Highly Selective Room-Temperature Suzuki-Miyaura Coupling of Bromo-2-sulfonyloxypyridines for Unsymmetrical Diarylpyridines

Article abstract of DOI:10.1021/acs.joc.0c00793

A new and mild synthetic approach has been developed for the synthesis of pharmaceutically important unsymmetrical diarylpyridines via chemoselective Suzuki-Miyaura coupling reactions of bromo-2-sulfonyloxypyridines. Most reactions allow for facile access to aryl-2-sulfonyloxypyridines at room temperature in yields of 5-99% with excellent chemoselectivity in the presence of Pd(OAc)2 (2.0 mol %) and Ad2BnP (2.4 mol %). The second arylation of the remaining tosyl or triflyl group in the monoarylpyridine derivatives obtained was successfully accomplished for the synthesis of unsymmetrical 2,3-, 2,4-, 2,5-, and 2,6-diarylpyridine derivatives. Furthermore, a one-pot synthesis of unsymmetrical diarylpyridines starting from bromo-2-sulfonyloxypyridine was accomplished to demonstrate the practical convenience. Finally, with this method, an antibacterial agent, a topoisomerase inhibitor, and etoricoxib, a nonsteroidal anti-inflammatory drug, were successfully synthesized from the corresponding bromo-2-hydroxypyridines in overall yields of 80, 86, and 49%, respectively.

Full text of DOI:10.1021/acs.joc.0c00793

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Article
Highly Selective Room-Temperature Suzuki-Miyaura Coupling of
Bromo-2-Sulfonyloxypyridines for Unsymmetrical Diarylpyridines
Young-Kyo Jeon, Jae-Yeon Lee, Seo-Eun Kim, and Won-Suk Kim
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00793 • Publication Date (Web): 06 May 2020
Downloaded from pubs.acs.org on May 11, 2020
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Highly Selective Room-Temperature Suzuki-Miyaura Coupling of
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Bromo-2-Sulfonyloxypyridines for Unsymmetrical Diarylpyridines
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Young-Kyo Jeon,† Jae-Yeon Lee,† Seo-Eun Kim, and Won-Suk Kim*
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Department of Chemistry and Nanoscience, Ewha Womans University, Seoul 120-750, South Korea.
wonsukk@ewha.ac.kr
ABSTRACT: A new and mild synthetic approach has been developed for the synthesis of pharmaceutically important unsymmetrical
diarylpyridines via chemoselective Suzuki-Miyaura coupling reactions of bromo-2-sulfonyloxypyridines. Most reactions allow for facile
access to aryl-2-sulfonyloxypyridines at room temperature in yields of 5% to 99% with excellent chemoselectivity in the presence of
Pd(OAc)2 (2.0 mol %) and Ad2BnP (2.4 mol %). The second arylation of the remaining tosyl or triflyl group in the monoarylpyridine
derivatives obtained was successfully accomplished for the synthesis of unsymmetrical 2,3-, 2,4-, 2,5-, and 2,6-diarylpyridine derivatives.
Furthermore, a one-pot synthesis of unsymmetrical diarylpyridines starting from bromo-2-sulfonyloxypyridine was accomplished to
demonstrate the practical convenience. Finally, with this method, an antibacterial agent, topoisomerase inhibitor, and Etoricoxib, a non-
steroidal anti-inflammatory drug, were successfully synthesized from the corresponding bromo-2-hydroxypyridines in overall yields of
80%, 86%, and 49%, respectively.
INTRODUCTION
Suzuki-Miyaura cross-coupling reactions are the most widely used method to form carbon-carbon bonds due to
the easy availability, low tosicity and high stability by boronic acids compared to other cross-coupling reagents.1
Particularly, interest in chemoselective Suzuki-Miyaura coupling of heteroaryl halides for the pharmacetically
important classes has gradually increased.2 These reactions generally take advantage of the different reactivities
by the electrophilic sites or intrinsic polarities of the ring carbon.2d The relevance of N-heteroaryl halide such as
pyridines as scaffold for natural products, pharmaceuticals and argochemicals is remarkable.3 Pyridines are also
widely applied in the field of synthetic chemistry such as in catalysis, supramolecular chemistry, and materials
science.4 Among the pyridine derivatives, unsymmetrical 2,3-, 2,4- and 2,6-diarylpyridine stuructures form the
core of many bioactive compounds having antipyretic, antibacterial, antiinflammatory and anticancer activities
(Figure 1).5 Thus, synthesis of unsymmetrical diarylpyridines via chemoselective Suzuki-Miyaura cross-coupling
reactions has been developed employing various dihalopyridines (Scheme 1, eq 1).6 However, in general,
monoarylation of dihalopyridines is slow, requiring more than 12 h to proceed to completion, and is carried out
at elevated temperature to obtain the monoarylpyridine derivatives in moderate to good yields. Furthermore, due
to the intrinsic polarization of the C-2 and C-4 positions of the pyridine ring system, the reaction of 2,4-
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dibromopyridine provided a lower yield compared to chemoselective reactions using other dibromopyridines.6b,
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2d
Therefore, it is still necessary to develop a general, mild and expedient method for the synthesis of
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unsymmetrical diarylpyridines via chemoselective Suzuki-Miyaura reactions. Recently, we have successfully
demonstrated the chemoselective Suzuki-Miyaura cross-coupling reaction of 3,5- and 4,6-dibromo-2-
tosyloxypyridines in our efforts to improve methods for trisubstituted pyridines synthesis.7 Seeking to expand
upon this work, we envisaged an alternative method to contribute to the present approaches for the synthesis of
unsymmetrical 2,3-, 2,4-, 2,5-, and 2,6-diarylpyrines by employing bromo-2-sulfonyloxypyridines (Scheme 1, eq
2).
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Figure 1. Selected Bioactive Compounds Containing the Unsymmetrical Diarylpyridine Structure.
HO
O
S
O
N
Cl
N
MeO
Ph
OH
N
HN
N
Ph
N
Antibacterial agent
(MPBI)
COX-2 inhibitor
(Etoricoxib)
Topoisomerase inhibitor
N
N
MeO
MeO
OH
OMe
O
N
O
N
N
N
N
H
OMe
Ph
HO
Anticancer agent
A2B adenosin receptor
antagonist
Estrogen receptor ligand
In general, the selectivity of Br over sulfonate esters such as OTs or OTf on the aryl moiety in Pd-catalyzed
cross-coupling reactions is well established.8 However, the selectivity of Br to OTs or OTf attached at the C-2
position of the pyridine moiety has not been widely investigated.9 For example, when 5-bromo-2-
tosyloxypyridine was used in coupling with 1.5 equiv. of phenylboronic acid under the condition of 5 mol %
Pd(OAc)2, 20 mol % PPh3, and 2.5 equiv. K3PO4 in 1,4-dioxane at 110 oC, 2,5-diphenylpyridine and 5-phenyl-2-
tosyloxypyridine were obtained in 48% and 30% yields, respectively.9c These results indicate the Br group on the
pyridine ring has priority over the OTs group, but the OTs group at the C-2 position on the pyridine ring is
considerably reactive. Moreover, when 3-bromo-2-trifluoromethanesulfonyloxypyridine and tributylvinyltin was
employed in the presence of Pd2(dba)3, TFP, and LiCl in THF at 65 oC, 3-bromo-2-vinylpyridine was only isolated
in 65% yield.9b This result indicates that the oxidative addition of OTf group at the 2-position on the pyridine ring
is faster than the oxidative addition of the Br group at the 3-position under the reaction conditions mentioned
above. Thus, for the effecitve synthesis of unsymmetrical diarylpyridines from bromo-2-sulfonyloxypyridines, it
is necessary to employ an efficient catalyst system to suppress the reactivity of the OTs or OTf group at the C-2
position of pyridine for the first arylation. Unlike other methods, we expected that our strategy for the
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chemoselective Suzuki-Miyaura reactions would be a general and expedient method to proceed at room
temperature and employ readily prepared starting materials. Furthermore, to the best of our knowledge,
chemoselective cross-coupling reaction of bromo-2-sulfonyloxypyridines at room temperature has not yet been
reported. With these considerations in mind, we report herein chemoselective cross-coupling reaction of bromo-
2-sulfonyloxypyridines and the subsequent arylation of the remaining sulfonyl group for the synthesis of
biologically relevant unsymmetrical 2,3-, 2,4-, 2,5-, and 2,6-diarylpyrines.
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Scheme 1. Synthetic Methods for 2,3-, 2,4-, 2,5- and 2,6-Diarylpyridines.
B(OH)2
R1
B(OH)2
Br
R1
R1
R2
N
N
N
Pd(0), heat
Pd(0), heat
TfO/Br
high catalyst loading
TfO/Br
R2
(1)
B(OH)2
Br/Cl
B(OH)2
R2
Br/Cl
R1
R2
N
N
N
Pd(0), heat
Pd(0), heat
Br/I
high catalyst loading
R1
< 99% selectivity
R1
B(OH)2
R2
B(OH)2
OR
N
OR
R1
R2
N
N
(2)
Pd(0), rt
Pd(0), heat
Br
low catalyst loading
this work
R1
R = Ts, Tf
R1
> 99% selectivity
RESULTS AND DISCUSSION
The requisite bromo-2-sulfonyloxypyridines 3, 5, 7, and 10 were readily prepared in good yield from bromo-2-
hydroxypyridines 1, 4, 6, and 8 via tosylation or triflation employing p-toluenesulfonyl chloride 2 or
trifluoromethanesulfonic anhydride 9, respectively (Scheme 2).
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Scheme 2. Preparation of Bromo-2-sulfonyloxypyridines
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9
Br
Br
Et3N, DMAP
O
S
+
+
CH2Cl2, rt, 1 h
Cl
Cl
N
OH
OH
N
OTs
OTs
O
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11
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89%
1
2
3
Et3N, DMAP
O
S
CH2Cl2, rt, 1 h
Br
N
Br
N
O
87%
4
2
5
Br
Br
Et3N, DMAP
O
S
+
+
CH2Cl2, rt, 1 h
Cl
O
N
OH
N
OTs
78%
6
2
7
Br
Br
Pyridine
O
S
O O
O
O
S
CH2Cl2, 0 °C to rt, 5 h
CF3
CF3
N
OH
N
OTf
87%
10
8
9
Optimiaztion of the chemoselective Suzuki-Miyaura cross-coupling reaction was initiated employing 5-
bromo-2-tosyloxypyridine 3 and phenylboronic acid 11 (Table 1). When the reaction was conducted using 2.0
equiv. of 11, 4 mol % Pd(OAc)2, 5 mol % Ad2BnP and 2.2 equiv. K2CO3 in toluene at 50 oC, the desired product
3a was obtained in only 90% yield in 3 h (Table 1, entry 1). However, the use of a small amount of water in
toluene led to the highest isolated yield in 20 min (Table 1, entry 2). Utilizing P(Cy)3 instead of Ad2BnP as the
ligand furnished the cross-coupled product 3a in 88% yield in 30 min (Table 1, entry 3). When Xphos, Sphos or
Ruphos was used as the ligand, 3a was afforded in moderate-to-good yield along with symmetrical diarylated
product 12 (Table 1, entries 4-6). When more water was added, 3a was isolated in a slightly lower 98% yield
(Table 1, entries 7 and 8). In addition, when the reactions were carried out in MeOH or EtOH instead of H2O, 3a
was obtained in 98% or 94% yield, respectively (Table 1, entries 9 and 10). Next, we extensively screened
amounts of catalyst, ligand, and boronic acid. For example, when the reactions were performed at 50 oC or 100
oC using low loadings of Pd(OAc)2 and Ad2BnP in 30:1 toluene/H2O, 3a was isolated in 99% yield (Table 1,
entries 11-13). Surprisingly, conducting the reaction at room temperature afforded 3a in 99% yield in 20 min
(Table 1, entry 14), but the use of 1.6 equiv. of 11 furnished 3a in a low yield in 60 min due to the the competitive
homocoupling of phenylboronic acid (Table 1, entry 15). Finally, when the reaction was carried out using 1.8
equiv. of 11, 2 mol % Pd(OAc)2, 2.4 mol % Ad2BnP and 2.2 equiv. K2CO3 in 30:1 toluene/H2O at 25 oC, 3a was
obtained in 99% yield in 20 min (Table 1, entry 16). In addition, when the reaction was conducted at 100 oC using
Ad2BnP or P(Cy)3 in the presence of 1.8 equiv. of 11, 3a was isolated in 99% or 95% yield, respectively. (Table
1, entries 17 and 18).
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Table 1. Optimization of the Chemoselective Suzuki-Miyaura Reaction Employing 3 and 11.a
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9
Pd(OAc)2 (X mol %)
Ligand (Y mol %)
Br
B(OH)2
+
+
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11
12
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K2CO3 (2.2 equiv.)
Solvent, Temp., Time
N
OTs
N
N
OTs
3
11
Ligand X (mol %) Y (mol %)
3a
12
Equiv.
