A simple, modular method for the synthesis of 3,4,5-trisubstituted pyrazoles

Article abstract of DOI:10.1021/jo800321p

(Chemical Equation Presented) A modular approach for the regiocontrolled preparation of pyrazoles bearing substituents on all three carbon atoms is described. Central to this method is the use of a switchable metal-directing group (MDG) to enable sequential direct lithiation of the 3- and 5-positions of the pyrazole ring. Pyrazole boronic esters obtained from these lithiated intermediates can undergo efficient Suzuki cross-coupling under the developed nonaqueous conditions, which minimize undesirable protolytic deboronation. Halogenation of the 4-position provides the means for substitution at the remaining carbon atom.

Full text of DOI:10.1021/jo800321p

A Simple, Modular Method for the Synthesis of
3,4,5-Trisubstituted Pyrazoles
Mark McLaughlin,* Karen Marcantonio, Cheng-yi Chen, and
Ian W. Davies
Process Research, Merck Research Laboratories, P.O. Box
2000, Rahway, New Jersey 07065
mark_mclaughlin@merck.com
FIGURE 1. Modular approach to polyfunctionalized pyrazoles.
ReceiVed February 07, 2008
Of particular interest was the Suzuki cross-coupling reaction
since this is well-established as a dependable process applicable
to many substrate types.3 However, at the outset of our studies
in this area, the preparation and use of pyrazole boronic acids
had received limited attention in the literature. One report4 by
Young and co-workers at Merck, which served as the basis for
our own efforts, described the use of N-THP pyrazole in the
preparation of pyrazole-5-boronic acid. The overall yield for
this process from pyrazole was 38%, and an attempt to cross-
couple the prepared boronic acid with an aryl bromide afforded
only 32% yield.
More recently, two reports relevant to our research appeared
in the literature. Building upon Young’s work, Rault described
the preparation of a pyrazole boronate ester 6 and demonstrated
its use in Suzuki cross-coupling reactions, although the yields
were only moderate and required relatively high catalyst
loadings (5 mol %).5 Concurrently, Fu documented an excellent
general procedure for the Suzuki cross-coupling of nitrogen-
containing heterocycles that were previously known to be
difficult substrates for this reaction.6 This report featured only
one example of a pyrazole-5-boronic acid participating in a
cross-coupling with bromobenzene. Given our need to prepare
a variety of pyrazole-based intermediates for use in drug
discovery work, we required a more general and robust method
for the synthesis of these derivatives. In this Note, we are now
able to disclose our own results toward an efficient means for
elaboration of the pyrazole nucleus.
A modular approach for the regiocontrolled preparation of
pyrazoles bearing substituents on all three carbon atoms is
described. Central to this method is the use of a switchable
metal-directing group (MDG) to enable sequential direct
lithiation of the 3- and 5-positions of the pyrazole ring.
Pyrazole boronic esters obtained from these lithiated inter-
mediates can undergo efficient Suzuki cross-coupling under
the developed nonaqueous conditions, which minimize
undesirable protolytic deboronation. Halogenation of the
4-position provides the means for substitution at the remain-
ing carbon atom.
In recent years, the pyrazole ring system has proven to be an
increasingly popular heterocycle for the synthesis of pharma-
ceutically active compounds.1 In support of drug development
programs at Merck, we had reason to investigate potential
methods for the preparation of functionalized pyrazoles. Specif-
ically, we required a simple method by which the pyrazole ring
could be elaborated in a regiocontrolled fashion to provide
polysubstituted pyrazole derivatives. Our general approach to
this problem (Figure 1) was to develop a modular synthesis
based around the concept of a switchable metal-directing group
(MDG). We envisaged that controlled access to metalated
pyrazoles would open the door to a variety of reactions for
further functionalization, including cross-coupling technologies.2
We initially set out to define the optimal conditions for the
preparation of pyrazole boronate 6. In the best procedure,
N-THP-pyrazole can be obtained in essentially quantitative yield
by treatment of pyrazole with 1.05 equiv of 3,4-dihydro-2H-
(3) Reviews: (a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457–2483.
(b) Suzuki, A. In Metal-Catalyzed Cross-Coupling Reactions; Diederich, F.,
Stang, P. J., Eds.; Wiley-VCH: Weinheim, Germany, 1998; Chapter 2. (c) Suzuki,
A. J. Organomet. Chem. 1999, 576, 147–168. (d) Miyaura, N. Top. Curr. Chem.
2002, 219, 11–59. (e) Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire,
M. Chem. ReV. 2002, 102, 9633–9695. (f) Kotha, S.; Lahiri, K.; Kashinath, D.
Tetrahedron 2002, 58, 9633–9695. (g) Bellina, F.; Carpita, A.; Rossi, R. Synthesis
2004, 15, 2419–2440.
(4) Young, M. B.; Barrow, J. C.; Glass, K. L.; Lundell, G. F.; Newton, C. L.;
Pellicore, J. M.; Rittle, K. E.; Selnick, H. G.; Stauffer, K. J.; Vacca, J. P.;
Williams, P. D.; Bohn, D.; Clayton, F. C.; Cook, J. J.; Krueger, J. A.; Kuo,
L. C.; Lewis, S. D.; Lucas, B. J.; McMasters, D. R.; Miller-Stein, C.; Pietrak,
B. L.; Wallace, A. A.; White, R. B.; Wong, B.; Yan, Y.; Nantermet, P. G. J. Med.
Chem. 2004, 47, 2995–3008.
(1) Elguero, J. ComprehensiVe Heterocyclic Chemistry; Katritzky, A. R., Rees,
C. W., Scriven, E. F. V., Eds.; Pergamon: Oxford, 1996; Vol. 5.
(2) The directed metalation/cross-coupling tactic has been extensively studied
by Prof. Snieckus. For recent examples, see: (a) Blanchet, J.; Macklin, T.; Ang,
P.; Metallinos, C.; Snieckus, V. J. Org. Chem. 2007, 72, 3199–3206. (b) Alessi,
M.; Larkin, A. L.; Ogilvie, K. A.; Green, L. A.; Lai, S.; Lopez, S.; Snieckus, V.
J. Org. Chem. 2007, 72, 1588–1594. For an example of regioselective pyrazole
metalation, see: (c) Paulsen, A. F.; Eskildsen, J.; Vedsø, P.; Begtrup, M. J. Org.
Chem. 2002, 67, 3904–3907.
(5) Ge´rard, A.-L.; Bouillon, A.; Mahatsekake, C.; Collot, V.; Rault, S.
Tetrahedron Lett. 2006, 47, 4665–4669.
(6) Kudo, N.; Perseghini, N.; Fu, G. C. Angew. Chem., Int. Ed. 2006, 45,
1282–1284.
10.1021/jo800321p CCC: $40.75
Published on Web 04/30/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 4309–4312 4309

