One-step synthesis of 3-cyano-6-methyl-4-thienyl-5,6,7,8-tetrahydro[1,6] naphthyridine-2(1H)-thiones and annelated heterocyclic systems on their basis [4]

Full text of DOI:10.1007/s11172-005-0133-7

Russian Chemical Bulletin, International Edition, Vol. 53, No. 10, pp. 2353—2354, October, 2004
2353
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Oneꢀstep synthesis of 3ꢀcyanoꢀ6ꢀmethylꢀ4ꢀthienylꢀ
5,6,7,8ꢀtetrahydro[1,6]naphthyridineꢀ2(1H )ꢀthiones
and annelated heterocyclic systems on their basis
A. A. Shestopalov, A. V. Gromova, L. A. Rodinovskaya, K. G. Nikishin, V. P. Litvinov, and A. M. Shestopalovꢀ
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (095) 135 5328. Eꢀmail: shchem@dol.ru
A broad spectrum of biological activity of substituted
ployed as an oxidant of intermediate substituted aminoꢀ
naphthyridines (from drugs to chemicals for plant protecꢀ
tion) gives impetus to a search for routes to these comꢀ
pounds.1 Naphthyridines containing vicinal cyano and
thiol groups, which are widely used to obtain naphthyridiꢀ
nes annelated with other heterocycles, are of great synꢀ
thetic potential.1,2
In this communication, oneꢀstep synthesis of substiꢀ
tuted 3ꢀcyanoꢀ5,6,7,8ꢀtetrahydro[1,6]naphthyridineꢀ
2(1H )ꢀthiones and new polyannelated heterocycles on
their basis is presented. The Et3Nꢀcatalyzed multicompoꢀ
nent reaction of 1ꢀmethylpiperidinꢀ4ꢀone (1), cyanoꢀ
thioacetamide (2), thiophenecarboxaldehydes 3a,b, and
sodium thiosulfate in boiling ethanol for a short time
yielded naphthyridines 4. Sodium thiosulfate was used
as a dehydrogenating agent for intermediate hydrogeꢀ
nated naphthyridines 5, which increases the yields of
naphthyridines 4 to 60—63%. Earlier, Na2S2O3 was emꢀ
4,5ꢀdihydrothiophenes into aminothiophenes.3 Unlike
other oxidants (bromine or hydrogen peroxide) used to
oxidize hydrogenated pyridineꢀ2(1H )ꢀthiones,2 Na2S2O3
does not oxidize pyridineꢀ2(1H )ꢀthiones into the correꢀ
sponding bis(2ꢀpyridyl) disulfides.
Naphthyridines 4 are convenient reagents in cascade
reactions1,4 used in the synthesis of polyannelated hetꢀ
erocycles 6 and 7. The reaction of naphthyridine 4a
with ethyl 4ꢀchloroacetoacetate 8 in boiling EtOH in
the presence of EtONa gave pyrido[2´,3´:4,5]thieꢀ
no[2,3ꢀb][1,6]naphthyridine 6. Under analogous conꢀ
ditions, the reaction of compound 4a with chloroꢀ
acetylurethan
9 afforded pyrimido[4´,5´:4,5]thieꢀ
no[2,3ꢀb][1,6]naphthyridine 7, which represents an earꢀ
lier unknown heterocyclic system.
1
H NMR spectra were recorded on a Bruker AMꢀ300 specꢀ
trometer (300 MHz) in DMSOꢀd6 with Me4Si as the internal
3, 5: R = 2ꢀthienyl (a), 3ꢀthienyl (b).
Reagents and conditions: i. EtOH, Et3N, Na2S2O3•5 H2O, ∆, 0.5 h; ii. 1) 2.5 M EtONa, EtOH, ∆, 0.5 h; 2) 10% HCl.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 10, pp. 2252—2253, October, 2004.
1066ꢀ5285/04/5310ꢀ2353 © 2004 Springer Science+Business Media, Inc.

