Elizabeth R. Jarvo

Synthesis of Enantioenriched Triarylmethanes by Stereospecific Cross-Coupling Reactions†

Coupling with inversion: Chiral diarylmethanol derivatives undergo a stereospecific nickel-catalyzed cross-coupling reaction with aryl Grignard reagents (see scheme). The reaction proceeds with inversion of configuration and high enantiospecificity. The method has been applied to the asymmetric synthesis of a triarylmethane-based anti-cancer compound.

Stereospecific Nickel-Catalyzed Cross-Coupling Reactions of Benzylic Ethers and Esters

Conspectus This Account presents the development of a suite of stereospecific alkyl–alkyl cross-coupling reactions employing nickel catalysts. Our reactions complement related nickel-catalyzed stereoconvergent cross-coupling reactions from a stereochemical and mechanistic perspective. Most reactions of alkyl electrophiles with low-valent nickel complexes proceed through alkyl radicals and thus are stereoablative; the correct enantioselective catalyst can favor the formation of one enantiomer. Our reactions, in contrast, are stereospecific. Enantioenriched ethers and esters are cleanly converted to cross-coupled products with high stereochemical fidelity. While mechanistic details are still to be refined, our results are consistent with a polar, two-electron oxidative addition that avoids the formation of radical intermediates. This reactivity is unusual for a first-row transition metal. The cross-coupling reactions engage a range of benzylic ethers and esters, including methyl ethers, tetrahydropyrans, tetrahydrofurans, esters, and lactones. Coordination of the arene substituent to the nickel catalyst accelerates the reactions. Arenes with low aromatic stabilization energies, such as naphthalene, benzothiophene, and furan, serve as the best ligands and provide the highest reactivity. Traceless directing groups that accelerate reactions of sluggish substrates are described, providing partial compensation for arene coordination. Kumada, Negishi, and Suzuki reactions provide incorporation of a broad range of transmetalating agents. In Kumada coupling reactions, a full complement of Grigard reagents, including methyl, n-alkyl, and aryl Grignard reagents, are employed. In reactions employing methylmagnesium iodide, ligation of the nickel catalyst by rac-BINAP or DPEphos provides the highest yield and stereospecificity. For all other Grignard reagents, Ni(dppe)Cl2 has emerged as the best catalyst. Negishi cross-coupling reactions employing dimethylzinc are reported as a strategy to increase the functional group tolerance of the reaction. We also describe Suzuki reactions using arylboronic esters. These reactions provided the first example in the series of a switch in stereochemical outcome. The reactions maintain stereospecificity, but reactions employing different achiral ligands provide opposite enantiomers of the product. Use of an N-heterocyclic carbene ligand, SIMes, provides inversion, consistent with our prior work in Kumada and Negishi coupling reactions. Use of the electron-rich phosphine PCy3, however, provides retention with stereospecificity, signaling a change in the mechanistic details. Potential applications of the reported cross-coupling reactions include the synthesis of medicinal agents containing the 2-arylalkane and 1,1-diarylalkane moieties, which are pharmacophores in medicinal chemistry. These moieties are found in compounds with activity against a broad range of indications, including cancer, heart disease, diabetes, osteoporosis, smallpox, tuberculosis, and insomnia. We highlight representative examples of bioactive compounds that we have prepared with high enantioselectivity employing our methods, as well as the discovery of a new anti-cancer agent.

Stereospecific Nickel-Catalyzed Cross-Coupling Reactions of Alkyl Grignard Reagents and Identification of Selective Anti-Breast-Cancer Agents†

Alkyl Grignard reagents that contain β-hydrogen atoms were used in a stereospecific nickel-catalyzed cross-coupling reaction to form C(sp(3))-C(sp(3)) bonds. Aryl Grignard reagents were also utilized to synthesize 1,1-diarylalkanes. Several compounds synthesized by this method exhibited selective inhibition of proliferation of MCF-7 breast cancer cells.

