HETEROCYCLES

Short Paper | Regular issue | Vol. 83, No. 11, 2011, pp. 2597-2600
Received, 26th July, 2011, Accepted, 5th September, 2011, Published online, 7th September, 2011.
DOI: 10.3987/COM-11-12318

■ An Efficient Approach for the One-Pot Synthesis of Ethyl 4-Oxo-4H-benzo[d][1,3]oxazine-2-carboxylates

Farzad Nikpour,* Mahnaz Sharafi-Kolkeshvandi, and Asrin Bahmani

Department of Chemistry, Faculty of Science, University of Kurdistan, Sanandaj, Pasdaran Bivd., P.O.Box 66135-416, Iran

Abstract

Simple one-pot synthesis of ethyl 4-oxo-4H-benzo[d][1,3]oxazine-2-carboxylates is described by condensation reaction of anthranilic acid derivatives with ethyl 2-chloro-2-oxoacetate in CHCl3. High yields of the products obtain in high purity with simple work-up.

4H-3,1-Benzoxazin-4-ones as an important class of fused heterocyclic compounds have considerable interest owing to their industrial1 and wide biological2 applications. They are found in nature3,4 and have been used as key intermediates in the synthesis of a wide variety of biologically important heterocyclics such as quinazolinones5 and quinolines.6 The reactivity and chemical behavior of 4H-3,1-benzoxazin- 4-ones are due to the susceptibility of the C-4 carbonyl to nucleophilic attack.7 The chemistry of 2-alkyl, 2-aryl and 2-hetero substituted 4H-3,1-benzoxazin-4-ones has been reviewed by Coppola.8
Contrary to the parent compounds 2-alkyl and 2-aryl 4H-3,1-benzoxazin-4-ones, very few synthetic routes have ever been published for 2-functionalized substitutions such as 2-carboxylate groups.9 The most accessible method for the synthesis of ethyl 4-oxo-4H-benzo[d][1,3]oxazine-2-carboxylate has proven to be the one based on the reaction of anthranilic acid with diethyl oxalate in high temperature and then cyclization reaction of the separated ethyl (2-carboxyphenyl)oxamate with acetic anhydride under reflux codition.9a Since the effective methods to modify the preparation of such highly important compounds are still a worthwhile effort in heterocycles synthesis, herein, we wish to report a simple and efficient protocol for the one-pot synthesis of ethyl 4-oxo-4H-benzo[d][1,3]oxazine-2-carboxylates using condensation and cyclization reaction of anthranilic acid derivatives with ethyl 2-chloro-2-oxoacetate in the presence of triethylamine under mild reaction conditions. We observed when the anthranilic acid derivatives 1 react with two equimolar amounts of ethyl 2-chloro-2-oxoacetate in the presence of triethylamine in CHCl3, ethyl 4-oxo-4H-benzo[d][1,3]oxazine-2-carboxylates 3 are obtained in high yields without need to separation and purification of the intermediates ethyl (2-carboxyphenyl)oxamates, and also without need to use of any catalysts (Scheme 1).

The reaction conditions are mild with very simple work-up of the reaction mixture. Results are summarized in Table 1.

The proposed mechanism is shown in scheme 2.

In the first step, condensation reaction of anthranilic acids 1 with ethyl 2-chloro-2-oxoacetate (2) in the presence of Et3N produces the intermediates 4 and 5 respectively. Then, cyclization reaction of 5 under reflux condition of the mixture in CHCl3 leads to the desired benzoxazine-4-ones 3.
The identification and characterization of the products were carried out by means of their physical and spectroscopic data. In IR spectra of compounds 3, lactone and ester CO-stretching bands observe in about 1770-1755 cm-1 and 1740-1725 cm-1 respectively. Also, these two carbonyl groups appear in about 158-160 ppm in 13C NMR. In the case of 13C NMR of 3d, two additional carbonyl groups related to the reaction of OH substitution with 2 are appeared at about 159 and 170 ppm. In all cases molecular ion peaks with good abundances appear in Mass-spectral.
In conclusion, a simple and convenient procedure is described for the one-pot synthesis of ethyl 4-oxo-4H-benzo[d][1,3]oxazine-2-carboxylates 3 by first, condensation reaction of anthranilic acid derivatives with ethyl 2-chloro-2-oxoacetate and then, cyclization reaction of the mixture in CHCl3 under reflux condition. The reactions were carried out under mild conditions in the absence of any catalyst. High yields of the products obtained in high purity with simple work-up.

