Sonogashira reaction terminal acetylenes

In 1980 Sonogashira reported a convenient synthesis of ethynylarenes - the Pd-catalyzed cross-coupfing of bromo- or iodoarenes with trimethylsilylacetylene followed by protiodesilylation in basic solution [15]. Prior to this discovery, formation of terminal acetylenes required manipulation of a preformed, two-carbon side chain via methods that include halogenation/dehydrohalogenation of vinyl- and acetylarenes, dehalogenation of /1,/1-dihaloalkenes, and the Vils-meier procedure [ 14]. With the ready availability of trialkylsilylacetylenes, the two-step Sonogashira sequence has become the cornerstone reaction for the construction of virtually all ethynylated arenes used in PAM and PDM synthesis (vide infra). 

Besides palladium catalysts, nickel was also found to be an effective catalyst for the Sonogashira reaction in aqueous media. Recently, Beletskaya et al. reported a Ni(PPh3)2Cl2/CuI-catalyzed Sonogashira coupling reaction of terminal acetylenes with aryl iodides in aqueous dioxane in high yields (Eq. 4.19).39... 

Cross-coupling of terminal acetylenes used as nucleophiles with aryl or alkenyl halides (referred to as the Sonogashira-Hagihara, or SH, reaction) is a versatile method of synthesis for acetylenic compounds, which are rapidly gaining importance as advanced new materials and building blocks for implementing unusual molecular architectures. 

In spite of the common conception that Ni catalysts are useless in the Sonogashira reaction, NiCl2(PPh3) has been disclosed as being able to catalyze the cross-coupling of aryl iodides with terminal acetylenes in aqueous dioxane, in the presence of Cul.147... 

Halopyridines, like simple carbocyclic aryl halides, are viable substrates for Pd-catalyzed crosscoupling reactions with terminal acetylenes in the presence of Pd/Cu catalyst. The Sonogashira reaction of 2,6-dibromopyridine with trimethylsilylacetylene afforded 2,6-bis(trimethylsilyl-ethynyl)pyridine (130), which was subsequently hydrolyzed with dilute alkali to provide an efficient access to 2,6-diethynylpyridine (131) [106]. Extensions of the reactions to 2-chloropyridine, 2-bromopyridine, and 3-bromopyridine were also successful albeit at elevated temperatures [107]. 

In 1987, Yamanaka s group described a Pd-catalyzed reaction of halothiazoles with terminal acetylenes [51]. While the yield for the Sonogashira reaction of 2-bromo-4-phenylthiazole (89) with phenylacetylene to afford 90 was moderate (36% after desilylation), the coupling of 4-bromothiazole and 5-bromo-4-methylthiazole with phenylacetylene gave the desired internal acetylenes 91 and 92 in 71% and 65% yield, respectively. 

In 1987, Yamanaka s group described the Pd-catalyzed reactions of halothiazoles with terminal acetylenes [22a]. Submission of 4-bromo- and 5-bromo-4-methyloxazoles to the Sonogashira reaction conditions with phenylacetylene led to the expected internal acetylenes. 

Substituted propargylic carbonates react with terminal acetylenes in the presence of a catalytic amount of Pd(PPh3)4 and Cul to produce Sonogashira-type cross-coupling products (Eq. 9.114) [84]. Presumably, the reaction proceeds through an allenylpalladium complex. Addition of a salt, such as KBr, increased the yield of the coupling product. Only tetrasubstituted allenes could be obtained by this procedure. 

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. ... 

The Sonogashira reaction of 2-iodothiophene with 2-methyl-3-butyne-2-ol or trimethylsilylacetylene under phase transfer conditions using sodium hydroxide as base led to the formation of the expected products, which released their end group spontaneously under the applied conditions giving rise to the intermediate formation of 2-ethynylthiophene. This terminal acetylene, in turn, reacted with another molecule of aryl halide, yielding either non symmetrical or symmetrical diarylethynes. When 2-methyl-3-butyn-2-ol was used as acetylene equivalent68 it was possible to introduce a benzothiophene moiety in the second step, while the reaction of 2-iodothiophene and trimethylsilylacetylene led to the formation of l,2-bis(2 -thienyl)acetylene (6.47.),69... 

Efficiency of the deprotection and coupling reactions are critical to the success of any iterative solid-phase synthesis. Shown in Scheme 1 is a triad of reactions for phenylacetylene oligomer synthesis trimethylsilyl deprotection,28 29 triazene unmasking of an iodobenzene,30 and the Sonogashira coupling of a terminal acetylene with an aryl iodide.31-33 Representative procedures for each step in this sequence are included at the end of this chapter. 

Scheme 2. Mechanism of the Sonogashira reaction for Pd/ Cu-catalyzed cross-coupling of sp2-C halides with terminal acetylenes.

The Sonogashira cross-coupling reaction of terminal acetylenes with aryl or vinyl halides is a powerful tool for generation of carbon-carbon bonds between sp2- and sp-carbon. Numerous molecules of interest can be generated from a wide variety of aryl or vinyl halides (Scheme 3) [18-23],... 

The regioselective coupling reaction of 2,3-dibromobenzo[/ ]furan with several terminal acetylenes was achieved using a palladium-catalyzed Sonogashira reaction, as exemplified in Equation (91) <2003S925>. 

An elegant method for linking terminal alkynes with aromatic compounds and olefins is the Sonogashira reaction [15]. The palladium-catalyzed reaction enables the simultaneous introduction of two or even more alkyne units and thereby makes it possible to synthesize acetylene derivatives, for example hexaalkynyl-benzenes [16], (eq. (7)), which can be obtained only with difficulty by other methods. It has been shown by Herrmann, Beller, and co-workers that the copper reagent is not necessary as a co-catalyst for the coupling of terminal alkynes with sp -carbon halides. By using phosphapalladacyclic catalysts 1 the... 

The Sonogashira reaction is of considerable value in heterocyclic synthesis. Heteroaryl halides like bromooxazoles are viable substrates for the Pd-catalyzed cross-coupling reactions with terminal acetylene in the presence of Pd/Cu catalyst. In 1987, Yamanaka s group described the Pd-catalyzed reactions of halothiazoles with terminal acetylenes [50]. Submission of 4-bromo- (72) and 5-bromo-4-methyloxazoles (73) to the Sonogashira reaction conditions with phenylacetylene led to the expected acetylenes (74 and 75). 

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