Chemoselective Synthesis of Arylpyridines through Suzuki–Miyaura Cross-Coupling Reactions

Article abstract of DOI:10.1002/ejoc.201701718

4-Bromo-2,3,5-trichloro-6-iodopyridine has been synthesized for the first time and applied in chemo- and site-selective Suzuki–Miyaura cross-coupling reactions. This novel starting material allows the selective synthesis of pentaarylpyridines with up to f

Full text of DOI:10.1002/ejoc.201701718

A Journal of
Accepted Article
Title: Chemoselective Synthesis of Arylpyridines via Suzuki-Miyaura
Cross-Coupling Reactions
Authors: Rodisnel Perdomo Rivera, Peter Ehlers, Lars Ohlendorf,
Eugenio Torres Rodriguez, Alexander Villinger, and Peter
Langer
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701718
Link to VoR: http://dx.doi.org/10.1002/ejoc.201701718
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10.1002/ejoc.201701718
European Journal of Organic Chemistry
1
Chemoselective Synthesis of Arylpyridines via Suzuki–Miyaura Cross-
Coupling Reactions
Rodisnel Perdomo Rivera,a,c Peter Ehlers,a,b Lars Ohlendorf,a Eugenio Torres
Rodríguez,c Alexander Villinger,a Peter Langera,b,*
a Universität Rostock, Institut für Chemie, A.-Einstein-Str. 3a, 18059 Rostock, Germany
E-mail: peter.langer@uni-rostock.de; https://www.langer.chemie.uni-rostock.de/
b
Leibniz-Institut für Katalyse e.V. an der Universität Rostock, A.-Einstein-Str. 29a,
18059 Rostock, Germany
c
University of Granma, Study Center of Applied Chemistry, Carretera de Manzanillo
Km 17½, 85100, Bayamo, Granma, Cuba.
Abstract:
4-Bromo-2,3,5-trichloro-6-iodopyridine has been synthesized for the first time and
applied in chemo- and site-selective Suzuki-Miyaura cross-coupling reactions. This
novel starting material allows the selective synthesis of pentaarylpyridines with up to
four different aryl substituents.
Keywords: Cross-coupling; Suzuki–Miyaura reaction; chemoselectivity; palladium;
pyridines
Introduction
Pyridine and its derivatives are associated with diverse pharmacological properties, such
as antimicrobial,1,2 anticancer,3 anticonvulsant,4 antiviral,5 anti-HlV,6 antifungal and
antimycobacterial activities.7 In addition to medicinal properties of pyridine derivatives,
important other applications have been reported in the field of synthetic chemistry, such
as catalysis, supramolecular chemistry as well as materials science.8 All these results
have increased the interest of the international scientific community in the development
of new and efficient procedures for the synthesis of polyfunctionalized pyridines.
Although several methodologies have been described for the synthesis of
polysubstituted pyridines so far, many of those are limited, because they are not
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economically viable or require many synthetic transformation steps. In 2014, Schmitt et
al. reported the first synthesis of pentaarylpyridine with five different aryl groups in 13
steps.9 Later, Yamaguchi and co-workers presented a regiocontrolled thermal [4+2]
cycloaddition of tetraarylthiophene S-oxide and 2-cyanopyridine to give various
pentaarylpyridines.10 Recently, the same group completed the synthesis of
pentaarylpyridines containing five different aryl groups by a ring transformation /
coupling approach.11 Although this method introduces different aryl substituents on the
pyridine moiety with good regioselectivity, the diversity of functional groups is limited
by the presence of three fixed aryl groups of the key intermediate, namely, 3-hydroxy-
2,5,6-triarylpyridine. Additionally, Nishiwaki and co-workers published the synthesis of
various polyarylated pyridines using condensation reactions of enamino esters with
enones assisted by microwave.12
The Palladium catalyzed Suzuki-Miyaura reaction displays one of the most relevant
methodologies for the construction of biaryls or polyarylated compounds, what is
mainly based on the low toxicity and stability against air and moisture of the employed
boronic acids as well as its good functional group tolerance.13 In these reactions
arylchlorides are favorable coupling partners, despite their low reactivity, due to their
broader availability and lower costs compared to corresponding aryl bromides or –
iodides.14 To overcome the low reactivity of arylchlorides several electron-rich and
sterical encumbered phosphine and NHC ligands have been developed allowing the
cross-coupling of arylchlorides in high yield under mild conditions.15
During the last years, the use of palladium catalysts in site-selective cross-coupling
reactions of polyhalogenated heterocycles gained an increasing interest.16 Recently, our
group described the synthesis of pentaarylpyridines17 as well as the site-selective
synthesis of other arylated pyridines18 using cheap and commercially available
pentachloropyridine as substrate. These reactions give access to highly functionalized
pyridines by cross-coupling reactions. However, in some cases, it was difficult to
achieve site-selective reactions at specific positions of the pyridine core. In particular,
the synthesis of tri- and tetraarylated pyridines was not possible by employment of
pentachloropyridine as starting material, as the sequential coupling of aryl rings to the
pyridine ring led to changes of the electronic situation of the central pyridine core
structure. Thus, we envisioned that such compounds might be accessible by a chemo-
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selective approach overwriting electronic effects responsible for the poor site-
selectivity.
Results and Discussion
Starting Material Synthesis
In order to improve the selectivity of Suzuki cross-coupling reactions at positions 4 and
6 of the pyridine ring, we focused on the synthesis of the novel starting material 4-
bromo-2,3,5-trichloro-6-iodopyridine
(3).
Commercially
available
2,3,5-
trichloropyridine was transformed, following the procedure described by Bobbio et
al.,19 to 2,3,5-trichloro-4-iodopyridine (2) in 75 % yield. Subsequently, the desired
pyridine derivative 3 could be synthesized in 77 % yield adapting a similar procedure
by lithiation, followed by bromination using 1,2-dibromotetrachloroethane (Scheme 1).
It is important to note that the initially generated 6-lithiated species 2a instantaneously
isomerized by migration of the heavy halogen to the less basic 4-lithiated isomer 2b.
The constitution of 3 was independently confirmed by X-ray crystallographic analysis
(Figure 1).
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Scheme 1. Synthesis of starting material 3. i: 1) 1(1.0 equiv.), LDA (1.0 equiv.), THF,
-78 °C, 2 h; 2) I2 (1.2 equiv.), THF, -78 °C, 2 h. ii: 1) 2 (1.0 equiv.), LiTMP (1.0 equiv.),
THF, -100 °C, 2 h; 2) C2Br2Cl4 (3.3 equiv.), THF, -78 °C, 2 h.
Figure 1. Ortep of compound 320
Site selective Suzuki-Miyaura reactions
Synthesis of 4-Bromo-2,3,5-trichloro-6-arylpyridines 4
With substrate 3 in hand, we optimized the reaction conditions for the synthesis of
monoarylpyridines 4 (Table 1). As the C-I bond in postion 2 of starting material should
be highly active, we started our optimization with the cheap and easy available
Pd(PPh3)4 as catalyst and chose K3PO4 as base and toluene as solvent based on our
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previous experiences on the arylation of pyridines.17 After some experimentation, we
found that the best yield of 4a (78%) was obtained when the reaction was carried out
using Pd(PPh3)4 (5 mol%) as the catalyst in a solvent mixture of toluene, water and
ethanol (entry 3). However, employment of Pd(OAc)2 and PCy3 as a more active
catalyst system did not give the desired product. Instead, the diarylated pyridine was
formed as the main product (entry 4).
Table 1. Optimization for the synthesis of 4a.
Entr
y
Catalyst
(mol%)
Base
Solvent
PhB(OH)2
(equiv.)
4a
(%)a
(equiv.)
Toluene
1
2
Pd(PPh3)4 (5)
Pd(PPh3)4 (5)
K3PO4 (1.1)
K3PO4 (1.5)
1.1
1.5
40
60
Toluene
Toluene/H2O/
EtOH (6:1:1)
3
Pd(PPh3)4 (5)
K3PO4 (1.5)
K3PO4 (1.1)
1.5
1.1
78
-
Pd(OAc)2 (5),
P(Cy)3(10)
Toluene
4
a Yield of isolated products.
The reaction of 3 with various arylboronic acids, using our optimized conditions (Table
1, entry 3), afforded 4-bromo-2,3,5-trichloro-6-arylpyridines 4a-k in 60 – 86 % yield
(Table 2). The best yields were obtained for the reactions of 3 with 2-
methoxyphenylboronic acid 4i and 4-tolylboronic acid 4b. Slightly lower yields were
obtained when electron-poor arylboronic acids were employed (cf. compounds 4h, j, k).
A reaction at another position was not observed, showing the high degree of
chemoselectivity at position 6. The structure of 4b was independently confirmed by X-
ray crystallographic analysis (Figure 2).
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Table 2. Chemoselective synthesis of monoarylated pyridines 4a-k.
Br
Br
Cl
I
Cl
Cl
Cl
Ar
Cl
Cl
i
+
Ar B(OH)2
N
N
4a-k
3
Br
Br
N
Br
N
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
N
MeO
Me
4c (73%)
4b (83%)
4a (78%)
Br
Br
Br
Cl
Cl
Cl
Cl
S
Cl
Cl
Cl
Cl
Cl
MeO
N
N
N
F
4e (77%)
4f (81%)
4d (73%)
Br
Br
Br
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
O2N
N
N
N
OMe
4i (86%)
F3C
4g (78%)
4h (60%)
Br
Br
Cl
Cl
Cl
Cl
Cl
Cl
N
N
Cl
NC
4j (60%)
4k (69%)
Reaction conditions i: 3 (0.3 mmol), ArB(OH)2 (1.5 equiv.), K3PO4 (1.5 equiv.),
Pd(PPh3)4 (5 mol%), Toluene/EtOH/H2O (6:1:1), 22 h, 100 °C; yield of isolated
products.
