Palladium/phosphite-catalyzed 1,4-addition of arylboronic acids to acrylic acid derivatives

Article abstract of DOI:10.1021/jo702546t

(Chemical Equation Presented) 1,4-Addition of arylboronic acids to acrylic acid derivatives proceeds efficiently in the presence of a palladium catalyst system of Pd(OAc)₂/(PhO)₃P to produce the corresponding 3-arylpropionic acid derivatives. The use of the phosphite ligand is the key to conducting the addition smoothly with suppressing the competing Mizoroki-Heck-type oxidative coupling.

Full text of DOI:10.1021/jo702546t

bipyridine,7 Pd0/CHCl3,8 and palladacycles,9 which selectively
promote the 1,4-addition in preference to MH coupling, have
been reported. However, in most cases using such catalyst
systems, substrates are limited to enones and enals, and R,â-
unsaturated esters are usually converted to MH coupling
products predominantly.6a,b,d Exceptionally, it has been reported
that a PdII/bipyridine catalyst allows the 1,4-addition of some
crotonates and cinnamates,7 but there has been, to our knowl-
edge, no selective example for the palladium-catalyzed 1,4-
addition of arylboronic acids to more simple esters, â-unsub-
stituted acrylates, to form 3-arylpropionic acid derivatives.
3-Arylpropionic acids and their derivatives are useful building
blocks in organic synthesis10 and known to exhibit interesting
biological activities.11 During our continuous study of transition
metal-catalyzed arylation of unsaturated compounds using
arylboron reagents,12 we observed a notable ligand effect in the
palladium-catalyzed reaction of arylboronic acids with acrylates
that the use of triphenyl phosphite can suppress MH coupling
to give the corresponding 3-arylpropionates selectively. We
report herein the results for the arylation of acrylate esters and
related compounds.
Palladium/Phosphite-Catalyzed 1,4-Addition of
Arylboronic Acids to Acrylic Acid Derivatives
Hakaru Horiguchi, Hayato Tsurugi, Tetsuya Satoh,* and
Masahiro Miura*
Department of Applied Chemistry, Faculty of Engineering,
Osaka UniVersity, Suita, Osaka 565-0871, Japan
satoh@chem.eng.osaka-u.ac.jp;
miura@chem.eng.osaka-u.ac.jp
ReceiVed NoVember 28, 2007
When phenylboronic acid (1a) (1.2 mmol) was treated with
n-butyl acrylate (2a) (1 mmol) in the presence of Pd(OAc)2 (0.05
mmol) and Na2CO3 (2 mmol) as catalyst and base, respectively,
in DMF (5 mL) at room temperature under air, the oxidative
MH coupling proceeded catalytically to produce n-butyl cin-
namate (4a) in 59% yield (Table 1, entry 1). A small amount
of biphenyl (5a) was also formed as the oxidative homocoupling
product of 1a,13 but no 1,4-adduct, n-butyl 3-phenylpropionate
1,4-Addition of arylboronic acids to acrylic acid derivatives
proceeds efficiently in the presence of a palladium catalyst
system of Pd(OAc)2/(PhO)3P to produce the corresponding
3-arylpropionic acid derivatives. The use of the phosphite
ligand is the key to conducting the addition smoothly with
suppressing the competing Mizoroki-Heck-type oxidative
coupling.
(6) (a) Nishikata, T.; Yamamoto, Y.; Miyaura, N. Angew. Chem., Int.
Ed. 2003, 42, 2768. (b) Nishikata, T.; Yamamoto, Y.; Miyaura, N.
Organometallics 2004, 23, 4317. (c) Nishikata, T.; Yamamoto, Y.; Miyaura,
N. Chem. Lett. 2005, 34, 720. (d) Gini, F.; Hessen, B.; Minnaard, A. J.
Org. Lett. 2005, 7, 5309. (e) Nishikata, T.; Yamamoto, Y.; Miyaura, N.
AdV. Synth. Catal. 2007, 349, 1759.
