Asymmetric palladium-catalyzed hydroarylation of styrenes and dienes

Article abstract of DOI:10.1016/j.tet.2011.02.027

Alkenes are desirable and highly versatile starting materials for organic transformations, and well-known substrates for palladium catalysis. Typically, these reactions result in the formation of a new alkene product via β-hydride elimination. In contrast to this scenario, our laboratory has been involved in the development of alkene hydro- and difunctionalization reactions, where β-hydride elimination can be controlled. We report herein the development of an asymmetric palladium-catalyzed hydroarylation, which yields diarylmethine products in up to 75% ee. Interestingly, a linear free energy relationship is observed between the steric bulk of the ligand within a certain range and the ee of the reaction.

Full text of DOI:10.1016/j.tet.2011.02.027

Tetrahedron 67 (2011) 4435e4441
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Asymmetric palladium-catalyzed hydroarylation of styrenes and dienes
,
Susanne M. Podhajsky a, Yasumasa Iwai b, Amanda Cook-Sneathen c, Matthew S. Sigman a
*
a Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City, UT 84112, United States
b Kyorin Pharmaceutical Co., Ltd, 1848 Nogi, Nogi-machi, Shimotuga-gun, Tochigi-ken 329-0114, Japan
c Department of Chemistry, University of Michigan, 930 N. University, Ann Arbor, MI 48109-1055, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 17 January 2011
Received in revised form 10 February 2011
Accepted 11 February 2011
Available online 17 February 2011
Alkenes are desirable and highly versatile starting materials for organic transformations, and well-
known substrates for palladium catalysis. Typically, these reactions result in the formation of a new
alkene product via
b
-hydride elimination. In contrast to this scenario, our laboratory has been involved in
-hydride elimination can be
the development of alkene hydro- and difunctionalization reactions, where
b
controlled. We report herein the development of an asymmetric palladium-catalyzed hydroarylation,
which yields diarylmethine products in up to 75% ee. Interestingly, a linear free energy relationship is
observed between the steric bulk of the ligand within a certain range and the ee of the reaction.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Alkenes
Asymmetric catalysis
Hydroarylation
Palladium-catalyzed
LnPdX
LnPdX2
Nu
1. Introduction
Nu
LnPdHX
R
Nu
R
R
β
-Hydride
Nucleopalladation
Nu = R'OH, R'2NH, R'M
Scheme 1. Wacker- and Heck-type alkene functionalization.
Alkenes are attractive starting materials for organic synthesis,
since they can be easily functionalized using a plethora of both ox-
Elimination
idative and reductive mono- and difunctionalization methods.1
A
subset of these methods have centered around Pd-catalyzed olefin
functionalization processes highlighted by the Wacker and Heck
reactions.2 Mechanistically, in both processes, initial alkene
mechanistic manifold (Scheme 2), wherein a Pd-hydride B is
formed via oxidation of the alcohol solvent, followed by insertion of
the alkene into the Pd-hydride and reaction of the resulting Pd
attack is followed by
b-hydride elimination and product release
(Scheme 1).3,2 Unfortunately, the chiral information present in the
Pd-alkyl intermediate is generally lost in the b-hydride elimination
p
-benzyl or p-allyl intermediate D with an exogenous reagent.
step. Several methods to avoid this process have been reported,4,5
both to retain stereochemical information and to achieve further
functionalization. These include the use of substrates set up to
Me2CHOH
Me2CO
R
X
PdLn
X
X
H
R
form a quaternary chiral center, where
b-hydride elimination is not
PdLn
PdLn
possible,6e10 formation of a stabilized intermediate, such as a Pd
H
A
B
C
p
-allyl complex,11e18 or rapid conversion of the Pd-alkyl complex to
H
Cl
X
a
different intermediate to effectively outcompete -hydride
b
PdLn
X
R
elimination.19e21
PdLn
C
LnPd
In our laboratory, we have been interested in the functionali-
zation of styrenes and dienes, which can form Pd -benzyl or
H
R
p
D
D'
H
p
-allyl intermediates to undergo further functionalization. We have
been able to successfully develop both alkene hydro-11,12,15 and
R'M
O2
MX
H
difunctionalization reactions13,14 using this approach. To access the
R
R'
R'
R
LnPd0
A
PdLn
D
hydrofunctionalized products, we have utilized
a
unique
E
F
Scheme 2. Proposed mechanism for Pd-catalyzed hydroarylation of styrenes and
dienes.
