Copper-Catalyzed Carbonylative Cross-Coupling of Alkyl Iodides and Amines

A general copper-catalyzed carbonylative cross-coupling between amines and alkyl iodides is reported. Using a simple combination of catalytic amounts of copper(I) chloride and N,N,N’,N”,N”-pentamethyldiethylenetriamine in the presence of sodium hydroxide under carbon monoxide pressure, a broad range of alkyl iodides and amines can be efficiently coupled to the corresponding amides that are obtained in good to excellent yields. Notable features of this process – the first one relying on a base metal catalyst – include the availability and low cost of the catalytic system, its successful use with primary, secondary, tertiary alkyl iodides and all classes of amines – with no or limited competing nucleophilic substitution without CO incorporation – as well as its efficiency with complex alkyl iodides and amines. Mechanistic studies demonstrated that a radical pathway is operative and the key role of CO.     

N-Cyanomethyl-β-chloroamines: a convenient source of aziridinium ions

N-Cyanomethyl-β-chloroamines smoothly react with a range of alcohols or amines to give regio- and stereoselectively 1,2-aminoethers or 1,2-diamines. The reaction proceeds through the formation of an intermediate aziridinium ion. The N-cyanomethyl group can then be cleaved easily.     

Synthesis of alpha-substituted allylic amines via a modified bruylants reaction

Silver tetrafluoroborate, used as an iminium ion promoter from alpha-amino nitriles, is an efficient additive in the Bruylants reaction involving vinylic Grignards. Improved yields of allylic amines were obtained when the starting alpha-amino nitrile was treated with this silver salt prior to its reaction with the vinylic Grignard. This improvement was not observed in the case of acetylenic Grignards. The reactivity of other vinyl organometallics (M = Zn, Li, Al, Cu, Si) was briefly examined.     

Beyond Friedel and Crafts: Directed Alkylation of C−H Bonds in Arenes

Alkylation of arenes is one of the most fundamental transformations in chemical synthesis and leads to privileged scaffolds in many areas of science. Classical methods for the introduction of alkyl groups to arenes are mostly based on the Friedel–Crafts reaction, radical additions, metalation, or prefunctionalization of the arene: these methods, however, suffer from limitations in scope, efficiency, and selectivity. Moreover, they are based on the innate reactivity of the starting arene, favoring the alkylation at a certain position and rendering the introduction of alkyl chains at other positions much more challenging. This can be addressed by the use of a directing group that facilitates, in the presence of a metal catalyst, the regioselective alkylation of a C?H bond. These directed alkylations of C?H bonds in arenes will be comprehensively summarized in this Review.     

Reaction of azetidines with chloroformates

The reaction of an azetidine with a chloroformate can give either the dealkylated heterocycle or the ring-opened product (gamma-chloroamine), which can further cyclize to the oxazinanone. A general study of this underrated reaction was conducted and revealed that azetidines can undergo smooth nucleophilic ring-opening reactions to highly functionalized gamma-chloroamines in the presence of a variety of alkyl chloroformates under mild reaction conditions. Yields are usually good, and parameters governing this reaction were evaluated. [reaction: see text].     

A general,versatile and divergent synthesis of selectively deuterated amines

Deuterated organic molecules are of utmost importance in many areas of science and have been recently intensively investigated in medicinal chemistry due to their enhanced metabolic stability. The development of efficient and broadly applicable methods for the selective incorporation of deuterium atoms into organic molecules from readily available starting materials and reagents is therefore of extreme importance. Such methods however often lack generality and selectivity, notably in the nitrogen series. With nitrogen-containing molecules being indeed ubiquitous in medicinal chemistry, there is a strong need for efficient methods enabling the selective synthesis of deuterated amines. In this perspective, we report herein a general, versatile, divergent and metal-free synthesis of amines selectively deuterated at their α and/or β positions. Upon simple treatment of readily available ynamides with a mixture of triflic acid and triethylsilane, either deuterated or not, a range of amines can be smoothly obtained with high levels of deuterium incorporation by a unique sequence involving a domino keteniminium/iminium activation.

A general, versatile, divergent and metal-free synthesis of amines selectively deuterated at their α and/or β positions and relying on a simple treatment of ynamides with triflic acid and triethylsilane, either deuterated or not, is reported.     

Transient Directing Groups in Metal−Organic Cooperative Catalysis

The direct functionalization of C−H bonds is among the most fundamental chemical transformations in organic synthesis. However, when the innate reactivity of the substrate cannot be utilized for the functionalization of a given single C−H bond, this selective C−H bond functionalization mostly relies on the use of directing groups that allow bringing the catalyst in close proximity to the C−H bond to be activated and these directing groups need to be installed before and cleaved after the transformation, which involves two additional undesired synthetic operations. These additional steps dramatically reduce the overall impact and the attractiveness of C−H bond functionalization techniques since classical approaches based on substrate pre-functionalization are sometimes still more straightforward and appealing. During the past decade, a different approach involving both the in situ installation and removal of the directing group, which can then often be used in a catalytic manner, has emerged: the transient directing group strategy. In addition to its innovative character, this strategy has brought C−H bond functionalization to an unprecedented level of usefulness and has enabled the development of remarkably efficient processes for the direct and selective introduction of functional groups onto both aromatic and aliphatic substrates. The processes unlocked by the development of these transient directing groups will be comprehensively overviewed in this review article.