Gold(i)- and rhodium(iii)-catalyzed formal regiodivergent C-H alkynylation of 1-arylpyrazolones

Article abstract of DOI:10.1039/c8ob00585k

Formal regiodivergent C-H alkynylation of 1-aryl-5-pyrazolones has been realized under the catalysis of Rh(iii) and Au(i) complexes by using a hypervalent iodine reagent as the alkyne source. Mechanistic studies indicate that the regioselectivity is ascribed to not only the choice of the catalyst but also the nature of the substrate. The substrate scope and functional group compatibility have been fully examined.

Full text of DOI:10.1039/c8ob00585k

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
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Gold(I)- and Rhodium(III)- Catalyzed Formal Regiodivergent C−H
Alkynylation of 1-arylpyrazolones
Received 00th January 20xx,
Accepted 00th January 20xx
Xueli Wang,a, b Xingwei Li,b Yao Zhang
*
a and Lixin Xia
a
*
DOI: 10.1039/x0xx00000x
www.rsc.org/
Formal regiodivergent C−H alkynylaꢀon of 1-aryl-5-pyrazolones
has been realized under the catalysis of Rh(III) and Au(I)
complexes by using a hypervalent iodine reagent as the alkyne
source. The mechanistic studies indicate that the regioselectivity is
ascribed to not only the choice of catalyst but also the nature of
substrate. The substrate scope and functional group compatibility
have been fully examined.
Previous work
TIPS
H
TIPS-EBX
cat. Au (I)
TIPS-EBX
cat. Pd (II)
TIPS
H
(1)
(2)
N
N
R
N
R
R
O
N
O
R
R
O
H
TIPS-EBX
cat. Au(I)
TIPS-EBX
cat. Rh(III)
R
H
N
N
Pyrazolones and their derivatives are important structural moieties
that are widely used in the synthesis of pharmaceuticals,1
biologically active compounds,2 and natural products.3 Therefore,
enormous efforts have been devoted to effective synthesis of
pyrazolones.4 In the past several decades, transition metal-
catalyzed C−H acꢀvaꢀon has emerged as an atom- and step-
economic, environmental friendly, and benign alternative to the
classical synthetic methods.5 On the other hand, alkynylation of
arenes represents an important method to access arylalkynes.6
Although it is highly desirable to realize oxidative alkynylation of
arenes using 1-alkynes owing to the high atom-economy and ready
availability of such alkynes, this has only been sporadically realized
R = alkyl/aryl
R = 2-pyridyl
TIPS
TIPS
This work
TIPS
H
TIPS-EBX
cat. Au(I)
TIPS-EBX
cat. Rh(III)
N
N
N
O
R
O
(3)
O
N
R
N
N
TIPS
H
R = Alkyl
R = H
Scheme 1. Metal-Catalyzed Site-Selective Alkynylation
due to competitive homocoupling of terminal alkynes.7 alkynylation of arenes by resorting to C-H activation strategy using
stable Rh, Co, Ru and Ir catalysts.10 In 2014, Yu group realized an
Consequently, alkynylation using
a
versatile electrophilic
effective alkynylation of ethers using this alkynylating reagent
through radical C(sp3)–H bond functionalization under metal-free
reaction conditions.11 In addition, in 2016 Waser also reported the
thrifty oxyalkynylation of diazo compounds under mild conditions
using an inexpensive copper catalyst.12
alkynylating reagent may serve to solve this challenge. Thus, the
silylethynyl-1,2-benziodoxol-3(1H)-one (silyl-EBX) which was
introduced by Zhdankin has recently risen to prominence as an
efficient alkynylating reagent.8 In particular, Waser and coworkers
demonstrated
functionalization
of
various
electron-rich
heterocycles such as indoles, pyrroles, and furans using TIPS-EBX
with Au(I) or Pd(II) being a catalyst under relatively mild synthetic
conditions (Scheme 1, eq 1).9 Quite recently, Loh, our group,
Glorius, and others have significantly broadened the scope of C-H
Despite the impressive progress, the selective alkynylation of a
specific C−H bond remains a major challenge. Ideally, the selecꢀvity
is controllable by way of different catalytic conditions. In this
regard, the ortho- and para-selective alkynylation of anilines using
AuCl as a catalyst and TIPS-EBX as an electrophilic alkynylation
equivalent has been accomplished. This selectivity was dictated by a
mechanism containing a directing effect of the nitrogen functional
group.13 The C2- or C3-selective alkynylation of indoles and other
heterocycles has also been achieved under different reaction
conditions.14 In 2016, our group and Patil have independently
reported site-selective alkynylation of 2-pyridones and
a.College of Chemistry, Liaoning University, Shenyang 110036, China.
