Convenient selective synthesis of pyrano[2,3-d]pyrimidines

Article abstract of DOI:10.1007/s11172-008-0308-0

A selective method for the synthesis of substituted and annulated pyrano[2,3-d]pyrimidines consisting in acylation of 2-amino-3-cyano-4H-pyrans with acetic anhydride has been developed. It was shown for the first time that acid catalysis is more efficient in this reaction, rather than base catalysis as it has been believed earlier.

Full text of DOI:10.1007/s11172-008-0308-0

Russian Chemical Bulletin, International Edition, Vol. 57, No. 10, pp. 2223—2226, October, 2008
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Convenient selective synthesis of pyrano[2,3ꢀd]pyrimidines
Yu. M. Litvinov and A. M. Shestopalov
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5328. Eꢀmail: amsh@ioc.ac.ru
A selective method for the synthesis of substituted and annulated pyrano[2,3ꢀd]pyrimidines
consisting in acylation of 2ꢀaminoꢀ3ꢀcyanoꢀ4Hꢀpyrans with acetic anhydride has been
developed. It was shown for the first time that acid catalysis is more efficient in this reaction,
rather than base catalysis as it has been believed earlier.
Key words: pyrano[2,3ꢀd]pyrimidine, 2ꢀaminoꢀ3ꢀcyanoꢀ4Hꢀpyrans annulated heterocycles,
acylation, acid catalysis.
Scheme 1
Heterocycles containing pyrano[2,3ꢀd]pyrimidine
fragment possess antibacterial and fungicide activity,1—3
as well as are patented as the leucoforms of thermoꢀ,
tensoꢀ and electrosensitive dyes.
One of the principal methods for the synthesis of
substituted pyrano[2,3ꢀd]pyrimidinꢀ4ꢀones includes the
reaction of acetic anhydride with substituted 2ꢀaminoꢀ
3ꢀcyanoꢀ4Hꢀpyrans with no catalyst or in the presence of
basic catalysts (e.g., pyridine). However, this reaction
is not always selective. Thus, the reaction of ethyl 2ꢀaminoꢀ
3ꢀcyanoꢀ4,6ꢀdiphenylꢀ4Hꢀpyranꢀ5ꢀcarboxylate with
acetic anhydride without a catalyst stops on the step of
acylation of the amino group to afford ethyl 2ꢀacetylꢀ
aminoꢀ3ꢀcyanoꢀ4,6ꢀdiphenylꢀ4Hꢀpyranꢀ5ꢀcarboxylate.
Analogous reactivity of annulated 2ꢀaminoꢀ3ꢀcyanoꢀ4Hꢀ
pyrans in the absence of a catalyst was observed earlier.
We decided to study the selectivity of this reaction.
The reaction of 2ꢀaminoꢀ7,7ꢀdimethylꢀ5ꢀoxoꢀ4ꢀphenylꢀ
5,6,7,8ꢀtetrahydroꢀ4Hꢀchromenꢀ3ꢀcarbonitrile (1) with
acetic anhydride in the presence of pyridine afforded
Nꢀacetyl derivative 2 in low yield since the reaction is
accompanied by strong resinification. On the contrary,
the reaction of ethyl 2ꢀaminoꢀ3ꢀcyanoꢀ6ꢀmethylꢀ4ꢀpheꢀ
nylꢀ4Hꢀpyranꢀ5ꢀcarboxylate (3) with acetic anhydride
under heating for 10 h in the absence of a catalyst led to
tar
ethyl 2,7ꢀdimethylꢀ4ꢀoxoꢀ5ꢀphenylꢀ3,5ꢀdihydroꢀ4Hꢀ
pyrano[2,3ꢀd]pyrimidineꢀ6ꢀcarboxylate (4), whereas
the reaction in the presence of pyridine gave a tarꢀlike
mixture of products (TLC) (Scheme 1).
i. 2 h; ii. 10 h.
yield increases to 67% and the reaction time considerably
decreases: from 6—10 h in the absence of the catalyst to
5—10 min in the presence of the catalyst.