The transition metal-catalyzed 1,4-conjugate addition of
organometallic reagents to R,â-unsaturated carbonyl compounds
is a powerful tool for C-C bond formation. Among the various
reagents, organoboron compounds are highly useful due to their
commercial availability, stability, and low toxicity.1 Since
Miyaura and co-workers reported the rhodium-catalyzed 1,4-
addition of arylboronic acids to enones as pioneering work,2
the conjugate arylation has been widely developed.3 Meanwhile,
the palladium-catalyzed version has been less explored, probably
due to the fact that a Mizoroki-Heck-type oxidative coupling
(MH coupling)4 takes place often competitively. Recently,
several catalyst systems including Pd0/SbCl3,5 cationic PdII,6 PdII/
(7) (a) Lu, X.; Lin, S. J. Org. Chem. 2005, 70, 9651. (b) Lin, S.; Lu, X.
Tetrahedron Lett. 2006, 47, 7167.
(8) Yamamoto, T.; Iizuka, M.; Ohta, T.; Ito, Y. Chem. Lett. 2006, 35,
198.
(9) (a) He, P.; Lu, Y.; Dong, C.-G.; Hu, Q.-S. Org. Lett. 2007, 9, 343.
(b) Suzuma, Y.; Yamamoto, T.; Ohta, T.; Ito, Y. Chem. Lett. 2007, 36,
470. (c) He, P.; Lu, Y.; Hu, Q.-S. Tetrahedron Lett. 2007, 48, 5283. (d)
Bedford, R. B.; Betham, M.; Charmant, J. P. H.; Haddow, M. F.; Orpen,
A. G.; Pilarski, L. T.; Coles, S. J.; Hursthouse, M. B. Organometallics 2007,
26, 6346.
(10) For example, see: (a) Yamanouchi, T.; Yamane, H. Japanese Patent
JP 63250356, 1988. (b) Cui, D.-M.; Zhang, C.; Kawamura, M.; Shimada,
S. Tetrahedron Lett. 2004, 45, 1741.
(11) For example, see: (a) Andersson, K.; Boije, M.; Gottfries, J.;
Inghardt, T.; Li, L.; Lindstedt, A. E.-L. PCT Int. Appl. 1999, WO9962871.
(b) Yan, L.; Huo, P.; Doherty, G.; Toth, L.; Hale, J. J.; Mills, S. G.; Hajdu,
R.; Keohane, C. A.; Rosenbach, M. J.; Milligan, J. A.; Shei, G.-J.; Chrebet,
G.; Bergstrom, J.; Card, D.; Quackenbush, E.; Wickham, A.; Mandala, S.
M. Bioorg. Med. Chem. Lett. 2006, 16, 3679.
(1) For reviews, see: (a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95,
2457. (b) Suzuki, A. J. Organomet. Chem. 1998, 576, 147. (c) Miyaura, N.
In Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.; de Meijere, A.,
Diederich, F., Eds.; Wiley-VCH: Weinheim, Germany, 2004; pp 41-123.
(2) Sakai, M.; Hayashi, H.; Miyaura, N. Organometallics 1997, 16, 4229.
(3) (a) Fagnou, K.; Lautens, M. Chem. ReV. 2003, 103, 169. (b) Hayashi,
T.; Yamasaki, K. Chem. ReV. 2003, 103, 2829. (c) Miura, T.; Murakami,
M. Chem. Commun. 2007, 217.
(4) For recent examples, see: (a) Jung, Y. C.; Mishra, R. K.; Yoon, C.
H.; Jung, K. W. Org. Lett. 2003, 5, 2231. (b) Andappan, M. M. S.; Nilsson,
P.; Larhed, M. Chem. Commun. 2004, 218. (c) Andappan, M. M. S.; Nilsson,
P.; von Schenck, H.; Larhed, M. J. Org. Chem. 2004, 69, 5212. (d) Yoon,
C. H.; Yoo, K. S.; Yi, S. W.; Mishra, R. K.; Jung, K. W. Org. Lett. 2004,
6, 4037. (e) Akiyama, K.; Wakabayashi, K.; Mikami, K. AdV. Synth. Catal.
