Synthesis of Styrenes by Palladium(II)-Catalyzed Vinylation of Arylboronic Acids and Aryltrifluoroborates by Using Vinyl Acetate

Article abstract of DOI:10.1002/chem.200802744

Reactions of aromatic and heteroaromatic boronic acids or aryltrifluoroborate salts with vinyl acetate in the presence of a palladium(II) catalyst give the corresponding styrenes in good yields. This Heck reaction proceeds with microwave heating in less t

Full text of DOI:10.1002/chem.200802744

DOI: 10.1002/chem.200802744
Synthesis of Styrenes by Palladium(II)-Catalyzed Vinylation of Arylboronic
Acids and Aryltrifluoroborates by Using Vinyl Acetate
Jonas Lindh,[a] Jonas Sꢀvmarker,[a] Peter Nilsson,[a] Per J. R. Sjçberg,[b] and
Mats Larhed*[a]
Abstract: Reactions of aromatic and
heteroaromatic boronic acids or aryltri-
fluoroborate salts with vinyl acetate in
the presence of a palladium(II) catalyst
give the corresponding styrenes in
good yields. This Heck reaction pro-
ceeds with microwave heating in less
than 30 min at 1408C in the absence of
base and tolerates a variety of substitu-
ents. No palladium reoxidant is needed
and the vinylation is performed under
non-inert conditions. Mass spectrome-
try (electrospray ionization mass spec-
trometry (ESIMS) and tandem mass
spectrometry (MS/MS)) was used to
identify cationic palladium-containing
complexes in ongoing reactions. The
key intermediates that have been de-
tected, together with experiments that
used deuterated vinyl acetate, support
the existence of catalytically active pal-
ladium hydride species, and that it is
the arylation of ethylene, not vinyl ace-
tate, which generates the styrene prod-
uct. The mechanism of the reaction is
discussed in terms of the palladium(II)
intermediates mentioned above.
Keywords: Heck reaction
· mass
spectrometry · mechanistic studies ·
palladium · styrene
Introduction
thermore, organic stannanes are toxic and often complicate
chromatographic product purification.[8]
Efficient and low-cost synthesis of styrenes is of great inter-
est in many fields of organic chemistry because they consti-
tute substrates for oxidation,[1] metathesis,[2] and Diels–
Alder reactions,[3] for example, and serve as precursors to
functionalized polymers. To meet this demand, several
metal-catalyzed Heck and cross-coupling methods for the
smooth preparation of styrenes by vinylation of aryl halides
have been reported by using pressurized ethylene,[4] vinyl
stannanes,[5] vinyl silicon compounds,[6] and vinyl boronic
compounds.[7] The use of ethylene suffers from practical
problems associated with the handling of flammable pressur-
ized gases, whereas the transmetallation reactants listed
above are expensive and provide poor atom efficiency. Fur-
Arylboronic acids can provide styrenes by Suzuki cou-
pling with vinyl halides[9] or vinyl sulfonic acid esters.[10]
Aryl- and vinylboronic acids are relatively stable, widely
commercially available, and have low toxicity, which makes
them very attractive coupling agents. The more recently in-
troduced aryltrifluoroborates represent a new, valuable class
of arylation agents.[11] Innovative methods for iridium-cata-
À
lyzed C H borylation of arenes have enabled even easier
access to these classes of organometallic reactants.[12] How-
ever, no methods for Heck-type vinylation of arylboronic
compounds are presently available for the preparation of
styrene derivatives.
From earlier experiences in the field of palladium(II)-cat-
alyzed oxidative Heck reactions,[13,14] it occurred to us that it
should be possible to produce styrenes from arylboronic
acids by using cheap and simple vinyl acetate (VA)[15] as the
vinylating agent. According to this hypothesis, the reaction
would proceed without any addition of base or external pal-
ladium reoxidant because b-acetate elimination should allow
for the regeneration of the active palladium(II) species.[16]
We herein report the first oxidative Heck-type method for
direct small-scale synthesis of styrenes from arylboronic
acids or aryltrifluoroborates together with ESIMS and MS/
MS analyses of palladium-containing cationic reaction inter-
mediates. The findings support a palladium(II) hydride
[a] J. Lindh, J. Sꢀvmarker, Dr. P. Nilsson, Prof. M. Larhed
Department of Medicinal Chemistry
Organic Pharmaceutical Chemistry
Uppsala University, BMC, Box-574
SE-751 23 Uppsala (Sweden)
E-mail: Mats@orgfarm.uu.se
[b] Dr. P. J. R. Sjçberg
Department of Physical and Analytical Chemistry
Uppsala University, BMC, Box-599
SE-751 23 Uppsala (Sweden)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200802744.
