α-Oxocarboxylic Acids as Three-Carbon Insertion Units for Palladium-Catalyzed Decarboxylative Cascade Synthesis of Diverse Fused Heteropolycycles

Article abstract of DOI:10.1021/acs.orglett.1c00493

A novel palladium-catalyzed decarboxylative cascade cyclization for the assembly of diverse fused heteropolycycles by employing α-oxocarboxylic acids as three-carbon insertion units is reported. This protocol enables the synthesis of isoquinolinedione- and indolo[2,1-a]isoquinolinone-fused benzocycloheptanones in moderate to good yields by the use of different aryl iodides, including alkene-tethered 2-iodobenzamides and 2-(2-iodophenyl)-1H-indoles. Notably, the approach achieves simultaneous construction of both six- and seven-membered rings via sequential intramolecular carbopalladation, C-H activation, and decarboxylation.

Full text of DOI:10.1021/acs.orglett.1c00493

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Letter
α‑Oxocarboxylic Acids as Three-Carbon Insertion Units for
Palladium-Catalyzed Decarboxylative Cascade Synthesis of Diverse
Fused Heteropolycycles
Liwei Zhou, Shujia Qiao, Fengru Zhou, Xinyu Xuchen, Guobo Deng, Yuan Yang,* and Yun Liang*
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ABSTRACT: A novel palladium-catalyzed decarboxylative cascade cyclization for the assembly of diverse fused heteropolycycles by
employing α-oxocarboxylic acids as three-carbon insertion units is reported. This protocol enables the synthesis of
isoquinolinedione- and indolo[2,1-a]isoquinolinone-fused benzocycloheptanones in moderate to good yields by the use of different
aryl iodides, including alkene-tethered 2-iodobenzamides and 2-(2-iodophenyl)-1H-indoles. Notably, the approach achieves
simultaneous construction of both six- and seven-membered rings via sequential intramolecular carbopalladation, C−H activation,
and decarboxylation.
Scheme 1. Palladium-Catalyzed Cascade Cyclization and the
Reaction Mode of α-Oxocarboxylic Acids
ascade reactions that enable the construction of multiple
Cbonds in a single operation have emerged as a powerful
tool for the synthesis of diverse carbo- and heterocycles due to
its high efficiency and step-economy.1,2 Among them, of
particular interest to synthetic chemists is palladium-catalyzed
cascade cyclization of alkene-tethered aryl halides involving
palladacycles owing to not only the existing C−H activation
process but also the versatility of palladacycles generated by an
intramolecular carbopalladation/C−H activation sequence.2 In
earlier studies, the pioneering work reported by Grigg and co-
workers3 achieved the construction of heteropolycycles via
direct reductive elimination of palladacycles, and this strategy
was further developed by several other groups.4,5 Afterward,
another novel transformation of palladacycles involving
sequential [1,4]-Pd shift, C−H activation, and reductive
elimination process was disclosed by Zhu et al.6 However,
these reported conversions were limited to the inherent C−H
bond as the terminated functional group, thus resulting in poor
product diversity. Recently, significant breakthroughs in this
field have been made in the capture of palladacycles by coupling
partners (Scheme 1a).7−9 Despite great progress, the scope of
these coupling partners (such as diaziridinones, α-diazocarbonyl
compounds, dibromomethane, aryl iodides, arynes, o-bromo-
benzoic acids, [60]fullerene, and activated alkynes) was
Received: February 9, 2021
Published: March 29, 2021
https://doi.org/10.1021/acs.orglett.1c00493
© 2021 American Chemical Society
Org. Lett. 2021, 23, 2878−2883
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generally limited to construct five- and six-membered rings by
inserting one- or two-atom units. Methods for forging a seven-
membered ring are still elusive so far. Therefore, developing new
coupling reagents to target this goal is in great demand.
