Rhodium(iii)-catalyzed unreactive C(sp3)-H alkenylation of N-alkyl-1H-pyrazoles with alkynes

Article abstract of DOI:10.1039/c9ob01531k

The first example of pyrazole-directed rhodium(iii)-catalyzed unreactive C(sp³)-H alkenylation with alkynes has been described, which showed a relatively broad substrate scope with good functional group compatibility. Moreover, we demonstrated that the transitive coordinating center pyrazole could be easily removed under mild conditions.

Full text of DOI:10.1039/c9ob01531k

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DOI: 10.1039/C9OB01531K
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3
Rhodium(III)-Catalyzed Unreactive C(sp )−H Alkenylation of N-
alkyl-1H-pyrazoles with Alkynes
a
a
a
a
a
Tongyu Li,† Chang Liu,† Shaonan Wu, Chen Chen* and Bolin Zhu*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
3
The first example of pyrazole-directed rhodium(III)-catalyzed bond strength of inert C(sp )−H bond. As our continued interest
3
in rhodium(III)-catalyzed C−H functionalization using alkynes as
unreactive C(sp )−H alkenylation with alkynes has been described,
2
6
coupling partners. We set out to develop a rhodium(III)-
which showed relatively broad substrate scope with good
functional group compatibility. Moreover, we demonstrated that
the transitive coordinating center pyrazole could be easily removed
under mild conditions.
3
catalyzed pyrazole-directed unreactive C(sp )−H alkenylation
with alkynes (Scheme 1c). The challenges associated with
realizing this transformation are twofold. First, pyrazole
directed C−H activation reactions are more challenging and the
2
7
related reports are relatively rare, probably due to the weak
Transition-metal-catalyzed C−H activation has emerged as a
powerful strategy to accomplish various direct C−H
functionalization reactions, which has found many applications
in the construction of C−X bonds. Especially, rhodium(III)
catalysts have shown good performance with respect to high
activity, high selectivity, and good functional group tolerance.
In recent years, a variety of rhodium(III)-catalyzed C−H
coordinating ability of pyrazole which hinders C−H
2
8
3
transformations.
Second,
unreactive
C(sp )−H
1
functionalization is one of the most challenging C−H
2
2
9
functionalization processes. Herein we report the first
3
example of rhodium(III)-catalyzed unreactive C(sp )−H
3
alkenylation of N-alkyl-1H-pyrazoles with alkynes.
functionalization has been developed, which enables the
formation of carbon−carbon and carbon−heteroatom bond. A
4
2
a) Previous work: C(sp )-H activation/Alkenylation
variety of coupling partners were conducted in rhodium(III)-
R1
DG
DG
[TM]
Ar
R1
R2
5
catalyzed C−H transformations, such as methyleneoxetanones,
Ar
+
6
7
H
7
-azabenzonorbornadienes,
2,2-difluorovinyl
tosylates,
R2
8
9
10
sulfoxonium ylides, diazo compounds, ketenes, 2-carboxyl
b) Previous work: C(sp3)-H activation/Alkenylation
H
R1
1
1
12
13
14
allylic alcohols, alkenes, alkynes and strained rings.
R1
R2
N
Alkynes are important coupling partners which have been
N
[Rh]
+
widely used in transition-metal-catalyzed C−H activation
R2
systems.1
3,
15
Since Hong’s pioneering work, especially in
16
3
c) This work: Unreactive C(sp )-H activation/Alkenylation:
2
recent years, transition-metal-catalyzed directed C(sp )−H
alkenylation reactions with alkynes have attracted many
researchers’ interest. A variety of transition metals, including
R1
N
N
R1
R2
[Rh]
N
N
+
H
rhodium,17 cobalt, palladium, nickel, rhenium, iridium,
18
19
20
21
22
R2
2
3
24

challenge: weak coordinating ability of pyrazole
ruthenium, and manganese, have been used to catalyze this

unreactive C(sp3)-H activation, alkenylation
2
5
type of reaction (Scheme 1a). In 2015, Wang and co-workers
3
reported a rhodium(III)-catalyzed benzylic C(sp )−H alkenylation Scheme 1. Transition-metal-catalyzed C-H activation/alkenylation
reactions of 8-methylquinolines with alkynes (Scheme 1b).
