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M.N. Elinson et al.: Fast and efficient approach to pyrano[2,3-d]pyrimidinesꢂ
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202–203°C (lit [10] mp 203°C); H NMR: δ 2.25 (s, 3H, CH3), 3.08 (s,
3H, CH3), 3.35 (s, 3H, CH3), 4.28 (s, 1H, CH), 7.05–7.15 (m, 4H, Ar), 7.28
(s, 2H, NH2).
generates the anion A of N,N′-dialkyl barbituric acid. Then
Knoevenagel condensation of aldehyde 1 with barbituric
acid anion A takes place with the elimination of hydrox-
ide anion and formation of corresponding 5-benzylide-
nepyrimidine-2,4,6(1H,3H,5H)-trione 4. The subsequent
hydroxide-promoted Michael addition of malononitrile to
electron deficient Knoevenagel adduct 4 followed by intra-
molecular cyclization leads to corresponding pyrano[2,3-
d]pyrimidine 3 with regeneration of barbituric acid anion
A at the last step. Generation of the intermediate products
B and C in this cascade of reactions can be noted.
7-Amino-5-(4-methoxyphenyl)-1,3-dimethyl-2,4-dioxo-1,3,4,5-tet-
rahydro-2H-pyrano-[2,3-d]pyrimidine-6-carbonitrile (3c)ꢀThis
compound was obtained from 1c and 2a; yield 1.53 g (90%); mp 225–
226°C (lit [10] mp 225–227°C); 1H NMR: δ 3.15 (s, 3H, CH3), 3.39 (s, 3H,
CH3), 3.68 (s, 3H, OCH3), 4.36 (s, 1H, CH), 6.32 (s, 2H, NH2), 6.74 (d, J ꢀ= ꢀ
8.4 Hz, 2H, Ar), 7.12 (d, J ꢀ= ꢀ 8.4 Hz, 2H, Ar).
7-Amino-5-(4-fluorophenyl)-1,3-dimethyl-2,4-dioxo-1,3,4,5-tet-
rahydro-2H-pyrano[2,3-d]pyrimidine-6-carbonitrile (3d)ꢀThis
compound was obtained from 1d and 2a; yield 1.51 g (92%); mp 229–
232°C (lit [10] mp 230–232°C); 1H NMR: δ 3.13 (s, 3H, CH3), 3.39 (s, 3H,
CH3), 4.38 (s, 1H, CH), 6.69 (s, 2H, NH2), 6.90 (t, J ꢀ= ꢀ 8.7 Hz, 2H, Ar), 7.19
(dd, J ꢀ= ꢀ 8.1 Hz and 5.1 Hz, 2H, Ar).
Conclusion
7-Amino-5-(2-chlorophenyl)-1,3-dimethyl-2,4-dioxo-1,3,4,5-tet-
rahydro-2H-pyrano[2,3-d]pyrimidine-6-carbonitrile (3e)ꢀThis
compound was obtained from 1e and 2a; yield 1.57 g (91%); mp 236–
238°C (lit [10] mp 237–238°C); 1H NMR: δ 3.07 (s, 3H, CH3), 3.37 (s, 3H,
CH3), 4.87 (s, 1H, CH), 7.16–7.42 (m, 6H, Ar, NH2).
Potassium fluoride (KF) is an efficient catalyst for selec-
tive solvent-free multicomponent transformation of alde-
hydes, N,N′-dialkyl barbituric acids and malononitrile
into substituted pyrano[2,3-d]pyrimidine-6-carbonitriles
in excellent (89–95%) yields. This new process opens an
efficient and convenient solvent-free multicomponent
way to synthesize substituted pyrano[2,3-d]pyrimidines
– the promising compounds for a variety of biomedical
applications.
7-Amino-5-(4-chlorophenyl)-1,3-dimethyl-2,4-dioxo-1,3,4,5-tet-
rahydro-2H-pyrano[2,3-d]pyrimidine-6-carbonitrile (3f)ꢀThis
compound was obtained from 1f and 2a; yield 1.60 g (93%); mp 239–
241°C (lit [16] mp 241–242°C); 1H NMR: δ 3.08 (s, 3H, CH3), 3.35 (s, 3H,
CH3), 4.35 (s, 1H, CH), 7.18–7.47 (m, 6H, Ar, NH2).
