Reactions and uses of alkynyliodonium salts

Polycoordinated iodine(III) chemistry has experienced a renaissance in the last decade, largely due to the ready availability of alkynyliodonium and the related alkenyliodonium species. Moreover, the carbon-carbon triple bond is one of the oldest, simplest and most useful functional groups in organic chemistry. Besides the common hydrocarbon acetylenes, a large variety of functionalized alkynes are known and play an important role in numerous organic 

---

With the discovery and use of alkynyliodonium salts, a new class of electrophilic alkynylation reagents has emerged. Because of their impressive reactivity, they could be broadly used to introduce acetylenes on carbon nucleophiles, heteroatoms, or metals. Nevertheless, with the exceptions of the alkynylation of nitrogen and new applications in the synthesis of alkynyl-metal complexes, most research on alkynyliodonium salts has been concentrated in the years 1985-1995, with rare more recent breakthroughs. In particular, very few applications using modem catalytic methods have appeared, in stark contrast to the use of aryhodonium salts in arylation reactions [99]. One of the possible reasons for this drying out of the field is the relatively low stability of alkynyliodonium salts, which often makes their use challenging. 

Reactions of alkynyliodonium salts 119 with nucleophiles proceed via an addition-elimination mechanism involving alkylidenecarbenes 120 as key intermediates. Depending on the structure of the alkynyliodonium salt, specific reaction conditions, and the nucleophile employed, this process can lead to a substituted alkyne 121 due to the carbene rearrangement, or to a cyclic product 122 via intramolecular 1,5-carbene insertion (Scheme 50). Both of these reaction pathways have been widely utilized as a synthetic tool for the formation of new C-C bonds. In addition, the transition metal mediated cross-coupling reactions of alkynyliodonium salts are increasingly used in organic synthesis. 

The initial conceptualization of the agelastatin A problem took on the form shown below (Scheme 5).17 The key transform in this sequence features intramolecular addition of an amide-derived anion to a tethered alkynyliodonium salt within 33. The alkylidenecarbene generated from this nucleophilic addition, 32, then has a choice of two diastereotopic C-H bonds (Ha or Hb) for 1,5 insertion. Reaction with Ha would provide an advanced intermediate 31 en route to the target 28. Successful execution of this plan would extend alkynyliodonium salt chemistry in three new directions (1) use of an amine derivative as a nucleophile, (2) intramolecularity in the nucleophile addition step, and (3) diastereoselectivity upon alkylidenecarbene C-H insertion. At the initiation of this project, a lack of precedent on any of these topics suggested that focused scouting experiments to assess feasibility would be prudent before beginning work towards the natural product itself. 

The pareitropone project began quite by accident after an unexpected observation expanded our thinking about potentially accessible targets for alkynyliodonium salt/alkylidenecarbene chemistry (Scheme 18). Treatment of the tosylamide iodonium salt 125 with base under standard conditions was designed to provide no more than routine confirmation of the aryl C-H insertion capabilities, which were first exposed in indoleforming reactions using tosylanilide anion nucleophiles and propynyl(phenyl)iodonium triflate,5b of the intermediate carbene 126. However, this substrate did not perform as expected, since only trace amounts of the 1,5 C-H insertion product 127 was detected. One major product was formed, and analysis of its spectral data provided yet another surprising lesson in alkynyliodonium salt chemistry for us. The data was only consistent with the unusual cycloheptatriene structure 129. 

The use of hypervalent iodine reagents in carbon-carbon bond forming reactions is summarized with particular emphasis on applications in organic synthesis. The most important recent methods involve the radical decarboxylative alkylation of organic substrates with [bis(acyloxy)iodo]arenes, spirocyclization of para- and ortho-substituted phenols, the intramolecular oxidative coupling of phenol ethers, and the reactions of iodonium salts and ylides. A significant recent research activity is centered in the area of the transition metal-mediated coupling reactions of the alkenyl-, aryl-, and alkynyliodonium salts. 

The predominant formation of five-membered carbocydes or heterocycles 122 (Scheme 50) via a sequential conjugate addition-carbene insertion pathway is generally observed in the reactions of the appropriate alkynyliodonium salts 119 (R = long alkyl chain or other group with C-H bond available at C5) with various relatively hard nucleophiles. Typical nucleophiles used to initiate these selective cyclizations are enolate, azide, sulfinate, tosylamide, thioamide and some other anions. 

Cyclopentannelated tetrahydrofurans 169 [129] and substituted dihydro-furans 171 [130] can be synthesized by the treatment of functionalized al-kynyliodonium salts 168 and 170 with the appropriate nucleophile (Scheme 64). Alkynyliodonium salts 168 and 170, the key precursors in these reactions, are conveniently prepared from the appropriate alkynylstannanes and can be used without additional purification. 

Anions of secondary-sulfonamides, especially N-substituted tosylamidate ions, have emerged as premier partners for C-N bond forming reactions with alkynyliodonium salts. To a much lesser extent secondary-carboxamidate ions have also been used for this purpose. For example, the sequential treatment of -substituted tosylamides with n-butyllithium and phenyl(trimethylsi-lylethynyl)iodonium triflate (26) affords the corresponding N-trimethylsi-lylethynyl-p-toluenesulfonamides, which can be desilylated with tetrabutylam-monium fluoride in wet THF (Scheme 51) [ 151 ]. It is noteworthy that the presence of such groups as n-Bu and CH2 = CH(CH2)2- in the tosylamidate ions did... 

