Synthesis of 4-Aryl-2-aminopyridine derivatives and related compounds

Article abstract of DOI:10.1080/00397910902898601

A short, efficient, and high-yielding synthesis of 4-aryl-2-aminopyridine derivatives has been developed. The route employs two palladium-catalyzed processes, the Suzuki reaction and the Buchwald-Hartwig amination, as the key steps. The same approach has

Full text of DOI:10.1080/00397910902898601

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Synthesis of 4-Aryl-2-
aminopyridine Derivatives and
Related Compounds
Vladimir Pavlovic a , Milos Petkovic b , Stanimir
Popovic b & Vladimir Savic b
a Faculty of Chemistry , University of Belgrade ,
Belgrade, Serbia
b Faculty of Pharmacy , University of Belgrade ,
Belgrade, Serbia
Published online: 29 Oct 2009.
To cite this article: Vladimir Pavlovic , Milos Petkovic , Stanimir Popovic & Vladimir
Savic (2009) Synthesis of 4-Aryl-2-aminopyridine Derivatives and Related Compounds,
Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 39:23, 4249-4263, DOI: 10.1080/00397910902898601
To link to this article: http://dx.doi.org/10.1080/00397910902898601
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Synthetic Communications1, 39: 4249–4263, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902898601
Synthesis of 4-Aryl-2-aminopyridine Derivatives
and Related Compounds
Vladimir Pavlovic,1 Milos Petkovic,2 Stanimir Popovic,2 and
Vladimir Savic2
1Faculty of Chemistry, University of Belgrade, Belgrade, Serbia
2Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia
Abstract: A short, efficient, and high-yielding synthesis of 4-aryl-2-aminopyridine
derivatives has been developed. The route employs two palladium-catalyzed
processes, the Suzuki reaction and the Buchwald–Hartwig amination, as the
key steps. The same approach has been used for preparation of the corresponding
quinoline derivatives. In addition, a brief study of biological properties showed
the anticancer potential of these compounds.
Keywords: Aminopyridines, aminoquinolines, palladium catalysis, synthesis
INTRODUCTION
Aminopyridines constitute an important class of organic compounds. As
pharmacophores, they are present in many biologically active derivatives
or themselves show a range of physiological activities.[1] They are parti-
cularly interesting as modulators of the activity of various kinases.[1]
The planarity and hydrogen-bonding ability of the 2-aminopyridine
moiety resemble the related properties of the adenosinetriphosphate
(ATP) 6-aminopurine fragment, making this class of compounds a good
candidate for developing the ATP-competitive kinase inhibitors. In
Received January 12, 2009.
Address correspondence to Vladimir Savic, Faculty of Pharmacy, University
of Belgrade, Vojvode Stepe 450, 11000 Belgrade, Serbia. E-mail: vladimir.savic@
pharmacy.bg.ac.rs
4249

4250
V. Pavlovic et al.
Scheme 1. Proposed synthesis of aminopyridine derivatives.
addition, these compounds, because of their chelating ability, have been
commonly used as ligands for various transition metals.[2]
In our ongoing study of different aspects of amino-substituted pyri-
dine derivatives and related compounds, we aimed to develop a synthetic
route for an efficient preparation of these compounds, with potential to
access a range of possible isomers. In addition, the method had been
envisaged to allow for effective application using combinatorial=parallel
synthesis methodologies. Our synthetic strategy for the preparation of the
2-aminopyridine derivatives was based on the palladium (Pd)–catalysed
processes as outlined in Scheme 1. 4-Halopyridines are commercially
available precursors and can be arylated using the Suzuki reaction.[3]
The following steps, oxidation and subsequent chlorination of the
N-oxide, were expected to afford a substrate ideally suited for the
Buchwald–Hartwig amination procedure.[4] Obviously, the only issue
with this synthetic strategy is regiochemistry of the chlorination step,
which may result in a mixture of products when nonsymmetrical
arylpyridine-N-oxides are used.
RESULTS AND DISCUSSION
Initial results are summarized in Scheme 2 and Table 1. The Suzuki
reaction was carried out with 4-bromopyridine 1 and either p-methyl or
m-trifluoromethylphenylboronic acid 2 in degassed dimethylformamide
(DMF)=H2O using Pd(OAc)2=PPh3 as the catalytic system and afforded
Scheme 2. Synthesis of 2-arylamino-4-arylpyridine derivatives.

4-Aryl-2-aminopyridine Derivatives
4251
Table 1. Synthesis of 2-arylamino-4-arylpyridine derivativesa
Yield (%) Yield (%) Yield (%) Yield (%)
of 5
Entry
R1
R2
of 3
of 4
of 7
a
b
c
d
e
f
g
h
i
p-Me
p-Me
p-Me
p-Me
p-Me
m-CF3
m-CF3
m-CF3
m-CF3
m-CF3
m-CF3
80
97
69
p-MeO
2-Naphthylb
60
54
68
97
84
m-MeO
p-Et
p-MeO
70
66
54
63
j
k
l
m-CF3 2-Naphthylb
aYields after dry-flash chromatography.
bNaphthyl amine used for the amination step.
the expected product 3 in good yield (entries a, f, Table 1). Comparable
results were obtained using 4-chloro- or 4-iodopyridine derivatives.
The following step, oxidation of compound 3 to produce N-oxide 4,
employed m-chloroperoxibenzoic acid (MCPBA). The product was iso-
lated in almost quantitative yields (entries b, g, Table 1) and then, with-
out further purification, was submitted to the chlorination conditions
using POCl3 as reagent=solvent to afford chloride 5 in 50–60% yield over
two steps.[5] Because the position 4(C) of the arylpyridine 4 was blocked
by the substituent, the reaction afforded a single product. Finally, the
amination of compound 5 using various amines performed with
Pd2(dba)3, 2,2-bis(diphenylphosphino)-1,1-binaphtyl (BINAP) as
a
ligand, and Cs2CO3 as a base, produced final product 7 in moderate to
good yields (entries d, e, i–l, Table 1).
The described synthetic route is straightforward and high-yielding,
and it potentially may have wide application in the preparation of various
arylaminopyridines. The use of halopyridines isomeric to compound 1 as
starting materials would provide an access to various isomeric products
of type 7.
The same approach has been applied for preparation of the rela-
ted quinoline derivatives, as outlined in Scheme 3 and Table 2.
3-Bromoquinoline was coupled effectively with various boronic acids
under conditions previously described. Subsequent oxidation, carried
out with MCPBA in CH2Cl2, was as efficient as in the case of the pyridine