7-Amino-5-(3-bromophenyl)-1,3-dimethyl-2,4-dioxo-1,3,4,5-tet-
rahydro-2H-pyrano[2,3-d]pyrimidine-6-carbonitrile (3g)ꢀThis
compound was obtained from 1g and 2a; yield 1.79 g (92%); mp 215–
217°C (lit [10] mp 217°C); 1H NMR: δ 3.16 (s, 3H, CH3), 3.40 (s, 3H, CH3),
4.38 (s, 1H, CH), 6.47 (s, 2H, NH2), 7.11 (t, J ꢀ= ꢀ 7.3 Hz, 1H, Ar), 7.19 (d, J ꢀ= ꢀ
7.3 Hz, 1H, Ar), 7.27 (d, J ꢀ= ꢀ 8.0 Hz, 1H, Ar), 7.44 (s, 1H, Ar).
Experimental
All melting points were measured with a Gallenkamp melting point
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apparatus and are uncorrected. H NMR (300 MHz) spectra were
recorded with a Bruker Avance II-300 at ambient temperature in
7-Amino-1,3-dimethyl-5-(4-nitrophenyl)-2,4-dioxo-1,3,4,5-tet-
rahydro-2H-pyrano[2,3-d]pyrimidine-6-carbonitrile (3h)ꢀThis
compound was obtained from 1h an 2a; yield 1.69 g (95%); mp 211–
214°C (lit [10] mp 212–214°C); 1H NMR: δ 3.06 (s, 3H, CH3), 3.35 (s, 3H,
CH3), 4.51 (s, 1H, CH), 7.49 (s, 2H, NH2), 7.55 (d, J ꢀ= ꢀ 8.1 Hz, 2H, Ar), 8.15
(d, J ꢀ= ꢀ 8.1 Hz, 2H, Ar).
DMSO-d6 solutions.
General procedure for 3a–k
A mixture of benzaldehyde 1a–h (5 mmol), N,N′-dialkyl barbituric
acid 2a,b (5 mmol), malononitrile (5 mmol) and potassium fluo-
ride (KF; 0.029 g, 0.5 mmol) was stirred at 60°C for 15 min, and then
cooled to 20°C. Water (10 mL) was added, the mixture was stirred for
15 min and filtered to isolate the solid product, which was washed
with water (2 ꢀ× ꢀ 5 mL), ice-cold ethanol (5 mL), and dried under
reduced pressure.
7-Amino-1,3-diethyl-2,4-dioxo-5-phenyl-1,3,4,5-tetrahydro-
2H-pyrano[2,3-d]pyrimidine-6-carbonitrile (3i)ꢀThis compound
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was obtained from 1a and 2b; yield 1.51 g (89%); mp 147–150°C; H
NMR: δ 1.01 (t, J ꢀ= ꢀ 7.3 Hz, 3H, CH3), 1.22 (t, J ꢀ= ꢀ 7.3 Hz, 3H, CH3), 3.67–
3.82 (m, 2H, CH2), 3.90–4.05 (m, 2H, CH2), 4.33 (s, 1H, CH), 7.15–7.40
(m, 7H, Ar, NH2); 13C NMR (75 MHz, DMSO-d6): δ 12.6, 13.8, 35.8, 36.4,
37.8, 58.6, 89.2, 119.0, 126.7, 127.2 (2C), 128.3 (2C), 144.0, 149.1, 150.9,
157.7, 160.0 ppm; IR (KBr): ν 3382, 3187, 2208, 1687, 1632, 1486, 1382,
1238 cm-1; MS (EI): m/z (%) 338 (7) [M]+, 271 (32), 184 (100), 131 (73),
103 (86), 70 (81), 56 (74), 44 (95). Anal. Calcd for C18H18N4O3: C, 63.89;
H, 5.36; N, 16.56. Found: C, 63.71; H, 5.47; N, 16.42.
7-Amino-1,3-dimethyl-2,4-dioxo-5-phenyl-1,3,4,5-tetrahydro-
2H-pyrano[2,3-d]pyrimi-dine-6-carbonitrile (3a)ꢀThis com-
pound was obtained from 1a and 2a; yield 1.47 g (95%); mp 219–222°C
(lit [11] mp 210°C); 1H NMR: δ 3.08 (s, 3H, CH3), 3.36 (s, 3H, CH3), 4.32
(s, 1H, CH), 7.15–7.39 (m, 7H, Ar, NH2).
7-Amino-1,3-diethyl-5-(4-fluorophenyl)-2,4-dioxo-1,3,4,5-tet-
7-Amino-1,3-dimethyl-5-(4-methylphenyl)-2,4-dioxo-1,3,4,5-tet-
rahydro-2H-pyrano[2,3-d]pyrimidine-6-carbonitrile (3j)ꢀThis
rahydro-2H-pyrano[2,3-d]pyrimidine-6-carbonitrile (3b)ꢀThis compound was obtained from 1f an 2b; yield 1.60 g (90%); mp 159–
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compound was obtained from 1b and 2a; yield 1.48 g (91%); mp 162°C (lit [10] mp 160–162°C); H NMR: δ 1.01 (t, J ꢀ= ꢀ 7.3 Hz, 3H, CH3),
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