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Synlett 2012(4): 601-606  
DOI: 10.1055/s-0031-1290346
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

A Pd-Catalyzed Cascade Protocol towards 2-Alkyl-4-aryl-4H-benz[1,4]oxazin-3-ones from Aryl Amines and 2-(2-Halophenoxy)alkanoates

Gaofeng Fenga, Fangling Yinb, Fengjiang Chena, Qingbao Songb, Chenze Qi*a
a The Institute of Applied Chemistry, Shaoxing University, Shaoxing 312050, P. R. of China
b College of Chemical Engineering and Material Science, Zhejiang University of Technology, Hangzhou 310027, P. R. of China
Fax: +86(575)88345682; e-Mail: qichenze@usx.edu.cn;
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Publication History

Received 22 November 2011
Publication Date:
10 February 2012 (online)

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Abstract

A cascade process, consisting of Pd-catalyzed intermolecular amination and subsequent thermal intramolecular amidation, has been established for efficient one-pot synthesis of 4H-benz[1,4]oxazin-3-ones from anilines and 2-(2-halophenoxy)alkanoates. Use of Cs2CO3 as the base was found to be determinant for the process and alkyl groups attached to the α position of alkanoates are beneficial for achieving good yields. Various substrates were compatible to afford the desired products in good to excellent yields. It is an attractive process for synthesizing a library of 4H-benz[1,4]oxazin-3-ones.

Key words

cascade reaction - palladium catalysis - amination - 4H-benz[1,4]oxazin-3-ones - lactamization

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13

Initially, CuI was tried as the catalyst under various conditions, but only trace amount of 1a was observed.

14

Other 2-(2-halophenoxy)alkanoates used in this work were prepared in excellent yields (95-98%) under the similar conditions.

16

General Procedure for the Synthesis of 4 H -Benz[1,4]oxazin-3-ones: To a 10-mL pressurized process vial were added magnetic stir bar, Pd(OAc)2 (6.8 mg, 0.03 mmol, 10 mol%), (±)-BINAP (18.7 mg, 0.03 mmol, 10 mol%), ethyl 2-(2-halophenoxy)alkanoates (0.30 mmol), and Cs2CO3 (195 mg, 0.6 mmol). The loaded vial was then sealed with a rubber cap. The vial was evacuated and backfilled with nitrogen through the cap (this procedure was repeated several times). The anhyd and degassed toluene (3 mL) and aryl amine (0.45 mmol) were added by syringe through the cap. The resultant mixture was heated at 90 ˚C for 24 h in an oil bath, and then filtrated through Celite with washing with EtOAc. The combined filtrate was concen-trated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with EtOAc and petroleum ether (60-90 ˚C) to afford 1. [¹7] [¹8] The structures and yields of the products are given in Tables  [²] and  [³] .

17

Physical and spectroscopic data for 4-naphthanyl-4H-benz[1,4]oxazin-3-one (1n): yellow crystalline solid; mp 146-147 ˚C; R f 0.55 (EtOAc-hexane, 25%). IR (film): 1682, 1370 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 7.95 (d, J = 8.0 Hz, 1 H), 7.91 (d, J = 8.0 Hz, 1 H), 7.55-7.61 (m, 2 H), 7.39-7.49 (m, 3 H), 7.07 (d, J = 8.0 Hz, 1 H), 6.94 (dd, J = 8.4, 8.4 Hz, 1 H), 6.70 (dd, J = 8.0, 8.0 Hz, 1 H), 6.20 (d, J = 8.0 Hz, 1 H), 4.91, 4.84 (AB q, J = 15.6, 15.6 Hz, 2 H). ¹³C NMR (100 MHz, CDCl3): δ = 164.6, 144.8, 134.9, 132.3, 130.7, 130.1, 129.8, 128.8, 127.55, 127.52, 126.8, 126.0, 124.2, 122.9, 122.4, 117.1, 116.9, 68.3. MS (+ESI): m/z = 298 (53) [M + Na+], 572 (100) [2 M + Na+]. Anal. Calcd for C18H13NO2: C, 78.53; H, 4.76; N, 5.09. Found: C, 78.56; H, 4.79; N, 4.98.

18

Physical and spectroscopic data for 2-ethyl-4-(4-methyl-phenyl)-4H-benz[1,4]oxazin-3-one (1r): yellowish crystalline solid; mp 95-96 ˚C; R f 0.72 (EtOAc-hexane, 25%). IR (film): 1689, 1368 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 7.34 (d, J = 8.0 Hz, 2 H), 7.16 (d, J = 8.0 Hz,
2 H), 7.06 (dd, J = 8.0, 1.2 Hz, 1 H), 6.99 (ddd, J = 8.0, 8.0, 1.6 Hz, 1 H), 6.85 (ddd, J = 8.0, 8.0, 1.6 Hz, 1 H), 6.44 (dd, J = 8.0, 1.2 Hz, 1 H), 4.66 (dd, J = 8.4, 4.4 Hz, 1 H), 2.44 (s, 3 H), 1.95-2.10 (m, 2 H), 1.16 (t, J = 7.6 Hz, 3 H). ¹³C NMR (100 MHz, CDCl3): δ = 166.3, 143.8, 138.7, 133.6, 130.8, 130.6 (2 ×), 128.5 (2 ×), 123.9, 122.2, 117.3, 116.6, 78.8, 23.9, 21.3, 9.6. MS (+ESI): m/z = 290 (28) [M + Na+], 557 (100) [2 M + Na+]. Anal. Calcd for C17H17NO2: C, 76.38; H, 6.41; N, 5.24. Found: C, 76.36; H, 6.39; N, 5.37.