Reductive acylamination of pyridine N-oxide with aminopyridines and their N-p-tolylsulfonyl derivatives

Article abstract of DOI:10.1007/s11178-005-0134-x

Pyridine N-oxide reacts with 2- and 3-aminopyridines and their N-p-tolylsulfonyl derivatives in alkaline medium in the presence of p-toluenesulfonyl chloride to give N-p-tolylsulfonyl-2,2′- and 2,3′-dipyridylamines, respectively, as a result of reductive acylamination. In the reactions with 4-aminopyridine and 4-p-tolylsulfonyl- aminopyridine, their N-p-tolylsulfonyl- and N,N-bis(p-tolylsulfonyl) derivatives are formed, while reductive acylamination does not occur. 2005 Pleiades Publishing, Inc.

Full text of DOI:10.1007/s11178-005-0134-x

Russian Journal of Organic Chemistry, Vol. 41, No. 1, 2005, pp. 128-130. Translated from Zhurnal Organicheskoi Khimii, Vol. 41, No. 1, 2005,
pp. 128-130.
Original Russian Text Copyright Ó 2005 by Solekhova, Kurbatov.
Reductive Acylamination of Pyridine N-Oxide
with Aminopyridines and Their N-p-Tolylsulfonyl Derivatives
M. A. Solekhova and Yu. V. Kurbatov
Alisher Navoi Samarkand State University, Universitetskii bul’var 15, Samarkand, 703004 Kazakhstan
Received July 24, 2003
Abstract—Pyridine N-oxide reacts with 2- and 3-aminopyridines and their N-p-tolylsulfonyl derivatives in alkaline
medium in the presence of p-toluenesulfonyl chloride to give N-p-tolylsulfonyl-2,2'- and 2,3'-dipyridylamines,
respectively, as a result of reductive acylamination. In the reactions with 4-aminopyridine and 4-p-tolylsulfonyl-
aminopyridine, their N-p-tolylsulfonyl- and N,N-bis(p-tolylsulfonyl) derivatives are formed, while reductive
acylamination does not occur.
chemical properties [3]; therefore, reactions with these
compounds could give different results.
We previously reported [1, 2] on the reductive acyl-
amination of pyridine N-oxide (I) with aromatic amines
(aniline, p-methoxyaniline, and their N-p-tolylsulfonyl
derivatives) in the presence of p-toluenesulfonyl chloride
(II) and a base, which afforded N-p-tolylsulfonyl-
substituted 2-arylaminopyridines in high yields. In
continuation of these studies, in the present work we per-
formed analogous reactions with heteroaromatic amines,
2-, 3-, and 4-aminopyridines III–V and their N-p-tolyl-
sulfonyl derivatives VI–VIII. Isomeric aminopyridines,
2- and 4-aminopyridines, on the one hand, and 3-amino-
pyridine, on the other, exhibit qualitatively different
The reactions were carried out at room temperature
in a two-phase system (chloroform–water) in the
presence of p-toluenesulfonyl chloride (II) and potassium
or sodium hydroxide or carbonate as a base. The reaction
of pyridine N-oxide (I) with 2-aminopyridine (III)
followed the reductive acylamination pattern and led to
formation of N-p-tolylsulfonyl-2,2'-dipyridylamine (IX) in
34–58% yield; in addition, 22–35% of the acylation
product, 2-p-tolylsulfonylaminopyridine (VI) was isolated
(Scheme 1).
Scheme 1.
7V&O
1
1
&O
2
,
27V
$
,,
2+
+ 2
,,
1
1
1
1+
1+7V
1 7V
,,,
9,
%
+
%
$
7V2+
1
1
1
1
1
1
27V
7V
7V
,;
1070-4280/05/4101-0128Ó2005 Pleiades Publishing, Inc.