However, the more challenging alkenylation of unreactive
C(sp )−H bond remains rare so far, probably due to the higher
We initiated our studies with the screening of reaction
conditions by reacting N-(tert-butyl)-1H-pyrazole 1a with
diphenylacetylene 2a under various reaction parameters. The
combination of 1a (1.0 equiv), 2a (2.0 equiv),
3
a. Address here. Tianjin Key Laboratory of Structure and Performance for Functional
Molecules, MOE Key Laboratory of Inorganic-Organic Hybrid Functional Material
Chemistry, College of Chemistry, Tianjin Normal University, Tianjin 300387, P. R.
China. E-mail: hxxycc@tjnu.edu.cn, hxxyzbl@tjnu.edu.cn
Cp*Rh(MeCN)
Ag CO
3
(SbF
6
)
2
(5 mol%), Cu(OAc)
2
·H
2
O (1.0 equiv) and
o
2
3
(0.2 equiv) in DCE at 100 C for 24 h was found to be
†
These authors contributed equally to this work.
optimal, affording 3aa in 81% isolated yield (Table 1, entry 1).
The reaction efficiency significantly decreased in the absence of
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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O rP gl ea na si ce &d Bo i on mo to al e dc juu l sa tr mC ha er mg i ins ts ry
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Journal Name
Ag
yield, respectively (entries 2 and 3). Furthermore, the use of
Cp*RhCl with AgSbF or Cp*Rh(OAc) instead of
Cp*Rh(MeCN) (SbF led to greatly attenuated reactivity, and
aa was not observed in both cases (entries 4 and 5). Decreasing
the reaction temperature to 80 C led to 3aa in 15% yield and
incomplete conversion of 1a (entry 6). The use of MeCN or HFIP
as solvent led to inferior results comparable to those obtained
using DCE (entries 7 and 8). Moreover, changing the loading of
2 3 2 2
CO or Cu(OAc) ·H
View Article Online
O, and 3aa was obtained in 55% and 16% diarylacetylenes containing trimethylsilyl, thienyl, or
naphthalenyl moieties were also compa
D
t
O
ibI:le10.
i
1
n
03
t
9
h
/Cis9Ore
B
a
0
c
15ti
3
o
1
n
K
(3am-3ao), while 3an and 3ao were obtained in moderate
[
]
2 2
6
2
stereoselectivity. It is noteworthy that complete
stereoselectivity was obtained was achieved when 2m was
employed, exclusively giving 3am in 48% yield. Furthermore,
C−H activation of 1a with aliphatic alkynes was also achieved,
affording 3ap-3ar in 66%-76% yields. To our delight, when
unsymmetrical phenyl alkyl alkynes, such as 1-phenylpropyne,
was employed, exclusively giving 3as in 88% yield with the
3
6 2
)
3
o
2
a to 1.2 equiv. renders the reaction less efficient, and 3aa was methyl installed adjacent to the N-(tert-butyl)-1H-pyrazole core.
only obtained in 73% yield (entry 9). When the reaction was Unfortunately, dimethoxyphenyl acetylene 2t and
performed in air instead of under a nitrogen atmosphere, the phenylacetylene 2w failed to undergo this transformation.
Given that N-(tert-butyl)-1H-pyrazole contain three potential
C(sp )−H bond, we were pleased to find that only
monoalkenylation products were obtained without any
multialkenylation products for every case.
result was poorer, which demonstrated that an inert
atmosphere was important for this transformation (entry 10).
