An Efficient Synthesis of 2-Substituted Quinazolin-4(3H)-ones Catalyzed by Iron(III) Chloride

Ramamohan Mekala; Raghunadh Akula; Raghavendra Rao Kamaraju; Chandrasekhar Kothapalli Bannoth; Sridhar Regati; Jayaprakash Sarva

doi:10.1055/s-0033-1340786

Synlett, Table of Contents

Synlett 2014; 25(6): 821-826
DOI: 10.1055/s-0033-1340786

letter

An Efficient Synthesis of 2-Substituted Quinazolin-4(3H)-ones Catalyzed by Iron(III) Chloride

Authors

Ramamohan Mekala

^aTechnology Development Centre, Custom Pharmaceutical Services, Dr. Reddy's Laboratories Ltd, Bollaram Road, Miyapur, Hyderabad, 500049, India Fax: +91(40)44658699 Email: sarvaj@drreddys.com

^bDepartment of Chemistry, Jawaharlal Nehru Technological University, Anantapur, Andhra Pradesh 515002, India
Raghunadh Akula

^aTechnology Development Centre, Custom Pharmaceutical Services, Dr. Reddy's Laboratories Ltd, Bollaram Road, Miyapur, Hyderabad, 500049, India Fax: +91(40)44658699 Email: sarvaj@drreddys.com
Raghavendra Rao Kamaraju

^aTechnology Development Centre, Custom Pharmaceutical Services, Dr. Reddy's Laboratories Ltd, Bollaram Road, Miyapur, Hyderabad, 500049, India Fax: +91(40)44658699 Email: sarvaj@drreddys.com
Chandrasekhar Kothapalli Bannoth

^bDepartment of Chemistry, Jawaharlal Nehru Technological University, Anantapur, Andhra Pradesh 515002, India
Sridhar Regati

^aTechnology Development Centre, Custom Pharmaceutical Services, Dr. Reddy's Laboratories Ltd, Bollaram Road, Miyapur, Hyderabad, 500049, India Fax: +91(40)44658699 Email: sarvaj@drreddys.com
Jayaprakash Sarva*

^aTechnology Development Centre, Custom Pharmaceutical Services, Dr. Reddy's Laboratories Ltd, Bollaram Road, Miyapur, Hyderabad, 500049, India Fax: +91(40)44658699 Email: sarvaj@drreddys.com

Abstract

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Abstract

A simple and highly efficient synthesis of 2-substituted quinazolin-4(3H)-ones by the iron(III) chloride catalyzed reaction of isatoic anhydride with various amidoxime derivatives was developed. Several aryl and alkyl amidoximes were screened to demonstrate the scope of the methodology.