The reaction found by us is versatile and allows one to
synthesize pyranopyrimidines 4—13 (Scheme 2) from
various substituted and annulated 2ꢀaminoꢀ4Hꢀpyranꢀ
Changing the reaction conditions and catalysts, we for
the first time found that the reaction of acetic anhydride
with 2ꢀaminoꢀ4Hꢀpyranꢀ3ꢀcarbonitrile 3 in the presence
of catalytic amounts (0.1 equiv.) of sulfuric acid proceeds
with high selectivity to form substituted and annulated
pyrano[2,3ꢀd]pyrimidinꢀ4ꢀone 4. At the same time, the
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 10, pp. 2181—2184, October, 2008.
1066ꢀ5285/08/5710ꢀ2223 © 2008 Springer Science+Business Media, Inc.

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Russ.Chem.Bull., Int.Ed., Vol. 57, No. 10, October, 2008
Litvinov and Shestopalov
Scheme 2
1, 15
1: R = Me, Ar = Ph
3: R = OEt, Ar = Ph
4: R = OEt, Ar = Ph
5: R = Me, Ar = 2ꢀClC6H4
6: R = Me, Ar = Ph
7: R = H, Ar = 2ꢀC4H3S
10: X = O, Ar = Ph
11: X = S, Ar = 4ꢀMeOC6H4
12: Ar = Ph
14: R = Me, Ar = 2ꢀClC6H4
15: R = H, Ar = 2ꢀC4H3S
17: Ar = 4ꢀClC6H4
18: X = O, Ar = Ph
19: X = S, Ar = 4ꢀMeOC6H4
20: Ar = Ph
21: Ar = 4ꢀClC6H4
13: Ar = 4ꢀClC6H4
3ꢀcarbonitriles 1, 3, 14—21. All the pyrano[2,3ꢀd]pyriꢀ
midines obtained, except 10, have not been described in
the literature.
If an OH group is present in the molecule of the startꢀ
ing pyran (compounds 16, 20, and 21), it also undergoes
acylation. The structures of compounds obtained were
confirmed by the 1H and 13C NMR and IR spectroscopic
data. In the IR spectra of compounds 4—12 synthesized,
there is no absorption of a nitrile group, whereas a wide
intensive absorption band in the region 3100—2700 cm–1

Synthesis of pyrano[2,3ꢀd]pyrimidines
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 10, October, 2008
2225
(t, 3 H, CH3CH2, J = 6.9 Hz); 2.25 (s, 3 H, C(2)CH3); 2.40 (s, 3 H,
C(7)CH3); 4.03 (q, 2 H, CH3CH2, J = 6.9 Hz); 4.79 (s, 1 H,
H(5)); 7.22 (m, 5 H, C6H5); 12.49 (br.s, 1 H, NH). 13C NMR,
δ: 13.87, 18.41, 20.94, 35.87, 60.23, 100.62, 107.89, 126.64,
128.04, 128.10, 144.10, 158.21, 158.67, 159.93, 161.97, 165.64.
6ꢀAcetylꢀ5ꢀ(2ꢀchlorophenyl)ꢀ2,7ꢀdimethylꢀ3,5ꢀdihydroꢀ
4Hꢀpyrano[2,3ꢀd]pyrimidinꢀ4(3H)ꢀone (5). The yield was 55%,
m.p. 235—237 °C. Found (%): C, 61.62; H, 4.48; N, 8.50.
C17H15ClN2O3. Calculated (%): C, 61.73; H, 4.57; N, 8.47.
IR (ν/cm–1): 3080—2600 (NH); 1696 (C=O). 1H NMR, δ: 2.18,
2.23, 2.25 (all s, 3 H each, C(2)CH3, C(7)CH3, C(=O)CH3);
5.22 (s, 1 H, H(5)); 7.27 (m, 4 H, C6H4); 12.37 (br.s, 1 H, NH).
