Synthesis of nitro N,N′-dipyridinylamines via oxidative nucleophilic substitution of hydrogen

Article abstract of DOI:10.1055/s-2007-990896

The amination of 3-nitropyridines with aromatic amides generated from various aminopyridine derivatives proceeded unexpectedly in the position para to the nitro group, giving the oxidative nucleophilic substitution of hydrogen (ONSH) derived compounds. After optimization, this reaction allowed easy access to interesting 3-nitro-substituted N,N′-dipyridinylamines. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-990896

3868
PAPER
Synthesis of Nitro N,N¢-Dipyridinylamines via Oxidative Nucleophilic
Substitution of Hydrogen
S
a
ynthesis of
Nitro
a
N
,
N
¢
-Dipyr
n
idinylamine
s
a-Irina Patriciu,a,b,c Christelle Pillard,a Adriana-Luminiţa Fînaru,b Ioan Săndulescu,c Gérald Guillaumet*a
Institut de Chimie Organique et Analytique, UMR CNRS 6005, Université d’Orléans, BP 6759, 45067 Orléans, Cedex 2, France
Fax +33(2)38417281; E-mail: gerald.guillaumet@univ-orleans.fr
b
c
Laboratorul de Sinteză Bio-organică şi Analiză Structurală, Universitatea Bacău, 157 Calea Mărăşeşti, 600115 Bacău, Romania
Catedra de Tehnologie Chimică şi Cataliză, Facultatea de Chimie, Universitatea Bucureşti, Bd. Regina Elisabeta Nr. 4-12,
030018 Bucureşti, Romania
Received 18 April 2007; revised 20 September 2007
Abstract: The amination of 3-nitropyridines with aromatic amides
generated from various aminopyridine derivatives proceeded unex-
pectedly in the position para to the nitro group, giving the oxidative
nucleophilic substitution of hydrogen (ONSH) derived compounds.
After optimization, this reaction allowed easy access to interesting
3-nitro-substituted N,N¢-dipyridinylamines.
N
N
Br HN
N
N
N
N
N
N
1
2
Key words: heterocycles, pyridines, amination, nucleophilic aro-
matic substitution, palladium
Br O2N
O2N
X
Br
+
N
N
N
N
N
H
4d
5a–c
3
Synthetic approaches to aminopyridine derivatives con-
tinue to receive considerable attention both due to their
presence in numerous natural products1 and due to their
potential application in the synthesis of a wide variety of
compounds with pharmacological activity.2 Strategies for
the selective synthesis of aminopyridine derivatives in-
clude modification of commercially available aminopy-
idines,3 selective nitration and reduction of pyridines,4
and de novo construction of the pyridine nucleus incorpo-
rating properly disposed amino groups,5 as well as nucleo-
philic substitution of halopyridines with appropriate
amines.6
X = F, Cl, Br
Scheme 1
As a consequence, we decided to generate the C–N bond
by nucleophilic substitution of a leaving group in the 2-
position of the 3-nitropyridine ring and the results of our
studies are presented herein.
Treatment of 3-bromo-2-(methylamino)pyridine (4d)
with lithium hexamethyldisilazide (LiHMDS), in tetrahy-
drofuran (THF) at 60 °C, to form the anion, and the addi-
tion of 2-chloro-3-nitropyridine (5b) did not lead to the
expected product 3. Surprisingly, this reaction gave ac-
cess to a mixture of two different compounds, 6 and 7, in
27% and 12% yield, respectively. The starting aminopyri-
dine 4d was also partially recovered (41%) (Scheme 2).
Nucleophilic aromatic substitution (SNAr) is one of the
most widely used approaches for the functionalization of
aromatics and forms the backbone of various important
syntheses of pharmaceuticals and potential drugs.7
In connection with our previous studies to develop the
univocal synthesis of dihydrodipyridopyrazines8
(DHDPP) 1 (Scheme 1), which are potential antitumor
compounds,9 we considered that the nucleophilic aromat-
ic substitution could be exploited in the construction of
the key intermediate 3.
Preliminary NMR and MS analysis of compound 6 re-
vealed the presence of five aromatic hydrogens over two
pyridine rings (with the next protons sequences: para/
meta/ortho and para/meta) and all substituents (bromine,
chlorine and nitro groups) still present. This indicated that
the major product 6 formed through nucleophilic aromatic
substitution of hydrogen (SNH) in the position para to the
Br
NO2
Cl
Br
N
NO2
Cl
Br
N
NO2 Br
N
base, THF
+
+
N
N
H
N
N
N
N
N
N
4d
5b
6
7
Scheme 2
SYNTHESIS 2007, No. 24, pp 3868–3876
x
x.
x
x
.
2
0
0
7
Advanced online publication: 15.11.2007
DOI: 10.1055/s-2007-990896; Art ID: T07107SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Nitro N,N¢-Dipyridinylamines
3869
nitro group; compound 7 presumably resulted from a nu- From these observations, we supposed that under these
cleophilic attack of 4d on 6.
conditions, the amination of 5b with 4d proceeded with
para selectivity to the nitro group via ONSH and the re-
sulting compound 6 was formed accompanied, in small
amounts, by the corresponding product of the SNAr reac-
tion (7).
Nucleophilic substitution in nitroarenes has been exten-
sively studied by Makosza and co-workers, who showed
that the SNAr of a leaving group often competes with other
processes such as oxidative nucleophilic substitution of
hydrogen (ONSH) or vicarious nucleophilic substitution Considering our preliminary results, we decided to study
(VNS) and the factors responsible for the reactions course the scope and limitation of the amination of 3-nitropy-
are various and difficult to control.10 In nitroaromatic ridines in the position para to the nitro group by the
rings there is usually more than one position (ortho and ONSH reaction with several types of aminopyridines.
para) in which the ONSH or VNS can take place, thus the
As a starting point, by modifying the parameters of this re-
action, we tried to get higher yields of 6 and, if possible,
to prevent the nucleophilic attack of 4d on the ONSH re-
sulting product. To this purpose, evaluation of the influ-
ences of experimental conditions of anion formation and
of the ONSH reaction was carried out; a summary of the
orientation of the substitution is highly sensitive to steric
hindrance.11–14 For example, it was shown that the ONSH
reaction of substituted nitrobenzenes with phenylacetoni-
trile derivatives, proceeds exclusively in the para position
to the nitro group, and no ortho-isomers were detected.12
It was also reported that the SNH reaction between ni-
main results is presented in Table 1.
trobenzene and aniline or substituted benzamides pro-
The preliminary experiments with LiHMDS showed that
ceeds in high yield in the position para to the nitro group
the anion formation could best be conducted using 2.2
under mild conditions, without the need for an auxiliary
equivalents of LiHMDS in THF, at 60 °C for three hours.
leaving group or external oxidant.15,16
Under these conditions, compound 6 was isolated in 32%
yield, accompanied by 8% of the SNAr product (7)
(Table 1, entry 3). Replacement of LiHMDS by another
base such as LDA, was not appropriate as only degrada-
In our case, the amination of 2-chloro-3-nitropyridine
(5b) with 3-bromo-2-(methylamino)pyridine (4d) pro-
ceeded with para selectivity to the nitro group and no fur-
ther oxidizing reagent was necessary to isolate 6.
Table 1 Optimization of the Experimental Conditions
Br
N
NO2 Br
N
Br
NO2
Br
NO2
Cl
base
THF
+
+
N
N
N
N
N
H
N
Cl
N
N
N
4d
5b
6
7
Entry
Anion formation (solvent = THF)
ONSH
Base
Equiv of Temp
Time
(h)
Temp
(°C)
Time
(h)
Co-solvent Recovered Yield
Yield
of 7 (%)
base
1.1
4.4
2.2
2.2
2.2
(°C)
4d (%)
of 6 (%)
1
2
LiHMDS
60
3
r.t.
r.t.
r.t.
r.t.
r.t.
50
50
50
50
r.t.
r.t.
r.t.
50
overnight
overnight
overnight
overnight
overnight
overnight
3 h
–
35
3
35
32
27
–
12
10
8
60
3
–
15
3
60
3
–
20
4
60
1
–
41
12
–
a
5
LDA
60
3
–
–
6
–
14
37
34
35
21
30
53
–
8
7
–
15
5
8
3 h
PhNO2
PhNO2
–
10
–
9
LiHMDS
2.2
2.2
60
60
3
3
1 h
32
–
10
11
12
13
1 h
25
10
trace
–
1 h
PhNO2
DMSO
–
trace
a
1 h
–
a
LDA
overnight
–
–
–
a Only degradation of starting materials was observed.
