【J. Org. Chem. 】新型甲基化替代试剂，完美解决吡唑甲基化N1/N2选择性问题！

N-甲基吡唑是一种非常重要的药物分子片段，但是由于吡唑环的易互变异构特性， 同时甲基的体积较小，这种选择性差异很小，因此不同区位异构产物的两个过渡态之间缺乏空间区分， N-甲基化过程中通常会得到混合物。选择性制备N1-甲基化产物是一个非常有挑战性的课题。

之前有文献报道，选择性进行N-甲基化的方法，就是先用SEM保护基先保护其中一个N, 然后再用进行甲基化生成鎓盐，最后脱保护得到 区域选择性地得到N-甲基化产物。但是此种方法只适用于特殊结构的吡唑类化合物，没有通用性。

【J. Am. Chem. Soc. 2009, 131,3042–3048】

近期，Genentech公司的Yang和Dalton发现了一种替代性甲基化试剂----氯甲基三异丙氧基硅烷（CAS: 18162-82-8，已商业化）可以完美解决吡唑N-甲基化的选择性问题，这种大位阻的替代甲基化试剂可以对吡唑杂环进行高选择性的N-甲基化反应。选择性烷基化后在TBAF和水存在下，能够容易地进行脱硅基反应，生成N-甲基吡唑。对多种吡唑底物，获得了92:8到>99:1的N1/N2异构体比率，并且产率良好。【J. Org. Chem.2024, 89, 4221−4224. DOI: 10.1021/acs.joc.3c02841】

替代甲基化试剂的筛选，大位阻的三异丙酯选择性最好。

烷基化后，一锅法直接加入TBAF进行脱硅基化反应得到最终的N-甲基化产物。

反应操作：

Alkylation procedure: All reactions were conducted in a 20 mL vial with a sure-link cap with a magnetic stir bar. To a 20 mL screw cap vial was added: 3-(4-fluorophenyl)-1H-pyrazole (1.0 equiv., 1.54 mmol, 0.250 g), dimethyl sulfoxide (2.5 mL, 10 mL/g, 35 mmol) and potassium bis(trimethylsilyl)amide as a solution (0.91 mol/L) in THF (1.5 equiv., 2.31 mmol, 0.91 mol/L). The vial was placed in an aluminum block at 60 ℃ and stirred for 30 min. To this solution was added: (chloromethyl)triisopropoxysilane (1.5 equiv., 2.31 mmol, 96 mass%).

Protodesilylation procedure: After 16 h, tetrabutylammonium fluoride as a solution (1 mol/L) in THF (2.0 equiv., 3.08 mmol, 1 mol/L) and water (10 mL/g, 139 mmol) were added to the reaction mixture at 60 ℃. Samples were analyzed for conversion and assay yield by reverse phase HPLC (6 uL reaction sample in 500 uL diluent: 8:2 ACN/Water). Assay yield was calculated with reference to biphenyl internal standard (mass/mass) with an absorbance correction factor applied where required.

Workup: For a 250 mg scale (substrate) reaction with 2.5 mL DMSO, 0.5 mL of 10% (g/g) NaHCO3 and 0.3 mL of brine was added to the reaction mixture with 5.0 mL of i-PrOAc. Mixture was shaken and the aqueous layer was separated. The aqueous layer is then back extracted with i-PrOAc (3x). In the last wash, 0.2 mL 14% (g/g) Na2SO4 is added to the mixture to ensure drying of the organic layer. The combined organic layers were then dried over MgSO4, filtered and concentrated via rotary evaporation.

Chromatography: Reaction crude was dissolved in a minimal amount of DCM and directly loaded onto a prepacked silica column. Purification was completed by flash chromatography (Combiflash) with gradient elution from 0 to 20% i-PrOAc / heptanes over 40 mins. HPLC Analysis Method: Column: XBridge BEH C18, 3x100mm, 2.5 um. Rate: 0.7mL/min, 30 oC, 220 nm UV detection. Mobile Phase A: 0.05% TFA in Water, Mobile Phase B: 0.05% TFA in ACN. Elution: 0-0.5’ 2%B; 4’ 35%B; 7-10’ 90%B, 10.1-12’ 2% B.

参考文献：

1、J. Am. Chem. Soc. 2009, 131,3042–3048

2、

J. Org. Chem.