4252
V. Pavlovic et al.
Scheme 3. Synthesis of aminoquinoline derivatives.
derivatives affording N-oxide 11. The chlorination step of the 3-aryl-N-
oxide derivative 11 produced, as expected, two products (12 and 13), with
13 being the major one. The amination of chloro derivative 13 afforded
2-amino quinoline derivative 14 in good yields (entries d, f, n, Table 2).
The 4-chloro isomer 12 underwent amination under the same conditions,
with comparable results, to produce 15 (entries e, j, Table 2).
We also briefly studied the biological potential of the synthesized pyr-
idine and quinoline derivatives. These compounds showed antiproliferative
Table 2. Synthesis of aminoquinoline derivativesa
Yield (%) Yield (%) Yield (%)b Yield (%) Yield (%)
Entry
R1
R2
of 10
of 11
of 13=12
of 14
of 15
a
b
c
d
e
f
g
h
i
H
H
H
H
H
76
98
65 (2:1)
m-MeO
m-MeO
p-Et
67
63
60
63
H
p-MeO
p-MeO
p-MeO
p-MeO p-MeO
p-Me
p-Me
55
79
87
92
63 (1:1)
j
k
l
m
n
p-Me
p-Me p-MeO
73 (1.5:1)
56
aYields after dry-flash chromatography.
bRatio of the products is in parentheses.

4-Aryl-2-aminopyridine Derivatives
4253
activity against several cancer cell lines such as HeLa, Fem-X, and K562,
and this is now under detailed investigation.
In conclusion, a short and efficient syntheses of 4-aryl-2-aminopyri-
dine derivatives has been developed, and the same strategy has been
applied for preparation of the corresponding quinoline derivatives.
Further study of this process and its application in synthesis of a diverse
set of compounds using the combinatorial=parallel synthesis is under
way. An additional brief study of a biological profile of these compounds
showed that they possess anticancer activity, and this is now under
detailed investigation.
EXPERIMENTAL
Melting points were determined on a Kofler hot-stage apparatus and are
uncorrected. 1H and 13C nuclear magnetic resonance (NMR) spectra
were recorded using a Varian Gemini 2000 instrument at 200 MHz and
50 MHz respectively. Chemical shifts are given in parts per million (d)
downfield from tetramethylsilane (TMS) as the internal standard. Unless
otherwise specified, deuterochloroform was used as a solvent. Mass spec-
tral (MS) data were recorded using an Agilent MSD TOF spectrometer
coupled with Agilent 1200 HPLC and Agilent Tecnology 6890 instru-
ments with MSD 5975C. High-performance liquid chromatography
(HPLC) employed an HP 1100 instrument with ultraviolet (UV) detector
and reversed-phase Zorbax Extend-C18 column. Flash chromatography
employed silica gel 60 (230–400 mesh), and thin-layer chromatography
(TLC) was carried out using alumina plates with 0.25-mm silica layer
(Kieselgel 60 F254, Merck).
General Procedure for Suzuki Reaction
Boronic acid (4.28 mmol) was added to a solution of 4-bromopyridine
hydrochloride (3.94 mmol) in degassed dimethylformamide (DMF)
(56 mL), followed by NaHCO3 (13.85 mmol) dissolved in degassed H2O
(11.2 mL), Pd(OAc)2 (0.394 mmol), and PPh3 (0.788 mmol). The mixture
was then heated and stirred at 90–95ꢀC (oil-bath temperature) under
nitrogen atmosphere for 18 h. After being cooled to room temperature,
the mixture was diluted with Et2O (120 mL), washed with H2O
(3 ꢁ 40 mL), and dried (Na2SO4). The solvent was then evaporated under
reduced pressure, and the residue was purified by flash or dry-flash chro-
matography to afford pyridine derivative.

