Iridium-catalyzed borylation of thiophenes: versatile, synthetic elaboration founded on selective C-H functionalization

Article abstract of DOI:10.1016/j.tet.2008.02.111

Iridium-catalyzed borylation has been applied to various substituted thiophenes to synthesize poly-functionalized thiophenes in good to excellent yields. Apart from common functionalities compatible with iridium-catalyzed borylations, additional functional group tolerance to acyl (COMe) and trimethylsilyl (TMS) groups was also observed. High regioselectivities were observed in borylation of 3- and 2,5-di-substituted thiophenes. Electrophilic aromatic C-H/C-Si bromination on thiophene boronate esters is shown to take place without breaking the C-B bond, and one-pot C-H borylation/Suzuki-Miyaura cross-coupling has been accomplished on 2- and 3-borylated thiophenes.

Full text of DOI:10.1016/j.tet.2008.02.111

Tetrahedron 64 (2008) 6103–6114
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Iridium-catalyzed borylation of thiophenes: versatile, synthetic elaboration
founded on selective C–H functionalization
*
Ghayoor A. Chotana, Venkata A. Kallepalli, Robert E. Maleczka, Jr., Milton R. Smith, III
Department of Chemistry, Michigan State University, East Lansing, MI 48824-1322, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Iridium-catalyzed borylation has been applied to various substituted thiophenes to synthesize poly-
functionalized thiophenes in good to excellent yields. Apart from common functionalities compatible
with iridium-catalyzed borylations, additional functional group tolerance to acyl (COMe) and trime-
thylsilyl (TMS) groups was also observed. High regioselectivities were observed in borylation of 3- and
2,5-di-substituted thiophenes. Electrophilic aromatic C–H/C–Si bromination on thiophene boronate
esters is shown to take place without breaking the C–B bond, and one-pot C–H borylation/Suzuki–
Miyaura cross-coupling has been accomplished on 2- and 3-borylated thiophenes.
Received 30 January 2008
Received in revised form 4 February 2008
Accepted 4 February 2008
Available online 16 April 2008
Keywords:
C–H activation
Iridium
Ó 2008 Elsevier Ltd. All rights reserved.
Catalysis
Borylation
Thiophenes
One-pot reactions
Suzuki–Miyaura cross-coupling
Bromination
1. Introduction
functionalize, thiophenes,14,15 their synthetic utility is limited when
compared to non-biochemical methods.
Thiophenes comprise an important heterocyclic class with di-
verse applications ranging from the design of advanced materials1–3
to the treatment of various diseases4–7 (Fig. 1). Consequently, their
synthesis has garnered keen interest.
Lithiation reactions are some of the oldest and most prevalent
means for functionalizing C–H bonds in heterocycles. More re-
cently, attention has turned to other methods for derivatizing
C–H16–18 and C–X18–22 bonds in heterocycles with an emphasis on
transition metal catalyzed processes that obviate the requirement
for stoichiometric metal. While the emerging methodologies can
There are two fundamentally different approaches for synthe-
sizing substituted thiophenes. The first entails construction of the
thiophene ring from appropriate precursors with the most com-
mon examples stemming from early syntheses of thiophene from
C4 carbonyl compounds and P2S5.8,9 The second general approach
to substituted thiophenes involves derivatizing an existing thio-
phene core. Examples of the latter case include halogenations,
alkylations, and metalations. The first metalation examples were
mercurations reported by Volhard in 1892,10 and Thomas described
the generation and reactivity of 2-thiophenylmagnesium iodide
by magnesium reduction of 2-iodothiophene in 1908.11 Organo-
lithiation reactions of thiophenes, pioneered by Gilman,12 have
proved to be particularly versatile because, like mercuration, the
thiophene C–H bond can be functionalized directly. The thienyl
lithium intermediates that result react readily with various elec-
trophiles.13 While biological systems can assemble, as well as
n-Hex
n-Hex
S
S
S
S
x
n-Hex
n-Hex
Regioregular poly(3-hexylthiophene)
(PlexcoreTM OS P3HT, Plextronics, Inc.)
S
MeO
N
O
Cl
H
N
S
O
S
N
OAc
O
CO2H
Cephalothin
Clopidogrel
(Plavix®, Bristol-Myers Squibb, Inc.)
(Keflin®, Lilly, Inc.)
* Corresponding author. Tel.: þ1 517 355 9715x166; fax: þ1 517 353 1793.
E-mail address: smithmil@msu.edu (M.R. Smith III).
Figure 1. Selected thiophene-derived articles of commerce.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.02.111

6104
G.A. Chotana et al. / Tetrahedron 64 (2008) 6103–6114
sometimes bypass intermediates for certain syntheses, they can
also offer selectivities that complement metalation reactions. In this
contribution we examine the scope and limitations of Ir-catalyzed
C–H borylation applied to the synthesis of thiophene boronate
esters.
ligand systems were not made when the dipyridyl system was
effective.
For phosphine based catalysis, the phosphine (typically a
bidentate ligand) and the Ir precatalyst, (
h
5-Ind)Ir(cod) (Ind¼
indenyl, cod¼1,4-cyclooctadiene), are simply combined with the
borane, substrate, and solvent (if used) in a reaction vessel. The
resulting mixture is then heated to effect borylation.28 While
the dtbpy system operates at room temperature, generation of the
catalysts must be done as follows.34,35 First, the HBPin and the Ir
2. Results and discussion
Aryl boronate esters are versatile reagents that are widely used
in the construction of carbon–carbon and carbon–heteroatom
bonds. Prior to 1995, aryl boronate esters were typically prepared by
reacting an organometallic intermediate, generated from an arene
or aryl halide and stoichiometric quantities of a metalating agent,
with a boron electrophile (Fig. 2). In 1995, Miyaura and co-workers
reported the synthesis of arylboronates by the Pd-catalyzed cross-
coupling of tetraalkoxydiboron reagents with haloarenes, including
3-iodobenzothiophene.23 Subsequently, Masuda and co-workers
devised related conversions using dialkoxyboranes,24 including the
synthesis of 2-thienyl boronate esters.25 These transformations
were important advances because (i) substoichiometric quantities
of Pd catalysts served as the metalating agents, and (ii) the mild
reaction conditions can accommodate functional groups that are
incompatible with organomagnesium or organolithium reagents.
precatalyst, [Ir(m2-OMe)(h
4-cod)]2 are combined. Then the dipyr-
idyl ligand, in most cases 4,40-di-tert-butyl-2,20-dipyridyl (dtbpy), is
dissolved in a suitable solvent and the resulting solution is added
to the HBPin/[Ir(m2-OMe)(
orange solution. The order of operations is critical as addition of
dtbpy to [Ir(m2-OMe)(
4-cod)]2 produces a pale green solution that
h
4-cod)]2 mixture, generating a deep
h
exhibits diminished activity upon addition of HBPin followed by
substrate. Although HBPin was used exclusively in this study, it
should be noted that B2Pin2, a more active borylating agent, is less
effective for catalyst generation. Should circumstances warrant use
of B2Pin2, it is critical that the catalyst generation be carried out
with HBPin. Lastly, we note that despite being touted for its air-
stability, solid samples of [Ir(m2-OMe)(h
4-cod)]2 gradually darken
when stored on the bench top and catalytic activity of ‘aged’ pre-
catalyst is diminished relative to pristine samples.
Table 1 displays borylation results for an expanded slate of
2-substituted thiophenes. Entries 1–3 show that the tolerance
for heavier halogens and esters exhibited for arenes extends to
thiophenes. Entry 4 is noteworthy in that the TMS group can be
transformed while leaving the BPin intact (vide infra). It seemed
likely that substituents that compromise arene borylations might be
compatible for thiophenes since heterocyclic substrates are usually
more susceptible to borylation than arenes. This indeed proved to
be the case for entry 5 where the acyl product 5 was obtained. This
appears to be a limit for compatibility as the analogous product
6, though generated in small quantities, was not isolated from the
Stoichiometric
S
S
metalation
H/X
M
B(OR)3
H
B(OR)2
or
Catalytic
(RO)2B B(OR)2
S
S
transition metal catalyst
H/X
B(OR)2
Figure 2. Routes to 2-thiophenyl boronate esters via stoichiometric or catalytic met-
alation protocols.
Table 1
Ir-catalyzed borylations of 2-substituted thiophenesa
In 1999, we reported an Ir-catalyzed reaction that coupled ben-
zene andpinacolborane(HBPin)toyieldPhBPingeneratinghydrogen
gas as the sole byproduct.26 Recognizing that this transformation’s
simplicity could offer advantages over traditional routes to arylboron
compounds, we explored the generality of this reaction with arenes,
including the first extensions to heterocyclic substrates.27–29 Despite
improvements in catalyst generation,28,30 application of this meth-
odology to substituted thiophenes is limited to five substrates:
2-methylthiophene,31–33 2-cyanothiophene,32 2-bromothiophene,32
2-methoxythiophene,33 and 2-trifluoromethylthiophene.33 These
reactions yield 5-borylated products exclusively in accord with the
preference for borylation of C–H bonds adjacent to formally sp3-
hybridized heteroatoms in five-membered heterocycles. Clearly, the
restriction of previous studies to 2-substituted substrates raises
questions regarding the feasibility of this reaction when the sub-
stitution pattern is varied and the range of substituents is expanded.
Entry
1
Substrate
Reaction time
Product
Yieldb
92
%
S
PinB
PinB
I
S
I
1 h
1
S
S
Cl
Cl
2
3
10 min
30 min
78
94
Br
Br
2
S
PinB
CO2Me
S
CO2Me
3
S
PinB
TMS
S
TMS
C(O)Me
C(O)H
4
5
30 min
30 min
93
85
4
S
PinB
PinB
C(O)Me
C(O)H
S
2.1. Borylation of 2-substituted thiophenes
5
As noted above, the reported borylations of 2-substituted thio-
phenes display excellent regioselectivity for 5-borylated products.
Nevertheless, the range of substituents that have been surveyed
is limited compared to aromatic substrates. Before detailing our
findings, comments regarding the catalyst system are warranted.
Most of the chemistry in this paper utilizes a dipyridyl-ligated
catalyst that is generated in situ. However, this catalyst system was
ineffective for electron-rich substrates. For these cases, phosphine
supported catalysts gave better results. Comparisons between the
S
S
6
d
dc
6
a
Reactions were carried out with 3 mol % Ir catalyst in n-hexane at room tem-
perature with 1.5–2.0 equiv HBPin. For details see Section 4.
b
Yields are for isolated products.
GC/MS data show that 6 (or an isomer) accounts for w10% of the reaction
c
mixture. GC/MS and NMR data indicate that significant reduction of the formyl
group occurs.

