Efficient, High-Yield, One-Pot Protocol for the Synthesis of 1,2,4-Oxadiazine Derivatives

Abstract

1,2-Diaza-1,3-dienes easily react as Michael acceptors with arylamidoximes in a one-pot, high-yield heterocyclization process. Depending on the linear or cyclic structure of the ene mojety, 1,2,4-oxadiazin-5-ones or spiro cycloalkyl-1,2,4-oxadiazin-5-one derivatives can be directly obtained.

Key words

1,2-diaza-1,3-dienes - arylamidoximes - nucleophilic additions - cyclizations - spiro compounds

References and Notes

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8

One-Pot Procedure for the Preparation of 1,2-Diaza-1,3-butadiene Derivatives 4a-j 1,2-Diazabuta-1,3-diene 1a-f (1 mmol), prepared and used as a EE/EZ-isomer mixture, [6a] and arylamidoxime 2a-c (1 mmol) were dissolved in alcohol (8 mL) with magnetic stirring, and the reaction mixture was allowed to stand at r.t. until disappearance of the reagents and the formation of Michael adduct 3a-j (0.33-4.0 h, monitored by SiO₂ TLC). A stoichiometric amount of NaH was added, and the crude reaction mixture was allowed to stand at r.t. until the complete disappearance of 3a-j was observed by TLC analysis (0.5-8.0 h). After removal of the solvent in vacuo, the residue was suspended in H₂O, neutralized with 2 N HCl, extracted with CH₂Cl₂, and the organic extracts dried. After filtering, the organic solvent was evaporated, and the solid residue was crystallized from the appropriate solvent.

9

Data for Michael Adduct 3f
White powder from EtOAc-n-pentane, mp 99-100 ˚C (dec.). IR (KBr): 3490, 3395, 2995, 1765, 1730, 1700, 1640, 1590, 1545 cm^-¹. ^¹H NMR (400 MHz, DMSO-d ₆): δ = 1.91 (s, 3 H, CH₃), 3.67 (s, 6 H, 2 × OCH₃), 4.98 (s, 1 H, CH), 6.29 (s, 2 H, NH₂), 7.36-7.43 (m, 3 H, Ar), 7.61 (d, J = 8.0 Hz, 2 H, Ar), 10.15 (s, 1 H, NH). ^¹³C NMR (100 MHz DMSO-d ₆): δ = 12.90, 51.86, 51.93, 84.33, 126.08, 128.20, 129.72, 132.07, 148.14, 152.82, 154.46, 169.25. MS: m/z (%) = 322 [M⁺] (0.6), 291 (0.5), 263 (1), 249 (1), 136 (15), 115 (58), 83 (100). Anal. Calcd for C₁₄H₁₇N₃O₅: C, 54.72; H, 5.58; N, 13.67. Found: C, 54.73; H, 5.61; N, 13.62.

10

Data for Methyl 2-[1-(5-Oxo-3-phenyl-5,6-dihydro-4 H -1,2,4-oxadiazin-6-yliden)ethyl]-1-hydrazinecarboxylate (4f)
Pink powder from CH₂Cl₂-PE (40-60 ˚C), mp 148-149 ˚C (dec.). IR (KBr): 3420, 3390, 3320, 2990, 1770, 1740, 1620, 1575 cm^-¹. ^¹H NMR (400 MHz, DMSO-d ₆): δ = 1.97 (s, 3 H, CH₃), 3.61 (s, 3 H, OCH₃), 6.88 (br s, 1 H, NH), 7.52-7.63 (m, 3 H, Ar), 7.98 (d, J = 6.8 Hz, 2 H, Ar), 9.93 (br s, 1 H, NH), 11.43 (br s, 1 H, NH). ^¹³C NMR (100 MHz DMSO-d ₆): δ = 12.12, 51.81, 93.61, 127.25, 128.30, 128.85, 132.48, 152.38, 154.36, 160.94, 181.72. ESI-MS: m/z calcd for C₁₃H₁₄N₄O₄: 290.1; found: 291 [M+1].

12

Typical One-Pot Procedure for the Synthesis of Spirocycloalkyl-1,2,4-oxadiazin-5-one Derivatives 5a-d
To a solution of arylamidoxime 2b,c (1 mmol) in EtOH (4 mL), 1-cycloalkenyl-1-diazene 1g-j (1 mmol), prepared as previously reported and dissolved in EtOH (4 mL), was added dropwise at r.t. with magnetic stirring. The reaction mixture was allowed to stand at r.t. until the disappearance of the reactants (0.5-6.0 h) and the formation of the pertinent 1,4-adduct 3. The crude reaction mixture was then treated with NaH (1 equiv) until complete disappearance of the intermediate was observed by TLC analysis (0.5-4.0 h). After removal of the solvent in vacuo, the residue was suspended in H₂O, neutralized with 2 N HCl, extracted with CH₂Cl₂, and the organic extracts dried. After filtering, the organic solvent was evaporated and the solid residue was crystallized from the appropriate solvent.

13

Data for Methyl 2-{12-Oxo-9-phenyl-7-oxa-8,11-diazaspiro[5.6]dodec-8-en-1-yliden}-1-hydrazine-carboxylate (5b)
White powder from THF-n-pentane, mp 218-219 ˚C (dec.). IR (Nujol): 3368, 3187, 1749, 1713, 1616 cm^-¹. ^¹H NMR (400 MHz, DMSO-d ₆): δ = 1.34-1.40 (m, 1 H, cy), 1.66-1.99 (m, 5 H, cy), 2.19-2.27 (m, 1 H, cy), 2.90-2.94 (m, 1 H, cy), 3.62 (s, 3 H, OCH₃), 7.44-7.51 (m, 3 H, Ar), 7.65 (d, J = 6.8 Hz, 2 H, Ar), 10.23 (s, 1 H, NH), 11.28 (s, 1 H, NH). ^¹³C NMR (100 MHz, DMSO-d ₆): δ = 19.83, 22.97, 24.75, 31.24, 51.87, 79.43, 127.19, 128.47, 129.44, 131.03, 150.26, 153.64, 154.41, 167.10. ESI-MS: m/z calcd for C₁₆H₁₈N₄O₄: 330.1; found: 331 [M + 1].