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Russ.Chem.Bull., Int.Ed., Vol. 65, No. 9, September, 2016
Chudinov et al.
Table 2. Synthesis of Nꢀpyridinylacetamide 1ꢀoxide 3a—f from
aminopyridines 1a—f via preꢀdiazotization
Preparation of Nꢀpyridinylacetamides 2a—f by diazotization
of aminopyridines and their subsequent oxidation to Nꢀpyridinylꢀ
acetamide 1ꢀoxides 3a—f (general procedure). Aminopyridines
1a—f were converted to Nꢀpyridinylacetamides 2a—f upon treatꢀ
ment with the system NaNO2—H3PO4—MeCN according to
the procedure described above. Without isolation, glacial acetic
acid (7 mL) was added to the reaction mixture, which was heated
to 80—85 °C. Then, a 30% aqueous solution of hydrogen perꢀ
oxide (6 mL) was added in portions with continuous stirring. The
reaction mixture was stirred at this temperature for 7—8 h. The
reaction course was monitored by TLC (eluent hexane—acetone,
1 : 3) and GCꢀMS. Upon reaction completion, the reaction mixꢀ
ture was neutralized with 10% aqueous solution of NaHCO3 and
extracted with dichloromethane (2×30 mL). Compounds 3a—f
were purified by column chromatography (dichloromethane).
Yields and m.p. of Nꢀoxides 3a—f are summarized in Table 2.
NMR spectra and m.p. of synthesized compounds correspond to
the data published for authentic samples.
2, 3 NHAca
R´
τ/hb
Yield (%)
77
M.p./°C
a
b
c
d
e
f
2
2
2
2
4
3
H
8
141—143
(140—14114)
164—167
5ꢀBr
5ꢀCl
6ꢀMe
H
7
7
7
8
7
78
76
70
64
68
(165—16815)
150—151
(150—15116)
129—131
(130—13216)
293—295
(294—29617)
208—210
H
(209—21118)
a Position of substituent NHAc.
b Reaction time.
c Literature data are given in parentheses.
This work was financially supported by the Russian
Foundation for Basic Research (Project No. 14ꢀ03ꢀ00743a),
the analytical part of the work was financially supported
by the Ministry of Education and Science of the Russian
Federation (State Contract "Science", Project No. 2387).
Experimental
Aminopyridines 1a—g were commercially available from Sigꢀ
maꢀAldrich, acetonitrile (reagent grade), 98% phosphoric acid
(reagent grade, d 1.870 g L–1), 30% hydrogen peroxide (reagent
grade, d 1.40 g L–1). Purification was performed on silica gel for
chromatography (40—60 μm). Reaction progress and purity of
products were monitored by TLC on SorbfilꢀAF 254 plates, usꢀ
ing benzene—ethanol (9 : 2) or hexane—ethyl acetate (1 : 3) as
eluents. Spots of compounds were visualized under UV light at
λ = 254 nm. Compounds were analyzed on an Agilent 7890/5975C
chromatograph with a quadrupole mass spectrometer as a detecꢀ
References
1. R. N. Butler, Chem. Rev., 1975, 75, 241.
2. A. N. Tretjakov, E. A. Krasnokutskaya, D. A. Gorluschko,
V. D. Filimonov, Tetrahedron Lett., 2011, 52, 85.
3. E. A. Krasnokutskaya, A. Zh. Kassanova, M. T. Estaeva,
V. D. Filimonov, Tetrahedron Lett., 2014, 55, 3771.
4. E. A. Krasnokutskaya, N. I. Semenischeva, V. D. Filimonov,
P. A. Knochel, Synthesis, 2007, 81.
5. T. Ross Kelly, F. Lang, J. Org. Chem., 1996, 61, 4623.
6. C. Helgen, C. Bochet, Heterocycles, 2006, 67, 797.
7. P. Mahajan, J. Mahajan, S. Mhaske, Syntheses Commun.,
2013, 43, 2508.
8. I. N. Azerbaev, I. A. Poplavskaya, R. G. Kurmangalieva,
S. F. Khalilova, Chem. Heterocycl. Compd. (Engl. Transl.),
1978, 14, 1241 [Khim. Geterotsikl. Soedin., 1978, 1525].
9. J. Epsztajn, A. Bieniek, J. Kowalska, Tetrahedron Lett., 1991,
47, 1697.
1
tor (EI, 70 eV), carrier gas nitrogen. H and 13C NMR spectra
were recorded on a Bruker ACꢀ300 spectrometer (300 MHz) in
DMSOꢀd6, using SiMe4 as an internal standard. Melting points
of compounds were determined in a capillary tube, using a MP50
Melting point system heating stage (Mettlertoledo).
Synthesis of Nꢀpyridinylacetamides 2a—g upon treatment with
a mixture of NaNO2—H3PO4 in a paste with acetonitrile (general
procedure). Phosphoric acid (0.7 mL, 12 mmol) was added to
acetonitrile (0.5 mL, 9.5 mmol), the resulting mixture was cooled
to 10—15 °C. Then, a mixture of aminopyridine 1a—g (2 mmol)
and sodium nitrite (0.56 g, 8 mmol) preꢀtriturated in a mortar
was added in small portions at such a rate that allowed us to
avoid vigorous liberation of nitrogen oxides. The resulting paste
was thoroughly triturated and allowed to stand at 10—15 °C for
10 min and then at 20 °C for the period of time indicated in
Table 1. The reaction progress was monitored by TLC (eluent
hexane—acetone, 1 : 3) and GCꢀMS. Upon completion, the
reaction mixture was diluted with water, neutralized with
NaHCO3, and extracted with ethyl acetate. The organic layer
was separated and dried with Na2SO4, the solvent was evaporated.
Compounds 2a—g were purified by recrystallization from ethanol.
Yields and m.p. of compounds 2a—g are summarized in Table 1.
NMR spectra and m.p. of compounds obtained correspond to
the data published for authentic samples.
10. J. Epsztajn, A. Bieniek, M. Ptotka, K. Suwald, Tetrahedron
Lett., 1989, 45, 7469.
11. CH Pat. 578870; Chem. Abstr., 1976, 80, 134907.
12. L. Sudha, S. Manogaran, J. Mol. Struc., 1985, 129, 137.
13. Nan Zheng, Angew. Chem., Int. Ed., 2007, 46, 7509.
14. M. A. Lipton, J. Med. Chem., 1978, 21, 874.
15. US Pat. 3163655; Chem. Abstr., 1965, 62, 10419b.
16. G. Lesher, Sterling Drug Inc., US Pat. 3907798 A, 1975.
17. В. Uno, K. Kano, N. Kaida, Spectrochimica Acta, 1989, 45,
9, 937—943.
18. D. Herz, D. Murty, J. Org. Chem., 1960, 25, 12, 2242.
Received January 22, 2016;
in revised form June 3, 2016