Synthesis of tetraarylpyridines by chemo-selective Suzuki-Miyaura reactions of 3,5-dibromo-2,6-dichloropyridine

Article abstract of DOI:10.1039/c5ob00866b

Chemoselective Suzuki-Miyaura reactions on 3,5-dibromo-2,6-dichloropyridine were studied. The optimized reaction conditions allow for the facile access of 3-aryl- and 3,5-diarylpyridines in good yields. Suzuki-Miyaura reactions of the selectively synthesi

Full text of DOI:10.1039/c5ob00866b

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Synthesis of tetraarylpyridines by chemo-selective
Suzuki–Miyaura reactions of 3,5-dibromo-
2,6-dichloropyridine†
Cite this: DOI: 10.1039/c5ob00866b
Sebastian Reimann,a,b Silvio Parpart,a Peter Ehlers,a,b Muhammad Sharif,b,c
Anke Spannenbergb and Peter Langer*a,b
Received 29th April 2015,
Accepted 21st May 2015
Chemoselective Suzuki–Miyaura reactions on 3,5-dibromo-2,6-dichloropyridine were studied. The opti-
mized reaction conditions allow for the facile access of 3-aryl- and 3,5-diarylpyridines in good yields.
Suzuki–Miyaura reactions of the selectively synthesized 2,6-dichloro-3,5-diarylpyridines gave the corres-
ponding 2,3,5,6-tetraarylpyridines, containing two different aryl moieties.
DOI: 10.1039/c5ob00866b
www.rsc.org/obc
of the nitrogen atom and/or by steric or chelating effects of
functional groups. In contrast, chemo-selective cross-coupling
Introduction
Pyridines represent one of the most widely studied classes of reactions take usually advantage from different rates of the oxi-
heterocycles to date. Pyridine and its derivatives can be found dative addition of Pd(0) to the C–X bond. In this regard many
in many natural products and are of great importance in research groups, including ours, studied selective functionali-
pharmaceutical and agrochemical research.1 Pyridines are zations of N-heterocycles by cross-coupling reactions.5
found in nearly all branches of synthetic chemistry, such as Recently, the group of Schmitt and, independently, our own
catalysis, supramolecular chemistry and coordination chemi- group reported the first selective pentafold arylation of pyri-
stry as well as material science.2 Thus, new and efficient syn- dine derivatives by cross-coupling methods.6 The synthetic
thetic methodologies are required for the synthesis of strategy and the type of pyridine substrate employed by both
functionalized pyridines. In this context, palladium catalyzed groups were completely different.
cross coupling reactions offer a convenient and versatile
Palladium catalyzed cross-coupling reactions of tetrahaloge-
method for the introduction of various functionalities to the nated pyridines, containing both chlorine and bromine
pyridine core, starting from easy accessible halogenated pyri- leaving groups at the same time, have, to the best of our
dines. Today, Suzuki–Miyaura reactions are by far the most knowledge, not been previously reported. The first attack of Pd
prominent variant of palladium catalyzed cross-coupling reac- catalyzed cross coupling reactions of polyhalogenated sub-
tions.3 This fact is attributed to the broad and easy accessibi- strates usually occurs at the sterically least hindered and at
lity of boronic acids, their low toxicity and high stability against the electronically most deficient position. The employment of
air and moisture. Moreover, boronic acids allow mild reaction polyhalogenated pyridines containing different types of
conditions and a facile separation of inorganic by-products halogen atoms, which in fact possess different leaving group
with low toxicity.