G.A. Chotana et al. / Tetrahedron 64 (2008) 6103–6114
6105
borylation of 2-formylthiophene owing to reduction of the formyl
group by HBPin. In the absence of Ir catalyst, HBPin does not reduce
2-formylthiophene at room temperature. It is noteworthy that
Christophersen and co-workers have successfully performed a
Pd-catalyzed Masuda coupling of HBPin with 2-bromo-3-for-
mylthiophene without complications arising from reduction.36
ortho to CN appears to be favored. Contrary to a literature report
noting its instability,36 7b was sufficiently stable to be persistent in
the isolated isomer mixture.
Isomer mixtures were also observed for Cl, Br, Me, and p-tolyl
(p-Tol) substituents (entries 2–4 and 8). For these substrates, the
5-borylated isomers are the major products and the relative isomer
ratios (a/b) for Cl, Br, and Me follow the trend seen in arenes.37 For
the p-Tol substituted substrate (entry 8) the selectivity is suffi-
ciently high for 14a to be synthetically useful. As compared to Rh
and Pd catalysts that favor borylation of benzylic C–H bonds,38–40 Ir
catalysts are highly selective for aromatic over benzylic C–H bond
functionalization,27,28 even for substrates with hindered arene C–H
bonds like p-xylene.41 Thus, it is noteworthy that borylation of the
thiophene C–H bonds is favored. In particular, formation of 14b
indicates that functionalization of relatively hindered thiophene
C–H bonds is possible when arene C–H bonds are present. This
might not prove to be general, particularly for compounds where
electron-deficient o- or m-substituted aryl groups are present.
The selectivity for acyl, ester, and trimethylsilyl substituents was
excellent and 2-borylated products were not detected. For the
methyl ester substrate (entry 6), the selectivity is consistent with
that observed in borylations of 4-benzonitriles, and the steric
profiles of acyl and TMS groups are likely similar or greater.
Certainly, the closest comparison to our work is the related
Ir-catalyzed silylations described by Ishiyama and Miyaura.42 Even
though these reactions require much higher temperatures, which
2.2. Borylation of 3-substituted thiophenes
In contrast to 2-substituted thiophenes, both C–H bonds flank-
ing S in 3-substituted thiophenes are potentially accessible for
borylation. In the absence of electronic effects, borylation at the
5-position should be generally favored. However, selectivities will
likely be lower than those for arenes since the distance between
neighboring substituents increases as the number of ring atoms
decreases.37
Indeed, some of these expectations are born by the data in Table
2. In cases where isomer mixtures resulted (Table 2 entries 1–4
and 8), 2.0 equiv of thiophene was used to minimize losses arising
from diborylation. Regiochemical assignment is straightforward
4
3
from the magnitudes of j JHHj (w2 Hz) and j JHHj (w5 Hz) for the
respective a and b isomers. 3-Cyanothiophene gave the poorest
regioselectivity with 2-borylated product 7b being the major iso-
mer. While CN is one of the smallest substituents, previous work
shows that borylation ortho to H is preferred relative to CN for
arenes,37 and the results for entry 1 are the first where borylation
Table 2
Borylations of 3-substituted thiophenesa
Entry
1
Substrate
Conditions
5-Borylated product
3-Borylated product
a/bb
Yieldc
54d
%
S
S
S
PinB
BPin
0.5 equiv HBPin, 1 h
1:1.13
CN
CN
CN
7a
7b
S
S
S
BPin
PinB
2
0.5 equiv HBPin, 1 h
3.5:1
66d
Cl
Cl
Cl
Br
8b
8a
S
S
S
S
BPin
PinB
3
4
5
6
7
0.5 equiv HBPin, 1 h
0.5 equiv HBPin, 1 h
1.2 equiv HBPin, 15 min
1.2 equiv HBPin, 1 h
8.9:1
8.9:1
72d
67d
82
Br
Br
9a
9b
S
S
BPin
PinB
Me
Me
Me
10a
10b
S
S
S
PinB
d
d
d
>99:1
>99:1
C(O)Me
C(O)Me
CO2Me
11a
S
PinB
95
CO2Me
12a
S
S
PinB
1.2 equiv HBPin, 30 min
0.9 equiv HBPin, 1 h
>99:1
>32:1
79
TMS
TMS
13a
S
S
S
PinB
BPin
8
74d
p-Tol
p-Tol
p-Tol
14a
14b
a
Reactions were carried out with 3 mol % or pregenerated Ir catalyst in n-hexane at room temperature with 1.5–2.0 equiv HBPin. For details see Section 4.
Isomer ratios were determined by GC analysis of the crude reaction mixture.
Yields are reported for isolated products and are based on starting thiophene unless otherwise noted. Isomers were not separated.
Yield based on HBPin.
b
c
d

6106
G.A. Chotana et al. / Tetrahedron 64 (2008) 6103–6114
we frankly consider to be a very minor drawback, their selectivities
for silylation at the 5-position relative to the 2-position of 3-
methyl- and 3-chlorothiophene (99:1 and 49:1, respectively) are
better than those for borylation, while regioselectivity for silylation
of methyl 3-thiophenecarboxylate (49:1) was marginally worse
than that for borylation (Table 2, entry 6) It must be emphasized
that 2-tert-butyl-1,10-phenanthroline was the ligand that engen-
dered these selectivities. The silylation selectivity for dtbpy-ligated
catalysts is more appropriate for directly comparing silylation and
borylation. Though limited to a single example, the silylation
regioselectivity for 3-methylthiophene (5-isomer/2-isomer¼2.5:1)
is considerably worse than the 8.9:1 selectivity for borylation using
the same precatalyst and ligand (Table 2, entry 4). Borylations using
2-tert-butyl-1,10-phenanthroline were not attempted because the
ligand is not commercially available. Nevertheless, regioselectiv-
ities for thiophene borylations can be improved by altering the
catalyst’s coordination sphere.
In spite of the regioselectivity that silylation offers, two factors
limit its synthetic utility. First, the silylating agent (tert-Bu2F2Si2) is
not commercially available. Second, the synthetic elaborations of
aryl and heteroaryl silanes are less well developed compared to the
analogous boron chemistry. Certainly, future developments in
arylsilane chemistry could change this situation.43,44
There are other existing methods for selectively functionalizing
3-substituted thiophenes at the 5-position. The two most common
approaches are (i) electrophilic substitutions that are selective for
5-substitution when the 3-substituent is electron withdrawing
and/or the electrophile is sterically hindered,45,46 and (ii) directed
ortho metalations (DoMs) where the 3-substituent is a poor di-
rected metalation group (DMG).47–49
surprising if C–X scission led to catalyst deactivation for these
substrates.
The potential for C–X activation also raises questions regarding
the regiochemistry of the monoborylated products. Even though
halogen tolerance is a hallmark of Ir-catalyzed C–H borylations, the
observation of a single regioisomer from the borylation does not
prove that the halogen regiochemistry is maintained. Assumptions
of this type have led to mischaracterization of products arising from
directed metalations of 2,5-dihalothiophenes,51 where rearrange-
ment of the metalated intermediates via ‘halogen dance’ mecha-
nisms can lead to 2,4-dihalogenated products.52
13C NMR data offer the first line of evidence against a similar
rearrangement occurring in C–H borylations. By comparing the 13
C
chemical shifts of monosubstituted thiophene I to thiophene and
17 (vide infra) to 2,5-dimethylthiophene (Fig. 3), increments of the
13
-
2
-
C chemical shifts (IBC and IBC 3) for the BPin group can be esti-
mated (Table 4). While we are not aware of previous reports of IBC
-3
values, the magnitudes and trends for the BPin IBC values are in
-
2
line with those in the literature.53
Using IBC and IBC for the BPin group and the 13C increment
-2
-3
values for Br substitution on a thiophene nucleus,52 the
d (
13C)
values for 16 and isomers A–D, which are generated by permuting
H, Br, and BPin positions, have been calculated and the data are
listed in Table 5. The Cipso resonances attached to BPin are not ob-
served and assignment of the quaternary carbons is not certain.
However, the methine carbon can be unambiguously assigned and
the calculated methine shifts are indicated by boldface type. Isomer
16 gives the best fit to the data with the largest deviation observed
for the C-2. This error is considerably smaller than the magnitude of
-2
the corresponding IBC value. The two remaining calculated shifts
for 16, which include the methine resonance, fit the data very
well. The fit to calculated shifts for isomer A, the analogue to the
regioisomer that arises when lithiated 2,5-dibromothiophene
rearranges, is poor with a large error in the shift for C-3, which is
adjacent to BPin substituted carbon. Of the remaining isomers B–D,
isomer C is the only candidate whose calculated values approach
the fit found for 16. We discount this possibility because (i) there
is no precedent for ‘halogen dance’ rearrangement to this
regioisomer, and (ii) the error in the methine shift, which is
assigned unambiguously, is large. The final piece of confirming
evidence comes from a chemical reaction of 16. We have observed
that borylated products in crude reaction mixtures are susceptible
to protodeborylation when heated with a source of acidic pro-
tons.54 Protodeborylation of 16 regenerates 2,5-dibromothiophene,
which is consistent with the assigned regiochemistry (Fig. 4).
For 2,5-dimethylthiophene, electronic effects likely impact the
borylation rates since the steric energies of methyl and bromine
substituents are similar. The overall rate reduction in this case is
consistent with results from arene borylations, where electron-rich
substrates are significantly less reactive than electron poor ones.
Thus, borylation at room temperature with the dtbpy-ligated cat-
alyst is impractical (Table 3, entry 3). Although this catalyst system
has been reported to operate effectively at elevated temperatures,
only 12% conversion was achieved after 16 h when the borylation
was carried out with the Ir/dtbpy catalyst at 80 ꢀC. We find that
phosphine ligated catalysts are well-suited for substrates of this
type, even though elevated temperatures are required for bor-
ylation. Indeed, the combination of the Ir precatalyst (Ind)Ir(cod)
and 1,2-bis(dimethylphosphino)ethane (dmpe) promoted smooth
borylation at 150 ꢀC, and compound 17 was isolated in excellent
yield (Table 3, entry 4).
When compared to DoMs, the selectivities for entries 2, 3, 5, and
6, are atypical. Even with relatively poor DMGs like Cl or Br at C-3,
DoM at C-2 for thiophenes is often favored. Consequently, pro-
tection/deprotection at C-2 can be required for selective synthesis
of 3,5-substituted compounds via DoM.50 Since Ir-catalyzed bor-
ylation favors functionalization at the 5-position, it complements
DoM nicely.
2.3. Borylation of 2,5-disubstituted thiophenes
Borylation of 2,5-disubstituted thiophenes are more challenging
for two reasons. First, the 3- and 4-C–H bonds are less reactive
towards borylation even in the absence of steric constraints, as
evidenced by the results in Table 1. Second, the 2- and 5-sub-
stituents will further impede borylation.
The results for borylations of 2,5-disubstituted thiophenes are
shown in Table 3. For the symmetrically substituted substrates in
entries 1–3, regioselectivity is not an issue, making them the logical
starting points for discussion. The first obvious difference from
the data in Tables 1 and 2 is that borylation requires prolonged
reactions times with Cl>Br[Me. ortho-Substituents impede bor-
ylations of C–H bonds of substituted arenes, with steric effects
almost certainly being responsible.
The relative ordering of the rates for thiophenes may not be
a simple matter of steric effects. For example, borylation of 2,5-di-
chlorothiophene slowed markedly after an initial conversion surge.
This rate diminution was accompanied by precipitation of brown
particles, suggesting that catalyst may be decomposing. Never-
theless the conversion was complete in 20 h and product 15 was
isolated in good yield (Table 3, entry 1). The borylation of 2,5-
dibromothiophene was more problematic, and only 89% conversion
of the substrate was observed after 48 h at room temperature with
9 mol % Ir catalyst loadings. Consequently, compound 16 was iso-
lated in modest yield (Table 3, entry 2). Given the highly reactive
For unsymmetrical chlorothiophene substrates, borylations
typically gave isomer mixtures (Table 3, entries 5–7). The borylation
regiochemistries were assigned either from the relative chemical
shifts of the methine protons (18a,b and 20a,b) or by jJHHj values
(19a and b). Compound 18a was also prepared independently (vide
nature of C–X bonds in a-halogenated thiophenes, it would not be