Synthesis 2007, No. 24, 3868–3876 © Thieme Stuttgart · New York

3870
O.-I. Patriciu et al.
PAPER
tion of the reaction mixture was observed (Table 1, entries
5 and 13).
Table 2 Reaction of N-Substituted Aminopyridines with 3-Nitro-
pyridine
Z
Z
NO2
After anion formation and addition of 2-chloro-3-nitropy-
ridine (5b), variation of the temperature and of the reac-
tion times did not have a significant influence on the
yields of the ONSH and SNAr products (Table 1, entries
3,6 and 7).
1. LiHMDS (2.2 equiv), THF
NO2
N
NH
R
N
N
R
N
2.
8
(1.1 equiv)
4a–h
9a–g
N
PhNO2 (10 equiv), THF
Under similar conditions, the use of 2-fluoro-3-nitropyri-
dine (5a) or 2-bromo-3-nitropyridine (5c) as substrate, did
not improve the results described above. On the contrary,
the former gave the ONSH product in very low yield and
the latter brominated compound led to an inseparable mix-
ture of products (results not shown).
Entry
4
R
Z
Product
9a
Yield (%)
1
2
3
4
5
6
7
8
4a
H
H
30a
38
86b
75
88
71
85
–
4b
4c
4d
4e
4f
H
Br
H
9b
H
9c
Knowing that in many cases of ‘spontaneous’ ONSH
(without external oxidant), the nitrobenzene could itself
act as an oxidant,17 thus increasing the yield of reaction,
we also examined the influence of the solvent system. In-
deed, the best yield of the ONSH was obtained by addition
of nitrobenzene to the reaction mixture. As shown in
Table 1 (entry 11), when the ONSH reaction of 5b was
carried out at room temperature for one hour, in the pres-
ence of 10 equivalents of nitrobenzene, we obtained a
53% yield of 6 and only traces of 7. We believe that ni-
trobenzene may act as both an oxidant and a co-solvent in
our reaction system (compare Table 1, entries 10, 11 and
12). To verify this hypothesis, nitrobenzene was replaced
with DMSO, but in this case only degradation of the reac-
tion mixture was observed (Table 1, entry 12).
Me
Me
Bu
Bu
PMB
Br
H
9d
9e
Br
H
9f
4g
9g
c
4h
Br
–
a Compound 9a was also generated in quantitative yield by refluxing
9g in TFA.
b Compound 9c was obtained in only 36% when the amination reac-
tion was performed between 4c and 2-chloro-5-nitropyridine using
the methodology of palladium-catalyzed intermolecular coupling.
c No reaction occurred, 60% of starting material was recovered and
degradation was observed; PMB = p-methoxybenzyl.
For all the above reasons, we supposed that the formation
of 6 arose through an ONSH mechanism: deprotonation of
aminopyridine generates the amide ion, which is required
for nucleophilic attack at the para position of nitropyri-
dine, forming the expected s-complex intermediate and
the oxidative sequence then proceeded spontaneously.
NH2
N
N
1. LiHMDS (2.2 equiv), THF
NO2
N
N
NO2
11
2.
10
70%
N
(1.1 equiv)
8
PhNO2 (10 equiv), THF
As a second part of our work, using the optimized reaction
conditions developed for 5b, we examined the possibility
of introducing other commercial (4a, 4c, 4g) or synthetic
(4d, 4e, 4f, 4h) N-substituted aminopyridines to the para
position of 3-nitropyridine (8). The results obtained are
collected in Table 2 and Table 3.
NO2
N
N
N
NH
1. LiHMDS (2.2 equiv), THF
As shown in Table 2 (entries 3–7), the reaction of 3-nitro-
pyridine (8) with 2-N-substituted aminopyridines 4c–g,
under these optimized conditions, proceeded exclusively
in the position para to the nitro group, giving the ONSH
products 9c–g in good yields that were even higher than in
the case of the corresponding experiment of 2-chloro-3-
nitropyridine 5b with 4d. Only the aminopyridines 4a and
4b led to the corresponding nitro-substituted N,N¢-dipy-
ridinylamines 9a and 9b in low yields (Table 2, entries 1
and 2). Compound 9a was also generated in quantitative
yield by refluxing 9g in TFA.18 Surprisingly, no reaction
occurred in the case of 4h; 60% of starting material was
recovered and degradation was observed (Table 2, entry
8).
NO2
N
2.
65%
N
13
12
(1.1 equiv)
PhNO2 (10 equiv), THF
8
Scheme 3 ONSH reaction of 3-nitropyridine (8) with 3-(methyl-
amino)pyridine (10) and 4-(methylamino)pyridine (12). Compounds
11 and 13 were obtained in 25% and 22% yields when the amination
reaction was performed using the palladium-catalyzed intermolecular
coupling (see Scheme 4).
(methylamino)pyridine (12), and the ONSH products 11
and 13 were obtained in 70% and 65% yields, respectively
(Scheme 3).
Under the same conditions, 3-nitropyridine (8) reacted
similarly with 3-(methylamino)pyridine (10) and 4-
It is worth mentioning that, in order to prove the structure
of compounds 9c, 11 and 13, the amination reactions were
Synthesis 2007, No. 24, 3868–3876 © Thieme Stuttgart · New York

PAPER
Synthesis of Nitro N,N¢-Dipyridinylamines
3871
N
NH
NO2
4c
N
N
N
N
N
N
36%
9c
NH
Pd(OAc)2
Xantphos
NO2
10
N
K2CO3
dioxane
25%
NO2
11
Cl
N
16
NH
NO2
N
12
N
N
N
22%
13
Scheme 4 Reagents and conditions: amine (1.2 equiv), 2-chloro-5-nitropyridine (1 equiv), Pd(OAc)2 (10%), Xantphos (20%), K2CO3 (1.5
equiv), 1,4-dioxane (solvent).
performed between amines 4c, 10 and 12 as reactant and from 8% to 32% and the corresponding SNAr derivatives
2-chloro-5-nitropyridine (16) as substrates, using palladi- 15a–d (Table 3, entries 1–4).
um-catalyzed intermolecular coupling. The reactions con-
When the amination reaction was performed between 5b
and 2-aminopyridine (4a), the ONSH compound 14a was
obtained in low yield (Table 3, entry 1) but only traces of
the SNAr product 15a were observed. A similar low yield
for the ONSH reaction was obtained when 4a reacted with
3-nitropyridine (8) (Table 2, entry 1). These results sug-
gest that 2-aminopyridine (4a) is not an appropriate ami-
nation agent for 3-nitropyridine (8) or 2-substituted-3-
ducted under modified conditions described by Yin and
Buchwald19 and according to our optimized protocol20 [1
equiv halide, 1.2 equiv amine, 10% Pd(OAc)2, 20% Xant-
phos, 1.5 equiv K2CO3 and 1,4-dioxane as solvent], led to
the expected products but in lower yields to those ob-
tained by the ONSH process. As illustrated in Scheme 4,
following this procedure, the products 9c, 11 and 13 were
obtained in only 36%, 25% and 22% yields, respectively.
nitropyridine 5b under these optimized reaction condi-
In order to probe the para selectivity of the amination re- tions.
actions under our optimal reaction conditions, we also ex-
amined the reaction of 2-chloro-3-nitropyridine (5b) in
the presence of 2-aminopyridines 4a, 4c, 4e and 4g. The
results are summarized in Table 3.
It should be noted that, in the case of the reaction of 5b
with N-substituted 2-aminopyridine 4c, 4e and 4g, the
SNAr reaction becomes a significant process (Table 3, en-
tries 2–4). Moreover, in the case of 2-(methylamino)pyri-
We observed that the use of 2-chloro-3-nitropyridine (5b) dine (4c), the main product is 15b, resulting from an SNAr
as substrate in reactions with 4a, 4c, 4e and 4g, led to the reaction of the halogen, in 40% yield, while only 8% of
expected ONSH compounds 14a–d with yields ranging the ONSH derived compound 14b was isolated (Table 3,
entry 2).
Table 3 Regioselectivity of the Amination Reactions
NO2
NO2
Cl
1. LiHMDS (2.2 equiv), THF
NO2
+
N
NH
R
N
N
R
N
N
R
N
N
N
R
N
5b (1.1 equiv)
2.
