Catalyst-controlled regioselectivity in the synthesis of branched conjugated dienes via aerobic oxidative heck reactions

Article abstract of DOI:10.1021/ja307371w

Pd-catalyzed aerobic oxidative coupling of vinylboronic acids and electronically unbiased alkyl olefins provides regioselective access to 1,3-disubstituted conjugated dienes. Catalyst-controlled regioselectivity is achieved by using 2,9-dimethylphenanthroline as a ligand. The observed regioselectivity is opposite to that observed from a traditional (nonoxidative) Heck reaction between a vinyl bromide and an alkene. DFT computational studies reveal that steric effects of the 2,9-dimethylphenanthroline ligand promote C-C bond formation at the internal position of the alkene.

Full text of DOI:10.1021/ja307371w

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Communication
Catalyst-Controlled Regioselectivity in the Synthesis of Branched
Conjugated Dienes via Aerobic Oxidative Heck Reactions
Changwu Zheng, Dian Wang, and Shannon S. Stahl
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 21 Sep 2012
Downloaded from http://pubs.acs.org on September 24, 2012
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Catalyst-Controlled Regioselectivity in the Synthesis of Branched
Conjugated Dienes via Aerobic Oxidative Heck Reactions
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Changwu Zheng, Dian Wang, and Shannon S. Stahl*
Department of Chemistry, University of Wisconsin-Madison, 1101 University Avenue, Madison, WI 53706, United States
Supporting Information Placeholder
Scheme 1. Regioisomeric Conjugated Dienes Potentially
Accessible via Heck-Type Cross-Coupling Reactions.
ABSTRACT: Pd-catalyzed aerobic oxidative coupling of
vinylboronic acids and electronically unbiased alkyl olefins
provides regioselective access to 1,3-disubstituted conjugated
dienes. Catalyst-controlled regioselectivity is achieved by
using 2,9-dimethylphenanthroline as a ligand. The observed
regioselectivity is opposite to that observed from a traditional
(non-oxidative) Heck reaction between a vinyl bromide and an
alkene. DFT computational studies reveal that steric effects of
the 2,9-dimethylphenanthroline ligand promote C–C bond-
formation at the internal position of the alkene.
Mizoroki-Heck Reaction
H
Linear
R1 = electron-
R2
R2
[LnPd]
R1
H
+
X
R1
+ B:
– BH+X-
A
withdrawing group
R2
or
H
Branched
R1 = electron-
donating group
R2
[LnPd]
H
+
(HO)2B
R1
+ [O]
– M[O]H
R1
Oxidative Heck Reaction
B
Heck-type coupling reactions provide a versatile strategy to
convert vinylic C–H bonds into C–C bonds, 1 and one
promising application of these methods is the synthesis of
conjugated dienes via coupling of alkenes and vinyl halides or
vinylboronic acids (Scheme 1). The scope of these reactions is
severely limited, however, by challenges in controlling the
product regioselectivity. The selectivity is typically under
substrate control. The linear product A is obtained with
electron-deficient alkenes, such as acrylates and styrenes,2 and
also can be favored through the use of coordinating directing
groups in the substrate.3 Selective formation of branched
dienes (B) is rare and typically only observed with electron-
rich alkenes, such as vinyl amides.4,5 Ideally, selectivity could
be established via catalyst control, thereby enabling
electronically unbiased alkyl olefins to be used as effective
substrate partners.6 The groups of Sigman7 and Zhou8 recently
demonstrated catalyst-controlled regioselectivity in the
synthesis of styrenes via Heck-type coupling of alkenes with
arylboronic acids (linear selectivity),7a aryl diazonium salts
Chart 1. Ligand Effects on the Oxidative Heck Coupling of
Styrenylboronic Acid and Octene.a
10% Pd(TFA)2
20% Ligand (L1-L10)
OH
B
+
Ph
C6H13
Ph
OH
H
C6H13
O2 (1 atm), NMP
40 °C, 2-6 h
– B(OH)3
3a
1a
2a
% yieldb (branched:linear)c
O
Pd(TFA)2
with
no ligand
N
N
N
N
N
N
N
9% (1:5) L1 0% (n.d.) L2 3% (1:2)d
L3 6% (1:4)d
L4 <1% (1:5)
O
N
N
N
N
N
N
Bn
Me
Me
L5 19% (5:1)
L6 29% (5:1)
L7 35% (12:1)
N
N
N
N
N
N
(linear
selectivity)7b
and
aryl
triflates
(branched
Me
Me
nBu
nBu
Ph
Ph
selectivity).8,9,10 Here, we report a PdII-catalyzed method for
aerobic oxidative coupling of vinylboronic acids and
electronically unbiased alkenes to prepare 1,3-disubstituted
dienes. These results represent the first general method for
catalyst-controlled regioselectivity in Heck-type synthesis of
dienes. Additional experimental studies and DFT calculations
provide insights into the origin of the reaction selectivity.
