Direct electrophilic acylation of n-substituted pyrazoles by anhydrides of carboxylic acids

Article abstract of DOI:10.1055/s-0033-1338923

A simple, convenient and scalable approach to 1-substituted 4-acylpyrazoles through direct acylation of pyrazoles by anhydrides of aliphatic, aromatic and fluorinated carboxylic acids in the presence of concentrated sulfuric acid as a catalyst is described. Target ketones were obtained in 41-86% isolated yields in high purity without laborious purification. The scope and limitations of the method are discussed.

Full text of DOI:10.1055/s-0033-1338923

2188▌
PAPER
paper
Direct Electrophilic Acylation of N-Substituted Pyrazoles by Anhydrides of
Carboxylic Acids
Acylation of N-Substituted Pyrazoles
Ilya V. Taydakov,*a Sergey S. Krasnoselskiyb
a
P.N. Lebedev Physical Institute of the Russian Academy of Sciences, Leninskiy prospect 53, 119991 Moscow, Russian Federation
Fax +7(495)6000603; E-mail: taidakov@gmail.com
b
People’s Friendship University of Russia, Miklukho-Maklaya str. 6, 117198 Moscow, Russian Federation
Received: 10.03.2013; Accepted after revision: 30.04.2013
The earliest works,2a,b from the beginning of the 20th cen-
Abstract: A simple, convenient and scalable approach to 1-substi-
tury, required very drastic conditions (200–250 °C, sealed
tuted 4-acylpyrazoles through direct acylation of pyrazoles by an-
tubes) to obtain the desired ketones 1 and 2, and the yields,
where reported, were low. Of course, they are now only of
hydrides of aliphatic, aromatic and fluorinated carboxylic acids in
the presence of concentrated sulfuric acid as a catalyst is described.
Target ketones were obtained in 41–86% isolated yields in high pu- historical interest. However, over the last several decades
rity without laborious purification. The scope and limitations of the
method are discussed.
very little effort was made to improve this reaction. Clas-
sical Friedel–Crafts conditions are not always suitable for
Key words: electrophilic aromatic acylation, heterocycles, ke-
tones, catalysis
acylation of pyrazoles. Satisfactory results were achieved
with polyalkyl substituted compounds,3 but in other cases
the yields of ketones were dispiritingly low.4 Moreover,
some pyrazoles are unstable in the presence of AlCl3 or,
Substituted 4-acylpyrazoles are useful building blocks in conversely, form complexes that are too stable and unre-
heterocyclic chemistry,1 and a lot of information about the active under these conditions. Tin(II) chloride was also
utilization of pyrazole ketones as pharmaceutical interme- tested for this reaction as catalyst but with limited suc-
diates is covered by patent literature.1d Nevertheless, di- cess.5
rect electrophilic introduction of an acyl fragment to the
A special class of direct acylation methods include
pyrazole ring has not been sufficiently investigated. Only
reactions6 with active acylation agents such as oxalyl
a few examples of direct acylation have been described,
chloride or oxalic acid methyl ester chloride. These reac-
tions always require a large excess of acyl chloride and
some of which are summarized in Scheme 1.
lead to formation of α-carbonyl compounds that are be-
O
Cl
yond the scope of this communication. Other synthetic
approaches to 4-acylpyrazoles involve different transfor-
mations of the side chain, for example, reaction of organo-
metallic reagents with pyrazolic Weinreb amides,7 or a
reversed strategy based on the interaction of aliphatic
Weinreb amides with 4-pyrazolyllithium.8 Both reactions
require low temperatures, tetrahydrofuran as solvent, and
strict protection against oxygen and moisture.