2,8,8ꢀTrimethylꢀ5ꢀphenylꢀ5,7,8,9ꢀtetrahydroꢀ4Hꢀchromenoꢀ
[2,3ꢀd]pyrimidineꢀ4,6(3H)ꢀdione (6). The yield was 42%,
m.p. >300 °C. Found (%): C, 71.23; H, 5.88; N, 8.41. C20H20N2O3.
Calculated (%): C, 71.41; H, 5.99; N, 8.33. IR (ν/cm–1):
3052—2656 (NH); 1672 (C=O). 1H NMR, δ: 0.97, 1.08 (both s,
3 H each, C(8)(CH3)2); 2.10 (m, 2 H, CH2); 2.24 (s, 3 H,
C(2)—CH3); 2.52 (m, 2 H, CH2); 5.01 (s, 1 H, H(5)); 7.27 (m,
5 H, C6H4); 12.40 (br.s, 1 H, NH).
2ꢀMethylꢀ5ꢀ(2ꢀthienyl)ꢀ5,7,8,9ꢀtetrahydroꢀ4Hꢀchromenoꢀ
[2,3ꢀd]pyrimidineꢀ4,6(3H)ꢀdione (7). The yield was 47%,
m.p. 230—233 °C. Found (%): C, 61.05; H, 4.51; N, 8.82.
C16H14N2O3S. Calculated (%): C, 61.13; H, 4.49; N, 8.91.
IR (ν/cm–1): 3080—2620 (NH); 1672 (C=O). 1H NMR, δ: 1.99
(m, 2 H, CH2); 2.28 (s, 3 H, CH3); 2.38, 2.69 (both m, 2 H
each, 2 CH2); 5.04 (s, 1 H, H(5)); 6.85 (m, 2 H, H(3´), H(4´));
7.25 (m, 1 H, H(5´)); 12.64 (br.s, 1 H, NH). 13C NMR, δ:
19.78, 20.81, 26.57, 26.78, 36.24, 101.09, 114.41, 123.96, 124.21,
126.40, 147.46, 158.67, 161.91, 165.70, 195.74.
is present, which corresponds to the stretching vibrations
of the NH group of the pyrimidine fragment with strong
hydrogen bonds. In the H NMR spectra of compounds
1
4—13, the signal for the 2ꢀMe group as a singlet in the
region 2.25—2.33 ppm and the signal for the proton of
the pyran ring in the region 4.79—5.22 ppm are observed,
as well as the signal for the NH group as a broad singlet in
the region 12.40—12.70 ppm.
In conclusion, a simple and convenient selective
method for the synthesis of pyrano[2,3ꢀd]pyrimidinꢀ
4ꢀones consisting in the reaction of 2ꢀaminoꢀ3ꢀcyanoꢀ
4Hꢀpyrans with acetic anhydride in the presence of cataꢀ
lytic amounts of sulfuric acid has been developed.
Experimental
Melting points were measured on the Kofler apparatus.
IR spectra were recorded on a Specord M82 spectrometer
in KBr pellets (1 : 200). 1H NMR spectra were recorded on a
Bruker WMꢀ250 and Bruker AMꢀ300 spectrometers (250 and
300 MHz, respectively) in DMSOꢀd6. 13C NMR spectra were
recorded on a Bruker ACꢀ200 spectrometer (50.32 MHz) in
DMSOꢀd6 (the JMODXH procedure).
The starting 2ꢀaminoꢀ4Hꢀpyrans 1, 3, 14—21 were obtained
by the standard threeꢀcomponent procedure9 from equimolar
amounts of aromatic aldehyde, malononitrile and the correꢀ
sponding nucleophilic agent (acetoacetic ester, acetylacetone,
resorcinol, 3ꢀmethylꢀ1ꢀphenylpyrazolinꢀ5ꢀone, 4ꢀhydroxyꢀ
coumarin, 4ꢀhydroxythiocoumarin, kojic acid).