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Figure 2. Ortep of compound 4k20
Synthesis of 4,6-Diaryl-2,3,5-trichloropyridines 5
We envisioned that 3 might also be an ideal substrate for chemoselective diarylation of
pyridine by Suzuki–Miyaura reactions, directed at positions 4 and 6 (Table 3), while
previously employed pentachloropyridine resulted in selective formation of 2,6-
diarylpyridines.
Table 3. Optimization of the synthesis of 5a
Entry
1
Catalyst
(mol%)
Base
4-TolB(OH)2 Temp.
t
5a
(%)a
50
(equiv.)
(equiv.)
2.5
(°C)
100
(h)
19
Pd(PPh3)4 (5)
K3PO4 (2.5)
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2b
3b
Pd(PPh3)4 (5)
K3PO4 (2.5)
K3PO4 (3.0)
2.5
3.0
130
130
31
31
59
62
Pd(PPh3)4 (5)
Pd(OAc)2 (5),
P(Cy)3 (10)
19
19
19
19
19
4
5
6
7
8
K3PO4 (2.0)
K3PO4 (2.1)
K3PO4 (2.5)
K3PO4 (3.0)
K3PO4 (3.5)
2.0
2.1
2.5
3.0
3.5
100
100
75
81
67
58
38
Pd(OAc)2 (5),
P(Cy)3 (10)
Pd(OAc)2 (5),
P(Cy)3 (10)
100
100
Pd(OAc)2 (5),
P(Cy)3 (10)
Pd(OAc)2 (5),
P(Cy)3 (10)
100
a Yield of isolated products; b using xylene (mixture of isomers) was used as solvent
During the optimization process (Table 3), it became apparent that a catalytic system
based on Pd(OAc)2 and PCy3 is superior to the employment of Pd(PPh3)4. Moreover, we
realized that the isolated yield is highly sensitive to the employed amount of K3PO4 and
the arylboronic acid. Hence, the best yield (81%) of product 5a was obtained when the
reaction was carried out using Pd(OAc)2/PCy3 and 2.1 equivalents of the arylboronic
acid (entry 5). Generally, in all cases trace amounts of monoarylated and triarylated
product have been detected by TLC analysis, leading to slightly diminished yields of the
isolated product.
Using our optimized conditions, we were able to synthesize various 2,3,5-trichloro-4,6-
diarylpyridines 5 in moderate to very good yield (Table 4). All reactions took place
selectively at positions 4 and 6 of the pyridine moiety. The moderate yields of some
products (5g, 5h) can be explained by the formation of substantial amounts of
triarylated side-products using electron-poor arylboronic acids by electronically
activating intermediates and products.
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Table 4. Synthesis of 2,4-diarylated pyridines 5a-h
Br
Ar
Cl
I
Cl
Cl
Cl
Ar
Cl
Cl
i
Ar B(OH)2
+
N
N
5a-h
3
Cl
N
Me
OMe
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
N
N
Cl
Me
5b (77%)
MeO
5a (81%)
5c (54%)
CN
Et
Me
Me
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
N
Me
N
N
NC
5d (66%)
5e (72%)
Et
5f (58%)
Me
CF3
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
N
N
F3C
5g (34%)
5h (35%)
Reaction conditions i: 3 (0.26 mmol), ArB(OH)2 (2.1 equiv.), K3PO4 (2.1 equiv.),
Pd(OAc)2 (5 mol%), PCy3 (10 mol%), Toluene/nBuOH/H2O (6:1:1), 19 h, 100 °C.
Next, we studied the chemoselective synthesis of diarylated pyridines 6a-c, containing
two different aryl substituents. These compounds were prepared in a two-step
procedure, starting from compound 4b (Table 5). The yields are not affected by the
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nature of the substituents employed. However, practical separation problems of the
corresponding triarylated side products are the main reason for the moderate isolated
yields.
Table 5. Synthesis of 2,4-diarylated pyridines 6a-c
CN
NO2
OMe
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
N
N
N
Me
Me
Me
6a (50%)
6b (55%)
6c (48%)
Reaction conditions i: 4b (0.29 mmol), ArB(OH)2 (1.5 equiv.), K3PO4 (1.5 equiv.),
Pd(PPh3)4 (5 mol%), Toluene/nBuOH/H2O (6:1:1), 19 h, 100 °C.
In the following studies, we attempted to realize the selective synthesis of triarylated
pyridines using 2.5-4.5 equiv. of the appropriate arylboronic acid. However, in all cases,
we isolated only inseparable mixtures of the expected 3,5-dichloro-2,4,6-triarylpyridine
7a and of tetraarylated 3-chloro-2,4,5,6-tetraarylpyridine 8a (cf. Supporting
Information; Scheme 2). This is surprising, as position 6, located adjacent to the
nitrogen atom, was expected to be significantly more reactive than positions 3 and 5,
due to electronic reasons.
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Scheme 2. Synthesis of a mixture of pyridines 7 and 8
To overcome this drawback, we studied the applicability of pyridines 5 and 6 as starting
materials for the synthesis of 2,4,6-triarylated pyridines 9 and 10. To our delight, the
Suzuki-Miyaura reaction of 5a with 1.2 equivalents of the corresponding arylboronic
acids, in the presence of Pd(PPh3)4, delivered the triarylated products 9a-d (Table 6).
The moderate yield can be explained by difficulties during column chromatography and
are independent from the substitution pattern of the employed arylboronic acid.
Table 6. Synthesis of triarylated pyridines 9a-d.
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Me
Me
Cl
Cl
Cl
Cl
OMe
N
N
Me
OMe
Me
9a (57%)
9b (49%)
Me
Me
Cl
Cl
Cl
Cl
N
N
Me
F
Me
Cl
9d (50%)
9c (38%)
Reaction conditions i: 5a (0.28 mmol), ArB(OH)2 (1.2 equiv.), K3PO4 (1.2 equiv.),
Pd(PPh3)4 (5 mol%), Toluene, 20 h, 100 °C.
The Suzuki-Miyaura reaction of 6a, containing two different aryl groups, afforded the
triarylated pyridines 10a-c, which contain three different aryl rings, in good yields
ranging from 61-77 % (Table 7).
Table 7. Synthesis of triarylated pyridines 10a-c.
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Reaction conditions i: 6a (0.27 mmol), ArB(OH)2 (1.2 equiv.), K3PO4 (1.2 equiv.),
Pd(PPh3)4 (5 mol%), Toluene, 20 h, 100 °C.
Finally, we studied the employment of synthesized compounds 6, 9 and 10 for the
synthesis of pentaarylpyridines, using our previously reported conditions.14
Pentaarylated pyridines 11a,b, containing three different aryl groups, were formed in
excellent yields by reacting triarylated pyridine 9a with 4-tolylboronic acid and 4-tert-
butylphenylboronic acid, respectively (Table 8). Single crystal X-ray analysis
independently proved the structure of pentaarylpyridine 11a (Figure 3). Furthermore,
the Suzuki-Miyaura reaction of 6a gave pentaarylpyridines 12a and 12b, containing
three different aryls groups, in 93 and 75 % yields, respectively. In the same manner,
the Suzuki-Miyaura reaction of pyridines 10a and 10b resulted in arylation of positions
3 and 5 of the pyridine nucleus. The yields vary considerably, 90 % for 13a and 50 %
for 13b, which might be due to side reactions of the aryl chloride moiety in position 2 of
the starting material 10b. However, the catalyst favors reaction at positions 3 and 5 of
the pyridine, although two aryl rings are located in both ortho-positions, leaving the aryl
chloride moiety in position 2 intact for further functionalization.
Table 8. Synthesis of Pentaarylpyridines 11, 12 and 13.
11a,b Ar1=Ar2≠Ar3≠Ar4
12a,b Ar1≠Ar2≠Ar3=Ar4
13a,b Ar1≠Ar2≠Ar3≠Ar4
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Reaction conditions i: 6a, 9a, 10a or 10b, ArB(OH)2 (2.0 equiv. per C-Cl bond.), K3PO4
(2.0 equiv. per C-Cl bond), PdCl2(CH3CN)2 (5 mol%), SPhos (10 mol%), Toluene, 20 h,
100 °C.
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Figure 3. Ortep of compound 11a20
Conclusions
In conclusion, we have developed an efficient method for the chemo- and site-selective
synthesis of various substituted arylated pyridines by palladium-catalyzed cross-
coupling reactions of newly synthesized 4-bromo-2,3,5-trichloro-6-iodopyridine (3).
Our developed methodology shows a very good functional group tolerance for the
selective synthesis of mono-, di- and triarylated pyridines which can be easily converted
to corresponding fully arylated products in good yields.
