Synthesis of Trisubstituted Pyridines via Chemoselective Suzuki–Miyaura Coupling of 3,5- and 4,6-Dibromo-2-tosyloxypyridines

Article abstract of DOI:10.1002/adsc.201600950

Chemoselective Suzuki–Miyaura reactions on 3,5- and 4,6-dibromo-2-tosyloxypyridines have been studied for the preparation of trisubstituted pyridines. The optimized conditions allow for a facile access to 3,5- and 4,6-diaryl-2-tosyloxypyridines in yields of 8 to 99%. Further functionalization such as palladium-catalyzed amination and copper-free Sonogashira reaction of the tosylate group in the diarylpyridine derivatives obtained was accomplished for the synthesis of novel and biologically relevant trisubstituted pyridines. The formal synthesis of ficuseptine, a bioactive alkaloid, has also been achieved via the palladium-catalyzed cross-coupling reaction of 3,5-dibromo-2-tosyloxypyridine in 5 steps from 3,5-dibromo-2-hydroxypyridine with 50% overall yield. (Figure presented.).

Full text of DOI:10.1002/adsc.201600950

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DOI: 10.1002/adsc.201600950
Synthesis of Trisubstituted Pyridines via Chemoselective Suzuki–
Miyaura Coupling of 3,5- and 4,6-Dibromo-2-tosyloxypyridines
Cho-Hee Park,+a Yong-Ju Kwon,+a In-Young Oh,a and Won-Suk Kima,*
a
Department of Chemistry and Nano Science, Ewha Womans University, Seoul 120-750, South Korea
Fax : (+82)-2-3277-2384; e-mail: wonsukk@ewha.ac.kr
+
C.-H. Park and Y.-J. Kwon equally contributed to this work.
Received: August 26, 2016; Revised: October 19, 2016; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600950.
Abstract: Chemoselective Suzuki–Miyaura reactions substituted pyridines. The formal synthesis of ficu-
on 3,5- and 4,6-dibromo-2-tosyloxypyridines have septine, a bioactive alkaloid, has also been achieved
been studied for the preparation of trisubstituted via the palladium-catalyzed cross-coupling reaction
pyridines. The optimized conditions allow for a facile of 3,5-dibromo-2-tosyloxypyridine in 5 steps from
access to 3,5- and 4,6-diaryl-2-tosyloxypyridines in 3,5-dibromo-2-hydroxypyridine with 50% overall
yields of 8 to 99%. Further functionalization such as yield.
palladium-catalyzed amination and copper-free So-
nogashira reaction of the tosylate group in the diaryl- Keywords: chemoselective Suzuki–Miyaura reaction;
ACHTUNGTRENNUNG
Introduction
boron sites. Thus, we hypothesized that the use of or-
thogonal functionalization of dibromo-2-tosyloxypyri-
Pyridines are a common moiety found in biologically dines through Suzuki–Miyaura cross-coupling reac-
active natural products and are important building tions, followed by further functionalization of the
blocks in pharmaceuticals and agrochemicals.[1] They tosyl group would allow for the facile preparation of
are also integral to synthetic chemistry fields such as 2,3,5- and 2,4,6-trisubstituted pyridines (Scheme 1).
catalysis, supramolecular chemistry and coordination
In general, the selectivity of palladium-catalyzed
chemistry.[2] Among the pyridine derivatives, 2,3,5- cross-coupling for Br over OTs on an aryl moiety is
and 2,4,6-trisubstituted pyridines serve as synthons for well established.[7] Even though excess amounts of ar-
compounds with antibacterial and anticancer activity
(Figure 1).[3]
Thus, several methods for the synthesis of 2,3,5-
and 2,4,6-trisubsituted pyridines employing transition
metal catalysis or organocatalysts have been investi-
gated.[4] Nervertheless, due to their usefulness in the
aforementioned areas, new and efficient synthetic
methods are still necessary for the preparation of tri-
substituted pyridines. Today, Suzuki–Miyaura cross-
coupling reactions have become the most widely used
method to form carbon-carbon bonds due to the mild
reaction conditions, low toxicity, and high stability af-
forded by boronic acids compared to other cross-cou-
pling substrates.[5] Particularly, interest in chemoselec-
tive cross-coupling reactions has increased in recent
years.[6] These reactions generally take advantage of
the different reactivities of the electrophilic sites or Figure 1. Bioactive compounds containing a pyridine moiety.
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Scheme 2. Preparation of 3,5- and 4,6-dibromo-2-tosyloxy-
pyridines.
Scheme 1. Synthesis of 2,3,5- and 2,4,6-trisubstituted pyri-
dines via chemoselective Suzuki reactions.
2.7 equivalents of phenylboronic acid, Pd(OAc)2, and
K2CO3 with a ligand in toluene furnished the cross-
ylboronic acids are employed, the monoarylated prod- coupled product 7a in good-to-excellent yields within
uct is obtained as major product in excellent yield 20 h. When Pd(OAc)2 and a ligand such as Xphos,
due to the low reactivity of aryl tosylates.[7a,b,e] Howev- Sphos, Ruphos, and Brettphos were employed, the de-
er, fewer studies have been conducted on the selectiv- sired product 7a was obtained in good yields along
ity for Br over OTs on the pyridine moiety.[8] Recent- with significant amounts of triarylated product 8
ly, Wang and co-workers reported the palladium-cata- (Table 1, entries 1–5). However, utilizing either
lyzed Suzuki–Miyaura cross-coupling reactions em- P(Cy)3 or Ad2BnP as the ligand provided only the de-
ploying 2-tosyloxypyridines.[8b] While they demon- sired product 7a without loss of the tosyl group.
strated that the Br group on the pyridine ring can be When the reactions were performed at either 1008C
selectively arylated over the OTs group in coupling or 808C in the presence of Ad2BnP, the reactions did
with arylboronic acid, this reaction provided signifi- not go to completion due to competitive homocou-
cant amounts of diarylated product. For example, pling of the phenylboronic acid (Table 1, entries 6 and
when 5-bromo-2-tosyloxypyridine was employed in 7). Next, we extensively screened bases, solvents, and
the presence of Pd(OAc)2, PPh3 and K3PO4 in 1,4-di- temperature. As a result, the use of Ad2BnP in the
oxane at 1108C, 5-phenyl-2-tosyloxypyridine and 2,5- presence of Pd(OAc)2 and K2CO3 in toluene at 508C
diphenylpyridine were obtained in 30% and 48% led to the highest isolated yields (Table 1, entries 8
yields in 7 h. These results indicate that the tosylate and 19). Surprisingly, when the reaction was per-
group attached to the C-2 position of the pyridine formed at room temperature, product 7a was also ob-
moiety is a quite reactive group. Thus, to achieve our tained in 99% yield in 20 h (Table 1, entry 9). Further-
goals, we need to suppress the reactivity of the tosy- more, when less than 2.7 equivalents of phenylboronic
late group at the C-2 position of pyridine by employ- acid were used, product 7a was isolated in a lower
ing an efficient catalyst system.
yield in 15 h (entries 17 and 18). However, utilizing
With these considerations in mind, we report 4.0 equivalents of phenylboronic acid 6 resulted in
herein the chemoselective Suzuki–Miyaura cross-cou- a shortened reaction time providing the desired prod-
pling reactions of 3,5- and 4,6-dibromo-2-tosyloxypyr- uct 7a in 99% isolated yield (Table 1, entry 19). In ad-
idnes with boronic acids and the subsequent function- dition, when 4.0 equivalents of phenylboronic acid
alization of the remaining tosyl group for the synthe- were used in the presence of Xphos in toluene at
sis of 2,3,5- and 2,4,6-trisubsituted pyridines.
1008C, triarylated product 8 was obtained as major
product (Table 1, entry 20).
With the optimized conditions (cf., Table 1, entry 8)
in hand, we first examined the scope of the Pd-cata-
lyzed chemoselective Suzuki–Miyaura cross-coupling
Results and Discussion
The 3,5- and 4,6-dibromo-2-tosyloxypyridines were reaction with various boronic acids (Table 2). Inexpli-
prepared from 3,5-dibromo-2-hydroxypyridine 1 and cably, the use of 2.7 equivalents of boronic acid under
4,6-dibromo-2-hydroxypyridine 4[9] via tosylation the optimized conditions was not optimal for all sub-
(Scheme 2).
strates. However, in most cases, the use of 4.0 equiva-
Subsequently, optimization of the chemoselective lents of boronic acid under the optimized conditions
Suzuki–Miyaura cross-coupling reaction was initially provided the corresponding products in a short time
attempted using 3,5-dibromo-2-tosyloxypyridine 3 and without reacting with the tosyl group. As illustrated in
phenylboronic acid 6. As shown in Table 1, the use of Table 2, utilizing arylboronic acids containing elec-
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Table 1. Optimization of the chemoselective Suzuki–Miyaura reaction employing 3 and 6.[a]
[a]
Reaction conditions: 1.0 equiv. of 3, phenylboronic acid 6, 2.2 equiv. of base, 4 mol% of catalyst, 5 mol%
of ligand, toluene (0.1M).
Isolated yield.
Reaction time based on complete consumption of boronic acid as determined by TLC analysis.
[b]
[c]
tron-neutral, electron-donating, and electron-with- giving the desired product 7k in 99% yield. Heteroar-
drawing groups furnished the coupled products in ylboronic acids such as benzothiophen-2-ylboronic
good-to-excellent yields. When sterically hindered 2- acid and 3-thienylboronic acid reacted with 3,5-dibro-
methoxyphenylboronic acid was used, however, the mo-2-tosyloxypyridine 3 to form the corresponding
reaction was sluggish and gave the desired product 7f coupled products 7l and 7m in 99% yield, respective-
in 8% yield with 13% conversion after 48 h. When ly, while 3-furanylboronic acid furnished the desired
a 4-tert-butoxycarbonyl-substituted arylboronic acid product 7n in 11% yield with 12% conversion after
was employed, the reaction did not go to completion 24 h due to competitive homocoupling of the boronic
in 24 h. However, increasing the reaction temperature acid.
from 508C to 1008C, provided full conversion and fur-
Next, we turned our attention towards 4,6-dibromo-
nished the coupled product 7j in 99% yield in 50 min. 2-tosyloxypyridine 5 as the electrophile. Pleasingly,
Furthermore, the non-aryl boronic acid (E)-styrylbor- the reaction conditions [cf., Pd(OAc)2, Ad2BnP,
onic acid also proved effective as a coupling partner, K2CO3, toluene, 508C] that proved effective with 3,5-
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Table 2. Chemoselective Suzuki–Miyaura reaction employing 3 and various boronic acids 9.[a]
[a]
Reaction conditions: 1.0 equiv. of 3, 4.0 equiv. of boronic acid, 2.2 equiv. of K2CO3, 4 mol% of Pd(OAc)2, 5 mol% of
Ad2BnP, toluene (0.1M), 508C.
