Methylation of 4-nitro-3(5)-pyrazolecarboxylic acid

Article abstract of DOI:10.1016/j.tetlet.2009.02.223

Reactions of 4-nitro-3(5)-pyrazolecarboxylic acid dipotassium salt with different methylating agents in various solvents have been investigated to improve the synthesis of isomeric 1-methyl-4-nitro-3- and -5-pyrazolecarboxylic acids.

Full text of DOI:10.1016/j.tetlet.2009.02.223

Tetrahedron Letters 50 (2009) 2624–2627
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Tetrahedron Letters
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Methylation of 4-nitro-3(5)-pyrazolecarboxylic acid
b
b
Andrzej Regiec a, Henryk Mastalarz a, , Agnieszka Mastalarz , Andrzej Kochel
*
a Department of Organic Chemistry, Faculty of Pharmacy, Wrocław Medical Academy ul. Grodzka 9, 50-137 Wrocław, Poland
b Faculty of Chemistry, Wrocław University, 14 F. Joliot-Curie Street, 50-383 Wrocław, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Reactions of 4-nitro-3(5)-pyrazolecarboxylic acid dipotassium salt with different methylating agents in
various solvents have been investigated to improve the synthesis of isomeric 1-methyl-4-nitro-3- and
-5-pyrazolecarboxylic acids.
Received 17 November 2008
Revised 1 February 2009
Accepted 27 February 2009
Available online 5 March 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Pyrazoles
Selective methylation
Regiochemistry
Chemoselectivity
Heterocyclic nitro acids and their derivatives are important
starting materials in chemical synthesis. They are utilized as pre-
cursors to obtain various biologically active compounds especially
if appropriate amino acids are not easily available. Our interest in
heterocyclic amino acid derivatives was stimulated by the synthe-
sis of 5-benzoylamine-N-(4-chlorophenyl)-3-methyl-4-isothiazol-
ecarboxamide, (Denotivir ITCL, Vratizolin)1 and the discovery of
its broad spectrum of pharmacological activity. Since this com-
pound was put into medical practice as an antiviral drug with
anti-inflammatory and immunotropic activity, a number of other
biologically active 5-amino-4-isothiazolecarboxylic acid deriva-
tives have been reported.2 Bioisoster imidazole analogues of
Denotivir3 have revealed strong anti-inflammatory and immuno-
tropic activity which has prompted us to synthesize their pyrazole
analogues. Presented herein are our preliminary studies on the
synthesis of 1-methyl-4-amino-3- and -5-pyrazolecarboxylic acid
derivatives as outlined in Scheme 1. Amongst various 4-nitropy-
razoles particular attention should be paid to 1-methyl-4-nitro-
3- and -5-pyrazolecarboxylic acids (4 and 5, respectively) because
of their synthetic utility as well as the biological activities of their
derivatives. Several synthetic applications of both isomeric N-
methyl-4-nitropyrazolecarboxylic acids were reported recently
including their use in the synthesis of potential drugs for Alzhei-
mer’s disease, cerebral apoplexy, manic-depressive illness, schizo-
phrenia, cancer, type II diabetes and obesity,4,5 ulcer inhibitors,
secretion inhibitors, antitussive and antiemetic compounds,6 cyto-
kinin antagonistic compounds,7 analgesics, anti-depressives, anti-
phlogistics, antipyretics,6,8 herbicides and insecticides.9–11
Herein, we present various attempts towards the selective
methylation of 4-nitro-3(5)-pyrazolecarboxylic acid in order to ob-
tain the required N-methyl isomers with the highest possible
yields and purity which is essential for further synthesis of com-
pounds for biological testing.
