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

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.

N-nitrosodihydropyrazoles - dihydroisoxazoles - microwave activation - elimination

References and Notes

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1b Kim D. Lee J. Shim PJ. Lim JI. Doi T. Kim S. J. Org. Chem.  2002,  67:  772 

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4 Mizuno K. Ichinose N. Tamai T. Otsuji Y. J. Org. Chem.  1992,  57:  4669 

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7 Molchanov AP. Stepakov AV. Kostikov RR. Zh. Org. Khim.  2004,  40:  1561 ; Russ. J. Org. Chem.; 2004, 40: 1512

8

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.

9

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

10

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

11

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] ).

12

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.

13

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

14

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.

15

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

16a Grigorova TN. Ogloblin KA. Komendantov MI. Zh. Org. Khim.  1972,  8:  2197 

16b Grigorova TN. Ogloblin KA. Komendantov MI. Zh. Org. Khim.  1973,  9:  711 ; Russ. J. Org. Chem.; 1973, 9: 732