Temp. Time
Yield
Yield
Entry
Solvent
toluene
b
b
(oC)
(%)
90
99
88
76
81
63
(%)
11
(min)
of
3a
12
Ad2BnP
Ad2BnP
P(Cy)3
1
2
3
4
5
6
2.0
2.0
2.0
2.0
2.0
2.0
4.0
4.0
4.0
4.0
4.0
4.0
5.0
5.0
5.0
5.0
5.0
5.0
50
50
50
50
50
50
180
20
30
30
30
40
-
toluene:H2O (30:1)
toluene:H2O (30:1)
toluene:H2O (30:1)
toluene:H2O (30:1)
toluene:H2O (30:1)
-
-
XPhos
SPhos
23
18
36
RuPhos
Ad2BnP
Ad2BnP
7
8
2.0
2.0
4.0
4.0
5.0
5.0
toluene:H2O (20:1)
toluene:H2O (10:1)
50
50
50
50
98
98
-
-
Ad2BnP
Ad2BnP
9
2.0
2.0
4.0
4.0
5.0
5.0
toluene:MeOH (30:1) 50
50
70
98
94
-
-
10
toluene:EtOH (30:1)
50
Ad2BnP
Ad2BnP
11
12
2.0
2.0
3.0
2.0
5.0
2.4
toluene:H2O (30:1)
toluene:H2O (30:1)
50
50
20
20
99
99
-
-
Ad2BnP
Ad2BnP
Ad2BnP
Ad2BnP
Ad2BnP
P(Cy)3
13
14
15c
16
17
18
2.0
2.0
1.6
1.8
1.8
1.8
2.0
2.0
2.0
2.0
2.0
2.0
2.4
2.4
2.4
2.4
2.4
2.4
toluene:H2O (30:1)
toluene:H2O (30:1)
toluene:H2O (30:1)
toluene:H2O (30:1)
toluene:H2O (30:1)
toluene:H2O (30:1)
100
25
15
20
60
20
15
20
99
99
89
99
99
95
-
-
-
-
-
-
25
25
100
100
a
Reaction conditions: 1.0 equiv. of 3, phenylboronic acid 11, 2.2 equiv. of K2CO3, X mol % of catalyst, Y mol % of ligand,
solvent (0.1 M).
b
c
Isolated yield.
Reaction time based on complete consumption of boronic acid as determined by TLC analysis.
Under the optimized coupling conditions, 3 and various boronic acids 13 were employed to examine the scope
of the Pd-catalyzed chemoselective Suzuki-Miyaura cross-coupling reaction (Table 2). In general, arylboronic
acids with electron-neutral and -donating groups afforded the desired products 3a-3e in 99% yield at 25 oC. In
addition, to attest the feasibility of this method, the coupling reaction was carried out on a large scale (3.05 mmol),
providing 3a in 99% yield in 30 min. On the other hand, sterically hindered ortho-substituted methoxy
arylboronic acid furnished the coupled product 3f in 14% yield with 18% conversion after 22 h. However,
utilizing P(Cy)3 instead of Ad2BnP as the ligand at 100 oC afforded 3f in 94% yield in 1.5 h. The use of arylboronic
acids containing electron-withdrawing fluoro, chloro, and tert-butoxycarbonyl groups provided the respective
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coupled products 3g, 3h, 3i in 99% yield at 25 oC. Furthermore, heteroaryl boronic acids such as benzothiophen-2-
ylboronic acid reacted with 5-bromo-2-tosyloxyprydine 3 to form 3j in 99% yield in 6 h, while 3-thienyl- and
furanylboronic acids afforded 3k and 3l in 55% and 5% yield with 56% and 13% conversion, respectively.
However, when the reactions were performed at 100 oC employing P(Cy)3, 3k was isolated in 99% yield in 1.5 h
and 3l was obtained in 71% yield with 77% conversion after 14 h due to the competitive homocoupling of 3-
furanylboronic acid.
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11
12
13
14
15
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17
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Table 2. Chemoselective Suzuki-Miyaura Reaction Employing 3 and Boronic acid 13.a
R1
Br
Pd(OAc)2, Ad2BnP, K2CO3
B(OH)2
+
R1
toluene:H2O (30:1), 25 o
C
N
OTs
N
OTs
3
13
3a 3l
-
MeO
MeS
N
OTs
N
OTs
N
OTs
N
, (99%), 4.5 h
F
OTs
3a
, (99%), 20 min,
(99%)b, 30 min
3b
, (99%), 50 min
3c
3d
, (99%), 12 h
Cl
MeO
OMe
N
N
OTs
OTs
N
OTs
N
OTs
c
d
3f
, (14%), (18%) , 22 h ,
(94%)e, 1.5 h
3e
3g
, (99%), 5.5 h
, (99%), 40 min
3h
, (99%), 30 min
tBuO2C
S
O
S
N
OTs
N
OTs
N
OTs
N
OTs
c
d
c
d
3k
, (55%), (56%) , 13 h , 3l
3i
3j
, (5%), (13%) , 14 h ,
(71%)e, (77%)c, 14 hd
, (99%), 1.5 h
, (99%), 6 h
(99%)e, 1.5 h
a
Reaction conditions: 1.0 equiv. 3, 1.8 equiv. of 13, 2.2 equiv. of K2CO3, 2 mol % of Pd(OAc)2, 2.4 mol % of Ad2BnP,
toluene:H2O (30:1, 0.1 M), 25 oC.
b
c
d
e
Large scale: 3.05 mmol of 3 was used.
Conversion.
Reaction time based on complete consumption of boronic acid as determined by TLC analysis.
P(Cy)3 instead of Ad2BnP, 100 oC.
Next, we focused on the use of 3-, 4-, and 6-bromo-2-sulfonyloxypyridines 14 as the electrophile. Pleasingly,
the optimized reaction conditions (cf., Pd(OAc)2, Ad2BnP, K2CO3, toluene/H2O (30:1), 25 oC) that successfully
demonstrated with 5-bromo-2-tosyloxypyridine 3 were also effective for the chemoselective Suzuki-Miyaura
reactions of 14. As illustrated in Table 3, the use of various types of boronic acids 13 furnished the
monoarylpyridine derivatives 4a-4l in 76% to 99% yield. When 3-thienylboronic acid reacted with 4-bromo-2-
tosyloxyprydine, the desired product 4f was obtained in 76% yield with 82% conversion after 20 h. However,
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utilizing P(Cy)3 as the ligand at 100 oC furnished 4f in 94% yield in 20 min. Surprisingly, when performing the
reactions with 3-bromo-2-trifluoromethanesulfon-yloxypyridine under the optimized conditions, all reactions
proceeded well without reacting with the OTf group at the C-2 position of pyridine, furnishing 4i-4l in yields
ranging from 87 to 96%.
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9
Table 3. Chemoselective Suzuki-Miyaura Reaction Employing 14 and Boronic acid 13.a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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R1
Br
Pd(OAc)2, Ad2BnP, K2CO3
toluene:H2O (30:1), 25 o
B(OH)2
+
R1
C
N
OR
N
OR
R = Ts, Tf
R = Ts, Tf
4a-4l
14
13
N
OTs
N
OTs
N
OTs
N
OTs
MeO
F
Cl
4a
4b
, (99%), 3 h
4c
, (99%), 30 min
4d
, (99%), 50 min
, (99%), 20 min
OTBS
tBuO2C
OTs
F3C
S
OTs
OTs
OTs
N
N
N
N
b
c
4f
, (76%), (82%) , 20 h ,
(94%)d, 20 min
4e
, (98%), 2 h
4g
, (99%), 5.5 h
4h
, (97%), 3.5 h
CO2tBu
F
N
OTf
N
OTf
N
OTf
N
OTf
4i
, (90%), 40 min
4j
4k
4l
, (90%), 4 h
, (96%), 1.5 h
, (87%), 40 min
a
Reaction conditions: 1.0 equiv. of 14, 1.8 equiv. of 13, 2.2 equiv. K2CO3, 2 mol % of Pd(OAc)2, 2.4 mol % of Ad2BnP,
toluene:H2O (30:1, 0.1 M), 25 oC.
b
c
d
Conversion.
Reaction time based on complete consumption of boronic acid as determined by TLC analysis.
P(Cy)3 instead of Ad2BnP, 100 oC.
Encouraged by these cross-coupling results, we investigated the synthesis of unsymmetrical diaryl-substituted
pyridines present in many biologically active compounds. As shown in Table 4, when the optimized reaction
conditions (cf., Pd(OAc)2, SPhos, K2CO3, toluene/H2O (30:1), 100 C)10 were used in the Suzuki reaction with
o
aryl-2-sulfonyloxypyridines and boronic acids, the unsymmetrical diarylpyridines 5a-5l were successfully
obtained in yields ranging from 90 to 99%. However, 3-thienylboronic acid afforded 5g in 90% yield with 94%
conversion in 10 h due to the homocoupling of 3-thienylboronic acid.
We next turned our attention to a one-pot synthesis of unsymmetrical diarylpyridines to demonstrate the
practical convenience of this method. Pleasingly, when the coupling reaction was carried out employing 5, the
unsymmetrical diarylpyridine 5e was obtained in overall 97% in 1.5 h (Scheme 3).
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Table 4. Suzuki-Miyaura Reaction Employing Aryl-2-sulfonyloxypyridines 15 and Boronic acids 13.a
R2
R2
7
8
9
Pd(OAc)2, SPhos, K2CO3
B(OH)2
+
R1
toluene:H2O (30:1), 100 o
C
N
N
OR
R1
10
11
12
13
14
15
16
17
18
19
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R = Ts, Tf
15
13
5a 5l
-
N
N
N
N
F
MeO
CO2tBu
OMe
F
5a
5b
5c
5d
, (99%), 2 h
, (99%), 10 min
, (99%), 1 h
, (92%), 1 h
OTBS
OTBS
S
N
N
F
F
N
N
OMe
, (98%), 50 min
OTBS
b
c
5e
5f
5h
, (96%), 30 min
, (90%), 5 h
5g
, (90%), (94%) , 10 h
CF3
N
N
N
N
CF3
5l
, (94%), 1 h
SMe
5i
, (99%), 45 min
5j
5k
, (99%), 40 min
, (96%), 2.5 h
a
Reaction conditions: 1.0 equiv. of 15, 2.0 equiv. of 13, 2.2 equiv. K2CO3, 4 mol % of Pd(OAc)2, 5 mol % of SPhos,
toluene:H2O (30:1, 0.1 M), 100 oC.
b
c
Conversion.
Reaction time based on complete consumption of boronic acid as determined by TLC analysis.
Scheme 3. A Sequential One-Pot Synthesis of Unsymmetrical Diarylpyridine.
B(OH)2
B(OH)2
F
13b
13a
Pd(OAc)2,
OMe
N
Br
N
OTs
Pd(OAc)2, SPhos,
100 oC, 1 h
F
Ad2BnP, K2CO3,
toluene:H2O (30:1),
25 oC, 30 min
5
5e
OMe
overall 97%
Finally, to attest the viability of the chemoselective Suzuki-Miyaura coupling reaction of bromo-2-
sulfonyloxypyridines and the subsequent arylation of the remaining sulfonate group, we applied our method to
the synthesis of several biologically significant compounds (Scheme 4). For example, the antibacterial agent,
MPBI 17, previously synthesized in three steps from 2,6-dibromopyridine in 34% yield,5e was prepared from 6-
bromo-2-hydroxypyridine 4 via tosylation, chemoselective Suzuki-Miyaura coupling and subsquent arylation of
the remaining OTs group in overall yields of 80% (Schemes 4, eq 1). Next, for the synthesis of topoisomerase
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inhibitor 21,5d 4,6-dibromo-2-tosyloxypyridine 18 was selected as a starting material, which was previously
prepared from 4,6-dibromo-2-hydroxypyridine11 in 90% yield.7 The chemoselective Suzuki-Miyaura reaction
was carried out using 18 and 4.0 equiv. of boronic acid 19 to obtain 20 in 99% yield within 32 h at rt. The second
arylation of the tosylate group of pyridine 20, followed by the deprotection of the TBS group furnished the target
compound 21 in 97% yield (Scheme 4, eq 2).
9
Finally, a non-steroidal anti-inflammatory drug, Etoricoxib 28,5a,5f,6e,12 previously synthesized via a six steps
sequence from 3-bromo-5-chloro-2-hydroxypyridine 22,5a was synthesized in four steps from 22 (Scheme 4, eq
3). Triflation of 22, followed by the chemoselective Suzuki-Miyaura coupling reaction employing boronic acid
24 afforded monoaryl-substituted pyridine 25 in 86% yield over two steps. Oxidation of 25 by 30% hydrogen
peroxide and catalytic amount of sodium molybdate in the presence of sulfuric acid proceeded to furnish sulfone
26 in 94% yield. Lastly, when the Suzuki reaction of 26 and 2-methylpyridine-5-boronic acid 27 was conducted
under the optimized conditions (cf., Pd(OAc)2, SPhos, K2CO3, toluene/H2O (30:1), 100 oC), the desired product
28 was obtained in 12% with 49% conversion in 20 h. However, when the reaction was conducted utilizing P(Cy)3
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o
and NaHCO3 in 1,4-dioxane/H2O (1:1) at 80 C, 28 was obtained in 60% yield in 1.5 h. The synthesis of
Etoricoxib was successfully completed from 22 in overall yields of 49%.
Scheme 4. Synthesis of MPBI 17, Topoisomerase inhibitor 21, and Etoricoxib 28.
