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Synlett 2018; 29(07): 912-917
DOI: 10.1055/s-0036-1591544
letter
© Georg Thieme Verlag Stuttgart · New York

Metal-Free Oxidative C(sp3)–N Coupling by HBr and DMSO: A Novel Synthesis of 2,3-Dihydroquinazolin-4(1H)-ones

Narjes Rezaei
School of Chemistry, College of Science, University of Tehran, PO Box 14155-6455, Tehran, Iran   Email: parvizrashidi2@ut.ac.ir
,
Ehsan Sheikhi
School of Chemistry, College of Science, University of Tehran, PO Box 14155-6455, Tehran, Iran   Email: parvizrashidi2@ut.ac.ir
,
Parviz Rashidi Ranjbar*
School of Chemistry, College of Science, University of Tehran, PO Box 14155-6455, Tehran, Iran   Email: parvizrashidi2@ut.ac.ir
› Author AffiliationsThis research was supported by the Research Council of the University of Tehran.
Further Information

Publication History

Received: 21 November 2017

Accepted after revision: 16 January 2018

Publication Date:
15 February 2018 (online)

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Abstract

A metal-free oxidative C(sp3)–N coupling process has been developed for the synthesis of 2,3-dihydroquinazolin-4(1H)-ones. The reaction between primary amines, isatoic anhydride, and benzylic alcohols in the presence of HBr in DMSO at 80 °C affords 2,3-dihydroquinazolin-4(1H)-ones in excellent yields. Under these reaction conditions, benzylic alcohols react with in situ generated bromodimethylsulfonium bromide to form alkoxysulfonium intermediates. These intermediates undergo an oxidative cyclization reaction with primary amines and isatoic anhydride to produce the title products.

Key words

C–N bond formation - metal-free reactions - oxidative coupling - HBr in DMSO - 2,3-dihydroquinazolin-4(1H)-one
 