5.0 equiv. of boronic acid.
Conversion.
The reaction was conducted at 1008C.
[b]
[c]
[d]
[e]
Reaction time based on complete consumption of boronic acid as determined by TLC analysis.
dibromo-2-tosyloxypyridine 3 were also optimal for 2-tosyloxypyridine (Scheme 3). Pleasingly, 7a under-
the Pd-catalyzed chemoselective Suzuki–Miyaura went reduction to furnish 11 in 92% yield, Suzuki re-
cross-coupling reaction with 5. As shown in Table 3, action to afford 12 in 95% yield, and detosylation to
a variety of heteroaryl- and arylboronic acids with give 13 in 99% yield. In particular, Pd-catalyzed ami-
electron neutral, electron-donating, and electron-with- nation and Cu-free Sonogashira reaction, which to
drawing groups were transformed into diarylpyridine date have not yet been investigated, employing
derivatives 10a–10n in 20% to 99% yields.
diaryl-substituted pyridine furnished the coupled
Encouraged by the viability of this chemoselective products 14 and 15 in 99% and 85% yields, respec-
Suzuki–Miyaura reaction for the synthesis of 3,5- and tively. In addition, iron-catalyzed sp2–sp3 coupling of
4,6-diaryl-2-tosyloxypyridines, we next turned our at- 10a with isopropylmagnesium bromide provided prod-
tention to the preparation of the 2,3,5- and 2,4,6-tri- uct 16 in 53% yield.
substituted pyridines found in many biologically
Finally, to demonstrate the feasibility of the regio-
active compounds. A tosylate group attached to the selective Pd-catalyzed Suzuki–Miyaura coupling reac-
C-2 position of pyridine is a reactive group in cou- tion of 3,5- and 4,6-dibromo-2-tosyloxypyridines, we
pling reactions such as Suzuki coupling,[8b,10] Sonoga- applied our method to a formal synthesis of ficusep-
shira coupling,[8b] Kumada coupling,[11] amination[12] tine [4,6-bis(4-methoxyphenyl)-1,2,3-trihydroindolizi-
and reduction.[13] We, therefore, began to modify the dinium chloride] 20, an indolizidinium alkaloid isolat-
aforementioned methods for the preparation of tri- ed from the leaves of Ficus septica in 1990.[3a,14] As
substituted pyridines employing 3,5- and 4,6-diphenyl- shown in Scheme 4, treatment of alkyne 17 with 7d
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Table 3. Chemoselective Suzuki–Miyaura reaction employing 5 and various boronic acid 9.[a]
[a]
Reaction conditions: 1.0 equiv. of 5, 4.0 equiv. of boronic acid, 2.2 equiv. of K2CO3, 4 mol% of Pd(OAc)2, 5 mol% of
Ad2BnP, toluene (0.1M), 508C.
5.0 equiv. of boronic acid.
Conversion.
[b]
[c]
[d]
Reaction time based on complete consumption of boronic acid as determined by TLC analysis.
prepared from 3 via chemoselective Suzuki–Miyaura boronic acids. Moreover, it was found that diarylpyri-
coupling under Cu-free Sonogashira conditions fur- dine derivatives prepared in this manner can be fur-
nished pyridine 18 in 90% yield. Pd/C-catalyzed hy- ther transformed into trisubstituted pyridines by func-
drogenation, followed by desilylation of pyridine 18 tionalization of the tosyl group. Particularly, Pd-cata-
in MeOH provided pyridylpropanol 19 in 95% lyzed amination and Cu-free Sonogashira reactions
yield.[15] Finally, employing MsCl and Et3N to cyclize employing diarylpyridines provided the coupled prod-
19 and form the indolizidinium ring furnished the an- ucts in good-to-excellent yields. Finally, the formal
tibacterial ficuseptine 20 in 79% yield.[16]
synthesis of ficuseptine 20 was achieved in five steps
and 50% overall yield from 3,5-dibormo-2-hydroxy-
pyridine 1 employing chemoselective Suzuki and Cu-
free Sonogashira couplings as the key steps.
Conclusions
In conclusion, we have described the chemoselective
Suzuki–Miyaura reactions employing 3,5- and 4,6-di-
bromo-2-tosyloxypyridines. Most reactions proceeded
well without reacting with the tosyl group under the
optimized conditions of 4 mol% of Pd(OAc)2,
5 mol% of Ad2BnP and 2.2 equivalents of K2CO3 in
toluene at 508C. The scope of this methodology has
Experimental Section
General Considerations
Unless otherwise indicated, all chemical reagents were pur-
chased from commercial suppliers and were used without
been explored employing aryl-, vinyl- and heteroaryl- further purification. All reactions were carried out in oven-
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Scheme 3. Various functionalization of 3,5- and 4,6-diphen-
yl-2-tosyloxypyridines. a: HCOOH, 5 mol% of Pd(OAc)2,
5 mol% of dppp, Et3N, DMF, 608C, 1 h. b: 4-methoxyphe-
nylboronic acid, 4 mol% of Pd(OAc)2, 5 mol% of Sphos,
K2CO3, toluene, 508C, 2.5 h. c: NaOH, THF/MeOH (1/1),
508C, 1 h. d: Aniline, 5 mol% of Pd(OAc)2, 60 mol% of
dppf, K2CO3, toluene, 1108C, 6 h. e: Phenylacetylene,
3 mol% of Pd(OAc)2, 7 mol% of Xphos, K3PO4, t-BuOH,
858C, 1 h. f: Isopropylmagnesium bromide, 20 mol% of
FeCl3, THF/NMP (1/5), À308C, 1 h.
Scheme 4. Synthesis of ficuseptine 20.
anhydrous CH2Cl2 (6 mL) was stirred at room temperature
for 20 h. The reaction mixture was quenched with H2O and
extracted with diethyl ether (3ꢀ10 mL). The organic phase
was collected, dried over anhydrous MgSO4, filtered and
concentrated under reduced pressure. The crude product
was purified by column chromatography over silica gel
(hexane/ethyl acetate=20:1) to obtain the pyridine 3 as
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). Prod-
ucts were detected by viewing under a UV light, by staining
with an anisaldehyde solution composed of acetic acid, sul-
furic acid, and MeOH, or by staining with a KMnO4 solu-
tion composed of potassium carbonate, sodium hydroxide,
and water. Flash column chromatography was performed on
silica gel (70–230 mesh). Yields refer to chromatographically
and spectroscopically pure compounds unless otherwise
noted. 1H and 13C NMR spectra were recorded on
a 300 MHz NMR spectrometer. Chemical shifts are reported
as d values relative to internal SiMe4 or chloroform (d=0.00
1
a white solid; yield: 655.2 mg (1.61 mmol, 80%). H NMR
(300 MHz, CDCl3): d=8.23 (d, J=2.3 Hz, 1H), 8.08 (d, J=
2.3 Hz, 1H), 7.95 (d, J=8.4 Hz, 2H), 7.37 (d, J=8.0 Hz,
2H), 2.46 (s, 3H); 13C NMR (75 MHz, CDCl3): d=153.1,
147.2, 145.7, 145.2, 133.6, 129.7, 128.8, 117.9, 112.0, 21.7;
Data are consistent with those reported in the literature.[8a]
Preparation of 4,6-Dibromo-2-hydroxypyridine (4)
1
1
for H and d=77.0 for 13C) or DMSO-d6 (d=2.50 for H
and d=39.5 for 13C). IR spectra were measured as neat oils
and solids on an FT-IR spectrometer. HR-MS data were ob-
tained by electron ionization and fast atom bombardment
with a double-focusing high-resolution magnetic sector mass
analyzer.
4,6-Dibromo-2-hydroxypyridine was prepared as according
to the cited literature procedure.[9]
4,6-Dibromo-2-tosyloxypyridine (5)
A solution of 4,6-dibromo-2-hydroxypyridine (2.0 mmol),
TsCl (2.4 mmol), Et3N (4.0 mmol) and DMAP (10 mol%) in
anhydrous CH2Cl2 (6 mL) was stirred at room temperature
for 20 h. The reaction mixture was quenched with H2O and
extracted with diethyl ether (3ꢀ10 mL). The organic phase
was collected, dried over anhydrous MgSO4, filtered and
3,5-Dibromo-2-tosyloxypyridine (3)
A solution of 3,5-dibromo-2-hydroxypyridine (2.0 mmol),
TsCl (2.4 mmol), Et3N (4.0 mmol) and DMAP (10 mol%) in
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concentrated under reduced pressure. The crude product
was purified by column chromatography over silica gel
(hexane/ethyl acetate=20:1) to obtain the pyridine 5 as
a white solid; yield: 732.8 mg (1.80 mmol, 90%); mp 86–
888C; Rf 0.32 (hexane/ethyl acetate=5:1). IR (neat): n=
(0.237 mmol, 96%); mp 170–1748C; Rf 0.27 (hexane/ethyl
acetate=5:1). IR (neat): n=3446, 2073, 1638, 1376, 1176,
1
1085, 884, 698, 552 cmÀ1; H NMR (300 MHz, CDCl3): d=
8.42 (d, J=2.5 Hz, 1H), 7.88 (d, J=2.5 Hz, 1H), 7.74 (d, J=
8.4 Hz, 2H), 7.43 (d, J=8.2 Hz, 2H), 7.36 (d, J=8.2 Hz,
2H), 7.25 (d, J=7.9 Hz, 2H), 7.19 (dd, J=2.4 Hz and
5.9 Hz, 4H), 2.40 (s, 3H), 2.38 (d, J=2.2 Hz, 6H); 13C NMR
(75 MHz, CDCl3): d=153.1, 144.7, 144.3, 138.7, 138.3, 138.1,
136.1, 134.3, 133.5, 131.8, 129.8, 129.3, 129.1, 129.0, 128.9,
128.4, 126.8, 21.6, 21.2, 21.1; HR-MS-EI: m/z=429.1401
[M+], calcd. for C26H23NO3S+: 429.1399.