Experimental Section
Synthesis of 4-bromo-2,3,5-trichloro-6-iodopyridine (3)
An oven-dried 100 ml Schlenk-Flask was charged with 3 ml n-butyllithium/hexane-
Solution (2.5 M). The hexane was removed under reduced pressure and 7.5 ml of dry
THF was added. The resulting solution was cooled down to –40 °C for 15 minutes and
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(7.41mmol, 1.25 ml) of 2,2,6,6-Tetramethylpiperidine was slowly added. Afterwards it
was allowed to warm to 0 °C (icebath) and stirred for 30 minutes at this temperature.
The mixture was again cooled to -78 °C and stirred for 30 minutes at this temperature.
In another Schlenk-Flask a solution of 2,3,5-trichloro-4-iodopyridine (3.73 mmol,
1.15 g) in 4 ml THF was prepared and added slowly to the LiTMP solution at -100 °C .
The reaction mixture was stirred for 2 h. During this time a suspension appears. In a
third Schlenk-Flask a solution of 1,2-dibromotetrachloroethane (11.24 mmol,
3.66 g = excess) in 11.5 ml THF was prepared and cooled to -78 °C. The reaction
mixture was transferred into the solution of 1,2-dibromotetrachloroethane by funnel and
was stirred for additional 2 hours at - 78 °C. The mixture was allowed to warm to room
temperature overnight. The reaction mixture was diluted with water and extracted with
ethyl acetate. The combined organic layers were dried with Na2SO4, filtered and
concentrated in vacuum. The residue was purified by column chromatography using
heptane/dichloromethane (10/1) as eluent.
4-bromo-2,3,5-trichloro-6-iodopyridine (3): colorless crystalline solid; yield: 77 %
13
(1.118 g); mp 172 - 173 °C. C-NMR (62.9 MHz, CDCl3): δ = 146.2 (CHetar), 138.9
(CHetar), 134.0 (CHetar), 132.7 (CHetar), 115.0 (CHetar). MS (EI, 70 eV): m/z (%) = 391
(M+, 17), 389 (M+, 65), 387 (M+, 100), 385 (M+, 48), 264 (12), 262 (42), 260 (65), 258
(34), 183 (12), 181 (40), 179 (38), 146 (13), 144 (21), 127 (77), 120 (12), 118 (16), 111
(17), 109 (47), 74 (23), 47 (11). HR-MS (EI): m/z = calcd. for C5NBrCl3I (M+H+)
37
384.73189; found: 384.73204; calcd. for C5NBrCl2 ClI (M+H+) 386.72894 found
386.72920; calcd. for C5N81BrCl3I (M+H+) 386.72984; found 386.72920; calcd. for
37
C5NBrCl37Cl2I (M+H+) 388.72599; found 388.72642; calcd. for C5N81BrCl2 ClI
(M+H+) 388.72689 ; found 388.72642; calcd. for C5N81BrCl37Cl2I (M+H+) 390.72394;
found 390.72389; calcd. for C5NBr37Cl3I (M+H+) 390.72304; found 390.72389. Anal.
calcd. for C5NBrCl3I: C, 15.51; H, 3.62; found: C, 15.65; H, 3.71.
Synthesis of 4-Bromo-2,3,5-trichloro-6-arylpyridines (4a–k)
An oven-dried, argon-flushed sealable glass tube was charged with 4-bromo-2,3,5-
trichloro-6-iodopyridine 3 (0.3 mmol, 115.9 mg), Pd(PPh3)4 (5 mol%, 17.3 mg), the
appropriate arylboronic acid (0.45 mmol) and K3PO4 (0.45 mmol, 95.53 mg) followed
by a mixture of toluene/ water/ ethanol (6:1:1, 4 mL); The tube was sealed with a Teflon
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valve and stirred at 100 °C for 19 h. The cooled reaction mixture was diluted with water
and extracted with CH2Cl2. The combined organic layers were dried with Na2SO4,
filtered and concentrated in vacuum. The residue was purified by column
chromatography using heptane/dichloromethane as eluent.
4-bromo-2,3,5-trichloro-6-phenylpyridine (4a)
4a was synthesized according to general procedure using 4-bromo-2,3,5-trichloro-6-
iodopyridine 3 (0.3 mmol, 115.9 mg) and phenylboronic acid (0.45 mmol, 54.9 mg) and
was purified via column chromatography (heptane/dichloromethane). White solid;
yield: 79 mg (78 %). mp. 111-112 °C. 1H-NMR (300 MHz, CDCl3): δ = 7.67 - 7.69 (m,
2H, CHAr), 7.47-7.49 (m, 3H, CHAr). 13C-NMR (75.0 MHz, CDCl3): δ = 154.9
(CAr/Hetar), 146.9 (CAr/Hetar), 137.0 (CAr/Hetar), 136.7 (CAr), 131.0 (CAr/Hetar), 130.7
(CAr/Hetar), 129.7 (2CHAr), 129.4 (2CHAr), 128.2 (CHAr). MS (EI, 70 eV): m/z (%) = 341
(M+, 17), 339 (M+, 63), 338 (M+, 13), 337 (M+, 100), 335 (M+, 51), 304 (37), 303 (11),
302 (82), 300 (51), 223 (45), 222 (13), 221 (71), 186 (16), 185 (18), 160 (17), 151 (37),
150 (11), 120 (18), 118 (23), 111 (10), 110 (11), 80 (10), 51 (11). HR-MS (ESI):
m/z = calcd. for C11H5BrCl3N (M+H+) 335.87437; found: 335.87405; calcd. for
37
81
C11H5BrCl2 ClN (M+H+) 337.87191; found 337.87132; calcd. for C11H5 BrCl3N
(M+H+) 337.87191; found 337.87132; calcd. for C11H5BrCl37Cl2N (M+H+) 339.86925;
81
37
found 339.86946; calcd. for C11H5 BrCl2 ClN (M+H+) 339.86925; found 339.86946.
Anal. calcd. for C11H5BrCl3N: C, 39.15; H, 1.49; N, 4.15 found: C, 39.22; H, 1.60 ; N,
4.19
4-bromo-2,3,5-trichloro-6-p-tolylpyridine (4b)
4b was synthesized according to general procedure using 4-bromo-2,3,5-trichloro-6-
iodopyridine 3 (0.3 mmol, 115.9 mg) and p-tolylboronic acid (0.45 mmol, 61.2 mg) and
was purified via column chromatography (heptane/dichloromethane). White solid;
1
yield: 87 mg (83 %). mp. 113 - 114 °C. H-NMR (300 MHz, CDCl3): δ = 7.57 (d,
3
13
3J = 8.1 Hz, 2H, CHAr), 7.26 (d, J = 8.1 Hz, 2H, CHAr), 2.40 (s, 3H, CH3). C-NMR
(75 MHz, CDCl3): δ = 154.9 (CAr/Hetar), 146.8 (CAr/Hetar), 140.0 (CAr/Heta), 140.0 (CAr),
136.9 (CAr), 133.9 (CAr/Hetar), 130.6 (CAr/Hetar), 129.3 (2CHAr), 128.9 (2CHAr), 21.4
(CH3). MS (EI, 70 eV): m/z (%) = 355 (M+, 16), 354 (M+, 13), 353 (M+, 66), 352 (M+,
30), 351 (M+, 100), 350 (M+, 29), 349 (M+, 52), 348 (M+, 13), 318 (15), 316 (29), 314
(19), 237 (10), 235 (17), 200 (12), 164 (20), 118 (12). HR-MS (ESI): m/z = calcd. for
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37
C12H7NBrCl3 (M+H+) 348.88220; found: 348.88204; calcd. for C12H7NBrCl2 Cl
(M+H+) 350.87925, found 350.87956; calcd. for C12H7N81BrCl3 (M+H+) 350.88015,
foud 350.87956; calcd. for C12H7NBr37Cl2Cl (M+H+) 352.87630, found 352.87636;
calcd. for C12H7N81Br37ClCl2 (M+H+) 352.87720, found 352.87636. Anal. calcd. for
C12H7NBrCl3: C, 41.01; H, 2.01; N, 3.99 found: C, 41.19; H, 2.16; N, 4.09.
4-bromo-2,3,5-trichloro-6-(4-methoxyphenyl)pyridine (4c)
4c was synthesized according to general procedure using 4-bromo-2,3,5-trichloro-6-
iodopyridine 3 (0.3 mmol, 115.9 mg) and 4-methoxyphenylboronic acid (0.45 mmol,
68.4 mg) and was purified via column chromatography (heptane/dichloromethane).
1
White solid; yield: 80 mg (73 %). mp. 143 - 144 °C. H-NMR (300 MHz, CDCl3):
3
3
δ = 7.70 (d, J = 8.9 Hz, 2H, CHAr), 7.00 (d, J = 8.9 Hz, 2H, CHAr), 3.88 (s, 3H,
OCH3). 13C-NMR (75.0 MHz, CDCl3): δ = 161.1 (C-OCH3), 154.8 (CAr/Hetar), 146.9
(CAr/Hetar), 137.2 (CAr), 131.3 (2CHAr), 130.6 (CAr/Hetar), 130.5 (CAr/Hetar), 129.3 (CAr/Hetar),
113.9 (2CHAr), 55.7 (OCH3). MS (EI, 70 eV): m/z (%) = 371 (M+, 17), 370 (M+, 8), 369
(M+, 65), 368 (M+, 14), 367 (M+, 100), 365 (M+, 52), 354 (5), 352 (7), 326 (11), 324
(16), 322 (8), 317 (5), 289 (10), 287 (6), 253 (5), 251 (7), 210 (7), 208 (11), 181 (5), 138
(7), 118 (5). HR-MS (ESI): m/z = calcd. for C12H7ONBrCl3 (M+H+) 364.87711; found:
37
364.87736; calcd. for C12H7ONBrCl2 Cl (M+H+) 366.87416 ; found 366.87499; calcd.
for C12H7ON81BrCl3 (M+H+) 366.87506; found 366.87499; calcd. for
37
C12H7ON81BrCl2 Cl (M+H+) 368.87211; found 368.87229; calcd. for
C12H7ONBrCl37Cl2
(M+H+)
368.87121;
found
368.87229;
calcd.
for
C12H7ON81BrCl37Cl2 (M+H+) 370.86916; found 370.86951; calcd. for C12H7ONBr37Cl3
(M+H+) 370.86826; found 370.86951. Anal. calcd. for C12H7BrCl3NO: C, 39.22; H,
1.92; N, 3.81 found: C, 39.35; H, 2.01; N, 4.02.
