Aromatic heterocycles 2 synthesis

Thionyl chloride (SOCl2) is the most versatile of all sulfur transfer reagents in heterocyclic synthesis. The sulfur-oxygen bond renders the sulfur atom more electrophilic the possibility of ready removal by elimination of the oxygen atom allows easy aromatization of many of the initially formed sulfur heterocycles. Two general reviews of the chemistry of thionyl chloride are available.53 Both cover the literature up to about 1970. 

As the examples in Scheme 9 illustrate, treatment of a styrenyl ether, such as 35, with 5 mol%Ru catalyst la under an atmosphere of Ar (14 h) leads to the formation of 36 and 37 in 42% and 41% isolated yield, respectively. When the reaction is performed under an atmosphere of ethylene, 36 is obtained in 91 % yield. Furthermore, as exemplified by the conversion of 38a to 39a, electronic properties of the aromatic moieties exhibit little influence on the facility of the catalytic heterocycle synthesis. Eight-membered rings are appropriate substrates as well (Scheme 9 38b—>39b). 

Our study of heterocyclic compounds is directed primarily to an understanding of their reactivity and importance in biochemistry and medicine. The synthesis of aromatic heterocycles is not, therefore, a main theme, but it is useful to consider just a few examples to underline the application of reactions we have considered in earlier chapters. From the beginning, we should appreciate that the synthesis of substituted heterocycles is probably not best achieved by carrying out substitution reactions on the simple heterocycle. It is often much easier and more convenient to design the synthesis so that the heterocycle already carries the required substituents, or has easily modified functions. We can consider two main approaches for heterocycle synthesis, here using pyridine and pyrrole as targets. 

Aromatic fiuorination by the silver ion-promoted decomposition of aryl-diazo sulfides is similar to the Balz-Schiemann process. It provides efficient utilization of stoichiometric levels of fluoride ion, but has yet to be used for heterocyclic synthesis (91JOC4993). 

Dehydrochlorination of pentachlorocyclopropane, formed from trichloroethylene and sodium trichloroacetate as a source of dichlorocarbene, yields tetrachloro-cyclopropene [150], a particularly versatile reagent for various applications. It is a reasonably reactive dienophile [151], a reagent applicable to heterocyclic synthesis [152], and an electrophile for aromatic substitutions [153] and additions to alkenes [154] in the presence of Lewis acids. 

Reviews (a) V. Dave and E. W. Wamhoff, The Reactions of Diazoacetic Esters with Alkenes, Alkynes, Heterocyclic and Aromatic Compounds, in W. G. Dauben, ed., Organic Reactions, Vol. 18, Chap. 3, John Wiley Sons, New York, 1970. (b) G. Maas, Top. Curr. Chem., 137, 75 (1987). (c) J. Salaun, Chem. Rev., 89, 1247 (1989). (d) A. Demonceau, A. J. Hubert, and A. F. Noels, Basic Principles in Carbene Chemistry and Applications to Organic Synthesis, in A. F. Noels, M. Graziani, and A. J. Hubert, eds., Metal Promoted Selectivity in Organic Synthesis, p. 237, Kluwer Academic, Dordrecht, 1991. 

While the early examples of this cyclocondensation process typically involved a / -ketoester, aromatic aldehyde and urea, the scope of this heterocycle synthesis has now been extended considerably by variation of all three building blocks, allowing access to a large number of multifunctionalized pyrimidine derivatives. For this particular heterocyclic scaffold the acronym DHPM has been adopted in the literature and is also used throughout this chapter. Owing to the importance of multi-component reactions in combinatorial chemistry there has been renewed interest in the Biginelli reaction, and the number of publications and patents describing... 

It turns out that we must protect the phenol as its methyl ether 127 and that 126 is best used as an amidine-ester rather than the double enamine. The synthesis is then quite short. We have barely scratched the surface of aromatic heterocyclic synthesis in this chapter but the encouraging message is that cyclisation is easy and that cyclisations to form aromatic compounds are the easiest of all. Disconnect with confidence ... 

The use of nitro aromatics as dipolarophiles in cycloaddition reactions has shown great utility in heterocyclic synthesis. The reaction of 3-substituted-4-nitroisoxazoles (299) with trisubstituted oxazolium 5-oxides (300) affords an intermediate adduct (301) which eliminates carbon dioxide and nitrous acid to afford 3,4,6-trisubstituted pyrrolo[3,4-r/]isoxazoles (302) (Scheme 56) <93G633>. 

The heterobenzene ( -C5H5P)2Cr can be directly prepared by the metal-ligand vapor cocondensation technique. This heterocycle is aromatic and prefers ( -coordination to -coordination. For pyridine, cr-coordination via a lone pair is highly preferred over bonding that utihzes the tt-electron system. Therefore the direct synthesis of jj -pyridine metal complexes requires the N-atom to be blocked by means of substitution in the 2,6-positions ... 

The ability of the Dieckmann reaction to tolerate heteroatoms in the ring-forming sequence of atoms has led to its extensive use in heterocyclic synthesis. Many complex systems containing heterocyclic rings have been prepared by routes that include this reaction, and twth aromatic and alicyclic rings have been constructed. A variety of bases and solvents have been employed and representative examples are illustrated in Scheme 45. 

Radicals can be generated from aromatic compounds by different methods and can be used for heterocycles synthesis. This is illustrated by the synthesis " in modest yield (45%) of benzoquinolones (phenan-thridones) starting with 2-aminobenzanilides (such as 4.43, Scheme 4.47). The amino group is converted to the stable (even when dry) dia-zonium fluoroborate (4.44) from which an aiyl radical is generated by action of metallic copper. The radical then adds to a double bond of the second benzene ring (Scheme 4.47) to form radical 4.45, which is resonance delocalized. An oxidative step (even just exposure to air) is then required to achieve the fully aromatic system of the phenanthridone (4.46). 

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