Suzuki-Miyaura coupling reaction of boronic acids and ethyl glyoxylate: Synthetic access to mandelate derivatives

Article abstract of DOI:10.1002/ejoc.200800881

The palladium-catalyzed coupling reaction of arylboronic acids with ethyl glyoxylate provides a straightforward method for the synthesis of mandelic esters. Pd₂(dba)₃·CHCl₃ in combination with 2-di-tert-butylphosphanylbiphenyl as the catalytic system and Cs ₂CO₃ as the base were used. The reaction tolerates a wide range of functionalized boronic acids. Mandelic esters were isolated in good-to-excellent yields with a variety of neutral, slightly electron-rich, and slightly electron-poor substituents. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800881

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200800881
Suzuki–Miyaura Coupling Reaction of Boronic Acids and Ethyl Glyoxylate:
Synthetic Access to Mandelate Derivatives
Irene Notar Francesco,[a,b] Alain Wagner,*[b] and Françoise Colobert*[a]
Keywords: C–C coupling / Boronic acids / Boron / Glyoxylates / Palladium
The palladium-catalyzed coupling reaction of arylboronic
acids with ethyl glyoxylate provides straightforward
method for the synthesis of mandelic esters. Pd2(dba)3·CHCl3
in combination with 2-di-tert-butylphosphanylbiphenyl as
the catalytic system and Cs2CO3 as the base were used. The
reaction tolerates a wide range of functionalized boronic
acids. Mandelic esters were isolated in good-to-excellent
yields with a variety of neutral, slightly electron-rich, and
slightly electron-poor substituents.
a
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
by a palladium/thioether–imidazolinium chloride system.[7]
In connection with a project devoted to extend new devel-
opments around the Suzuki coupling reaction,[8] we recently
described the first stereoselective application of Pd-cata-
lyzed addition of boronic acids to aldehydes for the synthe-
sis of pure chiral carbinols.[9]
Herein we report a new catalytic system for the Pd-cata-
lyzed coupling reaction of arylboronic acids and ethyl
glyoxylate to give an original method for the preparation of
α-hydroxy esters. Indeed, mandelate derivatives are impor-
tant synthetic building blocks in preparative organic chem-
istry owing to their versatile functional groups, which may
be easily transformed into other functionalities, for exam-
ple, diols, halo or amino derivatives, and epoxides. This
methodology provides an efficient strategy for the addition
of organometallic compounds to highly functionalized
glyoxylates under mild conditions.
Introduction
As a result of their high stability, easy handling, and non-
toxicity, organoboronic acids are useful reagents for car-
bon–carbon bond formation reactions with various electro-
philes in the presence of transition metals.[1] Recently, more
attention has been directed to the addition of a metal–car-
bon bond to electrophiles bearing a carbon–heteroatom
double bond. Particularly, the addition of organometallic
reagents to aldehydes remains an attractive topic, especially
for the asymmetric issue of the products, and it is relatively
undiscovered if we consider the limited examples in which
transition metals are used. In 1998, Miyaura and coworkers
reported that 1,2-addition of phenylboronic acid to alde-
hydes was catalyzed by a rhodium(I) complex.[2] In the fol-
lowing years, different procedures using Rh catalysts were
developed.[3] In comparison to Rh catalysts, Pd catalysts
for the 1,2-addition of arylboronic acids to aldehydes are
relatively rare. Ohta described addition reactions of aryl-
boronic acids to aromatic aldehydes catalyzed by Pd/PPh3
complexes in the presence of chloroform.[4] Kondo and
Aoyama reported the Pd(OAc)2/tol-binap complex as a
chloroform-free catalyst.[5] Hu proposed anionic pallada-
cycles for the 1,2-addition of arylboronic acids to aromatic
and aliphatic aldehydes at room temperature.[6] More re-
cently, Shirai and Kuriyama described efficient 1,2-addition
reactions of aryl-, heteroaryl-, and alkenylboronic acids to
aromatic, heteroaromatic, and aliphatic aldehydes catalyzed
Results and Discussion
Our first experiment was performed by the addition of
phenylboronic acid (2 equiv.) to ethyl glyoxylate (1 equiv.)
by using the conditions already described,[4,9] that is,
Pd2(dba)3·CHCl3
(1.25 mol-%),
triphenylphosphane
(5 mol-%), and Cs2CO3 (1 equiv.) in toluene at 80 °C, and
we obtained ethyl mandelate 3a as the cross-coupling prod-
uct in only 40% yield (Scheme 1).