2ꢀAcetylaminoꢀ7,7ꢀdimethylꢀ5ꢀoxoꢀ4ꢀphenylꢀ5,6,7,8ꢀtetraꢀ
hydroꢀ4Hꢀchromeneꢀ3ꢀcarbonitrile (2). Pyridine (0.75 mL) was
added to a solution of pyran 1 (0.98 g, 3 mmol) in acetic
anhydride (2.5 mL) and the mixture was refluxed for 2 h (TLCꢀ
monitoring). Product 2 was isolated as a precipitate from the
dark brown solution on cooling to 4 °C. The precipitate was
washed with ethanol and light petroleum and recrystallized from
ethanol. The yield was 0.28 g (28%), m.p. 228—230 °C. Found
(%): C, 71.50; H, 6.05; N, 8.53. C20H20N2O3. Calculated (%):
C, 71.41; H, 5.99; N, 8.33. IR (ν/cm–1): 3160 (N—H); 2212
(C≡N), 1668 (amideꢀI), 1576 (amideꢀII). 1H NMR, δ: 1.00,
1.09 (both s, 3 H each, C(7)—(CH3)2); 2.20 (s, 3 H, CH3—CO);
2.28 (ABꢀsystem, 2 H, C(8)H2, J = 18.3 Hz); 2.67 (ABꢀsystem,
2 H, H2C(6), J = 18.0 Hz); 5.49 (s, 1 H, H(4)); 7.33 (m, 5 H,
C6H5); 11.45 (br.s, 1 H, NH). 13C NMR, δ: 13.59, 18.00, 38.76
(overlap with the signal for DMSO), 57.26, 60.02, 107.18, 119.58,
126.68, 127.07, 128.30, 144.77, 156.47, 158.39, 165.34.
Pyrano[2,3ꢀd]pyrimidines 4—13 (general procedure).
2ꢀAminoꢀ3ꢀcyanoꢀ4Hꢀpyran (5 mmol), acetic anhydride (5 mL),
and concentrated sulfuric acid (0.5 mmol) were mixed. The
reaction mixture obtained was refluxed for 10 min, cooled to
room temperature and kept for 1 day. A precipitate formed was
filtered off, washed with water (3×5 mL), ethanol (5 mL), and light
petroleum (5 mL). The product obtained was recrystallized from
ethanol and dried at 120 °C until the weight became constant.
Ethyl 2,7ꢀdimethylꢀ4ꢀoxoꢀ5ꢀphenylꢀ3,5ꢀdihydroꢀ4Hꢀpyranoꢀ
[2,3ꢀd]pyrimidineꢀ6ꢀcarboxylate (4). The yield was 67%,
m.p. 255—256 °C. Found (%): C, 66.05; H, 5.46; N, 8.62.
C18H18N2O4. Calculated (%): C, 66.31; H, 5.52; N, 8.59.
IR (ν/cm–1): 3160—2700 (NH); 1712 (C=O). 1H NMR, δ: 1.12
8ꢀAcetoxyꢀ2ꢀmethylꢀ5ꢀphenylꢀ3,5ꢀdihydroꢀ4Hꢀchromenoꢀ
[2,3ꢀd]pyrimidinꢀ4ꢀone (8). The yield was 75%, m.p. 295—297 °C.
