Practical synthesis of 1,3-diaryl-5-alkylpyrazoles by a highly regioselective N-arylation of 3,5-disubstituted pyrazoles with 4- fluoronitrobenzene

Article abstract of DOI:10.1016/S0040-4039(00)00849-2

3-Aryl-5-alkylpyrazoles undergo a highly regioselective arylation on N-1 atom with 4-fluoronitrobenzene in the presence of base to yield the corresponding 1-(4-nitrophenyl)pyrazoles. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00849-2

Tetrahedron Letters 41 (2000) 5321±5324
Practical synthesis of 1,3-diaryl-5-alkylpyrazoles by a highly
regioselective N-arylation of 3,5-disubstituted pyrazoles with
4-¯uoronitrobenzene
Xiao-jun Wang,a,* Jonathan Tan,a Karl Grozinger,a Raj Betageri,b Tom Kirraneb
and John R. Proudfootb
aDepartment of Chemical Development, Boehringer Ingelheim Pharmaceuticals Inc., Ridge®eld, CT 06877, USA
bDepartment of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals Inc., Ridge®eld, CT 06877, USA
Received 19 April 2000; revised 16 May 2000; accepted 17 May 2000
Abstract
3-Aryl-5-alkylpyrazoles undergo a highly regioselective arylation on N-1 atom with 4-¯uoronitrobenzene
in the presence of base to yield the corresponding 1-(4-nitrophenyl)pyrazoles. # 2000 Elsevier Science Ltd.
All rights reserved.
The most common route to N-arylpyrazoles involves condensation of 1,3-diketones with aryl-
hydrazines. In this reaction unsymmetrical 1,3-diketones generally yield a mixture of two regioi-
somers in a ratio which depends on the nature of 1,3-diketones.1 We recently required an ecient
entry into a variety of 1-(4-nitrophenyl)-3-aryl-5-alkylpyrazoles 2, and since direct condensation
of aryl alkyl 1,3-diketones with arylhydrazines proceeded to give the undesired isomeric 1-(4-
nitrophenyl)-3-alkyl-5-arylpyrazole 1 as a major component,2 we sought an alternative approach
to these molecules. We were particularly interested in a practical synthesis of pyrazole 3, which we
needed in large quantities.
In this communication we describe our ®ndings that direct N-arylation of pyrazoles 4 with
4-¯uoronitrobenzene (5) using potassium tert-butoxide as a base in DMSO at 70ꢀC for 1 hour
* Corresponding author.
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00849-2

5322
a€ords pyrazoles 2 with high regioselectivity in excellent yields (Scheme 1 and Table 1).3,4 We
found that the previously reported conditions,2c,5a d such as K2CO3/DMF, K2CO3/DMSO,
KOH/Bu4NBr, KOtBu and NaH/THF, required longer times and gave moderate to good yields,
with similar regioselectivity observed. A practical synthesis of pyrazole 3 was developed using this
approach. The starting pyrazoles 4 were prepared by condensation of the corresponding 1,3-
diketones with hydrazine.6
Table 1
N-Arylation of pyrazole 4 with 4-¯uoronitrobenzene (5) (Scheme 1)

5323
Scheme 1.
For the pyrazole anion of 4, there are two equivalent resonance forms, and therefore a regio-
isomeric mixture of 1 and 2 would be expected from N-arylation (Scheme 1). The observed
regioselectivity of this process may be attributable to the steric hindrance of the non-twisted aryl
ring1,7 that prohibits access to the nitrogen atom next to the aromatic ring by the electrophile
leading to isomer 2. With the opposing isopropyl group instead of ethyl (Entry 2), the regio-
selectivity was lower, suggesting a steric e€ect for both the aryl and isopropyl groups. Consistent
with our rationale, the less sterically demanding furan ring leads to lower selectivity (Entries 9
and 10). Electronic e€ects may also be a€ecting the regioselectivity.1 It is noteworthy that pyrazoles
with electron-withdrawing groups on the aryl ring (Entries 3 and 10) showed higher regioselectivity
than did the parent substrates (Entries 2 and 9), while a lower selectivity was observed for pyrazole
with an electron-donating group (Entry 4). In general, pyrazoles with more electron-de®cient
aromatic substituents (Entries 5 through 8) gave higher regioselectivity. The structures of iso-
meric products 1 and 2 were supported by NOE experiments: a strong NOE e€ect was observed
between the methylene protons of the alkyl group and the ortho-proton of the nitrophenyl group
in isomer 2 and was absent in isomer 1.8
Using this highly regioselective N-arylation as a key step, we developed a scalable, three-step
synthesis of pyrazole 3, a key intermediate for our program, with an overall yield of 60% (Scheme 2).
Thus, condensation of 3-acetylpyridine (6) with methyl propionate in the presence of t-BuOK
yielded 1,3-diketone 7 as the enol. In a one-pot operation, the reaction mixture was neutralized
with concentrated HCl, and then treated with hydrazine. Pyrazole 8 was isolated in 72% yield by
concentration, followed by adding water. N-Alkylation of 8 with 4-¯uoronitrobenzene (5) gave
the desired regioisomer 9 in 90% isolated yield after removal of the other regioisomer (2.5%) by
trituration with a 1:1 mixture of hexane and ethyl acetate. Reduction of 9 was carried out using
HCO2NH4/5% Pd on carbon in a mixture of methanol and THF to give pyrazole 3. This
Scheme 2.

5324
operation was carried out on a greater than 500 g scale, and proved to be very practical. Analogous
pyrazoles were also scaled up along the same lines.
In conclusion, N-arylation of 3-aryl-5-alkylpyrazoles yields 1,3-aryl-5-alkylpyrazoles in a
highly regioselective manner, and it can serve as a general approach to this type of molecules.
References
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4. A representative procedure: To a solution of 3-phenyl-5-ethylpyrazole (1.0 g, 5.81 mmol) in DMSO (5 mL) was
added solid potassium tert-butoxide (0.72 g, 6.39 mmol) followed by addition of 4-¯uoronitrobenzene (0.65 mL,
6.10 mmol) through a syringe. The resulting mixture was heated to 70ꢀC and kept at this temperature for 30 min.
It was then cooled to room temperature and quenched with water (50 mL). The precipitate was collected by
®ltration and oven-dried in vacuo. The solid was triturated in a 2:1 mixture of hexane and ethyl acetate (20 mL)
for 30 min, then collected by ®ltration and dried to give 1-(4-nitrophenyl)-3-phenyl-5-ethylpyrazole (1.70 g, 92%);
m.p. 112±113ꢀC. 1H NMR (400 MHz, CDCl3): 8.39, 7.79 (ABq, J=9.1 Hz, 4H, ArH), 7.90 (m, 2H, PhH), 7.45 (m,
2H, PhH), 7.38 (m, 1H, PhH), 6.66 (s, 1H, PyH), 2.86 (q, J=7.52 Hz, 2H, CH2CH3), 1.38 (t, J=7.52 Hz, 3H,
CH2CH3). MS m/e 294 (20, MH+), 265 (25), 264 (100). Anal. calcd for C17H15N3O2: C, 69.61; H, 5.15; N, 14.32.
Found: C, 69.65; H, 5.19; N, 14.43.
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8. Some minor regioisomers 1 were independently synthesized by a known procedure,2 if not isolated from the N-
arylation.