The Sonogashira Coupling

The coupling of terminal alkynes 25 with aryl or vinyl halides under palladium catalysis is known as the Sonogashira reaction. The catalytic process 

The reaction has received widespread current usage as a result of the huge interest generated by the potential of ene-diyne antibiotics. Symmetrical ene-diyne moieties of such molecules may be synthesised in one step from the appropriate alkyne and (Z)-dihaloethene 26. More usually, however, the reaction is performed sequentially, thereby allowing different functionality on each of the alkyne units. 

As is the case with the Suzuki coupling, the geometry of the alkene is generally preserved. This is illustrated by the couplings of 27 and 28 with 1-heptyne. 

The protocol given for this reaction involves the coupling of acetylene with 2 equiv. of iodobenzene 29 and is representative of the reaction. 

Caution All procedures should be carried out in a fume hood. Disposable vinyl or latex gloves and safety glasses should be worn. 

In the case of sluggish reactions, where air poisoning of the catalyst often causes the reaction to come to a standstill, multiple couphngs may help to drive the reactions to completion. If Sonogashira couphngs are performed on a support-bound aryl halide, the acid labihty of the formed alkynes must influence the sohd-phase hnker selection. Thus, alkynes formed in the coupling reaction may decompose to a ketone in the presence of aqueous TFA [124, 160]. 

Pd precipitation was minimized using the bidentate ligand dppp. Anhydrous solvents had to be used to avoid the oxidation of CO to formic acid inducing Pd bleeding [162]. To avoid consumphon of Pd , easily oxidized alcohols such as MeOH (which would give formaldehyde or methyl formate) had to be avoided 

In order to prevent the direct cychzation, CsOAc was found to be the base of choice with respect to basicity and solubility in DMF. 

Despite these efforts, the carbonylahon reachons were still rather sluggish and proceeded only on a timescale of a few days. Stoichiometric amounts of PdCl2(PPh3)2 had to be used, and the co-reagent CBr4 caused partial cleavage of the silyl-linker. 

A related reachon involves tandem reactions, with cationic Pd-aUyl complexes 

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Because the Sonogashira coupling process outlined in Scheme 18 is initiated by the in situ reduction of palladium(n) to palladium(o), it would be expected that palladium(o) catalysts could be utilized directly. Indeed, a catalytic amount of tetrakis(triphenylphosphine)-... 

Scheme 19. The Sonogashira coupling in Nicolaou s synthesis of (12S)-HETE (78).

Scheme 21. The Sonogashira coupling reaction in Nicolaou s dynemicin A model study.

Carbon-carbon bond formation reactions and the CH activation of methane are another example where NHC complexes have been used successfully in catalytic applications. Palladium-catalysed reactions include Heck-type reactions, especially the Mizoroki-Heck reaction itself [171-175], and various cross-coupling reactions [176-182]. They have also been found useful for related reactions like the Sonogashira coupling [183-185] or the Buchwald-Hartwig amination [186-189]. The reactions are similar concerning the first step of the catalytic cycle, the oxidative addition of aryl halides to palladium(O) species. This is facilitated by electron-donating substituents and therefore the development of highly active catalysts has focussed on NHC complexes. 

More recently, a study with di- and mono-carbene Pd(II) complexes has demonstrated that the Sonogashira coupling of activated and non-activated aryl iodides can be carried out in an aqueous, aerobic medium and in the absence of amines. These results suggest that the moisture-sensitive copper-acetylide may not be present in this particular transformation, and that a Pd-acetyhde could be formed by deprotonation of the coordinated alkyne instead of transmetallation [130]. 

The coupling of terminal alkynes with organic halides, known as the Castro-Stephens-Sonogashira reaction, has wide applications in synthesis. The most widely used method is the Sonogashira coupling, using a combination of palladium and copper as the catalyst.13 Recently,... 

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. 

McLaughlin and co-workers have described a one-pot copper-free Sonogashira alkynylation and base-mediated indolization reaction to access 1,2-disubstituted indoles 125 and azaindoles from o-chloroanilines 123 <060L3307>. A ligand-, copper, and amine-free variant of the Sonogashira coupling was used by Srinivasan and co-workers to access 2-substituded indoles <06T5109>. 

Another palladium-catalyzed coupling reaction that has been successfully performed on soluble polymers is the Sonogashira coupling. Xia and Wang have presented an approach in which the PEG 4000 utilized simultaneously serves as polymeric support, solvent, and phase-transfer catalyst (PTC) in both the coupling and... 

Recent developments in palladium-catalyzed coupling reactions have arisen in the pyrimidine field as well. The Sonogashira coupling of bromopyrimidine 85 with alkynes 86 produced pyrimidines 87, important intermediates reported by Hart and co-workers in their approach to the cylindrospermopsin substructure . 

Tandem Sonogashira reactions starting with iodopyrrole 122 have furnished the dipyrrolylacetylene 124, and dimerization of 123 gives 125 [86], The Sonogashira coupling has also been reported for enol triflate 55 reacting with an /V-protected propargyl amine [81]. 

Dolphin has employed the Sonogashira coupling of terminal alkynes with zinc(II)-10-iodo-5,15-diphenylporphyrin (126) to prepare a series of alkynyl derivatives 127 [87], and similar syntheses of p-alkynyl porphyrins have been described [88]. 