The most versatile method for preparing alkynyl(phenyl)iodonium triflates employs the iodonium transfer reaction between cyano(phenyl)iodonium triflate (348) and alkynylstannanes. The interaction of a large variety of readily available p-functionalized alkynylstannanes 349 with reagent 348 under very mild conditions provides ready access to diverse p-functionalized alkynyliodonium salts 350 in excellent yields (Scheme 2.100) [458,482,483]. This procedure is particularly useful for the preparation of various complex. 

Alkynyl(phenyl)iodonium salts have found synthetic application for the preparation of various substituted alkynes by the reaction with appropriate nucleophiles, such as enolate anions [980,981], selenide and telluride anions [982-984], dialkylphosphonate anions [985], benzotriazolate anion [986], imidazolate anion [987], N-functionalized amide anions [988-990] and transition metal complexes [991-993]. Scheme 3.291 shows several representative reactions the preparation of Ai-alkynyl carbamates 733 by alkynylation of carbamates 732 using alkynyliodonium triflates 731 [989], synthesis of ynamides 735 by the alkyny-lation/desilylation of tosylanilides 734 using trimethylsilylethynyl(phenyl)iodonium triflate [990] and the preparation of Ir(III) a-acetylide complex 737 by the alkynylation of Vaska s complex 736 [991]. 

In 2014, Nachtsheim and co-workers reported the alkynylation of azlactmies with trimethylsilyl alkynyliodonium salt 12 (Scheme 4) [42]. The products obtained were easily transformed into various amino acid derivatives. The reaction was also successful in the case of aliphatic substituted alkynes, although C-H insertion was observed as a minor pathway. Interestingly, the use of EBX reagents led to exclusive formation of C-H insertion products, indicating that the same intermediate was not formed in both reactions. 

The alkynylation of heteroatoms is interesting, as it gives access to highly reactive and useful acetylene derivatives. Because of the nucleophilicity of heteroatoms, the Umpolung approach represented by alkynyliodonium salts is especially attractive. In several cases, evidence has been gathered that these reactions also proceed via a conjugated addition/a-eUmination/l,2-shift mechanism. 

The alkynylation of phosphorus nucleophiles has been less investigated (Scheme 7). Ochiai and co-workers first demonstrated in 1987 that the alkynylation of triphenyl-phosphine was possible with alkynyliodonium tetrafluoroborate salts under light irradiation (Scheme 7, A) [69]. The reaction most probably involves radical intermediates. In 1992, Stang and Critell showed that light irradiation was not needed if alkynyliodonium triflates were used [70]. Later, this methodology could be extended to other triaryl- or alkyl phosphines [71, 72]. In 1990, Koser and Lodaya also reported the synthesis of alkynylphosphonates by the Arbusov reaction of alkynyliodonium tosylates with trialkyl phosphites (Scheme 7, B) [73]. Alternatively, the same compotmds can be obtained by the reaction of alkynyliodonium tosylates with sodium phosphonate salts [74]. 

Surprisingly, the synthetic potential of cyclic hypervalent iodine reagents has been overlooked for a long time. Prior to 2009, only Kitamura and co-workers reported the use of an iodobenzoic acid-based reagent, but in this case the proton-ated open form was used [38]. Since 2009, however, EBX reagents have been broadly applied in alkynylation reactions and have proven in many instances to be superior to the previously used alkynyliodonium salts. 

In contrast to the alkynylation of acidic C-H bonds which can also be achieved using alkynyliodonium salts, the direct C-H functionalization of aromatic compounds or olefins has never been realized with this class of reagents so far. However, after several unsuccessful attempts using palladium or copper catalysts and alkynyliodonium salts for the alkynylation of heterocycles, Waser and Brand reported in 2009 the first efficient alkynylation of indoles using TIPS-EBX 52 and AuCl as catalyst (Scheme 18) [117]. With indole, selective C3-aIkynylation was obtained. The reaction was tolerant to many functional groups such as bromides, acids, or alcohols. The method was already used in the synthesis of starting materials for Friedel-Crafts reactions of aminocyclopropanes [118] and for hydroamidation to access indole c -enamides [119]. In 2010, Nevado and de Haro demonstrated that alkynylation was also possible using directly terminal propiolic ester derivatives and (diacetoxyiodo)benzene as co-oxidant [120]. 

However, in this case the electron-rich 1-methoxypropyne was used as the monoalkyne. First, 108 was converted into yne-ynamide 109 by three steps, including a Sonogashira reaction with trimethylsilylacetylene and the ynamide formation based on the alkynyliodonium salt 105. Yne-ynamide 109 was then alkylated with iodopen-tane, and subsequent desilylation with TBAF provided the diyne 110 (44% yield over two steps). The key cyclotrimerization of diyne 110 with 1-methoxypropyne was carried out in toluene at room temperature in the presence of 10 mol % of Wilkinson s catalyst and afforded chemo- and regioselectively carbazole 111 (82% yield, isomer... 

---