G.A. Chotana et al. / Tetrahedron 64 (2008) 6103–6114
6107
Table 3
Borylations of 2,5-disubstituted thiophenes
Entry
1
Substrate
Conditions
3-Borylated product
4-Borylated product
a/ba
Yieldb
%
S
Cl
Cl
S
Cl
Br
Cl
Br
3 mol % Ir/dtbpy, 1.5 equiv HBPin, rt, 20 h
d
d
86
56
PinB
Br
15
S
Br
S
S
2
3
4
5
6
7
9 mol % Ir/dtbpy, 2.5 equiv HBPin, rt, 48 hc
3 mol % Ir/dtbpy, 1.5 equiv HBPin, rt, 20 h
2 mol % Ir/dmpe, 1.5 equiv HBPin, 150 ꢀC, 16 h
6 mol % Ir/dtbpy, 2.0 equiv HBPin, rt, 28 hd
3 mol % Ir/dtbpy, 1.5 equiv HBPin, rt, 18 h
3 mol % Ir/dtbpy, 1.5 equiv HBPin, rt, 20 h
3 mol % Ir/dtbpy, 1.5 equiv HBPin, rt, 6 h
d
d
d
d
d
PinB
Me
16
S
Me
Me
Br
Me
Me
Cl
Me
Me
Br
d
PinB
Me
17
S
S
d
97
87
86
89
93
PinB
Cl
17
S
S
Cl
Cl
Cl
Br
BPin
Me
S
2.0:1e,f
PinB
Cl
18a
18b
S
S
Me
I
S
2.3:1g
5.7:1h
>99:1
Cl
Me
I
BPin
I
PinB
Cl
19a
19b
S
S
S
Cl
PinB
BPin
20a
20b
S
Cl
PinB
TMS
S
Cl
TMS
8
9
d
21
S
S
Cl
C(O)Me
C(O)Me
d
d
d
d
d
d
d
d
d
Br
10
d
a
Isomer ratios were determined by GC analysis of the crude reaction mixtures.
Yields are reported for isolated products and are based on starting thiophene unless otherwise noted. Isomers were not separated.
Initially, 6 mol % Ir/dtbpy catalyst loading and 1.5 equiv HBPin was used. After 36 h, conversion had ceased and the reaction flask was charged with an additional 3 mol %
b
c
Ir/dtbpy and 1.0 equiv HBPin.
d
Initially, 3 mol % Ir/dtbpy catalyst loading and 1.5 equiv HBPin was used. After 8 h, the reaction flask was charged with an additional 3 mol % Ir/dtbpy and 0.5 equiv HBPin.
e
Assignment of isomers based on the 1H chemical shifts of the methine protons: 18a, 7.10 ppm, 18b, 6.94 ppm.
f
Compound 18a was prepared independently. See Scheme 2.
Compound 19a was identified by j JHHj¼1.2 Hz for the coupling between the methine and methyl protons. j JHHj was not resolved for 19b.
g
4
5
h
Assignment of isomers based on the 1H chemical shifts of the methine protons: 20a, 7.31 ppm, 18b, 6.87 ppm.
infra). The variations in isomer ratios reflect relative differences in
steric energies for the substituents. When the relative steric are
sufficiently great, single isomers can be attained as indicated by
compound 21 (Table 3, entry 8). The acyl compatibility seen in
Tables 1 and 3 did not extend to the 2-acyl-5-halothiophenes in
entries 9 and 10.
The synthetic utility for the unsymmetrically 2,5-disubstituted
thiophenes is more limited than for the other substrates that have
been discussed to this point; however, it should be noted that
certain substrates for which we would expect good selectivities
(e.g., 2-fluoro compounds) were not surveyed because of their
limited commercial availability.
S
S
Me
Me
124.9
126.7
137.3
Table 4
Carbon-13 chemical shifts
13
-
-
d
(
C) (ppm) and BPin increments IBC 2 for I and IBC 3 for 17
124.7
Position
I
17
S
S
PinB
Me
Me
-2
-3
d
IBC
d
IBC
I
17
C-2
C-3
C-4
C-5
da
d
150.8
da
13.5
d
PinB
137.1
128.2
132.3
10.4
1.5
7.4
(a)
(b)
130.7
136.1
6.0
ꢁ1.2
13
Figure 3. Compounds and C NMR chemical shift data used to estimate (a) IBC-2 and
a
(b) IBC-3 values.
Cipso resonance was not observed.

6108
G.A. Chotana et al. / Tetrahedron 64 (2008) 6103–6114
Table 5
Calculated carbon-13 chemical shifts
d
(
13C) (ppm) for 16 and isomers A–D (methine resonances indicated in bold)
Position
16
A
B
C
D
C-2
C-3
C-4
C-5
125.0 (3.1)b
da
da
118.5 (ꢁ3.4)
115.4 (4.5)
140.4 (4.6)
da
109.9 (ꢁ1.0)
119.9 (ꢁ2.0)
da
da
119.9 (9.0)
133.3 (L2.5)
120.3 (ꢁ1.6)
124.4 (2.5)
115.5 (4.6)
131.2 (L4.6)
136.2 (0.4)
110.3 (ꢁ0.6)
140.3 (4.5)
a
No data was calculated for Cipso resonances.
Deviations from fit to experimental data are shown in parentheses.
b
S
S
S
1.5 equiv HBPin,
1.5 mol % [Ir(OMe)COD]2
3.0 mol % dtbpy
Br
Br
PinB
Br
Br
Br
BPin
S
Me
Me
2% conversion
PinB
Br
16
A
B
rt, 8 h
Br
22
S
S
Br
Br
PinB
1.5 equiv HBPin,
2.0 mol % (Ind)Ir(COD)
2.0 mol % dmpe
BPin
Br
Br
C
D
22
4% conversion
Figure 4. Compound 16 and its regioisomers A–D.
150 °C, 6 h
2.4. Attempted borylation of 2,3,5-trisubstituted thiophenes
1.5 equiv HBPin,
2.0 mol % (Ind)Ir(COD)
2.0 mol % dmpe
S
S
Cl
Cl
Cl
BPin
For 2,3,5-trisubstituted thiophenes, the 4-position is flanked
by two ortho substituents. Since the H–C–C bond angles in five-
membered heterocycles are larger than those in six-membered
rings, the 4-position in 2,3,5-trisubstituted thiophenes should be
more accessible for borylation. However, only about 2% boryla-
tion was observed for 3-bromo-2,5-di-methylthiophene (22) for
attempted room temperature borylation with the [Ir(m2-OMe)-
(COD)]2/dtbpy catalyst (Fig. 5). The outcome was similar for the
(Ind)Ir(COD)/dmpe system at 150 ꢀC. Apart from steric hindrance
for borylation, the electron-rich nature of 3-bromo-2,5-di-methyl-
thiophene could also be responsible for this low reactivity. Thus,
borylation of an electron-deficient substrate, 3-bromo-2,5-di-
chlorothiophene (23), was attempted using the [Ir(m2-OMe)(COD)]2/
dtbpy system at room temperature and the borylation reaction
stalled after w5% conversion. The borylation of this substrate was
also tested using (Ind)Ir(COD) and dmpe at 150 ꢀC. This reaction gave
a 73% isolated yield of a single product, which surprisingly proved to
be compound 2.
150 °C, 2 h
Br
Br
23
2
73% yield
Figure 5. Attempted borylations of 2,3,5-trisubstituted thiophenes.
Ir–Cl reduction by HBPin to regenerate the active catalyst. Either
scenario requires 2 equiv of HBPin for each equivalent of compound
2 that is produced. Hence, the 73% yield for 1.5 equiv of HBPin in-
dicates that the transformation is nearly quantitative.
2.5. Synthetic elaborations of borylated thiophenes
The synthetic utility of the thiophene boronate esters in Tables
1–3 hinges on their ability to participate in subsequent trans-
formations. One attractive feature of Ir-catalyzed borylations is
their amenability to one-pot reactions where subsequent trans-
formations of the crude boronate esters can be accomplished
without removing the spent Ir catalysts.
Preliminary studies show that one-pot C–H borylation/Suzuki–
Miyaura cross-couplings can be accomplished on 2- and 3-bory-
lated intermediates 21 and 24 (Scheme 1). The Suzuki–Miyaura
couplings utilized aryl bromides to avoid the potential homocou-
pling of intermediates 21 and 24, and Pd(PPh3)4 was used as the
The conversion of 23 to 2 is noteworthy in that the least hin-
dered chloride is selectively cleaved. Although there is no direct
supporting evidence, a plausible mechanism for the formation of
2 involves selective reduction of the 5-chloro substituent in 23 by
HBPin to afford 3-bromo-2-chlorothiophene, which is then bory-
lated to give 2. Alternatively, the transformation could proceed via
C–Cl oxidative addition of 23 to Ir, C–B reductive elimination, and
1. 1.5 equiv HBPin, 3.0 mol % dtbpy,
1.5 mol% [Ir(OMe)(COD)]2,
hexanes, rt, 0.5 h
3. 1.2 equiv 3-bromobenzotrifluoride,
2 mol% Pd(PPh3)4,1.5 equiv
K3PO4·nH2O, 80 °C, 8 h
S
2. Remove volatiles, 0.5 h
S
S
Me
Me
BPin
TMS
Me
CF3
24
25
85% yield
1. 1.5 equiv HBPin, 3.0 mol % dtbpy,
1.5 mol% [Ir(OMe)(COD)]2,
hexanes, rt, 10 h
3. 1.2 equiv 3-bromotoluene, 2 mol%
Pd(PPh3)4, 1.5 equiv K3PO4·nH2O,
80 °C, 6 h
S
S
S
Cl
TMS
Cl
Cl
TMS
2. Remove volatiles, 1 h
PinB
21
Me
26
61% yield
Scheme 1. One-pot C–H borylation/Suzuki–Miyaura cross-couplings of substituted thiophenes.

