Chiral N,N Ligands Enabling Palladium-Catalyzed Enantioselective Intramolecular Heck–Matsuda Carbonylation Reactions by Sequential Migratory and CO Insertions

Article abstract of DOI:10.1002/anie.201805831

Unprecedented enantioselective intramolecular Heck carbonylation reactions of arenediazonium salts were enabled by a chiral N,N ligand. This reaction constitutes the first enantioselective Heck carbonylation that proceeds through migratory insertion followed by CO insertion. The enantioenriched functionalized dihydrobenzofurans were obtained in good to high yields and enantiomeric ratios of up to 98:2 under mild and operationally simple reaction conditions.

Full text of DOI:10.1002/anie.201805831

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Accepted Article
Title: N,N-Chiral Ligands Enabling Palladium-catalyzed
Enantioselective Intramolecular Heck-Matsuda Carbonylation
Reactions by Sequential Migratory and CO Insertions
Authors: Carlos Roque Duarte Correia, Rafaela Costa Carmona, and
Otto Daolio Köster
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201805831
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10.1002/anie.201805831
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N,N-Chiral Ligands Enabling Palladium-catalyzed Enantioselective
Intramolecular Heck-Matsuda Carbonylation Reactions by
Sequential Migratory and CO Insertions.
Rafaela C. Carmona,[a] Otto D. Köster[a] and Carlos Roque Duarte Correia*[a]
Dedication ((optional))
Abstract: Unprecedented enantioselective intramolecular Heck
carbonylation reactions were achieved employing arenediazonium
salts and N,N-chiral ligand. This methodology encompasses the first
examples of an enantioselective Heck carbonylation through
migratory insertion followed by CO insertion sequence. The
enantioenriched functionalized dihydrobenzofurans were obtained in
good to high yields and enantiomeric ratios up to 98:2 under mild and
operationally simple reaction conditions.
the created stereocenter (Scheme 1B). Additionally, a variety of
nucleophiles can be used to react with the PdII intermediates,
such as aromatic, organometallic compounds and CO.[8] Among
them, the latter has the advantage to yield an acyl-palladium
intermediate prone to further nucleophilic attack, thus leading to a
diversity of carbonylated compounds.[3a] These reactions are
known as carbonylative Heck reactions and can follow two distinct
fates: i) an endocarbonylative pathway where the insertion of CO
happens just after the oxidative addition, followed by the migratory
insertion, leading to cyclic ketones (Scheme 1C top);[9] ii) an
exocarbonylative pathway, where the CO insertion occurs after
the migratory insertion into the double bond (Scheme 1C
bottom).[10] Despite the potential of the intramolecular
carbonylative Heck reaction to produce enantioenriched carbonyl
compounds, this transformation is underexplored in the literature.
To the best of our knowledge, there are only two enantioselective
examples for the endocarbonylative pathway[11] and no examples
for the exocarbonylation were reported to date.[5l, 12]
The palladium catalyzed asymmetric Heck reaction is one of the
most robust methodologies for efficient formation of C–C bonds
and its intramolecular version is widely employed to achieve
variable ring sizes.[1] The combination of its tolerance to different
functional groups and substitution patterns in the alkene portion
together with the development of cascade reactions turned the
asymmetric intramolecular Heck reaction into a key method to
reach molecular complexity in total synthesis of complex
molecules.[2, 3]
The asymmetric intramolecular Heck reaction can be
classified into three classes[4] depending on the mechanism
sequence involved after oxidative addition (Scheme 1). The key
issue to achieve enantioselectivity in these reactions is related to
the -elimination step, which should be controlled to avoid losing
the newly formed stereocenter. There are a few different ways to
overcome this problem, including directed elimination (Scheme
1A) and cascade reactions by capturing the -alkyl-palladium
intermediate leading to -elimination away from the stereogenic
center (Schemes 1B and 1C).
After the oxidative addition, the classical intramolecular Heck
reaction occurs via migratory insertion followed by the -
elimination step (Scheme 1A). This strategy has been
substantially explored and is commonly employed for quaternary
stereocenters formation,[5] preventing the -elimination step to
destroy the new stereocenter.[6] Regarding the cascade
methodologies, the enantioselective polyene cascade sequence
has been extensively developed and was applied in a wide range
of natural products total synthesis.[7] This transformation happens
fundamentally via sequential migratory insertions, trapping the -
alkyl-palladium intermediate by other alkene moiety, preserving
[a]
Dra R. C. Carmona, O. D. Köster, Prof. Dr. C. R. D. Correia
Institute of Chemistry, University of Campinas
Josué de Castro, 10384-612, São Paulo (Brazil)
E-mail: roque@iqm.unicamp.br
Scheme 1. Outline of the Intramolecular Heck Reaction.