PhNO2 (10 equiv), THF
N
Cl
4a,c,e,g
14a–d
15a–d
Entry
4
R
14
Yield (%)
15
Yield (%)
trace
40
1
2
3
4
4a
4c
4e
4g
H
14a
14b
14c
14d
15
8
15a
Me
Bu
PMB
15b
15c
15d
32
20
20a
20
a Compound 15c was also generated in 49% yield when the amination reaction was performed between 4e and 14c using palladium-catalyzed
intermolecular coupling.
Synthesis 2007, No. 24, 3868–3876 © Thieme Stuttgart · New York

3872
O.-I. Patriciu et al.
PAPER
3-Bromo-2-(methylamino)pyridine (4d)
In order to complete our studies on the formation of SNAr
products, we examined the Pd(0)-catalyzed amination of
14c with amine 4e under the previously described condi-
tions (Scheme 4). As expected, this reaction led to the
same compound 15c in 49% yield.
GP 1 was followed using 2-amino-3-bromopyridine (4b) and MeI
as starting materials. Purification by flash chromatography (PE–
EtOAc, 9:1→7:3) afforded 4d (87%) as a yellow oil.
The analytical data were in accord with literature values.8d
In conclusion, in the present paper we have shown that in-
teresting 3-nitro-substituted N,N¢-dipyridinylamines may
be easily obtained through oxidative nucleophilic substi-
tution of hydrogen in the position para to the nitro group
of 3-nitropyridine, using the metal amides of a range of
aminopyridines as reactant. In the case of 2-chloro-3-ni-
tropyridine, the amination reaction proceeded exclusively
para to the nitro group, giving mainly the ONSH com-
pounds with acceptable yields, accompanied with small
amounts of the corresponding SNAr derivative.
2-(Butylamino)pyridine (4e)
GP 1 was followed using 2-aminopyridine and 1-bromobutane as
starting materials. Purification by flash chromatography (PE–
EtOAc, 9:1→8:2→7:3) afforded 4e (70%) as beige crystals.
The analytical data were in accord with literature values.22
3-Bromo-2-(butylamino)pyridine (4f)
GP 1 was followed using 2-amino-3-bromopyridine (4b) and 1-bro-
mobutane as starting materials. Purification by flash chromatogra-
phy (PE–EtOAc, 9:1→7:3) afforded 4f (80%) as a dark-yellow oil.
The analytical data were in accord with literature values.8d
3-Bromo-2-(4-methoxybenzyl)aminopyridine (4h)
GP 1 was followed using 2-amino-3-bromopyridine (4b) and 4-
methoxybenzyl chloride as starting materials. Purification by flash
chromatography (PE–EtOAc, 9:1→8:2→7:3) afforded 4h (38%) as
a yellow oil.
All air-sensitive experiments were performed under an inert atmo-
sphere of argon. THF and dioxane were distilled from sodium ben-
zophenone ketyl prior to use. MeOH was distilled over CaCl2 and
stored under an inert atmosphere over 3 Å molecular sieves. DMF
was purified by distillation over CaH2 and stored under an inert at-
mosphere over 4 Å molecular sieves. Petroleum ether (PE), where
used, had a boiling range of 40–60 °C. All commercially available
IR (ATR): 2931, 3425 cm–1.
1
1H NMR (250 MHz, CDCl3): d = 3.80 (s, 3 H, CH3), 4.59 (d, J = 5.4
Hz, 2 H, CH2), 5.24 (br s, 1 H, NH), 6.44 (dd, J = 4.9, 7.8 Hz, 1 H,
Hpy), 6.87 (d, J = 8.6 Hz, 2 H, 2 × Harom), 7.28 (d, J = 8.6 Hz, 2 H,
2 × Harom), 7.60 (dd, J = 1.5, 7.8 Hz, 1 H, Hpy), 8.07 (dd, J = 1.5, 4.9
Hz, 1 H, Hpy).
13C NMR (63 MHz, CDCl3): d = 45.3 (CH2), 55.4 (CH3), 105.6
(Cq), 113.6 (CHpy), 114.1 (2 × CHarom), 129.0 (2 × CHarom), 131.3
(Cq), 139.6 (CHpy), 146.8 (CHpy), 154.5 (Cq), 159.0 (Cq).
reagents were used without further purification. H and 13C NMR
spectra were recorded on a Bruker Avance DPX 250 spectrometer
(at 250 MHz and 63 MHz, respectively) or on a Bruker Avance II
400 spectrometer (at 400 MHz and 100 MHz, respectively) at
25 °C, using TMS as an internal standard. Chemical shifts (d) are re-
ported in parts per million (ppm) and the coupling constants (J) are
reported in hertz (Hz). IR spectra were recorded on a Thermo-Nico-
let AVATAR 320 AEK0200713 spectrometer using the ATR tech-
nique (germanium crystal) and reported in cm–1. Mass spectra were
recorded on a Perkin–Elmer mass spectrometer SCIEX API 300 us-
ing an ion spray (IS) ion source. Flash column chromatography was
carried out with Merck Silica Gel 60 N (spherical, neutral, 63–200
mm) and analytical TLC on Merck Kieselgel 60 F254 sheets. HRMS
(ESI-TOF) was performed on a Micromass LC TOF spectrometer.
Melting points were determined on a Büchi 510 melting point appa-
ratus in open capillaries and are uncorrected.
MS (IS): m/z = 293.00 ([M + 1]+, 79Br), 295.00 ([M + 1]+, 81Br).
3-(Methylamino)pyridine (10)
This compound was prepared according to the methodology de-
scribed in the literature.23
Yield: 79%; dark-yellow oil.
The analytical data were in accord with literature values.24
2-Amino-3-bromopyridine (4b)
ONSH Reaction; General Procedure (GP 2)
2-Amino-3-bromopyridine was prepared via a modification of a lit-
erature procedure21 described by Turner, using 1,2-dibromoethane
as a brominating agent.
The analytical data were in accord with literature values.8d
To a stirred solution of amine (1 equiv) in anhydrous THF (0.2
mmol/mL) at r.t. was added LiHMDS (1M in THF, 2.2 equiv). The
resulting mixture was heated at 60 °C for 3 h and then cooled to
0 °C. In a second round-bottom flask, nitrobenzene (10 equiv) was
added to a solution of nitropyridine (1.1 equiv) in THF (0.5 mmol/
mL). This last preparation was slowly added to the reaction mixture
at 0 °C and then stirred at r.t. for 1 h before being hydrolyzed
through the addition of H2O (2.5 mL/mL THF). The mixture was
extracted with EtOAc (3 × 2.5 mL/mL THF) and the combined or-
ganic phase was washed with brine (3 × 2.5 mL/mL THF) and dried
over MgSO4. The solvent was removed under reduced pressure and
the residue was purified on a column of silica gel (PE–EtOAc).
3-Bromo-2-[(N-substituted)amino]pyridines 4d, 4f, 4g and 2-
(Butylamino)pyridine (4e); General Procedure8e (GP 1)
To a suspension of NaH (60% in mineral oil, 1.1 equiv) in THF (4d,
4f, 4e) or DMF (4g) (0.4 mmol/mL solvent) was added slowly the
appropriate aminopyridine (1 equiv) in THF or DMF (0.5 mmol/mL
solvent) at 0 °C. The mixture was stirred at 40 °C for 30 min (or
stirred at r.t. in DMF) and then the halogenated derivative (1.1
equiv) was added. The resulting mixture was heated to 60 °C (or
stirred at r.t. in DMF). The reaction was monitored by TLC and,
when complete consumption of starting material was achieved,
quenched with H2O (2.5 mL/mL solvent) and extracted with CH2Cl2
or EtOAc (3 × 2.5 mL/mL solvent). The combined organic layers
were dried over MgSO4 and the solvent was removed under reduced
pressure to give a crude product which was purified by flash chro-
matography.
N-(3-Bromopyridin-2-yl)-N-(6-chloro-5-nitropyridin-2-yl)-N-
methylamine (6)
Prepared according to GP 2 from 3-bromo-2-(methylamino)pyri-
dine (4d) and 2-chloro-3-nitropyridine (5b). Purification by flash
chromatography on silica gel (PE–EtOAc, 9:1→7:3) gave product
6.
Yield: 53%; brown solid; mp 95 °C.
IR (ATR): 1321 cm–1.
