Copper‐Catalyzed Trifluoromethylazidation of Alkynes: Efficient Access to CF₃‐Substituted Azirines and Aziridines

Abstract

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.

(Imidazol‐2‐yl)methyl‐1,3‐propanediones: Regioselective C–H Functionalization of the Imidazole Ring by Acylacetylene/Aldehyde Pairs

“…Examples include the gold-catalyzed annulation of nitroalkynes with indoles, [9] iridium-photocatalyst-promoted decarboxylative alkynylation of carboxylic acids, [10] gold-catalyzed rearrangement of O-propargylic formaldoximes, [11] iron-assisted cycloaddition reaction of diynes with phosphaalkynes, [12] gold-catalyzed cyclization of 2-alkynyl-N-propargylanilines, [13] alkyne oxidation/C-H functionalization under the action of Zn(OTf ) 2 , [14] rhodium-catalyzed cycloadditions of alkynes with cyclopropylideneacetamides, [15] sunlightdriven decarboxylative alkynylation of α-keto acids with bromoacetylenes, [16] copper-initiated trifluoromethylazidation of alkynes, [17] synthesis of chiral allenoates through the asymmetric C-H insertion of α-diazo esters into terminal alkynes with the help of copper compounds, [18] and Pd-catalyzed cross-coupling of terminal alkynes with ene-yne-ketones. Examples include the gold-catalyzed annulation of nitroalkynes with indoles, [9] iridium-photocatalyst-promoted decarboxylative alkynylation of carboxylic acids, [10] gold-catalyzed rearrangement of O-propargylic formaldoximes, [11] iron-assisted cycloaddition reaction of diynes with phosphaalkynes, [12] gold-catalyzed cyclization of 2-alkynyl-N-propargylanilines, [13] alkyne oxidation/C-H functionalization under the action of Zn(OTf ) 2 , [14] rhodium-catalyzed cycloadditions of alkynes with cyclopropylideneacetamides, [15] sunlightdriven decarboxylative alkynylation of α-keto acids with bromoacetylenes, [16] copper-initiated trifluoromethylazidation of alkynes, [17] synthesis of chiral allenoates through the asymmetric C-H insertion of α-diazo esters into terminal alkynes with the help of copper compounds, [18] and Pd-catalyzed cross-coupling of terminal alkynes with ene-yne-ketones.…”

Telescoped, Divergent, Chemoselective C1 and C1‐C1 Homologation of Imine Surrogates: Access to Quaternary Chloro‐ and Halomethyl‐Trifluoromethyl Aziridines

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Ac onceptually novel, high-yielding,m ono-or bishomologation was realized with lithium halocarbenoids and enables the one-step,fully chemocontrolled assembly of anew class of quaternary trifluoromethyl aziridines.T rifluoroacetimidoyl chlorides (TFAICs) act as convenient electrophilic platforms,e nabling the addition of either one or two homologating elements by simply controlling the stoichiometry of the process.M echanistic studies highlighted that the homologation event, carried out with two different carbenoids (LiCH 2 Cl and LiCH 2 F), leads to fluoromethyl analogues in which the first nucleophile is employed for constructing the cycle and the second for decorating the resulting molecular architecture.The constitutive presence of at rifluoromethyl group (CF 3 ) within an organic framework deeply modulates its physicochemical properties,t hus rendering the scaffold ah ighly valuable entity across the chemical sciences. [1] Incorporating such af unctionality within at hree-membered nitrogen cycle would result in unique motifs (CF 3 -aziridines) [2] featuring interesting reactivity,s ynthetic versatility,a nd pharmacological properties determined by the interaction of this lipophilic core with biological targets.T his innate potential is reflected in intensive efforts towards the development of efficient tactics for preparing CF 3 -aziridines.I n2 015 Liu developed at wo-step Cu-catalyzed trifluoromethylazidationo fa lkynes followed by the addition of nucleophiles to the intermediate azirines (Scheme 1a), [3] while Stirling and Novµkdisclosed in 2018 the metal-free alkenylation/cyclization of amines with trifluoroalkenyl iodonium salts (Scheme 1b). [4] Each of these strategies leads to structurally different motifs,though in both cases tertiary CF 3 -bearing carbon atoms are obtained, presenting well-defined relative placement of substituents:Lius work delivers a-aryl-a-substituted-trifluoromethylaziridines, whereas the Stirling-Novµkp rotocol delivers unsubstituted trifluoromethylaziridines.Historically,t he conceptual simplicity of ring-closure operations (3-exo-tet)onformal b-substituted CF 3 -containing amine derivatives emerged as avaluable tool for accessing the targeted scaffolds (Scheme 1c).

…”

“…The constitutive presence of at rifluoromethyl group (CF 3 ) within an organic framework deeply modulates its physicochemical properties,t hus rendering the scaffold ah ighly valuable entity across the chemical sciences. [1] Incorporating such af unctionality within at hree-membered nitrogen cycle would result in unique motifs (CF 3 -aziridines) [2] featuring interesting reactivity,s ynthetic versatility,a nd pharmacological properties determined by the interaction of this lipophilic core with biological targets.T his innate potential is reflected in intensive efforts towards the development of efficient tactics for preparing CF 3 -aziridines.I n2 015 Liu developed at wo-step Cu-catalyzed trifluoromethylazidationo fa lkynes followed by the addition of nucleophiles to the intermediate azirines (Scheme 1a), [3] while Stirling and Novµkdisclosed in 2018 the metal-free alkenylation/cyclization of amines with trifluoroalkenyl iodonium salts (Scheme 1b). [4] Each of these strategies leads to structurally different motifs,though in both cases tertiary CF 3 -bearing carbon atoms are obtained, presenting well-defined relative placement of substituents:Lius work delivers a-aryl-a-substituted-trifluoromethylaziridines, whereas the Stirling-Novµkp rotocol delivers unsubstituted trifluoromethylaziridines.…”

“…TFAICs reacted extremely well, independent of either the electronic or steric properties of the substituents (Scheme 3). Accordingly,a ll halogens (3,(24)(25)(26)(27), including the reactive iodine (28)o rt he trifluoromethyl group (29 and 30), furnished the bis-homologated adducts in high yields after short reaction times.C hloromethyllithium proved to be highly selective,a s observed in the cases of nitriles,r egardless their relative position (31-33), and an ester (34). This selectivity is quite noteworthy since these functionalities are known to be highly susceptible to attack by carbanions.Embodying hydrocarbon functionalities such as aryl (35, 37,and 38)oraliphatic groups (39-41)d oes not alter the efficiency,i ncluding ac ase of significant steric hindrance (42).…”

Catalytic Enantioselective Aza‐Benzoin Reactions of Aldehydes with 2H‐Azirines

“…[9d] While pioneering works are influential, practical applications of these protocols are always affected by their scope,t oacertain extent. [10] And also,t he model of stereocontrol for the assembly of chiral aziridine derivatives is still in its infancy. Therefore,n ew and efficient synthetic strategies are needed to complement existing protocols.…”