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
Herein, we report the first enantioselective intramolecular
exocarbonylative Heck reaction through the combination of
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10.1002/anie.201805831
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arenediazonium salts and N,N-chiral ligands. This catalytic
system allowed the synthesis of enantioenriched functionalized
dihydrobenzofurans under mild and operationally simple reaction
conditions. It is worth pointing out that this is also the first time in
which arenediazonium salts were employed intramolecularly in an
enantioselective transformation.[13]
also evaluated and the corresponding dihydrobenzopyran 2h was
formed exclusively in 85% yield (65:35 er). Regardless of its lower
enantioselectivity compared to the 5-membered ones, the
exocarbonylative pathway was preferred and no cyclic ketone
product from an eventual endocarbonylation was observed.
Table 2. Enantioselective intramolecular carbonylative Heck reaction.
The study toward the enantioselective exocarbonylative
intramolecular Heck reaction was initiated by the investigation of
the catalytic system. The arenediazonium salt 1a was chosen as
the model substrate and after a few experiments, the use of
Pd(TFA)2, ZnCO3 and MeOH, under CO atmosphere was found
as an ideal condition to evaluate different N,N-chiral ligands
(Table1). Gratifyingly, the bis-oxazoline (S)-BOx L1 furnished the
desired product 2a in quantitative yield and 95:5 enantiomeric
ratio (er). The pyridine-oxazoline (S)-PyOxL2 also provided the
product in good er, however in lower yield. In contrast, the use of
quinoline-oxazoline (S)-QuinOX L3 yielded the product in very
low enantioselectivity. Finally, the pyrazine and pyrimidine bis-
oxazolines L4 and L5, highly efficient ligands toward asymmetric
Heck-Matsuda reaction,[14] were successful in affording the
product in excellent yields and enantiomeric ratios.
a 5.5 mol% of ligand (S)-PyraBOx L4 was employed. Isolated yields are shown
and enantiomeric ratios were determined by chiral SFC analysis.
These encouraging results prompted the extension of the
methodology by using boronic acids as coupling partners (Table
3). The model arenediazonium salt 1a was submitted to the
reaction conditions above together with 2-thienylboronic acid 3a
to furnish the desired product 4aa in 91% yield and 95:5 er.
Interestingly, the use of boronic acids bearing heteroatoms
surpassed the competitive formation of 2a by the addition of the
methanol, used as the solvent, into the acyl palladium
intermediate.
Table 1. Ligand evaluation.
Table 3. Enantioselective intramolecular carbonylative Heck reaction with
boronic acids.a
a 11 mol% of ligand was employed. Yields were determined by 1H NMR and
enantiomeric ratios were determined by chiral SFC analysis.
Despite the efficiency shown by L4 and L5, ligand L1 revealed
a slightly higher efficiency after some optimization in the reaction
conditions involving the amount of catalyst, base and temperature.
With the reaction conditions established, the reaction scope
regarding the arenediazonium salt structure was evaluated (Table
2). The use of the arenediazonium salts containing methyl,
chlorine or methoxy substituents on the aromatic ring (R1)
furnished the corresponding products 2b, 2c and 2d in good
yields and enantioselectivities. The influence of substituents on
the double bond (R2) was also evaluated. Notably, the product 2e
was obtained in 50% yield and good enantioselectivity with the
corresponding aromatic benzofuran not being observed (See SI
for details). This was an interesting result since the corresponding
arenediazonium salt 1e contains R2=H on the alkene moiety,
which could allow a fast -elimination and consequent loss of the
stereogenic center. Additionally, other substituents on the double
bond (R2) were also tolerated and products 2f and 2g containing
a phenyl and an isopropyl group were obtained in 89% yield (98:2
er) and 67% yield (84:16 er) respectively. The feasibility of
expanding this methodology to provide 6-membered cycles was
a Isolated yields are shown and enantiomeric ratios were determined by chiral
SFC analysis. b 40% of the corresponding methyl ester 2a was observed.
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10.1002/anie.201805831
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Different heteroaromatic boronic acids were tolerated and the
products 4ab, 4ac and 4ad were preferentially formed in good
yields
and
enantioselectivities.
The
use
of
2-
methoxyphenylboronic acid 3e furnished the desired product 4ae
in good enantioselectivity, however the corresponding
methoxylated product 2a was also observed in 1:1 ratio.