O
N
N
Me
5, 47%
O
Ph
reflux
ClOC-COCl
N
N
O
Ph
R2
Me
Li
AlCl3
PhCOCl
250 °C
1
O
O
N
AcCl
N
O
N
N
R1
N
N
Ph
Ph
Na2Cr2O7
O
Me
N
HO
Me
4, 60%
Me
7
H2SO4
85%
–78 °C
57%
N
AlCl3
PhNO2
reflux
N
Ph
PhCOCl
N
Me
N
N
N
O
2
N
MeMgBr
O
MnO2
Ph
Me
Me
9
Ph
N
CH2Cl2
91%
–5 °C
89%
O
6
Me
N
N
N
Me
Me
8
3, 6%
Scheme 2 Synthesis of 4-acylpyrazole by side chain modification
Scheme 1 Direct acylation of substituted pyrazoles
SYNTHESIS 2013, 45, 2188–2192
Alternatively, pyrazolic aldehydes can be converted into
secondary alcohols by the reaction with Grignard of or-
ganolithium reagents, followed by oxidation of alcohols9
Advanced online publication: 12.06.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1338923; Art ID: SS-2013-Z0195-OP
© Georg Thieme Verlag Stuttgart · New York

PAPER
Acylation of N-Substituted Pyrazoles
2189
with active MnO2 in dichloromethane or by a H2SO4 in 64% isolated yield. Again, no experimental data
Na2Cr2O7/H2SO4 mixture in a water–acetone solution10 were reported. Because of the lack of experimental details
(Scheme 2). The last method is based on full pyrazole ring for this reaction, we decided to publish the results of our
construction by condensation of polycarbonyl compounds study in this area.
with substituted hydrazines (Scheme 3).11
O
R3
R2
Me
R2
O
O
Δ
N
N
O
O
H
+
MeOH
N
R1
14
N
N
N
H2SO4
O
R3
R3
+
N
R1
Me
NH2
HCl
80%
15
O
13
9, 13, 16a–e
10
Scheme 4 Direct acylation of 1-substituted pyrazole by carboxylic
acid anhydrides
Me
Me
O
O
O
O
CF3CH2OH
> 90%
Me
Me
H
N
N
+
+
Me
NH2
11
During our initial experiments, 1-methylpyrazole
(1 equiv) was heated at reflux in a large excess of acetic
anhydride (5–7 equiv) and 10% H2SO4 (by weight relative
to the amount of pyrazole used) (Scheme 4). The reaction
time was 6–7 hours, and the isolated yield of 1-methyl-4-
acetylpyrazole was 50–63%. The requirement to scale the
reaction up prompted us to research the scope and limita-
tions of the reaction in more detail.
12
Scheme 3 Synthesis of 4-acylpyrazole by ring construction
One of the critical disadvantages of the ring construction
strategy is the lack of regioselectivity, since unsymmetri-
cal dicarbonyl compounds can form two isomers of ke-
tone.12 This problem can be partially overcome13 by the
use of a specific solvent, 2,2,2-trifluoroethanol, during a
specific three-component condensation reaction, but im-
plementation of the method on a larger scale seems quite
challenging.
First, we established that the amount of anhydride could
be significantly reduced to 1.5 moles of anhydride per
mole of substituted pyrazole (Table 1). Nevertheless, in
large-scale experiments, it was necessary to increase this
ratio to 2.5–4 mole of anhydride per mole pyrazole to con-
trol thermal conditions. The optimum reaction tempera-
ture was 140–150 °C.
Recently, we described14 a general multistep synthetic ap-
proach to isomeric ketones bearing the pyrazole moiety
based on degradation of pyrazolylmalonic acid deriva-
tives. As a result of our continuing interest in heterocyclic
β-diketones, we wanted to find a more economic and prac-
tical synthetic route to N-substituted 4-acylpyrazoles. We
found that N-substituted pyrazoles can be smoothly acyl-
ated by various anhydrides of carboxylic acid in the pres-
ence of a catalytic amount of concentrated sulfuric acid
and investigated in detail the scope and limitations of the
reaction. To the best of our knowledge, only three cases of
the preparation of 4-acetyl pyrazoles by the reaction of al-
kyl substituted pyrazoles with acetic anhydride under acid
catalysis conditions have been reported. The first work
was published in 1974 in an obscure Russian journal,15
and the original publication was inaccessible. However,
according to the record in Chemical Abstracts, two iso-
meric pyrazoles (1,3- and 1,5-dimethylpyrazole) were ac-
ylated by acetic anhydride in the presence of HClO4 or
H2SO4.16 No experimental details were reported because
acylation was one of the intermediate stages of the synthe-
sis. The second study was described in a US patent17 is-
sued in 2004, in which 1,5-dimethyl-3-(trifluoromethyl)-
1H-pyrazole was acylated by Ac2O with H2SO4 as a cata-
lyst. The desired ketone was obtained in 22% overall yield
after eight days heating to reflux. No explicit data were re-
ported in the patent. Unfortunately, we were unable to re-
peat the reaction.