Key words

heterocycles - polycycles - ketones - catalysis - iron - quinazolinones

Full Text

References

References and Notes

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12 2-Substituted Quinazolin-4(3H)-ones 8a–m; General Procedure The appropriate amidoxime 7 (1.1 mmol) and FeCl₃ (10 mol%) were added sequentially to a solution of isatoic anhydride (6; 1 mmol.) in 1,4-dioxane (10 mL), and the mixture was stirred at 80 °C for 2–9 h until the reaction was complete (TLC). The mixture was then diluted with EtOAc (10 mL) and washed with H₂O (2 × 5 mL). The organic layer was dried (Na₂SO₄), filtered, and concentrated under reduced pressure to give a crude product that was purified by column chromatography (silica gel, 30% EtOAc–hexanes). All new compounds gave satisfactory analytical and spectroscopic results. 2-(4-Aminophenyl)quinazolin-4(3H)-one (8e) Yellow solid; yield: 284 mg (78%); mp 250–254 °C; ¹H NMR (400 MHz, DMSO-d ₆): δ = 5.83 (s, 2 H, NH₂), 6.62 (d, J = 8.8 Hz, 2 H, ArH), 7.40 (t, J = 6.9 Hz, 1 H, ArH), 7.61 (d, J = 8.3 Hz, 1 H, ArH), 7.76 (t, J = 6.8 Hz, 1 H, ArH), 7.95 (d, J = 8.8 Hz, 2 H, ArH), 8.08 (dd, J = 6.9, 1 Hz, 1 H, ArH), 12.06 (br s, 1 H, NH); ¹³C NMR (100 MHz, DMSO-d ₆): δ = 113.0, 121.5, 125.3, 125.8, 126.9, 128.7, 129.1, 134.4, 149.6, 152.2, 152.4, 162.4; MS: m/z = 238.1 [M + H]; HRMS (ESI): m/z [M + H] calcd for C₁₄H₁₂N₃O: 238.0980; found: 238.0969. 2-[4-(Methylsulfanyl)phenyl]quinazolin-4(3H)-one (8g) White solid; yield: 383 mg (93%); mp 237–239 °C; ¹H NMR (400 MHz, DMSO-d ₆): δ = 2.55 (s, 3 H, SCH₃), 7.40 (d, J = 8.4 Hz, 2 H, ArH), 7.50 (t, J = 7.2 Hz, 1 H, ArH), 7.72 (d, J = 7.6 Hz, 1 H, ArH), 7.83 (t, J = 7.6 Hz, 1 H, ArH), 8.13–8.16 (m, 3 H, ArH), 12.48 (br s, 1 H, NH); ¹³C NMR (400 MHz, DMSO-d ₆): δ = 14.1, 120.8, 125.1, 125.8, 126.4, 127.4, 128.0, 128.6, 134.6, 143.0, 148.7, 151.78, 162.2; MS: m/z = 269.0 [M + H]; HRMS (ESI): m/z [M + H] calcd for C₁₅H₁₃N₂OS: 269.07486; found: 269.07446. 2-(5-Fluoropyridin-2-yl)quinazolin-4(3H)-one (8j) Brown solid; yield: 296 mg (80%); mp 180–183 °C; ¹H NMR (400 MHz, CDCl₃): δ = 7.51–7.56 (m, 1 H, ArH), 7.61–7.65 (m, 1 H, ArH), 7.77–7.80 (m, 2 H, ArH), 8.35 (d, J = 7.4 Hz, 1 H, ArH), 8.51 (d, J = 2.9 Hz, 1 H, ArH), 8.63 (dd, J = 8.8, 4.8 Hz, 1 H, ArH), 10.76 (br s, 1 H, NH); ¹³C NMR (100 MHz, CDCl₃): δ = 122.2, 123.7 (d, J = 5.4 Hz), 124.4 (d, J = 18.4 Hz), 126.7, 127.4, 127.9, 134.6, 137.2 (d, J = 25.2 Hz), 144.7, 147.9, 148.9, 161.1 (d, J = 260.0 Hz), 161.3; MS: m/z = 242.1 [M + H]; HRMS (ESI): m/z [M + H] calcd for C₁₃H₉N₃OF: 242.0730; found: 242.0722. 2-(Cyclopropylmethyl)quinazolin-4(3H)-one (8k) White solid; yield: 279 mg (91%); mp 210–213 °C; ¹H NMR (400 MHz,, CDCl₃): δ = 0.38–0.42 (m, 2 H, CH₂), 0.70–0.73 (m, 2 H, CH₂), 1.14–1.21 (m, 1 H, CH), 2.70 (d, J = 7.6 Hz, 2 H, CH₂), 7.26–7.49 (m, 1 H, ArH), 7.68 (d, J = 7.6 Hz, 1 H, ArH), 7.74–7.79 (m, 1 H, ArH), 8.28 (dd, J = 6.8, 1.2 Hz, 1 H, ArH), 10.20 (br s, 1 H, NH); ¹³C NMR (100 MHz, DMSO-d ₆): δ = 4.2, 9.2, 39.2, 120.8, 125.7, 126.0, 126.8, 134.3, 149.0, 157.2, 161.8; MS: m/z = 201.1 [M + H]; HRMS (ESI): m/z [M + H] calcd for C₁₂H₁₃N₂O: 201.1028; found: 201.1037. 2-(4-Nitrobenzyl)quinazolin-4(3H)-one (8m) Light-brown solid; yield: 383 mg (89%); mp >300 °C; ¹H NMR (400 MHz, DMSO-d ₆): δ = 4.11 (s, 2 H, PhCH₂), 7.48 (t, J = 7.4 Hz, 1 H, ArH), 7.58 (d, J = 8.4 Hz, 1 H, ArH), 7.65 (d, J = 8.4 Hz, 2 H, ArH), 7.75–7.79 (m, 1 H, ArH), 8.08 (d, J = 6.9 Hz, 1 H, ArH), 8.20 (d, J = 8.8 Hz, 2 H, ArH), 12.49 (br s, 1 H, NH); ¹³C NMR (100 MHz, DMSO-d ₆): δ = 40.7, 121.3, 123.6, 125.7, 126.4, 126.9, 128.3, 128.6, 130.4, 134.4, 144.4, 154.9, 161.7; MS: m/z = 282.0 [M + H]; HRMS (ESI): m/z [M + H] calcd for C₁₅H₁₂N₃O₃: 282.0879; found: 282.0877.

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