Cross Sonogashira coupling

Pd-catalyst Pd(PPh3)2Cl2 or Pd(PPhs)4 Cu(l)-salt Cul or CuBr base Et2NH, EtsN, (Chx)2NH, ( -Pr)2NEt solvent MeCN, THF, EtOAc 

The mechanism of the Sonogashira cross-coupling follows the expected oxidative addition-reductive elimination pathway. However, the structure of the catalytically active species and the precise role of the Cul catalyst is unknown. The reaction commences with the generation of a coordinatively unsaturated Pd species from a Pd complex by reduction with the alkyne substrate or with an added phosphine ligand. The Pd then undergoes oxidative addition with the aryl or vinyl halide followed by transmetallation by the copper(l)-acetylide. Reductive elimination affords the coupled product and the regeneration of the catalyst completes the catalytic cycle. 

The novel heliannane-type sesquiterpenoid (-)-heliannuol E was synthesized in the laboratory of K. Shishido. Interest in the total synthesis of this natural product was not only spurred by its irregular terpenoid structure and significant biological activity but the need to establish the absolute stereochemistry at the C2 and C4 stereocenters. The Sonogashira reaction was utilized to prepare the 3-arylpropargyl alcohol by coupling of a heavily substituted aryl iodide with an unprotected propargyl alcohol in quantitative yield. 

The concise formal total synthesis of mappicine was accomplished using an intramolecular hetero Diels-Alder reaction as the key step by M. lhara and co-workers. Introduction of the necessary acetylenic moiety at the C2 position was achieved by the Sonogashira cross-coupling of a 2-chloroquinoline derivative with TMS-acetylene. Several substituents at the C3 position were investigated, and it was found that the unprotected hydroxymethyl substituent gave almost quantitative yield of the desired disubstituted alkyne product. 

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A palladium catalyst with a less electron-rich ligand, 2,2-dipyridyl-methylamine-based palladium complexes (4.2), is effective for coupling of aryl iodides or bromides with terminal alkynes in the presence of pyrrolidine and tetrabutylammonium acetate (TBAB) at 100°C in water.37 However, the reactions were shown to be faster in NMP solvent than in water under the reaction conditions. Palladium-phosphinous acid (POPd) was also reported as an effective catalyst for the Sonogashira cross-coupling reaction of aryl alkynes with aryl iodides, bromides, or chlorides in water (Eq. 4.18).38... 

Stevens, P.D., Li, G.F., Fan, J.D., Yen, M. and Gao, Y. (2005) Recycling of homogeneous Pd catalysts using superparamagnetic nanoparticles as novel soluble supports for Suzuki, Heck, and Sonogashira cross-coupling reactions. Chemical Communications (35), 4435-4437. 

A recent publication by the group of Barbarella has disclosed the rapid preparation of poorly soluble unsubstituted and modified a-quinque- and sexithiophenes by the extensive use of bromination/iodination steps and microwave-assisted Suzuki and Sonogashira cross-couplings (Scheme 6.16) [42]. Suzuki reactions were either carried out under solvent-free conditions on a strongly basic potassium fluoride/ alumina support for the synthesis of soluble oligothiophenes, or in solution phase for the preparation of the rather insoluble a-quinque- and sexithiophenes. In both cases, 5 mol% of [l,l -bis(diphenylphosphino)ferrocene]dichloropalladium(II)... 

Scheme 6.32 Scaffold decoration of heterocycles using Sonogashira cross-coupling chemistry.

The bromine atoms in 2,5-dibromo-l,3,4-thiadiazole 54 undergo a palladium-catalyzed Stille reaction with the organostannyl derivative 55 (Equation 7) <1998CEJ2211>. The thiadiazole 54 was co-polymerized with diethynyl benzene 56 (Equation 8) and diethynyl pyrrole in a Sonogashira cross-coupling reaction <2005MM4687>. 

A methodology for the synthesis of substituted thiazolo[3,2-rz]benzimidazoles 250 from 2-propargylmercapto benzimidazole 249 was developed based on a tandem Sonogashira cross-coupling with iodoaryls and a subsequent exocyclic heterocyclization (Equation 109) <2004TL5747>. 

In addition, Rollin et al.26 have also developed a new modified Sonogashira cross-coupling reaction of OZTs, in which copper(i) is used in catalytic amount, allowing the formation of C-C bonds to produce alkynyloxazoles (Scheme 65). 

A similar Sonogashira cross-coupling reaction has been successfully extended to vinylic and heteroaromatic tellurium dichlorides. ... 

The Sonogashira cross-coupling of bromoalkenes is a useful method for making C—C bonds to terminal acetylenes [161]. It tolerates a variety of functional groups, and is catalyzed by a combination of Pd and Cu, through a cuprous acetylide intermediate. 

Figure 3.44 Catalytic cycle for the Pd-catalyzed Sonogashira cross-coupling the cuprous acetylide intermediate is highlighted in gray.

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],... 

Scheme 10.2 shows a protocol for synthesizing 1 and its further transformation into 4 [13a,d], Monolithiation of the diiodide 9 followed by treatment with S8 and AcCI generated 1. Next, a Sonogashira cross-coupling reaction with trimethylsilyl-acetylene afforded 10 in high yield. Desilylation was obtained upon treatment with n-Bu4NF, which provided the terminal alkyne 4. 

Scheme 10.7 depicts the synthesis of an OPE3 one-terminal wire compound by repeated Sonogashira cross-couplings [13c]. The synthesis takes advantage of the more reactive iodide as compared with the bromide, which allows for stepwise scaffolding. Thus, two concomitant Pd-catalyzed cross-couplings of 23 produced 24. The terminal alkyne obtained after desilylation was subsequently cross-coupled with 1 to afford 25. 

Scheme 4. Palladium(0)-catafyzed syntheses of mannoside dimers using Sonogashira cross-coupling reactions.

Scheme 5 Alkynones 8 by modified Sonogashira cross coupling of acid chlorides 7 and alkynes 4...

Scheme 6 Trimethylsilyl alkynones 8a-e by modified Sonogashira cross coupling...

The Sonogashira cross-coupling reaction was applied to p-phenylethynes and 2-chloroquinoline. The resulting compounds are blue-green emitters. Their electrogenerated chemiluminescence properties were reported <03CC2146>. 

A, A -dimethylaniline group has been synthesized by a copper-free Sonogashira cross-coupling reaction using microwave irradiation as the source of energy <2006EJO2344>. The electrochemical and photophysical properties of the triad were systematically investigated by techniques such as time-resolved fluorescence and transient absorption spectroscopy. 

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