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FULL PAPER
mediated release of ethylene, which subsequently undergoes
oxidative Heck arylation to provide the styrene product.
was not necessary. A solvent screen (Table 1, entries 6, 10–
14) showed that DMF gave the best result to produce only
6% of the deboronated product 3 f. Performing the reaction
in the absence of a palladium catalyst resulted in no product
formation (Table 1, entry 8), whereas ligand-free conditions
provided a very low yield of 2 f (5%; Table 1, entry 9). By
using dppp and DMF at 1408C for 30 min (Table 1, entry 6),
we were pleased to find that the reaction was essentially
limited to monoarylation. Even after the addition of one
equivalent of the highly efficient palladium oxidant p-benzo-
quinone, no stilbene formation from a second oxidative
Heck arylation of the styrene formed in situ was detect-
ed.[14,19] Another interesting observation was the complete
absence of homocoupled boronic acids, which are often de-
Results and Discussion
A reaction protocol that used 4-biphenylboronic acid (1 f,
1 mmol) and VA (10 equiv) was selected as an appropriate
[17]
test system. Initial microwave
experiments were conduct-
ed in sealed vessels at 1408C with an irradiation time of
30 min. Previously employed base-free oxidative Heck con-
ditions, with PdACHTUNGTRENNUNG(OAc)2 (2 mol%) and 2,9-dimethyl-1,10-phe-
nanthroline (dmphen, 2.2 mol%) as the catalytic system and
DMF as the solvent were used.[14] The reaction gave a poor
yield of styrene 2 f, extensive deboronation afforded 3 f, and
also led to the formation of a cis/trans mixture of styryl
ester 4 f (Table 1, entry 1). As evident from Table 1, the
monodentate ligands triphenylphosphane and tri-o-tolyl-
tected in small amounts in oxidative Heck reactions.[20,21]
A
tenfold increase in the amount of catalyst, or the use of a
palladium(0) complex, provided lower yields of 2 f (57–
60%; Table 1, entries 15 and 16). Performing the reaction in
the presence of bases, such as NaOAc and Et3N, led to ex-
tensive formation of 3 f.
Next, time and temperature investigations were conduct-
ed with the aim of reducing the reaction time and increasing
the isolated yield (Table 2). The original conditions that in-
Table 1. Vinylation of 4-biphenylboronic acid (1 f): Influence of reaction
parameters, part 1.[a]
Entry
Ligand
Solvent
Isolated yield[b] [%]
2 f
3 f
4 f
1
2
3
4
5
6
7
dmphen
dmphen
PPh3
DMF
MeCN
DMF
DMF
DMF
DMF
DMF
DMF
DMF
MeCN
toluene
dioxane
acetone
H2O
5
14
3
2
8
4
5
17
17
14
n.d.
n.d.
trace
trace
n.d.
n.d.
n.d.
trace
trace
trace
trace
trace
trace
trace
Table 2. Vinylation of 4-biphenylboronic acid (1 f): Influence of reaction
parameters, part 2.[a]
P
N
trace
43
Entry
T
[8C]
t
VA
[equiv]
Ratio of
Yield of
dppe
dppp
dppb
none
none
dppp
dppp
dppp
dppp
dppp
dppp
dppp
G
2 f/3 f[b]
2 f[c] [%]
77[c]
6
4
1
2
3
4
5
6
7
8
100
100
120
140
140
140
160
RT
140
140
140
140
140
6 h
3 h
1 h
1 h
30 min
10 min
5 min
72 h
30 min
30 min
30 min
30 min
30 min
10
10
10
10
10
10
10
10
2
4
6
8
15
90:10
90:10
90:10
90:10
90:10
90:10
90:10
90:10
60:40
75:25
85:15
85:15
90:10
77
68
74
4
n.d.