4-bromo-2,3,5-trichloro-6-(4-fluorophenyl)pyridine (4d)
4d was synthesized according to general procedure using 4-bromo-2,3,5-trichloro-6-
iodopyridine 3 (0.3 mmol, 115.9 mg) and 4-fluorophenylboronic acid (0.45 mmol,
63.0 mg) and was purified via column chromatography (heptane/dichloromethane).
1
White solid; yield: 78 mg (73 %). mp. 148 - 149 °C. H-NMR (300 MHz, CDCl3):
δ = 7.67-7.74 (m, 2H, CHAr), 7.13 - 7.21 (m, 2H, CHAr). 13C-NMR (75.0 MHz, CDCl3):
1
δ = 163.5 (d, J = 250.6 Hz, CAr-F), 153.8 (CHetar), 147.0 (CHetar), 137.1 (CHetar), 132.7
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4
3
(d, J = 3.3 Hz, CAr), 131.5 (d, J = 8.5 Hz, 2CHAr), 131.1 (CHetar), 130.6 (CHetar), 115.3
2
19
(d, J = 21.9 Hz, 2CHAr). F-NMR (282 MHz, CDCl3): δ = -110.49. MS (EI, 70 eV):
m/z (%) = 359 (M+, 17), 358 (M+, 8), 357 (M+, 61), 356 (M+, 12), 355 (M+, 100), 353
(M+, 50), 322 (20), 320 (44), 318 (26), 241 (29), 240 (8), 239 (46), 204 (10), 178 (13),
169 (22), 120 (13), 118 (16). HR-MS (ESI): m/z = calcd. for C11H4NBrCl3F (M+H+)
37
352.85712, found: 352.85730; calcd. for C11H4NBrCl2 ClF (M+H+) 354.85417; found
354.85455; calcd. for C11H4N81BrCl3F (M+H+) 354.85508, found 354.85455; calcd. for
37
C11H4N81BrCl2 ClF
(M+H+)
(M+H+)
356.85213;
found
356.85190;
calcd.
for
C11H4NBrCl37Cl2F
356.85122;
found
356.85190;
calcd.
for
C11H4N81BrCl37Cl2F (M+H+) 358.84918; found 358.84890; calcd. for C11H4NBr37Cl3F
(M+H+) 358.84827; found 358.84890. Anal. calcd. for C11H4BrCl3FN: C, 37.17; H,
1.13; N, 3.94 found: C, 37.14; H, 1.23; N, 4.16.
4-bromo-2,3,5-trichloro-6-(3-methoxyphenyl)pyridine (4e)
4e was synthesized according to general procedure using 4-bromo-2,3,5-trichloro-6-
iodopyridine 3 (0.3 mmol, 115.9 mg) and 3-methoxyphenylboronic acid (0.45 mmol,
68.4 mg) and was purified via column chromatography (heptane/dichloromethane).
1
White solid; yield: 85 mg (77 %). mp. 128 - 129 °C. H-NMR (250 MHz, CDCl3):
3
3
4
4
δ = 7.40 (pt, J = 7.9 Hz, 1H, CHAr), 7.25 (ddd, J = 6.67 Hz, J = 1.6 Hz, J = 1.0 Hz,
4
4
3
1H, CHAr), 7.18 (dd, J = 2.6 Hz, J = 1.6 Hz, 1H, CHAr), 7.02 (ddd, J = 8.2 Hz,
4
13
4J = 2.6 Hz, J = 1.0 Hz, 1H, CHAr), 3.87 (s, 3H, OCH3). C-NMR (63 MHz, CDCl3):
δ = 159.3 (C-OCH3), 154.8 (CAr/Hetar), 146.9 (CAr/Hetar), 137.9 (CAr), 137.0 (CAr/Hetar),
131.1 (CAr/Hetar), 130.8 (CAr/Hetar), 129.3 (CHAr), 121.7 (CHAr), 115.5 (CHAr), 114.8
(CHAr), 55.4 (OCH3). MS (EI, 70 eV): m/z (%) = 371 (M+, 18), 370 (M+, 19), 369 (M+,
65), 368 (M+, 61), 367 (M+, 100), 366 (M+, 79), 365 (M+, 51), 364 (M+, 37), 341, 340
(14), 339 (15), 338 (23), 337 (20), 336 (13), 302 (18), 300 (12), 289 (10), 223 (10), 221
(15), 210 (13), 208 (18), 138 (10), 118 (10). HR-MS (ESI): m/z = calcd. for
37
C12H7ONBrCl3 (M+H+) 364.87711, found: 364.87699; calcd. for C12H7ONBrCl2 Cl
(M+H+) 366.87416; found 366.87451; calcd. for C12H7ON81BrCl3 (M+H+) 366.87506,
37
found 366.87451; calcd. for C12H7ON81BrCl2 Cl (M+H+) 368.87211; found 368.87179;
calcd. for C12H7ONBrCl37Cl2 (M+H+) 368.87121; found 368.87179; calcd. for
C12H7ON81BrCl37Cl2 (M+H+) 370.86916, found 370.86922; calcd. for C12H7ONBr37Cl3
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(M+H+) 370.86826; found 370.86922. Anal. calcd. for C12H7BrCl3NO: C, 39.22; H,
1.92; N, 3.81 found: C, 39.40; H, 2.03; N, 3.99.
4-bromo-2,3,5-trichloro-6-(thiophen-2-yl)pyridine (4f)
4f was synthesized according to general procedure using 4-bromo-2,3,5-trichloro-6-
iodopyridine 3 (0.3 mmol, 115.9 mg) and 2-thienylboronic acid (0.45 mmol, 57.6 mg)
and was purified via column chromatography (heptane/dichloromethane). White solid;
1
yield: 83 mg (81 %). mp. 98 - 99 °C. H-NMR (300 MHz, CDCl3): δ = 8.08 (dd,
4
3
4
4J = 3.0 Hz, J = 1.3 Hz, 1H, CHHetar), 7.69 (dd, J = 5.1 Hz, J = 1.3 Hz, 1H, CHHetar),
7.40 (dd, 3J = 5.1 Hz, 4J = 3.0 Hz, 1H, CHHetar). 13C-NMR (75 MHz, CDCl3): δ = 149.5
(CHetar), 146.6(CHetar), 137.4(CHetar), 137.1(CHetar), 130.2(CHetar), 129.7(CHetar), 128.8
(CHHetar), 128.7(CHHetar), 125.2(CHHetar). MS (EI, 70 eV): m/z (%) = 347 (M+, 19), 346
(M+, 9), 345 (M+, 70), 344 (M+, 15), 343 (M+, 100), 341 (M+, 49), 310 (19), 308 (40),
306 (24), 229 (13), 227 (19), 157 (12), 118 (12), 45 (12). HR-MS (ESI): m/z = calcd.
for C9H3NBrCl3S (M+H+) 340.82297; found 340.82284; calcd. for C9H3N81BrCl3S
37
(M+H+) 342.82092; found 342.82059; calcd. for C9H3NBrCl2 ClS (M+H+) 342.82002;
37
found 342.82059; calcd. for C9H3N81BrCl2 ClS (M+H+) 344.81797; found 344.81780;
calcd. for C9H3NBrCl37Cl2S (M+H+) 344.81707; found 344.81780; calcd. for
C9H3N81BrCl37Cl2S (M+H+) 346.81502; found 346.81466; calcd. for C9H3NBr37Cl3S
(M+H+) 346.81412; found 346.81466. Anal. calcd. for C9H3BrCl3NS: C, 31.47; H, 0.88;
N, 4.08 found: C, 31.60; H, 1.20; N, 4.29.
4-bromo-2,3,5-trichloro-6-(3-nitrophenyl)pyridine (4g)
4g was synthesized according to general procedure using 4-bromo-2,3,5-trichloro-6-
iodopyridine 3 (0.3 mmol, 115.9 mg) and 3-nitrophenylboronic acid (0.45 mmol,
75.1 mg) and was purified via column chromatography (heptane/dichloromethane).