α-Oxocarboxylic acids have become among the most versatile
synthons for constructing C−C and C−heteroatom bonds in
organic synthesis.10 A myriad of elegant methods via
decarboxylative coupling have been reported by Ge, Wang,
Duan, and Goossen et al.11,12 However, the overwhelming
majority of methods focus on the use of α-oxocarboxylic acids as
an acylation reagent under transition-metal, photoredox, or
oxidation catalysis (Scheme 1b). Accordingly, the exploitation
of a new transformation model of α-oxocarboxylic acids is
urgently required. Inspired by our interest in the cascade
reactions involving the functionalization of palladacycles,9,12 we
envision that α-oxocarboxylic acids can couple with pallada-
cycles to construct polycyclic compounds. Herein, we report a
palladium-catalyzed decarboxylative cascade cyclization of
alkene-tethered aryl iodides with 2-(2-bromoaryl)-2-oxoacetic
acids for the synthesis of diverse fused heteropolycycles
(Scheme 1c). Notably, a seven-membered ring can be formed
by 2-(2-bromoaryl)-2-oxoacetic acids as three-carbon insertion
units.
several palladium salts, such as PdCl2(PPh3)2, PdCl2, and
Pd(PPh3)4 (entries 2−4). The removal of ligand PPh3 was found
to have a negative effect on this decarboxylative tandem reaction
(entry 5). Other ligands were then screened, and PCy3 gave a
better outcome. Unfortunately, attempts using other bases, such
as K2CO3, Cs2CO3, and KOAc, indicated that all of them were
inferior to K3PO4 (entries 10−12). We next turned our attention
to solvents. Replacing DMA with DMF could promote the
conversion efficiency (entry 13), whereas other solvents resulted
in significantly diminished or even trace yields (entries 14−16).
Eventually, both decreasing and increasing reaction temperature
displayed worse efficiency than this result at 120 °C (entries 17
and 18). Satisfactorily, the reaction scaled up to 1 mmol of 1a
could yield 67% of product 3aa (entry 13).
With the optimal reaction conditions determined, we set out
to investigate the generality of this transformation (Scheme 2).
The scope of imides 1 was initially examined. This protocol was
applicable to a broad range of imides 1, thus affording
isoquinolinedione-fused benzocycloheptanones 3aa−pa in
Scheme 2. Synthesis of Isoquinolinedione-Fused
a
Benzocycloheptanones
Our investigation commenced with the cascade reaction of N-
benzyl-2-iodo-N-methacryloylbenzamide 1a with 2-(2-bromo-
phenyl)-2-oxoacetic acid 2a (Table 1). Fortunately, the
anticipated tetracyclic isoquinolinedione-fused benzocyclohep-
tanone 3aa was obtained in 40% yield under common catalytic
conditions composed of Pd(OAc)2, PPh3, and K3PO4 in DMA at
120 °C (entry 1). Various parameters were subsequently
examined to acquire the optimal reaction conditions. PdCl2
was proven to be the most efficient catalyst by investigating
a
Table 1. Optimization of the Reaction Conditions
b
entry
[Pd]
ligand
base
solvent
yield (%)
1
2
3
4
5
6
7
8
Pd(OAc)2
PdCl2(PPh3)2
PdCl2
Pd(PPh3)4
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PPh3
PPh3
PPh3
PPh3
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K2CO3
Cs2CO3
KOAc
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMF
DMSO
MeCN
toluene
DMF
DMF
40
trace
66
trace
59
26
46
63
68
trace
trace
45
75 (67)
45
32
trace
67
dppf
Pt-Bu3
X-phos
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
9
10
11
12
13
14
15
16
e
c
17
18
d
PdCl2
39
a
Reaction conditions: 1 (0.2 mmol), 2 (1.5 equiv), PdCl2 (10 mol
a
Reaction conditions: 1a (0.2 mmol), 2a (1.5 equiv), [Pd] (10 mol
%), ligand (20 mol %), base (3 equiv), and solvent (2 mL) at 120 °C
%), PCy3 (20 mol %), K3PO4 (3 equiv), and DMF (2 mL) at 120 °C
b
under N2 for 12 h. N-Benzyl-2-bromo-N-methacryloylbenzamide
b
c
d
e
c
d
under N2 for 12 h. Isolated yield. At 100 °C. At 140 °C. 1a (1
mmol) was used.
was used. 2-(2-Iodophenyl)-2-oxoacetic acid was used. 2-(2-
Chlorophenyl)-2-oxoacetic acid was used.
