A facile synthesis of 3,5-halo and aryl 1H-pyridin-2-ones from pyridinium N-(pyridin-2-yl)aminide

Article abstract of DOI:10.1016/j.tet.2013.05.065

The synthesis of halogenated and arylated 1H-pyridin-2-ones starting from pyridinium N-(pyridin-2-yl)aminides is described. The synthetic pathway involves the reaction of pyridinium N-(5-bromopyridin-2-yl)aminide, N-(3-bromo-5- chloropyridin-2-yl)aminide or N-(3,5-dibromopyridin-2-yl)aminide with different boronic acids to afford monosubstituted and disubstituted aminides in good yields. An additional bromination in the 3-position of N-(5-arylpyridin-2-yl) aminides was performed. Finally, reduction of the N-N bond followed by the reaction of the corresponding 2-aminopyridines with sodium nitrite/sulfuric acid in water yields 3,5-disubstituted 1H-pyridin-2-ones in good yields.

Full text of DOI:10.1016/j.tet.2013.05.065

Tetrahedron 69 (2013) 6088e6094
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A facile synthesis of 3,5-halo and aryl 1H-pyridin-2-ones
from pyridinium N-(pyridin-2-yl)aminide
*
Fabiana Filace, David Sucunza, M. Luisa Izquierdo, Carolina Burgos ,
*
Julio Alvarez-Builla
ꢀ
Departamento de Quimica II, Universidad de Alcala, 28871 Alcala de Henares, Madrid, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 April 2013
Received in revised form 15 May 2013
Accepted 17 May 2013
Available online 23 May 2013
The synthesis of halogenated and arylated 1H-pyridin-2-ones starting from pyridinium N-(pyridin-2-yl)
aminides is described. The synthetic pathway involves the reaction of pyridinium N-(5-bromopyridin-2-
yl)aminide, N-(3-bromo-5-chloropyridin-2-yl)aminide or N-(3,5-dibromopyridin-2-yl)aminide with
different boronic acids to afford monosubstituted and disubstituted aminides in good yields. An addi-
tional bromination in the 3-position of N-(5-arylpyridin-2-yl)aminides was performed. Finally, reduction
of the NeN bond followed by the reaction of the corresponding 2-aminopyridines with sodium nitrite/
sulfuric acid in water yields 3,5-disubstituted 1H-pyridin-2-ones in good yields.
Keywords:
1H-Pyridin-2-ones
Pyridinium N-(pyridin-2-yl)aminide
Diazonium salts
Ó 2013 Elsevier Ltd. All rights reserved.
R1
1. Introduction
Cl
z
Functionalized 1H-pyridin-2-ones have emerged as an impor-
tant class of organic azaheterocycles due to their presence in nu-
merous natural and synthetic products that have diverse biological
activities.1 In the same way, halogenated 1H-pyridin-2-ones are an
important subclass of pyridines and they have formed the basis of
cardiotonic agents, antiviral drugs and fungicides.2 Consequently,
a wide variety of synthetic methods have been developed for the
preparation of 1H-pyridin-2-ones, including the construction of the
heterocyclic skeleton from acyclic precursors3 and the modification
of the heterocyclic core, frequently through the pyridinium salt or
N-oxide.4 Unfortunately, most of the available approaches for the
synthesis of pyridones are not general for the preparation of ha-
logenated 1H-pyridin-2-ones. In this context, the Vilsmeier re-
action of enaminones has recently been applied by Dong and co-
workers as an elegant approach to halogenated 1H-pyridin-2-
ones.5
N
H
O
2
R2
R2
N
- N
+
N
N
O
3
H
1a
R3
Br
O
4
N
H
On the other hand, it is a well-known axiom in heterocyclic
chemistry6 that transformation of 2-aminoazines into the corre-
sponding diazonium salts under standard conditions furnishes 2-
pyridones in an easy one-pot process.
Scheme 1. Substituted 1H-pyridin-2-ones 2e4 prepared in this work from pyridinium
N-pyridin-2-ylaminide 1a.
In recent years our research group has been interested in the
chemistry of pyridinium N-pyridin-2-ylaminide 1a (Scheme 1).
Compound 1a is a stable heterocyclic betaine in which the exocyclic
nitrogen anion is stabilized by the presence of a pyridinium moiety
and also by a pyridine ring in which the charge is delocalized. This
compound has proven to be a versatile scaffold in a wide range of
transformations, including regioselective halogenations that avoid
the use of the aggressive molecular halogen and generate 3,5-
mono- or dihalogenated aminides, or in Suzuki cross-coupling
* Corresponding authors. E-mail address: carolina.burgos@uah.es (C. Burgos).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.05.065

F. Filace et al. / Tetrahedron 69 (2013) 6088e6094
6089
Table 1
reactions. Moreover, the NeN bond reduction yields the corre-
sponding 2-aminopyridine derivatives.7 Taking into consideration
the versatility of this compound, we report here an easy application
of this chemistry to the preparation of compounds 2e4 (Scheme 1).