Found (%): C, 67.73; H, 4.74; N, 8.02. C20H16N2O4. Calculated
(%): C, 68.96; H, 4.63; N, 8.04. IR (ν/cm–1): 3050—2600
1
(NH); 1768 (C=O). H NMR, δ: 2.26, 2.30 (both s, 3 H each,
CH3, C(=O)—CH3); 5.16 (s, 1 H, H(5)); 6.89 (d, 1 H, H(7),
J = 8.4 Hz); 7.03 (s, 1 H, H(9)); 7.23 (m, 6 H, C6H5 + H(6));
12.45 (br.s, 1 H, NH). 13C NMR, δ: 20.62, 20.82, 37.67, 99.63,
110.15, 118.35, 121.91, 126.32, 127.34, 128.28, 130.13, 145.35,
149.42, 149.63, 158.50, 161.18, 162.12, 168.72.
4ꢀ(4ꢀChlorophenyl)ꢀ3,7ꢀdimethylꢀ1ꢀphenylꢀ4,6ꢀdihydropyrꢀ
azolo[4´,3´:5,6]pyrano[2,3ꢀd]pyrimidinꢀ5(1H)ꢀone (9). The
yield was 68%, m.p. >300 °C. Found (%): C, 67.81; H, 4.12;
N, 13.05. C22H17ClN4O2. Calculated (%): C, 65.27; H, 4.23; N,
1
13.84. IR (ν/cm–1): 2950—2600 (NH). H NMR, δ: 1.92, 2.31
(both s, 3 H each, C(6)—CH3, C(2)—CH3); 5.06 (s, 1 H, H(5));
7.32—7.75 (m, 9 H, C6H5 + C6H4); 12.60 (br.s, 1 H, NH).
10ꢀMethylꢀ7ꢀphenylꢀ7,9ꢀdihydroꢀ6H,8Hꢀbenzo[b]pyranoꢀ
[3´,4´:5,6]pyrano[2,3ꢀd]pyrimidineꢀ6,8ꢀdione (10). The yield
was 57%, m.p. >300 °C (Ref. 10: m.p. >300 °C). Found (%):
C, 69.03; H, 3.99; N, 7.94. C21H14N2O4. Calculated (%):
C, 70.39; H, 3.94; N, 7.82. IR (ν/cm–1): 2950—2600 (NH);
1720 (C=O). 1H NMR, δ: 2.33 (s, 3 H, CH3); 4.86 (s, 1 H,
H(7)); 7.25—7.95 (m, 9 H, (C6H5 + H(1)—H(4)); 12.70 (br.s,
1 H, NH). 13C NMR, δ: 20.80, 34.24, 100.94, 105.02, 113.11,
116.38, 122.39, 124.61, 126.71, 127.94, 128.30, 132.63, 142.34,
151.98, 159.19, 161.70.
7ꢀ(4ꢀMethoxyphenyl)ꢀ10ꢀmethylꢀ7,9ꢀdihydroꢀ6H,8Hꢀbenzoꢀ
[b]thiopyrano[3´,4´:5,6]pyrano[2,3ꢀd]pyrimidineꢀ6,8ꢀdione (11).
The yield was 72%, m.p. >300 °C. Found (%): C, 66.21; H,
4.12; N, 6.84. C22H16N2O4S. Calculated (%): C, 65.33; H, 3.99;

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Litvinov and Shestopalov
N, 6.93. IR (ν/cm–1): 2950—2600 (NH); 1664 (C=O). 1H NMR,
δ: 2.33 (s, 3 H, C(2)—CH3); 3.67 (s, 3 H, OCH3); 5.05 (s, 1 H,
H(7)); 6.80 (d, 2 H, H(3´), H(5´), J = 8.0 Hz); 7.17 (d, 2 H,
H(2´), H(6´), J = 8.2 Hz); 7.68, 8.30 (both m, 3 H, 1 H,
H(1)—H(4)); 12.68 (br.s, 1 H, NH).
References
1. A. H. Bedair, H. A. Emam, N. A. ElꢀHady, K. A. R. Ahmed,
A. M. ElꢀAgrody, Farmaco, 2001, 56, 965.
2. M. M. Khafagy, A. H. F. A. ElꢀWahab, F. A. Eid, A. M.
ElꢀAgrody, Farmaco, 2002, 57, 715.
