A modified procedure for the palladium catalyzed borylation/Suzuki-Miyaura cross-coupling of aryl and heteroaryl halides utilizing bis-boronic acid

Article abstract of DOI:10.1016/j.tet.2015.04.026

Abstract A modified Pd-catalyzed method of forming aryl- and heteroarylboron species and a two-step, one-pot borylation/Suzuki-Miyaura cross coupling using the atom economical tetrahydroxydiboron (bis-boronic acid, BBA) is reported. By using ethylene glycol as an additive, the new method results in increased yields, lower BBA loading, faster reaction times, and a broader reaction scope, including previously problematic substrates such as heterocycles.

Full text of DOI:10.1016/j.tet.2015.04.026

Tetrahedron 71 (2015) 5758e5764
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A modified procedure for the palladium catalyzed borylation/
Suzuki-Miyaura cross-coupling of aryl and heteroaryl halides
utilizing bis-boronic acid
y
y
*
Gary A. Molander , Sarah L.J. Trice , Brittany Tschaen
Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104-6323, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A modified Pd-catalyzed method of forming aryl- and heteroarylboron species and a two-step, one-pot
borylation/Suzuki-Miyaura cross coupling using the atom economical tetrahydroxydiboron (bis-boronic
acid, BBA) is reported. By using ethylene glycol as an additive, the new method results in increased yields,
lower BBA loading, faster reaction times, and a broader reaction scope, including previously problematic
substrates such as heterocycles.
Received 13 February 2015
Received in revised form 8 April 2015
Accepted 9 April 2015
Available online 15 April 2015
Dedicated to Professor Barry M. Trost, an
inspirational mentor and chemist, on his
receipt of the 2014 Tetrahedron Prize for
Creativity in Organic Chemistry
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Bis-boronic acid
Tetrahydroxydiboron
Borylation
Cross-coupling
1. Introduction
coupled products. More recently, borylations using BBA through
a nickel-catalyzed reaction have also been reported.
4
The Suzuki-Miyaura reaction is one the most widely used cat-
The palladium catalyzed method utilizing BBA to generate
2
2
1
alytic methods for forming C(sp )eC(sp ) bonds. Miyaura bor-
ylation is often used to access aryl- and heteroarylboron reagents
used in this process. Although bis(pinacolato)diboron is effective as
a borylating agent, its lack of atom economy and the challenges
associated with removing the by-product pinacol during purifica-
arylboronic acids made use of Buchwald’s second generation XPhos
5
palladium preformed catalyst (XPhos-Pd-G2). Bench stable XPhos-
Pd-G2 allows ease of reaction set-up outside a glove box and leads
to a more rapid in situ formation of the requisite Pd(0) species. The
protocol initially developed was not without some limitations.
Thus, although the method allowed efficient borylation of aryl
chlorides, bromides as well as iodides, and triflates produced yields
2
tion are often problematic for some applications. Significant im-
provements in borylating procedures were reported in 2010,
through the development of the first direct metal-catalyzed syn-
thesis of arylboronic acids via palladium-catalyzed cross-coupling
2 2
comparable to those published with B Pin , mesylates showed no
conversion to the desired borylated species using BBA. For many
substrates, there is an advantage in using mesylates as opposed to
halides or triflates; mesylates are often less expensive to prepare
and easier to handle. Additionally, phenols are sometimes more
readily available than the corresponding aryl halides, and having
the option to use them as starting materials greatly enhances the
scope and utility of cross-coupling reactions. Another challenge in
the previously reported protocol was presented by substrates em-
bedded with reducible functional groups. Using the earlier Pd-
catalyzed BBA borylation, functional groups such as aldehydes,
ketones, and nitro groups generated were observed to produce
reduced side products that led to lower yields of the desired
of aryl chlorides with bis-boronic acid [BBA, tetrahydroxydiboron,
3
B
2
(OH)
4
]. This method offers
a
more efficient and atom-
Pin ) de-
, this tactic allows
economical alternative to the bis(pinacolato)diboron (B
rived approaches. By obviating the use of B Pin
2
2
2
2
facile synthesis of a variety of boronic acid derivatives and facili-
tates the purification of trifluoroborate salts or the desired cross-
*
Corresponding author. Tel.: þ1 215 573 8604; e-mail address: gmolandr@sas.
upenn.edu (G.A. Molander).
y
These authors contributed equally.
http://dx.doi.org/10.1016/j.tet.2015.04.026
0
040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

G.A. Molander et al. / Tetrahedron 71 (2015) 5758e5764
5759
trifluoroborate. The prior method was also limited in the scope of
heterocycles that could be used to provide borylated products in
reasonable yield.
Herein is outlined a protocol for aryl- and heteroaryl borylation
that resolves some of these outstanding issues in a manner, that is,
both effective and experimentally facile.
Subsequent to the initial report of the Pd-catalyzed borylation of
aryl and heteroaryl halides utilizing BBA, an efficient one-pot bor-
ylation/Suzuki crossecoupling reaction, extending even further the
2
. Results and discussion
6
use of the method, was published. Prior to this publication, there
7
To address the issues encountered with the aforementioned Pd-
had been few reports of one-pot, two-step couplings. Although
catalyzed BBA borylation method, a modification to the protocol
that offers several advantages has been developed. It was hypoth-
esized that a modified ‘hybrid’ of the two commonly used bor-
these previous efforts demonstrated the ability to eliminate the
need to isolate the boron species, the methods were limited by high
requisite catalyst loadings and/or refluxing in ethereal solvents. The
mild, one-pot conditions using the more atom economical BBA,
ethanol as solvent, and low catalyst loads (0.1e1.0 mol %) was
therefore an improvement to the existing methods. A useful finding
evolving from the BBA study involved utilizing heteroaryl halides as
the electrophillic partner in the Suzuki cross-coupling, completely
eliminating the need to borylate them (Scheme 1). Although re-
versing the roles of the coupling partners is an option when both
halides are readily accessible, this approach may not be optimal in
more complex syntheses such as in the later stages of a natural
product or drug candidate synthesis. Furthermore, the one-pot
borylation/Suzuki cross-coupling of two heterocycles using the
previous BBA protocol was unsuccessful and represented a major
limitation of the method.
