Selective vicarious nucleophilic amination of 3-nitropyridines

Article abstract of DOI:10.1039/b008660f

Nine 3-nitropyridine compounds and 4-nitroisoquinoline have been aminated in the 6-position (for 4-nitroisoquinoline in the 1-position) by vicarious nucleophilic substitution reactions. Two amination reagents were used, hydroxylamine and 4-amino-1,2,4-triazole. The yields were from moderate to good. Use of hydroxylamine gave an easy work-up procedure by which almost pure product was obtained directly, but 4-amino-1,2,4-triazole gave better yields of the aminated product for some of the substrates. By this, a general method for the preparation of 3- or 4-substituted-2-amino-5-nitropyridines was obtained.

Full text of DOI:10.1039/b008660f

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Selective vicarious nucleophilic amination of 3-nitropyridines
Jan M. Bakke, Harald Svensen and Raffaela Trevisan
Department of Chemistry, Norwegian University of Science and Technology,
Sem Sælands vei 8, NO-7491 Trondheim, Norway
1
Received (in Cambridge, UK) 26th October 2000, Accepted 22nd December 2000
First published as an Advance Article on the web 24th January 2001
Nine 3-nitropyridine compounds and 4-nitroisoquinoline have been aminated in the 6-position (for 4-nitro-
isoquinoline in the 1-position) by vicarious nucleophilic substitution reactions. Two amination reagents were
used, hydroxylamine and 4-amino-1,2,4-triazole. The yields were from moderate to good. Use of hydroxylamine
gave an easy work-up procedure by which almost pure product was obtained directly, but 4-amino-1,2,4-triazole
gave better yields of the aminated product for some of the substrates. By this, a general method for the preparation
of 3- or 4-substituted-2-amino-5-nitropyridines was obtained.
for this type of reaction are comparatively simple. Two different
Introduction
amination reagents were used, hydroxylamine and 4-amino-
1,2,4-triazole. Several of the products have not been reported
previously. The reaction is outlined in Scheme 1.
We have reported a new method for the nitration of pyridine
compounds. This has made a number of β-nitropyridines
readily available, and we are now exploring the chemistry of
these compounds.1 The electron deficient nature of the pyridine
ring is enhanced by the introduction of the nitro group in the
3-position. These compounds would therefore be expected to be
susceptible to attack by nucleophiles, with attack at the posi-
tions ortho- and para- to the nitro group being favoured. We
have reported one such reaction, the addition of sodium sulfite
to 3-nitropyridine to give 5-hydroxyaminopyridine-2-sulfonic
acid as the final product.2 In extension of this, we now report
the vicarious amination3 of 4- and 5-substituted 3-nitro-
pyridines. The goal was to obtain 2-amino-5-nitropyridines
selectively which would be useful starting compounds for the
synthesis of biological active compounds. The 2,5 substitution
pattern of pyridine is the base for many pharmaceuticals and
crop protecting agents. However, in general it has been difficult
to obtain this pattern with high regioselectivity.4 With a number
of 2-amino-5-nitropyridine compounds available, it would be
possible to synthesise a large number of 2,5-substituted pyrid-
ines as both these groups may be substituted with a number of
substituents, for example by the Sandmeyer reaction (the nitro
group first requiring reduction to an amino group).
Some examples of syntheses of aminonitropyridines have
been reported. Thus, Wozniak et al. aminated some 3-nitro-
pyridines by liquid ammonia–potassium permanganate. This
procedure gave mixtures of ortho and para isomers (relative to
the nitro group).5 Seko and Miyake reported the amination of a
few substituted nitropyridines by the use of O-methylhydroxyl-
amine as aminating agent.6 However, they did not report results
for any 4- or 5-substituted 3-nitropyridines. Makosza and
Bialecki used sulfenamides as aminating agents. With 4-ethoxy-
3-nitropyridine this gave 2-amino-4-ethoxy-5-nitropyridine
(75% yield) and with 6-methoxy-3-nitropyridine gave 2-amino-
3-nitro-6-methoxypyridine (42%).7 2-Amino-5-nitropyridines
have also been obtained by nitration of 2-aminopyridines, the
resulting nitramines were rearranged to the 2-amino-5-
nitropyridines. This procedure is not suitable for large scale
synthesis and also gave considerable amounts of the 2-amino-3-
nitropyridine isomers.8
Scheme 1
Results and discussion
Hydroxylamine as aminating agent (Procedure A)
Reaction of a number of 3-nitropyridines with hydroxyl-
amine and base afforded 2-amino-5-nitropyridines as the only
observed isomer. The yields are given in Table 1. Seko and
Miyake used zinc dichloride as a catalyst in their reaction with
O-methylhydroxylamine and claimed it to be essential for the
reaction.6 We found that our reaction took place without zinc
dichloride, but use of one equivalent increased the yield from
45 to 54% (Table 1, entries 1 and 2). Ethanol was found to be
the best solvent for the reaction, but methanol and even water
could be used (Table 1, entries 3 and 4). Potassium hydroxide
was used as base, potassium methoxide (from potassium tert-
butoxide) in dry methanol gave a lower yield (Table 1, entry 3).