REDUCTIVE ACYLAMINATION OF PYRIDINE N-OXIDE
129
Scheme 2.
ꢂꢃ3\1+
When the reaction was performed with N-p-tolyl-
sulfonyl derivative VI as probable intermediate (instead
of aminopyridine III), reductive acylamination of N-oxide
I also occurred, and compound IX was obtained in 39%
yield. These data confirm the proposed scheme of acyl-
amination of aminopyridine III, and the above reaction
may be regarded as a method of synthesis of amide IX.
Pyridine N-oxide (I) reacted in a similar way with 3-amino-
pyridine (IV) and 3-p-tolylsulfonylaminopyridine (VII);
in both cases, the product was N-p-tolylsulfonyl-2,3'-
dipyridylamine (X) (Scheme 2).
,9
2+
7V2+ꢀꢁꢁꢁ+&O
+ 2
,,
,
1
1
ꢂꢃ3\1+7V
7V
9,,
1
;
Scheme 3.
Unlike 2- and 3-aminopyridines, 4-aminopyridine (V)
and its N-p-tolylsulfonyl derivative VIII underwent
acylation to give 4-bis(p-tolylsulfonyl)aminopyridine (XI).
The most probable reason is the higher basicity of amine
V (pKa = 9.1) relative to 2- and 3-aminopyridines (III,
pKa = 7.2; IV, pKa = 6.6 [3]). Another factor responsible
for the lack of substitution and the occurrence of repeated
acylation of isomer V is strong delocalization of the
negative charge on the exocyclic nitrogen atom in
intermediate C, which is typical of para-substituted
arenes (hetarenes), and hence sharp reduction of its
nucleophilicity.
+ 2ꢀꢁ+
7V2+
ꢂ
,;ꢀꢁ;
1
1+
;,,ꢀꢁ;,,,
ꢀꢁꢂ3\ꢀꢃ,;ꢀꢁ;,,ꢄꢅꢀꢆꢂ3\ꢀꢃ;ꢀꢁ;,,,ꢄꢇ
1
1
and extracted with several portions of chloroform, the
extracts were combined with the organic phase, dried
over sodium sulfate, and evaporated, and the residue was
washed with diethyl ether and hot ethanol to obtain 1.6 g
(62%) of amide VI, mp 210–211°C (from ethanol);
published data [5]: mp 213–214°C. The solvent was
distilled off to isolate 0.58 g (17%) of compound IX,
mp 150–151°C (from acetonitrile), Rf 0.9. Found, %:
C 62.7; H 4.4; N 12.86. C17H15N3O2S. Calculated, %:
C 62.8; H 4.6; N 12.92.
7V
1
1
&
The acid solution was made alkaline by adding
potassium carbonate to pH 8–9 and extracted with diethyl
ether, and the extract was evaporated to isolate 0.11 g
(11%) of unreacted amine III, mp 55–56°C.
The structure of compounds IX and X was proved by
their acid hydrolysis to 2,2'- and 2,3'-dipyridylamines XII
and XIII, respectively (Scheme 3).
The described reactions attract interest from the
viewpoint of synthesis of sulfonamides, dihetarylamines,
and also amines themselves, which are potential
physiologically active compounds.
When potassium hydroxide was used as a base, the
yields of products IX and VI were 60 and 31%,
respectively.
Acyalmination of pyridine N-oxide (I) with
N-(2-pyridyl)-p-toluenesulfonamide (VI). A solution
of 2 mmol of pyridine N-oxide (I), 2 mmol of amide VI,
and 4 mmol of p-toluenesulfonyl chloride (II) in 12 ml of
chloroform was mixed with 6 ml of a 10% aqueous
solution of potassium carbonate, and the mixture was
stirred for 2 h at 20°C and treated as described above.
We isolated 0.35 g (70%) of unchanged amide VI with
mp 210–211°C (from ethanol) and 0.11 g (17%) of
compound IX with mp 150–151°C (Rf 0.9).
EXPERIMENTAL
The progress of reactions and the purity of products
were monitored by paper chromatography (no. 2, fast)
using the system 1-butanol–hydrochloric acid–water
(50:7:14, by volume); the chromatograms were developed
with Dragendorff’s spray reagent [4].
Acylamination of pyridine N-oxide (I) with
2-aminopyridine (III). Asolution of 10 mmol of pyridine
N-oxide (I), 10 mmol of 2-aminopyridine (III), and
20 mmol of p-toluenesulfonyl chloride (II) in 22 ml of
chloroform was mixed with 10 ml of a 10% aqueous
solution of potassium carbonate, and the mixture was
stirred for 2 h at 20°C. The aqueous phase was separated
When potassium hydroxide was used as a base, the
yield of IX was 39%.
Acylamination of pyridine N-oxide (I) with
3-aminopyridine (IV).Asolution of 10 mmol of N-oxide
RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 41 No. 1 2005