1
White solid; yield: 89 mg (78 %). mp. 166 - 167 °C. H-NMR (250 MHz, CDCl3):
4
3
4
4
δ = 8.60 (pt, J = 1.7 Hz, 1H, CHAr), 8.34 (ddd, J = 8.3 Hz, J = 2.3 Hz, J = 1.1 Hz,
3
4
4
1H, CHAr), 8.05 (ddd, J = 7.8 Hz, J = 1.7 Hz, J = 1.1 Hz, 1H, CHAr), 7.68 (pt,
3J = 8.0 Hz, 1H, CHAr). 13C-NMR (63 MHz, CDCl3): δ = 152.0 (CAr/Hetar), 148.0
(CAr/Hetar), 147.5 (CAr), 138.0 (CAr), 137.5 (CAr/Hetar), 135.4 (CHAr), 132.4 (CAr/Hetar),
130.9 (CAr/Hetar), 129.4 (CHAr), 124.7 (CHAr), 124.5 (CHAr). MS (EI, 70 eV): m/z
(%) = 386 (M+, 19), 385 (M+, 10), 384 (M+, 66), 383 (M+, 14), 382 (M+, 100), 380 (M+,
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54), 340 (12), 338 (46), 337 (10), 336 (70), 334 (35), 324 (10), 301 (16), 299 (10), 257
(27), 255 (26), 220 (15), 187 (11), 185 (32), 118 (11). HR-MS (ESI): m/z = calcd. for
37
C11H4O2N2BrCl3 (M+H+) 379.85162; found: 379.85154; calcd. for C11H4O2N2BrCl2 Cl
81
(M+H+) 381.84867; found 381.84911; calcd. for C11H4O2N2 BrCl3 (M+H+) 381.84958;
found 381.84911; calcd. for C11H4O2N2BrCl37Cl2 (M+H+) 383.84572; found 383.84618;
81
37
calcd. for C11H4O2N2 BrCl2 Cl (M+H+) 383.84663; found 383.84618; calcd. for
C11H4O2N2Br37Cl3
(M+H+)
385.81277,
found
385.84350;
calcd.
for
81
C11H4O2N2 BrCl37Cl2 (M+H+) 385.84368; found 385.84350. Anal. calcd. for
C11H4BrCl3N2O2: C, 34.55; H, 1.05; N, 7.33 found: C, 34.36; H, 1.15; N, 7.19.
4-bromo-2,3,5-trichloro-6-(4-(trifluoromethyl)phenyl)pyridine (4h)
4h was synthesized according to general procedure using 4-bromo-2,3,5-trichloro-6-
iodopyridine 3 (0.3 mmol, 115.9 mg) and 4-(trifluoromethyl)phenylboronic acid
(0.45 mmol, 85.5 mg) and was purified via column chromatography
1
(heptane/dichloromethane). White solid; yield: 73 mg (60 %). mp. 123 - 124 °C. H-
NMR (250 MHz, CDCl3): δ = 7.82 (d, 3J = 8.5 Hz, 2H, CHAr), 7.75 (d, 3J = 8.5 Hz, 2H,
13
5
CHAr). C-NMR (63 MHz, CDCl3): δ = 153.3 (CAr/Hetar), 147.3 (CAr/Hetar), 140.0 (q, J
2
= 1.1 Hz, CAr), 137.3 (CAr/Hetar), 132.0 (CAr/Hetar), 131.6 (q, J = 32.7 Hz, (CAr), 130.9
3
1
(CAr/Hetar), 129.8 (2CHAr), 125.3 (q, J = 3.7 Hz, 2CHAr), 123.8 (q, J = 272.8 Hz, CF3).
19F-NMR (235 MHz, CDCl3): δ = - 62.89 (ArCF3). MS (EI, 70 eV): m/z (%) = 409
(M+, 17), 408 (M+, 9), 407 (M+, 63), 406 (M+, 14), 405 (M+, 100), 404 (M+, 7), 403
(M+, 53), 386 (8), 372 (33), 371 (10), 370 (74), 368 (47), 291 (41), 290 (14), 289 (64),
257 (12), 255 (18), 254 (19), 253 (13), 228 (19), 219 (24), 218 (14), 200 (11), 193 (14),
185 (12), 169 (11), 155 (17), 153 (18), 145 (11), 123 (12), 122 (11), 121 (10), 75 (17),
74 (10), 69 (18). HR-MS (EI): m/z = calcd. for C12H4NBrCl3F3 [M]+: 402.85393;
found: 402.85369; calcd. for C12H4NBrCl2 37ClF3 : 404.85098; found 404.85134; calcd.
for C12H4N81BrCl2 37ClF3 : 406.84893; found 406.84873.
Anal. calcd. for
C12H4BrCl3F3N: C 35.55, H 0.99, N 3.45; found: C 35.75, H 1.03 , N 3.36.
4-bromo-2,3,5-trichloro-6-(2-methoxyphenyl)pyridine (4i)
4i was synthesized according to general procedure using 4-bromo-2,3,5-trichloro-6-
iodopyridine 3 (0.3 mmol, 115.9 mg) and 2-methoxyphenylboronic acid (0.45 mmol,
68.4 mg) and was purified via column chromatography (heptane/dichloromethane). Pink
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1
solid; yield: 94 mg (86 %). mp. 123 - 124 °C. H-NMR (250 MHz, CDCl3): δ = 7.37-
3
4
7.48 (m, 1H, CHAr), 7.27 (dd, J = 7.0 Hz, J = 2.1 Hz, 1H, CHAr), 6.97-7.09 (m, 2H,
13
CHAr), 3.81 (s, 3H, OCH3). C-NMR (63 MHz, CDCl3): δ = 156.6 (C-OCH3), 153.9
(CAr/Hetar), 146.6 (CAr/Hetar), 135.9 (CAr/Hetar), 133.0 (CAr/Hetar), 131.1 (CH), 131.0
(CAr/Hetar), 130.1 (CH), 126.5 (CAr), 120.7 (CHAr), 111.0 (CHAr), 55.5 (OCH3). MS (EI,
70 eV): m/z (%) = 369 (M+, 15), 367 (M+, 23), 365 (M+, 12), 334 (46), 333 (15), 332
(100), 331 (13), 330 (64), 317 (10), 304 (21), 302 (21), 273 (11), 271 (12), 253 (37),
252 (12), 251 (57), 225 (11), 223 (27), 222 (10), 221 (22), 216 (16), 210 (15), 208 (20),
201 (11), 188 (11), 187 (13), 185 (12), 151 (15), 147 (12), 138 (18), 120 (14), 118 (20),
111 (11), 63 (12), 62 (6), 39 (8). HR-MS (EI): m/z = calcd. for C12H7ONBrCl3 [M]+:
37
364.87711; found: 364.87695; calcd. for C12H7ONBrCl2 Cl: 366.87416; found
81
37
366.87456; calcd. for C12H7ON BrCl2 Cl: 368.87211; found 368.87198. Anal. calcd.
for C12H7BrCl3NO: C 39.22, H 1.92, N 3.81; found: C 39.52, H 2.45, N 3.46.
4-bromo-2,3,5-trichloro-6-(4-cyanophenyl)pyridine (4j)
4j was synthesized according to general procedure using 4-bromo-2,3,5-trichloro-6-
iodopyridine 3 (0.3 mmol, 115.9 mg) and 4-cyanophenylboronic acid (0.45 mmol,
66.1 mg) and was purified via column chromatography (heptane/dichloromethane).
1
White solid; yield: 64 mg (60 %). mp. 195 - 196 °C. H-NMR (250 MHz, CDCl3):
13
δ = 7.74-7.84 (m, 4H, CHAr). C-NMR (63 MHz, CDCl3): δ = 152.6 (CAr/Hetar), 147.4
(CAr/Hetar), 140.7 (CAr/Hetar), 137.5 (CAr/Hetar), 132.3 (CAr/Hetar), 132.0 (2CHAr), 130.9
(CAr/Hetar), 130.2 (2CHAr), 118.2 (C≡N), 113.5 (CAr). MS (EI, 70 eV): m/z (%) = 366
(M+, 17), 365 (M+, 9), 364 (M+, 64), 363 (M+, 14), 362 (M+, 100), 361 (M+, 8), 360
(M+, 52), 329 (36), 328 (12), 327 (79), 325 (50), 248 (39), 247 (13), 246 (61), 212 (10),
211 (20), 210 (21), 187 (10), 185 (28), 176 (38), 163 (10), 155 (14), 153 (15), 150 (12),
124 (12), 123 (19) 122 (11), 120 (34), 118 (49), 110 (10), 99 (15), 92 (12), 76 (10), 75
(19), 74 (12). HR-MS (EI): m/z = calcd. for C12H4N2BrCl3 [M]+: 359.86180; found:
81
359.86197; calcd. for C12H4N2 BrCl3: 361.85975; found 361.85963; calcd. for C12H4N2
37
81
81BrCl2 Cl: 363.85680; found 363.85706; calcd. for C12H4N2 BrCl37Cl2: 365.85385;
found 365.85453. Anal. calcd. for C12H4BrCl3N2: C 39.77, H 1.11, N 7.73; found: C
40.24, H 1.36, N 7.39.
4-bromo-2,3,5-trichloro-6-(4-chlorophenyl)pyridine (4k)
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4k was synthesized according to general procedure using 4-bromo-2,3,5-trichloro-6-
iodopyridine 3 (0.3 mmol, 115.9 mg) and 4-chlorophenylboronic acid (0.45 mmol,
70.4 mg) and was purified via column chromatography (heptane/dichloromethane).
