Heterocycles from aromatic compounds

Leonid Belen kii was born in Moscow, and he graduated from M. V. Lomonosov Moscow State University in 1953 with Professor A. P. Terentiev as supervisor in organic chemistry. Since 1955, he has worked as junior, senior (since 1966), and leading scientist (since 1988) at N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, where he obtained his Ph.D. degree (1963) under the direction of Professor Ya. L. Gol dfarb and his Degree of Dr. Chem. Sci. (1974) and rank of Professor in Chemistry (1991). His scientific interests include all aspects of chemistry of heterocyclic and aromatic compounds, particularly electrophilic substitution in benzene, thiophene, furan, and azole series as well as organosulfur chemistry. 

The synthesis has been applied to a great variety of Mannich bases derived from aromatic compounds and from heterocycles, such as indole, pyridine, quinoline, coumar-in, etc.104 Compound 198, for instance, yields the pyranopyridine shown in equation 84104. 

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). 

The synthesis of aromatic heterocycles from propargylic compounds 12AJO108. 

Acridine is a heterocyclic aromatic compound obtained from coal tar that is used in the syn thesis of dyes The molecular formula of acndine is C13H9N and its ring system is analogous to that of anthracene except that one CH group has been replaced by N The two most stable reso nance structures of acridine are equivalent to each other and both contain a pyndine like struc tural unit Wnte a structural formula for acridine... 

Halides derived from certain heterocyclic aromatic compounds are often quite reac tive toward nucleophiles 2 Chloropyridme for example reacts with sodium methoxide some 230 million times faster than chlorobenzene at 50°C... 

From the preparative point of view, reactions of heterocyclic aromatic compounds with nucleophilic reagents are very important, especially the reactions of their quaternary salts containing a formal enamine grouping in the molecule. 

Heterocyclic enamines A -pyrroline and A -piperideine are the precursors of compounds containing the pyrrolidine or piperidine rings in the molecule. Such compounds and their N-methylated analogs are believed to originate from arginine and lysine (291) by metabolic conversion. Under cellular conditions the proper reaction with an active methylene compound proceeds via an aldehyde ammonia, which is in equilibrium with other possible tautomeric forms. It is necessary to admit the involvement of the corresponding a-ketoacid (12,292) instead of an enamine. The a-ketoacid constitutes an intermediate state in the degradation of an amino acid to an aldehyde. a-Ketoacids or suitably substituted aromatic compounds may function as components in active methylene reactions (Scheme 17). 

In a saturated heterocyclic compound the situation is very different from that in an aromatic compound. The volume requirement of a... 

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. 

Further exploitation of the molecular shape feature has led more recently to the design of another series of clathrate hosts by substituting on the allene rigid backbone bulky groups 22>, Representative compounds of this new host family are 20 and 21. The allene 20 (R = t-butyl) shows an interesting clathration behaviour upon crystallization from various environments, including alicyclic and aromatic compounds, heterocycles, cyclic ketones and eyclohexaneamine 26>. 

As discussed in Chapter 6, nitro compounds are converted into amines, oximes, or carbonyl compounds. They serve as useful starting materials for the preparation of various heterocyclic compounds. Especially, five-membered nitrogen heterocycles, such as pyrroles, indoles, and pyrrolidines, are frequently prepared from nitro compounds. Syntheses of heterocyclic compounds using nitro compounds are described partially in Chapters 4, 6 and 9. This chapter focuses on synthesis of hetero-aromatics (mainly pyrroles and indoles) and saturated nitrogen heterocycles such as pyrrolidines and their derivatives. 

The interstellar dust was shown to contain quinone derivatives as well as oxygen-rich condensed aromatic compounds the quinones were present in both hydrated and carboxylated form. Very little nitrogen was present in the compounds detected. The cometary material, however, contained condensed nitrogen heterocycles. Hardly any oxygen was detected in the solid phase of the cometary dust it possibly evaporates from the tail of the comet in the form of water or oxidized carbon compounds. The authors assume that these analytical results could lead to a reconsideration of the current biogenesis models (Kissel et al 2004 Brownlee, 2004). 

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... 

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... 

We know that aromatic compounds, polynuclear and heterocyclic compounds follow Huckel s rule in which they have a (4n + 2) system of n electrons and the protons attached to such systems are extremely deshielded due to the circulating sextet of n electrons. As a result, the signals of aromatic protons appear at a very low field than those observed even for benzene. The tau value of benzene is T = 2.63. From this the aromaticity of a compound can be verified. 

The cydoaddition of different 1,3-dipoles such as azides [331, 341] and diazoalkanes [342-344] to acceptor-substituted allenes was thoroughly investigated early and has been summarized in a comprehensive review by Broggini and Zecchi [345], The primary products of the 1,3-dipolar cycloadditions often undergo subsequent fast rearrangements, for example tautomerism to yield aromatic compounds. For instance, the five-membered heterocycles 359, generated regioselectively from allenes 357 and diazoalkanes 358, isomerize to the pyrazoles 360 (Scheme 7.50) [331]. 

A number of nitrogen heterocyclic, aromatic compounds, riboflavin 26, folic acid 27a and biopterin 27b, isolated from natural sources, are related in structure to natural redox enzyme cofactors. The electrochemistry of these and related compounds has been studied extensively. 

Other heterocyclic compourtds containing four sulfur atoms - tetrathiocines 196, 197 - were synthesized from activated aromatic compounds, in particular 1,2-dialkoxybenzenes or 2,3-dialkoxynaphthalenes, and sulfur monochloride in acetic acid in fairly good yields (1989PS111 Scheme 97). Biphenyl 154 treated with S2CI2 under the same conditions yielded 1,2-dithiines (see Section 4.3). 

Peracid oxidation of the D-homo-oestrone derivative (59) gave the C-ring aromatic compound (60). ° Mono- or tri-formylation with DMF-POCI3 of 17-methylene-steroids led to the unsaturated aldehydes (61) or the dimethylamino-bisaldehydes (62) which were readily converted with NHa-EtOH into the heterocycles (63). 14-Azidopregnanes are available from the reactions of A -... 

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