Palladium catalyzed synthesis of mandelate derivatives from arylboronic acids and glyoxylate hemiacetals

Article abstract of DOI:10.1016/j.tetlet.2017.05.035

NHC-coordinated cyclometalated palladium(II) catalyzed addition of arylboronic acids to methyl 2-hydroxy-2-methoxyacetate gave corresponding various functionalized methyl mandelate derivatives in good yields.

Full text of DOI:10.1016/j.tetlet.2017.05.035

Accepted Manuscript
Palladium Catalyzed Synthesis of Mandelate Derivatives from Arylboronic
Acids and Glyoxylate Hemiacetals
Mariko Sugaya, Tetsuya Yamamoto, Hiraku Shinozaki
PII:
S0040-4039(17)30616-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.05.035
TETL 48928
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
17 April 2017
8 May 2017
12 May 2017
Please cite this article as: Sugaya, M., Yamamoto, T., Shinozaki, H., Palladium Catalyzed Synthesis of Mandelate
Derivatives from Arylboronic Acids and Glyoxylate Hemiacetals, Tetrahedron Letters (2017), doi: http://dx.doi.org/
10.1016/j.tetlet.2017.05.035
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Palladium Catalyzed Synthesis of Mandelate
Derivatives from Arylboronic Acids and
Glyoxylate Hemiacetals
Leave this area blank for abstract info.
Mariko Sugayaa, Tetsuya Yamamotob, ∗ and Hiraku Shinozaki

1
Tetrahedron Letters
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Palladium Catalyzed Synthesis of Mandelate Derivatives from Arylboronic Acids and
Glyoxylate Hemiacetals
Mariko Sugayaa, Tetsuya Yamamotob, ∗ and Hiraku Shinozakib
a Department of Materials Science and Engineeing, Graduate School of Engineering, Tokyo Denki University, 5 Senju Asahi-cho Adachi-ku, Tokyo 120-8551,
Japan
b Department of Applied Chemistry, School of Engineering, Tokyo Denki University, 5 Senju Asahi-cho Adachi-ku, Tokyo 120-8551, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
NHC-coordinated cyclometalated palladium(II) catalyzed addition of arylboronic acids to
methyl 2-hydroxy-2-methoxyacetate gave corresponding various functionalized methyl
mandelate derivatives in good yields.
Received in revised form
Accepted
2009 Elsevier Ltd. All rights reserved.
Available online
Keywords:
N-heterocyclic carbene
Palladium catalysis
1,2-Addition
Arylboronic acid
Glyoxylate hemiacetal
As mandelate derivatives are scalable synthetic building
blocks and will be readily transformed to other utilized
functionalized molecules such as 1,2-diols β-amino alcohols and
α-amino acid derivatives, they are key intermediates for various
medicine such as Plavix1 and Duloxetine.2 The traditional
syntheses of mandelate derivatives are two routes, the hydrolysis
of cyanohydrins3 and the Friedel-Crafts arylation of glyoxalate
derivatives,2,4,5 although each have their specific limitations. The
former route needs the use of toxic cyano reagents such as HCN
in its synthetic process. The latter route is limited to electron-rich
aromatic compounds5c,e and five-membered heteroaromatic
compounds.2,5a,b,d–g In the past two decades, transition-metal
catalyzed 1,2-addition of arylboron reagents to carbonyl
compounds has been developed as the one of the important
glyoxylate hemiacetals which have a similar structure as
methanediol and envisaged that the palladium catalysts would be
useful for the arylation of glyoxylate hemiacetals using
arylboronic acids (Scheme 1).
synthesis of benzylic alcohols with wide range of functional
6–8
group.
Although the catalytic additions have been applied to
synthesis of mandelate derivatives from glyoxalates,9 the use of
glyoxalate hemiacetals as substrate have not been examined in
these reaction.
Scheme 1. Strategy of Pd-catalyzed 1,2-addition to hemiacetal.
Previously, we demonstrated that the NHC-coordinated
cyclometalated palladium (II) complexes have excellent catalytic
activity for the hydroxymethylation of arylboronic acids using
aqueous formaldehyde.8c Although aqueous formaldehyde is an
equilibrium mixture of formaldehyde and its hydrated form
(methanediol) and the dominant form is methanediol in this
equilibrium,10 the palladium catalyzed hydoxymethylation of
arylboronic acids was proceeded smoothly and effectively. From
Table 1 lists the survey of a NHC-coordinated cyclometalated
palladium (II) complex in the arylation of methyl 2-hydroxy-2-
methoxyacetate 2 using 4-biphenylboronic acid 3a. Predictably,
complex 1a acted as a suitable catalyst for this reaction with 0.5
mol% catalyst loading and provided the corresponding alcohol 4a
in 88% yield (entry 1). Methyl or phenylthio-substituted NHC
coordinated complexes 1b and 1c that exhibited remarkable
catalytic activity compared to 1a in the catalytic
t—he—re—sults, we have focused our attention on structures of
∗ Corresponding author. Tel.: +81-3-5284-5456; e-mail: t-yamamoto@mail.dendai.ac.jp