Synthesis 2007, No. 24, 3868–3876 © Thieme Stuttgart · New York

PAPER
Synthesis of Nitro N,N¢-Dipyridinylamines
3873
1H NMR (250 MHz, CDCl3): d = 3.53 (s, 3 H, CH3), 6.10 (d, J = 9.1
Hz, 1 H, Hpy), 7.24 (dd, J = 4.6, 7.9 Hz, 1 H, Hpy), 8.06–8.13 (m,
2 H, Hpy), 8.53 (dd, J = 1.6, 4.6 Hz, 1 H, Hpy).
13C NMR (63 MHz, DMSO-d6): d = 110.6 (CHpy), 113.4 (CHpy),
118.1 (CHpy), 133.2 (CHpy), 137.1 (Cq), 138.1 (CHpy), 145.3 (CHpy),
147.6 (CHpy), 152.9 (Cq), 157.9 (Cq).
13C NMR (63 MHz, CDCl3): d = 37.0 (CH3), 106.5 (CHpy), 119.3
(Cq), 124.8 (CHpy), 135.1 (Cq), 136.3 (CHpy), 143.4 (CHpy), 144.6
(Cq), 149.0 (CHpy), 154.0 (Cq), 157.7 (Cq).
MS (IS): m/z = 216.50 [M + 1]+.
HRMS (EI): m/z [M]+ calcd for C10H8N4O2: 216.06473; found:
216.0644.
MS (IS): m/z = 343.0 ([M + 1]+, 79Br), 345.0 ([M + 1]+, 81Br).
N-(3-Bromopyridin-2-yl)-N-(5-nitropyridin-2-yl)amine (9b)
Prepared according to GP 2 from 2-amino-3-bromopyridine (4b)
and 3-nitropyridine (8). Purification by flash chromatography on
silica gel (PE–EtOAc, 100:0→96:4→7:3) gave product 9b.
HRMS (EI): m/z [M]+ calcd for C11H8N4O235Cl79Br: 341.95191;
found: 341.9509.
N2,N6-Bis(3-bromopyridin-2-yl)-N2,N6-dimethyl-3-nitropyri-
dine-2,6-diamine (7)
Yield: 38%; yellow cotton-like solid; mp 178 °C.
IR (ATR): 1337, 1504, 3373 cm–1.
1H NMR (250 MHz, CDCl3): d = 6.86 (dd, J = 4.7, 7.8 Hz, 1 H,
Hpy), 7.86 (dd, J = 1.6, 7.8 Hz, 1 H, Hpy), 8.28 (dd, J = 1.6, 4.7 Hz,
1 H, Hpy), 8.31 (br s, 1 H, NH); 8.43 (dd, J = 2.8, 9.4 Hz, 1 H, Hpy),
8.65 (d, J = 9.4 Hz, 1 H, Hpy), 9.13 (d, J = 2.8 Hz, 1 H, Hpy).
13C NMR (63 MHz, CDCl3): d = 108.0 (Cq), 110.8 (CHpy), 118.9
(CHpy), 133.7 (CHpy), 139.0 (Cq), 141.2 (CHpy), 145.3 (CHpy), 146.4
(CHpy), 149.5 (Cq), 157.7 (Cq).
LiHMDS (1M in THF, 0.3 mL, 0.294 mmol) was slowly added, un-
der an Ar atmosphere, to a solution of 3-bromo-2-(methylamino)py-
ridine (4d; 25 mg, 0.134 mmol) in anhydrous THF (2 mL). The
solution was stirred for 3 h at 60 °C and then cooled to 0 °C. A so-
lution of N-(3-bromopyridin-2-yl)-N-(6-chloro-5-nitropyridin-2-
yl)-N-methylamine (6; 50 mg, 0.147 mmol) in anhydrous THF (2
mL) was then slowly added. The resulting mixture was stirred at
45 °C for 17 h before cooling to r.t. and hydrolyzed with H2O (10
mL). The aqueous solution was extracted with EtOAc (3 × 10 mL)
and the combined organic phases are washed with brine (3 × 10
mL), dried (MgSO4), filtered and concentrated under reduced pres-
sure. Purification of the product by column chromatography (PE–
EtOAc, 8:2→7:3→0:10) yielded product 7.
MS (IS): m/z = 295.00 ([M + 1]+, 79Br), 297.00 ([M + 1]+, 81Br).
HRMS (EI): m/z [M]+ calcd for C10H7N4O279Br: 293.97524; found:
293.9760.
Yield: 45%; yellow solid; mp 129 °C.
IR (ATR): 1320, 1414 cm–1.
Palladium-Catalyzed N-Arylation; General Procedure18,19 (GP
3)
1H NMR (400 MHz, CDCl3): d = 3.43 (s, 3 H, CH3), 3.51 (s, 3 H,
CH3), 5.88 (d, J = 8.9 Hz, 1 H, Hpy), 6.94 (dd, J = 4.7, 7.8 Hz, 1 H,
Hpy), 7.18 (dd, J = 4.7, 7.9 Hz, 1 H, Hpy), 7.94 (dd, J = 1.5, 7.8 Hz,
1 H, Hpy), 8.02 (dd, J = 1.5, 7.9 Hz, 1 H, Hpy), 8.10 (d, J = 8.9 Hz,
1 H, Hpy), 8.16 (dd, J = 1.5, 4.7 Hz, 1 H, Hpy), 8.52 (dd, J = 1.5, 4.7
Hz, 1 H, Hpy).
13C NMR (100 MHz, CDCl3): d = 36.7 (CH3), 38.5 (CH3), 100.7
(CHpy), 117.1 (Cq), 119.8 (Cq), 122.3 (CHpy), 124.1 (CHpy), 127.1
(Cq), 137.3 (CHpy), 142.9 (CHpy), 143.2 (CHpy), 147.1 (CHpy), 148.7
(CHpy), 151.7 (Cq), 155.2 (Cq), 157.2 (Cq), 157.6 (Cq).
A round-bottom flask flushed with nitrogen was charged with Xant-
phos (20% mol) and anhydrous dioxane (0.02 mmol/mL). After de-
gassing, Pd(OAc)2 (10% mol) was introduced and the mixture was
stirred under nitrogen for 10 min. In a second round-bottom flask,
heteroaryl halide (1 equiv), amine (1.2 equiv) and K2CO3 (1.5
equiv) were poured into anhydrous dioxane (0.05 mmol, halide/
mL). The the Pd(OAc)2/Xantphos solution was transferred via a
cannula and the resulted mixture was subsequently refluxed under
Ar with vigorous stirring. The progress of reaction was monitored
by TLC. After cooling, the residue was filtered off through a Celite
pad and washed with CH2Cl2 and MeOH. The solvent was evapo-
rated and the residue was purified by column chromatography.
MS (IS): m/z = 495 ([M + 1]+), 517 ([M + Na]+).
HRMS (EI): m/z [M – NO2]+ calcd for C17H14N579Br2: 445.96159;
found: 445.9600.
N-Methyl-N-(5-nitropyridin-2-yl)-N-(pyridin-2-yl)amine (9c)
Method I: Prepared according to GP 2 from 2-(methylamino)pyri-
dine (4c) and 3-nitropyridine (8). Purification by flash chromatog-
raphy on silica gel (PE–EtOAc, 9:1→8:2) afforded product 9c
(86%).
N-(5-Nitropyridin-2-yl)-N-(pyridin-2-yl)amine (9a)
Method I: Prepared according to GP 2 from 2-aminopyridine (4a)
and 3-nitropyridine (8). Purification by flash chromatography on
silica gel (PE–EtOAc: 9:1→8:2) afforded product 9a (30%).
Method II: Prepared according to GP 3 from 2-chloro-5-nitropyri-
dine (16) and 2-(methylamino)pyridine (4c). Purification by flash
chromatography on silica gel (PE–EtOAc, 9:1→7:3) afforded prod-
uct 9c (36%).
Method II:17 Compound 9g (50 mg, 0.15 mmol) was dissolved in
TFA (3 mL) and the mixture was refluxed overnight. After cooling,
the solvent was removed and the crude material was dissolved in
EtOAc (10 mL), washed with a sat. NaHCO3 (3 × 10 mL) and then
with brine (3 × 10 mL). The organic extracts were dried (MgSO4)
and the solvent was removed under reduced pressure. The residue
was purified by column chromatography over silica gel (PE–
EtOAc, 8:2→7:3) to give 9a (100%).
Yellow solid; mp 104–105 °C.
IR (ATR): 1337, 1495 cm–1.
1H NMR (250 MHz, CDCl3): d = 3.68 (s, 3 H, CH3), 6.96 (d, J = 9.5
Hz, 1 H, Hpy), 7.15–7.20 (m, 1 H, Hpy), 7.30 (d, J = 8.1 Hz, 1 H,
Hpy), 7.74 (ddd, J = 1.2, 7.5, 8.1 Hz, 1 H, Hpy), 8.16 (dd, J = 2.8, 9.5
Hz, 1 H, Hpy), 8.50 (dd, J = 1.2, 4.8 Hz, 1 H, Hpy), 9.14 (d, J = 2.8
Hz, 1 H, Hpy).
