Organic halides alkyne reactions

Several Pd(0) complexes are effective catalysts of a variety of reactions, and these catalytic reactions are particularly useful because they are catalytic without adding other oxidants and proceed with catalytic amounts of expensive Pd compounds. These reactions are treated in this chapter. Among many substrates used for the catalytic reactions, organic halides and allylic esters are two of the most widely used, and they undergo facile oxidative additions to Pd(0) to form complexes which have o-Pd—C bonds. These intermediate complexes undergo several different transformations. Regeneration of Pd(0) species in the final step makes the reaction catalytic. These reactions of organic halides except allylic halides are treated in Section 1 and the reactions of various allylic compounds are surveyed in Section 2. Catalytic reactions of dienes, alkynes. and alkenes are treated in other sections. These reactions offer unique methods for carbon-carbon bond formation, which are impossible by other means. 

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. 

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,... 

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. 

Another versatile domino process for the synthesis of carbocycles as well as heterocycles is the Pd-catalyzed reaction of organic halides or triflates with alkynes or allenes, which contain a carbo- or heteronucleophile in close vicinity to these functionalities (see Scheme 6/1.75) [133]. 

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. 

Alkylation of Alkynes. Organic halides can alkylate acetylenes in the presence of Lewis acids. In most cases, however, the products are more reactive than the starting acetylenes. This and the ready polymerization of acetylenes under the reaction conditions result in the formation of substantial amounts of byproducts. Allyl, benzyl, and tert-alkyl halides giving stable carbocations under mild conditions are the best reagents to add to acetylenes.44 56... 

The reaction of heterocyclic lithium derivatives with organic halides to form a C-C bond has been discussed in Section 3.3.3.8.2. This cannot, however, be extended to aryl, alkenyl or heteroaryl halides in which the halogen is attached to an sp2 carbon. Such cross-coupling can be successfully achieved by nickel or palladium-catalyzed reaction of the unsaturated organohalide with a suitable heterocyclic metal derivative. The metal is usually zinc, magnesium, boron or tin occasionally 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 heterocycles with suitable alkenes and alkynes, usually referred to as the Heck reaction, is also discussed in this section. 

The addition of H—X, where X = F, Cl, Br and I, to alkenes, dienes and alkynes has been extensively studied from both mechanistic1-3 and synthetic standpoints. While it is one of the earliest methods employed for the synthesis of organic halides, it can often lead to mixtures of products, and the direct conversion of the corresponding alcohols is more commonly used nowadays. The early literature abounds with examples of this reaction in which either mixtures of products are formed, or the products are not well characterized. Few major advances have been reported in more recent times which overcome the synthetic disadvantages of this direct process. It can nevertheless be the method of choice for the synthesis of certain substrates. 

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

Benzylpalladation.11 Benzyl halides do not undergo usual radical cyclizations effected with organic halides, but do undergo Pd-catalyzed cyclization with alkenes and alkynes. A typical reaction is formulated in equation (I). The leaving group can also be Br, I, or OMs, but not OCOOCH3 or OCOCH3. Attempts to cyclize 1 with... 

New reports of organozirconium-organic halide cross-coupling reactions have almost completely stopped. Nevertheless, the palladium-catalyzed cross-coupling of vinyl zir-conocenes (from alkyne hydrozirconation) with vinyl halides has been employed in the synthesis of the lipid isobutylamide natural product anacyclin (equation 98). ... 

With a combination of organic halide, alkene or alkyne, and palladium catalyst, the reaction may take a superficially similar, but different pathway other than a Heck-type reaction. In these, the halogen is retained in the products, as an alkyl or vinyl halide. These results occur when the starting organic halide is allyl, a- to a carbonyl or similar group, or attached to a perhalogenated carbon atom. In much of the early work, mixtures with Hecklike elimination products were obtained, due to elimination caused by the presence of amine bases in the reaction mixture (equation 165)323. 

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