Double couplings of dibromothiophenes using boronic acids And boronates

Article abstract of DOI:10.1055/s-0028-1083262

One-pot double couplings of dibromothiophenes have been investigated. Standard Suzuki couplings work well for 2,4-di-bromothiophene, but are much more sensitive to steric effects in the case of 2,3-dibromothiophene. By using the recently reported potassium borates, though, good yields for both dibromothiophene isomers can be achieved. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0028-1083262

138
PAPER
Double Couplings of Dibromothiophenes Using Boronic Acids and Boronates
D
ouble Coupl
a
D
ib
m
Department of Chemistry, Middle Tennessee State University, Murfreesboro, TN 37129, USA
Fax +1(615)8985182; E-mail: shandy@mtsu.edu
Received 17 October 2008
coupled product was isolated, the overall yield was quite
Abstract: One-pot double couplings of dibromothiophenes have
been investigated. Standard Suzuki couplings work well for 2,4-di-
bromothiophene, but are much more sensitive to steric effects in the
case of 2,3-dibromothiophene. By using the recently reported potas-
modest. Further analysis of the crude reaction mixture
demonstrated that much of the material balance was
monocoupled thiophenes.9 Further attempts noted that
sium borates, though, good yields for both dibromothiophene iso- catalyst decomposition appeared to be rapid. This decom-
mers can be achieved.
position could be greatly reduced by degassing the reac-
tion mixture prior to the addition of the palladium catalyst.
Further, reducing the temperature of the first coupling to
80 °C as well as cutting the reaction time to three hours
also improved the yield of the dicoupled product. In a
brief survey of reaction conditions, a slight increase in
yield was noted by employing DMF as the solvent and
aqueous sodium carbonate as the base.10 The ratio of DMF
to water was important, as highly aqueous conditions
(>30% water by volume) resulted in poor conversion. Ad-
ditionally, the use of 2 M sodium carbonate (as had been
employed in many of our previous double couplings) re-
sulted in poor reproducibility. The problem may be due to
precipitation of the sodium carbonate upon addition to the
DMF, which then appears to facilitate catalyst decompo-
sition and precipitation as palladium black. Dilution to a 1
M sodium carbonate resolved this issue and proved gener-
ally satisfactory.
Key words: Suzuki couplings, regioselectivity, heteroaromatics,
thiophenes, cross-coupling reactions, palladium catalysis
Substituted thiophenes are highly important molecules
present in a wide range of compounds of biological and
materials interest.1 Although many routes have been de-
veloped for the preparation of such compounds, the most
widely employed method for the installation of carbon
substituents is transition-metal-catalyzed cross-coupling
chemistry.2 Such reactions have been used innumerable
times and with great efficiency.
As part of a project aimed at improving the efficiency of
cross-coupling chemistry for the preparation of multiply
substituted heteroaromatics, we have been exploring the
use of one-pot double Suzuki couplings.3 Prior work has
focused more on azoles,4 but more recently has begun to
examine thiophenes.5
p-TolylB(OH)2
Pd(Ph3P)4, K3PO4
dioxane–H2O, 90 °C
S
S
The regioselectivity of couplings of dibromothiophenes is
fairly well established.6,7 In particular, the work of de Lera
demonstrated that the initial site of coupling of 2,3-dibro-
mothiophene in Stille, Suzuki, or Sonogashira couplings
is always at C2 (Scheme 1).7 Generally good yields were
achieved for many of these couplings. At the same time,
little was done with regard to the possibility of conducting
a second coupling at the remaining bromide. Indeed, there
have been no prior reports of one-pot double couplings on
2,3- or 2,4-dibromothiophenes.8
Br
p-Tolyl
then
4-FC6H4B(OH)2
Br
4-FC6H4
48%
Scheme 2
These reaction conditions proved quite satisfactory for a
range of aryl boronic acids, including the sterically hin-
dered 2-methoxyphenylboronic acid, as well as an alke-
nylboronic acid (Table 1). In general, overall yields are
good, although the double coupling in which 2-thienylbo-
ronic acid is used in the first coupling is unexpected low
(Table 1, entry 7), particularly in light of the much better
result when this same boronic acid is used in the second
coupling (entry 8).
