Mild Transition-Metal-Free Amination of Fluoroarenes Catalyzed by Fluoride Ions

Dehe, Daniel; Munstein, Isabel; Reis, Andreas; Thiel, Werner R.

doi:10.1021/jo102063s

Cited by 33 publications

(12 citation statements)

References 81 publications

(40 reference statements)

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“…The procedure is based on the reaction of readily available N-trimethylsilylamines with acid fluorides in the presence of catalytic fluoride ion. Formally, the fluoride ion reacts with the silylated amine to form a 'hypervalent' silicon species, 4 which readily decomposes to produce volatile TMSF and an amine anion intermediate, which is higher in energy and more nucleophilic/reactive than the corresponding free amine. Although often stable to water, and less reactive than acid chlorides toward alcohols, acid fluorides react efficiently with amines to give the expected amide products.…”

Section: Syn Thesismentioning

confidence: 99%

A Trimethylsilylamine-Acyl Fluoride Amide Bond Forming Protocol for Weakly Nucleophilic Amines that is Amenable to the Parallel Synthesis of Di(hetero)arylamides

Zamiri

Grierson

2016

Synthesis

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The reaction of a 2-pyridinone-based acid fluoride with the N-TMS derivatives of different weakly nucleophilic heteroaryl/arylamines in acetonitrile containing catalytic fluoride ion provides a clean, efficient and simple means to access a diverse range of polar di(hetero)arylamide structures. This amide bond forming protocol is readily amenable to the parallel synthesis of compound libraries.Key words amide coupling, di(hetero)arylamide, acid fluoride, heteroarylamine, N-TMS activation, parallel synthesisThe screening of compound libraries has repeatedly demonstrated its effectiveness as a research tool in drug discovery. In particular, when mechanistic and/or structural details for the therapeutic target are lacking, compound library screening is one of very few options possible to identify new and/or groundbreaking avenues for drug development. In our laboratory, parallel synthesis is used to connect and functionalize novel scaffolds into libraries of bioactive molecules containing different architectures. In particular, amide bond formation was used to generate molecules that possess a di(hetero)arylamide (DHA) substructure. The screening of a 256-membered library containing 119 DHA compounds identified four novel and related molecules 1-4 (Figure 1) that block HIV-1 replication by a mechanism involving perturbation of the alternative splicing events leading to production of key HIV regulatory proteins. 1a,b For the construction of the amide bond, a wide range of peptide (amide) bond forming reagents and conditions are available. 2 However, in our library project, where electrondeficient (weakly nucleophilic) heterocyclic amines were engaged, 3 the yield of the DHA product in reactions using the acid chloride method and different peptide coupling reagents rarely exceeded 10-30%. In fact, the formation of complex mixtures of polar compounds was generally observed, complicating workup and isolation/purification of the desired product. To advance the anti-HIV project, and other applications for the DHA library, it became important to develop a new amide synthesis protocol.

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Section: Syn Thesismentioning

confidence: 99%

A Trimethylsilylamine-Acyl Fluoride Amide Bond Forming Protocol for Weakly Nucleophilic Amines that is Amenable to the Parallel Synthesis of Di(hetero)arylamides

Zamiri

Grierson

2016

Synthesis

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“…1 ). In contrast, halogenated benzoic acid derivatives are easily functionalized through cross-coupling [ 4 – 5 ] or nucleophilic aromatic substitution reactions (S N Ar) [ 6 – 7 ]. Benzoic acids (e.g., 2 ) are relatively weak acids, even with highly electron-withdrawing substituents on the aromatic core [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and stability of strongly acidic benzamide derivatives

Diness¹,

Bjerrum²,

Begtrup³

2018

Beilstein J. Org. Chem.

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Reactivity studies of strong organic acids based on the replacement of one or both of the oxygens in benzoic acids with the trifluoromethanesulfonamide group are reported. Novel derivatives of these types of acids were synthesized in good yields. The generated N-triflylbenzamides were further functionalized through cross-coupling and nucleophilic aromatic substitution reactions. All compounds were stable in dilute aqueous solutions. Studies of stability under acidic and basic conditions are also reported.

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“…22 A theoretical study, using DFT methods, has used the relative stabilities of isomeric σ -adduct intermediates to predict regioselectivity patterns in the substitution of polyfluoroaromatics. 26 The catalysis by transition metals of cross-coupling reactions of polyfluoroarenes has been reviewed. 24 The regioselectivity of reaction of substituted pentafluorobenzenes by 1,2,3-benzotriazole has been shown to depend on the nature of the substituent, the base used, and also on the solvent, toluene or acetonitrile.…”

mentioning

confidence: 99%

“…There have been reviews of couplings catalysed by palladium 70 and by palladium in combination with copper. 74 Using palladium catalysis, arenes substituted with a 2-pyridylsulfinyl group have been shown to react with alkenes at the ortho positions which may lead to disubstituted products such as (26). 73 It has been shown that using a palladium-N-heterocyclic carbene catalyst, the reaction of aryl halides with Michael acceptors may result either in conjugate addition or Heck substitution, depending on the base used.…”

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confidence: 99%

“…75 The ortho allylation of aryl and heteroaryl sulfoxides may be achieved, in metal-free conditions, by reaction with microwave heating with allyl silanes and triflic anhydride. Various steps including oxidative addition of the aryl 26) iodide to the catalyst, reaction with the acetylene, and reductive elimination to give the product were identified with elimination likely to be rate limiting. 77 There have been studies of the palladium-catalysed reactions of aryl halides with indium homoenolates to yield β-aryl ketones, 78 and of aryl halides ee with water-tolerant alkyl indium reagents to give alkylated arenes.…”

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confidence: 99%

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