Rhodium(I)-catalyzed 1,4-addition of arylboronic acids to acrylic acid in water: One-step preparation of 3-arylpropionic acids

Article abstract of DOI:10.1055/s-0030-1260319

A practical method for the one-step preparation of 3-arylpropionic acids through rhodium-catalyzed 1,4-addition of arylboronic acids to acrylic acid is reported. The method is applicable to a broad scope of aryl boronic acids and displays a wide functional group tolerance operating in water as the optimal reaction medium. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0030-1260319

LETTER
2517
Rhodium(I)-Catalyzed 1,4-Addition of Arylboronic Acids to Acrylic Acid in
Water: One-Step Preparation of 3-Arylpropionic Acids
O
ne-Ste
p
Preparat
i
ion of
3
c
-Arylpropi
o
onic
A
cids las R. Vautravers, Bernhard Breit*
Institut für Organische Chemie und Biochemie, Freiburg Institute for Advanced Studies (FRIAS), Albert-Ludwigs-Universität Freiburg,
Albertstr. 21, 79104 Freiburg, Germany
Fax +49(761)2038715; E-mail: bernhard.breit@chemie.uni-freiburg.de
Received 12 July 2011
Table 1 Reaction Conditions for the 1,4-Addition of Phenylboron
Reagents to Acrylic Acida
Abstract: A practical method for the one-step preparation of 3-
arylpropionic acids through rhodium-catalyzed 1,4-addition of aryl-
boronic acids to acrylic acid is reported. The method is applicable
to a broad scope of aryl boronic acids and displays a wide functional
group tolerance operating in water as the optimal reaction medium.
O
O
BX2
+
Cat. (2.5 mol%)
OH
OH
solvent (0.1 M)
75 °C, 16 h
Key words: boronic acids, acrylic acid, water, conjugate addition,
rhodium
Entry Catalystb
PhBX2
Solvent
H2O
Yield (%)d
c
1
2
[Rh(cod)OH]2
[Rh(cod)OH]2
[Rh(cod)OH]2
[Rh(cod)OH]2
[Rh(cod)OH]2
[Rh(cod)Cl]2
[Rh(cod)2BF4]
[RhCl3·3H2O]
[Ir(cod)Cl]2
PhB(pin)
PhBF3K
31
52
0
Formation of C–C bonds via rhodium catalysis has be-
come a powerful emergent tool in organic synthesis.1 Of
particular value is the rhodium-catalyzed conjugate addi-
tion of arylboronic acids to activated and unactivated al-
kenic substrates (Miyaura–Hayashi reaction) such as
enones,2 unsaturated esters,3 aldehydes,4 amides,5 phos-
phonates,6 sulfones,7 allyl amines,8 allyl sulfones,9 boryl-
alkenes,10 bicyclic alkenes11 and vinyl-12 and
alkynylarenes.13 However, to the best of our knowledge,
the use of a,b-unsaturated carboxylic acids as Michael ac-
ceptors in such a transformation is unknown.14 This is sur-
prising since the resulting 3-arylpropionic acids are highly
selective agonists of the sphingosine-1-phosphate recep-
tor (S1P1) and therefore of significant interest to medici-
nal chemistry.15 Herein, we disclose a one-step protocol
for the preparation of 3-arylpropionic acids employing the
first rhodium-catalyzed 1,4-addition of arylboronic acids
to acrylic acid16 yielding valuable 3-arylpropionic acids
employing water as the optimal reaction medium
(Scheme 1).
H2O
3
Ph4BNa
H2O
4
(PhBO)3
H2O
93
96
93
12
0
5
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
H2O
6
H2O
7
H2O
8
H2O
9
H2O
<10
0
10
11
12
13
[Ru(cod)Cl2]n
[Rh(cod)OH]2
[Rh(cod)OH]2
[Rh(cod)OH]2
H2O
t-BuOH
acetone
dioxane
64
54
0
a Reaction conditions: [Rh(cod)OH]2 (0.005 mmol), acrylic acid (0.2
mmol) and PhBX2 (0.5 mmol) in degassed solvent (1.8 mL) were
heated in a closed Schlenk vessel at 75 °C for 16 h under argon.17
b cod: 1,5-cyclooctadiene.
O
O
B(OH)2
+
c pin: pinacol.
Cat.
OH
d Isolated yields.
OH
FGR
FGR
Scheme 1 1,4-Addition of arylboronic acids to acrylic acid
Phenylboronic pinacol ester and potassium phenyltrifluo-
roborate showed modest activity in the presence of
[Rh(cod)OH]2 in water (31% and 52% respectively, en-
tries 1 and 2). While sodium tetraphenylborate was com-
pletely ineffective (entry 3), phenylboroxine, an
alternative reagent for phenylboronic acid, gave high
yields in this 1,4-addition process (93%, entry 4), compa-
rable to its parent compound (96%, entry 5). [Rh(cod)Cl]2
was also shown to be effective in such a transformation
(93%, entry 6).18 Notably, the reaction between phenylbo-
ronic acid and acrylic acid was run on a 2.5-mmol scale
and furnished slightly lower yield (82%; see Supplemen-
As a model system, we studied the reaction of phenylbo-
ronic acid with acrylic acid employing standard condi-
tions used for the Miyaura–Hayashi reaction (Table 1)
and first looked at the influence of the nature of the orga-
noboron reagent.
SYNLETT 2011, No. 17, pp 2517–2520
x
x
.x
x
.2
0
1
1
Advanced online publication: 19.09.2011
DOI: 10.1055/s-0030-1260319; Art ID: B13111ST
© Georg Thieme Verlag Stuttgart · New York