* Corresponding author. Tel.: þ1 801 585 0774; fax: þ1 801 581 8433; e-mail
address: sigman@chem.utah.edu (M.S. Sigman).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.02.027

4436
S.M. Podhajsky et al. / Tetrahedron 67 (2011) 4435e4441
1.5 mol% LPd(allyl)Cl
Using this manifold, we have developed a Pd-catalyzed hydro-
O
O
chlorination/hydroalkoxylation of styrenes11 as well as two distinct
hydroarylation procedures for styrenes using aryl stannanes and
aryl boronic esters, respectively (Scheme 3).22,23 While the stan-
nane procedure works moderately well for dienes, the boronic ester
method does not give significant amounts of diene hydroarylation
products. Therefore, we developed an additional method using
boronic esters, optimized specifically for dienes.15 It should be
noted that even though all of the hydroarylation methods utilize
(ꢀ)-sparteine either as a ligand on Pd or as a base, the products are
generally formed in <5% ee. Of note, several diene substrates gave
approximately 10% ee.
6 mol% (−)-sparteine
Ph
Ph
B
6 mol% tBuOK
IPA, balloon O2, 55 °C
BocHN
BocHN
1a
2a
3a
3 equiv.
Ph
Ph
O
N
O
N
N
N
L1
L2
70% yield
<5% ee
62% yield
6% ee
O
2.5 mol% Pd[(−)-sparteine]Cl2
N
N
O
O
OTf
−
40 mol% ( )-sparteine
N
PhSnBu3
1.5 equiv.
Ph
O
N
N
75 mol% MnO2
IPA, 25 psi O2, 60 °C
iPr iPr
BF4
76% yield
40% yield
L3·HBF4
14% yielda
<5% ee
L4·HOTf
8% yielda
32% ee
3.5 mol% Pd[(−)-sparteine]Cl2
40 mol% (−)-sparteine
Bu3Sn
O
75 mol% MnO2
IPA, 25 psi O2, 60 °C
Scheme 4. Asymmetric hydroarylation using chiral carbenes. aThe Pd carbene com-
plex was formed in situ before addition of the remaining reagents (see SD for details).
tBu
tBu
1.5 equiv.
O
0.75 mol% [Pd(SIiPr)Cl2]2
6 mol% (−)-sparteine
i
(6%) was found for the PrBiox-derived NHC, and a 32% ee was
Ph
B
Ph
6 mol% tBuOK
IPA, balloon O2, 55 °C
observed with the menthol-derived NHC introduced by Glorius and
co-workers.34 Unfortunately, this was accompanied by a significant
loss in catalyst activity, and since this ligand could not be easily
modified, this result was not pursued further.
We hypothesized that the generally low enantioselectivity may
be due to the chiral information being too far removed from the
catalytic center, and therefore decided to investigate bidentate li-
gands, since they should provide a more rigid steric environment,
and potentially place the chiral substituents closer to Pd.
O
3 equiv.
81% yield
Ph
0.75 mol% Pd[(−)-sparteine]Cl2
20 mol% (−)-sparteine
O
B
O
Ph
Ph
Ph
0.5 mol% tBuOK
IPA, balloon O2, 75 °C
3 equiv.