Yellow powder; mp 188–189 °C.
IR (ATR): 1215, 1338, 3019 cm–1.
1H NMR (250 MHz, DMSO-d6): d = 7.01–7.06 (m, 1 H, Hpy), 7.71–
7.79 (m, 2 H, Hpy), 7.90 (d, J = 9.4 Hz, 1 H, Hpy), 8.31 (d, J = 4.7
Hz, 1 H, Hpy), 8.38 (dd, J = 2.8, 9.4 Hz, 1 H, Hpy), 9.06 (d, J = 2.8
Hz, 1 H, Hpy), 10.67 (br s, 1 H, NH).
13C NMR (63 MHz, CDCl3): d = 37.2 (CH3), 109.1 (CHpy), 118.9
(CHpy), 121.1 (CHpy), 132.2 (CHpy), 137.0 (Cq), 138.5 (CHpy), 145.7
(CHpy), 149.1 (CHpy), 156.6 (Cq), 160.2 (Cq).
MS (IS): m/z = 230.8 [M + 1]+.
HRMS (EI): m/z [M]+ calcd for C11H10N4O2: 230.08038; found:
230.0791.
Synthesis 2007, No. 24, 3868–3876 © Thieme Stuttgart · New York

3874
O.-I. Patriciu et al.
PAPER
N-(3-Bromopyridin-2-yl)-N-methyl-N-(5-nitropyridin-2-
yl)amine (9d)
HRMS (EI): m/z [M]+ calcd for C14H15N4O279Br: 350.03784; found:
350.0367.
Prepared according to GP 2 from 3-bromo-2-(methylamino)pyri-
dine (4d) and 3-nitropyridine (8). Purification by flash chromatog-
raphy on silica gel (PE–EtOAc, 8:2→7:3) gave product 9d.
N-(4-Methoxybenzyl)-N-(5-nitropyridin-2-yl)-N-(pyridin-2-
yl)amine (9g)
Prepared according to GP 2 from 2-(4-methoxybenzylamino)pyri-
dine (4g) and 3-nitropyridine (8). Purification by flash chromatog-
raphy on silica gel (PE–EtOAc, 9:1→8:2→5:5) gave product 9g.
Yield: 75%; dark-green solid; mp 103–105 °C.
IR (ATR): 1292, 1332, 1499 cm–1.
1H NMR (250 MHz, CDCl3): d = 3.55 (s, 3 H, CH3), 6.27 (d, J = 9.3
Hz, 1 H, Hpy), 7.23 (dd, J = 4.6, 7.9 Hz, 1 H, Hpy), 8.06 (dd, J = 1.6,
7.9 Hz, 1 H, Hpy), 8.15 (dd, J = 2.8, 9.3 Hz, 1 H, Hpy), 8.55 (dd,
J = 1.6, 4.6 Hz, 1 H, Hpy), 9.10 (d, J = 2.8 Hz, 1 H, Hpy).
13C NMR (63 MHz, CDCl3): d = 36.9 (CH3), 107.2 (CHpy), 119.6
(Cq), 124.6 (CHpy), 132.7 (CHpy), 136.9 (Cq), 143.3 (CHpy), 146.2
(CHpy), 149.0 (CHpy), 154.8 (Cq), 160.1 (Cq).
Yield: 85%; brown-red gum.
IR (ATR): 1246, 1331, 1467 cm–1.
1H NMR (250 MHz, CDCl3): d = 3.75 (s, 3 H, CH3), 5.44 (s, 2 H,
CH2), 6.78 (d, J = 8.5 Hz, 2 H, 2 × Harom), 6.87 (d, J = 9.3 Hz, 1 H,
Hpy), 7.12 (dd, J = 5.0, 7.3 Hz, 1 H, Hpy), 7.23–7.26 (m, 3 H, Hpy and
2 × Harom), 7.67 (ddd, J = 1.8, 7.3, 7.9 Hz, 1 H, Hpy), 8.11 (dd,
J = 2.8, 9.3 Hz, 1 H, Hpy), 8.49 (dd, J = 1.8, 5.0 Hz, 1 H, Hpy), 9.11
(d, J = 2.8 Hz, 1 H, Hpy).
13C NMR (63 MHz, CDCl3): d = 51.8 (CH2), 55.2 (CH3), 109.5
(CHpy), 113.9 (2 × CHarom), 119.4 (CHpy), 121.2 (CHpy), 128.7
(2 × CHarom), 129.5 (Cq), 132.3 (CHpy), 137.1 (Cq), 138.3 (CHpy),
145.8 (CHpy), 149.2 (CHpy), 155.7 (Cq), 158.7 (Cq), 160.0 (Cq).
MS (IS): m/z = 309.3 ([M + 1]+, 79Br), 311.3 ([M + 1]+, 81Br).
HRMS (EI): m/z [M]+ calcd for C11H9N4O279Br: 307.99089; found:
307.9908.
HRMS (EI): m/z [M – Br]+ calcd for C11H9N4O2: 229.07255; found:
229.0718.
MS (IS): m/z = 337.5 [M + 1]+.
N-Butyl-N-(5-nitropyridin-2-yl)-N-(pyridin-2-yl)-amine (9e)
Prepared according to GP 2 from 2-(butylamino)pyridine (4e) and
3-nitropyridine (8). Purification by flash chromatography on silica
gel (PE–EtOAc, 100:0→9:1) gave product 9e.
HRMS (EI): m/z [M]+ calcd for C18H16N4O3: 336.12224; found:
336.1223.
N-Methyl-N-(5-nitropyridin-2-yl)-N-(pyridin-3-yl)amine (11)
Method I: Prepared according to GP 2 from 3-(methylamino)pyri-
dine (10) and 3-nitropyridine (8). Purification by flash chromatog-
raphy on silica gel (PE–EtOAc, 9:1→7:3→6:4→4:6) gave product
11 (70%).
Yield: 88%; dark-red gum.
IR (ATR): 1331, 1467 cm–1.
1H NMR (250 MHz, CDCl3): d = 0.89 (t, J = 7.3 Hz, 3 H, CH3),
1.32–1.44 (m, 2 H, CH2), 1.62–1.74 (m, 2 H, CH2), 4.18 (t, J = 7.6
Hz, 2 H, CH2), 6.73 (d, J = 9.4 Hz, 1 H, Hpy), 7.18–7.23 (m, 1 H,
Hpy), 7.27 (d, J = 8.0 Hz, 1 H, Hpy), 7.75 (ddd, J = 1.9, 7.5, 8.0 Hz,
1 H, Hpy), 8.09 (dd, J = 2.8, 9.4 Hz, 1 H, Hpy), 8.52 (dd, J = 1.9, 4.8
Hz, 1 H, Hpy), 9.12 (d, J = 2.8 Hz, 1 H, Hpy).
Method II: Prepared according to GP 3 from 2-chloro-5-nitropyri-
dine (16) and 3-(methylamino)pyridine (10). Purification by flash
chromatography on silica gel (CH2Cl2–MeOH, 100:0→98:2) gave
product 11 (25%).
13C NMR (63 MHz, CDCl3): d = 13.9 (CH3), 20.2 (CH2), 30.2
(CH2), 49.5 (CH2), 109.0 (CHpy), 119.9 (CHpy), 121.4 (CHpy), 132.1
(CHpy), 136.7 (Cq), 138.6 (CHpy), 146.1 (CHpy), 149.6 (CHpy), 156.1
(Cq), 160.2 (Cq).
MS (IS): m/z = 273.00 ([M + 1]+).
HRMS (EI): m/z [M]+ calcd for C14H16N4O2: 272.12733; found:
Dark-yellow crystals; mp 101–103 °C.
IR (ATR): 1297, 1336, 1507 cm–1.
1H NMR (250 MHz, CDCl3): d = 3.60 (s, 3 H, CH3), 6.40 (d, J = 9.4
Hz, 1 H, Hpy), 7.44 (dd, J = 4.7, 8.2 Hz, 1 H, Hpy), 7.65–7.69 (m,
1 H, Hpy), 8.08 (dd, J = 2.8, 9.4 Hz, 1 H, Hpy), 8.60–8.62 (m, 2 H,
Hpy), 9.08 (d, J = 2.5 Hz, 1 H, Hpy).