7ꢀAcetoxymethylꢀ2ꢀmethylꢀ5ꢀphenylꢀ3H,5Hꢀpyrano[2´,3´:5,6]ꢀ
pyrano[2,3ꢀd]pyrimidineꢀ4,9ꢀdione (12). The yield was 52%,
m.p. >300 °C. Found (%): C, 64.07; H, 4.05; N, 7.14. C20H16N2O6.
Calculated (%): C, 63.16; H, 4.24; N, 7.36. IR (ν/cm–1):
2950—2600 (NH); 1756 (C=O). 1H NMR, δ: 1.99 (s, 3 H,
CH3COOCH2); 2.30 (s, 3 H, C(2)—CH3); 4.88 (dd, 2 H,
CH3COOCH2, J = 14.3 Hz, J = 15.0 Hz); 5.05 (s, 1 H, H(5);
6.48 (s, 1 H, H(8)); 7.29 (m, 5 H, C6H5); 12.56 (br.s, 1 H, NH).
13C NMR, δ: 20.25, 21.07, 38.64 (overlap with the signal
for DMSO), 60.62, 98.40, 113.86, 127.58, 128.06, 128.66, 137.02,
140.23, 150.20, 159.46, 160.18, 161.82, 161.97, 169.68.
7ꢀAcetoxymethylꢀ5ꢀ(4ꢀchlorophenyl)ꢀ2ꢀmethylꢀ3H,5Hꢀ
pyrano[2´,3´:5,6]pyrano[2,3ꢀd]pyrimidineꢀ4,9ꢀdione (13).
The yield was 69%, m.p. >300 °C. Found (%): C, 57.14; H,
3.83; N, 6.44. C20H15ClN2O6. Calculated (%): C, 57.91;
H, 3.64; N, 6.75. IR (ν/cm–1): 2950—2600 (NH); 1760 (C=O).
1H NMR, δ: 2.00 (s, 3 H, CH3COOCH2); 2.31 (s, 3 H, C(2)—CH3);
4.88 (dd, 2 H, CH3COOCH2, J = 14.6 Hz, J = 14.4 Hz); 5.09
(s, 1 H, H(5)); 6.50 (s, 1 H, H(8)); 7.31 (d, 2 H, H(2´), H(6´),
J = 7.7 Hz); 7.39 (d, 2 H, H(3´), H(5´), J = 7.9 Hz); 12.63 (br.s,
1 H, NH).
3. F. A. Eid, A. H. F. A. ElꢀWahab, A. M. E.ꢀH. A. Gameel,
M. A. M. Khafagy, Acta Pharm., 2004, 54, 13.
4. JP Pat. 62242685; Chem. Abstr., 1988, 109, 24243.
5. Marchalin, D. Ilavsky, J. Kovac`´, M. Bruncko, Collect. Czech.
Chem. Commun., 1990, 55, 718.
6. Z. H. Khalil, A. A. AbdelꢀHafez, A. A. Geies, A. M. K.
ElꢀDean, Bull. Chem. Soc. Jpn, 1991, 64, 668.
7. H. A. A. ElꢀNabi, Pharmazie, 1997, 52, 28.
8. C. Seoane, J. L. Soto, M. Quinteiro, J. Prakt. Chem., 1986,
328, 35.
9. A. M. Shestopalov, Yu. M. Emel´yanova, V. N. Nesterov,
Izv. Akad. Nauk, Ser. Khim., 2003, 1103 [Russ. Chem. Bull.,
Int. Ed., 2003, 52, 1164].
10. E. M. A.Yakout, N. M. Ibrahim, Kh. M. Ghoneim, M. R.
H. Mahran, J. Chem. Res. (M), 1999, 2818.
This work was partially financially supported by
the Russian Academy of Sciences (Program 8P of the
Presidium of RAS).
Received October 17, 2007;
in revised form February 29, 2008