Intermolecular Mizoroki-Heck Reaction of Aliphatic Olefins with High Selectivity for Substitution at the Internal Position
Intermolecular Mizoroki-Heck Reaction of Aliphatic Olefins with High Selectivity for Substitution at the Internal Position
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DOI：
10.1002/anie.201201806
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发表时间：
2012-01-01
影响因子：
16.6
通讯作者：
Zhou, Jianrong (Steve)
中科院分区：
文献类型：
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作者：
Qin, Liena;Ren, Xinfeng;Zhou, Jianrong (Steve)
Mizoroki-Heck 反应通常是指有机（拟）卤化物和烯烃之间 Pd 催化的 C-C 键形成。如今，它已成为制备取代烯烃的有力工具。[1]分子间 Heck 反应的一个关键问题是控制芳基插入烯烃的位点。对于在两个烯属位点[2]上具有显着电子差异的带有取代基的烯烃，例如丙烯酸酯[3]和乙烯基醚[4]，可以轻松实现高区域选择性。然而，脂肪族烯烃通常缺乏两个烯烃位置之间的内在电子差异，并且实现良好的区域控制一直具有挑战性[方程(1)，方案1]。[5, 6]为了诱导末端插入，配位基团通常存在于烯烃上以充当螯合物。[7]螯合策略还用于氧化 [8] 和脱羧 [9] Heck 反应以实现区域选择性。最近，Sigman 和 Werner 报道了即使对于没有螯合基团的烯烃也具有高末端选择性。 [10]对于脂肪族烯烃来说，除少数特殊情况外，高内选择性也很难实现。 [11]例如，卡布里等人。据报道，烯烃插入到阳离子芳基-Pd中间体中可能会偏向内部位置，但选择性太低而无法合成。 [12]作为一种特殊情况，烯丙醇具有优异的内部选择性，因为由于其羟基的诱导作用，内部碳原子上的电子密度降低了[方程（2），方案1]。感应效应在几个键上很快就会减弱。因此，对于高烯丙醇，选择性急剧下降[Eq.(3)，Scheme1]。在此，我们报告了一种通过使用一组二茂铁基双膦配体以高内选择性进行脂肪族烯烃 Heck 反应的通用方法 [Eq.(4)，方案 1]。 Heck 产品 α-烷基苯乙烯可以通过不对称催化过程轻松转化为各种手性结构单元。 [13]它们也是生物活性天然产物[14]和候选药物合成的中间体。[15] α-烷基苯乙烯过去是通过2-烯基亲电子试剂或2-烯基金属试剂的交叉偶联来制备的。我们的新方法直接使用简单的烯烃，不需要预活化烯烃底物。最初，我们使用 1-萘基三氟甲磺酸酯和 1-辛烯以及 dppf 的模型反应作为钯催化剂的支持配体（图 1）。令我们惊讶的是，观察到碱基的显着效应（图 1）。特别是，当使用三乙胺和Hünig碱等三烷基胺时，观察到三氟甲磺酸芳基酯的显着还原，并且得到相应的还原产物，收率高达50％。 [16]相反，当使用乌洛托品时，没有检测到还原副产物，并且以几乎定量的产率形成了 Heck 产物。通过 GC 测定，所需异构体 2-芳基-1-辛烯与所有其他异构体的比例为 13:1。 [17]值得指出的是，这个比率并不等同于区域选择性。乌洛托品是一种相对较弱的路易斯碱，[18]，它不会强烈竞争阳离子 (dppf) Pd (Ar) 中间体上的空位。此外，根据布雷特规则，其β氢原子不能消除将氢化物提供给钯。相比之下，当使用更基础的供体碱 DBU 和 DABCO 时，仅形成少量 Heck 产物。其他碱如 2, 6-二甲基吡啶、质子海绵和 Li2CO3 的产率比乌洛托品低得多。在1-萘基三氟甲磺酸酯与1-辛烯的模型反应中，我们筛选了多种双膦配体来改善反应
The Mizoroki–Heck reaction generally refers to Pd-catalyzed CÀC bond formation between organic (pseudo) halides and olefins. Today, it has become a powerful tool to prepare substituted olefins.[1] A key issue in intermolecular Heck reactions is the control of the site where aryl groups insert into olefins. High regioselectivity can be easily achieved for olefins carrying substituents with a significant electronic difference at the two olefinic sites,[2] such as acrylates [3] and vinyl ethers.[4] Aliphatic olefins, however, generally lack intrinsic electronic differentiation between two olefinic positions and it has been challenging to achieve good regiocontrol [Eq.(1), Scheme 1].[5, 6] To induce terminal insertion, coordinating groups are often present on olefins to serve as chelates.[7] The chelation strategy was also used in oxidative [8] and decarboxylative [9] Heck reactions to achieve regioselectivity. Recently, Sigman and Werner reported high terminal selectivity even for olefins without chelating groups.[10] For aliphatic olefins, high internal selectivity also proved very difficult to achieve, except a few special cases.[11] For example, Cabri et al. reported that olefin insertion into cationic aryl–Pd intermediates can be biased toward the internal position, but the selectivity was too low to be synthetically useful.[12] As a special case, allylic alcohol gave excellent internal selectivity, because owing to the inductive effect of its hydroxy group the electronic density on the internal carbon atom is decreased [Eq.(2), Scheme 1]. The inductive effect quickly diminishes over several bonds. Thus, for homoallylic alcohol the selectivity dropped drastically [Eq.(3), Scheme1]. Herein, we report a general method for Heck reactions of aliphatic olefins in high internal selectivity, by using a set of ferrocene-based bisphosphine ligands [Eq.(4), Scheme 1]. The Heck products, α-alkylstyrenes can be readily converted to various chiral building blocks by asymmetric catalytic processes.[13] They are also intermediates in the synthesis of bioactive natural products [14] and drug candidates.[15] The α-alkylstyrenes used to be prepared by crosscouplings of 2-alkenyl electrophiles or 2-alkenyl metallic reagents. Our new method directly uses simple olefins and does not require preactivation of olefin substrates. Initially, we used a model reaction of 1-naphthyl triflate and 1-octene and dppf as supporting ligand for the palladium catalyst (Figure 1). To our surprise, a dramatic effect of bases was observed (Figure 1). In particular, when trialkylamines, such as triethylamine and Hünig s base, were used, significant reduction of aryl triflate was observed, and the corresponding reduction product was obtained in up to 50% yield.[16] In contrast, when urotropine was used, no reduction byproduct was detected and Heck products were formed in almost quantitative yield. The ratio of the desired isomer, 2-aryl-1-octene versus all other isomers was 13: 1, determined by GC.[17] It is worth pointing out that this ratio is not equivalent to regioselectivity. Urotropine is a relatively weak Lewis base,[18] and it does not compete strongly for the vacant site on a cationic (dppf) Pd (Ar) intermediate. Furthermore, its βhydrogen atom cannot eliminate to donate a hydride to palladium, according to Bredt s rule. In comparison, when the more basic and donating bases DBU and DABCO were used, only small amounts of Heck products were formed. Other bases such as 2, 6-lutidine, proton sponge, and Li2CO3 gave much lower yields than urotropine. In the model reaction of 1-naphthyl triflate and 1-octene, we have screened many bisphosphine ligands to improve the