Synthesis of new 1-(but-2-ynyl)pyrazoles containing a pyrrolidine or diethylamine moiety and their muscarinic properties

Article abstract of DOI:10.1002/1521-4184(200209)335:7<339::AID-ARDP339>3.0.CO;2-C

The synthesis of two series of 1-(but-2-ynyl)pyrazole containing a pyrrolidine or a diethylamine moiety, respectively, is described, together with their muscarinic receptor affinities.

Full text of DOI:10.1002/1521-4184(200209)335:7<339::AID-ARDP339>3.0.CO;2-C

Arch. Pharm. Pharm. Med. Chem. 2002, 7, 339–346
New 1-(But-2-ynyl)pyrazoles 339
María Isabel
Synthesis of New 1-(But-2-ynyl)pyrazoles
Containing a Pyrrolidine or Diethylamine Moiety
and Their Muscarinic Properties
Rodríguez-Francoa,
Isabel Dorronsoroa,1)
Albert Badíab,
,
Josep E. Bañosb
The synthesis of two series of 1-(but-2-ynyl)pyrazole containing a pyrrolidine or a di-
ethylamine moiety, respectively, is described, together with their muscarinic recep-
tor affinities.
a
Instituto de Química Médica
(C.S.I.C.), Madrid, Spain
Departamento de
b
Farmacología, de
Terapéutica, y de
Keywords: 1-(But-2-ynyl)pyrazoles; Muscarinic properties; Alzheimer’s disease
Toxicología, Facultad de
Medicina, Universidad
Autónoma de Barcelona,
Bellaterra, Spain
Received: January 28, 2002
pounds that displayed selectivity between the different
muscarinic receptor subtypes [7].
Introduction
Alzheimer’s disease (AD), one of the major challenges
facing modern neuropharmacology, is characterised by
a vast degeneration of brain cholinergic function and the
formation of neurofribrillary tangles and beta amyloid
(Aβ) plaques [1]. Extensive efforts have been undertak-
en in research on cholinomimetic agents that either acti-
vate postsynaptic muscarinic receptors (e.g. arecoline,
oxotremorine) or inhibit acetylcholinesterase (e.g. ta-
crine, donepezil), as neurotransmitter replacement ther-
apy and potential treatment for the cognitive symptoms
in AD [2]. Since recent research has revealed that mus-
carinic agonists can actually slow down the progress of
AD, halting the formation of both neurofibrillary tangles
[3] and Aβ plaques [4], current interest in these drugs
has increased.
Continuing with our work on several heterocyclic families
(e.g. 1,2,4-thiadiazolidinones, imidazoles, and pyr-
azoles) that display acetylcholinesterase inhibition
[8–10] or muscarinic properties [11, 12], now we are in-
terested in the synthesis of new oxotremorine-like com-
pounds derived from pyrazoles and pyrrolidine or diethyl-
amine (Figure 1, general formula I) as potential
muscarinic agents.
Oxotremorine (Figure 1) has long been known to act as a
potent muscarinic agonist [5], moderately selective for
the central nervous system, and since its discovery in
1961 numerous structural modifications have been re-
ported, including aromatic replacement of the pyrrolidine
or the pyrrolidinone ring. In this context, the derivative
U-80816, in which the pyrrolidine ring of oxotremorine
was replaced by an imidazolic framework, showed cen-
tral cholinergic agonist effects with minimal peripheral
side effects [6]. On the other hand, the replacement of
the pyrrolidinone ring by an isoxazole yielded com-
Figure 1
Results and discussion
As shown in Scheme 1, treatment of starting N-unsubsti-
tuted pyrazoles with propargyl bromide and a base yield-
ed the corresponding acetylenic intermediates (1–7),
that then were subjected to a Mannich reaction using the
appropriate secondary amine, to afford the desired prod-
ucts 8–14 (a, b).
1)
This paper comprises a part of the PhD Thesis of Isa-
bel Dorronsoro.
Correspondence: María Isabel Rodríguez-Franco, Instituto
de Química Médica (C.S.I.C.), Juan de la Cierva 3,
28006 Madrid, Spain. Phone: +34 91 562 2900, Fax:
+34 91 564 4852, e-mail: IsabelRguez@iqm.csic.es.
Two general methods were employed for the N-alkylation
of the pyrazolic ring, depending on the nature of the sub-
© 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0365-6233/07/0339 $ 17.50+.50/0

340 Rodríguez-Franco et al.
Arch. Pharm. Pharm. Med. Chem. 2002, 335, 339–346
Table 1. Reaction between 3,5-dimethylpyrazole and
propargyl bromide.Yield of isolated acetylenic (5) and al-
lene derivative (5Ј).
Base
Solvent Temp./Time
5
5Ј
(%) (%)
NaH
NaH
DMF
DMF
Reflux/4 h
25 °C/16 h 15 20
38 16
NaOH 1.25 N, TBAB Tol., H2O 25 °C/24 h 48
–
35
NaOH 25 N, TBAB Tol., H2O 25 °C/5 h
Scheme 1. (i) Propargyl bromide, base.(ii) Pyrrolidine or
diethylamine, paraformaldehyde, cuprous chloride
(cat.), acetic acid, dioxane.
–
DMF: Dimethylformamide; TBAB: tetrabutylammonium
bromide; Tol: toluene.
stituent in the heterocycle.Since in the case of pyrazoles
with electron-withdrawing substituents, the pyrazolate
anion is easily obtained using a soft base, treatment of
3,5-bis(ethoxycarbonyl)- and 4-benzyloxy-3,5-bis-
(ethoxycarbonyl)- with propargyl bromide using potassi-
um carbonate in boiling acetone afforded acetylenic in-
termediates 1 and 2, in good yields (92 and 98 %, re-
spectively). When the above mentioned reaction condi-
tions were applied to 3(5)-ethoxycarbonyl-4-nitro-1H-
pyrazole of non-symmetric structure, the two possible
isomers were obtained 3 (3-ethoxycarbonyl-) and 4 (5-
ethoxycarbonyl-), also in good yield (39 and 60 %, re-
spectively), as the result of the alkylation in each nitro-
gen atom.
