Synthesis of Carbocycles and Heterocycles

Abstract In this chapter different types of domino-processes are described which consist of the combination of cationic, anionic, radical, pericyclic and transition metal-catalyzed as well other reactions. The methodology is used for the highly effective synthesis of carbocycles and heterocycles as well as of natural products and other interesting materials. It is also employed as an efficient tool in combinatorial chemistry. 

Synthesis of Carbocyclic and Heterocyclic 7r-Electron Systems with Pentafulvenoid Chloroformamidinium Chlorides K. Hafner and H.-P. Krimmer, Angew. Chem., Int. Ed. Engl., 1980,19, 199-201. 

N. Sotomayor, E. Lete, Aryl and Heteroaryllithium Compounds by Metal-Halogen Exchange. Synthesis of Carbocyclic and Heterocyclic Systems, Curr. Org. Chem. 2003, 7, 275-300. 

Stannyl ketyl radicals were generated from an amide carbonyl group and when incorporated in cinnamic enamides, indolizidinone rings can be assembled [37]. Du and Curran have shown that a-thioaminoalkyl radicals such as 24 resulting from the addition of a tris(trimethylsilyl)radical onto N-aryl thiocarbamates, thioamides or thioureas 22, can be exploited in the context of the synthesis of carbocyclic and heterocyclic fused quinolines 23 (Scheme 8) [38]. 

This chapter emphasizes recent applications of microwave technology in the synthesis of carbocycles and heterocycles by cycloaddition reactions. In these applications, it is clearly demonstrated that it is possible to use two different types of... 

When alkyne TT-activation meets pinacol-type [l,2]-rearrangement On the invention of domino reactions for the synthesis of carbocycles and heterocycles 13SL1471. 

AlkenyIphosphonium salts and alkenylphosphine oxides are both of use in the synthesis of carbocyclic and heterocyclic systems, and new routes to these derivatives are of value. Cycloalkenes react... 

Abstract Several routes to access ruthenium (Ru)-vinylidene complexes are described, the majority of which employ alkynes and a Ru source as the starting materials. The successful application of Ru-vinylidenes as efficient pre-catalysts for the synthesis of carbocyclic and heterocyclic compoimds by ring-closing metathesis (RCM) of a, -dienes, and in the synthesis of polymers by ring-opening metathesis polymerization (ROMP) of cyclooctene, norbomene, 5-substituted norbomene, and dicyclopentadiene is fully illustrated. Relevant aspects concerning the activity and selectivity of this type of Ru complexes in metathesis reactions are highlighted. 

Diels-Alder-type Reactions. The Diels-Alder reaction has long been recognized and employed as a highly important transformation for the synthesis of carbocycles and heterocycles. Following the Yb(OTf)3-catalyzed Povarov (imino variant of the Diels-Alder reaction) reaction of cyclopentadiene or dihydrofuran with in situ formed imines, other RE(OTf)3 catalysts have been employed to study this transformation. One example is the three-component coupling of anilines, formaldehyde, and electron-rich... 

In this chapter, the scope, mechanism, and recent progress of zirconocene (Il)-mediated cyclization reactions are introduced. Zirconocene(II) is a very important reagent for organometallic chemistry, synthetic chemistry, and polymer chemistry. Zirconocene(II) is capable of coordinating with unsaturated compounds. Further reactions could lead to zirconocene(IV) species, zirconacycles, C-C bond formation, C-X bond formation, and synthesis of carbocycles and heterocycles. Zirconocene(lI)-mediated cyclization of bis(alkynyl)silane gives zirconacyclobu-tene-silacyclobutene complexes, which could react with alkyne, bis(alkynyl)silane, ketone, nitrile, and isocyanate and could be applied in the synthesis of various valuable products. 

The transition-metal-catalyzed intramolecular hydroarylation of alkynes has emerged in recent years as a powerful tool for the atom-economical synthesis of carbocyclic and heterocyclic compotmds [101-104], including coiunarin derivatives [105-109]. In this context, Kitamura and coworkers have described the high-yield preparation of several angelicin derivatives 50 by intramolecular hydroarylation of 4-benzofuranyl alkynoates 49 using Pd(OAc)2 as catalyst (Scheme 23) [110]. The starting materials 49 are easily accessible substrates that can be generated by the condensation of... 

The transition-metal-catalyzed crossed [2 + 2 + 2] alkyne cyclotrimerization for the construction of a benzene unit also found uses in the synthesis of carbocyclic and heterocyclic natural products. Although this version has its challenges in the chemo-and regioselective outcome, its advantages are evident and lie in less labor-intensive syntheses of the alkyne building blocks. 