3450, 3110, 2534, 2144, 1559, 1376, 1179, 796, 724, 554 cmÀ1
;
1H NMR (300 MHz, CDCl3): d=7.94 (d, J=8.5 Hz, 2H),
7.56 (d, J=1.3 Hz, 1H), 7.38 (d, J=8.0 Hz, 2H), 7.25 (d, J=
1.3 Hz, 1H), 2.47 (s, 3H); 13C NMR (75 MHz, CDCl3): d=
156.0, 146.0, 139.5, 136.0, 132.9, 129.7, 129.2, 129.1, 117.3,
21.8; HR-MS-FAB: m/z=405.8748 [M+H]+, calcd. for
C12H10Br2NO3S+: 405.8751.
3,5-Bis(4-vinylphenyl)pyridin-2-yl 4-methylbenzenesulfo-
nate (7c): General procedure I was used employing 3,5-di-
bromo-2-tosyloxypyridine (0.247 mmol) and (4-vinylphenyl)-
boronic acid (0.988 mmol), and the reaction was completed
in 30 min. Flash chromatography on silica gel using hexane/
ethyl acetate (10:1) provided pure 7c as a white solid; yield:
107.0 mg (0.236 mmol, 96%); mp 54–608C; Rf 0.6 (hexane/
ethyl acetate=2:1). IR (neat): n=3046, 1698, 1600, 1377,
General Procedure I for Synthesis of Diaryl-2-pyridyl
4-Methylbenzenesulfonates
A round bottom flask was charged with dibromo-2-tosyloxy-
pyridine (1.0 equiv), boronic acid (4.0 equiv), K2CO3
(2.2 equiv), Ad2BnP (5 mol%) and Pd(OAc)2 (4 mol%).
Toluene (2.5 mL) was then added to the flask. The reaction
mixture was stirred at 508C under argon purged flask. After
completion of the reaction as monitored by TLC analysis,
the reaction solution was extracted by ethyl acetate (3ꢁ
10 mL). The combined organic layer was then concentrated,
and the residue was purified by flash column chromatogra-
phy on silica gel to obtain the desired product.
1089, 895, 828, 695, 552, 481 cmÀ1 1H NMR (300 MHz,
;
CDCl3): d=8.49 (d, J=2.5 Hz, 1H), 7.94 (d, J=2.5 Hz, 1H),
7.75 (d, J=8.3 Hz, 2H), 7.53 (d, J=2.3 Hz, 4H), 7.44 (s,
4H), 7.21 (d, J=8.2 Hz, 2H), 6.76 (dd, J=10.9 Hz and
17.6 Hz, 2H), 5.82 (d, J=17.6 Hz, 2H), 5.33 (dd, J=4.1 Hz
and 11.2 Hz, 2H), 2.41 (s, 3H); 13C NMR (75 MHz, CDCl3):
d=153.1, 144.8, 144.6, 138.5, 137.6, 137.5, 136.1, 135.9, 135.7,
135.5, 134.1, 133.9, 129.3, 129.28, 128.6, 128.3, 127.1, 126.9,
126.2, 114.7, 114.68, 21.6; HR-MS-EI: m/z=453.1398 [M+],
calcd. for C28H23NO3S+: 453.1399.
3,5-Diphenyl-2-pyridyl 4-methylbenzenesulfonate (7a):
General procedure I was used employing 3,5-dibromo-2-to-
syloxypyridine (0.246 mmol) and phenylboronic acid
(0.984 mmol), and the reaction was completed in 1 h. Flash
chromatography on silica gel using hexane/ethyl acetate
(10:1) provided pure 7a as a white solid; yield: 98.2 mg
(0.245 mmol, 99%); mp 176–1808C; Rf 0.21 (hexane/ethyl
acetate=5:1). IR (neat): n=3034, 2923, 1591, 1377, 1175,
3,5-Bis(4-methoxyphenyl)-2-pyridyl 4-methylbenzenesul-
fonate (7d): General procedure I was used employing 3,5-di-
bromo-2-tosyloxypyridine (0.246 mmol) and (4-methoxyphe-
nyl)boronic acid (1.230 mmol), and the reaction was com-
pleted in 6 h. Flash chromatography on silica gel using
hexane/ethyl acetate (5:1) provided pure 7d as a white solid;
yield: 104.6 mg (0.227 mmol, 92%); mp 48–508C; Rf 0.34
(hexane/ethyl acetate=2:1). IR (neat): n=3439, 3054, 2051,
1
1090, 889, 819, 695, 545 cmÀ1; H NMR (300 MHz, CDCl3):
d=8.50 (d, J=2.5 Hz, 1H), 7.95 (d, J=2.5 Hz, 1H), 7.75 (d,
J=8.4 Hz, 2H), 7.59–7.56 (m, 2H), 7.51–7.40 (m, 8H), 7.23
(d, J=8.0 Hz, 2H), 2.43 (s, 3H); 13C NMR (75 MHz,
CDCl3): d=153.3, 144.9, 144.87, 139.1, 136.5, 136.3, 134.8,
134.2, 129.4, 129.2, 129.17, 129.0, 128.5,128.47, 128.4, 128.3,
127.1, 21.7; HRMS-EI: m/z=401.1083 [M+], calcd. for
C24H19NO3S+: 401.1086.
2,3,5-Triphenylpyridine (8): General procedure I was used
employing 3,5-dibromo-2-tosyloxypyridine (0.246 mmol),
phenylboronic acid (0.984 mmol) and RuPhos (5 mol%),
and the reaction was completed in 7 h. Flash chromatogra-
phy on silica gel using hexane/ethyl acetate (20:1) provided
pure 7a; yield: 72.8 mg (0.181 mmol, 74%) and 8; yield:
1
1608, 1513, 1436, 1377, 1249, 1177, 1033, 826 cmÀ1; H NMR
(300 MHz, CDCl3): d=8.40 (d, J=2.5 Hz, 1H), 7.86 (d, J=
2.5 Hz, 1H), 7.75 (d, J=8.5 Hz, 2H), 7.50 (d, J=8.7 Hz,
2H), 7.41 (d, J=8.7 Hz, 2H), 7.23 (d, J=8.3 Hz, 2H), 7.00
(d, J=8.8 Hz, 2H), 6.93 (d, J=8.8 Hz, 2H), 3.85 (d, J=
1.3 Hz, 6H), 2.42 (s, 3H); 13C NMR (75 MHz, CDCl3): d=
159.9, 159.7, 152.9, 144.8, 143.9, 138.3, 135.9, 134.3, 130.4,
129.3, 128.9, 128.6, 128.4, 128.2, 127.1, 114.6, 113.9, 55.3,
55.28, 21.6; HR-MS-EI: m/z=461.1299 [M+], calcd. for
C26H23NO5S+: 461.1297.
3,5-Bis(3-methoxyphenyl)-2-pyridyl 4-methylbenzenesul-
fonate (7e): General procedure I was used employing 3,5-di-
bromo-2-tosyloxypyridine (0.246 mmol) and (3-methoxyphe-
nyl)boronic acid (0.984 mmol), and the reaction was com-
pleted in 5 h. Flash chromatography on silica gel using
hexane/ethyl acetate (10:1) provided pure 7e as a white
solid; yield: 111.7 mg (0.242 mmol, 98%); mp 102–1048C; Rf
0.3 (hexane/ethyl acetate=3:1). IR (neat): n=3442, 2950,
16.0 mg (0.052 mmol, 21%) as
a white solid; Rf 0.28
(hexane/ethyl acetate=5:1). 1H NMR (300 MHz, CDCl3):
d=8.93 (d, J=2.3 Hz, 1H), 7.91 (d, J=2.3 Hz, 1H), 7.68–
7.7.65 (m, 2H), 7.51–7.46 (m, 2H), 7.43–7.38 (m, 3H), 7.30–
7.22 (m, 8H); 13C NMR (75 MHz, CDCl3): d=155.8, 146.6,
139.8, 139.76, 137.3, 136.8, 135.9, 134.9, 129.8, 129.5, 129.1,
128.3, 128.1, 127.9, 127.8, 127.3, 127.1; Data are consistent
with those reported in the literature.[17]
1
2841, 1596, 1378, 1173, 1042, 858, 773, 695 cmÀ1; H NMR
(300 MHz, CDCl3): d=8.49 (d, J=2.5 Hz, 1H), 7.94 (d, J=
2.5 Hz, 1H), 7.75 (d, J=8.4 Hz, 2H), 7.39 (t, J=8.0 Hz,
1H), 7.33 (t, J=8.0 Hz, 1H), 7.23 (d, J=8.0 Hz, 2H), 7.16–
7.13 (m, 1H), 7.09–7.05 (m, 2H), 7.00–6.91 (m, 3H), 3.86 (s,
3H), 3.81 (s, 3H), 2.43 (s, 3H); 13C NMR (75 MHz, CDCl3):
d=160.1, 159.5, 153.2, 144.9, 144.87, 139.0, 137.7, 136.1,
3,5-Di-p-tolyl-2-pyridyl 4-methylbenzenesulfonate (7b):
General procedure I was used employing 3,5-dibromo-2-to-
syloxypyridine (0.247 mmol) and p-tolylboronic acid
(0.988 mmol), and the reaction was completed in 7 h. Flash
chromatography on silica gel using hexane/ethyl acetate
(10:1) provided pure 7b as a white solid; yield: 102.0 mg
Adv. Synth. Catal. 0000, 000, 0 – 0
7
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135.9, 134.1, 130.2, 129.5, 129.4, 128.8, 128.4, 121.5, 119.4,
114.5, 114.2, 113.7, 112.8, 55.3, 55.2, 21.6; HR-MS-EI: m/z=
461.1295 [M+], calcd. for C26H23NO5S+: 461.1297.