Table 1 Initial Optimization
Entry
Pyrazole/Ac2O ratio Temp
(°C)a
Time
(h)
Yield of 9
(%)
1
2
3
4
5
6
1:7
reflux
reflux
reflux
80
7
5
61
50
58
21
46
63
1:4
1:1.5
1:7
7
10
10
3
1:1.5
1:1.5
100
150c
a Catalyst H2SO4 (10% by weight), reaction on a 50 mmol scale, under
N2.
b Isolated yield.
c In sealed tube, bath temperature.
Special attention was paid to determining the optimal
amount of catalyst. A series of experiments was carried
out with a mixture of 1,3-dimethylpyrazole and acetic an-
hydride (1:2.5 molar ratio, 10 mmol scale) and various
amounts of catalyst. n-Decane was added to the mixture as
an internal standard. The reaction mixtures were stirred at
120 °C continuously and, at equal time intervals, an ali-
quot of the mixture was taken, quenched with a measured
volume of saturated K2CO3 solution, extracted by vortex-
Finally, the third reaction, reported in 2009,18 briefly de-
scribed the acylation of 1-methyl-3-(4-nitrophenyl)-1H-
pyrazole by Ac2O in the presence of a catalytic amount of
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 45, 2188–2192

2190
I. V. Taydakov, S. S. Krasnoselskiy
PAPER
Figure 1 Conversion plots for different catalyst concentrations [plot A: no catalyst (line 1), 0.1% (line, 1% (line 3), 5% (line 4), 10% (line 5)
catalyst by weight] and conversion rates after 300 min heating at different catalyst loading (plot B).
ing with a constant volume of CH2Cl2, and analyzed by rial was regenerated after typical workup. Neither could
GC. The internal standard was used to verify the complete we observe acylation of 1-methylpyrazole by the crude
extraction and reproducibility. The concentration of pyr- anhydride of cyclopropanecarboxylic acid (150 °C, 5 h).
azole and ketone was determined by comparison against The reason for this may be the significant amount of N,N-
calibration curves; the results are shown in Figure 1.
dicyclohexylurea, formed as a by-product during the prep-
aration of the anhydride,19 which could not be completely
separated from the anhydride. The urea is likely to react
with sulfuric acid, thus destroying the catalyst. Phthalic
anhydride was also inactive in this reaction even under
drastic conditions (200 °C, 16 h).
As shown in Figure 1 (plot A, line 1), no reaction proceed-
ed in the absence of catalyst, and the reaction rate in-
creased almost linearly with increasing amount of catalyst
(within a 0–10% range of catalyst by weight). This data is
explicitly represented in plot B. We found that the optimal
sulfuric acid concentration was 2–4% by weight of the Electron-withdrawing groups in the pyrazole moiety led
pyrazole amount used. At high concentrations of sulfuric to inhibition of the reaction. In contrast to the patent da-
acid, the reaction proceeded faster, but the overall yield ta,17 preparation of ketone from 1-methyl-3-trifluoro-
decreased due to the formation of considerable amounts of methyl pyrazole under the described conditions failed.
resin in the reaction mass.
Pyrazoles with NO2, halogen, COOH, or COR groups also
remained unchanged under these conditions.
This reaction seems to be common for aliphatic, aromatic,
and fully or partially fluorinated aliphatic acid anhydrides. The reaction time was found to depend heavily on the
Some representative examples are summarized in Table 2. temperature. At 150 °C, some reactions were complete
within 1–3 h for reactions performed on a 0.1–0.5 mole
Table 2 Direct acylation of pyrazoles
scale. Low-boiling anhydrides of fluorinated carboxylic
acids required 10–24 h reflux to reach 40–50% yields. A
far more reasonable solution was to conduct the reaction
in sealed tubes at a temperature of 100–120 °C.
Compound R1
R2
R3
Temp
(°C)
Time Yield
(h)
(%)a
9
Me
H
Me
refluxb
refluxb
150
5
5
69
81
79
76
86
48
41
The presence of oxygen did not decrease the yields signif-
icantly, but purer products were obtained when the reac-
tion was performed under a nitrogen atmosphere.
