Deaminative meta-C-H alkylation by ruthenium(ii) catalysis.
ABSTRACT: Precise structural modifications of amino acids are of importance to tune biological properties or modify therapeutical capabilities relevant to drug discovery. Herein, we report a ruthenium-catalyzed meta-C-H deaminative alkylation with easily accessible amino acid-derived Katritzky pyridinium salts. Likewise, remote C-H benzylations were accomplished with high levels of chemoselectivity and remarkable functional group tolerance. The meta-C-H activation approach combined with our deaminative strategy represents a rare example of selectively converting C(sp3)-N bonds into C(sp3)-C(sp2) bonds.
Project description:Described is a cross-electrophilic, deaminative coupling strategy harnessing Katritzky salts as a new species of electrophile in Ni/photoredox dual catalytic reductive cross-coupling reactions. Distinguishing features of this arylation protocol include its mild reaction conditions, high chemoselectivity, and adaptability to a variety of complex substrates [i.e., pyridinium salts derived from amines and partners derived from (hetero)aryl bromides].
Project description:Primary amines are often cheap, naturally occurring, and chemically diverse starting materials. For these reasons, deaminative functionalization of amines has emerged as an important area of research. Recent advances in C-N activation transform simple α-1° and α-2° amines into alkylating reagents via Katritzky pyridinium salts. We report a complementary method that activates sterically encumbered α-3° primary amines through visible light photoredox catalysis. By condensing α-3° primary amines with electron-rich aryl aldehyde, we enable an oxidation and deprotonation event, which generates a key imidoyl radical intermediate. A subsequent β-scission event liberates alkyl radicals for coupling with electron-deficient olefins for the generation of unnatural γ-quaternary amino acids and other valuable synthetic targets.
Project description:The use of pyridinium-activated primary amines as photoactive functional groups for deaminative generation of alkyl radicals under catalyst-free conditions is described. By taking advantage of the visible light absorptivity of electron donor-acceptor complexes between Katritzky pyridinium salts and either Hantzsch ester or Et<sub>3</sub> N, photoinduced single-electron transfer could be initiated in the absence of a photocatalyst. This general reactivity platform has been applied to deaminative alkylation (Giese), allylation, vinylation, alkynylation, thioetherification, and hydrodeamination reactions. The mild conditions are amenable to a diverse range of primary and secondary alkyl pyridiniums and demonstrate broad functional group tolerance.
Project description:Electrosynthesis has received great attention among researchers in both academia and industry as an ideal technique to promote single electron reduction without the use of expensive catalysts. In this work, we report the electrochemical reduction of Katritzky salts to alkyl radicals by sacrificing the easily accessible metal anode. This catalyst and electrolyte free platform has broad applicability to single electron transfer chemistry, including fluoroalkenylation, alkynylation and thiolation. The deaminative functionalization is facilitated by the rapid molecular diffusion across microfluidic channels, demonstrating the practicality that outpaces the conventional electrochemistry setups.
Project description:By employing an N-heterocyclic carbene (NHC) catalyst, we developed a versatile catalytic system that enables deaminative cross-coupling reactions of aldehydes with redox-active pyridinium salts. Katritzky pyridinium salts behave as single-electron oxidants capable of generating alkyl radicals enabled by the redox properties of the enolate form of Breslow intermediates. The resultant alkyl radical undergoes efficient recombination with the NHC-bound aldehyde-derived carbonyl carbon radical for the formation of a C-C bond. The mild and transition metal-free reaction conditions tolerate a broad range of functional groups, and its utility has been further demonstrated by the modification of a series of peptide feedstocks and application to the three-component dicarbofunctionalization of olefins.
Project description:The reductive cross-coupling of sp3-hybridized carbon centers represents great synthetic values and insurmountable challenges. In this work, we report a nickel-catalyzed deaminative cross-electrophile coupling reaction to construct C(sp)?C(sp3), C(sp2)?C(sp3), and C(sp3)?C(sp3) bonds. A wide range of coupling partners including aryl iodides, bromoalkynes, or alkyl bromides are stitched with alkylpyridinium salts that derived from the corresponding primary amines. The advantages of this methodology are showcased in the two-step synthesis of the key lactonic moiety of (+)-compactin and (+)-mevinolin. The one-pot procedure without isolation of alkylpyridinium tetrafluoroborate salt is also proven to be successful. This cross-coupling strategy of two electrophiles provides a highly valuable vista for the convenient installation of alkyl substituents and late functionalizations of sp3 carbons.
Project description:Selective modification of heteroatom-containing aromatic structures is in high demand as it permits rapid evaluation of molecular complexity in advanced intermediates. Inspired by the selectivity of deaminases in nature, herein we present a simple methodology that enables the NH<sub>2</sub> groups in aminoheterocycles to be conceived as masked modification handles. With the aid of a simple pyrylium reagent and a cheap chloride source, C(sp<sup>2</sup>)‒NH<sub>2</sub> can be converted into C(sp<sup>2</sup>)‒Cl bonds. The method is characterized by its wide functional group tolerance and substrate scope, allowing the modification of >20 different classes of heteroaromatic motifs (five- and six-membered heterocycles), bearing numerous sensitive motifs. The facile conversion of NH<sub>2</sub> into Cl in a late-stage fashion enables practitioners to apply Sandmeyer- and Vilsmeier-type transforms without the burden of explosive and unsafe diazonium salts, stoichiometric transition metals or highly oxidizing and unselective chlorinating agents.
Project description:An alkyl-alkyl cross-coupling of Katritzky alkylpyridinium salts and organoboranes, formed in situ via hydroboration of alkenes, has been developed. This method utilizes the abundance of both alkyl amine precursors and alkenes to form C(sp3)-C(sp3) bonds. This strategy is also effective with alkynes, enabling a C(sp3)-C(sp2) cross-coupling. Under these mild conditions, a broad range of functional groups, including protic groups, is tolerated. As seen with previous alkylpyridinium cross-couplings, mechanistic studies support an alkyl radical intermediate.
Project description:A dual catalytic manifold that enables site-selective functionalization of unactivated <i>sp</i><sup><i>3</i></sup> C-O bonds in cyclic acetals with aryl and alkyl halides is reported. The reaction is triggered by an appropriate σ*-p orbital overlap prior to <i>sp</i><sup><i>3</i></sup> C-O cleavage, thus highlighting the importance of conformational flexibility in both reactivity and site selectivity. The protocol is characterized by its excellent chemoselectivity profile, thus offering new vistas for activating strong <i>σ sp</i><sup><i>3</i></sup> C-O linkages.
Project description:A unique C(sp<sup>3</sup>)-H/C(sp<sup>3</sup>)-H dehydrocoupling of <i>N</i>-benzylimines with saturated heterocycles is described. Using super electron donor (SED) 2-azaallyl anions and aryl iodides as electron acceptors, single-electron-transfer (SET) generates an aryl radical. Hydrogen atom transfer (HAT) from saturated heterocycles or toluenes to the aryl radical generates alkyl radicals or benzylic radicals, respectively. The newly formed alkyl radicals and benzylic radicals couple with the 2-azaallyl radicals with formation of new C-C bonds. Experimental evidence supports the key hydrogen-abstraction by the aryl radical, which determines the chemoselectivity of the radical-radical coupling reaction. It is noteworthy that this procedure avoids the use of traditional strong oxidants and transition metals.