N-Alkylation is an important reaction in pyrazole chemistry. It
is well known that methylation of unsymmetrically substituted
pyrazole derivatives usually gives mixtures of both possible alkyl-
ation products. The ratios of these products depend not only on the
O
O
O
O
OCH3
OCH3
OH
N
N
N
N
N
N
H3C
NO2
H3C
NO2
H3C
NH2
4
6
2
K
OK
N
CH3X
N
NO2
1
O
O
O
H3C
H3C
H3C
N
OCH3
OH
OCH3
N
N
N
N
N
NO2
NH2
NO2
7
5
3
* Corresponding author. Tel.: +48 071 7840347; fax: +48 071 7840341.
E-mail address: necr0c0w@gazeta.pl (H. Mastalarz).
Scheme 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.223

A. Regiec et al. / Tetrahedron Letters 50 (2009) 2624–2627
2625
reaction conditions but also on the form of the alkylated pyrazole
(neutral molecule or its ionic form).12 To the best of our knowl-
edge, no studies of solvent influence on 4-nitro-3(5)-pyrazolecarb-
oxylic acid methylation have been conducted so far.
O(3)
O(1)
O(4)
O(3)
C(5)
O(1)
C(5)
N(3)
C(2)
O(2)
O(4)
We found that 4-nitro-3(5)-pyrazolecarboxylic acid can form a
stable dipotassium salt 1 on treatment with a methanolic KOH
solution. This salt, after separation and drying, can react with
methylating agents in various solvents, usually giving mixtures
of the following compounds: N-methyl carboxylic acids 4 and 5
and their methyl esters 2 and 3, sometimes accompanied by unre-
acted starting material (Scheme 1). Products of methylation were
found in different molar proportions depending on the nature of
the solvent and methylating agent used. The final composition of
methylation products was established using 1H NMR spectroscopy
(Table 1).
N(3)
C(1)
O(2)
C(1)
C(3)
C(2)
N(2)
N(2)
N(1)
C(3)
C(4)
C(4)
N(1)
4
5
Figure 1. ORTEP plots of molecules 4 and 5 (50% probability level).
Several trials using less reactive methylating agents such as
Me3PO4, Me3PO3 and Me2CO3 or other solvents (formamide, tolu-
ene, acetonitrile) were unsuccessful. If the reaction was carried
out at temperatures of 70 °C, mostly unchanged dipotassium salt
1 was recovered. At elevated temperatures (80 °C or higher) the
product of decarboxylation, namely N-methyl-4-nitropyrazole
was usually obtained.
CHCl3–methanol 3:1 as eluents) product which melted at 165–
167 °C and which is very close to its reported value. The 1H NMR
spectrum of this product indicated it to be 1-methyl-4-nitro-5-pyr-
azolecarboxylic acid 5 contaminated with a considerable amount
of impurity, probably the isomeric 3-carboxylic acid 4. After sev-
eral recrystallizations from butanone its melting point increased
to 173–175 °C, but still a trace of impurity was detectable using
1H NMR spectroscopy [signal near 3.90 ppm (DMSO-d6)].
Initial experiments showed that methylation of dipotassium
salt 1 can be accomplished with satisfactory results only if a polar
solvent and moderately (MeI) or highly reactive methylating
agents (Me2SO4, TosMe) are used. The composition of the methyl-
ation products depended strongly on the solvent, Table 1. Gener-
ally, in aprotic polar solvents (acetone, DMF) ester 2 was formed
in the highest proportion while in polar and protic methanol, acid
5 and its ester 3 were the major products. It should be mentioned
that using methanol as solvent for this reaction always resulted in
a mixture of acids 4 and 5 accompanied with esters 2 and 3 even if
an excess of base and methylating agent were added. This fact sug-
gested that simultaneous reaction of the solvent with the methy-
lating agent occurred resulting in formation of dimethyl ether as
a side product. The results obtained may be explained taking into
account the expected differences between the chemical behaviour
of dipotassium salt 1 in protic and aprotic solvents as outlined in
Figure 2.
During isolation of the reaction products it proved difficult to
separate and purify the isomeric N-methyl acids 4 and 5 in com-
parison to the purification of their methyl esters. For this reason,
all procedures resulting in formation of esters 2 and 3 only, should
be appreciated as especially valuable for preparative purposes.
