Catalytic asymmetric cross-coupling

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A relay catalysis strategy for enantioselective nickel-catalyzed migratory hydroarylation forming chiral α-aryl alkylboronates

4.3 C–C Bond-Forming Reactions via Cross-Coupling

New chiral phosphine ligands containing (η 6-arene)chromium and catalytic asymmetric cross-coupling reactions

Cross-coupling reactions have emerged as powerful methods to form carbon-carbon and carbon-heteroatom bonds in a vast array of synthetic contexts. Nickel-catalyzed reductive cross-coupling reactions have opened up a new mode of reactivity, allowing for the cross-coupling of bench-stable electrophiles as both coupling partners. Asymmetric variants, which use a chiral ligand, increase molecular complexity by introducing stereocenters with high levels of enantioselectivity. Application of this methodology to an array of electrophiles has led to the development of a number of transformations incorporating both C(sp2)-hybridized electrophiles (aryl iodides, alkenyl bromides, and acyl chlorides) and C(sp3)-hybridized electrophiles (benzyl chlorides and α-chloronitriles). Herein we discuss our most recent efforts in the development and application of Ni-catalyzed asymmetric cross-coupling reactions with alkenyl electrophiles. First, the expansion of our previously developed methodology has allowed for bulky trimethylsilyl groups on the benzyl chloride electrophile, providing chiral allylic silane products in good yield and enantioselectivity. The utility of these products with both traditional and newly developed methodology is highlighted. Following this, we describe the development of reaction conditions that proceed with benzyl N-hydroxyphthalimide esters. This approach proceeds through a decarboxylative strategy, generates previously accessible radical intermediates, and proceeds with the use of a homogenous reductant. Our investigations into the mechanism on the cross-coupling of alkenyl bromides and benzyl chlorides is also disclosed, where we first identified the formation of alkenyl chloride and alkenyl iodide intermediates under the reaction conditions. This inspired us to develop a Ni-catalyzed alkenyl triflate halogenation in order to prepare alkenyl halide synthetic intermediates.

Ethyl 3-bromo-3, 3-difluoropropionate (1) was prepared in an overall yield of 75% from the radical addition of dibromodifluoromethane to ethyl vinyl ether under Na2S2O4 initiation, followed by oxidation of the acetal with Caro acid. The treatment of 1 with active zinc dust in anhydrous DMF at room temperature produced the zinc reagent ZnBrCF2CH2CO2C2H5 (2). The cross coupling of the zinc reagent 2 with aryl (alkenyl) halides (R−X) in DMF using Pd(0)−Cu(I) as cocatalyst stereoselectively provided the β-fluoro-α,β-unsaturated esters (RCFCHCO2C2H5 4) directly and in moderate yields. An E/Z ratio ranging from 3:2 to 1:0 was observed. This is the first example that Cu(I) can improve the selectivity of the cross-coupling reaction. Mechanistic studies revealed that zinc reagent 2 underwent stereoselective elimination to produce (Z)-1-fluoro-2-(ethoxycarbonyl)ethenylzinc reagent 6, and then the cross-coupling of 6 with aryl(alkenyl) halides under palladium(0) catalysis afforded the β-fluoro-α,β-unsaturated esters 4.

Review: 116 refs.

Palladium-catalysed coupling reactions have gained importance as a tool for the production of pharmaceutical intermediates and to a lesser extent also for the production of agrochemicals, flavours and fragrances, and monomers for polymers. In this review only these cases are discussed where it seems highly likely that the technology is or has been used for ton-scale production. We document twelve cases where the Mizoroki–Heck reaction was used to arylate an alkene. In two of these cases allylic alcohols were arylated, leading to the aldehyde or the ketone. The Suzuki reaction has been used mostly to produce biaryl compounds from aryl halides and arylboronic acid derivatives. Twelve processes were recorded. Ortho-tolyl-benzonitrile, a biaryl compound produced via the Suzuki reaction, is used as an intermediate in six different pharmaceuticals all belonging to the Sartan group of blood pressure-lowering agents. The Kumada–Corriu reaction in which an aryl or alkenyl Grignard is coupled to an aryl or alkenyl halide was used nine times. In these coupling reactions palladium is often replaced by the much cheaper nickel or iron catalysts. The Negishi reaction couples an arylzinc halide with an aryl or alkenyl halide. These reactions are fast and highly selective; the only drawback being the stoichiometric zinc waste. Two cases were found. In one of these it was possible to use only a catalytic amount of zinc (double metal catalysis). The Sonogashira reaction couples a terminal alkyne to an aryl or alkenyl halide. Three cases were found. Acetylene is usually not coupled as such in view of its instability. Instead, trimethylsilylacetylene or the acetylene acetone adduct is used. Finally, one case was found of a palladium-catalysed allylic substitution and one case of a CH-activation reaction to form a benzocyclobutane ring. Most of these reactions were implemented in production in the past ten years.