1641, 1494, 1435, 1370, 1170, 1091, 1014, 886, 718, 548 cmÀ1
;
1H NMR (300 MHz, CDCl3): d=8.46 (d, J=2.4 Hz, 1H),
7.87 (d, J=2.4 Hz, 1H), 7.74 (d, J=8.3 Hz, 2H), 7.47 (dd,
J=8.6 Hz and 11.4 Hz, 4H), 7.38 (dd, J=8.9 Hz and
10.9 Hz, 4H), 7.26 (d, J=8.3 Hz, 2H), 2.45 (s, 3H);
13C NMR (75 MHz, CDCl3): d=153.4, 145.2, 145.1, 138.7,
137.0, 135.2, 134.9, 134.7, 134.69, 134.1, 133.0, 130.5, 129.5,
129.4, 128.8, 128.4, 128.3, 21.7; HR-MS-EI: m/z=469.0303
[M+], calcd. for C24H17Cl2NO3S+: 469.0306.
3,5-Bis(2-methoxyphenyl)-2-pyridyl 4-methylbenzenesul-
fonate (7f): General procedure I was used employing 3,5-di-
bromo-2-tosyloxypyridine (0.245 mmol) and (2-methoxyphe-
nyl)boronic acid (1.225 mmol), and the reaction was com-
pleted in 48 h. Flash chromatography on silica gel using
hexane/ethyl acetate (5:1) provided pure 7f as a white solid;
yield: 8.9 mg (0.019 mmol, 8%); mp 134–1368C; Rf 0.38
(hexane/ethyl acetate=2:1). IR (neat): n=3442, 2065, 1636,
Di-tert-butyl 4,4’-[2-(tosyloxy)pyridine-3,5-diyl]dibenzoate
(7j): General procedure I was used employing 3,5-dibromo-
2-tosyloxypyridine (0.246 mmol) and (4-(tert-butoxycarbo-
nyl)phenyl)boronic acid (0.984 mmol), and the reaction was
completed in 50 min. Flash chromatography on silica gel
using hexane/ethyl acetate (10:1) provided pure 7j as
a white solid; yield: 146.0 mg (0.243 mmol, 99%); mp 84–
908C; Rf 0.59 (hexane/ethyl acetate=2:1). IR (neat): n=
3436, 2981, 1707, 1634, 1378, 1295, 1171, 1112, 1017, 811,
1
1497, 1421, 1374, 1254, 1172, 1026, 754, 550 cmÀ1; H NMR
(300 MHz, CDCl3): d=8.42 (d, J=2.4 Hz, 1H), 7.91 (d, J=
2.4 Hz, 1H), 7.77 (d, J=8.4 Hz, 2H), 7.40–7.30 (m, 3H),
7.25–7.21 (m, 3H), 7.06–6.92 (m, 4H), 3.79 (d, J=8.5 Hz,
6H), 2.41 (s, 3H); 13C NMR (75 MHz, CDCl3): d=156.7,
156.5, 153.5, 146.8, 144.4, 142.5, 134.9, 133.0, 131.3, 130.6,
129.8, 129.6, 129.3, 128.4, 125.8, 125.0, 124.1, 121.0, 120.4,
111.2, 111.0, 55.5, 55.4, 21.6; HR-MS-EI: m/z=461.1298
[M+], calcd. for C26H23NO5S+: 461.1297.
708 cmÀ1
;
1H NMR (300 MHz, CDCl3): d=8.52 (d, J=
2.5 Hz, 1H), 8.09 (d, J=8.6 Hz, 2H), 8.02 (d, J=8.6 Hz,
2H), 7.97 (d, J=2.5 Hz, 1H), 7.75 (d, J=8.4 Hz, 2H), 7.61
(d, J=8.6 Hz, 2H), 7.53 (d, J=8.6 Hz, 2H), 7.23 (d, J=
8.1 Hz, 2H), 2.42 (s, 3H), 1.63 (s, 9H), 1.61 (s, 9H);
13C NMR (75 MHz, CDCl3): d=165.2, 165.1, 153.6, 145.5,
145.1, 140.0, 139.0, 138.5, 135.3, 134.0, 131.9, 131.8, 130.2,
129.5, 129.4, 129.0, 128.4, 128.3, 126.8, 81.3, 81.2, 28.13,
28.10, 21.6; HR-MS-EI: m/z=601.2130 [M+], calcd. for
C34H35NO7S+: 601.2134.
3,5-Bis(4-(methylthio)phenyl)pyridin-2-yl 4-methylbenze-
nesulfonate (7g): General procedure I was used employing
3,5-dibromo-2-tosyloxypyridine (0.245 mmol) and (4-(meth-
ylthio)phenyl)boronic acid (0.980 mmol), and the reaction
was completed in 30 min. Flash chromatography on silica
gel using hexane/ethyl acetate (10:1) provided pure 7g as
a white solid; yield: 120.0 mg (0.243 mmol, 99%); mp 62–
668C; Rf 0.37 (hexane/ethyl acetate=3:1). IR (neat): n=
3441, 2071, 1639, 1430, 1375, 1174, 999, 874, 808, 661 cmÀ1
;
3,5-Di[(E)-styryl]pyridin-2-yl 4-methylbenzenesulfonate
(7k): General procedure I was used employing 3,5-dibromo-
2-tosyloxypyridine (0.246 mmol) and (E)-styrylboronic acid
(0.984 mmol), and the reaction was completed in 1.5 h.
Flash chromatography on silica gel using hexane/ethyl ace-
tate (10:1) provided pure 7k as a yellow solid; yield:
111.0 mg (0.245 mmol, 99%); mp 58–658C; Rf 0.47 (hexane/
ethyl acetate=3:1). IR (neat): n=3442, 2345, 2074, 1637,
1H NMR (300 MHz, CDCl3): d=8.43 (d, J=2.5 Hz, 1H),
7.87 (d, J=2.5 Hz, 1H), 7.73 (d, J=8.3 Hz, 2H), 7.47 (d, J=
8.5 Hz, 2H), 7.35 (q, J=8.5 Hz, 4H), 7.25–7.22 (m, 4H),
2.51 (d, J=1.7 Hz, 6H), 2.42 (s, 3H); 13C NMR (75 MHz,
CDCl3) d 153.1, 144.9, 144.4, 139.4, 139.3, 138.3, 135.6, 134.2,
132.8, 131.1, 129.4, 129.36, 128.4, 128.35, 127.3, 126.7, 125.9,
21.6, 15.4, 15.3; HR-MS-EI: m/z=493.0843 [M+], calcd. for
+
C26H23NO3S3 : 493.0840.
1373, 1176, 1094, 963, 844, 725 cmÀ1 1H NMR (300 MHz,
;
3,5-Bis(4-(trifluoromethyl)phenyl)pyridin-2-yl 4-methyl-
benzenesulfonate (7h): General procedure I was used em-
ploying 3,5-dibromo-2-tosyloxypyridine (0.247 mmol) and
(4-(trifluoromethyl)phenyl)boronic acid (0.988 mmol), and
the reaction was completed in 2 h. Flash chromatography on
silica gel using hexane/ethyl acetate (20:1) provided pure 7h
as a white solid; yield: 131.0 mg (0.244 mmol, 99); mp 180–
1828C; Rf 0.6 (hexane/ethyl acetate=3:1). IR (neat): n=
CDCl3): d=8.23 (d, J=2.3 Hz, 1H), 8.08 (d, J=2.3 Hz, 1H),
7.97 (d, J=8.3 Hz, 2H), 7.54 (d, J=7.1 Hz, 2H), 7.48 (d, J=
6.8 Hz, 2H), 7.41–7.29 (m, 8H), 7.18–7.00 (m, 4H), 2.40 (s,
3H); 13C NMR (75 MHz, CDCl3): d=153.2, 145.2, 144.6,
136.3, 136.2, 134.1, 133.1, 132.5, 132.3, 131.4, 129.6, 128.7,
128.6, 128.5, 128.47, 128.3, 126.9, 126.6, 124.9, 123.4, 119.9,
21.6; HR-MS-EI: m/z=453.1397 [M+], calcd. for
C28H23NO3S+: 453.1399.
3442, 2074, 1637, 1373, 1176, 1093, 963, 844, 725, 547 cmÀ1
;
3,5-Bis(benzo[b]thiophen-2-yl)pyridin-2-yl 4-methylben-
1H NMR (300 MHz, CDCl3): d=8.56 (d, J=2.5 Hz, 1H),
7.96 (d, J=2.5 Hz, 1H), 7.77–7.57 (m, 10H), 7.24 (d, J=
8.3 Hz, 2H), 2.43 (s, 3H); 13C NMR (75 MHz, CDCl3): d=
153.8, 145.9, 145.4, 139.7, 139.1, 138.1, 135.0, 134.0, 131.1 (q,
J=12.0 Hz), 130.4 (q, J=12.0 Hz), 129.6, 129.5, 128.4, 127.9,
127.5, 126.3, 126.23, 126.18, 126.1, 125.7, 125.55, 125.50,
125.45, 125.40, 122.1, 21.6; HR-MS-EI: m/z=537.0831 [M+],
calcd. for C26H17F6NO3S+: 537.0833.
3,5-Bis(4-chlorophenyl)-2-pyridyl 4-methylbenzenesulfo-
nate (7i): General procedure I was used employing 3,5-di-
bromo-2-tosyloxypyridine (0.245 mmol) and (4-chlorophe-
nyl)boronic acid (1.225 mmol), and the reaction was com-
pleted in 1 h. Flash chromatography on silica gel using
hexane/ethyl acetate (10:1) provided pure 7i as a white
solid; yield: 114.5 mg (0.243 mmol, 99%); m.p 190–1948C;
Rf 0.63 (hexane/ethyl acetate=2:1). IR (neat): n=3455,
ACHTUNGTRENzNUGN enesulfonate (7l): General procedure I was used employing
3,5-dibromo-2-tosyloxypyridine (0.245 mmol) and benzo[b]-
thiophen-2-ylboronic acid (0.980 mmol), and the reaction
was completed in 1 h. Flash chromatography on silica gel
using hexane/ethyl acetate (10:1) provided pure 7l as
a white solid; yield: 124.5 mg (0.243 mmol, 99%); mp 168–
1708C; Rf 0.53 (hexane/ethyl acetate=3:1). IR (neat): n=
3455, 1636, 1419, 1373, 1170, 1091, 887, 822, 755, 697 cmÀ1
;
1H NMR (300 MHz, CDCl3): d=8.52 (d, J=2.4 Hz, 1H),
8.23 (d, J=2.5 Hz, 1H), 7.93 (d, J=8.4 Hz, 2H), 7.87–7.78
(m, 5H), 7.59 (s, 1H), 7.40–7.37 (m, 4H), 7.26 (d, J=8.0 Hz,
2H), 2.41 (s, 3H); 13C NMR (75 MHz, CDCl3): d=152.8,
145.3, 143.8, 140.2, 140.0, 139.99, 139.7, 138.3, 136.6, 135.2,
134.2, 139.7, 129.5, 128.8, 125.4, 125.3, 125.2, 125.0, 124.7,
124.3, 124.0, 122.3, 122.0, 121.9, 121.4, 21.7; HR-MS-EI: m/
+
z=513.0526 [M+], calcd. for C28H19NO3S3 : 513.0526.