Although the synthesis of ester 2 was previously reported in the lit-
erature,5 no physical data were given for this compound. Thus,
both esters 2 and 3 were hydrolyzed to the corresponding acids
4 and 5 in order to identify their structures. The melting points
of the resulting nitro acids were compared with literature values13
which showed significant discrepancies. We found that isomeric
acids 4 and 5 have melting points of 167–171 °C and 181–182 °C,
respectively, while the melting points of 1-methyl-4-nitro-3-pyra-
zolecarboxylic and 1-methyl-4-nitro-5-pyrazolecarboxylic acids
were reported previously13 as 171–173 °C and 162–165 °C, respec-
tively. Regarding the fact that there is no direct evidence in the lit-
erature for the structures of these two acids it was necessary to
perform a detailed chemical analysis of our obtained compounds
to unambiguously establish their structures. Elemental analyses
and 1H/13C NMR spectral data confirmed both hydrolysis products
4 and 5 to be N-methylpyrazole nitro acids. The 2D COSY 1H NMR
spectrum of compound 4 exhibited a weak coupling between the
N-methyl group and the pyrazole ring proton which suggested this
derivative to be the 3-substituted isomer. This was confirmed by X-
ray crystallography which finally allowed full assignment of the
structures for both of the obtained acids (Fig. 1). Additionally, syn-
thesis of nitro acid 5 according to the procedure described previ-
ously5 gave the chromatographically pure (TLC with ethanol or
According to our assumptions dipotassium salt 1 when dis-
solved in polar aprotic solvents may exist in dianionic form A or
as intramolecular monoanion complex B in which the nitrogen
atom nearest to the carboxylic group is shielded by the coordinated
potassium cation. When methylation of 1 is carried out in aprotic
solvents then, considering B as the predominant form, formation
K+
O
O
O
O
N
Table 1
N
+ K+
Results of the methylation of 1 depending on the reaction conditions expressed as the
ratio of relative molar amounts of reaction products
N
N
O2N
O2N
A
B
Conditions
Compound
2
3
4
5
1
CH3OH
O
Me2SO4/MeOH
Me2SO4/DMF
Me2SO4/Me2CO
TosMe/MeOH
TosMe/DMF
TosMe/Me2CO
MeI/MeOH
2
2
4
2
3
4
3
1
1
5
2
2
0.5
Trace
0
1
0
3
2
0.5
0
2
0.3
0
2
0
1
5
1
0
Trace
0
Trace
0
0
0
0
0
1
O
O
O
H
N
N
CH3O-
+
NH
O2N
N
O2N
Trace
2
Trace
Trace
1
Trace
D
C
MeI/DMF
MeI/Me2CO
Figure 2.

2626
A. Regiec et al. / Tetrahedron Letters 50 (2009) 2624–2627
of 2 and 4 will be preferred due to steric hindrance. In protic meth-
anol, protonation of 1 is inevitable resulting in formation of tauto-
meric anions C and D from which D will dominate due to its higher
polarity. Being more susceptible to methylation, the pyridine-type
nitrogen atom of D is located nearer to the carboxylic moiety
resulting in a higher proportion of methylation products 3 and 5.
Another mechanism can be considered involving initial O-methyl-
ation accompanied with further intramolecular N-methylation
resulting in the formation of nitro acid 5.
In conclusion, the experiments described have revealed that use
of an appropriate solvent can enable partial control of the methyl-
ation of 1 resulting in a higher yield of the required isomer. Several
attempts to convert both nitro acids 4 and 5 to their amino ana-
logues were performed but none gave satisfactory results. Reduc-
tion of methyl ester 2 with H2/Pd was previously described5 and
is easily reproducible. Unfortunately, this procedure failed with
methyl ester 3; also, catalytic reduction of a mixture of both esters
could not be accomplished. Methyl 1-methyl-4-amino-5-pyrazole-
carboxylate (7) was obtained in satisfactory yield using sodium
dithionite as reducing agent. Both amino esters 6 and 7 are stable
enough to perform elemental and spectral analyses but should not
be stored for prolonged periods as they decompose in air and/or
the presence of light.
homogenous sample from each crude reaction mixture was
dissolved in 0.5 mL of DMSO-d6 and the 1H NMR spectrum was re-
corded (see Table 1).