Several recent studies in our lab have focused on
regioselective aerobic oxidative coupling reactions of alkenes
and arenes with nitrogen-ligated PdII catalysts. 11 In this
context, our attention was drawn to recent work by Larhed,12
Jung,13 and others,14 highlighting the use of nitrogen ligands in
Pd-catalyzed aerobic oxidative coupling of boronic acids and
alkenes. Although these reactions were limited to examples of
substrate-controlled regioselectivity (e.g., with acrylates as the
alkene coupling partner), this work suggested that chelating
nitrogen ligands might enable regioselective oxidative Heck
reactions with electronically unbiased alkenes.
L8 90% (20:1)e
L9 75% (20:1)
L10 3% (10:1)d
a
Reaction conditions: vinyl boronic acid (1.5 equiv), alkene (0.2
mmol), NMP (0.5 mL). Reactions were monitored on GC using 4-
methylanisole as the internal standard. b GC yield. c Determined by
1
d
GC and H NMR. Pd(TFA)2 (20 mol%) and ligand (40 mol%)
were used. e LiTFA (0.2 equiv) was added.
Our initial efforts focused on the reaction of (E)-
styrenylboronic acid 1a and 1-octene. Use of previously
reported oxidative Heck conditions led to limited success (<
40% yield of diene; see Supp. Info. for full screening data),
but variation of the PdII source, ancillary ligand and solvent
showed that good yields and regioselectivity could be
achieved with Pd(nc)(TFA)2 (TFA = trifluoroacetate, nc =
neocuproine
= 2,9-dimethyl-1,10-phenanthroline) as the
catalyst and N-methylpyrrolidone as the solvent. The ligand
effects depicted in Chart 1 provide useful insights. Bipyridine
and phenanthroline, which have been used in other Pd-
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catalyzed aerobic oxidative Heck reactions,2f,14a led to very
low yields and favored formation of the linear diene product,
similar to the results obtained with Pd(TFA)2 in the absence of
an ancillary ligand. Improved yields and a preference for the
branched diene isomer were observed upon using chelating
ligands with substituents adjacent to the nitrogen atoms of the
ligand (L5–L10). The best result was observed with
neocuproine (L8); with this ligand, the branched diene was
obtained in 90% yield with 20:1 selectivity over the linear
isomer.15
To assess the generality of these catalytic conditions, we
investigated the reaction of (E)-styrenylboronic acid with a
number of different terminal olefins (Table 1). Good yields
were observed with substrates bearing a wide range of
functional groups, including ethers, ketones, esters,
of the TMS group to afford 1-phenylbutadiene (3q). Electron-
deficient alkenes such as vinylboronic pinacol ester and
styrene afford the linear products (3r and 3s).
1
2
3
4
5
6
7
8
One appeal of oxidative Heck reactions for the synthesis of
dienes is the straightforward accessibility of the vinylboronic
acids via hydroboration of alkynes. In this context, we
evaluated reactions of a number of different vinylboronic
acids with various alkene coupling partners (Table 2). Diverse
substituted styrenylboronic acids were compatible with the
reaction conditions and led to branched dienes in good-to-
excellent yields and regioselectivities (products 4a-4f, 4j, 4l-
4p). Of particular note is the compatibility of aryl bromide
substituents, which implies that Pd0 reacts more rapidly with
O2 than the Ar–Br bond.18,19 Products from cis-alkenyl- and
β,β-disubstituted alkenylboronic acids were also obtained (4i,
4j). Vinylboronic acids with aliphatic substitution on the vinyl
group were somewhat less reactive than the styrenylboronic
acids, but good yields and regioselectivities were still
observed (products 4g-4i, 4q-4r). If needed, a modest
improvement in the yield can be obtained with higher catalyst
loading (cf. product 4k).