Adv. Synth. Catal. 0000, 000, 0 – 0
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3,5-Di(thiophen-3-yl)pyridin-2-yl 4-methylbenzenesulfo-
nate (7m): General procedure I was used employing 3,5-di-
bromo-2-tosyloxypyridine (0.245 mmol) and thiophen-3-yl-
boronic acid (1.225 mmol), and the reaction was completed
in 3 h. Flash chromatography on silica gel using hexane/
ethyl acetate (10:1) provided pure 7m as a white solid;
yield: 100.5 mg (0.243 mmol, 99%); mp 128–1308C; Rf 0.4
(hexane/ethyl acetate=3:1). IR (neat): n=3442, 2347, 2079,
8.2 Hz, 2H), 7.31 (d, J=8.1 Hz, 2H), 7.23 (s, 1H), 7.21 (d,
J=1.1 Hz, 2H), 2.48 (s, 3H), 2.42 (d, J=6.2 Hz, 6H);
13C NMR (75 MHz, CDCl3): d=157.6, 156.4, 153.5, 144.9,
139.8, 139.6, 134.8, 134.4, 134.39, 129.8, 129.5, 129.2, 128.8,
126.9, 126.8, 116.3, 110.8, 21.6, 21.2, 21.19; HR-MS-EI:
m/z=429.1398 [M+], calcd. for C26H23NO3S+: 429.1399.
4,6-Bis(4-vinylphenyl)pyridin-2-yl 4-methylbenzenesulfo-
nate (10c): General procedure I was used employing 4,6-di-
bromo-2-tosyloxypyridine (0.245 mmol) and (4-vinylphenyl)-
boronic acid (0.980 mmol), and the reaction was completed
in 30 min. Flash chromatography on silica gel using hexane/
ethyl acetate (20:1) provided pure 10c as a white solid;
yield: 110.5 mg (0.244 mmol, 99%); m.p: 142–1468C; Rf 0.56
(hexane/ethyl acetate=3:1). IR (neat): n=3439, 2341, 2070,
1636, 1440, 1370, 1173, 1089, 741, 668 cmÀ1
;
1H NMR
(300 MHz, CDCl3): d=8.41 (d, J=2.4 Hz, 1H), 8.0 (d, J=
2.4 Hz, 1H), 7.84 (d, J=8.3 Hz, 2H), 7.62 (t, J=2.2 Hz,
1H), 7.50 (dd, J=1.3 Hz and 3.0 Hz, 1H), 7.43–7.40 (m,
1H), 7.35 (d, J=2.2 Hz, 2H), 7.33 (dd, J=1.4 Hz and
5.0 Hz, 1H), 7.26 (d, J=8.2 Hz, 2H), 2.41 (s, 3H); 13C NMR
(75 MHz, CDCl3): d=152.5, 145.0, 143.5, 137.2, 136.9, 134.4,
134.1, 131.0, 129.4, 128.5, 127.6, 127.2, 125.9, 125.7, 125.1,
123.4, 121.8, 21.6; HR-MS-EI: m/z=413.0216 [M+], calcd.
1637, 1371, 1174, 1082, 646, 552, 482 cmÀ1
;
1H NMR
(300 MHz, CDCl3): d=7.98 (d, J=8.3 Hz, 2H), 7.82 (d, J=
1.2 Hz, 1H), 7.74 (d, J=8.5 Hz, 2H), 7.63 (d, J=8.3 Hz,
2H), 7.54 (d, J=8.3 Hz, 2H), 7.44 (d, J=8.3 Hz, 2H), 7.38
(d, J=8.1 Hz, 2H), 7.24 (d, J=1.2 Hz, 1H), 6.82–6.71 (m,
2H), 5.85 (dd, J=7.0 Hz and 17.6 Hz, 2H), 5.34 (dd, J=
3.1 Hz and 11.0 Hz, 2H), 2.48 (s, 3H); 13C NMR (75 MHz,
CDCl3): d=157.7, 156.0, 153.1, 145.0, 138.9, 138.7, 136.7,
136.3, 136.1, 135.8, 134.4, 129.5, 128.7, 127.2, 127.0, 126.9,
126.4, 116.4, 115.3, 114.9, 111.1, 21.7; HR-MS-EI: m/z=
453.1397 [M+], calcd. for C28H23NO3S+: 453.1399.
+
for C20H15NO3S3 : 413.0214.
3,5-Di(furan-3-yl)pyridin-2-yl 4-methylbenzenesulfonate
(7n): General procedure I was used employing 3,5-dibromo-
2-tosyloxypyridine (0.246 mmol) and furan-3-ylboronic acid
(1.230 mmol), and the reaction was completed in 24 h. Flash
chromatography on silica gel using hexane/ethyl acetate
(10:1) provided pure 7n as a white solid; yield: 10.4 mg
(0.0273 mmol, 11%); mp 96–1008C; Rf 0.21 (hexane/ethyl
acetate=5:1). IR (neat): n=3450, 2925, 1637, 1508, 1440,
4,6-Bis(4-methoxyphenyl)pyridin-2-yl 4-methylbenzene-
sulfonate (10d): General procedure I was used employing
4,6-dibromo-2-tosyloxypyridine (0.244 mmol) and (4-me-
thoxyphenyl)boronic acid (1.220 mmol), and the reaction
was completed in 2 h. Flash chromatography on silica gel
using hexane/ethyl acetate (10:1) provided pure 10d as
a white solid; yield: 107.0 mg 0.232 mmol, 95%); mp 122–
1268C; Rf 0.26 (hexane/ethyl acetate=3:1). IR (neat): n=
3446, 2843, 2054, 1607, 1521, 1371, 1249, 1180, 1084, 925,
1
1372, 1174, 875, 762, 597 cmÀ1; H NMR (300 MHz, CDCl3):
d=8.23 (d, J=2.3 Hz, 1H), 7.99 (d, J=3.6 Hz, 2H), 7.95 (s,
1H), 7.87 (d, J=2.4 Hz, 1H), 7.75 (s, 1H), 7.51 (dt, J=
1.7 Hz and 5.2 Hz, 2H), 7.34 (d, J=8.1 Hz, 2H), 6.77 (d, J=
1.1 Hz, 1H), 6.67 (d, J=1.0 Hz, 1H), 2.46 (s, 3H); 13C NMR
(75 MHz, CDCl3): d=152.7, 145.2, 144.3, 143.4, 142.4, 142.3,
139.1, 134.8, 134.5, 129.5, 128.8, 127.7, 122.2, 119.9, 118.9,
109.1, 108.5, 21.7; HR-MS-EI: m/z=381.0674 [M+], calcd.
for C20H15NO5S+: 381.0671.
820 cmÀ1
;
1H NMR (300 MHz, CDCl3): d=7.97 (d, J=
4,6-Diphenylpyridin-2-yl 4-methylbenzenesulfonate (10a):
General procedure I was used employing 4,6-dibromo-2-to-
syloxypyridine (0.247 mmol) and phenylboronic acid
(0.988 mmol), and the reaction was completed in 2 h. Flash
chromatography on silica gel using hexane/ethyl acetate
(20:1) provided pure 10a as a white solid; yield: 98.1 mg
(0.244 mmol, 99%); mp 118–1208C; Rf 0.53 (hexane/ethyl
acetate=3:1). IR (neat): n=3438, 2348, 1612, 1368, 1174,
8.3 Hz, 2H), 7.73–7.58 (m, 3H), 7.58 (d, J=8.8 Hz, 2H),
7.36 (d, J=8.2 Hz, 2H), 7.12 (d, J=1.2 Hz, 1H), 7.00 (d, J=
8.8 Hz, 2H), 6.90 (d, J=8.8 Hz, 2H), 3.85 (d, J=1.7 Hz,
6H), 2.46 (s, 3H); 13C NMR (75 MHz, CDCl3): d=160.8,
160.7, 157.6, 156.0, 153.0, 144.9, 134.4, 130.1, 129.5, 129.47,
128.7, 128.2, 115.4, 114.5, 113.8, 109.9, 55.3, 55.2, 21.6; HR-
MS-EI: m/z=461.1296 [M+], calcd. for C26H23NO5S+:
461.1297.
1
1083, 962, 795, 666, 560 cmÀ1; H NMR (300 MHz, CDCl3):
4,6-Bis(3-methoxyphenyl)pyridin-2-yl 4-methylbenzene-
sulfonate (10e): General procedure I was used employing
4,6-dibromo-2-tosyloxypyridine (0.247 mmol) and (3-me-
thoxyphenyl)boronic acid (0.988 mmol), and the reaction
was completed in 3 h. Flash chromatography on silica gel
using hexane/ethyl acetate (10:1) provided pure 10e as
a white solid; yield: 112.8 mg (0.244 mmol, 99%); mp 80–
828C; Rf 0.34 (hexane/ethyl acetate=3:1). IR (neat): n=
3464, 3003, 2837, 1602, 1549, 1373, 1288, 1178, 1088, 956,
d=8.00 (d, J=8.4 Hz, 2H), 7.84 (d, J=1.2 Hz, 1H), 7.80–
7.76 (m, 2H), 7.67–7.64 (m, 2H), 7.53–7.48 (m, 3H), 7.42 (t,
J=3.3 Hz, 3H), 7.38 (d, J=8.4 Hz, 2H), 7.25 (s, 1H), 2.48
(s, 3H); 13C NMR (75 MHz, CDCl3): d=157.6, 156.5, 153.7,
145.0, 137.4, 137.2, 134.4, 129.6, 129.5, 129.1, 128.7, 128.5,
127.0, 126.9, 116.9, 111.5, 30.8, 21.6; HR-MS-FAB: m/z=
402.1160 [(M+H)+], calcd. for C24H20NO3S+: 402.1164.