Titanium‐Mediated Amination of Grignard Reagents Using Primary and Secondary Amines

The synthesis of anilines through the formation of an aryl– nitrogen bond is a powerful method for the preparation of natural products and pharmaceutical targets. Although palladium catalysis has proven to be an expedient and practical method for this type of bond construction, the use of electrophilic aminating reagents with nucleophilic organometallic reagents presents an alternative strategy. This approach typically requires synthesis and isolation of the electrophilic nitrogen source; methods that use amines directly increase the appeal of this strategy. Transitionmetal-catalyzed amination of organometallic reagents with N-chloroamines has been demonstrated by a number of research groups. Although several of these methods were amenable to generation of the N-chloroamines in situ, none of these reports utilized the nonisolable primary N-chloroamines; thus establishing the need for a new method to address these challenging substrates. Herein, we report the one-pot chlorination and titanium-mediated coupling of Grignard reagents with amines, including primary amines. Our investigations began with examination of the reaction between N-chlorocyclohexylamine and Grignard or arylzinc reagents in the presence of a series of catalysts or promoters (Table 1). A one-pot procedure to prepare the electrophilic N-chloroamines in situ was utilized. In the absence of additive, no desired aniline was formed (Table 1, entry 1). Notably, in the presence of either nickel catalyst or diamine ligand, negligible to modest yields of desired product were observed (Table 1, entries 2 and 3). We hypothesized that an aryltitanium intermediate may provide a suitably nucleophilic reaction partner that could best decomposition of the Nchloroamine (Scheme 1). Use of [Ti(OiPr)4] with Grignard reagent provided the best yield of the desired product (Table 1, entry 6). A series of primary amines reacted smoothly under the one-pot procedure (Table 2). Steric bulk on the adjacent carbon atom is well-tolerated, with a,a-disubstituted amines providing some of the best yields (Table 2, entries 5–7). Configuration is conserved when starting with a chiral amine (Table 2, entry 10). The reaction conditions tolerate protected alcohols and amines as well as a terminal alkyne (Table 2, entries 9–12). Use of unbranched primary amines generally resulted in lower yields. Next we turned our attention to functionalized secondary amines, including the synthesis of the biologically active biarylpiperazine substructure (Table 3). Functionalized cyclic and acyclic secondary amines were found to be very effective substrates under the reaction conditions. Diallylamine, a substrate that shows potential for being part of a protecting group strategy, gave the desired aniline in good yield (Table 3, entry 2). Primary nitriles were well tolerated (Table 3, entry 3), as were ethyl and benzyl carbamates (Table 3, entries 5 and 9). Arylpiperazines that incorporate functional groups including pyridine, nitrile, and 2-furanyl underwent smooth cross-coupling under the reaction conditions and provided biarylpiperazines (Table 3, entries 6–8). These types of structures are of particular interest because of the myriad of biological activities associated with the biarylpiperazine pharmacophore. The synthesis of an N-aryl homopiperazine was also examined (Table 3, entry 9), thus demonstrating Table 1: Optimization with Cyclohexylamine.

Palladium-Catalyzed Cascade Reaction for the Synthesis of Substituted Isoindolines**

