Alkynyliodonium derivatives

In contrast, alkynyl dialkyl phosphate esters, 78, are formed in good isolated yields by either the treatment of alkynyliodonium triflates with (R0)2P02Na or the reaction of terminal alkynes with [hydroxy(phosphoryloxy)iodo]benzene, 77 [Eq. (34)], or the sequential treatment of alkynylsilanes with PhIO Et20Bp3 followed by aqueous (R0)2P02Na [Eq. (35)) [61]. These new, alkynyliodonium-derived, acetylenic esters have potent biological activity [4] in particular, the alkynyl benzoates are protease inhibitors [62], whereas the alkynyl dialkylphos-phates, 78, are inhibitors of a bacterial phosphotriesterase [63]. 

The regiochemistry of the hydrozirconation of disubstituted stannyl- [24, 167-170] and silyl- [171] acetylenes and boron- [118, 172-175] and zinc- [34, 126] alkynyl derivatives result in the formation of 1,1-dimetallo compounds. Hydrozirconation of alkynyliodonium salts affords alkenylchlorozirconocenes with the Zr-C bond geminal to the iodonium moiety [176]. These zirconocene complexes allowed the preparation of ( )-trisubstituted olefins (Scheme 8-20). 

Stang etal. (94JA93) have developed another alkynyliodonium salt mediated approach for the synthesis of y-lactams including bicyclic systems containing the pyrrole moiety. This method is based on the formation of 2-cyclopentenones 114 via intramolecular 1,5-carbon-hydrogen insertion reactions of [/3-(p-toluenesulfonyl)alkylidene]carbenes 113 derived from Michael addition of sodium p-toluenesulfinate to /3-ketoethynyl(phenyl) iodonium triflates 112 (Scheme 32). Replacing 112 by j8-amidoethynyl (phenyl)iodonium triflates 115-119 provides various y-lactams as outlined in Eqs. (26)-(30). 

Intramolecular bicyclization of tosylamide with alkynyliodonium salt (see Scheme 31), developed by Feldman and co-workers (95JA7544), is also applicable to the synthesis of A-tosylpiperidine derivatives related to polycyclic alkaloids (Eq. 40). Examples leading to seven-membered rings have also been reported. 

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. 

Only the azide anion amongst the multitude of possible nitrogen nucleophiles had reported utility in alkynyliodonium salt addition chemistry at the inception of this project. Therefore, extension of this chemistry to amines and amide derivatives occupied our attention at the outset. The requirement for a soft, polarizable nucleophile limited our options, and screening a primary amine as well as some common amide derivatives in the prototype transformation 35 + 36 - 38 led to the first sense that this goal was achievable (Scheme 6).5a c In fact, the common amine protecting group tosyl proved to be the most effective modulator of amine nucleophilicity in this assay. Interestingly, amide pKa does not... 

Conversion of the alkynylstannane within 149 into the corresponding alkynyliodonium salt 150 proceeded as expected, and this fragile intermediate was treated immediately with base at low temperature (Scheme 23). TLC analysis of the crude reaction mixture indicated only a single off-baseline product, quite visible as a bright purple spot. Isolation of this compound by chromatography and characterization by standard spectral techniques led to the realization that the desired cycloheptatrienylidene product 151 had been formed in good yield. Careful examination of the crude reaction mixture s H NMR spectrum did not provide any indication that a 1,6 C-H insertion-derived... 

Various 2-substituted benzofurans 165 are obtained by the interaction of iodo-nium salts 164 with sodium phenoxide in methanol (Scheme 63) [126, 127]. This reaction proceeds via the intramolecular alkylidene carbene insertion into the ortho-CH bond of the phenoxy ring. Furopyridine derivatives 167 can be prepared similarly by the intramolecular aromatic C-H insertion of the alkylidenecarbenes generated by the reaction of alkynyliodonium tosylates 166 with potassium salts of 4- or 3-hydroxypyridines [128]. 

Alkylidenecarbenes 124, formed from alkynyliodonium salts 123 and 1-naphthol derivatives, undergo 1,6-C-H insertion at the />m"-position to yield bcnzo[z/ ]chromcncs 125 (Scheme 41) <2001TL6031>. The alkylidenecarbene formed from alkynyliodonium salt 123 and 2-methylnaphthalen-l-ol, can undergo 1,6-C-H insertion at both the /imposition and at the 2-methyl substituent, resulting in a 2 1 mixture of 2,9-dimethylbenzo[r/c ]chromcne and 2-methyl-4//-benzo[ ]chromene (Equation 59) <2001TL6031>. 

