Palladium-catalyzed Aerobic Benzannulation of Pyrazoles with Alkynes

Full text of DOI:10.1002/bkcs.12175

Communication
DOI: 10.1002/bkcs.12175
BULLETIN OF THE
J. Y. Song et al.
KOREAN CHEMICAL SOCIETY
Palladium-catalyzed Aerobic Benzannulation of Pyrazoles with Alkynes
†,
Jae Yeong Song,† Jin Hyeok Jang,† Shih-Ching Chuang,‡, and Jung Min Joo
*
*
†Department of Chemistry and Chemistry Institute for Functional Materials, Pusan National University,
Busan 46241, Republic of Korea. *E-mail: jmjoo@pusan.ac.kr
‡Department of Applied Chemistry, National Chiao Tung University, Hsinchu 30010, Taiwan.
*E-mail: jscchuang@faculty.nctu.edu.tw
Received November 28, 2020, Accepted December 2, 2020
Keywords: Pyrazole, Alkyne, Oxygen, Palladium, C─H activation
Pd-catalyzed C─H functionalization of heteroarenes has been
established as an important strategy to access heteroarene-
containing extended π-systems.1 In particular, alkynes have
been useful building blocks in the development of ben-
zannulated heteroaromatic systems.2 In these processes, two
new C─C bonds are formed by functionalizing two C─H
bonds of the heteroarene ring. Thus, it is necessary to employ
stoichiometric quantities of oxidants, which are usually
expensive and toxic metal oxidants.3 Alternatively, oxygen
has been used as an environmentally friendly oxidant in Pd-
catalyzed oxidative transformations.4 However, the regenera-
tion of Pd(II) species from Pd(0) species in alkyne annulation
has mostly been dependent on the use of Ag or Cu salts, pre-
sumably because of the inhibitory effect of alkynes strongly
coordinated to palladium.5
We recently reported Pd-catalyzed benzannulation reac-
tions of pyrazoles with internal alkynes, in which Cu
(OAc)2ÁH2O was employed as a stoichiometric oxidant
Scheme 1(A)).6 This method was useful for rapidly for-
ming fluorescent tetraaryl indazoles and was later applied
to the synthesis of fluorescent polymers.7 However, the
use of stoichiometric quantities of metal oxidants limits
their application for synthesizing fluorescent materials
because it is difficult to completely remove residual cop-
per, which is likely to coordinate to the nitrogen heterocy-
cles.8 To eliminate the dependency on metal oxidants, we
developed Pd-catalyzed aerobic C─H annulation of
pyrazoles using oxygen as the sole oxidant Scheme 1(B)).
The difference between the Cu-mediated reactions and this
method and its scope are described.
palladium acetate species throughout the reaction.9 Sol-
vent screening indicated that DMA was the optimal
medium (entries 8–10). Purging with oxygen followed by
heating under a closed cap afforded 2a in a higher yield
than using an oxygen balloon (entry 11). The improve-
ment was more evident with relatively unreactive
pyrazoles (e.g. 2b: 48% vs. 78% yields). The reaction set
up on the benchtop resulted in a slightly reduced yield
compared to those performed under an oxygen atmosphere
(entry 12).
The scope of the aerobic benzannulation method was
studied by varying the pyrazole substituents (Table 2). Var-
ious alkyl groups at the nitrogen atom of the pyrazole ring,
including the SEM protecting group, were tolerated (entries
1–5). However, N-phenyl pyrazole did not undergo a ben-
zannulation reaction, presumably because of the formation
of a palladacycle through the ortho-position of the phenyl
ring (entry 6).10 Both C3-methyl- and trifluoromethyl-
substituted pyrazoles were converted to the corresponding
benzannulation products in good yields (entries 7 and 8).