abilities, allows to introduce an additional parameter to
In particular, site- and chemo-selective cross-coupling reac- control the regioselectivity of the reactions. Herein, we report
tions found increasing attention in recent years, as they allow our results regarding chemo-selective Suzuki–Miyaura reac-
the iterative introduction of various functionalities.4 Site selec- tions of 3,5-dibromo-2,6-dichloropyridine. Palladium catalyzed
tive cross-coupling reactions of pyridines can be mainly con- cross-coupling reactions of this type of substrate have not been
trolled by electronic effects induced by the withdrawing nature reported to date. Classic reactions are also very rare. The
employment of 3,5-dibromo-2,6-dichloropyridine as a sub-
strate allows to change the regioselectivity of cross-coupling
aUniversität Rostock, Institut für Chemie, A.-Einstein-Str. 3a, 18059 Rostock,
reactions as compared to 2,3,5,6-tetrachloropyridine and
Germany. E-mail: peter.langer@uni-rostock.de
bLeibniz-Institut für Katalyse e.V. an der Universität Rostock, A.-Einstein-Str. 29a,
pentachloropyridine.6b
18059 Rostock, Germany
cDepartment of Chemistry, COMSATS Institute of Information Technology 22060,
Results and discussion
Abbottabad, Pakistan
†Electronic supplementary information (ESI) available. CCDC 1062102 and
3,5-Dibromo-2,6-dichloropyridine 3 was synthesized according
1062103. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c5ob00866b
to a modified literature procedure in two steps.7 Commercially
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Scheme 3 Synthesis of compounds 4a–f: (i) 3 (1.0 equiv.), R-B(OH)2
(2.4 equiv.), PdCl2(PPh3)2 (5 mol%), K3PO4 (3.0 equiv.), toluene, 100 °C,
20 h.
Scheme 1 Synthesis of 3; (i) 1, Br2, AcOH, 20 h, 20 °C; (ii) 2, NaNO2,
HCl, 20 h, 20 °C (38% isolated yield after two steps).
the catalyst. Lower amounts of catalyst or boronic acid did not
afford higher yields.
Using our optimized conditions, the reaction of 3 with elec-
tron donating, electron withdrawing and sterically demanding
boronic acids afforded the corresponding 2,6-dichloro-3,5-dia-
rylpyridines 4a–f in 58–74% yield and with very good chemo-
selectivity (Scheme 3 and Table 2).
The structure of compound 4a was independently con-
firmed by X-ray crystal structure analysis, which unambigu-
ously proved the constitution of the molecule (Fig. 1). The
phenyl groups in position 3 and 5 are twisted out of plane
Scheme 2 Optimization
pyridine.
– synthesis of 2,6-dichloro-3,5-diphenyl-
available 2,6-diaminopyridine (1) was converted into 2,6- from the central pyridine moiety.
diamino-3,5-dibromopyridine (2) using bromine in glacial
Subsequently, 2,6-dichloro-3,5-diarylpyridines 4a and 4d
acetic acid. The following diazotization of 2 in the presence of were used for the synthesis of corresponding tetraarylpyri-
NaNO2 and hydrochloric acid yielded 3 (Scheme 1). This struc- dines, containing two different aryl moieties. The same con-
turally simple molecule has, to the best of our knowledge, ditions, which already gave excellent results for the synthesis
never been employed as a substrate in Pd catalyzed cross- of 3,5-dichloro-2,6-diarylpyridines 4a–f, were successfully
coupling reactions before.
employed to prepare the desired products.7 The reactions of
Subsequently, a general catalytic system for the twofold 4a,f with various boronic acids, possessing electron donating
chemo-selective Suzuki–Miyaura reaction of 3,5-dibromo-2,6- or electron withdrawing substituents, afforded the desired
dichloropyridine 3 with phenylboronic acid was developed tetraarylpyridines 5a–d in good yields (Scheme 4 and Table 3).