4254
V. Pavlovic et al.
4-p-Tolyl-pyridine (3a)
Flash chromatography (SiO2, 1:1,v=v petroleum ether–diethyl ether)
afforded the product (80%) as white solid, mp ¼ 89–90ꢀC.
1H NMR (200 MHz, CDCl3) d 2.42 (s, 3 H), 7.26–7.32 (m, 2 H),
7.48–7.57 (m, 4 H), 8.65–8.65 (m, 2 H); 13C NMR (200 MHz, CDCl3) d
21.18, 121.39, 126.82, 129.39, 135.21, 139.20, 148.24, 150.21. m=z ¼ 169
(Mþ), 154, 141, 127, 115, 103, 91, 77, 63. C12H11N required m=
z þ 1 ¼ 170.0964; found: m=z þ 1 ¼ 170.0961.
4-(3-Trifluoromethyl-Phenyl)-pyridine (3f)
Flash chromatography (SiO2, 7:3,v=v chloroform-diethyl ether) afforded
the product (68%) as colorless oil.
1H NMR (200 MHz, CDCl3) d 7.51–7.54 (m, 2 H), 7.59–7.74 (m,
2 H), 7.84–7.88 (m, 2 H), 8.70–8.73 (m, 2 H); 13C NMR (200 MHz,
CDCl3) d 121.66, 123.88, 125.78, 129.71, 130.33, 132.12, 139.20, 146.92,
150.56. m=z ¼ 223 (Mþ), 204, 183, 154, 127, 111, 95,75. C12H8F3N
required m=z þ 1 ¼ 224.0682; found: m=z þ 1 ¼ 224.0689.
3-Phenylquinoline (10a)
Dry-flash chromatography (SiO2, 65:35,v=v petroleum ether–ethyl
acetate) afforded the product (76%) as white solid, mp ¼ 50–51ꢀC.
1H NMR (200 MHz, CDCl3) d 7.4–7.78 (m, 7 H, arom.), 7.9 (d, 1 H),
8.17 (d, 1 H), 8.33 (d, 1 H), 9.20 (d, 1 H); 13C NMR (200 MHz, CDCl3) d
127.1, 127.5, 128.0, 128.2, 129.1, 129.2, 129.5, 133.4, 147.1, 149.7. m=
z ¼ 205 (Mþ), 176, 151, 102. C15H11N required m=z þ 1 ¼
206.0964; found m=z þ 1 ¼ 206.0971.
3-(4-Methoxyphenyl)quinoline (10g)
Dry-flash chromatography (SiO2, 8:2,v=v petroleum ether–ethyl acetate)
afforded the product (55%) as white solid, mp ¼ 48–49ꢀC.
1H NMR (200 MHz, CDCl3) d 3.88 (s, 3 H), 7.03–7.09 (m, 2 H,
arom.), 7.52–7.74 (m, 4 H, arom.), 7.85 (d, 1 H), 8.12 (d, 1 H), 8.24 (d,
1 H), 9.16 (d, 1 H); 13C NMR (200 MHz, CDCl3) d 55.3, 114.7, 126.9,
127.9, 128.1, 128.5, 129.1, 129.2, 130.3, 132.3, 147.1, 149.9, 159.8. m=
z ¼ 235 (Mþ), 220, 192, 165, 139, 117. C16H13NO required m=
z þ 1 ¼ 236.1070; found m=z þ 1 ¼ 236.1067.

4-Aryl-2-aminopyridine Derivatives
4255
3-p-Tolylquinoline (10k)
Dry-flash chromatography (SiO2, 7:3,v=v petroleum ether–ethyl acetate)
afforded the product (79%) as white solid, mp ¼ 47–48ꢀC.
1H NMR (200 MHz, CDCl3) d 2.44 (s, 3 H), 7.26–7.36 (m, 2 H,
arom.), 7.53–7.90 (m, 4 H, arom.), 7.87 (d, 1 H), 8.13 (d, 1 H), 8.28 (d,
1 H), 9.18 (d, 1 H); 13C NMR (200 MHz, CDCl3) d 21.2, 127.0, 127.3,
128.0, 129.2, 129.9, 132.8, 133.8, 134.9, 138.1, 147.2, 149.9. m=z ¼ 219
(Mþ), 204, 189, 165, 108. C16H13N required m=z þ 1 ¼ 220.1121; found
m=z þ 1 ¼ 220.1118.
General Procedure for the Preparation of Pyridine/Quinoline-N-oxide
Derivatives
MCPBA (3.54 mmol) was added to a solution of pyridine=quinoline
derivative (2.72 mmol) in CH2Cl2 (30 mL). After being stirred for 48 h
at room temperature, the mixture was extracted with 10% solution of
NaHCO3 (3 ꢁ 20 mL). The organic layer was then separated, and the
water layer was extracted with CH2Cl2 (2 ꢁ 30 mL). The combined
organic layers were dried (Na2SO4), and the solvent was evaporated
under reduced pressure. The crude pyridine-N-oxide was used in the next
step without further purification.
General Procedure for the Preparation of Chloro Pyridine/Quinoline
Derivatives
Pyridine=quinoline-N-oxide (1.9 mmol) was placed in a round-bottom
flask, followed by POCl3 (9 mL). The mixture was then stirred and heated
at reflux for 18 h under an N2 atmosphere. Toluene (20 mL) was then
added, and the mixture was evaporated under reduced pressure. The resi-
due was suspended in NaHCO3 solution (10%, 20 mL) and then extracted
with CH2Cl2(2 ꢁ 20 mL). The combined organic layers were dried
(Na2SO4), and the solvent was evaporated under reduced pressure. The
residue was purified by flash or dry-flash chromatography to afford the
product.
2-Chloro-4-p-tolyl-pyridine (5c)
Flash chromatography (SiO2, dichloromethane) afforded the product
(69%) as white solid, mp ¼ 55–57ꢀC.

