PdII-Catalyzed Oxidative Tandem aza-Wacker/Heck Cyclization for the Construction of Fused 5,6-Bicyclic N,O-Heterocycles

Article abstract of DOI:10.1002/asia.201800646

A Pd^II-catalyzed oxidative tandem cyclization was developed for the construction of fused 5,6-bicyclic N, O-heterocycles. This reaction was enabled by the combined use of a 3-methylpyridine ligand and pentafluorobenzoic acid additive. A range of heterocyclic products with different substituents could be prepared in moderate to good yields via this methodology. Several transformations, including a scaled-up preparation of product 2 a, were also carried out showing the good applicability of our methodology.

Full text of DOI:10.1002/asia.201800646

CHEMISTRY
AN ASIAN JOURNAL
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Accepted Article
Title: Pd(II)-Catalyzed Oxidative Tandem aza-Wacker/Heck Cyclization
for the Construction of Fused 5,6-Bicyclic N,O-Heterocycles
Authors: Chenghao Ye, Xuezhen Kou, Jingzhao Xia, Guoqiang Yang,
Li Kong, Quhao Wei, and Wanbin Zhang
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Pd(II)-Catalyzed Oxidative Tandem aza-Wacker/Heck Cyclization
for the Construction of Fused 5,6-Bicyclic N,O-Heterocycles
Chenghao Ye,[a] Xuezhen Kou,[a] Jingzhao Xia,[a] Guoqiang Yang,[a] Li Kong,*[b] Quhao Wei,*[b] and
Wanbin Zhang*[a]
Abstract:
A
Pd(II)-catalyzed oxidative tandem cyclization was
tandem cyclization.[5] Yang developed two catalytic systems for
aza-Wacker/Heck tandem cyclizations, with construction of chiral
fused 5,5-bicyclic N-heterocycles, a significant achievement in the
area of asymmetric aza-Wacker-type reactions.(Scheme 1, a)[6]
Sasai has also developed a similar reaction employing his SPRIX
ligand.[7] However, these reactions remain limited to the
construction of five-membered rings, possibly due to the
nucleopalladation step entropically favoring the formation of
smaller ring systems. Very recently, Gong divulged a Pd(II)-
catalyzed aza-Wacker/Heck tandem cyclization for the generation
of fused 6,5-bicyclic N-heterocycles but only moderate yields
were obtained and high catalyst loadings were required (Scheme
1, b). [8] In a continuation of our research concerning Wacker-type
reactions,[10] herein, we report a Pd(II)-catalyzed oxidative tandem
cyclization for the preparation of 5,6-bicyclic N,O-heterocycles.
The aforementioned reports utilize the amide group of
acrylamides as the nitrogen-nucleophile and the electron-
deficient C=C bond of the acrylamide as the second olefin-
electrophile. In this study, we employ N-alkoxy amides as a
nitrogen-nucleophile and the electron-rich C=C bond as the
second olefin-electrophile.[11]
developed for the construction of fused 5,6-bicyclic N, O-heterocycles.
This reaction was enabled by the combined use of a 3-methylpyridine
ligand and pentafluorobenzoic acid additive. A range of heterocyclic
products with different substituents could be prepared in moderate to
good yields via this methodology. Several transformations, including
a scaled up preparation of product 2a, were also carried out showing
the good applicability of our methodology.
Nitrogen-containing heterocycles are basic skeletons of natural
and pharmaceutical products, and also important building blocks
for organic synthesis, thus the development of methods for the
synthesis of such compounds are at the center of organic
chemistry.[1] The preparation of fused nitrogen-containing
heterocycles is one of the important areas of this field; the
complexity and rigidity of fused nitrogen-containing heterocycles
make them good candidates for drug backbones.[2] Transition-
metal-catalyzed tandem cyclizations are recognized as a class of
efficient reactions for the construction of polycyclic compounds,
including heterocycles.[3] Oxidative tandem cyclizations possess
several advantages: They are simple to operate, are not air
sensitive, and exhibit good compatibility with various halogen-
substituents. However, transition-metal-catalyzed oxidative
tandem cyclizations have not been widely studied, possibly due
to the catalytic efficiency being highly dependent on the structure
of the substrates.[4-8]
The development of Wacker-type reactions has been a long-
standing research topic for organic chemists.[9] From
a
mechanistic aspect, after nucleopalladation of the olefin bond, a
carbon-bonded Pd(II) intermediate is generated, which can
partake in subsequent reaction steps. This is an ideal reaction for
triggering oxidative tandem cyclizations for the construction of
polycyclic heterocycles. Sasai reported the first oxy-Wacker/Heck
[a]
C. Ye, X. Kou, Dr. G. Yang, Prof. Dr. W. Zhang
Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs
School of Chemistry and Chemical Engineering
Shanghai Jiao Tong University,
800 Dongchuan Road, Shanghai 200240, China
E-mail: wanbin@sjtu.edu.cn
Homepage: http://wanbin.sjtu.edu.cn
[b]
L. Kong, Q. Wei
6th People's Hospital South Campus
Shanghai Jiao Tong University,
Scheme 1. Pd(II)-catalyzed oxidative tandem cyclizations for construction of
polycyclic N-heterocycles.
