One-Pot Regioselective Synthesis of Imidazole and 2,3-Dihydroquinazolinone Derivatives – An Easy Access to ‘Nature-Like Molecules’; Part XIII in the 
Series: ‘Studies on Novel Synthetic Methodologies’

Koneni V. Sashidhara; Gopala Reddy Palnati; Ranga Prasad Dodda; Srinivasa Rao Avula; Priyanka Swami

doi:10.1055/s-0033-1339466

Synlett, Table of Contents

Synlett 2013; 24(14): 1795-1800
DOI: 10.1055/s-0033-1339466

letter

One-Pot Regioselective Synthesis of Imidazole and 2,3-Dihydroquinazolinone Derivatives – An Easy Access to ‘Nature-Like Molecules’; Part XIII in the Series: ‘Studies on Novel Synthetic Methodologies’

Koneni V. Sashidhara*

^aMedicinal and Process Chemistry Division, Central Drug Research Institute, CSIR-CDRI, Lucknow, 226 001, India Fax: +91(522)2623405 Email: sashidhar123@gmail.com Email: kv_sashidhara@cdri.res.in

,

Gopala Reddy Palnati

^aMedicinal and Process Chemistry Division, Central Drug Research Institute, CSIR-CDRI, Lucknow, 226 001, India Fax: +91(522)2623405 Email: sashidhar123@gmail.com Email: kv_sashidhara@cdri.res.in

,

Ranga Prasad Dodda

^aMedicinal and Process Chemistry Division, Central Drug Research Institute, CSIR-CDRI, Lucknow, 226 001, India Fax: +91(522)2623405 Email: sashidhar123@gmail.com Email: kv_sashidhara@cdri.res.in

,

Srinivasa Rao Avula

^aMedicinal and Process Chemistry Division, Central Drug Research Institute, CSIR-CDRI, Lucknow, 226 001, India Fax: +91(522)2623405 Email: sashidhar123@gmail.com Email: kv_sashidhara@cdri.res.in

,

Priyanka Swami

^bMedicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Raebareli 229 010, India

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Abstract

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Abstract

A mild and highly practical regioselective synthesis of imidazole and 2,3-dihydroquinazolinone derivatives from 5-alkyl-4-hydroxyisophthalaldehydes with suitable substrates in acetic acid is reported. Further exploration of the molecular diversity of 2,3-dihydroquinazolinone is demonstrated by the synthesis of diverse pharmacologically relevant natural-product-like scaffolds.

Key words

one-pot synthesis - regioselective synthesis - imidazole - 2,3-dihydroquinazolinone - 5-alkyl-4-hydroxyisophthalaldehydes - nature-like molecules

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References

References and Notes

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15 Typical Method for the Preparation of Compound 4b via MCR A mixture of 5-ethyl-4-hydroxyisophthalaldehyde (1b, 1.0 mmol), NH₄OAc (2, 1.5 mmol), and 4,4′-dimethoxybenzil (3, 1.0 mmol) in AcOH (5 mL) was heated at 110 °C with stirring for 4.0 h (progress of the reaction was monitored by TLC). After completion of the reaction, the reaction mixture was diluted with H₂O (25 mL), followed by extraction with CHCl₃ (2 × 25 mL). The combined extracts were dried over Na₂SO₄ and dried under high vacuum to afford the crude product. It was subjected to further purification by column chromatography (silica 100–200) using 20% EtOAc–hexane as eluent. The desired product 4b was obtained as a yellow solid; yield 85%; mp 135–137 °C. IR (KBr): 3527, 3010, 2964, 1660, 1239, 1032 cm^–1. ¹H NMR (300 MHz, DMSO-d ₆): δ = 12.51 (s, 1 H), 11.09 (s, 1 H), 10.12 (s, 1 H), 8.30 (d, J = 2.1 Hz, 1 H), 8.18 (d, J = 2.0 Hz, 1 H), 7.45 (d, J = 8.6 Hz, 4 H), 7.00–6.89 (m, 4 H), 3.78 (s, 3 H), 3.77 (s, 3 H), 2.70 (q, J = 7.4 Hz, 2 H), 1.23 (t, J = 7.4 Hz, 3 H). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 197.7, 159.0, 144.9, 133.4, 133.2, 129.8, 128.2, 123.6, 121.7, 115.0, 114.7, 56.0, 22.8, 14.6. ESI-MS: m/z = 429 [M + H]⁺.
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18 General Procedure for the Preparation of 9c via MCR A mixture of 4-hydroxy-5-propylisophthalaldehyde (1c, 1.0 mmol), methylamine (7, 1.5 mmol), and isatoicanhydride (8, 1.0 mmol) in AcOH (5.0 mL) was stirred in a round-bottom flask for 2.0 h at 110 °C (initially effervescence was observed due to the generation of CO₂ gas). Upon completion of the reaction, the reaction mixture was diluted with H₂O (25 mL), followed by extraction with CHCl₃ (2 × 25 mL). The combined organic phases were dried over anhyd Na₂SO₄ and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (100–200) in 40% CH₂Cl₂–hexane solvent system. The required compound was obtained as a white solid; yield 78%; mp 173–175 °C. IR (KBr): 3516, 3412, 3015, 2934, 1650, 1190, 1042 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 11.39 (s, 1 H), 9.84 (s, 1 H), 7.96 (d, J = 7.7 Hz, 1 H), 7.48 (s, 1 H), 7.42 (s, 1 H), 7.31–7.28 (m, 1 H), 6.90–6.85 (m, 1 H), 6.59 (d, J = 7.8 Hz, 1 H), 5.72 (s, 1 H), 4.59 (s, 1 H), 2.88 (s, 3 H), 2.64 (t, J = 7.4 Hz, 2 H), 1.66–1.59 (m, 2 H), 0.94 (t, J = 7.2 Hz, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 196.5, 163.8, 160.7, 145.4, 135.3, 133.7, 132.7, 130.6, 129.6, 128.5, 119.8, 115.6, 114.3, 73.5, 31.8, 31.2, 22.4, 13.9. ESI-MS: m/z = 325 [M + H]⁺.

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