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unprotected alcohols, silyl and silylether groups, and
16
phthalimide.
Good-to-exclusive regioselectivity was
observed in these reactions, favoring formation of the
branched diene product (3a-3n). As expected, the electron-rich
vinyl ether and vinyl amide substrates undergo oxidative
coupling to afford the branched diene products (3o and 3p).
The vinyl ether product hydrolyzes under the reaction
conditions, resulting in the α,β-unsaturated methyl ketone.17
Vinyltrimethylsilane represents a formal ethylene equivalent;
oxidative Heck coupling of this alkene substrate results in loss
Table 2. Diene Synthesis via Oxidative Heck Coupling of
Diverse Vinylboronic Acids and Terminal Olefins.a
OH
Pd(TFA)2 (10 mol%)
B
L8 (20 mol%)
R1
+
OH
R1
R
R
LiTFA (20 mol%)
4
Table 1. Diene Synthesis via Oxidative Heck Coupling of
2
1
NMP , O2, 40 o
C
% yieldb (branched:linear)c
(E)-Styrenylboronic Acid and Terminal Olefins.a
OH
Pd(TFA)2 (10 mol%)
Ph
B
L8 (20 mol%)
+
OH
Ar
Ph
Ph
R
R
LiTFA (20 mol%)
O
3
1a
2
NMP , O2, 40 o
C
% yieldb (branched:linear)c
F
4ke 23 h, 66%, 10:1
4kc 16 h, 76%, 10:1g
Ar =
OMe
4a 5 h, 83%, 10:1 4bd 4.5 h, 60%, 5:1
Ph
Ph
C6H13
Ph
(CH2)4OAc Ph
Ar
O
3a 6 h, 83%, 20:1
3bd 8.5 h, 80%, 10:1
3cd 8.5 h, 75%, 7:1
Br
4cd 5.5 h, 72%, 8:1 4d 6.5 h, 65%, 8:1
Me
Ar =
OEt
OMe Me
Ph
Ph
Ph
Si(Me)3
4ld,e 4.5 h, 68%, 10:1 4md,e 5 h, 86%, 13:1
Ph
O
OH
Si(iPr)3
3dd,e 4.5 h, 87%, 5:1
3e 3.5 h, 57%, >20:1
3f 2 h, 75%, >20:1
Ar
O
R
Ph
Si(iPr)3
Ph
Ph
Ar =
F3C
N
F3C
3gd,e 2.5 h, 88%, 12:1
Br
R =
4ee 4 h, 85%, >20:14fe 5 h, 74%, >20:1
O
(4n)
(4o)
(1 mmol) 3 h, 74%, 10:1
3he 2 h, 86%, >20:1
3i 4 h, 83%, 5:1
(10 mmol) 6 h, 64%, 11:1
OBn
4nd,e 3.5 h, 81%, 15:1 4o 7 h, 73%, 12:1
OSi(tBu)Ph2
R
Ph
3jd 4 h, 83%, 8:1
OSi(tBu)Ph2
Ph
O
O
(4g)
OSi(tBu)Ph2
3k 7 h, 85%, 15:1
R =
OH
(4h)
OBn
OBn
Br
Ph
3ld 7 h, 86%, 8:1
Ph
OH
4g 7 h, 53%, 12:1 4h 7 h, 64%, 10:1
Ph
4p 3.5 h, 70%, >20:1
3m 7 h, 83%, 8:1
3nd 1 h, 54%, 5:1
nC6H13
O
O
O
R
N
Ph
4i 10 h, 38%, 14:1f
Ph
N
O
Ph
R = OnBu
(4q)
(4r)
R = Si(Me)3
3q 0.5 h, 58%
R =
MeO
3o 1 h, 82%, >20:1
3p 2.5 h, 76%, >20:1
OBn
Ph
O
B
4q 2.5 h, 58%, >20:1 4r 5 h, 65%, >20:1
O
4j 7 h, 67%, 20:1
O
Ph
Ph
3s 8 h, 52%, <1:20
3r 2.5 h, 50%, <1:20
aThe reactions were performed with vinyl boronic acid (1.5
equiv), alkene (0.2 mmol) in NMP (0.5 mL) at 40 °C. bIsolated
yields. cBranched:linear selectivity determined by GC and 1H
aReaction conditions: vinyl boronic acid (1.5 equiv), alkene (0.2
mmol) in NMP (0.5 mL). bIsolated yields. cBranched:linear
selectivity determined by GC and 1H NMR spectroscopy.