TABLE 1. Synthesis of Monoarylated Pyrazolesa
FIGURE 2. Comparsion of aqueous versus nonaqueous solvent systems
for Suzuki coupling of pyrazole boronate 6 (yields determined by
quantitative LC analysis).
pyran (DHP) and catalytic TFA in toluene at 80 °C.7 Concentra-
tion of the reaction mixture affords a crude product that is
sufficiently pure for direct use in the ensuing regioselective
deprotonation reaction (THP ) MDG). Treatment with n-BuLi
in THF lithiates the 5-position of the pyrazole ring. Quenching
with B(Oi-Pr)3 and then pinacol/AcOH yields the boronic ester,
which greatly facilitates isolation (relative to the boronic acid).
The pinacol boronate 6 is a stable solid that is easily isolated
(80% yield) by crystallization from heptane.
With ready access to boronate 6, the applicability of known
procedures for Suzuki cross-coupling was studied. In our hands,
the use of aqueous solvents for this reaction led to protolytic
deboronation as a troublesome side reaction, and the conversion
of aryl halide suffered accordingly (Figure 2).8 Consequently,
we attempted the same cross-coupling under alternative condi-
tions and discovered that protolytic deboronation is effectively
suppressed by eliminating bulk water from the system (Figure
2). This modification allows for efficient cross-coupling using
only 1 equiv of 6, and high yields were realized for a variety of
aryl chlorides, bromides, and iodides (Table 1). For convenience,
the crude cross-coupled products were deprotected and isolated/
characterized as the corresponding HCl salts 8.9 The efficiency
of the developed cross-coupling conditions is clearly demon-
strated by the high purity of the “crude” products isolated from
these reactions. The overall isolated yield for the coupling/
deprotection/salt formation sequence is shown in Table 1.
Having secured a series of monoarylated pyrazole HCl salts,
we turned our attention toward the development of techniques
for further elaboration of the pyrazole ring (Figure 3). To this
end, we investigated the possibility that reintroduction of the
THP group (8b to 9b) would be selective for the other nitrogen
atom of the pyrazole ring. This would potentially allow for a
second metalation of the ring and subsequent functionalization.
In the event, subjection of the monoarylated free-base pyrazole
to the previously developed conditions for installation of the
N-THP group led to highly selective reaction at the nitrogen
furthest from the aryl substituent and afforded compound 9b in
high yield.
a Reaction conditions: Boronate 6 (100 mol %), aryl halide (100 mol
%) Pd(dba)2 (2 mol %), PCy3 ·HBF4 (2.4 mol %), K3PO4 (300 mol %),
1,4-dioxane (10 mL/g), 80 °C, 16 h, then extractive workup and
treatment with HCl/MeOH at rt. b Yields refer to isolated material.
FIGURE 3. Regioselective deprotection/reprotection of monoarylpyra-
zole 7b and demonstration of the direct MDG switch (7b to 9b)
followed by boronate (10b) formation (BPin ) pinacol boronate).
(7) Important modifications to the existing literature procedure that are
relevant to larger-scale operation of this chemistry include reduced excess of
DHP (1.05 vs 1.5 equiv) and controlled addition of this reagent at 80 °C to
avoid a serious exotherm observed using an “all-in” mode (see Supporting
Information for further details). Distillative workup was also eliminated. For
further details regarding the kinetic profile of this reaction, see: Schafer, W. A.;
Hobbs, S.; Rehm, J.; Rakestraw, D. A.; Orella, C.; McLaughlin, M.; Ge, Z.;
Welch, C. J. Org. Process Res. DeV. 2007, 11, 870–876.
With this knowledge, we postulated that under the appropriate
conditions it would be possible to simply equilibrate the THP
group onto the thermodynamically most stable position in a
single process (7b to 9b), without the need for a two-step
deprotection/reprotection sequence.
To our satisfaction, treatment of 7b with 1 equiv of DHP
and 5 mol % of TFA in toluene at 60 °C directly furnished 9b
in good yield. It was established that the newly positioned MDG
in 9b again served to facilitate pyrazole ring deprotonation using
(8) Proteolytic deboronation of heterocyclic substrates can be problematic
and was observed by Prof. Fu when employing a pyrazole-4-boronic acid
substrate (ref 6).
(9) Alternatively, the THP-pyrazoles are stable to chromatography and can
be isolated (pure) using this technique.
4310 J. Org. Chem. Vol. 73, No. 11, 2008

