Pd-Catalyzed Domino Imidoylation/Heck/C(sp2)-H Cyclization: Isocyanide Relay Strategy toward Tricyclic-Fused Heterocycles Containing an All-Carbon Quaternary Center

Article abstract of DOI:10.1021/acs.orglett.0c02503

A palladium-catalyzed domino process for the quick assembly of tricyclic-fused heterocycles starting from aryl iodides and functionalized isocyanides containing a disubstituted terminal alkene has been developed. The process is triggered by intermolecular isocyanide insertion, followed by Heck-type carbopalladation of the intramolecular alkene moiety and subsequent C(sp2)-H activation. Moreover, an asymmetric version of this reaction could also be realized in good yield with moderate enantioselectivity after preliminary exploration of chiral ligands.

Full text of DOI:10.1021/acs.orglett.0c02503

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Letter
Pd-Catalyzed Domino Imidoylation/Heck/C(sp2)−H Cyclization:
Isocyanide Relay Strategy toward Tricyclic-Fused Heterocycles
Containing an All-Carbon Quaternary Center
Fan Teng, Yan Peng, Xilong Wang, Weiming Hu, Huaanzi Hu, Yimiao He, Shuang Luo,*
and Qiang Zhu*
Cite This: https://dx.doi.org/10.1021/acs.orglett.0c02503
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ABSTRACT: A palladium-catalyzed domino process for the quick assembly of tricyclic-fused heterocycles starting from aryl iodides
and functionalized isocyanides containing a disubstituted terminal alkene has been developed. The process is triggered by
intermolecular isocyanide insertion, followed by Heck-type carbopalladation of the intramolecular alkene moiety and subsequent
C(sp2)−H activation. Moreover, an asymmetric version of this reaction could also be realized in good yield with moderate
enantioselectivity after preliminary exploration of chiral ligands.
In recent years, palladium-catalyzed imidoylation of
functionalized isocyanides has attracted extensive attention in
the synthesis of N-containing heterocyclic scaffolds.5 In these
reactions, migratory insertion of isocyanides to a Pd(II) species
generates the key imidoyl Pd(II) intermediates, which can be
captured by various intramolecular functional groups,6
including the carbonyl oxygen of amides,6a,b aromatic C−H
bonds,6c−i alkynes,6j,k and alkenes,6m,n leading to heterocyclic
compounds such as oxazoles, phenanthridines, indole-fused
derivatives, and cyclic ketoimines. In 2016, our group designed
a palladium-catalyzed imidoylative Heck reaction, which
represented an uncommon example of bimolecular Heck-
type reaction with reversed regioselectivity via a well-defined
reaction sequence (Scheme 1c).6n In this isocyanide-involved
relay strategy, intermolecular isocyanide insertion initiated the
reaction. The following intramolecular Heck-type carbopalla-
dation gave intermediate C, which underwent favorable β-
he facile construction of heterocycle-fused compounds
Tbearing all-carbon quaternary centers occupies an
important field in organic chemistry and continues to be a
hot topic.1 With the development of organometallic chemistry,
palladium-catalyzed carbopalladation-initiated Heck-type dom-
ino reactions provide a versatile avenue to meet this demand.2
To make the domino sequence proceed, σ-alkylpalladium
intermediate A lacking β-hydrogens should be formed, which
unfortunately is an unfavorable process in the case of
intermolecular Heck reactions between aryl halides and 1,1-
disubstituted olefins (Scheme 1a). However, when an aryl
halide and disubstituted terminal alkene are linked, the
reversed regioselectivity for intramolecular carbopalladation is
preferred, delivering the key neopentyl C(sp3)−Pd species B
predominantly (Scheme 1b). Following this strategy, fruitful
transformations based on intermediate B have been extensively
explored.3 When R contains a pendent phenyl group,
subsequent C(sp2)−H cyclization takes place to give spiro-
fused architectures. Although this process is quite efficient in
bond formation and molecular complexity generation, the
intrinsic disadvantage of the monomolecular reaction limits
quick assembly of diversified products.4 To date there is still a
dearth of intermolecular carbopalladation-initiated C−H
activation applied to the synthesis of fused heterocycles.
