Three-Component Nef-Huisgen Access to 1,2,4-Triazoles

Abstract

We present herein a new three-component triazole synthesis involving a Nef-Huisgen cascade. After the α-addition of acyl chlorides onto isocyanides (Nef reaction), the resulting imidoyl chloride is treated with tetrazoles under suitable activation (ZnCl₂). The resulting adduct is unstable and evolves according to the Huisgen reaction.

Nef - isocyanide - tetrazoles - Huisgen - triazoles

References and Notes

For general reviews on Ugi- and Passerini-based multicomponent reactions, see:

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5

Typical Procedure for 4a: Cyclohexyl isocyanide (1 mmol) and p-fluorobenzoyl chloride (1 mmol) were heated neat for 1 h in a CEM microwave at 60 ˚C (50 W) and finally dissolved in toluene (2 mL). To this solution was added ZnCl₂ in THF (0.1 mL of a 1 M solution) followed by the addition of phenyl tetrazole (1 mmol, 1 equiv). The reaction mixture was then heated overnight at 80 ˚C. Hydrolysis followed by extraction and flash column chromatography afforded 4a as a yellow oil (280 mg, 79%).
Spectroscopic Data for Triazole 4a: 1H NMR (400 MHz, CDCl3): d = 8.35 (dd, J H-H = 8.3, J H-F = 5.6 Hz, 2H), 7.65-7.35 (m, 5H), 7.21 (t, J H-H = J H-F = 8.3 Hz, 2H), 4.33 (tt,
J = 12.3, 3.7 Hz, 1H), 2.15 (q, J = 11.8 Hz, 2H), 1.92 (d,
J = 11.8 Hz, 2H), 1.83 (d, J = 11.8 Hz, 2H), 1.65 (d, J = 10.6 Hz, 1H), 1.34-1.15 (m, 3H). 13C NMR (100.6 MHz, CDCl3): d = 183.6, 166.8 (d, J C-F = 256.1 Hz), 157.5, 151.9, 134.4 (d, JC-F = 9.5 Hz), 133.5 (d, J C-F = 2.2 Hz), 131.1, 130.1, 129.3, 128.0, 116.1 (d, J C-F = 22.0 Hz), 59.2, 32.6, 26.3, 25.1.IR (thin film): 2933, 2857, 2360, 1663, 1597, 1506, 1440, 1307, 1235, 1157 cm^-¹. HRMS: m/z calcd for C₂₁H₂₀FN₃O: 349.1590; found: 349.1601.

6 El Kaim L. Grimaud L. Tetrahedron  2009,  65  in press

7 For a use of benzotriazole in Ugi-type couplings, see: Katritzky AR. Mohapatra PP. Singh S. Clemens N. Kirichenko K. J. Serb. Chem. Soc.  2005,  70:  319