Regioselective synthesis of unsymmetrical 3,5-dialkyl-1-arylpyrazoles

Article abstract of DOI:10.1021/ol0001822

(matrix presented) 3-Alkoxylmethyl-5-alkylpyrazoles undergo regioselective N-arylation with 4-fluoronitrobenzene in the presence of base to yield the corresponding 1-(4-nitro-phenyl)pyrazoles. Further elaboration of these intermediates furnishes a practic

Full text of DOI:10.1021/ol0001822

ORGANIC
LETTERS
2000
Vol. 2, No. 20
3107-3109
Regioselective Synthesis of
Unsymmetrical
3,5-Dialkyl-1-arylpyrazoles
Xiao-jun Wang,* Jonathan Tan, and Li Zhang
Department of Chemical DeVelopment, Boehringer Ingelheim Pharmaceuticals Inc.,
Ridgefield, Connecticut 06877
xwang@rdg.boehringer-ingelheim.com
Received July 11, 2000
ABSTRACT
3-Alkoxylmethyl-5-alkylpyrazoles undergo regioselective N-arylation with 4-fluoronitrobenzene in the presence of base to yield the corresponding
1-(4-nitro-phenyl)pyrazoles. Further elaboration of these intermediates furnishes a practical synthesis of unsymmetrical 3,5-dialkyl-1-arypyrazoles.
A tentative explanation of the observed regioselectivities is provided.
In connection with a recent medicinal chemistry program,
we required a practical synthesis of unsymmetrical 3,5-
dialkyl-1-arylpyrazoles. We were particularly interested in
the large-scale synthesis of 3-isopropyl-5-ethylpyrazole 1 and
3-methyl-5-ethylpyrazole 2. Aromatic substitution of N-
on arylation of pyrazole 3 with 4-fluoronitrobenzene 4
(Scheme 1). We anticipated that the isopropyl and ethyl
Scheme 1
nonsubstituted pyrazoles with activated halogenated benzenes
such as 4-fluoronitrobenzene has been a powerful method
for synthesis of N-arylpyrazoles.1 However, the reaction
generally gives a mixture of two regioisomers since pyrazole
is an ambident nucleophile. In an effort to directly introduce
the 4-nitrophenyl on pyrazole nitrogen, we initially focused
groups in pyrazole 3 would have different steric require-
ments2 and arylation would favor the regioisomer 3a which
would be subsequently transformed to pyrazole 1. Surpris-
(1) (a) Kost, A. N.; Grandberg, I. I. In Progress in Pyrazole Chemistry;
Kartrizky, A. R., Boulton, A. J., Eds.; AdVances in Heterocyclic Chemistry;
Academic Press: New York, 1966; Vol. 6, p 347. (b) Elguero, J. In
Pyrazoles and their Benzo DeriVatiVes; Katrizky, A. R., Rees, C. W., Eds.;
ComprehensiVe Heterocyclic Chemistry; Pergamon Press: Oxford, 1984;
Vol. 5, p 167.
(2) Wang, X.-j.; Tan, J.; Grozinger, K.; Betageri, R.; Kirrane, T.;
Proudfoot, J. R. Tetrahedron Lett. 2000, 41, 5321.
10.1021/ol0001822 CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/02/2000

ingly, arylation of pyrazole 3 using t-BuOK as base in DMSO
at 70 °C afforded a 1.2:1 mixture of pyrazoles 3a and 3b.3
Although a careful chromatographic purification separated
the two isomers, it was clearly an impractical approach to
the pyrazole 1, which we needed in a large quantity. By
extension, one can suppose that this approach would not
furnish a practical synthesis of pyrazole 2.
7:1 mixture of 5a and 5b, in agreement with a chelation
effect. The same reaction was conducted in THF using
t-BuOLi, NaH, and EtMgBr as bases, respectively, and a
very similar ratio of 5a and 5b was obtained in each case.
These bases showed sluggish reactions with less conversion
compared with the potassium salt. Arylation of pyrazole 6
in THF yielded products 6a and 6b in a ratio of 16:1,
suggesting that a stronger chelation effect by the branched
ether side chain led to a significant improvement of regio-
selectivity, in agreement with the Thorpe-Ingold effect. Here
as well, DMSO as solvent gave a 2:1 mixture of isomers 6a
and 6b. With pyrazoles 7 and 8, both bearing a larger R2
group (i-Pr), arylation yielded regioisomers 7a and 7b as a
4:1 mixture and 8a and 8b as a 11:1 mixture in THF,
respectively, in contrast to 1:1 mixtures in DMSO. The
regioselectivity for the latest two cases is slightly lower than
those of 5 and 6, probably due to the presence of the more
steric demanding i-Pr group.
As shown in Scheme 2, we envisioned that the presence
of an appropriately positioned chelating group such as I
Scheme 2
Using the newly devised approach to control regioselec-
tivity, a practical synthesis of pyrazole 1 was achieved as
outlined in Scheme 4. The THP groups of the mixture of 6a
Scheme 4
might block access of the electrophile and favor arylation
on the pyrazole anion II, leading regioselectively to N-
arylpyrazole IV.4 The alkoxy group of IV could be further
converted to the isopropyl group in 1 and methyl group in 2
later in the synthesis. We began this study with pyrazole 5,
and the related results are summarized in Scheme 3.
Scheme 3
and 6b were deprotected with p-TsOH in aqueous methanol,
and major isomer 9a was isolated in 62% yield over three
steps5 simply by crystallization of the crude material in a
4:1 mixture of hexane and ethyl acetate. MnO2 oxidation of
9a followed by the Wittig reaction of the resulting ketone
10 gave vinyl compound 11 in 60% yield. Reduction of the
double bond and nitro group in 11 was conducted in one
pot with 10% Pd/C under H2, yielding pyrazole 1.
As for the scale-up of pyrazole 2, the crude mixture of 5a
and 5b (7:1) was similarly treated with p-TsOH in aqueous
methanol. The resulting major isomer 12a, free of its
regioisomer 12b, was isolated in 45% yield over three steps5
by recrystallization from 4:1 mixture of hexane and ethyl
acetate (Scheme 5). On treatment of 12a with 10% Pd/C
under H2 in the presence of concentrated HCl, pyrazole 2
Arylation was first carried out with 4-fluoronitrobenzene
using t-BuOK as base in DMSO at 70 °C for 1 h, and a 1:1
mixture of regioisomers 5a and 5b was obtained. When THF
was used as solvent instead of DMSO, arylation produced a
(4) (a) Brunner, H.; Scheck, T. Chem. Ber. 1992, 125, 701. (b) Luo, Y.;
Potvin, P. G. J. Org. Chem. 1994, 59, 1761. (c) Tarrago, G.; Ramdani, A.
J. Heterocycl. Chem. 1980, 17, 137. (d) Khan, M. A.; Lynch, B. M. J.
Heterocycl. Chem. 1970, 7, 1237.
(3) Malhotra, N.; Falt-Hansen, B.; Becher, J. J. Heterocycl. Chem. 1991,
28, 1837.
(5) Pyrazoles 5-8 were made from condensation of their corresponding
propargylic ketones with hydrazine and used directly without purification.
3108
Org. Lett., Vol. 2, No. 20, 2000