Compounds 2 are related to the non-nucleoside compounds de-
scribed as inhibitors of RNA-dependent RNA viral polymerase
and are useful for the treatment of hepatitis C.2a In addition, this
system has been described by Knochel and co-workers as an in-
termediate in the preparation of Etoricoxib, using a methodology of
directed metalations in the presence of TMPMgCl$LiCl [(2,2,6,6-
tetramethylpiperidyl)-derived bases].8 Compounds 3 have been
described very recently in the synthesis of Perampanel, a triaryl 2-
pyridone that acts as a selective non-competitive antagonist of
AMP-type ionotropic glutamate receptors implicated in the path-
ogenesis of epilepsy and other neurological diseases.9 Finally, the 3-
bromo-5-aryl derivatives 4 are intermediates in the synthesis of
compounds that have a phosphodiesterase 10A inhibitory effect
and are useful in the prevention or treatment of schizophrenia.10
Arylation and halogenation of N-aminides
N
+
N
-N
+
-
N
N
N
i
1a
Y
X
B
A
1b (X = Br, Y = H)
1c (X = Cl, Y = Br)
1d (X, Y = Br)
6a-c (A = Ar, B = H)
6d-f (A = Cl, B = Ar)
6g-i (A, B = Ar)
ii
6j-l (A = Ar, B = Br)
i) ArB(OH)2, K2CO3, Pd(PPh3)4, toluene/ethanol
ii) NBS, CH2Cl2
Entry Methoda Starting
material
6
A
B
Yield
(%)
1
A
A
A
A
A
A
B
B
B
C
C
C
1b
6a
91
X¼Br, Y¼H
2. Results and discussion
2
1b
6b
6c
6d
6e
6f
88
87
88
80
51
56
78
81
74
89
91
Me
The general strategy for preparation of compounds 2e4 from 1a
is outlined in Scheme 2. This sequence is based on the efficient
preparation of substituted amines 5, obtained by NeN-reduction of
arylated pyridinium N-aminides 6 whereas compounds 6 were
obtained from halogenated pyridinium N-aminides using a pre-
viously reported methodology.7
X¼Br, Y¼H
3
1b
SMe
X¼Br, Y¼H
4
1c
Cl
Cl
Cl
SMe
X¼Cl, Y¼Br
5
1c
A
B
A
B
SO Me
N
N
- N
X¼Cl, Y¼Br
+
N
N
H
O
N
5
NH2
6
1c
2-4
X¼Cl, Y¼Br
B
A
6
7
1d
6g
6h
6i
Me
OEt
Ac
Me
OEt
Ac
N
- N
X, Y¼Br
+
1a
N
8
1d
X, Y¼Br
Y
X
1b-d
Scheme 2. General strategy for preparation of compounds 2e4 from 1a.
9
1d
X, Y¼Br
10
11
6a
6j
Br
Br
Br
The synthesis began with the N-aminides N-(5-bromopyridin-2-
yl)pyridinium aminide 1b, N-(3-bromo-5-chloropyridin-2-yl)pyr-
idinium aminide 1c and N-(3,5-dibromopyridin-2-yl)pyridinium
aminide 1d. These compounds were obtained by selective haloge-
nation of N-(pyridin-2-yl)pyridinium aminide 1a7j and they were
coupled with different boronic acids. Under previously reported
standard conditions,7h the coupling of aminides 1b and 1c took
place efficiently in the presence of the corresponding boronic acid
(1.5 equiv), K2CO3 (10 equiv) and Pd(PPh3)4 (5 mol %) in toluene/
ethanol (20:1) (method A) to afford the 5-arylated (entries 1e3,
Table 1) or 3-arylated (or heteroarylated) products (entries 4e6,
Table 1). Compound 1d underwent a double Suzuki process (entries
7e9, Table 1) in the presence of boronic acid (3 equiv), K2CO3
(20 equiv) and Pd(PPh3)4 (5 mol %) in toluene/ethanol (4:1)
(method B).
A¼Ar, B¼H
6b
6k
6l
Me
A¼Ar, B¼H
12
6c
SMe
A¼Ar, B¼H
a
Method A: aminide (1 mmol), boronic acid (1.5 mmol), K2CO3 (10 mmol),
Pd(PPh3)4 (5 mol %), toluene/EtOH (20:1). Method B: aminide (1 mmol), boronic acid
(3 mmol), K2CO3 (20 mmol), Pd(PPh3)4 (5 mol %), toluene/EtOH (4:1). Method C:
aminide (1 mmol), NBS (1.1 mmol), CH2Cl2.
pyridine ring to afford the corresponding aminides 6jel.7b,d The
halogenation was accomplished under previously reported condi-
tions, which involved the use of NBS in dichloromethane at room
temperature (entries 10e12, Table 1).
Having the halogenated and arylated substrates 6del in hand,
the next step was the preparation of the corresponding 2-
In most cases the aryl- or diaryl-aminides were obtained in
excellent yields. Only in the reaction involving 3-pyridyl boronic
acid in the presence of aminide 1c was the yield disappointing
(entry 6, Table 1). Compounds 6aec are suitable substrates to un-
dergo a new, chemoselective, bromination in the 3-position of the

6090
F. Filace et al. / Tetrahedron 69 (2013) 6088e6094
aminopyridines 5 by removing the pyridinium fragment using
different methodologies developed in our group.7 The reduction of
the NeN bond was performed using two alternative methods. Thus,
2-aminopyridines 5dei were satisfactorily obtained using zinc and
glacial acetic acid (method D, entries 1e6, Table 2), whereas com-
pounds 5jel were synthesized using formic acid/triethylamine in
the presence of platinum on carbon to avoid a concomitant
debromination (method E, Entries 7e9, Table 2).
sodium nitrite in dilute sulfuric acid followed by displacement by
water [method F: 2-aminopyridine (1 mmol) in pyridine, NaNO2
(5 mmol), sulfuric acid (2.6 mL), H2O (1 mL)].11
Under optimal conditions, amines 5def and 5jel reacted to give
2-pyridones 2aec and 4aec with yields shown in Table 3 (entries
1e3 and 7e9). When these conditions were applied to 5d (entry 1,
Table 3), a concomitant oxidation on the sulfur group was observed
to give 2a, with Ar¼4-MeeSOePh, as the sole final product. How-
ever, this simultaneous oxidation was not observed for the other
methylthio derivative 5l ( entry 9, Table 3), fromwhich compound 4c
was obtained (Ar¼4-MeeSePh)dalbeit in only 33% yield. When
these conditions were applied to diarylated derivatives 5gei only
poor yields were achieved. Moderate yields of final products could be
obtained, however, on employing 10 equiv of sodium nitrite (entries
4e6, method G, Table 3). In order to improve yields for compounds 3,
we explored the possibility of using a different method to generate
the diazonium salt, i.e., tert-butyl nitrite/CuO in aqueous ethanol
(method H).12 Unfortunately, this method failed and only afforded
the desired 2-pyridinones in very low yield. It is worth noting that
compounds 2b, 4a and 4b were obtained in excellent yields and that
the yields were almost satisfactory in all other cases.
