Efficient Copper Catalyzed Multi-component Synthesis of N-acyl amidines via Acyl Nitrenes

Abstract

Direct synthetic routes to amidines are desired, as they are widely present in many biologically active compounds and organometallic complexes. N-Acyl amidines in particular can be used as a starting material for the synthesis of heterocycles and have several other applications. Here, we describe a fast and practical copper catalyzed 3-component reaction of aryl acetylenes, amines and easily accessible 1,4,2-dioxazol-5-ones to N-acyl amidines, generating CO<sub>2</sub> as the only by-product. Transformation of the dioxazolones on the Cu-catalyst generates acyl nitrenes that rapidly insert into the copper acetylide Cu-C bond rather than undergoing an undesired Curtius rearrangement. For non-aromatic dioxazolones, [Cu(OAc)(Xantphos)] is a superior catalyst for this transformation, leading to full substrate conversion within 10 minutes. For the direct synthesis of N-benzoyl amidine derivatives from aromatic dioxazolones, [Cu(OAc)(Xantphos)] proved to be inactive, but moderate to good yields were obtained when using simple CuI as the catalyst. Mechanistic studies revealed the aerobic instability of one of the intermediates at low catalyst loadings, but the reaction could still be performed in air for most substrates when using catalyst loadings of 5 mol%. The herein reported procedure does not only provide a new, practical and direct route to N-acyl amidines, but also represents a new type of<br>C-N bond formation.

Experiments and DFT Computations Combine to Decipher Fe-Catalyzed Amidine Synthesis through Nitrene Transfer and Nitrile Insertion

“…3 Moreover, recent work has shown that intermingling them to experimental investigations is a very powerful approach. 4,5 In the present work, we have used this approach to try to understand the mechanism of formation of amidines through a multicomponent reaction associating a hydrocarbon, a nitrile and an amine delivered as a nitrene.…”

“…7,8 As a matter of fact, 2 the amidine function allows to form strong ionic or H-bond interactions or to chelate transition metals which has led to its inclusion in many enzyme substrates or inhibitors. 9,10 This strong interest motivates continuous efforts to design new synthetic routes to a large panel of amidine derivatives, especially sulfonyl- [11][12][13][14] and acyl- 5,15 amidines. Amidine syntheses have been devised from many functional groups (amides and thioamides, isonitriles) 16 but more generally amidines are accessible from condensation of primary amines with electrondeficient nitriles 16,17 (or acetals).…”

“…18,19 In the past fifteen years, several metal-catalyzed multicomponent reactions have been reported to produce amidines efficiently from a hydrocarbon, an amine and a nitrogen reagent which is often a nitrene precursor. 5,[11][12][13]15,[20][21][22][23][24] As a typical example, when an alkyne was reacted with a secondary amine and an organic azide in presence of a Cu I (or Ag I ) salt, a triazolyl copper species was proposed to be the key intermediate in the coupling of the nitrene to the alkyne after liberation of N 2 . [11][12][13]21 Very recently, a similar reaction was developed by Van Vliet et al using as nitrene precursors 1,4,2-dioxazol-5-ones which liberate CO 2 when forming an acylnitrene, and the mechanism of the reaction was investigated by 31 P NMR and DFT calculations.…”

“…[11][12][13]21 Very recently, a similar reaction was developed by Van Vliet et al using as nitrene precursors 1,4,2-dioxazol-5-ones which liberate CO 2 when forming an acylnitrene, and the mechanism of the reaction was investigated by 31 P NMR and DFT calculations. 5 Intriguingly, nitriles were used scarcely in these multicomponent processes: reaction with phenyl diazonium produces the highly electrophilic nitrilium cation which can be trapped by a sulfonamide. 20 In this respect, it must be noted that the catalytic formation of amidines from nitriles by a totally different synthetic method has been reported in a limited number of cases.…”

Copper(I)-Mediated Decarboxylative N-Arylation of Dioxazolones: Synthesis of N-Aryl Amides

“…In 2019, a copper(I)-catalyzed synthesis of N -acyl amidines using dioxazolones was unveiled by de Bruin and co-workers (Scheme 2 ). 17 The reaction protocol initially resulted in an N -acyl copper nitrene intermediate that inserted into a [Cu]–C(sp) bond with subsequent formation of an N -allenyl amide after protodemetalation. The target N -acyl amidines were finally formed after the addition of an amine.…”