Palladium-catalyzed coupling of pyrazole triflates with arylboronic acids

Article abstract of DOI:10.1021/jo0477897

A general protocol for the palladium-mediated Suzuki coupling reaction of pyrazole inflates and aryl boronic acids has been developed. The use of additional dppf ligand was determined to increase product yields allowing for the use of a broad range of rea

Full text of DOI:10.1021/jo0477897

Palladium-Catalyzed Coupling of Pyrazole
Triflates with Arylboronic Acids
SCHEME 1
Curt A. Dvorak,* Dale A. Rudolph, Sandy Ma, and
Nicholas I. Carruthers
Johnson & Johnson Pharmaceutical Research &
Development, L.L.C., 3210 Merryfield Row,
San Diego, California 92121
air-stable, nontoxic, and commercially available boronic
acids as the organometallic coupling partners.
There have been several literature reports of coupling
reactions performed on halopyrazoles. Wang et al.
4
cdvorak@prdus.jnj.com
performed Suzuki, Stille, and Sonogashira couplings on
5
Received December 17, 2004
1-aryl-5-bromopyrazoles. Zhang and co-workers utilized
a Suzuki coupling of a 5-bromopyrazole while exploring
the structure-activity relationships of endothelin an-
tagonists. In addition, Organ et al.6 has prepared a
library of COX-2 inhibitors from 4-(5-iodo-3-methyl-
pyrazolyl)phenylsulfonamide and aryl boronic acids by
solution phase Suzuki coupling utilizing a solid-supported
catalyst. However, we wished to avoid the harsh reaction
conditions necessary to form the requisite halopyrazole
(
3 3
POCl , POBr , etc.). As for the corresponding pseudo-
A general protocol for the palladium-mediated Suzuki
coupling reaction of pyrazole triflates and aryl boronic acids
has been developed. The use of additional dppf ligand was
determined to increase product yields allowing for the use
of a broad range of reaction substrates.
halopyrazoles, Organ noted that the Suzuki reaction
failed with the 1-arylpyrazole 5-mesylate and 5-phos-
phate analogues, thus prompting the suggestion that
these heterocyclic precursors might not be suitable
7
substrates for the oxidative addition of the palladium(0).
More recently, Collins8 and co-workers reported the
successful application of 3(5)-pyrazolyl nonaflates in
palladium-catalyzed cross-coupling reactions. However,
they also mentioned that the cross coupling with pyrazole
triflates was capricious even under nonaqueous condi-
tions. Not surprisingly, there have been few reports of
Suzuki cross-coupling reactions accomplished with pyra-
Recently, we were interested in a general, mild, and
efficient method for incorporating an aryl ring onto a
pyrazole scaffold. Additionally, it was desirable to add
this point of diversity at a late stage in the synthetic
sequence. While there are many new and novel methods
1
available for the assembly of the pyrazole nucleus, the
most general remains the condensation of a 1,3-dicar-
bonyl compound or equivalent with a hydrazine deriva-
9
zole triflates. Nonetheless, we chose to explore the scope
and utility of pyrazole triflates as possible substrates in
the palladium catalyzed Suzuki reaction for the synthesis
of aryl pyrazoles. In this paper, we wish to communicate
the progress of this endeavor.
Pyrazolones 4a-e were available from commercial
sources. Pyrazolones 4f and 4g were made according to
the procedure of Mendoza et al.10 by treatment of 2-oxo-
cyclohexanecarboxylic acid ethyl ester with methyl and
phenyl hydrazines, respectively. Pyrazole triflates 5a-g
2
tive. Although this condensation is straightforward, the
formation of regioisomers with N-substituted hydrazines
can be problematic (Scheme 1). Another major drawback
is the necessity to “custom make” the required dicarbonyl
components, i.e., 1, for the condensation reaction.
Thus, we chose to explore transition-metal catalysis
as a means of installing the aryl unit onto the fully
assembled pyrazole via a carbon-carbon bond-forming
reaction. Specifically, we chose to examine the Suzuki
3
reaction, which is unaffected by the presence of water,
(4) Wang, X.; Tan, J.; Grozinger, K. Tetrahedron Lett. 2000, 41, 4713.
