A Regiospecific Approach to N-Alkylpyrazoles and the Derived N-Oxides Using 5-endo-dig Cyclisations of Alkynyl Nitrosamines

Abstract

5-endo-dig Cyclisations of N-nitroso derivatives of homopropargylic amines, catalysed by silver nitrate on silica gel proceed smoothly at ambient temperature in chlorinated solvents to give essentially quantitative yields of the corresponding pyrazole-N-oxides, deoxygenation of which gives excellent yields of the related N-alkylpyrazoles in a regiospecific manner.

Key words

5-endo-dig cyclisations - catalysis - pyrazole-N-oxides

References and Notes

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9

Similar cyclisations, but of hydroxy-substituted homopropargylamine derivatives, lead to pyrroles also in exceptionally high yields: Hayes, S. J.; Knight, D. W.; Singkhonrat, J.; Sharland, C. M. paper in preparation.

10

Dunford, D.; Knight, D. W.; Song, C. unpublished results.

11

Imines 8 were prepared by stirring equivalent amounts of the corresponding aldehydes and amines in dry Et₂O for 16 h, followed by drying (MgSO₄) and evaporation. Solutions of the acetylides 7 (BuLi, THF, -78 ˚C, 0.5 h) were treated with BF₃˙THF complex (1.3 equiv) for 0.25 h and the resulting solution added to one of the imine 8 in THF maintained at
-78 ˚C. After 3 h, the mixture was quenched with KH₂PO₄ buffer (pH 7) and the products extracted into Et₂O. Silica gel column chromatography (typically eluted with EtOAc-PE, 1:4) when necessary delivered 50-80% yields of the propargylamines 6.

12

The amines 6 were stirred at 0 ˚C with concd HCl (2 equiv) for 5 min, the resulting solutions were diluted with Et₂O (10 mL g^-¹) followed by the addition of aq NaNO₂ [1.2 equiv in H₂O (10 mL g^-¹)]. The solutions were then stirred without cooling for 3 h and the N-nitrosamines 5 were extracted into Et₂O. Typically, no purification was required after a H₂O and brine wash, according to NMR analysis.

13

The N-nitrosamines 5 displayed richly detailed ^¹H NMR spectra indicative of the existence of two rotameric forms.

14

In general, an N-nitrosamine 5 (1 equiv) was stirred with 10 mol% AgNO₃ on SiO₂ (Aldrich; 0.2 equiv) in dry CHCl₃ (1 mL 0.1 mmol^-¹ of nitrosamine) at ambient temperature with complete exclusion of light (Al foil) until TLC indicated complete reaction. The pyrazole-N-oxides 9 were then isolated by filtration through Celite, which was then washed thoroughly with fresh CHCl₃, and evaporation of the combined filtrates. Dry CH₂Cl₂ could equally well be used. Characterization was by ^¹H NMR and ^¹³C NMR spectroscopy and high resolution MS.
N -Benzyl-3-isobutyl-5-phenylpyrazole- N -oxide (9b, Table 1, Entry 2)
^¹H NMR (400 MHz, CDCl₃): δ = 0.85 (6 H, d, J = 6.7 Hz, 2 × Me), 1.70-1.87 (1 H, m), 2.32 (2 H, d, J = 7.3 Hz, CH₂), 5.38 (2 H, s, PhCH₂), 6.17 (1 H, s, 4-H), 7.15 (2 H, dd, J = 8.0, 1.4 Hz, 2 × PhH), 7.19-7.31 (4 H, m, 4 × PhH), 7.35-7.39 (2 H, m, 2 × PhH), 8.15 (2H, dd, J = 8.5, 1.3 Hz, 2 × PhH). ^¹³C NMR (100 MHz, CDCl₃): δ = 22.3 (2 × Me), 27.6 (CH), 35.3 (CH₂), 45.5 (PhCH₂), 98.3 (4-CH), 126.4 (2 × PhCH), 127.0 (2 × PhCH), 127.9 (PhCH), 128.4 (C), 128.5 (PhCH), 128.6 (C), 128.7 (2 × PhCH), 128.9 (2 × PhCH), 132.2 (C), 135.7 (C). MS (APCI): m/z (%) = 307 (100) [M⁺ + H]. HRMS: m/z calcd for C₂₀H₂₃N₂O [M]: 307.1810; found: 307.1802 [M⁺ + H].