2 2
ylating agents (B Pin and BBA) could address some of the
challenges/limitations associated with both of the reagents. In
particular, the ‘in situ’ formation of a boronate ester using BBA and
ethylene glycol could potentially exhibit some of the positive
qualities of both reagents, namely stability, low cost, and atom
economy (Scheme 2).
Scheme 2. Comparison of boron reagents.
To build on the existing borylation methods using this new
strategy, the use of an improved borylating protocol was in-
vestigated. Upon optimization of the method, the addition of stoi-
chiometric amounts of the inexpensive and readily available
ethylene glycol during the borylation of aryl halides was de-
termined to allow a two-fold decrease in the amount of BBA re-
quired. Furthermore, the addition of ethylene glycol resulted in
a marked rate acceleration for the borylation, as well as a decrease
in the amount of catalyst required for heterocyclic substrates as
well as an improvement in the overall scope and yield.
As demonstrated in Table 1, substrates that were challenging
under the previously reported conditions led to higher isolated
yields of the RBF K salts in substantially shorter reaction times with
3
the addition of ethylene glycol.
In general, the reaction rates were accelerated 2e3 times, with
sometimes dramatically enhanced yields. For example, the yield of
Scheme 1. A comparison of previous one-pot borylation/cross-coupling methods.
3-trifluoroboratoquinoline improved dramatically from 68 to 92%
Many heteroaryl systems are notoriously difficult substrates to
cross-couple.8 Heteroarylboron species, especially boronic acids,
are often unstable and prone to decomposition even at room
temperature.9 This decomposition is exacerbated by the high
temperatures and strong base sometimes needed in cross-coupling
reactions, and therefore a large excess of the heterocyclic boronic
acid is usually required for successful transformations.1 Boronic
acids also form dimeric and cyclic trimeric anhydrides, making the
amount of material actually used somewhat challenging to assess.
For these reasons, the synthesis, storage, and subsequent cross-
coupling of more stable, ‘protected’ boron species in the form of
boronate esters and trifluoroborates remains an active area of re-
search. Although boronate esters, such as Suginome’s 1,8-
in less than half the reaction time (entry 3, Table 1). Another in-
teresting result was observed with the previously unreactive 2- and
3-substituted thiophenes (entries 5 and 9, Table 1) and 1,3-
difluoro-2-chlorobenzene (entry 10, Table 1). Using the modified
reaction conditions, these substrates were obtained in moderate to
good yield, with the latter performing better at reduced
temperatures.
Because of the reduction of reaction time, functional group
tolerance also improved under the modified ethylene glycol pro-
cedure. In particular, the benzaldehyde derivative (entry 14, Table
1) was obtained in slightly higher yield, but more importantly,
the observed palladium-catalyzed reduction product was reduced
from 30% to 13%. The new, modified procedure also has the po-
tential to advance the area of mesylate borylation, as the method
provided product from a mesylated substrate in moderate yield
(entry 15, Table 1). Additionally, this method was shown to be ro-
bust on a larger scale by obtaining comparable yields on both
a 1.5 mmol scale and a 1.0 g scale (entry 12, Table 1).
0
11
naphthalenediamineboranes [RB(dan)] and Burke’s MIDA boro-
9
nates eloquently address the stability associated with boronic
acids, they must be hydrolyzed back to the boronic acids to be
cross-coupled and therefore are not atom economical. As demon-
strated frequently in the literature, trifluoroborates (RBF K) remain
3
the more atom economical choice for protecting boron coupling
partners for storage, and numerous methods have been reported
with high-yielding coupling.
To evaluate the potential advantages of the new ethylene glycol
method further, we investigated the one-pot borylation/cross-
coupling of heterocyclic substrates. Previous studies indicated that
10

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G.A. Molander et al. / Tetrahedron 71 (2015) 5758e5764
Table 1
RBF K synthesis with and without the use of ethylene glycol additive
Table 2
3
One-pot borylation/cross-coupling process
when two aromatic substrates were cross-coupled, the overall yield
of the process was greatly dependent on, which aryl halide was
borylated in situ and, which aryl halide was added in the second
step as the electrophile. These studies indicated that heteroaryl
substrates typically react more effectively when used as the elec-
trophilic component of the cross-coupling and are therefore added
to the reaction after the borylation of the first aryl halide is com-
plete, as attempts to use the heteroaromatic substrate as the
borylated component in the cross-coupling step often resulted in
The results outlined in Table 1 (entries 12 and 13) revealed that
borylation of pyridines proceeded well at 65 C. An investigation
ꢀ
was undertaken to determine if a two-step borylation/cross-cou-
pling process could be achieved on pyridine derivatives at this same
temperature. 5-Chloro-2-fluoropyridine and 3-chlorophenol were
chosen as partners because previous methods (without ethylene
glycol) were effective in borylating the phenol derivative in the first
step followed by cross coupling the pyridine derivative in the sec-
ond step, but attempts to reverse the order (borylation of the pyr-
idine derivative) with the previously developed procedure proved
5
low yields or no reaction at all. Additionally, the coupling of two
heteroaromatic halides proved to be unsuccessful using the pre-
vious BBA one-pot method. To expand the utility of the current
method, we applied the ethylene glycol conditions to borylate
a series of heteroaromatic substrates and subsequently cross-
coupled them in one pot with either an aryl or heteroaryl cou-
pling partner (Table 2).
5
ineffective, even when an increased Pd loading was used. The
ethylene glycol method developed herein has now been shown to
be quite effective in borylating pyridine derivatives, with sub-
sequent cross-coupling with the phenolic halide providing the
desired product in one pot in 78e82% overall yield on a 1.5 mmol or
The borylation of 3-bromoquinoline (Table 1, entry 3) was im-
proved using the ethylene glycol method and allowed a significant
decrease in catalyst loading. Therefore, it was a logical starting
point to test the effectiveness of the new method on the one-pot
borylation/cross-coupling. The results of borylation of 3-
bromoquinoline and in situ coupling with a second heteroaryl ha-
lide proved to be successful with addition of ethylene glycol. Three
different heteroaryl halides were tested as electrophiles, and
overall yields between 84 and 95% were observed (Table 2, entries
7.6 mmol scale (Table 2, entry 4). Additionally, it was shown that
the methoxy-substituted pyridine was also effective in borylation,
with subsequent cross-coupling with an aryl and heteroaryl halide
(Table 2, entries 6 and 7).