Both acetylenic and allenic pyrazoles showed spectro-
scopic data in agreement with their structures.Complete
assignment of all chemical shifts, of special interest for
the identification of structural isomers (3 and 4; 6 and 7;
6Ј and 7Ј), was undertaken using two-dimensional ex-
periments such as heteronuclear single quantum coher-
ence (HSQC) for one-bond correlations, and heteronu-
clear multiple bond correlation (HMBC) for two and three
bond correlations. For instance, compound 6 was identi-
fied as the 3-methylpyrazole derivative since there was a
HMBC correlation between the acetylenic methylene
protons (δH = 4.7 ppm) and the protonated pyrazolic car-
bon 5 (δC = 129 ppm). However, in the HMBC diagram of
compound 7 the same methylene protons correlated
with the non-protonated pyrazolic C-5 (δC = 138 ppm),
showing that it was the 5-methylpyrazole isomer.
However, in the case of pyrazoles with alkyl substituents,
a stronger base is necessary to deprotonate the pyrazol-
ic ring [13], but this strong base could also promote the
acetylenic-allene transposition, affording the corre-
sponding allene as the major product [14]. In fact, then
3,5-dimethylpyrazole was treated with propargyl bro-
mide using sodium hydride as base in boiling dimethyl-
formamide only the allene 5Ј was isolated in 35 % yield.
1
In the H NMR spectra of acetylenes 1–7 and allenes
5Ј–7Ј remarkable differences were observed, both in
chemical shifts and in coupling constants (see experi-
mental part).For example, protons belonging to the acet-
ylenic chain showed a constant coupling of approx.
2.5 Hz, whereas the corresponding protons of the al-
lenic derivatives displayed a higher constant (approx.
6.5 Hz).
In order to obtain the desired acetylenic intermediate as
the major product, several experimental conditions were
tested using the simplest 3,5-dimethylpyrazole as start-
ing material (Table 1).The best result was obtained using
aqueous sodium hydroxide 1.25 N in the presence of
tetrabutylammonium bromide in a biphasic system of tol-
uene and water.
Treatment of acetylenic intermediates 1–7 with pyrrolid-
ine or diethylamine, paraformaldehyde, acetic acid, and
a catalytic amount of cuprous chloride in dioxane as sol-
vent gave the desired final oxotremorine-like pyrazoles
8–14 (a, b), that showed spectroscopic data in agree-
ment with their structures, the most significant of which
are collected in Table 2. In their 1H-NMR spectra the two
methylene groups of the butynyl chain appeared as tri-
plets at 4.7–5.4 and 3.3–3.5 ppm, respectively, with a
coupling constant of about 2 Hz. In HMBC experiments,
the most deshielded triplet showed a correlation with
pyrazolic C5, being assigned to CH2(1Ј), whereas the
The above optimised conditions were applied to 3(5)-
methylpyrazole that, due to its non-symmetric structure,
can be alkylated in one pyrazolic nitrogen atom or in the
other, afforded mixtures of two isomers. In both cases,
the acetylenic derivative was obtained as the major
product (6: 30 %; 7: 20 %), although the corresponding
allene could also be isolated in minor proportions (6Ј:
6 %; 7Ј: 4 %).

Arch. Pharm. Pharm. Med. Chem. 2002, 335, 339–346
New 1-(But-2-ynyl)pyrazoles 341

342 Rodríguez-Franco et al.
Arch. Pharm. Pharm. Med. Chem. 2002, 335, 339–346
less deshielded triplet, which displayed connectivity with
the first carbon of the amine fragment (Cα), was attribut-
ed to CH2(4Ј).
Experimental
Chemistry
Reagents and solvents were purchased from common com-
mercial suppliers and were used without further purification.
The following pyrazoles were synthesised according to the lit-
erature: 3,5-bis(ethoxycarbonyl)-1H-pyrazole [16] and 4-ben-
zyloxy-3,5-bis(ethoxycarbonyl)-1H-pyrazole [17]. Chromato-
graphic separations were performed on silica gel, using the fol-
lowing techniques: flash column chromatography (CC, using
Kieselgel 60 Merck of 230–400 mesh) and preparative centrifu-
gal thin layer chromatography (CTLC, on a circular plate coated
with a 1 mm layer of Kieselgel 60 PF254 gipshaltig, Merck, using
a Chromatotron®). Compounds were detected with UV light
(254 nm), iodine chamber, or ninhydrin.
The affinities of synthesised oxotremorine-like pyrazoles
8–14 (a, b) for muscarinic receptors were determined by
assessing the inhibition of specific [3H]-(R )-quinuclidinyl
benzilate ([3H]-QNB) binding to rat brain membranes. In
general, compounds showed IC50 > 100 µM, except
compounds collected in Table 3 that displayed moderat-
ed affinity for muscarinic receptors in rat central nervous
system, being pyrrolidine derivatives (series a) better
than diethylamine analogs (series b). In general, pyr-
azoles with electron-withdrawing substituents displayed
better results than pyrazoles with alkyl groups. It is
worth mentioning that derivatives 11 a and 11 b, with an
ethoxycarbonyl group in position 5, showed the best af-
finities for muscarinic receptors, whereas their corre-
sponding isomers 10 a, b with the same substituent, but
in position 3, were inactive.The same effect could be ob-
served in the couple 14 a (5-methylpyrazole, active) and
13 a (3-methylpyrazole, inactive). The above finding
pointed out that a substituent in position 5 could be use-
ful for the biological activity of these compounds, and this
conclusion will be used in future studies.
Nuclear magnetic resonance spectra were recorded in CDCl3
solutions, using Varian Unity-500, Varian XL-300, and Gemini-
200 spectrometers. Typical spectral parameters for 1H NMR
were: spectral width 10 ppm, pulse width 9 µs (57°), data size
32 K.The acquisition parameters in decoupled 13C NMR spec-
tra were: spectral width 16 kHz, acquisition time 0.99 s, pulse
width 9 µs (57°), data size 32 K. Chemical shifts are reported in
δ values (ppm) relative to internal Me4Si and J values are re-
ported in hertz.Other experiments such HSQC (Heteronuclear
Single-Quantum Coherence) and HMBC (Heteronuclear Multi-
ple Bond Correlation) were obtained in standard conditions.