13
Me
Et
Et
Et
Et
Et
3-Me
5-Me
3-Me
3-Me
3-Me
3-Me
Me
16a
16b
16c
16d
16e
i-Pr
n-Pr
Ph
3
Separation of acylated pyrazoles was not a complicated
process – volatile compounds were removed by vacuum
evaporation, and the residue was treated with an excess of
cold NaOH solution to reach a final pH of 8–9. Ketone
was then extracted with an appropriate solvent (typically
ethyl acetate or CH2Cl2) and, after evaporation of the sol-
vent, the product was purified by distillation or crystalli-
zation.
150
3
170
1
CHF2
CF3
refluxc
refluxd
10
24
a Reactions performed on a 200 mmol scale under N2.
b Bath temperature 160 °C.
c Bath temperature 120 °C.
In conclusion, the described procedure is straightforward,
convenient, and scalable, and can be used for the prepara-
tion of a diverse range of 1-substituted 4-acylprazoles
with aliphatic, aromatic, and fluorinated substituents on
the carbonyl fragment.
d Bath temperature 60 °C.
Application of N-unsubstituted pyrazoles did not produce
any reaction; with these substrates only the starting mate-
Synlett 2013, 45, 2188–2192
© Georg Thieme Verlag Stuttgart · New York

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Acylation of N-Substituted Pyrazoles
2191
Reagents and solvents (synthetic grade) were purchased from
Merck KGaA (Germany) and Acros Organics (Belgium). Substituted
pyrazoles were purchased from Art-Chem GmbH (Campus Berlin-
1-(1-Ethyl-3-methyl-1H-pyrazol-4-yl)butan-1-one (16b)
Yield: 27.4 g (76%); light-yellow oil; bp 115–117 °C/3 Torr.
1H NMR (300 MHz, CDCl3): δ = 7.83 (s, 1 H, CH), 4.12 (m, 2 H,
CH2), 2.68 (m, 2 H, CH2), 2.47 (s, 3 H, CH3), 1.72 (m, 2 H, CH2),
1.50 (t, J = 7.4 Hz, 3 H, CH3), 0.98 (t, J = 6.7 Hz, 3 H, CH3).
13C NMR (50 MHz, CDCl3): δ = 195.1, 150.5, 132.3, 120.3, 46.9,
42.6, 17.7, 15.2, 14.1, 13.8.
1
Buch, Germany). H, 13C, and 19F NMR spectra were recorded in
CDCl3 with Bruker AC-300 and Bruker AC-200 spectrometers op-
1
erated at 300, 50, and 188 MHz, respectively, at 25 °C. All H
chemical shifts are reported in ppm, relative to TMS (δ = 0.00 ppm);
13C shifts are reported in ppm, relative to CDCl3; 19F shifts are re-
ported in ppm, relative to CFCl3. Mass spectra were recorded with
a Finnigan INCOS-50 system (EI, 70 eV, direct insertion). GC anal-
ysis was performed with a Varian 3800 instrument equipped with
FID and a 15 m × 0.53 mm × 0.5 μm Zebron ZB-5 capillary col-
umn (Phenomenex, USA) using helium (5 mL/min) as a carrier gas
in the temperature programming mode.
MS (EI, 70 eV): m/z (%) = 180 (16) [M]+, 137 (100) [M – Pr]+,
109 (63) [M – (CO-Pr)]+.
Anal. Calcd for C10H16N2O: C, 66.63; H, 8.95; N, 15.54. Found: C,
66.57; H, 8.83; N, 15.71.
(1-Ethyl-3-methyl-1H-pyrazol-4-yl)(phenyl)methanone (16c)
Yield: 36.8 g (86%); yellow oil; bp 189–192 °C/6 Torr.
1H NMR (300 MHz, CDCl3): δ = 7.81 (m, 2 H, CH), 7.72 (s, 1 H,
CH-pyr), 7.50 (m, 3 H, CH), 4.12 (m, 2 H, NCH2), 2.52 (s, 3 H,
CH3), 1.50 (t, J = 6.4 Hz, 3 H, CH3).
