Pd-catalyzed synthesis of arylacetic acid derivatives from boronic acids

Article abstract of DOI:10.1039/b100834j

A palladium(0)-catalyzed cross-coupling reaction between arylboronic acids or esters and α-bromoacetic acid derivatives is described which allows the synthesis of various functionalized arylacetic acid derivatives under mild conditions.

Full text of DOI:10.1039/b100834j

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Pd-catalyzed synthesis of arylacetic acid derivatives from boronic acids†
Lukas J. Gooßen*
Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, D-45470 Mülheim an der Ruhr, Germany.
E-mail: goossen@mpi-muelheim.mpg.de; Fax: +49-208-306-2985; Tel: +49-208-306-2392
Received (in Cambridge, UK) 23rd January 2001, Accepted 22nd February 2001
First published as an Advance Article on the web 21st March 2001
A palladium(0)-catalyzed cross-coupling reaction between
arylboronic acids or esters and a-bromoacetic acid deriva-
tives is described which allows the synthesis of various
functionalized arylacetic acid derivatives under mild con-
ditions.
this effect, we varied both the steric and the electronic properties
of the ligand (entries 1–9). Tri(m-tolyl)phosphine gives only
poor selectivities, which led us to conclude that the steric bulk
of the tri(o-tolyl)phosphine is responsible for the good selectiv-
ities. Additionally, the lower selectivities observed for tri(o-
ethylphenyl)-, tri(m-xylyl)-, tri(mesityl)-, and di-tert-butyl-
biphenyl-2-ylphosphine indicate that the ligand must not be too
electron-rich. These combined requirements are best fulfilled
with tri(1-naphthyl)phosphine, and indeed, this ligand leads to
enhanced product selectivity. Chelating phosphines such as
(±)-BINAP totally inhibited the reaction, suggesting that the
catalytic cycle proceeds through mono-ligated palladium
complexes.
Both palladium(II) acetate and tris(dibenzylideneacetone)
dipalladium(0) can be used as palladium(0) precursors and show
no significant differences in activity (entries 3, 14). However,
the amount of biaryl formed is slightly higher when pallad-
ium(II) acetate is used. This suggests that the boronic acid
initially acts as a reducing agent for the palladium(II). Since a
slight excess of boronic acid is usually added, this reaction has
no influence on the isolated yields.
The choice of the base also affects the product selectivity
(entries 3, 10, 11 and 8, 15). Both K2CO3 and K3PO4 are equally
suitable as bases. However, at room temperature, shorter
reaction times were often observed with potassium phosphate.
KF was inferior for most substrates since larger amounts of the
reduction products were formed. Only in the case of some
electron-poor boronic acids did KF become the base of choice
(see also Table 2). Other bases, for instance triethylamine, were
significantly less active. Best results were obtained with excess
amounts of base.
THF proved to be by far the most effective solvent. In
acetonitrile, the reaction was much slower and the use of more
polar solvents, e.g. DMF, drastically decreased the amount of
isolable products. This could indicate that hydrolysis of the ester
occurs. In THF, however, the presence of small quantities of
Methylenecarboxy groups are key functionalities in many
biologically active compounds such as the antiinflammatory
and analgesic drugs Indomethacin or Aclofenac.1 A mild and
efficient procedure for the introduction of the methylene-
carboxy group into functionalized molecules is thus of great
interest. Traditional syntheses involve multistep procedures that
are often incompatible with sensitive functionalities.2 Alter-
natively, transition metal-catalyzed cross-coupling reactions
between aryl halides and Reformatsky reagents,3 tin,4 copper,5
and other enolates,6 or ketene acetals have been employed.7
Some electrochemical syntheses have also been reported.8
However, especially for applications in combinatorial chem-
istry, most of these syntheses are quite inconvenient due to the
instability or toxicity of the reagents or the required bases.
We imagined that the inverse approach of combining an aryl-
metal species with an a-halocarbonyl derivative might be an
interesting alternative, especially for substrates containing
sensitive functions such as enolizable keto-groups. Due to their
easy handling and long shelf life, arylboronic acid derivatives
would be the starting materials of choice, particularly for small-
scale reactions. Arylboronic esters have recently become widely
accessible from aryl halides by in situ coupling reactions that
tolerate many functional groups.9,10 In order to permit an
application of the outlined coupling reaction in drug discovery,
it is of utmost importance to overcome the necessity of using
highly toxic reagents such as thallium carbonate.11 Initial
studies were carried out with phenylboronic acid and ethyl
bromoacetate (Scheme 1).