[a] Laboratoire de Stéréochimie (UMR CNRS 7509), Université
Louis Pasteur (ECPM),
25 rue Bequerel, 67087 Strasbourg Cedex 2, France
Fax: 33-3-90242744
E-mail: fcolober@chimie.u-strasbg.fr
[b] Novalyst Discovery Bioparc Boulevard Sébatien Brant,
B. P. 30170, 67405 Illkirch Cedex, France
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Scheme 1. Initial coupling experiment.
5692
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 5692–5695

Suzuki–Miyaura Coupling Reaction of Boronic Acids and Ethyl Glyoxylate
Because ligands always play important roles in metal-cat- Table 2. Palladium-catalyzed addition of boronic acids to ethyl
glyoxylate.[a]
alyzed chemistry, we then turned our attention to the effect
of ligands. We screened a wide range of mono- and biden-
tate ligands (Figure 1).
Figure 1. Tested phosphane ligands in Pd-catalyzed addition of
phenylboronic acid to ethyl glyoxylate.
Through the screening process (Table 1), it was observed
that electronic effects and steric hindrance played important
roles in this system. Among various bidentate phosphanes
with large bite angles and rigid or nonrigid skeletons
(Table 1, entries 2–7), only diphos exhibited average cata-
lytic activity (Table 1, entry 2). The dppp and dppb ligands
(Table 1, entries 4 and 5), in which the phosphorus atoms
are 1,3- and 1,4-positioned, respectively, have no catalytic
activity. Furthermore, more-rigid biphosphanes
1 or
dpephos as well as xantphos (Figure 1; Table 1, entries 3, 6,
7) were ineffective. To our delight, biarylphosphane ligands
gave the desired product with isolated yields of 55% for S-
phos[10] and 78% for 2-di-tert-butylphosphanylbiphenyl (2)
(Table 1, entries 8 and 9) in reaction times of 7 and 8 h,
Table 1. Ligand effects in Pd-catalyzed addition of phenylboronic
acid to ethyl glyoxylate.
Entry
Ligand
Time [h]
Yield [%][c]
[a]
1
2
3
4
5
6
7
8
9
10
PPh3
24
18
24
27
27
24
24
7
40
51
Trace
0
0
0
diphos[b]
ligand 1[b]
dppb[b]
dppp[b]
dpephos[b]
xantphos[b]
S-phos[a]
ligand 2[a]
dppf[b]
0
55
78
0
[a] The reactions were carried out with ethyl glyoxylate (solution in
toluene, 50%) (1 mmol), boronic acid (1.5 mmol), Cs2CO3 (1 mmol),
Pd2(dba)3·CHCl3 (0.0125 mmol), and 2-di-tert-butylphosphanylbi-
phenyl (0.05 mmol) in dry toluene (3 mL) at 80 °C. [b] After column
chromatography with unmetalated silica (see Supporting Information).
8
30
[a] Reactions were carried out by using 5 mol-% ligand. [b] Reac-
tions were carried out by using 2.5 mol-% ligand. [c] Isolated yields.
Eur. J. Org. Chem. 2008, 5692–5695
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5693

I. N. Francesco, A. Wagner, F. Colobert
SHORT COMMUNICATION
and we succeeded to decrease the amount of boronic acid poor yield of 41% (Table 2, entry 8). The palladium-cata-
involved in this reaction from 2 to 1.5 equiv. Bidentate lyzed coupling reaction of ethyl glyoxylate with electron-
phosphanes with large bite angles such as dppf (Table 1, rich thiophene boronic acid gave the corresponding coup-
entry 10), which was an excellent ligand in Rh-catalyzed ad- ling product in quantitative yield (Table 2, entry 10).
ditions of boronic acids to aldehydes,[2b] was completely in-
effective under our reaction conditions.