The one-pot borylation of 3-chlorothiophene and 3-
chlorophenol was also limited by the role of the respective
1
e3).

G.A. Molander et al. / Tetrahedron 71 (2015) 5758e5764
5761
halides as the nucleophile or electrophile using the glycol-free
4.2. General procedure A: palladium catalyzed borylation of
method. Specifically, the substituted phenol could be borylated,
and subsequently the 3-substituted thiophene could be utilized as
the electrophile. However, the reverse order was not tolerated.
Using the ethylene glycol-added method, the reverse order reaction
heteroaryl halides with ethylene glycol additive and their
conversion to trifluoroborates
To an oven dried glass vessel capable of being sealed with
(
borylation of the thiophene and cross coupling of the resulting
a Teflon cap (for microwave vials) was added XPhosePd-G2
organoboron species with 3-chlorophenol) could be accomplished
in a moderate yield (entry 8). Although the ethylene glycol signif-
icantly improved the viability for several examples, the borylation
of 2-bromobenzonitrile still proved to be challenging, and a yield
comparable to that previously reported was obtained (Table 2,
entry 13).
2 4
(5.89 mg, 7.5 mmol), XPhos (7.14 mg, 15 mmol), B (OH) (203 mg,
2.25 mmol), KOAc (441 mg, 4.5 mmol), and halide (only if a solid).
The vessel was sealed, evacuated, and filled with an inert gas (4ꢁ).
EtOH (15 mL, degassed) was added via syringe followed by the
addition of ethylene glycol (280 mg, 250 mL, 4.5 mmol) and the
halide (1.5 mmol) in a similar manner (if applicable). The reaction
was heated to the specified temperature until the starting material
was consumed (monitored by GC). The reaction was cooled to rt
and filtered through a very thin pad of Celite and decolorizing
carbon (eluting with 5ꢁ10 mL of EtOAc) and concentrated. The
crude reaction was dissolved in EtOAc (10 mL), transferred to
a separatory funnel, and then H O (10 mL) was added. The layers
2
were separated, and the organic layer was washed with brine
(5 mL). The combined aqueous layers were extracted with EtOAc
Interestingly, while we were exploring the new method with
ethylene glycol, a paper by Bello and Schmidt-Leithoff reported
the effects of adding diols to tetrakis(dimethylamino)diboron on
12
the borylation of halides and triflates. This work reported an
improvement in yields in the presence of bulkier diols, which they
attribute to the ThorpeeIngold effect. The authors hypothesize
that a boronate ester is formed by addition of the diol. However, in
that study the reactions could not be carried out in alcoholic
solvents.
(3ꢁ5 mL) dried (Na
2 4
SO ), filtered, and concentrated. MeOH
(
w15 mL) was added to concentrated crude reaction mixture,
ꢀ
which was cooled to 0 C. To this reaction mixture, KHF
2
(1 mL of
3
. Conclusion
ꢀ
4.5 M soln, 4.5 equiv) was added. The reaction was stirred at 0 C
for 10 min before removing the bath and allowing the reaction
The borylation and one-pot borylation/cross coupling methods
mixture to stir for 20 min (or until conversion to trifluoroborate is
previously reported utilizing BBA were advancements to alterna-
tive methods. However, one major limitation was the inability to
use select heteroaryl halides as they often proved difficult to
borylate, leading to modest yields of the trifluoroborates. There-
fore, the role of heteroaryl halides in a one-pot borylation/cross-
coupling sequence was limited to the electrophilic partner in re-
actions with aryl nucleophiles, affording the cross-coupled prod-
uct in good to excellent yield. Because of this limitation, the
method did not yield the cross-coupling between two heteroaryls
in good yields using the one-pot method. The results of continued
investigations as described in this paper support the development
of an improved Pd catalyzed borylation and cross-coupling
method. It is hypothesized that the success of the new method
can be attributed to the formation of the bisboronate ester in situ,
lending stability to the borylating agent and subsequently the
newly formed arylboron species. Owing to the formation of a more
stable intermediate, the amount of BBA required has been reduced
by half. Further, the borylation/cross coupling using the improved
method increases the flexibility in the order of the reaction (i.e.,
which halide is borylated and, which acts as the electrophile), thus
filling a previously identified gap. Also of note is the fact that
ethylene glycol is inexpensive, especially when compared to its
pinacol counterpart. It is also readily available and easily removed
from the reaction mixture during an aqueous workup. Results
indicate that this modified method involving the addition of eth-
ylene glycol offers a significant and practical improvement to
previous methods.
11
complete as observed by B). The resulting mixture was concen-
trated and then lyophilized overnight to remove any traces of H O.
The compound was purified with continuous Soxhlet extraction
8 h or by complete disappearance of RBF K in the thimble as
2
(
3
11
determined by B NMR). The collected solvent was concentrated
until a minimum amount of acetone (w3 mL) remained. The ad-
2
dition of Et O (w25 mL) led to the precipitation of the desired
product.
4.3. General procedure B: general procedure for the
palladium-catalyzed borylation of heteroaryl halides with
ethylene glycol additive and their Suzuki cross-coupling with
heteroaryl halides
To an oven dried glass vessel capable of being sealed with
a Teflon cap (for microwave vials) was added XPhosePd-G2
(11.8 mg, 15
2 4
mmol), XPhos (14.3 mg, 30 mmol), B (OH) (203 mg,
2.25 mmol), KOAc (441 mg, 4.5 mmol), and halide (only if a solid).
The vessel was sealed, evacuated, and filled with an inert gas (4ꢁ).