b.Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023,
China. E-mail: lixinxia@lnu.edu.cn, zhangyao@lnu.edu.cn.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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isoquinolones under complementary Au(I) and Rh(III) catalyzed
conditions using this alkynylating reagent (Scheme 1, eq 2).15 With
our ongoing interest
Table 1. Optimization studies.a
entry catalyst
additive
T (oC)
yieldb (%)
1
2
3c
4
5
6
7
8
9
[RhCp*Cl2]2/AgSbF6
-
-
-
-
80
80
80
50
100
80
80
80
80
65
43
63
60
50
73
< 5
50
42
[IrCp*Cl2]2/AgSbF6
[RhCp*(MeCN)3](SbF6)2
[RhCp*Cl2]2/AgSbF6
[RhCp*Cl2]2/AgSbF6
[RhCp*Cl2]2/AgSbF6
[RhCp*Cl2]2/AgSbF6
[RhCp*Cl2]2/AgSbF6
[RhCp*Cl2]2/AgSbF6
-
aReaction conditions: 2-aryl-3-pyrazolone (0.20 mmol), silyl-EBX
Na2CO3
Pyridine
Li2CO3
Zn(OTf)2
(0.24 mmol), [RhCp*Cl2]2 (4 mol %), AgSbF6(16 mol %), Na2CO3 (0.3
mmol), DCE (2.0 mL), 80 °C,12 h, sealed tube under nitrogen.
bIsolated yield after column chromatography.
aReaction conditions: 1a (0.20 mmol), 2a (0.24 mmol), catalyst (4
mol %), AgSbF6(16 mol %), additive (1.5 equiv) in a solvent (2.0 mL)
at 50-100 oC under N2 for 12 h. bIsolated yield after column
chromatography. c[RhCp*(MeCN)3](SbF6)2 (8 mol %) was used as a
catalyst.
Scheme 2. Rh(III)-Catalyzed C-H Activation Assisted by Pyrazolonea,b
With the optimized conditions in hand, we next examined the
scope and generality of this catalyst system (Scheme 2). 3-Methyl-1-
aryl-1H-pyrazol-5-one bearing both electron-donating and
-
in site-selective C–H bond functionalization and the importance of
pyrazolones in organic synthesis, we herein report Au(I)- and Rh(III)-
catalyzed formal regiodivergent C−H alkynylaꢀon of pyrazolones
(Scheme 1, eq 3).
