Nickel‐Catalyzed C(sp2)−C(sp3) Kumada Cross‐Coupling of Aryl Tosylates with Alkyl Grignard Reagents

Aryl tosylates are an attractive class of electrophiles for cross‐coupling reactions due to ease of synthesis, low price, and the employment of C−O electrophiles, however, the reactivity of aryl tosylates is low. Herein, we report the Ni‐catalyzed C(sp2)−C(sp3) Kumada cross‐coupling of aryl tosylates with primary and secondary alkyl Grignard reagents. The method delivers valuable alkyl arenes by cross‐coupling with challenging alkyl organometallics possessing β‐hydrogens that are prone to β‐hydride elimination and homo‐coupling. The reaction is catalyzed by an air‐ and moisture stable‐Ni(II) precatalyst. A broad range of electronically‐varied aryl tosylates, including bis‐tosylates, underwe…

Cobalt−NHC Catalyzed C(sp 2 )−C(sp 3 ) and C(sp 2 )−C(sp 2 ) Kumada Cross‐Coupling of Aryl Tosylates with Alkyl and Aryl Grignard Reagents

Eisenkatalysierte Kreuzkupplungen in der Synthese von Pharmazeutika: Streben nach Nachhaltigkeit

Iron-Catalyzed C(sp2)-C(sp3) Cross-Coupling of Alkyl Grignard Reagents with Polyaromatic Tosylates

Iron‐Catalyzed Cross‐Couplings in the Synthesis of Pharmaceuticals: In Pursuit of Sustainability

The scarcity of precious metals has led to the development of sustainable strategies for metal-catalyzed cross-coupling reactions. The establishment of new catalytic methods using iron is attractive owing to the low cost, abundance, ready availability, and very low toxicity of iron. In the last few years, sustainable methods for iron-catalyzed cross-couplings have entered the critical area of pharmaceutical research. Most notably, iron is one of the very few metals that have been successfully field-tested as highly effective base-metal catalysts in practical, kilogram-scale industrial cross-couplings. In this Minireview, we critically discuss the strategic benefits of using iron catalysts a…

Structures and energetic properties of 4-halobenzamides

The amide bond represents one of the most fundamental functional groups in chemistry. The properties of amides are defined by amidic resonance (nN→π*C=O conjugation), which enforces planarity of the six atoms comprising the amide bond. Despite the importance of 4-halo-substituted benzamides in organic synthesis, molecular interactions and medicinal chemistry, the effect of 4-halo-substitution on the properties of the amide bond in N,N-disubstituted benzamides has not been studied. Herein, we report the crystal structures and energetic properties of a full series of 4-halobenzamides. The structures of four 4-halobenzamides (halo = iodo, bromo, chloro and fluoro) in the N-morpholinyl series h…

N-Methylcaprolactam as a Dipolar Aprotic Solvent for Iron-Catalyzed Cross-Coupling Reactions: Matching Efficiency with Safer Reaction Media

Although iron‐catalysis provides a powerful alternative to the more conventional palladium and nickel in the cross‐coupling arena, the major limitation is the necessity for carcinogenic N‐methylpyrrolidone as a co‐solvent in the vast majority of catalytic reactions. Herein, we introduce N‐methylcaprolactam as an efficient, non‐toxic and practical dipolar aprotic solvent for iron‐catalyzed C(sp2)−C(sp3) alkylative cross‐coupling of aryl chlorides and tosylates. The utility of this method is reflected by its wide substrate scope, high yields and capacity to cross‐couple challenging alkyl organometallics prone to b‐hydride elimination and homocoupling. Considering the broad utility of iron‐cat…

N-Acyl-glutarimides: Effect of Glutarimide Ring on the Structures of Fully Perpendicular Twisted Amides and N–C Bond Cross-Coupling