Table 2
Reduction of aminides 6del
A
B
N
N
+
-
N
N
NH2
B
A
5d-f (A = Cl, B = Ar)
5g-i (A, B = Ar)
5j-l (A = Ar, B = Br)
6d-f (A = Cl, B = Ar)
6g-i (A, B = Ar)
6j-l (A = Ar, B = Br)
Entry Methoda Starting
5
A
B
Yield (%)
Table 3
material
Preparation of 2-pyridones 2e4
A
B
A
B
A
B
1
2
3
D
D
D
6d
5d
5e
5f
Cl
Cl
Cl
70
65
44
SMe
+
N
H
O
N
N
N
NH2
6e
6f
SO Me
N
2a-c, A = Cl, B = Ar
3a-c, A, B = Ar
4a-c, A = Ar, B = Br
N
5d-f, A = Cl, B = Ar
5g-i, A, B = Ar
5j-l, A = Ar, B = Br
Entry Methoda Starting Compound
material
A
B
Yield (%)
4
5
6
7
8
D
D
D
E
6g
6h
6i
5g
5h
5i
95
91
51
83
98
Me
OEt
Ac
Me
OEt
Ac
1
2
3
F
F
F
5d
5e
5f
2a
2b
2c
Cl
Cl
Cl
60
80
50
SOMe
SO Me
N
6j
5j
Br
Br
E
6k
5k
Me
4
5
6
7
8
G
G
G
F
5g
5h
5i
3a
3b
3c
4a
4b
50
51
44
87
73
Me
OEt
Ac
Me
OEt
Ac
9
E
6l
5l
Br
82
SMe
a
Method D: aminide (1 mmol), Zn (20 mmol), acetic acid (15 mL). Method E:
aminide (0.32 mmol), Pt/C (5 mmol %), HCOOH/Et3N.
5j
Br
Br
Once again, the arylated and diarylated amines were obtained in
good to excellent yields, especially in the case of compounds 5g and
5k (entries 4 and 8, Table 2), which was obtained in almost quan-
titative yield. The reaction of 3-pyridyl derivative 6f (entry 3, Table
2) again led to only moderate yield. A similar result was obtained
with compound 6i (entry 6, Table 2), which has an acetyl sub-
stituent, and this can be attributed to possible competition of
a carbonyl reduction. Attempts to increase this yield by using
method E were unsuccessful.
F
5k
Me
9
F
5l
4c
Br
33
SMe
a
Method F: 2-aminopyridine (1 mmol), NaNO2 (5 mmol), sulfuric acid (2.6 mL),
H2O (1 mL). Method G: 2-aminopyridine (1 mmol), NaNO2 (10 mmol), sulfuric acid
(5.2 mL), H2O (1 mL).
Treatment of 2-aminopyridines with sodium nitrite in an acidic
medium affords the corresponding diazonium salts, which easily
decompose and react with diverse nucleophilic reagents. However,
diazonium salts of 2-aminopyridines decompose particularly rap-
idly and immediately react with the aqueous solvent to give the
corresponding 2-pyridones.6 Taking this fact into consideration, we
planned to prepare the 1H-pyridin-2-ones 2e4 through a di-
azotization process, using pyridine as solvent in the presence of
3. Conclusions
A selective, facile and efficient route to prepare a series of 3,5-
disubstituted 1H-pyridin-2-ones is described. The versatility of N-
(pyridin-2-yl)aminide 1a was exploited to synthesize 2-
aminopyridines 5 through the prior introduction of halo and/or

F. Filace et al. / Tetrahedron 69 (2013) 6088e6094
6091
different aryl groups to supply compounds 6ael and subsequent
reduction of the NeN bond. Diazonium salts were then generated
under standard conditions and for these reactive substrates the
addition of water is very rapid. In this way we obtained 2-pyridones
2e4 very easily. This route could prove to be very useful, especially
for compounds 2 and 4 given the difficulty in generating haloge-
nated 2-pyridones.
(KBr) nmax (cmꢁ1): 1595, 1465, 1375, 1287, 1134; 1H NMR (300 MHz,
CD3OD):
d
8.80 (2H, d, J¼5.5 Hz), 8.07 (1H, t, J¼7.6 Hz), 7.96 (1H, d,
J¼2.3 Hz), 7.85 (2H, ap t, J¼6.8 Hz), 7.71 (1H, dd, J¼8.7, 2.3 Hz), 7.46
(2H, d, J¼8.5 Hz), 7.31 (2H, d, J¼8.5 Hz), 6.62 (1H, d, J¼8.7), 2.51
(3H, s); 13C NMR (75 MHz, CD3OD):
d 162.3, 144.7, 144.5, 138.1,
137.8, 136.9, 135.7, 128.6, 128.3,126.8, 125.2, 112.2, 15.9; HRMS (ESI-
TOF, CH3OH): calcd for C17H16N3S: [MþH]þ 294.1065, found
294.1031.
4. Experimental section
4.1. General remarks
4.2.4. N-[5-Chloro-3-(4-methylthiophenyl)pyridin-2-yl]pyridinium
aminide (6d). Orange solid (288 mg, 88%, ethyl acetate), mp
163e164 ꢀC; IR (KBr) nmax (cmꢁ1): 1575, 1489, 1425, 1384, 1142; 1H
All melting points were determined in open capillary tubes on
a Stuart Scientific SMP3 melting point apparatus and are un-
corrected. IR spectra were obtained on a PerkineElmer FTIR spec-
trum 2000 spectrophotometer. 1H and 13C NMR spectra were
recorded on either a Varian Gemini (200 MHz), Varian Mercury VX-
300, Varian Unity 300 or 500 MHz spectrometer at room temper-
NMR (300 MHz, CD3OD):
d
8.67 (2H, d, J¼5.9 Hz), 8.07 (1H, t,
J¼7.2 Hz), 7.81 (2H, ap t, J¼7.2 Hz), 7.65 (2H, d, J¼8.4 Hz), 7.55 (1H,
d, J¼2.6 Hz), 7.33 (2H, d, J¼8.4 Hz), 7.28 (1H, d, J¼2.6 Hz), 2.52 (3H,
s); 13C NMR (75 MHz, CD3OD):
d 162.3, 155.2, 145.6, 144.0, 139.1,
138.4, 137.8, 136.5, 130.7, 128.5, 127.3, 125.1, 15.7; HRMS (ESI-TOF,
35
CH3OH): calcd for C17
328.0709.