G.A. Chotana et al. / Tetrahedron 64 (2008) 6103–6114
6109
catalyst. The yields for the two-step sequences in Scheme 1 are re-
spectable and may improve with use of more efficient Pd catalysts.
Although aromatic C–H bromination of aryl boronic esters (to
synthesize brominated aryl boronic esters) is unknown, there are
examples where aryl/heteroaryl boronic acids have been bromi-
nated.55–57 Thus, we reasoned that the products of the inefficient
borylations of 2,3,5-trisubstituted thiophenes could conceivably be
obtained by brominating borylation products 15 and 17.
the bromination of 26 confers synthetic utility for the selective
coupling of BPin over TMS in compound 21. Compound 28 can be
further derivatized as indicated by the Suzuki–Miyaura cross-
coupling that yields 29 in Scheme 3. 2-Halo-3,5-diarylthiophenes
are quite rare.59–61 Nevertheless, related compounds substituted
at the 2-position exhibit interesting physical62 and biological63,64
properties.
Attempted bromination of 15 with Br2 in CHCl3 was ineffective
even after 24 h at 100 ꢀC, and the reaction between 15 and NBS
in acetonitrile58 yielded a mixture of products. In addition to the
desired C–H brominated product, GC/MS analysis indicated that
products were resulting from C–BPin scission. In contrast, com-
pound 17 reacted rapidly with Br2 in CHCl3 to give tetrasubstituted
27 in 82% yield (Scheme 2). Excess bromine led to bromination
of the thiophene methyl groups and should hence be avoided. The
enhanced reactivity of 17 relative to 15 arises from replacing
chlorides with more electron donating methyl groups.
3. Conclusions
From this study, Ir-catalyzed borylations offer significant ver-
satility for derivatizing thiophene scaffolds. In general, regiose-
lectivities complement those established for DoM, making the
combination of these two methodologies particularly attractive. In
addition, the results concerning the elaboration of these boronate
esters are encouraging, even though subsequent transformations
are not extensively surveyed in this contribution. It should be
emphasized that even though the procedures reported herein were
carried out using a glovebox, this chemistry is amenable to more
standard laboratory settings. We plan on publishing these details
separately. We are actively exploring the chemistry of these com-
pounds, as well as applying these synthetic approaches to other
heterocyclic systems.
Br2, CHCl ,
rt, 2 min3
S
S
Me
Me
Me
Me
BPin
BPin
Br
17
27
82% yield
4. Experimental
NBS, CH3CN,
rt, 12 h
S
S
4.1. General considerations
Cl
TMS
Cl
BPin
Br
4.1.1. Materials
BPin
21
18a
[Ir(m2-OMe)(COD)]2 and (Ind)Ir(COD) were prepared as per the
literature procedures.65,66 Pinacolborane (HBPin) was generously
supplied by BASF and was distilled before use. 2-Trimethylsilyl-
thiophene,67 3-trimethylsilylthiophene,68 and 3-p-tolylthiophene69
were prepared per the literature procedures. 2-Chloro-5-trime-
thylsilylthiophene was prepared following the literature procedure
for the synthesis of 2-bromo-5-trimethylsilylthiophene.70 All other
commercially available chemicals were purified before use. Solid
substrates were sublimed under vacuum. Liquid substrates were
distilled before use. n-Hexane was refluxed over sodium, distilled,
and degassed. Dimethoxy ethane (DME), ether, and tetrahydrofu-
ran were obtained from dry stills packed with activated alumina
and degassed before use. Silica gel (230–400 Mesh) was purchased
from EMDÔ.
91% yield
S
S
Cl
TMS
Cl
Br
NBS, CH3CN,
rt, 12 h
Me
Me
26
28
91% yield
Scheme 2. Bromination reactions of thiophenyl boronate esters.
Although we have evaluated the scope of C–H brominations of
other substrates, related brominations of trimethylsilyl groups offer
synthetic utility as indicated in Scheme 2. The TMS group in 21 is
selectively cleaved by N-bromosuccinimide (NBS) yielding boro-
nate ester 18a as a single isomer. This route is clearly preferable
to borylation of 5-bromo-2-chlorothiophene, which yielded ap-
preciable quantities of isomer 18b (Table 3, entry 5). We also found
that compound 26 reacts with NBS in similar fashion to afford
4.1.2. General methods
All reactions were monitored by GC-FID (Varian CP-3800; col-
umn type: WCOT fused silica 30 mꢂ0.25 mm ID coating CP-SIL 8
CB), GC-FID method: 70 ꢀC, 2 min; 20 ꢀC/min, 9 min; 250 ꢀC, 20 min.
All reported yields are for isolated materials.1H and 13C NMR spectra
were recorded on a Varian Inova-300 (300.11 and 75.47 MHz, re-
spectively), Varian VXR-500 or Varian Unity-500-Plus spectrometer
(499.74 and 125.67 MHz, respectively) and referenced to residual
solvent signals (7.24 and 77.0 ppm for CDCl3, respectively). 11B NMR
spectra were recorded on a Varian VXR-300 operating at 96.29 MHz
and were referenced to neat BF3$Et2O as the external standard.
All coupling constants are apparent J values measured at the in-
dicated field strengths. Elemental analyses were performed at
Michigan State University using a Perkin–Elmer Series II 2400
CHNS/O Analyzer. GC/MS data were obtained using a Varian Saturn
2200 GC/MS (column type: WCOT fused silica 30 mꢂ0.25 mm ID
coating CP-SIL 8 CB). High-resolution mass spectra were obtained at
the Mass Spectrometry Core of the Research Technology Support
Facility (RTSF) at Michigan State University. Melting points were
measured on a MEL-TEMPÒ capillary melting apparatus and are
uncorrected.
thiophene 28 in excellent yield, indicating that a-TMS cleavage is
selective over benzylic and aromatic bromination. This is significant
because the C(sp2)–Si bonds in TMS substituted arenes and het-
erocycles do not readily undergo cross-coupling reactions. Thus,
1.0 equiv
F3C
CF3
Cl
m-Tol
Cl
S
m-Tol
BPin
S
2.0 mol% Pd(PPh3)4,
.
1.5 equiv K3PO4 nH2O,
Br
CF3
DME, 80 °C, 7 h
F3C
28
29
84% yield
Scheme 3. A Suzuki–Miyaura cross-coupling reaction of thiophene 29.

6110
G.A. Chotana et al. / Tetrahedron 64 (2008) 6103–6114
4.1.3. Regioisomer assignment of borylation products of
3-substituted thiophenes by 1H NMR spectroscopy
was added to the dmpe test tube and the resulting solution was
then mixed with (Ind)Ir(COD). This catalyst solution was added to
a Schlenk flask equipped with a magnetic stirring bar. Substituted
thiophene (1 mmol, 1 equiv) was added to the Schlenk flask. The
Schlenk flask was closed, brought out of the glove box, and was
heated at 150 ꢀC in an oil bath. The reaction was monitored by GC-
FID/MS. After completion of the reaction, the volatile materials
were removed on a rotary evaporator. The crude material was
dissolved in CH2Cl2 and passed through a short plug of silica to
afford the corresponding borylated product.
S
S
H
BPin
BPin
H
R
H
H
R
a
b
meta coupling
0.7-1.2 Hz
ortho coupling
4.5-5.0 Hz
From the 1H NMR coupling constants J, the two regioisomers
obtained by the borylation of 3-substituted thiophenes can be
distinguished unambiguously. In case of the 2,4-borylated product,
the value of the four-bond (meta) coupling constant 4JH–H is usually
around 0.7–1.2 Hz. While in case of the 2,3-borylated product, the
4.2.3.1. 2-(5-Iodothiophen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaboro-
lane (1). The general borylation procedure A was applied to 2-
iodothiophene (111 mL, 210 mg, 1 mmol,1 equiv) and HBPin (218 mL,
192 mg, 1.50 mmol, 1.50 equiv) for 1 h. The product was isolated as
a white solid (310 mg, 92% yield, mp 48–49 ꢀC). 1H NMR (CDCl3,
3
value of the three-bond (ortho) coupling constant JH–H is usually
500 MHz):
d
7.27 (d, J¼3.5 Hz, 1H), 7.25 (d, J¼3.5 Hz, 1H), 1.31 (br s,
around 4.5–5.0 Hz. Since these two ranges of coupling constants are
quite far apart, the two regioisomers can easily be distinguished by
the value of 1H NMR coupling constant.
12H, 4CH3 of BPin); 13C NMR {1H} (CDCl3, 125 MHz):
d 138.5 (CH),
138.3 (CH), 84.3 (2C), 81.5 (C), 24.7 (4CH3 of BPin); 11B NMR (CDCl3,
~
96 MHz):
d
28.7; FTIR (neat) nmax: 2978, 2932, 1522, 1418, 1314,
1267, 1142, 1064, 1018, 853, 663 cmꢁ1; GC/MS (EI) m/z (% relative
intensity): Mþ 336 (100), 321 (13), 250 (6), 236 (14), 209 (12), 167
(43). Anal. Calcd for C10H14BIO2S: C, 35.75; H, 4.20. Found: C, 36.04;
H, 4.24.
4.2. Catalytic borylation of substituted thiophenes
4.2.1. General procedure A (borylation with heteroaromatic
substrate as the limiting reactant)
The [Ir] catalyst was generated by a modified literature pro-
tocol,34 where in a glove box, two separate test tubes were charged
with [Ir(m2-OMe)(COD)]2 (10 mg, 0.015 mmol, 3 mol % Ir) and dtbpy
(8 mg, 0.03 mmol, 3 mol %). Excess HBPin (1.5–2 equiv) was added
to the [Ir(m2-OMe)(COD)]2 test tube. n-Hexane (1 mL) was added
to the dtbpy containing test tube in order to dissolve the dtbpy. The
dtbpy solution was then mixed with the [Ir(m2-OMe)(COD)]2 and
HBPin mixture. After mixing for 1 min, the resulting solution was
transferred to the 20 mL scintillation vial equipped with a magnetic
stirring bar. Additional n-hexane (2ꢂ1 mL) was used towash the test
tubes and the washings were transferred to the scintillation vial.
Substituted thiophene (1 mmol, 1 equiv) was added to the scintil-
lation vial. The reaction was stirred at room temperature and was
monitored by GC-FID/MS. After completion of the reaction, the
volatile materials were removed on a rotary evaporator. The crude
material was dissolved in CH2Cl2 and passed through a short plug of
silica to afford the corresponding borylated product.
4.2.3.2. 2-(4-Bromo-5-chlorothiophen-2-yl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane (2). The general borylation procedure A was applied
to 2-chloro-3-bromothiophene (110
and HBPin (192 L, 218 mg, 1.50 mmol, 1.50 equiv) for 10 min. The
product was isolated as a white solid (253 mg, 78% yield, mp 60–
61 ꢀC). 1H NMR (CDCl3, 500 MHz):
7.38 (s, 1H), 1.30 (br s, 12H,
4CH3 of BPin); 13C NMR {1H} (CDCl3, 125 MHz):
138.9 (CH), 133.2
(C), 112.0 (C), 84.6 (2C), 24.7 (4CH3 of BPin); 11B NMR (CDCl3,
mL, 197 mg, 1 mmol, 1 equiv)
m
d
d
~
d 28.5; FTIR (neat) nmax: 2980, 2932, 1523, 1425, 1340,
96 MHz):
1267, 1142, 1041, 852, 661 cmꢁ1; GC/MS (EI) m/z (% relative in-
tensity): Mþ 324 (100), 322 (73), 309 (45), 281 (26), 264 (29), 243
(38). Anal. Calcd for C10H13BBrClO2S: C, 37.13; H, 4.05. Found: C,
37.20; H, 4.16.
Note. Attempted borylation of 2,5-dichloro-3-bromothiophene
with borylation procedure C also gave the same product where C–Cl
bond was borylated and the single monoborylated product was
isolated in 73% yield (see attempted borylation of tri-substituted
thiophene). Only one of the two C–Cl bonds is activated with che-
moselectivity greater than 99%. The NMR data matched with the
borylated product of 2-chloro-3-bromothiophene as described
above.
4.2.2. General procedure B (borylation with HBPin as the limiting
reactant)
In a glove box, two separate test tubes were charged with [Ir(m2
-
OMe)(COD)]2 (10 mg, 0.015 mmol, 3 mol % Ir) and dtbpy (8 mg,
0.03 mmol, 3 mol %). HBPin (1 mmol, 1 equiv) was added to the
[Ir(m2-OMe)(COD)]2 test tube. n-Hexane (1 mL) was added to the
dtbpy containing test tube in order to dissolve the dtbpy. The dtbpy
solution was then mixed with the [Ir(m2-OMe)(COD)]2 and HBPin
mixture. After mixing for one minute, the resulting solution was
transferred to the 20 mL scintillation vial equipped with a magnetic
stirring bar. Additional n-hexane (2ꢂ1 mL) was used to wash the
test tubes and the washings were transferred to the scintillation
vial. Excess 3-substituted thiophene (2–4 equiv) was added to the
scintillation vial. The reaction was stirred at room temperature and
was monitored by GC-FID/MS. After completion of the reaction, the
volatile materials were removed on a rotary evaporator. The crude
material was dissolved in CH2Cl2 and passed through a short plug of
silica to afford the corresponding borylated product/products.
4.2.3.3. Methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thio-
phene-2-carboxylate (3). The general borylation procedure A was
applied to methyl-2-thiophenecarboxylate (116
1 equiv) and HBPin (192 L, 218 mg,1.50 mmol,1.50 equiv) for 0.5 h.
The product was isolated as a white solid (252 mg, 94% yield, mp
114–117 ꢀC). 1H NMR (CDCl3, 500 MHz):
7.79 (d, J¼3.7 Hz,1H), 7.53
(d, J¼3.7 Hz, 1H), 3.87 (s, 3H, CO2CH3), 1.33 (br s, 12H, 4CH3 of BPin);
13C NMR {1H} (CDCl3,125 MHz):
162.6 (C]O),139.4 (C),136.9 (CH),
133.9 (CH), 84.6 (2C), 52.2 (CO2CH3), 24.7 (4CH3 of BPin); 11B NMR
mL,142 mg,1 mmol,
m
d
d
~
d 29.1; FTIR (neat) nmax: 2970, 1719, 1527, 1354,
(CDCl3, 96 MHz):
1248,1145,1097, 852, 832, 752, 665 cmꢁ1; GC/MS (EI) m/z (% relative
intensity): Mþ 268 (71), 253 (91), 237 (56),182 (100). Anal. Calcd for
C12H17BO4S: C, 53.75; H, 6.39. Found: C, 53.44; H, 6.44.
4.2.3.4. Trimethyl(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thio-
phen-2-yl)silane (4). The general borylation procedure was
applied to 2-trimethylsilylthiophene (312 mg, 2 mmol, 1 equiv)
and HBPin (435 L, 384 mg, 3.00 mmol, 1.50 equiv) for 30 min. The
product was isolated as a white solid (523 mg, 93% yield, mp
4.2.3. General procedure C
In a glove box, (Ind)Ir(COD) (8.3 mg, 0.02 mmol, 2.00 mol % Ir)
and dmpe (3 mg, 0.02 mmol, 2.00 mol %) were weighed in two
A
m
separate test tubes. HBPin (218 mL, 190 mg, 1.50 mmol, 1.50 equiv)

