Transition metal-mediated reactions in organic synthesis

Transition Metal Mediated Reactions in Organic Synthesis 

This week s Highlights focuses on three transition metal-catalyzed reactions. Jin-Quan Yu of Cambridge University reports (Organic Lett. 2003, 5, 4665-4668) that Pd nanoparticles catalyze the hydrogenolysis of benzylic epoxides. The reaction proceeds with inversion of absolute configuration (1 - 2). 

Laurel Schafer of the University of British Columbia reports (Organic Lett. 2003, 5, 4733-4736) that terminal alkynes undergo smooth hydroamination with a Ti catalyst. The intermediate imine 4 can be hydrolyzed to the aldehyde 5 or reduced directly to the amine 6. The alkyne to aldehyde conversion has previously been carried out by hydroboration/oxidation (J. Org. Chem. 1996, 61, 3224), hydrosilylation/oxidation (Tetrahedron Lett. 1984, 25, 321), or Ru catalysis (J. Am. Chem. Soc. 2001, 123, 11917). There was no previous general procedure for the anti-Markownikov conversion of a terminal alkyne to the amine. 

The construction of enantiomerically-pure carbocycles is a general problem in organic synthesis. Dirk Trauner (UC Berkeley) reports (Organic Lett. 2003, 5, 4113-4115) an elegant intramolecular Heck cyclization. The alcohol 7 is readily prepared in enantiomerically-pure form. Conditions can be varied so that either 8 or 9 is the dominant product from the cyclization. 

The usual selectivities are observed, with aryl alkyl ketones and alkyl methyl ketones being reduced with high enantioselectivity (1 - 2 and 3 - 4)). That 5 is reduced to 6 with high ee, with the reducing enzymes differentiating between an ethyl and an n-pentyl group, is even more impressive. 

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Transition metal-mediated reactions in organic synthesis... 

To date, the most commonly used transition metal-promoted cycloaddition in organic synthesis is the Pauson-Khand reaction. First reported by Pauson and Khandin 1973 [9],this transformation is the cobalt-mediated [2+2+1] cycloaddition of an alkyne, an alkene and carbon monoxide to form a cyclopentenone, Eq. (1). Although mechanistic understanding is Hmited, the accepted mechanism for the transformation is depicted in Fig. 2. Loss of two equivalents of CO followed by complexation of an alkyne produces 1. Subsequent loss of CO from... 

Chapter 5 includes complete coverage of the transition metals-mediated carbon-carbon bond forming reactions. Pd-, Ni-, Cr-, Zr- and Cu-catalyzed reactions such as Heck, Negishi, Sonogashira, Suzuki, Hiyama, Stille, Kumada reactions are covered in adequate details including the applications of these reactions in organic synthesis. 

A considerable number of reactions of CpRh(/x-CO)(/x- ) ) -F3CC=CCF3)RhCp have been reported which illustrates the diversity of products that can be obtained in transition metal alkyne chemistry see Organic Synthesis Using Metal-mediated Coupling Reactions). Reaction of this complex with dimethyldiazomethane forms a mixtme of (147) and (148), and on recrystallization (148) converts to (149) by... 

Although the process, which is called P-hydride elimination or simply p-elimination, is useful in organic synthesis, it competes with other reactions, thereby limiting its value. In general, since P-elimination is rapid, transition metal mediated reactions of species bearing P-hydrogens often fail. 

Since Reppe s discovery of the cyclotrimerization of acetylene to benzene in the presence of nickel carbonyl-phosphine complexes, the use of nickel catalysts in many organic transformations has become popular. Transition metal complex catalysis provides many elegant entries to carbon-carbon bond-forming reactions in organic synthesis. One notable example is carbocyclic ring expansion mediated by nickel(O) complexes. ... 

Pyrrolo[3,2-df pyridazines are a class of interesting and useful A -heterocycles [40—42]. However, synthetic methods for such heterocyclic compounds have been very much limited such as condensation of pyrrole-2,3-diones with hydrazine. There are no reports on one-pot multi-component synthesis of pyrrolo[3,2-(f py-ridazines [43]. Moreover, synthetic methods for pyrrole-2,3-diones are also very limited [43]. On the other hand, transition-metal-mediated reactions of azides are of great importance and versatility in organic synthesis, because azides could be readily transformed into a wide variety of valuable A -containing natural products and medicinal agents [44-50]. 

Over the past several decades, the application of transition metal-mediated reactions has become more and more important in organic synthesis. Just like organo-catalytic reactions and enzymatic processes, transition metal-mediated reactions can also prodnce molecnlar complexity using only catalytic amounts of mediators. In particnlar, a variety of methods have been developed for the formation of different types of bonds, inclnding C—C, C—H, C—N, C—O, C—S and C—P bonds, which provide synthetic chemists with novel tools for total synthesis. 

This chapter has taken the reader through a number of microwave-assisted methodologies to prepare and further functionalize 2-pyridone containing heterocycles. A survey of inter-, intramolecular-, and pericyclic reactions together with electrophilic, nucleophilic and transition metal mediated methodologies has been exemplified. Still, a number of methods remain to be advanced into microwave-assisted organic synthesis and we hope that the smorgasbord of reactions presented in this chapter will inspire to more successful research in this area. 

The use of hypervalent iodine reagents in carbon-carbon bond forming reactions is summarized with particular emphasis on applications in organic synthesis. The most important recent methods involve the radical decarboxylative alkylation of organic substrates with [bis(acyloxy)iodo]arenes, spirocyclization of para- and ortho-substituted phenols, the intramolecular oxidative coupling of phenol ethers, and the reactions of iodonium salts and ylides. A significant recent research activity is centered in the area of the transition metal-mediated coupling reactions of the alkenyl-, aryl-, and alkynyliodonium salts. 

Reactions of alkynyliodonium salts 119 with nucleophiles proceed via an addition-elimination mechanism involving alkylidenecarbenes 120 as key intermediates. Depending on the structure of the alkynyliodonium salt, specific reaction conditions, and the nucleophile employed, this process can lead to a substituted alkyne 121 due to the carbene rearrangement, or to a cyclic product 122 via intramolecular 1,5-carbene insertion (Scheme 50). Both of these reaction pathways have been widely utilized as a synthetic tool for the formation of new C-C bonds. In addition, the transition metal mediated cross-coupling reactions of alkynyliodonium salts are increasingly used in organic synthesis. 

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