13C NMR (63 MHz, CDCl3): d = 39.4 (CH3), 106.7 (CHpy), 124.6
(CHpy), 132.5 (CHpy), 134.4 (CHpy), 136.3 (Cq), 141.3 (Cq), 146.2
(CHpy), 148.4 (CHpy), 148.6 (CHpy), 160.7 (Cq).
272.1274.
HRMS (EI): m/z [M – C2H5]+ calcd for C12H11N4O2: 243.08820;
found: 243.0888.
MS (IS): m/z = 231.00 [M + 1].
HRMS (EI): m/z [M – H]+ calcd for C11H9N4O2: 229.07255; found:
229.0718.
N-(3-Bromopyridin-2-yl)-N-butyl-N-(5-nitropyridin-2-
yl)amine (9f)
Prepared according to GP 2 from 3-bromo-2-(butylamino)pyridine
(4f) and 3-nitropyridine (8). Purification by flash chromatography
on silica gel (PE–EtOAc, 9:1→8:2) gave product 9f.
N-Methyl-N-(5-nitropyridin-2-yl)-N-(pyridin-4-yl)amine (13)
Method I: Prepared according to GP 2 from 4-(methylamino)pyri-
dine (12) and 3-nitropyridine (8). Purification by flash chromatog-
raphy on silica gel (PE–EtOAc, 1:9→0:100) gave product 13
(65%).
Yield: 71%; dark-red gum.
IR (ATR): 1330, 1491 cm–1.
1H NMR (250 MHz, CDCl3): d = 0.89 (t, J = 7.3 Hz, 3 H, CH3),
1.34–1.43 (m, 2 H, CH2), 1.64–1.76 (m, 2 H, CH2), 4.04 (t, J = 7.7
Hz, 2 H, CH2), 6.17 (d, J = 9.3 Hz, 1 H, Hpy), 7.22 (dd, J = 4.6, 7.9
Hz, 1 H, Hpy), 8.05 (dd, J = 1.6, 7.9 Hz, 1 H, Hpy), 8.12 (dd, J = 2.8,
9.3 Hz, 1 H, Hpy), 8.56 (dd, J = 1.6, 4.6 Hz, 1 H, Hpy), 9.09 (d,
J = 2.8 Hz, 1 H, Hpy).
13C NMR (63 MHz, CDCl3): d = 13.9 (CH3), 20.3 (CH2), 30.0
(CH2), 49.9 (CH2), 107.1 (CHpy), 120.3 (Cq), 124.3 (CHpy), 132.6
(CHpy), 136.6 (Cq), 143.2 (CHpy), 146.3 (CHpy), 148.9 (CHpy), 153.9
(Cq), 159.8 (Cq).
Method II: Prepared according to GP 3 from 2-chloro-5-nitropyri-
dine (16) and 4-(methylamino)pyridine (12). Purification by flash
chromatography on silica gel (PE–EtOAc, 5:5→3:7) gave product
13 (22%).
Yellow-beige powder; mp 155–156 °C.
IR (ATR): 1291, 1330, 1496 cm–1.
1H NMR (250 MHz, CDCl3): d = 3.64 (s, 3 H, CH3), 6.82 (d, J = 9.4
Hz, 1 H, Hpy), 7.25 (d, J = 6.0 Hz, 2 H, Hpy), 8.16 (dd, J = 2.5, 9.4
Hz, 1 H, Hpy), 8.65 (d, J = 6.0 Hz, 2 H, Hpy), 9.12 (d, J = 2.5 Hz,
1 H, Hpy).
MS (IS): m/z = 351.00 ([M + 1]+, 79Br), 353.0 ([M + 1]+, 81Br).
Synthesis 2007, No. 24, 3868–3876 © Thieme Stuttgart · New York

PAPER
Synthesis of Nitro N,N¢-Dipyridinylamines
3875
13C NMR (63 MHz, CDCl3): d = 38.3 (CH3), 108.4 (CHpy), 119.4
(2 × CHpy), 132.6 (CHpy), 137.1 (Cq), 145.9 (CHpy), 151.6
(2 × CHpy), 151.9 (Cq), 159.9 (Cq).
MS (IS): m/z = 307.00 ([M + 1]+, 35Cl), 309.00 ([M + 1]+, 37Cl).
HRMS (EI): m/z [M]+ calcd for C14H15N4O2 35Cl: 306.08835; found:
306.0881.
MS (IS): m/z = 231.00 [M + 1]+.
N-(6-Chloro-5-nitropyridin-2-yl)-N-(4-methoxybenzyl)-N-(py-
ridin-2-yl)amine (14d)
Prepared according to GP 2 from 2-(4-methoxybenzylamino)pyri-
dine (4g) and 2-chloro-3-nitropyridine (5b). Purification by flash
chromatography on silica gel (PE–EtOAc, 9:1→7:3→5:5) gave
product 14d.
HRMS (EI): m/z [M – NO2]+ calcd for C11H9N4O2: 229.07255;
found: 229.0718.
N-(6-Chloro-5-nitropyridin-2-yl)-N-(pyridin-2-yl)amine (14a)
Prepared according to GP 2 from 2-aminopyridine (4a) and 2-chlo-
ro-3-nitropyridine (5b). Purification by flash chromatography on
silica gel (PE–EtOAc, 9:1) gave product 14a.
Yield: 20%; brown gum.
Yield: 15%; yellow-beige powder; mp 139–140 °C.
IR (ATR): 1479, 1514, 3388 cm–1.
1H NMR (400 MHz, CDCl3): d = 6.92 (d, J = 8.1 Hz, 1 H, Hpy), 7.06
(dd, J = 5.0, 7.5 Hz, 1 H, Hpy), 7.69 (ddd, J = 1.8, 7.5, 8.1 Hz, 1 H,
Hpy), 8.22 (d, J = 6.0 Hz, 1 H, Hpy), 8.37–8.39 (m, 2 H, Hpy and
NH), 8.50 (d, J = 6.0 Hz, 1 H, Hpy).
13C NMR (63 MHz, CDCl3): d = 112.3 (CHpy), 114.0 (CHpy), 119.6
(CHpy), 133.4 (Cq), 138.7 (CHpy), 143.7 (Cq), 144.8 (Cq), 148.2
(CHpy), 150.3 (CH), 152.0 (Cq).
IR (ATR): 1320, 1466, 1151 cm–1.
1H NMR (250 MHz, CDCl3): d = 3.76 (s, 3 H, CH3), 5.37 (s, 2 H,
CH2), 6.72–6.81 (m, 3 H, Hpy and 2 × Harom), 7.16–7.27 (m, 4 H,
2 × Hpy and 2 × Harom), 7.69–7.75 (m, 1 H, Hpy), 8.08 (d, J = 9.1 Hz,
1 H, Hpy), 8.53–8.54 (m, 1 H, Hpy).
13C NMR (63 MHz, CDCl3): d = 52.2 (CH2), 55.3 (CH3), 108.3
(CHpy), 114.0 (2 × CHarom), 119.7 (CHpy), 121.7 (CHpy), 129.1 (Cq),
129.4 (2 × CHarom), 135.3 (Cq), 136.3 (CHpy), 138.6 (CHpy), 144.2
(Cq), 149.5 (CHpy), 155.2 (Cq), 157.6 (Cq), 159.0 (Cq).
MS (IS): m/z = 371.00 ([M + 1]+, 35Cl), 373.00 ([M + 1]+, 37Cl).
HRMS (EI): m/z [M]+ calcd for C18H15N4O335Cl: 370.08327; found:
MS (IS): m/z = 251.3 ([M + 1]+, 35Cl), 253.3 ([M + 1]+, 37Cl).
HRMS (EI): m/z [M]+ calcd for C10H7N4O235Cl: 250.02575; found:
370.0844.
250.025.
HRMS (EI): m/z [M – NO2]+ calcd for C10H7N335Cl: 204.03285;
found: 204.0320.
N2,N6-Dimethyl-3-nitro-N2,N6-dipyridin-2-ylpyridine-2,6-di-
amine (15b)
Prepared according to GP 2 from 2-(methylamino)pyridine (4c) and
2-chloro-3-nitropyridine (5b). Purification by flash chromatogra-
phy on silica gel (PE–EtOAc, 9:1→8:2) gave product 15b.
N-Methyl-N-(6-chloro-5-nitropyridin-2-yl)-N-(pyridin-2-
yl)amine (14b)
Prepared according to GP 2 from 2-(methylamino)pyridine (4c) and
2-chloro-3-nitropyridine (5b). Purification by flash chromatogra-
phy on silica gel (PE–EtOAc, 9:1→8:2) gave product 14b.
