A Ni-catalyzed Negishi cross-coupling with 1,1-disubstituted styrenyl aziridines has been developed. This method delivers valuable β-substituted phenethylamines via a challenging reductive ...elimination that affords a quaternary carbon. A novel electron-deficient olefin ligand, Fro-DO, proved crucial for achieving high rates and chemoselectivity for C–C bond formation over β-H elimination. This ligand is easy to access, is stable, and presents a modular framework for reaction discovery and optimization. We expect that these attributes, combined with the fact that the ligands impart distinct electronic properties to a metal, will support the invention of new transformations not previously possible using established ligands.
The first direct aziridination of triaryl‐substituted alkenes was achieved by means of an electrochemical process that could extend to multisubstituted styrenes. Specifically, hexafluoroisopropanol ...sulfamate was used as a nucleophilic nitrogen source. Mechanistic experiments suggest that this electrochemical process proceeds by stepwise formation of two C−N bonds through reactions between cationic carbon species and the sulfamate.
Az is: An electrochemical aziridination of triaryl ethylene was achieved by an alkene activation pathway with sulfamate as a nitrogen source. Two stepwise electron transfers were key to the construction of C−N bonds from congested and conjugation‐stabilized alkenes. With this approach, tri‐ and tetrasubstituted styrenes were also converted into the corresponding aziridines.
The development of new chemical transformations based on catalytic functionalization of unactivated C-H bonds has the potential to simplify the synthesis of complex molecules dramatically. Transition ...metal catalysis has emerged as a powerful tool with which to convert these unreactive bonds into carbon-carbon and carbon-heteroatom bonds, but the selective transformation of aliphatic C-H bonds is still a challenge. The most successful approaches involve a 'directing group', which positions the metal catalyst near a particular C-H bond, so that the C-H functionalization step occurs via cyclometallation. Most directed aliphatic C-H activation processes proceed through a five-membered-ring cyclometallated intermediate. Considering the number of new reactions that have arisen from such intermediates, it seems likely that identification of distinct cyclometallation pathways would lead to the development of other useful chemical transformations. Here we report a palladium-catalysed C-H bond activation mode that proceeds through a four-membered-ring cyclopalladation pathway. The chemistry described here leads to the selective transformation of a methyl group that is adjacent to an unprotected secondary amine into a synthetically versatile nitrogen heterocycle. The scope of this previously unknown bond disconnection is highlighted through the development of C-H amination and carbonylation processes, leading to the synthesis of aziridines and β-lactams (respectively), and is suggestive of a generic C-H functionalization platform that could simplify the synthesis of aliphatic secondary amines, a class of small molecules that are particularly important features of many pharmaceutical agents.
This Minireview describes recent advances toward the synthesis of fluoro‐, monofluoromethyl‐, difluoromethyl‐, and trifluoromethyl‐substituted three‐membered rings such as cyclopropanes, aziridines, ...epoxides, episulfides, cyclopropenes, and 2 H‐azirines. The main synthetic methodologies since 2016 for cyclopropanes and since 2010 for the other three‐membered rings are reported.
Better with three: Fluorinated three‐membered rings are valuable compounds with many applications. In this Minireview, the synthesis of fluoro‐, monofluoromethyl‐, difluoromethyl‐, and trifluoromethyl‐substituted cyclopropanes, cyclopropenes, aziridines, azirines, epoxides, and thiiranes over the past decade are described.
Benzastatins have unique structures probably derived from geranylated p-aminobenzoic acids. The indoline and tetrahydroquinoline scaffolds are presumably formed by cyclization of the geranyl moiety, ...but the cyclization mechanism was unknown. We studied the benzastatin biosynthetic gene cluster of Streptomyces sp. RI18; functions of the six enzymes encoded by it were analyzed by gene disruption in a heterologous host and in vitro enzyme assays. We propose the biosynthetic pathway for benzastatins in which a cytochrome P450 (BezE) is responsible for the cyclization of geranylated p-acetoxyaminobenzoic acids; BezE catalyzes elimination of acetic acid to form an iron nitrenoid, nitrene transfer to form an aziridine ring, and nucleophilic addition of hydroxide ion to C-10 and chloride ion to C-9 to generate the indoline and tetrahydroquinoline scaffolds, respectively. Discovery of this enzyme, which should be termed cytochrome P450 nitrene transferase, provides an important insight into the functional diversity of cytochrome P450.