(
5) Zhang, J.; Didierlaurent, S.; Fortin, M.; Lefrancois, D.; Uridat,
tolerates a broad range of functional groups, and utilizes
E.; Vevert, Jean Paul. Bioorg. Med. Chem. Lett. 2000, 10, 2575.
6) Organ, M. G.; Mayer, S. J. Comb. Chem. 2003, 5, 118.
(
(1) (a) Singh, S. K.; Reddy, M. S.; Shivaramakrishna, S.; Kavitha,
(7) For corresponding aryl sulfonate Suzuki couplings, see: (a)
Nguyen, H.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125,
11818. (b) Percec, V.; Bae, J.; Hill, D. H. J. Org. Chem. 1995, 60, 1060.
For vinyl phosphate coupling, see: Lepifre, F.; Buon, C.; Rabot, R.;
Bouyssou, P.; Coudert, G. Tetrahedron Lett. 1999, 40, 6373.
(8) Bourrain, S.; Ridgill, M.; Collins, I. Synlett 2004, 795.
(9) (a) Stille reaction performed on a pyrazole triflate: Regan, J.;
Breitfelder, S.; Cirillo, P.; Gilmore, T.; Graham, A. G.; Hickey, E.;
Klaus, B.; Madwed, J.; Moriak, M.; Moss, N.; Pargellis, C.; Pav, S.;
Proto, A.; Swinamer, A.; Tong, L.; Torcellini, C. J. Med. Chem. 2002,
45, 2994. (b) Suzuki reaction on N-Boc derivative: PTC WO 03/
051797. (c) For N-Boc-indazole, see: Patel, M.; Rodgers, J. D.; McHugh,
R. J.; Johnson, B. L.; Cordova, B. C.; Klabe, R. M.; Bacheler, L. T.;
Erickson-Viitanen, S. and Ko, S. Bioorg. Med. Chem. Lett. 1999, 9,
3217.
D.; Vasudev, R.; Babu, J. M.; Sivalakshmidevi, A.; Rao, Y. K.
Tetrahedron Lett. 2004, 45, 7679. (b) Lee, K. Y.; Kim, J. M.; Kim, J.
N. Tetrahedron Lett. 2003, 44, 6737. (c) Aggarwal, V. K.; Vincente, J.;
Bonnet, R. V. J. Org. Chem. 2003, 68, 5381. (d) Grotjahn, D. B.; Van,
S.; Combs, D.; Lev, D. A.; Schneider, C.; Rideout, M.; Meyer, C.;
Hernandez, G.; Mejorado, L. J. Org. Chem. 2002, 67, 9200. (e) Haddad,
N.; Baron, J. Tetrahedron Lett. 2002, 43, 2171. (f) Molteni, V.;
Hamilton, M. M.; Mao, L.; Crane, C. M.; Termin, A. P.; Wilson, D. M.
Synthesis 2002, 1669. (g) Katritzky, A. R.; Wang, M.; Zhang, S.;
Voronkov, M. V. J. Org. Chem. 2001, 66, 6787. (h) Huang, Y. R.;
Katzenellenbogen, J. A. Org. Lett. 2000, 2, 2833. (i) Katritzky, A. R.;
Denisenko, A.; Denisenko, S. N. J. Heterocycl. Chem. 2000, 37, 1309.
(
2) Gilchrist, T. L. Heterocyclic Chemistry, 3rd ed.; Longman Press:
Essex England, 1997.
3) (a) reviews: Suzuki, A. J. Organomet. Chem. 1999, 576, 147.
b) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(
(10) Mendoza, J.; Garcia-Ochoa, S.; Prados, P.; Parra, E. Tetrahe-
dron 1986, 42, 2377.
(
10.1021/jo0477897 CCC: $30.25 © 2005 American Chemical Society
4188
J. Org. Chem. 2005, 70, 4188-4190
Published on Web 04/14/2005

TABLE 1. Pyrazole Triflate Synthesis
TABLE 3. Suzuki Coupling of Pyrazole Triflates
a
no.