8[d]
9
trace
trace
22
21
24
19
12
5
7
5
43
21
48
44
48
60
57
80
10
11
12
13
14
15[e]
16[f]
77[d]
66
58
71[e]
[f]
9
–
–
–
–
DMF
DMF
[f]
10
11
12
13
[f]
[a] Reaction conditions: A 5 mL microwave-transparent vial was charged
with 1 f (1.0 mmol), VA (10.0 mmol), a Pd source (0.02 mmol), a ligand
(0.022 mmol), and solvent (2 mL). The vial was capped under air and ex-
posed to temperature-controlled microwave irradiation (1408C, 30 min).
dppe=1,2-bis(diphenylphosphino)ethane, dppp=1,3-bis(diphenylphos-
phino)propane, and dppb=1,4-bis(diphenylphosphino)butane. n.d.=not
detected by GC–MS analysis of the crude mixture. [b] Isolated yield
>95% pure according to GC–MS. [c] Average yield from two reactions.
[f]
[f]
–
[a] Reaction conditions: A 5 mL microwave-transparent vial was charged
with 1 f (1.0 mmol), VA (2.0-15 mmol), Pd(OAc)2 (0.02 mmol), dppp
AHCTUNGTRENNUNG
(0.022 mmol), and DMF (2 mL). The vial was capped under air and ex-
posed to temperature-controlled microwave irradiation. [b] Determined
by GC–MS and 1H NMR. [c] Isolated yield >95% pure according to
GC–MS. [d] Average yield from two reactions. [e] Stirred at room tem-
perature. [f] Yield not determined.
[d] No catalyst added. [e] 0.2 mmol Pd
ACHTUNGRTEN(NUNG OAc)2 and 0.22 mmol dppp was
used. [f] 0.01 mmol Pd2A(dba)3 was used as the Pd source.
CHTUNGTRENNUNG
phosphane also resulted in low-yielding reactions (Table 1,
entries 3 and 4). From the literature, it is well known that
chelating phosphane ligands impose high reactivity and
good selectivity for internal palladium(0)-catalyzed arylation
of electron-rich olefins under cationic conditions.[18] Thus, bi-
dentate phosphane ligands with three different alkyl tethers
(C2–C4) were tested (Table 1, entries 5–7), from which dppp
was found to be the most promising, providing an isolated
yield of 77% of the desired product 2 f. Despite the poten-
tial problem of phosphane oxidation, an inert atmosphere
volved microwave heating at 1408C for 30 min were, howev-
er, further established as an appropriate protocol because
they provided a consistently high yield of 2 f (Table 2,
entry 5). The outcome was only slightly improved by extend-
ing the irradiation time to 60 min (80 versus 77%; Table 2,
entry 4). Hence, 30 min was selected as the standard heating
time for further studies. A reaction in a sealed vessel was
performed at room temperature to study the outcome with-
out microwave heating. The isolated yield of 71% was ac-
ceptable, but the reaction time required to reach full conver-
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M. Larhed et al.
Table 3. Vinylation of a set of arylboronic acids, aryltrifluoroborates, and a vinylboronic acid.[a]
sion was long (72 h, Table 2,
entry 8). All attempts to de-
crease the amount of VA
(10 equiv) were fruitless be-
cause a lower amount gave ex-
Entry
1
Boronic compound
Product
Yield[b]
74
tensive deboronation, and
a
larger quantity had no positive
impact on the product yield
(Table 2, entries 9–13). No di-
ACHTUNGTRENNUNGarylated product was observed,
even when only two equiva-
lents of VA were used.
2
71
With suitable non-inert con-
ditions at hand, a series of vi-
nylations by using fourteen ad-
ditional boronic precursors was
performed as presented in
Table 3. Electron-rich hetero-
cyclic 2a was isolated in 74%
yield after a straightforward re-
3
4
83
78
action
(Table 3,
entry 1).
Chloro-functionalized 1b gave
no side products from palladi-
um(0) activation of the chlo-
ride[22] or from benzylic cleav-
age, providing product 2b in
71% yield (Table 3, entry 2).
