Palladium-Catalyzed β-Arylation of α-Keto Esters

Article abstract of DOI:10.1021/acs.orglett.7b00761

A catalyst system derived from commercially available Pd₂(dba)₃ and P^tBu₃ has been applied to the coupling of α-keto ester enolates and aryl bromides. The reaction provides access to an array of β-stereogenic α-keto esters. When the air-stable ligand precursor P^tBu₃·HBF₄ is employed, the reaction can be carried out without use of a glovebox. The derived products are of broad interest given the prevalence of the α-keto acid substructure in biologically important molecules.

Full text of DOI:10.1021/acs.orglett.7b00761

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed β‑Arylation of α‑Keto Esters
Blane P. Zavesky, Samuel L. Bartlett, and Jeffrey S. Johnson*
Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290, United States
S
* Supporting Information
ABSTRACT: A catalyst system derived from commercially
available Pd2(dba)3 and PtBu3 has been applied to the coupling
of α-keto ester enolates and aryl bromides. The reaction
provides access to an array of β-stereogenic α-keto esters. When
the air-stable ligand precursor PtBu3·HBF4 is employed, the
reaction can be carried out without use of a glovebox. The
derived products are of broad interest given the prevalence of
the α-keto acid substructure in biologically important molecules.
that have hampered efforts to fully explore the scope of these
reactions. For example, the sequence of iron chloride, rare
Earth metal or hafnium triflate-catalyzed alkylation of active
methylene compounds with benzylic alcohols22,23 and sub-
sequent aerobic deacylation24 used by our laboratory to access
β-aryl α-keto esters has proven to be intolerant of tert-butyl
esters, bulky β-alkyl substituents, and electron-poor, hindered,
or heterocyclic aryl groups (Scheme 1b). While other methods
for the synthesis of α-keto esters exist, the scopes of many of
these reactions encompass only aryl α-keto esters.25,26
To gain entry to a wider array of β-aryl α-keto esters, we
considered the development of a palladium-catalyzed α-
arylation reaction of n-alkyl α-keto esters. Formation of a
carbon−carbon bond by utilizing the acidic nature of α-keto
esters would constitute an underutilized consonant disconnec-
tion of these compounds. Additionally, if successful, this
method would allow for a variety of electronically diverse β-aryl
α-keto esters to be generated from a single, easily accessible
substrate.
he synthesis of α-keto acids and their derivatives has
Tgarnered substantial attention due to their importance in
biochemistry1,2 as well as natural product and bioactive
compound synthesis.3−6 Furthermore, this versatile functional
group can serve as a precursor for substituted glycolate
products7−18 and α-amino acid derivatives via the enantiose-
lective transfer hydrogenation of α-imino esters19,20 or
transamination of α-keto esters.21 Chiral β-aryl α-keto esters
are useful electrophiles in dynamic kinetic resolution (DKR)
reactions, including Ru-catalyzed asymmetric transfer hydro-
genation reactions12−14 and Rh-catalyzed enantioconvergent
arylation reactions (Scheme 1a).17 These reactions allow for the
construction of stereochemically complex glycolate products
from racemic starting materials. Unfortunately, current
methods to prepare these substrates have some limitations
Scheme 1. β-Aryl α-Keto Esters: Synthetic Utility and
Preparation
Since the first example of a carbonyl enolate arylation
reaction, reported in 1973 by Semmelhack and co-workers,27
the scope of this reaction has been dramatically expanded. The
reaction has grown to include the use of ketones, aldehydes,
amides, esters, amino acids, nitriles, and activated methylene
compounds as substrates.28−32 We were especially encouraged
by the widespread use of tetralones in α-arylation reac-
tions,33−43 a class of compounds that should have acidities
similar to those of α-keto esters. However, n-alkyl α-keto esters
present a unique set of challenges. A slow reductive elimination
from a Pd enolate species could lead to competitive β-hydride
elimination.44 Furthermore, our laboratory and others have
observed that α-keto esters with enolizable protons decompose
via homoaldol and lactonization in the presence of inorganic
bases such as K2CO3.45
With all of these considerations in mind, we set out to
explore the Pd-catalyzed α-arylation reaction of n-alkyl α-keto
Received: March 14, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00761
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esters. tert-Butyl α-keto ester 1a (Table 1) was chosen as a
