James Sanderson

Synthesis
DOI: 10.1055/s-0037-1611788

A comparative study of various widely used methods of reductive amination is reported. Specifically, such reducing agents as H2, Pd/C, hydride reagents [NaBH4, NaBH3CN, NaBH(OAc)3], and CO/Rh2(OAc)4 system were considered. For understanding the selectivity and activity of the reducing agents reviewed herein, different classes of starting materials were tested, including aliphatic and aromatic amines, as well as aliphatic and aromatic aldehydes and ketones. Most important advantages and drawbacks of the methods, such as selectivity of the target amine formation and toxicity of the reducing agents were compared. Methods were also considered from the viewpoint of green chemistry.
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© Georg Thieme Verlag Stuttgart · New York

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A mild and highly efficient translocation of alkenes by dual visible‐light‐cobalt catalysis has been developed. By the proper choice of ligands, isomerization over one position or more than one position with tolerance of a variety of functional groups can be selectively achieved.

Abstract

We report herein that thermodynamic and kinetic isomerization of alkenes can be accomplished by the combination of visible light with Co catalysis. Utilizing Xantphos as the ligand, the most stable isomers are obtained, while isomerizing terminal alkenes over one position can be selectively controlled by using DPEphos as the ligand. The presence of the donor–acceptor dye 4CzIPN accelerates the reaction further. Transformation of exocyclic alkenes into the corresponding endocyclic products could be efficiently realized by using 4CzIPN and Co(acac)₂ in the absence of any additional ligands. Spectroscopic and spectroelectrochemical investigations indicate Co^I being involved in the generation of a Co hydride, which subsequently adds to alkenes initiating the isomerization.

Mix and match: New protocols for controlled reduction of carboxamides to either alcohols or amines were established using a combination of sodium hydride (NaH) and zinc halides (ZnX₂). Use of a different halide on ZnX₂ dictates the selectivity, where the NaH‐ZnI₂ system delivers alcohols and NaH‐ZnCl₂ gives amines.

Abstract

New protocols for controlled reduction of carboxamides to either alcohols or amines were established using a combination of sodium hydride (NaH) and zinc halides (ZnX₂). Use of a different halide on ZnX₂ dictates the selectivity, wherein the NaH‐ZnI₂ system delivers alcohols and NaH‐ZnCl₂ gives amines. Extensive mechanistic studies by experimental and theoretical approaches imply that polymeric zinc hydride (ZnH₂)_∞ is responsible for alcohol formation, whereas dimeric zinc chloride hydride (H−Zn−Cl)₂ is the key species for the production of amines.

ChemBeads: Glass beads coated with solid chemical reagents (ChemBeads) were developed to enable the delivery of nanomolar quantities of solid chemical reagents efficiently. By exploring the concept of preferred screening sets, the flexibility and generality of this technology for high‐throughput reaction screening was validated.

Abstract

Technologies that enable rapid screening of diverse reaction conditions are of critical importance to methodology development and reaction optimization, especially when molecules of high complexity and scarcity are involved. The lack of a general solid dispensing method for chemical reagents on micro‐ and nanomole scale prevents the full utilization of reaction screening technologies. We herein report the development of a technology in which glass beads coated with solid chemical reagents (ChemBeads) enable the delivery of nanomole quantities of solid chemical reagents efficiently. By exploring the concept of preferred screening sets, the flexibility and generality of this technology for high‐throughput reaction screening was validated.

A radical approach: A photoelectrochemical method has been developed for the C−H alkylation of heteroarenes with organotrifluoroborates under oxidant‐free conditions. A variety of heteroarenes can be functionalized with primary, secondary, and tertiary alkyl groups with excellent regio‐ and chemoselectivity.

Abstract

A photoelectrochemical method for the C−H alkylation of heteroarenes with organotrifluoroborates has been developed. The merger of electrocatalysis and photoredox catalysis provides a chemical oxidant‐free approach for the generation and functionalization of alkyl radicals from organotrifluoroborates. A variety of heteroarenes were functionalized using primary, secondary, and tertiary alkyltrifluoroborates with excellent regio‐ and chemoselectivity.

Under control: Reactions that involve the addition of carbon‐centered radicals to basic heteroarenes, followed by formal hydrogen atom loss, have become widely known as Minisci‐type reactions. Whilst the original protocols for radical generation remain in active use today, they have been joined in recent years by a new array of radical generation strategies that allow use of a wider variety of radical precursors that often operate under milder conditions.

