Synthesis of 6-nitroderivatives of oxazolo[3,2-a]-pyridines and their reactions with nucleophiles

Article abstract of DOI:10.3390/80600460

5-Nitro-2-pyridone can be selectively N-phenacylated, and the resulting phenacylpyridones I undergo cyclization to 6-nitrooxazolo[3,2-a]pyridinium salts II. These salts II readily react with ammonia and aliphatic amines leading to the products of pyridine ring opening - previously unknown 1-amino-2-nitro-4- (oxazole-2-yl)butadienes-1,3. Reaction of salts II with water lead to hydrolytic cleavage of the oxazole fragment.

Full text of DOI:10.3390/80600460

Molecules 2003, 8, 460-466
molecules
ISSN 1420-3049
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Second Eurasian Meeting on Heterocyclic Chemistry
“Heterocycles in Organic and Combinatorial Chemistry“
Synthesis of 6-Nitroderivatives of Oxazolo[3,2-a]-pyridines and
Their Reactions with Nucleophiles
Alexander A. Bush and Eugene V. Babaev*
Chemistry Department, Moscow State University, Moscow 119899, Russia
* Author to whom correspondence should be addressed; e-mail: babaev@org.chem.msu.su
Received: 13 May 2003; in revised form: 17 June 2003 / Accepted: 17 June 2003 / Published: 30 June
2003
Abstract: 5-Nitro-2-pyridone can be selectively N-phenacylated, and the resulting
phenacylpyridones I undergo cyclization to 6-nitrooxazolo[3,2-a]pyridinium salts II. These
salts II readily react with ammonia and aliphatic amines leading to the products of pyridine
ring opening - previously unknown 1-amino-2-nitro-4-(oxazole-2-yl)butadienes-1,3.
Reaction of salts II with water lead to hydrolytic cleavage of the oxazole fragment.
Keywords: 5-Nitro-2-pyridone, oxazolo[3,2-a]pyridine, butadiene, nitrodiene, aminodiene,
oxazolyldiene.
Introduction
The aromatic oxazolo[3,2-a]pyridinium ring system, first prepared by Bradsher [1] and Kroehnke
[2], has attracted recent attention due to its several modes of reaction with nucleophiles and the
possibility of obtaining a wide variety of heterocyclic structures (oxazoles, pyridines, indolizines,
various azolopyridines and azinopyridines) starting from this bicyclic system (for a review, see [3]).
The key feature of the reactivity of the oxazolo[3,2-a]pyridinium cation is the possibility of cleavage of
either the 5-membered ring (in reactions with alkali, hydrosulfide, ammonia and primary amines,

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461
CH-acids) or the 6-membered ring (in reactions with secondary amines). One would expect that
introduction of an electron withdrawing group into the 6-membered ring of this bicycle might
dramatically increase its π-deficiency, causing predominant nucleophilic attack on the pyridine
fragment.
In this communication we report our successful attempt to prepare 6-nitro derivatives of the
oxazolo[3,2-a]pyridines and preliminary studies of their reactions with nucleophiles (hydrolysis,
ammonolysis, and reactions with aliphatic amines).
Results and Discussion
Phenacylation of 5-nitro-2-pyridone
The standard route to oxazolo[3,2-a]pyridinium salts is the cyclization of N-phenacyl-2-pyridones,
which in turn could be obtained either by hydrolysis of 2-halo-N-phenacylpyridinium salts or by
phenacylation of 2-pyridones. Suitable precursors of 6-nitrooxazolo[3,2-a]pyridinium salts would
therefore be N-phenacylated derivatives of readily available 5-nitro-2-pyridone or 5-nitro-2-
halopyridines. Our attempts to perform phenacylation of 2-chloro-5-nitropyridine were unsuccessful.
On the other hand, selective N-alkylation of the salts of 5-nitro-2-pyridone was reported in literature.
We found that the sodium salt of 5-nitro-2-pyridone undergoes selective N-alkylation in reactions with
phenacylbromides leading to phenacyl pyridones I (Scheme 1).
Scheme 1.
X
Br
O
O2N
O
O
N
NaOMe, MeOH, 60oC
O2N
N
O
H
I
X
X = Me, Cl, NO2
The reaction is complete after 10-12 hours, and the yields vary from 40% (X=NO2) up to 80%
(X=Cl). The alkylation is easily monitored by TLC (since the Rf values of the products I lay in-
between the values of the reactants), and there were no signs of formation of alternative O-alkylated
products (for spectral differences between N- and O-phenacylated isomers of 2-hydroxypyridine see
1
[4]). The compounds I have been characterized by H-NMR spectra (Table I) and MS; in the mass-
spectra of the pyridones I the expected molecular ions were observed.