Alkynyliodonium ions, 1 and 2, are hypervalent iodine species in which one or two alkynyl ligands are bound to a positively charged iodine(III) atom. They are sensitive to nucleophiles, especially at the /1-carbon atom(s) of the alkynyl ligand(s), and for that reason, the isolation of stable alkynyliodonium salts generally requires the incorporation of nucleofugic anions. A list of known alkynyliodonium compounds (i.e. as of 4/1/94), containing 134 iodonium salts derived from 103 iodonium ions, and references (5-45) to their preparation and characterization are presented in Table 1. Among these compounds, alkynyl(phenyl)iodonium sulfonates and tetrafluoroborates are the most common, while alkynyl(alkyl)iodonium salts of any kind are unknown. 

The first alkynyliodonium salt, (phenylethynyl)phenyliodonium chloride, synthesized in low yields from (dichloroiodo)benzene (3) and lithium phenylacetylide (equation 1), was reported in 196526. This chloride salt is unstable and readily decomposes to a 1 1 mixture of chloro(phenyl)acetylene and iodobenzene. It was not until the 1980s, however, that alkynyliodonium salts became generally available. This was made possible by the introduction of sulfonyloxy-/l3-iodanes as synthetic reagents46 and by the recognition that iodosylbenzene (4) can be activated either with boron trifluoride etherate or with triethy-loxonium tetrafluoroborate31. These reagents are now widely employed for the conversion of terminal alkynes and their 1-silyl and 1-stannyl derivatives to alkynyliodonium salts (equations 2 and 3). A more exhaustive survey of iodine(III) reagents that have been... 

Despite the synthetic possibilities suggested by this early study, the chemistry of the alkynyliodonium salts lay dormant until the mid-1980s. In 1986, Ochiai and his coworkers published an important communication which shaped much of the later thinking on the reactions of alkynyliodonium ions with nucleophiles28. When / -dicarbonyl enolates are treated with alkynyliodonium tetrafluoroborates containing a long (> three carbons) alkyl chain, derivatives of cyclopentene are produced. This is illustrated in equation 41 for the... 

MCI reactions of alkynyliodonium salts with enolates derived from active methylene compounds containing two acidic CH bonds follow a divergent course that leads to furans, presumably via carbenic insertion into enolic OH bonds (equation 122)28. In the reaction of acetylacetonate ion with the l-decynyl(phenyl)iodonium ion, CH insertion is competitive with OH insertion (equation 123)28. 

Lithium dialkynylcuprates behave similarly with alkynyliodonium tosylates and lead to conjugated diynes (equation 133)109. Unsymmetrical diynes can be prepared with moderate selectivity by this method, although they are accompanied by symmetrical diynes derived from the alkynyliodonium component. The treatment of lithium diphenyl- and dialkylcuprates with alkynyliodonium tosylates has also been investigated and affords alkyl- and phenyl-substituted alkynes (equation 134)109. 

The seminal paper which led to the revival of alkynyliodonium chemistry was published by Ochiai et al in 1986. The reaction of p-diketone enolates with alkynyliodonium tetrafluoroborates containing an alkyl chain led to the formation of cyclopentene derivatives such as (81). 1 ... 

In contrast, the reaction of a range of P-dicarbonyl nucleophiles with a variety of alkynyliodonium salts substituted with an alkyl group possessing a y-CH bond results in the cyclopentene products derived by carbene insertion [51] as illustrated in Scheme 3-5. In fact, as shown in Eq. (22), the alkyl chain need not be restricted to the alkynyliodonium salt but may instead be part of the enolate nucleophile [51]. 

The synthetic scope of the Thiele-Winter reaction of quinines with acetic anhydride can be increased by the use of triflic acid (eq 46). Reaction of cyclopropylacylsilanes with triflic acid in aprotic solvent affords the corresponding cyclobutanone or 2-silyl-4,5-dihydrofuran derivatives. Triflic acid can react with >-iodosylbenzoic acid to form a hypervalent iodine reagent, which reacts with 1-trimethylsilylalkynes to afford alkynyliodonium tri-flates bearing a carboxy group in high yields (eq 47). Reaction of (diacetoxyiodo)benzene [PhI(OAc)2] with excess triflic acid results in oligomerization of PhI(OAc)2- ... 

Preparation A common synthetic approach to alkynyliodonium salts involves the reaction of an electrophilic X -iodane with a terminal alkyne or its silylated, stannylated, or lithiated derivative. In the early 1980s, Koser and coworkers found that [hydroxy(tosyloxy)iodo]benzene 75 reacts with terminal alkynes 344 upon gentle heating in chloroform or dichloromethane to form alkynyliodonium tosylates 345 in moderate to low yield (Scheme 2.98) [199,471,476]. 

The electron-withdrawal of the triflyl group also helps stabilize the corresponding ynamine derivatives. These can be prepared by coupling the lithium salt of AAbenzyltriflamide with an alkynyliodonium trifiate in a sequence which probably proceeds... 

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. 

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]. 

Copper-catalyzed carbonylative coupling of ( )-a-(ethylsdanyl)-vinyl zircono-cene chloride derivatives with alkynyliodonium tosylates has been reported to be a mild method for the preparation of vinyl alkynyl ketones in good yields (Scheme 12.30) [39]. 

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