Isoindoline heterocycles have demonstrated potential in medicinal chemistry as they exhibit activity across diverse biological targets. They are present in molecules which act as bronchodilaters, N-methyl-d-aspartate agonists, multidrug resistance reversal agents, and fibrinogen receptor antagonists. While several approaches to the synthesis of unsubstituted or monosubstituted isoindolines have been reported, few methods exist to produce disubstituted isoindolines with high diastereoselectivity. In addition, there are no diastereoselective methods for the synthesis of 1,3-disubstituted isoindolines that allow for incorporation of readily available boronic acids, which are practical building blocks in medicinal chemistry. Synthetic methods for isoindoline synthesis that provide straightforward introduction of substitutents on the heterocycle would enable preparation of families of biologically significant compounds. We designed a cascade sequence for isoindoline synthesis that we anticipated could be catalyzed by a palladium(II) complex and would utilize boronic acids as a starting material (Scheme 1). The cascade reaction would initiate with arylation of imine 1. The resultant sulfonamide would engage the pendant allylic acetate by aminopalladation; b-acetoxy elimination would release the isoindoline product. A major challenge was identification of a catalyst with the appropriate electronic balance to facilitate all steps in the catalytic cycle. While nucleophilic arylation of imines requires electron-donating ligands, migratory insertion is generally promoted by palladium(II) catalysts with electrophilic character. We selected phosphinite palladacycle 3, which is a catalyst with demonstrated activity for arylation of imines, with the thought that the p-accepting phosphonite would balance s donation from the aryl group. In practice, we have found this complex to be an effective catalyst for our cascade sequence (see below). We began our investigation with reaction conditions similar to those employed for imine arylation. At room temperature, in the presence of catalyst 3, effective arylation of 1 with phenyl boronic acid occurs (Table 1, entry 1). Elevated reaction temperatures promote the cyclization reaction (Table 1, entry 2; Method A). Notably, isoindoline 2 is generated as a single diastereomer under these reaction conditions. Scheme 1. Proposed synthesis of isoindoline derivatives. L= ligand, Ts=4-toluenesulfonyl.

Stereospecific Cross-Coupling Reactions of Aryl-Substituted Tetrahydrofurans, Tetrahydropyrans, and Lactones

The stereospecific ring-opening of O-heterocycles to provide acyclic alcohols and carboxylic acids with controlled formation of a new C–C bond is reported. These reactions provide new methods for synthesis of acyclic polyketide analogs with complex stereochemical arrays. Stereoselective synthesis of the cyclic template is utilized to control relative configuration; subsequent stereospecific nickel-catalyzed ring-opening affords the acyclic product. Aryl-substituted tetrahydrofurans and tetrahydropyrans undergo nickel-catalyzed Kumada-type coupling with a range of Grignard reagents to furnish acyclic alcohols with high diastereoselectivity. Enantioenriched lactones undergo Negishi-type cross-coupling with dimethylzinc to afford enantioenriched carboxylic acids. Application in a two-step enantioselective synthesis of an anti-dyslipidemia agent is demonstrated.

Enantioselective silver-catalyzed propargylation of imines

A catalytic enantioselective method for the propargylation of aldimines is described. A silver catalyst ligated by a bidentate phoshpine is utilized to provide good yields and high ees for a variety of substrates. Homopropargylic sulfonamide products undergo facile silver-mediated cyclization to generate 2-pyrrolines, useful intermediates for alkaloid synthesis.

Intra- and Intermolecular Nickel-Catalyzed Reductive Cross-Electrophile Coupling Reactions of Benzylic Esters with Aryl Halides.

Nickel-catalyzed cross-electrophile coupling reactions of benzylic esters and aryl halides have been developed. Both inter- and intramolecular variants proceed under mild reaction conditions. A range of heterocycles and functional groups are tolerated under the reaction conditions. Additionally, the first example of a stereospecific cross-electrophile coupling of a secondary benzylic ester is described.

Decarboxylative Alkyl-Alkyl Cross-Coupling Reactions.

Alkyl with alkyl: A significant development in alkyl-alkyl cross-coupling reactions, namely the nickel-catalyzed decarboxylative Negishi coupling of N-hydroxyphthalimide esters, was recently reported by Baran and co-workers. This method enables the synthesis of various highly functionalized compounds, including natural product derivatives.

Stereospecific Intramolecular Reductive Cross-Electrophile Coupling Reactions for Cyclopropane Synthesis.

The stereospecific reductive cross-electrophile coupling reaction of 2-aryl-4-chlorotetrahydropyrans to afford disubstituted cyclopropanes is reported. This ring contraction presents surprises with respect to the stereochemical outcome of reaction of the alkyl halide moiety. While cross-coupling and reductive cross-electrophile coupling reactions of alkyl halides are typically stereoablative, using a chiral catalyst to set the stereocenter, this transformation proceeds with high stereochemical fidelity at the alkyl halide and ether bearing stereogenic centers. This approach provides straightforward access to highly substituted cyclopropanes in two steps from commercially available aldehydes.