Formation of a Carbon-Heteroatom Bond

The radical cations generated at the anode surface can dimerize before they diffuse into solution. The dimeric compound formed can then be cyclized in solution via formation of a carbon-heteroatom bond. The anodic oxidation of enaminones reported earlier [46] and also recently [47] could serve as an illustration of this type of intermolecular cyclization. 

Transition metal catalyzed insertion reactions offer a convenient route for the preparation of five membered heterocyclic rings. Besides intramolecular Heck-couplings and CO insertion, examples of the intramolecular insertion of an acetylene derivative constitute the majority of this chapter. Although some of these processes involve the formation of a carbon-heteroatom bond, they are discussed here. 

A significant part of the examples of transition metal catalyzed formation of five membered heterocycles utilizes a carbon-heteroatom bond forming reaction as the concluding step. The palladium or copper promoted addition of amines or alcohols onto unsaturated bonds (acetylene, olefin, allene or allyl moieties) is a prime example. This chapter summarises all those catalytic transformations, where the five membered ring is formed in the intramolecular connection of a carbon atom and a heteroatom, except for annulation reactions, involving the formation of a carbon-heteroatom bond, which are discussed in Chapter 3.4. 

Many heterocyclic rings are made by the formation of a carbon-heteroatom bond and it is important when planning this to get the oxidation level of the carbon electrophile right. If we disconnected either C-N bond of the pyrrole 8, we get back to a ketone and an amine 9. If we disconnected the imine in imidazole 10 we should also get back to a ketone and an amine 11. Both 9 and 11 are unstable and neither is likely to be a real intermediate but the point is worth making. These carbon electrophiles are at the aldehyde or ketone oxidation level. 

Examples of syntheses involving the formation of a carbon-heteroatom bond are rare. Equation (20) shows one such reaction <1996CB1541>. 

The enhanced tendency toward the formation of five- and six-membered rings is also widely exploited in methods developed to synthesize heterocyclic systems. In these cases, ring formation involves the creation of a carbon-heteroatom bond. A set of representative examples is shown in Scheme 2.112. 

More recently, a radical-mediated variation of this addition-fragmentation has been explored. The reaction, summarized in Scheme 77 for a one-carbon expansion, involves the generation of a radical at the terminus of a chain by homolytic cleavage of a carbon-heteroatom bond. Addition of the radical to the carbonyl produces a bicyclic intermediate, which on cleavage of the alternate bond regenerates the ketone carbonyl group with formation of a new radical. The sequence is terminated by the reduction of the radical with the tributyltin hydride reagent. The near neutral conditions of the reaction avoid the reclo-... 

Nucleophilic attack on Pd-bound ligands, be they a, tt, or (t-tt, provides an assortment of excellent methods for the formation of carbon-carbon and carbon-heteroatom bonds, as represented by general transformations shown in Scheme 1. In particular, these processes have provided three major methods for the formation of the carbon-heteroatom bonds, and they have extensively been applied to the synthesis of natural products. More recently, the Pd-catalyzed cross-coupling has also been developed so as to be applicable to the formation of C— N, C—O, and other carbon-heteroatom bonds, as discussed in Sect. III.3, even though the current scope of their application to natural product synthesis is still rather limited. 

A number of methods are available for the preparation of aromatic polymers. The majority of these methods involve the formation of a chemical bond between a carbon atom and a heteroatom. Typical of these are, for example, aromatic polycarbonates the latter are prepared by the reaction of a dihydric phenol with phosgene or derivative thereof.The polymerization proceeds via formation of a carbon-oxygen bond. A similar situation is encountered with the class of polyarylates — the polyesters from dihydric phenols and aromatic diacids. " ... 

In 2000, Fiirstner et al. reported platinum-catalyzed reaction of alkynyl allyl ethers 1 to tetrahydrofuran derivatives 2 (Scheme 27.1) [2]. After this pioneering work, the TT-acidic metal-catalyzed tandem carbon-heteroatom bond formation/1,3-migration reaction became a powerful synthetic method of polysubstituted heteroarenes, since the aromatization process often drives the migration of various carbon functional groups involving cleavage of a carbon-heteroatom bond. 