TABLE 2. THP Switch and Boronic Ester Synthesisa
TABLE 3. Synthesis of 3,5-diarylated pyrazolesa
a Reaction conditions: DHP (100 mol %), TFA (5 mol %), toluene
(10 mL/g), 60 °C for 2-3 h. Isolate switched intermediate and treat
THF solution (10 mL/g) with n-BuLi (105 mol %) at -50 °C then
B(Oi-Pr)3 (110 mol %), pinacol (110 mol %), and AcOH (200 mol %)
at rt. b Yields refer to isolated material. c LDA (105 mol %) used as the
base, added to mixture of substrate/B(Oi-Pr)3 at -60 °C.
a Reaction conditions: Boronate (100 mol %), aryl halide (100 mol %)
Pd(dba)2 (2 mol %), PCy3.HBF4 (2.4 mol %), K3PO4 (300 mol %),
1,4-dioxane (10 mL/g), 80 °C, 16 h, then extractive workup and
treatment with HCl/MeOH at rt. b Yields refer to isolated material.
n-BuLi and the resultant lithiated species could be smoothly
transformed into the corresponding pinacol boronic ester 10b.
This novel MDG switch and subsequent metalation proved to
be fairly general for a series of monoarylated pyrazoles obtained
from the initial cross-couplings (Table 2). Notably, heteroatom-
bearing substrates such as 9a or 9c can be selectively metalated
and converted into boronic esters. Substrates featuring more
reactive functional groups (9e and 9f) can also be utilized,
provided LDA is used as the base.10
Introduction of a second aryl substituent onto these intermedi-
ates (10) via Suzuki cross-coupling was again efficiently
accomplished using the developed nonaqueous conditions. Table
3 depicts the variety of 3,5-diarylated pyrazoles (11) that were
synthesized, and again, the crude products were directly
converted to their HCl salts for ease of isolation.
FIGURE 4. Elaboration to triarylpyrazole 14.
pyrazole. Central to this approach is the novel use of an easily
switchable metal-directing group to enable sequential direct
lithiation of the 3- and 5-positions of the pyrazole ring. A key
aspect of this work is the development of an effective procedure
for the Suzuki cross-coupling of pyrazole boronic esters, which
overcomes the problem of competitive deboronation typically
encountered under previously described conditions. The flex-
ibility and generality of the developed method was demonstrated
by the efficient and regiocontrolled preparation of numerous
mono-, di-, and triarylated pyrazoles, which are of potential
utility as heterocyclic building blocks for the synthesis of
pharmaceutically active compounds.
Further complexity can be introduced by way of the 4-bromo
derivatives, which can be easily prepared by NBS treatment of
the THP-protected 3,5-diarylpyrazoles (e.g., 12). Suzuki cross-
coupling of these 4-bromo compounds (13) allows for introduc-
tion of a third distinct aryl substituent onto the pyrazole ring in
good yield (Figure 4).
In summary, we have described an efficient and modular
strategy for the functionalization of all three carbon atoms of
Experimental Section
Suzuki Cross-Coupling of Pyrazole Boronic Esters and
HCl Salt Formation. To an 8 mL vial equipped with a stirbar and
septum were charged the pyrazole boronate (6 or 10a-f) (1 mmol),
(10) Ethyl ester 7e suffered double addition of n-BuLi leading to a tertiary
alcohol.
J. Org. Chem. Vol. 73, No. 11, 2008 4311