EtOH (15 mL, degassed) was added via syringe followed by the
addition of ethylene glycol (280 mg, 250 mL, 4.5 mmol) and the
halide (1.5 mmol) in a similar manner (if applicable). The reaction
was heated to the specified temperature until the starting material
was consumed (as monitored by GC). The reaction was cooled, and
a needle attached to a manifold under an inert atmosphere was
inserted into the septum, and 3 equiv of degassed K
.5 mL, 4.5 mmol) was added via syringe, and the reaction was
allowed to sit for 5 min. Then the second halide was added in
a similar manner (as a solution in 500 L of degassed EtOH or THF if
3 4
PO (1 M,
4
4
4
. Experimental section
m
.1. General considerations
a solid). The manifold needle was removed, and the reaction was
heated to the specified temperature for 24 h. The reaction was
cooled to rt and filtered through a very thin pad of Celite, eluting
with 5ꢁ10 mL of EtOAc, and then concentrated. The crude reaction
was dissolved in EtOAc (10 mL), transferred to a separatory funnel,
New compounds were characterized by H NMR, 13C NMR, 11
1
B
19
NMR (when applicable),
F
NMR (when applicable), high-
resolution mass spectrometry, and melting points for solids.
1
13
11
Known compounds were characterized by H NMR, C NMR,
B
and then saturated NaHCO
was extracted with EtOAc (3ꢁ5 mL). The combined organics were
dried (Na SO ), filtered, and concentrated. The desired compound
3
(10 mL) was added. The aqueous layer
NMR (if relevant), and F NMR (if relevant). H and 13C NMR
spectra were recorded at 500 and 125.8 MHz, respectively. Melting
points are uncorrected. HRMS data were obtained using either ESI
or CI and obtained by a TOF mass spectrometer.
19
1
2
4
was purified by silica gel column chromatography, eluting with
EtOAc/hexane.

5762
G.A. Molander et al. / Tetrahedron 71 (2015) 5758e5764
4
.4. Potassium 3,5-difluorophenyl-trifluoroborate (Table 1,
(126 MHz, DMSO)
d 172.8, 156.7, 149.3, 138.5, 134.2, 126.5, 126.5,
5
11
entry 1)
126.2, 125.8, 121.2, 39.5, 24.7. B NMR (128 MHz, DMSO-d ) d 3.64.
6
19
F NMR (471 MHz, DMSO-d
6
)
d
ꢂ135.4.
ꢀ
General procedure A was used at 80 C for 20 min with 1-chloro-
,5-difluorobenzene (223 mg, 168 L, 1.5 mmol) to yield the desired
compound as a white solid (265 mg, 80% yield). Spectral data were
3
m
4.10. Potassium (2,6-dimethylphenyl)trifluoroborate (Table 1,
3
entry 7)
ꢀ
1
in accordance with those of published results. Mp: >225 C.
NMR (500 MHz, acetone-d
6.97 (d, J¼5.7 Hz, 2H), 6.59e6.47 (m,
H). C NMR (125.8 MHz, DMSO-d
162.4 (dd, J¼243 Hz), 113.4
H
ꢀ
6
)
d
General procedure A was used at 80 C for 1 h with 2-chloro-1,3-
dimethylbenzene (140.6 mg, 1.5 mmol) to yield the desired com-
pound as an off-white solid (218.9 mg, 69% yield). Spectral data
13
1
6
)
d
1
1
(
d
d, J¼15.4 Hz), 100.6 (d, J¼25.5 Hz). B NMR (128.4 MHz, acetone-
)
d
3.4 (m). 19F NMR (338.8 MHz, acetone-d
6
)
d
ꢂ114.9, ꢂ143.2.
were in accordance with those of published results. Mp: >225 C.
ꢀ
6
1
H NMR (500 MHz, DMSO-d
6
)
d
6.80 (t, J¼7.4 Hz, 1H), 6.71 (d,
13
4
.5. Potassium 4-aminophenyl-trifluoroborate (Table 1,
J¼7.4 Hz, 2H), 2.34 (s, 6H). C NMR (126 MHz, DMSO-d
126.6, 124.7, 23.3 (dd, J¼6.3, 3.8 Hz).
6
) d 141.0,
5
entry 2)
ꢀ
General procedure A was used at 80 C for 2 h with 4-
chloroaniline (191 mg, 1.5 mmol) to yield the desired compound
as an off-white solid (244 mg, 82% yield). Spectral data were in
4.11. Potassium 4-nitrophenyl-trifluoroborate (Table 1,
entry 8)
5
ꢀ
1
ꢀ
accordance with those of published results. Mp: >225 C. H NMR
General procedure A was used at 80 C for 25 min with 1-chloro-
4-nitrobenzene (236.33, 1.5 mmol) to yield the desired compound
as a tan solid (236.5 mg, 69% yield). Spectral data were in accor-
(
2
1
500 MHz, acetone-d
6
)
d
7.19 (d, J¼7.4 Hz, 2H), 6.45 (d, J¼7.4 Hz,
13
H), 3.96 (s, 2H). C NMR (125.8 MHz, DMSO-d 146.0, 132.5,
6
) d
11
19
ꢀ
1
13.5. B NMR (128.4 MHz, acetone-d
6
)
d
4.1 (m). F NMR
dance with those of published results. Mp: >225 C. H NMR
(500 MHz, DMSO-d
(
338.8 MHz, acetone-d
6
)
d
ꢂ141.5.
6
)
d
8.00 (d, J¼8.1 Hz, 2H), 7.60 (d, J¼8.0 Hz, 2H).
1
3
C NMR (126 MHz, DMSO-d
6
)
d
146.5, 132.8, 121.8. HRMS (ESI)
ꢂ
4
.6. Potassium (quinolin-3-yl)trifluoroborate (Table 1,
calcd for C
6
H
4
NO
2
F
3
B [M] 190.0287, found 190.0296.
13
entry 3)
4
.12. Potassium thien-2-yltrifluoroborate (Table 1, entry 9)13
ꢀ
General procedure A was used at 80 C for 30 min with 3-
bromoquinaldine (266 mg, 1.5 mmol) to yield the desired com-
pound as a pale yellow solid (324 mg, 92% yield). Spectral data were
ꢀ
General procedure A was used at 80 C for 45 min with 2-
chlorothiophene (177.9 mg, 1.5 mmol) to yield the desired com-
pound as an off-white solid (77.3 mg, 27% yield). Spectral data were
ꢀ
1
in accordance with those of published results. Mp: >225 C.