Methyl 1-methyl-4-nitro-3-pyrazolecarboxylate (2): Dipotassium
salt 1 (2.33 g, 10 mmol) was suspended in 15 mL of dry acetone
and cooled on an ice bath with stirring, then a solution of Me2SO4
(2.5 mL) in 10 mL of acetone was added dropwise over 15 min. The
reaction mixture was stirred at room temperature for 1 h and then
refluxed for 3 h. After this time, the solid residue was filtered off,
acetone was evaporated in vacuo to dryness and the solid residue
was extracted in a Soxhlet apparatus with CCl4 (also, CHCl3 or
CH2Cl2 can be used) from which, after partial evaporation of the
solvent to about 20 mL and cooling to À5 °C, white crystals of
the final product were collected. Yield 1.25 g (68%) mp 122–
123 °C. 1H NMR (CDCl3, 300 MHz) d [ppm] = 3.92, 3.94, 8.10; 13C
NMR (CDCl3, 75 MHz) d [ppm] = 40.5, 53.1, 131.0, 135.0, 138.3,
160.3. Elemental anal. [%]. Calcd for C6H7N3O4: C, 38.93; H, 3.81;
N, 22.70. Found: C, 38.71; H, 3.99; N, 22.52.
Methyl 1-methyl-4-nitro-5-pyrazolecarboxylate (3): Dipotassium
salt 1 (2.33 g, 10 mmol) was suspended in 25 mL of dry methanol
and cooled on an ice bath with stirring, then 2.5 mL of Me2SO4
was added dropwise over 15 min. After 1 h, the ice bath was re-
moved and the reaction mixture was stirred at room temperature
for 2 h and additionally refluxed for 1 h. Next, 0.56 g (10 mmol) of
pulverized KOH was dissolved in the reaction mixture with stirring
and the methanol was evaporated to dryness under reduced pres-
sure. The resulting solid residue was dried in vacuo for 24 h and
suspended in 20 mL of dry DMF. To the resulting mixture, 1.2 mL
of Me2SO4 was added dropwise over 15 min and the reaction mix-
ture was stirred for 2 h at room temperature. After evaporation of
the solvent in vacuo, the resulting solid residue was extracted in a
Soxhlet apparatus with CCl4, from which after cooling to À5 °C, es-
ter 2 crystallized (0.65 g, 35%) as a side product. The filtrate was
evaporated and the resulting oily residue containing mostly 5-pyr-
azolecarboxylic methyl ester was purified by column chromatogra-
phy on silica gel with chloroform as eluent, giving after
recrystallization from heptane, 0.95 g (50%) of product 3, mp 38–
41 °C. 1H NMR (CDCl3, 300 MHz) d [ppm] = 3.93, 3.94, 7.92; 13C
NMR (CDCl3, 75 MHz) d[ppm] = 39.3, 53.5, 130.9, 134.7, 134.9,
158.6. Elemental anal. [%]. Calcd for C6H7N3O4: C, 38.93; H, 3.81;
N, 22.70. Found: C, 39.09; H, 4.08; N, 22.47.
CCDC 683477 for compound 4 and CCDC 683478 for compound
5
contain crystallographic details which are available at
www.ccdc.cam.ac.uk/conts/retrieving.html or can be ordered, free
of charge, from the following address: Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge CB21EZ; fax: (+44)1223-
336-033 or deposit@ccdc.cam.ac.uk.