Mass spectra (MS) were obtained by electronic impact (EI) at
70 eV in a Hewlett-Packard 5973 spectrometer (with direct in-
sertion probe) and by atmospheric pressure chemical ionisa-
tion (APCI) or electrospray in a Hewlett-Packard MSD 1100
spectrometer.Elemental analyses were carried out in a Perkin-
Elmer 240C equipment in the Centro de Química Orgánica
‘Manuel Lora-Tamayo’(CSIC) and the results are within ± 0.4 %
of the theoretical values.
Table 3. Muscarinic affinities using [3H]-QNB as radio-
ligand.
General procedures for the N-alkylation of pyrazoles
Compound
IC50 (µM)
Method A: A mixture of the corresponding pyrazole (10 mmol),
propargyl bromide (10 mmol), and K2CO3 (10 mmol) in acetone
(50 mL) was refluxed for 2–5 hours. Then, crude material was
poured into crushed ice (50 mL) and extracted with CH2Cl2 (3 ×
50 mL).The organic solution was dried (Na2SO4) and evaporat-
ed to dryness in vacuo and the residual syrup was purified by
chromatography on silica gel, as showed for individual prod-
ucts.
8 a
11 a
11 b
14 a
57.6 ± 15.0
45.2 ± 20.0
40.6 ± 6.4
80.2 ± 5.9
5.5 ± 1.0
carbachola
Method B: A mixture of pyrazole (10 mmol), propargyl bromide
(10 mmol), and tetrabutylammonium bromide (2 mmol) in tolu-
ene (25 mL) was treated with 1.25 N aq. sodium hydroxide
(25 mL) at room temperature or reflux, as indicated in each
case, until a TLC control did not show starting materials.Then,
the organic phase was separated, the aqueous layer extracted
with CH2Cl2 (3 × 50 mL) and the resulting organic solution was
dried and evaporated to dryness in vacuo, to give syrups that
were purified by chromatography on silica gel, as indicated in
each case.
a Taken from Ref. [15].
From this study we can conclude that oxotremorine-like
pyrazoles derived from pyrrolidine (series a), especially
with an electron-withdrawing substituent in the pyrazolic
position 5, show moderate activity for muscarinic recep-
tors in the rat central nervous system.
3,5-Bis(ethoxycarbonyl)-1-prop-2-ynyl-1H-pyrazole (1)
Reagents and conditions: 3,5-bis(ethoxycarbonyl)-1H-pyra-
zole (500 mg, 2.4 mmol), propargyl bromide (356 mg, 267 µL,
2.4 mmol), K2CO3 (332 mg, 2.4 mmol), refluxing acetone,
2 hours (Method A). Purification: CC, hexane:ethyl acetate
(4 : 1), Rf = 0.4. Yield 550 mg (92 %). Colourless syrup. Anal.
Calcd for C12H14N2O4 (250.25): C, 57.94; H, 5.64; N, 11.19.
Found: C, 57.68; H, 5.72; N, 11.21. 1H-NMR (CDCl3), δ: 7.36 (s,
1 H), 5.42 (d, 2 H, J = 2.4 Hz), 4.40 (q, 2 H, J = 7.1 Hz), 4.38 (q,
2 H, J = 7.1 Hz), 2.38 (t, 1 H, J = 2.4 Hz), 1.38 (t, 6 H, J =
Acknowledgements
The authors gratefully acknowledge the financial sup-
ports of C.I.C.Y.T. (SAF 99-098) and Comunidad de
Madrid (08.5/0045.1/99) and the fellowship to one of us
(I.D.) from the Fundación Ramón Areces.

Arch. Pharm. Pharm. Med. Chem. 2002, 335, 339–346
New 1-(But-2-ynyl)pyrazoles 343
2.18 (s, 3 H), 2.15 (s, 3 H). 13C-NMR (CDCl3), δ: 202.8, 149.2,
7.1 Hz).13C-NMR (CDCl3), δ:161.3, 158.7, 142.8, 133.4, 114.2,
139.3, 106.6, 98.4, 86.8, 13.3, 11.3.
76.7, 73.9, 61.7, 61.3, 42.5, 14.3, 14.1.
3-Methyl-1-prop-2-ynyl-1H-pyrazole (6), 5-methyl-1-prop-2-
ynyl-1H-pyrazole (7), 3-methy-1-propa-1,2-dienyl-1H-pyrazole
(6Ј), and 5-methyl-1-propa-1,2-dienyl-1H-pyrazole (7Ј)
4-Benzyloxy-3,5-bis(ethoxycarbonyl)-1-prop-2-ynyl-1H-
pyrazole (2)
Reagents and conditions: 4-benzyloxy-3,5-bis(ethoxycarbo-
nyl)-1H-pyrazole (193 mg, 0.6 mmol), propargyl bromide
(89 mg, 67 µL, 0.6 mmol), K2CO3 (84 mg, 0.6 mmol), refluxing
acetone, 3 hours (Method A). Purification: CC, hexane : ethyl
acetate (1 : 1), Rf = 0.7.Yield 210 mg (98 %). Colourless syrup.
Anal. Calcd for C19H20N2O5 (356.39): C, 64.04; H, 5.66; N, 7.86.
Found: C, 64.15; H, 5.72; N, 7.90. 1H-NMR (CDCl3), δ:
7.48–7.29 (m, 5 H), 5.31 (d, 2 H, J = 2.5 Hz), 5.11 (s, 2 H), 4.40
(q, 2 H, J = 7.2 Hz), 4.33 (q, 2 H, J = 7.2 Hz), 2.38 (t, 1 H, J =
2.5 Hz), 1.36 (t, 6 H, J = 7.2 Hz), 1.32 (t, 6 H, J = 7.2 Hz).
13C-NMR (CDCl3), δ: 160.5, 158.4, 147.6, 136.4, 134.8, 128.2,
128.1, 128.0, 124.8, 77.5, 76.8, 73.9, 61.4, 61.0, 43.5, 14.3, 13.9.