NMR (500 MHz, acetone-d 9.02 (s, 1H), 8.18 (s, 1H), 7.90 (d,
J¼8.1 Hz, 1H), 7.75 (d, J¼7.6 Hz, 1H), 7.52 (t, J¼6.9 Hz, 1H), 7.40 (t,
H
ꢀ
1
6
)
d
in accordance with those of published results. Mp: >225 C. H
1
3
NMR (500 MHz, DMSO-d
6
) d 7.2 (m, 1H), 6.92e6.8 (m, 2H). C NMR
13
J¼7.0 Hz, 1H). C NMR (125.8 MHz, DMSO-d
6
)
d
155.8, 147.3, 138.0,
(125.8 MHz, CDCl 127.0, 126.9, 124.4.
3
) d
11
1
29.1, 128.7, 128.2, 127.9, 125.7. B NMR (128.4 MHz, acetone-d
3.5 (q, J¼49.6 Hz). F NMR (338.8 MHz, acetone-d
6
)
1
9
d
6
)
d
ꢂ141.9.
4.13. Potassium (2,6-difluorophenyl)trifluoroborate (Table 1,
entry 10)
4
.7. Potassium (2-methylquinolin-4-yl)trifluoroborate(Table
ꢀ
1, entry 4)
General procedure A was used at 0 C for 72 h with 2-chloro-1,3-
difluorobenzene (222.8 mg, 1.5 mmol) to yield the desired com-
ꢀ
ꢀ
1
General procedure A was used at 80 C for 30 min with 4-
pound as an off-white solid (217.9 mg, 66% yield). Mp: >225 C; H
1
3
chloroquinaldine (266 mg, 1.5 mmol). The desired trifluoroborate
existed as an inseparable mixture of the internal salt and the po-
tassium trifluoroborate (194 mg, 52% yield). Therefore reasonable
spectra could not be obtained.
NMR (500 MHz, DMSO-d
(126 MHz, DMSO-d
6
)
d
7.10 (m, 1H), 6.67 (m, 2H). C NMR
6
) d
166.2 (dd, J¼241.8, 17.5 Hz), 127.9 (t,
19
J¼10.5 Hz), 110.10 (dd, J¼22.6, 7.7 Hz). F NMR (471 MHz, DMSO-
11
d
6
)
d
ꢂ103.47, ꢂ132.20. B NMR (128 MHz, DMSO-d
6
) d 2.02. HRMS
ꢂ
(ESI) calcd for C
6
H F
3 5
B [M] 181.0248, found 181.0254.
4
.8. Potassium thien-3-yltrifluoroborate (Table 1, entry 5)13
4
.14. Potassium 1H-indol-5-yl-trifluoroborate (Table 1,
ꢀ
13
General procedure A was used at 80 C for 3.5 h with 3-
entry 11)
chlorothiophene (178 mg, 1.5 mmol) to yield the desired com-
pound as an off-white solid (227 mg, 80% yield). Spectral data were
ꢀ
General procedure A was used at 80 C for 50 min with 5-
chloroindole (227.4 mg, 1.5 mmol) to yield the desired compound
as a tan solid (122.9 mg, 37% yield). Spectral data were in accor-
ꢀ
1
in accordance with those of published results. Mp: >225 C.
NMR (500 MHz, acetone-d 7.16 (s, 1H), 6.99 (s, 1H), 6.97 (d,
J¼4.6 Hz, 1H). C NMR (125.8 MHz, DMSO-d 132.5, 124.9, 123.2.
H
6
) d
13
ꢀ
1
6
)
d
dance with those of published results. Mp>200 C. H NMR
(500 MHz, DMSO-d 10.54 (br s, 1H) 7.48 (s, 1H), 7.11e7.09 (m,
3H), 6.26e6.21 (m, 1H). C NMR (126 MHz, DMSO-d
25.5, 123.0, 122.5, 109.0, 100.5.
1
1
19
B NMR (128.4 MHz, acetone-d
6
)
d
3.1 (q, J¼52.6 Hz). F NMR
6
) d
13
(
338.8 MHz, acetone-d
6
)
d
ꢂ138.6.
6
) 134.8, 127.0,
1
4
1
.9. Potassium (2-methylquinolin-8-yl)trifluoroborate (Table
, entry 6)5
4.15. Potassium 6-fluoropyridin-3-yltrifluoroborate (Table 1,
13
entry 12)
ꢀ
General procedure A was used at 80 C for 1 h with 8-chloro-2-
methylquinoline (178 mg, 1.5 mmol) to yield the desired compound
as a tan solid (243.2 mg, 65% yield). Spectral data were in accor-
ꢀ
General procedure A was used at 65 C for 3 h with 5-chloro-2-
fluoropyridine (197.3 mg, 1.5 mmol) to yield the desired compound
ꢀ
1
ꢀ
1
dance with those of published results. Mp: >225 C. H NMR
500 MHz, DMSO)
8.20 (d, J¼7.6, 1H), 7.84 (s, 1H), 7.69 (d, J¼7.6,
H), 7.39 (t, J¼6.9, 1H), 7.33 (d, J¼8.1, 1H), 2.67 (s, 3H). C NMR
as a white solid (230.7 mg, 76% yield). Mp: >225 C. H NMR
(500 MHz, DMSO-d 8.09 (s, 1H), 7.86e7.74 (m, 1H), 6.85 (dd,
J¼8.0, 1.9 Hz, 1H). C NMR (126 MHz, DMSO-d 162.7 (d,
(
1
d
6
) d
13
13
6
) d

G.A. Molander et al. / Tetrahedron 71 (2015) 5758e5764
5763
J¼230.7 Hz), 150.1 (d, J¼12.6 Hz), 145.18 (d, J¼6.2 Hz), 107.81 (d,
4.21. 3-(Thien-2-yl)quinolone (Table 2, entry 3)
11
19
J¼34.8 Hz). B NMR (128 MHz, DMSO-d
6
)
d
3.02. F NMR
(
C
471 MHz, DMSO-d
6
).
d
ꢂ73.3, ꢂ138.8. HRMS (ESI) calcd for
General procedure B was used. Silica gel column chromatogra-
phy (0e100% EtOAc/hexane) was used to obtain the desired com-
ꢂ
H
5 3
BF
4
N [M] 164.0295, found 164.0301.