4,6-Di-p-tolylpyridin-2-yl 4-methylbenzenesulfonate (10b):
General procedure I was used employing 4,6-dibromo-2-to-
syloxypyridine (0.248 mmol) and p-tolylboronic acid
(0.992 mmol), and the reaction was completed in 8 h. Flash
chromatography on silica gel using hexane/ethyl acetate
(20:1) provided pure 10b as a white solid; yield: 103.8 mg
(0.242 mmol, 97%); mp 148–1508C; Rf 0.58 (hexane/ethyl
acetate=3:1). IR (neat): n=3445, 2347, 2102, 1616, 1372,
769 cmÀ1
;
1H NMR (300 MHz, CDCl3): d=7.96 (d, J=
8.4 Hz, 2H), 7.80 (d, J=1.1 Hz, 1H), 7.43–7.20 (m, 6H),
7.25–7.20 (m, 2H), 7.14 (t, J=2.0 Hz, 1H), 7.01 (dd, J=
2.0 Hz and 8.0 Hz, 1H), 6.96–6.92 (m, 1H), 3.85 (d, J=
11.4 Hz, 6H), 2.46 (s, 3H); 13C NMR (75 MHz, CDCl3): d=
160.1, 159.9, 157.5, 156.3, 153.6, 145.1, 138.9, 138.7, 134.3,
130.3, 129.6, 129.56, 128.7, 119.5, 119.2, 117.2, 114.9, 114.89,
112.8, 112.7, 111.9, 55.4, 55.3, 21.6; HR-MS-EI: m/z=
461.1296 [M+], calcd. for C26H23NO5S+: 461.1297.
1177, 1083, 925, 808, 758, 662 cmÀ1 1H NMR (300 MHz,
;
CDCl3): d=8.00 (d, J=8.3 Hz, 2H), 7.80 (d, J=1.2 Hz, 1H),
7.67 (d, J=8.2 Hz, 2H), 7.56 (d, J=8.1 Hz, 2H), 7.38 (d, J=
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4,6-Bis(2-methoxyphenyl)pyridin-2-yl 4-methylbenzene-
sulfonate (10f): General procedure I was used employing
4,6-dibromo-2-tosyloxypyridine (0.246 mmol) and (2-me-
thoxyphenyl)boronic acid (1.230 mmol), and the reaction
was completed in 48 h. Flash chromatography on silica gel
using hexane/ethyl acetate (10:1) provided pure 10f as
a white solid; yield: 22.8 mg (0.049 mmol, 20%); mp 102–
1048C; Rf 0.24 (hexane/ethyl acetate=3:1). IR (neat): n=
3447, 2838, 1605, 1496, 1373, 1248, 1169, 1126, 927, 804, 754,
(300 MHz, CDCl3): d=7.95 (d, J=8.4 Hz, 2H), 7.73 (d, J=
1.2 Hz, 1H), 7.70 (d, J=8.7 Hz, 2H), 7.57 (d, J=8.7 Hz,
2H), 7.47 (d, J=8.7 Hz, 2H), 7.38–7.33 (m, 4H), 7.19 (d, J=
1.2 Hz, 1H), 2.49 (s, 3H); 13C NMR (75 MHz, CDCl3): d=
157.7, 155.4, 152.6, 145.2, 136.0, 135.8, 135.7, 135.5, 134.3,
129.6, 129.5, 128.8, 128.7, 128.3, 128.2, 116.4, 111.6, 21.7;
HR-MS-FAB:
m/z=470.0386
[M+H]+;
calcd.
for
C24H18Cl2NO3S+: 470.0384.
Di-tert-butyl 4,4’-[6-(tosyloxy)pyridine-2,4-diyl] diben-
zoate (10j): General procedure I was used employing 4,6-di-
bromo-2-tosyloxypyridine (0.247 mmol) and [4-(tert-butoxy-
carbonyl)phenyl]boronic acid (0.988 mmol), and the reaction
was completed in 30 min. Flash chromatography on silica
gel using hexane/ethyl acetate (20:1) provided pure 10j as
a white solid; yield: 147.2 mg (0.245 mmol, 99%): mp 70–
728C; Rf 0.53 (hexane/ethyl acetate=3:1). IR (neat): n=
3447, 2978, 1714, 1604, 1369, 1297, 1170, 930, 774, 665,
551 cmÀ1
;
1H NMR (300 MHz, CDCl3): d=8.02 (d, J=
1.2 Hz, 1H), 7.96 (d, J=8.4 Hz, 2H), 7.42–7.31 (m, 6H),
7.25 (d, J=5.6 Hz, 1H), 7.08–6.93 (m, 4H), 3.83 (d, J=
5.0 Hz, 6H), 2.45 (s, 3H); 13C NMR (75 MHz, CDCl3): d=
157.1, 156.6, 153.8, 150.3, 144.7, 134.5, 131.4, 130.5, 130.4,
130.2, 129.5, 128.9, 127.2, 127.1, 124.4, 121.0, 120.6, 113.8,
111.4, 111.36, 55.54, 55.5, 21.6; HR-MS-EI: m/z=461.1296
[(M+H)+], calcd. for C26H23NO5S+: 461.1297.
4,6-Bis[4-(methylthio)phenyl]pyridin-2-yl
4-methylben-
568 cmÀ1 1H NMR (300 MHz, CDCl3): d=8.12 (d, J=
;
A
8.4 Hz, 2H), 7.99 (dd, J=8.4 Hz and 13.7 Hz, 4H), 7.88 (d,
J=1.0 Hz, 1H), 7.80 (d, J=8.5 Hz, 2H), 7.70 (d, J=8.4 Hz,
2H), 7.38 (d, J=8.2 Hz, 2H), 7.28 (d, J=1.1 Hz, 1H), 2.48
(s, 3H), 1.63 (s, 18H); 13C NMR (75 MHz, CDCl3): d=
165.2, 164.9, 157.7, 155.5, 152.9, 145.2, 140.8, 140.7, 134.3,
133.0, 132.8, 131.5, 130.2, 129.6, 129.57, 128.7, 126.9, 126.7,
117.4, 112.3, 81.5, 81.3, 28.1, 21.6; HR-MS-FAB: m/z=
602.2215 [M+H]+; calcd. for C34H36NO7S+: 602.2212.
ing 4,6-dibromo-2-tosyloxypyridine (0.246 mmol) and (4-
(methylthio)phenyl)boronic acid (165.3 mg, 0.984 mmol),
and the reaction was completed in 1 h. Flash chromatogra-
phy on silica gel using hexane/ethyl acetate (10:1) provided
pure 10g as a white solid; yield: 120.5 mg, (0.244 mmol,
99%); mp 98–1028C; Rf 0.41 (hexane/ethyl acetate=3:1).
IR (neat): n=3452, 2924, 2348, 1602, 1371, 1177, 1084, 926,
816, 664 cmÀ1
;
1H NMR (300 MHz, CDCl3) d 7.96 (d, J=
4,6-Di[(E)-styryl]pyridin-2-yl 4-methylbenzenesulfonate
(10k): General procedure I was used employing 4,6-dibro-
mo-2-tosyloxypyridine (0.246 mmol) and (E)-styrylboronic
acid (0.984 mmol), and the reaction was completed in 1.5 h.
Flash chromatography on silica gel using hexane/ethyl ace-
tate (10:1) provided pure 10k as a yellow solid; yield:
110.7 mg (0.244 mmol, 99%); mp 148–1508C; Rf 0.49
(hexane/ethyl acetate=3:1). IR (neat): n=3441, 2083, 1633,
8.3 Hz, 2H), 7.74 (d, J=1.1 Hz, 1H), 7.67 (d, J=8.6 Hz,
2H), 7.55 (d, J=8.5 Hz, 2H), 7.372–7.311 (m, 4H), 7.23 (d,
J=8.6 Hz, 2H), 7.16 (d, J=1.1 Hz, 1H), 2.50 (d, J=2.1 Hz,
9H); 13C NMR (75 MHz, CDCl3): d=157.7, 155.9, 152.9,
145.0, 141.1, 140.7, 134.3, 133.96, 133.4, 129.5, 128.7, 127.2,
127.1, 126.3, 125.8, 115.8, 110.6, 21.7, 15.2, 15.18; HR-MS-
EI: m/z=493.0843 [M+], calcd. for C26H23NO3S3 : 493.0840.
+
4,6-Bis[4-(trifluoromethyl)phenyl]pyridin-2-yl 4-methyl-
benzenesulfonate (10h): General procedure I was used em-
ploying 4,6-dibromo-2-tosyloxypyridine (0.243 mmol) and
(4-(trifluoromethyl)phenyl)boronic acid (0.972 mmol), and
the reaction was completed in 1 h. Flash chromatography on
silica gel using hexane/ethyl acetate (20:1) provided pure
10h as a white solid; yield: 128.0 mg (0.238 mmol, 98%); mp
148–1508C; Rf 0.73 (hexane/ethyl acetate=3:1). IR (neat):
n=3437, 2943, 2078, 1637, 1327, 1170, 1119, 1069, 924,
1599, 1541, 1371, 1175, 973, 784, 692, 549 cmÀ1 1H NMR
;
(300 MHz, CDCl3): d=7.96 (d, J=8.3 Hz, 2H), 7.51 (d, J=
6.9 Hz, 2H), 7.44 (d, J=6.9 Hz, 2H), 7.46–7.28 (m, 9H),
7.24 (d, J=4.1 Hz, 1H), 7.20 (s, 1H), 7.00 (s, 1H), 6.96 (d,
J=4.1 Hz, 1H), 6.91 (d, J=3.6 Hz, 1H), 2.44 (s, 3H);
13C NMR (75 MHz, CDCl3): d=157.6, 154.7, 149.7, 144.9,
136.2, 135.7, 134.5, 134.3, 134.2, 129.5, 129.0, 128.8, 128.74,
128.7, 128.6, 127.14, 127.1, 126.0, 124.8, 118.7, 110.4, 21.7;
HR-MS-EI: m/z=453.1400 [M+], calcd. for C28H23NO3S+:
453.1399.