Received: July 28, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02503
© XXXX American Chemical Society
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a
Scheme 1. Domino Heck Reaction in Heterocycle Synthesis
Table 1. Optimization of the Reaction Conditions
entry
catalyst
ligand
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
DPPE
Ad2PnBu
base
additive
yield (%)
53
1
2
3
4
5
6
7
8
9
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd2(dba)3
PdCl2
Pd(acac)2
Pd(OAc)2
Pd(OAc)2
K2CO3
−
−
−
Cs2CO3
CsOPiv
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
68
79
b
c
PivOH
AcOH
PivOH
PivOH
PivOH
PivOH
PivOH
84 (53, 47 )
37
80
47
12
49
23
10
a
Reaction conditions: 1a (0.1 mmol), 2a (0.15 mmol), Pd catalyst
(10 mol %), PPh3 (20 mol %), base (0.12 mmol), and additive (0.12
mmol) at 80 °C in toluene under Ar. A solution of 1a in toluene (1
mL) was added to the reaction mixture (in 1.0 mL of toluene) via a
b
syringe pump within 1 h. Isolated yields are shown. MeCN as the
c
solvent. 1,4-Dioxane as the solvent.
and this slightly improved the yield to 84% (entry 4). As an
acidic additive, AcOH was less effective than PivOH, reducing
the yield of 3aa to 37% (entry 5). The designed product was
delivered in much lower yields when other solvents, such as
MeCN and 1,4-dioxane, were employed (entry 4). A number
of other palladium catalysts were investigated, including
Pd2(dba)3, PdCl2, and Pd(acac)2, but they did not show
better reactivity than Pd(OAc)2 (entries 6−8). Finally,
screening of the phosphine ligands DPPE and Ad2PnBu
resulted in lower product yields (entries 9 and 10).
Remarkably, competing activation of the pendent benzylic
C(sp2)−H leading to the spiro-fused product was not observed
in any of these cases.
Following these optimization studies, the substrate scope
was investigated using a variety of aryl iodides (ArI) under the
optimized reaction conditions (Scheme 2). In this cascade
reaction, changing the electronic properties of substituents on
the ArI had no obvious influence on the product yield. That is,
ArI bearing electron-donating groups provided the 2H-
indeno[1,2-b]pyridine derivatives in moderate yields (3ab,
3ac, 3ah, 3ao), and electron-withdrawing groups on ArI were
also well-tolerated, giving the products in 56−80% yield (3ad−
am). Interestingly, halo-substituted ArI were also tolerated,
which thus providing the potential for further derivatization
(3ae−ag and 3al). However, the yields decreased obviously
when the ortho position of the phenyl ring was substituted with
a fluoro or cyano group, which indicated that the steric effect
of substituent groups would somehow hinder the trans-
formation (3ad vs 3am, 3ae vs 3al). For the disubstituted
substrate 1-iodo-3,5-dimethylbenzene, the target product could
also be achieved in 73% yield (3an). When 1-iodo-3-
methylbenzene was subjected to the reaction, two regioisomers
were obtained (3ao and 3ao′), and the less sterically hindered
product 3ao was favored in a ratio of 2.7:1. A similar result was
also observed when 2-iodonaphthalene was used in this
procedure (3aq). Apart from iodobenzene analogues, the
iodo-substituted heterocycle 2-iodothiophene could also be
applied in this reaction system, generating 3ap in 37% yield.
hydride elimination to achieve cyclic ketoimines bearing
exocyclic methylene. As a logical extension of this work, we
envision that when a functionalized isocyanide embedding a
1,1-disubstituted alkene block is applied, a bimolecular domino
isocyanide insertion/Heck reaction/C−H activation might be
realized (Scheme 1d). In this process, the key neopentyl
C(sp3)−Pd intermediate D is formed from the isocyanide and
ArI. Without a β-hydrogen to eliminate, intermediate D
undergoes C−H functionalization alternatively, providing
polycyclic products. Introducing the isocyano group amelio-
rates the present dilemma of generating the neopentyl C(sp3)−
Pd intermediate intermolecularly, which is necessary for the
subsequent C−H functionalization. As a result, tricyclic-fused
heterocycles containing an all-carbon quaternary center such as
2H-indeno[1,2-b]pyridines, important core frameworks fre-
quently found in drug and biologically active molecules, can be
accessed.7
To test this hypothesis, ethyl 2-(3-benzylbut-3-en-1-yl)-2-
isocyanomalonate (1a) was selected as the model substrate
because of its possibility to deliver both the polycyclic and
spiro-fused products. Enlightened by previous works on
functionalized isocyanide-involved cycloimidoylative reac-
tions,6m,n the desired tricyclic-fused product 3aa was
successfully achieved in 53% yield in the presence of Pd(OAc)2
(10 mol %), PPh3 (20 mol %), and K2CO3 (1.2 equiv) in
PhMe (entry 1, Table 1). The isolated yield of 3aa could be
further improved when Cs2CO3 and CsOPiv were used
(entries 2 and 3). Considering its hygroscopic property,
CsOPiv was formed in situ by mixing Cs2CO3 with PivOH,
B
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alkene moiety gave the designed products 3ba and 3ca in 60%
and 77% yield, respectively. When the ester moiety in 1 was
changed to a methyl ester, the reaction was conducted
efficiently, affording the product in 73% yield (3da). However,
the yield decreased dramatically to 41% when the length of the
carbon chain between the isocyanide group and alkene group
was reduced by one carbon (3ea). This result might be
ascribed to the large ring tension of the C(sp3)−Pd
intermediate. When substrate 1f was applied in the reaction,
the corresponding product 3fa was generated in 75% yield. In
order to increase the practicability, the reaction was conducted
on a 1.0 mmol scale, and 3aa was achieved in 76% yield.