N-Acyl-glutarimides have emerged as the most reactive precursors for N-C(O) bond cross-coupling reactions to date, wherein the reactivity is driven by ground-state destabilization of the amide bond. Herein, we report a full study on the effect of a glutarimide ring on the structures, electronic properties, and reactivity of fully perpendicular N-acyl-glutarimide amides. Most notably, this report demonstrates the generality of deploying N-acyl-glutarimides to achieve full twist of the acyclic amide bond, and results in the discovery of N-acyl-glutarimide amide with an almost perfect twist value, τ = 89.1°. X-ray structures of five new N-acyl-glutarimides are reported. Reactivity studies in t…

Cyclic ureas (DMI, DMPU) as efficient, sustainable ligands in iron-catalyzed C(sp2)–C(sp3) coupling of aryl chlorides and tosylates

Iron-catalyzed cross-coupling has emerged as a powerful tool for sustainable catalysis. However, by far the most common ligand in iron-catalyzed cross-couplings for preparative and industrial applications is reprotoxic NMP. Herein, we report that cyclic ureas (DMI, DMPU) are efficient and sustainable alternatives to NMP in iron-catalyzed alkylations of aryl chlorides and tosylates with alkyl Grignard reagents. This environmentally benign method accomplishes traditionally challenging C(sp2)–C(sp3) cross-coupling with organometallics possessing β-hydrogens with efficiency matching or superseding NMP. The reaction is compatible with a variety of electrophilic functional handles. Applications t…

N-Butylpyrrolidone (NBP) as a non-toxic substitute for NMP in iron-catalyzed C(sp2)–C(sp3) cross-coupling of aryl chlorides

Although iron catalyzed cross-coupling reactions show extraordinary promise in reducing the environmental impact of more toxic and scarce transition metals, one of the main challenges is the use of reprotoxic NMP (NMP = N-methylpyrrolidone) as the key ligand to iron in the most successful protocols in this reactivity platform. Herein, we report that non-toxic and sustainable N-butylpyrrolidone (NBP) serves as a highly effective substitute for NMP in iron-catalyzed C(sp2)–C(sp3) cross-coupling of aryl chlorides with alkyl Grignard reagents. This challenging alkylation proceeds with organometallics bearing β-hydrogens with efficiency superseding or matching that of NMP with ample scope and br…

Iron‐Catalyzed C( sp 2 )−C( sp 3 ) Cross‐Coupling of Chlorobenzamides with Alkyl Grignard Reagents: Development of Catalyst System, Synthetic Scope, and Application

Iron-Catalyzed C(sp2)–C(sp3) Cross-Coupling of Chlorobenzenesulfonamides with Alkyl Grignard Reagents: Entry to Alkylated Aromatics

Alkylated benzosulfonamides are compounds of high importance in organic synthesis, including the production of pharmaceuticals, agrochemicals, and plasticizers. We report the iron-catalyzed C(sp2)–C(sp3) cross-coupling of chlorobenzosulfonamides with alkyl Grignard reagents under mild and sustainable conditions. Electronically and sterically varied benzosulfonamides as well as challenging alkyl organometallics containing β-hydrogen afford alkylated benzosulfonamides in high to excellent yields. Sulfonamide represents the most reactive activating group for iron-catalyzed cross-coupling. The process affords alkylated benzenesulfonamides poised for medicinal chemistry applications and traceles…

2-Methyltetrahydrofuran: A Green Solvent for Iron-Catalyzed Cross-Coupling Reactions

Iron‐catalyzed cross‐coupling reactions allow sustainable formation of C−C bonds using cost‐effective, earth‐abundant base‐metal catalysis for complex syntheses of pharmaceuticals, natural products, and fine chemicals. The major challenge to maintain full sustainability of the process is the identification of green and renewable solvents that can be harnessed to replace the conventional solvents for this highly attractive reaction. Herein, iron‐catalyzed cross‐coupling of aryl chlorides and tosylates with challenging organometallic reagents possessing β‐hydrogens is found to proceed in good to excellent yields with the green, sustainable, and eco‐friendly 2‐methyltetrahydrofuran (2‐MeTHF) a…