Palladium-catalyzed reaction between aryl or alkenyl halides and (1-carbalkoxy-1-alkenyl)zinc iodides. A new class of unmasked β-substituted acrylate α-anion equivalents

Palladium‐catalysed Suzuki–Miyaura cross‐couplings of organoboronic acids or organotrifluoroborates with aryl and alkenyl halides or triflates have become classic methods for generating carbon–carbon bonds. For this reaction, not only sp2‐hybridized but also sp3‐hybridized organoboron derivatives can be employed. However, alkylboronic acids or trifluoroborates are generally less reactive than arylboron derivatives. The coupling of primary alkylboronic acids or alkyltrifluoroborates with aryl or alkenyl halides is well known, and the reaction gives the coupling products with high selectivities, relatively high turnover numbers and in good yields with several catalysts. On the other hand, secondary alkylboronic acids or trifluoroborates, except for cyclopropylboron derivatives, are much less reactive, and very few catalyst are able to activate such compounds. Because of the hybridization of cyclopropanes, which confers significant aromatic character, several reactions have successfully been performed with cyclopropylboronic acids or trifluoroborates. The stereochemistries of substituted cyclopropylboron derivatives were maintained in the course of the reactions. For all these couplings with primary or secondary alkylboron derivatives, aryl iodides, bromides, chlorides or triflates and alkenyl iodides, bromides or triflates were employed. Alkenyl chlorides have attracted less attention. The reactions with alkenyl halides are stereoselective. A few examples of couplings between sp3‐hybridized organoboronic acids and alkyl halides have also been reported.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

Asymmetric reductive cross-electrophile coupling is a powerful method to forge C–C bonds and access enantioenriched small molecules, which can be further functionalized to access scaffolds present in natural products and bioactive pharmaceutical agents. However, an innate challenge of this methodology is identifying a chiral catalyst that achieves optimal cross-selectivity and stereocontrol. Herein, we report studies on the asymmetric cross-coupling of C(sp3) electrophiles, such as benzyl chlorides, α-chloroesters, and N-hydroxyphthalimide esters, with several classes of C(sp2) electrophiles. We describe the asymmetric Ni-catalyzed reductive cross-coupling of (hetero)aryl iodides and benzyl chlorides to prepare enantioenriched 1,1-diarylalkanes. As part of these studies, a new chiral bi(oxazoline) ligand, 4-HeptylBiOX, was developed to obtain products in synthetically useful yield and enantioselectivity. This novel ligand is demonstrated to expand the substrate scope of these stereoconvergent reductive cross- couplings to include the asymmetric cross-coupling of α-chloroesters with aryl iodides, and sterically hindered N-hydroxyphthalimide esters with alkenyl bromides. Model studies have been initiated to study the application of these reactions toward the total synthesis of cylindrocyclophane natural products.

Electrochemical asymmetric catalysis has emerged as a sustainable and promising approach to the production of chiral compounds and the utilization of both the anode and cathode as working electrodes would provide a unique approach for organic synthesis. However, precise matching of the rate and electric potential of anodic oxidation and cathodic reduction make such idealized electrolysis difficult to achieve. Herein, asymmetric cross-coupling between α-chloroesters and aryl bromides is probed as a model reaction, wherein alkyl radicals are generated from the α-chloroesters through a sequential oxidative electron transfer process at the anode, while the nickel catalyst is reduced to a lower oxidation state at the cathode. Radical clock studies, cyclic voltammetry analysis, and electron paramagnetic resonance experiments support the synergistic involvement of anodic and cathodic redox events. This electrolytic method provides an alternative avenue for asymmetric catalysis that could find significant utility in organic synthesis.

The palladium-catalyzed coupling of an aziridinylzinc chloride intermediate with alkenyl and aryl halides has been demonstrated. The method provides products with retention of aziridine stereochemistry. The utility of the coupling procedure is illustrated in the synthesis of structures related to l-furanomycin.

The scope concerning the Negishi coupling of stannylated aziridine (I) with alkenyl and aryl halides is examined.

Palladium-catalyzed cross-coupling reaction of alkenylalkoxysilanes with aryl and alkenyl halides in the presence of a fluoride ion