Diarylacetylenes with electronically different para-substitu-
ents were also coupled with N-methylpyrazole under aero-
bic conditions (entries 9–11). However, reactions with
alkyl alkynes yielded only trace amounts of the desired
products. This suggests a limitation of the aerobic method
compared to the Cu-mediated reaction, which afforded
moderate yield (not shown).6
To further compare the aerobic and Cu-mediated methods,
1:1 annulation reactions of phenylpyrazoles with an alkyne
were performed (Scheme 2). The general reactivity of
pyrazoles indicates that electrophilic substitution occurs at the
C4 position, whereas deprotonation with a strong base favors
the C5 position.11 The aerobic method was superior to the Cu
method for C─H annulation at the pyrazole C5 position, as the
added carboxylate-assisted metalation of the acidic C─H bond
Scheme 2(A)).12 However, these two methods did not produce
significantly different results for the annulation at the C4
position Scheme 2(B)). Interestingly, the least reactive C3
position was functionalized, preferentially generating the
corresponding 1:2 annulation product (4c) over the 1:1 annula-
tion product (4b). This result suggests that after the first
Reaction optimization was performed using N-
methylpyrazole and diphenylacetylene (Table 1). The ini-
tial experiment under an oxygen balloon resulted in low
conversion and was significantly less efficient than the
original protocol using Cu(OAc)2ÁH2O (entries 1 and 2).
However, the addition of AcOH and KOAc increased the
yield (entries 3 and 4). More importantly, the combination
of carboxylic acids and carboxylate salts afforded consis-
tently high yields, among which sodium acetate and acetic
acid proved to be optimal (entries 5–7). Presumably, the
buffer was beneficial to provide a balance among
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Table 2. Substrate scope of C─H annulation.a
Scheme 1. Benzannulation of pyrazoles using oxidants.
Table 1. C─H annulation of N-methylpyrazole.a
Entry Oxidant
Additive
Solvent Yield (%)
1b
Cu
(OAc)2ÁH2O
–
DMA
63
2
3
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
Air
–
DMA
DMA
DMA
DMA
DMA
29
43
64
68
76(75)d
68
AcOH
KOAc
KOAc/AcOH
NaOAc/AcOH
NaOPiv/PivOH DMA
NaOAc/AcOH
NaOAc/AcOH
NaOAc/AcOH
NaOAc/AcOH
NaOAc/AcOH
4
5c
6c
7c
8c
DMSO 21
PhCl
DMF
DMA
DMA
9c
38
64
78(77)d
72
10c
11c,e
12c,f
a Reaction conditions: a pyrazole (0.20 mmol), diarylacetylene
(0.60 mmol), Pd(OAc)2 (0.010 mmol), NaOAc (0.20 mmol), AcOH
(0.20 mmol), DMA (0.20 M), 120ꢀC, 16 h, under O2. Isolated yields.
a Reaction conditions: N-methylpyrazole (0.20 mmol),
diphenylacetylene (0.60 mmol), Pd(OAc)2 (0.010 mmol), additive
(0.40 mmol), solvent (0.20 M), 120ꢀC, 16 h, O2 balloon. Yield
determined by 1H NMR.
b With Cu(OAc)2ÁH2O (0.60 mmol).
c With a carboxylate and carboxylic acid (0.20 mmol, each).
d Isolated yield.
e Purged with O2 and heated under a closed cap.
f Prepared on the benchtop and heated under a closed cap.
addition of the alkyne, the second addition was more facile
than ring closure with the phenyl group. In addition, this repre-
sents the first example of C3,C4-benzannulation of a pyrazole
Scheme 2. 1:1 Annulation of phenylpyrazoles. 1H NMR yield.
Isolated yield in parentheses.
to provide a (2H)-indazole.
were achieved. Complementary to the Pd-catalyzed, Cu-
mediated annulation reaction of pyrazoles, this aerobic
approach will be useful in providing various indazoles
In conclusion, we developed Pd-catalyzed aerobic annu-
lation reactions of pyrazoles. Using oxygen as an oxidant,
1:2 and 1:1 annulation reactions of pyrazoles with alkynes
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Acknowledgments. This work was funded by the National
Research Foundation of Korea (NRF-2019R1A2C1007852
and NRF-2019R1A4A1028007. Supporting Information.
Additional supporting information may be found online in
the Supporting Information section at the end of the article.
The corrected version Supporting Information. Experimental
procedures,compound characterization data, and NMR spec-
tra can be found online in the Supporting Information section
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