Reagents and conditions: 3(5)-methyl-1H-pyrazole (1.0 g,
11.6 mmol), propargyl bromide (1.34 g, 1.0 mL, 11.6 mmol),
tetrabutylammonium bromide (748 mg, 2.3 mmol), NaOH
1.25 N (16 mL), toluene (60 mL), room temperature, 48 hours
(Method B). A flash column chromatography using as eluent
mixtures of hexane:ethyl acetate of increasing polarity, 50 : 1
(ca. 250 mL), 25 : 1 (ca. 250 mL), 14.1 (ca. 200 mL), and 7 : 1
(ca. 200 mL), gave two fractions, each composed of a mixture
of two compounds. The first band afforded the allenic isomers
6Ј and 7Ј (190 mg), and the second band yielded the mixture of
the acetylenic intermediates 6 and 7 (830 mg).
The mixture of 6Ј and 7Ј was then separated into its single com-
ponents by a centrifugal circular thin layer chromatography, us-
ing the following mixtures of hexane:ethyl acetate, 100 : 1 (ca.
100 mL), 75 : 1 (ca. 50 mL), and 50 : 1 (ca. 50 mL).
3-Ethoxycarbonyl-4-nitro-1-prop-2-ynyl-1H-pyrazole (3) and
5-ethoxycarbonyl-4-nitro-1-prop-2-ynyl-1H-pyrazole (4)
Reagents and conditions: 3(5)-ethoxycarbonyl-4-nitro-1H-
pyrazole (900 mg, 4.9 mmol), propargyl bromide (734 mg,
550 µL, 4.9 mmol), K2CO3 (672 mg, 4.9 mmol), refluxing ace-
tone, 2 hours (Method A). Purification: CC, hexane : ethyl ace-
tate (3 : 1).
6Ј: Colourless syrup, yield 84 mg (6 %), Rf = 0.7 (hexane : ethyl
acetate, 20 : 1). Anal. Calcd for C7H8N2 (120.15): C, 69.98; H,
1
6.70; N, 23.31. Found: C, 69.59; H, 7.05; N, 23.36. H-NMR
(CDCl3), δ:7.38 (t, 1 H, J = 2.3 Hz), 7.06 (t, 1 H, J = 6.4 Hz), 6.09
(d, 1 H, J = 2.3 Hz), 5.56 (d, 2 H, J = 6.4 Hz), 2.26 (s, 3 H).
13C-NMR (CDCl3), δ: 202.5, 149.2, 129.3, 105.3, 98.2, 86.5,
13.2.
3: Rf = 0.5.Yield 424 mg (39 %). Colourless syrup. Anal. Calcd
for C9H9N3O4 (223.19): C, 48.43; H, 4.06; N, 18.83. Found: C,
48.59; H, 3.97; N, 18.90. 1H-NMR (CDCl3), δ: 7.93 (s, 1 H), 5.03
(d, 2 H, J = 2.7 Hz), 4.34 (q, 2 H, J = 7.2 Hz), 2.46 (t, 1 H, J =
2.7 Hz), 1.29 (t, 3 H, J = 7.2 Hz). 13C-NMR (CDCl3), δ: 157.5,
135.2, 134.5, 130.6, 75.2, 74.9, 63.2, 42.0, 13.4.
7Ј: Colourless syrup, yield 35 mg (4 %), Rf = 0.6 (hexane : ethyl
acetate, 20 : 1). Anal. Calcd for C7H8N2 (120.15): C, 69.98; H,
1
6.70; N, 23.31. Found: C, 69.77; H, 7.00; N, 23.23. H-NMR
4: Rf = 0.4.Yield 663 mg (60 %). Colourless syrup. Anal. Calcd
for C9H9N3O4 (223.19): C, 48.43; H, 4.06; N, 18.83. Found: C,
48.31; H, 4.17; N, 18.72. 1H-NMR (CDCl3), δ: 8.42 (s, 1 H), 4.99
(d, 2 H, J = 2.5 Hz), 4.40 (q, 2 H, J = 7.2 Hz), 2.49 (t, 1 H, J =
2.5 Hz), 1.29 (t, 3 H, J = 7.2 Hz). 13C-NMR (CDCl3), δ: 159.8,
139.1, 134.1, 129.7, 77.6, 73.8, 62.5, 43.2, 13.8.
(CDCl3), δ:7.40 (d, 1 H, J = 1.7 Hz), 7.04 (t, 1 H, J = 6.5 Hz), 6.00
(d, 1 H, J = 1.7 Hz), 5.51 (d, 2 H, J = 6.5 Hz), 2.27 (s, 3 H).
13C-NMR (CDCl3), δ: 203.1, 138.6, 138.1, 106.6, 98.7, 87.0,
11.5.
Centrifugal circular thin layer chromatography of the mixture of
the acetylenic intermediates 6 and 7, using as eluent hexane:
ethyl acetate of increasing polarity, 50 : 1 (ca. 100 mL), 25 : 1
(ca. 100 mL), and 7 : 1 (ca. 50 mL), allowed the isolation of both
compounds.
3,5-Dimethyl-1-prop-2-ynyl-1H-pyrazole (5) [18]
Reagents and conditions: 3,5-dimethyl-1H-pyrazole (1.5 g,
15.6 mmol), propargyl bromide (2.3 g, 1.7 mL, 15.6 mmol),
tetrabutylammonium bromide (1.26 g, 4.0 mmol), NaOH 1.25 N
(10 mL), toluene (50 mL), room temperature, 24 hours (Method
B). Eluent: hexane : ethyl acetate (5 : 1), Rf = 0.5. Yield 1.0 g
(48 %). Colourless syrup. Anal. Calcd for C8H10N2 (134.18): C,
71.61; H, 7.51; N, 20.87. Found: C, 71.50; H, 7.34; N, 21.16.
