Adamantylation of azoles with 1,3-dehydroadamantane. Selective N-adamantylation of pyrazoles

Abstract

The main procedure for the synthesis of N-and C-adamantyl-containing pyrazoles is based on acidcatalyzed adamantylation of pyrazoles with various functional derivatives of adamantane [1][2][3][4][5][6]. However, this method ensures fairly poor yields of the target products and requires strongly acidic medium. A promising method for the preparation of N-adamantylsubstituted pyrazoles involves as initial compound strained [3.3.1]propellane, 1,3-dehydroadamantane (I), which is characterized by a high proton affinity (pyrazoles are weak NH acids; pK a of unsubstituted pyrazole is 14.0 [7])We previously synthesized a series of N-adamantylsubstituted imidazoles by reaction of 1,3-dehydroadamantane with the corresponding imidazoles [8]. In the present communication we report for the first time on the N-adamantylation of pyrazole (IIa), 4-bromopyrazole (IIb), and 3,5-dimethylpyrazole (IIc) with 1,3-dehydroadamantane (I). The reactions were carried by heating equimolar amounts of compound I and pyrazoles IIa-IIc at 65-101°C over a period of 2-6 h, and the corresponding 1-adamantylpyrazoles IIIa-IIIc were obtained in 71-80% yield.Analysis of the products by gas chromatographymass spectrometry showed that the main reaction direction is adamantylation at the NH nitrogen atom of the pyrazole ring and that the contribution of C-adamantylation does not exceed 10%. The described procedure ensures preparation of N-adamantyl-substituted pyrazoles in good yields under relatively mild conditions. 1-(1-Adamantyl)-1H-pyrazole (IIIa).A solution of 2.92 g (0.041 mol) of pyrazole IIa in 20 ml of dioxane was added to a solution of 5 g (0.037 mol) of 1,3-dehydroadamantane (I) in 30 ml of dioxane. The mixture was heated for 2 h under reflux, the solvent was distilled off, and the residue was washed with water, dried under reduced pressure, and recrystallized from propan-2-ol. Yield 6.57 g (71%), colorless crystals, mp 52-54°C; published data [7]: mp 51-53°C. 1 H NMR spectrum, δ, ppm: 1.70 s (6H, CH 2 , Ad), 2.08 s (6H CH 2 , Ad), 2.15 s (3H, CH, Ad), 6.20 s (1H), 7.40 s (1H), 7.80 s (1H). Mass spectrum, m/z (I rel , %): 202 (100) [M] + , 145 (61) [M -C 4 H 9 ] + , 135 (26) [Ad] + , 119 (67) [Ad -C 3 H 6 ] + , 79 (25) [Ad -C 4 H 8 ] + . 1-(1-Adamantyl)-4-bromo-1H-pyrazole (IIIb).A solution of 5.44 g (0.037 mol) of pyrazole IIb in 15 ml of tetrahydrofuran was added to a solution of 5 g (0.037 mol) of 1,3-dehydroadamantane (I) in 20 ml of tetrahydrofuran. The mixture was heated for 4 h under R 1 = R 2 = R 3 = H (a); R 1 = R 3 = H, R 2 = Br (b); R 1 = R 3 = Me, R 2 = H (c).