Stereoselective Pd-Catalyzed Decarboxylative Allylation: Assembly of Highly Functionalized Allylic Amines Bearing a Quaternary Center

Article abstract of DOI:10.1021/acs.orglett.9b00673

Here, we report a practical and reliable methodology to direct construction of tri- and tetrasubstituted olefins bearing an allylic amine, with the concomitant construction of the sterically congested quaternary stereocenter through stereoselective pallad

Full text of DOI:10.1021/acs.orglett.9b00673

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Stereoselective Pd-Catalyzed Decarboxylative Allylation: Assembly
of Highly Functionalized Allylic Amines Bearing a Quaternary Center
Linlin Shi,† Yingdong He,† Yuanyuan Chang,† Nan Zheng,† Zhen Yang,*,†,‡ and Jianxian Gong*,†
†State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate
School, Shenzhen 518055, China
‡Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education and Beijing National Laboratory for
Molecular Science (BNLMS), and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China
S
* Supporting Information
ABSTRACT: Here, we report a practical and reliable methodology to direct construction of tri- and tetrasubstituted olefins
bearing an allylic amine, with the concomitant construction of the sterically congested quaternary stereocenter through
stereoselective palladium-catalyzed cascade decarboxylation of vinyloxazolidinones.
Scheme 1. Palladium-Catalyzed Cascade Reactions of Cyclic
Carbonates
ighly substituted olefins play a vital role in bioscience,
medicine, and chemistry. Stereodefined olefins are
H
important resources in both laboratories and industries.1−5
Allylic amines, which belong to a class of functional amines, are
the basic structural unit in many natural products and
pharmaceuticals.6 However, the syntheses of certain sub-
stituted allylic amines with different substituents bearing a
quaternary center7−9 are significantly challenging. In particular,
the stereoselective syntheses of highly substituted allylic
amines with different substituents remain quite difficult. A
convenient synthetic route to these allylic amines involves the
direct transformation of the allylic substrates via transition
metal catalysis. In this regard, excellent strategies such as
classical substitution of allylic compounds,10 hydroamina-
tions,11 and metal-catalyzed direct functionalization of the
C−H bond (Scheme 1A) have been reported.12 However, the
metal-catalyzed synthesis has limited applications because of
the harsh reaction conditions, low yields, undesirable side
reactions, and poor stereochemical control.
Vinyl cyclic carbonates (VCCs) are important in modern
organic chemistry owing to their multifaceted reactivity and
ease of preparation (Scheme 1B).13 In this context, the
palladium-catalyzed cascade decarboxylative transformation,
largely developed by Zhang,14 Kleij,15 Zhao,16 and Glorius,17 is
a reliable approach for syntheses of different important allylic
manifolds. These reactions involve the release of CO2 and the
formation of a highly reactive Pd-π-allyl intermediate, which
can readily undergo nucleophilic addition to form allylic
compounds.
Recently, Kleij and co-workers reported an efficient method
for the stereocontrolled syntheses of substituted allylic amines
by palladium-catalyzed decarboxylation of VCCs, followed by
Received: February 22, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00673
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
an intermolecular nucleophilic addition of amines.15d This is
the first example on the stereoselective synthesis of allylic
amines based on vinyl cyclic carbonates (Scheme 1B).
a
Scheme 3. Scope of Carbonate Partners
Metal catalysts containing halide ligands are ubiquitous
because of the stable metal−halide interaction. Recently, the
control of halide ligands has been proven to be an important
strategy in tuning the reactivity of the transition metal catalysts.
Despite the prevalence of this functionality, its widespread
application in the development of transition metal catalysts
begun only recently.18 We herein describe an unprecedented
stereoselective palladium-catalyzed decarboxylation of vinyl-
oxazolidinones to generate allylic amines (Scheme 1C). This
practical and reliable conversion gave good to excellent yields
and stereoselectivities, required mild conditions, and had a
broad substrate scope and easy accessibility of reagents.
The details related to the optimization of the reaction
conditions are provided in the Supporting Information. With
the optimized reaction conditions in hand, we investigated
various protecting groups for vinyloxazolidinones (Scheme 2)
Scheme 2. Scope of Protecting Groups in
a
Vinyloxazolidinones
a
Reaction conditions: A (0.04 mmol), Pd catalyst (5 mol %), L2 (8
mol %), TBAI (15 mol %) in THF stirred at 50 °C for 2.5 h.
substrate (4f) on the aromatic rings shows good compatibility.
After verifying the general scope of vinyloxazolidinones with
2a, we proceeded to investigate its feasibility for the formation
of allylic amines bearing a tertiary center via the Pd-catalyzed
transformation. Interestingly, the same substitution patterns of
vinyloxazolidinones were also allowed, affording the desired
derivative (4g−l). Apart from simple aryl groups in the
vinyloxazolidinones, more important synthetic functional
groups can easily produced into the desired compounds,
including 1,3-dicarbonyl reagents.
Furthermore, the range of highly substituted olefins
containing allyllic amine was investigated in detail through
optimized reaction conditions (Scheme 4). Different function-
