Copper-mediated alkyne formation

Various functionalized alkynes can be submitted to carbocupration reactions, such as alkoxyalkynes,150 alkynyl carbamates,151 acetylenic orthoesters,152 and thioalkynes.153 The carbocupration of orthoesters, for example, 204, has been used to prepare a-substituted esters of the type 206 by acidic hydrolysis of the adduct 205 (Scheme 51).152 This allows the formation of regioisomers that are not accessible by copper-mediated addition to acetylenic esters. A stereoselective synthesis of trisubstituted alkenes has been described by Normant et al.lSd> starting from phenylthio-acetylene 207. Carbocupration with lithium di- -butylcuprate affords the intermediate 208 which, upon addition of /z-butyllithium, undergoes a 1,2-metalate rearrangement to the vinylcuprate 209. The latter can be trapped with various electrophiles, for example, ethyl propiolate, providing product 210 with complete regio- and stereocontrol. 

A unique method to generate the pyridine ring employed a transition metal-mediated 6-endo-dig cyclization of A-propargylamine derivative 120. The reaction proceeds in 5-12 h with yields of 22-74%. Gold (HI) salts are required to catalyze the reaction, but copper salts are sufficient with reactive ketones. A proposed reaction mechanism involves activation of the alkyne by transition metal complexation. This lowers the activation energy for the enamine addition to the alkyne that generates 121. The transition metal also behaves as a Lewis acid and facilitates formation of 120 from 118 and 119. Subsequent aromatization of 121 affords pyridine 122. 

More attractive copper-catalyzed (mediated) transformations of allenes into alkynes were reported by Caporusso and co-workers [27f, 73-75], Allenes 142 were converted into alkynes 143 by treatment with stoichiometric amounts of a cuprate species, as exemplified in Scheme 14.35. The problem of regioselective formation of either alkyne 143 or allene 144 was solved by the proper choice of the organometallic species. Preferential formation of alkynes 143 could be achieved employing cuprates such as R3Cu(CN)ZnCl-LiCl, which are prepared from organozinc compounds. On the other hand, reactions of organomagnesium derived cuprates (R3CuBr)Mg-LiBr mostly provided allenes 144 as major components. 

The reaction was applied to the formation of arylcopper used for homocoupling and coupling reactions, which have already been described in Section IV.B.2. In addition, it was established that the simple use of copper(I) salts in polar solvents permitted the transmetallation from tin to copper. The transient vinylcopper reagent was subjected to various intramolecular reactions such as coupling with vinyl halides , addition to a, /S-unsaturated ketones , to a, /3-unsaturated esters and addition to a, /3-alkynic esters . In addition to copper(I) halides, the reaction can be mediated by copper(I) cyanide and... 

Rearrangement processes of alkyltitanocene dichlorides that occur under electron impact have been investigated using deuterium labelling. A novel type of zirconium-mediated coupling reaction of alkynes with vinyl bromide to afford 2,3-disubstituted dienes has been reported (see Scheme 105), and an inter-intramolecular reaction sequence has been proposed for the observed formation of vinylcyclohexadienes and/or methylenecycloheptadienes from the copper-catalysed reaction of zirconacyclo-pentadienes with allylic dichlorides. The essential step in these processes appears to be transmetallation of the zirconium-carbon bond of the zirconacyclopentadiene to produce a more reactive copper-carbon bond. New phosphorus heterocycles, e.g. (417), have been constructed by the thermal rearrangement of a [l,4-bis(trimethylsilyl)->/ -cyclooctatetraene]- ,3,5-triphospha-7-hafhanorbomadiene complex (416). 

In another copper-catalyzed reaction, cross-coupling of alkynes with phosphi-ne-boranes was followed by surprising oxidation to yield ketones (Scheme 69) [122]. The active species was proposed to be a copper phosphido-borane complex, formed by proton transfer to a Cu-OH group. Formation of a Cu-acetylide followed by P-C reductive elimination would then yield a phosphino-alkyne, whose subsequent Cu-mediated air oxidation yields the ketone. 

A rhodium(III)/copper(II)-mediated process was reported to provide tetra-substituted enol esters in a trans-selective fashion. Overall, the reaction consists of a heteroaryl acyloxylation of alkynes. The process was initiated by a rhodium(III)-catalyzed C-2-selective activation of electron-rich het-eroarenes, such as benzo[I>]furan, and furan. Upon addition across an alkyne, a transmetalation to copper(II) enabled reductive C—O bond formation (14AGE14575). 

A plausible catalytic cycle for the direct asymmetric aldol reaction is shown in Fig. 7. Key to the success of the reaction is chemoselective enolate formation of ynones 8 in the presence of enolizable aldehydes, which is mediated by soft-soft interaction 10 between the ynone moiety and the copper catalyst. This interaction selectively acidifies the a-protons of ynones. The aldol addition of chiral Cu (I) enolate 12 to an aldehyde affords copper aldolate 13. The soft-soft interaction between the Cu(I) atom and the n electrons of the alkyne moiety in 13 would help suppress the imdesired retro-aldol reaction due to the existence of additional coordination. Nevertheless, facile protonation of imstable 13 and formation of aldol product 14 is crucial, rationahzing the inquiry of (sub)stoichiometric amounts of trifluoroethanol. Protonation of 13 regenerates the copper alkoxide catalyst. 

Cross-coupling. Heteroarenes, such as 1,3,4-oxadiazole and oxazole, efficiently undergo a copper(II) chloride-mediated oxidative coupling with terminal alkynes (eq 34). Electron-rich alkynes effectively coupled with 2-phenyl-1,3,4-oxadiazole, although electron-deficient substrates led to a decreased yield. The 1,3,4-oxadiazoles with various substituents at the 2-position were also suitable substrates, but the slow addition of terminal alkynes was essential to avoid undesired diyne formation. The desired 2-alkynyl-5-aryloxazoles were obtained in DMSO at 150 °C. 

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