3
Table 1. Effects of Reaction Parametersa
Cp*Rh(MeCN)3(SbF6)2 (5 mol%)
Ph
Cu(OAc)2 H O (1.0 equiv)
2
N
N
Ph
Ph
Ag2CO3 (0.2 equiv)
DCE, 100 oC, N2, 24 h
N
N
+
Table 2. Variation of alkynes 2a,b
Ph
optimal conditions
1
a
2a
3aa
Cp*Rh(MeCN)3(SbF6)2 (5 mol%)
R1
Cu(OAc)2 H O (1.0 equiv)
(
1.0 equiv)
(2.0 equiv)
2
N
N
R1
R2
N
Ag2CO3 (0.2 equiv)
DCE, 100 oC, N2, 24 h
N
+
3aab
entry
change to optimal conditions
none
R2
1
2
3
4
81%
55%
16%
NDc
1a
2
3
(
1.0 equiv)
(2.0 equiv)
without Ag
without Cu(OAc)
[Cp*RhCl with AgSbF
Cp*Rh(MeCN) (SbF
Cp*Rh(OAc) Instead of
Cp*Rh(MeCN) (SbF
2 3
CO
Me
Et
tBu
2
2
•H O
N
N
N
N
N
2
]
2
6
Instead of
N
N
N
3
6 2
)
NDc
tBu
5
2
Me
Cl
Et
3
aa, 81%
3ab, 91%
3ac, 88%
3ad, 51%
3
6 2
)
o
6
7
8
9
the reaction was run at 80 C
MeCN as solvent
HFIP as solvent
15%
NDc
NDc
73%
68%
F
Br
CF3
N
N
N
N
N
N
N
N
2a (1.2 equiv)
F
F
Cl
Br
CF3
1
0
2
in air instead of N atmosphere
a
c
b
3ae, 60%
3af, 42%
3ag, 42%
Me
All reactions were carried out in sealed tube and run on 0.2 mmol scale. Isolated yield.
ND = Not detected.
3ah, 20%
Cl
Me
N
N
N
N
With an optimized set of conditions in hand, we then
N
N
N
N
surveyed the substrate scope of alkynes in order to survey the
generality of this reaction. As shown in Table 2, diarylalkynes
Me
F
Me
Cl
3ak, 33%
2
b-2d bearing electron-donating substituents on para-position
3aj, 75%
of aromatic ring reacted effectively, to provide the
3ai(3ai'), 52%, (5:4)
corresponding products (3ab-3ad) in moderate to excellent
S
N
N
Si
N
yields
(51%-91%).
Moreover,
electron-withdrawing
N
N
N
N
N
substituents at para-positions of the phenyl groups, including
fluoro, chloro, bromo and trifluoromethyl, were also tolerated,
and the desired products, 3ae-3ah, were obtained in 20%-60%
yields. Notably, halide substituents (Cl, Br) were found to be
compatible with this reaction, providing an opportunity to
further functionalization. Diarylalkynes with electronically
distinct substituents (methyl and fluoro), 2i, was also tested, a
mixture of products (3ai and 3ai’) were obtained in 52%
combined yields with moderate regioselectivity (5:4).
Substrates bearing methyl or chloro group at the meta-position
on the phenyl ring proceeded smoothly, afforded 3aj and 3ak in
S
3
al, 46%
3am, 48%
3an, 68%, Z:E = 3:2
3ao, 38%, Z:E = 2:1
N
Et
Et
N
Pr
Pr
3aq, 72%
N
Bu
Bu
N
Ph
N
N
N
N
3
ap, 76%
3ar, 66%
3as, 88%
Cl
Cl
MeO
OMe
7
5% and 33% yield, respectively. To our disappointment,
2t
2u
2v
2w
substituents at ortho-position of aromatic ring were found to be
incompatible, likely due to steric congestion (2u and 2v).
Dimethyl substituted diarylacetylene 2l reacted smoothly to
give the corresponding product 3al in 46% yield. Gratifyingly,
a
All reactions were carried out in sealed tube and run on 0.2 mmol scale. b isolated yield.
2
| J. Name., 2012, 00, 1-3
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The scope of N-alkyl-1H-pyrazoles was also investigated. As
shown in Table 3, N-isopropyl-1H-pyrazoles 1b, N-ethyl-1H-
pyrazoles 1c, and N-(sec-butyl)-1H-pyrazoles 1d all selectively
View Article Online
39/C
Cp*RhCl2 DOI: 10
[
.
C
1
p
0
*R
h
Cl
2]29OB01531K
N
E
N
Ph
Ph
N
RhCp*L
Ph
N
Cu(OAc)2 H2O
Ag2CO3
N
Ph
alkenylated
at
the
β-methyl
position,
providing
3aa
N
Cp*RhOAc
X
monoalkenylation product 3ba-3da in moderate to good yields.
1a
HOAc
protonation
complexation
Furthermore, the directing group scope of this reaction was also
N
RhCp*L
Ph
Ph
N
3
investigated, 2-pyridyl directing group also provided C(sp )−H
N
N
RhCp*OAc
RhCp*L
Ph
F
N
N
alkenylation product 3ea in 71% yield. N-(trimethylsilyl)-1H-
H
A
3
pyrazole 1f was not suitable substrate for this C(sp )−H bond
X
Ph
D
3
X
alkenylation process. Probably due to C(sp )−Si bond can be
migratory insertion
C-H activation
easily cleaved. Moreover, N-cyclopentyl-1H-pyrazole 1g did not
give the desired product 3ga, and only the starting material was
recovered. It is probable that methylene units are generally less
reactive in C−H activation.