1H-NMR (CDCl3), δ: 5.74 (s, 1 H), 4.68 (d, 2 H, J = 2.5 Hz), 2.28
(t, 1 H, J = 2.5 Hz), 2.21 (s, 3 H), 2.13 (s, 3 H).13C-NMR (CDCl3),
δ: 147.9, 139.0, 105.8, 77.4, 72.9, 38.4, 13.3, 10.8. EM (EI,
70 eV), m/z : 133 (100 %), 134 (M+, 56 %).
6: Colourless syrup, yield 413 mg (30 %), Rf = 0.3 (hexane :
ethyl acetate, 7 : 1). Anal. Calcd for C7H8N2 (120.15): C, 69.98;
H, 6.70; N, 23.31. Found: C, 69.80; H, 7.01; N, 23.31. 1H-NMR
(CDCl3), δ: 7.31 (d, 1 H, J = 1.7 Hz), 5.906 (d, 1 H, J = 1.7 Hz),
4.68 (d, 2 H, J = 2.6 Hz), 2.36 (t, 1 H, J = 2.6 Hz), 2.12 (s, 3 H).
13C-NMR (CDCl3), δ: 148.8, 129.1, 105.3, 76.7, 74.0, 40.7,
13.1. EM (EI, 70 eV), m/z : 119 (100 %), 120 (M+, 53 %).
7: Colourless syrup, yield 293 mg (20 %), Rf = 0.2 (hexane :
ethyl acetate, 7 : 1). Anal. Calcd for C7H8N2 (120.15): C, 69.98;
H, 6.70; N, 23.31. Found: C, 70.01; H, 6.82; N, 23.17. 1H-NMR
(CDCl3), δ: 7.29 (d, 1 H, J = 2.0 Hz), 5.94 (d, 1 H, J = 2.0 Hz),
4.75 (d, 2 H, J = 2.5 Hz), 2.31 (t, 1 H, J = 2.5 Hz), 2.25 (s, 3 H).
13C-NMR (CDCl3), δ: 138.6, 138.0, 105.8, 77.0, 73.2, 38.7,
10.7. EM (EI, 70 eV), m/z : 119 (100 %), 120 (M+, 52 %).
3,5-Dimethyl-1-propa-1,2-dienyl-1H-pyrazole (5Ј)
To a suspension of NaH (104 mg, 2.6 mmol) and 3,5-dimethyl-
1H-pyrazole (250 mg, 2.6 mmol) in DMF (10 mL), a solution of
propargyl bromide (0.3 mL, 2.6 mmol) in DMF (2 mL) was add-
ed, and the mixture was refluxed for 4 hours.Solvent was evap-
orated to dryness and the crude material was redisolved in
CH2Cl2 (20 mL), washed with H2O (20 mL) and the organic so-
lution was dried (Na2SO4) and evaporated to dryness, yielding
a syrup that was purified on a silica gel column, using
CH2Cl2 : CH3OH (10 : 1) as eluent. From fractions of Rf = 0.6 al-
lene 5Ј was isolated as a pure colourless syrup (120 mg, 35 %
yield). Anal. Calcd for C8H10N2 (134.18): C, 71.61; H, 7.51; N,
20.87. Found: C, 71.48; H, 7.44; N, 21.08. 1H-NMR (CDCl3), δ:
6.91 (t, 1 H, J = 6.4 Hz), 5.77 (s, 1 H), 5.47 (d, 2 H, J = 6.4 Hz),
General method for preparing 1-(4-pyrrolidin-1-yl-but-2-ynyl)-
pyrazoles (series a) and diethyl-[4-(1H-pyrazol-1-yl)-but-2-
ynyl]-amines (series b)
To a mixture of paraformaldehyde (10 mmol), acetic acid
(10 mmol), and copper (I) chloride (0.18 mmol) in anhydrous
dioxane (20 mL), a solution of the amine (10 mmol) in dioxane
(10 mL) was added, and the resulting mixture was stirred to

344 Rodríguez-Franco et al.
Arch. Pharm. Pharm. Med. Chem. 2002, 335, 339–346
5.30 (t, 2 H, J = 1.7 Hz), 5.11 (s, 2 H), 4.40 (q, 2 H, J = 7.2 Hz),
4.33 (q, 2 H, J = 7.2 Hz), 3.38 (t, 2 H, J = 1.7 Hz), 2.45 (q, 4 H, J =
7.2 Hz), 1.35 (t, 3 H, J = 7.2 Hz), 1.33 (t, 3 H, J = 7.2 Hz), 0.99 (q,
4 H, J = 7.2 Hz). 13C-NMR (CDCl3), δ: 160.7, 158.4, 147.7,
136.5, 134.4, 128.3, 128.2, 128.1, 124.9, 80.6, 77.8, 77.6,
61.5, 61.2, 47.1, 44.2, 40.7, 14.3, 14.1, 12.5.
room temperature for 30 minutes.Then, a solution of the corre-
sponding 1-prop-2-ynyl-1H-pyrazole (10 mmol) in dry dioxane
(10 mL) was added and the mixture was refluxed for
2–10 hours. Solvent was evaporated to dryness in vacuo and
the resulting crude material was redissolved in water (50 mL),
neutralized with aq. K2CO3, extracted with CH2Cl2 (3 × 50 mL)
and dried with Na2SO3.Evaporation of the organic layer yielded
crude syrups that were purified on column chromatography
(CC) or centrifugal thin layer chromatography (CTLC), as indi-
cated for individual products.
3-Ethoxycarbonyl-4-nitro-1-(4-pyrrolidin-1-yl-but-2-ynyl)-1H-
pyrazole (10 a)
Reagents and conditions: 3 (100 mg, 0.49 mmol), pyrrolidine
(41 µL, 0.49 mmol), paraformaldehyde (15 mg, 0.49 mmol),
acetic acid (27 µL, 0.49 mmol), CuCl (1 mg, 0.01 mmol), reflux-
ing dioxane 3 hours. Purification: CC (ethyl acetate : methanol,
10 : 1), Rf = 0.2. Yield 51 mg (37 %). Colourless syrup. Anal.
