One-pot construction of dihydropyrimidinones in ionic liquids

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210 Mendeleev Commun. 2004

One-pot construction of dihydropyrimidinones in ionic liquids

Sushilkumar S. Bahekar,^a Sandip A. Kotharkar^b and Devanand B. Shinde*^b

a Department of Chemistry, National Cheng Kung University, Tainan-701, Taiwan, R.O.C.

b Department of Chemical Technology, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad (MS) – 431004, India.

Fax: +091 240 401833; e-mail: ssbahekar@rediffmail.com

DOI: 10.1070/MC2004v014n05ABEH001895

The use of the ionic liquid [bmim]Cl·2AlCl₃ for the preparation of dihydropyrimidinones is described.

In 1893, the Italian chemist Pietro Biginelli reported that the acid-catalysed one-pot cyclocondensation of ethyl acetoacetate, benzaldehyde and urea gave multifunctionalised dihydro- pyrimidones (DHPMs).¹ After nearly 100 years, a resurgence of interest occurred as evidenced by an increase in the number of publications and patents on both the synthesis^2–4 and biological activity^5–10 of these compounds. Antiviral, antitumor, antibacterial, potent calcium channel blocking and anti- inflammatory activities were ascribed to DHPMs. However, the Biginelli synthesis of DHPMs suffers from relatively low yields of products, in particular, when substituted aromatic aldehydes or thioureas are employed.^3,11–14 This has led to the recent dis- closure of several improved synthetic protocols for DHPMs, which involve either modification of the Biginelli synthesis¹¹

or the development of novel but more complex multistep strategies.^11–14 In addition, several combinatorial solid-phase approaches have been reported that use microwave conditions.^15,16

The Biginelli synthesis is an example of the use of less toxic chemicals. Thus, the use of catalysts that contain both Lewis acid and transition metal salts, e.g., BF₃–OEt₂,¹⁷ montmoril- lonite(KSF),¹⁸ polyphosphate ester¹⁹ and reagents such as InCl₃,²⁰ LiBr,²¹ CeCl₃·H₂O²² and Mn(OAc)₃·2H₂O²³ gave better yields of DHPMs.

Ionic liquids are environmentally benign alternative solvents for various chemical processes. They have attracted the atten- tion of chemists owing to their unique physical and chemical properties.^24,25 Because of their low vapour pressure, ionic

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Mendeleev Commun. 2004 211 species do not contribute to volatile organic compound emis-

sion. They have also been referred to as ‘designer solvents’²⁶ since their properties can be altered by the fine tuning of parameters such as the choice of the organic cation, inorganic anion and alkyl chain attached to the organic cation. These structural variations provide an opportunity to devise the most idealised solvent needed for a particular chemical process. Several reactions have been carried out in ionic liquids²⁷ including the Biginelli, Diels–Alder, Wittig and Pechman reactions, the benzoin condensation, catalytic hydrogenation and several enzyme catalysed reactions.²⁸

Chloroaluminate ionic liquids have been used in Friedel–

Crafts and other reactions where they play the dual role of both the Lewis acid catalyst and the solvent.²⁷ Thus, we decided to investigate the Biginelli synthesis under these conditions. Here we report a new synthesis of DHPMs in the presence of the Lewis acid [bmim]Cl·2AlCl₃ ionic liquid.

The composition of ionic liquids is expressed as the apparent mole fraction of AlCl₃, N. Accordingly, they are classified as basic, neutral and acidic liquids when N is 0–0.5, 0.5 and 0.5–0.67, respectively. The reaction of (thio)ureas, aldehydes and α-ketoesters was carried out in liquids with N = 0.33, 0.5 and 0.67, respectively. Positive results were obtained only in case of acidic ionic liquids as expected.

In order to study the effect of substituents on the reactivity of the reactants, a variety of aliphatic and aromaic aldehydes were used. The results are given in Table 1.^† In comparison with reported procedures,²⁹ the reaction time for the complete

† The purity of compounds was checked by TLC. The IR spectra were recorded on a JASCO spectrophotometer (Japan) using KBr pellets. The

1H and ¹³C NMR spectra in CDCl₃ were measu red on a FT-NMR spectrophotometer model Ac-300 F (Bruker, Germany) at 300 MHz using TMS as an internal standard. Satisfactory microanalysis data (±0.4% of calculated values) were obtained for all the compounds.

Typical experimental procedure. To a stirred mixture of urea or thio- urea (2.6 mmol), an appropriate α-ketoester (2 mmol) and an aldehyde (2 mmol), the ionic liquid [bmim]Cl·2AlCl₃ (11 mmol) was added, and the reaction mixture was stirred for an appropriate time at room tem- perature. The reaction mixture was quenched with cold 6M HCl (15 ml).

