An efficient synthesis of isomeric 1-(1-Alkyl-1H-pyrazolyl) ethanones

Article abstract of DOI:10.1002/jhet.869

A simple and versatile general method for the preparation of N-substituted 3-, 4-, or 5-acetylpyrazoles from corresponding acids via hydrolysis and decarboxylation of substituted diethyl [(1-alkyl-1H-pyrazolyl)carbonyl]malonates was developed. Title compounds were prepared in three steps without isolation of intermediates in 48-82% overall yield.

Full text of DOI:10.1002/jhet.869

1422
An Efficient Synthesis of Isomeric
1-(1-Alkyl-1H-pyrazolyl) Ethanones
Vol 49
a
b
*
Ilya Taydakov and Sergey Krasnoselskiy
aG.S Petrov Institute of Plastics, Perovskiy Proezd 35, Moscow 111024, Russia
bPeople’s Friendship University of Russia, Moscow 117198, Russia
*
E-mail: taidakov@gmail.com
Received October 7, 2010
DOI 10.1002/jhet.869
View this article online at wileyonlinelibrary.com.
A simple and versatile general method for the preparation of N-substituted 3-, 4-, or 5-acetylpyrazoles from
corresponding acids via hydrolysis and decarboxylation of substituted diethyl [(1-alkyl-1H-pyrazolyl)carbonyl]
malonates was developed. Title compounds were prepared in three steps without isolation of intermediates in
48–82% overall yield.
J. Heterocyclic Chem., 49, 1422 (2012).
Acylpyrazoles are the important intermediates in the
synthesis of pyrazole derivatives. The described methods
of their synthesis are: interaction of organomethallic
(Li or Mg) derivatives of pyrazole with nitriles [1], acyl
chlorides [2], or anhydrides of carbonic acids [3], decar-
boxylation of pyrazol ketoacids [4,5], by oxidation of alco-
hols or propenyl substituted pyrazoles [6], by condensation
of polycarbonyl compounds with hydrazines [7–9], by
multistep synthesis started from substituted alkynes
[10,11], by catalytic carbonilation of pyrazoles in the pres-
ence of Ru3(CO)12 [12] and by other methods. 4-Acylpyr-
azoles were also obtained [13,14] by direct acylation of
pyrazoles by acyl chlorides under drastic conditions
(150–200ꢀC).
The major disadvantages of the specified methods are:
multistage process, not readily available starting materials,
and, very often, low yields of target compounds. Besides,
not all of the methods can be easily scale-up.
Within the framework of our research project, there was
a necessity to develop a convenient and versatile method of
preparation of various N-substituted acetylpyrazoles.
Besides, this method should be applicable for preparation
of multigram quantities of target compounds. A simple
and general, three-step approach to synthesis of the title
compounds based on the ketonic degradation of substituted
acylmalonates have been developed (Scheme 1).
N-alkylation of ethyl 3-pyrazolecarboxylate with the subse-
quent separation of isomers and hydrolysis [17,18].
Acids 1 were converted to corresponding acyl chlorides
by interaction with SOCl2 (2 equiv.) in the presence of
catalytic amounts of DMF. Compounds 2 were obtained
in quantative yields.
To the best of our knowledge, the only one example of
acylation of diethyl malonate with the compound 2 was
described [17], but no further investigations were made.
Preliminary experiments have shown, that the highest
yields of the acylated compounds 3 could be achieved if
mixed magnesium (EtOMg) derivative of diethyl malonate
was used instead of sodium salt. The best results were
obtained when Et2O-EtOH (5–6%) mixture was used as a
solvent and reaction was performed in the sufficiently di-
luted solutions at 0–5ꢀC. Other solvents such as pure
EtOH, dioxane, Et2O, THF are much less effective due to
formation of gummy precipitate and considerable yields
decrease.
Saponification of the compounds 3 and subsequent
decarboxylation were performed by the refluxing of crude
3 with the excess of 20% aqueous HCl solution until CO2
evolution have ceased. The typical reaction time is 2–6 h,
depending uploads and the nature of the substitutients. As
pyrazoles are rather soluble in the acidic media, the acid
should be neutralized before extraction of the target ketone.
The best results were obtained, when pH was maintained at
7.5–8. To prevent too large dilution, the most part of HCl
was neutralized by the carefully addition of 50% KOH
solution to pH 4–5 with external cooling, and only after
N-Substituted pyrazolecarboxylic acid 1 were used as
starting materials. Many of these compounds are commer-
cially available, other could be prepared in any required quan-
tities by oxidation of alkylpyrazoles [15,16] or by means of
© 2012 HeteroCorporation

November 2012
An Efficient Synthesis of Isomeric 1-(1-Alkyl-1H-pyrazolyl) Ethanones
1423
Scheme 1
and solution of 300 mmol of acyl chloride (2) in 150 mL was
added dropwise with stirring. The resulted suspension was stirred
at the room temperature for 3 h and left overnight. Then it was
poured into the ice-HCl mixture (300 g of ice and 50 mL of conc.
