Rhodium-catalyzed heck-type coupling of boronic acids with activated alkenes in an aqueous emulsion

Article abstract of DOI:10.1055/s-2004-829161

Intermolecular couplings between arylboronic acids and activated alkenes catalyzed by a water-soluble tert-bulyl amphosrhodium complex were found to progress at room temperature and generated Heck-type products with high yields and excellent selectivity. Substitution on the alkene component encouraged the formation of products arising from a conjugate addition-protonation process. In the case of Heck product formation, it was necessary to add two equivalents of the alkene component whereby one equivalent is believed to act as a sacrificial hydride acceptor.

Full text of DOI:10.1055/s-2004-829161

2006
PAPER
Rhodium-Catalyzed Heck-Type Coupling of Boronic Acids with Activated
Alkenes in an Aqueous Emulsion
R
h-Catalyze
d
A
rylboro
a
nic Acid A
r
dditions
k
to Alkene
s
Lautens,* John Mancuso,1 Harpreet Grover
Davenport Chemical Laboratories, Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario, M5S 3H6,
Canada
Fax +1(416)9786083; E-mail: mlautens@chem.utoronto.ca
Received 12 May 2004
phosphines, such as the amphos class of ligands9
Abstract: Intermolecular couplings between arylboronic acids and
(Figure 1), were required to obtain high yields.
activated alkenes catalyzed by a water-soluble tert-butyl amphos–
rhodium complex were found to progress at room temperature and
generated Heck-type products with high yields and excellent selec-
tivity. Substitution on the alkene component encouraged the forma-
tion of products arising from a conjugate addition-protonation
process. In the case of Heck product formation, it was necessary to
add two equivalents of the alkene component whereby one equiva-
lent is believed to act as a sacrificial hydride acceptor.
It was of interest to determine if we could replace the
strained olefin coupling partner with other classes of ole-
fin to extend the reaction scope. Substrate 1 was tested
with a variety of activated alkenes, including Nakamura’s
protected cyclopropenone,10 maleic anhydride, hydro-
quinone, and 3-sulfolene but these did not generate any
desired cross-coupled products.
Key words: rhodium, Heck reaction, boron, olefination, alkyla-
tions
X
O
H
X
H
B
n
n
O
Transition-metal catalysis enjoys widespread use as a
method for the creation of carbon-carbon bonds with high
efficiency and often negligible byproduct formation.2 Pal-
ladium is usually the metal of choice for s-bond formation
as evidenced by the numerous coupling protocols in cur-
rent use.3 Cross-couplings using rhodium catalysts have
also been examined in search of protocols which could
display novel reactivity or selectivity. Rh-catalyzed aryla-
tion of olefins has been achieved with Ar-M species
where M = B, Si, and Sn in particular.4,5
[Rh(cod)Cl]2 (2.0 mol%)
t-Bu-amphos Cl (4.8 mol%)
SDS, Na2CO3,
CO2Me
CO2Me
1
Toluene/H2O (1:1), r.t.
X = CH2, O, NMe
62–99%
d.e. >20:1
n = 1, 2
Scheme 1 Rh(I)-catalyzed cascade-type reaction between bi-
functional arylboronate esters and strained olefins
P
P
Our recent studies determined that cross-coupling be-
tween arylboronic acids and styrene-type olefins or 2-vi-
nyl(azaheteroaromatics) could occur in neat water using
SDS as a surfactant with a Rh(I) catalyst.6 A bis(sulfonat-
ed) analogue of triphenylphosphine, TPPDS, was used to
solubilize the catalyst in the aqueous phase. Although the
presence of water is required to generate a catalytically-
active Rh(I)-OH intermediate,7 a competing protodemeta-
lation pathway was active, resulting in diminished yields
of product if boronic acid loading was low. The use of
SDS was beneficial in ameliorating chemical yields, but
organic co-solvents proved ineffective.
Cl-
Cl-
N
N
t-Bu-amphos
Cy-amphos
chloride
chloride
Figure 1 Bulky, electron-rich, water-soluble phosphine ligands
However, as shown in Scheme 2, tert-butyl acrylate gave
a product arising from a Heck-type addition. The newly
created double bond in 2 was formed selectively as the
trans isomer. Cyclopentenone gave product 3 arising from
a conjugate addition-protonation process. These examples
are interesting as they indicate that, in the acrylate case, b-
hydride elimination of rhodium is faster than ring closure.
For the case of the enone, in which b-hydride elimination
is not possible, protodemetalation of the rhodium is faster
than ring closure.
We recently reported a rhodium-catalyzed cascade-type
reaction in which an arylboronate ester bearing a pendant
Michael acceptor olefin (1) could cyclize onto strained
olefins with high diastereoselectivity (Scheme 1).8 The re-
action took place within an organic/aqueous emulsion em-
ploying SDS as phase transfer reagent. A salient feature of
this process was that bulky, electron rich, water-soluble
The generation of the Heck product for the reaction with
tert-butyl acrylate was unusual and unprecedented, con-
sidering that the reaction medium is 50% water. Previous
studies on the addition of arylrhodium intermediates to
alkenes showed a positive correlation between increasing
water content and decreasing Heck product formation.11
SYNTHESIS 2004, No. 12, pp 2006–2014
x
x.
x
x
.