G.A. Chotana et al. / Tetrahedron 64 (2008) 6103–6114
6111
61–62 ꢀC). 1H NMR (CDCl3, 500 MHz):
(d, J¼3.3 Hz, 1H), 1.32 (br s, 12H, 4CH3 of BPin), 0.30 (s, 9H, 3CH3 of
d
7.67 (d, J¼3.3 Hz, 1H), 7.31
300 MHz):
d
(9a) 7.49 (d, J¼1.2 Hz,1H), 7.46 (d, J¼1.2 Hz,1H),1.32 (br
s, 12H, 4CH3 of BPin), (9b) 7.48 (d, J¼5.0 Hz, 1H), 7.08 (d, J¼5.0 Hz,
TMS); 13C NMR {1H} (CDCl3, 75 MHz):
d
148.4 (C), 137.8 (CH), 135.0
1H), 1.34 (br s, 12H, 4CH3 of BPin); 13C NMR {1H} (CDCl3, 125 MHz):
(CH), 84.0 (2C), 24.8 (4CH3 of BPin), ꢁ0.1 (3CH3 of TMS); 11B NMR
d
(9a) 139.3 (CH),129.5 (CH),111.2 (C), 84.4 (2C), 24.7 (4CH3 of BPin);
(CDCl3, 96 MHz):
d
29.6; FTIR (neat) nmax: 3054, 2980, 2957, 1514,
11B NMR (CDCl3, 96 MHz):
d
29.0; FTIR (neat) nmax: 2980, 1518, 1415,
~
~
1435, 1346, 1331, 1259, 1250, 1142, 1072, 981, 841, 821, 758,
699 cmꢁ1; GC/MS (EI) m/z (% relative intensity): Mþ 282 (14), 267
(100), 239 (31), 167 (8). Anal. Calcd for C13H23BO2SSi: C, 55.31; H,
8.21. Found: C, 54.85; H, 8.74; HRMS (EI): m/z 282.1285 [(Mþ); calcd
for C13H23BO2SSi: 282.1281].
1350, 1143, 1026, 852, 665 cmꢁ1; GC/MS (EI) m/z (% relative in-
tensity): (9a) Mþ 289 (51), 290 (98), 288 (100), 275 (61), 273 (55),
247 (18), 245 (21), 230 (19), 204 (41), (9b) Mþ 289 (13), 290 (25), 288
(27), 275 (10), 273 (9), 209 (100), 189 (11), 167 (67). Anal. Calcd for
C10H14BBrO2S: C, 41.56; H, 4.88. Found: C, 41.74; H, 4.88.
4.2.3.5. 1-(5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-
2-yl)ethanone (5). The general borylation procedure A was applied
4.2.3.9. Borylation of 3-methylthiophene (10a and 10b). The general
borylation procedure B was applied to 3-methylthiophene (194 L,
196 mg, 2.00 mmol, 2.00 equiv) and HBPin (145 L,128 mg,1 mmol,
1 equiv) for 1 h. The ratio of two borylated products at the end
of reaction was 8.9:1 by GC-FID. The borylated product mixture
was isolated as colorless oil (150 mg, 67% yield). 1H NMR (CDCl3,
m
to 2-acetylthiophene (108
(175 L, 154 mg, 1.20 mmol, 1.20 equiv) for 0.5 h. The product was
isolated as a white solid (213 mg, 85% yield, mp 64–66 ꢀC). 1H NMR
(CDCl3, 500 MHz):
7.69 (d, J¼3.8 Hz, 1H), 7.54 (d, J¼3.8 Hz, 1H),
2.53 (s, 3H, COCH3), 1.31 (br s, 12H, 4CH3 of BPin); 13C NMR {1H}
m
L, 126 mg, 1 mmol, 1 equiv) and HBPin
m
m
d
300 MHz):
d
(10a) 7.42 (d, J¼0.7 Hz, 1H), 7.17 (t, J¼1.1 Hz, 1H), 2.27
(CDCl3, 125 MHz):
d
190.6 (C]O), 149.4 (C), 137.2 (CH), 132.6 (CH),
(d, J¼0.5 Hz, 1H), 1.32 (br s, 12H, 4CH3 of BPin), (10b) 7.46 (d,
J¼4.6 Hz,1H), 6.95 (d, J¼4.6 Hz,1H), 2.47 (s,1H),1.30 (br s,12H, 4CH3
84.6 (2C), 27.4 (COCH3), 24.7 (4CH3 of BPin); 11B NMR (CDCl3,
96 MHz):
d
29.2; FTIR (neat) nmax: 2980, 2934, 1669, 1520, 1348,
of BPin); 13C NMR {1H} (CDCl3, 125 MHz):
d (10a) 139.4 (CH), 138.9
~
1288, 1267, 1142, 1020, 852, 667 cmꢁ1; GC/MS (EI) m/z (% relative
intensity): Mþ 252 (77), 237 (100), 209 (15), 195 (8), 179 (5), 166
(33), 153 (14), 137 (12), 109 (6). Anal. Calcd for C12H17BO3S: C, 57.16;
H, 6.80. Found: C, 56.88; H, 7.06.
(C), 128.0 (CH), 83.9 (2C), 24.7 (4CH3 of BPin), 14.9 (CH3); 11B NMR
~
(CDCl3, 96 MHz):
d
29.5; FTIR (neat) nmax: 2978, 2930, 1550, 1441,
1371, 1327, 1302, 1271, 1143, 1028, 962, 854, 665 cmꢁ1; GC/MS (EI)
m/z (% relative intensity): (10a) Mþ 224 (100), 209 (27),181 (18),138
(44), (10b) Mþ 224 (100), 209 (68), 167 (64), 138 (54), 124 (61). Anal.
Calcd for C11H17BO2S: C, 58.95; H, 7.65. Found: C, 58.65; H, 8.09.
4.2.3.6. Borylation of 3-cyanothiophene (7a and 7b). The general
borylation procedure B was applied to 3-cyanothiophene (182
mL,
218 mg, 2.00 mmol, 2.00 equiv) and HBPin (145 L,128 mg,1 mmol,
m
4.2.3.10. 1-(5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-
3-yl)ethanone (11a). The general borylation procedure A was ap-
plied to 3-acetylthiophene (126 mg, 1 mmol, 1 equiv) and HBPin
1 equiv) for 1 h. The ratio of two borylated products at the end of
reaction was 1:1.13 by GC-FID. The borylated product mixture was
isolated as a white solid (126 mg, 54% yield). 1H NMR (CDCl3,
(174
isolated as colorless oil (206 mg, 82% yield). 1H NMR (CDCl3,
500 MHz):
8.26 (d, J¼1.1 Hz, 1H), 8.00 (d, J¼1.1 Hz, 1H), 2.50 (s, 3H,
COCH3), 1.32 (br s, 12H, 4CH3 of BPin); 13C NMR {1H} (CDCl3,
mL, 154 mg, 1.20 mmol, 1.20 equiv) for 15 min. The product was
300 MHz):
d
(7a) 8.13 (d, J¼1.2 Hz,1H), 7.75 (d, J¼1.2 Hz,1H),1.33 (br
s, 12H, 4CH3 of BPin), (7b) 7.62 (d, J¼4.9 Hz, 1H), 7.38 (d, J¼4.9 Hz,
d
1H), 1.36 (br s, 12H, CH3 of BPin); 13C NMR {1H} (CDCl3, 125 MHz):
d
(7a) 140.8 (CH),138.1 (CH),114.7 (C),111.9 (C), 85.1 (2C), 24.7 (4CH3
125 MHz): d 192.0 (C]O),143.8 (C),138.1 (CH), 137.0 (CH), 84.5 (2C),
of BPin), (7b) 132.7 (CH), 131.3 (CH), 118.2 (C), 115.1 (C), 84.8 (2C),
27.8 (COCH3), 24.8 (4CH3 of BPin); 11B NMR (CDCl3, 96 MHz):
d 29.2;
24.7 (4CH3 of BPin); 11B NMR (CDCl3, 96 MHz):
d
28.6; FTIR (neat)
FTIR (neat) nmax: 3098, 2980, 2934, 1680, 1530, 1448, 1381, 1373,
1340, 1305, 1215, 1143, 1024, 850, 667 cmꢁ1; GC/MS (EI) m/z (% rel-
ative intensity): Mþ 252 (21), 237 (55), 209 (100), 195 (9), 153 (22),
137 (19). Anal. Calcd for C12H17BO3S: C, 57.16; H, 6.80. Found: C,
56.77; H, 7.19.
~
nmax: 2980, 2231, 1429, 1319, 1142, 1039, 850, 628 cmꢁ1; GC/MS (EI)
m/z (% relative intensity): (7a) Mþ 235 (7), 220 (100), 192 (9), 149
(37), 136 (15), (7b) Mþ1 236 (100), 220 (78), 194 (51), 178 (33), 149
(36),136 (31). Anal. Calcd for C11H14BNO2S: C, 56.19; H, 6.00; N, 5.96.
Found: C, 55.74; H, 5.99; N, 6.00.
~
4.2.3.11. Methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thio-
4.2.3.7. Borylation of 3-chlorothiophene (8a and 8b). The general
phene-3-carboxylate (12a). The general borylation procedure A was
borylation procedure B was applied to 3-chlorothiophene (186
m
L,
applied to methyl 3-thiophenecarboxylate (121
1 equiv) and HBPin (174 L, 154 mg, 1.20 mmol, 1.20 equiv) for 1 h.
The product was isolated as a white solid (256 mg, 95% yield, mp
84–85 ꢀC). 1H NMR (CDCl3, 500 MHz):
8.31 (d, J¼1.0 Hz, 1H), 8.01
(d, J¼1.0 Hz, 1H), 3.84 (s, 3H, CO2CH3), 1.33 (br s, 12H, CH3 of BPin);
mL,142 mg,1 mmol,
237 mg, 2.00 mmol, 2.00 equiv) and HBPin (145 L,128 mg,1 mmol,
m
m
1 equiv) for 1 h. The ratio of two borylated products at the end of
reaction was 3.5:1 by GC-FID. The borylated product mixture was
isolated as a white solid (160 mg, 66% yield). 1H NMR (CDCl3,
d
300 MHz):
d
(8a) 7.43 (d, J¼1.0 Hz, 1H), 7.35 (d, J¼1.0 Hz, 1H), 1.32
13C NMR {1H} (CDCl3, 75 MHz):
d 163.1 (C]O), 138.8 (CH), 137.9
(br s,12H, 4CH3 of BPin), (8b) 7.51 (d, J¼5.0 Hz,1H), 7.01 (d, J¼5.0 Hz,
(CH), 134.9 (C), 84.4 (2C), 51.6 (CO2CH3), 24.7 (4CH3 of BPin); 11B
1H), 1.34 (br s, 12H, 4CH3 of BPin); 13C NMR {1H} (CDCl3, 125 MHz):
NMR (CDCl3, 96 MHz):
d
29.4; FTIR (neat) nmax: 3107, 2980, 2951,
~
d
(8a) 136.9 (CH),131.8 (C),126.7 (CH), 84.4 (2C), 24.7 (4CH3 of BPin);
1722, 1537, 1458, 1431, 1388, 1373, 1336, 1307, 1224, 1143, 1024, 987,
852, 752, 667 cmꢁ1; GC/MS (EI) m/z (% relative intensity): Mþ 268
(65), 253 (100), 237 (22), 225 (39), 211 (29), 193 (12), 182 (45), 169
(41), 137 (27). Anal. Calcd for C12H17BO4S: C, 53.75; H, 6.39. Found:
C, 53.54; H, 6.66.
11B NMR (CDCl3, 96 MHz):
d
29.0; FTIR (neat) nmax: 3107, 2980, 2932,
~
1522, 1421, 1356, 1336, 1142, 1026, 854, 665 cmꢁ1; GC/MS (EI) m/z
(% relative intensity): Mþ 244 (100), 246 (38), 231 (15), 229 (38), 209
(24), 158 (27). Anal. Calcd for C10H14BClO2S: C, 49.11; H, 5.77. Found:
C, 49.33; H, 5.81.
4.2.3.12. Trimethyl(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thio-
phen-3-yl)silane (13a). The general borylation procedure A was
applied to 3-trimethylsilylthiophene (156 mg, 1 mmol, 1 equiv) and
4.2.3.8. Borylation of 3-bromothiophene (9a and 9b). The general
borylation procedure B was applied to 3-bromothiophene (190
mL,
326 mg, 2.00 mmol, 2.00 equiv) and HBPin (145 L,128 mg,1 mmol,
m
HBPin (174
product was isolated as a white solid (222 mg, 79% yield, mp 87–
89 ꢀC). 1H NMR (CDCl3, 300 MHz):
7.71 (d, J¼1.0 Hz, 1H), 7.69 (d,
J¼1.0 Hz, 1H), 1.33 (br s, 12H, 4CH3 of BPin), 0.24 (s, 9H, 3CH3 of
mL, 154 mg, 1.20 mmol, 1.20 equiv) for 30 min. The
1 equiv) for 1 h. The ratio of two borylated products at the end of
reaction was 8.9:1 by GC-FID. The borylated product mixture was
isolated as a white solid (209 mg, 72% yield). 1H NMR (CDCl3,
d