We propose a possible catalytic cycle of this reaction that
shows that cationic PdII complexes are excellent catalysts
To investigate the scope and limitations of this coupling for the addition of arylboronic acids to carbon–heteroatom
reaction, we subjected various arylboronic acids bearing multiple bonds owing to their high Lewis acidity and the
different electron-donating and electron-withdrawing sub- existence of a vacant coordination site.[4,11] At first, oxidat-
stituents in the ortho, meta, and para positions of the phenyl ive addition of chloroform to phosphane-coordinated with
ring to the optimized catalytic system [i.e., Pd2(dba)3· Pd0 would give chloromethyl-coordinated PdII intermediate
CHCl3 (1.25 mol-%), 2-di-tert-butylphosphanylbiphenyl 4, which produces hydroxyl PdII species 5 by counteranion
(5 mol-%); Table 2].
exchange. Therefore, transmetalation between the aryl-
We observed a high difference in the yields among phenyl boronic acid and hydroxyl PdII species 5 occurs to generate
boronic acids having electron-donating or electron-with- aryl PdII intermediate 6 and after coordination of 6 to an
drawing groups. Nonactivated boronic acids with electron- aldehyde functionality, the insertion of the aldehyde into
withdrawing substituents in the para and meta positions the carbon–palladium bond occurs to give palladium alk-
(Table 2, entries 6 and 7) showed lower reactivities. How- oxide 7. Palladium alkoxide 7 is then hydrolyzed to give
ever, in the case of the p-fluoro-, p-bromo-, p-chloro-, and the corresponding alcohol and aryl PdII intermediate 6 is
p-trifluoromethylphenylboronic acids (Table 2, entries 11– recovered (Scheme 2).
13, 15), the corresponding ethyl mandelates were obtained
in good yields, and these new compounds with strong with-
drawing character should be very active for further reac-
tions. However, we observed high yields for the reaction
with aryl boronic acids having electron-donor substituents
(Table 2, entries 2–5, 9, 14). Additionally electron-donor
substituents in the ortho position (Table 2, entries 3, 4, 9)
had no influence on the yield, which indicates that the reac-
tion does not suffer from steric hindrance around the re-
acting center. Surprisingly, the mandelate derivative ob-
tained from 2-methylnaphthylboronic acid was formed in a
Conclusions
Efficient palladium-catalyzed addition of arylboronic
acids to ethyl glyoxylate was realized by using the catalytic
system of Pd2(dba)3·CHCl3/2-di-tert-butylphosphanylbi-
phenyl to afford differently substituted mandelic ester deriv-
atives in excellent yields. Further investigations on an asym-
metric version of this reaction are underway.
Experimental Section
General Procedure for Coupling of Boronic Acids and Ethyl Glyoxyl-
ate: To a suspension of boronic acid (1.5 mmol) and Cs2CO3
(1 mmol, 326 mg) in dry toluene (3 mL) was added Pd2(dba)3·
CHCl3 (0.0125 mmol, 13 mg), 2-di-tert-butylphosphanylbiphenyl
(0.05 mmol, 15 mg) and ethyl glyoxylate (1 mmol) under an atmo-
sphere of argon at room temperature. The temperature was in-
creased to 80 °C, and the mixture was stirred for 7–24 h. The reac-
tion was quenched with water (10 mL), and the resulting mixture
was extracted with dichloromethane (3ϫ15 mL). The combined
organic phase was dried with sodium sulfate, filtered, and concen-
trated under vacuum. The resulting crude mixture was purified by
flash chromatography with unmetalated silica (cyclohexane/
EtOAc).
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures and details of compound characteri-
zation.
Acknowledgments
We are grateful to Novalyst Discovery (www.Novalyst.com) for fin-
ancial support.
[1] a) N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457–2483; b)
A. Suzuki, J. Organomet. Chem. 1998, 576, 147–168; c) B.
Cornlis, W. A. Herrmann in Applied Homogeneous Catalysis
with Organometallic Compounds, VCH, New York, 1996; d) M.
Scheme 2. Proposed mechanism for the addition of arylboronic ac-
ids to ethyl glyoxylate.
5694
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 5692–5695

Suzuki–Miyaura Coupling Reaction of Boronic Acids and Ethyl Glyoxylate
Beller in Transition Metals for Organic Synthesis-Building
Blocks and Fine Chemicals, Wiley-VCH, New York, 1998.
a) M. Sakai, M. Ueda, N. Miyaura, Angew. Chem. Int. Ed.
1998, 37, 3279–3281; b) M. Sakai, M. Ueda, N. Miyaura, J.
Org. Chem. 2000, 65, 4450–4452.