2
0
0
4
Advanced online publication: 21.07.2004
DOI: 10.1055/s-2004-829161; Art ID: P04604SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Rh-Catalyzed Arylboronic Acid Additions to Alkenes
2007
Table 1 Cross-Coupling of Arylboronic Acids with tert-Butyl
Acrylate
O
2 equiv
O
t
CO2 Bu
A
t
2 equiv
CO2 Bu
Ar
Ar
[Rh(cod)Cl]2 (2.0 mol%)
t
CO2 Bu
CO2Me
t-Bu-amphos Cl (4.8 mol%)
SDS, Na2CO3, Toluene/H2O (1:1)
80 °C, 2–5 h
Ar B(OH)2
Bpin
[Rh(cod)Cl]2 (2.0 mol%)
t-Bu-amphos Cl (4.8 mol%),
SDS, Na2CO3,
2, 72%
B
CO2Me
t
CO2 Bu
Toluene/H2O (1:1), 12 h, r.t.
1
2 equiv
O
O
Entry
1
Arylboronic acid
Yield (%) Product (A/B)a
[Rh(cod)Cl]2 (2.0 mol%)
t-Bu-amphos Cl (4.8 mol%)
SDS, Na2CO3, Toluene/H2O (1:1)
80 °C, 2–5 h
CO2Me
>99b
4, (80:20)
3, 63%
B(OH)2
Scheme 2 Rh(I)-catalyzed cross-coupling of an arylboronate ester
with activated olefins. Bpin = 4,4,5,5-tetramethyl-1,3,2-dioxaborola-
nyl
2
3
>99
93
4, (90:10)
5, (86:14)
B(OH)2
This Heck-type process was further investigated using
substituted boronic acids (Table 1).12
4
5
99
99
6, (96:4)
B(OH)2
OMe
An excess of the olefin was used to ensure complete reac-
tion and competing protodeboronation of the boronic acid
was negligible. Phenylboronic acid (Table 1, entry 1) was
found to give predominantly the Heck product 4A over
the saturated or conjugate-addition product 4B. The ratio
of the two products could be improved to favor the unsat-
urated product by performing the reaction at room temper-
ature (entry 2). 2-Methylphenylboronic acid (entry 3) and
2-methoxyphenylboronic acid (entry 4) gave similar se-
lectivity for the Heck product although the yield declined
slightly in the former case. With 2-trifluoromethyl-phe-
nylboronic acid (entry 5), the conjugate addition product
7B was favored although the selectivity was not ideal. In
addition to a potential electronic effect due to the electron-
withdrawing character of CF3, there may be a consider-
able steric component, as this group has been determined
to be larger than a methyl group.13 Indeed, 2,6-dimeth-
ylphenylboronic acid (entry 7) is sterically bulky enough
to interfere with Rh-H elimination and gives high selectiv-
ity for the addition product 8B. 4-Methoxyphenylboronic
acid (entries 8 and 9) gives excellent selectivity for the
Heck product 9A regardless of the temperature as does 2-
methyl-4-methoxyphenylboronic acid (entry 10), which
yields only 10A. 3-Iodophenylboronic (entry 11) acid
gives good selectivity for the Heck product 11A and, more
interestingly, no oxidative addition of the aryl-iodide
bond is observed, positioning this coupling process as
complementary to palladium-based methods.
7, (30:70)
B(OH)2
CF3
6
7
95c
99
7, (2:98)
8, (5:95)
B(OH)2
8
99b
9, (93:7)
MeO
MeO
B(OH)2
9
99
98
9, (93:7)
10
10, (95:5)
B(OH)2
11
94
11, (81:19)
B(OH)2
I
12
13
>99
12, (86:14)
13, (60:40)
O
B(OH)2
>99b
B(OH)2
The introduction of an electron-withdrawing group, such
as an acetyl group at the 4-position of the ring (entry 12),
does not have a significant effect on selectivity. 3-Nitro-
phenylboronic acid (entry 13) gives poor selectivity at 80
°C but this selectivity can be improved to favor the Heck
product 13A at room temperature (entry 14).
O2N
14
>99
13, (87:13)
a Products A and B were isolated as mixture and the ratio was deter-
mined by 1H NMR.
b Reaction was conducted at 80 °C.
c Cyclohexyl–amphos Cl was used as ligand.
In an attempt to further favor the Heck product with phe-
nylboronic acid (entry 1), the pH of the reaction was mod-
ified to see if increasing basicity affected
protodemetalation. The water layer was replaced with a
NaHCO3–NaOH buffer with pH values of 8.06, 9.02,
Synthesis 2004, No. 12, 2006–2014 © Thieme Stuttgart · New York

2008
M. Lautens et al.
PAPER
10.04, and 12.26. Regardless of the pH, the selectivity re- 2-Thienylboronic acid (Table 2, entries 1 and 2) was
mained the same (9:1 in favor of 4A). Increasing the found to be very sensitive to the reaction conditions. Stan-
ligand loading from 4 mol% to 9 mol% or increasing the dard conditions, involving the use of Na2CO3 as base,
equivalents of acrylate had no effect on the selectivity.
gave very low yields of product, although the selectivity
was high for the Heck product 14A. Gratifyingly, this
problem was resolved by using fluoride as base, and re-
sulted in an improved yield, while retaining the excellent
selectivity. 3-Thienylboronic acid was found to be sensi-
tive to temperature. Conducting the reaction at 80 °C (en-
try 3), resulted in the formation of green-colored material,
which was suspected to be polymerized thiophene, in ad-
dition to the desired product 15A. Running the reaction at
room temperature (entry 4), gave not only an excellent
yield of product but improved the selectivity as well.
From this study, it was determined that sterics play a large
role in determining selectivity. Presumably, the environ-
ment around the rhodium center is crucial. 2-Trifluoro-
methylphenylboronic acid was a good choice to probe the
selectivity, and the use of tert-butyl-amphos Cl had given
a mixture of 7A and 7B, with the latter predominating.