Abstract

Reactions that involve the addition of carbon‐centered radicals to basic heteroarenes, followed by formal hydrogen atom loss, have become widely known as Minisci‐type reactions. First developed into a useful synthetic tool in the late 1960s by Minisci, this reaction type has been in constant use over the last half century by chemists seeking to functionalize heterocycles in a rapid and direct manner, avoiding the need for de novo heterocycle synthesis. Whilst the originally developed protocols for radical generation remain in active use today, they have been joined in recent years by a new array of radical generation strategies that allow use of a wider variety of radical precursors that often operate under milder and more benign conditions. The recent surge of interest in new transformations based on free radical reactivity has meant that numerous choices are now available to a synthetic chemist looking to utilize a Minisci‐type reaction. Radical‐generation methods based on photoredox catalysis and electrochemistry have joined approaches which utilize thermal cleavage or the in situ generation of reactive radical precursors. This review will cover the remarkably large body of literature that has appeared on this topic over the last decade in an attempt to provide guidance to the synthetic chemist, as well as a perspective on both the challenges that have been overcome and those that still remain. As well as the logical classification of advances based on the nature of the radical precursor, with which most advances have been concerned, recent advances in control of various selectivity aspects associated with Minisci‐type reactions will also be discussed.

Kinetic studies of the reactions of enol esters with SelectFluor show that these occur through a polar two‐electron mechanism.

Abstract

The reaction of enol esters with SelectFluor is facile and leads to the corresponding α‐fluoroketones under mild conditions and, as a result, this route is commonly employed for the synthesis of medicinally important compounds such as fluorinated steroids. However, despite the use of this methodology in synthesis, the mechanism of this reaction and the influence of structure on reactivity are unclear. A rigorous mechanistic study of the fluorination of these substrates is presented, informed primarily by detailed and robust kinetic experiments. The results of this study implicate a polar two‐electron process via an oxygen‐stabilised carbenium species, rather than a single‐electron process involving radical intermediates. The structure–reactivity relationships revealed here will assist synthetic chemists in deploying this type of methodology in the syntheses of α‐fluoroketones.

Cage match: A nickel(II) pre‐catalyst featuring the new double cage PAd2‐DalPhos ancillary ligand enables the first examples of Ni‐catalyzed C−N cross‐couplings of primary five‐ or six‐membered ring heteroarylamines and (hetero)aryl chlorides with synthetically useful scope.

Abstract

Base‐metal catalysts capable of enabling the assembly of heteroatom‐dense molecules by cross‐coupling of primary heteroarylamines and (hetero)aryl chlorides, while sought‐after given the ubiquity of unsymmetrical di(hetero)arylamino fragments in pharmacophores, are unknown. Herein, we disclose the new “double cage” bisphosphine PAd2‐DalPhos (L2). The derived air‐stable Ni^II pre‐catalyst C2 functions well at low loadings in challenging test C−N cross‐couplings with established substrates, and facilitates the first Ni‐catalyzed C−N cross‐couplings of primary five‐ or six‐membered ring heteroarylamines and activated (hetero)aryl chlorides, with synthetically useful scope that is competitive with Pd catalysis.

Sweet conversions: A chemoenzymatic route to cyclic aminodiols is described, incorporating a regioselective dehydration of biomass‐derived sugars with subsequent amine formation using transaminases. The direct transamination of sugars was also established to give aminopolyols, exemplified for the first time by conversion of the ketose d‐fructose, into either diastereoisomer of the amine product with complete stereoselectivity and in high purity.

Abstract

Carbohydrates are the major component of biomass and have unique potential as a sustainable source of building blocks for chemicals, materials, and biofuels because of their low cost, ready availability, and stereochemical diversity. With a view to upgrading carbohydrates to access valuable nitrogen‐containing sugar‐like compounds such as aminopolyols, biocatalytic aminations using transaminase enzymes (TAms) have been investigated as a sustainable alternative to traditional synthetic strategies. Demonstrated here is the reaction of TAms with sugar‐derived tetrahydrofuran (THF) aldehydes, obtained from the regioselective dehydration of biomass‐derived sugars, to provide access to cyclic aminodiols in high yields. In a preliminary study we have also established the direct transamination of sugars to give acyclic aminopolyols. Notably, the reaction of the ketose d‐fructose proceeds with complete stereoselectivity to yield valuable aminosugars in high purity.

Kinetic studies of the reactions of enol esters with SelectFluor show that these occur through a polar two‐electron mechanism.

Abstract

The reaction of enol esters with SelectFluor is facile and leads to the corresponding α‐fluoroketones under mild conditions and, as a result, this route is commonly employed for the synthesis of medicinally important compounds such as fluorinated steroids. However, despite the use of this methodology in synthesis, the mechanism of this reaction and the influence of structure on reactivity are unclear. A rigorous mechanistic study of the fluorination of these substrates is presented, informed primarily by detailed and robust kinetic experiments. The results of this study implicate a polar two‐electron process via an oxygen‐stabilised carbenium species, rather than a single‐electron process involving radical intermediates. The structure–reactivity relationships revealed here will assist synthetic chemists in deploying this type of methodology in the syntheses of α‐fluoroketones.