17
(1) MPBI
N
B(OH)2
B(OH)2
N
H
MeO
16
15
N
Pd(OAc)2, Ad2BnP, K2CO3
toluene:H2O (30:1), rt, 3 h
OTs
Pd(OAc)2, SPhos, K2CO3
N
MeO
N
OTs
toluene:H2O (30:1), 100 oC, 19 h
HN
Br
N
MeO
99%
93%
5
4b
17
21
(2) Topoisomerase inhibitor
OH
B(OH)2
TBSO
B(OH)2
OTBS
19
11
Pd(OAc)2, SPhos, K2CO3
Br
1. a)
Pd(OAc)2, Ad2BnP, K2CO3
toluene:H2O (30:1), rt, 32 h
HO
TBSO
toluene:H2O (30:1), 100 oC, 20 min
b) TBAF, THF, rt, 3 h
N
N
OTs
Br
N
OTs
99%
18
20
21
97%
28
(3) Etoricoxib
B(OH)2
SMe
MeS
24
Cl
Br
Cl
Br
Cl
Pd(OAc)2, Ad2BnP, K2CO3
toluene:H2O (30:1), rt, 11 h
Na2MoO4, H2SO4, H2O2
MeOH, 50 oC, 6 h
Tf2O, pyridine
CH2Cl2, 0 oC to rt, 8 h
N
OH
N
OTf
N
OTf
96%
90%
94%
25
22
23
O
S
O
S
Me
Condition A
: Pd(OAc)2, SPhos, K2CO3,
Me
toluene:H2O (30:1), 100 oC, 20 h,
O
B(OH)2
O
Cl
12% (49% conversion)
Cl
+
Me
N
Condition B
1,4-dioxane:H2O (1:1), 80 oC, 1.5 h, 60%
: Pd(OAc)4, P(Cy)3, NaHCO3,
N
OTf
N
N
26
27
28
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In conclusion, we have developed an efficient strategy for the synthesis of unsymmetrical 2,3-, 2,4-, 2,5-, and
2,6-diarylpyrines from the corresponding bromo-2-sulfonyloxypyridines. The chemoselective Suzuki-Miyaura
reactions of bromo-2-sulfonyloxy-pyridines proceeded well without reacting with the tosyl or triflyl group under
the optimized conditions of 2 mol % Pd(OAc)2, 2.4 mol % Ad2BnP and 2.2 equiv. K2CO3 in toluene/H2O (30:1)
at room temperature to afford the monoarylpyridine derivatives. In addition, the subsequent arylation of the
remaining sulfonate group was performed under the optimized conditions (cf., 4 mol % Pd(OAc)2, 5 mol % SPhos,
and 2.2 equiv. K2CO3 in toluene/H2O (30:1) at 100 °C) for the synthesis of unsymmetrical diarylpyridines. The
scope of this methodology was investigated by employing various boronic acids. Moreover, a one-pot synthesis
of unsymmetrical diarylpyridines starting from bromo-2-sulfonyloxypyridine was carried out to demonstrate the
practical convenience of the present method. Finally, the applicability of the proposed synthetic method was
demonstrated by the synthesis of three biologically active compounds, including MPBI, topoisomerase inhibitor,
and Etoricoxib, via the chemoselective Suzuki-Miyaura reactions and the subsequent arylation.
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EXPERIMENTAL SECTION
General Considerations
Unless otherwise indicated, all chemical reagents were purchased from commercial suppliers and were used
without further purification. All reactions were carried out in oven-dried glassware equipped with a magnetic stir
bar. Reactions were monitored by thin layer chromatography (TLC) with 0.25-mm pre-coated silica gel plates
(Kieselgel 60F254). Products were detected by viewing under a UV light, by staining with an anisaldehyde solution
composed of acetic acid, sulfuric acid, and MeOH, or by staining with a KMnO4 solution composed of potassium
carbonate, sodium hydroxide, and water. Flash column chromatography was performed on silica gel (70-230
1
mesh). Yields refer to chromatographically and spectroscopically pure compounds unless otherwise noted. H
and 13C spectra were recorded on a 300 MHz NMR spectrometer. Chemical shifts are reported as δ values relative
to internal SiMe4 or chloroform (δ 0.00 for 1H and δ 77.0 for 13C) or DMSO-d6 (δ 2.50 for 1H and δ 39.5 for 13C).
IR spectra were measured as neat oils and solids on a FT-IR spectrometer. HRMS data were obtained by electron
ionization and fast atom bombardment with a double-focusing high-resolution magnetic sector mass analyzer.
5-Bromopyridin-2-yl 4-methylbenzenesulfonate (3)
A solution of 5-bromo-2-hydroxypyridine (1 g, 5.75 mmol), TsCl (1.32 g, 6.90 mmol), Et3N (1.6 mL, 11.50 mmol)
and DMAP (0.035 g, 0.29 mmol) in anhydrous CH2Cl2 (17.4 mL) was stirred at 25 °C for 1 h. The reaction
mixture was quenched with NH4Cl(sat.) and extracted with Et2O (3 x 100 mL). The organic phase was collected,
dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude product was purified
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by column chromatography on silica gel (hexane/diethyl ether = 10:1) to obtain pure 3 (1.68 g, 5.12 mmol, 89%)
as a white solid. m.p: 74-80 °C; Rf 0.43 (hexane/ethyl acetate = 5:1); IR (neat) 3982, 3782, 2997, 2415, 1962,
1896, 1596, 1316, 973, 755 cm-1; 1H NMR (300 MHz, CDCl3) δ 8.29 (dd, J = 2.6 Hz and J = 0.4 Hz, 1H), 7.89-
7.85 (m, 3H), 7.37 (d, J = 8.5 Hz, 2H), 7.04 (d, J = 8.6 Hz, 1H), 2.46 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3)
δ 155.6, 149.2, 145.6, 142.6, 133.2, 129.8, 128.6, 118.6, 117.4, 21.7; HRMS (FAB) m/z [M + H]+ calcd for
C12H11BrNO3S 327.9644, found 327.9640.
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6-Bromopyridin-2-yl 4-methylbenzenesulfonate (5)
A solution of 6-bromo-2-hydroxypyridine (1 g, 5.75 mmol), TsCl (1.32 g, 6.90 mmol), Et3N (1.6 mL, 11.50 mmol)
and DMAP (0.035 g, 0.29 mmol) in anhydrous CH2Cl2 (17.4 mL) was stirred at 25 °C for 1 h. The reaction
mixture was quenched with NH4Cl(sat.) and extracted with Et2O (3 x 100 mL). The organic phase was collected,
dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude product was purified
by column chromatography on silica gel (hexane/diethyl ether = 10:1) to obtain pure 5 (1.64 g, 5.00 mmol, 87%)
as a white solid. m.p: 98-102 °C; Rf 0.31 (hexane/ethyl acetate = 5:1); IR (neat) 1983, 1924, 1811, 1562, 1373,
1171, 1092, 981, 886, 813 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.94 (d, J = 8.4 Hz, 2H), 7.61 (t, J = 7.9 Hz, 1H),
7.40-7.36 (m, 3H), 7.10 (d, J = 8.3 Hz, 1H), 2.47 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 155.9, 145.7, 141.6,
139.3, 133.4, 129.6, 129.0, 126.6, 113.9, 21.7; HRMS (FAB) m/z [M + H]+ calcd for C12H11BrNO3S 327.9644,
found 327.9647.
4-Bromopyridin-2-yl 4-methylbenzenesulfonate (7)
A solution of 4-bromo-2-hydroxypyridine (1 g, 5.75 mmol), TsCl (1.32 g, 6.90 mmol), Et3N (1.6 mL, 11.50 mmol)
and DMAP (0.035 g, 0.29 mmol) in anhydrous CH2Cl2 (17.4 mL) was stirred at 25 °C for 1 h. The reaction
mixture was quenched with NH4Cl(sat.) and extracted with Et2O (3 x 100 mL). The organic phase was collected,
dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude product was purified
by column chromatography on silica gel (hexane/diethyl ether = 10:1) to obtain pure 7 (1.47 g, 4.49 mmol, 78%)
as a white solid. m.p: 100-102 °C; Rf 0.31 (hexane/ethyl acetate = 5:1); IR (neat) 3118, 2923, 1624, 1554, 1385,
1266, 1110, 909, 808, 723, 597 cm-1; 1H NMR (300 MHz, CDCl3) δ 8.09 (d, J = 5.3 Hz, 1H), 7.90 (dd, J = 8.4
Hz and J = 4.9 Hz, 2H), 7.39-7.36 (m, 2H), 7.34 (s, 1H), 7.31 (d, J = 0.3 Hz, 1H), 2.46 (s, 3H); 13C{1H} NMR
(75 MHz, CDCl3) δ 157.2, 148.6, 145.6, 135.2, 133.4, 129.7, 128.6, 126.0, 119.1, 21.7; HRMS (FAB) m/z [M +
H]+ calcd for C12H11BrNO3S 327.9644, found 327.9618.
3-Bromopyridin-2-yl trifluoromethanesulfonate (10)
To a solution of 3-bromo-2-hydroxypyridine (1 g, 5.75 mmol), pyridine (0.6 mL, 7.48 mmol) in anhydrous
CH2Cl2 (29 mL) was added triflic anhydride (6.90 mmol) dropwise at 0 °C. The reaction mixture was stirred for
10 min and then allowed to warm to room temperature. After stirring for 5 h, the reaction mixture was quenched
with NH4Cl(sat.) and extracted with Et2O (3 x 100 mL). The organic phase was collected, dried over anhydrous
MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by column
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chromatography on silica gel (hexane/diethyl ether = 10:1) to obtain pure 10 (1.53 g, 5.00 mmol, 87%) as a
yellow oil. 1H NMR (300 MHz, CDCl3) δ 8.33 (dd, J = 1.7 Hz and J = 4.7 Hz, 1H), 8.08 (dd, J = 1.6 Hz and J
= 7.9 Hz, 1H), 7.30-7.26 (m, 1H); 13C{1H} NMR (75 MHz, CDCl3) δ 152.9, 146.8, 144.3, 125.1, 118.4 (q, J =
323.74 Hz), 110.8; Data are consistent with those reported in the literature.13
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General procedure I for the synthesis of aryl-2-sulfonyloxypyridines
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A sealed tube was charged with bromo-2-sulfonyloxypyridine (1.0 equiv.), boronic acid (1.8 equiv.), K2CO3 (2.2
equiv.), Ad2BnP (2.4 mol %) and Pd(OAc)2 (2 mol %). The sealed tube and contents were placed under vacuum
and back-filled with argon under a Schlenk line three times. Degassed anhydrous toluene and water (0.1 M,
toluene/water = 30:1) was then added under argon and the reaction mixture was stirred at 25 °C. After completion
of the reaction as monitored by TLC analysis, the reaction mixture was extracted with CH2Cl2 (3 x 10 mL). The
organic phase was collected, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The
crude product was purified by flash column chromatography on silica gel to obtain the desired product.
General procedure II for the synthesis of unsymmetrical diarylpyridines
A sealed tube was charged with aryl-2-sulfonyloxypyridine (1.0 equiv.), boronic acid (2.0 equiv.), K2CO3 (2.2
equiv.), SPhos (5 mol %) and Pd(OAc)2 (4 mol %). The sealed tube and contents were placed under vacuum and
back-filled with argon under a Schlenk line three times. Degassed anhydrous toluene and water (0.1 M,
toluene/water = 30:1) was then added under argon and the reaction mixture was stirred at 100 °C in an oil bath.
After completion of the reaction as monitored by TLC analysis, the reaction mixture was extracted with CH2Cl2
(3 x 10 mL). The organic phase was collected, dried over anhydrous MgSO4, filtered and concentrated under
reduced pressure. The crude product was purified by flash column chromatography on silica gel to obtain the
desired product.
5-Phenylpyridin-2-yl 4-methylbenzenesulfonate (3a)
General procedure I was used employing 5-bromo-2-tosyloxypyridine (100 mg, 0.305 mmol) and phenylboronic
acid (66.9 mg, 0.549 mmol). The reaction was completed in 20 min. Flash column chromatography on silica gel
using hexane/ethyl acetate (10:1) provided pure 3a (98.2 mg, 0.302 mmol, 99%) as a white solid. 1H NMR (300
MHz, CDCl3) δ 8.45 (d, J = 2.6 Hz, 1H), 7.95-7.90 (m, 3H), 7.51-7.42 (m, 5H), 7.36 (d, J = 8.0 Hz, 2H), 7.18
(d, J = 8.4 Hz, 1H), 2.45 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 156.1, 146.4, 145.3, 138.5, 136.4, 136.0,
133.6, 129.7, 129.1, 128.6, 128.4, 127.0, 115.7, 21.7; Data are consistent with those reported in the literature.9c
Large-scale Preparation of 5-Phenylpyridin-2-yl 4-methylbenzenesulfonate (3a)
General procedure I was used employing 5-bromo-2-tosyloxypyridine (1.00 g, 3.05 mmol) and phenylboronic
acid (669 mg, 5.49 mmol). The reaction was completed in 30 min. Flash column chromatography on silica gel
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using hexane/ethyl acetate (10:1) provided pure 3a (982 mg, 3.02 mmol, 99%) as a white solid. 1H NMR (300
MHz, CDCl3) δ 8.45 (d, J = 2.6 Hz, 1H), 7.95-7.90 (m, 3H), 7.51-7.42 (m, 5H), 7.36 (d, J = 8.0 Hz, 2H), 7.18
(d, J = 8.4 Hz, 1H), 2.45 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 156.1, 146.4, 145.3, 138.5, 136.4, 136.0,
133.6, 129.7, 129.1, 128.6, 128.4, 127.0, 115.7, 21.7; Data are consistent with those reported in the literature.9c
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5-(4-Vinylphenyl)pyridin-2-yl 4-methylbenzenesulfonate (3b)
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General procedure I was used employing 5-bromo-2-tosyloxypyridine (100 mg, 0.305 mmol) and (4-
vinylphenyl)boronic acid (81.2 mg, 0.549 mmol). The reaction was completed in 50 min. Flash column
chromatography on silica gel using hexane/ethyl acetate (10:1) provided pure 3b (106 mg, 0.302 mmol, 99%) as
a yellow solid. m.p: 126-130 °C; Rf 0.23 (hexane/ethyl acetate = 5:1); IR (neat) 2702, 1639, 1468, 1360, 1268,
1176, 1013, 880, 755 cm-1; 1H NMR (300 MHz, CDCl3) δ 8.44 (dd, J = 0.6 Hz and J = 2.7 Hz, 1H), 7.94-7.90
(m, 3H), 7.48 (s, 4H), 7.34 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 8.8 Hz, 1H), 6.78-6.68 (m, 1H), 5.80 (dd, J = 0.6 Hz
and J = 17.4 Hz, 1H), 5.30 (dd, J = 0.6 Hz and J = 11.1 Hz, 1H), 2.44 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3)
δ 156.0, 146.1, 145.3, 138.2, 137.6, 135.9, 135.5, 135.4, 133.5, 129.7, 128.5, 127.0, 126.9, 115.7, 114.7, 21.6;
HRMS (EI) m/z [M]+ calcd for C20H17NO3S 351.0929, found 351.0931.