The use of cyclohexyl-amphos Cl as ligand (Table 1, en-
try 6) gave complete selectivity for the saturated product.
This indicates that the ligand can exert a profound effect
on the selectivity of the reaction and on the propensity for
the rhodium center to either b-hydride elimination or pro- Boc-protected pyrrole-2-boronic acid (entry 5) was found
todemetalation. Another potential explanation is that the to be extremely unstable and simply deboronated, even
cyclohexyl ligand may render the Rh complex more wa- when using KF as base. The sensitivity of pyrrole-2-bo-
ter-soluble, resulting in longer residency of the rhodium ronic acids to Suzuki coupling conditions has been noted
intermediates in the aqueous phase and shifting the reac- previously in the literature.15 The protecting group is be-
tion pathway to favor protodemetalation.
Heterocyclic boronic acids14 are becoming more prevalent
as coupling partners for the Suzuki reaction and, as sever-
lieved to impact the stability of the substrate as the use of
SO2Ph as protecting group for the pyrrole nitrogen has
been reported to reduce the incidence of deboronation.16
al are now commercially available, a few of these sub- Indole-3-boronic acid (entry 6) was found to give an ex-
strates were tested (Table 2).
cellent yield of the Heck product 16A, the latter being a
potentially useful starting material for the synthesis of
tryptophan/tryptamine analogues.
Table 2 Cross-Coupling of Heteroarylboronic Acids with tert-Bu-
tyl Acrylate
As acrylates seemed to be excellent coupling partners, we
next looked at determining what effect the presence of
substituents had on the reaction. Initial tests quickly deter-
mined that the presence of a or b-substituents on the acry-
late partner had a deactivating effect, thus the reactions
were carried out at 80 °C with an excess of boronic acid
(Table 3).
A
t
2 equiv
CO2 Bu
Ar
Ar
t
CO2 Bu
Ar B(OH)2
[Rh(cod)Cl]2 (2.0 mol%)
t-Bu-amphos Cl (4.8 mol%),
SDS, Na2CO3,
B
t
CO2 Bu
Toluene/H2O (1:1), 12 h, r.t.
Entry
1
Heteroarylboronic acid
Yield (%)
42
Product (A/B)a
Methyl methacrylate (entry 1) gives the addition-protona-
tion product 17 in good yield. The substrates of entries 2
and 3, which have larger b-substituents, give analogous
products 18 and 19, respectively. Related substrates with
a-substituents also give saturated b-arylated products 20
and 21, respectively (entries 4 and 5). However, double
substitution at the b-position is not tolerated and the bo-
ronic acid simply deboronates. Acrylic acid also under-
went addition, but due to the high polarity of the product,
the material was lost during the work-up and purification.
Trans-chalcone was found to be a compatible substrate,
but purification of this addition product was problematic
as well.
14, (96:4)
B(OH)2
S
2
3
73b
83c
14, (97:3)
15, (89:11)
B(OH)2
S
4
5
>99
–
15, (96:4)
d
–
B(OH)2
N
Other classes of electrophiles were also examined and the
results are displayed in Table 4. Acrylamides exhibited
similar reactivity to acrylates and for entry 1, a mixture of
the addition product 22 and the Heck product was ob-
tained in a 9:1 ratio. An excess of boronic acid was re-
quired to obtain good yields of 22. However, tert-
butylacrylamide (entry 2) generated the Heck product 23
exclusively and in high yield. For N,N-dimethylacryl-
amide (entry 3), it was found that 24 was the sole product
only if an excess of the acrylamide was used. If excess bo-
ronic acid was used in the reaction, products resulting
Boc
6
99
16, (94:6)
B(OH)2
N
SO2Ph
a Products A and B were isolated as mixture and ratios were deter-
mined by 1H NMR.
b KF was used as base.
c Reaction was run at 80 °C.
d Only deboronated material was obtained.
Synthesis 2004, No. 12, 2006–2014 © Thieme Stuttgart · New York

PAPER
Rh-Catalyzed Arylboronic Acid Additions to Alkenes
2009
from double addition could be observed, whereby aryla- intermediates. The proposed catalytic cycle is depicted in
tion occurred twice at the b-position of the acrylamide. Scheme 3. Hydroxorhodium (I) transmetalates with the
Thus, it would appear that the amide substituents as well boronic acid to eliminate boric acid and generate the ac-
as reagent stoichiometry have a direct influence on the tive organorhodium(I) intermediate II. Addition to the ac-
type of product formed.
tivated alkene generates III, which in most cases is an
(oxa-p-allyl) rhodium species. The oxa-p-allyl intermedi-
ate will either protodemetalate to give IV and regenerate
I, or b-hydride eliminate to generate the Heck product V,
and rhodium hydride VI. In cases where rhodium hydride
VI is formed, it must be converted to I in order to propa-
gate the cycle. We considered that the excess alkene in the
reaction was acting as a sacrificial hydride acceptor
(Scheme 3, path A). This idea was tested by running the
reaction with equal amounts of boronic acid and alkene
(Scheme 4). If the tert-butyl acrylate was a sacrificial
Heck acceptor, then it would be expected that only a 50%
maximum yield of Heck product could be obtained, as one
equivalent of acrylate would be consumed for every
equivalent of Heck product formed. Since product yields
were so low, and since double addition product was ob-
served, it is highly likely that excess tert-butyl acrylate is
being used as a sacrificial hydride acceptor.11b The con-
sumption and lowering of the concentration of tert-butyl
acrylate in solution results in arylrhodium attack on the
newly formed Heck product 4A, which is also a good
Michael acceptor and leads to the formation of 4C. Proto-
demetalation of the boronic acid also occurs and reduces
N-Methylmaleimide and N-phenylmaleimide (entries 4
and 5) generated only addition products 25 and 26, respec-
tively in moderate yields. It should be noted that 26 is
structurally similar to phensuximide [( )-1-methyl-3-phe-
nyl-pyrrolidine-2,5-dione], a pharmaceutical agent for the
treatment of epilepsy.17 Furthermore, the synthesis of
phensuximide requires four steps, making the present pro-
cedure ideal for the generation of phensuximide ana-
logues.