ACKNOWLEDGEMENTS
We are thankful to the University of Kurdistan Research Council for the partial support of this work.

References

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10. General reaction procedure: In a 25 mL round flask a mixture of 1 mmol of an anthranilic acid derivative 1 and 2.2 mmol of triethylamine was stirred in CHCl3 at room temperature and then, 2.2 mmol of ethyl chloroformylformate (in the case of 1d, 3 mmol of Et3N and 3 mmol of 2) was added dropwised to this solution and the mixture was stirred in an ice bath for about 30 min. Then, the reaction mixture was refluxed for the times as indicated in Table 1. The solvent was removed under reduced pressure and the precipitate was washed with 2 mL of n-hexane (three times) and filtered to remove the trace residual of ethyl chloroformylformate. The products were washed with 10% aq. NaHCO3 and then with H2O and dried in air. They may be recrystallized from n-Hexane/EtOAc, if needed.; Ethyl 4-oxo-4H-benzo[d][1,3]oxazine-2-carboxylate (3a)
Mp 129-131 ºC [129-130 ºC9a,9d].
Ethyl 5-methyl-4-oxo-4H-benzo[d][1,3]oxazine-2-carboxylate (3b)
Mp 109-111 ºC. IR (KBr): ν = 1773, 1731 cm-1; 1H NMR (250.1 MHz, CDCl3): δ (ppm) = 1.40 (t, 3JHH = 7.0 Hz, 3H, CH3), 2.78 (s, 3H, CH3), 4.44 (q, 3JHH = 7.0 Hz, 2H, CH2), 7.39 (d, 3JHH = 7.2 Hz, 1H-Ar), 7.65 (m, 2H-Ar); 13C NMR (62.9 MHz, CDCl3): δ (ppm) = 14.1, 22.4, 63.6, 116.5, 126.6, 133.2, 135.9, 143.4, 146.2, 147.6, 157.0, 157.9; EI-MS (70 eV): m/z (%) = 233 (M+, 25); Anal. Calcd for C12H11NO4 (233.22): C, 61.80; H, 4.75; N, 6.01. Found: C, 61.77; H, 4.79; N, 6.06.
Ethyl 6,7-dimethoxy-4-oxo-4H-benzo[d][1,3]oxazine-2-carboxylate (3c)
Mp 204-206 ºC. IR (KBr): ν = 1751, 1728 cm-1; 1H NMR (250.1 MHz, CDCl3): δ (ppm) = 1.32 (t, 3JHH = 6.2 Hz, 3H, CH3), 3.91 and 3.94 (2s, 6H, OCH3), 4.35 (q, 3JHH = 6.2 Hz, 2H, CH2), 7.36 (s, 1H-Ar), 7.47 (s, 1H-Ar); 13C NMR (62.9 MHz, CDCl3): δ (ppm) = 14.4, 56.6, 57.0, 63.1, 107.9, 109.9, 111.2, 141.1, 146.7, 151.4, 156.6, 158.0, 158.1; EI-MS (70 eV): m/z (%) = 279 (M+, 59); Anal. Calcd for C13H13NO6 (279.24): C, 55.92; H, 4.69; N, 5.02. Found: C, 55.97; H, 4.65; N, 4.98.
Ethyl 6-(ethyl oxalato)-4-oxo-4H-benzo[d][1,3]oxazine-2-carboxylate (3d)