4256
V. Pavlovic et al.
1H NMR (200 MHz, CDCl3) d 2.42 (s, 3 H), 7.26–7.32 (m, 2 H),
7.40–7.43 (m, 1 H), 7.50–7.54 (m, 3 H), 8.40 (d, 1 H); 13C NMR
(200 MHz, CDCl3) d 21.21, 120.24, 121.74, 126.87, 129.98, 133.90,
139.98, 149.94, 151.49, 152.20. m=z ¼ 203 (Mþ), 188, 168, 139, 115, 91,
63. C12H10ClN required m=z þ 1 ¼ 204.0575; found: m=z þ 1 ¼ 204.0570.
2-Chloro-4-(3-trifluoromethyl-phenyl)-pyridine (5h)
Dry-flash chromatography (SiO2, 8:2,v=v dichloromethane–diethyl ether)
afforded the product (84%) as a pale yellow solid, mp ¼ 59–60ꢀC.
1H NMR (200MHz, CDCl3) d 7.44–7.50 (m, 1 H); 7.56–7.86 (m, 5 H);
8.49 (d, 1 H); 13C NMR (200MHz, CDCl3) d 120.52, 122.21, 123.96,
126.34, 129.91, 130.38, 131.86, 137.79, 150.07, 150.34, 152.52; signal from
CF3 not detected. m=z ¼ 257 (Mþ), 238, 222, 175, 153, 126, 101, 75.
C12H7ClF3N required m=z þ 1 ¼ 258.0292; found: m=z þ 1 ¼ 258.0288.
4-Chloro-3-phenylquinoline (12c)
Dry-flash chromatography (SiO2, 8:2,v=v petroleum ether–ethyl acetate)
afforded the product (22%) as colorless, thick oil.
1H NMR (200 MHz, CDCl3) d 7.45–7.58 (m, 5 H, arom.), 7.66–7.84
(m, 2 H, arom.), 8.17 (m, 1 H), 8.37 (m, 1 H), 8.86 (s, 1 H); 13C NMR
(200 MHz, CDCl3) d 124.7, 126.4, 128.0, 128.4, 129.6, 129.9, 130.1,
133.3, 136.3, 139.9, 147.9; 151.4. m=z ¼ 240 (Mþ þ 1), 231, 214, 148.
C15H10ClN required m=z þ 1 ¼ 240.0575; found m=z þ 1 ¼ 240.0582.
4-Chloro-3-(4-methoxyphenyl)quinoline (12i)
Dry-flash chromatography (SiO2, 7:3,v=v petroleum ether–ethyl acetate)
afforded the product (30%) as colorless, thick oil.
1H NMR (200MHz, CDCl3) d 3.89 (s, 3 H), 7.06 (m, 2 H), 7.50 (m, 2 H),
7.68–7.79 (m, 2 H, arom), 8.15 (m, 1H), 8.35 (m, 1H), 8.86 (s, 1H); 13C
NMR (200 MHz, CDCl3) d 55.3, 113.9, 124.6, 126.5, 127.9, 128.5, 129.6,
129.9, 132.8, 139.7, 147.7, 151.7, 159.7. m=z ¼ 270 (Mþ þ 1), 231, 214, 148.
C16H12ClNO required m=z þ 1 ¼ 270.0680; found m=z þ 1 ¼ 270.0690.
4-Chloro-3-p-tolylquinoline (12m)
Dry-flash chromatography (SiO2, 8:2,v=v petroleum ether–ethyl acetate)
afforded the product (24%) as white solid, mp ¼ 67–68ꢀC.

4-Aryl-2-aminopyridine Derivatives
4257
1H NMR (200 MHz, CDCl3) d 2.45 (s, 3 H), 7.26–7.48 (m, 4 H,
arom.), 7.64–7.81 (m, 3 H, arom.), 8.13 (d, 2 H), 8.34 (d, 1 H), 8.85 (s,
2 H); 13C NMR (200 MHz, CDCl3) d 21.3, 124.7, 126.4, 127.9, 129.2,
129.7, 129.8, 129.9, 133.2, 133.4, 138.3, 139.7, 147.9, 151.6. m=z ¼ 254
(Mþ þ 1), 217, 203, 189, 108. C16H12ClN required m=z þ 1 ¼ 254.0731;
found m=z þ 1 ¼ 254.0726.
2-Chloro-3-phenylquinoline (13c)
Dry-flash chromatography (SiO2, 8:2 v=v petroleum ether–ethyl acetate)
afforded the product (40%) as white solid, mp ¼ 51–52ꢀC.
1H NMR (200 MHz, CDCl3) d 7.44–7.59 (m, 6 H, arom.), 7.68–7.83
(m, 3 H, arom.), 8.08 (s, 1 H); 13C NMR (200 MHz, CDCl3) d 127.2,
127.3, 127.5, 128.3, 129.6, 130.4, 134.7, 138.8, 146.8, 149.5. m=z ¼ 239
(Mþ) 204, 176, 151, 102. C15H10ClN required m=z þ 1 ¼ 240.0575; found
m=z þ 1 ¼ 240.0569.
2-Chloro-3-(4-methoxyphenyl)quinoline (13i)
Dry-flash chromatography (SiO2, 7:3 v=v petroleum ether–ethyl acetate)
afforded the product (33%) as white solid, mp ¼ 74–75ꢀC.
1H NMR (200 MHz, CDCl3) d 3.88 (s, 3 H), 7.02 (m, 2 H), 7.47 (m,
2 H), 7.59 (m, 1 H), 7.69–7.85 (m, 3 H, arom), 8.08 (s, 1 H); 13C NMR
(200 MHz, CDCl3) d 55.3, 113.7, 127.2, 127.4, 128.3, 130.0, 130.2,
130.9, 134.5, 138.6, 146.7, 159.7. m=z ¼ 270 (Mþ þ 1), 231, 214, 148.
C16H12ClNO required m=z þ 1 ¼ 270.0680; found m=z þ 1 ¼ 270.0691.
2-Chloro-3-p-tolylquinoline (13m)
Dry-flash chromatography (SiO2, 8:2 v=v petroleum ether–ethyl acetate)
afforded the product (49%) as colourless, thick oil.
1H NMR (200MHz, CDCl3) d 2.44 (s, 3 H), 7.27 (m, 2 H), 7.42 (m,
2 H), 7.55 (m, 1 H), 7.69–7.84 (m, 2 H, arom.), 8.06 (d, 2 H); 13C NMR
(200 MHz, CDCl3) d 21.2, 127.2, 127.3, 127.5, 128.3, 129.0, 129.5, 130.3,
134.7, 134.8, 138.2, 138.7, 146.8. m=z ¼ 254 (Mþ þ 1), 231, 214, 154, 148.
C16H12ClN required m=z þ 1 ¼ 254.0731; found m=z þ 1 ¼ 254.0742.
General Procedure for the Preparation of Amino Pyridine/Quinoline
Derivatives
Chloropyridine=quinoline derivative (0.155 mmol), dry dioxane (3.3 mL),
4-ethylaniline (0.170 mmol), and Cs2CO3 (0.202 mmol) were placed in a

