The microwave assisted nucleophilic substitution of 4-hydroxy-6-methyl- 2(1H)-pyridones

Article abstract of DOI:10.1055/s-1999-2929

The condensation of 4-hydroxy-6-methyl-2(1H)-pyridones 1 with araliphatic amino compounds 2 gives rise to the 4-alkylamino-6-methyl-2(1H)- pyridones 3. Irradiation using an ordinary domestic microwave oven provides a fast and simple method for their preparation. However, under the conditions used, aliphatic and aromatic amines gave no reaction.

Full text of DOI:10.1055/s-1999-2929

LETTER
1747
The Microwave Assisted Nucleophilic Substitution of 4-Hydroxy-6-methyl-
2(1H)-pyridones
Dieter Heber,a* Edmont V. Stoyanovb*
a Department of Pharmaceutical Chemistry, University of Kiel, Gutenbergstr. 76, D-24118 Kiel, Germany
Fax +49/0431/8801118; E-mail: dheber@pharmazie.uni-kiel.de
b Department of Industrial Pharmacy, Faculty of Pharmacy, Medical University of Sofia, Dunav 2, BG-1000 Sofia, Bulgaria
Received 16 July 1999
solution (Table 1). Shorter irradiation times gave always
Abstract: The condensation of 4-hydroxy-6-methyl-2(1H)-pyri-
mixtures of starting compounds 1 and products 3. The
dones 1 with araliphatic amino compounds 2 gives rise to the 4-
pressure reaction tube used for these experiments must be
provided with a teflon ring to close the tube and to permit
alkylamino-6-methyl-2(1H)-pyridones 3. Irradiation using an ordi-
nary domestic microwave oven provides a fast and simple method
for their preparation. However, under the conditions used, aliphatic longer irradiation at 600 W. 4-Hydroxy-6-methyl-2(1H)-
pyridone (R1=H) did not react with 1-phenylethylamine
and aromatic amines gave no reaction.
neither did 1-ethyl-4-hydroxy-6-methyl-2(1H)-pyridone
with all used amines under the reaction conditions used.
Irradiation time for each experiment was determined by
tlc-control with pre-coated plates of silica gel every 2
minutes.
Key words: 4-alkylamino-6-methyl-2(1H)-pyridones, microwave
irradiation, condensation
In a recent paper1 one of us described the synthesis of 2-
imino-1,6(6H)-naphthyridin-5-ones with interesting anti-
tuberculosis activity. The reaction sequence involved the
Vilsmeier formylation of 1-alkyl-4-alkylamino-6-methyl-
2(1H)-pyridones 3 followed by condensation of the corre-
sponding heterocyclic carbaldehydes with methylene ac-
tive nitriles under Knoevenagel reaction conditions. The
preparation of the pyridones 3j,k described previously by
Castillo et al.2 requested long reaction times starting from
4-hydroxy-6-methyl-2-pyrone and the yields and the mo-
lar equivalents were not reported in this paper. Other
authors3,4 reported the preparation of compounds 3a and
3b using drastic reaction conditions (reflux in benzyl-
amine under nitrogen for 72 hours). In a previous paper5
on the preparation of 4-hydroxy- and 4-alkylamino-
2(1H)-pyridones we established that the reaction time re-
quested in a boiling solution of the amine ranges from 2 to
5 hours for the preparation of 3h-k.
Scheme 1
In order to save the 2-imino character of novel 1,6-naph-
thyridines synthesized for the determination of structure-
activity relationships of these heterocyclic compounds,
we needed a facile method for the preparation of the start-
ing 4-alkylamino-6-methyl-2(1H)-pyridones 3. In our re-
search work on amino acids we applied successfully
microwave irradiation which has been used to enhance a
great number of classical organic reactions.6-8 Thus, in a
typical procedure the nucleophilic substitution of the hy-
droxy group of 4-hydroxy-6-methyl-2(1H)-pyridones 1
was carried out using an excess of amine 2 (ratio 1 : 2 = 1
: 4.5) without any solvent under microwave irradiation for
a short of time (Scheme 1). It is noteworthy to mention
that the starting 4-hydroxypyridones 1 were isolated after
20 minutes at 100, 240 and 440 W so that no reaction had
taken place under these conditions. When switching to
600 W the process was accomplished after 14 - 20 minutes
and the reaction mixture had changed from suspension to
In order to establish the general behaviour of this reaction
under microwave conditions, several types of amino com-
pounds were studied. The following amines did not give
any reaction under the conditions described above: ali-
Synlett 1999, No. 11, 1747–1748 ISSN 0936-5214 © Thieme Stuttgart · New York

