One-step synthesis of substituted 4,8-dihydropyrano[3,2-b]pyran-4-ones [3]

Full text of DOI:10.1023/B:RUCB.0000035666.05686.89

724
Russian Chemical Bulletin, International Edition, Vol. 53, No. 3, pp. 724—725, March, 2004
Oneꢀstep synthesis of substituted
4,8ꢀdihydropyrano[3,2ꢀb]pyranꢀ4ꢀones
A. A. Shestopalov, L. A. Rodinovskaya, A. M. Shestopalov, and V. P. Litvinovꢀ
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (095) 135 5328. Eꢀmail: vpl@ioc.ac.ru
Kojic acid, which was first isolated from Aspergillus
actions of kojic acid (1) with malononitrile (2) and carboꢀ
oryzae, was used in reactions with arylidenemalononitriles
for the preparation of substituted 6ꢀaminoꢀ8ꢀarylꢀ2ꢀ
hydroxymethylꢀ4,8ꢀdihydropyrano[3,2ꢀb]pyranꢀ4ꢀones
as analogs of human immunodeficiency virus (HIV)
protease inhibitors.1—3 In continuation of studies of the
crossꢀreactions of carbonyl compounds with cyanoꢀ
acetic acid derivatives with the aim of developing conꢀ
venient oneꢀstep methods for the synthesis of funcꢀ
tionalized carboꢀ and heterocycles,4,5 we studied the reꢀ
nyl compounds 3—5 and developed a oneꢀstep proceꢀ
dure for the preparation of substituted 4,8ꢀdihydropyraꢀ
no[3,2ꢀb]pyranꢀ4ꢀones 6—8.
Compounds 6—8 were prepared in one step without
the preliminary synthesis and isolation of unsaturated niꢀ
triles by briefly refluxing equimolar amounts of the startꢀ
ing reagents 1 and 2 and the corresponding carbonyl comꢀ
pounds 3—5 in ethanol in the presence of catalytic
amounts of Et3N.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 690—691, March, 2004.
1066ꢀ5285/04/5303ꢀ0724 © 2004 Plenum Publishing Corporation