Initial efforts explored application of the conditions used
successfully on 4,5-dibromothiophene-2-carboxaldehyde
to a simple dibromothiophene such as 2,4-dibromo-
thiophene (Scheme 2). Interestingly, although some di-
S
S
Br
Ph
PhB(OH)2
Armed with these results, the same conditions were ap-
plied to 2,3-dibromothiophene (Table 2). The reactions
again afforded generally good results, although the yields
were definitely lower than those for the corresponding
couplings on 2,4-dibromothiophene. The reduced yields
are not the result of a less efficient first coupling. By sim-
ply running the first coupling under these reaction condi-
tions, the monocoupled products could be isolated in 80–
95% yield. Thus, the problem appears to be the steric hin-
Pd(Ph3P)4
K2CO3
dioxane, 100 °C
Br
Br
81%
Scheme 1
SYNTHESIS 2009, No. 1, pp 0138–0142
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Advanced online publication: 12.12.2008
DOI: 10.1055/s-0028-1083262; Art ID: C04508SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Double Couplings of Dibromothiophenes
139
Table 1 Double Suzuki Couplings of 2,4-Dibromothiophene
conditions to the double coupling of dibromothiophenes
worked as well or better than the corresponding double
Suzuki couplings using boronic acids.12
R1B(OH)2
Pd(Ph3P)4
aq Na2CO3 (1 M)
DMF, 80 °C
S
S
Br
R1
O
O
K+
then
O
R
–B
Br
R2
R2B(OH)2
aq Na2CO3 (1 M)
90 °C
1
Entry R1
R2
Isolated yield (%)
Figure 1 Structure of boronate salt 1
1
2
3
4
5
6
7
8
4-MeC6H4
4-FC6H4
(E)-PhC=CH
Ph
4-FC6H4
88
80
67
64
54
42
38
75
Using the boronate salts, the yields of double couplings
were generally higher for both the 2,3- and 2,4-dibro-
mothiophenes (Table 3). Further, although the couplings
of 2,3-dibromothiophenes still afforded slightly lower
yields than those in the 2,4-dibromothiophene, the differ-
ence is quite modest. As a result, it appears that steric is-
sues are less important.
4-MeC6H4
Ph
(E)-PhC=CH
Ph
2-MeOC6H4
Ph
2-MeOC6H4
Ph
Alkenyl boronate salts were also successful in these dou-
ble couplings (Table 3, entries 3 and 4). Quite encourag-
ingly, so was an ortho-substituted boronate (entries 5 and
6). It should be noted that the efficient preparation of this
particular boronate salt did require the use of the organo-
lithium route [halogen–metal exchange on 2-bromoani-
sole, followed by reaction with trimethyl borate and then
treatment with 1,1,1-tris(hydroxymethyl)ethane] as at-
tempts at preparing this boronate from the corresponding
boronic acid resulted in very low yields of the product.
Fortunately, the organolithium route afforded a nearly
quantitative yield of the desired boronate salt.
2-thienyl
Ph
2-thienyl
Table 2 Double Suzuki Couplings of 2,3-Dibromothiophene
R1B(OH)2
Pd(Ph3P)4
S
S
Br
R1
aq Na2CO3 (1 M)
DMF, 80 °C
then
R2B(OH)2
Br
R2
aq Na2CO3 (1 M)
90 °C
In conclusion, one-pot double couplings of dibromo-
thiophenes are clearly readily achievable. The use of bor-
onates as the coupling partners affords the products in
good yield for either dibromothiophene isomer. In some
preliminary studies, it appears that the same boronate re-
action conditions are applicable to a range of heteroaro-
matics, including pyrroles, furans, and pyridines. This has
not been the case in simple double Suzuki couplings,
where a different set of reaction conditions are required
for good yields with each different heteroaromatic. Thus,
the boronate couplings hold promise for the development
of a more general set of reaction conditions for these dou-
ble couplings. Studies to this end are under way and will
be reported in due course.
Entry R1
R2
Isolated yield (%)
1
2
3
4
5
6
7
8
4-MeC6H4
4-FC6H4
4-FC6H4
46
40
12
18
21
15
42
38
4-MeC6H4
Ph
(E)-PhC=CH
Ph
(E)-PhC=CH
Ph
2-MeOC6H4
Ph
2-MeOC6H4
Ph
2-thienyl
Ph
2-thienyl
drance that results from the presence of the initially cou-
pled group at C2. It is possible that employing a more
active catalyst may be sufficient to overcome this prob-
lem, but this option has not yet been explored.