2005, 347, 1569. (f) Enquist, P-A.; Lindh, J.; Nilsson, P.; Larhed, M. Green
Chem. 2006, 8, 338. (g) Delcamp, J. H.; White, M. C. J. Am. Chem. Soc.
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Soc. 2006, 128, 16384. (i) Penn, L.; Shpruhman, A.; Gelman, D. J. Org.
Chem. 2007, 72, 3875.
(12) (a) Oguma, K.; Miura, M.; Satoh, T.; Nomura, M. J. Am. Chem.
Soc. 2000, 122, 10464. (b) Oguma, K.; Miura, M.; Satoh, T.; Nomura, M.
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Nomura, M. Angew. Chem., Int. Ed. 2004, 43, 5063. (d) Ueura, K.; Satoh,
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Satoh, T.; Miura, M. J. Org. Chem. 2007, 72, 2255.
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10.1021/jo702546t CCC: $40.75 © 2008 American Chemical Society
Published on Web 01/15/2008
1590
J. Org. Chem. 2008, 73, 1590-1592

TABLE 1. Reaction of Phenylboronic Acid (1a) with n-Butyl
TABLE 2. Reaction of Arylboronic Acids 1 with Acrylic Acid
Derivatives 2a
Acrylate (2a)a
yield (%)b
temp time
(°C) (h)
5a
(mmol)
entry
ligand
base
3a
4a
1
2
3
4
5
6
7
8
9
Na2CO3 rt
48 tr
48 tr
59 (58)
5
26
0.06
0.07
0.24
0.02
0.04
0.03
0.02
tr
K3PO4
K3PO4
K3PO4
rt
100
100
3
1
6
1
1
1
1
1
1
1
3
1
1
3
tr
(PhO)3P
93 (79) tr
(PhO)3P
(PhO)3P
(PhO)3P
(PhO)3P
(PhO)3P
Na2CO3 100
K2CO3 100
Cs2CO3 100
60
76
89
39
3
29
92
85
tr
14
8
tr
16
5
tr
tr
tr
29
tr
9
KF
100
100
100
100
100
100
80
80
50
rt
tr
10c (PhO)3P
K3PO4
0.02
0.05
0.03
0.25
0.02
0.08
0.04
0.08
11
12
13
14
15
16
17
[(2-MeC6H4)O]3P K3PO4
[(4-MeC6H4)O]3P K3PO4
(EtO)3P
(PhO)3P
Ld
(PhO)3P
(PhO)3P
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
93
61
90
tr
4
36 83
a Reaction conditions: 1a (1.2 mmol), 2a (1 mmol), Pd(OAc)2 (0.05
mmol), ligand (0.05 mmol), base (2 mmol) in DMF (5 mL) under air. b GC
yield based on the amount of 2a used. The value in parentheses indicates
t
isolated yield. c Under N2. d L ) [(2,4-Bu2 C6H3)O]3P.
(3a), was detected. While K3PO4 was less effective as base for
the MH coupling (entry 2), 4a was formed in 26% yield at
100 °C (entry 3). Surprisingly, the addition of (PhO)3P (0.05
mmol) changed the direction of the reaction completely. Thus,
with (PhO)3P and K3PO4, the 1,4-addition of 1a to 2a took place
efficiently even under air to selectively afford 3a in 93% yield
within 1 h (entry 4). Among a number of bases examined
(entries 4-8), K3PO4 gave the best result. Without any base,
the reaction did not proceed catalytically (entry 9). Unlike the
MH coupling, the 1,4-addition needs no oxidant in principle.
