Catalytic Cycloisomerization–Fluorination Sequence of N‐Propargyl Amides by Iodoarene/HF⋅Pyridine/Selectfluor Systems

Abstract

As af irst example of metal-free and catalytic fluorinative transformationsofalkynes, we developed acycloisomerization-fluorination sequence of N-propargyl amides catalyzed by an iodine(III) species. The iodine(III) catalyst is in situ generated from iodoarene as aprecatalyst with Selectfluor as af luorinating oxidant in the presence of HF·pyridine.Fluorines ubstituents show am arked improvemento fp roperties, such as solubility,b ioavailability, and metabolic stability, in many examples of introducing fluorine into pharmaceuticals and bioactive substances. [1] Accordingly,e fficient introduction methods of fluorine into organic compounds have received much attention recently. [2] Amongt hem,t he combination of cyclization and fluorination reaction in as ingle operation provides highly efficient approaches to give fluorinated heterocycles from unsaturated compounds bearing ah eteroatom nucleophile. For the synthesis of fluorinated aliphatic heterocycles, variousm etal-catalyzed intramolecular aminofluorination [3] and oxyfluorinationr eactions [4] of alkenes [5] or their metal-free methods [6,7] have been developed. In contrastt ot he reactions of alkenes, the cycloisomerization-fluorination sequence of alkynes has been less studied. [8,9] Althoughg old catalysts with Selectfluor have been well employed for this sequence, the catalytic systemsw ere not effective on that of N-propargyl amides (see the Supporting Information). Also, to the best of our knowledge, metal-free methods for such sequence have not been achievedy et. Moreover,b ecause halocyclization reactions of N-propargyl amides by general halogenating reagents hardly bring about aromatization to halogenated oxazoles, [10] one-pot two-step methods, including metal catalysis for the synthesis of halogenated oxazoles, have been developed by Hashmi's and other groups(Scheme 1a). [10b,c, 11] One the other hand, as part of our studies on the metal-free synthesis of aromatic heterocyclest hrough the activation of alkynes by hypervalent iodine(III) reagents, [12] we have recently found the cycloisomerization-acetoxylation sequence of Npropargyl amides with PhI(OAc) 2 (PIDA) (Scheme 1b). [12a] This reaction, which can afford oxazoles bearing the acetoxyg roup in as ingleo peration, inspired us to examine the formation of fluorinated oxazoles. Herein, ametal-free and catalytic cycloisomerization-fluorinations equence of N-propargyl amides mediated by iodine(III) is described (Scheme 1c).In recent years, there has been ac onsiderable growth in the application of hypervalent iodine reagents to organic syntheses due to their low toxicity and transition-metal-like reactivities, such as an activation of unsaturated bonds, reductive elimination, and ligand exchange. [13] Particularly,( difluoroiodo)arenes (ArIF 2 )c an be used in fluorinative transformations of unsaturated compounds withouta ny metal catalysts. [14] These procedures have been extended to some metal-free cycloisomerization-fluorinationr eactions of alkenes. [15] For example, Hara et al. repo...

Fluorohydration of alkynes via I(I)/I(III) catalysis

“…Although the origin of this specificity requires clarification, this fluorohydration reaction constitutes a rare case of substrate specificity in small-molecule catalysis. It is envisaged that this organocatalytic variant of the venerable Kucherov reaction will find application in contemporary organofluorine chemistry [ 61 ] and contributes to the current interest in alkyne functionalisation via I(I)/I(III) catalysis [ 62 – 63 ].…”

Iodoarene-catalyzed cyclizations of N-propargylamides and β-amidoketones: synthesis of 2-oxazolines

“…Several related processes that operate under milder conditions have been reported in recent years but they suffer from issues such as limited substrate scope or the requirement for expensive reagents or transition metal salts [24–29]. Saito and co-workers have reported the cyclization of propargylamides to form oxazoles rather than oxazolines under stoichiometric and, more recently, catalytic hypervalent iodine conditions [30–31]. Various other methods for the cyclization of unsaturated amides have been reported [32–36].…”

Metal-free syntheses of oxazoles and their analogues based on λ3-iodane-mediated cycloisomerization/functionalization reactions or [2+2+1] cycloaddition type reactions

“…10 This catalytic systems were relatively effective on the reactions of aromatic amides bearing electron-withdrawing groups such as nitro and cyano groups and no substituted 1a giving rise to fluorinated oxazoles 7k-m and 7a in 49-76% yields, albeit no formation of MeO derivative 7d. Surprisingly, although the facile preparation of ArIF2 from and Selectfluor has been established by Shreeve et al in 2005, 33 this procedure has been not applied to the iodine(III)-catalysis until 2015.…”

“…5 As a part of our study on the synthesis of heterocycles from propargyl compounds, 6,7 we have developed the λ 3 -iodane-mediated oxidative cycloisomerization of N-propargyl amides for the preparation of oxazoles bearing oxygen functional group at their side chains (Section 2.1). 8 Furthermore, this metal-free oxidative cycloisomerization approaches have been extended to the divergent synthesis of furfuryl alcohols and furfurals (Section 2.2) 9 or catalytic synthesis of fluorinated oxazoles (Section 2.3) 10 as well as [2+2+1] cycloaddition type reactions of alkynes, nitriles and heteroatoms (Section 3). 11,12 The detailed synthetic and mechanistic study of these reactions will be discussed in the following sections.…”