1
White solid; yield: 77 mg (69 %). mp. 161 - 162 °C. H-NMR (250 MHz, CDCl3):
3
3
δ = 7.65 (d, J = 8.56 Hz, 2H, CHAr), 7.46 (d, J = 8.56 Hz, 2H, CHAr). 13C-NMR
(63 MHz, CDCl3): δ = 153.6 (CAr/Hetar), 147.1 (CAr/Hetar), 137.2 (CAr/Hetar), 136.0 (CAr),
135.0 (CAr/Hetar), 131.3 (CAr/Hetar), 130.8 (2CHAr), 130.7 (CAr), 128.5 (2CHAr). MS (EI,
70 eV): m/z (%) = 377 (M+, 6), 375 (M+, 32), 374 (M+, 10), 373 (M+, 83), 372 (M+, 13),
371 (M+, 100), 370 (M+, 6), 369 (M+, 45), 338 (31), 336 (49), 334 (26), 259 (17), 257
(54), 256 (10), 255 (57), 222 (10), 221 (10), 220 (15), 219 (12), 196 (12), 194 (12), 187
(14), 185 (41), 169 (11), 168 (15), 155 (12), 153 (12), 150 (12), 123 (14), 120 (25), 118
(33), 111 (13), 110 (12), 109 (10), 99 (12), 98 (17), 97 (20), 85 (10), 75 (20), 74 (14), 50
(10). HR-MS (EI): m/z = calcd. for C11H4NBrCl4 [M]+: 368.82757; found: 368.82764;
37
calcd. for C11H4NBrCl3 Cl: 370.82462; found 370.82506; calcd. for C11H4N
37
37
81BrCl3 Cl: 372.82258; found 372.82230; calcd. for C11H4N81BrCl2 Cl2: 374.81963;
found 374.81961. Anal. calcd. for C11H4BrCl4N: C 35.53, H 1.08, N 3.77; found: C
35.67, H 1.18, N 3.76.
Synthesis of 4,6-diaryl-2,3,5-trichloropyridines (5a–h)
An oven-dried, argon-flushed sealable glass tube was charged with 4-bromo-2,3,5-
trichloro-6-iodopyridine 3 (0.26 mmol, 100 mg), Pd(OAc)2 (5 mol%, 2.9 mg), PCy3
(10 mol%, 7.24 mg), the appropriate arylboronic acid (0.55 mmol) and K3PO4
(0.55 mmol, 115.12 mg) followed by a mixture of toluene/water/n-butanol (6:1:1,
4 mL). The tube was sealed with a Teflon valve and stirred at 100 °C for 19 h. The
cooled reaction mixture was diluted with water and extracted with CH2Cl2. The
combined organic layers were dried with Na2SO4, filtered and concentrated in vacuum.
The residue was purified by column chromatography using heptane/dichloromethane as
eluent.
2,3,5-trichloro-4,6-di-p-tolylpyridine (5a):
5a was synthesized according to general procedure using 4-bromo-2,3,5-trichloro-6-
iodopyridine 3 (0.26 mmol, 100 mg) and p-tolylboronic acid (0.55 mmol, 74.8 mg) and
was purified via column chromatography (heptane/dichloromethane). White solid;
1
yield: 76 mg (81 %). mp. 121 - 122 °C. H-NMR (300 MHz, CDCl3): δ = 7.65 (d,
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3J = 8.2 Hz, 2H, CHAr), 7.35 (d, 3J = 8.0 Hz, 2H, CHAr), 7.29 (d, 3J = 8.0 Hz, 2H, CHAr),
3
7.19(d, J = 8.1 Hz, 2H, CHAr), 2.46 (s, 3H, CH3), 2.43 (s, 3H, CH3). 13C-NMR
(75 MHz, CDCl3): δ = 154.9 (CAr/Hetar), 150.9 (CAr/Hetar), 147.1(CAr/Hetar), 139.5
(CAr/Hetar), 139.1 (CAr/Hetar), 134.1 (CAr/Hetar), 133.0 (CAr/Hetar), 129.4 (4CHAr), 129.0
(2CAr/Hetar), 128.8 (2CHAr), 128.3(2CHAr), 21.5 (CH3), 21.4 (CH3). MS (EI, 70 eV): m/z
(%) = 366 (M+, 7), 365 (M+, 34), 364 (M+, 24), 363 (M+, 97), 362 (M+, 33), 361 (M+,
100), 360 (M+, 13), 328 (32), 327 (11), 326 (50), 255 (9), 254 (11), 241 (7), 240 (14), 91
(8). HR-MS (ESI): m/z = calcd. for C19H14Cl3N (M+H+) 361.01863, found: 361.01827.
Anal. calcd. for C19H14Cl3N: C, 62.92; H, 3.89; N, 3.86 found: C, 62.89; H, 3.82; N,
3.95.
2,3,5-trichloro-4,6-bis(4-chlorophenyl)pyridine (5b)
5b was synthesized according to general procedure using 4-bromo-2,3,5-trichloro-6-
iodopyridine 3 (0.26 mmol, 100 mg) and 4-chlorophenylboronic acid (0.55 mmol,
86.0 mg) and was purified via column chromatography (heptane/dichloromethane).
1
White solid; yield: 80 mg (77 %). mp. 143 - 144 °C. H-NMR (300 MHz, CDCl3):
3
3
δ = 7.70 (d, J = 8.6 Hz, 2H, CHAr), 7.53 (d, J = 8.5 Hz, 2H, CHAr), 7.46 (d,
3
13
3J = 8.6 Hz, 2H, CHAr), 7.23 (d, J = 8.5 Hz, 2H, CHAr). C-NMR (75 MHz, CDCl3):
δ = 153.7 (CAr/Hetar), 149.9 (CAr/Hetar), 147.5 (CAr/Hetar), 135.8 (CAr/Hetar), 135.4 (CAr/Hetar),
135.0 (CAr/Hetar), 133.8 (CAr/Hetar), 130.9 (2CHAr), 129.9 (2CHAr), 129.5 (CAr/Hetar), 129.2
(2CHAr), 128.7 (CAr/Hetar), 128.5 (2CHAr). MS (EI, 70 eV): m/z (%) = 407 (M+, 21), 406
(M+, 12), 405 (M+, 65), 404 (M+, 19), 403 (M+, 100), 402 (M+, 13), 401 (M+, 63), 370
(26), 369 (11), 368 (54), 366 (42), 333 (14), 331 (15), 297 (15), 296 (15), 295 (21), 263
(12), 261 (38), 225 (22), 196 (15), 194 (22), 185 (13), 184 (15), 149 (18), 148 (27), 135
(11), 130 (24), 99 (15), 75 (14). HR-MS (ESI): m/z = calcd. for C17H8Cl5N (M+H+)
35
401.91721, found: 401.91763; calcd. for C17H8 Cl4 ClN: 403.91436, found: 403.9144;
35
calcd. for C17H8 Cl3 Cl2N: 405.91156; found 405.91234. Anal. calcd. for C17H8Cl5N:
C, 50.60; H, 2.00; N, 3.47 found: C, 50.74; H, 2.28; N, 3.54.
2,3,5-trichloro-4,6-bis(4-methoxyphenyl)pyridine (5c)
5c was synthesized according to general procedure using 4-bromo-2,3,5-trichloro-6-
iodopyridine 3 (0.26 mmol, 100 mg) and 4-methoxyphenylboronic acid (0.55 mmol,
83.6 mg) and was purified via column chromatography (heptane/dichloromethane).
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1
White solid; yield: 55 mg (54 %). mp. 122 - 123 °C. H-NMR (300 MHz, CDCl3):
3
3
δ = 7.74 (d, J = 8.9 Hz, 2H, CHAr), 7.23 (d, J = 8.9 Hz, 2H, CHAr), 7.06 (d,
3
3J = 8.9 Hz, 2H, CHAr), 6.99 (d, J = 8.9 Hz, 2H, CHAr), 3.89 (s, 3H, OCH3), 3.87 (s,
3H, OCH3). 13C-NMR (75 MHz, CDCl3): δ = 160.5 (C-OCH3), 160.0 (C-OCH3), 154.4
(CAr/Hetar), 150.6 (CAr/Hetar), 147.1(CAr/Hetar), 131.1 (2CHAr), 129.9 (2CHAr), 129.4
(CAr/Hetar), 129.0 (CAr/Hetar), 128.9 (CAr/Hetar), 128.1 (CAr/Hetar), 114.0 (2CHAr),
113.5(2CHAr), 55.35 (OCH3), 55.27 (OCH3). MS (EI, 70 eV): m/z (%) = 398 (M+, 7),
397 (M+, 32), 396 (M+, 21), 395 (M+, 96), 394 (M+, 22), 393 (M+, 100), 352 (8), 350
(8), 315 (7), 272 (7), 237 (8), 202 (8), 201 (13), 197 (9), 196 (11), 176 (7), 175 (11), 124
(7), 123 (7). HR-MS (EI): m/z = calcd. for C19H14O2NCl3 [M]+: 393.00846; found:
37
393.00705; calcd. for C19H14O2NCl2 Cl: 395.00551; found 395.00537; calcd. for
C19H14O2NCl37Cl2: 397.00256; found 397.00288. Anal. calcd. for C19H14Cl3NO2: C
57.82, H 3.58, N 3.55; found: C 58.08, H 3.69, N 3.49.
2,3,5-trichloro-4,6-bis(4-cyanophenyl)pyridine (5d)
5d was synthesized according to general procedure using 4-bromo-2,3,5-trichloro-6-
iodopyridine 3 (0.26 mmol, 100 mg) and 4-cyanophenylboronic acid (0.55 mmol,
80.8 mg) and was purified via column chromatography (heptane/dichloromethane).