75% yield
Ar
N
Cl
Cl
Cl
N
Ar
Pd
Pd
Ar
N
N
N
Cl
2.2. Initial study of bidentate ligands
N
Ar
[PdSIiPrCl2]2
Ar = 2,6-diisopropylphenyl
(−)-sparteine
Since phosphine-based ligands are known to be oxidatively
unstable, we decided to evaluate several classes of bidentate ni-
trogen ligands initially. Different combinations of oxazoline and
pyridine or quinoline moieties were synthesized and tested. Of
these ligands, BINAM (L10) and the valinol-derived bioxazoline L5
were the only ligands that did not promote the reaction at all. While
menthol-derived bioxazoline L6 as well as pyridine-oxazoline L7
and quinoline-oxazoline L8 gave some product with 10e14% ee,
bisoxazoline L11a gave by far the highest yield and ee (52% yield,
45% ee). Somewhat surprisingly, when bridged pyridine-oxazoline
L9 was tested, a racemic product was observed (Scheme 5).
Scheme 3. Non-asymmetric hydroarylation methodologies for styrenes and dienes.
Considering the diarylmethine moiety is of biological interest to
our laboratory24 and difficult to prepare in an enantiomerically
enriched form,25e29 we became interested in the development of
an enantioselective variant of the Pd-catalyzed conjugated alkene
hydroarylation reaction. Herein, we report our progress toward the
development of such a reaction.
2. Results and discussion
2.3. Bisoxazoline ligands
The boronic ester method was initially selected as a starting
point for the development of an asymmetric hydroarylation re-
action due to the lower toxicity and easier handling of boronic
esters compared to tin reagents. Additionally, it was thought that
carbenes are modular in nature and therefore a chiral N-hetero-
cyclic carbene (NHC) ligand could be found to promote the reaction
effectively. (ꢀ)-Sparteine, on the other hand, is notoriously difficult
to modify, and it had been previously shown that it cannot gener-
ally be simply replaced with other bidentate amine ligands.30e33
A systematic study of bisoxazoline ligands was carried out in
order to optimize the ligand, varying the substituent off the oxa-
zoline ring. Interestingly, a linear free energy relationship between
the sterics of the oxazoline substituent as defined by the Charton
parameter35e37 and the log of the enantiomeric ratio of the product
(corresponding to a relative rate of product formation for the two
enantiomers) was observed up to a certain point (Fig. 1). While
substituents with a tertiary carbon (such as (S)-iPrBox L11a and (S)-
diEtBox L11e) gave the predicted enantioselectivities, rapid pre-
cipitation of Pd metal along with diminished product formation
and ee was observed with (S)-tBuBox (L11g) (vide infra). Moreover,
when the dicyclohexyl-substituted Box ((S)-diCyBox L11f) was
synthesized and tested, the ee of the hydroarylation product was
found to be 63%, even though this substituent would be expected to
give a higher ee than the diethyl one.38 Overall, this implies that
over a certain range the enantioselectivity is dictated by the size of
2.1. Chiral NHC ligands
Thus, several NHCs were prepared with chiral backbones as well
as chiral substituents on nitrogen (Scheme 4). While all of these
successfully promote the reaction, the product was essentially ra-
cemic in all cases. When studying Biox-derived carbenes, a low ee

S.M. Podhajsky et al. / Tetrahedron 67 (2011) 4435e4441
4437
2.5 mol% Pd(MeCN)2Cl2
10 mol% ligand
O
O
Ph
Ph
B
5 mol% tBuOK
iPrOH, balloon O2, 55 °C
RHN
RHN
3 equiv.
O
O
O
N
O
N
N
N
iPr iPr
L6
L5 (iPrBiox)
R = Boc
R = Ac
<5% yielda
30% yieldb, 10% ee
O
O
N
N
N
N
L7 ((S)-iPrPyox)
R = Ac
L8 ((S)-iPrQuinox)
R = Ac
10% yield, 13% ee
15% yield, 14% ee
O
NMe2
NMe2
N
N
L9
L10 ((S)-BINAM)
R = Boc
R = Ac
10% yield, <5% ee
<5% yield
O
O
N
N
L11a ((S)-iPrBox)
R = Acc
37% yield, 36% ee
R = Boc
46% ee
Fig. 1. Charton plot using different Box ligands.