With electron donating groups on the pyridine ring, the reac-
tion was slower and it was necessary to add more hydroxyl-
amine and base after 5 hours of stirring (Table 1, entries 5,
6, 9, 10, 11, 12). Pure products were obtained by evaporation
of the organic phase after extraction, any by-products
remained in the water phase. The advantage of this procedure
is its selectivity, use of inexpensive hydroxylamine and the
easy work-up.
Thus, there is only a limited number of methods available for
the amination of nitropyridines and none of these have been
employed for an extensive number of substrates. A general pro-
cess for the preparation of these compounds might therefore be
of some use. The vicarious nucleophilic amination appeared to
be of special interest as both reagents and reaction conditions
4-Amino-1,2,4-triazole as aminating agent (Procedure B)
Katritzky and Laurenzo have reported amination of substi-
tuted nitrobenzenes by the use of 4-amino-1,2,4-triazole in a
376
J. Chem. Soc., Perkin Trans. 1, 2001, 376–378
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b008660f

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Table 1 Yields (isolated) for the amination of R-3-nitropyridines by hydroxylamine to give R-2-amino-5-nitropyridines
Entry
R
Base
Solvent
Yield (%)
Product
1
2
3
4
5
6
7
8
9
10
11
12
13
H
H
H
H
KOH
KOH
ButOK
KOH
KOH
KOH
CH3ONa
KOH
KOH
KOH
KOH
KOH
KOH
EtOH
EtOH
MeOH
H2O
EtOH
EtOH
MeOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
45a
54
42
26
42
56
30
2-Amino-5-nitropyridine
2-Amino-5-nitropyridine
2-Amino-5-nitropyridine
2-Amino-5-nitropyridine
2-Amino-4-methyl-5-nitropyridine
2-Amino-3-methyl-5-nitropyridine
Methyl 2-amino-5-nitroisonicotinate
Complex mixture
2-Amino-4-(1,3-dioxolan-2-yl)-5-nitropyridine
2-Amino-4-(2-methyl-1,3-dioxolan-2-yl)-5-nitropyridine
2-Amino-4-phenyl-5-nitropyridine
4-CH3
5-CH3
4-CO2CH3
4-CN
4-CHO (protected as the dioxolane)
4-COCH3 (protected as the dioxolane)
4-Ph
5-Ph
47
63
64
35
23
2-Amino-3-phenyl-5-nitropyridine
1-Amino-4-nitroisoquinoline
4-Nitroisoquinoline
a No ZnCl2 added.
Table 2 Yields (isolated) for the amination of R-3-nitropyridines by 4-amino-1,2,4-triazole to give R-2-amino-5-nitropyridines
Entry
R
Base
Solvent
Yield (%)
Product
1
2
3
4
5
6
7
8
9
10
11
12
13
H
H
H
H
ButOK
KOH
DMSO
DMSO
MeCN
DMF
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
76
56
26
44
61
59
11
2-Amino-5-nitropyridine
2-Amino-5-nitropyridine
2-Amino-5-nitropyridine
2-Amino-5-nitropyridine
2-Amino-4-methyl-5-nitropyridine
2-Amino-3-methyl-5-nitropyridine
Methyl 2-amino-5-nitroisonicotinate
Complex mixture
2-Amino-4-(1,3-dioxolan-2-yl)-5-nitropyridine
2-Amino-4-(2-methyl-1,3-dioxolan-2-yl)-5-nitropyridine
2-Amino-4-phenyl-5-nitropyridine
2-Amino-3-phenyl-5-nitropyridine
1-Amino-4-nitroisoquinoline
ButOK
ButOK
ButOK
ButOK
ButOK
ButOK
ButOK
ButOK
ButOK
ButOK
ButOK
4-CH3
5-CH3
4-CO2CH3
4-CN
4-CHO (protected as the dioxolane)
4-COCH3 (protected as the dioxolane)
4-Ph
5-Ph
47
65
79
66
65
4-Nitroisoquinoline
vicarious nucleophilic substitution reaction.9 We wished to
investigate this for the amination of 3-nitropyridines and
compare the results with those from the reactions with
hydroxylamine. Reaction of 3-nitropyridines with 4-amino-
1,2,4-triazole and base indeed gave 2-amino-5-nitropyridines
with the same high regioselectivity as the reaction with hydroxyl-
amine. The yields for the different substrates are given in
Table 2. The reaction was performed in dimethyl sulfoxide with
potassium tert-butoxide as base. Introductory experiments
indicated that the reaction had to be carried out in dilute solu-
tions, and also that the rate of addition of the nitropyridine to
the DMSO solution had to be sufficiently slow in order to avoid
formation of byproducts.