Scheme 2. Scope of α-Keto Ester Enolate Arylation
Reaction
model substrate to suppress competitive homoaldol addition.45
a
a
Table 1. Reaction Optimization
a
Reaction conditions: 1.0 equiv of 1a, 2.0 equiv of 2a, 3.0 equiv of
base, 2 mol % of Pd2dba3, 8 mol % of ligand, 110 °C, PhMe ([1a]0 =
b
0.2 M), 12 h. Reaction conducted with 1 mol % of Pd2(dba)3 and 4
mol % of PtBu3.
We first chose to probe the effect of the supporting ligand,
beginning with the electron-rich and sterically hindered ligand
tricyclohexylphosphine (entry 1), shown previously to be an
effective ligand in Pd-catalyzed enolate arylation reactions.46
When no appreciable quantity of desired coupled product 3a
was obtained, we moved on to the more sterically encumbered
ligand cataCXium A, which delivered keto ester 3a in
reasonable yield (entry 2). Encouraged by this result, we
switched to the Buchwald-type ligand DavePhos (entry 3),
which is also well-precedented to work in this type of
reaction.47 When a slight decrease in yield was observed, we
took inspiration from Hartwig’s arylation of malonate
derivatives,48 employing tri-tert-butylphosphine. This ligand
provided product 3a in an isolated yield of 85% (entry 4). The
a
Reaction conditions: 1.0 equiv of 1, 2.0 equiv of 2, 3.0 equiv of
K2CO3, 2 mol % of Pd2dba3, 8 mol % of PtBu3, PhMe ([1]0 = 0.2 M),
110 °C, 12 h. Reaction gave 69% yield when scale was increased to
2.7 mmol. Reaction conducted on 1 g scale.
b
c
tolerated various types of aryl groups allowing the synthesis of
products with meta substituents (3e) and ortho substituents
(3f). Of particular interest to us was the use of heterocyclic aryl
bromides. We were pleased to find that 3-bromopyridine and
unprotected 5-bromoindole proved to be viable coupling
partners (3g and 3h). The use of alkenyl halides resulted in
decomposition of the starting materials (not shown). In
addition to the parent substrate 1a, other α-keto esters were
evaluated in the enolate arylation reaction. As seen with
product 3j, this method allowed facile entry to α-keto esters
with bulky β-alkyl substituents. Additionally, decreasing the size
of the β-alkyl substituent did not significantly decrease the
yields (3k). Finally, in order to test the chemoselectivity of this
reaction, a substrate containing both an ester and an α-keto
ester was tested. Product 3l was generated without any
noticeable formation of a bis-arylated product, highlighting
the gentle nature of these reaction conditions. When β-
disubstituted α-keto esters were used in this reaction,
1
disparity between this isolated yield and the pristine H NMR
spectrum of the crude reaction mixture led us to believe that
some base-promoted decomposition to intractable materials
was occurring. Taking this into consideration, we sought to find
a more optimal base and found that the less basic potassium
carbonate improved the isolated yield of the reaction to 95%
(entry 6). Notably, product 3a was still formed in high yield
when 2 mol % of palladium was employed. (1 mol % of
Pd2(dba)3, entry 7).
With optimal conditions in hand, we next turned to analyzing
the scope of the Pd-catalyzed cross-coupling reaction (Scheme
2). First, a variety of aryl bromides were tested. Both electron-
rich and electron-poor aryl groups gave excellent results. For
instance, α-keto esters 3c and 3d, which would have been
difficult compounds to access using our previous routes (vide
supra), were obtained in excellent yields. The reaction also
B
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decomposition of the starting materials and low conversion to
the tertiary β-substituted product was observed (not shown).
The syntheses of products 3k (Scheme 2) and 3g (Scheme
3) were accomplished on a 1-g scale with yields almost identical
ACKNOWLEDGMENTS
■
The project described was supported by Award No. R35
GM118055 from the National Institute of General Medical
Sciences. We thank Dr. Scott Krabbe of these laboratories for
the synthesis of compound 1i.
Scheme 3. Practical Considerations Associated with the Title
Reaction
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00761.
Experimental procedures, characterization data for all
1
new compounds, and copies of H NMR and 13C NMR
spectra for all new compounds reported in the text
(PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jsj@unc.edu.
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Jeffrey S. Johnson: 0000-0001-8882-9881
Notes
The authors declare no competing financial interest.
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