For correct estimation of the efficacy of the methylation pro-
cess, 1H NMR spectra (300 MHz) of pure compounds l–5 in
DMSO-d6 were recorded at the beginning of the experiments. Cal-
culations of the relative molar concentrations of the methylation
products were performed based on integrations of their N–CH3 sig-
nals except of unchanged starting material which was identified by
its single aromatic proton signal (see Table 1).
1H NMR data for compounds 1–5 in DMSO-d6 [ppm]:
1 d = 8.45 (s);
2 d = 3.87 (s, 3H, O–CH3), 3.93 (s, 3H, N–CH3), 8.63 (s, 1H);
3 d = 3.96 (s, 3H, O–CH3), 3.98 (s, 3H, N–CH3), 8.37 (s, 1H);
4 d = 3.91 (s; 3H, N–CH3), 8.86 (s; 1H);
5 d = 4.03 (s; 3H, N–CH3), 7.99 (s; 1H).
1-Methyl-4-nitro-3-pyrazolecarboxylic and -5-pyrazolecarboxylic
acids (4 or 5): The appropriate ester 2 or 3 (1.85 g, 0.01 mol) was
dissolved in 40 mL of ethanol and 10 mL of 6% KOH solution was
added. The reaction mixture was left overnight, then neutralized
with 10% HCl and evaporated to dryness. The resulting solid resi-
due was extracted in a Soxhlet apparatus with acetone giving, after
evaporation of the solvent, the appropriate acid in almost quantita-
tive yield. Both N-methyl acids 4 and 5 may be additionally puri-
fied by recrystallization from acetone, butanone, ethyl acetate or
water.
Dipotassium salt of 4-nitro-3(5)-pyrazolecarboxylic acid (1): 4-Ni-
tro-3(5)-pyrazolecarboxylic acid (15.7 g, 0.1 mol) was suspended
in 200 mL of 5.6% methanolic KOH solution (1 M). The mixture
was stirred at room temperature for 2 h and refluxed for 30 min.
After evaporating the solvent under reduced pressure, the solid
residue was dried in vacuo over concd H2SO4 (24 h) and used with-
out purification as a starting material for further reactions.
Methyl 1-methyl-4-amino-3-pyrazolecarboxylate (6): To a solu-
tion of 2 (185 mg, 1 mmol) in 20 mL of methanol, a small amount
of 10% palladium on charcoal (about 1 mg) was added and the
reaction mixture was stirred vigorously under a hydrogen atmo-
sphere under normal pressure for 5 h. Next, the catalyst was fil-
tered off and the filtrate was evaporated to dryness in vacuo to
afford a brownish residue of crude methyl 4-amino-1-methyl-3-
pyrazolecarboxylate (6) (150 mg, 97%) mp 97–102 °C. Additional
purification by crystallization from cyclohexane gave an analytical
sample of white crystals, mp 99–104 °C, which slowly decomposed
in air with darkening. 1H NMR (CDCl3, 300 MHz) d [ppm] = 3.80 (s,
3H), 3.86 (s, 3H), 4.15 (s, 2H, br s), 6.93 (s, 1H); 13C NMR (CDCl3,
75 MHz) d [ppm] = 39.8, 51.4, 117.7, 129.4, 134.9, 163.8. Elemental
General procedure for examination of the methylation of 1: Dipo-
tassium salt 1 (0.47 g, 2 mmol) was suspended in 10 mL of appro-
priate water-free solvent and cooled in an ice bath to 0 °C with
stirring. Then, 4 mmol of the methylating agent (except CH3I which
was used in fourfold molar excess) was added to the reaction mix-
ture in several small portions over 15 min. The reaction mixture
was stirred for 2 h at room temperature, warmed to 55–60 °C (re-
flux) (40 °C when CH3I was used) for 1 h and left to stand overnight
at 40 °C with constant stirring. Finally, the reaction mixture was
carefully neutralized with 5% HCl to free the carboxylic acids from
their potassium salts, then evaporated to dryness under reduced
pressure and the solid residue was dried in vacuo over concd
H2SO4 (24 h). To test the results of the methylation, 10 mg of dry

A. Regiec et al. / Tetrahedron Letters 50 (2009) 2624–2627
2627
anal. [%]. Calcd for C6H9N3O2: C, 46.45; H, 5.85; N, 27.08. Found: C,
References and notes
46.24; H, 6.11; N, 27.10.