Dimethylformamide and tetrahydrofuran were also tried as
solvents but both gave lower yields than DMSO.
The use of the two amination reagents, hydroxylamine and
4-amino-1,3,4-triazole gave similar yields for several of the sub-
strates. For methyl 3-nitroisonicotinoate hydroxylamine gave
the better yield (30% vs. 11% with 4-amino-1,3,4-triazole) while
4-amino-1,3,4-triazole gave better results for 3-nitropyridine
(76% vs. 54% with hydroxylamine), 4-methyl-3-nitropyridine
(61% vs. 42% with hydroxylamine) and 4-phenyl-3-nitro-
pyridine (79% vs. 64% with hydroxylamine). For 4-cyano-
pyridine the yield was very low and a complex reaction mixture
was obtained. A substitution of the nitro group may have taken
place. It is known that the nitro group may be substituted when
situated at an electron deficient carbon.10 We have observed
such a reaction with 4-cyano-3-nitropyridine and sodium azide
by which 3-azido-4-cyanopyridine was obtained in high yield.11
Another possible side-reaction would be an intra- or inter-
molecular reduction of the nitro group to a nitroso group
(Scheme 2). This type of reaction is known for reaction of
nitrobenzene with aniline3 and we observed an analogous
reaction from sodium sulfite and 3-nitropyridine.2 The nitroso
compounds might then react further with amines to give azo
Scheme 2
compounds or with hydroxylamine to give azoxy compounds,
explaining the deep brown colour of the reaction mixture.
The acetyl and the formyl group had to be protected by use
of ethane-1,2-diol before the amination to avoid nucleophile
attack on the carbonyl group.
In conclusion, we have investigated two different procedures
to selectively transform 3-nitropyridines into 2-amino-5-
nitropyridines in moderate to good yields. The use of hydroxyl-
amine was a simpler and cheaper procedure. In large scale
preparations this procedure would be better because of the easy
work-up to give pure products even if the yields were only
J. Chem. Soc., Perkin Trans. 1, 2001, 376–378
377

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moderate for several of the substrates. The use of 4-amino-
1,2,4-triazole demanded an inert atmosphere and dimethyl
sulfoxide as solvent. As the yields were better for some of the
substrates this may be the preferred procedure for small-scale
preparations.