However, substitution of atmosphere from air to N2 significantly
decreased the yield of 3a (entry 10). While other triaryl
phosphites such as [(2-MeC6H4)O]3P and [(4-MeC6H4)O]3P
worked as well as (PhO)3P, (EtO)3P did not show any positive
effect (entries 11-13). At lower temperatures, the high yield
production of 3a could be attained by elongation of reaction
time (entries 14 and 16-17). Thus, 3a was obtained in 83%
yield even at room temperature after 36 h, along with minor
amounts of 4a and 5a (entry 17).
a Reaction conditions: 1 (1.2 mmol), 2 (1 mmol), Pd(OAc)2 (0.05 mmol),
(PhO)3P (0.05 mmol), K3PO4 (2 mmol) in DMF (5 mL) at 80 °C under air.
b GC yield based on the amount of 2 used. The value in parentheses indicates
isolated yield. c At 100 °C.
SCHEME 1. Reaction Pathways for the Arylation of
Acrylic Acid Derivatives 2
Table 2 summarizes results for the reaction using a number
of arylboronic acids 1b-g with acrylic acid derivatives 2a-e.
In the presence of the catalyst system of Pd(OAc)2/(PhO)3P with
K3PO4 as base, electron-rich (1b,c,f) and -deficient arylboronic
acids (1d,e,g) reacted with 2a smoothly to give the correspond-
ing n-butyl 3-arylpropionates 3b-g in satisfactory yields (entries
1-6). The bromo group in 1g was tolerable under the conditions.
Other alkenes such as ethyl and tert-butyl acrylates (2b,c),
acrylonitrile (2d), and N,N-dimethylacrylamide (2e) also un-
derwent the reaction with 1a to form conjugate arylation
products 3h-k (entries 7-10).
undergoes insertion of an acrylic acid derivative 2 to yield a
key palladium enolate intermediate B. Then, in the presence of
a triaryl phosphite ligand, hydrolysis of B rather than â-hydrogen
elimination appears to selectively take place to form 3. In the
reaction medium, water arisen from boronic acids or adventitious
The present reaction may be initiated by transmetalation of
a divalent palladium precursor with an arylboronic acid 1 to
form an arylpalladium intermediate A (Scheme 1). This
J. Org. Chem, Vol. 73, No. 4, 2008 1591

mmol), Pd(OAc)2 (0.05 mmol), (PhO)3P (0.05 mmol), K3PO4 (2
mmol), 1-methylnaphthalene (ca. 50 mg) as internal standard, and
DMF (5 mL). The resulting mixture was stirred under air at 80 °C.
GC and GC-MS analyses of the mixtures confirmed formation of
3, 4, and/or 5. Then, the mixture was cooled to room temperature,
and Et2O (100 mL) and water (100 mL) were added. After the
organic layer was washed by water (100 mL, three times) and dried
over sodium sulfate, the solvents were evaporated under vacuum.
The product was isolated by thin-layer chromatography on silica
gel, using hexane-ethyl acetate (99:1, v/v) as eluant.
one may be participated. While the exact function of the ligand
is not definitive at the present stage,14,15 one of the possibilities
is to crowd on the Pd center to prevent the â-hydrogen
elimination.16 In each run performed, a minor amount of biaryl
was formed. Once the oxidative homocoupling of 1 occurs, Pd0
species may be generated. Under air, this seems to be able to
be reoxidized to PdII, which circumvents catalyst deactivation.13
In summary, we have demonstrated that 1,4-addition of
arylboronic acids to acrylic acid derivatives can be performed
efficiently in the presence of a palladium catalyst system of
Pd(OAc)2/(PhO)3P. The use of the phosphite ligand dramatically
promotes the 1,4-addition and suppresses the competitive
Mizoroki-Heck-type oxidative coupling. Thus, this protocol
seems to provide a useful route to 3-arylpropionic acid deriva-
tives.