4258
V. Pavlovic et al.
round-bottom flask, followed by BINAP for pyridine derivatives or
4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (XANTPHOS), for
quinoline derivatives (0.0155 mmol), and Pd2(dba)3 (0.0155 mmol). The
mixture was then stirred and heated at reflux (ꢂ110ꢀC oil bath tempera-
ture) for 20 h. After being cooled to room temperature, the solvent was
evaporated, Et2O (30 mL) was added, and the solution washed with
H2O (3 ꢁ 15 mL). The organic layer was dried (Na2SO4), and the solvent
was then evaporated under reduced pressure. The residue was purified by
flash or dry-flash chromatography to afford the product.
(4-Methoxy-phenyl)-(4-p-tolyl-pyridin-2-yl)-amine (7d)
Dry-flash chromatography (SiO2, 9:1 v=v dichloromethane–diethyl ether)
afforded the product (60%) as a pale yellow solid, mp ¼ 144–146ꢀC.
1H NMR (200 MHz, CDCl3) d 2.39 (s, 3 H), 3.82 (s, 3 H), 6.88–6.95
(m, 4 H), d 7.14 (s, NH), 7.21–7.30 (m, 4 H), 7.41–7.46 (m, 2 H), 8.12 (d,
1 H); 13C NMR (200 MHz, CDCl3) d 21.18, 55.52, 104.97, 112.65, 114.74,
124.67, 126.82, 129.67, 132.42, 135.54, 139.30, 146.61, 151.16, 156.71,
157.15. m=z ¼ 290 (Mþ), 275, 247, 220, 199, 178, 153, 115, 91, 63.
C19H18N2O, required m=z þ 1 ¼ 291.14919; found: m=z þ 1 ¼ 291.15033.
Naphthalen-2-yl-(4-p-tolyl-pyridin-2-yl)-amine (7e)
Dry-flash chromatography (SiO2, 8:2 v=v petroleum ether–diethyl ether)
afforded the product (54%) as pale yellow solid in 54% yield,
mp ¼ 157–158ꢀC.
1H NMR (200 MHz, CDCl3) d 2.39 (s, 3 H), 6.98–7.05 (m, 2 H), 7.16
(s, 1 H), 7.23–7.27 (m, 3 H), 7.32–7.52 (m, 5 H), 7.73 (s, NH), 7.73–7.87
(m, 4 H), 8.28 (d, 1 H); 13C NMR (200 MHz, CDCl3) d 21.18, 106.06,
113.83, 115.69, 121.41, 124.34, 126.47, 126.80, 127.07, 127.65, 129.15,
129.69, 130.04, 134.39, 135.81, 138.16, 139.01, 148.77, 150.32, 156.51.
m=z ¼ 309 (Mþꢃ1), 290, 267, 247, 226, 202, 182, 155, 115, 96, 77.
C22H18N2 required m=z þ 1 ¼ 311.1543; found: m=z þ 1 ¼ 311.1553.
3-Methoxyphenyl-[4-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-amine (7i)
Dry-flash chromatography (SiO2, dichloromethane) afforded the product
(70%) as a pale yellow solid, mp ¼ 133–134.5ꢀC.
1H NMR (200MHz, CDCl3) d 6.60–6.66 (m, 1 H), 6.92–7.09 (m, 2 H),
7.15 (s, NH), 7.26 (t, 1 H), 7.56–7.81 (m, 4 H), 8.29 (d, 1 H); 13C NMR
(200MHz, CDCl3) d 55.24, 106.28, 106.33, 108.37, 112.78, 113.51, 123.93,