H
ClN3S: [MþH]þ 328.0670, found
15
ature. Chemical shifts are given in parts per million (ppm,
d)
downfield from TMS. Coupling constants (J) are in hertz (Hz) and
signals are described as follows: s, singlet; d, doublet; t, triplet; br,
broad; m, multiplet; ap, apparent, etc. High-resolution analysis
(TOF) was performed on an Agilent 6210 time-of-flight LC/MS sys-
tem. All reagents were obtained from commercial sources and were
used without further purification. Solvents were purified and dried
by standard procedures. TLC analyses were performed on silica gel
(Kieselgel 60 F254, Macherey-Nagel) and spots were visualized under
UV light. Column chromatography was carried out with silica gel 60
(40e63 mm, Merck) columns using the eluent reported in each case.
4.2.5. N-[5-Chloro-3-(4-methylsulfonylphenyl)pyridin-2-yl]pyr-
idinium aminide (6e). Orange solid (287 mg, 80%, ethyl acetate/
hexane), mp 178e180 ꢀC; IR (KBr) nmax (cmꢁ1): 1580, 1515, 1384,
1308, 1190, 1148; 1H NMR (300 MHz, CD3OD):
d 8.71 (2H, d,
J¼5.6 Hz), 8.12 (1H, t, J¼7.9 Hz), 8.00 (m, 4H), 7.85 (2H, ap t,
J¼6.9 Hz), 7.65 (1H, d, J¼2.6 Hz), 7.40 (1H, d, J¼2.6 Hz), 3.17 (3H, s);
13C NMR (75 MHz, CD3OD):
d 146.2, 145.9, 145.6, 140.4, 139.4, 138.4,
131.3, 129.1, 128.7, 128.6, 128.4, 126.7, 44.4; HRMS (ESI-TOF,
35
CH3OH): calcd for C17
360.0600.
H
ClN3O2S: [MþH]þ 360.0568, found
15
4.2. General procedures for the preparation of 5-aryl N-(pyr-
idin-2-yl)pyridinium aminides (6aec), 5-chloro-3-aryl N-(pyr-
idin-2-yl)pyridiniumaminides(6def), and3,5-biaryl N-(pyridin-
2-yl)pyridinium aminides (6gei)7e,g,h
4.2.6. N-[5-Chloro-3-(30-pyridin)pyridin-2-yl]pyridinium
aminide
(6f). Orange solid (144 mg, 51%, ethyl acetate/hexane), mp
54e56 ꢀC; IR (KBr) nmax (cmꢁ1): 1577, 1388, 1144, 1009; 1H NMR
(200 MHz, CD3OD):
d
8.88 (1H, br s), 8.69 (2H, d, J¼5.5 Hz),
Method A: A solution of aminide 1b7j or 1c7j (1 mmol), the
corresponding boronic acid (1.5 mmol), K2CO3 (10 mmol) and
Pd(PPh3)4 (5 mol %) in toluene/ethanol (20:1, 10 mL) was heated
under reflux for 12 h under an atmosphere of dry argon. The course
of the reaction was followed by TLC. Once the starting material had
been consumed, the system was allowed to cool down to room
temperature. The mixture was filtered through Celite and washed
with acetonitrile until colour was no longer observed in the filtrate.
The combined filtrates were evaporated to dryness. The crude
product was purified by flash chromatography, with ethanol as the
mobile phase, and recrystallized from a suitable solvent.
8.48 (1H, d, J¼4.2 Hz), 8.19 (1H, dt, J¼7.6, 1.8 Hz), 8.08 (1H, t,
J¼7.6 Hz), 7.82 (2H, ap t, J¼7.0 Hz), 7.62 (1H, d, J¼2.5 Hz),
7.50 (1H, dd, J¼7.6, 4.5 Hz), 7.36 (1H, d, J¼2.5); 13C NMR
(75 MHz, CD3OD):
d 161.1, 149.0, 146.9, 144.2, 144.0, 137.6,
137.2, 136.8, 127.2, 127.1, 123.5, 119.8, 116.5; HRMS (ESI-TOF,
CH3OH): calcd for C15
283.0744.
35
H
ClN4: [MþH]þ 283.0745, found
12
4.2.7. N-[3,5-Bis(4-methylphenyl)pyridin-2-yl]pyridinium aminide
(6g). See Ref. 7g.
Method B: N-(3,5-Dibromopyridin-2-yl)pyridinium aminide 1d7j
(1 mmol) and the corresponding boronic acid (3 mmol) were dis-
solved in a toluene/ethanol mixture (4:1, 10 mL). K2CO3 (20 mmol)
was added followed by Pd(PPh3)4 (5 mol %). After the addition, the
mixture was kept under argon with vigorous stirring for 5 min and
then heated under reflux for 12 h. As soon as the starting material
has been consumed, the mixture was allowed to cool down to room
temperature and was filtered through Celite and the residue
washed with acetonitrile. The filtrates were combined, the solvent
evaporated to dryness and the residue purified by flash chroma-
tography using ethanol as the mobile phase. Finally, the compounds
were recrystallized from a suitable solvent.
4.2.8. N-[3,5-Bis(4-ethoxyphenyl)pyridin-2-yl]pyridinium aminide
(6h). Red solid (320 mg, 78%, ethanol), mp 140e142 ꢀC; IR (KBr)
nmax (cmꢁ1): 1593, 1506, 1436, 1384, 1236, 1148; 1H NMR
(300 MHz, CD3OD):
d
8.70 (2H, d, J¼5.6 Hz), 7.97 (1H, t, J¼7.9 Hz),
7.86 (1H, d, J¼2.3 Hz), 7.78 (2H, ap t, J¼6.9 Hz), 7.65 (2H, d,
J¼8.6 Hz), 7.54 (1H, d, J¼2.3 Hz), 7.45 (2H, d, J¼8.6 Hz), 6.99e6.94
(4H, m), 4.13e4.03 (4H, m), 1.46e1.39 (6H, m); 13C NMR (75 MHz,
CD3OD): d 158.2, 157.9, 149.5, 143.8, 141.6, 136.5, 135.8, 130.9, 130.1,
127.1, 126.9, 126.2, 123.5, 114.5, 113.8, 103.9, 63.1, 15.2; HRMS (ESI-
TOF, CH3OH): calcd for C26H26N3O2: [MþH]þ 412.2025, found
412.2057.