Sulfur-containing 1c gave the
expected styrene product with-
out disturbing the catalytic
5
82
6
2 f
62[c]
71
7
system
(Table 3,
entry 3).
Ortho-, meta-, and para-biphe-
nylboronic acids 1d–f all per-
formed well, and no clear
trends in the outcome based
on the substitution pattern
could be observed (Table 3, en-
8
2g
62[c]
68
9
tries
4 and 5 and Table 2,
entry 5). To further extend the
range of coupling partners,
four different aryltrifluorobo-
rates were tested (Table 3, 1g,
1i, 1k, and 1m). These ionic
species all served as useful sub-
strates in the presence of the
sodium salt of trifluoroacetic
acid (NaTFA, 2 equiv), effi-
ciently replacing the common
use of water or TFA in cou-
pling reactions with aryltri-
fluoroborate salts.[11] Biphenyl-
trifluoroborate 1g worked
well, although the yield was
lowered compared with the
corresponding boronic acid 1 f
(Table 3, entry 6 and Table 2,
10
11
2h
66[c]
71
12
13
14
2i
46[c]
72
64
[a] Reaction conditions: A 5 mL microwave-transparent vial was charged with 2 (1.0 mmol), VA (10.0 mmol),
Pd(OAc)2 (0.02 mmol), dppp (0.022 mmol), and DMF (2 mL). The vial was capped under air and exposed to
microwave heating for 30 min at 1408C. [b] Isolated yield >95% pure by GC–MS. [c] NaTFA (2 mmol) was
AHCTUNGTRENNUNG
entry 5).
2-Naphthylboronic
used as an additive.
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Palladium(II)-Catalyzed Styrene Synthesis
FULL PAPER
acids 1h and 1j reacted smoothly, providing good yields of
2g and 2h (Table 3, entries 7 and 9), as did their correspond-
ing trifluoroborate analogues (Table 3, entries 8 and 10).
Electron-poor 1l and 1n also served as good substrates and
the corresponding styrenes 2i and 2j were isolated in 71 and
72% yield, respectively (Table 3, entries 11 and 13), whereas
trifluoroborate 1m gave a low yield (46%) of styrene deriv-
ative 2i (Table 3, entry 12). Finally, the protocol was extend-
ed to include vinylboronic acid 1o, which was successfully
coupled without a 1,2-migration of the alkenylpalladium(II)
intermediate to provide diene 2k in 64% yield (Table 3,
entry 14).[23] Notably, the reaction pressure never exceeded
2 bar.
ESIMS+ spectrum was immediately recorded by scanning
the first quadrupole (Q1) of a triple-quadrupole instrument.
Several groups of peaks of m/z signals corresponding to the
characteristic isotopic pattern of monopalladium complexes
were observed, whereas only a limited number of non-palla-
dium-containing cations were detected (Figure 1). The dif-
ferent complexes were labeled and classified according to
where in the catalytic cycle they might appear (Table 4).
Through the power of MS/MS, more accurate structural
propositions could be made for each of the complexes
(Table 4). The isotopic ions with the strongest and the
second-strongest intensity for each complex (containing
106Pd and 108Pd, respectively) were selected for further MS/
MS+ analysis. Importantly, the specific m/z 605 106Pd ion
was separated (Q1) and fragmented (Q2), enabling detec-
tion of a signal at m/z 577 (576.8). This signal originates
from the parent ion minus 28 units, indicating elimination of
ethylene from structurally proposed Bp2, followed by a loss
of HOAc (m/z 60). Arylpalladium complexes D–G exhibited
the expected MS characteristics as compared to previously
reported analogous cations.[31] The MS/MS+ collision-in-
duced-dissociation (CID) pattern of the m/z 699 ion sup-
ported the assignment of palladium hydride Hp2 due to the
loss of the p-coordinated styrene product (see the Support-
ing Information). Out of the three possible structures for
complex I (m/z 757, Table 4), Ip1 seems most probable, with
a CID-induced loss of styrene product (m/z 180) followed
by a loss of HOAc (m/z 60).
