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Synlett 2009(14): 2253-2256  
DOI: 10.1055/s-0029-1217724
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Copper-Mediated N-Arylation of Quinazolinediones

Collette S. Guya, Teyrnon C. Jones*b
a Department of Chemistry, University of Warwick, Coventry, CV4 7AL, UK
b Department of Medicinal Chemistry, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leics, LE11 5RH, UK
Fax: +44(1509)644925; e-Mail: teyrnon.jones@astrazeneca.com;
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Publikationsverlauf

Received 7 May 2009
Publikationsdatum:
03. August 2009 (online)

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Abstract

A mild, ligand-free method of arylating 2,4-quinazolinediones using arylboronates in the presence of copper salts is described. The reaction is tolerant of a variety of functional groups and works for arylboronic acid, arylboronic ester, and aryltrifluoroboronate donors. A catalytic variant is also described.

Key words

heterocycle - arylation - copper - cross-coupling - boronic

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19

A regiochemically controlled synthesis of quinazolinedione 3 was carried out using the route outlined in Scheme  [¹] (disconnection a). The material so obtained was spectros-copically identical to that generated by direct arylation of 1, confirming that the regiochemistry of substitution was limited to the free nitrogen position and not either of the available carbonyl oxygens.

21

Typical Procedure
3-Methylquinazoline-2,4 (1H,3H)-dione (200 mg, 1.14 mmol), 4-methoxyphenylboronic acid (345 mg, 2.27 mmol), Cu(OAc)2 (412 mg, 2.27 mmol), and Et3N (0.316 mL, 2.27 mmol) were suspended in CH2Cl2 (12 mL) along with 200 mg of activated 4 Å MS. The suspension was allowed to stir at r.t. for 20 h then partitioned between 1 M HCl (50 mL) and EtOAc (50 mL). The organic layer was isolated, dried (MgSO4), and concentrated in vacuo, and the residue was purified by flash chromatography (15% EtOAc-i-hexane)­ ­
to furnish 1-(4-methoxyphenyl)-3-methylquinazoline-2,4- (1H,3H)-dione (4) as a colourless solid (230 mg, 72%). ¹H NMR (400 MHz, CDCl3): δ = 8.1-8.4 (m, 1 H), 7.4-7.6 (m, 1 H), 7.1-7.3 (m, 3 H), 7.0-7.2 (d, 2 H), 6.59 (d, 1 H), 3.89 (s, 3 H), 3.52 (s, 3 H). ¹³C NMR (100 MHz, CDCl3): δ = 162.2, 159.9, 151.2, 141.7, 134.5, 129.9, 129.0, 128.5, 123.0, 115.5, 115.3, 115.0, 55.5, 28.3; MS (ES+): m/z = 281 [M - H]+.