4.2.9. N-[3,5-Bis(4-acetylphenyl)pyridin-2-yl]pyridinium
aminide
4.2.1. N-(5-Phenylpyridin-2-yl)pyridinium aminide (6a). See Ref. 7b.
(6i). Orange solid (330 mg, 81%, ethanol), mp 101e102 ꢀC; IR (KBr)
nmax (cmꢁ1): 3418, 1675, 1587, 1398, 1270, 1145; 1H NMR
4.2.2. N-[5-(4-Methylphenyl)pyridin-2-yl]pyridiniumaminide(6b). See
Ref. 7e.
(300 MHz, CD3OD):
d
8.75 (2H, d, J¼5.6 Hz), 8.15 (1H, t, J¼7.6 Hz),
8.10 (1H, d, J¼2.3 Hz), 8.09e8.07 (4H, m), 7.99 (2H, d, J¼8.6 Hz),
7.89 (2H, ap t, J¼6.9 Hz), 7.77 (1H, d, J¼2.3 Hz), 7.71 (2H, d,
J¼8.6 Hz), 2.67 (3H, s), 2.63 (3H, s); 13C NMR (75 MHz, CD3OD):
4.2.3. N-[5-(4-Methylthiophenyl)pyridin-2-yl]pyridinium
aminide
(6c). Orange solid (255 mg, 87%, ethyl acetate), mp 169e171 ꢀC; IR
d
198.8, 198.6, 162.1, 144.9, 144.5, 144.2, 143.4, 137.2, 135.7, 135.3,

6092
F. Filace et al. / Tetrahedron 69 (2013) 6088e6094
35
134.3, 129.3, 128.9, 127.1, 126.0, 124.5, 121.9, 121.7, 25.3, 25.2;
HRMS (ESI-TOF, CH3OH): calcd for C26H22N3O2: [MþH]þ 408.1707,
found 408.1684.
(ESI-TOF, CH3OH): calcd for C12
251.0385.
H
ClN2S: [MþH]þ 251.0404, found
12
4.4.2. 5-Chloro-3-(4-methylsulfonylphenyl)-2-pyridinamine
(5e).13 White solid (183 mg, 65%, ethyl acetate/hexane), mp
103e105 ꢀC; IR (KBr) nmax (cmꢁ1): 3471, 3300, 3182, 1624, 1597,
4.3. Bromination of N-5-(4-aryl)pyridin-2-yl]pyridinium
aminides 6aec
1146; 1H NMR (300 MHz, CDCl3):
d 8.06e8.02 (3H, m), 7.65 (2H, d,
Method C: A solution of NBS (1.2 mmol) in dichloromethane
(15 mL) was added dropwise to a stirred solution of N-(5-
arylpyridin-2-yl)pyridinium aminide (1 mmol) in dichloro-
methane (10 mL) at room temperature. The mixture was stirred for
3 h and the solvent was evaporated. The residue was purified by
column chromatography on silica gel with ethanol as eluent and
then recrystallized from the appropriate solvent.
J¼8.5 Hz), 7.35 (1H, d, J¼2.1 Hz), 4.62 (2H, br s), 3.09 (3H, s); 13C
NMR (75 MHz, CDCl3): d 153.7,146.4, 142.3, 140.3, 137.4, 128.3,128.1,
121.4, 120.6, 44.4; HRMS (ESI-TOF, CH3OH): calcd for
35
C12
H
ClN2O2S: [MþH]þ 283.0308, found 283.0372.
12
4.4.3. 5-Chloro-(3,30-bipyridin)-2-amine (5f). White solid (90 mg,
44%, ethyl acetate/hexane), mp 153e155 ꢀC; IR (KBr) nmax (cmꢁ1):
3397, 3322, 3202, 1650, 1458, 1244, 1032; 1H NMR (200 MHz,
4.3.1. N-[3-Bromo-5-(phenyl)pyridin-2-yl]pyridinium aminide(6j). See
Ref. 7d.
CDCl3):
J¼7.6, 1.7 Hz), 7.39 (1H, dd, J¼7.6, 4.9 Hz), 7.34 (1H, d, J¼2.1 Hz),
4.55 (2H, br s); 13C NMR (75 MHz, CD3OD):
154.3, 149.6, 146.4,
d
8.68e8.66 (2H, m), 8.05 (1H, d, J¼2.1 Hz), 7.77 (1H, dt,
d
4.3.2. N-[3-Bromo-5-(4-methylphenyl)pyridin-2-yl]pyridinium ami-
nide (6k). See Ref. 7d.
137.7, 136.1, 132.7, 123.9, 121.5, 119.2, 102.5; HRMS (ESI-TOF,
CH3OH): calcd for C10H395ClN3: [MþH]þ 206.0485, found
206.0488.
4.3.3. N-[3-Bromo-5-(4-methylthiophenyl)pyridin-2-yl]pyridinium
aminide (6l). Orange powder (337 mg, 91%, ethyl acetate/hexane),
mp 149e151 ꢀC; IR (KBr) nmax (cmꢁ1): 1590, 1469, 1443, 1381,
4.4.4. 3,5-Bis(4-methylphenyl)-2-pyridinamine (5g). White solid
(260 mg, 95%, ethanol), mp 121e123 ꢀC; IR (KBr) nmax (cmꢁ1): 3491,
3295, 3150, 1631, 1512, 1463, 1246; 1H NMR (300 MHz, CDCl3):
1247, 1151, 817, 670; 1H NMR (300 MHz, CD3OD):
d 8.78 (2H, d,
J¼7.2 Hz), 8.23 (1H, t, J¼8.0 Hz), 8.00 (1H, d, J¼2.0 Hz), 7.98e7.93
d
8.15 (1H, d, J¼2.3 Hz), 7.44 (1H, d, J¼2.3 Hz), 7.30e7.24 (4H, m),
7.15e7.08 (4H, m), 4.55 (2H, br s), 2.27 (3H, s), 2.24 (3H, s); 13C
NMR (75 MHz, CDCl3): 155.1, 145.0, 137.7, 136.6, 136.4, 135.4,
(3H, m), 7.45 (2H, d, J¼8.5 Hz), 7.31 (2H, d, J¼8.5 Hz), 2.51 (3H, s);
13C NMR (75 MHz, CD3OD):
d
162.3, 144.7, 142.5, 141.7, 138.1,
d
134.3, 127.3, 126.8, 125.4, 117.6, 105.4, 14.5; HRMS (ESI-TOF,
135.0, 129.8, 129.6, 128.6, 127.8, 126.1, 121.7, 21.3, 21.1; HRMS (ESI-
TOF, CH3OH): calcd for C19H19N2: [MþH]þ 275.1548, found
275.1547.