alized 1,3-dicarbonyl reagents were systematically varied, and a
series of highly substituted allylic amines with a tertiary center
(5a−c) or a quaternary center (3a, 5d−i) were obtained. In
most of the cases, the desired allylic amines were introduced
with good yields and selectivities (>20:1).
The stereoselectivities and yields were good with the various
esters tested. The use of diketones instead of ketoesters also
led to the desired substituted olefins with good stereo-
selectivities and yields. Furthermore, the steric effect in the
methodology was tested. As revealed by the product scope, the
presence of hydrogen and the use of methyl or ethyl group
(5h−i) functionalized ketoesters resulted in good reactivity
and gave excellent product yields. More complex substrates
with fused bulky blocks, such as cyclopentanone 1,3-dicarbonyl
reagents and cyclohexenone 1,3-dicarbonyl reagents (3a, 5d−
g), also showed the same compatibility, giving the desired
allylic amines with good yields and stereoselectivities.
a
Reaction conditions: A (0.04 mmol), Pd catalyst (5 mol %), L2 (8
mol %), TBAI (15 mol %) in THF stirred at 50 °C for 2.5 h.
in their palladium-catalyzed decarboxylation to allylic amines.
The highly activated sulfonyl group-protected derivatives (3a−
d) gave good stereoselectivities and yields of desired allylic
amines. Substrates with other general protecting groups on the
nitrogen atom (3e−i) were also tolerated under the optimized
reaction conditions and gave good yields of allylic amines
bearing a quaternary center.
The palladium-catalyzed decarboxylative addition of oxazo-
lidinones bearing various substituents was also explored in the
presence of ketoesters (Scheme 3). The transformation had
good functional group tolerance with both electron-with-
drawing (4d−e) and electron-donating (4a−c) substituents of
the aryl rings, giving the desired allylic amines in good yields
and high stereoselectivities. Additionally, a meta substituted
B
DOI: 10.1021/acs.orglett.9b00673
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Organic Letters
Letter
a
Scheme 4. Scope on the 1,3-Dicarbonyl Reagent Partners
Scheme 6. Proposed Mechanism
formed via the Pd-catalyzed oxidative addition of vinyl-
oxazolidinone followed by decarboxylation. It is well-known
that halide ions have the ability to affect metal catalytic
processes, including the formation of the Pd-catalyzed π-allyl
intermediate.19 Comparison with the calculation and analysis
provides useful insight into the origin of stereocontrol of vinyl
cyclocarbonate as substrates. In addition, it has been proven
that (Z)-palladacyclic intermediate C15h,i is an important
intermediate which exhibits the basic functions of activation of
different pronucleophiles. The palladacyclic intermediate C
could transform itself to afford intermediate D or E via proton
transfer upon reaction with 2-methylacetoacetate 2a. Nucleo-
philic addition and ligand dissociation led to the desired allylic
amines and regenerated the palladium catalyst.
In conclusion, we developed a practical stereoselective Pd-
catalyzed decarboxylative allylation to synthesize highly
substituted allylic amines bearing a tertiary or quaternary
center. The conversion proceeded under mild reaction
conditions, had a broad substrate scope and easy availability
of reactants, and gave good to excellent selectivities and yields,
thus providing an efficient and concise route to synthesize
some important highly substituted allylic amines. We are
confident that this protocol would allow the synthesis of many
important allylic analogues. This Pd-catalyzed process is
undoubtedly a supplementary strategy for the synthesis of
new allylic manifolds.
a
Reaction conditions: A (0.04 mmol), Pd catalyst (5 mol %), L2 (8
mol %), TBAI (15 mol %) in THF stirred at 50 °C for 2.5 h.
In order to prove the practicability of this methodology,
different experiments were conducted based on this Pd-
catalyzed decarboxylation transformation (Scheme 5). Com-
Scheme 5. Stereoselective Synthesis of Tetrasubstituted
Olefin Derivatives and Diallylated Compounds
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00673.
Experimental procedures and characterization data for
all new compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
parable yields of tetrasubstituted olefins with an allylic amine
group (6a) were also observed. The diallylated reactions were
also investigated to verify this transformation could maintain
the reactivity. It was necessary to increase the temperature and
prolong the reaction time for the formation of the
tetrasubstituted olefin derivatives (6a) and diallylated com-
pounds synthesis (6b and 6c).
We proposed a mechanism for the stereoselective Pd-
catalyzed decarboxylative allylation in Scheme 6. The allyl-Pd
species A and B and palladacyclic intermediate C are initially
*E-mail: zyang@pku.edu.cn.
*E-mail: gongjx@pku.edu.cn.
ORCID
Zhen Yang: 0000-0001-8036-934X
Jianxian Gong: 0000-0003-4331-0976
Notes
The authors declare no competing financial interest.
C
DOI: 10.1021/acs.orglett.9b00673
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ACKNOWLEDGMENTS
■
This work was supported by National Science Foundation of
China (Grant Nos. 21772008, 21632002, and U1606403),
Guangdong Natural Science Foundation (Grant Nos. 2016A0-
30306011 and 2017TQ04R032), Shenzhen Basic Research
Program (Grant Nos. JCYJ20170818090044432 and
JCYJ20180503182116931) and Qingdao National Laboratory
for Marine Science and Technology (Grant No. LMDBKF-
201703).
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DOI: 10.1021/acs.orglett.9b00673
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