Cyclohexyl-3,5-diphenyl-1H-pyrazole: 1H NMR (300 MHz,
CDCl3): δ = 7.71–7.79 (m, 2 H), 7.14–7.36 (m, 8 H), 6.42 (s, 1 H),
3.87–4.10 (m, 1 H), 1.08–2.16 (m, 10 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 150.0, 143.9, 133.9, 131.1, 128.9, 128.6, 128.4, 128.3,
127.2, 125.5, 102.9, 57.8, 33.3, 25.6, 25.1 ppm. GC–MS (EI, 70eV):
m/z (%) = 302 (30) [M]+, 247 (10), 233 (30), 220 (100), 191 (10).
1-Methyl-3,5-diphenyl-1H-pyrazole: 1H NMR (300 MHz, CDCl3):
δ = 7.72–7.78 (m, 2 H), 7.29–7.39 (m, 7 H), 7.19–7.25 (m, 1 H),
6.53 (s, 1 H), 3.07 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
150.4, 145.1, 133.3, 130.6, 128.70, 128.67, 128.59, 128.53, 127.6,
125.5, 103.2, 37.5 ppm. GC–MS (EI, 70eV): m/z (%) = 234 (100)
[M]+. HRMS (ESI): calcd. for C16H15N2 [M + H]+ 235.1230; found
235.1235.
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of the H and 13C NMR spectra.
Eur. J. Org. Chem. 2011, 4919–4924
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4923

X.-F. Wu, H. Neumann, M. Beller
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Received: May 10, 2011
Published Online: July 19, 2011
4924
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 4919–4924