Two alternative operational arylation pathways, employ-
ing two different olefinic counterparts, might be considered
for the studied transformation (Scheme 1). Either a) ethyl-
Scheme 1. Alternative vinylation pathways.
ene is first generated from VA and subsequently undergoes
a standard oxidative Heck arylation or, alternatively, b) sty-
rene formation occurs by carbopalladation of VA, followed
by styrene formation through b-acetate elimination.
Electrospray ionization (ESI)[24] is considered a soft mass
spectrometry ionization technique because it promotes few
fragmentation products and is, therefore, a valuable tool in
the analysis of delicate biomol-
To validate further and better characterize the proposed
observed complexes, a series of additional reactions were
analyzed by ESIMS+ and MS/MS+. Each component in the
standard reaction was substituted for a chemically equiva-
lent one, providing the analogous palladium(II) complexes
ecules[25] and organometallic
complexes.[26,27] Thus, online
ESIMS has been previously
used to study charged inter-
mediates in palladium-cata-
lyzed
reactions
such
as
Suzuki,[20,28] Heck,[29–31] and oxi-
dative Heck reactions.[27]
In this study, ESIMS analysis
was conducted to detect cat-
ionic palladium-containing re-
action intermediates in ongo-
ing vinylation reactions, and to
differentiate between vinyla-
tion pathway a) or b)
(Scheme 1). To initiate the
mechanistic investigation, the
room-temperature reaction de-
picted in Table 2, entry 8 was
chosen. An aliquot was with-
drawn from the reaction mix-
ture after 6 h and then diluted
Figure 1. ESIMS+ spectrum for the reaction of 1 f and VA at ambient temperature including MS/MS analysis
of m/z 106Pd Bp2. (Complexes denoted according to Table 4.)
tenfold
with
DMF.
The
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M. Larhed et al.
Table 4. Monocharged cationic palladium(II) complexes detected by ESIMS in oxidative Heck reactions.
tures of all palladium-contain-
ing signals from this experiment
were deduced by using MS/MS
and the results are presented in
Table 5. The compositions of all
ethylene, VA, or styrene-con-
taining ions were verified by
using [D6]VA, including the
[D7]Bp2 and [D4]Hp2 intermedi-
ates.
The m/z 605 signal in Table 4
indicates arylation of ethylene
and not VA (Scheme 1, path-
way a) because the MS/MS+
CID analysis shows the struc-
tural composition of ethylene
p-intermediate
Bp2.
The
[D6]VA study also supports this
conclusion with MS/MS+ isola-
tion and fragmentation of the
analogous m/z 612 106Pd [D7]Bp2
parent ion signal, indicating a
free [D4]ethylene dissociation
(loss of m/z 32), followed by a
[a] Reported m/z values based on 106Pd with dppp as the ligand and 1 f as the aryl substrate (Ar). [b] Structures
supported by MS/MS+ analysis.
in situ, but at different m/z ratios. Thus, boronic acid 1 f was
exchanged for 1j, VA for vinyl propionate, DMF for
DMSO, and dppp for the related Skewphos ligand ((2S,4S)-
(À)-2,4-bis(diphenylphosphino)pentane). The different re-
placements were separately evaluated, all providing produc-
tive reactions, yielding 36–68% of 2 f (2h in 63% yield),
and delivering the analogous and chemically equivalent pal-
ladium(II) intermediates according to ESIMS and MS/MS
analyses (see the Supporting Information for details). In a
final experiment, VA was exchanged for deuterated VA
([D6]VA) affording [D3]2 f, with no detected deuterium–hy-
drogen scrambling, in 59% isolated yield. Proposed struc-
loss of [D3]HOAc (m/z 63).[32] In the MS/MS fragmentation
pattern of m/z 699 (Table 4), loss of styrene product (m/z
180) gives the complex of m/z 519, supporting the presence
of Hp2. This hypothesis is further supported by the [D6]VA
experiment providing the palladium [D1]hydride complex of
m/z 520. Assuming this assignment is correct, the proposed
palladium hydride complex Hp2 constitutes a rare example
of a detected palladium hydride species[33] in an ongoing cat-
alytic Heck-type reaction.[30] We believe the absence of an
added base in the reaction mixture is highly important for
the stability and the catalytic role of the detected palladium
hydride.