HCl), stirred until all solid matter was dissolved and organic
phase was separated. Water phase was extracted with CH2Cl2
(2 Â 200 mL). Combined extracts were washed with brine and
evaporated at a reduced pressure. The resulted oil was used at
the next step without purification.
Crude compound 3 was refluxed with the 600 mL of 20% HCl
until decarboxylation was completed (no bubbles was obtained in
the bubble counter connected to the condenser) and cooled to a
room temperature. Acid was firstly neutralized by slowly addition
of 50% solution of NaOH with external cooling (the temperature
was maintained below +30ꢀC) and finally pH was adjusted to 8
by solid K2CO3. (Do not use NaOH for the compound 4i, acid
should be neutralized only by K2CO3). Mixture was extracted
with EtOA (3 Â 150 mL), organic phases were washed with
brine, dried over MgSO4 and evaporated in vacuo. The residue
was purified by distillation or crystallization.
that solid K2CO3 was added to reach necessary pH. After
usual workup crude ketones 4 were purified by crystalliza-
tion or distillation.
To investigate limitations of the developed method, sub-
stituted acyl chlorides were additionally prepared and
tested for the acylation. Good results were obtained with
N-alkylated acids, bearing Cl, Br, NO2, CF3 substitutions,
but our attempts to use 1H-pyrazole-3-carbonyl chloride
or 1H-pyrazole-4-carbonyl chloride were failed. No purifi-
cation was needed for intermediates, and all reactions can
be easily scaled-up to at least to 1.5 moles of starting
compounds without decrease of the yield (Table 1).
Thus, a simple and a versatile general method for the
preparation of N-substituted 3-, 4-, or 5-;acetylpyrazoles
from corresponding acids via hydrolysis and decarboxyl-
ation of substituted diethyl [(1-alkyl-1H-pyrazolyl)car-
bonyl]malonates 3 was reported.
1-(1-Methyl-1H-pyrazol-3-yl)ethanone (4a). Colorless oil,
EXPERIMENTAL
1
bp112–115ꢀC /11 Torr; H NMR (CDCl3): d 7.3 (s, 1H, CH),
6.7 (s, 1H, CH), 3.9 (s, 3H, N—CH3), 2.5 (s, 3H, CH3); 13C NMR
(CDCl3): d 193.3, 151.0, 131.5, 106.3, 39.1, 26.1; ms (EI, 70Ev):
m/z (%) 124 (27, M+), 109 (100, M+—CH3), 44 (22), 43 (16,
CH3CO+); Anal. Calcd. for C6H8N2O: C, 58.05; H,6.50; N, 22.57.
Found: C, 58.14; H, 6.63; N, 23.01.
General. Compounds 1(a-i) were purchased from Art-Chem
GmbH (Campus Berlin Buch, Germany). 1H NMR and 13C NMR
spectra were recorded on Bruker AC-300 and Bruker AM-300
instruments (300 and 75.5 MHz, respectively). Mass-spectra were
recorded on a Finnigan INCOS-50 instrument (EI, 70eV, direct
insertion).
1-(1-Alkyl-1H-pyrazolyl)ethanones (4a-i): General procedure.
To a stirred suspension of acid 1 (1 mol) in 100 mL of CCl4 0.5 mL of
dry DMF and 146 mL of thionyl chloride (238 g, 2 mol) were
subsequently added. The resulted mixture was carefully refluxed for
2 h until all the acid dissolved and vigorous gas evolution ceased.
The mixture was cooled to the room temperature and
evaporated to dryness under reduced pressure. The residue was
dissolved in 300 mL of dry benzene and evaporated to dryness
once again. This procedure was repeated in order to remove
unreacted SOCl2. Crude 1-alkyl-1H-pyrazole-carbonyl chlorides (2)
thus obtained in quantative yield, were used at the next step without
further purification.
1-(1-Ethyl-1H-pyrazol-3-yl)ethanone (4b). Colorless oil, bp
1
116–117ꢀC/18 Torr; H NMR (CDCl3): d 7.4 (s, 1H, CH), 6.7
(s, 1H, CH), 4.1 (q, 2H, J = 7.2 Hz, CH2), 2.5 (s, 3H, CH3), 1.4
(t, 3H, J = 7.2Hz, CH3); 13C NMR (CDCl3): d 193.75, 151.1,
129.9, 106.4, 47.5, 26.4, 15.5; ms (EI, 70Ev): m/z (%) 138 (33,
M+), 123 (100, M+-CH3), 95 (87, M+-CH3CO), 43(78.5,
CH3CO+); Anal. Calcd. for C7H10N2O: C, 60.85; H,7.30; N,
20.28. Found: C, 60.77; H, 7.63; N, 21.03.
Table 1
Synthesis of 1‐(1‐alkyl‐1H‐pyrazolyl) ethanones.