Phenyl vinyl sulfone (entry 6), gave 27 in low yield at
room temperature. At 80 °C, a competing double addition
process was observed, leading to a mixture of Heck prod-
uct 27 (65%) and the diarylethyl phenyl sulfone 27C
(8%). Enones were determined to be very reactive, as cy-
clopentenone (entry 7) gave the conjugate addition prod-
uct 28 in excellent yield. Surprisingly, no unsaturated
product was observed when using methyl vinyl ketone
(entry 8) and only 4-phenyl-2-butanone (29) was isolat-
ed.18
The reaction mechanism of this addition process is be-
lieved to involve low-valent hydroxorhodium19 species as
Table 3 Coupling of 4-Methoxyphenylboronic Acid to Functionalized Acrylates
Alkene
product
MeO
B(OH)2
[Rh(cod)Cl]2 (2.0 mol%)
t-Bu-amphos Cl (4.8 mol%),
SDS, Na2CO3, Toluene/H2O (1:1), 80 °C
Entry
1
Acrylate
BA/Acrylate
Product
Yield (%)a
73
OMe
1.5:1
2:1
17
18
MeO
O
OMe
O
2
3
80
81
O
O
O
O
OMe
1.5:1
19
Ph
OMe
O
O
OMe
Ph
O
4
5
6
1.5:1
20
21
–
68
94
O
O
O
O
O
MeO
1.5:1
O
OPh
MeO
OPh
b
1.5–3:1
–
–
O
O
a Isolated by column chromatography. Yields are based on alkene.
b Only deboronated material was obtained. BA = Boronic Acid.
Synthesis 2004, No. 12, 2006–2014 © Thieme Stuttgart · New York

2010
M. Lautens et al.
PAPER
the overall yield of products. The benefit of using excess tive effects. As for the alkene coupling partner, Heck
acrylate not only avoids double addition, but also im- products are observed only when there are no substituents
proves yields and allows for the catalytic cycle to proceed. at the a or b position. Substituents on the acrylate may
This requirement was also observed with the acrylamide render the (oxa-p-allyl) rhodium intermediate more basic
substrates.
through s-bond inductive electron-donation and thus pro-
tonation by water is a faster process. Double substitution
at the b-position blocks addition solely due to steric ef-
fects.
Studies by Herrmann have indicated that rhodium hydride
intermediates in water are actually in equilibrium with hy-
droxorhodium species (Scheme 3, path B).20 If this con-
version of Rh-H to Rh-OH is occurring in the present In summary, we have developed a method which allows
reaction system, it is not fast enough to avoid using excess for Heck-type products using rhodium catalysis at room
alkene as hydride acceptor.
temperature under mild conditions. The high selectivities
and yields are believed to result from the use of sterically-
hindered tert-butyl-amphos Cl as ligand for the Rh cata-
lyst. To date, unsubstituted acrylates, acrylamides and vi-
nyl sulfones are acceptable coupling partners.
Substitution on the alkene promotes a reaction pathway
involving conjugate addition-protodemetalation. We are
Concerning substrate effects, the presence of ortho-sub-
stituents on the boronic acid component hinders b-hydride
elimination, presumably by steric repulsion between the
substituents and the rhodium center. An electron-with-
drawing group on the aryl ring also lowers Heck product
formation to a lesser extent, possibly by reducing the hy-
dridic character of the benzylic hydrogens through induc-
Table 4 Coupling of Boronic Acids to Various Electrophilic Alkenes
1–2 equiv Alkene
product
R
B(OH)2
[Rh(cod)Cl]2 (2.0 mol%)
t-Bu-amphos Cl (4.8 mol%),
SDS, Na2CO3, Toluene/H2O (1:1), 80 °C
Entry
1
Alkene
R
BA/Alkene
2:1
Product
Yield (%)a
75b
NH2
OMe
22
MeO
O
NH2
O
2
3
4
OMe
OMe
OMe
1:2
23
24
25
84c
62c
51
MeO
MeO
H
N
H
N
O
O
O
O
1:2
N
N
1.5:1
O
O
O
O
O
N
N
MeO
O
5
6
OMe
OMe
1.5:1
1:2
26
27
29
Ph
O
O
N
N
MeO
MeO
Ph
21c
SO2Ph
SO2Ph
7
8
H
H
1:2
1:2
28
29
99c
98c
O
O
O
O
a Products were isolated by column chromatography.
b Yield is based on alkene. A 9:1 mixture of addition to Heck product was isolated.
c Yield is based on boronic acid and reaction was performed at r.t. BA = Boronic Acid.
