Studies of microwave-enhanced Suzuki-Miyaura vinylation of electron-rich sterically hindered substrates utilizing potassium vinyltrifluoroborate

Article abstract of DOI:10.1016/j.tetlet.2010.10.087

The Suzuki-Miyaura cross-coupling of sterically hindered and electron-rich ortho,ortho′-substituted aryl halides with potassium vinyltrifluoroborate utilizing microwave irradiation has been conducted while adjusting solvent ratio, irradiation time, and catalyst loading to find optimal conditions. Coupling of benzyl 3,5-bis(benzyloxy)-4-bromobenzoate leads to a mixture of the desired styrene derivative and the reduced product. 4-Bromo-1,3,5- trimethoxybenzene, methyl 4-bromo-3,5-dimethoxybenzoate, and mesitylene bromide were also coupled to test the breadth and scope of this methodology. Of these substrates tested only 4-bromo-1,3,5-trimethoxybenzene was not vinylated successfully, which is believed to be due to the electron-rich nature of this system.

Full text of DOI:10.1016/j.tetlet.2010.10.087

Tetrahedron Letters 51 (2010) 6748–6752
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Studies of microwave-enhanced Suzuki–Miyaura vinylation of electron-rich
sterically hindered substrates utilizing potassium vinyltrifluoroborate
Matthew D. Brooker a, Stefan M. Cooper Jr. b, Dena R. Hodges b, Rhiannon R. Carter b, Justin K. Wyatt b,
⇑
a Department of Chemistry, Trident Technical College, 7000 Rivers Ave. Charleston, SC 29455, USA
b Department of Chemistry and Biochemistry, College of Charleston, 66 George St., Charleston, SC 29424, USA
a r t i c l e i n f o
a b s t r a c t
The Suzuki–Miyaura cross-coupling of sterically hindered and electron-rich ortho,ortho0-substituted aryl
halides with potassium vinyltrifluoroborate utilizing microwave irradiation has been conducted while
adjusting solvent ratio, irradiation time, and catalyst loading to find optimal conditions. Coupling of ben-
zyl 3,5-bis(benzyloxy)-4-bromobenzoate leads to a mixture of the desired styrene derivative and the
reduced product. 4-Bromo-1,3,5-trimethoxybenzene, methyl 4-bromo-3,5-dimethoxybenzoate, and
mesitylene bromide were also coupled to test the breadth and scope of this methodology. Of these sub-
strates tested only 4-bromo-1,3,5-trimethoxybenzene was not vinylated successfully, which is believed
to be due to the electron-rich nature of this system.
Article history:
Received 5 September 2010
Revised 12 October 2010
Accepted 14 October 2010
Keywords:
Suzuki–Miyaura
Potassium vinyltrifluoroborate
Styrenes
Ó 2010 Elsevier Ltd. All rights reserved.
Palladium catalysis
Hindered aryl bromides
1. Introduction
2. Present Study
Substituted styrenes (typically assembled using a transition
metal-mediated cross-coupling) are useful intermediates in both
the formation of new polymeric material and in the formation of
specialty chemicals.1 Mild vinylation of aryl bromides and/or
Scheme 1 illustrates the first reaction of interest, and the two
possible products of the cross-coupling reaction; the desired viny-
lated product, benzyl 3,5-bis(benzyloxy)-4-vinylbenzoate (3) and
the reduced product, benzyl 3,5-bis(benzyloxy)benzoate (4). As
with conventional conditions14 the reduced product was observed
under microwave conditions but only in trace amounts (less than
1% of the total product distribution). Product ratios were deter-
mined, if necessary, using 1H NMR integration of the crude reaction
mixture using the methylene hydrogens from the benzyl ethers of
the starting material 1, as well as for the vinyl product 3; chemical
shifts of 5.18 ppm (s, 4H) and 5.14 ppm (s, 4H), respectively. The
amount of reduced product 4, if any, was determined by integra-
tion of the triplet at 6.80 ppm (t, J = 2.4 Hz, 1H).