647 cmÀ1
;
1H NMR (300 MHz, CDCl3): d=7.97 (d, J=
8.4 Hz, 2H), 7.89 (d, J=8.1 Hz, 2H), 7.86 (d, J=1.2 Hz,
1H), 7.77 (s, 4H), 7.66 (d, J=8.3 Hz, 2H), 7.39 (d, J=
8.2 Hz, 2H), 7.29 (d, J=1.2 Hz, 1H), 2.50 (s, 3H); 13C NMR
(75 MHz, CDCl3): d=157.9, 155.3, 152.6, 145.4, 140.5, 134.2,
131.8 (q, J=32.6 Hz), 131.5 (q, J=32.6 Hz), 129.7, 128.7,
127.6, 127.3, 126.34, 126.29, 126.24, 126.19, 125.74, 125.68,
125.63, 125.59, 125.5, 122.1, 122.0, 117.4, 112.7, 21.7; HR-
4,6-Bis(benzo[b]thiophen-2-yl)pyridin-2-yl 4-methylben-
AHCTUNGTREGzNNNU enesulfonate (10l): General procedure I was used employ-
ing 4,6-dibromo-2-tosyloxypyridine (0.246 mmol) and ben-
zo[b]thiophen-2-ylboronic acid (0.984 mmol), and the reac-
tion was completed in 3 h. Flash chromatography on silica
gel using hexane/ethyl acetate (10:1) provided pure 10l as
a pale yellow solid; yield: 117.0 mg (0.228 mmol, 93%); mp
192–0968C; Rf 0.32 (hexane/ethyl acetate=3:1). IR (neat):
n=3433, 2348, 1612, 1368, 1174, 1082, 962, 794, 666,
MS-FAB:
m/z=538.0913
[(M+H)+],
calcd.
for
C26H17F6NO3S+: 538.0912.
4,6-Bis(4-chlorophenyl)pyridin-2-yl 4-methylbenzenesulfo-
nate (10i): General procedure I was used employing 4,6-di-
bromo-2-tosyloxypyridine (0.245 mmol) and (4-chlorophe-
nyl)boronic acid (1.225 mmol), and the reaction was com-
pleted in 1.5 h. Flash chromatography on silica gel using
hexane/ethyl acetate (20:1) provided pure 10i as a white
solid; yield: 114.5 mg (0.243 mmol, 99%); mp 160–1648C; Rf
0.62 (hexane/ethyl acetate=3:1). IR (neat): n=3447, 2361,
560 cmÀ1 1H NMR (300 MHz, CDCl3): d=8.06 (d, J=
;
8.3 Hz, 2H), 7.86–7.77 (m, 7H), 7.42–7.36 (m, 6H), 7.25 (d,
J=0.4 Hz, 1H), 2.49 (s, 3H); 13C NMR (75 MHz, CDCl3):
d=157.6, 152.0, 146.5, 145.2, 142.5, 140.8, 140.1, 140.0, 139.9,
139.3, 134.1, 129.7, 129.0, 126.0, 125.5, 125.1, 124.7, 124.5,
124.4, 123.3, 122.7, 122.5, 122.49, 115.1, 110.6, 21.8; HR-MS-
+
EI: m/z=513.0526 [M+], calcd. for C28H19NO3S3 : 513.0527.
4,6-Di(thiophen-3-yl)pyridin-2-yl 4-methylbenzenesulfo-
nate (10m): General procedure I was used employing 4,6-di-
1
1636, 1542, 1375, 1171, 1089, 927, 825, 666 cmÀ1; H NMR
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bromo-2-tosyloxypyridine (0.244 mmol) and thiophen-3-yl-
boronic acid (1.220 mmol), and the reaction was completed
in 9 h. Flash chromatography on silica gel using hexane/
ethyl acetate (10:1) provided pure 10m as a brown solid;
yield: 92.0 mg (0.222 mmol, 91%); mp 98–1128C; Rf 0.44
(hexane/ethyl acetate=3:1). IR (neat): n=3441, 2070, 1609,
5 mL). The organic phase was collected, dried over anhy-
drous MgSO4, filtered and concentrated under reduced pres-
sure. The crude product was purified by column chromatog-
raphy over silica gel (Hexane/Ethyl acetate=20:1) to obtain
the pyridine 12 as a white solid; yield: 80.0 mg (0.237 mmol,
1
95%). H NMR (300 MHz, CDCl3): d=7.87 (s, 1H), 7.65 (d,
1
1556, 1368, 1305, 1162, 1090, 965, 787, 665 cmÀ1; H NMR
J=7.32, 2H), 7.47 (t, J=7.3 Hz, 2H), 7.41–7.26 (m, 8H),
6.77 (d, J=8.44 Hz, 2H), 3.75 (s, 1H); 13C NMR (75 MHz,
CDCl3): d=159.3, 155.4, 146.5, 140.1, 137.4, 136.9, 135.5,
134.4, 132.1, 131.1, 129.4, 129.0, 128.4, 128.0, 127.2, 127.0,
113.3, 55.1; the data are consistent with those reported in
the literature.[4c]
(300 MHz, CDCl3): d=7.96 (d, J=8.3 Hz, 2H), 7.68 (dd, J=
1.5 Hz and 2.8 Hz, 1H), 7.65 (dd, J=1.2 Hz and 4.1 Hz,
2H), 7.45 (dd, J=2.9 Hz and 5.0 Hz, 1H), 7.42 (m, 2H),
7.37 (d, J=8.1 Hz, 2H), 7.32 (dd, J=2.9 Hz and 5.0 Hz,
1H), 7.14 (d, J=1.2 Hz, 1H), 2.47 (s, 3H); 13C NMR
(75 MHz, CDCl3): d=157.6, 152.6, 147.7, 145.0, 140.5, 138.5,
134.3, 129.5, 128.7, 127.3, 126.2, 125.9, 125.6, 124.6, 124.0,
115.8, 110.3, 21.6; HR-MS-EI: m/z=413.0214 [M+], calcd.
3,5-Diphenylpyridin-2(1H)-one (13)
+
To a solution of pyridine 7a (0.249 mmol) in THF (5.0 mL)
and methanol (5.0 mL) was added 1N NaOH solution
(2.5 mL). The reaction mixture stirred at 508C for 1 h. The
mixture was diluted with ethyl acetate (10 mL), washed with
H2O and extracted with ethyl acetate (3ꢀ10 mL). The or-
ganic phase was collected, dried over anhydrous Na2SO4, fil-
tered and concentrated under reduced pressure to obtain
the pyridine 13 as a white solid; yield: 61.0 mg (0.247 mmol,
for C20H15NO3S3 :413.0214.
4,6-Di(furan-3-yl)pyridin-2-yl 4-methylbenzenesulfonate
(10n): General procedure I was used employing 4,6-dibro-
mo-2-tosyloxypyridine (0.248 mmol) and furan-3-ylboronic
acid (1.240 mmol), and the reaction was completed in 24 h.
Flash chromatography on silica gel using hexane/ethyl ace-
tate (10:1) provided pure 10n as a brown solid; yield:
28.2 mg (0.074 mmol, 30%); mp 128–1308C; Rf 0.41
(hexane/ethyl acetate=3:1). IR (neat): n=3441, 2070, 1620,
1
99%). H NMR (300 MHz, DMSO-d6): d=12.10 (br s, 1H),
1370, 1175, 1019, 871, 772, 665, 564 cmÀ1
;
1H NMR
7.96 (d, J=2.6 Hz, 1H), 7.82 (d, J=7.1 Hz, 2H), 7.73 (d, J=
2.6 Hz, 1H), 7.65 (d, J=7.3 Hz, 2H), 7.44–7.29 (m, 6H);
13C NMR (75 MHz, DMSO-d6): d=160.7, 137.6, 136.7,
136.3, 131.8, 130.0, 128.9, 128.4, 127.9, 127.4, 126.8, 125.5,
118.3; the data are consistent with those reported in the lit-
erature.[4d]
(300 MHz, CDCl3): d=7.94 (d, J=8.3 Hz, 2H), 7.89 (s, 1H),
7.73 (s, 1H) 7.52 (t, J=1.6 Hz, 1H), 7.43 (t, J=1.7 Hz, 1H),
7.37 (d, J=8.2 Hz, 3H), 7.01 (d, J=1.0 Hz, 1H), 6.72 (d, J=
1.0 Hz, 1H), 6.66 (d, J=1.1 Hz, 1H), 2.47 (s, 3H); 13C NMR
(75 MHz, CDCl3): d=157.7, 151.1, 145.1, 145.0, 144.5, 143.8,
142.0, 140.9, 134.4, 129.5, 128.7, 125.8, 123.6, 115.0, 109.7,
108.3, 108.2, 21.7; HR-MS-EI: m/z=381.0668 [M+], calcd.
for C20H15NO5S+: 381.0671.
2-Phenylamino-4,6-diphenylpyridine (14)
A
round-bottom flask was charged with pyridine 10a
(0.249 mmol), aniline (375 mmol), K2CO3 (0.500 mmol),
DPPF (0.150 mmol) and Pd(OAc)2 (5 mol%). Toluene
(1.9 mL) was then added to the flask. The reaction mixture
was stirred at 1108C for 6 h in under argon purging. Once
cooled, the reaction mixture was quenched with H2O and
extracted with ethyl acetate (3ꢀ5 mL). The organic phase
was collected, dried over anhydrous MgSO4, filtered and
concentrated under reduced pressure. The crude product
was purified by column chromatography over silica gel
(hexane/ethyl acetate=10:1) to obtain the pyridine 14 as
a pale green solid; yield: 80.0 mg (0.248 mmol, 99%).
1H NMR (300 MHz, CDCl3): d=8.08 (d, J=1.2 Hz, 2H),
8.11 (m, 2H), 7.68–7.65 (m, 2H), 7.55–7.40 (m, 9H), 7.39–
7.26 (m, 2H), 7.09 (t, J=7.2 Hz, 1H), 7.04 (d, J=1.2 Hz,
1H), 6.82 (s, 1H); 13C NMR (75 MHz, CDCl3): d=156.8,
156.2, 151.1, 140.6, 139.6, 139.2, 129.3, 128.9, 128.81, 128.76,
128.6, 127.0, 126.9, 122.6, 120.2, 110.8, 104.8; the data are
consistent with those reported in the literature.[18]
3,5-Diphenylpyridine (11)
A 10-mL round-bottom flask was charged with pyridine 7a
(0.250 mmol), Et3N (1.250 mmol), 1,3-bis(diphenylphosphi-
no)propane (5 mol%), Pd(OAc)2 (5 mol%) and formic acid
(0.750 mmol). DMF(1.7 mL) was then added to the flask.