aryl halide (1 mmol), K3PO4 (300 mol %), Pd(dba)2 (2 mol %),
PCy3.HBF4 (2.4 mol %), and 1,4-dioxane (3 mL). The heteroge-
neous mixture was agitated and purged with N2 for 10 min before
it was heated to 80 °C for 16 h. After this time, LC analysis of the
gray mixture normally indicated >98% conversion. The mixture
was diluted with brine (30 mL) and MTBE (70 mL), and the
separated organic was dried over Na2SO4. The filtered MTBE
solution was concentrated under reduced pressure, and the crude
residue was treated with HCl in MeOH (10 mL of stock solution)
at rt. Isolation of the HCl salts (8) was achieved by dilution with
MTBE and filtration of the resultant slurry. 5-(4-Fluorophenyl)-
1H-pyrazole hydrochloride (8a): Following this general procedure,
8a was obtained as an off-white solid (84%): mp ) 162-163 °C;
1H NMR (400 MHz, DMSO) δ 6.98 (d, J ) 2.4 Hz, 1H), 7.28 (dd,
J ) 8.4, 5.6 Hz, 2H), 7.98 (dd, J ) 8.4, 5.6 Hz, 2H), 8.08 (d, J )
2.4 Hz, 1H); 13C{1H} NMR (100 MHz, DMSO) δ 103.5, 116.1 (d,
JCF ) 20.1 Hz), 126.0, 128.6 (d, JCF ) 10.0 Hz), 133.8, 146.1,
163.6 (d, JCF ) 251.6 Hz). HRMS calcd for C9H8FN2 [M + H]+
163.06715, found 163.06749.
NaHCO3 (30 mL) and MTBE (70 mL), and then the separated
organic phase was washed with brine (30 mL) and dried over
Na2SO4. The filtered MTBE solution was concentrated under
reduced pressure, and the switched THP product 9 was isolated
following flash chromatography on silica gel using an appropriate
mixture of EtOAc/hexanes as the eluent. 3-(4-Fluorophenyl)-1-
(tetrahydropyran-2-yl)-1H-pyrazole (9a): Following this general
procedure, 9a was obtained as a colorless oil (86%): 1H NMR (400
MHz, CDCl3) δ 1.58-1.77 (m, 3H), 2.02-2.23 (m, 3H), 3.69-3.77
(m, 1H), 4.07-4.14 (m, 1H), 5.43 (dd, J ) 10.0, 2.4 Hz, 1H), 6.56
(d, J ) 2.4 Hz, 1H), 7.04-7.11 (m, 2H), 7.63 (d, J ) 2.4 Hz, 1H),
7.77-7.82 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 22.6, 25.1,
30.7, 68.0, 87.9, 103.3, 115.5 (d, JCF ) 20.1 Hz), 127.6, 129.1,
129.8, 150.9, 162.7 (d, JCF ) 241.5 Hz). HRMS calcd for C9H8FN2
[(M - THP) + H]+ 163.06715, found 163.06724.
Acknowledgment. The authors wish to thank Robert A.
Reamer (Dept. of Process Research, Merck and Co. Inc.) for
assistance with NMR data interpretation.
THP Switch. To an 8 mL vial equipped with a stirbar and septum
was charged the substrate 7 (1 mmol) followed by toluene (3 mL),
DHP (100 mol %), and TFA (5 mol %). The mixture was heated
at 60 °C for 3 h, then LC analysis indicated complete switching of
the THP group. The mixture was diluted into saturated aqueous
Supporting Information Available: Characterization data
and NMR spectra for all compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO800321P
4312 J. Org. Chem. Vol. 73, No. 11, 2008