Indion 190 Resin: A Green and Recyclable Catalyst for Facile and Efficient One-pot Synthesis of 3, 4-Dihydropyrimidin-2(1H)-one

Indion 190 수지: 편리한 친환경적인 재생 촉매를 이용한 효과적인 3, 4-Dihydropyrimidin-2(1H)-one의 one-pot합성

Recently Multi-component reactions (MCR’s) are governing importance due to its wide variety of applications in organic and medicinal chemistry. 1 MCR’s involves the reaction between three or more reactants in single reaction vessel to form new products, which essentially contain part of all starting materials.1 MCR’s are diversity oriented efficient and speedy reactions, due to which they have received tremendous attention in the drug discovery process.2 One of the MCR’s of current interest is the venerable Biginelli dihydropyrimidine synthesis.3 Today 3,4-dihydropyrimidin-2(1H)-ones (DHPM) and its derivatives have received considerable amount of attention due to its wide spectra of biological activities. Hence several attempts have been made to synthesize the DHPM (Scheme 1).

Scheme 1

In the attempt to prepare DHPM different types of acidic catalyst such as H2SO4, 5 BF3․EtOH/CuCl,6LaCl3․7H2O with catalytic concentrated HCl,7 CeCl3․7H2O,8 InCl3, 9 Heteropolyacids,10 BiCl3,11 Cu(OTf)2,12 TMSCl,13 LiClO4,14 LiBr,15 InBr3,16 Phenyl Pyruvic acid,17 FeCl3․6H2O/HCl,18 TMSI19 and CdCl2 20 have been used. Many of the above catalyst used are not ecofriendly and cause the problem during disposal. Further the methods used for synthesis of DHPM requires long reaction times, strong acidic condition, vigorous reaction conditions (high temperature) and they are difficult to handle on a large scale. The development of eco-friendly and recyclable catalytic system for Biginelli reaction is an active research area, in order to improve the reaction condition and yield. Hence we initiated the preparation of DHPM, by keeping in mind the development of green methodology and successfully attempted a single step efficient chemical method by using green catalyst, under mild condition.

Here in, we report a simple efficient and effective protocol for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones by one pot three component cyclocondensation reaction of 1,3 dicarbonyl compound (ethyl acetoacetate), aromatic aldehyde and urea using Indion 190 resin as a recyclable catalyst. An aldehydes, ethyl acetoacetate and urea in dichloromethane were stirred at reflux temperature in presence of Indion 190 resin. The reaction progress was monitored by TLC. After the completion of reaction, the reaction mixture and resin were separated by filtration. The solvent was removed under reduced pressure and the solid obtained was purified by recrystallisation from methanol. Isolated resin was washed with water, activated and reused for subsequent reaction. Physical and spectral data of known compounds are in agreement with those reported in the literature.20

Table 1.Indion 190 resin catalysed synthesis of Dihydropyrimidinones.

A broad range of structurally diverse aromatic and heterocyclic aldehydes have been used in this condensation (Table 1).α, β unsaturated aldehyde react selectively with aldehyde functional group whereas acid sensitive heterocyclic aldehydes exclusively gave dihydropyrimidones in high yield. We found that electron donating or withdrawing group on aromatic aldehydes gave almost good to excellent yield. Therefore the method can be use for wide range of reactants with different functional group. We have synthesized some novel compounds containing quinoline, pyrimidine, indole and coumarin units.

In conclusion, we have developed a simple, efficient and ecofriendly procedure for the synthesis of dihydropyrimidin-2(1H)-ones by condensation of ethyl acetoacetate, aldehydes and urea in presence of inexpensive and recyclable catalyst Indion 190 resin at mild reaction conditions.

General Experimental Section

All commercial reagents are used as received without purification, and all solvents were reagent grade. The reaction mixture was stirred magnetically in a round bottom flask and was monitored by TLC using on 0.25 mm E-Merck silica gel 60 F254 precoated glass plates, which were visualized with UV light, and then developed by using silica gel 60-120 mesh. Melting points were taken in open capillaries. The IR spectra were recorded on a Perkin-Elmer 257 spectrometer using KBr discs. 1H NMR and 13C NMR spectra in DMSO-d6 were recorded on VXR-300 MHz using TMS as internal standard.

General Procedure

A mixture of an aldehyde (10 mmol), ethyl acetoacetate (10 mmol), urea or thiourea (15 mmol) and Indion 190 resin (2 gm) in dichloromethane (5 ml) was stirred at reflux temperature for the appropriate time (1.5-3.5 hr). After completion of the reaction, as indicated by TLC, the solvent was removed under reduced pressure. The residue was washed with water and recrystallised from methanol.

Analytical and Spectral data for selected compounds.