2518
N. R. Vautravers, B. Breit
LETTER
Table 2 Scope of the Rhodium-Catalyzed 1,4-Addition of Arylbo-
tary Information). An excess of boronic acid proved nec-
essary due to competing protodeborylation.1a Using
cationic rhodium or Rh(III) precursors (entries 7 and 8) or
changing the metal catalyst from iridium (entry 9) to ru-
thenium (entry 10) were deleterious. A screening of suit-
able reaction media revealed water to be the optimal
medium in terms of catalyst activity (entries 5 and 11–13).
It is worth noting that the aqueous medium turns the pro-
cess heterogeneous, allowing for facile product separation
by simple EtOAc extraction. With the optimal, highly ac-
tive catalyst system in hand (Table 1, entry 5), we ex-
plored the substrate scope of the reaction (Table 2).
ronic Acids to Acrylic Acida (continued)
O
[Rh(cod)OH]2
(2.5 mol%)
B(OH)2
+
O
OH
H2O (0.1 M)
75 °C, 16 h
OH
FGR
FGR
Entry
Product
Yield (%)b
76
O
10
11
OH
S
Table 2 Scope of the Rhodium-Catalyzed 1,4-Addition of Arylbo-
ronic Acids to Acrylic Acida
72
O
O
OH
[Rh(cod)OH]2
(2.5 mol%)
B(OH)2
+
O
OH
O
12
13
71
95
H2O (0.1 M)
75 °C, 16 h
OH
FGR
FGR
OH
Entry
Product
Yield (%)b
96
O
H
O
O
1
2
OH
OH
O
a Reaction conditions: [Rh(cod)OH]2 (0.005 mmol), acrylic acid (0.2
mmol) and arylboronic acid (0.5 mmol) in degassed H2O (1.8 mL)
were heated in a closed Schlenk vessel at 75 °C for 16 h under argon.17
b Isolated yields.
80
90
c T = 100 °C.
OH
3
O
Good yields were obtained for the addition of phenylbo-
ronic acid and p-tolylboronic acid to acrylic acid (entries
1 and 2, 96% and 80% yield, respectively). Sterical hin-
drance is tolerated at the boronic acid reaction partner as
exemplified by the formation of 3-(2¢-methylphenyl)pro-
pionic acid (entry 3) and 3-(2¢,6¢-dimethylphenyl)propi-
onic acid (entry 4) in high yields (90% and 83%,
respectively). It is noteworthy that known alternative ac-
cesses to these compounds require multistep synthesis.19
Both electron-donating as well as electron-withdrawing
substituents in the arylboronic acid system were well tol-
erated (entries 5–9). Furthermore, aryl bromides are inert
under these reaction conditions, and allow further func-
tionalization via palladium-based cross-coupling method-
ology. Moreover, heteroaromatic boronic acids as well as
styryl boronic acids were efficient reaction partners (en-
tries 10–12), thus highlighting the wide functional group
tolerance of this catalyst system. Again, a previously re-
ported multistep-demanding synthesis of 3-(3¢-thie-
nyl)propionic acid could be replaced by our simple one-
step protocol (entry 10).20 Even though certain rhodium
catalysts are known to promote the addition of arylboronic
acids to aldehydes, an unprotected aldehyde function
proved compatible with the reaction conditions (entry 13).
OH
4c
83
O
OH
Br
F
O
OH
5
6
7
8
91
87
83
94
O
OH
F3C
O
OH
O
MeO
O2N
OH
9
90
O
Taking into account that a-deuterated 3-phenylpropionic
acid (100% deuteration in a-position, Scheme 2) is ob-
tained when benzene boronic acid reacts with acrylic acid
in D2O, the following mechanism could be proposed
OH
Synlett 2011, No. 17, 2517–2520 © Thieme Stuttgart · New York