The arenediazonium salt structure was evaluated next and
the presence of substituents on the aromatic ring (R1) furnished
selectively the corresponding products 4ba, 4ca, 4da and 4bb in
good yields and high enantioselectivities. Moreover, the presence
of a phenyl group on the alkene (R2) did not affect the reaction
efficiency affording the products 4fa and 4gb in good yields and
high enantiomeric ratios. In agreement with the proposed catalytic
i
cycle (see Scheme 3), the Pr group leads to a higher steric
hindrance with ligand substituent affording the corresponding
product 4ga in 85% yield and lower enantioselectivity.
The absolute stereochemistry was determined using the
Sparr reaction[15] to transform the carboxylic ester 2a (Table 2)
into the corresponding known[16] arene 6 through a double
nucleophilic addition of 1,5-organodimagnesium reagent formed
from diiodide 5 (Scheme 2).
Scheme 3. Proposed catalytic cycle.
Experimental Section
A 4 mL vial equipped with a magnetic stir bar was charged with
Pd(CF3CO2)2 (5 mol%, 0.005 mmol, 1.7 mg), (S)-Box L1 (10 mol%, 0.01
mmol, 3.2 mg), and MeOH (1.0 mL). The vial was capped and the mixture
was stirred at 40 oC for 5 minutes to form the precatalyst. Next, the vial
was cooled to room temperature and charged with ZnCO3 (0.5 equiv, 0.05
mmol, 6.3 mg) and the appropriate arenediazonium salt 1 (1.0 equiv, 0.10
mmol). The vial was closed with a rubber cap and a CO balloon was
attached. The CO was allowed to bubble into the reaction mixture for 30
seconds and then the reaction was stirred at 40 oC, under CO atmosphere,
until complete consumption of the arenediazonium salt (-naphthol test,
approx. 10-20 minutes). Next, the solvent was removed in vacuo and the
crude solubilized with EtOAc (2 mL). The resulting solution was filtered
through a short pad of silica gel and washed with EtOAc (3 x 4 mL). The
crude mixture was purified by flash chromatography to afford pure samples
of the corresponding Heck products
Scheme 2. The absolute configuration determination.
Based on the absolute configuration of carboxylic ester 2a, a
catalytic cycle starting from the oxidative addition on the
diazonium salt is proposed. Next, the alkene complexation to the
cationic palladium succeeds preferentially through the Si face of
the olefin moiety in the enantiodetermining transition state. In the
sequence, the carbopalladation takes place, followed by CO and
nucleophile insertions affording the corresponding (R)-2 and (R)-
4 products (Scheme 3).
In summary, we have developed the first enantioselective
intramolecular
exocarbonylative
Heck
reaction.
The
unprecedented use of chiral N,N-ligand in an intramolecular Heck
reaction together with the use of arenediazonium salts proved to
benefit the formation of the exocarbonyl product. The developed
methodology showed efficiency towards the synthesis of
enantioenriched and functionalized dihydrobenzofurans. Further
investigations to extend the mechanistic understanding and
substrate variability are ongoing in our laboratory and will be
reported in due course.
Acknowledgements
We thank the financial support of the São Paulo Research
Foundation (FAPESP grants: 2014/25770-6 and 2013/07600-3 [C.
R. D. C.]; 2013/10183-5 and 2018/00271-8 [R. C. C.]), and the
Brazilian National Research Council (CNPq grants 457027/2014-
2 and 305387/2013-8 [C.R.D.C.]). We also thank Dr. V. H. M. da
Silva and Prof. C. C. Oliveira for helpful discussions.
Keywords: enantioselective Heck reactions • intramolecular
Heck reactions• cascade reactions • N,N ligands • palladium
catalysis
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10.1002/anie.201805831
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COMMUNICATION
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10.1002/anie.201805831
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COMMUNICATION
Layout 2:
COMMUNICATION
R2
R. C. Carmona, O. D. Köster, C. R. D.
Correia*
[Pd]
O
The first enantioselective
intramolecular Heck
exocarbonylation
chiral N,N ligand
O
O
CO / Nucleophile
R1
Nu
R2
N2BF4
Page No. – Page No.
R1
mild conditions
operationally simple
up to 95%
N,N-Chiral Ligands Enabling
Palladium-catalyzed Enantioselective
Intramolecular Heck-Matsuda
Carbonylation Reactions by
Sequential Migratory and CO
Insertions.
up to 98:2 er
Nu=MeOH, ArB(OH)2
Remarkable Enantioselective Exocarbonylations: The first examples of novel
enantioselective intramolecular Heck carbonylations are reported employing
arenediazonium salts and N,N-chiral ligands. Enantioenriched dihydrobenzofurans
compounds were obtained through an unprecedented sequence of migratory
insertion followed by CO insertion.
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