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,... 

Other indoles that have been prepared using the Sonogashira coupling and cyclization sequence include 5,7-difluoroindole and 5,6,7-trifluoroindole [219], 4-, 5-, and 7-methoxyindoles and 5-, 6-, and 7-(triisopropylsilyl)oxyindoles [220], the 5,6-dichloroindole SB 242784, a compound in development for the treatment of osteoporosis [221], 5-azaindoles [222], 7-azaindoles [160], 2,2-biindolyls [223,176], 2-octylindole for use in a synthesis of carazostatin [224], chiral indole precursors for syntheses of carbazoquinocins A and D [225], a series of 5,7-disubstituted indoles [226], a pyrrolo[2,3-eJindole [226], an indolo[7,6-g]indole [227], pyrrolo[3,2,l-y]quinolines from 4-arylamino-8-iodoquinolines [228], optically active indol-2-ylarylcarbinols [229], 2-alkynylindoles [176], 7-substituted indoles via the lithiation of the intermediate 2-alkynylaniline derivative [230], and a variety of 2,5,6-trisubstituted indoles [231], This latter study employs tetrabutylammonium fluoride, instead of Cul or alkoxide, to effect the final cyclization of 215 to indoles 216 as summarized here. 

The cyclization of oalkynylanilines to indoles, which usually does not require palladium, has been described in Section 3.4. In view of their extensive research with this transformation, this reaction is often referred to as the Sakamoto-Yamanaka indole synthesis [211, 214-216, 220, 230, 231]. Although the cyclization of o-alkynylanilines, which are often obtained by the Sonogashira coupling (Section 3.4), is usually accomplished with base, Kundu used Pd(OAc)2 to effect the conversion of 348 to 349 [308]. 

Having pyrazinylacetylenes in hand, one could convert the alkynyne functionality into the corresponding ketone via hydration [33], Thus, the coupling of iodide 36 and acetylene 37 produced pyrazinylalkyne 38. Subsequent exposure of 38 to aqueous sodium sulfide and aqueous hydrochloric acid in methanol led to ketone 39. Such a maneuver provides additional opportunities for further manipulation of the alkynes derived from the Sonogashira coupling reactions. 

Oxidative addition of Pd(0) to a c/s-dihaloethylene gives an intermediate that can undergo 3-halide elimination. The C-Br or C-I bond is more prone to undergo (3-elimination than the much stronger C-Cl bond. The transmetallation and reductive elimination steps of the Sonogashira coupling have more time to occur when a C-Cl bond is (3 to Pd than when a C-Br or C-I bond is (3 to Pd. 

Other successful examples of catalysts containing NHC ligands are found in palladium- and nickel-catalyzed carbon-carbon bond formations. The catalyst development with these metals has focused in particular on Heck-type reactions, especially the Mizoroki-Heck reaction itself [Eq. (42)] and various cross coupling reactions [Eq. (43)], e.g., the Suzuki-Miyaura reaction ([M] = and the Kumada-Corriu reaction ([M] = MgBr). " Related reactions like the Sonogashira coupling [Eq. (44)]326-329 Buchwald-... 

New macromolecules 99 and 100 can easily be synthesized in four steps from l,2-bis(5-bromo-2-methyl-3-thienyl)perfluorocyclopentene by the Sonogashira coupling reaction (05T12256). 

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). 

The Sonogashira coupling of haloazoles and terminal acetylenes in the presence of a palladium(0)-copper(l) catalyst system usually proceeds readily. Its application has, in the beginning, been limited to iodoazoles, while recent examples frequently utilise bromo-heterocycles too. 

Besides serving as a platform for the construction of the pyrrole ring (see Chapter 3.), the Sonogashira coupling is also effective in functionalising the same system. Trimethylsilylacetylene was used as a surrogate to introduce acetylene groups into the 2 and 5-positions of pyrrole (6.43.), 2,5-diiodo-... 

The Sonogashira coupling of halopyridines was also achieved by other means. Resin bound bromopyridine derivatives, for example, underwent smooth coupling with acetylenes as well as with arylboronic acids and aryltin reagents.44 The advantageous effect of microwave irradiation on the coupling of halopyridines and trimethylsilylacetylene was also reported.45... 

The Sonogashira coupling of haloazines can be effected by a series of catalyst systems. Recently a lot effort was devoted to the development of a recyclable catalyst system. Kotschy and co-workers recently reported the use of palladium on charcoal as a convenient palladium source for this process, which allows for the separation and reuse of the catalyst at the end of the reaction (7.35.), The authors also demonstrated that, in spite of the absence of any substantial catalyst leaching, the catalytic activity of the reused Pd/C decreases on each run,49 a surprising phenomenon which was attributed to the dissolution and reprecipitation of the active catalyst in the course of the process. Pd(OH)2 on charcoal exhibited a similar activity in the Sonogashira coupling of bromopyridines.50... 

A systematic survey of the Sonogashira coupling of 2-halopyrimidines under mild conditions revealed that, in line with the expectations, the iodopyrimidines give excellent yield, while the reactivity of bromopyrimidines is mediocre and chloropyrimidines hardly react (7.37.).52 These results have, of course only limited relevance as increase of the reaction temperature might drive the coupling of the latter halopyrimidines to completion too. An example of the increased reactivity of chlorodiazines... 

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