The synthesis of the promazine 444 class of antipsychotics was pursued by medicinal chemists firom Lundbeck Pharmaceuticals (Deerfield, EL). Although the C—N and C S bond formations have been separately developed and optimized to practical use, the formation of multiple carbon-heteroatom bonds has been challenging. To this end, the researchers developed a palladium-catalyzed, three-component cross-coupling reaction in which the formation of one C—S bond from thiophenol 441 and aromatic halogenide 443 and two C—N bonds from amines 442 were accomplished in a one-pot tandem reaction fashion (Scheme 46.50). 

By far the most common way for organic molecules to enter late transition metal catalyzed reactions is oxidative addition. In this process a low valent palladium(O)3 or nickel(O) atom inserts into a carbon-heteroatom bond, usually of an aryl halide or sulfonate (Figure 1-2). The formation of the carbon-metal bond is accompanied by an increase in the oxidation number of the metal by 2. There are a series of factors determining the speed of the process. 

When reductive elimination from a late transition metal involves the formation of a carbon-carbon bond, the process is intramolecular and the groups have to be aligned cis to one another in the complex. In the formation of carbon-heteroatom bonds the reductive elimination from palladium might take place via competing pathways.16... 

The transition metal catalyzed synthesis of five membered heterocycles, particularly of condensed ring systems, has attracted considerable attention. The ease of the formation of five membered rings has been utilised both in intramolecular ring closure processes, and in the combination of two (three) fragments through the formation of a carbon-carbon and a carbon-heteroatom bond. This chapter is dedicated to examples, where the construction of the five membered heterocycle is achieved in a transition metal catalysed step. 

The palladium catalyzed iminoannulation and carboxyannulation of alkynes and an appropriate aryl/vinyl halide is an efficient tool to construct six membered nitrogen and oxygen heterocycles. The process encompasses the concomitant formation of a carbon-carbon and a carbon-heteroatom bond. 

The formation of a new carbon-carbon bond needs activation energy generally higher than that involved in a carbon-heteroatom bond breakage, and therefore the requirements for a catalyst, aiming to promote this kind of reaction, are stronger if... 

The cnc reaction is now considered to include not only all carbon enophiles, as in equation 1, but also those with one heteroatom (equation 2) and with two heteroatoms (equation 3). Those enophiles with one heteroatom invariably react in the fashion depicted, i.e., the formation of a C —C bond, as of course is the case with all carbon enophiles. Eue reactions that form C-C bonds (equations 1 and 2) are covered in Section D. 1.6.2. Heteroatom-carbon bond formation using singlet oxygen is treated in Section D.4.9. and ene reactions of selenium dioxide are covered in Section D.4.10. Ene reactions that establish a bond between carbon and a nitrogen are covered here. 

The hetero-cycloaddition of C—C unsaturated bonds with C=0 and C=N bonds constructs heterocycles through concerted formation of both a carbon—carbon and a carbon—heteroatom bond.177 The hetero-Pau-son—Khand reaction using CO, alkyne, carbonyl group is a typical hetero-[2 + 2 + 1]-cycloaddition, giving five-membered heterocycles. Hetero-Diels— Alder reaction, that is, hetero-[4 + 2]-addition, produces six-membered heterocycles. 

Transition-metal-catalyzed hetero-[2 + 2 + 2]-cy-cloaddition of alkynes with carbon—heteroatom multiple bonds, such as isocyanides, carbon dioxide, nitriles, aldehydes, and ketones, provides heteroare-nes and unsaturated heterocycles. This reaction can be categorized into two groups one is the reaction of l,a>-diynes 397 with carbon—heteroatom multiple bonds, and the other is reaction of the alkynes 399, having a carbon—heteroatom multiple bond with alkynes as illustrated in Scheme 127. The reaction of 1,6 -diynes 397 proceeds through formation of the metalacyclopentadiene intermediate 398 followed by insertion of a carbon—heteroatom multiple bond, such as heterocumulenes (route a),189 nitriles (route b),190 and carbonyls (route c).191 On the other hand, the... 

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