R1
R2
R3
triflate
yield (%)
4
4
4
4
4
4
4
a
b
c
d
e
f
CH3
H
CH3
Ph
Ph
CH3
Ph
CH3
CH3
CF3
CH3
CF3
-(CH2)4-
-(CH2)4-
H
H
H
H
H
5a
5b
5c
5d
5e
5f
62
45
60
92
60
88
97
g
5g
a
Isolated yield after chromatography on silica gel.
TABLE 2. Optimization of Suzuki Reaction Conditions
a
baseh
b
c
entry catalyst /additive
solvent T (°C) yield (%)
1
2
3
4
5
6
7
8
9
1
Pd(PPh3)4
K3PO4
K3PO4
Na2CO3 THF
KF THF
Na2CO3 DMF
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
THF
65
100
65
12
74
1
Pd(PPh3)4/KBrd
PdCl2(PPh3)2
dioxane
e
Pd(OAc)2/PCy3
rt
-
PdCl2(dppf)
80
65
100
100
100
100
51
43
68
79
83
10
PdCl2(dppf)
THF
PdCl2(dppf)
dioxane
dioxane
dioxane
dioxane
a
PdCl2(dppf)/PPh3
f
PdCl2(dppf)/dppf
0
Pd2(dba)3/dppfg
a
mol %. 16 h. c Isolated yield after chromatography on silica
b
8
gel. d 1.1 equiv. e 1 mol % Pd(OAc)2, 1.2 mol % of PCy3. 4 mol %.
f
g
dppf/Pd ) 1.5. h 3 equiv.
in Table 1 were made with excellent chemoselectivity by
treating the corresponding pyrazolones with N-phenyl-
trifluoromethanesulfonimide and a non-nucleophilic ter-
tiary amine base in methylene chloride. Attempts to use
the more reactive trifluoromethanesulfonyl anhydride as
the triflating agent afforded unwanted mixtures of N- and
O-triflation.
Table 2 outlines the reaction conditions that have been
examined thus far for the transformation of 5a to 6a. In
entry 1, the use of Pd(PPh
resulted in the formation of the desired coupled product
a albeit in low yield. The low yield was apparently due
3 4 3 4
) as a catalyst with K PO
6
to premature decomposition of the catalyst and the
precipitation of palladium black. The addition of 1.1 equiv
of KBr with Pd(PPh
temperature dramatically improved the coupling yield
entry 2). Suzuki and co-workers also observed improved
3 4
) and increasing the reaction
(
yields with the addition of KBr while exploring the
coupling of vinyl and aryl triflates.11 Nevertheless, these
conditions were not amenable to more complex pyrazole
substrates and substituted arylboronic acids.
a
Isolated yield after chromatography on silica gel. b 1.4 equiv
Utilizing PdCl
aqueous Na CO
coupling product 6a (entry 3). Switching to an electron
2
3 2
(PPh ) as the palladium source with
of 4-fluoroboronic acid, 1.4 eq of K3PO4, 4% PdCl2(dppf), and 2%
dppf utilized.
2
3
as the base provided only a trace of the
12
rich bulky phosphine ligand, the conditions developed by
Fu and co-workers for the coupling of aryl triflates at
13
(11) Ohe, T.; Miyaura, N.; Suzuki, A. J. Org. Chem. 1993, 58, 2201.
J. Org. Chem, Vol. 70, No. 10, 2005 4189

room temperature, were found to be ineffective (entry 4).
As shown in entry 5, the coupling of pyrazole triflate
on the boronic acid partner. In entries 8 and 11, both
the N-methyl- and N-phenylpyrazole triflates couple
smoothly with 4-methoxyphenylboronic acid in good
yields. Entries 7 and 10 demonstrate the coupling with
electron-poor aryl boronic acids. The sterically hindered
2-methylphenylboronic acid provides the corresponding
aryl pyrazoles with either the N-methyl or N-aryl func-
tionality in good yields (entries 9 and 12).
In summary, we have developed a general, mild, and
efficient route to aryl pyrazoles via the Suzuki cross-
coupling of pyrazole triflates. The coupling conditions
were found to be tolerant for a broad range of electronic
and steric variations in either the boronic acid or pyrazole
triflate components. Further investigations into the
chemistry of pyrazole triflates are ongoing.