An ideal system for stimuli-responsive and amphiphilic (block) polymers would be the copolymerization of aziridines with epoxides. However, to date, no copolymerization of these two highly strained ...three-membered heterocycles had been achieved. Herein, we report the combination of the living oxy- and azaanionic ring-opening polymerization of ethylene oxide (EO) and sulfonamide-activated aziridines. In a single step, well-defined amphiphilic block copolymers are obtained by a one-pot copolymerization. Real-time 1H NMR spectroscopy revealed the highest difference in reactivity ratios ever reported for an anionic copolymerization (with r 1 = 265 and r 2 = 0.004 for 2-methyl-N-tosylaziridine/EO and r 1 = 151 and r 2 = 0.013 for 2-methyl-N-mesylaziridine/EO), leading to the formation of block copolymers with monomodal and moderate molecular weight distributions (M w/M n mostly ≤1.3). The amphiphilic diblock copolymers were used to stabilize emulsions and to prepare polymeric nanoparticles by miniemulsion polymerization, representing a novel class of nonionic and responsive surfactants. In addition, this unique comonomer reactivity of activated-Az/EO allows fast access to multiblock copolymers, and we prepared the first amphiphilic penta- or tetrablock copolymers containing aziridines in only one or two steps, respectively. These examples render the combination of epoxide and aziridine copolymerizations via a powerful strategy for producing sophisticated macromolecular architectures and nanostructures.
Silver(I) promotes the highly chemoselective N-amidation of tertiary amines under catalytic conditions to form aminimides by nitrene transfer from PhINTs. Remarkably, this transformation proceeds ...in a selective manner in the presence of olefins and other functional groups without formation of the commonly observed aziridines or C–H insertion products. The methodology can be applied not only to rather simple tertiary amines but also to complex natural molecules such as brucine or quinine, where the products derived from N–N bond formation were exclusively formed. Theoretical mechanistic studies have shown that this selective N-amidation reaction proceeds through triplet silver nitrenes.
A highly easy and efficient metal-free methodology for the synthesis of polyaziridine-based polymers with controlled architectures and desired functionalities was developed by organocatalytic ...ring-opening polymerization (ROP) of N-sulfonyl aziridines with a carboxylic acid as initiator. 1,5,7-Triazabicyclo4.4.0dec-5-ene (MTBD) and phosphazene t-Bu-P4 organocatalysts have demonstrated high catalytic efficiency in connection with the controlled/living character of the ROP of 2-methyl-N-tosylaziridines (TsMAz) initiated by benzoic acid. Aryl carboxylic acids bearing an azido or a hydroxyl group as well as bio-derived vanillic acid and syringic acid and alkyl- and alkenyl-substituted carboxylic acids, such as acetic acid, palmitic acid, and methacrylic acid, can all initiate the ROP of TsMAz toward well-defined P(TsMAz)s. α,ω-Diamino telechelic, star-shaped P(TsMAz)s, and poly(styrene-co-methacrylic acid)-graft-poly(2-methyl-N-tosylaziridine) P(St-co-MAA)-g-P(TsMAz) have been conveniently synthesized from the corresponding multicarboxyl (macro)initiators. Finally, this protocol has been applied for the synthesis of a linear photoresponsive P(TsMAz) and an aggregation-induced emission (AIE)-active 4-arm P(TsMAz) star from the corresponding functionalized carboxylic acids.
Competitive copolymerization gives access to gradient copolymers with simple one-step and one-pot strategies. Due to the living nature of the sulfonyl-aziridine polymerization, gradient copolymers ...can be obtained with low dispersities and adjustable molar masses. The combination of different sulfonyl activating groups allowed to fine-tune the reactivity difference of the comonomers and thus an exact adjustment of the gradient strength. Sulfonyl-activated aziridines are to date the only monomer class providing access to gradient copolymers with reactivity ratios ranging from (1 ≤ r 1 ≤ 2; 1 ≥ r 2 ≥ 0.5) for statistical or soft gradient copolymers to block copolymers (r 1 ≥ 20, r 2 ≤ 0.02), only by adjusting the electron-withdrawing effect of the activation groups: the reactivity ratios were calculated by different models for a library of eight comonomers. This library was further used to classify between hard, medium, and soft gradients. From the data obtained from the monomer library, it was possible to predict polymerization rate coefficients (k p) for aziridines, which were not prepared so far: correlation of the shifts in the 13C NMR spectra, the Hammett parameters and secondary parameters such as calculated lowest unoccupied molecular orbital (LUMO) levels of the monomers and the natural charge at the electrophilic carbon, etc., were used to predict (co)monomer reactivity and the resulting gradient strength. We believe that our findings allow us to access tailored gradient copolymers with a controlled monomer sequence distribution depending on the chemical control of comonomer reactivity. With these systematic data on activated aziridines, also more complex copolymer structures can be predicted and prepared. Such materials might find application as linear polyethylenimine derivatives to act as functional polyelectrolytes, or predesigned compatibilizers and surface-active gradient copolymers by a predictable one-step copolymerization.
A novel method for convenient access to CF3‐containing azirines has been developed, and involves a copper‐catalyzed trifluoromethylazidation of alkynes and a photocatalyzed rearrangement. Both ...terminal and internal alkynes are compatible with the mild reaction conditions, thus delivering the CF3‐containing azirines in moderate to good yields. The azirines can be converted into various CF3‐substituted aziridines.
Az is: A novel method for convenient access to CF3‐containing azirines has been developed, and involves a copper‐catalyzed trifluoromethylazidation of alkynes and a photocatalyzed rearrangement. Both terminal and internal alkynes are compatible with this reaction and deliver azirines in moderate to good yields. The azirines can be further converted into various CF3‐substituted aziridines. TMS=trimethylsilyl.
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