R2 position in pyrazol ring
Yield of
To a mechanically stirred suspension of magnesium (8g, 330
mmol) in the mixture of 250-mL anhydrous Et2O and 30 mL of
absolute EtOH 1 mL of CCl4 was added, and the reaction mass
was stirred under argon atmosphere until reaction started. The be-
ginning of the reaction could be easily detected by gas evolution
and warming of the mixture. At this moment, the solution of 50.3
mL (52.9 g, 330 mmol) of diethyl malonate and 10 mL of ethanol
in 150 mL of Et2O was added dropwise at a such rate to main-
tained vigorous reflux. After addition had been completed, solu-
tion was refluxed for 2 h. During this period of time, all
magnesium was completely dissolved and dark clear solution
was obtained. It was cooled to 0ꢀC, diluted by 200 mL of Et2O
Entry
R1
3
4
5
4 (%)
4a
4b
4c
4d
4e
4f
4g
4h
4i
Me
Et
Et
i‐Pr
Me
Me
Et
Me
Me
COCH3
COCH3
COCH3
COCH3
H
H
H
H
H
H
H
H
67
75
82
77
71
73
81
53
48
Br
H
COCH3
H
H
H
H
H
COCH3
COCH3
COCH3
COCH3
CF3
H
NO2
Overall isolated yield calculated for three steps, 300 mmol scale.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1424
I. Taydakov and S. Krasnoselskiy
Vol 49
1-(4-Bromo-1-ethyl-1H-pyrazol-3-yl)ethanone (4c). Colorless
NMR (CDCl3): d 188.2, 140.8 (q, J = 38.7 Hz), 139.5, 122.5,
118.9, 109.7, 40.9, 28.3; ms (EI, 70Ev): m/z (%) 192 (36, M+),
177 (100, M+-CH3), 80 (17), 44 (53.5), 43 (72, CH3CO+); Anal.
Calcd. for C7H7F3N2O: C, 43.76; H, 3.67 N, 14.58. Found: C,
43.19; H, 4.03; N, 14.17.
1-(1-Methyl-4-nitro-1H-pyrazol-5-yl)ethanone (4i). White
needles, mp (ethylacetate-ether) 63–64ꢀC; bp 103–105ꢀC/3 Torr; 1H
NMR (CDCl3): d 8.0 (s,1H, CH), 3.9 (s, 3H, N—CH3), 2.65 (s, 3H,
CH3); 13C NMR (CDCl3): d 191.9, 137.6, 135.0, 39.4, 30.9; ms (EI,
70Ev): m/z (%) 169 (26, M+), 152 (56, M+ —OH), 83 (55), 43 (100,
CH3CO+); Anal. Calcd. for C6H7N3O3: C, 42.61; H,4.17; N, 24.84.
Found: C, 43.06; H, 4.51; N, 24.99.
crystals (ether), mp 60–61ꢀC; 1H NMR (CDCl3): d 7.5 (s, 1H, CH),
4.15 (q, 2H, J = 7.2 Hz, CH2), 2.5 (s, 3H, CO-CH3), 1.45
(t, 3H, J = 7.2Hz, CH3); 13C NMR (CDCl3):d 192.7, 145.8,
131.4, 93.8, 48.2, 27.0, 14.9; ms (EI, 70Ev): m/z (%) 218
(29.5, 81BrM+), 216 (30,79BrM+), 203 (74), 201(79), 175 (34),
173 (36), 43(100, CH3CO+); Anal. Calcd. for C7H9BrN2O: C,
38.73; H, 4.18; N, 12.91. Found: C, 38.99; H, 3.71; N, 13.54.
1-(1-Isopropyl-1H-pyrazol-3-yl)ethanone (4d). Light yellow oil,
1
bp101–102ꢀC/12 Torr; H NMR (CDCl3): d 7.4 (s, 1H, CH), 6.7
(s, 1H, CH), 4.53 (sept, 1H, J = 6.6Hz, CH), 2.6 (s, 3H, CO-CH3),
1.51 (d, 6H, J = 6.6Hz, CH3); 13C NMR (CDCl3): d 194.1, 150.7,
127.9, 106.1, 54.5, 26.3, 22.7; ms (EI, 70Ev): m/z (%) 152 (27.5
M+), 137 (40, M+-CH3), 95 (100), 43 (36.5, CH3CO+); Anal.