(Scheme 2; Table 1). During our optimization, the employment
The mono-substitution of 3,5-dibromo-2,6-dichloropyridine
of either XPhos or SPhos proved to be unsatisfactory in terms was next studied. The best yields were obtained using
of yields, due to the favored formation of 2,3,5,6-tetraphenyl- 1.2 equivalents of boronic acid, 5 mol% Pd(PPh3)4 as catalyst
pyridine. Likewise, the reaction proceeded sluggishly in the and 3.0 equivalents of K3PO4 as base in toluene. The reaction
presence of Pd(OAc)2 using the ligand-free protocol of Liu of 3 with different boronic acids afforded the corresponding
et al. in aqueous DMF at room temperature.8 In contrast, mono-arylated pyridines 6a–f in 49–64% yield and with good
the employment of P(Cy)3 and nBuPAd2 (Ad = adamantyl)5 chemo-selectivity. In case of compounds 6b and 6f, possessing
improved the yield to 70% and 80%, respectively. The best electron donating groups, the formation of 2,5-dichloro-3,5-
yield was obtained when 5 mol% of PdCl2(PPh3)2 was used as diarylpyridines was observed (Scheme 5 and Table 4).
Table 1 Optimization – synthesis of 2,6-dichloro-3,5-diphenylpyridine
PhB(OH)2 (equiv.)
Solvent
T (°C)
Pd source [mol%]
Ligand [mol%]
Yielda (%)
1
2
3
4
5
6
7
8
2.4
2.4
2.1
2.1
2.1
2.1
2.4
2.4
2.4
2.2
2.6
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
DMF/H2O
Toluene
Toluene
Toluene
Toluene
100
100
100
100
100
100
rt
100
100
100
100
Pd(PPh3)4 [5]
—
—
46
PdCl2(PPh3)2 [5]
PdCl2(CH3CN)2 [2.5]
PdCl2(CH3CN)2 [2.5]
PdCl2(CH3CN)2 [2.5]
PdCl2(CH3CN)2 [2.5]
Pd(OAc)2 [2]
PdCl2(PPh3)2 [3]
PdCl2(PPh3)2 [1]
PdCl2(PPh3)2 [5]
PdCl2(PPh3)2 [5]
82 (74)b
38
XPhos [5]
SPhos [5]
P(Cy)3 [5]
nBuPAd2 [5]
—
—
—
—
—
15
80
70
6
73
53
65
79
9
10
11
a GC yield using hexadecane as internal standard. b Isolated yield.
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Table 2 Synthesis of 2,6-dichloro-3,5-diarylpyridines 4a–f
4
R
Yields of 4a (%)
a
b
c
d
e
f
C6H5
74
58
60
68
69
50
4-tBuC6H4
4-(MeO)C6H4
4-(CF3)C6H4
3-(MeO)C6H4
2-(MeO)C6H4
Scheme 5 Synthesis of compounds 6a–f: (i) 3 (1.0 equiv.), R-B(OH)2
(1.2 equiv.), Pd(PPh3)4 (5.0 mol%), K3PO4 (3.0 equiv.), toluene, 100 °C,
20 h.
a Isolated yields.
Table 4 Synthesis of 3,5-dibromo-2-chloro-6-arylpyridines 6a–f
6
R
Yields of 6a (%)
a
b
c
d
e
f
C6H5
57
49
52
64
57
56
4-MeC6H4
4-tBuC6H4
4-PhC6H4
4-(CF3)C6H4
3-(MeO)C6H4
a Isolated yields.
Fig. 1 Molecular structure 4a. Displacement ellipsoids are drawn at the
30% probability level.
Scheme 4 Synthesis of compounds 5a–d: (i) 4a,f (1.0 equiv.), R2-
B(OH)2 (4.0 equiv.) Pd(dba)2 (2.5 mol%), nBuPAd2 (5.0 mol%), K3PO4
(4.0 equiv.), toluene, 100 °C, 20 h.
Fig. 2 Molecular structure of 6b. Displacement ellipsoids are drawn at
the 30% probability level.
Table 3 Synthesis of 2,3,5,6-tetraarylpyridines 5 starting from 4
5
R1
R2
Yields of 5a (%)
a
b
c
C6H5
C6H5
4-(CF3)C6H4
4-(CF3)C6H4
4-(MeO)C6H4
4-(CF3)C6H4
C6H5
79
74
75
58
Scheme 6 Optimization – synthesis of 7a.
d
4-(MeO)C6H4
a Isolated yields.
yields of tetraarylpyridine 7a. (Scheme 6, Table 5). The tetra-
fold coupling could be performed in excellent yield when the
amount of palladium catalyst was reduced to 1.25 mol%.