79
CH3OH): calcd for C17
372.0178.
H
BrN3S: [MþH]þ 372.0171, found
15
4.4. Reduction of N-(pyridin-2-yl)pyridinium aminides 6del7j
4.4.5. 3,5-Bis(4-ethoxyphenyl)-2-pyridinamine (5h). Yellow solid
(304 mg, 91%, ethanol), mp 135e137 ꢀC; IR (KBr) nmax (cmꢁ1): 3479,
3382, 2976, 1608, 1512, 1462, 1243, 1045; 1H NMR (300 MHz,
Method D: A suspension of the corresponding N-(pyridin-2-
yl)pyridinium aminide 6dei (1 mmol) in glacial acetic acid
(15 mL) and zinc dust (10 mmol) was stirred at room tempera-
ture for 5 h. When almost all of the Zn had disappeared, another
portion of Zn (10 mmol) was added and the mixture was stirred
for a further 24 h. The resulting suspension was filtered through
a Celite column and eluted with acetic acid. The eluate was e-
vaporated in vacuo and the product was purified by chroma-
tography on silica gel using ethyl acetate/hexane as eluent.
Finally, the compounds were recrystallized from a suitable
solvent.
CDCl3):
(4H, m), 6.99e6.91 (4H, m), 4.64 (2H, br s), 4.07e4.01 (4H, m),
1.45e1.39 (6H, m); 13C NMR (75 MHz, CDCl3):
158.6, 158.2, 154.7,
d
8.22 (1H, d, J¼2.3 Hz), 7.53 (1H, d, J¼2.3 Hz), 7.44e7.37
d
144.0, 136.4, 130.5, 129.8, 129.7, 127.7, 127.3, 121.7, 115.0, 114.9, 63.5,
63.4, 14.8; HRMS (ESI-TOF, CH3OH): calcd for C21H23N2O2: [MþH]þ
335.1760, found 335.1766.
4.4.6. 3,5-Bis(4-acetylphenyl)-2-pyridinamine (5i). White solid
(168 mg, 51%, ethanol), mp 182e184 ꢀC; IR (KBr) nmax (cmꢁ1): 3482,
3391, 3140, 1678, 1633, 1600, 1472, 1421, 1269; 1H NMR (300 MHz,
Method E: Platinum on activated carbon (5%) was suspended
in a solution of the corresponding aminide (0.32 mmol) in ace-
tonitrile (4 mL) and cooled in an ice bath. Formic acid (98%,
0.5 mL) in acetonitrile (1.5 mL) was added and a solution of
triethylamine (4.5 mL) in acetonitrile (3 mL) was added drop-
wise. The reaction mixture was heated under reflux for 3e4 h.
The mixture was allowed to cool down to room temperature and
was filtered. The filtrate was evaporated and the residue was
dissolved in water, made basic with sodium carbonate and
extracted with ethyl acetate. The combined organic phases were
dried over MgSO4, filtered and evaporated to dryness. The resi-
due was purified by column chromatography on silica gel (EtOAc/
hexane) and the compound was recrystallized from a suitable
solvent.
CDCl3):
J¼8.6 Hz), 7.65 (1H, d, J¼2.2 Hz), 7.63e7.59 (4H, m), 4.81 (2H, br s),
2.64 (3H, s), 2.61 (3H, s); 13C NMR (75 MHz, CDCl3):
197.5, 197.3,
155.2, 145.9, 142.3, 142.2, 136.6, 135.6, 129.3, 129.1, 128.9, 128.8,
126.5, 126.1, 120.8, 26.7, 26.6; HRMS (ESI-TOF, CH3OH): calcd for
C21H19N2O2: [MþH]þ 331.1447, found 331.1450.
d
8.38 (1H, d, J¼2.2 Hz), 8.07 (2H, d, J¼8.6 Hz), 8.00 (2H, d,
d
4.4.7. 3-Bromo-5-phenyl-2-pyridinamine
(66 mg, 83%), mp 114e116 ꢀC; IR (KBr) nmax (cmꢁ1): 3469, 3292,
3137,1639,1471; 1H NMR (300 MHz, CDCl3):
8.24 (1H, d, J¼2.1 Hz),
7.89 (1H, d, J¼2.1 Hz), 7.48e7.38 (4H, m), 7.34e7.29 (1H, m), 4.98
(2H, br s); 13C NMR (75 MHz, CDCl3):
154.5, 144.9, 138.9, 136.8,
(5j).14 White
solid
d
d
128.9, 127.4, 126.3, 104.9, 104.6; HRMS (ESI-TOF, CH3OH): calcd for
79
C11
H
BrN2: [MþH]þ 249.0028, found 249.0030.
10
4.4.1. 5-Chloro-3-(4-methylthiophenyl)-2-pyridinamine (5d).13 White
solid (175 mg, 70%, ethyl acetate/hexane), mp 108e110 ꢀC; IR (KBr)
nmax (cmꢁ1): 3435, 3286, 3159, 1623, 1566, 1455, 1094; 1H NMR
4.4.8. 3-Bromo-5-(4-methylphenyl)-2-pyridinamine
(5k). White
solid (82 mg, 98%), mp 153e155 ꢀC; IR (KBr) nmax (cmꢁ1): 3480,
3289, 3144, 1637, 1603, 1490, 1027; 1H NMR (300 MHz, CDCl3):
(75 MHz, CDCl3):
(4H, m), 4.90 (2H, br s), 2.50 (3H, s); 13C NMR (75 MHz, CDCl3):
154.2, 144.9,139.3, 137.4, 132.9,128.8, 127.1, 126.9, 126.8, 15.5; HRMS
d
7.96 (1H, d, J¼2.5 Hz), 7.35 (1H, d, J¼2.5 Hz), 7.32
d
8.22 (1H, d, J¼2.0 Hz), 7.85 (1H, d, J¼2.0 Hz), 7.35 (2H, d, J¼8.1 Hz),
7.21 (2H, d, J¼8.1 Hz), 4.90 (2H, br s), 2.36 (3H, s); 13C NMR (75 MHz,
d
CDCl3): d 166.6, 154.2, 144.7, 141.8, 138.8, 137.3, 133.9, 129.7, 126.2,

F. Filace et al. / Tetrahedron 69 (2013) 6088e6094
6093
79
21.1; HRMS (ESI-TOF, CH3OH): calcd for C12
263.0178, found 263.0128.
