Sonogashira reaction alkyne 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 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,... 

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]. 

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. 

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. 

Removal of the tri-wo-propylsilyl (TIPS) and tm-butyldimethylsilyl (TBS) protecting groups could be accomplished concomitantly with TBAF in tetrahydrofuran at 0 °C, but here competing elimination of the secondary bromide was observed. Better overall yields and cleaner conversion was observed when TBS ether was cleaved with 5 % aqueous HF in acetonitrile at 0 °C followed by removal of the acetylenic TIPS with TBAF under milder conditions of -78 °C.10 The diastereomers are not separated before the desilylation process therefore even a 3 1 mixture of E- and Z-enyne is obtained. Prelaureatin 4 and its F-isomer 17 are likewise goals in natural product synthesis. Crimmins and co-workers developed an own synthetic route to 4. The reaction sequence is similar up to aldehyde 55. Afterwards a Z-vinyl-iodide is selectively formed and the alkyne is introduced via a Sonogashira reaction. 

Van der Eycken s group developed a silver(I)-mediated synthesis of substituted furo[2,3-6]pyrazines.53 Starting from -methoxybenzyl-protected 3,5-dichloropyr-azine-2(l//)-ones 26 (Scheme 5.13), after a regioselective microwave-assisted Sonogashira reaction with various terminal alkynes, the cycloisomerization reaction could occur using AgOTf (2 mol%) with trifluoroacetic acid (TFA, 5 equiv) to yield... 

Alonso DA, Najera C, Pacheco MC (2004) Synthesis of ynones by palladium-catalyzed acylation of terminal alkynes with acid chlorides. J Org Chem 69 1615-1619 D Souza DM, Miiller TJJ (2008) Catalytic alkynone generation by Sonogashira reaction and its application in three-component pyrimidine synthesis. Nat Protoc 3 1660-1665 Karpov AS, Miiller TJJ (2003) A new entry to a three component pyrimidine synthesis by TMS-ynones via sonogashira-coupling. Org Lett 5 3451-3454... 

More recently, Lautens has also employed l-(2-iodophenyl)-pyrrole as a bifunctional aryl iodide/acceptor for the synthesis of substituted pyrrolo[l,2]quinolines (Scheme 34)[82], During Catellani s application of the Cassar-Sonogashira reaction to the ort/m-alkylation sequence [70] it was found that alkynes can undergo further carbopalladation reactions with arylpalladium(II) species. It was this reactivity which led Lautens to explore the use of bromoalkylalkynes as species which can undergo an ort/zo-alkylation, followed by a cyclocarbopalladation onto the alkyne,... 

A typical Sonogashira reaction involves heating an aryl halide, catalyst and a terminal alkyne with cuprous iodide and triethylamine. This reaction does not require the preparation of an organometallic reagent, because transmetaUation occurs via an alkynylcopper, formed in situ. The main use of the Sonogashira reaction in heterocyclic chemistry is probably for the synthesis of intermediates for ring synthesis. ... 

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],... 

Schreiber s early efforts in this area were focused on libraries of compounds having structural features reminiscent of rigid, complex, stereochemically rich natural products. In a key early example, solid-phase split-pool synthesis was used to generate a combinatorial library of over two million complex, polycyclic compounds derived from shikimic acid [17]. A stereoselective tandem acylation-nitrone cycloaddition was used to generate 18 tetracyclic scaffolds, to which 30 alkynes were coupled using a Sonogashira reaction, 62 amines were coupled via y -lactone aminolysis, and 62 carboxylic acids were coupled by alcohol esterification (Fig. 9.1-3(c)). In addition, a portion of the solid supports were left unreacted at each of the last three steps to generate a skip codon that further increased the diversity of the library. 

This process is commonly known as the Sonogashira reaction and has proven extraordinarily useful for the synthesis of a wide variety of aryl alkynes or enynes. When neighboring functionality exists, Pd and Cu salts are well known to effect cyclization to the corresponding hetero- or carbocycle. Thus, the reaction of terminal alkynes and aryl or vinylic halides bearing neighboring functionality often leads directly to heterocycles or carbocycles, providing a particularly useful synthesis of benzofurans and indoles. 

As discussed in Sect, ni.2.8.1, the Sonogashira alkyne synthesis f and related Heck-type alkynylation using terminal alkynes as reagents collectively offer widely applicable and generally satisfactory procedures for Pd-catalyzed alkynylation. Even so, various limitations and difficulties associated with the Sonogashira and related reactions have... 

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