4-Aryl-2-aminopyridine Derivatives
4259
129.42, 130.11, 130.26, 131.38, 131.74, 139.74, 141.62, 148.88, 149.10,
156.70, 160.61. m=z ¼ 343 (Mþꢃ1), 328, 300, 249, 202, 172, 142, 115, 77.
C19H15F3N2O, required m=z þ 1 ¼ 345.12092; found: m=z þ 1 ¼ 345.12147.
4-Ethylphenyl-[4-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-amine (7j)
Dry-flash chromatography (SiO2, 1:1 v=v petroleum ether–diethyl ether)
afforded the product (66%) as a white solid, mp ¼ 168–170ꢀC.
1H NMR (500 MHz, CDCl3) d 1.25 (t, 3 H), 2.65 (q, 2 H), 6.81 (s,
NH), 6.92 (dd, 1 H), 7.00–7.06 (m, 1 H), 7.19–7.22 (m, 2 H), 7.26–7.29
(m, 2 H), 7.55–7.58 (m, 1 H), 7.66–7.67 (m, 1 H), 7.72–7.74 (m, 1 H),
7.80 (s, 1 H), 8.3 (d, 1 H); 13C NMR (500 MHz, CDCl3) d 15.62, 28.28,
105.59, 113.14, 121.45, 123.80 (q), 125.24, 128.82, 129.45, 130.30,
131.26, 137.51, 139.78, 149.78, 149.04, 157.07. m=z ¼ 341 (Mþꢃ1), 327,
313, 286, 242, 202, 163, 128, 103, 77. C20H17F3N2 required m=
z þ 1 ¼ 343.1417; found: m=z þ 1 ¼ 343.1424.
4-Methoxyphenyl-[4-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-amine (7k)
Dry-flash chromatography (SiO2, 4:6 v=v petroleum ether–diethyl ether)
afforded the product (54%) as pale yellow solid, mp ¼ 141.5–142.5ꢀC.
1H NMR (200 MHz, CDCl3) d 3.83 (s, 3 H), 6.64 (s, NH), 6.84–6.97
(m, 4 H), 7.25–7.33 (m, 3 H), 7.51–7.78 (m, 4 H), 8.23 (d, 1 H); 13C NMR
(200 MHz, CDCl3) d 55.50, 104.89, 112.83, 114.74, 123.81 (q), 124.38,
125.40 (q), 129.42, 130.31, 132.88, 139.94, 149.12, 156.53, 158.02; signals
from CF3 and two quaternary C not detected. m=z ¼ 344 (Mþ), 329, 301,
202, 172, 142, 115, 77. C19H15F3N2O required m=z þ 1 ¼ 345.1209; found:
m=z þ 1 ¼ 345.1210.
Naphthalen-2-yl-[4-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-amine (7l)
Dry-flash chromatography (SiO2, dichloromethane) afforded the product
(63%) as a pale yellow solid, mp ¼ 164–165ꢀC.
1H NMR (500MHz, CDCl3) d 6.98 (s, NH), 7.00 (m, 1 H), 7.13 (s, 1 H),
7.26–7.41 (m, 1 H), 7.45–7.47 (m, 2 H), 7.56–7.57(m, 1 H), 7.66–7.68 (m,
1 H), 7.75–7.84 (m, 5 H), 7.91 (d, 1 H), 8.45 (d, 1 H); 13C NMR (500 MHz,
CDCl3) d 99.98, 106.34, 113.74, 116.06, 121.36, 123.79 (q), 123.93 (q),
125.48 (q), 126.55, 127.08, 127.66, 129.23, 129.51, 130.23 (q), 131.30,
131.56, 134.31, 137.76, 139.70, 148.93, 149.17, 156.67. m=z ¼ 363 (Mþꢃ1),
345, 322, 293, 266, 249, 219, 202, 181, 164, 146, 115, 95, 77. C22H15F3N2
required m=z þ 1 ¼ 365.12601; found: m=z þ 1 ¼ 365.12676.

4260
V. Pavlovic et al.
N-(3-Methoxyphenyl)-3-phenylquinolin-2-amine (14d)
Dry-flash chromatography (SiO2, 7:3 v=v dichloromethane–ethyl acetate)
afforded the product (76%) as dark-yellow oil.
1H NMR (200 MHz, CDCl3) d 3.71 (s, 3 H), 5.28 (s, NH), 6.45 (m,
1 H), 6.73 (d, 1 H), 6.92–7.07 (m, 2 H), 7.25–7.40 (m, 3 H), 7.58–7.70
(m, 2 H), 7.94 (s, 1 H), 8.07 (d, 1 H); 13C NMR (200 MHz, CDCl3) d
55.2, 106.9, 109.6, 113.7, 123.2, 123.4, 124.5, 126.8, 127.4, 128.2, 128.7,
128.8, 129.1, 131.0, 136.4, 140.0, 141.2, 150.7, 159.7. m=z ¼ 327
(Mþ þ 1), 231, 214, 148, 119. C22H18N2O required m=z þ 1 ¼ 327.1492;
found m=z þ 1 ¼ 327.1510.
N-(4-Ethylphenyl)-3-phenylquinolin-2-amine (14f)
Dry-flash chromatography (SiO2, 6:4 v=v dichloromethane–ethyl acetate)
afforded the product (63%) as dark-yellow oil.
1H NMR (200 MHz, CDCl3) d 1.21 (t, 3 H), 2.61 (q, 2 H), 6.94 (s,
NH), 7.11–7.16 (m, 2 H), 7.27–7.48 (m, 1 H), 7.50–7.67 (m, 9 H), 7.77
(s, 1 H), 7.87 (d, 1 H); 13C NMR (200 MHz, CDCl3) d 15.7, 28.2, 119.5,
123.2, 124.0, 126.2, 126.7, 127.2, 128.1, 128.3, 128.5, 129.2, 129.4,
129.5, 137.0, 137.1, 137.8, 138.3, 146.7, 151.4. m=z ¼ 325 (Mþ þ 1), 231,
214, 148, 119. C23H20N2 required m=z þ 1 ¼ 325.1699; found m=
z þ 1 ¼ 325.1710.
N-(4-Methoxyphenyl)-3-p-tolylquinolin-2-amine (14n)
Dry-flash chromatography (SiO2, 6:4 v=v dichloromethane–ethyl acetate)
afforded the product (56%) as dark-yellow oil.
1H NMR (200 MHz, CDCl3) d 2.45 (s, 3 H), 3.80 (s, 3 H), 6.70 (s,
NH), 6.88 (m, 1 H), 7.26–7.80 (m, 12 H), 13C NMR (200 MHz, CDCl3)
d 21.2, 55.5, 114.0, 121.1, 122.9, 124.1, 125.4, 126.1, 126.7, 127.2, 128.4,
129.0, 129.1, 129.3, 130.1, 130.5, 133.7, 134.2, 136.6, 138.4, 143.3,
146.9, 151.7, 155.1. m=z ¼ 340 (Mþ), 205, 191, 156, 131, 103.
C23H20N2O required m=z þ 1 ¼ 341.1648; found m=z þ 1 ¼ 341.1650.
N-(4-Methoxyphenyl)-3-phenylquinolin-4-amine (15e)
Dry-flash chromatography (SiO2, 7:3 v=v dichloromethane–ethyl acetate)
afforded the product (60%) as dark-yellow oil.
1H NMR (200 MHz, CDCl3) d 3.76 (s, 3 H), 6.07 (s, NH), 6.73–6.83
(m, 4 H), 7.26–7.44 (m, 3 H), 7.58–7.77 (m, 2 H), 8.08 (d, 1 H), 8.75 (s,