5-Ethoxycarbonyl-4-(3-1H-Indole)-6-methyl-3,4-dihydropyrimidin-2 (1H)–one (19)

IR (KBr): 3417, 3356, 3240, 2978, 1702, 1653, 1538, 1187, 1085, 870 cm-1

1H NMR DMSO-d6 (δ-ppm): 9.17 (s, 1H, NH), 7.04 (s, 1H, NH), 8.48 (s, 1H, NH), 7.76 (s, 1H), 7.18-7.34 (m, 4H), 5.23 (d, 1H, J = 3.7 Hz), 3.97 (q, 2H, J = 7.2 Hz), 2.24 (s, 3H), 1.15 (t, 3H, J = 7.2 Hz)

13C NMR DMSO-d6 (δ-ppm): 172.10, 155.25, 152.90, 136.90, 127.30, 123.20, 121.80, 119.10, 118.90, 111.15, 106.90, 104.35, 60.10, 34.15, 14.90, 13.90.

Elem. Anal. Calcd: C, 64.20 ; H, 5.72 ; N, 14.04 ; O, 16.04. Found : C, 63.89 ; H, 5.93 ; N, 14.37 ; O, 16.09.

5-Ethoxycarbonyl-4-(3-quinoline)-6-methyl-3,4-dihydropyrimidin-2 (1H)–one (20)

IR (KBr): 3408, 3365, 3280, 1698, 1640, 1513, 1227, 779 cm-1

1H NMR DMSO-d6 (δ-ppm): 9.25 (s, 1H, NH), 7.73 (s, 1H, NH), 8.32 (s, 1H), 7.63-7.79 (m, 4H), 7.80 (s, 1H), 5.12 (d, 1H, J = 2.8 Hz), 4.11 (q, 2H, J = 7.5 Hz), 2.28 (s, 3H), 1.09 (t, 3H, J = 7.5 Hz)

13C NMR DMSO-d6 (δ-ppm): 172.50, 155.25, 153.35, 148.10, 147.15, 135.05, 135.05, 129.10, 127.30, 126.45, 126.10, 104.50, 60.10, 53.00, 14.90, 13.90.

Elem. Anal. Calcd: C, 65.58 ; H, 5.50 ; N, 13.50 ; O, 15.42. Found : C, 65.63 ; H, 5.61 ; N, 13.42 ; O, 15.37.

5-Ethoxycarbonyl-4-(2-pyrimidine)-6-methyl-3,4-dihydropyrimidin-2(1H)–one (21)

IR (KBr): 3413, 3385, 3245, 2965, 1709, 1658, 1540, 1235, 1090, 780 cm-1

1H NMR DMSO-d6 (δ-ppm): 9.20 (s,1H, NH), 7.65 (s, 1H, NH), 8.42 (d, 2H, J = 7.5 Hz), 7.38(t, 1H, J = 7.5 Hz), 5.10(d, 1H, J = 3.5 Hz), 4.02 (q, 2H, J = 7.0 Hz), 2.23 (s, 3H), 1.11 (t, 3H, J = 7.0 Hz).

13C NMR DMSO-d6 (δ-ppm): 172.60, 168.70, 157.20, 155.85, 153.85, 119.90, 104.20, 60.10, 56.10, 15.15, 13.90

Elem. Anal. Calcd: C, 54.96 ; H, 5.38 ; N, 21.36 ; O, 18.30. Found : C, 54.84 ; H, 5.29 ; N, 22.04 ; O, 18.75.

5-Ethoxycarbonyl-4-(4-hydroxyl–2H(1)-benzopyran-2-one-3-yl)-6-methyl-3,4-dihydropyrimidin-2(1H)–one (24)

IR (KBr): 3389, 3240, 2943, 1721, 1705, 1619, 1562, 1235, 1123, 810 cm-1

1H NMR DMSO-d6 (δ-ppm): 11.85 (s, 1H, OH), 9.80 (s, 1H, NH), 7.69(s, 1H, NH), 7.30-7.80 (m, 4H), 4.85 (d, 1H, J = 3.5 Hz), 4.23 (q, 2H, J = 6.8 Hz), 2.35 (s, 3H), 1.21 (t, 3H, J = 6.8 Hz)

13C NMR DMSO-d6 (δ-ppm): 172.50, 171.20, 164.15, 155.10, 153.60, 152.20, 131.15, 129.80, 122.30, 121.10, 117.80, 116.25, 94.50, 60.20, 43.25, 15.15, 14.15

Elem. Anal. Calcd: C, 59.30 ; H, 4.68 ; N, 8.14 ; O, 27.88. Found : C, 59.24 ; H, 4.76 ; N, 8.07 ; O, 28.01.