The scope of isocyanides containing a racemic quaternary
carbon was also investigated (Scheme 4). The substrate with a
Scheme 2. Scope of ArI for the Synthesis of 2H-Indeno[1,2-
b]pyridine Derivatives
a
Scheme 4. Scope of Isocyanides Containing a Racemic
a
Quaternary Carbon
a
Reaction conditions: 1a (0.1 mmol), 2 (0.12 mmol), Pd(OAc)2 (10
mol %), PPh3 (20 mol %), Cs2CO3 (0.12 mmol), and PivOH (0.12
mmol) at 80 °C in Ar. A solution of 1a in toluene (1 mL) was added
to the reaction mixture (in 1.0 mL of toluene) via a syringe pump
b
within 1 h. Isolated yields are shown. 1.0 mmol scale.
Then studies with various isocyanide substrates were
conducted, and the results are summarized in Scheme 3.
Initially, substrates with a Me (1b) or Ph (1c) group on the
a
Reaction conditions: 4 (0.1 mmol), 2a (0.15 mmol), Pd(OAc)2 (10
mol %), PPh3 (20 mol %), Cs2CO3 (0.12 mmol), and PivOH (0.12
mmol) at 80 °C in Ar. A solution of 4 in toluene (1 mL) was added to
the reaction mixture (in 1.0 mL of toluene) via a syringe pump within
1 h. Isolated yields are shown.
Scheme 3. Scope of Isocyanides for the Synthesis of 2H-
a
Indeno[1,2-b]pyridine Derivatives
phenyl group provided the product 5aa in excellent yield
(96%) with good diastereoselectivity (7:1 d.r.), while the
methyl-substituted isocyanide yielded the corresponding
product 5ca in a much lower yield (51%) and diastereose-
lectivity (4.9:1 d.r.). This result indicated that substituents on
the alkene moiety exhibited a significant influence on the
chemical yield and diastereoselectivity. Moreover, α-propyl-
substituted isocyanide delivered the product 5ea in lower yield
with poorer d.r. than the α-isobutyl- and α-isopropyl-
substituted isocyanides (4d and 4f), suggesting that the steric
effect of the α-alkyl moiety of the isocyanide group was not
neglectable.
By analysis of the neopentyl C(sp3)−Pd intermediate D in
Scheme 1, we envisioned that a spiro-fused product might be
generated through C−H activation of the phenyl ring in R3 (R3
= Bn). However, when aryl iodides 1 was subjected to the
reaction conditions, the spiro-fused product was hardly
detected. We speculated that it might be hampered by the
higher flexibility of the benzyl group the imidophenyl moiety.
To this end, 2,6-disubstituted iodobenzene lacking ortho C−H
was used in the reaction. However, isocyanide insertion could
not proceed well due to the steric hindrance, and no desired
a
Reaction conditions: 1 (0.1 mmol), 2a (0.15 mmol), Pd(OAc)2 (10
mol %), PPh3 (20 mol %), Cs2CO3 (0.12 mmol), and PivOH (0.12
mmol) at 80 °C in Ar. A solution of 1 in toluene (1 mL) was added to
the reaction mixture (in 1.0 mL of toluene) via a syringe pump within
1 h. Isolated yields are shown.
C
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product was detected. Inspired by Zhu’s works about migratory
insertion of isocyanide to a transient σ−Csp3−Pd(II)
complex,8 N-(2-iodoaryl)-N-methylmethacrylamide 6 was
tested as the substrate with isocyanide 1a, and the desired
spiro-fused product 7 containing a methylene linked oxindole
scaffold would be achieved in 75% yield (Scheme 5).
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02503.