dIsolated as a mixture of branched and linear regioisomers. eSome
isomerization of the diene (< 5%) occurs during purification.
d
NMR spectroscopy. Isolated as a mixture of the branched and
linear regioisomers. Some isomerization of the diene (< 5%)
e
f
occurs during purification. cis-Octenylboronic acid used; (Z)-
4i:(E)-4i = 3.5:1. gCatalyst/additive loading doubled.
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Factors that govern regioselectivity in Heck-type coupling
reactions have been discussed extensively in the literature.1g,20
1
2
3
4
5
6
7
8
Black - Pathways for Si face
Gray - Pathways for Re face
‡
20.0
10.0
0.0
Neutral bidentate ligands lead to cationic [PdII(L2)(aryl/vinyl)-
(alkene)]+ intermediates that exhibit higher selectivity for
Markovnikov addition to the alkene, relative to neutral
PdII(L)(X)(aryl/vinyl)(alkene) intermediates formed with
neutral monodentate ligands. Electronic effects are not
sufficient to explain the present results, however, because
several bidentate ligands favor the linear coupling product (see
Chart 1). Steric effects undoubtedly play an important role in
these reactions, and it seems reasonable to expect that the
methyl groups of the neocuproine ligand disfavors the
transition state leading to the linear product (Scheme 2).
N
N
Bn Pd
‡
15.1
12.5
Ph
N
Pd
N
H
11.9
TSlinear(pro-S)
Ph
10.2
H
Bn
)
l
TSbranched(pro-S)
o
m
/
l
a
c
Linear
Pathways
Branched
Pathways
k
0.7
0.0
(
K
8
9
9
2
,
M
10
11
12
13
14
15
16
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19
20
21
22
23
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N
N
C
P
Pd
Ph
G
!
H
Ipro-S
Bn
-10.0
-20.0
-9.7
Scheme 2. Steric Effects that Favor Formation of Branched
Diene Products.
-13.4
N
N
Pd
N
Pd
N
Bn
H
Bn
+
+
H
N
N
N
N
Ph
Ph
Plinear(pro-S)
Ph
Ph
Pd
Pd
Pbranched(pro-S)
Vi
Vi
R
Bn
Bn
major
(branched) product
minor
(linear) product
R
Vi = vinyl group
R
Figure 1. Energies for the two regioisomeric alkene insertion
pathways involving the Si and Re face of the alkene. The
chemical structures of the Re-face insertion pathway and the +1
charges on all structures are omitted for clarity. See Supp. Info.
for additional details.
R
Vi
Vi
Linear products
Branched products
DFT calculations of the insertion of allylbenzene into a
neocuproine-ligated PdII–styrenyl species provide insights into
the relative energies of pathways leading to the branched and
linear dienes (Figure 1). 21 Multiple conformations of the
intermediates and transition states associated with this step are
possible, and the two prochiral faces of the alkene correspond
to diastereomeric intermediates and transition states. The most
favorable alkene insertion pathways are shown in Figure 1.