5-[4-(Methylthio)phenyl]pyridin-2-yl 4-methylbenzenesulfonate (3c)
General procedure I was used employing 5-bromo-2-tosyloxypyridine (100 mg, 0.305 mmol) and [4-
(methylthio)phenyl]boronic acid (95.1 mg, 0.549 mmol) and 5-bromo-2-tosyloxypyridine (0.305 mmol). The
reaction was completed in 4.5 h. Flash column chromatography on silica gel using hexane/ethyl acetate (10:1)
provided pure 3c (112 mg, 0.302 mmol, 99%) as a yellow solid. m.p: 106-110 °C; Rf 0.15 (hexane/ethyl acetate
1
= 5:1); IR (neat) 2993, 2346, 2098, 1915, 1590, 1464, 1370, 1174, 1095, 876, 721 cm-1; H NMR (300 MHz,
CDCl3) δ 8.42 (d, J = 2.3 Hz, 1H), 7.90 (dd, J = 3.0 Hz and J = 8.3 Hz, 3H), 7.43 (d, J = 8.6 Hz, 2H), 7.36-7.30
(m, 4H), 7.15 (d, J = 8.4 Hz, 1H), 2.50 (s, 3H), 2.44 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 156.0, 146.0,
145.3 139.4, 138.0, 135.3, 133.6, 132.8, 129.7, 128.5, 127.2, 126.7, 115.7, 21.7, 15.4; HRMS (EI) m/z [M]+ calcd
for C19H17NO3S2 371.0650, found 371.0651.
5-(4-Methoxyphenyl)pyridin-2-yl 4-methylbenzenesulfonate (3d)
General procedure I was used employing 5-bromo-2-tosyloxypyridine (100 mg, 0.305 mmol) and (4-
methoxyphenyl)boronic acid (83.4 mg, 0.549 mmol). The reaction was completed in 12 h. Flash column
chromatography on silica gel using hexane/ethyl acetate (10:1) provided pure 3d (107 mg, 0.302 mmol, 99%) as
a white solid. m.p: 135-140 °C; Rf 0.10 (hexane/ethyl acetate = 5:1); IR (neat) 2337, 1910, 1598, 1466, 1359,
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1248, 1175, 1019, 818, 738 cm-1; H NMR (300 MHz, CDCl3) δ 8.40 (d, J = 2.5 Hz, 1H), 7.92-7.86 (m, 3H),
7.44 (d, J = 8.8 Hz, 2H), 7.34(d, J = 8.1 Hz, 2H), 7.14 (d, J = 8.4 Hz, 1H), 6.98 (d, J = 8.8 Hz, 2H), 3.84 (s, 3H),
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2.44 (s, 3H); C{1H} NMR (75 MHz, CDCl3) δ 159.9, 155.6, 145.9, 145.2, 137.9, 135.6, 133.6, 129.7, 128.7,
128.5, 128.1, 115.7, 114.5, 55.3, 21.6; HRMS (EI) m/z [M]+ calcd for C19H17NO4S 355.0878, found 355.0881.
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General procedure I was used employing 5-bromo-2-tosyloxypyridine (100 mg, 0.305 mmol) and (3-
methoxyphenyl)boronic acid (83.4 mg, 0.549 mmol). The reaction was completed in 5.5 h. Flash column
chromatography on silica gel using hexane/ethyl acetate (10:1) provided pure 3e (107 mg, 0.302 mmol, 99%) as
a brown oil. Rf 0.15 (hexane/ethyl acetate = 5:1); IR (neat) 1925, 1747, 1593, 1466, 1370, 1299, 1174, 1094, 875,
755, 685, 561 cm-1; 1H NMR (300 MHz, CDCl3) δ 8.44 (d, J = 2.0 Hz, 1H), 7.91 (dd, J = 3.6 Hz and J = 8.4 Hz,
3H), 7.36-7.33 (m, 3H), 7.15 (dd, J = 0.4 Hz and J = 8.4 Hz, 1H), 7.10-7.06 (m, 1H), 7.02 (t, J = 4.1 Hz, 1H),
6.93 (dd, J = 0.8 Hz and J = 8.42 Hz, 1H) 3.84 (s, 3H), 2.44 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 160.0,
156.1, 146.3, 145.3, 138.5, 137.7, 135.8, 133.5, 130.1, 129.7, 128.5, 119.3, 115.6, 113.5, 112.8, 55.2, 21.6;
HRMS (EI) m/z [M]+ calcd for C19H17NO4S 355.0878, found 355.0876.
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5-(2-Methoxyphenyl)pyridin-2-yl 4-methylbenzenesulfonate (3f)
General procedure I with modifications (P(Cy)3 instead of Ad2BnP at 100 °C in an oil bath) was used employing
5-bromo-2-tosyloxypyridine (100 mg, 0.305 mmol) and (2-methoxyphenyl)boronic acid (83.4 mg, 0.549 mmol).
The reaction was completed in 1.5 h. Flash column chromatography on silica gel using hexane/ethyl acetate
(10:1) provided pure 3f (102 mg, 0.287 mmol, 94%) as a yellow solid. m.p: 102-106 °C; Rf 0.15 (hexane/ethyl
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acetate = 5:1); IR (neat) 2050, 1925, 1750, 1589, 1465, 1371, 1174, 1096, 1026, 876, 758, 682, 558 cm-1; H
NMR (300 MHz, CDCl3) δ 8.38 (dd, J = 0.8 Hz and J = 2.6 Hz, 1H), 7.96-7.91 (m, 3H), 7.36-7.33 (m, 3H), 7.27-
7.24 (m, 1H), 7.12 (dd, J = 0.7 Hz and J = 8.4 Hz, 1H), 7.05-7.00 (m, 2H), 3.79 (s, 3H), 2.44 (s, 3H); 13C{1H}
NMR (75 MHz, CDCl3) δ 156.4, 155.5, 148.3, 145.2, 140.9, 133.7, 133.4, 130.4, 129.8, 129.6, 128.5, 125.5,
121.0, 114.8, 111.2, 55.4, 21.6; HRMS (EI) m/z [M]+ calcd for C19H17NO4S 355.0878, found 355.0882.
5-(4-Fluorophenyl)pyridin-2-yl 4-methylbenzenesulfonate (3g)
General procedure I was used employing 5-bromo-2-tosyloxypyridine (100 mg, 0.305 mmol) and (4-
fluorophenyl)boronic acid (97%; 792 mg, 0.549 mmol). The reaction was completed in 40 min. Flash column
chromatography on silica gel using hexane/ethyl acetate (10:1) provided pure 3g (104 mg, 0.302 mmol, 99%) as
a white solid. m.p: 84-90 °C; Rf 0.21 (hexane/ethyl acetate = 5:1); IR (neat) 1747, 1659, 1595, 1453, 1369, 1268,
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1159, 1093, 1005, 831, 764, 692 cm-1; H NMR (300 MHz, CDCl3) δ 8.40 (d, J = 2.3 Hz, 1H), 7.93-7.88 (m,
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3H), 7.50-7.45 (m, 2H), 7.35 (d, J = 8.1 Hz, 2H), 7.18-7.12 (m, 3H), 2.45 (s, 3H); C{1H} NMR (75 MHz,
CDCl3) δ 162.9 (d, J = 248.4 Hz), 156.0, 146.1, 145.3, 138.3, 134.9, 133.5, 132.5 (d, J = 3.3 Hz), 129.7, 128.7
(d, J = 8.3 Hz), 128.5, 116.1 (d, J = 21.8 Hz), 115.7, 21.6; 19F{1H} NMR (282 MHz, CDCl3) δ -113.5; HRMS
(EI) m/z [M]+ calcd for C18H14FNO3S 343.0678, found 343.0676.
5-(4-Chlorophenyl)pyridin-2-yl 4-methylbenzenesulfonate (3h)
General procedure I was used employing 5-bromo-2-tosyloxypyridine (100 mg, 0.305 mmol) and (4-
chlorophenyl)boronic acid (95%; 90.4 mg, 0.549 mmol). The reaction was completed in 30 min. Flash column
chromatography on silica gel using hexane/ethyl acetate (10:1) provided pure 3h (109 mg, 0.302 mmol, 99%) as
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a white solid. m.p: 113-116 °C; Rf 0.23 (hexane/ethyl acetate = 5:1); IR (neat) 3062, 586, 1466, 1358, 1196, 1092,
876, 815, 691, 569 cm-1; 1H NMR (300 MHz, CDCl3) δ 8.42 (dd, J = 0.6 Hz and J = 2.7 Hz, 1H), 7.94-7.89 (m,
3H), 7.44 (s, 4H), 7.36 (d, J = 8.1 Hz, 2H), 7.19 (dd, J = 0.6 Hz and J = 8.4 Hz, 1H), 2.46 (s, 3H); 13C{1H} NMR
(75 MHz, CDCl3) δ 156.3, 146.2, 145.4, 138.3, 134.8, 134.7, 134.6, 133.5, 129.7, 129.3, 128.5, 128.2, 115.8,
21.7; HRMS (FAB) m/z [M + H]+ calcd for C18H15ClNO3S 360.0461, found 360.0464.
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tert-Butyl 4-[6-(tosyloxy)pyridin-3-yl]benzoate (3i)
General procedure I was used employing 5-bromo-2-tosyloxypyridine (100 mg, 0.305 mmol) and (4-(tert-
butoxycarbonyl)phenyl)boronic acid (95%; 122 mg, 0.549 mmol). The reaction was completed in 1.5 h. Flash
column chromatography on silica gel using hexane/ethyl acetate (10:1) provided pure 3i (129 mg, 0.302 mmol,
99%) as a white solid. m.p: 107-109 °C; Rf 0.22 (hexane/ethyl acetate = 5:1); IR (neat) 3060, 2978, 1710, 1469,
1371, 1295, 1172, 1118, 881, 774 cm-1; 1H NMR (300 MHz, CDCl3) δ 8.48 (dd, J = 0.6 Hz and J = 2.7 Hz, 1H),
8.07 (d, J = 8.7 Hz, 2 H), 7.98 (dd, J = 2.4 Hz and J = 8.4 Hz, 1H), 7.93 (d, J = 8.4 Hz, 2H), 7.57 (d, J = 8.7 Hz,
2H), 7.37 (d, J = 8.1 Hz, 2H), 7.21 (dd, J = 0.6 Hz and J = 8.4 Hz, 1H), 2.46 (s, 3H), 1.62 (s, 9H); 13C{1H} NMR
(75 MHz, CDCl3) δ 165.2, 156.6, 146.6, 145.4, 140.3, 138.6, 135.0, 133.6, 131.9, 130.2, 129.7, 128.6, 126.8,
115.8, 81.4, 28.2, 21.7; HRMS (FAB) m/z [M + H]+ calcd for C23H24NO5S 426.1376, found 426.1373.
5-(Benzo[b]thiophen-2-yl)pyridin-2-yl 4-methylbenzenesulfonate (3j)
General procedure I was used employing 5-bromo-2-tosyloxypyridine (100 mg, 0.305 mmol) and benzo[b]thien-
2-ylboronic acid (976 mg, 0.549 mmol). The reaction was completed in 6 h. Flash column chromatography on
silica gel using hexane/ethyl acetate (10:1) provided pure 3j (115 mg, 0.302 mmol, 99%) as a yellow solid. m.p:
169-173 °C; Rf 0.33 (hexane/ethyl acetate = 5:1); IR (neat) 3445, 1635, 1472, 1348, 1207, 1168, 1090, 866, 747,
557 cm-1; 1H NMR (300 MHz, CDCl3) δ 8.57 (d, J = 2.4 Hz, 1H), 8.02 (dd, J = 2.7 Hz and J = 8.6 Hz, 1H), 7.92
(d, J = 8.1 Hz, 2H), 7.85-7.78 (m, 2H), 7.53 (s, 1H), 7.39-7.35 (m, 4H), 7.17 (d, J = 8.7 Hz, 1H), 2.46 (s, 3H);
13C{1H} NMR (75 MHz, CDCl3) δ 156.4, 145.6, 145.4, 140.2, 139.7, 138.6, 137.6, 133.6, 129.8, 129.7, 128.6,
125.1, 124.9, 123.9, 122.3, 121.2, 116.0, 21.7; HRMS (EI) m/z [M]+ calcd for C20H15NO3S2 381.0493, found
381.0492.