■
sı
Experimental procedures and compound characteriza-
tion data (PDF)
a
Scheme 5. Synthesis of 4′H-Spiro[indene-2,3′-pyridine]
AUTHOR INFORMATION
Corresponding Authors
■
Shuang Luo − State Key Laboratory of Respiratory Disease,
Guangzhou Institutes of Biomedicine and Health, Chinese
Academy of Sciences, Guangzhou 510530, China; University of
Chinese Academy of Sciences, Beijing 100049, China;
Email: luo_shuang@gibh.ac.cn
Qiang Zhu − State Key Laboratory of Respiratory Disease,
Guangzhou Institutes of Biomedicine and Health, Chinese
Academy of Sciences, Guangzhou 510530, China; University of
Chinese Academy of Sciences, Beijing 100049, China; Guangxi
Key Laboratory of Natural Polymer Chemistry and Physics,
College of Chemistry and Materials, Nanning Normal
University, Nanning 530001, China; orcid.org/0000-0002-
1243-2391; Email: zhu_qiang@gibh.ac.cn
a
Reaction conditions: 1a (0.1 mmol), 6 (0.12 mmol), Pd(OAc)2 (10
mol %), P(4-MeOPh)3 (20 mol %), and Cs2CO3 (0.12 mmol) at 80
°C in Ar. A solution of 1a in 1,4-dioxane (1 mL) was added to the
reaction mixture (in 1.0 mL of toluene) via a syringe pump within 1 h.
The isolated yield is shown.
Last but not least, we investigated an asymmetric version of
this novel cascade reaction to deliver compounds with an all-
carbon quaternary stereocenter. The preliminary result with
SPINOL-derived phosphoramidite ligand L1 revealed that
product 3aa could be formed in 86% yield with a moderate
enantiomeric excess of 55%, while reaction with ligand L19
provided the product with slightly improved enantioselectivity,
albeit in a low yield (Scheme 6; for more details, see the
Supporting Information).
Authors
Fan Teng − State Key Laboratory of Respiratory Disease,
Guangzhou Institutes of Biomedicine and Health, Chinese
Academy of Sciences, Guangzhou 510530, China; University of
Chinese Academy of Sciences, Beijing 100049, China
Yan Peng − State Key Laboratory of Respiratory Disease,
Guangzhou Institutes of Biomedicine and Health, Chinese
Academy of Sciences, Guangzhou 510530, China; University of
Chinese Academy of Sciences, Beijing 100049, China
Xilong Wang − State Key Laboratory of Respiratory Disease,
Guangzhou Institutes of Biomedicine and Health, Chinese
Academy of Sciences, Guangzhou 510530, China; University of
Chinese Academy of Sciences, Beijing 100049, China
Weiming Hu − State Key Laboratory of Respiratory Disease,
Guangzhou Institutes of Biomedicine and Health, Chinese
Academy of Sciences, Guangzhou 510530, China; University of
Chinese Academy of Sciences, Beijing 100049, China
Huaanzi Hu − State Key Laboratory of Respiratory Disease,
Guangzhou Institutes of Biomedicine and Health, Chinese
Academy of Sciences, Guangzhou 510530, China; University of
Chinese Academy of Sciences, Beijing 100049, China
Yimiao He − Guangxi Key Laboratory of Natural Polymer
Chemistry and Physics, College of Chemistry and Materials,
Nanning Normal University, Nanning 530001, China;
orcid.org/0000-0003-0530-7426
a
Scheme 6. Studies of the Asymmetric Reaction
a
Reaction condition: 1a (0.1 mmol), 2a (0.15 mmol), Pd(dba)2 (10
mol %), L* (20 mol %), Cs2CO3 (0.12 mmol), and PivOH (0.12
mmol) at 80 °C in Ar. A solution of 1 in toluene (1 mL) was added to
the reaction mixture (in 1.0 mL of toluene) via a syringe pump within
1 h. Isolated yields are shown.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02503
In conclusion, we have developed a palladium-catalyzed
domino process for the quick assembly of tricyclic-fused
heterocycles starting from aryl iodides and functionalized
isocyanides containing a disubstituted terminal alkene. The
process is triggered by intermolecular isocyanide insertion,
followed by Heck-type carbopalladation of the intramolecular
alkene moiety and subsequent C(sp2)−H activation. Three C−
C bonds are formed sequentially with concurrent formation of
an all-carbon quaternary center. The isocyano group plays an
important role in this unusual intermolecular domino Heck/
C−H activation. Moreover, initial explorations of the
asymmetric reaction provided moderate enantioselectivity.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the National Natural Science
Foundation of China (21532009, 21772198, and 21871268),
the Natural Science Foundation of Guangdong Province of
China (2020A1515011428), the Guangzhou Regenerative
Medicine and Health-Guangdong Laboratory of China
D
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(2018GRZ110105017), and the BAGUI Scholar Program of
Guangxi Province of China for financial support.
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