The Mizoroki-Heck reaction generally refers to Pd-catalyzed C À C 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), Scheme 1]. 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, a-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 a-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 Hünigs 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-1octene versus all other isomers was 13:1, determined by GC. [17] It is worth pointing out that this rat...

In intermolecular Heck reactions of styrene and vinylarenes, the aryl and vinyl groups routinely insert at the β position. However, selective insertion at the α position has been very rare. Herein, we provide a missing piece in the palette of Heck reaction, which gave >20:1 α selectivity. The key to our success is a new ferrocene 1,1'-bisphosphane (dnpf) that carries 1-naphthyl groups. Our mechanistic studies revealed that the high α selectivity is partly attributable to the steric effect of dnpf. The rigid and bulky 1-naphthyl groups of dnpf sterically disfavor β insertion.

Benzofuran and 2,3-dihydrobenzofuran scaffolds are core components in a large number of biologically active natural and synthetic compounds including approved drugs. Herein, we report efficient synthetic protocols for preparation of libraries based on 3-carboxy 2-aryl benzofuran and 3-carboxy 2-aryl trans-2,3-dihydrobenzofuran scaffolds using commercially available salicylaldehydes, aryl boronic acids or halides and primary or secondary amines. The building blocks were selected to achieve variation in physicochemical properties and statistical molecular design and subsequent synthesis resulted in 54 lead-like compounds with molecular weights of 299-421 and calculated octanol/water partition coefficients of 1.9-4.7.

Neuer Ligand für alte Reaktion: Die Titelreaktion von Aryltriflaten mit aliphatischen Olefinen führt mit hoher Selektivität zur Substitution an der internen Position. Das Verhältnis des gewünschten Isomers (siehe Schema) zur Summe der anderen Isomere ist größer als 10:1. Entscheidend ist der verwendete Ferrocen‐Bisphosphan‐Ligand (R=1‐Naphthyl). Der Reaktionsmaßstab kann vergrößert werden, und die ungewünschten Isomere können chromatographisch abgetrennt werden.

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