13C NMR (50 MHz, CDCl3): δ = 189.7, 151.6, 139.9, 133.9, 131.5,
128.4, 128.1, 118.8, 46.9, 15.1, 13.7.
Acylation of Pyrazoles; General Procedure
To a stirred mixture of pyrazole (200 mmol) and the appropriate
acid anhydride (350 mmol, 1.75 equiv), concd H2SO4 (0.2 mL) was
added, and the resulting mixture was stirred under a nitrogen atmo-
sphere in an oil bath until the pyrazole was consumed. For low-
boiling components, this mixture was heated at reflux. Reaction
conditions (temperature and time) are given in Table 2. When the
reaction was complete, volatile compounds were removed under re-
duced pressure and the residue was poured onto 100 mL crushed
ice. The reaction mixture was neutralized under vigorous stirring by
the addition of 20% aqueous NaOH or (in the case of fluorinated ke-
tones) solid KHCO3 to adjust pH to 7–8. The ketone was extracted
with CH2Cl2 (3 × 50 mL) and the combined organic phases were
washed with brine (50 mL), dried over MgSO4, and evaporated un-
der reduced pressure. The resulting crude ketone was purified by ei-
ther distillation or recrystallization from the appropriate solvent.
MS (EI, 70 eV): m/z (%) = 214 (92) [M]+, 137 (100) [M – Ph]+, 109
(96) [M – (CO-Ph)]+, 77 (98) [Ph]+.
Anal. Calcd for C13H14N2O: C, 72.87; H, 6.59; N, 13.07. Found: C,
73.09; H, 6.78; N, 13.21.
1-(1-Ethyl-3-methyl-1H-pyrazol-4-yl)-2,2-difluoroethanone
(16d)
Yield: 18.1 g (48%); light-yellow crystalline solid; mp 42–43 °C;
bp 105–106 °C/10 Torr.
1H NMR (300 MHz, CDCl3): δ = 8.31 (s, 1 H, CH), 5.94 (t, J =
63 Hz, 1 H, CHF2), 4.16 (q, J = 6.7 Hz, 2 H, NCH2), 2.51 (s, 3 H,
CH3), 1.51 (t, J = 6.7 Hz, 3 H, CH3).
13C NMR (50 MHz, CDCl3): δ = 182.5 (t, J = 26 Hz), 153.1, 133.8
(t, J = 6.3 Hz), 113.5, 111.5 (t, J = 252 Hz), 47.3, 14.9, 13.9.
1-(1-Methyl-1H-pyrazol-4-yl)ethanone (9)
Yield: 17.1 g (69%); light-yellow crystalline solid; mp 55–56 °C
(hexane) {Lit.10 56–57 °C}; bp 96–98 °C/2 Torr.
1H NMR (300 MHz, CDCl3): δ = 7.80 (s, 1 H, CH), 7.85 (s, 1 H,
CH), 3.95 (s, 3 H, N-CH3), 2.48 (s, 3 H, CH3).
13C NMR (50 MHz, CDCl3): δ = 192.1, 140.2, 132.3, 124.1, 30.1,
27.6.
19F NMR (188 MHz, CDCl3): δ = –122 (d, J = 133.5 Hz).
MS (EI, 70 eV): m/z (%) = 188 (4) [M]+, 137 (100) [M – CHF2]+,
109 (88) [M – (CO – CHF2)]+, 51 (65) [CHF2]+.
MS (EI, 70 eV): m/z (%) = 124 (48) [M]+, 109 (100) [M – CH3]+.
Anal. Calcd for C8H10F2N2O: C, 51.06; H, 5.36; N, 14.89; F, 20.19.
Found: C, 51.13; H, 5.44; N, 15.07; F, 20.31.
Anal. Calcd for C6H8N2O: C, 58.05; H, 6.50; N, 22.57. Found: C,
57.96; H, 6.54, N, 22.68.
1-(1-Ethyl-3-methyl-1H-pyrazol-4-yl)-2,2,2-trifluoroethanone
(16e)
1-(1,3-Dimethyl-1H-pyrazol-4-yl)ethanone (13)
Yield: 22.4 g (81%); white crystalline solid; mp 39–40 °C; bp 89–
90 °C/1 Torr.