ꢀ
1
pound as a yellow solid (280 mg, 88% yield). Mp: 70e73 C. H NMR
500 MHz, CDCl
(
3
)
d
9.21 (d, J¼2.0 Hz, 1H), 8.28 (s, 1H), 8.10 (d,
4
.16. Potassium 6-methoxypyridin-3-yltrifluoroborate (Table
J¼8.2 Hz, 1H), 7.85 (d, J¼7.8 Hz, 1H), 7.70 (t, J¼7.0 Hz, 1H), 7.57 (t,
1, entry 13)
J¼7.1 Hz, 1H), 7.51 (d, J¼2.6 Hz, 1H), 7.41 (d, J¼4.2 Hz, 1H), 7.22e7.14
13
(
3
m, 1H). C NMR (125.8 MHz, CDCl ) d 148.7, 147.4, 140.9, 131.5,
ꢀ
General procedure A was used at 65 C for 3 h with 5-chloro-2-
methoxypyridine (215.4 mg, 1.5 mmol) to yield the desired com-
1
29.5, 128.6, 128.1, 127.9, 127.7, 127.4, 126.3, 124.6. IR (neat) 3066,
ꢂ1
1492 cm . HRMS (CIþ) calcd for C13
9
H NS 211.0456, found 211.0461.
ꢀ
1
pound as a white solid (284.6 mg, 88% yield). Mp: 200e205 C. H
NMR (500 MHz, DMSO-d
8.08 (s, 1H), 7.59 (d, J¼7.9 Hz, 1H), 6.58
162.4, 149.4,
6
)
d
.22. 3-(6-Fluoropyridin-3-yl)phenol (Table 2, entry 4)6
4
13
(
1
(
d, J¼8.0 Hz, 1H). C NMR (126 MHz, DMSO-d
42.6, 108.8, 52.7. 19F NMR (471 MHz, DMSO-d
6 6 4 3
128 MHz, DMSO-d ) d 3.28. HRMS (ESI) calcd for C H BNOF [M]
6
) d
11
6
)
d
ꢂ138.31. B NMR
General procedure B was used. Silica gel column chromatogra-
phy (0e100% EtOAc/hexane) was used to obtain the desired com-
pound as a white solid (221.8 mg, 78% yield). Spectral data were in
ꢂ
176.0495, found 176.0508.
ꢀ
1
accordance with those of published results. Mp: 105 C. H NMR
500 MHz, DMSO-d
9.63 (s, 1H), 8.47 (d, J¼2.6 Hz, 1H), 8.21 (td,
J¼8.2, 2.6 Hz, 1H), 7.37e7.22 (m, 2H), 7.11 (dd, J¼8.2, 2.4 Hz, 1H),
(
6
) d
4
.17. Potassium 4-formylphenyl-trifluoroborate and potas-
sium 4-(hydroxymethyl)phenyl-trifluoroborate (Table 1,
entry 14)
1
3
7
.04 (t, J¼2.1 Hz, 1H), 6.83 (dd, J¼8.2, 2.4 Hz, 1H). C NMR
126 MHz, DMSO-d
163.5, 161.6, 158.0,145.2 (d, J¼15.1 Hz), 140.3
(d, J¼8.1 Hz), 134.3, 130.2, 117.6, 115.2, 113.7, 109.6 (d, J¼37.7 Hz).
(
6
) d
ꢀ
General procedure A was used at 80 C for 1 h with 4-
bromobenzaldehyde (277.5 mg, 1.5 mmol) to yield a mixture of
desired carbonyl and alcohol as a white solid (235.7 mg, 73% yield).
4.23. 2-Fluoro-5-(thien-2-yl)pyridine (Table 2, entry 5)
General procedure B was used. Silica gel column chromatogra-
4
.18. Potassium naphthalen-1-yltrifluoroborate (Table 1,
phy (0e100% EtOAc/hexane) was used to obtain the desired com-
entry 15)
1
pound as a yellow oil (268.8 mg, 39% yield). H NMR (500 MHz,
CDCl
3
)
d
8.47e8.44 (m, 1H), 7.96 (ddd, J¼8.5, 7.5, 2.6 Hz, 1H), 7.35
ꢀ
General procedure A was used at 80 C for 4 h with naphthalen-
(
3
dd, J¼5.1, 1.1 Hz, 1H), 7.29 (dd, J¼3.6, 1.1 Hz, 1H), 7.11 (dd, J¼5.1,
1
-yl methanesulfonate (333.5 mg, 1.5 mmol) to yield the desired
compound as a white solid (210.1 mg, 60% yield). Mp: 205e207 C.
H NMR (500 MHz, DMSO-d 8.38 (d, J¼7.2 Hz, 1H), 7.69 (dd,
J¼5.8, 2.5 Hz, 1H), 7.57e7.53 (m, 2H), 7.31e7.24 (m, 3H). C NMR
126 MHz, DMSO-d 137.0, 133.4, 130.6, 129.0, 129.0, 127.8, 125.7,
13
.6 Hz, 1H), 6.96 (ddd, J¼8.5, 3.1, 0.5 Hz, 1H). C NMR (126 MHz,
ꢀ
3
CDCl ) d
163.0 (d, J¼240.3 Hz), 144.7 (d, J¼15.1 Hz), 139.2, 138.7 (d,
1
6
)
d
J¼7.5 Hz), 128.8, 126.1, 124.4, 109.8 (d, J¼39.0 Hz). HRMS (CIþ) calcd
13
NSF [MþH]þ 192.0483, found 192.0484.
9 7
for C H
(
1
(
6
) d
1
9
11
25.3,124.3,123.8. F NMR (471 MHz, DMSO-d
6 7 3
128 MHz, DMSO-d ) d 3.57. HRMS (ESI) calcd for C10H BF [M]
6
)
d
ꢂ135.3. B NMR
4.24. 3-(6-Methoxypyridin-3-yl)phenol (Table 2, entry 6)
ꢂ
195.0593, found 195.0593.