Initially, we focused on optimizing the vinylation of benzyl 3,5-
bis(benzyloxy)-4-bromobenzoate (1) (a compound that has been of
interest for this lab toward the synthesis of derivatives of the anti-
biotic cytosporone E14) using 9 mol % of the palladium catalyst,
[PdCl2(dppf)CH2Cl2], 5 equiv of potassium vinyltrifluoroborate
(2), 3 equiv of cesium carbonate, and 0.051 M solution of THF/
H2O (10:1), with respect to 1, at 150 °C (Table 1, entries 1–8). For
all the reactions that gave the desired product, 3, an average yield
of 51% was observed. Entries 5–7 demonstrate that time frames
longer than 20 min did not increase the yield above 57%. It is also
apparent from entries 1–4 that at least 20 min is needed to ensure
completion of the reaction. This is a significant improvement from
the 3–4 days required for the conventional process and a decrease
in the formation of the reduced product 4.14 Interestingly, the
iodides
using
trivinylcyclotriboroxane,1
vinylmagnesium
bromide,2 vinyltrimethylsilane,3 and vinylpolysiloxanes4 has been
observed. N-Heterocyclic carbenes bearing palladium (II) catalysts
have demonstrated high catalytic activity capable of coupling
unactivated aryl chlorides.5 Aryl bromides and activated aryl chlo-
rides also undergo mild palladium-catalyzed couplings at room
temperature with alkenes utilizing dicyclohexylmethylamine as a
base.6 Potassium vinyltrifluoroborate is a stable alternative that
circumvents the limitations of vinylboronic acids and derivatives
of vinylboronic esters.7–10 Molander first reported the Suzuki–
Miyaura cross-coupling vinylation of aryl halides with potassium
vinyltrifluoroborate in 2002;8 other examples have been reported
in the literature since.10–16 However, most of the literature is dom-
inated by Suzuki–Miyaura type couplings involving boronic acids
or their derivatives.5,6,12–21 This Letter investigates the Suzuki–
Miyaura cross-coupling reaction between various sterically hin-
dered and electron-rich arenes including benzyl 3,5-bis(benzyl-
oxy)-4-bromobenzoate (1, Scheme 1) with potassium
vinyltrifluoroborate (2) with the assistance of microwave
irradiation.
⇑
Corresponding author. Tel.: +1 843 953 6587; fax: +1 843 953 1404.
E-mail address: wyattj@cofc.edu (J.K. Wyatt).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.087

M. D. Brooker et al. / Tetrahedron Letters 51 (2010) 6748–6752
6749
BnO
Br
CO2Bn
BnO
CO2Bn BnO
CO2Bn
OBn
BF3K (2)
+
H
Cs2CO3, THF/H2O
Pd cat, time
OBn
OBn
1
3
4
MW, 150 °C
Scheme 1. Microwave-enhanced vinylation of benzyl 3,5-bis(benzyloxy)-4-bromobenzoate (1).
Table 1
Table 3
Effect of irradiation time on benzyl 3,5-bis(benzyloxy)-4-bromobenzoate (1)
Effect of catalyst and additives on the yield of benzyl 4-bromo-3,5-bis(benzyl-
oxy)benzoate (3)
Entrya
Time
1:3:4b
Yield of 3c
Entrya Catalystb
Mol %
2,6
Time
1:3:4c
Yield of
1
2
3
4
5
6
7
8
10 min ꢀ 2
10 min ꢀ 3
15 min ꢀ 2
15 min
20 min
30 min
0:1:trace
0:1:trace
0:1:trace
11:50:1
0:1:trace
0:1:trace
0:1:trace
0:1:trace
45
49
48
n/a
57
57
56
56
3d
11
PdCl2, X-Phos
30 min
2:1:trace
n/a
29
12
PdCl2, X-Phos
(2,6) ꢀ 2 30 min ꢀ 2 0:1:trace
13
PdCl2, PPh3
2,6
2,6
5,5
9
30 min
30 min
30 min
60 min
90 min
2.3:1:trace n/a
14
PdCl2, RuPhos
Pd(OAc)2, dppb
PdCl2(dppf)CH2Cl2
PdCl2(dppf)CH2Cl2
1.6:1:0
0:3:1
1:3:1
0:5:1
n/a
n/a
n/a
n/a
45 min
60 min
15b
16b
17b
9
a
9 mol % PdCl2(dppf)CH2Cl2, THF/H2O (10:1) at 0.051 M, 5 equiv of 2, 3 equiv
Cs2CO3, 150 °C.
a
b
c
THF:H2O (10:1) at 0.051 M, 5 equiv of 2, 3 equiv Cs2CO3, 150 °C.