Using optimized conditions, tetraarylpyridines 7a–e were
obtained in excellent yields. Lower yields were initially
observed for products 7f and 7g when sterically hindered
boronic acids were used. However, in these cases, the yields
could be significantly improved when the catalyst amount was
increased to 4.0 mol% (Scheme 7 and Table 6).
The structure of compound 6b was independently con-
firmed by X-ray crystal structure analysis (Fig. 2). Likewise to
compound 4a, the aryl ring is twisted out of plane from the
pyridine.
Finally, we studied the tetrafold arylation of pyridine 3. The
optimization showed that SPhos and nBuPAd2 gave excellent
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Finally, tetrafold Suzuki reactions of 2,6-dichloro-3,5-dibromo-
pyridine were also developed affording functionalized 2,3,5,6-
tetraarylpyridines in excellent yields.
Table 5 Optimization – synthesis 2,3,5,6-tetraphenylpyridine 7a
PhB(OH)2
(equiv.)
Ligand
[mol%]
Yielda
(%)
Pd source [mol%]
1
2
3
4
5
6
7
7
7
7
7
7
PdCl2(PPh3)2 [2.5]
Pd(PPh3)4 [2.5]
PdCl2(CH3CN)2 [2.5]
PdCl2(CH3CN)2 [2.5]
PdCl2(CH3CN)2 [2.5]
PdCl2(CH3CN)2 [1.25]
—
—
80
90
92
95
96
96
Experimental
General
P(Cy)3 [5]
nBuPAd2 [5]
SPhos [5]
SPhos [5]
All reactions were carried out in oven-dried pressure tubes
under argon atmosphere. Solvents for reactions were dried and
distilled by standard methods or purchased in extra dry
quality. Solvents for liquid chromatography and extraction
were always distilled prior to use (heptane, ethyl acetate,
dichloromethane). All chemicals, if not otherwise stated,
including, ligands, boronic acids and bases, were purchased
from commercial sources and used without further purifi-
cation. 1H-NMR spectroscopy: Bruker AV 300 (300 MHz) and
Bruker AV 400 (400 MHz). All NMR spectra presented in this
work were recorded in CDCl3 solution. All chemical shifts are
given in ppm. All coupling constants are indicated as J. Refer-
ences: TMS or residual CHCl3 were taken as internal standard.
Peak characterization: s = singlet, brs = broad singlet, d =
doublet, brd = broad doublet, t = triplet, dd = doublet of
doublet, q = quartet, m = multiplet. 13C-NMR spectroscopy:
Bruker AV 300 (75 MHz) and Bruker AV 400 (100 MHz). All
NMR spectra presented in this work were recorded in CDCl3
solution. All chemical shifts are given in ppm. All coupling
constants are indicated as J. References: TMS or residual
CHCl3 were taken as internal standard. Peak characterization:
d = doublet, t = triplet, q = quartet. DEPT method was used for
determining the presence of primary, secondary, tertiary and
quaternary carbon atoms. 19F-NMR spectroscopy: Bruker AV
300 (282 MHz). Mass spectrometry (MS): Finnigan MAT 95 XP
(electron ionization EI, 70 eV); 6890 N/5973 (Agilent), 6210
Time-of-Flight LC/MS (Agilent). Gas chromatography MS
(GCMS): Agilent HP-5890 with an Agilent HP-5973 Mass Selec-
tive Detector (EI) and HP-5 capillary column using helium
carrier gas. Only the measurements with an average deviation
from the theoretical mass of 2 mDa were accounted as
correct. High resolution MS (HRMS (ESI)): Agilent 1969A TOF.
a Isolated yields.