HOAc
Ph
Ph
N
Ph
Ph
Ph
N
N
Ph
N
RhCp*L
RhCp*L
N
Ph
N
C
coordina
tion
3
aa'
B
L = OAc or Cl
Ph
Table 3. Variation of 1a,b
Scheme 2. Proposed mechanism
Cp*Rh(MeCN)3(SbF6)2 (5 mol%)
Ph
Ph
Cu(OAc)2 H O (1.0 equiv)
Ph
Ph
DG
R2
2
DG
R2
Ag2CO3 (0.2 equiv)
DCE, 100 oC, N2, 24 h
R1
+
In order to highlight the synthetic utility of our strategy,
further chemical transformations of product 3aa were
conducted (Scheme 3). Under basic conditions, transitive
coordinating center pyrazole could be easily removed from
product 3aa in 3 minutes at room temperature, afforded the
R1
1
2a
3
(
1.0 equiv)
(2.0 equiv)
N
N
Ph
N
Ph
Ph
N
Ph
Ph
N
N
2
7a
important conjugated diene product 4 in 87% yield, which is
widely used as monomers in the polymer industry. Moreover,
further functionalization of the olefin moiety was demonstrated,
Ph
ba, 82%
3
3ca, 53%
3da, 22%
N
2
9o
3aa was readily hydrogenated to give 5 in 80% yield.
N
Ph
Ph
N
Ph
N
Ph
N
Si
Ph
ea, 71%
Ph
3ga, NDc
Pd/C
NH4COOH
MeOH, 80 o
3
3fa, NDc
Ph
Ph
7% yield
nBuLi
N
Ph
Ph
N
Ph
Ph
80% yield
N
N
MTBE, RT, 3 mins
C
a
c
All reactions were carried out in sealed tube and run on 0.2 mmol scale. b Isolated yield.
ND = Not detected.
4
5
3aa
8
Scheme 3. Further transformations of 3aa.
The possible mechanism of this reaction was proposed in
Scheme 2. First, the ligand exchange of Cp*RhCl
2
with
Cu(OAc) ·H
2
2
O to form the active species Cp*RhOAc. Then, Conclusions
complexation of N-(tert-butyl)-1H-pyrazole 1a with Cp*RhOAc
using the pyrazole group forms a Rh(III) complex A, followed by
In conclusion, this communication describes a rhodium(III)-
catalyzed unreactive C(sp )−H alkenylation of N-alkyl-1H-
pyrazoles with alkynes, which exhibits entire monoselectivity
and relatively broad substrate scope. Pyrazole is used as a
directing group to promote C(sp )−H alkenylation, which could
3
3
C(sp )−H activation to form five-membered rhodium complex B.
Subsequently, alkyne 2a coordinates with rhodium and follows
3
1
, 2-insertion into the C(sp )−Rh bond to give the seven-
3
membered rhodacycle D. Finally, intermediate
D was
protonated by HOAc to give the mono C−H alkenylation product be easily removed under basic conditions at room temperature
3
aa and regenerate the rhodium species to finish a catalytic in short reaction time. Further studies on pyrazole-directed
cycle. Probably due to the alkene moiety and pyrazole ring rhodium(III)-catalyzed unreactive C(sp )−H functionalization is
3
coordinate with rhodium simultaneously, intermediate E could
be formed prior to intermediate F, which suppress the
generation of multiple alkenylation product 3aa’. Moreover,
steric hindrance effect might be another reason for entire
monoselectivity.
currently underway in our laboratory.
We gratefully acknowledge National Natural Science
Foundation of China (21572160), the Science&Technology
Development Fund of Tianjin Education Commission for Higher
Education (2018KJ159) and the Program for Innovative
Research Team in University of Tianjin (TD13-5074) for
generous financial support.
Conflicts of interest
There are no conflicts to declare.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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0 X. Yang, S. Liu, S. Yu, L. Kong, Y. Lan and X. Li, OrgVi.ewLeAtrttic.,le2O0n1lin8e,
Notes and references
2
0, 2698.
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