Although all MS-detected cationic complexes might not
be catalytically active, the findings from the ESIMS investi-
gation support the reaction route in which ethylene is first
produced from VA and is thereafter arylated (pathway a,
Scheme 1). Association of VA with a palladium hydride
complex affords a charged p-intermediate Bp1 (I) followed
by migratory insertion (II) and b-elimination of the acetate
(III) to produce species Bp2 (see Scheme 2). Olefin dissocia-
tion generates free ethylene (IV), or possibly the acetate
dissociates leaving the ethylene coordinated to the palladi-
um (resulting in an undetected, intermediate). Subsequently,
it is reasonable to assume that transmetallation occurs (V)
leading to the cationic p-intermediate Hp1 (VI). Migratory
insertion (VII) is followed by b-hydride elimination (VIII)
to form complex Hp2, which dissociates (IX) to give the free
styrene product and a palladium hydride species. Alterna-
tively, complex Bp1 might be created directly from hydride
Hp2 in an associative ligand exchange process. The required
initial formation of a palladium hydride might result from
an oxidative Heck arylation of VA, with b-hydrogen elimi-
nation instead of a b-acetate elimination providing trace
Table 5. Monocharged cationic palladium(II) complexes detected by
ESIMS and supported by MS/MS analysis in oxidative Heck reactions by
using [D6]VA.
[a] Reported m/z values based on 106Pd with dppp as the ligand and 1 f as
the aryl substrate (Ar).
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Palladium(II)-Catalyzed Styrene Synthesis
FULL PAPER
[1] a) A. M. Al-Ajlouni, J. H. Espenson, J. Am. Chem. Soc. 1995, 117,
9243–9250; b) R. H. Fan, W. X. Li, Y. Ye, L. F. Wang, Adv. Synth.
Catal. 2008, 350, 1531–1536.
[2] A. K. Chatterjee, T. L. Choi, D. P. Sanders, R. H. Grubbs, J. Am.
Chem. Soc. 2003, 125, 11360–11370.
[3] T. Wagner-Jauregg, Synthesis 1980, 769–798.
[4] C. M. Kormos, N. E. Leadbeater, J. Org. Chem. 2008, 73, 3854–3858.
[5] a) N. A. Bumagin, N. P. Andriukhova, I. P. Beletskaya, Dokl. Akad.
Nauk SSSR 1989, 307, 375–378; b) D. Badone, R. Cecchi, U. Guzzi,
J. Org. Chem. 1992, 57, 6321–6323; c) G. A. Grasa, S. P. Nolan, Org.
Lett. 2001, 3, 119–122; d) J. M. Chretien, A. Mallinger, F. Zammat-
tio, E. Le Grognec, M. Paris, G. Montavon, J. P. Quintard, Tetrahe-
dron Lett. 2007, 48, 1781–1785.
[6] a) S. E. Denmark, Z. G. Wang, J. Organomet. Chem. 2001, 624, 372–
375; b) E. Alacid, C. Najera, Adv. Synth. Catal. 2006, 348, 2085–
2091; c) S. E. Denmark, C. R. Butler, J. Am. Chem. Soc. 2008, 130,
3690–3704.
[7] a) S. K. Stewart, A. Whiting, J. Organomet. Chem. 1994, 482, 293–
300; b) F. Kerins, D. F. OꢂShea, J. Org. Chem. 2002, 67, 4968–4971;
c) C. M. Coleman, D. F. OꢂShea, J. Am. Chem. Soc. 2003, 125, 4054–
4055; d) L. Joucla, G. Cusati, C. Pinel, L. Djakovitch, Tetrahedron
Lett. 2008, 49, 4738–4741.
[8] a) D. Crich, S. X. Sun, J. Org. Chem. 1996, 61, 7200–7201; b) P. Espi-
net, A. M. Echavarren, Angew. Chem. 2004, 116, 4808–4839;
Angew. Chem. Int. Ed. 2004, 43, 4704–4734.
[9] V. R. Lando, A. L. Monteiro, Org. Lett. 2003, 5, 2891–2894.
[10] T. M. Gøgsig, L. S. Sobjerg, A. T. Lindhardt, K. L. Jensen, T.
