Reductive amination of quinoline N-oxide with aminopyridines and their N-tozyl derivatives

Article abstract of DOI:10.1023/A:1020913929185

In reaction of quinoline N-oxide with 2-aminopyridine in the presence of tosyl chloride the substrate undergoes reductive amination into 2-pyridyl(2-quinolyl)amine, and with 3- and 4-aminopyridines reductive tosylamination occurs to furnish N-tosyl derivatives of the corresponding 3- and 4-pyridyl(2-quinolyl)amines. N-tosyl derivatives of aminopyridines also react along reductive tosylamination pathway.

Full text of DOI:10.1023/A:1020913929185

Russian Journal of Organic Chemistry, Vol. 38, No. 8, 2002, pp. 1192 1194. From Zhurnal Organicheskoi Khimii, Vol. 38, No. 8, 2002,
pp. 1243 1245.
Original English Text Copyright
2002 by Solekhova, Kurbatov.
Reductive Amination of Quinoline N-Oxide
with Aminopyridines and Their N-Tozyl Derivatives
M. A. Solekhova and Yu. V. Kurbatov
Alisher Navoi Samarkand State University, Samarkand, 703004 Uzbekistan
Received April 6, 2001
Abstract In reaction of quinoline N-oxide with 2-aminopyridine in the presence of tosyl chloride the
substrate undergoes reductive amination into 2-pyridyl(2-quinolyl)amine, and with 3- and 4-aminopyridines
reductive tosylamination occurs to furnish N-tosyl derivatives of the corresponding 3- and 4-pyridyl(2-
quinolyl)amines. N-tosyl derivatives of aminopyridines also react along reductive tosylamination pathway.
In reaction of quinoline N-oxide (I) with ammonia
in the presence of tosyl chloride (II) that activates the
substrate molecule by its in situ transformation into
an N-acyloxy cation a reductive amination occurs
resulting in a high yield of 2-aminoquinoline [1].
Unlike that the pyridine N-oxide under similar condi-
tions undergoes acylamination furnishing as main
products N-tosyl-2-aminopyridine (III) and tosyldi-
(2-pyridyl)amine, and amination occurs only as side
process [2]. The direction of reaction depends on the
activity of the heterocyclic system in the nucleophilic
substitution, on the nucleophilicity of the reagent
(respectively ammonia and the secondary arising
anion), on the ease of amide formation and its ioniza-
tion effected by basic agent, and on the side processes
that remove the reagents from the reach of the main
process.Among the latter the most important is the
alkaline hydrolysis of sulfonyl chloride. Therefore in
performing this type of reactions it cannot be
unambiguously predicted which among them will
prevail.
with ammonia [1], acylamination of pyridine N-oxide
[2] and also of oxide I with N-tosylanilide [3] we
report here on investigation of reaction between oxide
I and isomeric aminopyridines and N-tosyl derivatives
thereof. As we described before [4] oxide I with
2-aminopyridine (IV) in the presence of compound II
under phase-transfer conditions (chloroform water) in
alkaline medium (sodium hydroxide or carbonate
solution) underwent amination to afford 2-pyridyl(2-
quinolyl)amine (V) in 80% yield.
Proceeding from the above mentioned results of
the previously studied reaction of oxide I amination
Reaction of oxide I and 3-aminopyridine (VI)
under similar conditions gives rise to 3-pyridyl(tosyl)-
(2-quinolyl)amine (VII) but in significantly lower
yield (10 15%), and the main part of amine VI
remained unreacted.
Similarly oxide I reacts with 4-aminopyridine
(IX). Therewith as the main product arises 4-pyridyl-
(tosyl)(2-quinolyl)amine (X) in up to 53% yield, and
as a side reaction occurs acylation of amine IX.
In the acylamination reactions under study the
reactive form is presumably the secondary formed
N-tosylimide ions [5]. Therefore it was logical to try
as reagents monotosyl aminopyridine derivatives.
1070-4280/02/3808-1192$27.00 2002 MAIK Nauka/Interperiodica