Scheme 7 Synthesis of compounds 7a–f: (i) 3 (1.0 equiv.), R-B(OH)2
(7.0 equiv.), PdCl2(CH3CN)2 (1.25 mol%), SPhos (5.0 mol%), K3PO4 (7.5
equiv.), toluene, 100 °C, 19 h.
Table 6 Synthesis of 2,3,5,6-tetraarylpyridines 7 starting from 3
7
R
Yielda [%]
a
b
c
d
e
f
C6H5
96
91
97
97
4-MeC6H4
4-tBuC6H4
4-(CF3)C6H4
2-FC6H4
2-(MeO)C6H4
2,3,4-(MeO)3C6H2
99
86b
48b
g
a Isolated yields. b Using 4.0 mol% PdCl2(CH3CN)2 and 8.0 mol%
SPhos.
Conclusion
In conclusion, Suzuki–Miyaura reactions of 3,5-dibromo-2,6-
dichloropyridine allowed for the chemo-selective synthesis Only the measurements with an average deviation from the
of 3-bromo-2,6-dichloro-5-aryl-pyridines and 2,6-dichloro-3,5-
diaryl-pyridines in good to excellent yields. Palladium cata-
theoretical mass of 2 mDa were accounted as correct. Infrared
spectroscopy (IR): Nicolet 550 FT-IR spectrometer with ATR
lyzed coupling reactions of this substrate have, to the best of sampling technique for solids as well as liquids. Signal charac-
our knowledge, not been previously reported. Classic reactions
of this substrate are also very rare. The employment of 3,5-
terization: w = weak, m = medium, s = strong. X-ray crystallo-
graphy: Data were collected on a Bruker Kappa APEX II Duo
dibromo-2,6-dichloropyridine as the substrate allows, by diffractometer. The structure was solved by direct methods
and refined by full-matrix least-squares procedures on F2 with
employment of two different leaving groups, a complete
change of the regioselectivity as compared to reactions of
2,3,5,6-tetrachloropyridine and pentachloropyridine.6b The logr., 2008, A64, 112.). XP (Bruker AXS) was used for graphical
the SHELXTL software package (G. M. Sheldrick, Acta Crystal-
order of coupling reactions could be changed by the use of the
new substrate which contains both chlorine and bromine
representation. CCDC 986651–986652 contain the supplemen-
tary crystallographic data for this paper. Elemental analysis
leaving groups. The 2,6-dichloro-3,5-diarylpyridines proved to (EA): C/H/N/S – Microanalysator TruSpec CHNS (Leco). Melting
be excellent starting materials for further functionalizations,
point determination (mp): Micro-Hot-Stage Galen™ III Cam-
as shown by additional Suzuki–Miyaura reactions which led to
bridge Instruments. The melting points have not been cor-
tetraarylpyridines containing two different aryl moieties. rected. Thin layer chromatography (TLC): Merck Silica 60 F254
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on aluminum tin foil from Macherey–Nagel. Detection with UV was stirred at 100 °C for 20 h. The cooled reaction mixture was
light at 254 nm and/or 366 nm without dipping reagent. diluted with water and extracted with DCM. The combined
Column chromatography: Separation on Fluka silica gel 60 organic layers were dried (Na2SO4), filtered and the filtrate was
(0.063–0.200 mm, 70–320 mesh). Eluents were distilled before concentrated in vacuo. The residue was purified by column
use.
chromatography.