1
White solid; yield: 65 mg (66 %). mp. 232 - 233 °C. H-NMR (300 MHz, CDCl3):
δ = 7.88-7.84 (m, 4H, 4CHAr), 7.79 (d, 3J = 8.3 Hz, 2H, CHAr), 7.43 (d, 3J = 8.4 Hz, 2H,
CHAr). 13C-NMR (75 MHz, CDCl3): δ = 152.9 (CAr/Hetar), 149.3 (CAr/Hetar), 148.1
(CAr/Hetar), 140.5 (CAr/Hetar), 139.5 (CAr/Hetar), 132.7 (2CHAr), 132.0 (2CHAr), 130.3
(2CHAr), 130.0 (CAr/Hetar), 129.4 (2CHAr), 128.3 (CAr/Hetar), 118.2 (C≡N), 118.0 (C≡N),
113.6 (CAr), 113.4(CAr). MS (EI, 70 eV): m/z (%) = 388 (M+, 6), 387 (M+, 31), 386 (M+,
19), 385 (M+, 93), 384 (M+, 22), 383 (M+, 95), 352 (12), 351 (14), 350 (63), 349 (22),
348 (100), 313 (15), 286 (15), 278 (25), 277 (49), 252 (17), 251 (19), 250 (22), 224
(12), 187 (15), 185 (35), 176 (10), 175 (11), 174 (11), 161 (14), 156 (15), 150 (11), 143
(12), 138 (12), 126 (10), 125 (13), 112 (11), 102 (11), 100 (10), 99 (15), 76 (11), 75
(18). HR-MS (EI): m/z = calcd. for C19H8N3Cl3 [M]+: 382.97783; found: 382.97752;
37
calcd. for C19H8N3Cl2 Cl: 384.97488; found 384.97485; calcd. for C19H8N3Cl37Cl2:
386.97193; found 386.97304. Anal. calcd. for C19H8Cl3N3: C 59.33, H 2.10, N 10.92;
found: C 59.36, H 2.44, N 10.50.
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2,3,5-trichloro-4,6-bis(3,5-dimethylphenyl)pyridine (5e)
5e was synthesized according to general procedure using 4-bromo-2,3,5-trichloro-6-
iodopyridine 3 (0.26 mmol, 100 mg) and 3,5-dimethylphenylboronic acid (0.55 mmol,
82.5 mg) and was purified via column chromatography (heptane/dichloromethane).
1
White solid; yield: 72 mg (72 %). mp. 120 - 121 °C. H-NMR (300 MHz, CDCl3):
δ = 7.31 (s, 2H, CHAr), 7.13 (s, 1H, CHAr), 7.10 (s, 1H, CHAr), 6.89 (s, 2H, CHAr), 2.41
13
(s, 6H, 2CH3), 2.39 (s, 6H, 2CH3). C-NMR (75 MHz, CDCl3): δ = 155.3 (CAr/Hetar),
151.2 (CAr/Hetar), 147.0 (CAr/Hetar), 138.3 (2CAr/Hetar), 137.7 (2CAr/Hetar), 136.9 (CAr/Hetar),
135.8 (CAr/Hetar), 131.0 (CHAr), 130.7 (CHAr), 129.0 (CAr/Hetar), 128.9 (CAr/Hetar), 127.1
(2CHAr), 125.8 (2CHAr), 21.4 (2CH3), 21.3 (2CH3). MS (EI, 70 eV): m/z (%) = 394
(M+, 7), 393 (M+, 32), 392 (M+, 25), 391 (M+, 96), 390 (M+, 35), 389 (M+, 100), 388
(M+, 12), 356 (38), 355 (15), 354 (59), 268 (13), 169 (12), 152 (11), 151 (9), 133 (17),
77 (10). HR-MS (EI): m/z = calcd. for C21H18NCl3 [M]+: 389.04993; found: 389.04979;
37
calcd. for C21H18NCl2 Cl: 391.04698; found 391.04716; calcd. for C21H18NCl37Cl2:
393.04403; found 393.04448. Anal. calcd. for C21H18Cl3N: C 64.55, H 4.64, N 3.58;
found: C 64.34, H 4.58, N 3.38.
2,3,5-trichloro-4,6-bis(4-ethylphenyl)pyridine (5f)
5f was synthesized according to general procedure using 4-bromo-2,3,5-trichloro-6-
iodopyridine 3 (0.26 mmol, 100 mg) and 4-ethylphenylboronic acid (0.55 mmol,
82.5 mg) and was purified via column chromatography (heptane/dichloromethane).
1
White solid; yield: 59 mg (58 %). mp. 93 - 94 °C. H-NMR (300 MHz, CDCl3):
3
3
δ = 7.68 (d, J = 8.1 Hz, 2H, CHAr), 7.37 (d, J = 8.1 Hz, 2H, CHAr), 7.32 (d,
3
3J = 8.1 Hz, 2H, CHAr), 7.21 (d, J = 8.1 Hz, 2H, CHAr), 2.81-2.69 (m, 4H, 2CH2CH3),
3
3
1.33 (t, J = 6.7 Hz, 3H, CH2CH3), 1.29 (t, J = 6.7 Hz, 3H, CH2CH3). 13C-NMR
(75 MHz, CDCl3): δ = 154.9 (CAr/Hetar), 150.9 (CAr/Hetar), 147.1 (CAr/Hetar), 145.7
(CAr/Hetar), 145.1 (CAr/Hetar), 134.4 (CAr/Hetar), 133.1 (CAr/Hetar), 129.5 (2CH), 129.0
(CAr/Hetar), 128.9 (CAr/Hetar), 128.3 (2CHAr), 128.1 (2CHAr), 127.7 (2CHAr), 28.7
(CH2CH3), 28.6 (CH2CH3), 15.4 (CH2CH3), 15.1(CH2CH3). MS (EI, 70 eV): m/z
(%) = 394 (M+, 8), 393 (M+, 32), 392 (M+, 31), 391 (M+, 99), 390 (M+, 49), 389 (M+,
100), 388 (28), 378 (20), 377 (13), 376 (58), 375 (16), 374 (61), 253 (10), 240 (9), 188
(11), 187 (11), 181 (13), 180 (36), 179 (40), 144 (10), 127 (12), 126 (11), 119 (12), 105
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(14). HR-MS (EI): m/z = calcd. for C21H18NCl3 [M]+: 389.04993; found: 389.04880;
37
calcd. for C21H18NCl2 Cl: 391.04698; found 391.04634; calcd. for C21H18NCl37Cl2:
393.04403; found 393.04394. Anal. calcd. for C21H18Cl3N: C 64.55, H 4.64, N 3.58;
found: C 65.00, H 4.99, N 3.30.
2,3,5-trichloro-4,6-bis(3-chlorophenyl)pyridine (5g)
5g was synthesized according to general procedure using 4-bromo-2,3,5-trichloro-6-
iodopyridine 3 (0.26 mmol, 100 mg) and 3-chlorophenylboronic acid (0.55 mmol,
86.0 mg) and was purified via column chromatography (heptane/dichloromethane). Oil
1
colorless; yield: 35 mg (34 %). Rf (10 % ethyl acetate/ heptan) = 0.52. H-NMR
(300 MHz, CDCl3): δ = 7.73 (d, 4J = 1.8 Hz, 1H, CHAr), 7.63 (pdt, 3J = 6.8, 4J = 1.8 Hz,
1H, CHAr), 7.50-7.46 (m, 2H, CHAr), 7.35-7.45 (m, 2H, CHAr), 7.27-7.31 (m, 1H, CHAr),
7.14 - 7.21 (m, 1H, CHAr). 13C-NMR (75 MHz, CDCl3): δ = 153.5 (CAr/Hetar), 149.6
(CAr/Hetar), 147.6 (CAr/Hetar), 138.2 (CAr/Hetar), 137.0 (CAr/Hetar), 134.8 (CAr/Hetar), 134.2
(CAr/Hetar), 130.2 (CHAr), 129.7 (CAr/Hetar), 129.6 (CHAr), 129.6 (CHAr), 129.5 (CHAr),
129.5 (CHAr), 128.8 (CAr/Hetar), 128.5 (CHAr), 127.7 (CHAr), 126.6 (CHAr). MS (EI,
70 eV): m/z (%) = 407 (M+, 21), 406 (M+, 12), 405 (M+, 65), 404 (M+, 19), 403 (M+,
100), 402 (M+, 12), 401 (M+, 62), 370 (35), 369 (15), 368 (72), 367 (13), 366 (56), 333
(15), 331 (15), 298 (11), 297 (18), 296 (16), 295 (23), 263 (12), 261 (40), 225 (25), 200
(10), 196 (15), 194 (21), 185 (12), 184 (12), 166 (13), 165 (12), 149 (20), 148 (29), 135
(10), 130 (13), 123 (10), 117 (10), 111 (10), 99 (17), 75 (18). HR-MS (EI): m/z = calcd.
37
for C17H8NCl5 [M]+: 400.90939; found: 400.90909; calcd. for C17H8NCl4 Cl:
37
402.90644; found 402.90615; calcd. for C17H8NCl3 Cl2: 404.90349; found 404.90354.
Anal. calcd. for C17H8Cl5N: C 50.60, H 2.00, N 3.47; found: C 50.97, H 2.48, N 3.07.