Skrydstrup, J. Org. Chem. 2008, 73, 3404–3410.
[11] a) G. A. Molander, N. Ellis, Acc. Chem. Res. 2007, 40, 275–286;
b) S. Darses, J. P. Genet, Chem. Rev. 2008, 108, 288–325.
[12] a) J. Y. Cho, M. K. Tse, D. Holmes, R. E. Maleczka, M. R. Smith,
Science 2002, 295, 305–308; b) T. Ishiyama, J. Takagi, J. F. Hartwig,
N. Miyaura, Angew. Chem. 2002, 114, 3182–3184; Angew. Chem.
Int. Ed. 2002, 41, 3056–3058.
[13] a) H. A. Dieck, R. F. Heck, J. Org. Chem. 1975, 40, 1083–1090;
b) C. S. Cho, S. Uemura, J. Organomet. Chem. 1994, 465, 85–92;
c) X. L. Du, M. Suguro, K. Hirabayashi, A. Mori, T. Nishikata, N.
Hagiwara, K. Kawata, T. Okeda, H. F. Wang, K. Fugami, M. Kosugi,
Org. Lett. 2001, 3, 3313–3316; d) M. M. S. Andappan, P. Nilsson, M.
Larhed, Mol. Diversity 2003, 7, 97–106; e) M. M. S. Andappan, P.
Nilsson, M. Larhed, Chem. Commun. 2004, 218–219; f) M. M. S.
Andappan, P. Nilsson, H. von Schenck, M. Larhed, J. Org. Chem.
2004, 69, 5212–5218; g) S. S. Stahl, Angew. Chem. 2004, 116, 3480–
3501; Angew. Chem. Int. Ed. 2004, 43, 3400–3420; h) K. S. Yoo,
C. H. Yoon, K. W. Jung, J. Am. Chem. Soc. 2006, 128, 16384–16393;
i) J. A. Schiffer, A. B. Machotta, M. Oestreich, Synlett 2008, 2271–
2274; j) J. H. Delcamp, A. P. Brucks, M. C. White, J. Am. Chem. Soc.
2008, 130, 11270–11271; k) J. W. Ruan, X. M. Li, O. Saidi, J. L.
Xiao, J. Am. Chem. Soc. 2008, 130, 2424–2425; l) P. A. Enquist, J.
Lindh, P. Nilsson, M. Larhed, Green Chem. 2006, 8, 338–343.
[14] J. Lindh, P. A. Enquist, A. Pilotti, P. Nilsson, M. Larhed, J. Org.
Chem. 2007, 72, 7957–7962.
Scheme 2. Proposed mechanistic hypothesis based on MS-detected cat-
ionic palladium complexes.
amounts of product 4 f (see Table 1). This source of the pal-
ladium hydride is supported by the [D6]VA study and the
ESIMS detection of [D7]Bp2. The excess of VA and the high
reactivity of the unsubstituted ethylene explain the selectivi-
ty for monoarylation.
Conclusions
The new palladium(II)-catalyzed vinylation method allows
for fast synthesis of styrene derivatives from both electron-
rich and -poor arylboronic acids or aryltrifluoroborates and
low-cost vinyl acetate. This novel oxidative Heck reaction
does not require inert conditions or the addition of a reoxi-
dant or a base. ESIMS, MS/MS, and deuterium labelling
studies suggest that the reaction pathway involves a palladi-
um hydride and proceeds through arylation of ethylene.
This protocol might be considered as one of the simplest
and most convenient methods described for the direct syn-
thesis of styrene derivatives on a small scale.
[15] W. Cabri, I. Candiani, A. Bedeschi, R. Santi, J. Org. Chem. 1992, 57,
3558–3563.
[16] a) I. Arai, G. D. Daves, J. Am. Chem. Soc. 1981, 103, 7683–7683;
b) B. S. Williams, M. D. Leatherman, P. S. White, M. Brookhart, J.
Am. Chem. Soc. 2005, 127, 5132–5146.
[17] a) C. O. Kappe, Chem. Soc. Rev. 2008, 37, 1127–1139; b) P. Nilsson,
K. Olofsson, M. Larhed, Top. Curr. Chem. 2006, 266, 103–144.
[18] W. Cabri, I. Candiani, Acc. Chem. Res. 1995, 28, 2–7.