Under standard Suzuki conditions using tetrakis(triphenyl-
phosphine)palladium and potassium carbonate in DMF,12 only
trace amounts of the expected product 3 were detected. Instead,
redox reactions between the arylboronic acid and ethyl
bromoacetate predominated, leading to large amounts of
biphenyl 4 and benzene 5. This is not surprising since similar
systems have purposely been used in the synthesis of symmet-
rical biaryls.13 We have now discovered that the selectivity of
the reaction can be completely inverted when bulky, moderately
electron-donating phosphines are employed as ligands on
palladium. Selected results are shown in Table 1.
Table 1 Effects of the reaction conditions on the product distribution
Ligand
Conv. (%) 3a (%)
4a (%)
5a (%)
1
2
3
4
5
6
7
8
9
10b
11c
12d
13e
14f
15g
PPh3
95
75
100
100
100
80
100
100
< 5
100
100
90
34
3
38
23
12
19
15
15
31
7
< 1
15
20
6
< 5
75
< 1
10
5
5
2
5
< 1
7
28
< 1
< 1
< 1
2
P(m-Tol)3
P(o-Tol)3
P(o-EtPh)3
P(m-Xyl)3
P(Mes)3
P(t-Bu)2Biph
P(Nap)3
BINAP
P(o-Tol)3
P(o-Tol)3
P(o-Tol)3
P(o-Tol)33CN
P(o-Tol)3
P(Nap)3
86
51
80
80
67
88
—
78
36
14
35
89
91
Changing the ligand from triphenylphosphine to tri(o-
tolyl)phosphine significantly improves the selectivity towards
the desired coupling product and allows smooth conversions
even at room temperature. In order to determine the origin of
82
100
100
6
10
7
Conditions: 3 mol% Pd(OAc)2, 9 mol% ligand, 5 equiv. base, 2 equiv. H2O,
THF, 20 °C. a Selectivities determined by GC. b KF as base. c NEt3 as base.
d In DMF. e In acetonitrile. f (dba)3Pd2 instead of Pd(OAc)2. g K3PO4 as
base.
Scheme 1 Coupling of benzeneboronic acid and ethyl bromoacetate.
† Dedicated to Professor K. B. Sharpless on the occasion of his 60th
birthday.
DOI: 10.1039/b100834j
Chem. Commun., 2001, 669–670
This journal is © The Royal Society of Chemistry 2001
669

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Table 2 Pd-catalyzed synthesis of arylacetic acid derivatives
bromoacetic esters or a-bromoacetic amides represents a mild
and general approach to arylacetic acid derivatives. The simple
reaction protocol which involves only air-stable chemicals and
does not require absolutely dry solvents makes this reaction a
valuable alternative to the existing protocols, especially for
applications in combinatorial chemistry and drug discovery.
I thank M. Rössig and A. Söthe for technical assistance and
Professor Dr M. T. Reetz for generous support and constant
encouragement.
