Lithium Aluminium Hydride: From Stoichiometric Reduction to Catalysis

施莱辛格的LiAlH4，早在1940年的S时代就已为人所知，至今仍是一种主要的、非常有效的还原剂。这种“老的”丙氨酸试剂是大规模生产的，不仅对现代有机合成至关重要，而且在大规模的工业生产过程中也是必不可少的。2018年初，我们报道了一项引人注目的观察。如果在氢气而不是氮气中执行经典的亚胺还原(化学计量比的LiAlH4)，则LiAlH4可以在催化量(2.5mol%，1bar H2，85°C)下使用。这不仅方便了产品的加工，而且产生的锂铝盐废品也少得多。尽管有关于LiAlH4在催化剂中的作用的较早的报道，但通常需要的苛刻条件从未被邀请进行后续研究。我们观察到LiAlH4可以在非常温和的条件下用作催化剂，这与最近关于LiAlH4催化的各种报道是同时进行的。因此，这一主题构成了我们提案的核心，该提案分为以下几个子领域：a：提案的这一部分解决了廉价和容易获得的LiAlH4催化剂是否可以用于其他转化，如酮、亚胺和吡啶的硼氢化和硅氢化反应。我们早些时候可以证明，其中一些过程可以被第二族金属催化剂催化。这项拟议的研究将向我们展示简单的LiAlH4作为催化剂的可能性和局限性。B：本提案的这一部分专门研究了改性的LiAlH4催化剂，包括两个部分，其中探讨了用其他金属取代Li或Al。其中一些化合物是从文献中已知的，另一些是新的。将研究Li或Al取代对催化剂性能的影响。C：本部分研究了氢化物配体对LiAlH4的改性。它们可以被IBU这样的给电子基或RO这样的电子引出基团所取代，这些基团可能会对催化性能产生影响。一个特别有用的目标是手性铝酸盐配合物的合成：LiAlH2(L*)，其中L*是手性1，1‘-双-2-萘酚配体(BINOL)。其目标是将Noyori的手性但化学计量比使用的还原剂LiAlH(ETO)(BINOL)转化为对映选择性催化剂。我们的挑战是抑制配体的争抢，为此我们提出了一个基于大体积取代基的解决方案。D：杂双金属LiAlH4型催化剂催化的确切反应机理预计会相当复杂。密度泛函方法是研究这些催化循环细节的有力工具。中心问题是这两种不同的金属在催化过程中是否合作。该项目的这一部分将与埃尔兰根和国外的理论家合作执行。

Schlesinger’s LiAlH4, which is known already since the 1940’s, is today still a major, very powerful, reducing agent. This “old” alanate reagent is produced on a bulk scale and not only essential to modern organic synthesis but also in large scale industrial production processes. At the start of 2018 we reported on a remarkable observation. If one performs the classical imine-to-amine reduction (stoichiometric amounts of LiAlH4) under a H¬2 instead of a N2 atmosphere, LiAlH4 can be used in catalytic quantities (2.5 mol%, 1 bar H2, 85°C). This not only facilitates the product work-up but also produces much less Li/Al salt waste products. Although there are older reports on LiAlH4 in the role of catalyst, the harsh conditions generally needed never invited for follow-up research. Our observation that LiAlH4 can be used as a catalyst under very mild conditions, comes simultaneously with various very recent reports on LiAlH4 catalysis. This topical subject forms therefore the core of our proposal which is divided in the following sub-areas:A: This part of the proposal tackles the question whether the cheap and easily available LiAlH4 catalyst can be used in other transformations like in the hydroboration and hydrosilylation of ketones, imines and pyridines. We earlier could show that some of these processes can be catalyzed by group 2 metal catalysts. This proposed research will show us the possibilities and limitations of simple LiAlH4 as a catalyst. B: This section of the proposal specifically investigates modified LiAlH4 catalysts and consists of two parts in which the replacement of either Li or Al by other metals is explored. Some of the compounds are known from literature, others are new. The effects of Li or Al replacement on catalytic performance will be studied.C: This part investigates the modification of LiAlH4 by replacement of hydride ligands. These can be substituted by electron donating groups like iBu or electron withdrawing groups like RO, which may have effect on catalytic performance. One particular useful target represents the synthesis of chiral aluminate complexes: LiAlH2(L*) in which L* is a chiral 1,1’-bi-2-naphthol ligand (BINOL). The goal is to convert Noyori’s chiral but stoichiometrically used reducing agent, LiAlH(EtO)(BINOL), into an enantioselective catalyst. The challenge is to suppress ligand scrambling for which we propose a solution based on bulky substituents. D: The exact reaction mechanisms for catalysis with heterobimetallic LiAlH4-type catalysts are expected to be quite complex. DFT methods are a powerful tool for investigating the details of these catalytic cycles. Central question is whether the two different metals cooperate during catalysis. This part of the project will be executed in cooperation with theoreticians in Erlangen and abroad.