Synthesis 2004, No. 12, 2006–2014 © Thieme Stuttgart · New York

PAPER
Rh-Catalyzed Arylboronic Acid Additions to Alkenes
2011
B(OH)3
Ln
RhI
carborhodation
transmetalation
R
II
R
B(OH)2
III
RhILn
I
LnRh(OH)
β-H Elimination
H2O
H2
H2O
IV
B
R
R
R
A
LnRh(H)
R
V
VI
LnRh(OH)
Scheme 3 Proposed catalytic cycle for the intermolecular coupling process
The organic layer was washed with water and brine. The organic
layer was dried (MgSO4), the solvent removed under reduced pres-
sure and the residue purified by column chromatography.
t
CO2 Bu
4A, 2%
Ph
Ph
1 equiv
B(OH)2
t
1 equiv
CO2 Bu
t
CO2 Bu
4B, 8%
1-[2-tert-Butoxycarbonyl-(E)-vinyl]-2-[2-methoxy-carbonyl-
(E,Z)-vinyl]benzene (2)
Substrate 1 was used as a mixture of isomers (trans/cis, 85:15). The
product was found to be contaminated with a minor diastereomer
(the E-,Z-diene); pale yellow solid.
[Rh(cod)Cl]2 (2.0 mol%)
t-Bu-amphos Cl (4.8 mol%),
SDS, Na2CO3,
Ph
t
Toluene/H2O (1:1), 80 °C
CO2 Bu
4C, 15%
Ph
IR (film): 2978, 2951, 1711, 1633, 1478, 1435, 1367, 1317, 1152,
978, 868, 763 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.04 (d, J = 16.0 Hz, 1 H,), 7.94
(d, J = 16.0 Hz, 1 H,), 7.55 (m, 2 H), 7.38 (m, 2 H), 6.34 (d, J = 16.0
Hz, 1 H), 6.28 (d, J = 16.0 Hz, 1 H), 3.82 (s, 3 H), 1.54 (s, 9 H).
Scheme 4 One-to-one coupling test. Product yields were determi-
ned by 1H NMR
13C NMR (100 MHz, CDCl3): d = 166.8, 166.1, 165.7, 141.5, 140.1,
134.5, 134.1, 130.1, 130.0, 129.9, 129.8, 129.7, 127.5, 126.9, 126.8,
121.3, 80.8, 51.7, 35.3, 28.1.
currently investigating the reaction mechanism in terms of
substrates and ligand effects.
HRMS (EI): m/z [M – (C4H8)+] calcd for C13H12O4: 232.0740;
found: 232.0735.
Toluene and THF were distilled from sodium benzophenone ketyl
under nitrogen. Doubly-distilled water was degassed by exposure to
vacuum for 15 min followed by sparging under nitrogen for another
15 min. [Rh(cod)Cl]2 was purchased from Strem Chemicals, Inc.
tert-Butyl-amphos Cl was synthesized according to the procedure
outlined in ref.9b Cyclohexyl-amphos Cl was synthesized according
to ref.9c 1-(tert-Butoxycarbonyl)-1H-pyrrol-2-yl-boronic acid was
purchased from Frontier Scientific and 1-(phenylsulfonyl)-1H-in-
dol-3-ylboronic acid from Maybridge, Inc. 1H and 13C NMR spectra
were acquired on a Varian UNITY 400 MHz spectrometer. IR fre-
quencies were acquired using a Perkin-Elmer Spectrum 1000 FT-IR
spectrometer.
Methyl (2E)-3-[2-(3-Oxocyclopentyl)phenyl]acrylate (3)
The general procedure was followed, however, substrate 1 was used
as the diastereomerically pure trans-isomer; colorless oil.
IR (neat): 2979, 1742, 1716, 1631, 1435, 1320, 1276, 1173, 978,
766 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.08 (d, J = 15.6 Hz, 1 H), 7.57 (d,
J = 7.6 Hz, 1 H), 7.40 (t, J = 7.6 Hz, 1 H), 7.29 (m, 2 H), 6.37 (d,
J = 15.6 Hz, 1 H), 3.83 (s, 3 H), 3.79 (m, 1 H), 2.64 (dd, J = 18.4
Hz, 8.0 Hz, 1 H), 2.31–2.50 (m, 4 H), 2.00 (m, 1 H).
13C NMR (100 MHz, CDCl3): d = 217.6, 167.1, 141.9, 141.8, 133.5,
130.3, 127.2, 127.0, 125.4, 120.4, 51.7, 45.5, 38.4, 38.0, 30.6.
Coupling of Arylboron Substrates with an Alkene General Pro-
cedure
HRMS (EI): m/z [M+] calcd for C15H16O3: 244.1104; found:
244.1099.
To a 3 dram screwcap vial sealed with a rubber septum,
[Rh(cod)Cl]2 (0.02 equiv, 3.9 mg, 0.008 mmol) and tert-butyl-am-
phos chloride were added (0.048 equiv, 5.1 mg, 0.019 mmol, 1:1.2
Rh to ligand) and the vial was flushed under N2 for 5 min. Degassed
water (1 mL), degassed toluene (1 mL) and an olefin (2.0 equiv,
0.80 mmol) were added and left to stir under N2 for 5 min at r.t.
Na2CO3 (1.0 equiv, 42 mg, 0.40 mmol,), sodium dodecyl sulfate
(0.6 equiv, 69 mg, 0.24 mmol) and boronate ester (1 equiv, 0.4
mmol) were then added. An opaque yellow emulsion formed and
was heated at 80 ºC under N2 until all the starting material was con-
sumed. The progress of the reaction was monitored by TLC and was
usually complete after 2–5 h. The reaction mixture was then diluted
with Et2O (50 mL), stirred for 1 h, and the water layer was removed.
