O-pyrazolylpropynyl-hydroxylamines as versatile intermediates in the synthesis of compounds of pharmacological interest

Article abstract of DOI:10.1055/s-2001-16768

Through an optimised Pd/Cu-catalysed cross-coupling reaction of 4-iodopyrazoles with 2-propyn-1-ol, followed by Mitsunobu transformation with N-hydroxyphthalimide and subsequent hydrazinolysis, O-[(pyrazol-4-yl)-prop-2-ynyl]-hydroxylamines were obtained in good yields. Their usefulness as intermediates in the synthesis of pharmaceuticals is exemplified by the first reported intramolecular cyclization of O-(2-propynyl)-hydroxylamines to yield 4,5-dihydro-isoxazoles.

Full text of DOI:10.1055/s-2001-16768

PAPER
1711
O-Pyrazolylpropynyl-Hydroxylamines as Versatile Intermediates in the
Synthesis of Compounds of Pharmacological Interest
O
-Pyrazolylpropynyl-h
a
ydroxylam
r
ines:
V
e
í
rsatile
I
ntermediates in th
I
e
Synth
s
esis of Ph
a
armaceutica
b
ls el Rodríguez-Franco,* Isabel Dorronsoro,1 Ana Martínez
Instituto de Química Médica (C.S.I.C.), Juan de la Cierva 3, 28006 Madrid, Spain
Fax +34(91)5644853; E-mail: IsabelRguez@iqm.csic.es
Received 11 May 2001; revised 11 June 2001
The synthetic route began with the iodination of 3,5-dim-
ethyl-1H-pyrazole using elemental iodine in the presence
of ceric ammonium nitrate [ammonium hexanitratocerate
(IV): CAN] as the in situ oxidant, following the method
Abstract: Through an optimised Pd/Cu-catalysed cross-coupling
reaction of 4-iodopyrazoles with 2-propyn-1-ol, followed by Mit-
sunobu transformation with N-hydroxyphthalimide and subsequent
hydrazinolysis,
O-[(pyrazol-4-yl)-prop-2-ynyl]-hydroxylamines
were obtained in good yields. Their usefulness as intermediates in recently reported by us,12 obtaining 4-iodo-3,5-dimethyl-
the synthesis of pharmaceuticals is exemplified by the first reported
1H-pyrazole in very good yield (93%). This 4-iodopyra-
zole was treated with different alkylating agents to give
the N-substituted 4-iodopyrazoles 2a–c, which were then
coupled with 2-propyn-1-ol (propargyl alcohol) using
bis(triphenylphosphine)palladium dichloride and cuprous
iodide as catalysts (Scheme 1).
intramolecular cyclization of O-(2-propynyl)-hydroxylamines to
yield 4,5-dihydro-isoxazoles.
Key words: O-pyrazolylpropynyl-hydroxylamines, 3-pyrazolyl-
4,5-dihydro-isoxazoles, cross-coupling, Mitsunobu reaction, in-
tramolecular cyclisation
O
H3C
I
OH
Since the O-alkynylhydroxylamine moiety is currently
present in a wide variety of bioactive compounds (e.g.,
muscarinic agonists,2 calcium antagonists,3 antibiotics,4
insecticides,5 and fungicides6), its precursors represent
valuable intermediates in Medicinal Chemistry.
H3C
N
OH
HO
N
N
CH3 PdCl2(PPh3)2
O
N
R
N
DEAD
PPh3
CH3
3a–c
CuI, PPh3
60–73%
69–87%
O
R
2a–c
As a result of our research on the synthesis of biologically
active pyrazoles that showed muscarinic properties7 or se-
lective complexation of neurotransmitters,8 we are now
interested in the development of efficient synthetic path-
ways for O-pyrazolylpropynyl-hydroxylamines 1 (Fig-
ure) as useful intermediates in the synthesis of compounds
of potential pharmacological interest. Herein, we describe
the synthesis of the new pyrazolic intermediates 1 through
an optimised Pd/Cu-catalysed cross-coupling reaction9 of
4-iodopyrazoles with propargyl alcohol, followed by Mit-
sunobu transformation10 with N-hydroxyphthalimide and
subsequent hydrazinolysis. As a probe of the usefulness of
1 as intermediates of pharmaceuticals, the cyclisation of
O-(2-propynyl)-hydroxylamines to give 4,5-dihydro-
isoxazoles of potential interest as antithrombotic agents is
also described.11
CH3
N
NH2
O
H3C
N
O
N
O
CH3NHNH2
N
CH3
R
80–82%
N
1a–c
4a–c
CH3
R
a, R = CH2C6H5
b, R = CH2C6H4(4-OCH3)
c, R = COC6H2(2,4,6-CH3)
Scheme 1
Preliminary experiments of these cross-coupling reactions
were carried out using 1 equivalent of the corresponding
4-iodopyrazole, 1 equivalent of propargyl alcohol, 0.04
equivalents of PdCl2(PPh3)2 and 0.04 equivalents of CuI,
in diethylamine as solvent, as described for pyrazole de-
rivatives in a precedent work.13 Since under these experi-
mental conditions little or no reaction was observed, and
taking into account that an excess of the acetylenic com-
pound in a more strongly basic solvent could give better
results,14 reactions were repeated using 2 equivalents of
propargyl alcohol with piperidine as solvent. In these
modified conditions only 3c was obtained in moderate
yield (30%), but when 2a or 2b were used as starting ma-
terials no reaction was observed. Instead, the reaction so-
lution turned first brown and then black, due to the
precipitation of uncomplexed metallic palladium, which
is catalytically inactive.15 This problem could be prevent-
ed by adding 2 moles of triphenylphosphine per mole of
palladium, when the brown colour first appears, to regen-
R3
R1
N
N
O
N
O
NH2
R1
R2
1
R5
Figure
Synthesis 2001, No. 11, 28 08 2001. Article Identifier:
1437-210X,E;2001,0,11,1711,1715,ftx,en;Z04901SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