2,6-Dichloro-3,5-diphenylpyridine (4a). Starting with 3,5-
General procedure for the synthesis of starting material 3
dibromo-2,6-dichloropyridine
3
(100 mg, 0.327 mmol),
PdCl2(PPh3)2 (11.5 mg, 5.0 mol%), phenylboronic acid
(95.7 mg, 0.785 mmol), K3PO4 (208 mg, 0.981 mmol) and
toluene (4.0 mL), 4a was isolated as a colorless oil (73 mg,
74%); mp = 128–129 °C. 1H NMR (300 MHz, CDCl3): δ =
7.41–7.49 (m, 10H, CH), 7.67 (s, 1H, CH). 13C NMR (75 MHz,
CDCl3): δ = 128.5 (CH), 128.6 (CH), 129.2 (CH), 135.8 (C), 136.0
(C), 142.7 (CH), 146.8 (C–Cl). IR (ATR, cm−1): ˜ν = 3057 (w),
2921 (w), 2027 (w), 1959 (w), 1577 (m), 1530 (w), 1445 (m),
1384 (s), 1223 (w), 1120 (m), 1029 (m), 1006 (w), 870 (w), 765
(m), 700 (s), 671 (m), 650 (w), 598 (w), 523 (w), 464 (w), 377 (w).
GC-MS (EI, 70 eV): m/z (%): 303 (M+, 20), 299 (100), 264 (3), 229
(11), 228 (18), 227 (23), 203 (4), 202 (16), 201 (9), 176 (2), 150
(3), 132 (2), 126 (2), 114 (8), 101 (7), 100 (6), 88 (4), 77 (4), 75
(3), 51 (4). HRMS (EI, 70 eV): calcd for C17H11Cl2N (M+):
299.02631, found 299.02605 and calcd for C17H11Cl37ClN (M+):
301.02336, found 301.02348 and calcd for C17H1137Cl2N (M+):
303.02041, found 303.02057.
To a stirred solution of HOAc (200 mL/0.1 mol of 1; 100%) and
2,6-diaminopyridine 1 (10.9 g, 0.1 mol) was added bromine
(11.4 mL, 0.22 mol) at 10 °C. The temperature was allowed to
warm to 20 °C and the reaction mixture was stirred for
additional 20 h. Na2SO3 was added to the solution (20 mL, 0.1
M) and subsequently Na2CO3 (0.1 M) until a neutral pH-value
was reached. The latter was extracted with EtOAc (8 × 50 mL).
The combined organic layers were dried (Na2SO4), filtered and
the filtrate was concentrated in vacuo. 2,6-Diamino-3,5-di-
bromopyridine 2 was obtained as a brownish solid and used
for the second step without further purification.
To a stirred solution of HCl and 2,6-diamino-3,5-dibromo-
pyridine 2 (15 g, 0.056 mol) was added NaNO2 (9.3 g, 0.14 mol)
at room temperature. The solution was stirred for 20 h. Sub-
sequently, water was added (300 mL) and the latter was
extracted with EtOAc (3 × 50 mL). The combined organic layers
were dried (Na2SO4), filtered and the filtrate was concentrated
in vacuo. 2,6-Dichloro-3,5-dibromopyridine 3 was obtained as
colorless solid (6.5 g, 38% over two steps) after purification by
flash chromatography (n-hexane/EtOAc).
General procedure for the synthesis of 2,3,5,6-tetraaryl-
substituted pyridines 5a–d
An oven-dried and argon-flushed pressure tube was charged
with the appropriate 2,6-dichloro-3,5-diaryl-substituted pyri-
dines 4 (0.3 mmol), Pd(dba)2 (2.5 mol%), nBuPAd2 (5.0 mol%),
boronic acid (1.2 mmol) and K3PO4 (1.2 mmol) followed by
anhydrous toluene (5.0 mL). The tube was sealed with a Teflon
valve and the reaction mixture was stirred at 100 °C for 20 h.
The cooled reaction mixture was diluted with water and
extracted with DCM. The combined organic layers were dried
(Na2SO4), filtered and the filtrate was concentrated in vacuo.
The residue was purified by column chromatography.
3,5-Dibromo-2,6-dichloropyridine (3).
Compound 38 was isolated as a colorless solid; mp = 87–88 °C.