5-(Thiophen-3-yl)pyridin-2-yl 4-methylbenzenesulfonate (3k)
General procedure I with modifications (P(Cy)3 instead of Ad2BnP at 100 °C in an oil bath) was used employing
5-bromo-2-tosyloxypyridine (100 mg, 0.305 mmol) and 3-thienylboronic acid (98%; 71.6 mg, 0.549 mmol). The
reaction was completed in 1.5 h. Flash column chromatography on silica gel using hexane/ethyl acetate (10:1)
provided pure 3k (100 mg, 0.302 mmol, 99%) as a yellow solid. m.p: 76-78 °C; Rf 0.20 (hexane/ethyl acetate =
5:1); IR (neat) 3455, 3446, 2073, 1636, 1473, 1372, 1173, 1092, 876, 738, 569 cm-1; 1H NMR (300 MHz, CDCl3)
δ 8.46 (d, J = 2.4 Hz, 1H), 7.94-7.89 (m, 3H), 7.48-7.43 (m, 2H), 7.36-7.30 (m, 3H), 7.14 (d, J = 8.4 Hz, 1H),
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2.45 (s, 3H); C{1H} NMR (75 MHz, CDCl3) δ 155.6, 145.7, 145.3, 137.6, 137.3, 133.5, 130.9, 129.7, 128.5,
127.2, 125.7, 121.8, 115.9, 21.7; HRMS (ESI) m/z [M + H]+ calcd for C16H14NO3S2 332.0416, found 332.0415.
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5-(Furan-3-yl)pyridin-2-yl 4-methylbenzenesulfonate (3l)
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General procedure I with modifications (P(Cy)3 instead of Ad2BnP at 100 °C in an oil bath) was used employing
5-bromo-2-tosyloxypyridine (100 mg, 0.305 mmol) and 3-furanylboronic acid (97%; 63.3 mg, 0.549 mmol). The
reaction was completed in 14 h. Flash column chromatography on silica gel using hexane/ethyl acetate (10:1)
provided pure 3l (68.1 mg, 0.216 mmol, 71%; 77% conversion) as a white solid. m.p: 59-62 °C; Rf 0.25
(hexane/ethyl acetate = 5:1); IR (neat) 3450, 2953, 2859, 1597, 1463, 1299, 1097, 957, 843, 519 cm-1; 1H NMR
(300 MHz, CDCl3) δ 8.36 (dd, J = 0.6 Hz and J = 2.4 Hz, 1H), 7.90 (dd, J = 1.5 Hz and J = 6.8 Hz, 2H), 7.83
(dd, J = 2.4 Hz and J = 8.4 Hz, 1H), 7.73 (t, J = 1.5 Hz, 1H), 7.51 (t, J = 1.5 Hz, 1H), 7.35 (d, J = 8.1 Hz, 2H),
7.13 (dd, J = 0.9 Hz and J = 8.4 Hz, 1H), 6.65 (dd, J = 1.2 Hz and J = 2.0 Hz, 1H), 2.46 (s, 3H); 13C{1H} NMR
(75 MHz, CDCl3) δ 155.5, 145.3, 145.1, 144.3, 139.0, 137.1, 133.5, 129.7, 128.5, 127.8, 122.0, 115.9, 108.3,
21.7; HRMS (ESI) m/z [M + H]+ calcd for C16H14NO4S 316.0644, found 316.0643.
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6-Phenylpyridin-2-yl 4-methylbenzenesulfonate (4a)
General procedure I was used employing 6-bromo-2-tosyloxypyridine (100 mg, 0.305 mmol) and phenylboronic
acid (66.9 mg, 0.549 mmol). The reaction was completed in 20 min. Flash column chromatography on silica gel
using hexane/ethyl acetate (10:1) provided pure 4a (98.2 mg, 0.302 mmol, 99%) as a white solid. m.p: 100-
104 °C; Rf 0.23 (hexane/ethyl acetate = 5:1); IR (neat) 3079, 2351, 1559, 1436, 1366, 1169, 1079, 895, 770, 687,
545 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.93 (d, J = 8.3 Hz, 2H), 7.79 (t, J = 7.8 Hz, 1H), 7.71-7.67 (m, 2H),
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7.62 (d, J = 7.7 Hz, 1H), 7.39-7.32 (m, 5H), 7.03 (d, J = 7.9 Hz, 1H), 2.45 (s, 3H); C{1H} NMR (75 MHz,
CDCl3) δ 156.9, 156.1, 145.0, 140.7, 137.3, 134.3, 129.52, 129.5, 128.7, 128.5, 126.8, 118.5, 113.7, 21.6; HRMS
(FAB) m/z [M + H]+ calcd for C18H16NO3S 326.0852, found 326.0849.
6-(4-Methoxyphenyl)pyridin-2-yl 4-methylbenzenesulfonate (4b)
General procedure I was used employing 6-bromo-2-tosyloxypyridine (100 mg, 0.305 mmol) and 4-
methoxyphenyl)boronic acid (83.4 mg, 0.549 mmol). The reaction was completed in 3 h. Flash column
chromatography on silica gel using hexane/ethyl acetate (10:1) provided pure 4b (107 mg, 0.302 mmol, 99%) as
a white solid. m.p: 86-90 °C; Rf 0.14 (hexane/ethyl acetate = 5:1); IR (neat) 1910, 1749, 1599, 1444, 1372, 1252,
1177, 1083, 906, 814, 667, 558, 438 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.91 (d, J = 8.3 Hz, 2H), 7.72 (t, J =
7.8 Hz, 1H), 7.64 (d, J = 8.8 Hz, 2H), 7.52 (d, J = 7.7 Hz, 1H), 7.33 (d, J = 8.1 Hz, 2H), 6.94 (d, J = 7.9 Hz,
1H), 6.88 (d, J = 9.5 Hz, 2H), 3.82 (s, 3H), 2.44 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 160.6, 156.5, 155.7,
144.9, 140.5, 134.1, 129.6, 129.4, 128.4, 128.0, 117.5, 113.7, 112.5, 55.1, 21.4; HRMS (EI) m/z [M]+ calcd for
C19H17NO4S 355.0878, found 355.0876.
6-(4-Fluorophenyl)pyridin-2-yl 4-methylbenzenesulfonate (4c)
General procedure I was used employing 6-bromo-2-tosyloxypyridine (100 mg, 0.305 mmol) and (4-
fluorophenyl)boronic acid (97%; 79.2 mg, 0.549 mmol). The reaction was completed in 30 min. Flash column
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chromatography on silica gel using hexane/ethyl acetate (10:1) provided pure 4c (104 mg, 0.302 mmol, 99%) as
a white solid. m.p: 94-100 °C; Rf 0.20 (hexane/ethyl acetate = 5:1); IR (neat) 1912, 1725, 1597, 1513, 1444, 1374,
1176, 1085, 906, 816, 667, 557, 445 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.92 (d, J = 8.3 Hz, 2H), 7.79 (t, J =
8.2 Hz, 1H), 7.71-7.66 (m, 2H), 7.57 (d, J = 7.7 Hz, 1H), 7.35 (d, J = 8.1 Hz, 2H), 7.04 (q, J = 8.5 Hz, 3H), 2.46
(s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 165.2 (d, J = 249.9 Hz), 156.9, 155.1, 145.1, 140.9, 134.3, 133.5 (d,
J = 3.0 Hz), 129.6, 128.8, 128.7, 118.2, 115.5 (d, J = 21.6 Hz), 113.6, 21.7; 19F{1H} NMR (282 MHz, CDCl3) δ
-111.7; HRMS (EI) m/z [M]+ calcd for C18H14FNO3S 343.0678, found 343.0675.
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6-(4-Chlorophenyl)pyridin-2-yl 4-methylbenzenesulfonate (4d)
General procedure I was used employing 6-bromo-2-tosyloxypyridine (100 mg, 0.305 mmol) and (4-
chlorophenyl)boronic acid (95%; 90.4 mg, 0.549 mmol). The reaction was completed in 50 min. Flash column
chromatography on silica gel using hexane/ethyl acetate (10:1) provided pure 4d (109 mg, 0.302 mmol, 99%) as
a white solid. m.p: 114-116 °C; Rf 0.20 (hexane/ethyl acetate = 5:1); IR (neat) 2999, 2348, 1919, 1747, 1592,
1442, 1373, 1268, 1174, 1086, 904, 756, 555 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.91 (d, J = 8.3 Hz, 2H), 7.79
(t, J = 7.8 Hz, 1H), 7.64-7.56 (m, 3H), 7.35-7.25 (m, 4H), 7.02 (d, J = 8.0 Hz, 1H), 2.45 (s, 3H); 13C{1H} NMR
(75 MHz, CDCl3) δ 156.8, 154.8, 145.1, 140.9, 135.7, 135.6, 134.3, 129.5, 128.7, 128.6, 128.0, 118.3, 113.9,
21.6; HRMS (EI) m/z [M]+ calcd for C18H14ClNO3S 359.0383, found 359.0385.
4-[3-[(tert-Butyldimethylsilyl)oxy]phenyl]pyridin-2-yl 4-methylbenzenesulfonate (4e)
General procedure I was used employing 4-bromo-2-tosyloxypyridine (100 mg, 0.305 mmol) and 3-(tert-
butyldimethylsilyloxy)phenylboronic acid (122 mg, 0.549 mmol). The reaction was completed in 2 h. Flash
column chromatography on silica gel using hexane/ethyl acetate (10:1) provided pure 4e (136 mg, 0.299 mmol,
98%) as a white solid. m.p: 63-67 °C; Rf 0.38 (hexane/ethyl acetate = 5:1); IR (neat) 3441, 2070, 1637, 1544,
1326, 1166, 1124, 813, 744, 558 cm-1; 1H NMR (300 MHz, CDCl3) δ 8.27 (d, J = 5.1 Hz, 1H), 7.93 (d, J = 8.1
Hz, 2H), 7.40-7.31 (m, 4H), 7.27 (s, 1H), 7.19-7.16 (m, 1H), 7.05 (t, J = 2.1 Hz, 1H), 6.95-6.91 (m, 1H), 2.45 (s,
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3H), 1.01 (s, 9H), 0.24 (s, 6H); C{1H} NMR (75 MHz, CDCl3) δ 157.7, 156.3, 152.7, 148.4, 145.2, 138.2,
133.7, 130.2, 129.7, 128.6, 121.2, 120.7, 120.0, 118.7, 113.4, 25.6, 21.7, 18.2, -4.4; HRMS (ESI) m/z [M + H]+
calcd for C24H30NO4SSi 456.1666, found 456.1665.
4-(Thiophen-3-yl)pyridin-2-yl 4-methylbenzenesulfonate (4f)
General procedure I with modifications (P(Cy)3 instead of Ad2BnP at 100 °C in an oil bath) was used employing
4-bromo-2-tosyloxypyridine (100 mg, 0.305 mmol) and 3-thienylboronic acid (98%; 71.7 mg, 0.549 mmol). The
reaction was completed in 20 min. Flash column chromatography on silica gel using hexane/ethyl acetate (5:1)
provided pure 4f (95.0 mg, 0.287 mmol, 94%) as a yellow solid. m.p: 88-90 °C; Rf 0.11 (hexane/ethyl acetate =
5:1); IR (neat) 1929, 1753, 160, 1369, 1269, 1174, 1093, 944, 860, 755, 674, 557 cm-1; H NMR (300 MHz,
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CDCl3) δ 8.21 (d, J = 5.3 Hz, 1H), 7.91 (d, J = 8.4 Hz, 2H), 7.66-7.64 (q, J = 1.4 Hz, 1H), 7.44-7.41 (m, 1H),
7.39-7.32 (m, 3H), 7.26 (s, 1H), 7.26 (d, J = 0.9 Hz, 1H), 2.43 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 157.8,
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H]+ calcd for C16H14NO3S2 332.0416, found 332.0415.
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General procedure I was used employing 4-bromo-2-tosyloxypyridine (100 mg, 0.305 mmol) and [4-
(trifluoromethyl)phenyl]boronic acid (98%; 106 mg, 0.549 mmol). The reaction was completed in 5.5 h. Flash
column chromatography on silica gel using hexane/ethyl acetate (10:1) provided pure 4g (119 mg, 0.302 mmol,
99%) as a white solid. m.p: 106-110 °C; Rf 0.20 (hexane/ethyl acetate = 5:1); IR (neat) 3441, 2070, 1637, 1544,
1326, 1166, 1125, 909, 814, 744, 558 cm-1; 1H NMR (300 MHz, CDCl3) δ 8.33 (d, J = 5.1 Hz, 1H), 7.93 (d, J =
8.4 Hz, 2H), 7.73 (q, J = 6.6 Hz, 4H), 7.44 (dd, J = 1.5 Hz and J = 5.4 Hz, 1H), 7.38-7.32 (m, 3H), 2.46 (s, 3H);
13C{1H} NMR (75 MHz, CDCl3) δ 157.8, 151.4, 148.8, 145.4, 140.3, 133.5, 131.5 (q, J = 33.0 Hz), 129.7, 128.6,
127.5, 126.1 (q, J = 3.8 Hz), 123.8 (q, J = 271.5 Hz), 120.8, 113.7, 21.6; HRMS (FAB) m/z [M + H]+ calcd for
C19H15F3NO3S 394.0725, found 394.0723.