6112
G.A. Chotana et al. / Tetrahedron 64 (2008) 6103–6114
TMS); 13C NMR {1H} (CDCl3, 75 MHz):
d
142.4 (C), 141.9 (CH), 138.4
1304, 1265, 1145, 868, 700 cmꢁ1; GC/MS (EI) m/z (% relative in-
(CH), 83.8 (2C), 24.6 (4CH3 of BPin), ꢁ0.6 (3CH3 of TMS); 11B NMR
tensity): Mþ 238 (100), 223 (8), 181 (37). Anal. Calcd for
~
(CDCl3, 96 MHz):
d
29.5; FTIR (neat) nmax: 2980, 2955, 1510, 1410, 1325,
C12H19BO2S: C, 60.52; H, 8.04. Found: C, 60.62; H, 8.18.
1263, 1250, 1143, 1105, 1028, 902, 852, 839, 754, 667 cmꢁ1; GC/MS (EI)
m/z (% relative intensity): Mþ 282 (7), 267 (100), 239 (2), 167 (7). Anal.
Calcd for C13H23BO2SSi: C, 55.31; H, 8.21. Found: C, 54.68; H, 8.47;
HRMS (EI): m/z 282.1283 [(Mþ); calcd for C13H23BO2SSi: 282.1281].
4.2.3.17. Borylation of 2-chloro-5-bromothiophene (18a and 18b). The
general borylation procedure A was applied to 2-chloro-5-bromo-
thiophene (110 mL, 197 mg, 1 mmol, 1 equiv) and HBPin (290 mL,
256 mg, 2.00 mmol, 2.00 equiv) with 3 mol % [Ir] catalyst loading for
8 h. Additionally 3 mol % [Ir] and 0.5 equiv of HBPin were added and
the reaction was run for 20 more hours at room temperature. The
ratio of the two borylated products at the end of reaction was 2:1 by
GC-FID. The borylated product mixture was isolated as a white solid
4.2.3.13. Borylation of 3-p-tolylthiophene (14a and 14b). The gen-
eral borylation procedure B was applied to 3-p-tolylthiophene
(192 mg,1.1 mmol,1.1 equiv) and HBPin (145 mL,128 mg,1.00 mmol,
1.00 equiv) for 1 h. The ratio of two borylated isomers at the end of
reaction was 32:1 by GC-FID. The product was isolated as colorless
(281 mg, 87% yield). 1H NMR (CDCl3, 500 MHz):
1.30 (br s, 12H, 4CH3 of BPin), (18b) 6.94 (s, 1H), 1.30 (br s, 12H, 4CH3
of BPin); 13C NMR {1H} (CDCl3, 125 MHz):
(18a) 139.6 (C), 134.9
d (18a) 7.10 (s, 1H),
oil (223 mg, 74% yield). 1H NMR (CDCl3, 300 MHz):
d (14a) 7.91 (d,
J¼1.2 Hz,1H), 7.68 (d, J¼1.2 Hz,1H), 7.48–7.52 (m, 2H), 7.17–7.20 (m,
d
2H), 2.35 (s, 3H, CH3), 1.36 (br s, 12H, 4CH3 of BPin); 13C NMR {1H}
(CH), 108.3 (C), 84.0 (2C), 24.8 (4CH3 of BPin), (18b) 132.0 (CH), 128.9
(CDCl3, 75 MHz):
d
(14a) 143.8 (C), 136.8 (C), 136.2 (CH), 132.9 (C),
(C), 119.5 (C), 84.1 (2C), 24.8 (4CH3 of BPin); 11B NMR (CDCl3,
~
96 MHz): d 28.5; FTIR (neat) nmax: 2980, 1527, 1427, 1371, 1253, 1140,
129.5 (CH),126.9 (CH),126.4 (CH), 84.2 (2C), 24.8 (4CH3 of BPin), 21.1
(CH3); 11B NMR (CDCl3, 96 MHz):
d
29.4; FTIR (neat) nmax: 3090,
1028, 962, 848, 693 cmꢁ1; GC/MS (EI) m/z (% relative intensity): (18a)
Mþ 324 (100), 322 (78), 289 (67), 287 (64), 208 (40), 166 (34), (18b)
Mþ 324 (89), 322 (69), 309 (23), 245 (41), 243 (99), 203 (43), 201
(100), 166 (50). Anal. Calcd for C10H13BBrClO2S: C, 37.13; H, 4.05.
Found: C, 37.25; H, 4.05.
~
2978, 2928, 1547, 1441, 1379, 1371, 1329, 1311, 1269, 1143, 1026, 850,
819, 771, 667 cmꢁ1; GC/MS (EI) m/z (% relative intensity): Mþ 300
(100), 285 (12), 214 (12). Anal. Calcd for C17H21BO2S: C, 68.01; H,
7.05. Found: C, 68.54; H, 6.97; HRMS (EI): m/z 300.1360 [(Mþ); calcd
for C17H21BO2S: 300.1355].
Note. The data for the pure 18a is described in Section 4.2.6.
4.2.3.14. 2-(2,5-Dichlorothiophen-3-yl)-4,4,5,5-tetramethyl-1,3,2-di-
oxaborolane (15). The general borylation procedure A was applied
4.2.3.18. Borylation of 2-chloro-5-methylthiophene (19a and
19b). The general borylation procedure A was applied to 2-chloro-
to 2,5-di-chlorothiophene (107
HBPin (218 L, 192 mg, 1.50 mmol, 1.50 equiv) for 20 h. The product
was isolated as a white solid (240 mg, 86% yield, mp 35–36 ꢀC). 1H
NMR (CDCl3, 500 MHz): 6.94 (s, 1H), 1.30 (br s, 12H, 4CH3 of BPin);
m
L, 153 mg, 1 mmol, 1 equiv) and
5-methylthiophene (133 mg, 1 mmol, 1 equiv) and HBPin (218 mL,
m
192 mg, 1.50 mmol, 1.50 equiv) for 18 h. The ratio of two borylated
products at the end of reaction was 2.3:1 by GC-FID. The borylated
product mixture was isolated as a colorless semi solid (221 mg, 86%
d
13C NMR {1H} (CDCl3, 125 MHz):
d
137.1 (C), 131.1 (CH), 126.2 (C),
yield). 1H NMR (CDCl3, 300 MHz):
d
(19a) 6.77 (q, J¼1.2 Hz,1H), 2.35
84.0 (2C), 24.8 (4CH3 of BPin); 11B NMR (CDCl3, 96 MHz):
d
28.5;
(d, J¼1.2 Hz, 3H, CH3), 1.31 (br s, 12H, 4CH3 of BPin), (19b) 6.95 (s,
FTIR (neat) nmax: 2980, 1535, 1437, 1371, 1313, 1263, 1142, 1032, 966,
889, 848, 692 cmꢁ1; GC/MS (EI) m/z (% relative intensity): Mþ 278
(100), 280 (68), 263 (32), 265 (22), 243 Mꢁ35 (79), 245 (30), 201
(51). Anal. Calcd for C10H13BCl2O2S: C, 43.05; H, 4.70. Found: C,
43.26; H, 4.74.
1H), 2.60 (s, 3H, CH3), 1.28 (br s, 12H, 4CH3 of BPin); 13C NMR {1H}
~
(CDCl3, 125 MHz):
d (19a) 137.4 (C), 137.0 (C), 130.1 (CH), 83.6 (2C),
24.8 (4CH3 of BPin), 14.9 (CH3), (19b) 151.1 (C), 131.6 (CH), 125.4 (C),
83.4 (2C), 24.8 (4CH3 of BPin), 15.7 (CH3); 11B NMR (CDCl3, 96 MHz):
~
29.1; FTIR (neat) nmax: 2980, 2926, 1556, 1475, 1390, 1371, 1309,
d
1257, 1143, 1026, 966, 898, 850, 696 cmꢁ1; GC/MS (EI) m/z (% rela-
tive intensity): (19a) 258 Mþ (100), 243 (17), 223 (51), 181 (36), 153
(37), (19b) 258 Mþ (100), 243 (18), 223 (7), 201 (93), 172 (23). Anal.
Calcd for C11H16BClO2S: C, 51.10; H, 6.24. Found: C, 51.66; H, 6.58;
HRMS (EI): m/z 258.0653 [(Mþ); calcd for C11H16BClO2S: 258.06526].
4.2.3.15. 2-(2,5-Dibromothiophen-3-yl)-4,4,5,5-tetramethyl-1,3,2-di-
oxaborolane (16). The general borylation procedure A was applied
to 2,5-di-bromothiophene (113
mL, 142 mg, 1 mmol, 1 equiv) and
HBPin (218 L, 192 mg, 1.50 mmol, 1.50 equiv) with 6 mol % [Ir]
m
catalyst loading for 36 h. Additional 3 mol % [Ir] catalyst and 1 equiv
of HBPin was added at this stage and the reaction was run for 12
more hours at room temperature. The ratio of the starting material
to product after 48 h was 11:89. The product was isolated as a white
solid (206 mg, 56% yield, mp 72–73 ꢀC). 1H NMR (CDCl3, 500 MHz):
4.2.3.19. Borylation of 2-chloro-5-iodothiophene (20a and 20b). The
general borylation procedure A was applied to 2-chloro-5-iodo-
thiophene (122 mg, 0.5 mmol, 1 equiv) and HBPin (109 mL, 96 mg,
0.75 mmol, 1.50 equiv) for 20 h. The ratio of two borylated products
at the end of reaction was 5.7:1 by GC-FID. The borylated product
mixture was isolated as a white solid (165 mg, 89% yield). 1H NMR
d
7.09 (s, 1H), 1.31 (br s, 12H, 4CH3 of BPin); 13C NMR {1H} (CDCl3,
125 MHz):
d
135.8 (CH), 121.9 (C), 110.9 (C), 84.0 (2C), 24.8 (4CH3 of
BPin); 11B NMR (CDCl3, 96 MHz):
d
28.5; FTIR (neat) nmax: 2978,
(CDCl3, 300 MHz):
(20b) 6.87 (s, 1H), 1.31 (br s, 12H, 4CH3 of BPin); 13C NMR {1H}
(CDCl3, 125 MHz): (20a) 143.4 (C), 142.3 (CH), 84.0 (2C), 69.3 (C),
d (20a) 7.31 (s, 1H), 1.30 (br s, 12H, 4CH3 of BPin),
~
1525, 1365, 1307, 1248, 1143, 991, 962, 883, 848, 690 cmꢁ1; GC/MS
(EI) m/z (% relative intensity): Mþ 368 (100), 370 (51), 366 (52), 353
(18), 287 (56), 289 (59), 268 (28), 208 (77), 166 (69). Anal. Calcd for
d
24.8 (4CH3 of BPin), (20b) 132.8 (CH), 84.2 (2C), 81.1 (C), 24.8 (4CH3
of BPin); 11B NMR (CDCl3, 96 MHz):
d
28.3; FTIR (neat) nmax: 2978,
~
C
10H13BBr2O2S: C, 32.65; H, 3.56. Found: C, 32.92; H, 3.57.
1523, 1414, 1371, 1248, 1140, 1024, 966, 881, 848, 690 cmꢁ1; GC/MS
(EI) m/z (% relative intensity): (20a) Mþ 370 (100), 355 (13), 335
(29), 270 (25), 208 (15), 166 (11), (20b) Mþ 370 (100), 355 (10), 270
(24), 243 (13), 201 (32), 166 (21). Anal. Calcd for C10H13BIClO2S: C,
32.42; H, 3.54. Found: C, 32.58; H, 3.38.
4.2.3.16. 2-(2,5-Dimethylthiophen-3-yl)-4,4,5,5-tetramethyl-1,3,2-di-
oxaborolane (17). The general borylation procedure C was applied
to 2,5-di-methylthiophene (228
neat HBPin (435 L, 384 mg, 3.00 mmol, 1.50 equiv) for 16 h at
150 ꢀC. The product was isolated as a colorless semi solid (460 mg,
97% yield). 1H NMR (CDCl3, 300 MHz):
6.81 (d, J¼1.2 Hz, 1H), 2.59
(s, 3H, CH3), 2.38 (d, J¼0.4 Hz, 3H, CH3), 1.30 (br s, 12H, 4CH3 of
BPin); 13C NMR {1H} (CDCl3, 125 MHz):
150.8 (C), 136.1 (C), 130.7
(CH), 83.0 (2C), 24.8 (4CH3 of BPin), 15.6 (CH3), 14.7 (CH3); 11B NMR
mL, 224 mg, 2 mmol, 1 equiv) and
m
d
4.2.3.20. (5-Chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thio-
phen-2-yl)trimethylsilane (21). The general borylation procedure A
was applied to 2-chloro-5-trimethylsilylthiophene (382 mg, 2 mmol,
d
1 equiv) and HBPin (435
mL, 384 mg, 3.00 mmol, 1.50 equiv) for 6 h.
~
d 29.3; FTIR (neat) nmax: 2978, 2924, 1493, 1394,
(CDCl3, 96 MHz):
The single borylated product was isolated as a solid (589 mg, 93%

