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Synlett 2010(14): 2063-2066  
DOI: 10.1055/s-0030-1258513
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

A Simple Preparative Synthesis of Epoxy[1,3]oxazino(or oxazolo)[2,3-a]-isoindoles and Their Thia Analogues via IMDAF

Fedor I. Zubkov*, Timur R. Galeev, Eugeniya V. Nikitina, Irina V. Lazenkova, Vladimir P. Zaytsev, Alexey V. Varlamov
Organic Chemistry Department, Peoples’ Friendship University of Russia, 6 Miklukho-Maklaya St., Moscow 117198, Russian Federation
Fax: +7(495)9522644; e-Mail: fzubkov@sci.pfu.edu.ru;
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Publication History

Received 7 May 2010
Publication Date:
22 July 2010 (online)

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Abstract

Azomethines, easily prepared from 5-(R)-furfurals and 1,3- or 1,2-amino alcohols (aminothiols), react under mild conditions with maleic anhydride affording 8,10a-epoxy[1,3]oxa(thia)-zino[2,3-a]isoindole-7- and 7,9a-epoxy[1,3]oxa(thia)zolo[2,3-a]isoindole-6-carboxylic acids. The reaction proceeds through initial N-acylation with subsequent intramolecular exo-Diels-Alder cycloaddition and stereoselectively leads to the exo adducts. The ‘one-pot’ synthetic protocol is also presented.

Key words

furan - Diels-Alder reaction - stereoselective synthesis - [1,3]oxazolo[2,3-a]isoindoles - [1,3]oxazino[2,3-a]isoindoles - IMDAF

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Synthesis of Epoxy[1,3]oxazino[2,3- a ]isoindole-7-carboxylic acids (3a-f): Typical Procedure by Way of Example (6a R *,7 S *,8 R *,10a S *,10b R *)-8-Bromo-6-oxo-3,4,6,6a,7,8-hexahydro-2 H -8,10a-epoxy[1,3]oxazino[2,3- a ]isoindole-7-carboxylic acid (3Ac) and (6a R *,7 S *,8 R *,10a S *,10b S *)-8-Bromo-6-oxo-3,4,6,6a,7,8-hexahydro-2 H -8,10a-epoxy[1,3]oxazino[2,3- a ]isoindole-7-carboxylic acid (3Bc) To a stirred solution of 5-bromofurfural (5.0 g, 29 mmol) and 3-aminopropanol (2.2 mL, 29 mmol) in CH2Cl2 (50 mL) anhyd MgSO4 powder (7 g, 60 mmol) was added at r.t. After ca. 24 h, the MgSO4 was filtered off and the CH2Cl2 evaporated. The residue was diluted with acetone (30 mL), and then a solution of maleic anhydride (3.13 g, 32 mmol) in acetone (20 mL) was added. The resulting yellow transparent mixture was kept for ca. 4 h at 24 ˚C. Then the yellow precipitate was filtered off, washed twice with acetone (2 ¥ 20 mL), and dried in air to give the title acids 3c as a white powder (3.9 g, 41% yield). Isomeric ratio 3Ac/3Bc = 5:1; mp (for isomeric mixture) 208-209 ˚C. IR (KBr): νmax = 1670 (CON), 1751 (COOH), 3136 (COOH) cm-¹. ¹H NMR (600 MHz, DMSO-d 6, 25 ˚C): δ (major isomer 3Ac): 12.60 (br s, 1 H, CO2H), 6.73 and 6.55 (2 d, ³ J 9,10 = 5.5 Hz, 1 H and 1 H, 9-H and 10-H), 5.18 (s, 1 H, 10b-H), 4.07 (dd, ² J 2A,2B = 11.7, ³ J 2A,3eqv = 4.1 Hz, 1 H, 2-HA), 3.90-3.86 (m, 2 H, 4-HA and 2-HB), 3.09 (dd, ² J 4B,4A = 12.4, ³ J 4B,3eqv = 3.4 Hz, 1 H, 4-HB), 2.98 and 2.96 (2 d, ³ J 6a,7 = 8.9 Hz, 1 H and 1 H, 7-H and 6a-H), 1.62-1.55 (m, 1 H, 3-HA), 1.46-1.48 (m, 1 H, 3-HB) ppm; δ (minor isomer 3Bc): 12.60 (br s, 1 H, CO2H), 6.76 and 6.48 (2 d, ³ J 9,10 = 5.5 Hz, 1 H and 1 H, 9-H and 10-H), 5.37 (s, 1 H, 10b-H), 4.07 (dd, ² J 2A,2B = 11.7, ³ J 2A,3eqv = 4.1 Hz, 1 H, 2-HA), 3.85-3.82 (m, 2 H, 4-HA and 2-HB), 3.66 (dd, ² J 4B,4A = 11.7, ³ J 4B,3 = 2.0 Hz, 1 H, 4-HB), 2.98 and 2.96 (2 d, ³ J 6a,7 = 8.9 Hz, 1 H and 1 H, 7-H and 6a-H), 1.62-1.55 (m, 1 H, 3-HA), 1.46-1.48 (m, 1 H, 3-HB) ppm. ¹³C NMR (100.6 MHz, D2O/NaOD, 25 ˚C): δ (major isomer 3Ac): 173.1 and 171.6 (CO2H and 6-C), 138.6 (10-C), 132.4 (9-C), 86.2 and 81.2 (10a-C and 8-C), 83.7 (10b-C), 66.0 (2-C), 51.4 (br s, 7-C), 51.1 (6a-C), 37.0 (4-C), 22.7 (3-C) ppm. EI-MS (70 eV): m/z (%) = 331 (1) [M+, for Br8¹], 329 (1), 303 (3), 301 (5), 286 (7), 285 (7), 284 (7), 250 (10), 232 (25), 230 (25), 201 (11), 199 (11), 175 (13), 173 (11), 137 (18), 199 (12), 86 (100), 85 (18), 65 (15), 56 (24), 41 (18), 39 (19). Anal. Calcd for C12H12BrNO5 (328.99): C, 43.66; H, 3.66; N, 4.24. Found: C, 43.51; H, 3.53; N, 4.16.

