Sonogashira reaction synthesis

The original Sonogashira reaction uses copper(l) iodide as a co-catalyst, which converts the alkyne in situ into a copper acetylide. In a subsequent transmeta-lation reaction, the copper is replaced by the palladium complex. The reaction mechanism, with respect to the catalytic cycle, largely corresponds to the Heck reaction.Besides the usual aryl and vinyl halides, i.e. bromides and iodides, trifluoromethanesulfonates (triflates) may be employed. The Sonogashira reaction is well-suited for the synthesis of unsymmetrical bis-2xy ethynes, e.g. 23, which can be prepared as outlined in the following scheme, in a one-pot reaction by applying the so-called sila-Sonogashira reaction ... 

The Sonogashira reaction is a transition metal-catalyzed coupling reaction which is widely used for the preparation of alkyl-, aryl- and diaryl-substituted acetylenes (Table 4.7) [120]. This reaction is a key step in natural product synthesis and is also applied in optical and electronic applications. Sonogashira reactions involve the use of an organic solvent with a stoichiometric portion of a base for capturing the... 

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,... 

R. Roy, S. K. Das, F. Santoyo-Gonzalez, F. Hemandez-Mateo, T. K. Dam, and C. F. Brewer, Synthesis of sugar-rods with phytohemagglutinin cross-linking properties by using the palladium-catalyzed Sonogashira reaction, Chem. Eur. J., 6 (2000) 1757-1762. 

F. Perez-Balderas and F. Santoyo-Gonzalez, Synthesis of deeper calix-sugar-based on the Sonogashira reaction, Synlett, 11 (2001) 1699-1702. 

The second example involves the synthesis of ortho-dipropynylated arenes (Scheme 4.12b), which serve as precursors to tribenzocyclyne by way of an alkyne metathesis reaction (see also Scheme 6.31). Here, a Sonogashira reaction was carried out in a pre-pressurized (propyne at ca. 2.5 bar) sealed microwave vessel in a standard single-mode microwave reactor. Double-Sonogashira coupling of the dibromodiiodo-benzene was completed within 20 min at 110 °C [30]. 

The Sonogashira reaction has enjoyed tremendous success in the synthesis of almost all types of heteroarylacetylenes because of the extremely mild reaction conditions and great tolerance of nearly all types of functional groups. A representative reaction with conditions akin to Sonogashira s original conditions is shown below [62] ... 

Advantage has been taken of the aforementioned observations in the synthesis of a terthiophene natural product, arctic acid (147) [123]. Pd-catalyzed carbonylation of bromobisthiophene 25, obtained from the Kumada coupling of 2-thienylmagnesium bromide and 2,5-dibromothiophene, gave bithiophene ester 144, which was converted to iodide 145 by reaction with iodine and yellow mercuric oxide. Subsequent propynylation of 145 was then realized using the Sonogashira reaction with prop-l-yne to give bisthienyl alkyne 146, which was subsequently hydrolyzed to 5 -(l-propynyl)-2,2 -bithienyl-5-carboxylic acid (147), a natural product isolated from the root of Arctium lappa. 

The Sonogashira reaction is of considerable value in heterocyclic synthesis. It has been conducted on the pyrazine ring of quinoxaline and the resulting alkynyl- and dialkynyl-quinoxalines were subsequently utilized to synthesize condensed quinoxalines [52-55], Ames et al. prepared unsymmetrical diynes from 2,3-dichloroquinoxalines. Thus, condensation of 2-chloroquinoxaline (93) with an excess of phenylacetylene furnished 2-phenylethynylquinoxaline (94). Displacement of the chloride with the amine also occurred when the condensation was carried out in the presence of diethylamine. Treatment of 94 with a large excess of aqueous dimethylamine led to ketone 95 that exists predominantly in the intramolecularly hydrogen-bonded enol form 96. 

Wang s approach for the synthesis of enyne-allenes focused on ene-allenyl iodide 45 (Scheme 14.12) [24]. Palladium-catalyzed Sonogashira reaction of 45 with terminal alkynes 46 (R= Ph or CH2OH) proceeded smoothly under mild reaction conditions in the presence of the cocatalyst cuprous iodide and n-butylamine. The initially formed enyne-allene 47b with substituent R= CH2OH cyclized spontaneously to the corresponding a-methylstyrene derivative 48. 

I 3 Organic Synthesis on Polymeric Supports Sonogashira reactions... 

In a formal total synthesis of matrine (116), Yamanaka and coworkers used the Sonogashira reaction of pyridyl halides as the means to form C—C bonds <86CPB2018>. For instance, bromonaphthyridinone 114 was coupled with 3-butyn-l-ol to furnish alkynylnaphthyridinone 115, an intermediate towards matrine (116). 

The Sonogashira reaction has become the most widely used of the palladium-catalyzed alkynylation methods due to its generality and reliability, particularly in the context of total synthesis. Some recent examples are shown in Figure 10.1 4,174a-174c... 

Scheme 4. The McGill synthesis of fexofenadine (3) involving a Sonogashira reaction.

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