6600 Nanfeng Hwy, Shanghai 200240, China
E-mail: qushuikongli@163.com; weiqh191@126.com
Previously, we realized a Pd(II)-catalyzed aerobic aza-Wacker-
type reaction and a Pd(II)-catalzyed aerobic aminoxygenation of
olefins for the construction of isoindolinones.[10f,12] We next turned
our attention to the construction of polycyclic compounds bearing
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Scheme 2. Ligand Screening.
an isoindolinone skeleton. We designed substrate 1, which
contains an O-allyl group, to trap the carbon-palladation
intermediate thus allowing for the construction of an additional 6-
membered ring. After preliminary screening of the reaction
conditions (See SI), we found that only BQ was able to promote
the reaction as an oxidant. Since this type of substrate is unstable
under basic oxidative conditions, we propose that an acid additive
may inhibit the decompose of substrate, thus increasing the
yield.[13] In addition, acid additive may also supply counterion to
exchange with OAc, thus affecting the catalytic ability of Pd(II)
center. It was found that 2-oxo-2-phenylacetic acid was able to
increase the yield from 28% to 40% in THF solvent. Solvent
screening showed that 1,4-dioxane was the best solvent for this
cyclization reaction. Different ligands were then screened to
obtain a better result (Scheme 2). The bidentate ligands 2,2’-
bispyridine and 1,10-phenanthroline provided little activity,
whereas the monodentate ligands pyridine and quinoline
promoted the reaction, giving the desired cyclized product 2a in
46% and 43% yields, respectively. With these promising
preliminary results in hand, we decided to screen a series of
substituted-pyridine ligands. Pyridine bearing a 2-methyl group
led to an improvement in the catalytic activity; however,
substituents such as Cl, CN, and OMe at the 2-position mostly
inhibited the reaction. Interestingly, pyridine ligands bearing these
substituents at the 3- or 4- positions successfully catalyzed the
cyclization. This phenomenon may be caused by the coordinating
effect of the Cl, CN, and OMe groups at the 2-position. Electron-
donating substituents at the 3-position could enhance the yield
more than substituents at the 2- and 4-positions. We next
screened several pyridine ligands bearing two methyl groups at
different positions, in order to obtain a higher yield of the desired
product. However, it appears that an additional methyl group at a
different position on the ring is detrimental to the product yield.
Thus, the best ligand was found to be 3-methylpyridine (3-MePy).
Different carboxylic acids were tested to improve the yield (Table
1). The results suggest that their is a relationship between product
yield and the acidity of the acids. For aliphatic carboxylic acids,
product yield increased with increasing acidity (entries 1-4);
however, too strong acid provided a lower yield (entry 5). The
screening of different aromatic carboxylic acids also indicated that
stronger acids can promote the reaction to give the desired
cyclization product in better yield (entries 6-8). Finally,
pentafluorobenzoic acid was found to be the best additive for this
aza-Wacker/Heck tandem cyclization (entry 8).
Table 1. Screening of Acid Additive.
entry
acid additive
HCO2H
pKa
3.74
4.74
5.03
3.15
0.23
4.21
2.15
1.60
yield (%)
61
1
2
3
4
5
6
7
8
CH3CO2H
55
(CH3)3CCO2H
citric acid•H2O
CF3CO2H
46
79
56
PhCO2H
46
PhCOCO2H
C6F5CO2H
73
86
With the optimized reaction conditions in hand, the substrate
scope was examined (Scheme 3). Substrates with one electron-
donating substituent gave the desired products in better yields
than those bearing electron-withdrawing substituents (2b~2h).
For instance, product 2b bearing a OMe group at the 5-position
was obtained in 97% yield, whereas 2f bearing a CF3 group at the
same position was furnished in just 58% yield. Substrates bearing
two substituents were also employed in this reaction. However,
product 2i and 2j were obtained in only moderate yields due to
the instability of these substrates towards the oxidative conditions.