130
SOLEKHOVA, KURBATOV
I hydrochloride, 10 mmol of amine IV, and 20 mmol of
p-toluenesulfonyl chloride (II) in 40 ml of chloroform was
mixed with 60 ml of a 10% aqueous solution of potassium
carbonate, and the mixture was stirred for 2 h at 20°C.
The aqueous phase was separated and acidified with
concentrated hydrochloric acid, and the precipitate was
filtered off. We thus isolated 0.65 g (26%) of amide VII,
mp 187–188°C (from ethanol); published data [6]:
mp 190–191°C. The organic phase was dried over sodium
sulfate and evaporated, and the residue was washed with
diethyl ether and ethanol to isolate 0.92 g (38%) of
compound X with mp 83–85°C (from ethanol), Rf 0.6.
Found, %: N 12.83. C17H25N3O2S. Calculated, %:
N 12.92.
mixed with 50 ml of a 10% aqueous solution of sodium
hydroxide, and the mixture was stirred for 2 h at 20°C.
The aqueous phase was separated and acidified with
concentrated hydrochloric acid, and the precipitate was
filtered off and repeatedly washed with a solution of
sodium carbonate and with water. Yield of XI 1 g (80%),
mp 204–205°C (from ethanol) [8], Rf 0.7.
Hydrolysis of amides IX and X. A solution of
4 mmol of amide IX or X in 20 ml of concentrated
hydrochloric acid was heated for 12 h at the boiling point.
The mixture was evaporated to dryness, the residue was
washed with diethyl ether, and the solvent was distilled
off to leave p-toluenesulfonic acid. Yield 66 and 80%
from amides IX and X, respectively, mp 90–92°C;
published data [9]: mp 92°C. The material insoluble in
diethyl ether was dissolved in a minimal amount of water,
the solution was made alkaline by adding potassium
carbonate and was extracted with chloroform, and the
solvent was removed from the extract to isolate amine
XII {yield 68%, mp 94–95°C (from benzene); published
data [7]: mp 95°C} or XIII {yield 70%, mp 143–144°C
(from hexane); published data [10]: mp 143.8–144°C)}.
When an equivalent amount of potassium hydroxide
was used as a base, the yields of products VII and X
were 48 and 33%, respectively, and with the use of sodium
hydroxide, 36 and 46%, respectively.
Acylamination of pyridine N-oxide (I) with
N-(3-pyridyl)-p-toluenesulfonamide (VII). A solution
of 5 mmol of pyridine N-oxide hydrochloride, 5 mmol of
amide VII, and 10 mmol of p-toluenesulfonyl chloride
(II) in 40 ml of chloroform was mixed with 50 ml of a
10% aqueous solution of sodium hydroxide. The mixture
was then treated as described in the preceding experiment
to isolate 0.9 g (70%) of unchanged amide VII with
mp 188–190°C and 0.45 g (28%) of compound X with
mp 83–85°C, Rf 0.6. Found, %: N 12.80. C17H25N3O2S.
Calculated, %: N 12.92.
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of p-toluenesulfonyl chloride (II) in 80 ml of chloroform
was mixed with 40 ml of a 10% aqueous solution of
sodium hydroxide, and the mixture was stirred for 2 h at
20°C. The aqueous phase was separated and acidified
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was observed on mixing with an authentic sample of
N-(4-pyridyl)-p-tolenesulfonamide.
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The organic phase was dried over sodium sulfate and
evaporated, the semicrystalline residue was treated with
hot ethanol, the solution was cooled, and the precipitate
was filtered off to obtain 1.2 g (27%) of imide XI with
mp 204–205°C [8], Rf 0.7.
2002, vol. 38, p. 1192.
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Acylation of amide VIII under acylamination
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hydrochloride, 5 mmol of amide VIII [8], and 5 mmol of
p-toluenesulfonyl chloride (II) in 40 ml of chloroform was
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