REDUCTIVE AMINATION OF QUINOLINE N-OXIDE
1193
Actually, the reaction of oxide I with N-tosyl
derivatives of 2- (III), 3- (VIII), and 4-aminopyridine
(XI) under analogous conditions furnished the cor-
responding 2-tosylamino quinoline derivatives VII,
X, XII in considerably higher yield.
Amination of quinoline N-oxide (I) with amine
IV. A solution of 11 mmol of oxide I dihydrate,
13 mmol of amine IV, and 11 mmol of sulfonyl
chloride II in 100 ml of chloroform was stirred with
40 ml of 10% water solution of sodium hydroxide for
2 h at 20 C. The water layer was separated, several
times extracted with chloroform, combined chloro-
form solutions were dried with Na2SO4, the solvent
was distilled off, and the oily residue was several
times washed with hot water. The cooled water solu-
tion was extracted with ethyl ether, the extract was
dried on Na2SO4, the solvent was removed, and
0.3 g (25%) of unreacted amine IV was thus
recovered. The crystalline residue after washing with
water was amine V, Rf 0.7, yield 2 g (80%), mp
110 C (from hexane) (mp 108 C [8]), mp of picrate
240 C (mp 242 244 C [8]), mp of hydrochloride
114 C (mp 115 116 C [8]).
2-Py (III, XII), 3-Py (VII, VIII), 4-Py (X, XI).
The structure of amide XII was proved by acid
hydrolysis to amine V, and the structures of isomeric
Amination of quinoline N-oxide (I) with com-
pounds III, VI, XIII, IX, XI. A solution of
5.5 mmol of oxide I, 5.5 mmol of compound III, VI,
XIII, IX, XI, and 5.5 mmol of sulfonyl chloride II
in 50 ml of chloroform was stirred with 20% solution
of sodium hydroxide (in reaction with compound XI
was used 20% solution of sodium carbonate). The
stirring at 20 C was carried out for 2 h. The water
layer was separated, several times extracted with
chloroform, combined chloroform solutions were
dried with Na2SO4, the solvent was distilled off.
The remaining crystalline residue was washed with
5% solution of NaHCO3 to obtained reaction products
VII, X, XII. Below are given the amine number, its
3-Py (VI, VII, XIII), 4-Py (IX, X, XIV).
amides VII and X was confirmed by acid hydrolysis
to the corresponding amines XIV, XV and by
independent synthesis of the latter by condensation of
carbostyril with amines [6].
yield (%), mp ( C), Rf respectively: (VII)
127 128 (from ethanol), 0.8; (X) 53, 225 226
(from ethanol), 0.9; (XII) 58.4, 186 (from ethanol),
0.96; (VII) 85.8, 127 128 (from ethanol), 0.9;
(X) 36.7, 224 226 (from ethanol), 0.9.
10,
In reaction of compound XI was obtained as side
product N,N-ditosyl-4-aminopyridine XV; its struc-
ture was confirmed by hydrolysis to monotosyl deriv-
ative XI and further to amine IX.
The reactions described are of interest for the
synthesis of sulfonylamides of quinoline and pyridine
series, and also for preparation of the corresponding
amines. All these substances are potential biologically
active compounds.
Unreacted compounds III, VI, XI were recovered
from water solutions. From reaction with compound
XI was isolated a side product, N,N-ditosyl-4-amino-
pyridine XV, Rf 0.7, mp 204 205 C (from ethanol).
Found, %: N 8.5. C19Æ18N2O4S. Calculated, %:
N 9.0.
EXPERIMENTAL
Hydrolysis of amides VII, X, XII. In 5 ml of
concn. HCl was dissolved 2.7 g of amide VII, X, XII,
and the solution was boiled for 18 h. The reaction
mixture was evaporated to dryness, the residue was
washed with ethyl ether, dissolved in water, the
solution was alkalized with potassium carbonate and
extracted with chloroform. On removing the solvent
amines V, XIII, XIV were obtained. Below are given
The reaction progress was monitored and homo-
geneity of compounds obtained was checked by paper
chromatography (no. 2, fast) in the system 1-butanol
hydrochloric acid water (50: 7: 14), development
with Dragendorff reagent [7]. All the known com-
pounds were identified by melting point determina-
tion in a mixed probe with authentic samples.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 8 2002

1194
SOLEKHOVA, KURBATOV
the amine number, its yield (%), mp ( C): ( C):
of amide XI, mp 280 C (subl.) (mp 280 C (subl.)
[10]).
(V)
55, 108 (from hexane) (mp 108 C [8]);
87, 168 170 (from ethanol). Found, %:
(XIII)
N 18.75. C14Æ11N3. Calculated, %: N 19.0. (XIV)
65, 140 141 (from petroleum ether, bp 40 60 C).
Found, %: N 18.8. C14Æ11N3. Calculated, %: N 19.0.
REFERENCES
1. Solekhova, M.A., Kurbatov, Yu.V., Fiziko-khi-
micheskie issledovaniya sinteticheskikh i prirodnykh
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kand. Gos. Univ., 1984.
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5. Solekhova, M.A., Cand. Sci. (Chem.) Dissertaion,
Moscow, 1987.
Hydrolysis of amide XI. A solution of 1.5 mmol
of amide XI in 5 ml of concn. HCl was boiled for
10 h. The reaction mixture was evaporated to dry-
ness, the residue was washed with ethyl ether, the
solvent was evaporated to obtain 0.2 g (80%) of
p-toluenesulfonic acid, mp 90 92 C (mp 92 C [9]).
The dry residue was dissolved in a minimal volume
of water, alkalized with sodium carbonate, extracted
with ethyl ether to isolate 0.1 g (70%) of amine IX,
mp 156 157 C (mp 158 C [9]).
Synthesis of amines XIII and XIV. A mixture of
5 mmol of carbostyril, 5 mmol of amine VI or IX,
and 20 mmol of P2O5 was heated to 200 C for 19
24 h. The reaction mixture was dissolved in 10% HCl,
alkalized with potassium carbonate, the separated
precipitate was filtered off, mixed with alumina,
extracted with petroleum ether, and on removing the
solvent amine XIII or XIV was obtained. Below are
given the amine number, Rf, its yield (%), mp ( C):
(XIII) 0.25, 9, 168 170; (XIV) 0.3, 18, 140 141.
6. Zwart, C. and Wibaut, J.P., Rec. Trav. Chim., 1955,
vol. 74, pp. 1081 1084.
7. Hais, I.M. and Macek, K., Paper Chromatography.
A Comprehensive Treatise, Publishing House of the
Czechoslovak Academy of Sciences, 1963.
8. Diepolder, E., J. Pr. Chem., 1923, vol. 106,
pp. 53 65.
9. Dictionary of Organic Compounds, Buckingham, J.
and Macdonald, F.M., New York: Chapman and
Hall, 1995.
Hydrolysis of amide XV. In 5 ml of 95% ethanol
was dissolved 5 mmol of amide XV, and the solution
was boiled for 5 h. The reaction mixture was cooled,
the separated crystals were filtered off to obtain 67%
10. Grammaticatis, A., Bull. Soc. Chim., 1959,
pp. 480 492.
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