A mines are one of the most important structural motifs in pharmaceuticals, agrochemicals and organic materials 1,2 . Alkylation and reductive amination reactions are still commonly used to prepare and modify amines, and new methods derived from reductive amination, such as the borrowing hydrogen 3 strategy, have been reported [4][5][6][7] . Nevertheless, the most significant development in amine synthesis has been transition-metal-catalysed C-N coupling of aryl electrophiles (halides and pseudo halides) with amine nucleophiles [8][9][10][11] (Fig. 1a). The C-N coupling of alkyl electrophiles, however, is largely under-developed (Fig. 1a). A perceived difficulty is β -hydrogen elimination from a metal alkyl intermediate originated from oxidative addition of the alkyl electrophile, which has posed considerable challenges in analogous C-C crosscoupling of alkyl electrophiles [12][13][14] . Moreover, the product-yielding C(sp 3 )-N reductive elimination step is rarely demonstrated 15 . A notable exception is the light-induced, copper-catalysed C-N coupling of alkyl halides recently developed [16][17][18] . Nevertheless, the scope of amine nucleophiles is limited to carbazoles 16,18 and amides 17,19 . Alternative, formal C-N coupling of alkyl electrophiles via the addition of alkyl radicals to nitroarenes has been reported 20,21 .The group of Baran has recently trailblazed the use of redox-active esters derived from alkyl carboxylic acids as superior surrogates of alkyl halides in decarboxylative C-C cross-coupling reactions [22][23][24] . Extension to a decarboxylative carbon-heteroatom, particularly C-B bond formation has also been reported 19,[25][26][27][28][29] . The key attributes of alkyl carboxylic acids 30,31 are their unparalleled availability, stability and non-toxic nature, which are in stark contrast with alkyl halides, ketones and aldehydes. While several precedents of decarboxylative imidation 32 and amination 19,33 are known, they are limited to a narrow scope of very special substrates or intramolecular reactions. A general metal-catalysed decarboxylative C-N coupling of redox-active esters with anilines will provide valuable methodology for the synthesis of alkylated anilines (Fig. 1b), which requires alkyl halides and carbonyl compounds 6 as starting reagents using the currently standard methods of alkylation and reductive amination, respectively. Further foreseen advantages of such a decarboxylative amination include applicability to bulky primary and secondary alkyl groups and immunity to over-alkylation, both of which are major limitations of direct alkylation (Fig. 1b). Despite its conceptual simplicity and resemblance to decarboxylative C-C coupling, the intermolecular decarboxylative C-N coupling of redoxactive esters poses significant hurdles. The activation principle of redox-active esters originates from amide-bond synthesis; thus, amide formation can compete when amine nucleophiles are used. Moreover, decarboxylative C-C coupling reactions of redox-active esters were, until now, all init...
Alkyl aryl ethers are an important class of compounds in medicinal and agricultural chemistry. Catalytic C(sp )-O cross-coupling of alkyl electrophiles with phenols is an unexplored disconnection strategy to the synthesis of alkyl aryl ethers, with the potential to overcome some of the major limitations of existing methods such as C(sp )-O cross-coupling and S 2 reactions. Reported here is a tandem photoredox and copper catalysis to achieve decarboxylative C(sp )-O coupling of alkyl N-hydroxyphthalimide (NHPI) esters with phenols under mild reaction conditions. This method was used to synthesize a diverse set of alkyl aryl ethers using readily available alkyl carboxylic acids, including many natural products and drug molecules. Complementarity in scope and functional-group tolerance to existing methods was demonstrated.
Alkyl amines are an important class of organic compounds in medicinal and materials chemistry. Until now very have been very few methods for the synthesis of alkyl amines by metal-catalyzed cross-coupling of alkyl electrophiles with nitrogen nucleophiles. Described here is an approach to employ tandem photoredox and copper catalysis to enable the cross-coupling of alkyl N-hydroxyphthalimide esters, readily derived from alkyl carboxylic acids, with benzophenone-derived imines. Hydrolysis of the coupling products furnish alkylated primary amines. Primary, secondary, and tertiary alkyl groups can be transferred, and the coupling tolerates a diverse set of functional groups. The method allows rapid functionalization of natural products and drugs, and can be used to expedite syntheses of pharmaceuticals from readily available chemical feedstocks.
Cross-Coupling of Non-activated Alkyl Electrophiles via Nickel Hydride Catalysis. ChemRxiv. Preprint.
A glycosyl coupling reaction via photoinduced direct activation of thioglycosides and subsequent O-glycosylation in the absence of photosensitizer was developed for the first time. This reaction underwent a selectively homolytic cleavage of a C-S bond to generate a glycosyl radical, which was oxidized to an oxacarbenium ion by Cu(OTf)2, and a sequential O-glycosylation. A wide range of glycosides were synthesized in moderate to excellent yield using sugars, amino acids, or cholesterol as the acceptors.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.