4-Aryl-2-aminopyridine Derivatives
4261
1 H); 13C NMR (200 MHz, CDCl3) d 55.5, 114.5, 121.1, 122.0, 124.5,
125.0, 125.3, 128.1, 129.3, 129.4, 129.8, 136.2, 138.2, 144.5, 149.1,
151.9, 155.5. m=z ¼ 327 (Mþ þ 1), 231, 214, 148, 119. C22H18N2O
required m=z þ 1 ¼ 327.1492; found m=z þ 1 ¼ 327.1490.
N,3-Bis(4-methoxyphenyl)quinolin-4-amine (15j)
Dry-flash chromatography (SiO2, 7:3 v=v dichloromethane–ethyl acetate)
afforded the product (63%) as dark-yellow oil.
1H NMR (200 MHz, CDCl3) d 3.77 (s, 3 H), 3.84 (s, 3 H), 6.05 (s,
NH), 6.79 (m, 4 H), 6.99 (m, 2 H), 7.26–7.38 (m, 3 H), 7.57–7.75 (m,
2 H), 8.07 (d, 1 H), 8.74 (s, 1 H); 13C NMR (200 MHz, CDCl3) d 29.6,
55.3, 55.5, 114.6, 114.8, 121.1, 121.9, 124.3, 125.0, 125.3, 128.1, 129.0,
129.5, 130.5, 138.2, 144.6, 148.7, 151.8, 155.5, 159.6. m=z ¼ 357
(Mþ þ 1), 231, 214, 148. C23H20N2O2 required m=z þ 1 ¼ 357.1598; found
m=z þ 1 ¼ 357.1598.
ACKNOWLEDGMENTS
We thank the Serbian Ministry of Science (Grants 142071 and 142072)
and Faculties of Pharmacy and Chemistry for support.
REFERENCES
1. (a) Recent examples: Congreve, M.; Aharony, D.; Albert, J.; Callaghan, O.;
Campbell, J.; Carr, R. A. E.; Chessari, G.; Cowan, S.; Edwards, P. D.;
Frederickson, M.; McMenamin, R.; Murray, C. W.; Patel, S.; Wallis, N.
Application of fragment-based lead generation to the discovery of novel, cyclic
amidine b-secretase inhibitors with nanomolar potency, cellular activity, and
high ligand efficiency. J. Med. Chem. 2007, 50, 1124–1132; (b) Zhang, D.
Aminopyridines as protein kinase C inhibitors. Expert Opin. Ther. Pat.
2007, 17, 583–586; (c) Vianello, P. Aminopyridines: Selective AuroraA inhibi-
tors. Expert Opin. Ther. Pat. 2007, 17, 255–261; (d) Singh, T.; Sharma, S.;
Srivastava, V. K.; Kumar, A. Synthesis and pesticidal activities of some
substituted pyridine derivatives. Indian J. Chem. B 2006, 45B, 1557–1563; (e)
Stevens, K. L.; Jung, D. K.; Alberti, M. J.; Badiang, J. G.; Peckham, G. E.;
Veal, J. M.; Cheung, M.; Harris, P. A.; Chamberlain, S. D.; Peel, M. R.
Pyrazolo[1,5-a]pyridines as p38 kinase inhibitors. Org. Lett. 2005, 7, 4753–
4756; (f) Abdel-Aziz, A. A.-M.; El-Subbagh, H. I.; Kunieda, T. Lewis acid–
promoted transformation of 2-alkoxypyridines into 2-aminopyridines and
their antibacterial activity; part 2: Remarkably facile C–N bond formation.
Bioorg. Med. Chem. 2005, 13, 4929–4935.