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tert-Butyl 4-[2-(tosyloxy)pyridin-4-yl]benzoate (4h)
General procedure I was used employing 4-bromo-2-tosyloxypyridine (100 mg, 0.305 mmol) and [4-(tert-
butoxycarbonyl)phenyl]boronic acid (95%; 128 mg, 0.549 mmol). The reaction was completed in 3.5 h. Flash
column chromatography on silica gel using hexane/ethyl acetate (10:1) provided pure 4h (126 mg, 0.296 mmol,
97%) as a brown solid. m.p: 90-94 °C; Rf 0.11 (hexane/ethyl acetate = 5:1); IR (neat) 1934, 1712, 1602, 1467,
1377, 1296, 1173, 1110, 909, 846 cm-1; 1H NMR (300 MHz, CDCl3) δ 8.31 (dd, J = 0.6 Hz and J = 5.3 Hz, 1H),
8.10 (d, J = 8.6 Hz, 2H), 7.92 (d, J = 8.3 Hz, 2H), 7.63 (d, J = 8.6 Hz, 2H), 7.45 (dd, J = 1.5 Hz and J = 5.3 Hz,
1H), 7.37-7.32 (m, 3H), 2.45 (s, 3H), 1.62 (s, 9H); 13C{1H} NMR (75 MHz, CDCl3) δ 164.9, 157.7, 151.8, 148.6,
145.3, 140.4, 133.5, 132.9, 130.2, 129.6, 128.5, 126.8, 120.7, 113.6, 81.4, 28.1, 21.6; HRMS (FAB) m/z [M +
H]+ calcd for C23H24NO5S 426.1376, found 426.1372.
3-Phenylpyridin-2-yl trifluoromethanesulfonate (4i)
General procedure I was used employing 3-bromopyridin-2-yl trifluoromethanesulfonate (100 mg, 0.327 mmol)
and phenylboronic acid (71.8 mg, 0.589 mmol). The reaction was completed in 40 min. Flash column
chromatography on silica gel using hexane/ethyl acetate (10:1) provided pure 4i (89.2 mg, 0.294 mmol, 90%) as
a yellow oil. Rf 0.49 (hexane/ethyl acetate = 5:1); IR (neat) 2667, 2349, 1963, 1706, 1598, 1417, 1216, 1142,
1006, 887, 799, 698 cm-1; 1H NMR (300 MHz, CDCl3) δ 8.34 (dd, J = 1.9 Hz and J = 4.8 Hz, 1H), 7.89 (dd, J =
1.9 Hz and J = 7.6 Hz, 1H), 7.49-7.42 (m, 6H); 13C{1H} NMR (75 MHz, CDCl3) δ 153.1, 146.9, 141.5, 133.5,
129.0, 128.98, 128.9, 128.7, 124.3, 118.3 (q, J = 320.3 Hz); HRMS (EI) m/z [M]+ calcd for C12H8F3NO3S
303.0177, found 303.0177.
3-(3,5-Dimethylphenyl)pyridin-2-yl trifluoromethanesulfonate (4j)
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General procedure I was used employing 3-bromopyridin-2-yl trifluoromethanesulfonate (100 mg, 0.327 mmol)
and (3,5-dimethylphenyl)boronic acid (88.3 mg, 0.589 mmol). The reaction was completed in 1.5 h. Flash column
chromatography on silica gel using hexane/ethyl acetate (10:1) provided pure 4j (104 mg, 0.314 mmol, 96%) as
a yellow oil. Rf 0.40 (hexane/ethyl acetate = 5:1); IR (neat) 2927, 2349, 1956, 1750, 1604, 1416, 1215, 1141,
895, 755, 606, 523, 451 cm-1; 1H NMR (300 MHz, CDCl3) δ 8.31 (dd, J = 1.9 Hz and J = 4.8 Hz, 1H), 7.87 (dd,
J = 1.9 Hz and J = 7.6 Hz, 1H), 7.40 (dd, J = 4.7 Hz and J = 7.6 Hz, 1H), 7.08 (s, 3H), 2.37 (s, 6H); 13C{1H}
NMR (75 MHz, CDCl3) δ 153.1, 146.6, 141.4, 138.4, 133.3, 130.5, 129.1, 126.8, 124.2, 118.3 (q, J = 322.6 Hz),
21.1; HRMS (EI) m/z [M]+ calcd for C14H12F3NO3S 331.0490, found 331.0492.
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3-(4-Fluorophenyl)pyridin-2-yl trifluoromethanesulfonate (4k)
General procedure I was used employing 3-bromopyridin-2-yl trifluoromethanesulfonate (100 mg, 0.327 mmol)
and (4-fluorophenyl)boronic acid (97%; 85.0 mg, 0.589 mmol). The reaction was completed in 40 min. Flash
column chromatography on silica gel using hexane/ethyl acetate (10:1) provided pure 4k (91.4 mg, 0.284 mmol,
87%) as a yellow oil. Rf 0.49 (hexane/ethyl acetate = 5:1); IR (neat) 2858, 2348, 1902, 1754, 1602, 1514, 1418,
1219, 1140, 885, 807, 757, 605 cm-1; 1H NMR (300 MHz, CDCl3) δ 8.36 (dd, J = 2.1 Hz and J = 4.6 Hz, 1H),
7.87 (dd, J = 1.9 Hz and J = 7.7 Hz, 1H), 7.48-7.43 (m, 3H), 7.21-7.15 (m, 2H); 13C{1H} NMR (75 MHz, CDCl3)
δ 163.1 (d, J = 249.5 Hz), 153.0, 147.1, 141.4, 130.9 (d, J = 8.5 Hz), 129.5 (d, J = 3.5 Hz), 128.1, 124.4, 121.3
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(q, J = 320.5 Hz), 115.9 (d, J = 21.7 Hz); F{1H} NMR (282 MHz, CDCl3) δ -73.6, -122.1; HRMS (EI) m/z
[M]+ calcd for C12H7F4NO3S 321.0083, found 321.0078.
tert-Butyl 4-[2-[[(trifluoromethyl)sulfonyl]oxy]pyridin-3-yl]benzoate (4l)
General procedure I was used employing 3-bromopyridin-2-yl trifluoromethanesulfonate (100 mg, 0.327 mmol)
and [4-(tert-butoxycarbonyl)phenyl]boronic acid (131 mg, 0.589 mmol). The reaction was completed in 4 h.
Flash column chromatography on silica gel using hexane/ethyl acetate (10:1) provided pure 4l (118.7 mg, 0.294
mmol, 90%) as a white solid. m.p: 90-94 °C; Rf 0.23 (hexane/ethyl acetate = 5:1); IR (neat) 3412, 2982, 2349,
2147, 1945, 1712, 1606, 1418, 1293, 1130, 1009, 884 cm-1; 1H NMR (300 MHz, CDCl3) δ 8.39 (dd, J = 2.0 Hz
and J = 4.7 Hz, 1H), 8.11 (d, J = 8.6 Hz, 2H), 7.91 (dd, J = 2.1 Hz and J = 7.5 Hz, 1H), 7.53 (d, J = 8.6 Hz, 2H),
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7.50-7.46 (m, 1H), 1.63 (s, 9H); C{1H} NMR (75 MHz, CDCl3) δ 165.0, 152.9, 147.5, 141.5, 137.4, 132.4,
129.8, 128.9, 128.1, 124.4, 118.3 (q, J = 320.5 Hz), 81.5, 28.1; HRMS (EI) m/z [M]+ calcd for C17H16F3NO5S
403.0701, found 403.0699.
2-(4-Methoxyphenyl)-5-phenylpyridine (5a)
General procedure II was used employing 5-phenylpyridin-2-yl 4-methylbenzenesulfonate (100 mg, 0.307 mmol)
and (4-methoxyphenyl)boronic acid (93.5 mg, 0.615 mmol). The reaction was completed in 10 min. Flash column
chromatography on silica gel using hexane/ethyl acetate (10:1) provided pure 5a (79.4 mg, 0.304 mmol, 99%) as
a white solid. 1H NMR (300 MHz, CDCl3) δ 8.89 (d, J = 2.4 Hz, 1H), 8.01 (d, J = 8.9 Hz, 2H), 7.93 (dd, J = 2.2
Hz and J = 8.4 Hz, 1H), 7.75 (d, J = 8.3 Hz, 1H), 7.64 (d, J = 8.1 Hz, 2H), 7.50 (t, J = 7.4 Hz, 2H), 7.47 (d, J =
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7.6 Hz, 1H), 7.02 (d, J = 8.9 Hz, 2H), 3.83 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 160.5, 155.8, 147.9, 137.7,
135.0, 134.1, 131.6, 129.0, 128.1, 127.9, 126.9, 119.5, 114.1, 55.3; Data are consistent with those reported in the
literature.6a
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2-(4-Fluorophenyl)-5-phenylpyridine (5b)
General procedure II was used employing 5-phenylpyridin-2-yl 4-methylbenzenesulfonate (100 mg, 0.307 mmol)
and (4-fluorophenyl)boronic acid (97%; 88.7 mg, 0.615 mmol). The reaction was completed in 1 h. Flash column
chromatography on silica gel using hexane/ethyl acetate (10:1) provided pure 5b (75.8 mg, 0.304 mmol, 99%) as
a white solid. m.p: 142-146 °C; Rf 0.47 (hexane/ethyl acetate = 5:1); IR (neat) 1912, 1725, 1597, 1513, 1444,
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1374, 1176, 1085, 906, 816, 667 cm-1; H NMR (300 MHz, CDCl3) δ 8.91 (d, J = 2.3 Hz, 1H), 8.05-8.00 (m,
2H), 7.92 (dd, J = 2.2 Hz and J = 8.4 Hz, 1H), 7.73 (d, J = 8.3 Hz, 1H), 7.62 (d, J = 7.0 Hz, 2H), 7.51-7.38 (m,
3H), 7.16 (t, J = 8.7 Hz, 2H); 13C{1H} NMR (75 MHz, CDCl3) δ 163.5 (d, J = 248.4 Hz), 155.0, 148.0, 137.4,
135.1, 135.06, 134.8, 129.1, 128.6 (d, J = 8.3 Hz), 128.0, 126.9, 119.9, 115.7 (d, J = 21.6 Hz); 19F{1H} NMR
(282 MHz, CDCl3) δ -113.0; HRMS (EI) m/z [M]+ calcd for C17H12FN 249.0954, found 249.0954.
tert-Butyl 4-(5-phenylpyridin-2-yl)benzoate (5c)
General procedure II was used employing 5-phenylpyridin-2-yl 4-methylbenzenesulfonate (100 mg, 0.307 mmol)
and [4-(tert-butoxycarbonyl)phenyl]boronic acid (95%; 144 mg, 0.615 mmol). The reaction was completed in 1
h. Flash column chromatography on silica gel using hexane/ethyl acetate (10:1) provided pure 5c (93.6 mg, 0.282
mmol, 92%) as a white solid. m.p: 126-130 °C; Rf 0.42 (hexane/ethyl acetate = 5:1); IR (neat) 2348, 1904, 1747,
1593, 1424, 1267, 1190, 1095, 1021, 826 cm-1; 1H NMR (300 MHz, CDCl3) δ 8.94 (dd, J = 0.8 Hz J = 2.4 Hz,
1H), 8.10 (s, 4H), 7.92 (dd, J = 2.5 Hz and J = 8.4 Hz, 1H), 7.80 (dd, J = 0.8 Hz and J = 8.2 Hz, 1H), 7.62-7.59
(m, 2H), 7.50-7.42 (m, 3H), 1.62 (s, 9H); 13C{1H} NMR (75 MHz, CDCl3) δ 165.4, 154.8, 148.1, 142.5, 137.3,
135.4, 135.0, 132.2, 129.8, 129.0, 128.1, 126.9, 126.4, 120.6, 81.0, 28.1; HRMS (EI) m/z [M]+ calcd for
C22H21NO2 331.1572, found 331.1572.
2-(4-Fluorophenyl)-6-(2-methoxyphenyl)pyridine (5d)
General procedure II was used employing 6-(4-fluorophenyl)pyridin-2-yl 4-methylbenzenesulfonate (100 mg,
0.291 mmol) and (2-methoxyphenyl)boronic acid (88.5 mg, 0.582 mmol). The reaction was completed in 2 h.
Flash column chromatography on silica gel using hexane/ethyl acetate (10:1) provided pure 5d (80.5 mg, 0.288
mmol, 99%) as a yellow oil. Rf 0.47 (hexane/ethyl acetate = 5:1); IR (neat) 2038, 1901, 1789, 1585, 1451, 1241,
1166, 1100, 1025, 807, 755 cm-1; 1H NMR (300 MHz, CDCl3) δ 8.07 (q, J = 4.8 Hz, 2H), 7.98 (dd, J = 1.7 Hz
and J = 7.7 Hz, 1H), 7.81 (dd, J = 1.2 Hz and J = 7.8 Hz, 1H), 7.72 (t, J = 7.8 Hz, 1H), 7.57 (dd, J = 1.2 Hz and
J = 7.7 Hz, 1H), 7.37 (dq, J = 7.4 Hz and J = 3.4 Hz, 1H), 7.16-7.10 (m, 3H), 7.00 (d, J = 8.1 Hz, 1H), 3.85 (s,
3H); 13C{1H} NMR (75 MHz, CDCl3) δ 163.5 (d, J = 247.3 Hz), 157.2, 155.7, 155.5, 136.4, 135.8 (d, J = 2.9
Hz), 131.4, 129.9, 129.1, 128.7 (d, J = 7.5 Hz), 123.4, 121.0, 117.9, 115.4 (d, J = 21.3 Hz), 111.4, 55.5; 19F{1H}
NMR (282 MHz, CDCl3) δ -113.5; HRMS (EI) m/z [M]+ calcd for C18H14FNO 279.1059, found 279.1056.
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General procedure II was used employing 6-(4-fluorophenyl)pyridin-2-yl 4-methylbenzenesulfonate (100 mg,
0.291 mmol) and (3-methoxyphenyl)boronic acid (88.1 mg, 0.582 mmol). The reaction was completed in 50 min.