All boronic acids were from Frontier Scientific and used as re-
ceived. All other reagents and solvents were from Acros or Aldrich
and were used as received. Silica gel (Natlund) was used for all col-
umn chromatography and Sorbent Technologies silica TLC plates
were used to monitor all reactions. NMR data were recorded on a
JEOL ECX-300. IR spectra were recorded on a Varian 800 FTIR as
solutions in deuterochloroform. Melting points were determined us-
ing a Fisher-Johns hot stage and are uncorrected. All coupling reac-
tions were performed using a JKEM orbital shaker with a
temperature-controlled multiwell heating block.
Because catalyst stability was proving to be such an issue,
we were interested in finding an even more mild set of re-
action conditions or a more robust catalyst. Recently,
Miyaura and co-workers reported the Suzuki-type cou-
pling using stable boronate salts such as 111 (Figure 1). Of
great interest to us was their observation that these salts
reacted under very mild conditions: no added base, palla-
dium acetate as catalyst, and short, room temperature re-
actions. Gratifyingly, application of these same
Double Suzuki Couplings; 4-(4¢-Fluorophenyl)-2-
(4¢-tolyl)thiophene; Typical Procedure
2,4-Dibromothiophene (48.3 mg, 0.207 mmol) and 4-fluorophenyl-
boronic acid (31.8 mg, 0.228 mmol) were combined in a vial and
Synthesis 2009, No. 1, 138–142 © Thieme Stuttgart · New York

140
S. Varello, S. T. Handy
PAPER
Table 3 Double Boronate Couplings of Dibromothiphenes
boronate 1
Pd(OAc)2
DMF–H2O
S
S
Br
R1
then
boronate 1'
Br
R2
Entry
R1
R2
Isolated yield (2,4 product, %) Isolated yield (2,3 product, %)
1
2
3
4
5
6
7
8
4-MeC6H4
4-FC6H4
4-MeC6H4
Ph
95
71
64
65
81
94
77
81
85
64
70
67
64
61
62
73
4-FC6H4
(E)-PhC=CH
Ph
(E)-PhC=CH
Ph
2-MeOC6H4
Ph
2-MeOC6H4
Ph
2-thienyl
Ph
2-thienyl
dissolved in DMF (4 mL). Aq 1 M Na2CO3 (600 mL) was added and
the resultant solution was degassed by bubbling argon through the
solution for 10 min. (Ph3P)4Pd (6.9 mg, 0.103 mmol) was added and
the vial was sealed and shaken on an orbital shaker at 110 rpm at
80 °C for 3 h. Tolylboronic acid (27.8 mg, 0.228 mmol) and aq 1 M
Na2CO3 (600 mL) were then added and the mixture was shaken at
110 rpm at 90 °C for an additional 16 h. The final reaction mixture
was cooled, diluted with H2O (15 mL), and extracted with Et2O
(3 × 10 mL). The combined organic layers were dried (MgSO4), fil-
tered, and concentrated in vacuo. The crude product was purified on
silica gel using 1:3 CH2Cl2–hexanes as eluent13(Tables 1 and 2).
13C NMR (75 MHz, CDCl3): d = 145.7, 138.4, 129.6 (d, J = 10 Hz),
128.5 (d, J = 210 Hz), 127.6 (d, J = 8 Hz), 125.7, 125.2, 122.0,
121.5, 116.2 (d, J = 25 Hz), 110.7, 110.5, 21.3.
HRMS (EI): m/z calcd for C17H13FS: 268.3546; found: 268.3545.
3-(4¢-Fluorophenyl)-2-(4¢-tolyl)thiophene
Pale yellow oil.
IR (CDCl3): 3100, 3000, 1550, 1500, 1200, 960, 880, 840, 820 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.70–7.51 (m, 4 H), 7.43–7.32 (m,
4 H), 7.06 (d, J = 6.8 Hz, 2 H), 2.37 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 138.7, 136.9, 131.7, 130.8, 130.0,
129.5, 129.3, 129.0 (d, J = 8 Hz), 127.3 (d, J = 8 Hz), 126.9 (d,
J = 210 Hz), 124.8, 116.7 (d, J = 25 Hz), 21.4.
Double Boronate Couplings; 4-(4¢-Fluorophenyl)-2-
(4¢-tolyl)thiophene; Typical Procedure
2,4-Dibromothiophene (80 mg, 0.33 mmol), 4-fluorophenyl bor-
onate (87 mg, 0.34 mmol), and Pd(OAc)2 (2.2 mg, 0.015 mmol)
were combined in a vial and dissolved in DMF–H2O (4:1, 1 mL).