Scheme 5. Asymmetric hydroarylation using bidentate nitrogen ligands. a3 mol % li-
gand were used. b5 mol % Pd(MeCN)2Cl2, 20 mol % ligand, and 10 mol % KOtBu were
used, and the reaction was performed at room temperature. c2.5 mol % Pd((S)-iPrBox)
Cl2 was used along with 7.5 mol % (S)-iPrBox.
2.5 mol% Pd(MeCN)2Cl2
10 mol% (R)-PhBox
5 mol% tBuOK
R'
R'SnBu3
IPA, O2, 55 °C, 24 h
the oxazoline substituent, as would be expected. However, when
the substituent is too large, there is a change, possibly in the overall
catalyst structure or reaction mechanism, which perturbs the
enantioselectivity.
R
R
1
4
3
1.5 equiv.
entry
R
R'
4a
product eea
1
2
1a
)
45
42
40
NHBoc (
Ph (
)
Me (1c)
3b Me (1c)
4b
(
)
O
2.4. Optimization using organostannanes
a Determined by HPLC for entry 1, and GC
for entries 2 and 3, each equiooed with a
chiral stationary phase. b no KOtBu.
Interestingly, it was observed that when using an organo-
stannane instead of a boronic ester as the transmetallating agent,
a nearly identical ee was observed (Fig. 2, entry 1 vs Fig. 1). Addi-
tionally, changing from PhSnBu3 (4a) to an enol ether (4b) did not
affect the enantioselectivity substantially (entry 2). This seemed to
indicate that the enantiodetermining step occurred before trans-
metallation, and, excitingly, gave us an opportunity to develop a set
of reaction conditions that could be potentially used with a wide
variety of reagents. It was also observed that base was not required
for the reaction when using an organostannane, as similar results
were obtained with and without KOtBu (entry 3).
Fig. 2. Initial results using organostannanes.
2.5 mol% Pd(MeCN)2Cl2
10 mol% (S)-iPrBox
O
iPrOH, O2, 24 h
O
SnBu3
4b
1.5 equiv.
1c
3c
Since variation of the ligand substituents alone did not provide
sufficiently high enantioselectivity, it was decided to further ex-
plore the reaction conditions. For these studies, 4-methylstyrene
(1c) and an enol ether stannane (4b) were used, since both reaction
progress and ee could be conveniently monitored by GC.
The reaction was evaluated at different temperatures (Fig. 3). It
was found to be extremely slow at room temperature, but some-
what more efficient at elevated temperatures (65 ꢁC). Interestingly,
temperature only had a modest effect on enantioselectivity, and
thus further optimization was performed at 65 ꢁC.39
entry temp. time % yielda % eeb
1
2
3
4
rt
25 h
8
nd
49
48
46
rt
4 d
31
22
31
55 °C 19 h
65 °C 22 h
a
GC yied, determined using an
internal standard and response
factor. b determined by GC using a
chiral stationary phase.
Fig. 3. Temperature optimization for organostannes.

4438
S.M. Podhajsky et al. / Tetrahedron 67 (2011) 4435e4441
Next, different counterions on Pd were evaluated. However, the
solubility of O2 increases, leading to a more robust catalytic system.
