Please do not adjust margins
Organic & Biomolecular Chemistry
Page 2 of 4
COMMUNICATION
Journal Name
Table 1 Screening of C–H monoarylation of phenyl-1H-pyrazole 1.a
DOI: 10.1039/C9OB00806C
1:2
(eq.)
1:3
2:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
Conv
(%)
99
99
99
90
99
70
99
85
76
42
52
<5
2a
(%)
/
2b
(%)
99 (93)
40
20
20
20
6
20
23
22
16
10
0
Entry
Additive
Solvent
Scheme 2 Solvent- and acidic additive-free conditions for arylation of phenyl-1H-
pyrazole using 4-methoxyphenyl triflate and aryl halide as coupling partners.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
PivOH
PivOH
PivOH
MesCO2H
Ac-Val-OH
KNO3
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
toluene
1,4-dioxane
DMF
60
80
70
80
64
80
62
54
26
42
<5
42
90
aryl halide analogues as coupling partners (Scheme 2), which
resulted in either the formation of diarylation products in bigger
quantities (when X = Br) or a (much) lower general conversion
(when X = Cl, I); the triflate being the best option for selective
coupling. We were also pleased to achieve excellent conversion
and selectivity at g scale, in the coupling of 4-methoxyphenyl
triflate (5 mmol), with 3a isolated pure in 77% yield (0.96 g). We
thus used the solvent-free conditions determined to extend the
scope of azoles selective monoarylation and various
functionalized triflates were reacted with pyrazole or pyridine N-
directing heterocycles (Scheme 3). While the addition of solvent is
unnecessary when liquid reagents are used, in some cases, because
of phase-transfer issues due to the solid state of starting triflate or
azole, we added a minimum of PhCF3 (according to Table 1, entry 7).
The couplings of 4-methoxyphenyl triflate with phenyl-1H-pyrazole
operate with high selectivity in the presence of electron-donating or
electron-withdrawing groups in para-position of the pyrazole, thus
the monoarylated compounds 4a, 5a and 6a were isolated in 70-78%
yield. It might be noted that some amount of the 4-chlorophenyl
pyrazole reacted on itself that can be isolated from 5a (See SI).
Electron-rich triflates are also tolerated, but were found more
difficult to couple: from 4-isopropylphenyl triflate and 3-
methoxyphenyl triflate, monoarylated compounds 7a and 8a were
isolated in 37 and 62% yield, respectively. In the case of 2-naphtyl
triflate, the compound 9a could not be isolated from its diarylated
counterpart –showing the importance of a selectivity achieved above
80%– but 10a achieved from a nitroarylpyrazole and formed
exclusively was isolated in modest 15% yield. Difunctionalized 3,5-
dimethoxyphenyl triflate and 2- methoxyphenyl triflate were
successfully coupled to isolate 11a and 12a in 63% and 59% yield
respectively. While the coupling of 1-naphtyltriflate is achieved
(13a), we observed that the steric congestion expected from
polyaromatics does not specifically promote monoarylation since a
fast second arylation occurs spoiling the global selectivity desired. A
variety of electron-poor triflates, in which a useful functionality is
present,[10] was successfully coupled to phenyl-1H-pyrazole:
trifluoromethylated 14a and fluoroaryl compounds 16a and 18a
were isolated in 51, 30 and 33% yields, respectively. The ketone 15a
was isolated in 52% yield, while cyanoaryltriflate was found mostly
unreactive (17a).
-
-
-
-
-
-
-
-
CPME
HOAc
H2O
50
99
8
9
-
a Conditions: Phenyl-1H-pyrazole (1-3.0 equiv), phenyl triflate (1 equiv), [RuCl2(p-Cym)]2
(2.5 mol%), additive (30 mol%), K2CO3 (2-4.0 equiv), in solvent (0.125 M) at 110°C, 22 h
under argon. 1H NMR yield, isolated under bracket. PivOH: pivalic acid. Ac-Val-OH: N-
Acetyl-L-valine; PhCF3: trifluoromethylbenzene; CPME: methoxycyclopentane.
Ruthenium-catalysed o-C–H activation/functionalization of
pyrazole derivatives efficiently provides diarylated compounds
from 3 equiv of triflates, by using [RuCl2(p-Cym)]2 as precatalyst
in trifluoromethylbenzene (PhCF3) in the presence of
substoichiometric quantities of pivalic acid (30 mol %, Table 1,
entry 1).[3] Accordingly, our screening experiments devoted to
promote monoarylation from aryl triflates started with the
coupling of phenyl-1H-pyrazole
1 (2 equiv) with phenyl triflate
(1 equiv) using thus this latter in default (Table 1, entry 2).
Under these conditions, a mixture 60:40 of 2a:2b mono- and
diarylated compounds was respectively obtained. A significant
amount of diarylated compound (20%) was still formed under a
reduced ratio of triflate over pyrazole (1:3), whatever the acidic
additive used (Table 1, entries 3-5).[5a] The use of KNO3, tested
as additive,[8] only negatively affected the reaction, leading to a
much lower conversion despite a notable selectivity effect
(entry 6). We then explored solvent effects at 0.125 M, using
PhCF3, toluene, 1,4-dioxane, DMF, methoxycyclopentane,
acetic acid and water[6] (entries 7-13, respectively) to conclude
that anhydrous PhCF3 delivers the best conversion with
however a selectivity limited to 80% of monoarylated product.
Since the development of more sustainable synthetic
conditions includes the limitation of additional unnecessary
solvent, we were pleased to observe that under solvent-free
conditions (Table 1, entry 14)[9] a significant improvement in
monoarylation selectivity occurs (90% of 2a), with a total
conversion based on phenyl triflate. This selectivity
improvement was not only attributable to solvent-free
conditions, but was also due to the use of a sulfonate reagent.
Indeed, we achieved under comparable conditions the arylation
of phenyl-1H-pyrazole using of 4-methoxyphenyl triflate or
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins
Abidi, Oumaima