LETTER
One-Step Preparation of 3-Arylpropionic Acids
2519
(Scheme 3): transmetallation of arylboronic acid to
[Rh(I)]OH furnishes an arylrhodium(I) complex,12 which
after coordination of acrylic acid followed by insertion
into the Rh–Ar bond would provide the rhodium enolate,
which may be either O- or C-bound. Hydrolysis of this
rhodium enolate with water would release the desired 3-
arylpropionic acid and explains the a-deuterium incorpo-
ration upon use of D2O. The fact that we observed high
yield of the 1,4-addition product compared to a competing
protodeborylation of the arylboronic acid under the exper-
imental conditions applied, suggests that the insertion of
acrylic acid into the Rh–Ar bond is faster than the oxida-
tive addition of the carboxylic acid to the rhodium center
followed by the protolytic cleavage of the rhodium–aryl
bond.
Acknowledgment
This work was supported by the DFG, the International Research
Training Group ‘Catalysts and Catalytic Reactions for Organic Syn-
thesis’ (IRTG 1038), the Fonds der Chemischen Industrie, the
Krupp Foundation and the Humboldt Foundation (postdoctoral fel-
lowship to N.R.V.). We thank Umicore, BASF and Wacker for ge-
nerous gifts of chemicals.
References and Notes
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(2) (a) Sakai, M.; Hayashi, M.; Miyaura, N. Organometallics
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O
[Rh(cod)OH]2
B(OH)2
O
(2.5 mol%)
OH
+
D2O (0.12 M)
75 °C, 16 h
(95%)
D
OH
Scheme 2 1,4-Addition of phenylboronic acid to acrylic acid in
D2O
OH
(3) (a) Sakuma, S.; Sakai, M.; Itooka, N.; Miyaura, N. J. Org.
Chem. 2000, 65, 5951. (b) Chapman, C. J.; Frost, C. G. Adv.
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Ar—B(OH)2
Ar
O
[Rh]–OH
(4) Paquin, J.-F.; Defieber, C.; Stephenson, C. R. J.; Carreira,
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E. M. J. Am. Chem. Soc. 2005, 127, 10850.
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H2O
[Rh]
B(OH)3
OH
OH
O
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O
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O
OH
Scheme 3 Proposed reaction mechanism for the rhodium-catalyzed
1,4-addition of arylboronic acids to acrylic acid
(11) (a) Oguma, K.; Miura, M.; Satoh, T.; Nomura, M. J. Am.
Chem. Soc. 2000, 122, 10464. (b) Lautens, M.;
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In summary, we have developed the first rhodium-cata-
lyzed 1,4-addition of arylboronic acids to acrylic acid fur-
nishing valuable 3-arylpropionic acids in good to high
yields operating in water as the reaction medium. This
methodology is applicable to a variety of substrates, dis-
plays a wide functional group tolerance and expands the
scope of rhodium-catalyzed C–C bond-forming reactions.
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Supporting Information including experimental details and
spectroscopic data of all new compounds is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Synlett 2011, No. 17, 2517–2520 © Thieme Stuttgart · New York

2520
N. R. Vautravers, B. Breit
LETTER
(18) Frost and co-workers reported the failure of the reaction
(14) For non-rhodium-catalyzed use of a,b-unsaturated
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S. G.; Hajdu, R.; Keohane, C. A.; Rosenbach, M. J.;
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between 1-naphthalene boronic acid and free a,b-unsaturated
carboxylic acid with [Rh(COD)Cl]2 (see ref 3b). In our
hands, the use of 2-naphthalene boronic acid in the presence
of acrylic acid did not work with [Rh(COD)OH]2 either,
which tends to prove the poor reactivity of naphthalene
boronic acid derivatives when mixed together with free
carboxylic acid under such conditions.
(19) (a) Zhang, X.; De Los Angeles, J. E.; He, M.-Y.; Dalton,
J. T.; Shams, G.; Lei, L.; Patil, P. N.; Feller, D. R.; Miller,
D. D.; Hsu, F.-L. J. Med. Chem. 1997, 40, 3014.
(16) a- and b-Substituted a,b-unsaturated carboxylic acids did
not react under the conditions developed herein. Neither did
alkylboronic acids (methyl and butylboronic acids) nor
alkenylboronic acids (potassium vinyltrifluoroborate and
vinylboronic acid pinacol ester).
(b) Beaulieu, P. L.; Anderson, P. C.; Cameron, D. R.;
Croteau, G.; Gorys, V. C.; Grand-Maitre, C.; Lamarre, D.;
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(17) Slightly lower yields were obtained when non-degassed H2O
was used.
Synlett 2011, No. 17, 2517–2520 © Thieme Stuttgart · New York

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