Iron-Catalyzed C−O Bond Activation: Opportunity for Sustainable Catalysis

Oxygen-based electrophiles have emerged as some of the most valuable cross-coupling partners in organic synthesis due to several major strategic and environmental benefits, such as abundance and potential to avoid toxic halide waste. In this context, iron-catalyzed C-O activation/cross-coupling holds particular promise to achieve sustainable catalytic protocols due to its natural abundance, inherent low toxicity, and excellent economic and ecological profile. Recently, tremendous progress has been achieved in the development of new methods for functional-group-tolerant iron-catalyzed cross-coupling reactions by selective C-O cleavage. These methods establish highly attractive alternatives t…

Ligand Effect on Iron-Catalyzed Cross-Coupling Reactions: Evaluation of Amides as O-Coordinating Ligands

The development of new highly efficient O‐coordinating ligands for iron‐catalyzed C(sp2)−C(sp3) cross‐coupling reactions is reported. A structure‐reactivity study on the effect of amides as ligands in the industrially‐important iron‐catalyzed cross‐coupling of aryl chlorides with challenging organometallics possessing β‐hydrogens was performed. Investigation of a series of new 21 ligands that rationally vary in O‐coordination aptitude as well as sterics around the amide bond pinpointed the features that are important for catalysis. The study led to the discovery of several highly efficient ligands for cross‐coupling, including TMU (TMU=tetramethylurea), N‐cyclic and coordinating benzamides.…

Iron-Catalyzed C(sp2)–C(sp3) Cross-Coupling of Aryl Chlorobenzoates with Alkyl Grignard Reagents

Aryl benzoates are compounds of high importance in organic synthesis. Herein, we report the iron-catalyzed C(sp2)&ndash

Iron-catalyzed C(sp2)-C(sp3) cross-coupling at low catalyst loading

The iron-catalyzed C(sp2)–C(sp3) cross-coupling provides a highly economical route to exceedingly valuable alkylated arenes that are widespread in medicinal chemistry and materials science. Herein, we report an operationally-simple protocol for the selective C(sp2)–C(sp3) iron-catalyzed cross-coupling of aryl chlorides with Grignard reagents at low catalyst loading. A broad range of electronically-varied aryl and heteroaryl chlorides underwent the cross-coupling using challenging alkyl organometallics possessing β-hydrogens with high efficiency up to 2000 TON. A notable feature of the protocol is the use of environmentally-friendly cyclic urea ligands. A series of guidelines to predict cros…

Evaluation of Cyclic Amides as Activating Groups in N-C Bond Cross-Coupling: Discovery of N-Acyl-δ-valerolactams as Effective Twisted Amide Precursors for Cross-Coupling Reactions

The development of efficient methods for facilitating N-C(O) bond activation in amides is an important objective in organic synthesis that permits the manipulation of the traditionally unreactive amide bonds. Herein, we report a comparative evaluation of a series of cyclic amides as activating groups in amide N-C(O) bond cross-coupling. Evaluation of N-acyl-imides, N-acyl-lactams, and N-acyl-oxazolidinones bearing five- and six-membered rings using Pd(II)-NHC and Pd-phosphine systems reveals the relative reactivity order of N-activating groups in Suzuki-Miyaura cross-coupling. The reactivity of activated phenolic esters and thioesters is evaluated for comparison in O-C(O) and S-C(O) cross-c…

Front Cover: Iron-Catalyzed C−O Bond Activation: Opportunity for Sustainable Catalysis (ChemSusChem 20/2017)

Barriers to rotation in ortho-substituted tertiary aromatic amides: Effect of chloro-substitution on resonance and distortion

Planarity of the amide bond represents one of the most widely recognized properties of amides. Herein, we report a combined structural and computational study on the effect of ortho-substitution on resonance and barriers to rotation in tertiary aromatic amides. We demonstrate that ortho-chloro substitution in a class of benzamides that are important from the reactivity and medicinal chemistry perspective results in increased barriers to rotation around both the N-C(O) and C-C(O) axes. The effect of steric hindrance on structures, resonance energies, barriers to rotation, and proton affinities is discussed. The present study strongly supports the use of ortho-substitution in common benzamide…

CCDC 1969088: Experimental Crystal Structure Determination

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CCDC 1483077: Experimental Crystal Structure Determination

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CCDC 2082397: Experimental Crystal Structure Determination

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