Pd/Cu-catalyzed dual C-H bond carbonylation towards the synthesis of fluorazones

Article abstract of DOI:10.1039/c7cc01707c

Pd/Cu catalyzed oxidative dual C-H bond activation/carbonylation still remains a great challenge due to the generation of by-products via C-C bond formation. Herein we developed a straightforward Pd/Cu-catalyzed oxidative dual C-H bond carbonylation process to access biologically and pharmaceutically important fluorazones from easily available N-aryl pyrroles and CO. A wide range of functional groups were well tolerated in this transformation, and O₂ could be utilized as the only terminal oxidant to promote the oxidative carbonylation process.

Full text of DOI:10.1039/c7cc01707c

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Pd/Cu-Catalyzed Dual C-H Bond Carbonylation towards the
Synthesis of Fluorazones
Fan Liaoa, Renyi Shi*, b, Yuchen Shab, Jianhui Xiaa, Weilin Liao*, a and Aiwen Lei*, a, b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
cytostatic mytomycin derivatives.7 In view of the significance of
Pd/Cu catalyzed oxidaive dual C-H bond activation/carbonylation
still remains a great challenge due to the generation of by-
fluorazones in both pharmaceutical and biology, it is imperious for
us to find a simple and convenient approach to synthesize flurazone.
To the best of our knowledge, previous strategies for the synthesis of
flurazone suffer from some disadvantages, including usage of
complicated substrates that need to be pre-synthesized, harsh
reaction conditions and multi-step process (Scheme 1).8 On the base
of design above, we introduce the first Pd/Cu-catalyzed double C-H
functionalization/carbonylation strategy to construct fluorazones
from easily prepared N-arylpyrroles.
products via C-C bond formation. Herein we developed
a
straightforward Pd/Cu-catalyzed oxidative dual C-H bonds
carbonylation to access biologically and pharmaceutically
important fluorazone from easily available N-aryl pyrroles and CO.
A wide range of functional groups were well tolerated in this
transformation, and O2 could be utilized as the only terminal
oxidant to promote the oxidative carbonylation process.
O
N
CO is deemed to be a kind of cheap and easily available industry
feedstock. Carbonylation utilizing CO as the C1 linker represents
one of the most significant approaches to synthesize various
important carbonyl derivatives such as acids, amides, esters and
ketones.1 Recently the rapid development of transition-metal-
catalyzed C-H activation reactions2 has offered a new opportunity
for traditional carbonylation to meet the concept of “green chemistry”
and “atomic economy”.3 More and more attentions have been paid to
the Pd-catalyzed oxidative C-H carbonylation in the past years.4
However, most of the works focused on the synthesis of acids, esters
and amides utilizing water, alcohols and amines as the nucleophiles.
The oxidative carbonylation between two C-H bonds that has great
potential in constructing ketone derivatives still remains an
outstanding challenge due to 1. the difficulty in Pd-catalyzed dual C-
H bond activation; 2. the generation of by-products via non-CO-
insertion C-C bond formation; 3. the generation of other
carbonylative by-products from different nucleophiles. In 2012, our
group reported the first Pd-catalyzed dual C-H bond
activation/carbonylation to access xanthone derivatives.5 Inspired by
this work, we try to apply this dual C-H bonds
activation/carbonylation protocol to synthesize various fused
heterocycles.
HO/Cl
H
l
C 4
C
l
n
N
N
S
ph
Li
Li
HO
N
EtOCONMe2
MnO2
N
N
O
[
O
P
C
d
/
]
]
I
d
P
[
Br
H
N
N
O
N
N
CO
+
H
H
O
Scheme 1. Previous works to access fluorazones and our design
We chose 1-(3-methoxyphenyl)-1H-pyrrole 1a as the substrate to
investigate the reaction conditions. We found the highest yield was
obtained with the combination of PdCl2 (5 mol%) and
Cu(OAc)2•H2O (20 mol%) in a mixture of toluene and DMSO
(3.0/0.3 mL) under the atmosphere of CO/O2(the ratio is 7/1) at 100
oC for 24 h . Both palladium catalysts and copper salts played a very
crucial role in the reaction because no product was detected without
either PdCl2 or Cu(OAc)2•H2O (entries 8 and 9). After testing
different Pd catalysts, PdCl2 was proved to be the most efficient
catalyst (entries 2 and 3). The experiment results showed that the
yield decreased obviously when toluene and DMSO replaced the
mixed solvents. (entries 4 and 5). No product was obtained at all
when Cu(OAc)2•H2O was replaced by CuCl2•H2O (entry 6). If 2 eq.
of Cu(OAc)2•H2O was used as the oxidant instead of
Cu(OAc)2•H2O/O2, 16% yield could be achieved (entry 7). Other
Pyrrolo[1, 2-a]indol-9-ones(fluorazone) are recognized as
a
particularly useful class of compounds in medicinal chemistry. They
exhibit extraordinary biological and pharmaceutical properties (e.g.
psychostimulant activity, cytotoxic and photosensitizing properties).6
Furthermore, fluorazone also acts as the basic framework of
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common oxidant like BQ, AgCO3 and MnO2 were tested, no desired
With the optimized conditions in hand, the carbonylation of
