Infochemistry Scientific Center, ITMO University, 191002 St.-Petersburg, Russia.
Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center, Russian Academy of Sciences, 420008 Kazan, Russia.
Molecules. 2022 Aug 14;27(16):5178. doi: 10.3390/molecules27165178.
Elaboration of a convenient route towards donor-substituted pyrazoles from heteropropargyl precursors is challenging due to a number of thermodynamically favorable side reactions (e.g., acetylene-allene isomerization and Glaser homocoupling). In this work, Sonogashira cross-coupling conditions of 4--butylphenyl propargyl ether with benzoyl chloride followed by tandem Michael addition/cyclocondensation with hydrazine into 3,5-disubstituted pyrazole (kinetic control), as well as cycloisomerization conditions of ketoacetylene intermediate into 2,5-disubstituted furan (thermodynamic control), were established through a variation of the catalyst loading, solvent polarity, excess of triethylamine, and time of reaction. During the optimization of process parameters, a number of by-products represented by a monophosphine binuclear complex (PPhPdI) with two bridging iodine atoms and diyne were identified and isolated in the pure form. The quantum-chemical calculations and solution-state H/C NMR spectroscopy suggested that the 5(3)-(4--butylphenyloxy)methoxy-3(5)-phenyl-1-pyrazole exists in the tautomeric equilibrium in a polar methanol solvent and that individual tautomers could be characterized in case aprotic solvents employed. The pyrazole features a unique tetramer motif in the crystal phase formed by alternating 3(5)-phenyl-1-pyrazole tautomers, which was stabilized by N-H···N bonds and stacking interactions of pyrazole rings, whereas pyrazole dimers were identified in the gas phase.
从杂丙炔基前体制备供电子的吡唑时，由于存在许多热力学有利的副反应（例如，乙炔-丙二烯异构化和 Glaser 同偶联），因此开发一条方便的路线具有挑战性。在这项工作中，通过改变催化剂负载、溶剂极性、三乙胺过量和反应时间，建立了 4--丁基苯基丙炔基醚与苯甲酰氯的 Sonogashira 交叉偶联条件（动力学控制），以及酮炔中间体的串联迈克尔加成/环缩合与肼反应生成 3,5-取代吡唑（动力学控制），以及酮炔中间体的环异构化条件（热力学控制）。在优化工艺参数的过程中，鉴定并分离出了一系列以单核膦双核配合物（PPhPdI）和二炔为代表的副产物，这些副产物具有两个桥连碘原子。量子化学计算和溶液状态 H/C NMR 光谱表明，5(3)-(4--丁基苯氧基)甲氧基-3(5)-苯基-1-吡唑在极性甲醇溶剂中存在互变异构平衡，并且可以在使用非质子溶剂的情况下对各个互变异构体进行特征化。吡唑在由交替的 3(5)-苯基-1-吡唑互变异构体形成的晶体相中具有独特的四聚体图案，该图案由 N-H···N 键和吡唑环的堆积相互作用稳定，而吡唑二聚体则在气相中被鉴定出来。