The precipitate was filtered off, and the solid was purified by column chromatography (ethyl acetate–hexane) and characterised by IR, ¹H and

13C NMR spectroscopy and mass spectrometry.

5-Aceto-4-propyl-6-methyl-3,4-dihydropyrimidin-2(1H)-one 4c: mp 151–

152 °C. ¹H NMR ([²H₆]DMSO, 300 MHz) d: 8.94 (s, 1H, NH), 7.42 (s, 1H, NH), 4.09 (t, 1H, H-4, J 3.2 Hz), 2.18 (s, 3H, COMe), 2.16 [s, 3H, C(6)–Me], 1.20 (m, 4 H, CH₂CH₂Me), 0.82 (t, 3H, CH₂CH₂Me, J 7.0 Hz). ¹³C NMR, d: 194.5, 153.3, 147.8, 111.1, 50.5, 30.6, 19.3, 17.6, 14.2. IR (KBr, n/cm^–1): 3247, 3113, 2956, 1723, 1625. MS (70 eV, EI), m/z: 196 (M⁺, 1.27%).

Table 1 Dihydropyrimidinones 4a–s^a produced according to Scheme 1.

aAll compounds are characterised by IR, ¹H and ¹³C NMR spectroscopy and mass spectrometry. ^bThe optimised yield is based on the crystalline product obtained. ^cMelting points are uncorrected.

Entry R¹ R² X t/min Yield^b (%) Found mp^c/°C Reported mp/°C

4a 4-NO₂C₆H₄ Me O 80 97 231–232 (decomp.) 230 (decomp.)¹³

4b 3-NO₂C₆H₄ Me O 90 95 268–270 (decomp.) 267–269 (decomp.)³¹

4c Pr Me O 75 94 151–152 152–154³¹

4d Ph Me O 50 98 235–236 235–236¹³

4e 3-NO₂C₆H₄ OMe O 60 92 239–240 (decomp.) 240–241 (decomp.)³¹

4f 4-NO₂C₆H₄ OMe O 70 95 237–239 235–237²⁹

4g Ph OMe O 90 94 210–213 209–216¹³

4h 2-ClC₆H₄ OMe O 80 89 226–228 226–229³²

4i Et OMe O 55 90 184–186 184–185³¹

4j Pr OMe O 80 93 173–175 174–175³¹

4k 4-MeOC₆H₄ OMe O 60 97 194–196 191–193¹³

4l Ph OEt O 45 90 205–207 203–205²³

4m 3-NO₂C₆H₄ OEt O 60 91 227–229 227–228²³

4n 4-NO₂C₆H₄ OEt O 90 96 202–204 201–202³¹

4o 2-ClC₆H₄ OEt O 70 88 214–216 214–215²³

4p Et OEt O 60 96 179–183 179²³

4q Me₂CHCH₂ OEt O 75 87 185–186 185–186²³

4r 4-MeOC₆H₄ OEt O 80 95 209–212 207–210¹³

4s Ph OEt S 90 91 209–211 208–210³²

5-Methoxycarbonyl-4-(3-nitrophenyl)-6-methyl-3,4-dihydropyrimidin- 2(1H)-one 4e: mp 239–240 °C (decomp.). ¹H NMR ([²H₆]DMSO, 300 MHz) d: 9.31 (s, 1H, NH), 8.09–8.13 (m, 2H, Ar–H), 7.85 (s, 1H, NH), 7.63–7.70 (m, 2H, Ar–H), 5.31 (d, 1H, H-4, J 3.0 Hz), 3.35 (s, 3 H, COOMe, J 3.0 Hz), 2.28 [s, 3H, C(6)–Me]. ¹³C NMR, d: 165.5, 151.7, 149.6, 147.8, 146.6, 132.8, 130.1, 122.3, 120.8, 98.0, 53.3, 50.8, 17.8.

IR (KBr, n/cm^–1): 3358, 3244, 3102, 2957, 1701, 1641. MS (70 eV, EI), m/z: 291 (M⁺, 5.86%).

5-Methoxycarbonyl-4-(2-chlorophenyl)-6-methyl-3,4-dihydropyrimidin- 2(1H)-one 4h: mp 226–228 °C. ¹H NMR ([²H₆]DMSO, 300 MHz) d:

9.21 (s, 1H, NH), 7.59 (s, 1H, NH), 7.25–7.40 (m, 4H, Ar–H), 5.62 (d, 1H, H-4, J 2.5 Hz), 3.45 (s, 3H, COOMe), 2.30 [s, 3H, C(6)–Me].

13C NMR, d: 165.4, 151.3, 149.3, 141.4, 131.6, 129.4, 129.0, 128.6, 127.6, 97.6, 51.3, 50.6, 17.6. IR (KBr, n/cm^–1): 3367, 3221, 3103, 2948, 1714, 1698. MS (70 eV, EI), m/z: 280 (M⁺, 5.13%).

