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Synlett 2007(8): 1235-1238  
DOI: 10.1055/s-2007-977455
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthesis of 4,5-Dihydroisoxazoles from N-Nitroso-4,5-dihydropyrazoles under Microwave Activation

Alexander V. Stepakov*a, Ivan A. Galkina, Rafael R. Kostikova, Galina L. Starovaa, Zoya A. Starikovab, Alexander P. Molchanova
a Department of Organic Chemistry, St. Petersburg State University, Universitetskii pr. 26, St. Petersburg 198504, Russian Federation
Fax: +7(812)4286939; e-Mail: s.lab@pobox.spbu.ru; e-Mail: alstepakov@yandex.ru;
b Nesmeyanov Institute of Organometallic Compounds, Russian Academy of Sciences, Vavilova str. 28, Moscow 119991, Russian Federation
Further Information

Publication History

Received 21 November 2006
Publication Date:
08 May 2007 (online)

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Abstract

Substituted bicyclic and spirocyclic N-nitroso-4,5-dihydropyrazoles eliminate nitrogen under microwave irradiation within 3-8 minutes in solvent (chlorobenzene-DMF and chlorobenzene-AcOH) or in solvent-free conditions (on SiO2) to afford the corresponding 4,5-dihydroisoxazole derivatives. This methodology ­represents an improvement on thermolysis and allows 4,5-di­hydroisoxazole systems to be obtained in good yields.

Key words

N-nitrosodihydropyrazoles - dihydroisoxazoles - microwave activation - elimination

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General Procedures for the Synthesis of 4,5-Dihydro-isoxazolesProcedure a: N-Nitroso-4,5-dihydropyrazole 1 or 3 in PhCl-DMF (or PhCl-AcOH) was irradiated in a sealed reaction vial by the focused microwave reactor (Minotavr®) at 160 W for the time indicated in Table [1] (max. temp. 110 °C). The solvent was distilled off under reduced pressure, and the residue was purified by crystallization from methanol.
Procedure b: A mixture N-nitroso-4,5-dihydropyrazole 1 or 3 (500 mg) and 2 g silica gel (Chemapol LS 5/40) was irradiated in a focused microwave reactor (Minotavr®) at 160-200 W for the time indicated in Table [1] . In all reactions the compounds were isolated by adding acetone to the mix-ture and separating the silica gel by filtration. The solvent was removed from the filtrate under reduced pressure, and the residue was purified by crystallization from MeOH.

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The reaction vessel was placed in the MW reactor supplied with a safety valve for release of overpressure.

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After the set temperature of 110 °C is reached, the power regulates itself to maintain the reaction temperature.

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Heating of the reaction mixture in PhCl under microwave activation proceeds very slowly. The mixture of PhCl with a more polar solvent (AcOH or DMF) was used to allow for a rapid heating process. Use of the systems PhCl-AcOH and PhCl-DMF as solvents for realization of thermolysis of N-nitrosodihydropyrazoles by conventional heating leads to a decrease in the yields of the reaction products (see Table [1] ).

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Ethyl 5-(4-Tolyl)-4,6-dioxo-4,5,6,6a-tetrahydro-3a H -pyrrolo[3,4- d ]isoxazole-3-carboxylate (2b)
Mp 166-167 °C. IR (CHCl3): 1040, 1110, 1210, 1380, 1480, 1720, 3050 cm-1. 1H NMR (CDCl3): δ = 1.41 (t, 3 H, J = 7.3 Hz), 2.40 (s, 3 H), 4.44 (q, 2 H, J = 7.3 Hz), 4.89 (d, 1 H, J = 10.2 Hz), 5.71 (d, 1 H, J = 10.2 Hz), 7.15 (d, 2 H, J = 8.0 Hz), 7.29 (d, 2 H, J = 8.0 Hz). 13C NMR (CDCl3): δ = 14.4, 21.6, 54.2, 63.5, 82.6, 126.3, 128.4, 130.4, 140.0, 148.2, 158.8, 169.0, 170.2. Anal. Calcd for C15H14N2O5: C, 59.60; H, 4.67; N, 9.27. Found: C, 59.53; H, 4.71; N, 9.19.
Ethyl 5-(4-Chlorophenyl)-4,6-dioxo-4,5,6,6a-tetrahydro-3a H -pyrrolo[3,4- d ]isoxazole-3-carboxylate (2c)
Mp 159-161 °C. IR (CHCl3): 1050, 1100, 1200, 1390, 1490, 1720, 3050 cm-1. 1H NMR (acetone-d 6): δ = 1.39 (t, 3 H, J = 7.3 Hz), 4.43 (q, 2 H, J = 7.3 Hz), 5.09 (d, 1 H, J = 10.0 Hz), 6.06 (d, 1 H, J = 10.0 Hz), 7.26 (d, 2 H, J = 8.7 Hz), 7.44 (d, 2 H, J = 8.7 Hz). 13C NMR (DMSO-d 6): δ = 14.7, 55.2, 62.9, 82.6, 115.1, 125.0, 129.1, 149.3, 159.1, 160.1, 170.3, 172.1. Anal. Calcd for C14H11ClN2O5: C, 52.11; H, 3.44; N, 8.68. Found: C, 52.06; H, 3.49; N, 8.61.
Ethyl 5-(4-Ethylphenyl)-4,6-dioxo-4,5,6,6a-tetrahydro-3a H -pyrrolo[3,4- d ]isoxazole-3-carboxylate (2e)
Mp 152-154 °C. IR (CHCl3): 1040, 1110, 1210, 1380, 1470, 1720, 3050 cm-1. 1H NMR (CDCl3): δ = 1.21 (t, 3 H, J = 7.3 Hz), 1.42 (t, 3 H, J = 7.3 Hz), 2.54 (q, 2 H, J = 7.3 Hz), 4.45 (q, 2 H, J = 7.3 Hz), 4.87 (d, 1 H, J = 10.2 Hz), 5.69 (d, 1 H, J = 10.2 Hz), 7.18 (d, 2 H, J = 8.0 Hz), 7.32 (d, 2 H, J = 8.0 Hz). 13C NMR (DMSO-d 6): δ = 13.6, 14.4, 22.8, 54.5, 63.7, 82.6, 125.9, 127.8, 129.7, 139.5, 147.4, 158.6, 168.8, 169.9. Anal. Calcd for C16H16N2O5: C, 60.75; H, 5.10; N, 8.86. Found: C, 60.69; H, 5.14; N, 8.80.