withdrawing groups at the para position reacted smoothly to afford
the desired product in moderate to good yields (3b-3i), although
introduction of an EWG tends to attenuate the yield (3h and 3i). It is
noteworthy that easily functionalizable halogen groups were well
tolerated (3c-3e). Introduction of an ortho-fluoro group were also
tolerated, delivering 3j in 35% yield. The meta -Me and -OMe
groups were also compatible, and the coupling occurred at the less
We reasoned that 1-phenyl-1H-pyrazol-5-one contains
a
phenyl group that is prone to C-H activation when assisted by the
pyrazolone nitrogen coordination.16 In addition, this heterocycle is
also intrinsically reactive in
a
number of electrophilic
functionalization reactions.17 We initiated our studies by optimizing
the reaction conditions of the coupling of 3-methyl-1-phenyl-1H-
pyrazol-5-one (1a) with TIPS-EBX (2a), and the results were
summarized in Table 1. As for the catalyst, Rh(III) catalysts were our
first choice since they have proven highly efficient in catalytic C–H
alkynylation.10e, 15 When [RhCp*Cl2]2 was employed as a catalyst and
AgSbF6 as a halide abstractor, the desired product 3a was obtained
in 65% yield at 80 oC (entry 1). Cationic rhodium catalyst
[RhCp*(MeCN)3](SbF6)2 and the [IrCp*Cl2]2/AgSbF6 catalyst led to
slightly lower yields (entries 2 and 3). Effects of the reaction
o
temperature were then examined, and couplings at 50 °C or 100 C
both gave inferior results (entry 4−5). We also tested the effect of
acid and base additives. To our delight, the isolated yield of 3a was
improved to 73% in the presence of Na2CO3 (entry 6). Lewis acid
additives, such as Zn(OTf)2, led to lower efficiency (entry 9), which
stands in contrast to our previous studies.10e, 15b
aReaction conditions: 2-aryl-3-pyrazolone (0.20 mmol), TIPS-EBX
(0.24mmol), AuCl (5 mol %), pyridine (0.24 mmol), nBu2O (2.0 mL),
80 °C, 14 h, under nitrogen. bIsolated yield after column
chromatography.
2 | J. Name., 2018, 00, 1-3
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Scheme 3. Au-Catalyzed C4-Alkynylation of N-Alkyl Pyrazolonea,b
coupling reaction. Derivatives of 2,3-dimethyl-1-aryl-5-pyrazolone
bearing various electron-donating and electro-withdrawing
substituents, such as halogen (5c-5e,5j), methyl (5b, 5h), and CN
(5g) groups, at the para or meta position of the aryl ring all
underwent smooth coupling without significant variation of the
isolated yield (61%-82%). In contrast, the aryl ring with a para or
ortho OMe (5f, 5i) group gave rather low conversion, indicating that
a para electron-donating group lowered the reactivity. Besides, N-
ethyl and -propyl groups were also compatible (5k-5o), although
slightly lower yields were isolated due to steric hindrance.
N
[RhCp*Cl2
AgSbF6 (16 mol %)
] (4 mol %)
2
O
N
N
O
CD3COOD
(20 equiv)
N
a)
+
D/H
H/D
58% D
DCE, 80 oC, N2, 12 h
H
1a
TIPS-EBX
N
N
N
N
O
[RhCp*Cl2
]2 (4 mol %)
O
O
N
R
TIPS
N
AgSbF6 (16 mol %)
b)
+
Na2CO3 (1.5 equiv.)
DCE, 80 oC, N2, 12 h
CF3
CH3
A series of experiments have been conducted to investigate
the reaction mechanism (Scheme 4). H/D exchange experiments
has been performed between 1a and CD3COOD under the Rh(III)-
catalyzed conditions. Deuteration was detected at both ortho
positions of the benzene ring, indicating reversibility of the C−H
cleavage in the absence of any coupling partner (Scheme 4a). In
1i
1b
3b
3i
(R = Me): (R = CF3) = 1.2:1
N
N
[RhCp*Cl2]2 (4 mol %)
O
N
O
AgSbF6 (16 mol %)
N
TIPS
+
TIPS-EBX
c)
Na2CO3 (1.5 equiv.)