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462
Table 1. 1H-NMR spectra of pyridones I
Chemical shift, ppm
J, Hz
J46 J34
Х in Аr
4-Me
H6
H4
H3
-CH2-
HAr
7.95-7.93
7.37-7.35
8.45-8.40
8.32-8.27
8.18-8.15
7.65-7.62
9.17
8.16
6.50
5.60
3.2
9.4
4-NO2
4-Cl
9.22
9.20
8.24
8.19
6.59
6.52
5.74
5.73
2.8
3.1
10.1
9.7
Synthesis of 2-aryl-6-nitrooxazolo[3,2-a]pyridinium perchlorates.
The usual technique of cyclodehydration of N-phenacylpyridones to oxazolopyridinium salts
(dissolving a compound in concentrated sulfuric acid, diluting with water, and precipitating the product
with perchloric acid) was not appropriate for the case of nitropyridones I. The most successful
procedure required complete avoidance of water. This was achieved by pouring the reaction mixture of
pyridone I in sulfuric acid (containing few drops of HClO4) into anhydrous diethyl ether. The
precipitate formed corresponds to pure perchlorate II (Scheme 2).
Scheme 2.
8
O+
O
7
H2SO4
O
X
N
N
HClO4
O2N
O2N
3
5
-
ClO4
II
X
The 1H-NMR spectra (Table 2) clearly confirm the bicyclic structure of compounds II – the initial
singlet of the CH2-group disappears, and a new singlet corresponding to the H3 proton of the oxazole
ring appears at 9.1 ppm. The most downfield signal at 10.3 ppm corresponds to the H5 proton, located
ortho to the nitro group and the pyridinium heteroatom.
Table 2. 1H-NMR spectra of the salts II
Chemical shift, ppm.
J, Hz
J78
X in Ar
H5 (d) H7 (dd)
H8 (d)
8.43
H3 (s)
9.11
9.18
9.13
HAr (m)
J57
1.3
1.6
1.3
CH3
NO2
Cl
10.28
10.35
10.31
9.03
9.06
9.04
7.82-7.80; 7.35-7.32
8.47-8.42; 8.36-8.31
8.12-8.08; 7.87-7.82
9.3
10.0
9.8
8.51
8.46

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463
Reaction of the salts II with nucleophiles.
As we found had found earlier [5], oxazolo[3,2-a]pyridinium salts unsubstituted at the pyridine
fragment react with NaOH, NaSH and NH3 leading to the products of oxazole ring cleavage /
transformation, namely to N-phenacylpyridones, N-phenacylpyridinethiones, and imidazo[1,2-a]-
pyridines, respectively. In the case of the 6-nitroderivatives II all these reactions occur abnormally.
Reaction of the salts II with water rapidly resulted in starting N-phenacylpyridones I (Scheme 3).
Scheme 3.
O+
O
H2O
O
Ar
N
N
Ar
O2N
O2N
Reaction of the salts II with sodium hydrosulfide led to a complex mixture of products. Several
attempts to optimize the reaction conditions were unsuccessful. We suppose that the main reason of
abnormal behavior of the 6-nitro derivatives II (in contrast to the parent oxazolopyridines) may be due
either by the cleavage of more reactive nitropyridine fragment (leading to a probably unstable diene) or
even by the reduction of nitro group by hydrosulfide ion.
In the reactions with ammonia and primary amines oxazolopyridinium salts could be readily
transformed to imidazopyridines and their salts [1, 5]. However, the product formed in the reaction of
the 6-nitrooxazolo[3,2-a]pyridinium salt with anhydrous ammonia (in DMF) was not the expected
6-nitroimidazo[1,2-a]pyridine III (independently prepared as a reference compound), but rather the
diene IV. Mass-spectra indicated that the molecular formula corresponded to that of an adduct. In the
NMR spectrum of the product the signals of butadiene system were observed together with the peak of
amino group, thus confirming the proposed butadiene structure IV (Scheme 4).
Scheme 4.
O2N
O
Ar
92%
H2N
O+
Ar = p-MeC6H4
N
NH3
IV
Ar
N
O2N
14,5%
N
O2N
Ar
N
O2N
N
NH2
III

