The Sonogashira coupling reaction

The possibility of performing Sonogashira reactions without use of transition metals is undoubtedly very appealing. By using microwaves Erik Van der Eycken and his group were able to couple phenyl acetylene with different aryl halides at 175 °C using sodium carbonate and tetrabutylammonium bromide in water [lOOj. Reaction times varied from 5 to 25 min usually with good to excellent yields. The 

Sonogashira reaction. The first system consisted in the use of the oxime palladacycles 7a-f at elevated temperatures, without the aid of Cul or an amine base, for the coupling of aryl iodides and bromides. They also reported on the use of complex 48b in aqueous media for the coupling of aryl iodides and bromides and terminal acetylenes in excellent yields.  

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

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. 

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). 

Generally, the Sonogashira coupling reaction is achieved by a palladium-copper catalyzed reaction of aryl or vinyl halide and terminal alkyne [70-72], The presence of the copper co-catalyst is an obstacle, however, towards the metallodendritic approach of the system. In this context, only a few examples of copper-free procedures have been reported [73-77], involving for instance, in situ Pd(0) complex formation with bulky phosphines [78]. 

The Sonogashira coupling reaction was applied to the synthesis of phenyl acetylenes, which were used as substrates in the synthesis of spirodihydrobenzofurans, a central motif of some natural occurring antibiotics <03OL4425>. 

An efficient and convergent synthesis of the C(l)—C(ll) side chain 83 of leucascandrolide A has been achieved. The key bond connection was made through the use of a Sonogashira cross-coupling [53, 54]. Oxazolyl triflate 82 was treated with alkynamide 80 using the Sonogashira coupling reactions to provide the side chain precursor 83 (part of the synthesis of leucascandrolide A) [53, 54]. 

The Sonogashira reaction has been explored on laboratory scale towards the synthesis of fexofenadine and terbinafin. One of the key intermediates, arylalkyn-ol 40 for the synthesis of Fexofenadine (major metabolite of terfenadine) was achieved by the Sonogashira coupling reaction of 4-bromophenylacetic acid (39) and 3-butync-l-ol catalyzed by Pd(PPh3)4 [108]. 

The Sonogashira coupling reaction of terminal alkynes with aryl or vinyl halides is a useful tool for carbon—carbon bond formation, and has found wide employment in areas such as natural product synthesis, the pharmaceutical industry, and material sciences. Novel recyclable Pd catalysts with fluorous ponytails in the ligand 2,2 -bipyridine were reported in a copper-free Pd-catalyzed Sonogashira reaction in a fluorous biphasic system (FBS) (Equation 4.19). The catalysts are only soluble in perfluorinated solvents at room temperature [41],... 

The Sonogashira coupling reaction of aryl halides were attached to a PEG matrix as para-substituted benzoates was also reported [128]. It was shown that MW irradiation can reduce the reaction time from 3 h under conventional conditions to 1.5 min, and that yields of the products were approximately the same. Similarly, the cleavage proceeded faster under MW conditions (1 min compared with 5 h at 50 °C under conventional conditions). 

A rapid MW-assisted palladium-catalyzed coupling of heteroaryl and aryl boronic acids with iodo and bromo-substituted benzoic acids, anchored on TentaGel has been achieved [222]. An environmentally friendly Suzuki cross-coupling reaction has been developed that uses polyethylene glycol (PEG) as the reaction medium and palladium chloride as a catalyst [223]. A solvent-free Suzuki coupling has also been reported on palladium-doped alumina in the presence of potassium fluoride as base [224]. This approach has been extended to the Sonogashira coupling reaction wherein terminal alkynes couple readily with aryl or alkenyl iodides on palladium-doped alumina in the presence of triphenylphosphine and cuprous iodide (Scheme 8.89) [225]. 

The Sonogashira coupling reaction also illustrates the possibihties of this methodology. A small library of six supported aryl acetylenes was obtained according to Scheme 5.5-38. The supported propionic acid on the triethylammonium triflimide was esterified in MeCN in 90% yield. Coupling was realized in a parallel manner in MeCN, leading quantitatively to the aryl acetylenes in 20 min at room temperature (Scheme 5.5-43). The results are summarized in Table 5.5-8 [21,51]. 

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