DCE, 25 oC, N2, 10 min
1a
KIE = 1.5:1
addition,
a competition reaction using TIPS-EBX and two
[RhCp*Cl2]2 (4 mol %)
AgSbF6 (16 mol %)
N
N
N
O
O
electronically differentiated compounds 1b and 1i afforded the
corresponding products 3b and 3i in a ratio of 1.2:1, suggesting that
an electron-rich arene exhibited slightly higher reactivity (Scheme
4b). The measurement of kinetic isotope effect (KIE) has been
performed to further understand the C-H activation process. A
relatively small value KIE = 1.5:1 was obtained from two parallel
reactions (Scheme 4c), which suggested that the C−H bond cleavage
was not involved in the turnover-limiting step. On the basis of
previous literature and our experimental studies,10e we proposed a
plausible mechanism involving the formation of rhodacycles
(Scheme 4d). Initially, formation of [Cp*RhCl2] via ligand
substitution and chelation-assisted C−H acꢀvaꢀon of 1a produces a
rhodacycle intermediate A, followed by oxidative addition of the C−I
bond of silyl-EBX to generate a Rh(V) alkynyl benzoate intermediate
B. Subsequent C−C reducꢀve eliminaꢀon gives the alkynylated
product 3a along with a Rh(III) benzoate intermediate C. Finally,
protonolysis of C regenerates the Rh(III) catalyst and releases the 2-
iodobenzoate coproduct.10e
N
TIPS
TIPS-EBX
+
Na2CO3 (1.5 equiv.)
DCE, 25 oC, N2, 10 min
d5
1a-d5
d)
Scheme 4. Mechanistic Consideration of Rh(III)-Catalyzed
Alkynylation
On the other hand, the H/D exchange (D 50%) of 4a was
observed at the C(4) position of pyrazolone moiety when the
reaction was carried out under the Au(I)-catalyzed conditions in
Scheme 3 by using CD3COOD as a deuterium source (Figure S1 in
the Supporting Information). It surely suggests the relevancy of
electrophilicity at this position. Therefore, a plausible mechanism,
which involves an Au(I)/Au(III) cycle, has been proposed as a
working hypothesis (Scheme 5). The oxidative addition of Au(I) with
R-EBX leads to the formation of Au(III) alkynyl intermediate, which
hindered ortho position (3k and 3l). However, the coupling of a
meta bromo- or fluoro-substituted arene gave mixture of
a
regioisomeric products in good to high combined yields and in
2−5:1 regioselecꢀvity (3m-3n). The alkynylating reagent was
t
successfully extended to TBDPS-EBX, TES-EBX and Bu-EBX (3o-3t).
As has been previously observed,15b TMS- and Ph-EBX either failed
to participate in this reaction or reacted in poor efficiency (3u and
3v), likely due to lack of steric protection.10e, 15b
We reasoned that when the N-directing effect is overruled by
electronic effect of the heterocycle, the alkynylation may be
achieved at the most electron-rich C4 position of the heterocycle
via an electrophilic alkynylation pathway. The alkynylation of 2,3-
dimethyl-1-aryl-5-pyrazolone (4) with TIPS-EBX (2a) was then
explored using a gold catalyst. Indeed, after extensive screening,
the coupling of 2,3-dimethyl-1-aryl-5-pyrazolone with TIPS-EBX
proceeded smoothly at 80 °C, and the desired product 5a was
obtained in 71% yield when catalyzed by AuCl (Scheme 3). The C4-
selectivity was fully confirmed by 1H and 13C NMR analyses of the
product.18 We then moved on to investigate the scope of this
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In summary, we have developed a formal regiodivergent
C−H alkynylaꢀon of different 2-aryl-3-pyrazolones catalyzed by
rhodium and gold catalysts. The regioselectivity depends on
the nature of the substrate, as well as the choice of the
transition metal catalyst. Under the catalysis of Rh(III), the
alkynylation occurred at the aryl ring by the assistance of an N-
chelation group. The Au-catalyzed C4-selective alkynylation of
pyrazolones proceeded via an electrophilic pathway. Future
studies are directed to regiodivergent functionalization of
other heteroarenes via metal-catalyzed C−H acꢀvaꢀon.
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The authors declare no competing financial interest.
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Acknowledgements
The NSFC (grant Nos. 21502082, 21671089 and 21525208), the
Shenyang Natural Science Foundation of China (F16-103-4-00), and
Scientific Research Fund of Liaoning Province (LT2017010,
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DOI: 10.1039/C8OB00585K
Journal Name
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A transitionꢀmetalꢀcatalyzed formal regiodivergent C−H alkynylation of 1ꢀarylꢀ5ꢀpyrazolones is
described.