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464
Use of primary and secondary amines in the reaction with the salts II led to formation of analogous
aminobutadienes V (Scheme 5):
Scheme 5.
O+
4
O2N
NR2H
O
Ar
Ar
R2N
N
3
O2N
N
1
V
The NMR spectra of the obtained dienes (Table 3) were very similar to that of product IV. No
conclusions could be made regarding the exact configuration of the obtained dienes based only on the
NMR data (including various 2D NMR techniques examined) due to the small magnitude of the
coupling constants.
Table 3. 1H-NMR spectra of dienes III,V.
Chem. shifts, ppm.
H3, d H4, d Hoxazol, s HAr,
J, Hz
J34
R2N
R'
H1.
m
HR', s
HR
3.52
7.60-7.58
7.31-7.29
Morpholine
CH3
8.63 (s)
6.76
6.82
6.51
6.51
7.71
7.80
2.35
3.39
12.0
12.2
3.32
3.73
7.71-7.67
7.56-7.52
Pyrrolidine
Cl
8.81 (s)
2.92
1.73
7.56-7.53
7.23-7.21
7.53-7.51
7.23-7.21
7.53-7.51
7.23-7.21
9.22
NH2
CH3
CH3
CH3
8.95 (m)
6.94
7.13
7.05
6.03
6.08
6.11
7.46
7.27
7.28
2.38
2.38
2.38
13.3
14.0
12.6
(NH2)
1.47(tBu)
10.13(NH)
9.86
t-BuNH
9.71 (d)
13.7Hz
9.31 (d)
13.81 Hz
n-PrNH
(NH)
Conclusions
As we have demonstrated, insertion of the 6-nitrogroup into the pyridine ring of the oxazolo[3,2-a]-
pyridinium ring system dramatically changes its reactivity: first, the oxazole fragment of this bicycle
becomes hydrolytically unstable and second, an unusual selectivity is observed in reactions with
ammonia and primary amines, leading to previously unknown aminodienes and not imidazopyridines.

Molecules 2003, 8
465
Acknowledgments
This work was supported by INTAS (Grant No. INTAS 00-0711).
Experimental
General
1H- and C-NMR spectra were obtained using a Bruker AC 400 NMR spectrometer and were
recorded at 360 MHz. All reagents and chemicals were obtained from Acros or Merck and were used
as received unless otherwise noted.
13
Typical procedure for the preparation of N-phenacyl-5-nitro-2-pyridones (I).
To a solution of sodium hydroxide (35 mmol) in methanol (250 mL) 5-nitro-2-pyridone (30 mmol)
was added under vigorous stirring. After 10-15 min. of stirring, phenacylbromide (30 mmol) was
added to the reaction mixture. The mixture was refluxed for 1.5-2 hours. Reaction monitoring was
carried out by TLC (Merck “Silufol”, CHCl3-CCl4-EtOAc=1:1:2); Rf of N-phenacyl-2-pyridones
=0.45-0.49). Usually after cooling the reaction mixture was allowed to stand overnight at room
temperature. The precipitate (light-yellow needles) was filtered off, washed once with methanol and
twice with water and dried. Yields 40-78%; for the NMR data of compounds I see Table 1.
Typical procedure for the preparation of 2-Aryl-6-nitrooxazolo[3,2-a]pyridinium perchlorates (II)
The N-Phenacyl-2-pyridone (I, 10 mmol) was dissolved in concentrated sulfuric acid (10 mL) and
kept for 20-25 hours. Then 71% perchloric acid (2.5 mL, 25 mmol) was carefully added to the mixture
and after stirring 10-15 min. the solution was poured into vigorously stirred diethyl ether (500 mL).
After decanting the oily residue was mixed again with a fresh portion of ether (500 mL); this procedure
should be repeated until a pure white powder formed. The precipitate was filtered, washed with ether
and dried in vacuum over P2O5. Yields 95-98%; for the NMR data of compounds II see Table 2.
Typical procedure for the reaction of 2-aryl-6-nitrooxazolo[3,2-a]pyridinium perchlorates (II) with
aliphatic amines.
The oxazolo[3,2-a]pyridinium perchlorate (1 mmol) was added to a solution of the desired amine
(1 mL) in of anhydrous acetonitrile (20 mL) at 60°C with good stirring (for secondary amines) or in an
ultrasonic bath (for primary amines). These solutions were kept for 10 hours and then poured into cold
water (40-50 mL). After an appropriate period (ranging from three hours for primary amines to up to
two days for secondary amines) the aminooxazolylbutadiene precipitated as the needles of yellow or

Molecules 2003, 8
466
orange-yellow color. Crystals were separated, washed with water and dried. Yields 55-74% (primary
amines) and 48-51% (secondary amines). For the NMR data of the compounds V see Table 3.
Reaction of 2-(4-methylphenyl)-6-nitrooxazolo[3,2-a]pyridinium perchlorate with ammonia.
2-(4-Methylphenyl)-6-nitrooxazolo[3,2-a]pyridinium perchlorate (0.2 mmol) was dissolved in
anhydrous distilled DMF (2 mL) and mixed with a solution (1 mL) prepared by saturation of DMF
with gaseous ammonia (kept under 0°C). The reaction mixture immediately turned to deep red color.
This mixture was kept for 3 min. and then poured into cold water. The product precipitated as a yellow
powder, which was separated, washed with water and dried. Yield 93%; for the NMR data see Table 3.
References
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pyridol[2,1-b]thiazolium salts Chem. Ber., 1976, 109, 3653-3660.
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4. Babaev, E. V.; Efimov, A.V.; Maiboroda, D.A. Hetarenes with a nitrogen bridging atom. 1.
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