However, even at room temperature, small amounts of Pd metal
precipitate were observed. Unfortunately, lowering the tempera-
ture to 0 ꢁC led to only a trace of product (Fig. 4).
use of non-coordinating anions (OTf, OTs, BF4) led to <5% product in
each case, while acetate provided the product in 8% GC yield and
28% ee. The use of 1:1 mixtures of IPA and other cosolvents also did
t
not lead to any improvements. DCE, BuOH, and PhMe led to ex-
tremely slow reactions, while DMA provided the product in com-
parable yield (39%), but diminished ee (37%). It was also observed
that Pd(MeCN)2Cl2 was not completely soluble in IPA at room
temperature, and small amounts of Pd metal precipitate were
typically observed during the reaction. By preforming the Pd(iPr-
Box)Cl2 catalyst and using it in place of Pd(MeCN)2Cl2, these issues
could be avoided and slight increases in yield and ee were observed
(34% yield, 51% ee). The reaction was also performed with
Pd(MeCN)2Cl2 and no added ligand, which resulted in the forma-
tion of substantial amounts of Pd metal precipitate, and no product
formation.
2.5 mol% Pd((S)-tBuBox)Cl2
12.5 mol% (S)-tBuBox
10 mol% CuCl2
O
iPrOH, O2
O
SnBu3
4b
1c
3c
1.5 equiv.
entry
% yielda
% eeb
temp.
1
2
rt
0°C
18
5
75
78
a GC yield, determined using an
internal standard and response
factor. b Determined by GC using a
chiral stationary phase.
The effect of excess ligand was then studied in more detail
i
(Table 1). It was found that at <5 mol % of exogenous PrBox the
yield deteriorated, and at very low excess ligand loadings no re-
action was observed. Since copper additives are known to promote
Stille couplings, several different copper salts were added to the
reaction mixture.40,41 As bisoxazolines are known to bind to copper,
and decreased ees have been observed by our group in reactions
that contain ‘ligandless’ copper,19 enough ligand was added to li-
gate both Pd and Cu (Table 1, entries 5e9). It was found that CuCl2
gave the best result, furnishing product in 47% yield and 59% ee.
Using 10 instead of 5 mol % CuCl2 improved the yield slightly, and
interestingly, with CuCl2 present, excess ligand was not required for
the reaction (entries 10 and 11).
Fig. 4. Hydroarylation using (S)-tBuBox at lower temperatures.
At this point, the Pd((S)-tBuBox)Cl2-catalyzed hydroarylation
was also tested using boronic esters. Unfortunately, while ees of up
to 56% were observed for substrate 1b with phenyl boronic ester,
these results were found to be irreproducible.
Since formation of Pd black was observed with Pd((S)-tBuBox)
Cl2, several bisoxazoline derivatives were synthesized and tested in
hopes of discovering a ligand that would provide both good
enantioselectivity and a robust catalyst. Ligand L12 was synthe-
sized following a report by Paquin and co-workers, where a di-
methyl-substituted valinol-derived oxazoline was found to be
a good substitute for a tert-butyl oxazoline.43 This ligand was tested
using boronic esters, and found to be slightly more selective than
(S)-iPrBox (Eq. 1). However, the increase in ee was not substantial
enough to warrant further optimization for this ligand.
Table 1
Optimization for organostannes
i
Entry
mol % PrBox
mol % CuX2
% Yielda
% eeb
1
2
3
4
5
6
7
8
1.25
2.5
5
7.5
7.5
7.5
7.5
7.5
7.5
10
d
0
15
34
34
47
27
45
11
26
50
46
NA
50
54
51
59
56
55
8
d
d
d
5 mol % CuCl2
5 mol % CuCl
5 mol % CuF2
5 mol % Cu(OTf)2
5 mol % Cu(OAc)2
10 mol % CuCl2
10 mol % CuCl2
9
10
11
57
58
56
15
a
GC yield, determined using an internal standard and response factor.
Determined by GC using a chiral stationary phase.
b
With the idea in mind that a catalyst just slightly less sterically
t
bulky than BuBox was needed, ligand L13 was synthesized, fea-
2.5. Other bisoxazoline ligands
turing a tert-butyl-substituted oxazoline ring and an unsubstituted
oxazoline. Unfortunately, this ligand gave rather poor results. Next,
the bridging carbon was modified. It has been observed by Den-
mark and Stiff44 that placing rings of different sizes at this position
alters the angle between the two oxazoline rings, resulting in
a subtle change in the bite angle of the ligand. Ligands L14 and L15
were synthesized and tested to evaluate the effect of this on our
reaction. While this modification did result in improved ees com-
Since optimization of the reaction conditions led to only modest
improvements, other bisoxazoline derivatives were evaluated.