Coupling of Arylboronic Acids with tert-Butyl Acrylate
The general coupling procedure was followed. tert-Butyl acrylate (2
equiv) was used and the reactions were allowed to stir at r.t. over-
night. After workup, the crude reaction mixtures were purified by
passage through a silica plug, eluting only with hexanes. In all cas-
es, the product yields were near quantitative and the amount of un-
saturated (A) versus saturated (B) was estimated by 1H NMR
spectroscopy. Compounds A and B were not separable by silica gel
flash column chromatography and characterization is reported for
Synthesis 2004, No. 12, 2006–2014 © Thieme Stuttgart · New York

2012
M. Lautens et al.
PAPER
the major component. Compounds 4A,2,1 4B,22 4C,23 9A,21 11A,24
12A25 and 13A26 have been previously reported in the literature.
tert-Butyl (2E)-3-Thien-2-ylacrylate (14A)
Pale yellow oil.
IR (neat): 2977, 1703, 1626, 1391, 1367, 1310, 1283, 1208, 1149,
1044, 970, 852, 703 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.68 (d, J = 12.4 Hz, 1 H), 7.33 (d,
J = 4.0 Hz, 1 H), 7.22 (d, J = 2.8 Hz, 1 H), 7.03 (t, J = 4.0 Hz, 1 H),
6.18 (d, J = 12.4 Hz, 1 H), 1.53 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 166.0, 139.7, 135.9, 130.3, 127.8,
119.0, 80.4, 28.2.
tert-Butyl (2E)-3-(2-Methylphenyl)acrylate (5A)
Colorless oil.
IR (neat): 2977, 2930, 1709, 1632, 1484, 1367, 1319, 1151, 980,
872, 763 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.90 (d, J = 12.8 Hz, 1 H), 7.54 (d,
J = 6.0 Hz, 1 H), 7.26 (t, J = 6.0 Hz, 1 H), 7.20 (m, 2 H), 6.30 (d,
J = 12.8 Hz, 1 H), 2.44 (s, 3 H), 1.56 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 166.3, 141.1, 137.4, 133.5, 130.6,
130.1, 129.6, 128.4, 126.2, 126.1, 121.0, 80.4, 28.2, 19.7.
HRMS (EI): m/z [M+] calcd for C11H14O2S: 210.0717; found:
210.0714.
HRMS (EI): m/z [M+] calcd for C14H18O2: 218.1304; found:
tert-Butyl (2E)-3-Thien-3-ylacrylate (15A)
218.1306.
Colorless oil.
IR (neat): 2977, 1703, 1634, 1391, 1367, 1311, 1281, 1148, 978,
855, 786, 606 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.56 (d, J = 12.4 Hz, 1 H), 7.45 (s,
1 H), 7.31 (m, 1 H), 7.28 (d, J = 4.0 Hz, 1 H), 6.20 (d, J = 12.4 Hz,
1 H), 1.53 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 166.4, 137.7, 136.9, 127.3, 126.7,
125.1, 119.8, 80.3, 28.2.
tert-Butyl (2E)-3-(2-Methoxyphenyl)acrylate (6A)
Pale yellow oil.
IR (neat): 2977, 2934, 1705, 1631, 1598, 1489, 1367, 1324, 1247,
1150, 1027, 988, 875, 752 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.91 (d, J = 12.8 Hz, 1 H), 7.50 (d,
J = 6.0 Hz, 1 H), 7.32 (t, J = 6.0 Hz, 1 H), 6.95 (t, J = 6.0 Hz, 1 H),
6.90 (d, J = 6.4 Hz, 1 H), 6.45 (d, J = 12.8 Hz, 1 H), 3.87 (s, 3 H),
1.54 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 166.7, 158.1, 138.8, 131.0, 128.6,
123.6, 120.6, 120.5, 111.0, 80.1, 55.4, 28.2.
HRMS (EI): m/z [M+] calcd for C14H18O3: 234.1259; found:
HRMS (EI): m/z [M+] calcd for C11H14O2S: 210.0722; found:
210.0714.
tert-Butyl (2E)-3-[1-(Phenylsulfonyl)-1H-indol-3-yl]-acrylate
(16A)
234.1255.
Colorless solid.
IR (film): 2978, 1702, 1636, 1447, 1368, 1318, 1291, 1176, 1149,
1124, 978, 733, 684, 628 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.81–8.05 (m, 5 H), 7.72 (d, J =
16.4 Hz, 1 H), 7.32–7.60 (m, 5 H), 6.49 (d, J = 16.4 Hz, 1 H), 1.57
(s, 9 H).
13C NMR (100 MHz, CDCl3): d = 166.3, 137.7, 135.5, 134.2, 134.1,
129.4, 128.2, 127.8, 126.8, 125.4, 124.0, 120.6, 120.5, 118.5, 113.7,
80.5, 28.1.
tert-Butyl 3-[2-(Trifluoromethyl)phenyl]propanoate (7B)
Colorless oil.
IR (neat): 2980, 1729, 1455, 1368, 1315, 1039, 767 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.27–7.48 (m, 4 H), 3.10 (t, J =
8.0 Hz, 2 H), 2.55 (t, J = 8.0 Hz, 2 H), 1.44 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 171.8, 131.8, 130.8, 129.2, 127.8,
126.2, 126.1, 80.5, 36.8, 28.0, 27.7.
HRMS (EI): m/z [M+] calcd for C14H17O2F3: 274.1187; found:
HRMS (EI): m/z [M+] calcd for C21H21NO4S: 383.1188; found:
274.1180.
383.1191.
Anal. Calcd for C21H21NO4S: C, 65.78; H, 5.52; N, 3.65. Found: C,
65.65; H, 5.77; N, 3.89.
tert-Butyl 3-(2,6-Dimethylphenyl)propanoate (8B)
Pale yellow oil.