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  • 26 General Procedure for the Preparation of DHQZs 4a-p, Exemplified for 4a A mixture of propylamine (1 mmol) and isatoic anhydride (1 mmol) in DMSO (3 mL) was stirred for 20 min at 80 °C. Then, 4-chlorobenzyl alcohol (1 mmol) and HBr (48% aq., 1 mmol) were added to the reaction mixture and stirring was continued at 80 °C for 10 min. The progress of reaction was followed by TLC. After the reaction was complete, the reaction mixture was cooled to ambient temperature, quenched by addition of water (2 mL), and stirring was continued for 10 min at ambient temperature. The resulting precipitate was filtered, washed with water, dried, and recrystallized from ethanol to afford the pure product 4a. 2-(4-Chlorophenyl)-3-propyl-2,3-dihydroquinazolin-4(1H)-one (4a) White solid, yield: 0.291 g (97%); mp = 160–162 °C. 1H NMR (500.1 MHz, DMSO-d6 ): δ = 0.84 (3 H, t, J = 7.4 Hz, CH3), 1.42–1.52 (1 H, m, ABCDX3 system, CHC H DCH3), 1.53–1.63 (1 H, m, ABCDX3 system, CH CHDCH3), 2.73 (1 H, ddd, ABCDX3 system, 2 J = 13.8 Hz, 3 J = 8.6 Hz, 3 J = 5.7 Hz, NCHA H B), 3.85 (1 H, ddd, ABCDX3 system, 2 J =13.8 Hz, 3 J = 8.6 Hz, 3 J = 5.7 Hz, NCH AHB), 5.88 (1 H, d, J = 2.4 Hz, NHCH), 6.65 (1 H, d, J = 8.4 Hz, CH), 6.66 (1 H, t, J = 7.4 Hz, CH), 7.20 (1 H, dt, 3 J = 8.4, 4 J = 1.5 Hz, CH), 7.34 (2 H, d, J = 8.5 Hz, 2 CH), 7.39 (1 H, d, J = 2.4 Hz, NH), 7.42 (2 H, d, J = 8.5 Hz, 2 CH), 7.65 (1 H, dd,3 J = 7.4, 4 J = 1.1 Hz, CH). 13C NMR (125.8 MHz, DMSO-d6 ): δ = 11.61 (CH3), 21.26 (CH2CH3), 46.65 (NCH2), 69.83 (NCHN), 114.79 (CH), 115.54 (C), 117.73 (CH), 127.90, 128.43, 128.94 (3CH), 133.35 (C), 133.63 (CH), 140.77, 146.45 (2C), 162.59 (C=O). 2,3-Dihydro-2-(3-hydroxyphenyl)-3-propylquinazolin-4(1H)-one (4c) White solid, yield: 0.262 g (93%); mp = 198–200 °C. 1H NMR (500.1 MHz, DMSO-d6 ): δ = 0.85 (3 H, t, J = 7.4 Hz, CH3), 1.49 (1 H, m, ABCDX3 system, CHC H DCH3), 1.60 (1 H, m, ABCDX3 system, CH CHDCH3), 2.73 (1 H, ddd, ABCDX3 system, 2 J = 13.7 Hz, 3 J = 8.6 Hz, 3 J = 6.5 Hz, NCHA H B), 3.86 (1H, ddd, ABCDX3 system, 2 J =13.7 Hz, 3 J = 8.6 Hz, 3 J = 6.5 Hz, NCH AHB), 5.76 (1 H, d, J = 2.2 Hz, NHCH), 6.65 (1 H, d, J = 7.9 Hz, CH), 6.66 (1 H, t, J = 8.0 Hz, CH), 6.72 (1 H, dd, 3 J = 8.0 Hz, 4 J = 1.6 Hz, CH), 6.78 (1 H, s, CH), 6.79 (1 H, d, J = 7.9 Hz, CH), 7.14 (1 H, t, J = 7.9 Hz, CH), 7.20 (1 H, dt, 3 J = 8.0, 4 J = 1.4 Hz, CH), 7.29 (1 H, d, J = 2.2 Hz, NH), 7.68 (1 H, dd, 3 J = 8.0 Hz, 4 J = 1.2 Hz, CH), 9.49 (1 H, s, OH). 13C NMR (125.8 MHz, DMSO-d6 ): δ = 11.67 (CH3), 21.20 (CH2CH3), 46.61 (NCH2), 70.72 (NCHN), 113.47, 114.66 (2CH), 115.45, 115.78 (2C), 117.37, 117.43 (2CH), 127.89, 129.95, 133.51 (3CH), 143.26, 146.76 (2C), 157.96 (CH), 162.71 (C=O). 3-Butyl-2-phenyl-2,3-dihydroquinazolin-4(1H)-one (4d)19i White solid, yield: 0.255 g (91%); mp = 121 °C. 1H NMR (500.1 MHz, DMSO-d6 ): δ = 0.84 (3 H, t, J = 7.3 Hz, CH3), 1.23–1.30 (2 H, m, CH2), 1.41–1.49 (1 H, m, ABCDM2X3 system, CHC H DCH2CH3), 1.50–1.59 (1 H, m, ABCDM2X3 system, CH CHDCH2CH3), 2.74 (1 H, ddd, ABCDM2X3 system, 2 J = 13.7 Hz, 3 J = 8.3 Hz, 3 J = 5.8 Hz, NCHA H B), 3.88–3.94 (1 H, m, ABCDM2X3 system, NCH AHB), 5.85 (1 H, s, NHCH), 6.65 (1 H, d, J = 7.8 Hz, CH), 6.66 (1 H, t, J = 7.1 Hz, CH), 7.19 (1 H, t, J = 7.1 Hz, CH), 7.30–7.36 (6 H, m, 5CH and NH), 7.67 (1 H, d, J = 7.8 Hz, CH). 13C NMR (125.8 MHz, DMSO-d6 ): δ = 14.12 (CH3), 20.02 (CH2CH3), 30 (CH2CH2), 44.41 (NCH2), 70.56 (NCHN), 114.69 (CH), 115.51 (C), 117.52, 127.86, 126.6, 128.78, 128.94 (5CH), 133.53, 141.68 (2C), 146.71 (CH), 162.67 (C=O). 2,3-Dihydro-2-(4-methoxyphenyl)-3-phenylquinazolin-4(1H)-one (4h)27c White solid, yield: 0.300 g (91%); mp = 204 °C. 1H NMR (300 MHz, DMSO-d6 ): δ = 3.67 (3 H, s, OCH3), 6.22 (1 H, br s, CH), 6.71 (1 H, t, J = 7.7 Hz, CH), 6.76 (1 H, d, J = 7.7 Hz, CH), 6.84 (2 H, d, J = 8.6 Hz, 2 CH), 7.17 (1 H, t, J = 7.0 Hz, 1 CH), 7.22–7.35 (7 H, m, 7 CH), 7.55 (1 H, br s, NH), 7.73 (1 H, d, J = 7.7 Hz, CH). 13C NMR (75 MHz, DMSO-d6 ): δ = 55.00 (OCH3), 72.32 (NCHN), 113.65 (CH), 114.78 (C), 115.34 (CH), 117.43 (C), 125.95, 126.30, 127.91, 128.56 (4CH), 128.58 (C), 132.61 (CH), 133.68 (C), 140.83 (CH), 146.66 (C), 159.11 (CH), 162.33 (C=O). 2,3-Bis(4-chlorophenyl)-2,3-dihydroquinazolin-4(1H)-one (4m)27c Pale yellow solid, yield: 0.339 g (92%); mp = 249–251 °C. 1H NMR (500.1 MHz, DMSO-d6 ): δ = 6.35 (1H, s, NHCH), 6.74 (1 H, t, J = 7.4 Hz, CH), 6.79 (1 H, d, J = 8.1 Hz, CH), 7.28–7.31 (3 H, m, 3CH), 7.37–7.41 (6 H, m, 6CH), 7.68 (1 H, br s, NH), 7.74 (1 H, d, J = 7.7 Hz, CH). 13C NMR (125.8 MHz, DMSO-d6 ): δ = 72.35 (NCHN), 115.35 (CH), 115.45 (C), 118.28 (CH), 128.52 (C), 128.57, 128.93, 129.07, 129.10 (4CH), 130.82 (C), 133.55 (C), 134.51 (C), 139.66 (CH), 139.77 (CH), 146.98 (C), 162.76 (C=O).
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