Synthesis heterocyclic aromatic compounds

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formula of acridine is C13H9N, and its ring system is analogous to that of anthracene except that one CH group has been replaced by N. The two most stable resonance structures of acridine are equivalent to each other, and both contain a pyridine-like structural unit.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. 

Heterocyclic aromatic compounds can sometimes be reduced, particularly those which are electron-deficient. For example, reduction of pyridines gives 1,4-dihydropyridines (which are readily hydrolysed to 1,5-dicarbonyl compounds). Partial reduction of five-membered heteroaromatic compounds such as furans and pyrroles is also possible if these have electron-withdrawing substituents to stabilize the intermediate radical anion. For example, reduction of the furan 71 occurred with high selectivity to give the dihydrofuran 72, used in a synthesis of (-l-)-nemorensic acid (7.51).24... 

This family of foidamers consists of two, three, or five alternating aromatic heterocydes (pyridazine, pyrimidine, or pyrazine) and methyl-substituted aromatic carbocycles (tolyl, o-xylyl, or m-xylyl) cormected via urea groups (8 Figure 9.3) [14]. In a typical synthesis, heterocyclic diamine compounds were treated with aryl diisocyanate compounds to install a urea linkage between aromatic heterocyde and aromatic carbocyde (Umax = 5). 

Oxadiazoles and 1,2,4-oxadiazoles are heterocyclic aromatic compounds that appear in many bioactive molecules. Previous methods for the synthesis of 1,2,4-oxadiazoles include the coupling of amidoximes with carboxylic acid derivatives, aerobic C—H oxygenation of amidoximes, or a cyclization of nitrile oxides to nitriles. Telvekar and Takale developed the preparation of 1,2,4-oxadiazoles from substituted diketone derivatives through a Beckmann rearrangement process tScheme S.3S1. When treated with diphosphorus tetraiodide in dichloromethane at room temperature, dioximes 150 formed the Beckmann products, 1,2,4-oxadiazoles 151, in excellent yields. 

Rate and Regioselectivity in the Nitration of (Trifluoromethyl)benzene 474 Substituent Effects in Electrophilic Aromatic Substitution Activating Substituents 476 Substituent Effects in Electrophilic Aromatic Substitution Strongly Deactivating Substituents 480 Substituent Effects in Electrophilic Aromatic Substitution Halogens 482 Multiple Substituent Effects 484 Retrosynthetic Analysis and the Synthesis of Substituted Benzenes 486 Substitution in Naphthalene 488 Substitution in Heterocyclic Aromatic Compounds 489... 

The chemistry of the 1,3-dipole cycloaddition reaction, so elegantly elucidated by Professor Huisgen by the early 1960 s, appeared to be especially suited for the synthesis of aromatic polymers since the monomers could be recdily synthesized, and many of the dipolar additions gave high yields of 5-membered heterocyclic aromatic compounds. An inspection of the literature revealed that nitrili-mines, sydnones and nitrile oxide dipoles were especially suited. 

The reaction of A-acyliminium ions with nucleophilic carbon atoms (also called cationic x-amidoalkylation) is a highly useful method for the synthesis of both nitrogen heterocycles and open-chain nitrogen compounds. A variety of carbon nucleophiles can be used, such as aromatic compounds, alkcncs, alkyncs, carbcnoids, and carbanions derived from active methylene compounds and organometallics. 

Dihydro-1-vinylnaphthalene (67) as well as 3,4-dihydro-2-vinylnaphtha-lene (68) are more reactive than the corresponding aromatic dienes. Therefore they may also undergo cycloaddition reactions with low reactive dienophiles, thus showing a wider range of applications in organic synthesis. The cycloadditions of dienes 67 and 68 and of the 6-methoxy-2,4-dihydro-1-vinylnaphthalene 69 have been used extensively in the synthesis of steroids, heterocyclic compounds and polycyclic aromatic compounds. Some of the reactions of dienes 67-69 are summarized in Schemes 2.24, 2.25 and 2.26. In order to synthesize indeno[c]phenanthrenones, the cycloaddition of diene 67 with 3-bromoindan-l-one, which is a precursor of inden-l-one, was studied. Bromoindanone was prepared by treating commercially available indanone with NBS [64]. 