5
a with phenylboronic acid was accomplished with
PdCl (dppf) in DMF with aqueous Na CO as the base
2
2
3
to provide a modest yield of 6a. However, hydrolysis of
the triflate could be observed with aqueous conditions.
Good to fair yields of 6a were obtained using PdCl
as the catalyst with K PO in solvents such as THF or
dioxane (entries 6 and 7). The addition of PPh to the
2
(dppf)
3
4
3
reaction (entry 8) did provide an improvement of the
coupling yield, although these conditions have not been
fully explored. The addition of a slight excess of dppf
ligand with PdCl
considerable increase in the coupling yield (Table 2, entry
). The effects of adding extra dppf ligand were most
2
(dppf) (dppf/Pd ratio of 1.5) provided a
9
dramatic in reactions that failed to completely consume
the pyrazole triflate due to decomposition of the catalyst
and precipitation of palladium black. The addition of
Experimental Section
General Procedure for Pyrazole Triflation. To a 0.1 M
2 2
solution of the pyrazolone (4) in CH Cl were added N,N-
diisopropylethylamine (3 equiv) and N-phenyltrifluoromethane-
sulfonimide (1.2 eq). The mixture was then heated to reflux and
monitored by TLC (25-50% EtOAc/Hex). Upon disappearance
of the starting material (3-16 h), the mixture was cooled to room
more dppf ligand14 (>1.5 dppf/Pd) to PdCl
2
(dppf) resulted
in slower reaction rates requiring extended heating
times. More importantly, a dppf/Pd ratio of 1.5 in
conjunction with PdCl (dppf) as the palladium source
2
provided reaction conditions that were found to have
broader applicability to a diverse range of substrates.
2 3
Changing to Pd (dba) while maintaining a dppf/Pd ratio
of 1.5 yielded only 10% of the aryl pyrazole 6a (Table 2,
entry 10).
Table 3 demonstrates the scope of this general coupling
protocol toward the synthesis of arylpyrazoles. In entries
temperature, diluted with CH
and then dried over MgSO . Purification was performed on SiO
with a Hex/EtOAc gradient (0 to 25%).
2 2
Cl , washed with water and brine,
4
2
General Procedure for the Arylation of Pyrazole Tri-
flates. To a 0.1 M solution of the pyrazole triflate (5) in 1,4-
dioxane were added anhydrous K
3 4
PO (3 equiv), aryl boronic acid
(3 equiv), dppf (4 mol %), and PdCl dppf (8 mol %). The mixture
2
was then placed under nitrogen and immersed in an oil bath
preheated to 100 °C. After 16 h, the mixture was cooled and the
solvent removed in vacuo. The residue was taken up in toluene
and filtered on Celite. The filter cake was washed with toluene
1
-6 of Table 3, phenylboronic acid was coupled with
various pyrazole triflates. The reaction tolerates differing
substitution patterns on the pyrazole heterocycle. The
pyrazole nitrogen may have a free N-H or be substituted
with either aryl or alkyl moieties (entries 1 and 3 and
product 6a). The pyrazole ring may be substituted with
an electron-rich alkyl or an electron-withdrawing triflu-
oromethyl group (entries 3 and 4). In addition, the
pyrazole can be fused to a carbocyclic ring system (entries
and solvent removed. Purification was performed on SiO
a Hex/EtOAc gradient (0 to 25%).
2
with
Acknowledgment. We are grateful for a CORD
Fellowship for S.M. awarded by Johnson & Johnson
Corporate Office of Science and Technology. We also
thank James Edwards, Kate McElhone, and John Keith
for their help in the preparation of this manuscript as
well as Heather McAllister for the purification of triflate
5
and 6).
Entries 7-12 examine electronic and steric variations
5
a.
Supporting Information Available: General experimen-
(
12) Occhiato, E. G.; Trabocchi, A.; Guarna, A. J. Org. Chem. 2001,
tal information as well as characterization data for the
compounds synthesized. This material is available free of
charge via the Internet at http://pubs.acs.org.
6
4
1
6, 2459.
(
13) Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122,
020.
(
14) Ishiyama, T.; Itoh, Y.; Kitano, T.; Miyaura, N. Tetrahedron Lett.
997, 38, 3447.
JO0477897
4190 J. Org. Chem., Vol. 70, No. 10, 2005