Synthesis of Substituted Pyranopyrazoles under Neat Conditions via a Multicomponent Reaction

Abstract

A simple and efficient synthesis of pyranopyrazoles in good yields via a four-component reaction between an aromatic aldehyde, hydrazine hydrate, ethyl acetoacetate and malononitrile under neat conditions is described.

Key words

neat conditions - hydrazine hydrate - acetoacetate - pyranopyrazole

References and Notes

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14

General Procedure for Pyranopyrazoles: To a stirred mixture of hydrazine hydrate 1 (2 mmol) and ethyl acetoacetate 3 (2 mmol), aldehyde 2 (2 mmol) and malononitrile 4 (2 mmol) were added successively at r.t. with vigorous stirring for 3-11 min. The precipitated solid was filtered, and washed with a mixture of EtOAc-hexane (20:80). The product obtained was pure as found in TLC and ^¹H NMR and ^¹³C NMR spectroscopy. However, the products were further purified by recrystallization from EtOAc. Table  [¹] , entry 4: yellow solid; mp 158-161 ˚C. ^¹H NMR (500 MHz, DMSO-d ₆): δ = 1.75 (s, 3 H), 2.16 (s, 3 H), 2.46 (s, 2 H), 4.53 (s, 1 H), 6.85 (s, 1 H), 7.01 (d, 1 H, J = 12.0 Hz), 7.03 (d, 1 H, J = 8.4 Hz), 12.09 (br s, 1 H). ^¹³C NMR (125 MHz, DMSO-d ₆): δ = 10.3, 14.8, 39.8, 57.7, 98.1, 115.2, 121.3, 127.2, 130.9, 136.2, 140.9, 155.2, 159.0, 161.3. IR (KBr): 3484.5, 3239.7, 2195.3, 1638.0, 1597.6, 1493.4, 1399.4, 1116.5, 1057.3, 822.1, 749.0, 549.6 cm^-¹. LCQ-MS (ESI): m/z calcd for C₁₅H₁₃FN₄O: 284.0; found: 284.3. Anal. Calcd for C₁₅H₁₃FN₄O: C, 63.37; H, 4.61; N, 19.71. Found: C, 6 3.29; H, 4.52; N, 19.63.

15

Table  [¹] , entry 10: yellow solid; mp 145-147 ˚C. ^¹H NMR (500 MHz, DMSO-d ₆): δ = 1.76 (s, 3 H), 2.47 (s, 2 H), 4.58 (s, 1 H), 7.10 (d, 2 H, J = 10.0 Hz), 7.47 (d, 2 H, J = 10.0 Hz), 12.05 (br s, 1 H). ^¹³C NMR (125 MHz, DMSO-d ₆): δ = 10.3, 39.8, 57.2, 97.6, 120.3, 121.2, 130.2, 131.9, 136.2, 144.4, 155.2, 161.4. IR (KBr): 3476.7, 3232.8, 3100.4, 2193.4, 1648.6, 1600.0, 1490.9, 1401.1, 1069.1, 794.8, 749.3, 541.9 cm^-¹. LCQ-MS (ESI): m/z calcd for C₁₄H₁₁FN₄O: 270.0; found: 270.1. Anal. Calcd for C₁₄H₁₁FN₄O: C, 62.22; H, 4.10; N, 20.73. Found: C, 62.16; H, 4.22; N, 20.65.

16

Table  [¹] , entry 19: yellow solid; mp 168-170 ˚C. ^¹H NMR (500 MHz, DMSO-d ₆): δ = 1.75 (s, 3 H), 2.47 (s, 2 H), 3.69 (s, 3 H), 4.50 (s, 1 H), 6.83 (d, 2 H, J = 8.4 Hz), 7.04 (d, 2 H, J = 8.4 Hz), 12.05 (br s, 1 H). ^¹³C NMR (125 MHz, DMSO-d ₆): δ = 10.3, 35.9, 55.5, 58.1, 98.4, 114.3, 121.4, 129.0, 136.1, 136.9, 155.3, 158.5, 161.2. IR (KBr): 3481.4, 3253.2, 2925.3, 2191.1, 1642.5, 1600.8, 1492.0, 1392.8, 1258.4, 1172.1, 1031.2, 870.0, 804.4, 565.9 cm^-¹. LCQ-MS (ESI): m/z calcd for C₁₅H₁₄N₄O₂: 282.0; found: 282.0. Anal. Calcd for C₁₅H₁₄N₄O₂: C, 63.82; H, 5.00; N, 19.85. Found: C, 63.71; H, 5.15; N, 19.94.