Calcd for C14H18N4O4 (306.32): C, 54.89; H, 5.92; N, 18.29.
Found: C, 54.95; H, 5.73; N, 18.10. 1H-NMR (CDCl3), δ: 8.38 (s,
1 H), 4.98 (s, 2 H), 4.39 (q, 2 H, J = 7.2 Hz), 3.35 (s, 2 H), 2.56 (t,
4 H, J = 6.4 Hz), 1.34 (q, 4 H, J = 6.4 Hz), 1.30 (t, 3 H, J = 7.2 Hz).
13C-NMR (CDCl3), δ: 159.8, 139.0, 134.1, 129.5, 85.8, 74.1,
62.3, 52.7, 43.6, 43.1, 23.4, 13.8. EM (electrospray): 307
(MH+).
3,5-Bis(ethoxycarbonyl)-1-(4-pyrrolidin-1-yl-but-2-ynyl)-1H-
pyrazole (8 a)
Reagents and conditions: 1 (70 mg, 0.26 mmol), pyrrolidine
(24 µL, 0.28 mmol), paraformaldehyde (8 mg, 0.28 mmol), ace-
tic acid (15 µL, 0.28 mmol), CuCl (0.5 mg, 0.005 mmol), reflux-
ing dioxane 4 hours. Purification: CTLC (ethyl acetate : metha-
nol, 8 : 1).Yield 60 mg (65 %). Colourless syrup. Anal. Calcd for
C17H23N3O4 (333.39): C, 61.25; H, 6.95; N, 12.60. Found: C,
61.31; H, 6.73; N, 19.88. 1H-NMR (CDCl3), δ: 7.32 (s, 1 H), 5.39
(t, 2 H, J = 1.9 Hz), 4.32 (q, 4 H, J = 7.1 Hz), 3.34 (t, 2 H, J = 1.9
Hz), 2.50 (t, 4 H, J = 6.6 Hz), 1.72 (q, 4 H, J = 6.6 Hz), 1.35 (t,
6 H, J = 7.1 Hz). 13C-NMR (CDCl3), δ: 161.3, 158.6, 142.5,
133.3, 114.1, 81.4, 77.3, 61.5, 61.2, 52.3, 43.0, 42.4, 23.6,
14.2, 14.1.
Diethyl-[4-(3-ethoxycarbonyl-4-nitro-1H-pyrazol-1-yl)-but-2-
ynyl]-amine (10 b)
Reagents and conditions:3 (100 mg, 0.49 mmol), diethylamine
(50 µL, 0.49 mmol), paraformaldehyde (15 mg, 0.49 mmol),
acetic acid (27 µL, 0.49 mmol), CuCl (1 mg, 0.01 mmol), reflux-
ing dioxane 3 hours. Purification: CC (ethyl acetate : methanol,
10 : 1), Rf = 0.5. Yield 54 mg (39 %). Colourless syrup. Anal.
Calcd for C14H20N4O4 (308.34): C, 54.56; H, 6.54; N, 18.17.
Found: C, 54.31; H, 6.69; N, 18.22. 1H-NMR (CDCl3), δ: 8.39 (s,
1 H), 5.00 (s, 2 H), 4.39 (q, 2 H, J = 7.2 Hz), 3.50 (s, 2 H), 2.52 (q,
4 H, J = 7.2 Hz), 1.35 (t, 3 H, J = 7.2 Hz), 1.04 (t, 3 H, J = 7.2 Hz).
13C-NMR (CDCl3), δ: 159.8, 139.0, 134.1, 129.5, 84.9, 75.0,
62.5, 43.7, 47.3, 41.0, 13.9, 12.3. EM (electrospray): 309
(MH+).
Diethyl-{4-[3,5-bis(ethoxycarbonyl)-1H-pyrazol-1-yl]-but-2-
ynyl}-amine (8 b)
Reagents and conditions: 1 (100 mg, 0.4 mmol), diethylamine
(45 µL, 0.4 mmol), paraformaldehyde (13 mg, 0.4 mmol), acetic
acid (24 µL, 0.4 mmol), CuCl (0.8 mg, 0.008 mmol), refluxing
dioxane 2 hours. Purification: CC (ethyl acetate), Rf = 0.2.Yield
103 mg (80 %). Colourless syrup. Anal. Calcd for C17H25N3O4
(335.41): C, 60.88; H, 7.51; N, 12.53. Found: C, 60.92; H, 7.65;
N, 12.69. 1H-NMR (CDCl3), δ: 7.35 (s, 1 H), 5.41 (s, 2 H), 4.36
(q, 4 H, J = 7.2 Hz), 3.37 (s, 2 H), 2.45 (q, 4 H, J = 7.1 Hz), 1.38
(t, 6 H, J = 7.2 Hz), 0.99 (t, 6 H, J = 7.1 Hz).13C-NMR (CDCl3), δ:
161.2, 158.5, 142.4, 133.1, 114.1, 80.4, 77.7, 61.4, 61.1, 46.9,
42.9, 40.6, 14.2, 14.0, 12.4. EM (IE 70 eV), m/z : 123 (100 %),
335 (M+, 1 %).
5-Ethoxycarbonyl-4-nitro-1-(4-pyrrolidin-1-yl-but-2-ynyl)-1H-
pyrazole (11 a)
Reagents and conditions: 4 (90 mg, 0.4 mmol), pyrrolidine
(37 µL, 0.44 mmol), paraformaldehyde (13 mg, 0.44 mmol),
acetic acid (24 µL, 0.44 mmol), CuCl (0.8 mg, 0.008 mmol), re-
fluxing dioxane 5 hours.Purification:CC (ethyl acetate : metha-
nol, 20 : 1), Rf = 0.4.Yield 45 mg (37 %).Colourless syrup.Anal.
Calcd for C14H18N4O4 (306.32): C, 54.89; H, 5.92; N, 18.29.