5-Methoxycarbonyl-4-ethyl-6-methyl-3,4-dihydropyrimidin-2(1H)-one 4i: mp 184–186 °C. ¹H NMR ([²H₆]DMSO, 300 MHz) d: 8.96 (s, 1H, NH), 7.30 (s, 1H, NH), 4.01 (m, 1H, H-4), 3.59 (s, 3H, COOMe), 2.16 [s, 3H, C(6)–Me], 1.39 (q, 2H, CH₂Me, J 7.5 Hz), 0.77 (t, 3H, CH₂Me, J 7.5 Hz). ¹³C NMR, d: 165.9, 152.7, 148.6, 98.5, 51.3, 50.7, 29.5, 17.7, 8.4. IR (KBr, n/cm^–1): 3249, 3118, 2961, 1728, 1708, 1680. MS (70 eV, EI), m/z: 198 (M⁺, 0.59%).

5-Methoxycarbonyl-4-propyl-6-methyl-3,4-dihydropyrimidin-2(1H)-one 4j: mp 173–175 °C. ¹H NMR ([²H₆]DMSO, 300 MHz) d: 8.94 (s, 1H, NH), 7.31 (s, 1H, NH), 4.03 (t, 1H, H-4, J 3.2 Hz), 3.59 (s, 3 H, COOMe), 2.15 [s, 3H, C(6)–Me], 1.19–1.40 (m, 4H, CH₂CH₂Me), 0.82 (t, 3H, CH₂CH₂Me, J 6.7 Hz). ¹³C NMR, d: 165.8, 152.6, 148.3, 99.1, 50.6, 49.8, 17.6, 16.9, 13.6. IR (KBr, n/cm^–1): 3442, 3252, 3123, 2957, 1726, 1708, 1653. MS (70 eV, EI), m/z: 212 (M⁺, 0.43%).

5-Ethoxycarbonyl-4-ethyl-6-methyl-3,4-dihydropyrimidin-2(1H)-one 4p:

mp 185–186 °C. ¹H NMR ([²H₆]DMSO, 300 MHz) d: 8.82 (s, 1H, NH), 7.18 (s, 1H, NH), 4.03–4.09 (m, 3H, H-4 and OCH₂Me), 2.16 [s, 3 H, C(6)–Me], 1.41 (m, 2H, CH₂Me), 1.17 (t, 3H, OCH₂Me, J 6.0 Hz), 0.78 (t, 3H, CH₂Me, J 7.5 Hz). ¹³C NMR, d: 165.3, 152.6, 148.1, 98.7, 58.8, 51.2, 29.4, 17.5, 14.0 and 8.31. IR (KBr, n/cm^–1): 3250, 3123, 2962, 1723, 1703, 1675. MS (70 eV, EI), m/z: 212 (M⁺, 0.43%).

5-Ethoxycarbonyl-4-isobutyl-6-methyl-3,4-dihydropyrimidin-2(1H)-one 4q: mp 185–186 °C. ¹H NMR ([²H₆]DMSO, 300 MHz) d: 8.86 (s, 1H, NH), 7.32 (s, 1H, NH), 4.01–4.10 (m, 3H, H-4 and OCH₂Me), 2.16 [s, 3H, C(6)–Me], 1.69 (m, 1H, CH₂CHMe₂), 1.35 (m, 1H, CH₂CHMe₂), 1.17 (t, 3H, OCH₂Me, J 7.0 Hz), 1.10 (m, 1H, CH₂CHMe₂), 0.85 (d, 6 H, CH₂CHMe₂, J 6.5 Hz). ¹³C NMR, d: 165.1, 152.6, 147.9, 100.2, 58.8, 48.1, 45.8, 23.5, 22.7, 21.3, 17.4, 14.0. IR (KBr, n/cm^–1): 3447, 3244, 3112, 2951, 1701, 1652. MS (70 eV, EI), m/z: 241 (M⁺+ 1, 1.08%).

R²

O O

R¹ H

O

H₂N NH₂ X

N NH R²

O R¹

H X

1 2 3

Scheme 1 4

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212 Mendeleev Commun. 2004

conversion of starting materials 1, 2 and 3 into products 4 is considerably reduced and the yields of the products are higher.

The method works equally well for urea, thiourea and aliphatic or aromatic aldehydes. Compounds containing electron-with- drawing or electron-releasing groups give the best yield and the highest purity. Furthermore, the ionic system used acted as both a Lewis acid catalyst and a solvent, which is important in reactions where stoichiometric amounts are used.

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Received: 26th January 2004; Com. 04/2221