H
BrN2: [MþH]þ
TOF, CH3OH): calcd for C19H18NO: [MþH]þ 276.1388, found
12
276.1391.
4.4.9. 3-Bromo-5-(4-methylthiophenyl)-2-pyridinamine (5l). White
solid (77 mg, 82%), mp 172e174 ꢀC; IR (KBr) nmax (cmꢁ1): 3450,
4.5.5. 3,5-Bis(4-ethoxyphenyl)-2(1H)-pyridinone (3b). Yellow solid
(171 mg, 51%, ethanol), mp 158e160 ꢀC; IR (KBr) nmax (cmꢁ1): 2925,
3280, 3121, 1630, 1590, 1473; 1H NMR (300 MHz, CDCl3):
d
8.21 (1H,
1650, 1510, 1475, 1246; 1H NMR (300 MHz, CDCl3):
d 13.3 (1H, br s),
d, J¼1.7 Hz), 7.84 (1H, d, J¼1.7 Hz), 7.37 (2H, d, J¼8.3 Hz), 7.28 (2H, d,
7.79 (1H, d, J¼2.4 Hz), 7.71 (2H, d, J¼8.7 Hz), 7.53 (1H, d, J¼2.4 Hz),
J¼8.3 Hz), 4.99 (2H, br s), 2.49 (3H, s); 13C NMR (75 MHz, CDCl3):
7.35 (2H, d, J¼8.7 Hz), 7.00e6.90 (4H, m), 4.13e4.00 (4H, m), 1.42
d
154.4, 144.8, 138.6, 137.9, 133.6, 128.3, 127.1, 126.7, 104.7, 15.9;
(6H, t, J¼7.0 Hz); 13C NMR (75 MHz, CDCl3):
d 163.2, 158.8, 158.4,
79
HRMS (ESI-TOF, CH3OH): calcd for C12
found 294.9892.
H
12
BrN2S: [MþH]þ 294.9899,
138.5, 130.8, 130.6, 129.8, 129.0, 128.8, 126.9, 121.2, 114.9, 114.3, 63.5,
63.4, 14.84, 14.82; HRMS (ESI-TOF, CH3OH): calcd for C21H22NO3:
[MþH]þ 336.1594, found 336.1586.
4.5. Preparation of 1H-pyridin-2-ones 2aec, 3aec and 4aec
4.5.6. 3,5-Bis(4-acetylphenyl)-2(1H)-pyridinone (3c). Yellow solid
(146 mg, 44%, ethyl acetate/ethanol), mp 274e276 ꢀC; IR (KBr) nmax
(cmꢁ1): 2919, 1659, 1602, 1359, 1259; 1H NMR (300 MHz, CDCl3):
Method F: A solution of sodium nitrite (5 mmol) in water (1 mL)
was dropped into sulfuric acid (2.6 mL) at 0 ꢀC. This solution was
added dropwise to a stirred solution of the corresponding 2-
pyridinamine 5del (1 mmol) in a minimal amount of pyridine at
d
12.95 (1H, br s), 8.04 (2H, d, J¼8.4 Hz), 8.02 (2H, d, J¼8.4 Hz), 7.97
(1H, d, J¼2.4 Hz), 7.86 (2H, d, J¼8.4 Hz), 7.73 (1H, d, J¼2.4 Hz), 7.56
0
ꢀC. The reaction mixture was stirred for 2 h at 0 ꢀC. For the
(2H, d, J¼8.4 Hz), 2.63 (3H, s), 2.62 (3H, s); 13C NMR (75 MHz,
preparation of compounds 3 another portion of sodium nitrite
(5 mmol) in water (1 mL) and sulfuric acid (2.6 mL) was dropped
into the solution containing the corresponding 2-pyridinamines
5gei (method G). The reaction mixture was stirred for 2 h at 0 ꢀC.
Water (4 mL) was added. After 16 h at room temperature, ice was
added. The precipitate was filtered off and washed with cold water
to give the corresponding 1H-pyridin-2-one. The products 3aec
were purified by chromatography on silica gel using ethyl acetate/
hexane/triethylamine 5.9:4:0.1 as eluent. Analytical samples of
compounds 2aec, 3aec and 4aec were recrystallized from a suit-
able solvent.
CDCl3): d 197.6, 197.3, 162.2, 140.2, 139.7, 136.6, 132.3, 130.5, 129.7,
129.8, 129.3, 128.8, 128.5, 125.8, 114.8, 26.7, 26.6; HRMS (ESI-TOF,
CH3OH): calcd for C21H18NO3: [MþH]þ 332.1287, found 332.1318.
4.5.7. 3-Bromo-5-(phenyl)-2(1H)-pyridinone (4a).10 Yellow solid
(217 mg, 87%, ethyl acetate/ethanol), mp 205e207 ꢀC; IR (KBr) nmax
(cmꢁ1): 2865, 1652, 1597, 1499, 1269; 1H NMR (300 MHz, CDCl3):
d
13.15 (1H, br s), 8.18 (1H, d, J¼2.3 Hz), 7.71 (1H, d, J¼2.3 Hz),
7.43e7.34 (5H, m); 13C NMR (75 MHz, CDCl3):
d
160.8, 143.4, 135.0,
131.3, 129.3, 127.9, 125.8, 122.2, 115.8; HRMS (ESI-TOF, CH3OH):
calcd for C11H799BrNO: [MþH]þ 249.9862, found 249.9860.
