Insight into Radical Initiation, Solvent Effects, and Biphenyl Production in Iron-Bisphosphine Cross-Couplings.

Iron-bisphosphines have attracted broad interest as highly effective and versatile catalytic systems for two- and three-component cross-coupling strategies. While recent mechanistic studies have defined the role of organoiron(II)-bisphosphine species as key intermediates for selective cross-coupled product formation in these systems, mechanistic features that are essential for catalytic performance remain undefined. Specifically, key questions include the following: what is the generality of iron(II) intermediates for radical initiation in cross-couplings? What factors control reactivity toward homocoupled biaryl side-products in these systems? Finally, what are the solvent effects in these reactions that enable high catalytic performance? Herein, we address these key questions by examining the mechanism of enantioselective coupling between α-chloro- and α-bromoalkanoates and aryl Grignard reagents catalyzed by chiral bisphosphine-iron complexes. By employing freeze-trapped 57Fe Mössbauer and EPR studies combined with inorganic synthesis, X-ray crystallography, reactivity studies, and quantum mechanical calculations, we define the key in situ iron speciation as well as their catalytic roles. In contrast to iron-SciOPP aryl-alkyl couplings, where monophenylated species were found to be the predominant reactive intermediate or prior proposals of reduced iron species to initiate catalysis, the enantioselective system utilizes an iron(II)-(R,R)-BenzP* bisphenylated intermediate to initiate the catalytic cycle. A profound consequence of this radical initiation process is that halogen abstraction and subsequent reductive elimination result in considerable amounts of biphenyl side products, limiting the efficiency of this method. Overall, this study offers key insights into the broader role of iron(II)-bisphosphine species for radical initiation, factors contributing to biphenyl side product generation, and protocol effects (solvent, Grignard reagent addition rate) that are critical to minimizing biphenyl generation to obtain more selective cross-coupling methods.

General method for iron-catalyzed multicomponent radical cascades-cross-couplings.

Transition metal­catalyzed cross-coupling reactions are some of the most widely used methods in chemical synthesis. However, despite notable advantages of iron (Fe) as a potentially cheaper, more abundant, and less toxic transition metal catalyst, its practical application in multicomponent cross-couplings remains largely unsuccessful. We demonstrate 1,2-bis(dicyclohexylphosphino)ethane Fe­catalyzed coupling of α-boryl radicals (generated from selective radical addition to vinyl boronates) with Grignard reagents. Then, we extended the scope of these radical cascades by developing a general and broadly applicable Fe-catalyzed multicomponent annulation­cross-coupling protocol that engages a wide range of π-systems and permits the practical synthesis of cyclic fluorous compounds. Mechanistic studies are consistent with a bisarylated Fe(II) species being responsible for alkyl radical generation to initiate catalysis, while carbon-carbon bond formation proceeds between a monoarylated Fe(II) center and a transient alkyl radical.

Oxidation of 8-thioguanosine gives redox-responsive hydrogels and reveals intermediates in a desulfurization pathway.

A disulfide made by oxidation of 8-thioguanosine is a supergelator. The hydrogels are redox-responsive, as they disassemble upon either reduction or oxidation of the S-S bond. We also identified this disulfide, and 2 other compounds, as intermediates in oxidative desulfurization of 8-thioG to guanosine.

Fe-catalyzed three-component dicarbofunctionalization of unactivated alkenes with alkyl halides and Grignard reagents.

A highly chemoselective iron-catalyzed three-component dicarbofunctionalization of unactivated olefins with alkyl halides (iodides and bromides) and sp2-hybridized Grignard reagents is reported. The reaction operates under fast turnover frequency and tolerates a diverse range of sp2-hybridized nucleophiles (electron-rich and electron-deficient (hetero)aryl and alkenyl Grignard reagents), alkyl halides (tertiary alkyl iodides/bromides and perfluorinated bromides), and unactivated olefins bearing diverse functional groups including tethered alkenes, ethers, protected alcohols, aldehydes, and amines to yield the desired 1,2-alkylarylated products with high regiocontrol. Further, we demonstrate that this protocol is amenable for the synthesis of new (hetero)carbocycles including tetrahydrofurans and pyrrolidines via a three-component radical cascade cyclization/arylation that forges three new C-C bonds.

Intra- and intermolecular Fe-catalyzed dicarbofunctionalization of vinyl cyclopropanes.

Design and implementation of the first (asymmetric) Fe-catalyzed intra- and intermolecular difunctionalization of vinyl cyclopropanes (VCPs) with alkyl halides and aryl Grignard reagents has been realized via a mechanistically driven approach. Mechanistic studies support the diffusion of alkyl radical intermediates out of the solvent cage to participate in an intra- or intermolecular radical cascade with a range of VCPs followed by re-entering the Fe radical cross-coupling cycle to undergo (stereo)selective C(sp2)-C(sp3) bond formation. This work provides a proof-of-concept of the use of vinyl cyclopropanes as synthetically useful 1,5-synthons in Fe-catalyzed conjunctive cross-couplings with alkyl halides and aryl/vinyl Grignard reagents. Overall, we provide new design principles for Fe-mediated radical processes and underscore the potential of using combined computations and experiments to accelerate the development of challenging transformations.

Mechanism of nitrones and allenoates cascade reactions for the synthesis of dihydro[1,2-a]indoles.

Quantum mechanical calculations (DLPNO-CCSD(T) and dispersion-corrected DFT) are employed to gain insights into the mechanism and selectivity in the catalytic synthesis of dihydropyrido[1,2-a]indoles from the cascade reaction between nitrones and allenes. Implications for controlling diverging pathways is discussed.

Templating and Catalyzing [2+2] Photocycloaddition in Solution Using a Dynamic G-Quadruplex.

We describe a templating/covalent capture strategy that enables photochemical formation of 8 cyclobutanes in one noncovalent assembly. This process was characterized by experiment and quantum mechanical/molecular mechanics (ONIOM) calculations. Thus, KI and 16 units of 5'-cinnamate guanosine form a G-quadruplex where C=C π bonds in neighboring G4 -quartets are separated by 3.3 Å, enabling [2+2] photocycloaddition in solution. This reaction is high-yielding (>90 %), regio- and diastereoselective. Since all components are in dynamic equilibrium this photocycloaddition is catalytic in K+ .

Mechanism of Nakamura's Bisphosphine-Iron-Catalyzed Asymmetric C(sp2)-C(sp3) Cross-Coupling Reaction: The Role of Spin in Controlling Arylation Pathways.

Quantum mechanical calculations are employed to investigate the mechanism and origin of stereoinduction in asymmetric iron-catalyzed C(sp2)-C(sp3) cross-coupling reaction between Grignard reagents and α-chloroesters. A coherent mechanistic picture of this transformation is revealed. These results have broad implications for understanding the mechanisms of iron-catalyzed cross-coupling reactions and rational design of novel iron-based catalysts for asymmetric transformations.