IR (neat): 2977, 1729, 1467, 1367, 1294, 1255, 1147, 854, 768 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.05 (m, 3 H), 2.97 (m, 2 H), 2.40
(m, 2 H), 2.38 (s, 6 H), 1.51 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 172.5, 137.4, 136.1, 128.1, 125.9,
80.3, 34.5, 28.0, 25.1, 19.6.
HRMS: m/z [M+] calcd for C14H22O2: 234.1614; found: 234.1619.
Intermolecular Cross-Coupling of Arylboronic Acids with Acti-
vated, Substituted Alkenes
The general coupling procedure was followed. 4-Methoxyphenyl-
boronic acid was used as the nucleophilic coupling partner. The
crude products were purified by silica gel column chromatography.
Compounds 17,27 20,28 22,29 24,30 27,31 2832 and 2929 have been pre-
viously reported in the literature.
Isopropyl (3RS)-3-(4-Methoxyphenyl)hexanoate (18)
Light yellow oil.
tert-Butyl (2E)-3-(4-Methoxy-2-methylphenyl)acrylate (10A)
Pale yellow oil.
IR (neat): 2958, 2872, 1731, 1612, 1513, 1466, 1373, 1302, 1248,
1178, 1108, 1037, 831 cm–1.
IR (neat): 2976, 1704, 1628, 1603, 1456, 1256, 1145, 1049, 981,
864, 813, 765 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.10 (d, J = 8.6 Hz, 2 H), 6.83 (d,
J = 8.6 Hz, 2 H), 4.90 (m, 1 H), 3.79 (s, 3 H), 3.04 (m, 1 H), 2.51
(m, 2 H), 1.55 (m, 4 H), 1.16 (d, J = 6.4 Hz, 3 H), 1.08 (d, J = 6.4
Hz, 3 H), 0.86 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 172.3, 158.3, 136.4, 128.6, 113.9,
67.6, 55.4, 42.6, 41.5, 38.9, 21.9, 20.7, 14.2.
1H NMR (400 MHz, CDCl3): d = 7.83 (d, J = 12.4 Hz, 1 H), 7.51 (d,
J = 6.8 Hz, 1 H), 6.72 (m, 2 H), 6.20 (d, J = 12.4 Hz, 1 H), 3.81 (s,
3 H), 2.42 (s, 3 H), 1.54 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 166.7, 160.7, 140.6, 139.4, 127.8,
126.1, 118.4, 115.7, 111.9, 80.1, 55.1, 28.2, 19.9.
HRMS (EI): m/z [M+] calcd for C15H20O3: 248.1406; found:
248.1412.
HRMS (EI): m/z [M+] calcd for C16H24O3: 264.1725; found:
264.1725.
Synthesis 2004, No. 12, 2006–2014 © Thieme Stuttgart · New York

PAPER
Rh-Catalyzed Arylboronic Acid Additions to Alkenes
2013
Methyl (3RS)-3-(4-Methoxyphenyl)-3-phenylpropanoate (19)
(3RS)-3-(4-methoxyphenyl)-1-phenylpyrrolidine-2,5-dione (26)
Yellow solid.
Yellow solid.
IR (film): 2954, 1737, 1610, 1513, 1437, 1513, 1437, 1255, 1159,
1029, 831, 725, 700 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.13–7.29 (m, 7 H), 6.82 (d, J =
8.8 Hz, 2 H), 4.51 (t, J = 8.0 Hz, 1 H), 3.76 (s, 3 H), 3.58 (s, 3 H),
3.03 (d, J = 7.6 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 173.3, 158.1, 143.8, 135.6, 128.5,
126.4, 113.9, 55.2, 51.6, 46.2, 40.8.
IR (film): 1711, 1513, 1178 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.25–7.53 (m, 7 H), 6.95 (d, J =
8.8 Hz, 2 H), 4.18 (dd, J = 6.2, 12.8 Hz, 1 H), 3.84 (s, 3 H), 3.40 (dd,
J = 12.8, 24.8 Hz, 1 H), 3.00 (dd, J = 6.2, 24.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 177.2, 175.6, 159.6, 132.2, 129.5,
129.3, 129.0, 128.7, 126.7, 114.9, 89.5, 55.6, 45.5, 37.6.
HRMS (EI): m/z [M+] calcd for C17H15O3N: 281.1052; found:
281.1048.
HRMS (EI): m/z [M+] calcd for C17H18O3: 270.1256; found:
270.1250.
2,2-Bis(4-methoxyphenyl)ethyl Phenyl Sulfone (27C)
Phenyl (3RS)-3-(4-Methoxyphenyl)butanoate (21)
Colorless oil.
Light yellow oil.
IR (neat): 1510, 1303, 1248, 1136, 1032 cm–1.
IR (neat): 2935, 1755, 1612, 1513, 1460, 1360, 1248, 1193, 1035,
808, 749, 690 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.35 (t, J = 8.4 Hz, 1 H), 7.16–7.21
(m, 4 H), 6.95 (d, J = 8.2 Hz, 2 H), 6.86 (d, J = 8.2 Hz, 2 H), 3.81
(s, 3 H), 3.08 (dd, J = 7.6, 13.2 Hz, 1 H), 2.96 (m, 1 H), 2.78 (dd,
J = 6.8, 13.2 Hz, 1 H), 1.32 (d, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 174.9, 158.5, 150.9, 131.3, 130.2,
129.6, 125.9, 121.7, 114.1, 55.5, 42.1, 39.2, 17.1.