1H NMR (300 MHz, CDCl3): δ = 8.13 (s, 1H, CH). 13C NMR
(75 MHz, CDCl3): δ = 118.9 (C-Br), 146.5 (CH), 148.5 (C–Cl). IR
(ATR, cm−1): ˜ν = 3081 (w), 3028 (w), 1516 (m), 1371 (s), 1324
(m), 1297 (m), 1222 (w), 1165 (s), 1053 (m), 1037 (s), 921 (m),
845 (w), 712 (m), 667 (m), 622 (w), 588 (m), 496 (m), 462 (m).
GC-MS (EI, 70 eV): m/z (%): 305 (M+, 100), 303 (39), 272 (10),
270 (15), 268 (7), 228 (7), 226 (14), 224 (9), 191 (7), 189 (6), 164
(4), 153 (6), 147 (10), 145 (16), 112 (5), 110 (14), 86 (5), 84 (16),
75 (26), 74 (9), 49 (11). HRMS (EI, 70 eV): calcd for C5HBr2Cl2N
(M+): 302.78473, found 302.784924 and calcd for
C5HBr81BrCl2N (M+): 304.78268, found 304.782710 and calcd
for C5H81Br2Cl2N (M+): 306.78064, found 306.780338 and calcd
for C5H81Br2Cl37ClN (M+): 308.77769, found 308.777837. Anal.
calcd for C5HBr2Cl2N (305.78): C, 19.64; H, 0.33; N, 4.659.
Found: C, 19.80; H, 0.3439; N, 4.658.
2,6-Bis(4-methoxyphenyl)-3,5-diphenylpyridine (5a). Start-
ing with 2,6-dichloro-3,5-diphenylpyridine 5a (128 mg,
0.29 mmol), Pd(dba)2 (4.2 mg, 2.5 mol%), nBuPAd2 (5.2 mg,
5.0 mol%), 4-methoxyphenylboronic acid (175 mg,
1.15 mmol), K3PO4 (245 mg, 1.15 mmol) and toluene (5.0 mL),
5a was isolated as a colorless solid (102 mg, 79%); mp =
1
204–206 °C. H NMR (300 MHz, CDCl3): δ = 3.66 (s, 6H, MeO),
6.65–6.69 (m, 4H, CH), 7.14–7.20 (m, 10H, CH), 7.34–7.38 (m,
4H, CH), 7.60 (s, 1H, CH). 13C NMR (75 MHz, CDCl3): δ = 55.2
(MeO), 113.1 (CH), 127.0 (CH), 128.3 (CH), 129.4 (CH), 131.4
(CH), 132.5 (C), 133.3 (C), 140.1 (C), 141.2 (CH), 154.6 (C),
159.3 (C). IR (ATR, cm−1): ˜ν = 3054 (w), 3030 (w), 2951 (w), 2929
(w), 2834 (w), 1604 (s), 1577 (m), 1506 (s), 1446 (s), 1421 (s),
1386 (m), 1299 (m), 1246 (s), 1172 (s), 1108 (w), 1074 (w), 1030
General procedure for the synthesis of 2,6-dichloro-3,5-diaryl-
substituted pyridines 4a–f
An oven-dried and argon-flushed pressure tube was charged (m), 1005 (w), 911 (w), 878 (w), 837 (s), 792 (m), 769 (s), 756
with 3,5-dibromo-2,6-dichloropyridine
3
(0.33 mmol), (m), 733 (w), 699 (s), 641 (m), 619 (w), 559 (m), 538 (m), 524
PdCl2(PPh3)2 (5.0 mol%), boronic acid (0.8 mmol) and K3PO4 (w), 417 (w). GC-MS (EI, 70 eV): m/z (%): 444 (M+, 21), 443 (72),
(0.98 mmol), followed by anhydrous toluene (4.0 mL). The 442 (100), 400 (3), 399 (9), 398 (9), 355 (9), 341 (3), 328 (2), 292
tube was sealed with a Teflon valve and the reaction mixture (2), 281 (2), 207 (3), 184 (5), 183 (6), 177 (9), 170 (4), 169 (5).