2
hydroxymethylation of arylboronic acids8c although showed
slightly poor catalytic activity in this reaction (entries 2 and 3).
The catalytic activity significantly decreased by replacing the
2,6-diisopropylphenyl group of 1a with mesityl groups (entry 4).
Further optimization of reaction conditions of the 1a-
catalyzed addition of 4-biphenylboronic acid 3a and hemiacetal 2
is summarized in Table 2. Although high polar solvent such as
DMF was no effective for the reaction, the yield by the use of
low polor solvents such as 1,4-dioxane, THF and 1,2-
dichloroethane instead of toluene provided almost the same
yields (entries 1–4). Carbonate salts such as Cs2CO3 and K2CO3
were slightly less effective than K3PO4 for this addition (entries 5
and 6). The yield was declined to 39% by the use of CsF. (entry
7). Ethyl 2-hydroxy-2-ethoxyacetate instead of hemiacetal 2 was
usable for this reaction and afforded the corresponding ethyl 2-
([1,1'-biphenyl]-4-yl)-2-hydroxyacetate in 81% yield (entry 8).
Table 1. Survey of NHC-coordinated cyclometalated palladium
(II) complexes
O
1a d
0.25 mol%
(0.5 mol% Pd)
O
B(OH)2
HO
HO
OMe
+
OMe
K3PO4 (2 equiv.)
Ph
OMe
4a
tolene (1 mL)
70 C, 2 h
in a sealed tube
2
3a
3 equiv.
0.5 mmol
Ph
N
R
Table 2. The optimization of reaction conditions
N
C
N
N
C
Pd
Pd
Pd
Cl
Cl
Cl
Cl
Pd
C
C
N
N
N
N
Entry
Base
Solvent
1,4-Dioxane
THF
Yield (%)a
R
1d
1a
1b
1c
: R = H
: R = Me
: R = SPh
1
2
3
4
5
6
7
8c
K3PO4
K3PO4
K3PO4
K3PO4
Cs2CO3
K2CO3
CsF
81
82
Entry
Catalyst
Yield (%)a
DCEb
75
1
2
3
4
1a
1b
1c
1d
88
83
85
67
DMF
trace
67
Touene
Touene
Touene
Touene
71
a
Isolated Yields.
39
Then, we examined the correlation of the yield of 4a on the
K3PO4
81
amount of hemiacetal 2 in 1a catalyzed addition of 3a (Figure 1).
The yields tended to rise as the increase of the amount of 1a. In
the region of 1–2 equivalent of hemiacetal 2, the yields and the
amount of hemiacetal 2 showed good linear correlation. The
yield improved dramatically by using more than 2 equivalent of
hemiacetal 2 but scarcely raised even if the amount of hemiacetal
2 increased to 4 from 3 equivalent.
a Isolated yields
b 1,2-Dichloroethane
c Ethyl 2-hydroxy-2-ethoxyacetate was used instead of 2.
The scope and limitation of the 1a-catalyzed addition of
arylboronic acids with various functional groups to hemiacetal 2
is summarized in Table 3. Naphthalen-2-ylboronic acid and weak
electron donating or withdrawing groups such as methylthio,
trifluoromethyl, tert-butyl and methoxycarbonyl groups
substituted arylboronic acids were converted to the desired
products
in
good
to
excellent
yields,
but
4-
methoxyphenylboronic acid and 4-acetylphenylboronic acid gave
the corresponding alcohols in moderate yields (entries 1, 3–5 and
9–12). Moreover, the reaction proceeded smoothly even though
sterically bulky arylboronic acids such as Naphthalen-1-
ylboronic acid and 2,5-dimethylphenylboronic acid was used
(entries 2 and 6). Bromo substituted arylboronic acids reacted in
moderate yields, although the bromine atom on the aromatic ring
remained intact in this reaction condition (entry 7).
Heteroarylboronic acids such as furan-, thiophen- and
pyridineboronic acids were useful for this reaction but were low
reactivity (entries 13–15).
In conclusion, we developed the palladium catalyzed arylation
of methyl 2-hydroxy-2-methoxyacetate using aryl- and
heteroarylboronic acids to give corresponding various
functionalized methyl mandelate derivatives.
Figure 1. The dependence of the yield of 4a on the amount of 2

3
Table 3. Substrate scope of arylboronic acids
Acknowledgments
We thank the Instrumental Analysis Laboratory, University of
Toyama and Doshisha University for the HRMS measurements
and acknowledge Mrs. A. Sato at A Rabbit Science Co., Ltd. for
elemental analysis. This work was supported by the Sasakawa
Scientific Research Grant from The Japan Science Society.
Entry
1
Arylboronic acid 3
Product 4
Yield (%)a
82
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Isolated yield.
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d 1.0mmol of 3o was used.

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Highlights
• Synthesis of mandelate derivatives from
hemiacetals such as methyl 2-hydroxy-2-
methoxyacetate.
• Cyclometalated NHC-Pd(II) complex was used
as highly reactive catalyst.
• The reactions showed functional groups
tolerance.

6