4.5.1. 5-Chloro-3-(4-methylsufinylphenyl)-2(1H)-pyridinone
(2a). White solid (160 mg, 60%, ethanol), mp 235e237 ꢀC; IR (KBr)
nmax (cmꢁ1): 3128, 3043, 2852,1640, 1556,1041; 1H NMR (300 MHz,
4.5.8. 3-Bromo-5-(4-methylphenyl)-2(1H)-pyridinone (4b). Yellow
solid (192 mg, 73%, ethyl acetate/ethanol), mp 209e211 ꢀC; IR (KBr)
nmax (cmꢁ1): 2924, 2854, 2771, 1646, 1617, 1514, 1035; 1H NMR
DMSO):
d
7.92 (2H, d, J¼8.2 Hz), 7.78 (1H, d, J¼2.6 Hz), 7.70e7.67
(300 MHz, CDCl3):
d, J¼2.2 Hz), 7.28 (2H, d, J¼8.4 Hz), 7.22 (2H, d, J¼8.4 Hz), 2.37 (3H,
s); 13C NMR (75 MHz, CDCl3):
160.7, 143.3, 137.8, 132.1, 130.9,
d
13.00 (1H, br s), 8.15 (1H, d, J¼2.2 Hz), 7.69 (1H,
(3H, m), 2.75 (3H, s); 13C NMR (75 MHz, DMSO):
d
159.3, 145.1,
138.8, 137.2, 133.4, 129.0, 128.6, 122.8, 110.9, 42.7; HRMS (ESI-TOF,
CH3OH): calcd for C12
268.0183.
d
35
H
11
ClNO2S: [MþH]þ 268.0194, found
129.9, 125.7, 122.2, 115.8, 21.1; HRMS (ESI-TOF, CH3OH): calcd for
79
C12
H
BrNO: [MþH]þ 264.0019, found 263.9987.
10
4.5.2. 5-Chloro-3-(4-methylsufonylphenyl)-2(1H)-pyridinone
(2b).8 White solid (227 mg, 80%, ethanol), mp 238e240 ꢀC;
IR (KBr) nmax (cmꢁ1): 3418, 3058, 2762, 1642, 1614, 1307, 1155;
4.5.9. 3-Bromo-5-(4-methylthiophenyl)-2(1H)-pyridinone
(4c). Yellow solid (97 mg, 33%, methanol), mp 240e242 ꢀC; IR (KBr)
nmax (cmꢁ1): 2853, 1645, 1495, 1247, 1032; 1H NMR (300 MHz,
1H NMR (200 MHz, DMSO):
d
8.00 (2H, d, J¼8.5 Hz), 7.92 (2H, d,
J¼8.5 Hz), 7.84 (1H, d, J¼2.7 Hz), 7.72 (1H, d, J¼2.7 Hz), 3.22
(3H, s); 13C NMR (75 MHz, DMSO):
159.2, 139.9, 139.4,
CD3OD):
d
8.35 (1H, d, J¼2.3 Hz), 7.73 (1H, d, J¼2.3 Hz), 7.47 (2H, d,
J¼8.6 Hz), 7.35 (2H, d, J¼8.6 Hz), 2.50 (3H, s); 13C NMR (75 MHz,
d
DMSO): d 157.3, 141.0, 136.6, 131.5, 131.1, 125.9, 125.5, 117.7, 115.3,
79
139.2, 134.0, 128.6, 128.2, 127.7, 126.1, 43.0; HRMS (ESI-TOF,
14.2; HRMS (ESI-TOF, CH3OH): calcd for C12
295.9745, found 295.9746.
H
11
BrNOS: [MþH]þ
35
CH3OH): calcd for C12
284.0226.
H
ClNO3S: [MþH]þ 284.0148, found
11
Acknowledgements
4.5.3. 5-Chloro-3-(30-pyridin)-2(1H)-pyridinone (2c).15 White solid
(103 mg, 50%, ethanol), mp 237e239 ꢀC; IR (KBr) nmax (cmꢁ1): 3415,
Financial support from Instituto de Salud Carlos III (REDinREN,
RD6/0016/0016) for University of Alcala (UAH GC 2012-001 and
UAH2011/EXP-027) and a grant from the University of Alcala (F.F.)
are gratefully acknowledged.
1649, 1579, 1420; 1H NMR (500 MHz, CD3OD):
d 8.92 (1H, br s), 8.56
ꢀ
(1H, br s), 8.20 (1H, d, J¼7.8 Hz), 7.86 (1H, d, J¼2.8 Hz), 7.61 (1H, d,
ꢀ
J¼2.8 Hz), 7.53 (1H, dd, J¼7.8, 5.3 Hz); 13C NMR (125 MHz, CD3OD):
d
162.3, 149.7, 149.4, 141.9, 138.1, 134.3, 131.4, 129.9, 124.9, 114.7;
HRMS (ESI-TOF, CH3OH): calcd for C10H385ClN2O: [MþH]þ 207.0320,
found 207.0323.
Supplementary data
4.5.4. 3,5-Bis(4-methylphenyl)-2(1H)-pyridinone (3a). Yellow solid
(137 mg, 50%, ethanol), mp 219e221 ꢀC; IR (KBr) nmax (cmꢁ1): 2918,
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2013.05.065.
1639, 1511, 1478, 1299; 1H NMR (300 MHz, CDCl3):
d 13.4 (1H, br s),
7.85 (1H, d, J¼2.5 Hz), 7.66 (2H, d, J¼8.1 Hz), 7.56 (1H, d, J¼2.5 Hz),
References and notes
7.34 (2H, d, J¼8.1 Hz), 7.25e7.20 (4H, m), 2.38 (3H, s), 2.37 (3H, s);
13C NMR (75 MHz, CDCl3):
d 163.4, 139.0, 137.8, 137.1, 133.7, 133.6,
1. Belen’kii, L. I.; Gramenitskaya, V. N.; Evdokimenkova, Y. B. Adv. Heterocycl. Chem.
2011, 102, 1e137.
131.3, 130.6, 129.8, 129.1, 128.6, 125.7, 121.2, 21.3, 21.1; HRMS (ESI-

6094
F. Filace et al. / Tetrahedron 69 (2013) 6088e6094
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