Found: C, 55.03; H, 5.73; N, 18.20. 1H-NMR (CDCl3), δ: 7.97 (s,
1 H), 5.09 (s, 2 H), 4.43 (q, 2 H, J = 7.2 Hz), 3.35 (s, 2 H), 2.51
(m, 4 H), 1.73 (m, 4 H), 1.33 (t, 3 H, J = 7.2 Hz). 13C-NMR
(CDCl3), δ: 157.9, 135.4, 135.2, 130.8, 83.3, 75.7, 63.4, 52.6,
43.1, 42.7, 23.7, 13.7. EM (electrospray): 307 (MH+).
4-Benzyloxy-3,5-bis(ethoxycarbonyl)-1-(4-pyrrolidin-1-yl-
but-2-ynyl)-1H-pyrazole (9 a)
Reagents and conditions: 2 (100 mg, 0.28 mmol), pyrrolidine
(26 µL, 0.31 mmol), paraformaldehyde (9.3 mg, 0.31 mmol),
acetic acid (17 µL, 0.31 mmol), CuCl (0.6 mg, 0.006 mmol), re-
fluxing dioxane 4 hours.Purification:CC (ethyl acetate : metha-
nol, 20 : 1), Rf = 0.4.Yield 28 mg (38 %).Colourless syrup.Anal.
Calcd for C24H29N2O5 (425.51): C, 67.75; H, 6.89; N, 6.58.
Found: C, 67.65; H, 6.73; N, 6.55. 1H-NMR (CDCl3), δ:
7.47–7.28 (m, 5 H), 5.31 (t, 2 H, J = 2.0 Hz), 5.10 (s, 2 H), 4.36
(q, 2 H, J = 7.2 Hz), 4.32 (q, 2 H, J = 7.2 Hz), 3.36 (t, 2 H, J = 2.0
Hz), 2.52 (t, 4 H, J = 6.6 Hz), 1.73 (q, 4 H, J = 6.6 Hz), 1.35 (t,
3 H, J = 7.2 Hz), 1.30 (t, 3 H, J = 7.2 Hz). 13C-NMR (CDCl3), δ:
160.7, 158.4, 147.7, 136.5, 134.5, 128.3, 128.2, 128.1, 124.9,
79.0, 77.6, 77.5, 61.4, 61.1, 52.3, 44.1, 43.0, 23.6, 14.3, 14.1.
Diethyl-[4-(5-ethoxycarbonyl-4-nitro-1H-pyrazol-1-yl)-but-2-
ynyl]-amine (11 b)
Reagents and conditions: 4 (90 mg, 0.40 mmol), diethylamine
(45 µL, 0.44 mmol), paraformaldehyde (13 mg, 0.44 mmol),
acetic acid (24 µL, 0.44 mmol), CuCl (0.8 mg, 0.008 mmol), re-
fluxing dioxane 5 hours.Purification:CC (ethyl acetate : metha-
nol, 10 : 1), Rf = 0.5.Yield 92 mg (74 %).Colourless syrup.Anal.
Calcd for C14H20N4O4 (308.34): C, 54.56; H, 6.54; N, 18.17.
Found: C, 54.66; H, 6.29; N, 18.31. 1H-NMR (CDCl3), δ: 7.97 (s,
1 H), 5.09 (s, 2 H), 4.45 (q, 2 H, J = 7.2 Hz), 3.34 (s, 2 H), 2.45 (q,
4 H, J = 7.2 Hz), 1.36 (t, 3 H, J = 7.2 Hz), 0.96 (t, 3 H, J = 7.2 Hz).
13C-NMR (CDCl3), δ: 157.8, 135.3, 135.1, 130.7, 82.5, 76.0,
63.3, 47.1, 42.6, 40.7, 13.6, 12.4. EM (electrospray): 309
(MH+).
Diethyl-{4-[4-benzyloxy-3,5-bis(ethoxycarbonyl)-1H-pyrazol-
1-yl]-but-2-ynyl}-amine (9 b)
Reagents and conditions: 2 (97 mg, 0.27 mmol), diethylamine
(31 µL, 0.30 mmol), paraformaldehyde (9 mg, 0.30 mmol), ace-
tic acid (16 µL, 0.30 mmol), CuCl (0.6 mg, 0.006 mmol), reflux-
ing dioxane 4 hours. Purification: CC (ethyl acetate), Rf = 0.3.
Yield 30 mg (25 %). Colourless syrup. Anal. Calcd for
C24H31N2O5 (427.52): C, 67.43; H, 7.31; N, 6.55. Found: C,
67.25;H, 7.40;N, 6.75. 1H-NMR (CDCl3), δ:7.47–7.29 (m, 5 H),

Arch. Pharm. Pharm. Med. Chem. 2002, 335, 339–346
New 1-(But-2-ynyl)pyrazoles 345
Diethyl-[4-(5-methyl-1H-pyrazol-1-yl)-but-2-ynyl]-amine (14 b)
3,5-Dimethyl-1-(4-pyrrolidin-1-yl-but-2-ynyl)-1H-pyrazole
(12 a)
Reagents and conditions: 7 (40 mg, 0.33 mmol), diethylamine
(38 µL, 0.37 mmol), paraformaldehyde (11 mg, 0.37 mmol),
acetic acid (20 µL, 0.37 mmol), CuCl (0.7 mg, 0.007 mmol), re-
fluxing dioxane 3 hours.Purification:CC (ethyl acetate : metha-
nol, 15 : 1).Yield 30 mg (44 %).Colourless syrup.Anal.Calcd for
C12H19N3 (205.30):C, 70.20;H, 9.33;N, 20.47.Found:C, 70.42;
H, 9.21; N, 20.37. 1H-NMR (CDCl3), δ: 7.35 (1 H, d, J = 1.6 Hz),
6.00 (1 H, d, J = 1.6 Hz), 4.84 (t, 2 H, J = 2.0 Hz), 3.35 (t, 2 H, J =
2.0 Hz), 2.49 (q, 4 H, J = 7.2 Hz), 2.30 (s, 3 H), 1.07 (t, 6 H, J =
7.2 Hz). 13C-NMR (CDCl3), δ: 138.6, 138.1, 105.8, 81.2, 78.4,
47.5, 41.5, 39.5, 12.5, 11.2.
