powerful synthetic tool for the functionalization of aromatic
compounds and heterocycles.6 To the best of our knowledge,
the first pyrazole arylation at C5 has been recently reported
by Sames and co-workers,7 where trisubstituted pyrazoles
were obtained by C-H activation after protecting group
migration. Activation at C4 has been reported by Santelli
et al.8
Scheme 2
In connection with a drug discovery program, we required
a methodology to quickly access 5-aryl-1-methyl-pyrazoles
to facilitate our structure-activity relationship (SAR) studies.
For that purpose, we started a research effort exploring the
C-H activation methodology on the N-methylpyrazole ring.
In this manuscript, our research group describes the selective
C5 arylation of N-methylpyrazoles mediated by palladium
complexes.
1-Methylpyrazole (1) was initially selected as starting
material for direct C-H palladium-mediated model valida-
tion. Experimental conditions reported in the literature by
Fagnou6b et al. were applied to 3-bromochlorobenzene, and
a mixture of three different arylated pyrazole derivatives were
isolated (Scheme 1). A general reactivity rule could be stated
While better selectivity was observed for bromo derivative
5b (5/1 ratio, 6b/7b), chloropyrazole (5a) (selectivity: 1/1
(6a/7a)) displayed more promising conversion (higher yield),
presumably due to its higher electronegativity. On the basis
of this, 3-chloro-1-methylpyrazol (5a) was selected for the
subsequent study and optimization due to its better conver-
sion profile. However, the chloro substituent at C4 improves
C3 reactivity, so an optimization study was mandatory for
selectivity improvement. On the basis of our experience in
automation tools, a statistical study was applied for the design
of experiments9 and optimization of the process, focused on
an optimal set of conditions that maximize conversion and
selectivity values.
Scheme 1
Optimization screening was performed to improve the C5/
C3 selectivity profile, maximizing C5 direct arylation.
Solvent, base, catalyst, ligand, and additive were screened.
A statistical study, using JMP software,10 was done for a
much better optimization, and a Design of Experiments
(DoE) design was performed using several factors (Table
1). Experimental conditions selected were compiled from
for 1-methylpyrazole (1) based on experimental results (yield
of isolated compounds). Direct C-H arylation reactivity for
1-methylpyrazole under palladium-mediated conditions was
C5 > C4 . C3 (same relationship was found by Sames and
co-workers7 with a pyrazole analogue).
To expand the SAR after the first arylation, we then chose
4-chloro-1-methyl-pyrazole (5a) and 4-bromo-1-methylpyra-
zole (5b) as scaffolds for further functionalization. An
arylated compound at C5 and bisarylated compound at C5
and C3 were surprisingly isolated (Scheme 2). The outcome
of that test clearly indicates that electron withdrawing groups
(EWGs) such as Cl or Br enhance C3 reactivity.
Table 1. Factors Selected for DoE Design
solvent
NMP
base
catalyst
ligand
additive
Bu4NOAc Pd(AcO)2
DavePhos
pivalic acid
chloroacetic
acid
DMA
THF
Et3N
Pd2dba3
XantPhos
iPr2EtN
PdCl2(PPh3)2 PCy3·HBF4
isobutyric
(tBu)2MeP·HBF4
PdCl2dppf acid
acetic acid
dioxane
IPA
water/IPA NaHCO3
CSF
KF
Na2CO3
no ligand
no additives
(tBu)3P·HBF4
Cs2CO3
Cy2MeN
K3PO4
(5) (a) Despotopoulou, C.; Klier, L.; Knochel, P. Org. Lett. 2009, 11,
3326–3329. (b) Cali, P.; Begtrup, M. Tetrahedron 2002, 58, 1595–1606.
(c) Pawlas, J.; Vedsoe, P.; Jakobsen, P.; Huusfeldf, P. O.; Begtrup, M. J.
Org. Chem. 2001, 66, 4214–4219. (d) Pawlas, J.; Vedsoe, P.; Jakobsen, P.;
Huusfeldf, P. O.; Begtrup, M. J. Org. Chem. 2000, 65, 9001–9006. (e)
Kristensen, J.; Begtrup, M.; Vedsoe, P. Synthesis 1998, 11, 1604–1608.
(6) For reviews on C-H direct arylation, see: (a) Alberico, D.; Scott,
M.; Lautens, M. Chem. ReV. 2007, 107, 174–238. Satoh, T.; Miura, M.
Chem. Lett. 2007, 36, 200. For Pd-catalyzed arylation of heterocycles: (b)
Lie´gault, B.; Lapointe, D.; Caron, L.; Vlassova, A.; Fagnou, K. J. Org.
Chem. 2009, 74, 1826–1834. For copper-catalyzed arylation of heterocycles:
(c) Do, H.-Q.; Kashif Khan, R. M.; Daugulis, O. J. Am. Chem. Soc. 2008,
130, 15185–15192. Review on transition metal catalysis for the synthesis
of heteroaryl-heteroarenes: (d) Bellina, F.; Rossi, R. Tetrahedron 2009, 65,
10269–10310.
literature reports and our own experience; then, 6 solvents,
10 bases, 4 catalyst, 5 ligands, and 4 additives were included
in the study for optimization screening. A total of 7200
reactions could be performed for full combination of the
entire experimental conditions selected; however, DoE design
(9) (a) Aggarwal, V.; Staubitz, A.; Owen, M. Org. Process Res. DeV.
2006, 10, 64–69. (b) Kuethe, J.; Tellers, D.; Weismann, S.; Yasuda, N.
Org. Process Res. DeV. 2009, 13, 471–477. (c) Mendiola, J.; Garc´ıa-Cerrada,
S.; De Frutos, O.; De la Puente, M. L.; Gu, R. L.; Khau, V. Org. Process
Res. DeV. 2009, 13, 292–296.
(7) Gikhman, R.; Jacques, T. L.; Sames, D. J. Am. Chem. Soc. 2009,
131, 3042–3048.
(8) Fall, Y.; Doucet, H.; Santelli, M. Synthesis 2010, 127–135.
Org. Lett., Vol. 12, No. 21, 2010
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