For reference, the RCM of 4a at room temperature overnight also provided the isomerized products in a small amount in addition to 6a as the major product. As the best overall yield was obtained in a reaction time of 10 min (entry 4), this condition was applied in the following MW reactions. Interestingly, the ring-closed products with double-bond migration 9a and 10a were obtained from substrate 4a as the major products in various ratios along with a small amount of 6a, as shown in entries 2–4. The reaction at a high temperature of 140 ☌ in CH 2Cl 2 as the solvent was achieved using sealed vials as the MW reactor. To shorten the reaction time, next, MW-assisted RCM was investigated. However, we do not have a plausible explanation for this reversed selectivity.Īs described above, the RCM reactions using Grubbs 2nd at room temperature took 120–150 min for the complete consumption of starting material 4a. Surprisingly, reversed regioselectivity was observed in the reaction of substrate 1c bearing a p-toluenesulfonyl substituent at the N1 position in DME, giving 3-allylated 3c (55%, entry 3), whereas 2c was formed as the major product (65%) and as the minor product (20%) in the MW-assisted Claisen rearrangement in DEA in our previous study.
Improved regioselectivity was observed for substrate 1d bearing an n-butyl group, affording 5-allylate 2d as the sole product in 97% yield (entry 4), whereas a mixture of 2d (65%) and 3d (20%) was obtained in the MW reaction with DEA. In the reaction of substrate 1b (R = benzyl), 5-allylated product 2b was obtained exclusively in a similar yield (98%, entry 2) as DEA ( 2b: 92%) reported previously. The MW reaction conditions were 200 ☌ and 30 min. First, the regioselectivity in the Claisen rearrangement of other substrates 1b– e with DME under microwave (MW) irradiation was investigated.
DEA must be removed by chromatography, whereas DME can be removed by evaporation. Another merit of using DME as a solvent is easier purification of the reaction products. Claisen Rearrangement of 4-Allyloxy-1H-pyrazoles in 1,2-DimethoxyethaneĪs mentioned in our previous paper, Claisen rearrangement of 1a in 1,2-dimethoxyethane (DME) showed improved regioselectivity for 2a (65%): 3a (1%) compared to the same reaction in N, N-diethylaniline (DEA) ( 2a (61%): 3a (3%)). Herein, we report the new synthesis of a pyrazole-fused heterocyclic skeleton, dihydrooxepinopyrazoles, from 1 via the combination of Claisen rearrangement and RCM and divergence of RCM products depending on reaction conditions. When 2 or 3 was further O-allylated, products 4 and 5 were suitable starting materials for RCM, leading to pyrazole 5,8-dihydro-1 H-oxepinopyrazoles ( 6) and 5,8-dihydro-2 H-oxepinopyrazoles ( 7), respectively. Therefore, we attempted to construct pyrazole-fused heterocycles based on 2 or 3. But, examples of synthesis of pyrazole-fused heterocyclic molecules using RCM are rare. Recently, the combination of Claisen rearrangement and ring-closing metathesis (RCM) provides a powerful approach to construct various polycyclics. Compound 2a or its structural isomer, 3-allyl-4-hydroxy-1 H-1-trityl pyrazole ( 3a), contains a hydroxyl group, which can be further O-functionalized. In our previous synthesis of withasomnines, the key intermediates were 4-allyloxy-1 H-1-tritylpyrazole ( 1a) and its Claisen rearrangement product, 5-allyl-4-hydroxy-1 H-1-tritylpyrazole ( 2a).
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