1. Machon´ , Z. Drug Future 1988, 13, 426–428. and references cited therein.
Methyl 1-methyl-4-amino-5-pyrazolecarboxylate (7): To a stir-
red solution of 3 (185 mg, 1 mmol) in 35 mL of 60% aqueous
methanol, 0.9 g of 80% sodium dithionite (about 4 mmol) was
added in several small portions over 30 min. Next, the reaction
mixture was stirred at 50 °C for 3 h and then left to stand over-
night at room temperature. After this time the solvent was evap-
orated and the solid residue was dried and triturated several
times with chloroform. After evaporation of the chloroform,
120 mg (75%) of a solid brown residue (mp 57–61 °C) was ob-
tained. The crude product could be crystallized from cyclohex-
ane–heptane mixture (2:1) giving light brownish coloured
crystals mp 65–68 °C, which slowly decomposed in air with
darkening. 1H NMR (CDCl3, 300 MHz) d [ppm] = 3.89 (s, 3H),
4.01 (s, 3H), 4.50 (s, 2H, br s), 7.09 (s, 1H); 13C NMR (CDCl3,
75 MHz) d [ppm] = 40.1, 51.4, 117.5, 126.9, 136.2, 160.7. Elemen-
tal anal. [%]. Calcd for C6H9N3O2: C, 46.45; H, 5.85; N, 27.08.
Found: C, 46.17; H, 5.98; N, 26.83.
2. Regiec, A.; Machon´ , Z.; Mie˛dzybrodzki, R.; Szymaniec, S. Arch. Pharm. Chem. Life
Sci. 2006, 339, 401–413. and references cited therein.
´
3. Regiec, A.; Mastalarz, H.; Mie˛dzybrodzki, R.; Smietan´ ska, K.; Jasztold-Howorko,
R. Lett. Drug Des. Discovery 2006, 3, 192–199.
4. Tsukamoto, T.; Yamamoto, T.; Tokunoh, R.; Kawamoto, T.; Okura. M.; Kori, M.;
Murase, K. E.P. 1847531(A1), 2007; Chem. Abstr. 2006, 145, 249200d.
5. Dunten, P. W.; Foley, L. H.; Huby, N. J. S.; Pietranico-Cole, S. L; Yun, W. U.S.
10459944, 2003; Chem. Abstr. 2003, 140, 59656f.
6. Rainer, G. U.S. 4317823, 1982; Chem. Abstr. 1981, 95, 43186u.
7. Hecht, S. M.; Jordis, U. U.S. 4282361, 1981; Chem. Abstr. 1981, 95, 87295b.
8. Schmidt, G.; Engel, W.; Eberlein, W.; Trummlitz, G.; Engelhardt, G. U.S.
4381303, 1983; Chem. Abstr. 1983, 98, 179430p.
9. Takigawa, S.; Shinke, S. E.P. 0350176, 1995; Chem. Abstr. 1990, 113, 23906r.
10. Kajino, H.; Morimoto, M. W.O. 2004060877 A1, 2004; Chem. Abstr. 2004, 141,
140434z.
11. Lahm, G. P.; Myers, B. J.; Selby, T. P.; Stevenson, T. M. E.P. 1265850 B1, 2007;
Chem. Abstr. 2001, 135, 272754q.
12. Tarrago, G.; Ramdani, A.; Elguero, J.; Espada, M. J. Heterocycl. Chem. 1980, 17,
137.
13. Perevalov, W. P.; Andreeva, M. A.; Baryshnenkova, L. I.; Manaev, J. A.; Yamburg,
G. C.; Stepanov, B. I.; Dubrovskaya, B. A. Khim. Geterotsikl. 1983, 12, 1676.