The coordinated alkene in intermediates Ipro-S and Ipro-R orients
perpendicular to the square plane of PdII. It then rotates into
the plane as it proceeds through the subsequent alkene-
insertion transition states, and the (pro-R)- and (pro-S)-isomers
of TSbranched and TSlinear show a preference for the branched
pathway, particularly for the lower-energy Si-face insertion
(ΔΔG‡ = 4.9 kcal/mol). If exchange between Ipro-S and Ipro-R is
facile, formation of the branched isomer is calculated to be
favored over the linear isomer by 2.3 kcal/mol. For both
pathways, alkene insertion is substantially downhill (≥ 9.7
kcal/mol) from Ipro-S to form the resulting PdII–alkyl
intermediate.
explanation takes into account the high temperatures required
for this reaction: 110 °C, relative to 40 °C for the oxidative
Heck reactions. Under the more-forcing conditions, the Pd
catalyst could decompose into Pd nanoparticles that promote
coupling via a "ligand-free" pathway.24 Potential support for
this hypothesis was obtained from dynamic light scattering
data, which reveal that Pd nanoparticles, 200–400 nm in
diameter, form under the Heck coupling conditions in eq 1.
Furthermore, independently prepared nanoparticles are
effective catalysts for the same reaction and afford the linear
product in nearly identical yield. 25 No nanoparticles are
detected from an oxidative Heck reaction with styrenylboronic
acid and octene. These observations highlight the uniqueness
of the oxidative Heck coupling conditions reported above.
Pd(OAc)2 (10 mol%)
neocuproine (20 mol%)
Na2CO3 (2.0 equiv)
Br
C6H13
C6H13
(1)
+
Ph
Ph
NMP , 110 oC, 11 h
57% yield
10:1 linear:branched
5:1 trans:cis
The results described here are notable not only for the
catalyst control over regioselectivity, but also for the ability to
access the branched regioisomer. Precedents for Heck-type
synthesis of dienes (including both traditional and oxidative
methods) with electronically unbiased alkenes are rare, and
essentially all known examples favor linear over branched
In conclusion, we have developed highly regioselective
oxidative Heck reactions that enable the preparation of
synthetically useful branched 1,3-disubstituted conjugated
dienes. The ability to achieve selectivity with electronically
unbiased alkenes complements recent advances by others, and
significantly expanding the scope and synthetic utility of Heck
coupling reactions.
products.6 In light of precedents for use of phenanthroline
22
ligands in traditional Heck coupling reactions,
we
investigated whether neocuproine could control the
regioselectivity of diene synthesis in a traditional Heck
coupling reaction. The coupling of β-bromostyrene and octene
with a Pd(OAc)2/neocuproine catalyst system led to a 57%
yield of diene (eq 1), but the linear regioisomer was strongly
favored (10:1) over the branched product.23 This outcome
potentially could be rationalized by invoking a neutral
pathway for alkene insertion [i.e., via a PdII(κ1-nc)(Br)-
(styrenyl)(octene) intermediate], which may favor formation
of the linear diene.20 An alternative, perhaps more likely,
ASSOCIATED CONTENT
Supporting Information
Full catalyst screening data, experimental procedures, product
characterization data for all products, and computational data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
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Corresponding Author
1
2
3
R.; Gutierrez, A. C.; Jamison, T. F. J. Am. Chem. Soc. 2011, 133,
19020.
( 10 ) The use of ionic liquids as solvents can enhance the
stahl@chem.wisc.edu
ACKNOWLEDGMENT
regioselectivity of certain Heck-type coupling reactions. See: (a) Mo,
J.; Xu, L. J.; Xiao, J. L. J. Am. Chem. Soc. 2005, 127, 751. (b) Mo, J.;
Xu, L.; Ruan, J.; Liu, S.; Xiao, J. Chem. Commun. 2006, 3591.
(11) (a) Campbell, A. N.; White, P. B.; Guzei, I. A.; Stahl, S. S. J.
Am. Chem. Soc. 2010, 132, 15116. (b) Izawa, Y.; Stahl, S. S. Adv.
Synth. Catal. 2010, 352, 3223. (c) Campbell, A. N.; Meyer, E. B.;
Stahl, S. S. Chem. Commun. 2011, 10257.
(12) See ref. 5a and the following: (a) Andappan, M. M. S.;
Nilsson, P.; Larhed, M. Chem. Commun. 2004, 218. (b) Andappan, M.