Scheme 5
Scheme 7
was obtained in excellent yield. 3-Ethyl-5-isopropylpyrazole
14, the regioisomer of 1, was made from deprotection of
the crude mixture 8a/8b, followed by hydrogenation of the
isolated major alcohol 13a (Scheme 6).6 This newly devised
Scheme 6
high vacuum distillation (Scheme 7). Condensation of 18
with hydrazine in THF at room temperature yielded pyrazole
19, which was directly subjected to aromatic substitution
without purification. Displacement of 4-fluoronitrobenzene
with pyrazole 19 in DMSO gave 20 as a single product as
anticipated. Subsequent treatment of the resulting crude 20
with a catalytic amount of p-TsOH in aqueous methanol led
to pyrazole 21 quantitatively. Pyrazole 21 was then subjected
to hydrogenation with 10% Pd/C in acetic acid under 40 psi
of H2 for 24 h yielding pyrazole 1, which was purified by
recrystallization from a mixture of hexane and ethyl acetate
with a recovery of 55% from 18. This facile process involved
no chromatography and the intermediates 18 through 21
needed no purification.
In conclusion, we have developed a new regioselective
approach toward unsymmetrical 3,5-dialkyl-1-arylpyrazoles.
On the basis of the observed results in solvents of different
polarity (DMSO and THF), it seems likely that association
between the substrate and the cation may play the major role
in directing the reaction.10 Given the different outcomes in
the two solvents, substituent sterics alone cannot be respon-
sible for the observed selectivities and the model in Scheme
2 appears to explain all our currently available data. As a
result, an efficient synthesis of 3-isopropyl-5-ethylpyrazole
1 and 3-methyl-5-ethylpyrazole 2 was achieved.
approach can certainly be extended to synthesis of unsym-
metrical N-arylpyrazoles bearing alkyl groups at the 3 and
5 positions, considering the good recovery of the intermedi-
ates 9a (62% yield), 12a (45% yield), and 13a (56%) without
chromatography. These intermediates could be easily con-
verted into a variety of analogous pyrazoles by functional-
ization of the hydroxy groups.
Encouraged by the regioselective arylation of 6, we
anticipated a substrate such as 19 with one more methyl
substituents on its side chain should have a stronger chelation
compared with that of 6. N-Arylation under the same
condition would therefore highly favor the regioisomer 20,
which is readily converted to 1. It may also be true that the
tertiary carbon of pyrazole 19 is sterically hindered enough
to effect a high degree of regioselectivity for N1-arylation.3,7,8
Thus, starting from commercially available 2-methyl-3-
butyn-2-ol (15), THP ether 16 was prepared in 93% yield9
and was treated with n-BuLi at -30 °C followed by amide
17 leading to the propargylic ketone 18 in 61% yield after
Acknowledgment. We wish to thank Dr. John R.
Proudfoot for helpful discussions during the course of this
work.
Note added after ASAP: Due to a processing error, this
Letter was posted ASAP on 9/2/00 with incorrect graphics
for Schemes 1 and 2. The correct version was posted on
9/7/00.
(6) The structures of all regioisomers were supported by NOE experi-
ments.
(7) Elguero, J.; Gonzalez, E.; Jacquier, R. Bull. Soc. Chim. Fr. 1968,
707.
(8) 3-tert-Butyl-5-ethylpyrzole (22) was subjected to the same N-arylation
with 4-fluoronitrobenzene to give 1-(4-nitrophenyl)-3-tert-butyl-5-ethyl-
pyrzole (23) as a single regioisomer.
(9) Chavez, F.; Godinez, R. Synth. Commmun. 1992, 22, 159.
(10) To support our rationale, N-arylation of 5 was carried out using
KOt-Bu as base in the presence of 1 equiv of 18-crown-6 in refluxing THF.
The reaction gave a 1:1 mixture of regioisomers 5a and 5b, in contrast
with a 7:1 mixture obtained without 18-crown-6.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for compounds 1, 2, 3a, 3b,
5, 9a, 9b, 10, 11, 12a, 12b, 13a, 13b, 14, and 17-23. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL0001822
Org. Lett., Vol. 2, No. 20, 2000
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