Employed Bu4NI.
Determined by 1H NMR integration of the crude mixture.
b
c
Isolated yield.
Determined by 1H NMR integration of the crude mixture.
Isolated yield.
d
average yield was observed to be lower if the times were divided
(av 47%) despite that many entries had the same overall irradiation
times. (i.e., entry 1 vs 5, 20 min; entries 2 and 3 vs 6, 30 min).
Entries 9 and 10, shown in Table 2, were designed to emulate
the conventional reaction, which required two additions of
9 mol % PdCl2(dppf)CH2Cl2 catalyst.14 In both cases the reactions
went to completion, but the yields were similar to entries 1–3 in
Table 1, where irradiation times were split to allow for the second
addition of the catalyst (av 47%). This suggested that only one addi-
tion of the catalyst (and only 9 mol %) was sufficient for the reac-
tion. (These reactions were monitored by TLC in between catalyst
loading and revealed that nearly all of the starting material, 1,
was consumed at the point of second addition).
Further optimization of the conditions in this cross-coupling
reaction probed the use of a variety of Pd (II) catalysts including:
[PdCl2(dppf)CH2Cl2], Pd(OAc)2 and PdCl2] and phosphine ligands,
where warranted, [X-Phos, RuPhos, and PPh3] (Table 3, entries
11–17). A few reactions (Table 3, entries 15–17) included the
addition of tetrabutylammonium iodide, which has been shown
to increase the nucleophilicity of the potassium organotrifluorobo-
rates,14,22 but it had no positive effect with our substrate. The only
reaction that yielded only the desired product was entry 12, which
employed PdCl2 and X-Phos.23 However, these reagents were
added as 2 mol % and 6 mol % respectively in two additions over
60 min (for a total of 4 mol % of PdCl2, and 12 mol % of X-Phos),
yielding only 29% yield of 3. Utilizing PPh3 or RuPhos (entries 13
and 14) also gave a poor product distribution, and these conditions
mirror Molander’s conditions for sterically hindered ortho,ortho0-
substituted electron-rich aryl halides.12 These results, along with
previous results, necessitated the employment of the original cat-
alyst PdCl2(dppf)CH2Cl2 versus PdCl2, X-Phos for success (Tables
1–3).12,22,21a
The effect of solvent molarity for the reaction was also reinves-
tigated (Table 4, entries 18–20), while keeping the solvent ratio of
THF/H2O (10:1).14 The optimum concentration was still deter-
mined to be the 0.051 M in comparison to entries 5 and 10 (Tables
1 and 2), under microwave conditions, but it was found that the
coupling could tolerate concentrations up to a 0.091 M solution
with a slight drop in yield (entry 19, Table 4).
During optimization of the conventional reaction12 it was found
that the reaction needed 5 equiv of potassium vinyltrifluoroborate
(2); therefore, this variable was studied again with the microwave
reaction (Table 5, entries 21 and 22). 2 was varied from 1.1 to
10 equiv where it was found that 5 equiv still gave the best overall
yield (57%; entries 5 and 6, Table 1). The use of 10 equiv was an
interesting result because when the reaction is under conventional
Table 4
Toleration of vinylation reaction to changes in solvent molarity with benzyl 3,5-bis-
(benzyloxy)-4-bromobenzoate (1)
Entrya
Time
Molarity
1:3:4b
Yield of 3c
18
19
20
30 min
30 min
30 min
0.027 M
0.091 M
0.18
7:15:1
0:1:trace
0:9:1
n/a
44
n/a
a
9 mol % PdCl2(dppf)CH2Cl2, THF/H2O (10:1) at 0.051 M, 5 equiv of 2, 3 equiv
Cs2CO3, 150 °C for 30 min.
b
Determined by 1H NMR integration of the crude mixture.