6ꢀAminoꢀ4,8ꢀdihidropyrano[3,2ꢀb]pyranꢀ4ꢀone
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 3, March, 2004
725
4 H, C(3´)H2, C(5´)H2); 2.24 (s, 3 H, Me); 2.42—2.73 (m, 4 H,
C(2´)H2, C(6´)H2); 4.32 (dd, 1 H, CH2, J = 15.2 Hz, J =
6.4 Hz); 4.38 (dd, 1 H, CH2, J = 15.2 Hz, J = 6.4 Hz); 5.68 (t,
1 H, OH, J = 6.4 Hz); 6.47 (s, 1 H, C(3)H); 6.94 (s, 2 H, NH2).
6ꢀAminoꢀ7ꢀcyanoꢀ2ꢀhydroxymethylꢀ1´ꢀmethylindaneꢀ
4,2´ꢀdioxoꢀ4,8,2´,3´ꢀtetrahydrospiro[pyrano[3,2ꢀb]pyranꢀ8,3´ꢀ
indole] (8) was prepared analogously. The yield was 89%, white
powder, m.p. 223—224 °C (from nitromethane). Found (%):
C, 61.31; H, 3.54; N, 11.68. C18H13N3O5. Calculated (%):
C, 61.54; H, 3.73; N, 11.96. IR, ν/cm–1: 3486, 3369, 3265, 3148
(OH, NH2); 2192 (CN); 1680, 1672 (CO); 1627 (δ NH2).
1H NMR, δ: 3.28 (s, 3 H, CH3); 3.98 (dd, 1 H, CH2, J =
15.6 Hz, J = 6.5 Hz); 4.10 (dd, 1 H, CH2, J = 15.6 Hz, J =
6.5 Hz); 5.43 (t, 1 H, OH, J = 6.5 Hz); 6.34 (s, 1 H, C(3)H);
7.15 (d, 1 H, C(7´)H, J = 7.9 Hz); 7.18 (t, 1 H, C(6´)H, J =
7.9 Hz, J = 7.7 Hz); 7.27 (d, 1 H, C(4´)H, J = 8.2 Hz); 7.32 (s,
2 H, NH2); 7.39 (t, 1 H, C(5´)H, J = 7.7 Hz, J = 8.2 Hz).
In the present study, spiroꢀfused heterocycles 7 and 8
were prepared for the first time. The advantage of the new
method is that it allows one to prepare compounds 6—8
in high yields (83—97%). It should also be stressed that
compound 7 can only be synthesized by the threeꢀcomꢀ
ponent reaction, since the attempted preparation of unꢀ
saturated nitrile 9 from malononitrile 2 and piperidinꢀ4ꢀ
one 4 afforded ultimately isoquinoline 10.5
1
The H NMR spectra were recorded on a Bruker DRX 500
spectrometer (500.13 MHz) in DMSOꢀd6 with Me4Si as the
internal standard. The IR spectra were measured on a Perkinꢀ
Elmer 577 instrument in KBr pellets. Elemental analysis was
carried out on a PerkinꢀElmer C,H,Nꢀanalyzer.
6ꢀAminoꢀ7ꢀcyanoꢀ2ꢀhydroxymethylꢀ8ꢀ[(4ꢀtrifluoromethylꢀ
thio)phenyl]ꢀ4,8ꢀdihydropyrano[3,2ꢀb]pyranꢀ4ꢀone (6). A mixꢀ
ture of kojic acid 1 (0.71 g, 0.005 mol), malononitrile (2) (0.33 g,
0.005 mol), aldehyde 3 (1.03 g, 0.005 mol), and Et3N (0.14 mL,
0.001 mol) in EtOH (20 mL) was refluxed for 15 min and kept at
4 °C for 12 h. The precipitate that formed was filtered off and
washed with ethanol and hexane. After recrystallization from
EtOH, compound 6 was obtained in a yield of 1.92 g (97%) as
colorless crystals, m.p. 224—226 °C. Found (%): C, 51.29;
H, 2.62; N, 6.85. C17H11F3N2O4S. Calculated (%): C, 51.52;
H, 2.80; N, 7.07. IR, ν/cm–1: 3498, 3385, 3264, 3167 (OH,
NH2); 2193 (CN); 1672 (CO); 1637 (δ NH2). 1H NMR, δ: 4.12
(dd, 1 H, CH2, J = 15.0 Hz, J = 6.2 Hz); 4.21 (dd, 1 H, CH2, J =
15.0 Hz, J = 6.2 Hz); 4.85 (s, 2 H, NH2); 5.52 (t, 1 H, OH, J =
6.2 Hz); 6.37 (s, 1 H, C(3)H); 7.24 (s, 2 H, NH2); 7.46 (d, 2 H,
C6H4, J = 7.1 Hz); 7.75 (d, 2 H, C6H4, J = 7.1 Hz).
6ꢀAminoꢀ7ꢀcyanoꢀ2ꢀhydroxymethylꢀ1´ꢀmethylꢀ4,8ꢀdihydroꢀ
spiro[pyrano[3,2ꢀb]pyranꢀ8,4´ꢀpiperidine]ꢀ4ꢀone (7) was preꢀ
pared analogously. The yield was 83%, white powder, m.p.
248—250 °C (from nitromethane). Found (%): C, 59.73; H, 5.84;
N, 13.97. C15H17N3O4. Calculated (%): C, 59.40; H, 5.65;
N, 13.85. IR, ν/cm–1: 3492, 3376, 3284, 3153 (OH, NH2); 2188
(CN); 1687 (CO); 1625 (δ NH2). 1H NMR, δ: 1.86—2.07 (m,
This study was financially supported by the Russian
Foundation for Basic Research (Project No. 02ꢀ03ꢀ
32063).
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Received March 15, 2004