Reagents and conditions: 5 (150 mg, 1.12 mmol), pyrrolidine
(102 µL, 1.23 mmol), paraformaldehyde (37 mg, 1.23 mmol),
acetic acid (67 µL, 1.23 mmol), CuCl (2 mg, 0.02 mmol), reflux-
ing dioxane 4 hours. Purification: CC (ethyl acetate : methanol,
20 : 1), Rf = 0.2. Yield 60 mg (25 %). Colourless syrup. Anal.
Calcd for C13H19N3 (217.31):C, 71.85;H, 8.81;N, 19.34.Found:
C, 71.92; H, 8.56; N, 19.52. 1H-NMR (CDCl3), δ: 5.78 (s, 1 H),
4.75 (t, 2 H, J = 2.0 Hz), 3.34 (t, 2 H, J = 2.0 Hz), 2.56–2.48 (m,
4 H), 2.26 (s, 3 H), 2.17 (s, 3 H), 1.78–1.71 (m, 4 H). 13C-NMR
(CDCl3), δ: 147.7, 138.9, 105.7, 80.3, 78.2, 52.5, 43.2, 38.9,
23.7, 13.4, 11.0.
Pharmacology
Diethyl-[4-(3,5-dimethyl-1H-pyrazol-1-yl)-but-2-ynyl]-amine
(12 b)
Muscarinic receptor binding studies were carried out by evalu-
ating the ability of compounds 8–14 (a, b), as free bases, to
compete with 50 pM [3H]-(R )-quinuclidinyl benzilate in a sus-
pension of brain membranes, as previously described [19].The
IC50 values were determined from displacement curves and the
values are here reported as means ± SEM of three independ-
ent experiments, each performed in triplicate.
Reagents and conditions:5 (109 mg, 0.44 mmol), diethylamine
(55 µL, 0.48 mmol), paraformaldehyde (15 mg, 0.5 mmol), ace-
tic acid (26 µL, 0.48 mmol), CuCl (1 mg, 0.01 mmol), refluxing
dioxane 5 hours. Purification: CC (ethyl acetate : methanol,
10 : 1), Rf = 0.2. Yield 20 mg (21 %). Colourless syrup. Anal.
Calcd for C13H21N3 (219.33):C, 71.19;H, 9.65;N, 19.16.Found:
C, 71.32; H, 9.47; N, 19.21. 1H-NMR (CDCl3), δ: 5.79 (s, 1 H),
4.78 (t, 2 H, J = 2.0 Hz), 3.42 (t, 2 H, J = 2.0 Hz), 2.52 (q, 4 H, J =
7.2 Hz), 2.28 (s, 3 H), 2.19 (s, 3 H), 1.03 (t, 6 H, J = 7.2 Hz).13C-
NMR (CDCl3), δ: 147.7, 138.9, 105.7, 79.4, 78.6, 47.2, 40.8,
39.0, 13.4, 12.4, 11.0.
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3-Methyl-1-(4-pyrrolidin-1-yl-but-2-ynyl)-1H-pyrazole (13 a)
Reagents and conditions: 6 (105 mg, 0.9 mmol), pyrrolidine
(80 µL, 0.96 mmol), paraformaldehyde (29 mg, 0.96 mmol),
acetic acid (53 µL, 0.96 mmol), CuCl (1.8 mg, 0.018 mmol), re-
fluxing dioxane 10 hours. Purification: CC (ethyl acetate :
methanol, 15 : 1). Yield 52 mg (29 %). Colourless syrup. Anal.
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(t, 2 H, J = 2.0 Hz), 2.59–2.50 (m, 4 H), 2.24 (s, 3 H), 1.78–1.71
(m, 4 H). 13C-NMR (CDCl3), δ: 149.0, 129.3, 105.4, 82.0, 77.1,
52.7, 43.2, 41.5, 23.7, 13.5.EM (electrospray), m/z :204 (MH+).
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Reagents and conditions: 6 (29 mg, 0.24 mmol), diethylamine
(27 µL, 0.26 mmol), paraformaldehyde (7.8 mg, 0.26 mmol),
acetic acid (13 µL, 0.26 mmol), CuCl (0.5 mg, 0.005 mmol), re-
fluxing dioxane 3 hours. Purification: CC (ethyl acetate : metha-
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H, 9.46; N, 20.19. 1H-NMR (CDCl3), δ: 7.47 (1 H, d, J = 2.2 Hz),
6.03 (1 H, d, J = 2.2 Hz), 4.86 (t, 2 H, J = 2.0 Hz), 3.44 (t, 2 H, J =
2.0 Hz), 2.51 (q, 4 H, J = 7.2 Hz), 2.25 (s, 3 H), 1.04 (t, 6 H, J =
7.2 Hz). 13C-NMR (CDCl3), δ: 149.0, 129.2, 105.4, 81.3, 77.8,
47.3, 41.5, 41.0, 13.5, 12.5.
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Reagents and conditions: 7 (97 mg, 0.8 mmol), pyrrolidine
(74 µL, 0.90 mmol), paraformaldehyde (27 mg, 0.90 mmol),
acetic acid (48 µL, 0.90 mmol), CuCl (1.6 mg, 0.016 mmol), re-
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1.6 Hz), 5.98 (d, 1 H, J = 1.6 Hz), 4.84 (t, 2 H, J = 2.0 Hz), 3.35 (t,
2 H, J = 2.0 Hz), 2.56–2.50 (m, 4 H), 2.31 (s, 3 H), 1.78–1.71 (m,
4 H).13C-NMR (CDCl3), δ:138.6, 138.0, 105.8, 81.0, 78.7, 52.6,
43.2, 39.3, 23.7, 11.0, EM(electrospray), m/z : 204 (MH+).
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