M. S.; Nilsson, P.; Schenck, H. V.; Larhed, M. J. Org. Chem. 2004,
69, 5212. (c) Enquist, P.-A.; Lindh, J.; Nilsson, P.; Larhed, M. Green
Chem. 2006, 8, 338. (d) Lindh, J.; Enquist, P.; Pilotti, Å.; Nilsson, P.;
Larhed, M. J. Org. Chem. 2007, 72, 7957.
(13) See ref. 2f and the following: Yoo, K. S; Park, C. P.; Yoon, C.
H.; Sakaguchi, S.; O'Neill, J.; Jung, K. W. Org. Lett. 2007, 9, 3933.
(14) (a) Park, C. P.; Kim, D.-P. J. Am. Chem. Soc. 2010, 132,
10102. (b) Gottumukkala, A. L.; Teichert, J. F.; Heijnen, D.; Eisink,
N.; van Dijk, S.; Ferrer, C.; van den Hoogenband, A.; Minnaard, A. J.
J. Org. Chem. 2011, 76, 3498.
(15) The beneficial effect of neocuproine as a ligand in substrate-
controlled oxidative Heck reactions has been noted in a number of
studies by Larhed and coworkers. See ref. 12.
4
5
6
7
8
9
We thank Dr. Doris Pun for assistance with dynamic light
scattering experiments and Paul White for assistance with DFT
calculations. We are grateful for financial support from the NIH
(R01 GM67163). Shanghai Institute of Organic Chemistry (SIOC
Postdoctoral Fellowship) for financial support of this work.
Computational resources was supported in part by National
Science Foundation Grant CHE-0840494.
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2010, 1399. (i) Mc Cartney, D.; Guiry, P. J. Chem. Soc. Rev. 2011,
40, 5122.
(2) See, for example: (a) Dieck, H. A.; Heck. R. F. J. Org. Chem.
1975, 40, 1983. (b) Crisp, G. T.; Glink, P. T. Tetrahedron 1994, 50,
2623. (c) Berthiol F.; Doucet, H.; Santelli, M. Synlett 2003, 841. (d)
Yoon, C. H.; Yoo, K. S.; Yi, S. W.; Mishra, R. K.; Jung, K. W. Org.
Lett. 2004, 6, 4037. (e) Hansen, A. L.; Ebran, J. P.; Ahlquist, M.;
Norrby, P. O.; Skrydstrup, T. Angew. Chem. Int. Ed. 2006, 45, 3349.
(f) Yoo, K. S.; Yoon, C. H.; Jung, K. W. J. Am. Chem. Soc. 2006, 128,
16384. (g) Ebran, J.-P.; Hansen, A. L.; Gøgsig, T. M.; Skrydstrup, T.
J. Am. Chem. Soc. 2007, 129, 6931. (h) Lemhadri, M.; Battace, A.;
Berthiol, F.; Zair, T.; Doucet, H.; Santelli, M. Synthesis 2008, 1142.
(3) (a) Crisp, G. T.; Gebauer, M. G. Tetrahedron 1996, 52, 12465.
(b) Delcamp, J. H.; Brucks, A. P.; White, M. C. J. Am. Chem. Soc.
2008, 130, 11270. (c) Pan, D.; Chen, A.; Su, Y.; Zhou, W.; Li, S.; Jia,
W.; Xiao, J.; Liu, Q.; Zhang, L.; Jiao, N. Angew. Chem. Int. Ed. 2008,
47, 4729. (d) Su Y.; Jiao N. Org. Lett. 2009, 11, 2980.
(4) (a) Vallin, K. S. A.; Zhang, Q. S.; Larhed, M.; Curran, D. P.;
Hallberg, A. J. Org. Chem. 2003, 68, 6639. (b) Hansen, A. L.;
Skrydstrup, T. Org. Lett. 2005, 7, 5585. (c) McConville, M.; Saidi,
O.; Blacker, J.; Xiao, J. J. Org. Chem. 2009, 74, 2692.
