Aryl halide-alkyne coupling

Reaction medium. By virtue of its attributes supercritical carbon dioxide deserves its increasing applications as a reaction medium in synthesis. These include epoxidation" with oxygen and PhCHO, rhodium-catalyzed hydroboration, Pd(0)-catalyzed 1,4-hydroarylation of enones" and Heck reaction in the presence of Pd-C," carbonylation of aryl halides, Glaser coupling of 1-alkynes (mediated by CuCy using a solid ba.se (NaOAc)," as well as seandium(III) perfluorooctanesulfonate-catalyzed Diels-Alder and hetero-Diels-Alder reaetions. ... 

Liu Z, Larock RC (2007) Palladium-catalyzed, sequential, three-component cross-coupling of aryl halides, alkynes, and arynes. Angew Chem Int Edit 46 2535-2538. doi 10.1002/ anie.200604969... 

SCHEME 23.21 Boron halide-mediated aryl aldehyde-alkyne coupling. 

Alkynes with EWGs are poor substrates for the coupling with halides. Therefore, instead of the inactive propynoate, triethyl orthopropynoate (350) is used for the coupling with aryl halides to prepare the arylpropynoate 351. The coupling product 353 of 3,3-dicthoxy-l-propyne (352) with an aryl halide is the precursor of an alkynal[260]. The coupling of ethoxy) tributylstan-nyl)acetylene (354) with aryl halides is a good synthetic method for the aryl-acetate 355[261]. 

Closely related to the Heck reaction is the Sonogashira reaction i.e. the palladium-catalyzed cross-coupling of a vinyl or aryl halide 20 and a terminal alkyne 21 ... 

Radical-mediated silyldesulfonylation of various vinyl and (a-fluoro)vinyl sulfones 21 with (TMSlsSiH (Reaction 25) provide access to vinyl and (a-fluoro)vinyl silanes 22. These reactions presumably occur via a radical addition of (TMSlsSi radical followed by /)-scission with the ejection of PhS02 radical. Hydrogen abstraction from (TMSlsSiH by PhS02 radical completes the cycle of these chain reactions. Such silyldesulfonylation provides a flexible alternative to the hydrosilylation of alkynes with (TMSlsSiH (see below). On oxidative treatment with hydrogen peroxide in basic aqueous solution, compound 22 undergoes Pd-catalyzed cross-couplings with aryl halides. 

Haloalkynes (R—C=C—X) react with ArSnBu3 and Cul to give R—C= C—Ar. Acetylene reacts with two equivalents of iodobenzene, in the presence of a palladium catalyst and Cul, to give 1,2-diphenylethyne. 1-Trialkylsilyl alkynes react with 1-haloalkynes, in the presence of a CuCl catalyst, to give diynes and with aryl triflates to give 1-aryl alkynes. Alkynes couple with alkyl halides in the presence of Sml2/Sm. Alkynes react with hypervalent iodine compounds " and with reactive alkanes such as adamantane in the presence of AIBN. ... 

The utility of the stepwise, double-coupling procedure is demonstrated in the parallel synthesis of Tamoxifen derivatives on solid support [127] (Scheme 1-29). 1-Alkenylboronates thus obtained by a diboration-cross coupling sequence are further coupled with p-silyUodobenzene supported on polymer resin. Using this strategy, each position about the ethylene core is modified by the appropriate choice of alkyne, aryl halide, and cleavage conditions for the synthesis of a library of Tamoxifen derivatives. 

There are a number of procedures for coupling of terminal alkynes with halides and sulfonates, a reaction that is known as the Sonogashira reaction.161 A combination of Pd(PPh3)4 and Cu(I) effects coupling of terminal alkynes with vinyl or aryl halides.162 The reaction can be carried out directly with the alkyne, using amines for deprotonation. The alkyne is presumably converted to the copper acetylide, and the halide reacts with Pd(0) by oxidative addition. Transfer of the acetylide group to Pd results in reductive elimination and formation of the observed product. 

There are many other transition-metal catalyzed coupling reactions that are based on organic halides in aqueous media. One example is the coupling of terminal alkyne with aryl halides, the Sonogashira coupling, which has been discussed in detail in the chapter on alkynes (Chapter 4). An example is the condensation of 2-propynyl or allyl halides with simple acetylenes in the presence of copper salts. 

This chemistry has been extended to terminal alkynes by first carrying out the cross-coupling of the alkyne and aryl halide using catalytic amounts of Pd and Cu salts and then employing catalytic amounts of Cul to affect the cyclization (Scheme 5).6... 

Transition metal-catalyzed transformations are of major importance in synthetic organic chemistry [1], This reflects also the increasing number of domino processes starting with such a reaction. In particular, Pd-catalyzed domino transformations have seen an astounding development over the past years with the Heck reaction [2] - the Pd-catalyzed transformation of aryl halides or triflates as well as of alkenyl halides or triflates with alkenes or alkynes - being used most often. This has been combined with another Heck reaction or a cross-coupling reaction [3] such as Suzuki, Stille, and Sonogashira reactions. Moreover, several examples have been published with a Tsuji-Trost reaction [lb, 4], a carbonylation, a pericyclic or an aldol reaction as the second step. 

The Sonogashira coupling is the Pd-catalyzed coupling of aryl halides and terminal alkynes [207], which, in the appropriate cases, can be followed by the spontaneous, or easily induced,... 

In the direct synthesis of aryl terminal alkynes via Pd-catalyzed cross-coupling of aryl halides with ethynylmetals, formation of diarylethynes is one of the potential side reactions. Indeed, the Kumada coupling of 2-iodo-5-methylthiophene (29) with ethynylmagnesium chloride gave the desired 2-ethynyl-5-methylthiophene (30) in only 35% yield, along with 24% of bis(5-methyl-2-thienyl)ethyne (31) [29], The high propensity for H-Mg exchange reaction to occur was blamed for the diarylethyne formation. 

Scheme 120 Cross coupling of aryl halides and alkynes or alkenes.

Heuze et al. (34) synthesized three generations of bis(tert-butylphosphine)- and bis(cyclohexylphosphine)-functionalized Pd(II) DAB dendritic complexes that serve as copper-free recoverable catalysts for the Sonogashira coupling between aryl halides and alkynes (Scheme 9). 

Terminal aryUkynes. -1 The coupling between ethynyltrimethylsilane and aryl halides in the presence of this catalyst and triethylamine provides a useful route to terminal alkynes. 

Wang, J.X., Liu, Z.X., Hu, Y.L., Wei, B.G. and Kang, L.Q., Microwave-assisted copper catalysed coupling reaction of aryl halides with terminal alkynes, Synth. Commun., 2002, 32, 1937-1945. 

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