2354
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 10, October, 2004
Shestopalov et al.
standard. IR spectra were recorded on a PerkinꢀElmerꢀ577 inꢀ
strument (KBr pellets). Elemental analysis was performed with
a PerkinꢀElmer C, H, Nꢀanalyzer.
reaction mixture was refluxed for 0.5 h, cooled to 25 °C, and
acidified with 10% HCl (3 mL). The precipitate that formed was
filtered off to give a colorless powder (0.65 g, 88%), m.p. > 300 °C
(from dioxane). Found (%): C, 58.18; H, 3.72; N, 11.08.
C18H15N3O2S2. Calculated (%): C, 58.52; H, 4.09; N, 11.37.
IR, ν/cm–1: 3410 (OH); 1625 (CONH). 1H NMR, δ: 2.84 (s,
3 H, Me); 3.38 (m, 2 H, C(8)H2); 3.47 (m, 2 H, C(7)H2);
4.16 (s, 2 H, C(5)H2); 6.05 (s, 1 H, C(3)H); 7.04 (d, 1 H,
C(3´)Hꢀthiophene, J = 3.2 Hz); 7.42 (dd, 1 H, C(4´)Hꢀthioꢀ
phene, J = 3.2 Hz, J = 5.5 Hz); 8.15 (d, 1 H, C(5´)Hꢀthiophene,
J = 5.5 Hz); 11.94 (s, 1 H, NH).
2ꢀHydroxyꢀ9ꢀmethylꢀ11ꢀ(2ꢀthienyl)ꢀ7,8,9,10ꢀtetrahydroꢀ
pyrimido[4´,5´:4,5]thieno[2,3ꢀb][1,6]naphthyridinꢀ4(3H )ꢀone
(7) was obtained analogously from naphthyridine 4a and chloroꢀ
acetylurethan 9 in 82% yield; colorless powder, m.p. > 300 °C
(from dioxane). Found (%): C, 54.82; H, 3.56; N, 14.87.
C17H14N4O2S2. Calculated (%): C, 55.12; H, 3.81; N, 15.12.
IR, ν/cm–1: 3508 (OH); 1642, 1704 (CONH). 1H NMR, δ: 2.84
(s, 3 H, Me); 3.43 (m, 2 H, C(8)H2); 3.53 (m, 2 H, C(7)H2);
4.18 (s, 2 H, C(5)H2); 7.00 (d, 1 H, C(3´)Hꢀthiophene, J =
3.3 Hz); 7.43 (s, 1 H, OH); 7.45 (dd, 1 H, C(4´)Hꢀthiophene,
J = 3.3 Hz, J = 4.6 Hz); 8.15 (d, 1 H, C(5´)Hꢀthiophene, J =
4.6 Hz); 11.58 (s, 1 H, NH).
3ꢀCyanoꢀ6ꢀmethylꢀ4ꢀ(2ꢀthienyl)ꢀ5, 6, 7, 8ꢀtetraꢀ
hydro[1,6]naphthyridineꢀ2(1H )ꢀthione (4a). A mixture of
1ꢀmethylpiperidinꢀ4ꢀone (1) (0.57 g, 5 mmol), cyanothioacetꢀ
amide (2) (0.50 g, 5 mmol), thiopheneꢀ2ꢀcarboxaldehyde (3a)
(0.56 g, 5 mmol), Na2S2O3•5H2O (1.90 g, 7.5 mmol), and Et3N
(0.3 mL, 2 mmol) in 30 mL of anhydrous ethanol was refluxed
for 0.5 h. The reaction mixture was kept at 4 °C for 12 h, diluted
with water (5 mL), and acidified with 10% HCl (0.3 mL). The
precipitate that formed was filtered off and washed with ethanol
and hexane to give compound 4a (0.92 g, 64%) as small orange
crystals, m.p. 259—263 °C (decomp.) (from nitromethane).
Found (%): C, 58.24; H, 4.37; N, 14.25. C14H13N3S2. Calcuꢀ
lated (%): C, 58.51; H, 4.56; N, 14.62. IR, n/cm–1: 2228 (CN);
1202 (CS). 1H NMR, d: 2.27 (s, 3 H, Me); 2.64 (m, 2 H,
C(8)H2); 2.88 (m, 2 H, C(7)H2); 3.11 (s, 2 H, C(5)H2); 7.24 (dd,
1 H, C(4´)Hꢀthiophene, J = 3.3 Hz, J = 4.6 Hz); 7.33 (d, 1 H,
C(5´)Hꢀthiophene, J = 3.3 Hz); 7.86 (d, 1 H, C(3´)Hꢀthiophene,
J = 4.6 Hz); 13.92 (s, 1 H, NH).
3ꢀCyanoꢀ6ꢀmethylꢀ4ꢀ(3ꢀthienyl)ꢀ5, 6, 7, 8ꢀtetraꢀ
hydro[1,6]naphthyridineꢀ2(1H )ꢀthione (4b) was obtained analoꢀ
gously from thiopheneꢀ3ꢀcarboxaldehyde (3b) in 60% yield; orꢀ
ange crystals, m.p. 255—258 °C (decomp.) (from nitromethane).
Found (%): C, 58.75; H, 4.18; N, 14.56. C14H13N3S2. Calcuꢀ
lated (%): C, 58.51; H, 4.56; N, 14.62. IR, ν/cm–1: 2220 (CN);
1208 (CS). 1H NMR, δ: 2.24 (s, 3 H, Me); 2.63 (m, 2 H,
C(8)H2); 2.86 (m, 2 H, C(7)H2); 3.03 (s, 2 H, C(5)H2);
7.23 (d, 1 H, C(4´)Hꢀthiophene, J = 4.3 Hz); 7.75 (d, 1 H,
C(5´)Hꢀthiophene, J = 4.3 Hz); 7.84 (s, 1 H, C(2´)Hꢀthioꢀ
phene); 13.87 (s, 1 H, NH).
References
1. V. P. Litvinov, Usp. Khim., 2003, 71, 75 [Russ. Chem. Rev.,
2003, 71 (Engl. Transl.)].
2. V. P. Litvinov, L. A. Rodinovskaya, Yu. A. Sharanin, A. M.
Shestopalov, and A. Senning, Sulfur Reports, 1992, 13, 1.
3. R. A. Rodinovskaya, A. M. Shestopalov, and K. S. Chunikhin,
Tetrahedron, 2002, 58, 4273.
4ꢀHydroxyꢀ9ꢀmethylꢀ11ꢀ(2ꢀthienyl)ꢀ7,8,9,10ꢀtetrahydroꢀ
pyrido[2´,3´:4,5]thieno[2,3ꢀb][1,6]naphthyridinꢀ2(1H )ꢀone (6).
A solution of EtONa prepared from metallic sodium (0.11 g,
5 mmol) and EtOH (10 mL) was added to a mixture of comꢀ
pound 4a (0.57 g, 2 mmol) and ethyl 4ꢀchloroacetoacetate 8
(0.33 g, 2 mmol) in 25 mL of anhydrous ethanol. The stirred
4. V. A. Artyomov, L. A. Rodinovskaya, A. M. Shestopalov, and
V. P. Litvinov, Tetrahedron, 1996, 52, 1011.
Received July 27, 2004