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HRMS (ESI, 70 eV): calcd for C31H26NO2 ([M + H]+): 444.19581, 96%); mp = 244–246 °C. 1H NMR (300 MHz, CDCl3): δ =
found 444.19624. Anal. calcd for C31H25NO2 (443.54): C, 83.95; 7.22–7.30 (m, 16H, CH), 7.47–7.51 (m, 4H, CH), 7.77 (s, 1H,
H, 5.68; N, 3.16. Found: C, 84.08; H, 5.728; N, 2.953.
CH). 13C NMR (75 MHz, CDCl3): δ = 127.5 (CH), 128.0 (CH),
128.1 (CH), 128.6 (CH), 129.8 (CH), 130.4 (CH), 134.6 (C), 139.8
(C), 139.9 (C), 141.5 (CH), 155.5 (C). IR (ATR, cm−1): ˜ν =
3080 (w), 3054 (w), 3023 (w), 2927 (w), 2857 (w), 1444 (m),
General procedure for the synthesis of 3-bromo-2,6-dichloro-
5-aryl-substituted pyridines 6a–f
An oven-dried and argon-flushed pressure tube was 1416 (s), 1386 (m), 1179 (w), 1072 (w), 1017 (w), 908 (m),
charged with 3,5-dibromo-2,6-dichloropyridine 3 (0.33 mmol), 854 (w), 779 (m), 757 (s), 732 (m), 690 (s), 537 (m), 528 (m),
Pd(PPh3)4 (5.0 mol%), boronic acid (0.4 mmol) and K3PO4 499 (m), 409 (w), 390 (w). GC-MS (EI, 70 eV): m/z (%): 384
(0.98 mmol), followed by anhydrous toluene (4.0 mL). The (M+, 16), 383 (66), 382 (100), 306 (3), 305 (3), 304 (10), 303 (7),
tube was sealed with a Teflon valve and the reaction mixture 302 (6), 276 (8), 190 (7), 189 (5), 188 (3), 183 (13), 77 (4). HRMS
was stirred at 100 °C for 20 h. The cooled reaction mixture was (ESI, 70 eV): calcd for C29H22N ([M + H]+): 384.17468, found
diluted with water and extracted with DCM. The combined 384.17447. Anal. calcd for C29H21N (383.48): C, 90.83; H, 5.52;
organic layers were dried (Na2SO4), filtered and the filtrate was N, 3.65. Found: C, 90.50; H, 5.329; N, 3.431.
concentrated in vacuo. The residue was purified by column
chromatography.
3-Bromo-2,6-dichloro-5-phenylpyridine (6a). Starting with
3,5-dibromo-2,6-dichloropyridine 3 (100 mg, 0.327 mmol),
Acknowledgements
Pd(PPh3)4 (18.9 mg, 5.0 mol%), phenylboronic acid (47.8 mg, The authors thank Prof. Dr R. Ludwig for scientific
0.392 mmol), K3PO4 (208 mg, 0.981 mmol) and toluene discussions. Financial support by the University of Rostock
(4.0 mL), 6a was isolated as a colorless oil (56 mg, 57%). 1H (scholarship of the interdisciplinary faculty of the University
NMR (300 MHz, CDCl3): δ = 7.39–7.48 (m, 5H, CH), 7.90 (s, 1H, of Rostock for S.R.) and by the State of Mecklenburg-
CH). 13C NMR (75 MHz, CDCl3): δ = 118.6 (C–Br), 128.6 (CH), Vorpommern is gratefully acknowledged.
129.0 (CH), 129.1 (CH), 135.1 (C), 137.0 (C), 144.6 (CH), 147.0
(C), 148.2 (C). IR (ATR, cm−1): ˜ν = 3054 (w), 2923 (w), 1809 (w),
1603 (w), 1562 (w), 1513 (m), 1446 (m), 1387 (s), 1336 (m),
1221 (m), 1171 (m), 1115 (m), 1076 (w), 1037 (w), 1013 (m),
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