Isolated yield.
c
Table 5
Table 2
The effect of varying equivalents of potassium vinyltrifluoroborate with benzyl 3,5-
bis-(benzyloxy)-4-bromobenzoate (1)
Effect of doubling the catalyst loading from
bis(benzyloxy)-4-bromobenzoate (1)
9 to 18 mol % with benzyl 3,5-
Entrya
Moles of 2
1:3:4b
Yield of 3c
Entrya
Time
1:3:4b
Yield of 3c
21
22
1.1
10
0:11:1
0:1:trace
n/a
44
9
10
15 min ꢀ 2
0:1:trace
0:1:trace
45
49
30, 15 min
a
a
9 mol % PdCl2(dppf)CH2Cl2, THF/H2O (10:1) at 0.051 M, 3 equiv Cs2CO3, 150 °C
for 30 min.
18 mol % PdCl2(dppf)CH2Cl2 (added in two equal 9 mol % portions), THF/H2O
(10:1) at 0.051 M, 5 equiv of 2, 3 equiv Cs2CO3, 150 °C.
b
Determined by 1H NMR integration of the crude mixture.
b
Isolated yield.
c
c
Determined by 1H NMR integration of the crude mixture.
Isolated yield.

6750
M. D. Brooker et al. / Tetrahedron Letters 51 (2010) 6748–6752
control the use of an extreme excess of 2 increases the yield to
87%.14 Notably, under microwave conditions the yield decreased
to 44% (Table 5, entry 22).
Decreasing the amount of H2O in the (THF/H2O) mixture was dis-
continued after these results due to the reduced yield compared
to the yield previously observed for a (10:1) ratio (Table 6, entry
24). These screenings also revealed that the 10:1 (THF/H2O) condi-
tions at 20 min and 30 min yielded identical (entry 24 in Table 6,
and entry 27 in Table 8), acceptable results of 77% yield of 3. (Inter-
estingly, similar reactivity occurred in Table 1, entries 5 and 7;
where 20 and 30 min irradiation times yielded 57% of 3). Ulti-
mately, the 9:1 (THF/H2O) mixture was the most successful, afford-
ing 3 with similar yields again at 20 and 30 min irradiation times
with 93% and 89%, (entry 29 in Table 8, and entry 27 in Table 7,
respectively).12 Increasing the reaction time for the 9:1 mixture
did not result in any improved results (not shown).
With the optimized reaction conditions (being 5 mol %
PdCl2(dppf)CH2Cl2, 5 equiv of potassium vinyltrifluoroborate,
3 equiv cesium carbonate, 0.051 M THF/H2O (9:1), and heating at
150 °C for 20 min) for 3 in hand we studied the applicability and
scope of our method with other activated, ortho,ortho0-hindered
aryl halides; 1-bromo-2,4,6-trimethoxybenzene 5 (Scheme 2),
methyl 3,5-dimethoxy-4-bromobenzoate 8 (Scheme 3), and 2-bro-
momesitylene 11 (Scheme 4).
Vinylation attempts of 2-bromo-1,3,5-trimethoxhybenzene 5
with our optimized (Scheme 2) conditions yielded only starting
material. Regardless of the time employed, (Table 9, entries 30–
32) the strongly activated ring is believed to account for this out-
come, as has been noted in the literature.12,14,20,21 It should be
noted here for the reader that although our methodology was
unproductive, Fu and Nolan’s pre-mentioned vinylation methods
appear to be more amenable to substrates involving extremely
electron-rich and sterically hindered aryl halides.5,6
The vinylation of methyl 4-bromo-3,5-dimethoxybenzoate 8
(see Scheme 3) was found to be strongly time dependent as the
time was increased from 20 min to 30 min. Entries 33 and 34 dem-
onstrate this observation (44% to 82%; respectively, Table 10).