G.A. Chotana et al. / Tetrahedron 64 (2008) 6103–6114
6113
yield, mp 68–69 ꢀC). 1H NMR (CDCl3, 500 MHz):
s, 12H, 4CH3 of BPin), 0.26 (s, 9H, 3CH3 of TMS); 13C NMR {1H} (CDCl3,
125 MHz): d 144.7 (C), 139.42 (CH), 139.37 (C), 83.7 (2C), 24.8 (4CH3 of
d
7.26 (s, 1H), 1.32 (br
brine (10 mL), followed by water (10 mL), dried over MgSO4 before
being concentrated under reduced pressure on a rotary evaporator.
Column chromatography (hexanes, Rf 0.5) furnished the product as
a colorless liquid (369 mg, 66% yield). 1H NMR (CDCl3, 300 MHz):
BPin), ꢁ0.24 (3CH3 of TMS); 11B NMR (CDCl3, 96 MHz):
d 29.1; FTIR
~
(neat) nmax: 2980, 1525, 1415, 1363, 1307, 1253, 1238, 1143, 993, 841,
758, 696 cmꢁ1; GC/MS (EI) m/z (% relative intensity) Mþ 316 (33), 301
(100), 281 (6), 201 (15). Anal. Calcd for C13H22BClO2SSi: C, 49.30; H,
7.00. Found: C, 49.16; H, 7.16.
d
7.27–7.37 (m, 3H), 7.13–7.16 (m, 1H), 7.12 (s, 1H), 2.39 (s, 3H, CH3),
0.31 (s, 9H, 3CH3 of TMS); 13C NMR {1H} (CDCl3, 75 MHz):
d
139.6
(C), 138.2 (C), 138.0 (C), 135.3 (CH), 134.3 (C), 129.3 (C), 129.1 (CH),
128.29 (CH), 128.27 (CH), 125.6 (CH), 21.5 (CH3), ꢁ0.3 (3CH3 of
~
TMS); FTIR (neat) nmax: 3040, 2957, 2922, 1606, 1408, 1252, 993,
4.2.4. Attempted borylation of trisubstituted thiophene
839, 781, 756, 700, 630 cmꢁ1; GC/MS (EI) m/z (% relative intensity):
Mþ 280 (49), 282 (19), 266 (100), 267 (48). Anal. Calcd for
4.2.4.1. 2-(4-Bromo-5-chlorothiophen-2-yl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane (2). The general borylation procedure C was applied
to 2,5-di-chloro-3-bromothiophene (232 mg, 1 mmol, 1 equiv) and
neat HBPin (218 m
L, 192 mg, 1.50 mmol, 1.50 equiv) for 2 h at 150 ꢀC.
C14H17ClSSi: C, 59.86; H, 6.10. Found: C, 59.56; H, 6.21.
4.2.6. Bromination
The product was isolated as a colorless solid (233 mg, 73% yield). The
spectroscopic data of this product matched with the data of bory-
lated product obtained from 2-chloro-3-bromo-thiophene as de-
scribed earlier.
4.2.6.1. 2-(4-Bromo-2,5-dimethylthiophen-3-yl)-4,4,5,5-tetramethyl-
1,3,2-dioxaborolane (27). 2-(2,5-Dimethylthiophen-3-yl)-4,4,5,5-
tetramethyl-1,3,2-dioxaborolane (17) (238 mg, 1 mmol, 1 equiv)
was dissolved in 2 mL of CHCl3 in a 20 mL scintillation vial equip-
ped with a magnetic stirring bar. Bromine (160 mg,1 mmol,1 equiv,
dissolved in 2 mL of CHCl3) was added dropwise during two min-
utes. The reaction was then quenched with water. The product was
extracted with CH2Cl2 (3ꢂ20 mL) and dried over MgSO4. Column
chromatography (hexane/CH2Cl2 1:1, Rf 0.7) furnished the desired
product as a white solid (260 mg, 82%, mp 55–56 ꢀC). 1H NMR
4.2.5. One-pot borylation/Suzuki coupling of substituted thiophenes
4.2.5.1. 2-Methyl-5-(3-(trifluoromethyl)phenyl)thiophene (25). The
general borylation procedure A was applied to 2-methylthiophene
(484 mL, 491 mg, 5 mmol, 1 equiv) and HBPin (870 mL, 768 mg,
6.00 mmol, 1.20 equiv) in a Schlenk flask for 0.5 h. The reaction
mixture was pumped down under high vacuum for 0.5 h to remove
the volatile materials. Pd(PPh3)4 (116 mg, 0.10 mmol, 2 mol %), 3-
(CDCl3, 300 MHz):
d
2.54 (s, 3H, CH3), 2.29 (s, 3H, CH3), 1.32 (br s,
147.9 (C),
12H, 4CH3 of BPin); 13C NMR {1H} (CDCl3, 125 MHz):
d
131.2 (C), 113.1 (C), 83.5 (2C), 24.8 (4CH3 of BPin), 16.2 (CH3), 14.5
(CH3); 11B NMR (CDCl3, 96 MHz):
d
29.5; FTIR (neat) nmax: 2978,
~
bromo-benzotrifluoride (837
mL, 1350 mg, 6.00 mmol, 1.2 equiv),
and DME (6 mL) were added to the Schlenk flask inside the glove
box. The Schlenk flask was then brought out of the glove box and
attached to a Schlenk line. K3PO4$nH2O (1592 mg, 1.50 equiv) was
added under N2 counter flow to the Schlenk flask. The flask was
stoppered and the mixture was heated at 80 ꢀC for 8 h. The flask
was cooled down to room temperature and 20 mL of water were
added to the reaction mixture. The reaction mixture was extracted
with ether (3ꢂ20 mL). The combined ether extractions were
washed with brine (20 mL), followed by water (10 mL), dried over
MgSO4 before being concentrated under reduced pressure on a ro-
tary evaporator. Column chromatography (hexanes, Rf 0.5) fur-
nished the product as white semi solid (1026 mg, 85% yield). 1H
2922, 1537, 1377, 1315, 1234, 1143, 852 cmꢁ1; GC/MS (EI) m/z
(% relative intensity): Mþ 317 (46), 318 (84), 316 (81), 303 (11), 301
(10), 261 (100), 259 (99), 237 (27), 195 (38), 180 (41). Anal. Calcd for
C12H18BBrO2S: C, 45.46; H, 5.72. Found: C, 45.54; H, 5.91.
4.2.7. General procedure D (substitution of TMS with Br)
TMS group were replaced with bromine by employing the lit-
erature conditions used for aromatic C–H bromination.58 Substrate
(1 mmol, 1 equiv) was added to a 20 mL scintillation vial equipped
with
a magnetic stirring bar. N-Bromosuccinamide (1 mmol,
1 equiv) was added in to the vial. Acetonitrile (3–5 mL) was also
added to the vial. The reaction mixture was stirred at room tem-
perature and was monitored by GC-FID/MS. After the completion of
the reaction, the volatile materials were removed on a rotary
evaporator and the crude product was passed through a short silica
plug to afford the brominated product.
NMR (CDCl3, 500 MHz):
d
7.77 (t, J¼0.8 Hz, 1H), 7.68 (d, J¼7.6 Hz,
1H), 7.42–7.48 (m, 2H), 7.15 (d, J¼3.5 Hz,1H), 6.73–6.75 (m,1H), 2.51
(s, 3H, CH3); 13C NMR {1H} (CDCl3, 125 MHz):
d 140.7 (C), 140.1 (C),
2
135.5 (C), 131.2 (q, JC–F¼32.6 Hz, C), 129.3 (CH), 128.5 (CH), 126.4
(CH), 124.1 (q, 1JC–F¼273 Hz, CF3), 124.0 (CH), 123.4 (q, 3JC–F¼3.6 Hz,
CH), 122.0 (q, 3JC–F¼3.6 Hz, CH), 15.4 (CH3); FTIR (neat) nmax: 3073,
4.2.7.1. 2-(5-Bromo-2-chlorothiophen-3-yl)-4,4,5,5-tetramethyl-
1,3,2-dioxaborolane (18a). The general bromination procedure D
was applied to (5-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxabor-
olan-2-yl)thiophen-2-yl)trimethylsilane (21) (317 mg, 1 mmol) for
12 h. The product was isolated as a white solid (295 mg, 91%, mp
~
2922, 2865, 1497, 1340, 1325, 1165, 1126, 1074, 790, 694 cmꢁ1; GC/
MS (EI) m/z (% relative intensity): Mþ 242 (100), 223 (4), 173 (6).
Anal. Calcd for C12H9F3S: C, 59.49; H, 3.74. Found: C, 59.38; H, 3.56.
4.2.5.2. (5-Chloro-4-m-tolylthiophen-2-yl)trimethylsilane (26). The
general borylation procedure A was applied to 2-chloro-5-trime-
thylsilylthiophene (382 mg, 2 mmol, 1 equiv) and HBPin (435 mL,
51–53 ꢀC). 1H NMR (CDCl3, 300 MHz):
CH3 of BPin); 13C NMR {1H} (CDCl3, 125 MHz):
(CH), 108.3 (C), 84.1 (2C), 24.8 (4CH3 of BPin); 11B NMR (CDCl3,
d
7.10 (s, 1H), 1.30 (br s, 12H,
139.6 (C), 134.9
d
~
96 MHz): d 28.5; FTIR (neat) nmax: 2978,1530,1427,1373,1311,1253,
384 mg, 3.00 mmol, 1.50 equiv) in a Schlenk flask for 10 h. The
reaction mixture was pumped down under high vacuum for 1 h to
remove the volatile materials. Pd(PPh3)4 (46 mg, 2 mol %), 3-
1142, 1028, 962, 848, 883, 848, 692 cmꢁ1; GC/MS (EI) m/z (% relative
intensity): Mþ 323 (48), 324 (100), 322 (81), 309 (21), 307 (14), 289
(38), 287 (36), 208 (23), 166 (22). Anal. Calcd for C10H13BBrClO2S: C,
37.13; H, 4.05. Found: C, 37.25; H, 4.19.
bromo-toluene (291 mL, 410 mg, 2.40 mmol, 1.2 equiv), and DME
(3 mL) were added to the Schlenk flask inside the glove box. The
Schlenk flask was then brought out of the glove box and attached to
a Schlenk line. K3PO4$nH2O (637 mg, 1.50 equiv) was added under
N2 counter flow to the Schlenk flask. The flask was stoppered and
the mixture was heated at 80 ꢀC for 6 h. The flask was cooled down
to room temperature and 10 mL of water were added to the re-
action mixture. The reaction mixture was extracted with ether
(3ꢂ10 mL). The combined ether extractions were washed with
4.2.7.2. 5-Bromo-2-chloro-3-m-tolylthiophene (28). The general
bromination procedure D was applied to (5-chloro-4-m-tolylth-
iophen-2-yl)trimethylsilane (26) (280 mg, 1 mmol) for 12 h. The
product was isolated as a colorless liquid (261 mg, 91%). 1H NMR
(CDCl3, 300 MHz):
d
7.29–7.31 (m, 3H), 7.15–7.18 (m, 1H), 7.02 (s,
139.3 (C),
1H), 2.38 (s, 3H, CH3); 13C NMR {1H} (CDCl3, 75 MHz):
d