Yield: 40%; light-yellow solid; mp 157–159 °C.
IR (ATR): 1289, 1324, 1422 cm–1.
Yield: 8%; beige solid; mp 120–121 °C.
IR (ATR): 1314, 1502 cm–1.
1H NMR (250 MHz, CDCl3): d = 3.66 (s, 3 H, CH3), 6.89 (d, J = 9.1
Hz, 1 H, Hpy), 7.18–7.23 (m, 1 H, Hpy), 7.27–7.33 (m, 1 H, Hpy),
7.77 (ddd, J = 1.2, 7.5, 8.2 Hz, 1 H, Hpy), 8.12 (d, J = 9.1 Hz, 1 H,
Hpy), 8.50 (dd, J = 1.2, 5.0 Hz, 1 H, Hpy).
13C NMR (63 MHz, CDCl3): d = 37.2 (CH3), 108.2 (CHpy), 118.8
(CHpy), 121.5 (CHpy), 128.8 (Cq), 136.1 (CHpy), 138.7 (CHpy), 144.1
(Cq), 149.2 (CH), 156.1 (Cq), 157.9 (Cq).
1H NMR (250 MHz, CDCl3): d = 3.64 (2 × s, 6 H, 2 × CH3), 6.59 (d,
J = 9.1 Hz, 1 H, Hpy), 6.80–6.85 (m, 1 H, Hpy), 6.93 (d, J = 8.2 Hz,
1 H, Hpy), 7.07–7.12 (m, 1 H, Hpy), 7.32 (d, J = 8.2 Hz, 1 H, Hpy),
7.55–7.62 (m, 1 H, Hpy), 7.66–7.73 (m, 1 H, Hpy), 8.08 (d, J = 9.1
Hz, 1 H, Hpy), 8.12–8.15 (m, 1 H, Hpy), 8.46–8.47 (m, 1 H, Hpy).
13C NMR (63 MHz, CDCl3): d = 36.7 (CH3), 37.4 (CH3), 103.6
(CHpy), 112.6 (CHpy), 117.9 (CHpy), 118.9 (CHpy), 120.4 (CHpy),
129.8 (Cq), 136.2 (CHpy), 137.9 (CHpy), 138.1 (CHpy), 147.9 (CHpy),
148.9 (CHpy), 150.2 (Cq), 156.7 (Cq), 157.7 (Cq), 157.9 (Cq).
MS (IS): m/z = 337.3 [M + 1]+.
HRMS (EI): m/z [M – NO2]+ calcd for C17H16N5: 290.14057; found:
MS (IS): m/z = 264.8 ([M + 1]+, 35Cl), 266.8 ([M + 1]+, 37Cl).
HRMS (EI): m/z [M]+ calcd for C11H9N4O235Cl: 264.04140; found:
290.1391.
264.0422.
N2,N6-Dibutyl-3-nitro-N2,N6-dipyridin-2-ylpyridine-2,6-di-
amine (15c)
Method I: Prepared according to GP 2 from 2-(butylamino)pyridine
(4e) and 2-chloro-3-nitropyridine (5b). Purification by flash chro-
matography on silica gel (PE–EtOAc, 100:0→9:1→8:2) gave prod-
uct 15c (20%).
N-Butyl-N-(6-chloro-5-nitropyridin-2-yl)-N-(pyridin-2-
yl)amine (14c)
Prepared according to GP 2 from 2-(butylamino)pyridine (4e) and
2-chloro-3-nitropyridine (5b). Purification by flash chromatogra-
phy on silica gel (PE–EtOAc, 100:0→9:1→8:2) gave product 14c.
Yield: 32%; dark-red gum.
IR (ATR): 1318, 1466 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.91 (t, J = 7.2 Hz, 3 H, CH3),
1.32–1.42 (m, 2 H, CH2), 1.63–1.71 (m, 2 H, CH2), 4.16 (t, J = 7.6
Hz, 2 H, CH2), 6.65 (d, J = 9.1 Hz, 1 H, Hpy), 7.21–7.24 (m, 1 H,
Hpy), 7.27 (d, J = 8.0 Hz, 1 H, Hpy), 7.78 (ddd, J = 2.0, 7.6, 8.0 Hz,
1 H, Hpy), 8.09 (d, J = 9.1 Hz, 1 H, Hpy), 8.53–8.54 (m, 1 H, Hpy).
13C NMR (63 MHz, CDCl3): d = 13.8 (CH3), 20.0 (CH2), 29.9
(CH2), 49.5 (CH2), 107.9 (CHpy), 119.8 (CHpy), 121.8 (CHpy), 132.7
(Cq), 136.0 (CHpy), 138.8 (CHpy), 144.2 (Cq), 149.6 (CHpy), 155.4
(Cq), 157.8 (Cq).
Method II: Prepared according to GP 3 from 2-(butylamino)pyri-
dine (4e) and butyl(6-chloro-5-nitropyridin-2-yl)pyridin-2-ylamine
(14c). Purification by flash chromatography on silica gel (PE–
EtOAc, 9:1→8:2) gave product 15c (49%).
Dark-red gum.
IR (ATR): 1414, 1466 cm–1.
1H NMR (250 MHz, CDCl3): d = 0.89–0.95 (td, J = 2.2, 7.2, 7.5 Hz,
6 H, 2 × CH3), 1.25–1.44 (m, 4 H, 2 × CH2), 1.65–1.80 (m, 4 H,
2 × CH2), 4.14–4.22 (m, 4 H, 2 × CH2), 6.37 (d, J = 9.1 Hz, 1 H,
Hpy), 6.82–6.87 (m, 1 H, Hpy), 6.94 (d, J = 7.5 Hz, 1 H, Hpy), 7.12–
7.17 (m, 1 H, Hpy), 7.28 (d, J = 8.2 Hz, 1 H, Hpy), 7.56–7.63 (m, 1 H,
Synthesis 2007, No. 24, 3868–3876 © Thieme Stuttgart · New York

3876
O.-I. Patriciu et al.
PAPER
Hpy), 7.69–7.76 (m, 1 H, Hpy), 8.03 (d, J = 9.1 Hz, 1 H, Hpy), 8.15
(dd, J = 1.2, 4.7 Hz, 1 H, Hpy), 8.50 (dd, J = 1.5, 5.0 Hz, 1 H, Hpy).
Kowaluk, E. A.; Bhagwat, S. S. Eur. J. Med. Chem. 2003,
38, 245.
(6) Brodbeck, B.; Püllmann, B.; Schmitt, S.; Nettekoven, M.
Tetrahedron Lett. 2003, 44, 1675.
13C NMR (63 MHz, CDCl3): d = 14.0 (CH3), 14.1 (CH3), 20.4
(CH2), 20.5 (CH2), 30.6 (CH2), 30.9 (CH2), 49.4 (CH2), 50.3 (CH2),
103.3 (CHpy), 113.1 (CHpy), 118.1 (CHpy), 120.1 (CHpy), 120.9
(CHpy), 129.3 (Cq), 136.5 (CHpy), 138.1 (CHpy), 138.2 (CHpy),
148.3 (CHpy), 149.5 (CHpy), 150.2 (Cq), 156.5 (Cq), 157.5 (Cq),
158.0 (Cq).
MS (IS): m/z = 421.5 [M + 1]+.
HRMS (EI): m/z [M – NO2]+ calcd for C23H28N5: 374.23447; found:
(7) (a) Terrier, F. Nucleophilic Aromatic Displacement; Verlag
Chemie: Weinheim, 1991. (b) Chupakhin, O. N.; Chaushin,
V. N.; van der Plas, H. C. Nucleophilic Aromatic
Substitution of Hydrogen; Academic Press: San Diego,
1994. (c) Niles, J. C.; Wishnok, J. S.; Tannenbaum, S. R. J.
Am. Chem. Soc. 2001, 123, 12147. (d) Cosimelli, B.;
Lamartina, L.; Spinelli, D. Tetrahedron 2001, 57, 8903.
(e) Morely, J. O.; Mattewas, T. P. Org. Biomol. Chem. 2006,
4, 359. (f) D’Anna, F.; Frenna, V.; Noto, R.; Pace, V.;
Spinelli, D. J. Org. Chem. 2006, 71, 5144.
(8) (a) Blanchard, S.; Rodriguez, I.; Kuehm-Caubère, C.;
Renard, P.; Pfeiffer, B.; Guillaumet, G.; Caubère, P.