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Letter
moderate to good yields. Various substituents on the nitrogen
atom, such as 4-MeBn, 4-FBn, Me, Et, Ph, and allyl groups, were
well-tolerated, and the desired products 3ba−ga were afforded
in 30−75% yields. Importantly, imide 1h with a phenyl group on
the alkene was able to undergo this cascade cyclization to furnish
product 3ha in 48% yield. Regarding the 2-iodobenzamide
moiety, a range of functional groups (Me, OMe, F, and Cl) in an
ortho or meta position relative to the amide group all could
survive, furnishing products 3ia−na in 46−85% yields.
However, imide 1o derived from 2-iodo-4-methylbenzamide
was not a viable substrate. The results indicated that the steric
effect had a vital influence on the construction of a seven-
membered ring. Substrates 1p and 1q containing only one amide
group were also tested, and 1q showed poor reactivity.
Remarkably, substrate derived from 2-bromobenzamide was
perfectly accommodated to provide product 3aa in 70% yield.
The scope of 2-(2-bromoaryl)-2-oxoacetic acids was then
explored (Scheme 2). A range of 2-oxocarboxylic acids 2b−k
were subjected to the optimal reaction conditions to furnish
isoquinolinedione-fused benzocycloheptanones 3ab−ak in 61−
87% yields. Various substituents on the benzene ring, including
both electron-donating (Me, OMe, and OPh) and electron-
withdrawing groups (F and Cl), were well-tolerated (3ab−ah).
Their electronic property and position had no obvious effect on
the reaction efficiency. Note that morpholinyl-, dimethyloxy-, or
dioxolyl-substituted 2-(2-bromoaryl)-2-oxoacetic acids could be
smoothly converted into products 3ai−ak. Gratifyingly, 2-(3-
bromothiophen-2-yl)-2-oxoacetic acid also exhibited good
reactivity, providing product 3al in 45% yield. Furthermore, 2-
(2-iodophenyl)-2-oxoacetic acid was also a suitable substrate.
However, only 35% of 3aa was isolated due to the formation of
the decarboxylation/decarbonylation side product.9d Unfortu-
nately, this protocol was not compatible with 2-(2-chlorophen-
yl)-2-oxoacetic acid.
indole could also furnish product 5aa, albeit with a lower yield.
Subsequently, a series of 2-(2-iodophenyl)-1H-indoles 4b−i
were examined. Substrates 4b−f bearing diverse substituents
(Me, F, Cl, and Br) on the indole undergo this cascade reaction
with 2a to deliver the target products 5ba−fa in 54−80% yields.
2-Phenylacryl- or 2-methylallyl-substituted indoles were also
competent substrates, affording products 5ga and 5ha in
moderate yields. Notably, the reaction of 2-(3-bromothio-
phen-2-yl)-2-oxoacetic acid with 4a proceeded efficiently,
delivering 51% of the target product 5al. Unfortunately, 2-(2-
iodophenyl)-1H-benzo[d]imidazole 1i was unreactive.
To gain insights into the reaction mechanism, the isotope
experiment was carried out by adding 5 equiv of D2O under the
optimal reaction conditions. The result indicated that pallada-
cycle C was formed in the reaction process. On the basis of our
experimental results and previous work,13 a plausible catalytic
cycle for this transformation was illustrated as Scheme 4. First,
Scheme 4. Control Experiment and Possible Reaction
Mechanism
To highlight the applicability of this cyclization cascade, we
next attempted the feasibility of the reaction of alkene-tethered
2-(2-iodophenyl)-1H-indoles 4a with 2-oxocarboxylic acids 2a
(Scheme 3). To our delight, indolo[2,1-a]isoquinolinone-fused
benzocycloheptanone 5aa was formed in 78% yield under the
above reaction conditions. Notably, the replacement of an
iodine atom with a bromine atom on the 2-(2-iodophenyl)-1H-
oxidation addition of the C−I bond to Pd(0) followed by
intramolecular carbopalladation forms intermediate B, which
undergoes C−H activation to generate fused palladacycle C.