Thus, (S)-tBuBox was tested again at lower temperatures and found
to be a viable ligand at room temperature, providing the product in
a rather low 18% yield, but in 75% ee, a best achieved thus far. It
should be noted that the (S)-iPrBox catalyst is not active under
these conditions (see Fig. 3). This showcases the fact that (S)-tBuBox
not only forms an active catalyst, but one that is significantly more
active than the (S)-iPrBox-derived one. The most likely reason for
the formation of Pd metal with (S)-tBuBox at 55 ꢁC is that the
hydroarylation is proceeding rapidly, but reoxidation of Pd0 is slow,
potentially due to lower concentration of O2 in solution.42 At lower
temperatures, the rate of hydroarylation decreases, while the
t
pared to iPrBox, the enantioselectivity was lower than that of Bu-
Box. Interestingly, the reactivity of the catalyst derived from ligand
L14 was found to be slightly lower compared to its ‘parent’ ligand
tBuBox, suggesting that a slightly larger bite angle alleviated the
steric crowding in this catalyst, leading to both lower reactivity and
enantioselectivity. Additionally, ligand L16 was synthesized, with
an unsubstituted bridging carbon. Ligands of this type have been

S.M. Podhajsky et al. / Tetrahedron 67 (2011) 4435e4441
4439
found to be deprotonated upon binding to metals,45,46 and are
therefore fundamentally different from typical Box ligands. Un-
fortunately, this ligand did not provide a particularly active or
enantioselective catalyst (Scheme 6).
and indeed found to give the expected product, albeit in low yield.
Unfortunately, when attempting to isolate the product derived
from enol ether stannane 4b, it was found to be inseparable from
the starting material, and therefore, styrene 1a was instead reacted
with PhSnBu3 (4a) (Eq. 2).
2.5 mol% Pd(MeCN)2Cl2
15 mol% L
10 mol% CuCl2
O
iPrOH, balloon O2
O
SnBu3
4b
1c
3c
1.5 equiv.
O
N
O
O
N
O
N
N
tBu
tBu
45 °C
21% yieldb 13% yieldb
tBu
L13
L14
rt
55 °C
24% yielda
29% ee
3. Conclusion
66% ee
70% ee
To summarize, we have made progress toward the development
of a Pd-catalyzed asymmetric hydroarylation of styrenes and di-
enes. Unfortunately, the use of O2 as the terminal oxidant restricts
the potential types of ligands to those stable to oxidative condi-
tions, precluding the use of typical phosphorus-based ligands. We
believe that this limitation is the main obstacle that needs to be
overcome to develop this reaction more fully. With this in mind, we
are currently pursuing the further advancement of this reaction in
two directions: by exploring new types of ligands, as well as new
mechanistic scenarios involving different oxidants and hydride
sources in order to remove oxygen.
O
N
O
O
O
N
N
N
iPr
iPr
tBu
tBu
L15
L16
rt
65 °C
8% yield
12% ee
15% yieldb
71% ee
Scheme 6. Bisoxazoline derivatives. aAfter 44 h. b10 mol % L14 and 5 mol % CuCl2 were
used.