1748
D. Heber, E. V. Stoyanov
LETTER
ml beaker which was filled with vermiculite, a polymeric
phatic primary amino compounds such as allylamine, pro-
pylamine, 2-hydroxyethylamine, and N,N-
material for covering hazardous compounds in packages.
After irradiation in an ordinary domestic microwave oven
(Panasonic NN-5206 with rotate plate) for the period shown in
Table 1, the reaction mixture was cooled. Adding ice-cold
ethyl acetate the separated solid was collected by filtration and
washed twice with ethyl acetate to give tlc pure compounds.
The compounds were recrystallized from MeOH, EtOH, or 2-
PrOH. TLC monitoring: precoated aluminium sheets, 0.2 mm
layer of silicagel Merck GF254, eluted by methylene chloride/
acetone/methanol (3:2:1, v/v); detection by Fluotest®
Universal (λ = 254/366 nm).
dibutylethylene diamine as well as methylamine and eth-
ylamine as water solution and the aromatic amines
aniline, p-toluidine, N-methylaniline, 4-hydroxyaniline,
and 4-aminopyridine and the secondary aliphatic amines
piperidine and diisobutylamine.
Structural assignment of 3(c-j) was made on the basis of
spectral data (1H NMR).
In conclusion, the present procedure for the amination of
4-hydroxy-2(1H)-pyridone 3 has some advantages over
the existing methods and will make a useful and important
addition to present methodologies. The main advantages
of this new method are short reaction times and excellent
yields.
1H-NMR spectroscopic data of some of 4-alkylamino-2(1H) -
pyridones 3 (300 MHz): 3a (DMSO-d6): δ = 2.01 (s, 3H, 6-
CH3), 4.20 (d, 2H, J= 5.8 Hz, CH2C6H5), 4.89 (s, 1H, H-3),
5.52 (s, 1H, H-5), 6.96 (t, 1H, J = 6.8 Hz, 4-N-H), 7.22-7.36
(m, 5H arom.), 10.43 (s, 1H, 1-N-H).
3b (CDCl3): δ = 2.23 (s, 3H, 6- CH3), 3.40 (s, 3H, N-CH3),
4.26 (d, 2H, J = 5.5 Hz, CH2C6H5), 4.40 (br.t, 1H, N-H), 5,52
(s, 2H, H-3 and H-5), 7.26-7.36 (5H arom.).
3c (DMSO-d6): δ = 2.21 (s, 3H, 6-CH3), 2.79 (t, 2H, J = 7.1
Hz, CH2C6H5), 3.19 (t, 2H, J = 7.5 Hz, N-CH2), 4.85 (s, 1H,
H-3), 5.48 (s, 1H, H-5), 6.45 (t, 1H, J = 5.3 Hz, NH-CH2),
7.17-7.32 (5H arom.), 10.39 (s, 1H, 1-N-H).
Acknowledgement
We are grateful to the DAAD, NATO Science Fellowship program
for supporting the present work.
3d (CDCl3): δ = 2.22 (s, 3H, 6-CH3), 2.88 (t, 2H, J = 6.9 Hz,
CH2C6H5), 3.23 (t, 2H, J = 7.1 Hz, N- CH2), 3.41 (s, 3H, N-
CH3), 4.04 (br.t., 1H, N-H), 5.41 (s, 1H, H-3), 5.53 (s, 1H, H-
5), 7.17-7.34 (m, 5H arom.).
3e (DMSO-d6): δ = 1.38 (d, 3H, J = 6.8 Hz, CH3-CH), 2.17 (s,
3H, 6-CH3), 3.23 (s, 3H, N-CH3), 4.41 (p, 1H, J = 6.8 Hz, CH-
CH3), 4.89 (s, 1H, H-3), 5.66 (s, 1H, H-5), 6.80 (d, 1H, J = 6.8
Hz, 4-N-H), 7.30-7.34 (m, 5H arom.).
3f (DMSO-d6): δ = 1.86 (d, 3H, J = 6.7 Hz, CH3-CH), 2.16 (s,
3H, 6-CH3), 4.48 (p, 1H, J = 6.9 Hz, CH-CH3), 5.09 (s, 2H,
CH2C6H5), 5.15 (q, 1H, J = 16 Hz, H-3), 5.71 (s, 1H, H-5),
7.03 (d, 1H, J = 6.8 Hz, NH-CH), 7.20-7.34 (m, 10H arom.).
3g (DMSO-d6): δ = 1.38 (d, 3H, J = 6.8 Hz, CH3-CH), 2.04 (s,
3H, 6- CH3), 2.75 (t, 2H, J = 7.6 Hz, CH2C6H5), 3.89 (t, 2H, J
= 7.9 Hz, N-CH2), 4.43 (p, 1H, J = 6.8 Hz, CH- CH3), 4.93 (s,
1H, H-3), 5.62 (s, 1H, H-5), 6.84 (t, 1H, J = 6.8 Hz, 4-N-H),
7.10-7.33 (m, 10H arom.).
References and Notes
(1) Ivanov, I. C.; Stoyanov, E. V.; Denkova, P. S.; Dimitrov, V.
S. Liebigs Ann./Recueil 1997, 1777.
(2) Castillo, S.; Ouadahi, H.; Herault, V. Bull. Soc. Chim. Fr.
1982, II, 257.
(3) Hung, N. C.; Bisagni, E. Synthesis 1984, 765.
(4) Rivalle, C.; Bisagni, E. J. Heterocycl. Chem. 1980, 17, 245.
(5) Ivanov, I. C.; Stoyanov, E. C.; Alexandrova, S. V.
Farmatsyia (Sofia), 1997, 44 (2), 3-6; C.A. 1997,
127:220596e.
(6) Giguere, R. J. Organic Synthesis: Theory and Application; Ed.
by JAI Press Inc. Vol. 1, 1989.
(7) Loupy, A.; Petit, A.; Hamelin, J.;Texier-Boullet, F.;
Jacquault, P.; Mathe, D; Synthesis 1998, 1213.
(8) Caddick, S.; Tetrahedron 1995, 51, 10403.
(9) General procedure: A mixture of 1 mmol of the
corresponding 4-hydroxy-2(1H)-pyridone 3 and 4.5 mmol of
benzyl-, 1-phenylethyl- or 2-phenylethylamine 2 was filled
into a 15 ml pressure tube (ALDRICH, with threaded type A
plug, length 10.2 cm and additionally provided with a teflon
ring). Then the reaction tube was placed in the center of an 800
Article Identifier:
1437-2096,E;1999,0,11,1747,1748,ftx,en;G18999ST.pdf
Synlett 1999, No. 11, 1747–1748 ISSN 0936-5214 © Thieme Stuttgart · New York