A Novel Mechanistic Paradigm for Cross-Coupling

 描述(由申请人提供)：过渡金属催化的交叉偶联的转化影响得到了很好的认可。在典型的钯催化的Suzuki或Hiyama联芳基交叉偶联反应中，一个基于芳基卤化物在Pd0处的氧化加成，有机金属亲核试剂与Pd0的易位反应的三步催化循环。 芳基钯(II)物种，还原消除，释放联芳基产物并使Pd0催化剂再生。虽然这种方法对Csp2-Csp2偶联非常有效，但事实证明，将Csp3中心扩展到2？和3？Csp3中心是具有挑战性的，主要是因为转金属速率较低，以及烷基钯中间体容易发生氢化物消除。尽管最近取得了进展，但在烷基交叉偶联的亲核成分方面仍然存在挑战，因为自交叉偶联化学开始以来，易位反应的性质基本上保持不变。因此，在传统的机械流形下操作的有机硼和有机硅协议中，转金属作用是速率限制，对这些过程的范围提供了严格的限制。到目前为止，旨在促进Csp3铃木交叉偶联转金属的策略都是基本的，基本上是无效的。通常，唯一的选择是放弃这些方法，而使用更多的活性有机金属试剂，如有机锌、-镁或-锡烷，它们缺乏工作台稳定性，严重限制了官能团的耐受性。 有毒的，和/或以对映体形式获取具有挑战性。在更理想的Suzuki和Hiyama偶合中，转金属化的局限性是这些过程在最基本水平上的固有机制，因此容易导致烷基硼和烷基硅在交叉偶联中失败。这项研究的目标是证明一种新的单电子机制范式，用于交叉偶联中的转金属作用，其中建立了双催化循环，将绕过当前交叉偶联协议中的缺陷。因此，从亲核有机金属物种产生自由基的光氧化还原催化循环可以将这些自由基引入贱金属催化循环，从而影响交叉偶联。单电子转移(SET)介导的转金属反应将在传统的双电子途径失败的情况下成功，因为它表现出与传统的交叉偶联互补的反应趋势，现在2？和3？Csp3亲核试剂为成功实施做好了准备。因此，几乎所有的交叉偶联都将在允许最大限度地容忍敏感的、无保护的官能团的条件下(例如，环境温度、中性pH)使用台架稳定、坚固的试剂和贱金属催化剂来设计成功，即使对于要求苛刻的Csp3杂化亲核试剂也是如此。

 DESCRIPTION (provided by applicant): The transformative impact of transition metal-catalyzed cross-coupling is well recognized. In the archetypal palladium-catalyzed Suzuki or Hiyama biaryl cross-coupling reactions, a three step catalytic cycle mechanistically based on oxidative addition of an aryl halide at Pd0, transmetalation of the organometallic nucleophile with an arylpalladium(II) species, and reductive elimination, which releases the biaryl product and regenerates the Pd0 catalyst. Although such methods are highly effective for Csp2-Csp2 coupling, extension to 2º and 3º Csp3 centers has proven challenging, owing primarily to lower rates of transmetalation as well as the propensity of the alkylpalladium intermediates to undergo facile ß-hydride elimination. Despite recent progress, challenges remain with the nucleophilic component of alkyl cross-couplings, because the nature of the transmetalation has remained principally unchanged since the inception of cross-coupling chemistry. As such, transmetalation is rate limiting in organoboron and organosilicon protocols operating under the traditional mechanistic manifold, providing severe restrictions on the scope of these processes. To date, strategies aimed at facilitating the transmetalation of Csp3 Suzuki cross-couplings are uniformly rudimentary and largely ineffective. Often, the only alternative is to abandon these approaches and utilize more reactive organometallic reagents such as organozincs, -magnesiums, or -stannanes, which lack bench stability, severely limit functional group tolerability, are considered toxic, and/or are challenging to access in enantiopure form. The limitations of the transmetalation in the more desirable Suzuki and Hiyama couplings are inherent to the mechanism of these processes at the most fundamental level, and thus predispose alkylborons and alkylsilicons for failure in cross-coupling. The goal of the research described herein is to demonstrate that a novel single electron mechanistic paradigm for transmetalation in cross-coupling, in which dual catalytic cycles are established, will circumvent deficiencies in current cross-coupling protocols. Thus, a photoredox catalytic cycle, generating radicals from nucleophilic organometallic species, can funnel these radicals into a base metal catalytic cycle that effects the cross-coupling. The single electron transfer (SET) mediated transmetalation that results will succeed in cases where the traditional two-electron pathway fails by exhibiting reactivity trends complementary to traditional cross-coupling, with 2º and 3º Csp3 nucleophiles now ideally primed for successful implementation. As a result, nearly all cross-couplings will be engineered to be successful using bench-stable, robust reagents and base metal catalysts under conditions (e.g., ambient temperatures, neutral pH) that will allow maximum tolerability of sensitive, unprotected functional groups, even with demanding 2º and 3º Csp3- hybridized nucleophiles.