[6] P. He, Y. Lu, C. G. Dong, Q. S. Hu, Org. Lett. 2007, 9, 343–
346.
[7] R. Shirai, R. Shimazawa, M. Kuriyama, J. Org. Chem. 2008,
[2]
[3]
73, 1597–1600.
[8] a) A.-S. Castanet, F. Colobert, T. Schlama, Org. Lett. 2000, 2,
3559–3561; b) A.-S. Castanet, F. Colobert, T. Schlama, J. Mol.
Catal. A 2002, 182–183, 481–487; c) A.-S. Castanet, F.
Colobert, P.-E. Broutin, M. Obringer, Tetrahedron: Asymmetry
2002, 13, 659–665; d) P.-E. Broutin, F. Colobert, Org. Lett.
2003, 5, 3281–3284; e) P.-E. Broutin, I. Cerna, M. Campaniello,
F. Leroux, F. Colobert, Org. Lett. 2004, 6, 4419–4422; f) F.
Colobert, A.-S. Castanet, O. Abillard, Eur. J. Org. Chem. 2005,
3334–3341; g) P.-E. Broutin, F. Colobert, Eur. J. Org. Chem.
2005, 1113–1128; h) P.-E. Broutin, F. F. Colobert, Org. Lett.
2005, 7, 3737–3740; i) G. Hernandez-Torres, S. Choppin, F.
Colobert, Eur. J. Org. Chem. 2006, 1455–1467.
[9] A. Novodomska, M. Dudicova, F. R. Leroux, F. Colobert, Tet-
rahedron: Asymmetry 2007, 18, 1628–1634.
[10] a) S. D. Walker, T. E. Barder, J. R. Martinelli, S. L. Buchwald,
Angew. Chem. Int. Ed. 2004, 43, 1871–1876; b) R. Martin, S. L.
Buchwald, Acc. Chem. Res. 2008, ASAP article.
a) A. Fürstner, H. Krause, Adv. Synth. Catal. 2001, 343, 343–
350; b) C. Moreau, A. S. Weller, C. G. Frost, Tetrahedron Lett.
2001, 42, 6957–6960; c) C. Bolm, J. Rudolph, J. Am. Chem.
Soc. 2002, 124, 14850–14851; d) I. Ozdemir, S. Demir, B. Ce-
tinkaya, J. Mol. Catal. A 2004, 215, 45–48; e) T. Focken, J.
Rudolph, C. Bolm, Synthesis 2005, 3, 429–436; f) S. U. Son,
S. B. Kim, J. A. Reingold, G. B. Carpenter, D. A. Sweigart, J.
Am. Chem. Soc. 2005, 127, 12238–12239; g) T. Focken, J. Ru-
dolph, C. Bolm, Synthesis 2005, 429–436; h) K. Suzuki, S. Ishii,
K. Kondo, T. Aoyama, Synlett 2006, 648–650; i) P. Wu, H. L.
Wu, B. J. Uang, J. Org. Chem. 2006, 71, 833–835; j) J. Chen,
X. Zhang, Q. Feng, M. Luo, J. Organomet. Chem. 2006, 691,
470–474; k) H. F. Duan, J. H. Xie, W. J. Shi, Q. Zhang, Q. L.
Zhou, Org. Lett. 2006, 8, 1479–1481; l) P. M. P. Gois, A. F.
Trindade, L. F. Veiros, V. André, M. T. Duarte, C. A. M.
Afonso, S. Caddick, F. G. N. Cloke, Angew. Chem. Int. Ed.
2007, 46, 5750–5753.
[11] a) B. Zhao, X. Lu, Org. Lett. 2006, 8, 5987–5990; b) G. Liu,
X. Lu, J. Am. Chem. Soc. 2006, 128, 16504–16505; c) S. Lin,
X. Lu, J. Org. Chem. 2007, 72, 9757–9760.
[4] T. Yamamoto, T. Ohta, Y. Ito, Org. Lett. 2005, 7, 4153–4155.
[5] K. Suzuki, T. Arao, S. Ishii, Y. Maeda, K. Kondo, T. Aoyama,
Tetrahedron Lett. 2006, 47, 5789–5792.
Received: September 10, 2008
Published Online: October 29, 2008
Eur. J. Org. Chem. 2008, 5692–5695
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5695