1712
M. I. Rodríguez-Franco et al.
PAPER
erate the active catalyst Pd(PPh3)2. Thus, the coupling of cological profiles (mainly antithrombotic,24 antiinflam-
4-iodopyrazoles 2a–c (1 equivalent) with 2-propyn-1-ol matory,25 and antibacterial26 activities) this reaction
(2 equivalents) in dry piperidine in the presence of represents a new and convenient way to obtain these prod-
bis(triphenylphosphine)palladium
dichloride ucts under mild reaction conditions.
[PdCl2(PPh3)2] (0.04 equivalents), cuprous iodide (0.04
equivalents) and triphenylphosphine (0.08 equivalents), at
room temperature for 24 hours, yielded the desired pyra-
zolylpropargyl alcohols in good yields (3a: 60%, 3b:
73%, 3c: 73%).
All new compounds showed combustion analysis and
spectroscopic data in agreement with their structures. Un-
equivocal assignment of all chemical shifts (1H and 13C
NMR) was undertaken using two-dimensional experi-
ments such as HMQC for one-bond correlations, and
Following Mitsunobu's methodology, from the reaction of HMBC for two and three bond correlations.
diethyl azodicarboxylate and triphenylphosphine (to form
In conclusion, we have obtained O-[(pyrazol-4-yl)-prop-
2-ynyl]-hydroxylamines in good yields, using an opti-
mised Pd/Cu-catalysed cross-coupling reaction of 4-io-
dopyrazoles with 2-propyn-1-ol, followed by Mitsunobu
transformation with N-hydroxyphthalimide and subse-
quent hydrazinolysis. We have also found the first exam-
ple of the intramolecular addition of an O-substituted
hydroxylamine to a triple bond, yielding the correspond-
a betaine),16 a pyrazolylpropargyl alcohol 3a–c, and the
nucleophilic N-hydroxyphthalimide,17 the phthalimides
4a–c were obtained in satisfactory yields (69–87%). Hy-
drazinolysis of the above protected intermediates 4a–c
with anhydrous methylhydrazine18 gave the desired O-
pyrazolylpropynyl-hydroxylamines 1a–c in good yields
(80–82%).
The O-[(pyrazol-4-yl)-prop-2-ynyl]-hydroxylamines 1a– ing isoxazoline.
c are unstable intermediates that must be used immediate-
ly after their synthesis, or converted into the correspond-
The analytical and synthetic methodologies were performed by us-
ing the facilities at our Institute as described in a recent work.27
Most starting materials were commercially available products and
were used without further purification. 2,4,6-Trimethylbenzoyl
chloride was obtained by refluxing the commercially available acid
with thionyl chloride for 8 h. 4-Iodo-3,5-dimethyl-1H-pyrazole (mp
136–137 °C (Lit.:28 137 °C) was obtained in 93% yield from 3,5-
dimethyl-1H-pyrazole (Aldrich) by an oxidative iodination in the
presence of ceric ammonium nitrate (CAN), as recently described
by us.12
ing hydrochloride derivative for storage purposes.
Standing at room temperature, they suffer a slow intramo-
lecular addition of the hydroxylamine group to the triple
bond, yielding isoxazolines. This reaction is faster in the
presence of a base; the treatment of 1c with sodium hy-
droxide in methanol at reflux for 3 hours gave a mixture
of the N-substituted and N-unsubstituted isoxazolines 5
and 6, as the result of an intramolecular addition of the
amine group of the O-substituted hydroxylamine to the
triple bond (Scheme 2). The reaction probably proceeds
through the initial formation of an enamine, which then
tautomerises to the more stable imine.19
N-Alkylation of 4-Iodo-3,5-dimethyl-1H-pyrazole; General
Procedure
To a mixture of 4-iodo-3,5-dimethyl-1H-pyrazole (1 equiv) and a
base (NaH or Et3N, 1 equiv), a solution of the corresponding alky-
lating agent (1 equiv) was added, and the reaction was stirred at r.t.
or under reflux until completion. The solvent was evaporated under
reduced pressure and the residue dissolved in CH2Cl2 (25 mL),
washed with H2O (3 25 mL) and sat. NaCl (25 mL), dried
(Na2SO4) and evaporated to dryness. The residual syrup was puri-
fied as described for individual compounds.
O
O
H3C
N
H3C
NH
NaOH
MeOH
1c
N
CH3
N
N
R
CH3
N
R
1-Benzyl-4-iodo-3,5-dimethyl-1H-pyrazole (2a)
5 (35%), R = COC6H2(2,4,6-CH3)
6 (25%), R = H
Following the general procedure, from 4-iodo-3,5-dimethyl-1H-
pyrazole (1.0 g, 4.5 mmol), NaH (60% dispersion in mineral oil,
198 g, 4.5 mmol), and benzyl bromide (0.5 mL, 4.5 mmol) in DMF
(30 mL) at r.t. for 18 h, a syrup was obtained that was purified by
silica gel flash chromatography (hexane–EtOAc, 3:1). The fractions
of Rf = 0.3 afforded 840 mg (60%) of 2a as a pure white solid.
Scheme 2
Although the intramolecular addition of amines to alkynes
to yield pyrrolidines or piperidines is a well-known reac-
tion, generally catalysed by transition20 or lanthanide21
metals, there are no examples of the analogous intramo-
lecular transformations involving O-alkynylhydroxy-
lamines. In fact, we found very few publications on the
Mp 85–86 °C.
1H NMR (CDCl3): = 7.02–7.28 (m, 5 H, Bn), 5.24 (s, 2 H, CH2),
2.21 (s, 3 H, 3-CH3), 2.14 (s, 3 H, 5-CH3).
13C NMR (CDCl3): = 149.4 (C-3 pyrazole), 140.7 (C-5 pyrazole),
addition of the amino group belonging to an O-substituted 136.6 (C-1 benzyl), 128.7 (C-2,-6 Bn), 127.7 (C-4 Bn), 126.6 (C-3,-
hydroxylamine22 or the hydroxylamine itself23 to a triple
5 Bn), 63.2 (C-4 pyrazole), 54.0 (CH2), 14.0 (3-CH3), 12.0 (5-CH3).
MS (EI): m/z = 312 (M+).
bond, instead, in all cases, the examples were intermolec-
ular additions yielding the corresponding linear oxime.
Consequently, to our knowledge, this is the first example
of the intramolecular addition of an O-substituted hydrox-
ylamine to a triple bond to give an isoxazoline. Since
some 3-(hetero)aryl-4,5-dihydroisoxazoles show pharma-
4-Iodo-1-(4-methoxybenzyl)-3,5-dimethyl-1H-pyrazole (2b)
From 4-iodo-3,5-dimethyl-1H-pyrazole (656 mg, 2.95 mmol), NaH
(60% dispersion in mineral oil, 118 mg, 2.95 mmol), and 4-meth-
oxy-benzyl bromide (0.4 mL, 2.95 mmol) in DMF (30 mL) at r.t. for
16 h, a syrup was obtained, which was purified by silica gel flash
Synthesis 2001, No. 11, 1711–1715 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
O-Pyrazolylpropynyl-Hydroxylamines: Versatile Intermediates in the Synthesis of Pharmaceuticals
1713
chromatography (hexane–EtOAc, 6:1). From the fractions of
Rf = 0.4, compound 2b was isolated (713 mg, 71% yield), as a pure
white solid.
3-[1-(4-Methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-prop-2-
yn-1-ol (3b)
Following the general method, from 2b (712 mg, 2.1 mmol), 2-pro-
pyn-1-ol (270 L, 4.58 mmol), PdCl2(PPh3)2 (46 mg, 0.08 mmol),
CuI (16 mg, 0.08 mmol) and PPh3 (46 mg, 0.16 mmol) in dry pipe-
ridine (4.5 mL), a syrup was obtained. Its purification on a silica gel
column (mixtures of hexane–EtOAc, 6:1 to 1:2) yielded 3b (408
mg, 73%) as a pure syrup (Rf = 0.1, hexane–EtOAc, 2:1).
Mp 43–44 °C.
1H NMR (CDCl3): = 6.99 (d, 2 H, J = 8.3 Hz, H-2,-6 Bn), 6.78 (d,
2 H, J = 8.3 Hz, H-3,-5 Bn), 5.15 (s, 2 H, CH2), 3.70 (s, 3 H, OCH3),
2.20 (s, 3 H, 3-CH3), 2.14 (s, 3 H, 5-CH3).
13C NMR (CDCl3): = 158.9 (C-4 Bn), 148.8 (C-3 pyrazole), 140.0
(C-5 pyrazole), 128.5 (C-1 Bn), 127.9 (C-2,-6 Bn), 113.9 (C-3,-5
Bn), 63.0 (C-4 pyrazole), 54.9 (CH2 Bn), 53.2 (OCH3), 13.8 (3-
CH3), 11.8 (5-CH3).
1H NMR (CDCl3): = 7.00 (d, 2H, J = 8.7 Hz, H-2,-6 Bn), 6.80 (d,
2H, J = 8.7 Hz, H-3,-5 Bn), 5.10 (s, 2H, CH2 Bn), 4.46 (s, 2H, C C-
CH2-OH), 3.74 (s, 3H, OCH3), 2.24 (s, 3H, 3-CH3), 2.17 (s, 3H, 5-
CH3).
13C NMR (CDCl3): = 159.1 (C-4 Bn), 150.0 (C-3 pyrazole), 142.3
(C-5 pyrazole), 128.4 (C-1 Bn), 128.1 (C-2,-6 Bn), 114.1 (C-3,-5
Bn), 101.6 (C-4 pyrazole), 91.0 (C C-CH2OH), 77.6 (C C-
CH2OH), 55.2 (CH2 Bn), 52.5 (OCH3), 51.6 (C C-CH2OH), 12.4
(3-CH3), 10.5 (5-CH3).
MS (EI): m/z = 342 (M+).
4-Iodo-3,5-dimethyl-1-(2,4,6-trimethylbenzoyl)-1H-pyrazole
(2c)
The reaction of 4-iodo-3,5-dimethyl-1H-pyrazole (3.8 g, 17 mmol),
Et3N (2.4 mL, 17 mmol), and 2,4,6-trimethylbenzoyl chloride (3.1
g, 17 mmol) in anhyd toluene (30 mL) under reflux for 8 h yielded
a syrup, which was chromatographed (silica gel; hexane–EtOAc,
20:1). The fractions of Rf = 0.5 were collected and evaporated to
dryness affording 5.8 g (92% yield) of 2c as a pure white solid.
MS (EI): m/z = 270 (M+).
3-[3,5-Dimethyl-1-(2,4,6-trimethylbenzoyl)-1H-pyrazol-4-yl]-
prop-2-yn-1-ol (3c)
From 2c (582 mg, 1.6 mmol), 2-propyn-1-ol (0.2 mL, 3.4 mmol),
PdCl2(PPh3)2 (37 mg, 0.06 mmol), CuI (12 mg, 0.06 mmol) and
PPh3 (31 mg, 0.12 mmol) in anhyd piperidine (3 mL), a syrup was
obtained, which was chromatographed (silica gel; mixtures of hex-
ane–EtOAc of increasing polarity, 10:1 to 8:1). From the fractions
of Rf = 0.2 (hexane–EtOAc, 7:1), compound 3c was isolated (348
mg, 73%) as a white solid.
Mp 107–108 °C.
1H NMR (CDCl3): = 6.87 (s, 2 H, Bz), 2.71 (s, 3 H, 3-CH3 pyra-
zole), 2.38 (s, 3 H, 4-CH3 Bz), 2.17 (s, 3 H, 5-CH3 pyrazole), 2.12
(s, 6 H, 2,6-CH3 Bz).
13C NMR (CDCl3): = 169.3 (CO), 153.1 (C-3 pyrazole), 144.0 (C-
5 pyrazole), 138.4 (C-4 Bz), 133.8 (C-2,-6 Bz), 132.1 (C-1 Bz),
127.5 (C-3,-5 Bz), 73.0 (C-4 pyrazole), 20.5 (4-CH3 Bz), 18.8 (2,6-
CH3 Bz), 14.8 (3-CH3 pyrazole), 13.8 (5-CH3 pyrazole).
Mp 113–115 °C.
1H NMR (CDCl3): = 6.86 (s, 2H, Bz), 4.47 (s, 2H, C C-CH2-OH),
2.69 (s, 3H, 3-CH3), 2.29 (s, 3H, 4-CH3 Bz), 2.18 (s, 3H, 5-CH3),
2.11 (s, 6H, 2,6-CH3 Bz).
MS (EI): m/z = 368 (M+).
13C NMR (CDCl3): = 171.2 (CO), 154.0 (C-3 pyrazole), 146.3 (C-
5 pyrazole), 139.3 (C-4 Bz), 134.4 (C-2,-6 Bz), 132.8 (C-1 Bz),
128.1 (C-3,-5 Bz), 104.0 (C-4 pyrazole), 95.1 (C C-CH2OH), 78.6
(C C-CH2OH), 51.5 (C C-CH2OH), 21.1 (4-CH3 Bz), 19.3 (2,6-
CH3 Bz), 13.7 (3-CH3), 12.7 (5-CH3).
3-(3,5-Dimethyl-1H-pyrazol-4-yl)-prop-2-yn-1-ols (3a–c);
General Procedure
Under a N2 atm, to a stirred solution of the corresponding iodopyra-
zole 2a–c (1 equiv) and 2-propyn-1-ol (2 equiv) in anhyd piperi-
dine, catalytic amounts of bis(triphenylphosphine)palladium
dichloride PdCl2(PPh3)2 (0.04 equiv) and cuprous iodide (CuI, 0.04
equiv) were added. The light-yellow mixture was stirred at r.t. and,
from the moment a brown colour began to develop (20–40 min),
PPh3 (0.08 equiv) was added, and the reaction was stirred under N2
for an additional 24 h. Then the solvent was evaporated to dryness
and the residue was redissolved in CH2Cl2 (25 mL), washed with
H2O (3 25 mL) and brine (25 mL). The organic solution was dried
(Na2SO4) and evaporated to dryness to yield syrups that were puri-
fied by silica gel flash chromatography.
MS (EI): m/z = 296 (M+).
2-[3-(3,5-Dimethyl-1H-pyrazol-4-yl)-prop-2-ynyloxy]-
isoindole-1,3-diones (4a–c); General Procedure
Diethyl azodicarboxylate (DEAD, 1.1 equiv) was added dropwise
to a stirred solution of the corresponding pyrazolylpropargyl alco-
hol 3a–c (1 equiv), N-hydroxyphthalimide (1 equiv) and PPh3 (1
equiv) in dry THF under N2, and the mixture was stirred for 48 h at
r.t. The solvent was removed in vacuo and the product was purified
as described for individual compounds.
3-(1-Benzyl-3,5-dimethyl-1H-pyrazol-4-yl)-prop-2-yn-1-ol (3a)
Following the general method, from 2a (839 mg, 2.7 mmol), 2-pro-
pyn-1-ol (349 L, 5.92 mmol), PdCl2(PPh3)2 (64 mg, 0.11 mmol),
CuI (21 mg, 0.11 mmol) and PPh3 (64 mg, 0.22 mmol) in anhyd pi-
peridine (5 mL), a syrup was obtained, which was chromatographed
(silica gel; mixtures of hexane–EtOAc of increasing polarity, 5:1 to
2:1). From the fractions of Rf = 0.2 (hexane–EtOAc, 2:1), com-
pound 3a was isolated (388 mg, 60%) as a pure syrup.
1H NMR (CDCl3): = 7.10 (m, 5 H, Bn), 5.10 (s, 2 H, CH2-Bn),
4.38 (s, 2 H, C C-CH2-OH), 2.19 (s, 3 H, 3-CH3), 2.09 (s, 3 H, 5-
CH3).
13C NMR (CDCl3): = 149.9 (C-3 pyrazole), 142.3 (C-5 pyrazole),
136.3 (C-1 Bn), 128.6 (C-2,-6 Bn), 127.5 (C-4 Bn), 126.7 (C-3,-5
Bn), 101.8 (C-4 pyrazole), 91.3 (C C-CH2OH), 77.8 (C C-
CH2OH), 52.9 (CH2 Bn), 51.1 (C C-CH2OH), 12.2 (3-CH3), 10.3
(5-CH3).
2-[3-(1-Benzyl-3,5-dimethyl-1H-pyrazol-4-yl)-prop-2-ynyloxy]-
isoindole-1,3-dione (4a)
Following the general method, from 3a (154 mg, 0.64 mmol), N-hy-
droxyphthalimide (105 mg, 0.64 mmol), PPh3 (168 mg, 0.64 mmol)
and DEAD (123 mg, 0.71 mmol) in THF (5 mL), compound 4a was
isolated as a pure colourless syrup (171 mg, 69%) after flash chro-
matography (hexane–EtOAc, 5:1 to 2:1), and two centrifugal circu-
lar TLC (hexane–EtOAc, 4:1 to 2:1).
1H NMR (CDCl3): = 7.70 (m, 4 H, phthalimide), 7.15 (m, 5 H,
Bn), 5.14 (s, 2 H, CH2-O), 5.10 (s, 2 H, CH2), 2.15 (s, 3 H, 3-CH3),
2.12 (s, 3 H, 5-CH3).
13C NMR (CDCl3): = 165.5 (CO), 149.8 (C-3 pyrazole), 142.1 (C-
5 pyrazole), 136.3 (C-1 Bn), 133.5 (C-4,-5 phthalimide), 132.7 (C-
2a,-6a phthalimide), 128.7 (C-2,-6 Bn), 127.4 (C-4 Bn), 126.9 (C-
3,-5 Bn), 123.3 (C-3, -6 phthalimide), 101.5 (C-4 pyrazole), 91.0
MS (EI): m/z = 240 (M+).
Synthesis 2001, No. 11, 1711–1715 ISSN 0039-7881 © Thieme Stuttgart · New York

1714
M. I. Rodríguez-Franco et al.
PAPER
(C C-CH2), 77.8 (C C-CH2), 52.9 (CH2Ph), 51.0 (C C-CH2), 12.2
(3-CH3), 10.2 (5-CH3).
Bn), 101.4 (C-4 pyrazole), 91.0 (C C-CH2), 77.4 (C C-CH2), 52.9
(CH2Ph), 50.0 (C C-CH2), 12.3 (3-CH3), 10.1 (5-CH3).
MS (EI): m/z = 385 (M+).
O-{3-[1-(4-Methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-
prop-2-ynyl}-hydroxylamine (1b)
Following the general method, 4b (84 mg, 0.20 mmol) and methyl-
hydrazine (9 mg, 0.20 mmol) in CH2Cl2 (2 mL) (5 h at r.t.) yielded
46 mg (80%) of 1b, as a pure colourless syrup.
1H NMR (CDCl3): = 7.00 (d, 2 H, J = 8.7 Hz, H-2,-6 Bn), 6.84 (d,
2 H, J = 8.7 Hz, H-3,-5 Bn), 5.10 (s, 2 H, CH2), 4.10 (s, 2 H, CH2-
O), 3.70 (s, 3 H, OCH3), 2.24 (s, 3 H, 3-CH3), 2.16 (s, 3 H, 5-CH3).
13C NMR (CDCl3): = 159.0 (C-4 Bn), 150.3 (C-3 pyrazole), 142.8
(C-5 pyrazole), 128.1 (C-1 Bn), 127.9 (C-2,-6 Bn), 114.0 (C-3,-5
Bn), 101.5 (C-4 pyrazole), 91.5 (C C-CH2), 77.5 (C C-CH2), 55.2
(CH2Ph), 52.3 (OCH3), 51.2 (C C-CH2), 12.4 (3-CH3), 10.6 (5-
CH3).
2-{3-[1-(4-Methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-
prop-2-ynyloxy}-isoindole-1,3-dione (4b)
From 3b (408 mg, 1.2 mmol), N-hydroxyphthalimide (195 mg, 1.2
mmol), PPh3 (313 mg, 1.2 mmol) and DEAD (229 mg, 1.3 mmol)
in THF (5 mL), a brown syrup was obtained, which was purified on
a silica gel column (mixtures of hexane–EtOAc of increasing polar-
ity, 8:1 to 2:1). The fractions of Rf = 0.5 (hexane–EtOAc, 1:1) were
evaporated to dryness, yielding 403 mg (82%) of 4b, as a pure co-
lourless syrup.
1H NMR (CDCl3): = 7.65 (m, 4 H, phthalimide), 6.95 (d, 2 H,
J = 8.7 Hz, H-2,-6 Bn), 6.74 (d, 2 H, J = 8.7 Hz, H-3,-5 Bn), 5.13 (s,
2 H, CH2), 4.46 (s, 2 H, CH2-O), 3.70 (s, 3 H, OCH3), 2.25 (s, 3 H,
3-CH3), 2.16 (s, 3 H, 5-CH3).
O-{3-[3,5-Dimethyl-1-(2,4,6-trimethylbenzoyl)-1H-pyrazol-4-
yl]-prop-2-ynyl}-hydroxylamine hydrochloride (1c HCl)
From 4c (100 mg, 0.22 mmol) and methylhydrazine (10 mg, 0.22
mmol) in CH2Cl2 (2 mL, 4 h at r.t.), a syrup was obtained, which
was dissolved in Et2O (10 mL) and treated with HCl yielding
1c HCl as a white solid (62 mg, 81% yield, mp 104–105 °C).
13C NMR (CDCl3): = 164.5 (CO), 159.0 (C-4 Bn), 150.2 (C-3
pyrazole), 142.6 (C-5 pyrazole), 133.8 (C-4,-5 phthalimide), 132.8
(C-2a, -6a phthalimide), 128.1 (C-1 Bn), 127.9 (C-2,-6 Bn), 123.0
(C-3,-6 phthalimide), 114.0 (C-3,-5 Bn), 101.8 (C-4 pyrazole), 91.1
(C C-CH2), 77.2 (C C-CH2), 55.2 (CH2Ph), 52.3 (OCH3), 51.7
(C C-CH2), 12.2 (3-CH3), 10.4 (5-CH3).
1H NMR (CD3OD): = 7.10 (s, 2H, Bz), 5.26 (s, 2H, C C-CH2),
MS (EI): m/z = 415 (M+).
+
5.13 (br s, 3H, NH3 ), 2.92 (s, 3H, 3-CH3), 2.50 (s, 3H, 5-CH3), 2.39
(s, 3H, 4-CH3 Bz), 2.29 (s, 6H, 2,6-CH3 Bz).
2-{3-[3,5-Dimethyl-1-(2,4,6-trimethylbenzoyl)-1H-pyrazol-4-
yl]-prop-2-ynyloxy}-isoindole-1,3-dione (4c)
13C NMR (CD3OD): = 172.2 (CO), 155.6 (C-3 pyrazole), 148.9
(C-5 pyrazole), 140.9 (C-4 Bz), 135.6 (C-2,-6 Bz), 134.0 (C-1 Bz),
129.1 (C-3,-5 Bz), 107.9 (C-4 pyrazole), 88.3 (C C-CH2), 81.4
(C C-CH2), 66.8 (C C-CH2), 21.3 (4-CH3 Bz), 19.3 (2,6-CH3 Bz),
13.8 (3-CH3), 12.5 (5-CH3).
From 3c (758 mg, 2.6 mmol), N-hydroxyphthalimide (418 mg, 2.6
mmol), PPh3 (670 mg, 2.6 mmol) and DEAD (490 mg, 2.8 mmol)
in THF (10 mL), a solid residue was obtained. Treatment with cold
MeOH (10 mL) yielded 4c as a white solid (mp 158–160 °C), which
was isolated by filtration (985 mg, 87%).
Intramolecular Cyclisation of 1c HCl
1H NMR (CDCl3): = 7.70 (m, 4 H, phthalimide), 6.84 (s, 2 H, Bz),
5.13 (s, 2 H, CH2-O), 2.61 (s, 3 H, 3-CH3 pyrazole), 2.25 (s, 3 H, 4-
CH3 Bz), 2.08 (s, 9 H, 5-CH3 pyrazole and 2,6-CH3 Bz).
13C NMR (CDCl3): = 170.8 (CO Bz), 163.4 (CO phthalimide),
154.0 (C-3 pyrazole), 147.1 (C-5 pyrazole), 139.3 (C-4 Bz), 134.6
(C-4,-5 phthalimide), 134.4 (C-2,-6 Bz), 132.7 (C-1 Bz), 128.7 (C-
2a,-6a phthalimide), 128.1 (C-3,-5 Bz), 123.6 (C-3,-6 phthalimide),
106.9 (C-4 pyrazole), 87.9 (C C-CH2), 80.3 (C C-CH2), 65.8
(C C-CH2), 21.2 (4-CH3 Bz), 19.3 (2,6-CH3 Bz), 13.6 (3-CH3 pyra-
zole), 12.7 (5-CH3 pyrazole).
To a solution of 1c HCl (38.3 mg, 0.11 mmol) in MeOH (3 mL),
NaOH (80 mg, 2.0 mmol) was added and the solution was refluxed
for 3 h. Then, the solvent was evaporated to dryness, the residue was
redissolved in H2O (2 mL), carefully neutralised with HCl (0.2 N),
and extracted with CH2Cl2 (3 10 mL). The organic solution was
washed with H2O, dried (Na2SO4), and evaporated to dryness, yield-
ing a mixture of products that were separated by preparative centrif-
ugal circular TLC (mixtures of increasing polarity, from hexane–
EtOAc, 12:1 to EtOAc–MeOH, 5:1).
From the fractions of Rf = 0.6 (hexane–EtOAc, 12:1), 3-[3,5-dime-
thyl-1-(2,4,6-trimethyl-benzoyl)-1H-pyrazol-4-yl]-4,5-dihydro-
isoxazole (5) was isolated as a pure syrup (12 mg, 35% yield).
1H NMR (CDCl3): = 6.86 (s, 2 H, Bz), 4.41 (t, 2 H, J = 10.0 Hz,
H-5 isoxazoline), 3.30 (t, 2 H, J = 10.0 Hz, H-4 isoxazoline), 2.82
(s, 3 H, 3-CH3 pyrazole), 2.30 (s, 3 H, 4-CH3 Bz), 2.26 (s, 3 H, 5-
CH3 pyrazole), 2.13 (s, 6 H, 2,6-CH3 Bz).
13C NMR (CDCl3): = 164.1 (CO), 151.7 (C-3 isoxazoline), 150.9
(C-3 pyrazole), 142.8 (C-5 pyrazole), 139.3 (C-4 Bz), 134.4 (C-2,-
6 Bz), 133.0 (C-1 Bz), 128.1 (C-3,-5 Bz), 107.2 (C-4 pyrazole), 68.4
(C-5 isoxazoline), 37.5 (C-4 isoxazoline), 21.2 (4-CH3 Bz), 19.3
(2,6-CH3 Bz), 14.8 (3-CH3 pyrazole), 13.8 (3-CH3 pyrazole).
MS (EI): m/z = 441 (M+).
O-[3-(3,5-Dimethyl-1H-pyrazol-4-yl)-prop-2-ynyl]-
hydroxylamines (1a–c); General Procedure
Methylhydrazine (1 equiv) was added dropwise to a stirred and ice-
cooled 0.1 N solution of the phathalimide derivative 4a–c (1 equiv)
in dry CH2Cl2. The reaction mixture was allowed to reach r.t. and
stirred for an additional 1–5 h. Then, a white solid was separated by
filtration, and the organic solution was evaporated to dryness, yield-
ing the pyrazolyl propargyl hydroxylamines 1a–c.
O-[3-(1-Benzyl-3,5-dimethyl-1H-pyrazol-4-yl)-prop-2-ynyl]-
hydroxylamine (1a)
From methylhydrazine (20 mg, 0.44 mmol) and 4a (171 mg, 0.44
mmol) in CH2Cl2 (5 mL, 1 h at r.t.), the hydroxylamine 1a was ob-
tained as a pure syrup (90 mg, 82%).
1H NMR (CDCl3): = 7.12 (m, 5 H, Bn), 4.76 (s, 2 H, CH2-O), 5.09
(s, 2 H, CH2), 2.16 (s, 3 H, 3-CH3), 2.11 (s, 3 H, 5-CH3).
MS (EI): m/z = 311 (M+).
The fractions of Rf = 0.2 (hexane–EtOAc, 12:1) were evaporated to
dryness, yielding 3-(3,5-dimethyl-1H-pyrazol-4-yl)-4,5-dihydro-
isoxazole (6) as a white solid (4.5 mg, 25% yield).
Mp 168–169 °C.
1H NMR (CDCl3): = 4.36 (t, 2 H, J = 9.8 Hz, H-5 isoxazoline),
3.29 (t, 2 H, J = 9.8 Hz, H-4 isoxazoline), 2.39 (s, 6 H, 3,5-CH3
pyrazole).
13C NMR (CDCl3): = 149.7 (C-3 pyrazole), 142.3 (C-5 pyrazole),
136.5 (C-1 Bn), 128.8 (C-2,-6 Bn), 127.2 (C-4 Bn), 126.7 (C-3,-5
Synthesis 2001, No. 11, 1711–1715 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
O-Pyrazolylpropynyl-Hydroxylamines: Versatile Intermediates in the Synthesis of Pharmaceuticals
1715
13C NMR (CDCl3): = 152.0 (C-3 isoxazoline), 144.3 (C-3,-5 pyra-
zole), 107.2 (C-4 pyrazole), 67.8 (C-5 isoxazoline), 37.4 (C-4 isox-
azoline), 13.2 (3,5-CH3 pyrazole).
(12) Rodríguez-Franco, M. I.; Dorronsoro, I.; Hernández-
Higueras, A. I.; Antequera, G. Tetrahedron Lett. 2001, 42,
863.
(13) Tolf, B.-R.; Dahlbom, R.; Theorell, H.; Åkeson, Å. Acta
Chem. Scand., Ser. B 1982, 36, 101.
MS (EI): m/z = 165 (M+).
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Linstrumelle, G. Tetrahedron Lett. 1993, 34, 6403.
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Application of Transition Metal Catalysts in Organic
Synthesis; Springer-Verlag: Berlin, 1999, 179.
(16) Mitsunobu, O. Synthesis 1981, 1.
Acknowledgement
The authors gratefully acknowledge the financial supports 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.
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(18) Xu, R.; Sim, M.-K.; Go, M.-L. J. Med. Chem. 1998, 41,
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Synthesis 2001, No. 11, 1711–1715 ISSN 0039-7881 © Thieme Stuttgart · New York