Aromatic heterocycle synthesis pyridines

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. 

Finally, a synthesis of 2-arylselenazopyridines has been reported to occur by reaction between aromatic selenoesters and pyridines with adjacent amino and chloro substituents, in the presence of butyllithium (equation 179)958. These previously unattainable heterocycles have potential use as pharmaceuticals. 

This chapter describes in general terms the types of reactivity found in the typical six- and five-membered aromatic heterocycles. We discuss electrophilic addition (to nitrogen) and electrophilic, nucleophilic and radical substitution chemistry. This chapter also has discussion of orf/to-quinodimethanes, in the heterocyclic context. Organometallic derivatives of heterocycles, and transition metal (especially palladium)-catalysed chemistry of heterocycles, are so important that we deal with these aspects separately, in Chapter 4. Emphasis on the typical chemistry of individual heterocyclic systems is to be found in the summary chapters (7, 10, 13, 15, 19 and 23), and a more detailed examination of typical heterocyclic reactivity and many more examples for particular heterocyclic systems are to be found in the chapters - Pyridines Reactions and Synthesis , etc. 

This article describes strategies for the use of the halogen-dance reaction in the functionalization of aromatic heterocycles, and the synthesis of two pyridine-derived natural products, caerulomycin C and WS75624 B (Figure 1). The origins of this research lie in the... 

It should be pointed out that perfluorinated aromatic heterocyclic compounds is another valuable feedstock for the synthesis of unsaturated fluorinated heterocycles. For example, fluorination of F-pyridine over C0F3 at 120°C results in saturation of both C=C, leading to 81 as principal product, along with smaller amount of F-l-azacyclohexadiene-1,3." Fluorination of substituted pyridine 115 over C0F3 gives diene 116 in a high yield. 

A similar approach was used in case of aromatic fluorinated heterocycles. Ring-fluorinated pyridines containing one, two, and three fluorine substituents are reviewed in Chapter 6, whUe Chapter 7 focuses on the synthesis and typical chemical transformations of aromatic heterocycles containing perfluoroalkyl groups. 

The reaction of zirconacyclobutene-silacyclobutene fused compound 46 formed from Si-tethered diyne 45 with Cp2Zr(II) species has been used in the synthesis of fused aromatic heterocycles 47 (Scheme 11.18) [20]. When the zirconacycles 46 reacted with nitriles, the corresponding pyrrolo[3,2-c]pyridines 47 were formed. This indicates the unexpectedly strong effects of the alkynylsilyl groups on this unusual skeletal rearrangement of zirconacycles. 

Acridine is a heterocyclic aromatic compound obtained from coal tar that is used in the synthesis of dyes. The molecular formula of acridine is C13H9N, and its ring system is analogous to that of anthracene except that one CH group has been replaced by N. The two most stable resonance structures of acridine are equivalent to each other, and both contain a pyridine-like structural unit. Write a structural formula for acridine. 

The Hantsch pyridine synthesis provides the final step in the preparation of all dihydrop-yridines. This reaction consists in essence in the condensation of an aromatic aldehyde with an excess of an acetoacetate ester and ammonia. Tlie need to produce unsymmetrically subsrituted dihydropyridines led to the development of modifications on the synthesis. (The chirality in unsymmetrical compounds leads to marked enhancement in potency.) Methyl acetoacetate foniis an aldol product (30) with aldehyde 29 conjugate addition of ethyl acetoacetate would complete assembly of the carbon skeleton. Ammonia would provide the heterocyclic atom. Thus, application of this modified reaction affords the mixed diester felodipine 31 [8]. 

Alkyne-nitrile cyclotrimerization is a powerful synthetic methodology for the synthesis of complex heterocyclic aromatic molecules.118 Recently, Fatland et al. developed an aqueous alkyne-nitrile cyclotrimerization of one nitrile with two alkynes for the synthesis of highly functionalized pyridines by a water-soluble cobalt catalyst (Eq. 4.62). The reaction was chemospecific and several different functional groups such as unprotected alcohols, ketones, and amines were compatible with the reaction.119 In addition, photocatalyzed [2+2+2] alkyne or alkyne-nitrile cyclotrimerization in water120 and cyclotrimerization in supercritical H2O110121 have been reported in recent years. 

Transition metal complexes have been used in a number of reactions leading to the direct synthesis of pyridine derivatives from acyclic compounds and from other heterocycles. It is pertinent also to describe two methods that have been employed to prepare difficultly accessible 3-alkyl-, 3-formyl-, and 3-acylpyridines. By elaborating on reported194,195 procedures used in aromatic reactions, it is possible to convert 3-bromopyridines to products containing a 3-oxoalkyl function196 (Scheme 129). A minor problem in this simple catalytic process is caused by the formation in some cases of 2-substituted pyridines but this is minimized by using dimethyl-formamide as the solvent.196... 

Our own group is also involved in the development of domino multicomponent reactions for the synthesis of heterocycles of both pharmacologic and synthetic interest [156]. In particular, we recently reported a totally regioselective and metal-free Michael addition-initiated three-component substrate directed route to polysubstituted pyridines from 1,3-dicarbonyls. Thus, the direct condensation of 1,3-diketones, (3-ketoesters, or p-ketoamides with a,p-unsaturated aldehydes or ketones with a synthetic equivalent of ammonia, under heterogeneous catalysis by 4 A molecular sieves, provided the desired heterocycles after in situ oxidation (Scheme 56) [157]. A mechanistic study demonstrated that the first step of the sequence was a molecular sieves-promoted Michael addition between the 1,3-dicarbonyl and the cx,p-unsaturated carbonyl compound. The corresponding 1,5-dicarbonyl adduct then reacts with the ammonia source leading to a DHP derivative, which is spontaneously converted to the aromatized product. 

In view of the development of the synthesis of various aromatic and heterocyclic compounds from pyrylium salts (80T679), the preparation of the unsubstituted pyrylium salt from pyridine is noteworthy (Scheme 269) (53CB1327). The pyridine-sulfur trioxide complex undergoes ring opening to the sodium salt of pent-2-ene-1,5-dial. This salt cyclizes in perchloric acid via the red oxonium salt. 

As a result of interaction of 843 and pyridine, the adduct 845 is formed [53], The structures of coordination compounds 844 and 845 were proved by x-ray diffraction. As shown above (Sec. 3.4.3.2), the direct ammonia synthesis [55,56] with participation of various ligands (especially aliphatic, aromatic, and heterocyclic amines, aminoalcohols), elemental metals (or their oxides), and NH4SCN in mostly non-aqueous media, opens definite possibilities for obtaining thiocyanate complexes. In this respect, transformation (4.9) should be mentioned [57] ... 

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