4262
V. Pavlovic et al.
2. (a) Deeken, S.; Proch, S.; Casini, E.; Braun, H. F.; Mechtler, C.; Marschner,
C.; Motz, G.; Kempe, R. Group 10 metal aminopyridinato complexes: Synth-
esis, structure, and application as aryl-Cl activation and hydrosilane polymer-
ization catalysts. Inorg. Chem. 2006, 45, 1871–1879; (b) Yilmaz, V. T.; Caglar,
S.; Harrison, W. T. A. Bis(saccharinato)copper(II) complexes with 2-amino-
methylpyridine and 2-aminoethylpyridine: Syntheses, crystal structures, spec-
tral and thermal characterizations of trans-[Cu(sac)2(ampy)2] and
[Cu(sac)2(aepy)(H2O)]
(ampy ¼ 2-aminomethylpyridine
and aepy ¼ 2-
aminoethylpyridine). J. Coord. Chem. 2005, 58, 549–558; (c) Fuhrmann, H.;
Brenner, S.; Arndt, P.; Kempe, R. Octahedral group 4 metal complexes that
contain amine, amido, and aminopyridinato ligands: Synthesis, structure,
and application in a-olefin oligo- and polymerization. Inorg. Chem. 1996,
35, 6742–6745.
3. (a) Stavenuiter, J.; Hamzink, M.; van der Hulst, R.; Zomer, G.; Westra, J. G.;
Kriek, E. Palladium-catalyzed cross-coupling of phenylboronic acid with het-
erocyclic aromatic halides. Heterocycles. 1987, 26, 2711–2716; (b) Ishikura,
M.; Oda, I.; Terashima, M. A simple and regioselective preparation of 2- or
3-substituted quinoline derivatives via dialkylquinolylboranes. Heterocycles
1985, 23, 2375–2386; (c) Yang, Y.; Martin, A. R. Synthesis of 5-arylated
indoles via palladium-catalyzed cross-coupling reaction of 5-indolylboronic
acid with aryl and heteroaryl halides. Heterocycles 1992, 34, 1395–1398; (d)
Peters, D.; Hornfeldt, A. B.; Gronowitz, S. Synthesis of various 5-substituted
uracils. J. Heterocycl. Chem., 1990, 27, 2165–2173; (e) Wellmar, U.;
Gronowitz, S.; Ho¨rnfeldt, A. B. Syntheses of various 5-(bromoaryl)-
substituted uracils. J. Heterocycl. Chem. 1995, 32, 1159–1163; (f) Lohse, O.;
Thevenin, P.; Waldvogel, E. The palladium-catalyzed Suzuki coupling of 2-
and 4-chloropyridines. Synlett, 1999, 45–48; (g) Zhang, H.; Kwong, F. Y.;
Tian, Y.; Chan, K. S. Base and cation effects on the Suzuki cross-coupling
of bulky arylboronic acid with halopyridines: Synthesis of pyridylphenols. J.
Org. Chem., 1998, 63, 6886–6890; (h) Cowden, C. J.; Hammond, D. C.;
Bishop, B. C.; Brands, K. M. J.; Davies, A. J.; Dolling, U. H.; Brewer, S. E.
An efficient and general synthesis of 3-substituted propionaldehydes using
the Suzuki–Miyaura coupling. Tetrahedron Lett. 2004, 6125–6128; (i) Tagata,
T.; Nishida, M. Palladium charcoal-catalyzed Suzuki-Miyaura coupling to
obtain arylpyridines and arylquinolines. J. Org. Chem. 2003, 68, 9412–9415;
(j) Billingsley, K.; Buchwald, S. L. Highly efficient monophosphine-based cat-
alyst for the palladium-catalyzed Suzuki-Miyaura reaction of heteroaryl
halides and heteroaryl boronic acids and esters. J. Am. Chem. Soc. 2007,
129, 3358–3366; (k) Alessi, M.; Larkin, A. L.; Ogilvie, K. A.; Green, L. A.;
Lai, L. S.; Snieckus, V. Directed ortho metalation-boronation and
Suzuki-Miyaura cross coupling of pyridine derivatives: A one-pot protocol
to substituted azabiaryls. J. Org. Chem. 2007, 72, 1588–1594.
4. (a) Li, J. J.; Wang, Z.; Mitchell, L. H. A practical Buchwald–Hartwig amina-
tion of 2-bromopyridines with volatile amines. J. Org. Chem. 2007, 72, 3606–
3607; (b) Urgaonkar, S.; Xu, J.; Verkade, J. G. Application of a new bicyclic
triaminophosphine ligand in Pd-catalyzed Buchwald–Hartwig amination

4-Aryl-2-aminopyridine Derivatives
4263
reactions of aryl chlorides, bromides, and iodides. J. Org. Chem. 2003, 68,
8416–8423; (c) Tewari, A.; Hein, N.; Zapf, A.; Beller, M. Efficient palladium
catalysts for the amination of aryl chlorides: A comparative study on the
use of phosphium salts as precursors to bulky, electron-rich phosphines.
Tetrahedron 2005, 61, 9705–9709; (d) Wolfe, J. P.; Tomori, H.; Sadihghi,
J. P.; Yin, J.; Buchwald, S. L. Simple, efficient catalyst system for the
palladium-catalyzed amination of aryl chlorides, bromides, and triflates. J.
Org. Chem. 2000, 65, 1158–1174; (e) Begouin, A.; Hesse, S.; Queiroz, M.-J.
R. P.; Kirsch, G. Palladium-catalyzed Buchwald–Hartwig coupling of deacti-
vated aminothiophenes with substituted halopyridines. Eur. J. Org. Chem.
2007, 1678–1682; (f) Sasaki, M.; Dalili, S.; Yudin, A. K. N-Arylation of
aziridines. J. Org. Chem. 2003, 68, 2045–2047.
5. (a) Bouet, A.; Heller, B.; Papamicael, C.; Dupas, G.; Oudeyer, S.; Marsais, F.;
Levacher, V. Preparation of new axially chiral bridged 2,20-bipyridines and
pyridyl monooxazolines (pymox): Evaluation in copper(I)-catalyzed enantio-
selective cyclopropanation. Org. Bio. Chem. 2007, 5, 1397–1404; (b) Anderson,
R. J.; Hill, J. B.; Morris, J. C. Concise total syntheses of variolin B and
deoxyvariolin B. J. Org. Chem. 2005, 70, 6204–6212.