(5) For leading references describing Heck-type reactions between
aryl coupling partners and electron-rich alkenes, see: (a) Andappan,
M. M. S.; Nilsson, P.; von Schenck, H.; Larhed, M. J. Org. Chem.
2004, 69, 5212. (b) Ruan, J.; Xiao, J. Acc. Chem. Res. 2011, 44, 614
and the references cited.
(6) Only isolated examples of Heck-type synthesis of conjugated
dienes with electronically unbiased alkenes have been reported in the
literature. The examples that exist typically favor formation of the
linear regioisomeric product (A, Scheme 1). See refs 2c, 2h and the
following: (a) Patel, B. A.; Heck, R. F. J. Org. Chem. 1978, 43, 3898.
(b) Kim, J.; Lee, J. T.; Yeo, K. D. Bull. Korean Chem. Soc. 1985, 6,
367. (c) Wang, G.; Mohan, S.; Negishi, E. Proc. Natl. Acad. Sci. U. S.
A., 2011, 108, 11344.
(16) Gas-liquid mixing can influence the outcome of the reaction.
The majority of yields in Tables 1 and 2 were obtained by vortexing
the reactions mixtures under 1 atm O2. Larger scale reactions were
carried out in a round-bottom flask (cf. Table 1, 3g).
(17) For related reactions of vinyl ethers with arylboronic acids,
see refs. 4c and 12b.
(18) Similar observations have been noted by Jung et al. in
competition studies of Ar–I and O2 substrates: Jung, Y. C.; Mishra, R.
K.; Yoon, C. H.; Jung, K. W. Org. Lett. 2003, 5, 2231.
(19) For fundamental studies of reactions of O2 with Pd0-alkene
complexes bearing a dimethylphenanthroline ligand, see: (a) Stahl, S.
S.; Thorman, J. L.; Nelson, R. C.; Kozee, M. A. J. Am. Chem. Soc.
2001, 123, 7188. (b) Popp, B. V.; Morales, C. M.; Landis, C. R.;
Stahl, S. S. Inorg. Chem. 2010, 49, 8200.
(20) Cabri, W.; Candiani, I.; Bedeschi, A. J. Org. Chem. 1993, 58,
7421.
(21) Final structures were optimized with the following method
(Gaussian 09): B3LYP; Stuggart RSC 1997 ECP basis sets for Pd; 6-
311+G (d, p) basis sets on all other atoms; polarizable continuum
solvation model (N,N-dimethylformamide); see Supporting
Information for computational details.
(22) See ref. 20 and the following: Cabri, W.; Candiani, I.;
Bedeschi, A.; Santi, R. Synlett 1992, 871.
(23) Pd(OAc)2 was used rather than Pd(TFA)2 in the Heck
coupling reaction in eq 1 based on literature precedents (e.g., ref. 6c).
Control experiments with the oxidative Heck coupling show that,
while Pd(OAc)2 is not as effective as Pd(TFA)2, good yields and high
branched selectivity can be achieved. See Supporting Information for
details.
(24) Control experiments show that the reaction in eq 1 does not
proceed at 40 °C. See Supporting Information for details. Ligand-
free/nanoparticle conditions for traditional Heck coupling reactions
commonly employ polar solvents: (a) Reetz, M. T.; Westermann, E.
Angew. Chem. Int. Ed. 2000, 39, 165. (b) de Vries, J. G. Dalton
Trans. 2006, 421. (c) Reetz, M. T.; de Vries, J. G. Chem. Commun.
2004, 1559.
(7) (a) Werner, E. W.; Sigman, M. S. J. Am. Chem. Soc. 2010, 132,
13981. (b) Werner, E. W.; Sigman, M. S. J. Am. Chem. Soc. 2011,
133, 9692.
(8) Qin, L. N.; Ren, X. F.; Lu, Y. P.; Li, Y. X.; Zhou, J. R. Angew.
Chem. Int. Ed. 2012, 51, 5915.
(25) See Supporting Information for details.
(9) A recent Ni-catalyzed Heck-type coupling of benzyl chlorides
and alkenes exhibits selectivity for the branched isomer: Matsubara,
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Linear
Branched
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Oxidative Heck Reaction
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Unbiased Alkenes
Vi
Branched
TS‡
R
Vi = vinyl group
Linear TS‡
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