The intramolecular Hiyama reaction is excellently suited for the construction of carbocyclic and heterocyclic ring systems of different size. In most examples, problems of induced diastereoselectivity are involved (Sections 1.3.3.3.9.2.2. and D.2.3.). In the total synthesis of the antitumor germacranolide ( )-costunolide from ( ,.E)-farnesol, the correctly substituted ( , )-cyclodecadiene moiety was constructed by an intramolecular Hiyama reaction22. 

The Alder-ene reaction has traditionally been performed under thermal conditions—generally at temperatures in excess of 200 °C. Transition metal catalysis not only maintains the attractive atom-economical feature of the Alder-ene reaction, but also allows for regiocontrol and, in many cases, stereoselectivity. A multitude of transition metal complexes has shown the ability to catalyze the intramolecular Alder-ene reaction. Each possesses a unique reactivity that is reflected in the diversity of carbocyclic and heterocyclic products accessible via the transition metal-catalyzed intramolecular Alder-ene reaction. Presumably for these reasons, investigation of the thermal Alder-ene reaction seems to have stopped almost completely. For example, more than 40 papers pertaining to the transition metal-catalyzed intramolecular Alder-ene reaction have been published over the last decade. In the process of writing this review, we encountered only three recent examples of the thermal intramolecular Alder-ene reaction, two of which were applications to the synthesis of biologically relevant compounds (see Section 10.12.6). 

Functionalized cyclopropenes are viable synthetic intermediates whose applications [99.100] extend to a wide variety of carbocyclic and heterocyclic systems. However, advances in the synthesis of cyclopropenes, particularly through Rh(II) carboxylate—catalyzed decomposition of diazo esters in the presence of alkynes [100-102], has made available an array of stable 3-cyclopropenecarboxylate esters. Previously, copper catalysts provided low to moderate yields of cyclopropenes in reactions of diazo esters with disubstituted acetylenes [103], but the higher temperatures required for these carbenoid reactions often led to thermal or catalytic ring opening and products derived from vinylcarbene intermediates (104-107). 

Cyclopropenes are now readily available from a number of synthetic procedures and substituents may readily be introduced through 1-metallated species. The application of cyclopropenes in synthesis has to date provided routes to a very wide range of carbocyclic and heterocyclic systems derived by inter- or intra-molecular addition,... 

Trapping the carbon-centred radical intramolecularly, particularly with an alkene, has been used extensively in organic synthesis. This valuable strategy has found many important apphcahons for the preparahon of carbocyclic and heterocyclic natural products. Intramolecular reachons are inherently more favourable than the corresponding intermolecular reachons due to entropic factors and are typically fast processes that provide a a-bond at the expense of a ir-bond. 

Based on a transformation described by Catellani and coworkers [80], Lautens s group [81] developed a series of syntheses of carbocycles and heterocycles from aryl iodide, alkyl halides and Mizoroki-Heck acceptors. In an early example, the authors described a three-component domino reaction catalysed by palladium for the synthesis of benzo-annulated oxacycles 144 (Scheme 8.37). To do so, they used an m-iodoaryl iodoalkyl ether 143, an alkene substimted with an electron-withdrawing group, such as t-butyl acrylate and an iodoalkane such as -BuI in the presence of norbomene. It is proposed that, after the oxidative addition of the aryliodide, a Mizoroki-Heck-type reaction with nor-bornene and a C—H activation first takes place to form a palladacycle PdCl, which is then alkylated with the iodoalkane (Scheme 8.37). A second C—H activation occurs and then, via the formation of the oxacycle OCl, norbomene is eliminated. Finally, the aryl-palladium species obtained reacts with the acrylate. The alkylation step of palladacycles of the type PdCl and PdCl was studied in more detail by Echavarren and coworkers [82] using computational methods. They concluded that, after a C—H activation, the formation of a C(sp )—C(sp ) bond between the palladacycle PdCl and an iodoalkane presumably proceeds by oxidative addition to form a palladium(IV) species to give PdC2. This stays, in contrast with the reaction between a C(sp )—X electrophile (vinyl or aromatic halide) and PdCl, to form a new C(sp )—C(sp ) bond which takes place through a transmetallation. 

It was shown [119-132] that three-substituted aluminacyclopentanes are highly reactive toward nucleophilic and electrophilic reagents and cross-coupling, demetallation, and carbocyclization reactions. As a result, effective one-pot methods for the synthesis of carbo- and heterocyclic and bifunctional acyclic compotmds were elaborated (Scheme 23). 

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