Terminal alkynes introduction

A multi-step reaction sequence was then realized to prepare the precursor (178) for the pivotal macrocyclization reaction. Alternate stepwise chain elongations were achieved according to Schemes 28 and 29. Reaction of the tosylate prepared from the alcohol 162 with lithium acetylide afforded the alkyne 174 (Scheme 28). Following the introduction of a tosylate at the upper branch, a one-carbon chain elongation of the terminal alkyne afforded the methyl alkynoate 175. A methyl cuprate 1,4-addition was used to construct the tri-substituted C double bond stereoselectively. For this purpose, the alkynoate 175 was initially transformed into the Z-configured a,/ -unsat-... 

Halogen atoms. The introduction of side-chains on 9-trifluoromethyl-paullone 409 can be accomplished applying a Stille coupling (Scheme 86, Section 5.2.1.1 (2005EJM655)). Similarly, a Heck reaction of iodo 409 with terminal alkenes under standard conditions affords 2-substituted paullones 413 exclusively as E-isomers. The reaction of terminal alkynes with 409 in the presence of cuprous iodide and a palladium catalyst in triethylamine furnishes the 2-alkynyl-paullones 412 (2000BMCL567). 

The introduction of CHj requires that the terminal alkyne C first become a carbanion and then be methylated. Such a carbanion, acting like the R group of RMgX, would react with the C==0 group of another molecule before it could be methylated. To prevent this, C==0 is protected by acetal formation before the carbanion is formed. The acetal is stable under the basic conditions of the methylation reactions. The aldehyde is later unmasked by acid-catalyzed hydrolysis. 

Click chemistry has been used extensively since its introduction in organic chemistry, due to the high efficiency and technical simplicity of the reaction [40]. The most popular click reaction has been the copper-catalyzed dipolar cycloaddition of a terminal alkyne and an azide to form... 

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... 

While vinylsilanes and -stannanes have been used primarily for the synthesis of vinyliodonium salts with one or two / -alkyl substituents in the vinyl moiety, the treatment of alkynes with oxyiodanes permits the introduction of oxygen functionality at jft-carbon. The conversion of terminal alkynes with [hydroxy(tosyloxy) iodo]benzene (HTIB) to alkynyliodonium tosylates (equation 8) and/or (j5-tosyloxyvinyl)iodonium tosylates [TsOC (R)=CHiPh, "OTs R = n-Pr, n-Bu, n-C5Hn, i-Pr, i-Bu] (equation 9), depending on the size of R, has already been discussed8,11. In at least three cases, E Z mixtures were... 

The introduction of acetylene, terminal alkynes or internal alkynes into methylene chloride solutions of iodosylbenzene and triflic acid [1 1, in situ generation of PhI(OH)OTf] results in the production of [j3-(trifluoromethanesulfonyloxy)vinyl]iodonium triflates (equation 172)78,133. Since the -configuration has been determined for selected members of this series (R1, R2 = n-Pr, H n-Bu, H), these reactions appear to proceed via stereoselective anti-additions of PhI(OH)OTf to the alkynes. 

An elegant method for linking terminal alkynes with aromatic compounds and olefins is the Sonogashira reaction [15]. The palladium-catalyzed reaction enables the simultaneous introduction of two or even more alkyne units and thereby makes it possible to synthesize acetylene derivatives, for example hexaalkynyl-benzenes [16], (eq. (7)), which can be obtained only with difficulty by other methods. It has been shown by Herrmann, Beller, and co-workers that the copper reagent is not necessary as a co-catalyst for the coupling of terminal alkynes with sp -carbon halides. By using phosphapalladacyclic catalysts 1 the... 

An original, and versatile route toward ulosonic acids has been recently elaborated by Wu et al. [103,104,105], It based on a simple introduction of a-keto acid moiety via propargylation of suitable monosaccharides derived aldehydes and subsequent oxidation of the terminal alkynes. As it is exemplified by preparation of KDO, coupling of 61 with 3-bromopropyne gave the a fr-adduct 139 (Scheme 30). Its bromination using NBS/AgNC>3 provided the bromoalkyne 140, which on reaction with KMnC>4 afforded the desired a-keto acid ester, easily convertible into the anomeric mixture of KDO derivatives 143. The yield of all intermediates were very high. 

Direct introduction of sp carbon to alkynes by the reaction of Cu acetylides with aryl and alkenyl halides to form arylalkynes and alkenylalkynes is known as the Castro reaction [1]. Later it was found that coupling of terminal alkynes (1-alkynes) with halides proceeds more smoothly by using Pd catalysts. There are two methods of Pd-catalyzed coupling, hi 1975 direct coupling of 1-alkynes catalyzed by a phosphine-Pd(O) complex in the presence of amines was reported by Heck and Cassar as an extension of the Heck reaction to 1-alkynes [2,3]. In the same year, Sonogashira and Hagihara found that the addition of Cul as a co-catalyst gave better results, and the Pd(0)-CuI-catalyzed reaction is called the... 

Substituents on the terminal alkyne 5 can be varied applying both protocols from aromatic to aliphatic, although method B allows the introduction of a wider variety of substituents on aromatic alkynes ranging from electron donating to electron withdrawing. Substituents on the 2-iodo aniline 6 can also be varied easily, but nitro groups require conditions B. 

The biselectrophilic reactivity motif of alkynones is also present in 3-substituted alkyl propiolates 2. Utilizing the previously described Michael addition/cyclocondensation approach with various binucleophiles allows the introduction of oxo/hydroxyl substituents to the heterocycle. An example of the concept is the copper(I)-catalyzed carboxylation of terminal alkynes, which allows the convenient synthesis of 3-substituted alkyl propiolates 2 a by trapping the intermediary carboxylate with methyl iodide. This one-pot procedure can be expanded to a three-component process by adding binucleophiles such as amidines 36 and hydrazines 20 to furnish the corresponding 2,6-disubstituted pyrimidin-4(3fl)-ones 54 and 1,5-disubsti-tuted 3-hydroxypyrazoles 55 in a one-pot fashion. The incorporation of nontoxic, abundant and economical carbon dioxide provides an environmentally benign access to interesting heterocyclic structures (Scheme 33) (2014ASC(356)3135). 

The Pd(PPh3)4-catalyzed reaction of terminal alkynes with diaryl disulfide or diaryl diselenide under pressurized carbon monoxide is found to lead to the regioselective introduction of carbon monoxide to the terminal position of the alkynes with excellent stereoselectivity, as shown in Scheme 6. ... 

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