2-Amino-4-(1,3-dioxolan-2-yl)-5-nitropyridine. This was
a
yellow solid, mp 175–177 ЊC; 1H-NMR (CDCl3): δ 3.9–4.3
(q, 4H, dioxolane protons), 5.18 (s, 1H, dioxolane proton), 6.57
(s, 1H, H3), 6.80 (s, 2H, NH2), 8.89 (s, 1H, H6); IR 3461, 1548,
1329 cmϪ1; anal. calcd. for C8H9N3O4: C, 45.50; H, 4.27; N,
19.91. Found: C, 45.27; H, 4.33; N, 19.56%.
Experimental
2-Amino-4-(2-methyl-1,3-dioxolan-2-yl)-5-nitropyridine. This
was an orange solid, mp 172–173 ЊC; IR (KBr): 3459, 3314,
The spectroscopic and analytical equipment used have been
reported elsewhere.1 Elemental analyses were carried out by the
Laboratory of Organic Elemental Analysis, Prague Institute of
Chemical Technology, Czech Republic. The organic extracts
were dried over MgSO4. The starting compounds were prepared
as described in earlier papers.1 Dinitrogen pentoxide was pre-
pared from dinitrogen tetroxide and ozone.12 Protection of the
carbonyl groups prior to amination and nitration was carried
out by standard methods.13,14
1
3191, 1691, 1521, 1425, 1369, 1203, 1026, 877 cmϪ1; H NMR
(CDCl3): δ 3.72 (m, 2H, dioxolane protons), 4.02 (m, 2H,
dioxolane protons), 5.01 (br s, 2H, NH2), 6.69 (s, 1H, H3), 8.42
(s, 1H, H6); anal. calcd. for C9H11N3O4: C, 48.00; H, 4.92; N,
18.66. Found: C, 48.08; H, 4.79; N, 18.67%.
2-Amino-4-phenyl-5-nitropyridine. This was a yellow solid,
mp 165–166 ЊC; IR (KBr): 3412, 3319, 3156, 1652, 1598, 1538,
1481, 1327, 1296, 1134, 848 cmϪ1; 1H NMR (CDCl3): δ 5.20 (br
s, 2H, NH2), 6.37 (s, 1H, H3), 7.29 (m, 2H, phenyl protons) 7.43
(m, 3H, phenyl protons), 8.85 (s, 1H, H6); anal. calcd. for
C8H9N3O4: C, 61.39; H, 4.22; N, 19.53. Found: C, 61.24; H,
4.42; N, 19.27%.
Amination of 3-nitropyridines
Procedure A, with hydroxylamine. The 3-nitropyridine com-
pound (10 mmol) in ethanol (50 ml) was added dropwise to a
stirred solution of hydroxylamine hydrochloride (30 mmol),
potassium hydroxide (80 mmol) and zinc dichloride (10 mmol)
in ethanol (100 ml). In some cases (Table 1, entries 5, 6, 9, 10,
11) more hydroxylamine (15 mmol) and potassium hydroxide
(20 mmol) were added after 5 hours of stirring. The reaction
mixture was stirred overnight at room temperature, and poured
into water (200 ml). The aqueous phase was extracted with
CH2Cl2 (3 × 100 ml), the combined organic phase washed with
water, dried and evaporated to give the 2-amino-5-nitropyridine
compound.
2-Amino-3-phenyl-5-nitropyridine. This was a yellow solid,
mp 175–176.5 ЊC (lit.15 176.5–177 ЊC); IR (KBr): 3473, 3299,
3116, 1645, 1574, 1485, 1444, 1353, 1334, 1307, 1127, 733 cmϪ1
.
1H NMR (CDCl3): δ 5.36 (br s, 2H, NH2), 8.18 (d, 1H, J = 2.58
Hz, H4), 7.50–7.60 (m, 5H, phenyl protons), 9.02 (d, 1H,
J = 2.58 Hz, H6).
1-Amino-4-nitroisoquinoline. This was a yellow solid, mp
277–280 (lit.16 283–287 ЊC); IR (KBr): 3417, 3338, 3087, 1671,
1617, 1580, 1510, 1492, 1449, 1401, 1363, 1285, 1256, 1030, 769
cmϪ1; 1H-NMR (DMSO-d6): δ 7.65 (dd, 1H, J = 8.30, 8.58 Hz,
H7), 7.87 (dd, 1H, J = 8.30, 8.58 Hz, H6), 8.40 (d, 1H, J = 8.30
Hz, H8), 8.45 (br s, 2H, NH2), 8.72 (d, 1H, J = 8.58 Hz, H5),
8.97 (s, 1H, H3); anal. calcd for C9H7N3O2: C, 57.14; H, 3.73; N,
22.21. Found: C, 57.89; H, 4.13; N, 22.09%.
Procedure B, with 4-amino-1,2,4-triazole. The 3-nitropyridine
compound (10 mmol) in dimethyl sulfoxide (30 ml) was added
dropwise to a stirred solution of 4-amino-1,2,4-triazole (35
mmol) and potasium tert-butoxide (20 mmol) in dimethyl
sulfoxide (60 ml) under nitrogen atmosphere. The reaction
mixture was stirred for 5 hours at room temperature, and then
poured into water (200 ml) saturated with NH4Cl.
The aqueous phase was extracted with CH2Cl2 (3 × 100 ml),
the combined organic phases evaporated, and the residue
recrystallized from water–methanol to give the 2-amino-5-
nitropyridine compound.
Acknowledgement
Generous support from The Norwegian Research Council is
gratefully acknowledged.
Physical and analytical data for the prepared compounds are
given below.
References
1 J. M. Bakke, E. Ranes, J. Riha and H. Svensen, Acta Chem. Scand.,
1999, 53, 141; J. M. Bakke, H. Svensen and E. Ranes, J. Chem. Soc.,
Perkin Trans. 2, 1998, 2477 and references cited therein.