General procedure B was used. Silica gel column chromatogra-
phy (0e100% EtOAc/hexane) was used to obtain the desired com-
ꢀ
1
pound as an off-white solid (257.2 mg, 86% yield). Mp: 86e88 C. H
NMR (500 MHz, CDCl
4
.19. 3-(Pyridin-3-yl)quinolone (Table 2, entry 1)
General procedure B was used. Silica gel column chromatog-
3
)
d
8.41 (d, J¼2.5 Hz, 1H), 7.79 (dd, 8.6, 2.5,
1
1
d
H), 7.72 (s, 1H), 7.29 (dd, 14.9, J¼7.0 Hz, 1H), 7.08e7.03 (d, J¼7.7 Hz,
13
3
H), 6.91e6.81 (m, 3H), 3.99 (s, 3H). C NMR (126 MHz, CDCl )
raphy (0e100% EtOAc/hexane) was used to obtain the desired
compound as a light yellow solid (293 mg, 95% yield). Mp:
163.8, 157.0, 144.7, 139.2, 138.2, 130.4, 130.4, 118.9, 114.9, 113.9,
þ
ꢀ
1
110.9, 54.2. HRMS (CIþ) calcd for C10
H12NO
2
[MþH] , 202.0868
97e100 C. H NMR (500 MHz, CDCl ) d 9.54 (s, 1H), 8.77 (d,
3
found 202.0868.
J¼5.2 Hz, 2H), 8.15 (d, J¼8.4 Hz, 1H), 7.92 (d, J¼7.9 Hz, 1H), 7.88 (d,
J¼7.9 Hz, 1H), 7.82 (t, J¼7.6 Hz, 1H), 7.74 (t, J¼7.7 Hz, 1H), 7.57 (t,
13
4.25. 2-Methoxy-5-(thien-2-yl)pyridine (Table 2, entry 7)
J¼7.4 Hz, 1H), 7.33e7.29 (m, 1H). C NMR (125.8 MHz, CDCl
3
)
d
154.9, 150.3, 149.4, 148.4, 137.2, 134.0, 132.0, 134.0, 132.0, 130.1,
29.4, 128.7, 128.0, 127.2, 122.9, 120.9. IR (neat) 3054, 1589,
General procedure B was used. Silica gel column chromatogra-
1
ꢂ1
phy (0e100% EtOAc/hexane) was used to obtain the desired com-
1
095 cm . HRMS (ESþ) calcd for C14
11
H N
2
(MþH) 207.0922,
1
pound as a yellow oil (286.9 mg, 79% yield). H NMR (500 MHz,
found 207.0922.
CDCl
3
)
d
8.42 (d, J¼2.3 Hz, 1H), 7.76 (dd, J¼8.6, 2.4 Hz, 1H), 7.26 (s,
1H), 7.21 (d, J¼3.5 Hz, 1H), 7.11e7.05 (m, 1H), 6.76 (d, J¼8.6 Hz, 1H),
13
4
.20. 3-(Furan-3-yl)quinolone (Table 2, entry 2)
3
3.96 (s, 3H). C NMR (126 MHz, CDCl ) d 163.7, 144.1, 140.9, 136.7,
1
C
28.2, 124.8, 124.2, 123.1, 111.1, 53.8. HRMS (CIþ) calcd for
General procedure B was used. Silica gel column chromatogra-
10
H
10NOS [MþH]þ 192.0483, found 192.0484.
phy (0e100% EtOAc/hexane) was used to obtain the desired com-
ꢀ
1
4.26. 3-(Thien-3-yl)phenol (Table 2, entry 8)6
pound as a yellow solid (246 mg, 84% yield). Mp: 86e89 C. H NMR
500 MHz, CDCl
9.08 (d, J¼1.9 Hz, 1H), 8.16 (s, 1H), 8.10 (d,
(
3
) d
J¼8.3 Hz, 1H), 7.91 (s, 1H), 7.82 (d, J¼7.9 Hz, 1H), 7.68 (t, J¼7.0 Hz,
General procedure B was used. Silica gel column chromatogra-
phy (0e100% EtOAc/hexane) was used to obtain the desired com-
pound as a tan solid (156.8 mg, 59% yield). Spectral data were in
13
1
3
H), 7.60e7.52 (m, 2H), 6.84 (s, 1H). C NMR (125.8 MHz, CDCl )
d
149.1, 147.3, 144.4, 139.3, 131.5, 129.4, 129.3, 128.3, 127.8, 127.2,
ꢂ1
ꢀ
1
1
C
25.8, 123.6, 108.8. IR (neat) 3346, 1617 cm . HRMS (CIþ) calcd for
accordance with those of published results. Mp: 94e95 C. H NMR
(500 MHz, CDCl
7.43 (dd, J¼2.8, 1.3 Hz,1H), 7.37 (m, 2H), 7.28 (m,
H
13 9
NO 195.0684 found 195.0682.
3
) d

5764
G.A. Molander et al. / Tetrahedron 71 (2015) 5758e5764
1
H), 7.20 (m, 1H), 7.09 (m, 1H), 6.80e6.76 (m, 1H), 5.07 (s, 1H). 13
C
4.31. 3-(2,6-Dimethylphenyl)thiophene (Table 2, entry 13)
NMR (126 MHz, CDCl
3
)
d
155.9, 142.0, 137.7, 130.3, 126.5, 126.4,
ꢀ
120.8, 119.4, 114.3, 113.6.
General procedure B was used at 65 C. Silica gel column chro-
matography (0e100% EtOAc/hexane) was used to obtain the de-
sired compound as a yellow oil (173.2 mg, 61% yield). H NMR
.27. 3-(Thien-3-yl)pyridine (Table 2, entry 9)14
1
4
(
500 MHz, CDCl
3
)
d
7.42 (dd, J¼5.1, 1.2 Hz, 1H), 7.23 (dd, J¼8.3,
General procedure B was used. Silica gel column chromatogra-
phy (0e100% EtOAc/hexane) was used to obtain the desired com-
pound as an off-white solid (151.8 mg, 63% yield). Spectral data
6.8 Hz, 1H), 7.18e7.13 (m, 3H), 6.87 (dd, J¼3.4, 1.2 Hz, 1H), 2.20 (s,
13
6H). C NMR (125.8 MHz, CDCl
3
)
d
141.5, 138.6, 134.3, 128.3, 127.4,
þ
127.2, 126.5, 125.5, 21.0. HRMS (CIþ) calcd for C12
H12S [M]
ꢀ
were in accordance with those of published results. Mp: 73e75 C.
188.0660, found 188.0654.