Method A
Method B
Yield (%)a
Comp. Ar
X
Yield (%)a
3a
3b
3c
3d
3e
3f
3g
3h
3i
3k
3l
3m
6
Phenyl
o-Tolyl
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
N(C5H10
85 (90)
90 (90)
80 (84)
84 (85)
79 (80c
90 (93)
70 (75)b
67 (74)c
40 (40)b
63 (70)
33 (33)b
31 (42)c
81 (89)
87 (91)
75 (79)
68 (70)
76 (79)
60 (65)
1-Naphthyl
p-MeO-Phenyl
p-Acetylphenyl
p-Tolyl
m-Chlorophenyl
p-Formylphenyl
m-Nitrophenyl
m-AcNH-Phenyl
2-Thienyl
Notes and references
‡ Synthesis of 4-bromobutyl phenylacetate (7): A 100 mL flask was charged
with palladium acetate (67.3 mg, 0.30 mmol), tri-1-naphthylphosphine (371
mg, 0.90 mmol), 4-bromobutyl bromoacetate (2b) (2.74 g, 10.0 mmol) and
an excess of potassium phosphate (10.61 g, 50.0 mmol). The reaction vessel
was purged with argon, a solution of benzeneboronic acid (1.46 g, 12.0
mmol) in THF (40 ml) was added and the reaction mixture was stirred at 20
°C overnight. The reaction slurry was then poured into water (300 mL) and
extracted 33 with 100 mL portions of dichloromethane. The combined
organic layers were dried over MgSO4, filtered, and the volatiles were
removed in vacuo. The residue was purified by fractional distillation. A
colorless oil (2.41 g, 89%) boiling at 91 °C/0.01 mbar was collected and
identified as the desired product. 1H NMR (300 MHz, CDCl3, 25 °C, TMS):
d = 7.33–7.26 (m, 5H), 4.12 (t, 3J (H,H) = 6 Hz, 2H), 3.62 (s, 2H), 3.38
(t, 3J (H,H) = 6 Hz, 2H), 1.87 (m, 2H), 1.79 (m, 2H) ppm; 13C NMR (75
MHz, CDCl3, 25°C, TMS): d = 171.5, 134.0, 129.2, 128.6, 127.1, 63.8,
41.4, 32.9, 29.2, 27.2 ppm; MS (70 eV): m/z (%): 270(6) [M+], 191(4),
179(4), 136(23), 91(100); HRMS: calcd. for C12H15BrO2 [M+]: 270.02555;
found: 270.02546; anal. calcd. for C12H15BrO2 (271.16): C, 53.16; H, 5.58;
N, 0.0; found: C, 52.96; H, 5.65; N, 0.0. The reactions in Table 1 and Table
2 were performed at least twice on 1 mmol scale using 0.05 mL tetradecane
as an internal GC standard. The products were isolated by column
chromatography (SiO2, hexane–ethyl acetate 10+1) and characterized by
means of 1H and 13C NMR as well as by GC-MS.
2-Fluorophenyl
Phenyl
)
7
Phenyl
O(C4H8)Br 72 (90)
68 (72)
Conditions: (A) 1.2 equiv. arylboronic acid, 3 mol% Pd(OAc)2, 9 mol%
P(Nap)3, 5 equiv. K3PO4, 2 equiv. H2O, 20 °C, THF; (B) 1.2 equiv. pinacol
boronate, 3 mol% Pd(OAc)2, 9 mol% P(Nap)3, 5 equiv. K3PO4, 2 equiv.
H2O, 20 °C, THF. a Isolated yields (GC-determined yields in parentheses).
b KF instead of K3PO4. c K2CO3 instead of K3PO4
water had no adverse effect on the reaction outcome so that
special drying of the solvent and the reagents is not required.
The generality and selectivity of the reaction were investi-
gated using a number of arylboronic acids 1a–m in combination
with several alkyl halides (Scheme 2).
§ The IUPAC name for pinacol boronates and pinacol borane is 2,3-bor-
anediyldioxy-2,3-dimethylbutane.
Scheme 2 Pd-catalyzed synthesis of arylacetic acid derivatives.
1 T. Y. Shen, Angew. Chem., 1972, 84, 512; Angew. Chem., Int. Ed. Engl.,
1972, 11, 460.
As can be seen in Table 2 (Method A), most substrates give
good yields. Electron-poor and electron-rich compounds are
equally suitable for the transformation. Even sterically hindered
compounds (o-tolylboronic acid) or substrates that are some-
times problematic in palladium-catalyzed reactions (nitro- or
heteroarenes) were successfully employed. Moreover, products
containing enolizable keto-groups are readily formed without
any signs of side products arising from undesired aldol
condensations.
Besides ethyl bromoacetate (2a), other bromoacetates (2c) or
-amides (2b) can be used. The high selectivity of the
transformation is demonstrated by the formation of compound
7‡ (Table 2): the arylation of 4-bromobutyl bromoacetate (2c)
takes place exclusively a to the carbonyl group even though a
primary alkyl bromide functionality is present.
