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ceeded with high regioselectivity, the 2-substituted-5-
nitropyridine compounds were the only detected prod-
ucts. The oxidative amination reactions were carried
out at low temperature in contrast to ours which were
carried out at temperatures between 20 and 50°C. It
occurred to us that this might be the reason for the
observed difference in regioselectivity. These reactions
probably proceed by a pathway in which the first step is
the reversible addition of ammonia and formation of
the intermediates 1a–c.3,4
ity of the permanganate anion in this solvent gave rapid
oxidation of the s-adduct before equilibrium was
obtained. On changing to a DMSO/water mixture, this
solvent effect would be expected to disappear and the
results confirmed this with a high regioselectivity for the
para isomer 2a. In the reaction run with DMSO/water
75/25 with an initial concentration of 7% NH3, di-2-(5-
nitropyridyl)amine (2d) was formed in higher yield than
that of 2-amino-5-nitropyridine (2a). In this reaction
the initially low concentration of ammonia (7%) was
reduced substantially by reaction with 3-nitropyridine
as well as oxidation with KMnO4, thus allowing the
already formed 2a to compete effectively as a nucleo-
phile giving 2d. However, by bubbling NH3 into the
solution, a constant concentration of ammonia was
maintained, this side reaction was suppressed and a
high yield of 2-amino-5-nitropyridine (2a) was
obtained.
These intermediates are then oxidised by KMnO4 to the
products 2a–c. If the irreversible oxidation is faster
than the thermodynamic equilibration of the three
intermediates, the product composition would reflect
the kinetic composition of the intermediates 1a–c. At
low temperature in liquid ammonia with KMnO4 well
dissolved, this may be the case. Therefore, if the reac-
tion could be carried out at higher temperature so that
the equilibration reaction would compete more success-
fully with the oxidation, we would expect a higher yield
of the presumably thermodynamically more stable para
isomer (2a). At the same time it would be of conve-
nience if the reactions could be run at ambient temper-
ature. Recently, Wozniak has reported results which
indeed indicate that this may be the case: from the
reaction of 3-nitropyridine with methylamine at −7°C,
2-methylamino-5-nitropyridine was the dominant
product, in contrast to the results from the reaction
with ammonia at −33°C.6
With these results in hand, we tried the reaction with
primary and secondary amines. Wozniak reacted sev-
eral nitropyridines in liquid methylamine at −7°C and
obtained a 65% yield of 2-methylamino-5-nitropyridine
together with a 3% yield of the di-aminated product
2,6-dimethylamino-3-nitropyridine.6 In a similar experi-
ment, we reacted 3-nitropyridine in butylamine with
KMnO4 and obtained a 92% yield (isolated) of 2-butyl-
amino-5-nitropyridine together with 2-butylamino-3-
nitropyridine (2%, GC area) and 4-butylamino-3-
nitropyridine (2%, GC area). Thus, the oxidative
amination of 3-nitropyridine in the alkylamine itself
gave a high yield of the para product both for methyl-
and butylamine.
We have therefore studied the reactions of 3-nitropy-
ridine with three different amino compounds, ammo-
nia, butylamine and diethylamine in different solvents
and under various reaction conditions. The results of
the reactions with ammonia are given in Table 1.
We also tried the reaction of 3-nitropyridine with
diethylamine (DEA) and KMnO4 under different con-
ditions. In DEA itself no reaction took place, and the
same was the case for a 25/75 mixture of DEA and
water. In DEA/diglyme 25/75 the regioselectivity was
low, giving 45% of the para isomer (corresponding to
2a) and 55% of the two ortho isomers (corresponding to
2b and 2c). However, in DEA/DMSO 25/75 with 5 mol
equivalents KMnO4, a good isolated yield (60%) and
very high regioselectivity (98% para product) were
These show the strong influence of the reaction condi-
tions, both on the rate of reaction and on the regio-
selectivity. The change from stirring with a magnetic
bar to supersonic mixing not only greatly increased the
rate of reaction, but also gave an increase in the relative
yield of the para product (2a). The reaction in pure
DMSO gave an increase in the yield of 3-nitro-4-
aminopyridine (2c), presumably because the high activ-
Table 1. Reaction of 3-nitropyridine with ammonia in the presence of KMnO4 (5 mol equivalents) at 22°C to give
2-amino-5-nitropyridine (2a), 2-amino-3-nitropyridine (2b) and 4-amino-3-nitropyridine (2c) and di-2-(5-nitropyridyl)amine
(2d)
Solvent
Conditions
Reaction time (h)
Conversion (%)
GC
Composition (%) (GC)
2a
2b
2c 2d
Water NH3 28%
Water NH3 28%
DMSO, NH3 Atmosphere
DMSO/Water 75/25, NH3 7%
DMSO/Water 75/25, NH3 7%,
Stirring
Supersonic mixing
20
3
3
15
15
20
80
80
85
90
7
68
43
3
1
0.2
–
–
10
11
37
1
–
–
–
55
–
44
Stream of NH3 passed through
98(66a)
2
a Isolated yield. The reaction was quenched by methanol, and the product was isolated by pouring the reaction mixture into water. The aqueous
phase was then filtered and extracted by dichloromethane. The product was transfered to an aqueous phase by extraction of the dichloromethane
by a 10% aq. HCl solution. The aqueous extract was neutralised, and extracted with ethyl acetate. Evaporation of the ethyl acetate extract gave
a crude product, which was recrystallised from water/methanol to give 2-amino-5-nitropyridine.
Bakke, Jan M
