Reaction of Alkynes with Organic Halides

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. Recently, 

Alkenyl and aryl iodonium salts have also been coupled with terminal alkynes. The reaction of (E)-[P-(trifluoromethanesulfonyloxy)- 

A potentially interesting development is the microwave-assisted transition-metal-free Sonogashira-type coupling reaction (Eq. 4.10). The reactions were performed in water without the use of copper(I) or a transition metal-phosphine complex. A variety of different aryl and hetero-aryl halides were reactive in water. The amount of palladium or copper present in the reaction system was determined to be less than 1 ppm by AAS-MS technique. However, in view of the recent reassessment of a similarly claimed transition-metal-free Suzuki-type coupling reaction, the possibility of a sub-ppm level of palladium contaminants found in commercially available sodium carbonate needs to be ruled out by a more sensitive anal 4ical method.  

Palladium/charcoal also could serve as a catalyst for Sonogashira reactions of peptides in aqueous media. Recently, Granja et al. used palladium/carbon associated with 4-diphenylphosphinobenzoic acid (4-DPPBA) or triphenylphosphine ligand to catalyze such a reaction in aqueous DMF (Eq. 4.16).  

Kotschy et al. also reported a palladium/charcoal-catalyzed Sono-gashira reaction in aqueous media. In the presence of Pd/C, Cul, PPhs, and i-Pr2NH base, terminal alkynes smoothly reacted with aryl bromides or chlorides, such as 2-pyiidyl chloride, 4-methylphenyl bromide, and so on, to give the expected alkyne products in dimethyl-acetamide (DMA)-H20 solvent. Wang et al. reported an efficient cross-coupling of terminal alkynes with aromatic iodides or bromides in the presence of palladium/charcoal, potassium fluoride, cuprous iodide, and triph-enylphosphine in aqueous media (THF/H2O, v/v, 3/1) at 60°C. The palladium powder is easily recovered and is effective for six consecutive runs with no significant loss of catalytic activity. 

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Cacchi, S., Fabrizi, G., Parisi, L. M. Nitrogen-containing heterocycles via palladium-catalyzed reaction of alkynes with organic halides or triflates. Heterocycles 2002, 58, 667-682. 

Syntheses of A-heterocycles via palladium-catalyzed reactions of alkynes with organic halides or triflates 02H(58)667. 

Alkynes undergo a variety of reactions using either Pd(II) or Pd(0), and each topic appears in separate chapters. Oxidative reactions of alkynes with Pd(II) are surveyed in Chapter 2.6, and Pd(0)-catalyzed reaction of alkynes with organic halides are summarized in Chapter 3.4, and other typical reactions of alkynes are treated in this chapter. Since benzynes are regarded as reactive alkynes, they are surveyed in this chapter. 

The reaction of thienyllithium with organic halides to form C—C bonds has been discussed in Section 2.10.4.7.2. This cannot, however, be extended to aryl, alkenyl or heteroaryl halides in which the halogen is attached to an sp carbon. Such cross-coupling can be successfully achieved by nickel or palladium-catalyzed reaction of the unsaturated organohalide with a suitable thienyl metal derivative. The metal is usually zinc, magnesium, boron or tin occassionally lithium, mercury, copper, and silicon derivatives of thiophene have also found application in such reactions. In addition to this type, the Pd-catalyzed reaction of halogenated thiophenes with suitable alkenes and alkynes, usually referred to as the Heck reaction, is also discussed in this section. Besides these, a few other miscellaneous Pd-catalyzed substitution reactions on thiophene will also be referred to. 

The reaction of certain palladium-heteroatom complexes to alkenes and alkynes is a versatile tool for the synthesis of alkanes and alkene having heteroatoms attached. In particular, the various B-B, B-Si, and B-Sn compounds can be used for palladium-catalyzed borylation of alkenes and alkynes (Scheme 5-2). Borostannylation takes place at ambient temperature, whereas silylboration " only proceeds at a temperature above 80 °C due to the slow oxidative addition of a B-Si bond to a palladium(O) catalyst. Both reactions selectively provide cz j-products via addition of silicone or tin to the internal carbon and boron. The reactions are compatible with various functional groups for both terminal and internal alkynes. Cross-coupling reaction of boranes with organic halides selectively occurs at the terminal C-B bonds to provide regiodefined and stereodefined alkenylboron, alkenylsilicon, and alkenyltin compounds. 