Mp 139-141 ºC. IR (KBr): ν = 1786, 1769, 1743 cm-1; 1H NMR (250.1 MHz, CDCl3): δ (ppm) = 1.34-1.26 (m, 6H, CH3), 4.38-4.26 (m, 4H, CH2), 7.69-7.36 (m, 3H- Ar); 13C NMR (62.9 MHz, CDCl3): δ (ppm) = 14.2, 14.4, 62.4, 63.1, 112.2, 119.9, 125.7, 137.5, 144.8, 147.5, 154.1, 158.2, 158.6, 159.8, 169.5; EI-MS (70 eV): m/z (%) = 335 (M+, 5); Anal. Calcd for C15H13NO8 (335.26): C, 53.74; H, 3.91; N, 4.18. Found: C, 53.71; H, 3.93; N, 4.15.
Ethyl 6-bromo-4-oxo-4H-benzo[d][1,3]oxazine-2-carboxylate (3e)
Mp 165-167 ºC. IR (KBr): ν = 1758, 1735 cm-1; 1H NMR (250.1 MHz, CDCl3): δ (ppm) = 1.45 (t, 3JHH = 6.2 Hz, 3H, CH3), 4.51 (q, 3JHH = 6.2 Hz, 2H, CH2), 7.32 (s, 3JHH = 8.2 Hz, 1H-Ar), 8.11 (s, 1H-Ar), 8.52 (d, 3JHH = 8.2 Hz, 1H-Ar). 13C NMR (62.9 MHz, CDCl3): δ (ppm) = 14.6, 64.1, 117.1, 119.3, 122.4, 134.8, 137.5, 139.3, 155.3, 160.7, 169.3. EI-MS (70 eV): m/z (%) = 299 [(M+ + 2), 10], 297 (M+, 9); Anal. Calcd for C11H8BrNO4 (298.09): C, 44.32; H, 2.70; N, 4.70. Found: C, 44.35; H, 2.68; N, 4.71.
Ethyl 6-chloro-4-oxo-4H-benzo[d][1,3]oxazine-2-carboxylate (3f)
Mp 169-171 ºC. IR (KBr): ν = 1767, 1739 cm-1; 1H NMR (250.1 MHz, CDCl3): δ (ppm) = 1.42 (t, 3JHH = 6.5 Hz, 3H, CH3), 4.46 (q, 3JHH = 6.5 Hz, 2H, CH2), 7.69 (d, 3JHH = 8.2 Hz, 1H-Ar), 7.96 (dd, 3JHH = 8.2 Hz, 4JHH = 1.5 Hz, 1H-Ar), 8.35 (d, 3JHH = 1.5 Hz, 1H-Ar); 13C NMR (62.9 MHz, CDCl3): δ (ppm) = 14.0, 63.9, 119.5, 124.6, 130.2, 131.4, 140.2, 143.7, 147.8, 156.4, 157.5; EI-MS (70 eV): m/z (%) = 255 [(M+ + 2), 6], 253 (M+, 18); Anal. Calcd for C11H8ClNO4 (253.64): C, 52.09; H, 3.18; N, 5.52. Found: C, 52.12; H, 3.20; N, 5.49.
Ethyl 7-chloro-4-oxo-4H-benzo[d][1,3]oxazine-2-carboxylate (3g)
Mp 107-109 ºC. IR (KBr): ν = 1759, 1738 cm-1; 1H NMR (250.1 MHz, CDCl3): δ (ppm) = 1.44 (t, 3JHH = 7.2 Hz, 3H, CH3), 4.49 (q, 3JHH = 7.2 Hz, 2H, CH2), 7.61 (d, 3JHH = 8.2 Hz, 1H-Ar), 7.82 (s, 1H-Ar), 8.18 (d, 3JHH = 8.2 Hz, 1H-Ar); 13C NMR (62.9 MHz, CDCl3): δ (ppm) = 14.0, 63.8, 116.5, 128.4, 130.2, 131.2, 143.5, 145.9, 148.8, 156.9, 157.5; EI-MS (70 eV): m/z (%) = 255 [(M+ + 2), 4], 253 (M+, 11); Anal. Calcd for C11H8ClNO4 (253.64): C, 52.09; H, 3.18; N, 5.52. Found: C, 52.13; H, 3.16; N, 5.49.