Deaminative Arylation of Amino Acid-derived Pyridinium Salts.
ABSTRACT: A Suzuki-Miyaura cross-coupling of ?-pyridinium esters and arylboroxines has been developed. Combined with formation of the pyridinium salts from amino acid derivatives, this method enables amino acid derivatives to be efficiently transformed into ?-aryl esters and amides. Under the mild conditions, broad functional group tolerance on both the amino acid derivatives and the arylboroxine are observed, including protic functional groups. Mechanistic studies support an alkyl radical intermediate, similar to other cross-couplings of alkylpyridinium salts.
Project description:A nickel-catalyzed reductive cross-coupling of alkylpyridinium salts and aryl bromides has been developed using Mn as the reductant. Both primary and secondary alkylpyridinium salts can be used, and high functional group and heterocycle tolerance is observed, including for protic groups. Mechanistic studies indicate the formation of an alkyl radical, and controlling its fate was key to the success of this reaction.
Project description:A Negishi cross-coupling of alkylpyridinium salts and alkylzinc halides has been developed. This is the first example of alkyl-alkyl bond formation via cross-coupling of an alkyl amine derivative with an unactivated alkyl group, and allows both primary and secondary alkylpyridinium salts to react with primary alkylzinc halides with high functional group tolerance. When combined with formation of the pyridinium salts from primary amines, this method enables the noncanonical transformation of NH2 groups into a wide range of alkyl substituents with broad functional group tolerance.
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: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 <i>meta</i>-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 <i>meta</i>-C-H activation approach combined with our deaminative strategy represents a rare example of selectively converting C(sp<sup>3</sup>)-N bonds into C(sp<sup>3</sup>)-C(sp<sup>2</sup>) bonds.
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: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:Pyridinium ylides are well recognized as dipoles for cycloaddition reactions. In its turn, the microwave-assisted interaction of N-(cyanomethyl)-2-alkylpyridinium salts with enaminones unexpectedly proceeds as a domino sequence of cycloisomerization and cyclocondensation reactions, instead of a 1,3-dipolar cycloaddition. The reaction takes place in the presence of sodium acetate as base and employs benign solvents. The optical properties of the resulting pyrido[2,3-b]indolizines were studied, showing green light emission with high fluorescence quantum yields.
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: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.