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The complete set of crystallographic data for ester 2a was deposited to the Cambridge Crystallographic Data Center under the deposition number CCDC 624122.

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Ethyl 7-Phenyl-6,8-dioxo-1-oxa-2,7-diazaspiro[4.4]non-2-ene-3-carboxylate (4a)
Mp 127-129 °C. IR (CHCl3): 920, 1060, 1150, 1270, 1390, 1490, 1710, 3050 cm-1. 1H NMR (CDCl3): δ = 1.40 (t, 3 H, J = 7.3 Hz), 3.11 (d, 1 H, J = 18.9 Hz), 3.35 (d, 1 H, J = 18.9 Hz), 3.43 (d, 1 , J = 18.2 Hz), 3.97 (d, 1 H, J = 18.2 Hz), 4.40 (q, 2 H, J = 7.3 Hz), 7.35 (d, 2 H, J = 7.3 Hz), 7.48 (t, 1 H, J = 7.3 Hz), 7.51 (d, 2 H, J = 7.3 Hz). 13C NMR (CDCl3): δ = 14.5, 42.4, 42.6, 63.1, 86.6, 126.6, 129.6, 129.7, 131.5, 151.2, 159.8, 171.8, 173.2. Anal. Calcd for C15H14N2O5: C, 59.60; H, 4.67; N, 9.27. Found: C, 59.66; H, 4.59; N, 9.19.
Ethyl 7-(4-Chlorophenyl)-6,8-dioxo-1-oxa-2,7-diaza-spiro[4.4]non-2-ene-3-carboxylate (4b)
Mp 179-181 °C. IR (CHCl3): 920, 1040, 1130, 1170, 1270, 1380, 1480, 1730, 3050 cm-1. 1H NMR (CDCl3): δ = 1.39 (t, 3 H, J = 7.3 Hz), 3.11 (d, 1 H, J = 18.9 Hz), 3.36 (d, 1 H, J = 18.9 Hz), 3.42 (d, 1 H, J = 18.2 Hz), 3.97 (d, 1 H, J = 18.2 Hz), 4.40 (q, 2 H, J = 7.3 Hz), 7.32 (d, 2 H, J = 8.7 Hz), 7.49 (d, 2 H, J = 8.7 Hz). 13C NMR (CDCl3 + acetone-d 6): δ = 14.3, 42.3, 42.4, 62.8, 86.7, 127.8, 129.7, 130.2, 135.0, 151.4, 159.7, 171.8, 173.2. Anal. Calcd for C15H13ClN2O5: C, 53.50; H, 3.89; N, 8.32. Found: C, 53.47; H, 3.93; N, 8.27.
Methyl 7-(4-Bromophenyl)-6,8-dioxo-1-oxa-2,7-diaza-spiro[4.4]non-2-ene-3-carboxylate (4f)
Mp 164-165 °C. IR (CHCl3): 920, 1050, 1140, 1170, 1290, 1380, 1490, 1720, 3050 cm-1. 1H NMR (CDCl3): δ = 3.09 (d, 1 H, J = 18.9 Hz), 3.34 (d, 1 H, J = 18.9 Hz), 3.39 (d, 1 H, J = 18.2 Hz), 3.92 (d, 1 H, J = 18.2 Hz), 3.94 (s, 3 H), 7.24 (d, 2 H, J = 8.7 Hz), 7.62 (d, 2 H, J = 8.7 Hz). 13C NMR (CDCl3): δ = 42.3, 42.4, 53.6, 86.5, 123.5, 128.0, 130.5, 132.9, 151.0, 160.2, 171.4, 172.9. Anal. Calcd for C14H11BrN2O5: C, 45.80; H, 3.02; N, 7.63. Found: C, 45.77; H, 2.98; N, 7.55.

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The complete set of crystallographic data for ester 4d was deposited to the Cambridge Crystallographic Data Center under the deposition number CCDC 624121.