Flash column chromatography on silica gel using hexane/ethyl acetate (10:1) provided pure 5e (80.5 mg, 0.288
mmol, 98%) as a white solid. m.p: 90-96 °C; Rf 0.42 (hexane/ethyl acetate = 5:1); IR (neat) 3734, 3610, 2998,
2347, 1745, 1574, 1449, 1270, 1039, 757, 568 cm-1; 1H NMR (300 MHz, CDCl3) δ 8.12-8.08 (m, 2H), 7.74 (t, J
= 7.7 Hz, 2H), 7.67-7.56 (m, 3H), 7.38 (t, J = 8.0 Hz, 1H), 7.14 (t, J = 8.8 Hz, 2H), 6.96 (dd, J = 2.6 Hz and J
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= 8.3 Hz, 1H), 3.88 (s, 3H); C{1H} NMR (75 MHz, CDCl3) δ 163.5 (d, J = 248.2 Hz), 160.0, 156.5, 155.6,
104.8, 137.5, 135.5 (d, J = 3.0 Hz), 129.6, 128.7 (d, J = 8.3Hz), 119.3, 118.6, 118.3, 115.5 (d, J = 21.5 Hz),
114.5, 112.6, 55.3; 19F{1H} NMR (282 MHz, CDCl3) δ -113.1; HRMS (EI) m/z [M]+ calcd for C18H14FNO
279.1059, found 279.1057.
2-(4-Fluorophenyl)-6-(naphthalen-2-yl)pyridine (5f)
General procedure II was used employing 6-(4-fluorophenyl)pyridin-2-yl 4-methylbenzenesulfonate (100 mg,
0.291 mmol) and naphthalen-2-ylboronic acid (100 mg, 0.582 mmol). The reaction was completed in 5 h. Flash
column chromatography on silica gel using hexane/ethyl acetate (10:1) provided pure 5f (78.4 g, 0.262 mmol,
90%) as a white solid. m.p: 123-126 °C; Rf 0.44 (hexane/ethyl acetate = 5:1); IR (neat) 3844, 2348, 1743, 1568,
1455, 1267, 1091, 906, 755, 489 cm-1; 1H NMR (300 MHz, CDCl3) δ 8.58 (s, 1H), 8.30 (dd, J = 1.7 Hz and J =
8.6 Hz, 1H), 8.17 (dd, J = 5.5 Hz and J = 8.9 Hz, 2H), 7.97-7.95 (m, 2H), 7.87-7.84 (m, 1H), 7.84-7.82 (m, 2H),
7.67-7.65 (m, 1H), 7.53-7.50 (m, 2H), 7.25-7.17 (m, J = 7.8 Hz, 2H); 13C{1H} NMR (75 MHz, CDCl3) δ 163.6
(d, J = 247.2 Hz), 156.8, 155.9, 137.6, 136.7, 135.6 (d, J = 3.7 Hz), 133.7, 133.5, 128.9, 128.7 (d, J = 2.2 Hz),
128.4, 127.7, 126.5, 126.3, 126.26, 124.7, 118.8, 118.4, 115.6 (d, J = 21.6 Hz); 19F{1H} NMR (282 MHz, CDCl3)
δ -113.0; HRMS (EI) m/z [M]+ calcd for C21H14FN 299.1110, found 299.1106.
4-[3-[(tert-Butyldimethylsilyl)oxy]phenyl]-2-(thiophen-3-yl)pyridine (5g)
General procedure II was used employing 4-[3-[(tert-butyldimethylsilyl)oxy]phenyl]pyridin-2-yl 4-
methylbenzenesulfonate (100 mg, 0.219 mmol) and 3-thienylboronic acid (98%; 56.2 mg, 0.439 mmol). The
reaction was completed in 10 h. Flash column chromatography on silica gel using hexane/ethyl acetate (20:1)
provided pure 5g (72.5 mg, 0.197 mmol, 90%; 94% conversion) as a yellow oil. Rf 0.24 (hexane/ethyl acetate =
10:1); IR (neat) 3446, 2955, 2857, 2070, 1596, 1545, 1471, 1253, 1210, 958, 837, 672 cm-1; 1H NMR (300 MHz,
CDCl3) δ 8.65 (d, J = 5.2 Hz, 1H), 7.95 (dd, J = 1.2 Hz and J = 3.0 Hz, 1H), 7.78 (d, J = 0.9 Hz, 1H), 7.71 (dd,
J = 1.2 Hz and J = 4.9 Hz, 1H), 7.43-7.40 (m, 1H), 7.38-7.33 (m, 2H), 7.27-7.24 (m, 1H), 7.13 (t, J = 2.0 Hz,
1H), 6.95-6.91 (m, 1H), 1.02 (s, 9H), 0.25 (s, 6H); 13C{1H} NMR (75 MHz, CDCl3) δ 156.3, 154.0, 150.0, 149.1,
142.2, 139.9, 130.1, 126.3, 126.2, 123.6, 120.6, 120.04, 120.0, 118.8, 118.4, 25.7, 18.2, -4.4; HRMS (FAB) m/z
[M + H]+ calcd for C21H26NOSSi 368.1505, found 368.1507.
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General procedure II was used employing 4-[3-[(tert-butyldimethylsilyl)oxy]phenyl]pyridin-2-yl 4-
methylbenzenesulfonate (100 mg, 0.219 mmol) and p-tolylboronic acid (59.7 mg, 0.439 mmol). The reaction was
completed in 30 min. Flash column chromatography on silica gel using hexane/ethyl acetate (20:1) provided pure
5h (79.0 mg, 0.210 mmol, 96%) as a white oil. Rf 0.37 (hexane/ethyl acetate = 5:1); IR (neat) 3410, 2956, 2859,
2065, 1637, 1596, 1543, 1386, 1204, 962, 839 cm-1; 1H NMR (300 MHz, CDCl3) δ 8.70 (dd, J = 0.8 Hz and J =
5.2 Hz, 1H), 7.94 (d, J = 8.0 Hz, 2H), 7.86 (d, J = 0.9 Hz, 1H), 7.38-7.23 (m, 5H), 7.15 (t, J = 2.0 Hz, 1H), 6.92
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(ddd, J = 1.2 Hz, J = 2.5 Hz and J = 7.9 Hz, 1H), 2.40 (s, 3H), 1.02 (s, 9H), 0.25 (s, 6H); C{1H} NMR (75
MHz, CDCl3) δ 158.0, 156.2, 149.9, 149.0, 140.1, 138.9, 136.6, 130.0, 129.4, 126.8, 120.5, 120.1, 119.9, 118.8,
118.4, 25.6, 21.2, 18.2, -4.4; HRMS (FAB) m/z [M + H]+ calcd for C24H30NOSi 376.2097, found 376.2096.
4-[3-[(tert-Butyldimethylsilyl)oxy]phenyl]-2-[4-(trifluoromethyl)phenyl]pyridine (5i)
General procedure II was used employing 4-[3-[(tert-butyldimethylsilyl)oxy]phenyl]pyridin-2-yl 4-
methylbenzenesulfonate (100 mg, 0.219 mmol) and [4-(trifluoromethyl)phenyl]boronic acid (98%; 85.1 mg,
0.439 mmol). The reaction was completed in 45 min. Flash column chromatography on silica gel using
hexane/ethyl acetate (20:1) provided pure 5i (93.1 mg, 0.217 mmol, 99%) as a white oil. Rf 0.24 (hexane/ethyl
acetate = 10:1); IR (neat) 3441, 3065, 2956, 2897, 2097, 1930, 1597, 1548, 1325, 1273, 1207, 1127, 838, 784
cm-1; 1H NMR (300 MHz, CDCl3) δ 8.75 (d, J = 5.1 Hz, 1H), 8.16 (d, J = 8.1 Hz, 2H), 7.91 (s, 1H), 7.75 (d, J =
8.1 Hz, 2H), 7.46 (dd, J = 1.5 Hz and J = 5.1 Hz, 1H), 7.37 (t, J = 7.8 Hz, 1H), 7.27 (d, J = 7.8 Hz, 1H), 7.15 (t,
J = 1.8 Hz, 1H), 6.95 (dd, J = 1.5 Hz and J = 8.0 Hz, 1H), 1.02 (s, 9H), 0.26 (s, 6H); 13C{1H} NMR (75 MHz,
CDCl3) δ 156.4, 156.37, 150.3, 149.4, 142.8, 139.7, 130.8 (q, J = 32.4 Hz), 130.2, 127.3, 125.7 (q, J = 3.73 Hz),
124.2 (q, J = 3.60 Hz), 121.1, 120.8, 120.1, 119.0, 118.8, 25.7, 18.2, -4.4; HRMS (FAB) m/z [M + H]+ calcd for
C24H27F3NOSi 430.1815, found 430.1811.
3-(3,5-Dimethylphenyl)-2-(p-tolyl)pyridine (5j)
General procedure II was used employing 3-(3,5-dimethylphenyl)pyridin-2-yl trifluoromethanesulfonate (100
mg, 0.302 mmol) and p-tolylboronic acid (82.1 mg, 0.604 mmol). The reaction was completed in 40 min. Flash
column chromatography on silica gel using hexane/ethyl acetate (10:1) provided pure 5j (81.6 mg, 0.299 mmol,
99%) as a white solid. m.p: 102-106 °C; Rf 0.31 (hexane/ethyl acetate = 5:1); IR (neat) 3079, 2351, 1559, 1436,
1366, 1169, 1079, 895, 770, 687, 545 cm-1; 1H NMR (300 MHz, CDCl3) δ 8.64 (dd, J = 1.9 Hz and J = 4.5 Hz,
1H), 7.66 (dd, J = 1.7 Hz and J = 7.7 Hz, 1H), 7.28-7.23 (m, 3H), 7.03 (d, J = 7.9 Hz, 2H), 6.89 (s, 1H), 6.79 (s,
2H), 2.30 (s, 3H), 2.22 (d, J = 24.3 Hz, 6H); 13C{1H} NMR (75 MHz, CDCl3) δ 157.0, 148.0, 140.0, 138.4, 137.6,
137.31, 137.3, 136.0, 129.6, 128.6, 128.4, 127.3, 121.6, 21.2, 21.1; HRMS (EI) m/z [M]+ calcd for C20H19N
273.1517, found 273.1521.
3-(3,5-Dimethylphenyl)-2-[4-(methylthio)phenyl]-pyridine (5k)
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General procedure II was used employing 3-(3,5-dimethylphenyl)pyridin-2-yl trifluoromethanesulfonate (100
mg, 0.302 mmol) and [4-(methylthio)phenyl]boronic acid (97%; 105 mg, 0.604 mmol). The reaction was
completed in 2.5 h. Flash column chromatography on silica gel using hexane/ethyl acetate (10:1) provided pure
5k (88.5 mg, 0.290 mmol, 96%) as a yellow oil. Rf 0.26 (hexane/ethyl acetate = 5:1); IR (neat) 2348, 1904, 1747,
1593, 1424, 1267, 1190, 1095, 1021, 826 cm-1; 1H NMR (300 MHz, CDCl3) δ 8.65 (dd, J = 1.9 Hz and J = 4.5
Hz, 1H), 7.68 (dd, J = 1.8 Hz and J = 7.8 Hz, 1H), 7.33-7.26 (m, 3H), 7.12 (dd, J = 1.8 Hz and J = 6.6 Hz, 2H),
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6.91 (s, 1H), 6.80 (s, 2H), 2.45 (s, 3H), 2.24 (s, 6H); C{1H} NMR (75 MHz, CDCl3) δ 156.2, 148.0, 139.7,
138.5, 138.1, 137.7, 136.9, 136.0, 130.1, 128.7, 127.2, 125.6, 121.7, 21.2, 15.5; HRMS (EI) m/z [M]+ calcd for
C20H19NS 305.1238, found 305.1235.
3-(3,5-Dimethylphenyl)-2-[4-(trifluoromethyl)phenyl]-pyridine (5l)
General procedure II was used employing 3-(3,5-dimethylphenyl)pyridin-2-yl trifluoromethanesulfonate (100
mg, 0.302 mmol) and [4-(trifluoromethyl)phenyl]boronic acid (117 mg, 0.604 mmol). The reaction was
completed in 1 h. Flash column chromatography on silica gel using hexane/ethyl acetate (10:1) provided pure 5l
(92.9 mg, 0.284 mmol, 94%) as a white solid. m.p: 102-106 °C; Rf 0.37 (hexane/ethyl acetate = 5:1); IR (neat)
2999, 2348, 1919, 1747, 1592, 1442, 1373, 1268, 1174, 1086, 904, 756, 555 cm-1; 1H NMR (300 MHz, CDCl3)
δ 8.68 (dd, J = 1.7 Hz and J = 4.7 Hz, 1H), 7.72 (dd, J = 1.7 Hz and J = 7.8 Hz, 1H), 7.50 (s, 4H), 7.32 (q, J =
13
4.2 Hz, 1H), 6.92 (s, 1H), 6.76 (s, 2H), 2.21 (s, 6H); C{1H} NMR (75 MHz, CDCl3) δ 155.5, 148.3, 143.9,
139.1, 138.6, 138.0, 136.6, 130.1, 129.6 (q, J = 32.4 Hz), 129.1, 127.3, 124.7 (q, J = 3.8 Hz), 124.2 (q, J = 272.4
Hz), 122.6, 21.2; HRMS (EI) m/z [M]+ calcd for C20H16F3N 327.1235, found 327.1231.