2 For common methods such as the hydrolysis of benzylnitriles, the
carbonylation of benzyl halides, or the Willgerodt reaction of acet-
ophenones see: J. March, Advanced Organic Chemistry, Wiley, New
York, 4th Edn., 1992, pp. 1281–1282; further methods: (a) T. Zincke,
Chem. Ber., 1869, 2, 738; (b) R. Quelet and J. Gavarret, Bull. Soc. Chim.
Fr., 1950, 1075; (c) J. B. Woell and H. Alper, Tetrahedron Lett., 1984,
25, 3791; (d) Prileshajew, Zh. Russ. Fiz.-Chim. O-va, 1910, 42, 1395.
3 (a) W. W. Leake and R. Levine, J. Am. Chem. Soc., 1959, 81, 1627; (b)
J. F. Fauvarque and A. Jutand, J. Organomet. Chem., 1979, 177, 273; (c)
F. Orsini and F. Pelizzoni, Synth. Comm., 1987, 17, 1389.
4 M. Kosugi, Y. Negishi, M. Kameyama and T. Migita, Bull. Chem. Soc.
Jpn., 1985, 58, 3383.
5 K. Okuro, M. Furuune, M. Miura and M. Nomura, J. Org. Chem., 1993,
58, 7606.
6 (a) M. van Leeuwen and A. McKillop, J. Chem. Soc., Perkin Trans. 1,
1993, 2433; (b) M. F. Semmelhack, B. P. Chong, R. D. Stauffer, T. D.
Rogerson, A. Chong and L. D. Jones, J. Am. Chem. Soc., 1975, 97, 2507;
(c) S. G. Lias and P. Ausloos, J. Am. Chem. Soc., 1977, 99, 4833; (d) M.
Kawatsura and J. F. Hartwig, J. Am. Chem. Soc., 1999, 121, 1473.
7 (a) C. Carfagna, A. Musco and C. Sallese, J. Org. Chem., 1991, 56, 261;
(b) T. Sakamoto, Y. Kondo, K. Masumoto and H. Yamanaka,
Heterocycles, 1993, 36, 2509; (c) F. Agnelli and G. A. Sulikowski,
Tetrahedron Lett., 1998, 39, 8807.
Many functionalized pinacol boronates§ (10) are conven-
iently accessible from aryl halides (8) and bispinacol diboron9
or pinacol borane (9).10 We thus considered it to be important to
extend our reaction to this substrate class (Scheme 3).
8 (a) J. Chaussard, J.-C. Folest, J.-Y. Nédélec, J. Périchon, S. Sibille and
M. Troupel, Synthesis, 1990, 369; (b) M. Durandetti, J.-Y. Nédélec and
J. Périchon, J. Org. Chem., 1996, 61, 1748; (c) J.-C. Folest, J. Périchon,
J. F. Fauvarque and A. Jutand, J. Organomet. Chem., 1988, 342, 259.
9 (a) T. Ishiyama, M. Murata and N. Miyaura, J. Org. Chem., 1995, 60,
7508; (b) T. Ishiyama, Y. Itoh, T. Kitano and N. Miyaura, Tetrahedron
Lett., 1997, 38, 3447.
Scheme 3
10 (a) M. Murata, T. Oyama, S. Watanabe and Y. Masuda, J. Org. Chem.,
1997, 62, 6458; (b) M. Murata, T. Oyama, S. Watanabe and Y. Masuda,
J .Org. Chem, 2000, 65, 164.
11 M. Sato, N. Miyaura and A. Suzuki, Chem. Lett., 1989, 1405.
12 N. Miyaura and A. Suzuki, Chem. Rev., 1995, 95, 2457.
13 (a) S. Yamaguchi, S. Ohno and K. Tamao, Synlett, 1997, 10, 1199; (b)
M. Moreno-Manas, M. Perez and R. Pleixats, J. Org. Chem., 1996, 61,
2346.
We were pleased to find that the best conditions for the
conversion of the boronic acids turned out also to be optimum
conditions for pinacol boronate and that the reaction usually
gives similar yields for both starting materials (Table 2, ‘method
B’).
In summary, the disclosed palladium-catalyzed cross-cou-
pling reaction between arylboronic acids or esters and a-
670
Chem. Commun., 2001, 669–670