2.6. Scope
Since it seemed the reaction for organostannanes had been
optimized as far as possible, we chose to evaluate different sub-
strates to probe the generality of the reaction (Table 2). In addition
to the substrates used for ligand optimization with boron, styrene
was found to be a viable substrate in combination with an electron
4. Experimental
4.1. General information
iPrOH (IPA) was distilled from CaH2; CDCl3 was dried by passing
through a plug of activated neutral alumina. Liquid styrene sub-
strates were purified by passing through a small plug of activated
poor aryl boronic ester. Furthermore, since p-allyl and p-benzyl Pd
complexes can be accessed with this method, a diene was tested
Table 2
Scope using boronic esters
Entry
1
Alkene
Ar
Product
% Yield
53
% ee
59
2
3
4
29
46
28
27
48
45

4440
S.M. Podhajsky et al. / Tetrahedron 67 (2011) 4435e4441
neutral alumina before use. PhSnBu3 was purchased from Gelest
Inc. NaOtBu was stored in a glove box, and removed immediately
prior to use. Unless otherwise noted, reactions were performed
under an atmosphere of N2 using standard Schlenk techniques.
Flash column chromatography was performed using EM Reagent
silica 60 (230e400 mesh). 1H NMR were obtained at 300 MHz and
referenced to the residual CHCl3 singlet at 7.26 ppm. 13C NMR were
obtained at 75 MHz and referenced to the center line of the CDCl3
triplet at 77.16 ppm. GC/MS were obtained on Agilent 6890 (EI)
20:1 split. IR spectra were recorded using a Nicolate FTIR in-
strument. HRMS (high resolution mass spectrometry) analysis was
performed using Waters LCP Premier XE. Melting points were
measured on a Thomas Hoover capillary melting point apparatus
and are uncorrected. Optical rotations were obtained (Na D line)
using a PerkineElmer Model 343 Polarimeter fitted with a micro
cell with a 1 dm path length; concentrations are reported in g/
100 mL. Chiral GC (gas chromatography) analysis was performed
using a Hewlett Packard HP 6890 Series GC system fitted with an
IR 3294, 2966, 1660, 1601, 1535, 1512, 1409, 1370, 1317, 1268 cmꢀ1
;
HRMS: (m/z) calcd 262.1208 obsd 262.1213 [MþH]þ; mp 93e96 ꢁC.
4.2.3. Methyl 4-(1-phenylethyl)benzoate (3d). The same procedure
as for 3a was followed, except 62.5 mg 1d (0.600 mmol, 1.00 equiv)
was used. The product was purified by flash column chromatog-
raphy eluting with 3% acetone/hexanes. Its spectral properties
matched those of the previously published compound.23 Yield:
66.4 mg (0.276 mmol, 46%, average of two experiments); 48% ee
20
(average of two experiments); [
a
]
3.7 (c 1.0, CHCl3).
D
4.2.4. (E)-1,3-Dimethoxy-5-(4-phenylbut-3-en-2-yl)benzene
(3e). The same procedure as for 3a was followed, except 78.1 mg 1d
(0.600 mmol, 1.00 equiv) was used. The product was purified by
flash column chromatography eluting with 2% acetone/hexanes. Its
spectral properties matched those of the previously published
compound.15 Yield: 45.7 mg (0.170 mmol, 28%, average of two ex-
periments); 45% ee (average of two experiments); [
CHCl3).
a
]
20 ꢀ14.5 (c 1.0,
D
HP-Chiral permethylated b-cyclodextrin column. SFC (supercritical
fluid chromatography) analysis was performed at 40 ꢁC, using
a Thar instrument fitted with a chiral stationary phase (as in-
dicated). Caution should be taken when heating flammable solvents in
the presence of O2.