The vial was sealed and stirred at r.t. for 3 h. The mixture rapidly
became dark brown. Tolyl boronate (86 mg, 0.34 mmol) was then
added and the mixture was stirred for an additional 16 h. The final
reaction mixture was diluted with H2O (4 mL) and extracted with
Et2O (3 × 3 mL). The combined organic layers were dried (MgSO4),
filtered, and concentrated in vacuo. The crude product was purified
on silica gel using 1:3 CH2Cl2–hexanes as eluent (Table 3).
HRMS (EI): m/z calcd for C17H13FS: 268.3546; found: 268.3547.
2-(4¢-Fluorophenyl)-3-(4¢-tolyl)thiophene
Pale yellow oil.
IR (CDCl3): 3100, 3000, 1500, 1220, 1160, 940, 880, 860 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.70–7.51 (m, 4 H), 7.39–7.32 (m,
3 H), 7.14 (t, J = 6.6 Hz, 2 H), 7.06 (d, J = 3.8 Hz, 1 H), 2.39 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 138.7, 136.9, 131.7 (d, J = 8 Hz),
130.8, 130.0, 129.5 (d, J = 200 Hz), 129.3, 129.0, 127.3, 126.9,
124.8 (d, J = 10 Hz), 115.8 (d, J = 22 Hz), 21.2.
4-(4¢-Fluorophenyl)-2-(4¢-tolyl)thiophene
Brown solid; mp 26–28 °C.
IR (CDCl3): 3100, 3000, 1500, 1240, 1160, 940, 820 cm–1.
HRMS (EI): m/z calcd for C17H13FS: 268.3546; found: 268.3543.
1H NMR (300 MHz, CDCl3): d = 7.60–7.42 (m, 4 H), 7.28–7.02 (m,
4-(2¢-Methoxyphenyl)-2-phenylthiophene
Pale yellow oil.
6 H), 2.38 (s, 3 H).
IR (CDCl3): 3100, 3000, 1500, 1250, 1140, 960, 820 cm–1.
13C NMR (75 MHz, CDCl3): d = 144.3, 138.1, 129.8, 128.4 (d, J = 8
Hz), 127.6 (d, J = 6 Hz), 127.3 (d, J = 195 Hz), 125.8, 125.7, 122.0,
121.5, 116.2 (d, J = 22 Hz), 110.6, 21.3.
1H NMR (300 MHz, CDCl3): d = 7.62–7.53 (m, 2 H), 7.42–7.24 (m,
5 H), 7.21 (t, J = 1 Hz, 1 H), 7.18 (d, J = 1 Hz, 1 H), 6.98 (d, J = 8
Hz, 2 H), 3.94 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 131.1, 129.2, 129.1, 128.4, 128.2,
127.8, 127.1, 125.8, 125.7, 122.6, 122.0, 121.1, 120.6, 111.7, 55.6.
HRMS (EI): m/z calcd for C17H13FS: 268.3546; found: 268.3544.
2-(4¢-Fluorophenyl)-4-(4¢-tolyl)thiophene
Yellow solid; mp 43–44 °C.
HRMS (EI): m/z calcd for C17H14OS: 266.3636; found: 266.3636.
IR (CDCl3): 3100, 3000, 1500, 1300, 1280, 1200, 900, 860, 820
cm–1.
1H NMR (300 MHz, CDCl3): d = 7.73–7.44 (m, 4 H), 7.33–7.02 (m,
6 H), 2.41 (s, 3 H).
2-(2¢-Methoxyphenyl)-4-phenylthiophene
Pale yellow oil.
IR (CDCl3): 3100, 3000, 1500, 1220, 1100, 960, 820 cm–1.
Synthesis 2009, No. 1, 138–142 © Thieme Stuttgart · New York

PAPER
Double Couplings of Dibromothiophenes
141
1H NMR (300 MHz, CDCl3): d = 7.76 (d, J = 1 Hz, 1 H), 7.69–7.61
(m, 3 H), 7.43 (d, J = 1 Hz, 1 H), 7.41–7.25 (m, 4 H), 7.02 (d, J = 8
Hz, 2 H), 3.92 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 136.1, 129.2, 129.1, 128.9, 128.7,
128.6, 127.8, 127.1, 126.4, 124.7, 123.6, 121.0, 120.6, 111.7, 55.2.
13C NMR (75 MHz, CDCl3): d = 137.6, 132.9, 131.4, 130.9, 130.1,
129.4, 129.2, 128.9, 128.6, 127.7, 126.5, 125.1, 124.0, 120.1.
HRMS (EI): m/z calcd for C18H14S: 262.3752; found: 262.3753.