HRMS (EI): m/z [M+] calcd for C17H18O3: 270.1256; found:
1H NMR (400 MHz, CDCl3): d = 7.64 (d, J = 7.6 Hz, 2 H), 7.49 (t,
J = 7.6 Hz, 1 H), 7.36 (t, J = 7.6 Hz, 2 H), 7.03 (d, J = 8.8 Hz, 4 H),
6.72 (d, J = 8.8 Hz, 4 H), 4.55 (t, J = 7.2 Hz, 1 H), 3.85 (d, J = 7.2
Hz, 2 H), 3.74 (s, 6 H).
13C NMR (100 MHz, CDCl3): d = 158.4, 139.8, 133.8, 133.1, 128.8,
128.5, 128.0, 114.1, 61.9, 55.2, 44.6.
HRMS (EI): m/z [M+] calcd for C22H22O4S: 382.1234; found:
382.1232.
270.1252.
Acknowledgment
(2E)-N-(tert-Butyl)-3-(4-methoxyphenyl)acrylamide (23)
Colorless solid.
IR (film): 1654, 1605, 1542, 1512, 1245, 1173, 827 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.53 (d, J = 15.6 Hz, 1 H), 7.43 (d,
J = 8.7 Hz, 2 H), 6.88 (d, J = 8.7 Hz, 2 H), 6.21 (d, J = 15.6 Hz, 1
H), 5.44 (br s, 1 H), 3.83 (s, 3 H), 1.43 (s, 9 H).
The Natural Sciences and Engineering Research Council of Canada
(NSERC), the Merck Frosst Centre for Therapeutic Research and
the University of Toronto are gratefully acknowledged for financial
support. HG thanks NSERC for a summer undergraduate scholar-
ship.
13C NMR (100 MHz, CDCl3): d = 165.6, 139.8, 129.2, 127.7, 119.6,
114.2, 55.3, 51.4, 28.9.
References
(1) Present address: Department of Chemistry, University of
Pittsburgh, Pittsburgh, Pennsylvania 15260, USA
HRMS (EI): m/z [M+] calcd for C14H19O2N: 233.1416; found:
233.1415.
(2) For general references on transition-metal catalysis, see:
(a) Cross-coupling Reactions: A Practical Guide; Miyaura,
N., Ed.; Springer: New York, 2002. (b) Transition Metal
Catalyzed Reactions; Murahashi, S.-I.; Davies, S. G., Eds.;
Blackwell Science: Oxford, 1999. (c) Diederich, F.; Stang,
P. J. Metal-Catalyzed Cross-Coupling Reactions; Wiley-
VCH: New York, 1998. (d)CatalyticAsymmetric Synthesis;
Ojima, I., Ed.; Wiley-VCH: New York, 2000.
(3) Tsuji, J. Palladium Reagents and Catalysis: Innovations in
Organic Synthesis; Wiley & Sons: New York, 1995.
(4) Reviews on Rh-catalyzed couplings: (a) Hayashi, T.;
Yamasaki, K. Chem. Rev. 2003, 103, 2829. (b) Fagnou, K.;
Lautens, M. Chem. Rev. 2003, 103, 169.
(2E)-3-(4-Methoxyphenyl)-N,N-dimethylpropanamide (24)
Colorless oil.
IR (neat): 1648, 1602, 1513, 1392, 1249, 1176, 1135, 835 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.64 (d, J = 15.4 Hz, 1 H), 7.48 (d,
J = 8.6 Hz, 2 H), 6.90 (d, J = 8.6 Hz, 2 H), 6.77 (d, J = 15.4 Hz, 1
H), 3.84 (s, 3 H), 3.16 (br s, 3 H), 3.07 (br s, 3 H).
13C NMR (100 MHz, CDCl3): d = 167.0, 160.8, 142.1, 129.3, 128.1,
115.0, 114.2, 113.9, 55.4, 37.3.
HRMS (EI): m/z [M+] calcd for C12H15O2N: 205.1103; found:
205.1094.
(5) Some recent examples with boron-based reagents:
(a) Chapman, C. J.; Frost, C. G. Adv. Synth. Catal. 2003,
345. (b) Yamamoto, Y.; Fujita, M.; Miyaura, N. Synlett
2002, 767. (c) Sakuma, S.; Miyaura, N. J. Org. Chem. 2001,
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(3RS)-3-(4-Methoxyphenyl)-1-methylpyrrolidine-2,5-dione (25)
Colorless solid.
IR (film): 1693, 1518, 1278, 1117 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.15 (d, J = 8.8 Hz, 2 H), 6.90 (d,
J = 8.8 Hz., 2 H), 3.99 (dd, J = 4.8, 9.6 Hz, 1 H), 3.81 (s, 3 H), 3.20
(dd, J = 9.6, 18.4 Hz, 1 H), 3.07 (s, 3 H), 2.81 (dd, J = 4.8, 18.4 Hz,
1 H).
13C NMR (100 MHz, CDCl3): d = 178.3, 176.5, 159.5, 129.7, 114.8,
55.6, 45.4, 37.4, 25.4.
HRMS (EI): m/z [M+] calcd for C12H13O3N: 219.0895; found:
219.0896.
(8) (a) Lautens, M.; Mancuso, J. Org. Lett. 2002, 4, 2105.
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Synthesis 2004, No. 12, 2006–2014 © Thieme Stuttgart · New York

2014
M. Lautens et al.
PAPER
(9) (a) Amphos iodide: Smith, R. T.; Baird, M. C. Inorg. Chim.
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(13) Conformational analysis of 4-substituted trifluoromethyl-
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Synthesis 2004, No. 12, 2006–2014 © Thieme Stuttgart · New York