4.3. Procedure for hydroarylation using PhSnBu3 (4a)
4.3.1. tert-Butyl (4-(1-phenylethyl)phenyl)carbamate (3a). Into
a dry 100 mL Schlenk flask were added 6.7 mg Pd((S)-iPrbox)Cl2
(0.015 mmol, 2.5 mol %), followed by 6.7 mg CuCl2 (0.06 mmol,
10 mol %), 16.0 mg (S)-iPrbox (0.06 mmol, 10 mol %), and 9.00 mL
IPA. A condenser and 3-way adapter fitted with a balloon of O2 were
added, and the flask was evacuated via water aspiration and refilled
with O2 three times while stirring. The resulting mixture was stir-
red for 30 min at room temperature. Then, 132 mg 1a (0.6 mmol,
1.00 equiv), and 330 mg PhSnBu3 4a (0.9 mmol, 1.50 equiv) were
added into a vial and dissolved in 2 mL IPA, and the solution was
added to the Schlenk flask dropwise via syringe. The remaining
1 mL IPA was used to rinse the vial, and added to the flask. The
resulting mixture was heated to 65 ꢁC for 24 h. It was then cooled to
room temperature, and stirred with 5 mL 1 M NaOH for 1 h. The
resulting mixture was transferred to a separatory funnel and di-
luted with Et2O. This was washed with a 1:1 mixture of brine and
H2O (1ꢂ10 mL), and the aqueous layer was extracted with Et2O
(3ꢂ10 mL). The combined organic layers were washed with brine
(1ꢂ20 mL), dried over MgSO4, and the solvent was removed under
reduced pressure. The residue was purified by flash column chro-
matography eluting with 4% acetone/hexanes, which yielded a clear
oil containing product and a small amount of tin byproduct. This
was therefore purified again by flash column chromatography
eluting with 4% EtOAc/hexanes. The pure product’s spectral prop-
erties matched those of the previously published compound.23
4.2. Scope using boronic esters
4.2.1. tert-Butyl (4-(1-phenylethyl)phenyl)carbamate (3a). Into
a dry 100 mL Schlenk flask were added 6.7 mg Pd((S)-iPrbox)Cl2
(0.015 mmol, 2.5 mol %), followed by 12.0 mg (S)-iPrbox
(0.045 mmol, 7.5 mol %), and 9.00 mL IPA. A condenser and 3-way
adapter fitted with a balloon of O2 were added, and the flask was
evacuated via water aspiration and refilled with O2 three times
while stirring. The resulting mixture was stirred for 30 min at room
temperature. Then, 132 mg 1a (0.6 mmol, 1.00 equiv), 266 mg 2a
(1.8 mmol, 3.00 equiv), and 3.4 mg KOtBu (0.03 mmol, 5.0 mol %)
were added into a vial and dissolved in 2 mL IPA, and the solution
was added to the Schlenk flask dropwise via syringe. The remaining
1 mL IPA was used to rinse the vial, and added to the flask. The
resulting mixture was heated to 55 ꢁC for 24 h. It was then cooled to
room temperature, and the solvent was removed under reduced
pressure. The residue was partitioned between H2O (10 mL) and
Et2O (20 mL), and the layers were separated. The organic layer was
washed with 1 M NaOH (1ꢂ10 mL), and the combined aqueous
layers were extracted with Et2O (3ꢂ10 mL), and dried over a 1:1
mixture of MgSO4 and silica gel. They were then filtered, and the
solvent was removed in vacuo. The product was purified by flash
column chromatography eluting with 5% acetone/hexanes, to give
the product as a clear oil. Its spectral properties matched those of
the previously published compound.23 Yield: 94.1 mg (0.316 mmol,
Yield: 65.6 mg (0.221 mmol, 37%, average of two experiments);
20
36% ee (average of two experiments); [
a
]
ꢀ4.5 (c 1.0, CHCl3).
D
53%, average of two experiments); 59% ee (average of two experi-
20
Supplementary data
ments); [
a
]
ꢀ6.8 (c 1.0, CHCl3).
D
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2011.02.027.
4.2.2. N-(4-(1-Phenylethyl)phenyl)acetamide (3b). The same pro-
cedure as for 3a was followed, except 96.7 mg 1b (0.600 mmol,
1.00 equiv) was used. The product was purified by flash column
chromatography eluting with 18% acetone/hexanes. At this stage, it
was found to contain small amounts of starting material (1b). It was
therefore crystallized from DCM/hexanes, which yielded pure
product as a white solid. Yield: 41.6 mg (0.174 mmol, 29%, average
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