The effect of different R2 substituents on the olefin was also
investigated (2k~2q). In general, the desired products were
obtained in moderate to good yields. For example, high yields
were observed for substrates bearing a MeO(CH2)3‒ or Ph(CH2)2‒
R2 group (2n and 2o). Substrate 1r bearing a methyl group as R3
gave the desired product in only 21% yield after hydrogenation of
olefin group by Pd/C, with an unidentified complex mixture of
byproducts formed. Similar situation was also observed for
substrates bearing an aryl R3 group (2s). In addition, when R2 is
H-atom, the substrate decomposed under our reaction conditions.
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catalytic activity but poor enantio-inducing ability. An additional
chiral stereogenic substituent significantly reduced the catalytic
activity (CL5 and CL6). The combination of CL5 and (R)-CPA1
provided product 2a in slightly higher ee (34%).
Scheme 4. Attempts of asymmetric catalysis.
To test the practicality of our methodology, a gram-scale reaction
using substrate 1a was carried out (Scheme 5). The product 2a
was obtained in 82% yield, which is comparable to the yield
shown in Table 2.
Scheme 3. Substrate Scope.
Attempts to establish an asymmetric version of our methodology
were not successful (Scheme 4). The use of chiral Binol-derived
phosphoric acid CPA1 as the acid additive gave the desired
product with 22% ee and 77% yield. However, ortho-Ph-
substituted CPA2, could only promote the reaction to give the
cyclized product in 12% ee, albeit in high yield. Four different
types of chiral ligands were also tested. Pyridine-oxazoline ligand
(CL1), which has shown excellent catalytic behavior for the Pd(II)-
catalyzed difunctionalizations of olefins,[14] showed poor results in
this reaction. Similarly low yields and enantioselectivity were
observed when using the bidentate ortho-sulfinyl-substituted
phenyl oxazoline ligand CL2 and the monodentate ligand CL3.[15]
Recently, the Yu group reported a novel class of quinoline-
acetamide ligands that showed excellent catalytic ability for
asymmetric C(sp3)-H arylation,[16] which was enabled by the
monodentate pyridine-type ligands used in previous reports.[17]
Therefore, several such ligands were also screened in our
reaction. CL4 just bearing one chiral center showed moderate
Scheme 5. Gram-Scale Reaction.
The cyclized product could be further manipulated (Scheme 6).
The olefin bond of product 2a was readily transformed to expoxide
3 by mCPBA or hydrogenated to give 4 via Pd/C catalysis. The
cleavage of the allylic C-O bond was achieved via Pd/C-catalyzed
hydrogenation in MeOH solvent with the concomitant reduction of
the olefin, giving 5 in 60% yield. The N-O bond could also be
cleaved using SmI2 as a reductant, giving allylic alcohol product 6
in 61% yield.
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Shanghai
Municipal
Education
Commission
(No.
201701070002E00030) are acknowledged for financial support.
The authors thank the Instrumental Analysis Center of SJTU.
Keywords: palladium • oxidative tandem cyclization •
heterocycles • pyridine ligand • aza-Wacker cyclization
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substrate (Scheme 7). Pd(II) catalyst coordinates with substrate
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H species undergoes reductive elimination and oxidation by BQ
to regenerate the Pd(II) catalyst.
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Scheme 7. Proposed Catalytic Cycle.
In conclusion, we have developed a Pd(II)-catalyzed oxidative
tandem cyclization for the construction of fused 5,6-bicyclic N,O-
heterocycles. The combination of 3-methylpyridine ligand and
pentafluorobenzoic acid additive effectively enabled this
cyclization. A range of substrates were tolerated under the
reaction conditions giving the desired heterocyclic products in
moderate to good yields. The transformations of product 2a were
also carried out to show the applicability of our methodology. The
asymmetric catalysis of this reaction appears challenging and the
development of new chiral ligands to induce high
enantioselectivity is currently under way in our group.
Acknowledgements
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The National Natural Science Foundation of China (Nos.
21302124, 21620102003, 21772119), Science and Technology
Commission of Shanghai Municipality (No. 15JC1402200), and
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For aza-Wacker-type reactions, see; e) F. Jiang, Z. Wu, W. Zhang,
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[11] Yang group has reported one example of substrate bearing electron-rich
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Chenghao Ye, Xuezhen Kou, Jingzhao
Xia, Guoqiang Yang, Li Kong,* Quhao
Wei,* Wanbin Zhang*
Page No. – Page No.
Pd(II)-Catalyzed Oxidative Tandem
aza-Wacker/Heck Cyclization for the
Construction of Fused 5,6-Bicyclic
N,O-Heterocycles
A Pd(II)-catalyzed tandem aza-Wacker/Heck cyclization was developed for the
construction of a range of fused 5,6-bicyclic N,O-heterocycles. This reaction was
enabled by the combination of 3-methylpyridine as a ligand and pentafluorobenzoic
as an acidic additive
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