In recent years, the importance of aliphatic nitro compounds has greatly increased, due to the discovery of new selective transformations. These topics are discussed in the following chapters Stereoselective Henry reaction (chapter 3.3), Asymmetric Micheal additions (chapter 4.4), use of nitroalkenes as heterodienes in tandem [4+2]/[3+2] cycloadditions (chapter 8) and radical denitration (chapter 7.2). These reactions discovered in recent years constitute important tools in organic synthesis. They are discussed in more detail than the conventional reactions such as the Nef reaction, reduction to amines, synthesis of nitro sugars, alkylation and acylation (chapter 5). Concerning aromatic nitro chemistry, the preparation of substituted aromatic compounds via the SNAr reaction and nucleophilic aromatic substitution of hydrogen (VNS) are discussed (chapter 9). Preparation of heterocycles such as indoles, are covered (chapter 10). 

Diathiadiphosphetane disulfides are probably the most studied and the most thermally and hydrolytically stable of all the phosphorus-chalcogen heterocycles. They contain a central four membered P2S2 ring and can be prepared from heating phosphorus pentasulfide with aromatic compounds. The most well-known of these is Lawesson s reagent (43), which is made from anisole and phosphorus pentasulfide,92 and is used extensively in organic synthesis procedures (see Section 5.4.1). Other dithiadiphosphetane disulfides of note are 44 and 45, formed from the reaction of phosphorus pentasulfide with ferrocene or 1 -bromonaphthalene respectively.93... 

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. 

In most of cases, the fluorine atom(s) or the CF3 group(s) is borne by aromatic rings. Synthesis of these compounds for the optimization of hits as well as for parallel synthesis is done using the numerous fluoro aromatic or heterocyclic compounds that are commercially available. These latter compounds generally come from aromatic fluorination or trifluoromethylation reactions (especially the Balz-Schiemann reaction) and from heterocyclization reactions. However, fluoroaliphatic chains and fluorofunctionalities are more and more present, because of their pharmacological properties. Some examples are given in this section. 

Diketene also is widely employed as a natural and synthetic fiber cross-linking agent, wood preservative and paper-sizing agent. Both it and /3-propiolactone have wide application as chemical intermediates. The synthetic applications of diketene for the synthesis of aromatic, heterocyclic and aliphatic compounds is exceptionally extensive (74ACR265). 

Effect of Heteroelements in Modifying Some Cyclizations — Polycyclic Aromatic Compounds from the Diene Synthesis , W. Davies and O. N. Porter, in Proceedings of a Symposium on Current Trends in Heterocyclic Chemistry , ed. A. Albert, G. M. Badger and C. W. Shoppee, Academic Press, New York, 1958, pp. 56-58. 

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. 

Interesting possibilities of synthesis arise when elimination leads to cyclic products. Such cyclization is fairly common with aromatic compounds. The mixture of products obtained from diphenylmethane contains about 25 per cent fluorene 2S> (Table 3). Similarly, benzophenone yields about 30 per cent fluorenone 20). The same method can be applied to the synthesis of heterocyclic compounds. Diphenylamine yields up to 30 per cent carbazol 26 di-phenylether about 10 per cent dibenzofurane 16). 

Superacid-promoted dicationic species containing heteroaromatic rings, where positive charge centres migrate through consecutive deprotonation-reprotonation steps, undergo cyclization reactions followed by aromatization and superacid-promoted elimination of benzene (Scheme 10).31 The process leads to the synthesis of aza-polycyclic aromatic compounds in moderate to good yields. Seven examples include pirazole, oxazole, and thiazole heterocycles. 

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 ... 

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