6114
G.A. Chotana et al. / Tetrahedron 64 (2008) 6103–6114
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22. Kalinin, V. N. Synthesis 1992, 413–432.
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27. Cho, J. Y.; Iverson, C. N.; Smith, M. R., III. J. Am. Chem. Soc. 2000, 122, 12868–
12869.
138.2 (C), 133.1 (C), 131.2 (CH), 129.1 (CH), 128.8 (CH), 128.4 (CH),
~
125.5 (CH), 124.0 (C), 108.3 (C), 21.4 (CH3); FTIR (neat) nmax: 3042,
2920, 2858, 1604, 1487, 1028, 972, 831, 789, 779, 700 cmꢁ1; GC/MS
(EI) m/z (% relative intensity): Mþ 287 (63), 288 (100), 290 (29), 287
(63), 251 (5), 171 (19). Anal. Calcd for C11H9BrClS: C, 45.94; H, 2.80.
Found: C, 45.96; H, 2.79.
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4.2.7.3. 5-(3,5-Bis(trifluoromethyl)phenyl)-2-chloro-3-m-tolylthio-
phene (29). In a glove box, a Schlenk flask, equipped with a magnetic
stirring bar, was charged with 2-(3,5-bis(trifluoromethyl)-
phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (82 mg, 0.24 mmol,
1.0 equiv). Two separate test tubes were charged with Pd(PPh3)4
(5.5 mg, 0.0048 mmol, 2 mol %) and 5-bromo-2-chloro-3-m-tol-
ylthiophene (28) (69 mg, 0.24 mmol, 1.0 equiv). DME (2 mL) was
used to transfer the contents of the test tubes into the Schlenk flask.
The Schlenkflaskwas then broughtoutof the glovebox andattached
to a Schlenk line. K3PO4$nH2O (319 mg,1.50 equiv) was added under
N2 counter flow to the Schlenk flask. The flask was stoppered and
the mixture was heated at 80 ꢀC for 7 h. At this point the reaction
mixture was allowed to cool to room temperature. The reaction
solution was then filtered through a thin pad of silica gel (eluting
with CH2Cl2) and the eluent was concentrated under reduced
pressure. The crude material so obtained was purified via flash
chromatography on silica gel (hexanes, Rf 0.5) to provide the Suzuki
product as a white solid (85 mg, 84% yield, mp 77–79 ꢀC). 1H NMR
41. Ishiyama, T.; Takagi, J.; Ishida, K.; Miyaura, N.; Anastasi, N. R.; Hartwig, J. F. J. Am.
Chem. Soc. 2002, 124, 390–391.
(CDCl3, 500 MHz):
d 7.94 (s, 2H), 7.80 (s, 1H), 7.41–7.40 (m, 2H), 7.38
42. Ishiyama, T.; Sato, K.; Nishio, Y.; Saiki, T.; Miyaura, N. Chem. Commun. 2005,
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3558.
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47. Highly selective functionalization of 3-methylthiophene by DoM typically re-
quires a hindered electrophile trap. Recently it has been shown that LiTMP
metalates the 5-position of 3-methyl thiophene with high selectivity: Smith, K.;
Barratt, M. L. J. Org. Chem. 2007, 72, 1031–1034.
(s, 1H), 7.37–7.33 (t, J¼7.8 Hz, 1H), 7.22–7.20 (d, J¼7.3 Hz, 1H), 2.43
(s, 3H, CH3); 13C NMR {1H} (CDCl3, 125 MHz):
d 140.1 (C), 138.3 (C),
137.1 (C), 135.6 (C), 133.4 (C), 132.6 (q, 2JC–F¼33.6 Hz, 2C), 129.1 (CH),
128.9 (CH), 128.5 (CH), 126.4 (CH), 126.2 (C), 125.5 (CH), 125.2 (q,
3JC–F¼3.8 Hz, 2 CH), 123.1 (q, JC–F¼272.8 Hz, CF3), 121.1 (septet,
1
3
~
JC–F¼3.9 Hz, CH), 21.4 (CH3); FTIR (neat) nmax: 3048, 2926, 1618,
1474, 1433, 1369, 1330, 1279, 1227, 1181, 1136, 1109, 1011, 891, 845,
789, 698, 684 cmꢁ1; HRMS (FABþ): m/z 420.0174 [Mþ; calcd for
48. Lomas, J. S.; Lacroix, J. C.; Vaissermann, J. J. Chem. Soc., Perkin Trans. 2 1999,
2001–2010.
C
19H11ClF6S: 420.0177].
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We thank BASF, Inc. for a generous gift of HBPin, and the
Michigan Economic Development Corp., NIH (GM63188) and the
Astellas USA Foundation for their generous financial support.
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