development of general conditions for the palladium-
catalyzed cross-coupling between a phosphorus derivative
and a pyrazole halogenated at the C3-, C4-, or C5-position
would be of interest. In this paper, we describe our effort
toward the development of such a coupling.
1a (1.5 equiv) was required to obtain the cross-coupled
product 3a in good yield (80%).
For 5-bromo-pyrazole 1b, compound 3a was formed
in 75% yield by using 1.5 equiv of 1b and 10 mol % of
Pd(OAc)2 (Table 2, entry 1). However, when the catalyst
loading was decreased to 5 mol %, 3a was only formed in
5% yield, and 1b was almost entirely recovered (Table 2,
entry 2). The replacement of XantPhos by dppf was
detrimental as 3a was isolated in 55% yield (Table 2,
entry 3), and more electron-rich phosphines such as dtpf
and dcpf were found to be poor ligands in this coupling
reaction (Table 2, entries 4 and 5).
At first, N-SEM protected 5-iodo-pyrazole 1a and
diethylphosphite 2a were chosen to commence our inves-
tigations. Compounds 1aand 2a were engaged in the cross-
coupling using the conditions described by Stawinski
et al. for the cross-coupling between aryl halides and
H-phosphonates.8 Under these conditions, product 3a
was formed in 37% yield (Table 1, entry 1). Montchamp
et al. recently reported that the use of additives, such as
ethylene glycol, can considerably increase the yield of the
cross-coupling by preventing palladium-black precipita-
tion and by stabilizing the P(III) tautomeric form of
phosphonylidene compounds.9 However, these conditions
did not appear to be beneficial in our case, as product
3a was formed in only 30% yield (Table 1, entry 2). A
screening of ligands was achieved, and among dppf,
S-Phos, and XantPhos, this latter was revealed to be the
best ligand. A 97% isolated yield in 3a was obtained when
1a (1.0 equiv), HꢀP(O)(OEt)2 (1.1 equiv), Pd(OAc)2
(10 mol %), XantPhos (20 mol %), KOAc (10 mol %),
and Et3N (1.3 equiv) were used (Table 1, entry 3). When
the catalyst loading was decreased to 2.5 mol %, the yield
of 3a dropped to 47% (Table 1, entry 4), and an excess of
Table 2. Reaction Parameters with 1ba
y
3a
entry
(mol %)
ligand
(yield)
1
10
5
XantPhos
XantPhos
dppf
75%b
5%b
55%b
12%c
9%c
2d
3
10
10
10
4
dtpf
Table 1. Preliminary Investigationsa
5
dcpf
a Conditions: Pd(OAc)2 (y mol %), ligand (2y mol %), Et3N
(1.8 equiv), 10 mol % KOAc in THF (0.06 M), reflux, 15 min, then 1a
and 2a were added in the minimum of THF. Refluxed until total
consumption of 2a, determined by TLC. b Determined by 1H NMR of
the crude mixture, using DMF as the internal standard. c Isolated yield.
d Reaction concentration: 0.25 M.
y
3a
Under the best conditions determined for 1a (conditions
A) and 1b (conditions B), the coupling reaction of halo-
pyrazoles with H-phosphonate esters 2aꢀ2e appeared to
be general, as the corresponding C5-phosphonylated com-
pounds were isolated in modest to good yields (11ꢀ86%).
In general, the use of conditions B rather than conditions A
resulted in significantly higher yields in the cross-coupled
products, even with the less reactive 5-bromo-pyrazole 1b.
Not surprisingly, the coupling attempt with diallylphos-
phite 2f led to a complex mixture, and the cross-coupled
product could not be isolated (Table 3, entry 11).
Secondary phosphine oxides 2gꢀj as well as H-phosphi-
nates 2kꢀm can also engage in the cross-coupling with 1a
and 1b to produce the corresponding phosphonylated
derivatives, as illustrated in Table 4. Modest to excellent
yields were obtained (19ꢀ94%), and once again conditions
B were found to be significantly superior to conditions A.
Most notably, we demonstrated that phosphonylidenes
directly substituted by an alkyl chain were suitable sub-
strates for this reaction (Table 4, entries 6ꢀ9 and 12ꢀ13),
despite their lower stability compared to aryl-substituted
phosphonylidenes.10 It is worth noting that, in the case of
entry
1a/2a
solvent
THF
(mol %)
ligand
dppf
(yield)
1
1.0:1.1
1.0:1.1
1.0:1.1
1.0:1.1
1.0:1.1
1.5:1.0
10
10
10
10
2.5
2.5
37%b
30%b
0%
97%c
47%c
80%c
2
toluene/EG
THF
dppf
3
S-Phos
4
THF
XantPhos
XantPhos
XantPhos
5d
6d,e
THF
THF
a Conditions: Pd(OAc)2 (y mol %), ligand (2y mol %), Et3N
(1.3 equiv), 10 mol % KOAc in THF (0.06 M), reflux, 15 min, then 1a
and 2a were added in a minimum of THF. Refluxed until total consump-
tion of the limiting reagent, determined by TLC. b Determined by 1H
NMR ofthe crude mixture, using DMF asthe internal standard. c Isolated
yield. d Reaction concentration: 0.25 M. e 1.8 equiv of Et3N were used.
(7) (a) Huang, Z.; Bravo-Altamirano, K.; Montchamp, J.-L. C. R.
Chim. 2004, 7, 763. (b) Dang, Q.; Zhou, C.; Zou, W.; Hua, Y. Prepara-
tion of pyrimidine derivatives useful as HIF prolyl hydraxylase inhibi-
tors for treatment of anemia. U.S. Patent 055,956, September 19, 2012.
(8) (a) Kalek, M.; Stawinski, J. Organometallics 2007, 26, 5840. (b)
Kalek, M.; Jezowska, M.; Stawinski, J. Adv. Synth. Catal. 2009, 351,
3207.
(9) (a) Deal, E. L.; Petit, C.; Montchamp, J.-L. Org. Lett. 2011, 13,
3270. (b) Berger, O.; Petit, C.; Deal, E. L.; Montchamp, J.-L. Adv. Synth.
Catal. 2013, 355, 1361.
Org. Lett., Vol. 15, No. 21, 2013
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