Institut de Chimie Moléculaire et des Matériaux d'Orsay, CNRS UMR 8182, Université Paris-Saclay, Bâtiment 420, 91405 Orsay cedex, France.
Laboratoire de Chimie Moléculaire (LCM), CNRS UMR 9168, Ecole Polytechnique, Institut Polytechnique de Paris, Route de Saclay, 91128 Palaiseau cedex, France.
J Org Chem. 2021 Jan 15;86(2):1769-1778. doi: 10.1021/acs.joc.0c02604. Epub 2021 Jan 6.
A computational study on the base-assisted orthogonal C-H arylation of azoles with halides is reported. Although concerted metalation-deprotonation (CMD) is favored under acetate assistance at the C5 site that displays the best balance of nucleophilic and acidic character, the most acidic C2 site may be selectively targeted under carbonate assistance by taking advantage of a carbanionic-type (or non-concerted) metalation-deprotonation mechanism (nCMD). For the latter, several experimental probes including base, ligand, and solvent effects have been collected in favor of an outer-sphere deprotonation process after the formation of a [(L)(N1-heteroaryl)PdArX] complex. However, no computational analysis of this fundamental elementary step has been so far provided. We have carried out a series of density functional theory (DFT) calculations that delineate the structural and energetic aspects of the nCMD pathway. Starting with the oxa(thia)zole-4-carboxylates selected in our group to engineer the competitive C2 vs C5 arylation in azoles, we show that the energy barrier of the C2 anion generation is lying unexpectedly lower than the prior heterocycle coordination to Pd that is eventually identified as the rate-determining step. These calculations provide satisfactory explanations for the experimental observations of the divergence between nCMD and CMD reactivity, and notably a lower barrier at the C2 site for the nCMD process. On the other hand, the nCMD process is ineffective at the C5 site. Evaluation of various azoles reveals that the nCMD mechanism at C2 is viable from the most acidic (benzo)oxazoles to moderately acidic (benzo)thiazoles, as well as weakly acidic imidazoles. In all cases, in accordance with previously reported experimental data in orthogonal direct C-H arylation of azoles, the nCMD route is found energetically competitive to the CMD one at C5 for all azoles, except for imidazole which needs stronger basic conditions than simple carbonate assistance. Additionally, the acetate ligand, which is the base of choice for CMD, was found inefficient for nCMD and the comparative performance of acetate vs carbonate to assist CMD in the azole series reveals also considerable changes from electronically close but environmentally divergent C5-H vs C2-H bonds.
本文报道了一种关于唑类化合物与卤化物之间碱基辅助的正交 C-H 芳基化的计算研究。虽然在醋酸盐辅助下，C5 位的协同金属化-去质子化（CMD）是有利的，因为它显示出最好的亲核性和酸性之间的平衡，但在碳酸盐辅助下，最酸性的 C2 位可能通过利用碳负离子型（或非协同）金属化-去质子化机制（nCMD）被选择性地靶向。对于后者，已经收集了包括碱、配体和溶剂效应在内的几种实验探针，有利于在形成 [(L)(N1-杂芳基)PdArX] 配合物后进行外球去质子化过程。然而，到目前为止，还没有对此基本的元反应进行计算分析。我们进行了一系列密度泛函理论（DFT）计算，描绘了 nCMD 途径的结构和能量方面。从我们小组选择的氧杂（硫）唑-4-羧酸酯开始，用于设计唑类化合物中竞争性的 C2 与 C5 芳基化，我们表明 C2 阴离子生成的能垒出乎意料地低于先前杂环配位到 Pd 的能垒，这最终被确定为速率决定步骤。这些计算为实验观察到的 nCMD 和 CMD 反应性之间的分歧提供了令人满意的解释，特别是对于 nCMD 过程，C2 位点的能垒更低。另一方面，nCMD 过程在 C5 位点无效。对各种唑类化合物的评估表明，nCMD 机制在 C2 位上对于最酸性的（苯并）恶唑类化合物到中等酸性的（苯并）噻唑类化合物以及弱酸性的咪唑类化合物都是可行的。在所有情况下，与之前报道的唑类化合物正交直接 C-H 芳基化的实验数据一致，nCMD 途径在除咪唑类化合物之外的所有唑类化合物中都与 C5 位的 CMD 途径具有竞争力，而对于咪唑类化合物，则需要比简单的碳酸盐辅助更强的碱性条件。此外，醋酸盐配体是 CMD 的首选碱，对于 nCMD 来说效率不高，并且醋酸盐与碳酸盐在唑类系列中辅助 CMD 的比较性能也揭示了电子上相近但环境上不同的 C5-H 与 C2-H 键之间的相当大的变化。