4-Phenyl-2-(2¢-thienyl)thiophene
Mp 73–74 °C (Lit.14 mp 74–76 °C).
HRMS (EI): m/z calcd for C17H14OS: 266.3636; found: 266.3633.
IR (CDCl3): 3100, 3000, 1500, 1240, 1160, 940, 820 cm–1.
3-(2¢-Methoxyphenyl)-2-phenylthiophene
1H NMR (300 MHz, CDCl3): d = 7.76–6.84 (m, 10 H).
13C NMR (75 MHz, CDCl3): d = 145.1, 139.1, 137.3, 133.9, 129.2,
127.9, 127.8, 126.3, 124.1, 123.4, 122.2, 119.2.
Pale yellow oil.
IR (CDCl3): 3100, 3000, 1500, 1240, 1140, 960, 800 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.65 (d, J = 7 Hz, 2 H), 7.45–7.26
(m, 5 H), 7.05 (dd, J = 6, 1 Hz, 2 H), 7.00 (t, J = 7 Hz, 2 H), 3.84 (s,
3 H).
13C NMR (75 MHz, CDCl3): d = 132.1, 131.8, 130.6, 130.4, 129.2,
128.6, 128.2, 127.9, 125.5, 125.0, 120.0, 116.8, 116.4, 111.4, 55.7.
HRMS (EI): m/z calcd for C14H10S2: 346.3972; found: 346.3970.
2-Phenyl-4-(2¢-thienyl)thiophene
White solid; mp 70–72 °C.
IR (CDCl3): 3100, 3000, 1500, 1240, 1160, 940, 820 cm–1.
HRMS (EI): m/z calcd for C17H14OS: 266.3636; found: 266.3638.
1H NMR (300 MHz, CDCl3): d = 7.68–7.64 (m, 2 H), 7.53 (d, J = 1
Hz, 1 H), 7.48–7.40 (m, 2 H), 7.36–7.30 (m, 2 H), 7.28–7.23 (m, 2
H), 7.08 (dd, J = 5, 4 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 145.2, 139.1, 137.4, 133.9, 129.1,
127.9, 127.8, 126.0, 124.1, 123.3, 122.2, 119.1.
2-(2¢-Methoxyphenyl)-3-phenylthiophene
Pale yellow oil.
IR (CDCl3): 3100, 3000, 1500, 1260, 1140, 920, 840 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.35–7.16 (m, 10 H), 6.85 (d, J = 8
Hz, 1 H), 3.90 (s, 3 H).
HRMS (EI): m/z calcd for C14H10S2: 346.3972; found: 346.3973.
13C NMR (75 MHz, CDCl3): d = 132.8, 131.0, 129.4, 129.3, 128.5,
128.2, 128.1, 127.6, 126.5, 125.2, 120.1, 120.0, 112.3, 109.7, 55.2.
3-Phenyl-2-(2¢-thienyl)thiophene
Mp 72–74 °C (Lit.14 mp 75–76 °C).
HRMS (EI): m/z calcd for C17H14OS: 266.3636; found: 266.3634.
IR (CDCl3): 3100, 3000, 1500, 1240, 1160, 940, 820 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.40–7.434 (m, 5 H), 7.30–6.85
4-Phenyl-2-(trans-styryl)thiophene
White solid; mp 44–46 °C.
IR (CDCl3): 3100, 3000, 1500, 1280, 980, 920, 820 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.73–7.21 (m, 13 H), 7.06 (d,
J = 12 Hz, 1 H).
(m, 5 H).
13C NMR (75 MHz, CDCl3): d = 137.4, 129.8, 129.6, 128.0, 127.9,
126.3, 126.0, 125.7, 124.4, 124.0, 122.4, 118.6.
HRMS (EI): m/z calcd for C14H10S2: 346.3972; found: 346.3971.
13C NMR (75 MHz, CDCl3): d = 132.3, 129.4, 129.1, 128.9, 128.8,
128.4, 127.7, 127.3, 126.6, 126.5, 125.8, 125.8, 122.1, 110.8.
2-Phenyl-3-(2¢-thienyl)thiophene
Brown solid; mp 68–69 °C.
HRMS (EI): m/z calcd for C18H14S: 262.3752; found: 262.3755.
IR (CDCl3): 3100, 3000, 1500, 1240, 1160, 940, 820 cm–1.