Tetrahedron 2002, 58, 3513. (b) Blanchard, S.; Rodriguez,
I.; Caubère, P.; Guillaumet, G. Synlett 2002, 1356. (c) Grig-
Alexa, I. C.; Finaru, A. L.; Ivan, L.; Caubère, P.; Guillaumet,
G. Tetrahedron Lett. 2004, 45, 2343. (d) Grig-Alexa, I. C.;
Garnier, E.; Finaru, A. L.; Ivan, L.; Jarry, C.; Léger, J.-M.;
Caubère, P.; Guillaumet, G. Synlett 2004, 2000. (e) Grig-
Alexa, I. C.; Finaru, A. L.; Ivan, L.; Caubère, P.; Guillaumet,
G. Synthesis 2006, 619. (f) Grig-Alexa, I. C.; Finaru, A. L.;
Caubère, P.; Guillaumet, G. Org. Lett. 2006, 8, 4187.
(9) (a) Caubère, P.; Guillaumet, G.; Rodriguez, I.; Vinter-
Pasquier, K.; Kuehm-Caubère, C.; Blanchard, S.; Atassi, G.;
Pierre, A.; Pfeiffer, B.; Renard, P. P. Eur. Pat. Appl. EP
96986, 1999; Chem. Abstr. 2000, 132, 22978.
374.2360.
N2,N6-Bis(4-methoxybenzyl)-3-nitro-N2,N6-dipyridin-2-ylpyri-
dine-2,6-diamine (15d)
Prepared according to GP 2 from 2-(4-methoxybenzylamino)pyri-
dine (4g) and 2-chloro-3-nitropyridine (5b). Purification by flash
chromatography on silica gel (PE–EtOAc, 9:1→7:3→5:5) gave
product 15d.
Yield: 20%; brown gum.
IR (ATR): 1247, 1325, 1511 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.74 (s, 3 H, CH3), 3.76 (s, 3 H,
CH3), 5.28 (s, 2 H, CH2), 5.29 (s, 2 H, CH2), 6.55 (d, J = 9.0 Hz,
1 H, Hpy), 6.70 (d, J = 8.6 Hz, 2 H, 2 × Harom), 6.76 (d, J = 8.6 Hz,
2 H, 2 × Harom), 6.81 (dd, J = 5.1, 7.0 Hz, 1 H, Hpy), 6.88 (d, J = 8.3
Hz, 1 H, Hpy), 7.05–7.08 (m, 3 H, Hpy and 2 × Harom), 7.19–7.23 (m,
3 H, Hpy and 2 × Harom), 7.50–7.55 (m, 1 H, Hpy), 7.58–7.62 (m, 1 H,
Hpy), 8.08 (d, J = 9.0 Hz, 1 H, Hpy), 8.12 (dd, J = 1.2, 5.1 Hz, 1 H,
Hpy), 8.45 (dd, J = 1.2, 4.6 Hz, 1 H, Hpy).
13C NMR (63 MHz, CDCl3): 51.8 (CH2), 52.8 (CH2), 55.3
(2 × CH3), 104.0 (CHpy), 113.1 (CHpy), 113.9 (4 × CHarom), 118.4
(CHpy), 119.5 (CHpy), 120.7 (CHpy), 127.9 (2 × CHarom), 128.2
(2 × CHarom), 129.9 (Cq), 130.2 (Cq), 130.6 (Cq), 136.6 (CHpy), 138.0
(CHpy), 138.4 (CHpy), 147.9 (CHpy), 149.2 (CHpy), 149.3 (Cq), 156.1
(Cq), 157.5 (Cq), 157.6 (Cq), 158.5 (Cq), 158.6 (Cq).
(b) Blanchard, S.; Rodriguez, I.; Tardy, C.; Baldeyrou, B.;
Bailly, C.; Colson, P.; Houssier, C.; Léonce, S.; Kraus-
Berthier, L.; Pfeiffer, B.; Renard, P.; Pierre, A.; Caubère, P.;
Guillaumet, G. J. Med. Chem. 2004, 47, 978.
(10) Makosza, M.; Wojciechowski, K. Heterocycles 2001, 54,
445.
(11) Makosza, M.; Surowiec, M. Tetrahedron 2003, 59, 6261.
(12) Makosza, M.; Staliński, K. Synthesis 1998, 1631.
(13) Makosza, M.; Sypniewski, M. Tetrahedron 1994, 50, 4913.
(14) Makosza, M.; Paszewski, M. Synthesis 2002, 2203.
(15) Stern, M. K.; Hileman, F. D.; Bashkin, J. K. J. Am. Chem.
Soc. 1992, 114, 9237.
MS (IS): m/z = 549.5 [M + 1]+.
HRMS (EI): m/z [M – NO2]+ calcd for C31H28N5O2: 502.22430;
found: 502.2225.
(16) Stern, M. K.; Cheng, B. K. J. Org. Chem. 1993, 58, 6883.
(17) (a) Stern, M. K.; Bashkin, J. K. U.S. Pat. 5117063, 1992;
Chem. Abstr. 1992, 117, 89948. (b) Bunnet, J. F.; Zahler, R.
E. Chem. Rev. 1951, 49, 273. (c) Stahly, G. B. J. Org.
Chem. 1985, 50, 3091. (d) Davis, R. B.; Pizzini, L. C.;
Benigni, J. D. J. Am. Chem. Soc. 1960, 82, 2913. (e) Davis,
R. B.; Pizzini, L. C. J. Org. Chem. 1960, 25, 1884.
(f) Treston, A.; Blakeley, R. L.; Zerner, B. J. Chem. Soc.,
Chem. Commun. 1980, 394. (g) Makosza, M.; Staliński, K.
Tetrahedron 1998, 54, 8797.
(18) Bouisssane, L.; El Kazzouli, S.; Léger, J.-M.; Jarry, C.;
Rakib, E. M.; Khouili, M.; Guillaumet, G. Tetrahedron
2005, 61, 8218.
(19) Yin, J.; Buchwald, S. L. Org. Lett. 2000, 2, 1101.
(20) Garnier, E.; Audoux, J.; Pasquinet, E.; Suzenet, F.; Poullain,
D.; Lebret, B.; Guillaumet, G. J. Org. Chem. 2004, 69, 7809.
(21) Turner, J. A. J. Org. Chem. 1983, 48, 3401.
(22) Zhang, Z.; Mao, J.; Zhu, D.; Wu, F.; Chen, H.; Wan, B.
Tetrahedron 2006, 62, 4435.
References
(1) (a) O’Hagan, D. Nat. Prod. Rep. 2000, 17, 435. (b) Pinder,
A. R. Nat. Prod. Rep. 1992, 9, 491. (c) Plunkett, A. O. Nat.
Prod. Rep. 1994, 11, 581. (d) Brody, F.; Ruby, P. R.
Pyridine and Its Derivatives. Part 1. Synthetic and Natural
Sources of the Pyridine Ring; Interscience: New York, 1960.
(2) (a) Quintela, J. M.; Peinador, C.; González, L.; Iglesias, R.;
Paramá, A.; Alvarez, F.; Sanmartin, M. L.; Riguera, R. Eur.
J. Med. Chem. 2003, 38, 265. (b) Van Rhee, A. M.; Jiang,
J.; Melman, N.; Olah, M. E.; Stiles, G. L.; Jacobson, K. A. J.
Med. Chem. 1996, 39, 2980. (c) Bever, C. T. Jr. CNS Drug
Rev. 1995, 1, 261. (d) Thomas, G. Medicinal Chemistry;
Wiley-VCH: Weinheim, 2002. (e) Kleeman, A.; Engel, J.;
Kutscher, B.; Reichert, D. Pharmaceutical Substances, 3rd
ed.; Thieme: Stuttgart, 1999, .
(3) Balboni, G.; Marastoni, M.; Merighi, S.; Borea, P. A.;
Tomatis, R. Eur. J. Med. Chem. 2000, 35, 979.
(4) Chen, B.-C.; Hynes, J. Jr.; Pandit, C. R.; Zhao, R.
Heterocycles 2001, 55, 951.
(5) Gfesser, G. A.; Bayburt, E. K.; Cowart, M.; DiDomenico, S.;
Gomtsyan, A.; Lee, C.-H.; Stewart, A. O.; Jarvis, M. F.;
(23) Krishnamurthy, S. Tetrahedron Lett. 1982, 23, 3315.
(24) Zakrzewski, P.; Gowan, M.; Trimble, L. A.; Lau, C. K.
Synthesis 1999, 1893.
Synthesis 2007, No. 24, 3868–3876 © Thieme Stuttgart · New York