Experiments running longer than 30 min did not show any in-
crease in yield. Both substrates 5 and 8 are similar in that they both
have the ortho,ortho0-hindering alkoxy groups but differ in the
functional group that is para to the bromo substituent. The success
of substrate 8 is believed to be attributed to the presence of the
electron-withdrawing methyl ester present in the molecule as seen
with substrate 3.
Although the reaction worked moderately well with 9 mol % of
the catalyst PdCl2(dppf)CH2Cl2 (Table 1, entries 5 and 6), decreas-
ing the catalyst loading was still desired. To directly explore this
variable the catalyst loading was sequentially adjusted from 9 to
3 mol %, (Table 6, entries 23–25). It was found that employing
3 mol % or 7 mol % of the catalyst resulted in incomplete reactions
or lowered yields (Table 6, entries 23 and 25). Using 7 mol % of the
referred catalyst was experimentally similar to using 9 mol % of the
catalyst, giving a 50% yield when compared to Table 1 (entries 5
and 6). Using 5 mol % of the catalyst PdCl2(dppf)CH2Cl2 produced
the desired product 3 with a 77% yield (Table 6, entry 24). This fac-
tor not only increased the yield, but further confirmed that only
one addition of the catalyst was needed and the presence of the re-
duced product 4 was also not seen via 1H NMR.
Solvent systems have been a particular point of interest in
cross-coupling reactions; particularly when microwave irradiation
is employed due to the need for a solvent with an appreciable
dielectric constant.19 A variety of solvents and solvent mixtures
have been employed with superb results in cross-coupling reac-
tions.5,6,12,14,21,22,21a,24 We chose to investigate the effects of chang-
ing the solvent ratios of THF and H2O and irradiation time with
respect to the optimized conditions: 5 mol % of PdCl2(dppf)CH2Cl2,
0.051 M solvent concentration, 5 equiv of 2 (CH2@CHBF3K), and
irradiation at 150 °C; THF/H2O ratios were varied from 11:1 to
9:1 irradiation times of 30 and 20 min were employed, respectively
(Tables 7 and 8).
Decreasing the water concentration of the solvent system re-
duced, which is demonstrated by entry 26 of Table 7, affording a
modest yield of 3 (61% yield), with no reduced product observed.
Table 6
Effect of molar percent of PdCl2(dppf)CH2Cl2 catalyst loading
Entrya
Mol % catalyst
1:3:4b
Yield of 3c
23
24
25
3
5
7
1:7:trace
0:1:0
0:1:trace
n/a
77
50
a
PdCl2(dppf)CH2Cl2, THF/H2O (10:1) at 0.051 M, 3 equiv Cs2CO3, 150 °C for
Mesitylene bromide (11) was chosen for its three moderately
activating methyl groups and the ortho,ortho0 hindrance of the bro-
mo substituent (Scheme 4). The vinylation of mesitylene bromide
11 (Scheme 4) was treated similarly to the 1,3,5-trimethoxyben-
zene 5 due to their electron-rich nature. Hence reaction times be-
gan at 30 min and ranged to 60 min (Table 11, entries 35–37).
Entry 36 showed a 67% yield of a (1:5.1:0:0) mixture of 11, 12,
13, and 14 after irradiation for 45 min with no stilbene side prod-
uct observed. Extending irradiation times increased the vinylated
product yield (80%) but also introduced the Heck product 14 (see
entry 37). This was an improvement over the conventional condi-
tions, which converted substrate 11 almost exclusively to the stil-
bene product 14.14 It should also be noted that Denmark and Butler
have recently reported superior results (99% yield) with substrate
11 via polyvinylsiloxanes.4b Buchwald has also modestly coupled
11 (using conventional conditions) with a 83% yield of 12 with
no side products.21a
In conclusion, microwave assistance (compared to the conven-
tional conditions)14 for this cross-coupling reaction has reduced
the amount of catalyst loading by over threefold from 18 to
5 mol %, it has demonstrated a dramatic decrease in reaction time
from 3 to 4 days to 20 min (nearly 300 times faster), and it has in-
creased the yield from 73% to 93% for benzyl ester 1. This investi-
gation also revealed that the reaction methodology is more
tolerant to solvent ratios with all substrates employed than previ-
30 min.
b
c
Determined by 1H NMR integration of the crude mixture.