Then, palladacycle C undergoes an oxidative addition with the
C−Br bond of 2-oxocarboxylic acid 2a to afford Pd(IV) species
D with the assistance of an ortho-chelating carboxyl group, which
has been demonstrated by the related reports.13 Immediately
after, sequential reductive elimination and decarboxylation of
intermediate D produces eight-membered palladacycle E.
Eventually, this catalytic cycle is accomplished by reductive
elimination of palladacycle E, thus resulting in the formation of
products 3 or 5 as well as active Pd(0) species.
Scheme 3. Synthesis of Indolo[2,1-a]isoquinolinone-Fused
a
Benzocycloheptanones
In conclusion, we have disclosed an efficient method for
synthesizing diverse fused heteropolycycles via a palladium-
catalyzed decarboxylative cascade cyclization of aryl iodides,
including alkene-tethered 2-iodobenzamides and 2-(2-iodo-
phenyl)-1H-indoles. In this novel conversion, 2-oxocarboxylic
acids are employed as coupling reagents to achieve three-carbon
unit insertion via an intramolecular Heck/C−H activation/
decarboxylation sequence, thus forging isoquinolinedione- and
indolo[2,1-a]isoquinolinone-fused benzocycloheptanones in
moderate to good yields. Remarkably, a seven-membered ring
is constructed in this reaction. Further applications of 2-
oxocarboxylic acids are underway in our laboratory.
a
Reaction conditions: 4 (0.2 mmol), 2a (1.5 equiv), PdCl2 (10 mol
%), PCy3 (20 mol %), K3PO4 (3 equiv), and DMF (2 mL) at 120 °C
under N2 for 12 h. Alkene-tethered 2-(2-bromophenyl)-1H-indole
was used.
b
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Org. Lett. 2021, 23, 2878−2883

Organic Letters
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Letter
Organic Functional Molecules of Hunan Province, Hunan
Normal University, Changsha, Hunan 410081, China
Guobo Deng − National & Local Joint Engineering Laboratory
for New Petro-chemical Materials and Fine Utilization of
Resources, Key Laboratory of Chemical Biology and
Traditional Chinese Medicine Research, Ministry of
Education, Key Laboratory of the Assembly and Application of
Organic Functional Molecules of Hunan Province, Hunan
Normal University, Changsha, Hunan 410081, China;
orcid.org/0000-0002-5470-5706
ASSOCIATED CONTENT
■
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00493.
Experimental procedures, full characterization of prod-
ucts, and NMR spectra (PDF)
Accession Codes
CCDC 2059100 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
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Complete contact information is available at:
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Notes
The authors declare no competing financial interest.
AUTHOR INFORMATION
ACKNOWLEDGMENTS
■
■
We thank the National Natural Science Foundation of China
(21901071 and 21971061), Natural Science Foundation of
Hunan Province (2020JJ5350), Scientific Research Fund of
Hunan Provincial Education Department (18A002 and
19B359), and Science and Technology Planning Project of
Hunan Province (2018TP1017) for financial support.
Corresponding Authors
Yuan Yang − National & Local Joint Engineering Laboratory
for New Petro-chemical Materials and Fine Utilization of
Resources, Key Laboratory of Chemical Biology and
Traditional Chinese Medicine Research, Ministry of Education,
Key Laboratory of the Assembly and Application of Organic
Functional Molecules of Hunan Province, Hunan Normal
University, Changsha, Hunan 410081, China; orcid.org/
0000-0002-9061-1758; Email: yuanyang@hunnu.edu.cn
Yun Liang − National & Local Joint Engineering Laboratory for
New Petro-chemical Materials and Fine Utilization of
Resources, Key Laboratory of Chemical Biology and
Traditional Chinese Medicine Research, Ministry of Education,
Key Laboratory of the Assembly and Application of Organic
Functional Molecules of Hunan Province, Hunan Normal
University, Changsha, Hunan 410081, China; orcid.org/
0000-0002-2550-9220; Email: yliang@hunnu.edu.cn
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