Calcd. for C8H12N2O: C, 63.13; H, 7.95; N, 18.41. Found: C,
63.29; H, 8.17; N, 18.75.
REFERENCES AND NOTES
1-(1-Methyl-1H-pyrazol-4-yl)ethanone (4e). Light brown
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erocycl Compd 1991, 27, 656.
1
crystals, bp 96–98ꢀC/2 Torr, mp 39–40ꢀC; H NMR (CDCl3): d
[2] Brooklyn, F. J Chem Soc [C] 1968, 466.
[3] Katritzky, A. R.; Abdel-Rahman, A. E.; Leahy, D. E.;
Schwarz, A. O. Tetrahedron 1983, 39, 4133.
[4] Rateb, L.; Soliman, G. J Chem Soc 1960, 1426.
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153.
[7] Molteni, V.; Hamilton, M. M.; Mao, L.; Crane, M. C.; Wilson,
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[8] Arya, V. P.; Grewal, R. S.; Kaul, C. L.; Ghate, S. P.; Mehta, D.
V.; George, T. J Pharm Sci 1969, 58, 432.
[9] Claisen, L. Liebigs Ann Chem 1897, 295, 320.
[10] Finar, O. J Chem Soc Perkin Trans 1 1973, 2008.
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Murai, S. J Org Chem 2000, 65, 4039.
[13] Balbiano, B. Gazz Chim Ital 1889, 19, 131.
[14] Grandberg, I. I. J Gen Chem USSR 1961, 31, 1765; Grand-
berg, I. I. Chem Abstr 1961, 25921.
[15] Broom, J. N.; Elder, S. J.; Hannan, T. C. P.; Pons, J. E.;
O’Hanlon, P.J. J Antbiot 1995, 48, 1336.
7.90(s, 1H, CH), 7.81(s, 1H, CH), 3.9 (s, 3H, N—CH3), 2.45 (s,
3H, CH3); 13C NMR (CDCl3): d 192.0, 140.1, 132.4, 124.1,
39.0, 27.6; ms (EI, 70Ev): m/z (%) 124 (24.5, M+), 109(100,
M+-CH3), 53 (16.7), 43 (31.4, CH3CO+), 42 (31.6); Anal.
Calcd. for C6H8N2O: C, 58.05; H, 6.50; N, 22.57. Found: C,
58.34; H, 6.67; N, 22.61.
1-(1-Methyl-1H-pyrazol-5-yl)ethanone (4f). Colorless oil, bp
1
84–85ꢀC/18 Torr; H NMR (CDCl3): d 7.4 (s, 1H, CH), 6.8 (s,
1H, CH), 4.1 (s, 3H, N—CH3), 2.4 (s, 3H, CH3); 13C NMR
(CDCl3): d 188.7, 138.4, 137,4, 111.8, 40.0, 28.1; ms (EI,
70Ev): m/z (%) 124 (50, M+), 109 (100, M+-CH3), 81 (14), 54
(36.4), 43 (58, CH3CO+); Anal. Calcd. for C6H8N2O: C, 58.05;
H, 6.50; N, 22.57. Found: C, 58.19; H, 6.81; N, 22.73.
1-(1-Ethyl-1H-pyrazol-5-yl)ethanone (4g). Colorless oil, bp
1
89–90ꢀC/20 Torr; H NMR (CDCl3): d 7.4 (s, 1H, CH), 6.8 (s,
1H, CH), 4.5 (q, 2H, J = 7.2 Hz, CH2), 2.5 (s, 3H, CH3), 1.3 (t,
3H, J = 7.2Hz, CH3); 13C NMR (CDCl3): d 188.5, 137.5,
112.1, 47.4, 28.4, 15.4; ms (EI, 70Ev): m/z (%) 138 (52, M+),
123 (100, M+-CH3), 95 (65, M+ -COCH3), 43 (17.5, CH3CO+);
Anal. Calcd. for C7H10N2O: C, 60.85; H, 7.30; N, 20.28.
Found: C, 61.11; H, 7.79; N, 20.09.
1-[1- Methyl -3-(trifluoromethyl)-1H-pyrazol-5-yl]ethanone
(4h). Colorless oil, bp 55–56ꢀC/3 Torr; 1H NMR (CDCl3): d
7.1 (s, 1H, CH), 4.2 (s, 3H, N—CH3), 2.5 (s, 3H, CH3); 13C
[16] Eidebenz, K. Arch Pharm 1943, 281, 171.
[17] Dal Monte, D. Gazz Chim Ital 1956, 86, 797.
[18] Snyder, H. R.; Verbanac, F.; Brigh, D. B. J Am Chem Soc
1952, 74, 3243.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet