1054
J. Eskildsen et al.
PAPER
Table 2 Synthesis of 1-Alkyl-5-halopyrazoles 3a–d and 4a–da
halogenation with simultaneous deoxygenation of 2-alky-
lpyrazole-1-oxides represents a straightforward procedure
for obtaining otherwise difficultly accessible 1-alkyl-5-
halopyrazoles, and provides a convenient route to new
substitution patterns that may well afford products of in-
terest for pharmaceutical applications.
POX3,CHCl3
N
O
N
2.5 h, 0 - 50 °C
N
N
X
R
2a-d
R
3,4a-d
Entry
R
Reactant X
Product Yieldb
(%)
1H (300 MHz) and 13C NMR (75 MHz) spectra were recorded on a
Varian instrument using TMS as internal standard. Flash chroma-
tography (FC) was performed using silica gel Merck 60 (230–400
mesh). Merck 60 type H was used for filtrations using silica gel.
Melting points are uncorrected. All solvents and reagents were of
analytical grade and purchased from Aldrich or Fluka and used
without further purification except CHCl3 wich was distilled prior
to use. Petroleum ether refers to the fraction boiling at 80–100 °C.
All products were colorless unless otherwise stated.
1
2
3
4
5
6
7
8
4-MeOC6H4CH2
4-MeOC6H4CH2
Benzyl
2a
2a
2b
2b
2c
2c
2d
2d
Cl
3a
4a
3b
4b
3c
4c
3d
4d
93
95
98
87
83
85
70
78
Br
Cl
Br
Cl
Br
Cl
Br
Benzyl
Allyl
Allyl
2-(4-Methoxybenzyl)pyrazole-1-oxide (2a)
4-Methoxybenzyl bromide11 (43.6 g, 0.217 mol) and 1 (14.1 g,
0.168 mol) were dissolved in CHCl3 (330 mL). The mixture was re-
fluxed for 5 h under a static positive N2 pressure of 0.4 bar. After
cooling to r.t., the mixture was poured into toluene (400 mL) and
extracted with 37% aq HCl (3 150 mL). The combined aqueous
layers were washed with toluene (20 mL) and cautiously basified
with 33% aq NaOH solution to pH >10 while cooling in an ice bath.
The aqueous layer was extracted with CHCl3 (200 + 3 100 mL)
Me
Me
a Reagents and conditions: All reactions were carried out in CHCl3
under N2 using 3–5 equiv POX3 at 50°C for 2 h 30 min.
b Isolated yield.
Table 3 Spectroscopical Data for 2-Alkylpyrazole-N-oxides 2, N-Alkyl-5-chloropyrazoles 3 and N-Alkyl-5-bromopyrazoles 4
Product
2a
1H NMR (300 MHz, CDCl3/TMS)
, J (Hz)
13C NMR (75 MHz, CDCl3/TMS),
3.81 (s, 3 H), 5.24 (s, 2 H), 6.11 (dd, 1 H, J = 3.9, 2.4), 6.77 (dd, 1 H, J = 3.9, 1.2), 6.90 48.0, 55.0, 101.1, 114.3, 118.2, 119.1,
(dd, 2 H, J = 7.2, 2.3), 7.22 (dd, 1 H, J = 2.4, 1.2), 7.30 (dd, 2 H, J = 7.2, 2.3)
126.0, 130.0, 159.7
2c
4.78 (ddd, 2 H, J = 6.0, 1.5, 1.2), 5.25 (ddt, 1 H, J = 17.1, 1.0, 1.5), 5.34 (ddt, 1 H,
J = 10.2, 1.0, 1.2), 5.95 (ddt, 1 H, J = 17.1, 10.2, 6.0), 6.17 (dd, 1 H, J = 3.9, 2.4), 6.99
(dd, 1 H, J = 3.9, 1.2), 7.21 (dd, 1 H, J = 2.4, 1.2)
46.8, 101.0, 118.4, 119.0, 119.8, 130.3
2dHBra
2d
3.90 (s, 3 H), 6.65 (br dd, 1 H, J = 3.5, 2.8), 8.11 (br d, 1 H, J = 3.5), 8.27 (br dd, 1 H,
J = 2.8, 1.2), 13.06 (br s, 1 H, exchangeable with D2O)
3.77 (s, 3 H), 6.12 (dd, 1 H, J = 3.7, 2.5), 6.97 (dd, 1 H, J = 3.7, 1.2), 7.17 (dd, 1 H, 32.2, 101.1, 119.1, 119.4
J = 2.5, 1.2)
2e
0.96 (t, 3 H, J = 7.4), 1.38 (m, 2 H), 1.83 (m, 2 H), 4.16 (t, 2 H, J = 7.2), 6.13 (dd, 1 H, 13.2, 19.3, 30.3, 44.9, 100.8, 118.5, 119.0
J = 3.9, 2.4), 6.98 (dd, 1 H, J = 3.9, 1.2), 7.18 (dd, 1 H, J = 2.4, 1.2)
2f
1.40 (d, 6 H, J = 6.9), 5.03 (sept, 1 H, J = 6.9), 6.10 (dd, 1 H, J = 3.9, 2.4), 6.90 (dd, 1 21.4, 47.1, 101.2, 115.1, 119.5
H, J = 3.9, 1.2), 7.14 (dd, 1 H, J = 2.4, 1.2)
3a
3.77 (s, 3 H), 5.27 (s, 2 H), 6.21 (d, 1 H, J = 2.0), 6.85 (d, 2 H, J = 8.8), 7.20 (d, 2 H, 52.2, 55.2, 105.1, 114.1, 127.0, 128.1,
J = 8.8), 7.51 (d, 1 H, J = 2.0)
129.1, 139.5, 159.4
3c
4.75 (ddd, 2 H, J = 5.5, 1.7, 1.4), 5.10 (dtd, 1 H, J = 17.1, 1.7, 1.1), 5.25 (dtd, 1 H,
J = 10.3, 1.4, 1.1), 5.96 (ddt, 1 H, J = 17.1, 10.3, 5.5), 6.21 (d, 1 H, J = 2.0), 7.50 (d, 1
H, J = 2.0)
51.4, 104.8, 118.0, 127.0, 132.0, 139.5
4a
4c
3.77 (s, 3 H), 5.30 (s, 2 H), 6.29 (d, 1 H, J = 1.9), 6.85 (dd, 2 H, J = 6.8, 2.2), 7.21 (dd, 53.3, 55.2, 108.8, 112.6, 114.1, 128.3,
2 H, J = 6.8, 2.2), 7.52 (d, 1 H, J = 1.9)
129.0, 140.5, 159.4
4.76 (ddd, 2 H, J = 5.5, 1.7, 1.4), 5.05 (dtd, 1 H, J = 17.1, 1.7, 1.1), 5.21 (dtd, 1 H,
J = 10.3, 1.4, 1.1), 5.93 (ddt, 1 H, J = 17.1, 10.3, 5.5), 6.27 (d, 1 H, J = 1.9), 7.48 (d, 1
H, J = 1.9)
52.5, 108.7, 112.7, 118.1, 132.1, 140.5
4d
3.87 (s, 3 H), 6.27 (d, 1 H, J = 1.9), 7.45 (d, 1 H, J = 1.9)
37.4, 108.5, 113.1, 140.0
a 1H NMR spectrum obtained in DMSO-d6.
Synthesis 2001, No. 7, 1053–1056 ISSN 0039-7881 © Thieme Stuttgart · New York