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变革性影响已得到充分认可。在典型的钯催化的Suzuki或Hiyama联芳基交叉偶联反应中，三步催化循环在机理上基于芳基卤化物在Pd 0处的氧化加成、有机金属亲核试剂与Pd 0的金属转移， 芳基钯（II）物质，和还原消除，其释放联芳基产物并再生Pd 0催化剂。尽管这些方法对于Csp 2-Csp 2偶联是高度有效的，但延伸至2º和3º Csp 3中心已被证明是具有挑战性的，这主要是由于较低的金属转移速率以及烷基钯中间体易于进行β-氢化物消除的倾向。尽管最近的进展，挑战仍然与亲核组分的烷基交叉偶联，因为transmetalation的性质基本上保持不变，因为交叉偶联化学的开始。因此，在传统的机械流形下操作的有机硼和有机硅方案中，金属转移是速率限制的，对这些方法的范围提供了严格的限制。迄今为止，旨在促进Csp 3 Suzuki交叉偶联的金属转移的策略都是不成熟的，并且在很大程度上无效。通常，唯一的替代方案是放弃这些方法，并使用更具反应性的有机金属试剂，例如有机锌、-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， 有毒和/或难以以对映体纯形式获得。在更理想的Suzuki和Hiyama偶联中的金属转移的限制是这些过程在最基本水平上的机制所固有的，因此使烷基硼和烷基硅易于在交叉偶联中失败。本文所述的研究的目标是证明，一种新的单电子机制的交叉偶联，其中建立双催化循环的transmetalation范式，将规避目前的交叉偶联协议的不足之处。因此，从亲核有机金属物质产生自由基的光氧化还原催化循环可以将这些自由基汇集到影响交叉偶联的贱金属催化循环中。单电子转移（SET）介导的金属转移将在传统的双电子途径失败的情况下成功，表现出与传统交叉偶联互补的反应性趋势，2º和3º Csp 3亲核试剂现在理想地为成功实施做好准备。因此，几乎所有的交叉偶联将被设计为在以下条件下使用工作台稳定的、稳健的试剂和贱金属催化剂是成功的（例如，环境温度，中性pH值），这将允许敏感的，未保护的官能团的最大耐受性，甚至与苛刻的2º和3º Csp 3-杂交亲核试剂。

 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.