2,3,5-trichloro-4,6-bis(4-(trifluoromethyl)phenyl)pyridine (5h)
5h was synthesized according to general procedure using 4-bromo-2,3,5-trichloro-6-
iodopyridine 3 (0.26 mmol, 100 mg) and 4-(trifluoromethyl)phenylboronic acid
(0.55 mmol, 104.5 mg) and was purified via column chromatography
1
(heptane/dichloromethane). White solid; yield: 43 mg (35 %). mp. 156 - 157 °C. H-
NMR (300 MHz, CDCl3): δ = 7.88 (d, 3J = 8.3 Hz, 2H, CHAr), 7.83 (d, 3J = 8.1 Hz, 2H,
3
3
CHAr), 7.76 (d, J = 8.3 Hz, 2H, CHAr), 7.44 (d, J = 8.1 Hz, 2H, CHAr). 13C-NMR
(75 MHz, CDCl3): δ = 153.6 (CAr/Hetar), 149.7 (CAr/Hetar), 147.9 (CAr/Hetar), 139.9
2
(CAr/Hetar), 138.8 (CAr/Hetar), 131.5 (q, J = 32.7 Hz, 2CAr), 130.0 (2CHAr), 129.9 (CAr),
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3
3
129.0 (2CHAr), 128.6 (CAr), 125.9 (q, J = 3.7 Hz, 2CHAr), 125.3 (q, J = 3.7 Hz,
1
1
2CHAr), 123.9 (q, J = 272.3 Hz, CF3), 123.8 (q, J = 272.3 Hz, CF3). 19F-NMR
(282 MHz, CDCl3): δ = -62.83 (ArCF3), -62.85 (ArCF3). MS (EI, 70 eV): m/z
(%) = 473 (M+, 27), 472 (M+, 18), 471 (M+, 83), 470 (M+, 19), 469 (M+, 85), 452 (12),
450 (13), 438 (11), 437 (14), 436 (66), 435 (22), 434 (100), 400 (10), 364 (10), 363
(14), 344 (13), 329 (12), 295 (21), 294 (12), 228 (18), 193 (13), 145 (12), 75 (11), 69
(18). HR-MS (EI): m/z = calcd. for C19H8NCl3F6 [M]+: 468.96210; found: 468.96243;
37
calcd. for C19H8NCl2 ClF6: 470.95915; found 470.95954; calcd. for C19H8NCl37Cl2F6:
472.95620; found 472.95697. Anal. calcd. for C19H8Cl3F6N: C 48.49, H 1.71, N 2.98;
found: C 48.43, H 1.98, N 2.82.
Synthesis of asymmetric 4,6-diaryl-2,3,5-trichloropyridines (6a–c)
An oven-dried, argon-flushed sealable glass tube was charged with 4-bromo-2,3,5-
trichloro-6-p-tolylpyridine 4b (0.29 mmol, 100 mg), Pd(PPh3)4 (5 mol%, 16.5 mg), the
appropriate arylboronic acid (0.43 mmol) and K3PO4 (0.43 mmol, 91 mg) followed by a
mixture of toluene/water/n-butanol (6:1:1, 4 mL); The tube was sealed with a Teflon
valve and stirred at 100 °C for 20 h. The cooled reaction mixture was diluted with water
and extracted with CH2Cl2. The combined organic layers were dried with Na2SO4,
filtered and concentrated in vacuum. The residue was purified by column
chromatography using heptane/ethyl acetate as eluent.
2,3,5-trichloro-4-(4-cyanophenyl)-6-p-tolylpyridine (6a)
6a was synthesized according to general procedure using 4-bromo-2,3,5-trichloro-6-p-
tolylpyridine 4b (0.29 mmol, 100 mg) and 4-cyanophenylboronic acid (0.43 mmol,
63.2 mg) and was purified via column chromatography (heptane/dichloromethane).
1
White solid; yield: 53 mg (50 %). mp. 191 - 192 °C. H-NMR (300 MHz, CDCl3):
3
3
δ = 7.85 (d, J = 8.6 Hz, 2H, CHAr), 7.65 (d, J = 8.2 Hz, 2H, CHAr), 7.43 (d,
3
13
3J = 8.6 Hz, 2H, CHAr), 7.30 (d, J = 7.9 Hz, 2H, CHAr), 2.43 (s, 3H, CH3). C-NMR
(75 MHz, CDCl3): δ = 155.3 (CAr/Hetar), 148.8 (CAr/Hetar), 147.5 (CAr/Hetar), 140.2
(CAr/Hetar), 139.9 (CAr/Hetar), 133.5 (CAr/Hetar), 132.6 (2CHAr), 129.5 (2CHAr), 129.4
(2CHAr), 128.9 (2CHAr), 128.0 (CAr/Hetar), 122,2 (CAr/Hetar), 118.2 (C≡N), 113.3
(CAr/Hetar), 21.4 (CH3). MS (EI, 70 eV): m/z (%) = 377 (M+, 7), 376 (M+, 31), 375 (M+,
24), 374 (M+, 96), 373 (M+, 34), 372 (M+, 100), 371 (14), 339 (29), 338 (12), 337 (45),
301 (10), 266 (19), 265 (24), 240 (10), 238 (10), 185 (11), 150 (10), 133 (15), 91 (18).
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HR-MS (EI): m/z = calcd. for C19H11N2Cl3 [M]+: 371.99823; found: 371.99710; calcd.
37
for C19H11N2Cl2 Cl: 373.99528; found 373.99417; calcd. for C19H81N2Cl37Cl2:
375.99233; found 375.99208. Anal. calcd. for C19H11Cl3N2: C 61.07, H 2.97, N 7.50;
found: C 61.33, H 3.24, N 7.34.
2,3,5-trichloro-4-(3-nitrophenyl)-6-p-tolylpyridine (6b)
6b was synthesized according to general procedure using 4-bromo-2,3,5-trichloro-6-p-
tolylpyridine 4b (0.29 mmol, 100 mg) and 3-nitrophenylboronic acid (0.43 mmol,
71.8 mg) and was purified via column chromatography (heptane/dichloromethane).
1
White solid; yield: 62 mg (55 %). mp. 113 - 114 °C. H-NMR (300 MHz, CDCl3):
3
4
4
4
δ = 8.38 (ddd, J = 8.2 Hz, J = 2.3 Hz, J = 1.2 Hz, 1H, CHAr), 8.22 (pt, J = 1.8 Hz,
3
1H, CHAr), 7.75 (pt, J = 7.9 Hz, 1H, CHAr), 7.67-7.63 (m, 3H, CHAr), 7.30 (d,
3J = 7.9 Hz, 2H, CHAr), 2.43 (s, 3H, CH3). 13C-NMR (75 MHz, CDCl3): δ = 155.5
(CAr/Hetar), 148.4( CAr/Hetar), 148.1 (CAr/Hetar), 147.5 (CAr/Hetar), 139.9 (CAr/Hetar), 137.1
(CAr/Hetar), 134.7 (CHAr), 133.5 (CAr/Hetar), 129.9 (CHAr), 129.4 (CHAr), 128.9 (CHAr),
128.5 (CAr/Hetar), 128.3 (CAr/Hetar), 124.1 (CHAr), 123.9 (CHAr), 21.4 (CH3). MS (EI,
70 eV): m/z (%) = 397 (M+, 6), 396 (M+, 33), 395 (M+, 20), 394 (M+, 97), 393 (M+, 24),
392 (M+, 100), 348 (25), 346 (26), 311 (13), 276 (19), 275 (13), 274 (10), 261 (10), 241
(18), 240 (30), 238 (20), 214 (11), 213 (16), 155 (14), 138 (13), 120 (27), 106 (17), 91
(17). HR-MS (ESI): m/z = calcd. for C18H11Cl3N2O2 ([M+H]+): 392.99589, found:
37
392.99597, calcd. for C18H11Cl2 ClN2O2: 394.99315, found 394.99326, calcd. for
C18H11Cl37Cl2N2O2 : 396.99061, found 396.99107. Anal. calcd. for C18H11Cl3N2O2: C
54.92, H 2.82, N 7.12; found: C 55.04, H 3.27, N 6.86.
2,3,5-trichloro-4-(3-methoxyphenyl)-6-p-tolylpyridine (6c)
6c was synthesized according to general procedure using 4-bromo-2,3,5-trichloro-6-p-
tolylpyridine 4b (0.29 mmol, 100 mg) and 3-methoxyphenylboronic acid (0.43 mmol,
65.3 mg) and was purified via column chromatography (heptane/dichloromethane).
1
Colorless viscous oil; yield: 51 mg (48 %). Rf = 0.73 (Heptan/ EA 4:1). H-NMR
3
3
(300 MHz, CDCl3): δ = 7.66 (d, J = 8.2 Hz, 2H, CHAr), 7.45 (dd, J = 7.96 Hz,
3
3
3J = 7.96 Hz, 1H, CHAr), 7.29 (d, J = 8.2 Hz, 2H, CHAr), 7.03 (ddd, J = 8.4 Hz,
5
4
4J = 2.6 Hz, J = 0.9 Hz, 1H, CHAr), 6.83-6.88 (m, 1H, CHAr), 6.82 (dd, J = 2.6 Hz,
13
4J = 1.7 Hz, 1H, CHAr), 3.87 (s, 3H, OCH3), 2.43 (s, 3H, CH3), C-NMR (75 MHz,
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