1H NMR (300 MHz, CDCl3): d = 765–7.47 (m, 2 H), 7.38–7.19 (m,
7 H), 7.08 (d, J = 5 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 137.6, 129.8, 129.7, 128.0, 127.9,
126.3, 125.8, 125.7, 124.5, 123.9, 122.7, 118.7.
2-Phenyl-4-(trans-styryl)thiophene
Yellow solid; mp 48–50 °C.
IR (CDCl3): 3100, 3000, 1500, 1260, 980, 940, 820 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.57 (d, J = 5 Hz, 2 H), 7.40–7.30
(m, 11 H), 7.26 (d, J = 12 Hz, 1 H).
HRMS (EI): m/z calcd for C14H10S2: 346.3972; found: 346.3972.
13C NMR (75 MHz, CDCl3): d = 145.4, 133.3, 129.4, 129.2, 128.9,
128.8, 128.4, 127.7 126.6, 126.5, 125.8, 125.7, 122.0, 110.6.
Acknowledgment
HRMS (EI): m/z calcd for C18H14S: 262.3752; found: 262.3755.
The financial support of the NIH (GM074662-01) is gratefully ack-
nowledged, as is the gift of boronic acids from Frontier Scientific.
3-Phenyl-2-(trans-styryl)thiophene
Yellow solid; mp 87–90 °C.
IR (CDCl3): 3100, 3000, 1500, 1240, 980, 900, 820 cm–1.
References
1H NMR (300 MHz, CDCl3): d = 7.55–725 (m, 11 H), 7.08–6.93 (m,
2 H), 6.68 (d, J = 12 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 137.4, 132.9, 131.3, 130.7, 130.1,
129.3, 129.2, 128.8, 128.4, 127.7, 126.6, 125.2, 123.8, 120.1.
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HRMS (EI): m/z calcd for C18H14S: 262.3752; found: 262.3754.
2-Phenyl-3-(trans-styryl)thiophene
White solid; mp 44–46 °C.
IR (CDCl3): 3100, 3000, 1500, 1260, 980, 940, 840 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.68 (d, J = Hz, 1 H), 7.60–7.25
(m, 10 H), 7.08–6.90 (m, 2 H), 6.65 (d, J = 12 Hz, 1 H).
(5) Handy, S. T.; Diyar, M. Tetrahedron Lett. 2007, 46, 8108.
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S. Varello, S. T. Handy
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(10) EtOH–toluene afforded poor conversions, while aqueous
dioxane was almost as efficient as DMF. In terms of base,
K2CO3 and K3PO4 afforded slightly lower (5–10%) yields.
(11) Yamamoto, Y.; Takizawa, M.; Yu, X.-Q.; Miyaura, N.
Angew. Chem. Int. Ed. 2008, 47, 928.
(12) The boronate salts were prepared as described in reference
11 starting from the commercially available boronic acids
with the exception of the o-methoxyphenyl boronate salt,
which was prepared via the organolithium route also
described in reference 11.
(13) The use of CH2Cl2–hexane mixtures for chromatography
was important as attempts to use EtOAc–hexanes or Et2O–
hexanes mixtures resulted in much lower isolated yields due
to limited product solubility in these solvents.
(6) (a) Raju, B.; Wu, C.; Kois, A.; Verner, E.; Okun, I.; Stavros,
F.; Chan, M. F. Bioorg. Med. Chem. Lett. 1996, 6, 2651.
(b) Tamao, K.; Nakamura, K.; Ishii, H.; Yamaguchi, S.;
Shiro, M. J. Am. Chem. Soc. 1996, 118, 12469.
(c) Karlsson, J. O.; Gronowitz, S.; Frejd, T. J. Org. Chem.
1982, 47, 374; and references cited therein (see reference 7).
(7) Pereira, R.; Iglesias, B.; de Lera, A. R. Tetrahedron 2001,
57, 7871.
(8) (a) Dang, T. T.; Rasool, N.; Dang, T. T.; Reinke, H.; Lander,
P. Tetrahedron Lett. 2007, 48, 845. (b) For an example
using a direct arylation variation, see: Nakano, M.; Satoh, T.;
Miura, M. J. Org. Chem. 2006, 71, 8309.
(9) These monocoupled thiophene products were used to
confirm the regioselectivity of the first coupling by
hydrodehalogenation of the remaining bromide and then
comparison with reported spectral data for the monoarylated
thiophenes.
(14) Sone, T.; Sato, K.; Umetsu, Y.; Toshino, A.; Takahashi, K.
Bull. Chem. Soc. Jpn. 1994, 67, 2187.
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