1
H NMR (500 MHz, DMSO-d
6
)
d
8.97 (d, J¼2.3 Hz, 1H), 8.48 (dd,
J¼4.8, 1.6 Hz, 1H), 8.08 (dt, J¼8.2, 1.9 Hz, 1H), 8.01 (dd, J¼2.9, 1.5 Hz,
Acknowledgements
1
H), 7.68 (dd, J¼5.0, 2.9 Hz, 1H), 7.63 (dd, J¼5.1, 1.4 Hz, 1H), 7.41 (dd,
13
J¼8.0, 4.8 Hz, 1H). C NMR (126 MHz, DMSO-d
6
) d 148.0, 147.1,
The authors thank the National Institutes of Health (R01-GM-
81376) for their generous support of this research, and AllyChem
138.1, 133.2, 130.7, 127.6, 126.0, 123.8, 122.2.
0
Co., Ltd. for providing the BBA used in this study.
4
.28. 3-(2,6-Difluorophenyl)thiophene (Table 2, entry 10)
General procedure B was used. Silica gel column chromatogra-
Supplementary data
phy (0e100% EtOAc/hexane) was used to obtain the desired com-
1
3
pound as a clear oil (165 mg, 56% yield). H NMR (500 MHz, CDCl )
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2015.04.026.
d
7.64 (m, 1H), 7.45e7.38 (m, 2H), 7.27e7.18 (m, 1H), 7.03e6.93 (m,
1
3
2
H). C NMR (125.8 MHz, CDCl
3
)
d
160.1 (d, J¼242.3 Hz), 128.8 (t,
J¼3.6 Hz), 128.4, 128.1 (t, J¼10.6 Hz), 126.3, 125.9 (m), 124.6, 119.7,
1
12.1e111.1 (m). 19F NMR (338.8 MHz, acetone-d
6
)
d
ꢂ112.7.
References and notes
1
. (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457; (b) Miyaura, N.; Yamada,
K.; Suzuki, A. Tetrahedron Lett. 1979, 20, 3437.
4
.29. 3-(Thien-2-yl)phenol (Table 2, entry 11)
2
. (a) Ishiyama, T.; Murata, M.; Miyuara, N. J. Org. Chem. 1995, 60, 7508; (b) Ish-
iyama, T.; Itoh, Y.; Kitano, T.; Miyaura, N. Tetrahedron Lett. 1997, 38, 3447.
. (a) Molander, G. A.; Trice, S. L. J.; Dreher, S. D. J. Am. Chem. Soc. 2010, 132, 17701;
(b) Bis-Boronic Acid (BBA, tetrahydroxydiboron) is commercially available from
SigmaeAldrich 754242.
General procedure B was used. Silica gel column chromatogra-
phy (0e100% EtOAc/hexane) was used to obtain the desired com-
3
1
3
pound as a tan solid (82.5 mg, 31% yield). H NMR (500 MHz, CDCl )
d
7.45 (dd, J¼2.8, 1.4 Hz, 1H), 7.39e7.36 (m, 2H), 7.25e7.32 (m, 1H),
4. Molander, G. A.; Cavalcanti, L. N.; García-García, C. J. Org. Chem. 2013, 78, 6427.
5. Molander, G. A.; Trice, S. L. J.; Kennedy, S. M.; Dreher, S. D.; Tudge, M. T. J. Am.
7
1
1
1
.21e7.19 (m, 1H), 7.09e7.08 (m, 1H), 6.80e6.77 (m, 1H), 4.78 (s,
1
3
Chem. Soc. 2012, 134, 11667.
H). C NMR (125.8 MHz, CDCl
3
)
d
155.9, 144.0, 136.1, 130.3, 125.1,
6. Molander, G. A.; Trice, S. L. J.; Kennedy, S. M.; Dreher, S. D.; Tudge, M. T. J. Org.
Chem. 2012, 77, 8678.
þ
23.5, 118.8, 119.3, 114.6, 112.9. HRMS (CIþ) calcd for C10
8
H SO [M]
7
. (a) Baudoin, O.; Cesario, M.; Gu eꢀ nard, D.; Gu eꢀ ritte, F. J. Org. Chem. 2002, 67,
199; (b) Baudoin, O.; Gu eꢀ nard, D.; Gu eꢀ ritte, F. J. Org. Chem. 2000, 65, 9268; (c)
76.0296, found 176.0303.
1
Billingsley, K. L.; Barder, T. E.; Buchwald, S. L. Angew. Chem., Int. Ed. 2007, 46,
5359; (d) Wang, L.; Cui, X.; Zhu, Z.; Wu, Y.; Li, J.; Wu, Y. Eur. J. Org. Chem. 2012,
4
.30. 2-(2,6-Dimethylphenyl)thiophene (Table 2, entry 12)
5
95.
8. Kinzel, T.; Zhang, Y.; Buchwald, S. L. J. Am. Chem. Soc. 2010, 132, 14073.
. Knapp, D. M.; Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc. 2009, 131, 6961.
0. (a) Molander, G. A.; Canturk, B. Angew. Chem., Int. Ed. 2009, 48, 9240; (b) Mo-
lander, G. A.; Jean-G eꢀ rard, L. Org. React. 2013, 79, 1.
1. Noguchi, N.; Hojo, K.; Suginome, M. J. Am. Chem. Soc. 2007, 129, 758.
2. Bello, C. S.; Schmidt-Leithoff, J. Tetrahedron Lett. 2012, 53, 6230.
ꢀ
General procedure B was used at 80 C. Silica gel column chro-
9
1
matography (0e100% EtOAc/hexane) was used to obtain the de-
sired compound as a yellow oil (119.7 mg, 42% yield). H NMR
1
1
1
1
(
500 MHz, DMSO-d
6
)
d
7.59 (d, J¼5.1 Hz, 1H), 7.19e7.08 (m, 4H),
13
6
d
.86 (d, J¼3.3 Hz, 1H), 2.06 (s, 6H). C NMR (126 MHz, DMSO-d
6
)
3. Molander, G. A.; Canturk, B.; Kennedy, L. J. Org. Chem. 2009, 74, 973.
14. Billingsley, K.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 3358.
140.3, 137.5, 133.5, 128.1, 127.4, 127.2, 126.5, 126.1, 20.4.