n-Butyl 3-phenylpropionate (3a) (entry 4 in Table 1):16 1H
NMR (400 MHz, CDCl3) δ 0.91 (t, J ) 7.3 Hz, 3H), 1.29-1.39
(m, 2H), 1.54-1.62 (m, 2H), 2.62 (t, J ) 7.3 Hz, 2H), 2.95 (t, J )
7.3 Hz, 2H), 4.07 (t, J ) 6.6 Hz, 2H), 7.18-7.21 (m, 3H), 7.25-
7.30 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 13.7, 19.1, 30.6,
31.0, 35.9, 64.3, 126.2, 128.2, 128.4, 140.5, 173.0; HRMS m/z calcd
for C13H18O2 (M+) 206.1307, found 206.1313.
n-Butyl 3-(2-bromophenyl)propionate (3g) (entry 6 in Table
2): 1H NMR (400 MHz, CDCl3) δ 0.92 (t, J ) 7.3 Hz, 3H), 1.30-
1.39 (m, 2H), 1.55-1.63 (m, 2H), 2.64 (t, J ) 8.1 Hz, 2H), 3.07
(t, J ) 8.1 Hz, 2H), 4.08 (t, J ) 6.6 Hz, 2H), 7.05-7.09 (m, 1H),
7.21-7.26 (m, 2H), 7.53 (d, J ) 7.7 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 13.7, 19.1, 30.6, 31.4, 34.1, 64.4, 124.3, 127.5, 128.0,
130.4, 132.8, 139.8, 172.7; HRMS (CI) m/z (MH+) calcd for C13H18-
BrO2 285.0490, found 285.0484.
Experimental Section
General Procedure for 1,4-Addition of Arylboronic Acids
with Acrylic Acid Derivatives. To a 20-mL two-necked flask were
added arylboronic acid 1 (1.2 mmol), acrylic acid derivative 2 (1
(14) Triaryl phosphites have been used as ligands for Pd-catalyzed cross-
coupling reactions. For recent examples, see: (a) Beller, M.; Zapf, A. Synlett
1998, 792. (b) Zhang, S.; Marshall, D.; Liebeskind, L. S. J. Org. Chem.
1999, 64, 2796. (c) Zapf, A.; Beller, M. Chem. Eur. J. 2000, 6, 1830. (d)
Bedford, R. B.; Hazelwood, S. L.; Limmert, M. E.; Albisson, D. A.; Draper,
S. M.; Scully, P. N.; Coles, S. J.; Hursthouse, M. B. Chem. Eur. J. 2003,
9, 3216. (e) Tsukada, N.; Sugawara, S.; Nakaoka, K.; Inoue, Y. J. Org.
Chem. 2003, 68, 5961. (f) Kayaki, Y.; Koda, T.; Ikariya, T. J. Org. Chem.
2004, 69, 2595. (g) Kayaki, Y.; Koda, T.; Ikariya, T. Eur. J. Org. Chem.
2004, 4989. (h) Ju, J.; Nam, H.; Jung, H. M.; Lee, S. Tetrahedron Lett.
2006, 47, 8673. (i) He, P.; Lu, Y.; Hu, Q.-S. Tetrahedron Lett. 2007, 48,
5283.
(15) During our investigation regarding this work, Hu’s and Bedford’s
groups reported that phosphite-based palladacycles promote 1,4-addition
of arylboronic acids to enones independently.9c,d In our case, a mechanism
involving a similar palladacycle intermediate formed in situ cannot be
excluded at the present stage. However, a ligand, tris[2,4-di(tert-butyl)-
phenyl] phosphite, which gave the best results in their work, was found to
be less effective in our system (entry 15 in Table 1).
Acknowledgment. This work was partly supported by a
Grant-in-Aid from the Ministry of Education, Culture, Sports,
Science and Technology, Japan.
Supporting Information Available: Standard experimental
procedure and characterization data of products. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO702546T
(16) A similar effect by diphosphine ligands added in a Rh-catalyzed
reaction of 1 with 2 was also observed. Zou, G.; Guo, J.; Wang, Z.; Huang,
W.; Tang, J. Dalton Trans. 2007, 3055.
1592 J. Org. Chem., Vol. 73, No. 4, 2008