1H NMR (300 MHz, CDCl3): δ = 7.75 (s, 1 H, CH), 3.84 (s, 3 H, N-
CH3), 2.55 (s, 3 H, CH3), 2.45 (s, 3 H, CH3).
13C NMR (50 MHz, CDCl3): δ = 192.1, 150.3, 134.4, 120.6, 38.6,
Yield: 19.9 g (41%); light-yellow oil; bp 71–72 °C/4 Torr.
1H NMR (300 MHz, CDCl3): δ = 7.94 (s, 1 H, CH), 4.17 (q, J =
6.4 Hz, 2 H, NCH2), 2.51 (s, 3 H, CH3), 1.54 (t, J = 6.6 Hz, 3 H,
CH3).
13C NMR (50 MHz, CDCl3): δ = 174.5 (q, J = 36 Hz), 153.8, 134.2
(d, J = 4.2 Hz), 116.6 (q, J = 289 Hz), 112.6, 47.4, 14.9, 13.7.
28.2, 13.7.
MS (EI, 70 eV): m/z (%) = 138 (33) [M]+, 123 (100) [M – CH3]+.
19F NMR (188 MHz, CDCl3): δ = –74.2 (s).
MS (EI, 70 eV): m/z (%) = 206 (13) [M]+, 137 (100) [M – CF3]+, 109
Anal. Calcd for C7H10N2O: C, 60.85; H, 7.30; N, 20.28. Found: C,
60.69; H, 7.35; N, 20.36.
(92) [M – (CO – CF3)]+, 69 (45) [CF3]+.
Anal. Calcd for C8H9F3N2O: C, 46.61; H, 4.40; N, 13.59; F, 27.65.
Found: C, 46.74; H, 4.29; N, 13.77; F, 27.81.
1-(1-Ethyl-5-methyl-1H-pyrazol-4-yl)-2-methylpropan-1-one
(16a)
Yield: 28.5 g (79%); light-yellow oil; bp 125–128 °C/8 Torr.
Large-Scale Preparation of 1-(1,3-Dimethyl-1H-pyrazol-4-
yl)ethanone (13)
1H NMR (300 MHz, CDCl3): δ = 7.83 (s, 1 H, CH), 4.10 (q, J =
7.4 Hz, 2 H, NCH2), 3.18 (m, 1 H, CH), 2.57 (s, 3 H, CH3), 1.41 (t,
J = 7.1 Hz, 3 H, CH3), 1.17 (d, J = 7.4 Hz, 6 H, CH3).
13C NMR (50 MHz, CDCl3): δ = 200.1, 142.0, 140.0, 118.6, 43.7,
37.6, 18.9, 17.7, 10.6.
In a 5 L reactor, equipped with a stirrer, a reflux condenser, an argon
inlet, thermometer and dropping funnel, 1,3-dimethyl-1H-pyrazole
(500 g, 5.2 mol) was added slowly with stirring to acetic anhydride
(1950 mL, 2125 g, 20.8 mol), while maintaining the temperature be-
low 45 °C. Concd H2SO4 (50 mL, 92 g, 0.94 mol) was added with
cooling and stirring and the mixture then was gradually heated to re-
flux and held at reflux for 6 h. The mixture was then cooled, evap-
orated at 70 °C/7 Torr, and treated with crushed ice (2 kg). By
MS (EI, 70 eV): m/z (%) = 180 (9) [M]+, 137 (100) [M – i-Pr]+, 109
(47) [M – (CO-i-Pr)]+.
Anal. Calcd for C10H16N2O: C, 66.63; H, 8.95; N, 15.54. Found: C,
66.75; H, 9.14; N, 15.61.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 45, 2188–2192

2192
I. V. Taydakov, S. S. Krasnoselskiy
PAPER
carefully addition of 40% NaOH solution, the pH of the reaction
mixture was adjusted to pH 8, then the organic phase was separated
and the aqueous phase was extracted with CH2Cl2 (2 × 1000 mL).
The combined organic phases were washed successively with H2O
(500 mL) and brine (500 mL), and dried over MgSO4. The solvent
was removed at 7 Torr, and the residue was distilled (110–112 °C/
10 Torr) to afford the target ketone (452 g, 63%) as thick, light-
yellow oil, which crystallized upon standing.
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Synlett 2013, 45, 2188–2192
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