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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