A Sequential One-Pot Synthesis of Unsymmetrical Diarylpyridine
A sealed tube was charged with 6-bromo-2-sulfonyloxypyridine 5 (100 mg, 0.305 mmol), (4-
fluorophenyl)boronic acid 13a (97%; 792 mg, 0.549 mmol), K2CO3, (92.6 mg, 0.671 mmol), Ad2BnP (2.9 mg,
0.007 mmol) and Pd(OAc)2 (1.4 mg, 0.006 mmol). The sealed tube and contents were placed under vacuum and
back-filled with argon under a Schlenk line three times. Degassed anhydrous toluene and water (0.1 M,
toluene/water = 30:1) was then added under argon and the reaction mixture was stirred at 25 °C. After 30 min, to
a solution of crude product was added (3-methoxyphenyl)boronic acid 13b (185 mg, 1.219 mmol), SPhos (6.3
mg, 0.015 mmol) and Pd(OAc)2 (2.7 mg, 0.012 mmol) and the reaction mixture was stirred at 100 °C in an oil
bath. After 1 h, the reaction mixture was extracted with CH2Cl2 (3 x 10 mL). The organic phase was collected,
dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude product was purified
by flash column chromatography on silica gel using hexane/ethyl acetate (10:1) to obtain pure 5e (82.8 mg, 0.296
mmol, 97%) as a white solid.
2-[4-(4,5-Diphenyl-1H-imidazol-2-yl)phenyl]-6-(4-methoxyphenyl)pyridine (17)
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General procedure II was used employing 6-(4-methoxyphenyl)pyridin-2-yl 4-methylbenzenesulfonate (100 mg,
0.281 mmol) and [4-(4,5-diphenyl-1H-imidazol-2-yl)phenyl]boronic acid (191 mg, 0.562 mmol). The reaction
was completed in 19 h. Flash column chromatography on silica gel using hexane/ethyl acetate (5:1) provided
pure 17 (125 mg, 0.261 mmol, 93%) as a white solid. m.p: 263-267 °C; Rf 0.10 (hexane/ethyl acetate = 5:1); IR
(neat) 3464, 2331, 2076, 1634, 1514, 1447, 1252, 1174, 1025, 801, 766, 698 cm-1; 1H NMR (300 MHz, DMSO)
δ 12.83 (s, 1H), 8.31 (d, J = 7.8 Hz, 2H), 8.22 (t, J = 7.3 Hz, 4H), 7.94 (d, J = 7.3 Hz, 2H), 7.85 (q, J = 3.3 Hz,
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1H), 7.55-7.733 (m, 10H), 7.10 (d, J = 8.7 Hz, 2H), 3.84 (s, 3H); C{1H} NMR (75 MHz, DMSO) δ 160.3,
155.5, 154.9, 145.2, 138.3, 138.2, 137.5, 135.1, 131.2, 131.0, 130.8, 128.7, 128.6, 128.5, 128.2, 128.1, 127.9,
127.1, 126.9, 126.6, 125.5, 118.1, 114.2, 55.3; HRMS (ESI) m/z [M + H]+ calcd for C33H26N3O 480.2077, found
480.2079.
4,6-Bis[3-[(tert-butyldimethylsilyl)oxy]phenyl]pyridin-2-yl 4-methylbenzenesulfonate (20)
General procedure I was used employing 4,6-dibromo-2-tosyloxypyridine11 (100 mg, 0.246 mmol) and 3-(tert-
butyldimethylsilyloxy)phenylboronic acid (248 mg, 0.983 mmol). The reaction was completed in 32 h. Flash
column chromatography on silica gel using hexane/ethyl acetate (50:1) provided pure 20 (161 mg, 0.244 mmol,
99%) as a white oil. Rf 0.67 (hexane/ethyl acetate = 5:1); IR (neat) 3460, 2956, 2897, 2858, 2074, 1635, 1550,
1377, 1284, 1253, 1163, 1089, 974, 841, 781 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.68 (d, J = 8.4 Hz, 2H), 7.75
(d, J = 0.9 Hz, 1H), 7.39-7.20 (m, 8H), 7.1 (t, J = 2.1 Hz, 1H), 6.96-6.88 (m, 2H), 2.45 (s, 3H), 1.02 (s, 18H),
0.25 (s, 6H), 0.24 (s, 6H); 13C{1H} NMR (75 MHz, CDCl3) δ 157.6, 156.4, 156.36, 156.1, 153.5, 145.0, 139.2,
138.8, 134.3, 130.2, 129.6, 129.5, 128.8, 121.2, 121.15, 120.13, 120.1, 118.8, 118.6, 117.1, 111.6, 25.7, 25.65,
21.7, 18.214, 18.210, -4.35, -4.36; HRMS (FAB) m/z [M + H]+ calcd for C36H48NO5SSi2 662.2792, found
662.2795.
3,3'-(6-Phenylpyridine-2,4-diyl)diphenol (21)
A
sealed tube was charged with 4,6-bis[3-[(tert-butyldimethylsilyl)oxy]phenyl]pyridin-2-yl 4-
methylbenzenesulfonate (100 mg, 0.151 mmol), phenylboronic acid (36.8 mg, 0.302 mmol), K2CO3, (45.9 mg,
0.332 mmol), SPhos (3.1 mg, 0.008 mmol) and Pd(OAc)2 (1.4 mg, 0.006 mmol). The sealed tube and contents
were placed under vacuum and back-filled with argon under a Schlenk line three times. Degassed anhydrous
toluene and water (0.1 M, toluene/water = 30:1) was then added under argon and the reaction mixture was stirred
at 100 °C in an oil bath. After stirring for 20 min, the solvent was evaporated under reduced pressure. The crude
product was used directly in the following step without further purification. To a solution of crude product in
THF was added TBAF (1.0 M in THF; 0.3 mL, 0.317 mmol) at rt. After stirring for 3 h, the reaction mixture was
quenched with NH4Cl(sat.) and extracted with ethyl acetate (3 x 10 mL). The organic phase was collected, dried
over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by
column chromatography on silica gel (hexane/diethyl ether = 1:3) to obtain pure 21 (49.7 mg, 0.146 mmol, 97%)
as a white solid. 1H NMR (300 MHz, DMSO) δ 9.63 (brs, 2H), 8.31 (dd, J = 1.5 Hz, 2H), 8.10 (d, J = 1.2 Hz,
1H), 8.01 (d, J = 1.2 Hz, 1H), 7.75 (t, J = 1.8 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.58-7.31 (m, 7H), 6.94-6.90
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(m, 1H), 6.90-6.86 (m, 1H); 13C{1H} NMR (75 MHz, DMSO) δ 158.0, 157.8, 156.5, 156.3, 149.7, 140.2, 139.2,
138.8, 130.2, 129.8, 129.2, 128.8, 126.9, 118.0, 117.7, 116.5, 116.48, 116.3, 116.2, 114.0, 113.7; Data are
consistent with those reported in the literature.5d
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3-Bromo-5-chloropyridin-2-yl trifluoromethanesulfonate (23)
To a solution of 3-bromo-5-chloro-2-hydroxypyridine (100 mg, 0.480 mmol) and pyridine (0.05 mL, 0.576 mmol)
in anhydrous CH2Cl2 (2.4 mL) was added triflic anhydride (0.09 mL, 0.576 mmol) dropwise at 0 °C. The reaction
mixture was stirred for 10 min and then allowed to warm to room temperature. After stirring for 8 h, the reaction
mixture was quenched with NH4Cl(sat.) and extracted with Et2O (3 x 10 mL). The organic phase was collected,
dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude product was purified
by column chromatography on silica gel (hexane/diethyl ether = 20:1) to obtain pure 23 (137 mg, 0.403 mmol,
96%) as a yellow oil. Rf 0.69 (hexane/ethyl acetate = 2:1); IR (neat) 3454, 3074, 2075, 1636, 1561, 1418, 1375,
1221, 1134, 1047, 818, 770, 526 cm-1; 1H NMR (300 MHz, CDCl3) δ 8.28 (d, J = 2.4 Hz, 1H), 8.08 (d, J = 2.4
Hz, 1H); 13C{1H} NMR (75 MHz, CDCl3) δ 151.3, 145.5, 143.4, 132.3, 118.4 (q, J = 319.3 Hz), 111.5; HRMS
(EI) m/z [M]+ calcd for C6H2BrClF3NO3S 338.8579, found 338.8580.
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5-Chloro-3-[4-(methylthio)phenyl]pyridin-2-yl trifluoromethanesulfonate (25)
General procedure I was used employing 3-bromo-5-chloropyridin-2-yl trifluoromethanesulfonate (100 mg,
0.294 mmol) and [4-(methylthio)phenyl]boronic acid (97%; 91.6 mg, 0.529 mmol). The reaction was completed
in 11 h. Flash column chromatography on silica gel using hexane/dichloromethane (30:1) provided pure 25 (102
mg, 0.265 mmol, 90%) as a white solid. m.p: 73-75 °C; Rf 0.18 (hexane/diethyl ether = 20:1); IR (neat) 3442,
2065, 1636, 1423, 1215, 1134, 1094, 891, 820, 613 cm-1; 1H NMR (300 MHz, CDCl3) δ 8.28(d, J = 2.7 Hz, 1H),
7.85 (d, J = 2.7 Hz, 1H), 7.37 (q, J = 6.6 Hz, 4H), 2.53 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 151.0, 145.0,
141.2, 140.5, 132.2, 129.8, 129.2, 128.5, 126.1, 118.3 (q, J = 324.6 Hz), 15.1; HRMS (ESI) m/z [M + H]+ calcd
for C13H10ClF3NO3S2 383.9743, found 383.9742.
5-Chloro-3-[4-(methylsulfonyl)phenyl]pyridin-2-yl trifluoromethanesulfonate (26)
To a solution of 5-chloro-3-[4-(methylthio)phenyl]pyridin-2-yl trifluoromethanesulfonate (100 mg, 0.261 mmol),
sodium molybdate (1.6 mg, 0.008 mmol) and sulfuric acid (97%; 0.01 mL, 0.104 mmol) in anhydrous MeOH
(2.6 mL) was added hydrogen peroxide (35% in water; 0.07 mL, 0.678 mmol) at room temperature. The reaction
mixture was heated to 55 °C in an oil bath and kept stirring for 6 h. The reaction mixture then was cooled to room
temperature and quenched with sodium thiosulfate solution (0.1 M). The organic solvent was removed under
reduced pressure and extracted with ethyl acetate (3 x 10 mL). The organic phase was collected, dried over
anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by column
chromatography on silica gel (hexane/ethyl acetate = 4:1) to obtain pure 26 (102 mg, 0.245 mmol, 94%) as a
white solid. m.p: 105-109 °C; Rf 0.36 (hexane/ethyl acetate = 2:1); IR (neat) 3464, 2061, 1637, 1424, 1316, 1216,
1153, 1031, 890, 833 cm-1; 1H NMR (300 MHz, CDCl3) δ 8.39 (d, J = 2.4 Hz, 1H), 8.10 (dd, J = 1.8 Hz and J =
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6.6 Hz, 2H), 7.91 (d, J = 2.7 Hz, 1H), 7.70 (dd, J = 2.1 Hz and J = 6.8 Hz, 2H), 3.13 (s, 3H); 13C{1H} NMR (75
MHz, CDCl3) δ 150.8, 146.7, 141.5, 140.8, 137.8, 132.5, 130.1, 128.4, 128.1, 118.3 (q, J = 320.8 Hz), 44.4;
HRMS (FAB) m/z [M + H]+ calcd for C13H10ClF3NO5S2 415.9642, found 415.9643.
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5-Chloro-6'-methyl-3-[4-(methylsulfonyl)phenyl]-2,3'-bipyridine (28)
A sealed tube was charged with 5-chloro-3-[4-(methylsulfonyl)phenyl]pyridin-2-yl trifluoromethanesulfonate
(100 mg, 0.241 mmol), (6-methylpyridin-3-yl)boronic acid (49.5 mg, 0.362 mmol), NaHCO3, (60.7 mg, 0.723
mmol), Pd(OAc)2 (2.2 mg, 0.0096 mmol) and P(Cy)3 (3.4 mg, 0.0120 mmol). The sealed tube and contents were
placed under vacuum and back-filled with argon under a Schlenk line three times. Degassed anhydrous 1,4-
dioxane and water (0.1 M, 1,4-dioxnae/water = 1:1) was then added under argon and the reaction mixture was
stirred at 80 °C in an oil bath. After stirring for 1.5 h, the reaction mixture was extracted with ethyl acetate (3 x
10 mL). The organic phase was collected, dried over anhydrous MgSO4, filtered and concentrated under reduced
pressure. The crude product was purified by flash column chromatography on silica gel (diethyl ether/ethyl
acetate = 2:1) to obtain pure 28 (51.8 mg, 0.144 mmol, 60%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.72
(d, J = 2.1 Hz, 1H), 8.39 (d, J = 1.8 Hz, 1H), 7.91 (d, J = 8.4 Hz, 2H), 7.74 (d, J = 2.4 Hz, 1H), 7.57 (dd, J =
2.4 Hz and J = 8.1 Hz, 1H), 7.41 (d, J = 8.4 Hz, 2H), 7.10 (d, J = 8.1 Hz, 1H), 3.09 (s, 3H), 2.54 (s, 3H); 13C{1H}
NMR (75 MHz, CDCl3) δ 158.5, 152.3, 149.8, 148.4, 137.8, 140.2, 137.9, 137.3, 135.3, 131.2, 131.1, 130.3,
127.9, 122.8, 44.5, 24.2; Data are consistent with those reported in the literature.6e
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ASSOCIATED CONTENT
Supporting Information
Copies of 1H, 13C spectra and HRMS data for all novel compounds prepared. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: wonsukk@ewha.ac.kr
Author Contributions
† Y.-K. Jeon and J.-Y. Lee equally contributed to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
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This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) (NRF-
2018R1A2B6005533, NRF-2019M1A2A2072417).
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REFERENCES
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