2 J. M. Bakke, E. Ranes, C. Rømming and I. Sletvold, J . Chem. Soc.,
Perkin Trans. 1, 2000, 1241.
2-Amino-5-nitropyridine. Mp 188–189 ЊC (lit.5 188–189 ЊC);
IR (KBr): 3501, 3363, 1648, 1632, 1583, 1570, 1494, 1473, 1333,
1285, 1129, 842 cmϪ1; 1H NMR (DMSO-d6): δ 6.50 (d, 1H, H3,
J = 9.39 Hz), 7.52 (br s, 2H, NH2), 8.12 (dd, 1H, H4, J = 2.80,
9.31 Hz) 8.84 (d, 1H, J = 2.78 Hz H6).
3 O. N. Chupakhin, V. N. Charushin and H. C. van der Plas,
Nucleophilic Aromatic Substitution of Hydrogen, Academic Press,
San Diego, CA, 1994, pp. 59–64.
2-Amino-4-methyl-5-nitropyridine. Mp 219–220 ЊC (lit.8
220 ЊC) IR (KBr): 3406, 3329, 3121, 1654, 1608, 1544, 1492,
4 E. F. V. Scriven, in book of abstracts from the 17th International
Congress of Heterocyclic Chemistry, IL-33, Vienna, 1999.
5 M. Wozniak, A. Baranski and B. Szpakiewicz, Liebigs Ann. Chem.,
1991, 875.
1
1452, 1372, 1332, 1290, 1279, 1109, 954, 841 cmϪ1; H NMR
(CDCl3): δ 2.61 (s, 3H, CH3), 5.03 (br s, 2H, NH2), 6.33 (s, 1H,
H3), 8.93 (s, 1H, H6).
6 S. Seko and K. Miyake, Chem. Commun., 1998, 1519.
7 M. Makosza and M. Bialecki, J. Org. Chem., 1998, 63, 4878.
8 N. P. Lewis and S. Z. Winfield, J. Am. Chem. Soc, 1955, 77, 3154.
9 A. R. Katritzky and K S. Laurenzo, J. Org. Chem., 1986, 51, 5039;
A R. Katritzky and K. S. Laurenzo, J. Org. Chem, 1988, 53, 3979.
10 A. J. Boulton and A. McKillop, in Comprehensive Heterocyclic
Chemistry, Vol. 2, A. R. Katritzky and C. W. Rees, eds., Pergamon,
Oxford, 1984, p. 55.
2-Amino-3-methyl-5-nitropyridine. Mp 256–257 ЊC (lit.8
255 ЊC); IR (KBr): 3450, 3321, 3119, 1851, 1583, 1477, 1422,
1343, 1292, 1109, 1040, 1018, 941, 770 cmϪ1; 1H NMR (DMSO-
d6): δ 2.11 (s, 3H, CH3), 5.03 (br s, 2H, NH2), 8.02 (d, 1H,
J = 1.94 Hz, H4), 8.74 (d, 1H, J = 1.94 Hz, H6).
11 E. Ranes, PhD Thesis, NTNU, 1999.
12 A. D. Harris, J. C. Trebellas and H. B. Jonassen, Inorg. Synth., 1967,
9, 83.
13 J. G. Rodriquez and N. Martines-Lopez, J. Heterocyc. Chem., 1989,
26, 135.
14 J. W. Beach, J. Heterocycl. Chem., 1997, 34, 1861.
15 V. N. Charushin and H. C. van der Plas, J. Org. Chem., 1983, 48,
2667.
2-Amino-4-methoxycarbonyl-5-nitropyridine (methyl 2-amino-
5-nitroisonicotinate). This was a light brown solid, mp 205–
206 ЊC; IR (KBr): 3441, 3309, 1733, 1649, 1457, 1344, 1303,
1
1279, 1180, 1079, 986, 876 cmϪ1; H NMR (CDCl3): δ 3.85 (s,
3H, CH3), 6.52 (s, 1H, H3) 7.84 (br s, 2H, NH2), 8.82 (s, 1H, H6);
anal. calcd. for C7H7N3O4: C, 42.65; H, 3.58; N, 21.31. Found:
C, 42.50; H, 3.87; N, 21.25%.
16 JP 59172472, 1984 (Chem. Abstr., 1984, 102, 113322z).
378
J. Chem. Soc., Perkin Trans. 1, 2001, 376–378