Cross-coupling Reactions of Terminal Alkynes with Organic Halides... 

In Grignard reactions, Mg(0) metal reacts with organic halides of. sp carbons (alkyl halides) more easily than halides of sp carbons (aryl and alkenyl halides). On the other hand. Pd(0) complexes react more easily with halides of carbons. In other words, alkenyl and aryl halides undergo facile oxidative additions to Pd(0) to form complexes 1 which have a Pd—C tr-bond as an initial step. Then mainly two transformations of these intermediate complexes are possible insertion and transmetallation. Unsaturated compounds such as alkenes. conjugated dienes, alkynes, and CO insert into the Pd—C bond. The final step of the reactions is reductive elimination or elimination of /J-hydro-gen. At the same time, the Pd(0) catalytic species is regenerated to start a new catalytic cycle. The transmetallation takes place with organometallic compounds of Li, Mg, Zn, B, Al, Sn, Si, Hg, etc., and the reaction terminates by reductive elimination. 

There are many other transition-metal catalyzed coupling reactions that are based on organic halides in aqueous media. One example is the coupling of terminal alkyne with aryl halides, the Sonogashira coupling, which has been discussed in detail in the chapter on alkynes (Chapter 4). An example is the condensation of 2-propynyl or allyl halides with simple acetylenes in the presence of copper salts. 

Furo[2,3- ]pyridines can be synthesized from alkynylpyridones and iodonium sources (Scheme 31) <20060L1113>. Iodine proved to be much more effective at promoting the iodocyclization reaction than other iodonium sources (ICl, A -iodosuccinimide (NIS)). The pyridinium triiodide salt, 104, can be converted into the corresponding pyridinone by treatment with an external source of iodide. In a variation of the reaction, a one-pot synthesis of the furopyridine derivatives 105 can be achieved, with overall yields of 79-92%, by treatment with iodine followed by sodium iodide without isolation of the triiodide salt. Another similar one-pot synthesis involves 3-iodo-2-pyridones, terminal alkynes, and organic halides in a series of two palladium cross-coupling reactions (Equation 45) <20030L2441>. This reaction could also be carried out in a two-step sequence, but the overall reaction yields were typically improved for the one-pot method. 

As described above (Section 5.2), the Stephens-Castro reaction of alkynylcopper with aryl and vinyl halides in boiling pyridine is a useful route to aryl and vinyl acetylenes. Direct cross-coupling of organic halides, such as sp halides, with terminal alkynes is a more convenient procedure. Such a reaction is not so easy, but it can be done using a Pd-complex catalyst [41]. Especially facile Pd-catalyzed cross-coupling of aryl and alkenyl halides with terminal alkynes proceeds smoothly under mild conditions in the presence of a cocatalyst of cuprous iodide in amine solvents [Eq. (28)] [42]. This methodology is now used widely for the constiuction of conjugated arylalkyne or enyne systems [43], as described below. It is attractive from a synthetic point of view because mild reaction conditions and simplicity of the procedure are associated with recent developments in modem acetylene chemistry [44]. 

The principal methods for forming the carbon-tin bond involve the reaction of organo-metallic reagents with tin compounds (equation 4-1), the reaction of stannylmetallic compounds with organic halides (equation 4-2), the reaction of tin or tin(II) compounds with alkyl halides (equation 4-3), the hydrostannation of alkenes or alkynes (equation 4-4), the reaction of acidic hydrocarbons with Sn-0 and Sn-N bonded compounds (equation 4-5), and carbonyl-forming eliminations (equation 4-6) the symbol sn represents 4Sn. 

Coupling reactions with organic halides 29-30 Cpfl iCB-catalyzcd hwlronumncsiaiion of alkynes 97 102 CpBr 251... 

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