[19] J. E. Bꢀckvall, A. Gogoll, Tetrahedron Lett. 1988, 29, 2243–2246.
[20] M. A. Aramendia, F. Lafont, M. Moreno-Manas, R. Pleixats, A. Ro-
glans, J. Org. Chem. 1999, 64, 3592–3594.
Acknowledgements
We gratefully acknowledge the Swedish Research Council and the Knut
and Alice Wallenberg Foundation. We also thank Riina Arvela, Met-
te L. H. Mantel, and Jason Soffe for critical review of this paper.
[21] C. Adamo, C. Amatore, I. Ciofini, A. Jutand, H. Lakmini, J. Am.
Chem. Soc. 2006, 128, 6829–6836.
[22] a) N. J. Whitcombe, K. K. Hii, S. E. Gibson, Tetrahedron 2001, 57,
7449–7476; b) A. F. Littke, G. C. Fu, Angew. Chem. 2002, 114,
4350–4386; Angew. Chem. Int. Ed. 2002, 41, 4176–4211.
Chem. Eur. J. 2009, 15, 4630 – 4636
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4635

M. Larhed et al.
[23] A. L. Hansen, J. P. Ebran, M. Ahlquist, P. O. Norrby, T. Skrydstrup,
Angew. Chem. 2006, 118, 3427–3431; Angew. Chem. Int. Ed. 2006,
45, 3349–3353.
[30] A. A. Sabino, A. H. L. Machado, C. R. D. Correia, M. N. Eberlin,
Angew. Chem. 2004, 116, 4489–4489; Angew. Chem. Int. Ed. 2004,
43, 4389–4389.
[31] A. Svennebring, P. J. R. Sjçberg, M. Larhed, P. Nilsson, Tetrahedron
2008, 64, 1808–1812.
[24] C. M. Whitehouse, R. N. Dreyer, M. Yamashita, J. B. Fenn, Anal.
Chem. 1985, 57, 675–679.
[32] Direct arylation of ethylene has not been attempted under our con-
ditions because of difficult handling and safety concerns. However
the reaction of 1 f with n-hexene gave a 67% isolated yield of mono-
arylated n-hexene as a mixture of isomers (40% terminal-trans,
40% terminal-cis, and 20% internal).
[25] J. B. Fenn, M. Mann, C. K. Meng, S. F. Wong, C. M. Whitehouse, Sci-
ence 1989, 246, 64–71.
[26] L. S. Santos, Eur. J. Org. Chem. 2008, 235–253.
[27] P. A. Enquist, P. Nilsson, P. Sjçberg, M. Larhed, J. Org. Chem. 2006,
71, 8779–8786.
[33] a) V. V. Grushin, Chem. Rev. 1996, 96, 2011–2033; b) I. D. Hills,
G. C. Fu, J. Am. Chem. Soc. 2004, 126, 13178–13179; c) M. M. Kon-
nick, B. A. Gandhi, I. A. Guzei, S. S. Stahl, Angew. Chem. 2006, 118,
2970–2973; Angew. Chem. Int. Ed. 2006, 45, 2904–2907; d) A. T.
Lindhardt, M. L. H. Mantel, T. Skrydstrup, Angew. Chem. 2008, 120,
2708–2712; Angew. Chem. Int. Ed. 2008, 47, 2668–2672.
[28] A. O. Aliprantis, J. W. Canary, J. Am. Chem. Soc. 1994, 116, 6985–
6986.
[29] a) L. Ripa, A. Hallberg, J. Org. Chem. 1996, 61, 7147–7155; b) J. M.
Brown, K. K. Hii, Angew. Chem. 1996, 108, 679–682; Angew. Chem.
Int. Ed. Engl. 1996, 35, 657–659; c) A. A. Sabino, A. H. L. Machado,
C. R. D. Correia, M. N. Eberlin, Angew. Chem. 2004, 116, 2568–
2572; Angew. Chem. Int. Ed. 2004, 43, 2514–2518.
Received: December 29, 2008
Published online: March 9, 2009
4636
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Chem. Eur. J. 2009, 15, 4630 – 4636