Asymmetric Cross-Coupling of Aryl Triflates to the Benzylic Position of Benzylamines
Asymmetric Cross-Coupling of Aryl Triflates to the Benzylic Position of Benzylamines
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DOI：
10.1002/anie.201201874
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发表时间：
2012-01-01
影响因子：
16.6
通讯作者：
Walsh, Patrick J.
中科院分区：
文献类型：
--
作者：
McGrew, Genette I.;Stanciu, Corneliu;Walsh, Patrick J.
新的过渡金属催化偶联方法的发展一直是人们研究的热点。[1]最近，直接芳基化作为一种更有效的方法来形成C12 C键。[2]然而，已证明某些类型的C13 H键难以芳基化，并且对于不对称方法来说代表了特定的挑战。我们设想了一种新的和潜在的非常强大的双催化剂循环非常弱酸性的苄基C2 H4基团的对映选择性官能化（方案1）。左手循环涉及钯催化的交叉偶联，通过氧化加成到Pd 0，与有机金属中间体E的M '进行金属交换以产生C，并还原消除以关闭循环。右手循环由η6-芳烃络合物的活化苄基CH基团的可逆去质子化引发，以生成E。从钯催化的循环中出现，F和游离芳烃G之间的芳烃交换释放产物并再生D。为了简化这种双催化剂系统极具挑战性的开发，我们将其分为三个阶段。在第一个，我们只专注于钯催化的左手循环，通过选择芳烃活化部分，{Cr（CO）3}，这将不会进行芳烃交换（即，F不与G反应）。这使得最初的概念验证交叉耦合成为可能，这在方案2中进行了总结。[3]在本项目的当前阶段，我们介绍了钯催化的对映体选择性版本的反应方案2，一个不寻常的动态动力学拆分（DKR）进行的反应。未来的工作（第3阶段）将集中在关闭右手循环。[4]由于我们提出的催化循环的一些独特特征，开发偶联反应的对映选择性版本以提供方案2中的化合物（如2）被认为特别具有挑战性。首先，方案2中的基于二芳基甲烷的产物比起始材料更酸性，并且可能预期导致对映体富集的产物的外消旋化。第二，我们提出的机制，在下面更详细地描述（方案3），涉及通过新的DKR实现对映选择性。[5]该机理要求可逆形成的锂化平面手性Cr加合物之一，1-Li或1-Li '，与对映体富集的钯催化剂进行金属交换比另一个快得多。总之，这些特征需要鉴定手性配体/金属络合物，其被精细地调节以在温和的反应条件下促进化学反应。在机理上，基于方案2中的化学，预期LiN（SiMe 3）2对[（η6-苄胺）Cr（CO）3]的初始去质子化是快速的。[3a]由于{Cr（CO）3}离域负电荷的能力，[6]锂化中间体1-Li和1-Li '（方案3）由于ipso和苄基碳原子之间的部分双键特征而预期是平面手性的和构型稳定的。[7]我们假设快速可逆的去质子-
The development of new transition-metal-catalyzed crosscoupling methods has been a focus of intense research.[1] More recently, direct arylations are emerging as a more efficient method to CÀC bond formations.[2] Certain types of CÀH bonds, however, have proven difficult to arylate, and represent a particular challenge for asymmetric processes. We envisioned a novel and potentially very powerful dual catalyst cycle for the enantioselective functionalization of very weakly acidic benzylic CÀH groups (Scheme 1). The left-hand cycle involves the palladium-catalyzed cross-coupling through oxidative addition to Pd0, transmetallation with M’of the organometallic intermediate E to generate C and reductive elimination to close the cycle. The right-hand cycle is initiated with reversible deprotonation of the activated benzylic CH groups of the η6-arene complex to generate E. Emerging from the palladium-catalyzed cycle, arene exchange between F and free arene G liberates the product and regenerates D. To simplify the extremely challenging development of such a dual catalyst system, we separated it into three phases. In the first, we focused solely on the palladium-catalyzed lefthand cycle by selecting an arene-activating moiety,{Cr (CO) 3}, which would not undergo arene exchange (ie, F does not react with G). This enabled the initial proof-of-concept crosscoupling, which is summarized in Scheme 2.[3] In the current phase of this project, we introduce the palladium-catalyzed enantioselective version of the reaction in Scheme 2, a reaction which proceeds by an unusual dynamic kinetic resolution (DKR). Future work (Phase 3) will focus on closing the righthand cycle.[4]Development of an enantioselective version of the coupling reaction to afford compounds like 2 in Scheme 2 was perceived to be particularly challenging because of some unique features of our proposed catalytic cycle. First, the diarylmethane-based products in Scheme 2 are more acidic than the starting materials, and might be expected to lead to racemization of the enantioenriched products. Second, our proposed mechanism, described in more detail below (Scheme3), involves achieving enantioselectivity through a novel DKR.[5] This mechanism requires that one of the reversibly formed lithiated planar-chiral Cr adducts, either 1-Li or 1-Li’, undergoes transmetallation with the enantioenriched palladium catalyst much faster than the other. Together, these characteristics require identification of a chiral ligand/metal complex which is exquisitely tuned to promote the chemistry under mild reaction conditions. Mechanistically, initial deprotonation of [(η6-benzylamine) Cr (CO) 3] by LiN (SiMe3) 2 was anticipated to be rapid based on the chemistry in Scheme 2.[3a] Because of the ability of {Cr (CO) 3} to delocalize negative charge,[6] the lithiated intermediates 1-Li and 1-Li’(Scheme 3) were expected to be planar chiral and configurationally stable owing to the partial double bond character between the ipso and benzylic carbon atoms.[7] We hypothesized that rapid and reversible deproto-