The reaction mixture was stirred at 608C for 1 h in under
argon purging. Once cooled, the reaction mixture was
quenched with H2O and extracted with ethyl acetate (3ꢁ
5 mL). The organic phase was collected, dried over anhy-
drous MgSO4, filtered and concentrated under reduced pres-
sure. The crude product was purified by column chromatog-
raphy over silica gel (hexane/ethyl acetate=10:1) to obtain
the pyridine 11 as a white solid; yield: 53.0 mg (0.229 mmol,
1
92%). H NMR (300 MHz, CDCl3): d=8.84 (d, J=1.7 Hz,
2H), 8.05 (s, 1H), 7.65 (d, J=7.1 Hz, 4H), 7.54–7.7.41 (m,
6H); 13C NMR (75 MHz, CDCl3): d=146.9, 137.7, 136.5,
132.8, 129.0, 128.1, 127.2; the data are consistent with those
reported in the literature.[4d]
2,4-Diphenyl-6-(phenylethynyl)pyridine (15)
2-(4-Methoxyphenyl)-3,5-diphenylpyridine (12)
A
round-bottom flask was charged with pyridine 10a
A
round-bottom flask was charged with pyridine 7a
(0.252 mmol), phenylacetylene (0.428 mmol), K3PO4
(0.250 mmol), (4-methoxyphenyl)boronic acid (0.500 mmol),
K2CO3 (0.550 mmol), SPhos (5 mol%) and Pd(OAc)2
(4 mol%). Toluene (1.7 mL) was then added to the flask.
The reaction mixture was stirred at 508C for 2.5 h under
argon purging. Once cooled, the reaction mixture was
quenched with H2O and extracted with ethyl acetate (3ꢁ
(0.353 mmol), XPhos (5 mol%) and Pd(OAc)2 (3 mol%). t-
BuOH (1.9 mL) was then added to the flask. The reaction
mixture was stirred at 858C for 1 h under argon purging.
Once cooled, the reaction mixture was filtered with ethyl
acetate. The filtrate was concentrated under reduced pres-
sure. The crude product was purified by column chromatog-
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raphy over silica gel (hexane/ethyl acetate=60:1) to obtain
the pyridine 15 as a yellow oil; yield: 70.6 mg (0.213 mmol,
85%); Rf 0.32 (hexane/ethyl acetate=20:1). IR (neat): n=
pleted in 15 min. The reaction mixture was filtered and con-
centrated under reduced pressure. The residue was purified
by column chromatography over silica gel (DCM/MeOH=
20:1) to obtain the alcohol 19 as a light brown oil; yield:
145.0 mg (0.415 mmol, 95%). 1H NMR (300 MHz, CDCl3):
d=8.68 (d, J=2.3 Hz, 1H), 7.69 (d, J=2.3 Hz, 1H), 7.53 (d,
J=8.8 Hz, 2H), 7.28 (d, J=8.4 Hz, 2H), 7.00 (dd, J=1.7 Hz
and J=8.8 Hz, 4H), 3.86 (d, J=4.8 Hz, 6H), 3.71 (t, J=
5.7 Hz, 2H), 2.99 (t, J=6.5 Hz, 2H), 1.98–1.89 (m, 2H);
13C NMR (75 MHz, CDCl3): d=159.7, 159.2, 156.9, 145.1,
136.7, 135.9, 133.8, 131.8, 130.2, 129.8, 128.0, 114.5, 113.9,
62.7, 55.4, 55.3, 32.5, 31.2; the data are consistent with those
reported in the literature.[14a]
3450, 3056, 2352, 2218, 1592, 1245, 1169, 1024, 756, 538 cmÀ1
;
1H NMR (300 MHz, CDCl3): d=8.11–8.08 (m, 2H), 7.88 (d,
J=1.5 Hz, 1H), 7.74–7.65 (m, 5H), 7.55–7.45 (m, 6H), 7.41–
7.38 (m, 3H); 13C NMR (75 MHz, CDCl3): d=158.6, 149.5,
143.8, 139.0, 137.9, 132.1, 129.3, 129.2, 129.1, 128.9, 128.7,
128.4, 127.3, 127.1, 123.9, 122.4, 118.1, 89.2, 89.0; HR-MS-
EI: m/z=331.1360 [M+], calcd. for C25H17N+: 331.1361.
2-Isopropyl-4,6-diphenylpyridine (16)
Pyridine 10a (0.249 mmol) and FeCl3 (0.050 mmol) were dis-
solved in THF (1.0 mL) and NMP (0.2 mL). Isopropylmag-
nesium bromide (0.87 mL, 2.0M, 1.743 mmol) was added
dropwise and the reaction mixture was stirred for 1 h at
À308C. The crude product was purified by column chroma-
tography over silica gel (hexane/ethyl acetate=20:1) to
obtain the pyridine 16 as a yellow oil; yield: 36.1 mg
(0.132 mmol, 53%); Rf 0.68 (hexane/ethyl acetate=5:1); IR
(neat): n=3451, 3057, 2961, 2352, 1600, 1453, 1160, 1065,
2,3-Dihydro-6,8-bis(4-methoxyphenyl)-1H-
indolizinium Chloride (Ficuseptine, 20)
Mesyl chloride (0.572 mmol) was added to alcohol 19
(0.286 mmol) and trimethylamine (0.858 mmol) in anhy-
drous CH2Cl2 (13 mL) with stirring at 08C and the mixture
was allowed to warm up to room temperature over 2 h. The
mixture was poured into saturated NaCl solution (30 mL).
The aqueous layer was washed with diethyl ether (3ꢀ
10 mL), followed by extraction with CHCl3 (3ꢁ20 mL). The
organic phase was collected and dried over anhydrous
CaCl2, filtered and concentrated under reduced pressure.
The crude product was purified by column chromatography
over silica gel (DCM/MeOH=30:1) to obtain the pyridine
20 as light brown solid; yield: 83.0 mg (0.226 mmol, 79%).
1H NMR (300 MHz, CDCl3): d=10.14 (s, 1H), 8.24 (d, J=
1.27 Hz, 1H), 7.85 (d, J=8.80 Hz, 2H), 7.44 (d, J=8.77 Hz,
2H), 7.05 (dd, J=8.8 Hz and 11.4 Hz, 4H), 5.05 (t, J=
7.6 Hz, 2H), 3.87 (d, J=16.83 Hz, 6H), 3.55 (t, J=7.6 Hz,
2H), 2.56 (m, 2H); 13C NMR (75 MHz, CDCl3): d=161.5,
161.1, 152.6, 140.4, 139.4, 138.8, 138.2, 129.9, 126.7, 125.3,
115.3, 115.0, 60.4, 55.7, 55.6, 32.4, 22.4; the data are consis-
tent with those reported in the literature.[14a]
761, 692 cmÀ1 1H NMR (300 MHz, CDCl3): d=8.15–8.11
;
(m, 2H), 7.77 (d, J=1.47 Hz, 1H), 7.73–7.70 (m, 2H), 7.55–
7.43 (m, 6H), 7.35 (d, J=1.45 Hz, 1H), 3.241 (m, 1H), 1.45
(d, J=6.87 Hz, 6H); 13C NMR (75 MHz, CDCl3): d=167.7,
157.0, 149.5, 140.0, 139.3, 129.0, 128.7, 128.6, 127.1, 127.07,
117.2, 116.2, 36.6, 22.7; HR-MS-EI: m/z=273.1519 [M+],
calcd. for C20H19N+: 273.1517.
3,5-Bis(4-methoxyphenyl)-2-{3-[(triethylsilyl)oxy]-
prop-1-yn-1-yl}pyridine (18)
A
round-bottom flask was charged with pyridine 7d
(0.500 mmol), triethyl(prop-2-yn-1-yloxy)silane
(0.650 mmol), K3PO4 (0.700 mmol), XPhos (7 mol%) and
Pd(OAc)2 (3 mol%). t-BuOH (4 mL) was then added to the
flask. The reaction mixture was stirred at 808C for 1 h under
argon purging. Once cooled, the reaction mixture was fil-
tered with ethyl acetate. The filtrate was concentrated under
reduced pressure. The crude product was purified by
column chromatography over silica gel (hexane/ethyl ace-
tate=10:1) to obtain the pyridine 18 as a pale brown solid;
yield: 207.8 mg (0.452 mmol, 90%); mp 55–608C; Rf 0.36
(hexane/ethyl acetate=3:1). IR (neat): n=3445, 2956, 2059,
Acknowledgements
This research was supported by the Basic Science Research
Program through the National Research Foundation of
Korea (NRF) (NRF-2015R1A1A1A05001334) and the New
& Renewable Energy of the Korea Institute of Energy Tech-
nology Evaluation and Planning (KETEP) (grant No.
20163030013900).
1
1629, 1515, 1250, 1086, 1023, 736, 538, 465 cmÀ1; H NMR
(300 MHz, CDCl3): d=8.73 (d, J=2.2 Hz, 1H), 7.79 (d, J=
2.2 Hz, 1H), 7.59–7.54 (m, 4H), 7.02–6.97 (m, 4H), 4.48 (s,
2H), 3.86 (d, J=2.6 Hz, 6H), 0.92 (t, J=7.6 Hz, 9H), 0.58
(q, J=7.6 Hz, 6H); 13C NMR (75 MHz, CDCl3): d=160.0,
159.6, 146.2, 139.2, 138.7, 135.3, 134.4, 130.4, 130.3, 129.4,
128.2, 114.6, 113.7, 90.3, 83.8, 55.3, 55.2, 51.8, 6.6, 4.4; HR-
MS-EI: m/z=459.2230 [M+], calcd. for C28H33NO3Si+:
459.2228.
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14 Synthesis of Trisubstituted Pyridines via Chemoselective
Suzuki–Miyaura Coupling of 3,5- and 4,6-Dibromo-2-
tosyloxypyridines
Adv. Synth. Catal. 2017, 359, 1 – 14
Cho-Hee Park, Yong-Ju Kwon, In-Young Oh,
Won-Suk Kim*
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ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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