product was detected (see SI). It is worth noting that the yield would various N-arylpyrroles were tested (Scheme 2). The reactions with
drop slightly after adding dppf which indicates that ligand would electron-rich groups gave high yields (2a, 2b and 2c). The desire
suppress the coordination of CO to Pd catalyst (entry 10). After product could be obtained in moderate yield by using N-phenyl
testing the different atmosphere, CO to O2 (1/7) could not be suitable pyrrole (2d). The site of methyl influenced this reaction partly: 58%
for the high yield of this transformation (entry 11, more details see yield was obtained in the presence of methyl substituted on the meta-
SI).
position while 34% yield on the para-position (2e and 2f). To our
delight, morpholine ring which widely exists in drugs also could be
compatible in this reaction (2g). Substrate substituted with halogens
including F and Cl furnished the corresponding carbonylation
products in moderate yields (2h and 2i), which could provide useful
handles for further synthetic transformations. On the other hand,
strong electron-withdrawing group lowered the yield obviously (2j).
Moderate yield was obtained utilizing 1-([1, 1'-biphenyl]-4-yl)-1H-
pyrrole as the reactant. Interestingly, 1-(benzo[d][1,3]dioxol-5-yl)-
1H-pyrrole and 1-(2,3-dihydrobenzo[b][1, 4]dioxin-6-yl)-1H-pyrrole
(2l and 2m) were well tolerated under the standard conditions.
Notably, a high selectivity profile was obtained in all derivatives
except 2l. In addition, the reaction could be applied to the synthesis
Table 1. Pd-Catalyzed Dual C-H Bond Carbonylation of 1a: effects of reaction
parameters.[a]
Entry Variation from"standard conditions"
Yield%
1
None
75
53
11
0
2
Pd(OAc)2 instead of PdCl2
of methyl 3-(1H-pyrrol-1-yl)thiophene-2-carboxylate
(
2n).
3
PdCl2(PPh3)2 instead of PdCl2
3.0 mL Toluene instead of mixed solvent
3.0 mL DMSO instead of mixed solvent
CuCl2•H2O instead of Cu(OAc)2•H2O
Substituents on the pyrrole ring also could be tolerated to access the
desired products (2o and 2p).
4
5
7
In order to get some insights into the mechanism of the reaction,
several control experiments were carried out under the standard
conditions. When we used methanol as the nucleophile in the model
reaction, 37% methyl 1-phenyl-pyrrole-2-carboxylate was obtained,
indicating that the initiation of the reaction is the C-H activation at
the 2-position of pyrrole (Scheme 3, Eq. 1). While kH/kD= 2.7 was
observed for the intermolecular KIE experiment, suggesting that the
phenyl C-H bond cleavage might be involved in the rate-determining
step (Eq. 2).9
6
0
7
2 eq. Cu(OAc)2•H2O instead of Cu(OAc)2•H2O/O2 16
8
No Cu(OAc)2•H2O
No PdCl2
0
9
0
10
11
Use 5 mol% dppf as ligand
CO/O2 =1/7
55
34
[a] Standard reaction conditions : 1a (0.2 mmol), PdCl2 (5 mol%), Cu(OAc)2 •H2O
(20 mol%), CO/O2 =7/1, toluene/DMSO =3.0/0.3, 100 oC, 24 h. The yields were
determined by GC, and were calibrated using biphenyl as the internal standard.
Scheme 3. Preliminary mechanistic studies.
Scheme 2. Pd-Catalyzed Dual C-H Bond Carbonylation with
various aryl pyrroles 1. Standard reaction conditions: 1 (0.2 mmol),
PdCl2 (5 mol%), Cu(OAc)2•H2O (20 mol%), CO/O2
= 7/1,
toluene/DMSO = 3.0/0.3 mL, 100 oC, 24 h. Isolated yield
2 | J. Name., 2012, 00, 1-3
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Scheme 4. Proposed mechanism
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Based on the previous studies,10 we proposed
a
plausible
mechanism
for
the
Pd-catalyzed
double C-H
functionalization/carbonylation. As show in the Scheme 4, the
reaction was initiated by the Pd-catalyzed C-H activation at the 2-
position of 1a to generate intermediate I. Then CO insertion
occurred to generate intermediate II followed by the intramolecular
phenyl C-H bond activation to achieve pallacycle III. Lastly, the
reductive elimination of III gave the final product and Pd(0) species
which was re-oxidized by O2 with the assistance of the copper co-
catalyst to regenerate Pd(II) complex.
Mo, M. C. Young and G. Dong, Chem. Soc. Rev., 2015, 44
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In summary, we have developed the Pd/Cu-catalyzed double C-H
bonds functionalization/carbonylation of N-aryl pyrroles. This
transformation provides an effective and straightforward protocol
towards the synthesis of biologically and synthetically useful
fluorazones from widely available substrates. The protocol is
distinguished for its simple catalytic system and its compatibility of
diverse functional groups. Therefore, we anticipate that this work
will contribute substantially to the development of Pd-catalyzed dual
C-H bonds activation/ carbonylation.
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Acknowledgement
This work was supported by the National Natural Science
Foundation of China (21390400, 21520102003, 21272180,
21302148), the Hubei Province Natural Science Foundation of China
(2013CFA081), the Research Fund for the Doctoral Program of
Higher Education of China (20120141130002), and the Ministry of
Science and Technology of China (2012YQ120060). The Program
of Introducing Talents of Discipline to Universities of China (111
Program) is also appreciated.
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