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‘One-Pot’ Synthesis of (5a R* ,6 S* ,9a S* ,9b R* )-5-Oxo-2,3,5,5a,6,7-hexahydro-7,9a-epoxy[1,3]thiazolo[2,3- a ]-isoindole-6-carboxylic acid (5a)
Freshly distilled furfural (1.8 mL, 21.7 mmol) was added in one portion at r.t. to a stirred solution of 2-aminoethanethiol hydrochloride (2.47 g, 21.7 mmol) and Et3N (3.0 mL, 21.7 mmol) in CHCl3 (15 mL). The mixture was stirred for 30 min then cooled to 0 ˚C, and a solution of maleic anhydride
(2.13 g, 21.7 mmol) in CHCl3 (10 mL) was added at this temperature. The mixture was warmed to r.t. and stirred overnight. The precipitate formed was collected by filtration and dried affording compound 5a (2.70 g, 49%) as a white solid; mp 155-156 ˚C(decomp). IR: νmax = 1742 (COOH), 1678 (NC=O) cm-¹. ¹H NMR (400 MHz, DMSO-d 6, 27 ˚C): δ = 6.57 (d, ³ J 8,9 = 5.6 Hz, 1 H, 9-H), 6.48 (dd, ³ J 8,9 = 5.6 Hz, ³ J 7,8 = 1.8 Hz, 1 H, 8-H), 5.66 (s, 1 H, 9b-H), 4.99 (d, ³ J 7,8 = 1.8 Hz, 1 H, 7-H), 4.07 (ddd, ² J = 11.2 Hz, ³ J = 5.6 Hz, ³ J = 2.5 Hz, 1 H, 2-HA), 3.18 (d, J 5a endo ,6 endo  = 8.7 Hz, 1 H, 6-H endo ), 3.09-2.92 (m, 2 H, 2-HB and 3-HA), 2.75-2.68 (m, 1 H, 3-HB), 2.49 (d, ³ J 5a endo ,6 endo  = 8.7 Hz, 1 H, 5a-H endo ) ppm. ¹³C NMR (100.6 MHz, DMSO-d 6, 27 ˚C): δ = 172.6 and 170.3 (5-C and CO2H), 137.7 (9-C), 133.8 (8-C), 92.1 (9a-C), 80.4 (7-C), 63.6 (9b-C), 52.5 and 45.7 (5a-C and
6-C), 44.9 (3-C), 31.9 (2-C) ppm. MS-EI (70 eV): m/z (%) = 253 (10) [M+], 209 (6), 156 (9), 155 (51), 154 (62), 127 (13), 122 (14), 111 (23), 108 (94), 99 (24), 96 (41), 88 (10), 85 (44), 80 (35), 71 (11), 68 (17), 61 (17), 60 (46), 56 (20), 55 (100), 45 (48), 43 (67). Anal. Calcd for C11H11NO4S (253.04): C, 52.16; H, 4.38; N, 5.53; S, 12.66. Found: C, 52.39; H, 4.47; N, 5.43; S, 12.31.