Isolated yield.
Table 7
Effect of different solvent ratios at 30 min of irradiation time
Entrya
Solvent ratio THF/H2O
1:3:4b
Yield of 3c
26
27
11:1
9:1
0:1:trace
0:1:0
61
89
a
5 mol % PdCl2(dppf)CH2Cl2, THF/H2O at 0.051 M, 3 equiv Cs2CO3, 150 °C for
30 min.
b
Determined by 1H NMR integration of the crude mixture.
Isolated yield.
c
Table 8
Effects of different solvent ratios at 20 min of irradiation time
Entrya
Solvent ratio THF/H2O
1:3:4b
Yield of 3c
28
29
10:1
9:1
0:1:trace
0:1:0
77
93
a
5 mol % PdCl2(dppf)CH2Cl2, THF/H2O at 0.051 M, 3 equiv Cs2CO3, 150 °C for
20 min.
b
Determined by 1H NMR integration of the crude mixture.
Isolated yield.
c

M. D. Brooker et al. / Tetrahedron Letters 51 (2010) 6748–6752
6751
MeO
Br
OMe
MeO
OMe MeO
OMe
OMe
BF3K (2) (5 eq)
+
H
Cs2CO3 (3 eq), THF/H2O (9:1)
PdCl2(dppf)CH2Cl2 (5 mol%)
MW, 150 °C
OMe
OMe
5
6
7
time
Scheme 2. Attempted vinylation of 2-bromo-1,3,5-trimethoxybenzoate (5) employing optimized conditions.
MeO
Br
CO2Me
MeO
CO2Me MeO
CO2Me
OMe
BF3K (2) (5 eq)
+
H
Cs2CO3 (3 eq), THF/H2O (9:1)
PdCl2(dppf)CH2Cl2 (5 mol%)
MW, 150 °C
OMe
OMe
8
9
10
time
Scheme 3. Vinylation of methyl 4-bromo-3,5-dimethoxybenzoate (8).
BF3K (2)
+
+
Br
H
Cs2CO3 (3 eq), THF/H2O (9:1)
PdCl2(dppf)CH2Cl2 (5 mol%)
MW, 150 °C
11
12
13
14
time
Scheme 4. Vinylation of mesitylene bromide (11).
Table 9
Vinylation attempts with 2-bromo-1,3,5-trimethoxybenzene (5)
present thus reducing the electron-rich nature of the aromatic ha-
lide (which is common to the Suzuki–Miyaura reaction in general).
Entrya
Time
5:6:7b
Yield of 6c
30
31
32
20 min
30 min
60 min
1:0:0
1:0:0
1:0:0
n/a
n/a
n/a
3. Experimental
3.1. Typical Suzuki–Miyaura coupling conditions
a
b
c
5 mol % PdCl2(dppf)CH2Cl2, THF/H2O (9:1) at 0.051 M, 3 equiv Cs2CO3, 150 °C.
Determined by 1H NMR integration of the crude mixture.
Isolated yield.
