Intermolecular Mizoroki–Heck Reaction of Aliphatic Olefins with High Selectivity for Substitution at the Internal Position

Abstract

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...

Aqueous Titanium Trichloride Promoted Reductive Cyclization of o‐Nitrostyrenes to Indoles: Development and Application to the Synthesis of Rizatriptan and Aspidospermidine

“…Most of the a-substituted onitrostyrenes 1i-1swere synthesized by aregioselective Heck reaction according to Zhous protocol. [16] Tr eatment of 1t and 1u with TiCl 3 under standard conditions provided 3,4-bridged indoles 2t and 2u in yields of 79 %and 82 %, respectively (Scheme 3). [17] Compound 2u, the identity of which was confirmed by X-ray crystallographic analysis, [18] is the core structural unit of aurantioclavine (3) and other related natural products.…”

“…[25] Regioselective Heck reaction between aryl triflate 14 and but-3-en-1-ol (15) according to Zhou provided terminal olefin 16 in 91 % yield. [16] Bromination of diol followed by chemoselective displacement of the benzyl bromide by sodium salt of 1H-1,2,4-triazole provided 17.T iCl 3 -promoted reductive cyclization of 17 afforded indole 18 (51 %) that was converted to rizatriptan (13)u nder standard conditions.W en ote that the classic Cadogan-Sundberg conditions wont be applicable to 17 because of the presence of an alkyl bromide function.…”

Iridium‐Catalyzed α‐Selective Arylation of Styrenes by Dual C−H Functionalization

“…[1] Forp rocesses involving styrenes,a rylation occurs predominantly at the bposition. [4] Ther elated intermolecular Fujiwara-Moritani reaction, which is most effective in the presence of directing groups,o perates under oxidative conditions and is attractive because it achieves CÀHarylation of alkenes by dual CÀHf unctionalization, thereby circumventing the preparation of an aryl (pseudo)halide (Scheme 1A). [4] Ther elated intermolecular Fujiwara-Moritani reaction, which is most effective in the presence of directing groups,o perates under oxidative conditions and is attractive because it achieves CÀHarylation of alkenes by dual CÀHf unctionalization, thereby circumventing the preparation of an aryl (pseudo)halide (Scheme 1A).…”

Highly Regioselective Indoline Synthesis under Nickel/Photoredox Dual Catalysis

“…The intermediacy of a discrete Heck reaction followed by hydroamination was ruled out by reacting 5d with 1-octene in the presence of independently synthesized Heck product 7a (Scheme 5a). 23 No formation of product 6a arising from 7a was observed, suggesting that it is not a competent intermediate. Next, we sought to investigate whether oxidation to Ni(III) was indeed responsible for product formation (Scheme 5b).…”