A dry 10 mL Pyrex tube (from CEM) fitted with an airtight rubber
septa was charged with a stir bar, potassium vinyltrifluoroborate
(2) (133 mg, 0.995 mmol), cesium carbonate (194 mg, 0.597 mmol),
PdCl2(dppf)CH2Cl2 (7.2 mg, 0.0099 mmol), and benzyl 3,5-bis(ben-
zyloxy)-4-bromobenzoate (1) (100 mg, 0.199 mmol) was flushed
with argon. Degassed THF (3.87 mL) and degassed deionized H2O
(0.430 mL) were then added. The rubber septum was replaced with
a septum cap from CEM to give a sealed system. The resulting rust-
red colored solution was placed in a CEM Discover microwave unit
and allowed to react for 30 min at 150 °C. The resulting brown solu-
tion was diluted with 7 mL of H2O and extracted with Et2O
(10 mL ꢀ 3). The combined organic layers were then washed with
1 M HCl (10 mL) and brine (10 mL). The clear, yellow solution was
dried over MgSO4 and filtered. The solvent was removed under re-
duced pressure using a rotary evaporator. The red-brown residue
was purified using flash chromatography (3% EtOAc/5% CHCl3/hex-
anes) to yield benzyl 3,5-bis(benzyloxy)-4-vinylbenzoate 3 as a col-
orless solid in 93% yield (76 mg). Mp = 102–103 °C. 1H NMR (CDCl3:
300 MHz): d 7.44–7.28 (m, 17H), 7.08 (dd, J = 18.1 and 12.2 Hz, 1H),
6.25 (dd, J = 18.0 and 2.5 Hz, 1H), 5.52 (dd, J = 12.2 and 2.6 Hz, 1H),
5.34 (s, 2H), 5.12 (s, 4H). 13C NMR (CDCl3: 300 MHz): 166.2, 157.6,
136.8, 136.2, 129.5, 128.8, 128.7, 128.4, 128.3, 128.2, 127.7, 127.0,
Table 10
Vinylation results with methyl 4-bromo-3,5-dimethoxybenzoate (8)
Entrya
Time
8:9:10b
Yield of 9c
33
34
20 min
30 min
1.5:1:0
0:1:0
44
82
a
b
c
5 mol % PdCl2(dppf)CH2Cl2, THF/H2O (9:1) at 0.051 M, 3 equiv Cs2CO3, 150 °C.
Determined by 1H NMR integration of the crude mixture.
Isolated yield.
Table 11
Vinylation of mesitylene bromide (11)
Entrya
Time
11:12:13:14b
Yield of 12b
35
36
37
30 min
45 min
60 min
1:4:0:0
1:5.1:0:0
1:9:0:1
37
67
80
a
5 mol % PdCl2(dppf)CH2Cl2, THF/H2O (9:1) at 0.051 M, 3 equiv Cs2CO3, 150 °C.
Yields and ratios determined by n-dodecane internal standard and 1H NMR
b
integration.
121.6, 120.4, 106.9, 71.0, 67.0. IR (solid):
m = 3063, 3026, 1708,
1623, 1567, 1120, 1114 cmꢁ1
.
3.2. Typical CEM Discover microwave settings
ously believed and that proper catalyst loading and correct irradi-
ation time can help eliminate the production of the reduced prod-
uct. It has also been shown that the vinylation with potassium
vinyltrifluoroborate is best accomplished with ortho,ortho0-substi-
tuted aryl halides with at least one electron-withdrawing group
Power: 150 W, ramp time: 02:00 min, hold time 30:00 min,
temperature: 150 °C, with stirring. The pressure feedback from
the CEM Discover instrument ranged from 150–175 psi.

6752
M. D. Brooker et al. / Tetrahedron Letters 51 (2010) 6748–6752
13. (a) Joucla, L.; Cusati, G.; Pinel, C.; Djakovitch, L. Tetrahedron Lett. 2008, 49,
Acknowledgments
4738–4741; (b) Caneque, T.; Cuadro, A. M.; Alvarez-Builla, J.; Vaquero, J. J.
Tetrahedron Lett. 2009, 50, 1419–1422.
The authors thank the NIH Grant Number P20 RR-016461 from
the National Center for Research Resources NIH SC-INBRE grant,
ACS PRF (Type G 39541-GB1), and the College of Charleston
Department of Chemistry and Biochemistry for support.
14. (a) Carter, R. R.; Wyatt, J. K. Tetrahedron Lett. 2006, 47, 6091–6094; (b) Using
conventional conditions this reaction needed 3–4 days at 150 °C to proceed to
completion and required 18 mol % (added in two equimolar catalytic portions)
of the palladium catalyst [PdCl2(dppf)CH2Cl2] along with 5 equiv of potassium
vinyltrifluoroborate to attain a 73% isolated yield.
15. (a) Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 6250–6284; (b) Kappe, C. O.;
Dallinger, D. Nat. Rev. Drug Disc. 2006, 5, 51–63; (c) Nilsson, P.; Olofsson, K.;
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