Cyclization reactions, aromatic compounds

Heterocyclic compounds are important targets in organic synthesis. They possess numerous biological activities and can be used as intermediates for further transformations. Starting from readily accessible starting materials, various photochemical cyclization reactions provide convenient methods to build up to a large variety of heterocycles several reviews deal with them. In this context, the cyclization of aromatic compounds plays an important role. In these reactions, as in many ground state reactions of aromatic compounds, the aromatic character is momentarily suppressed. In this chapter, some of these reactions are discussed. 

The reactivity of alkylthiazoles possessing a functional group linked to the side-chain is discussed here neither in detail nor exhaustively since it is analogous to that of classical aliphatic and aromatic compounds. These reactions are essentially of a synthetic nature. In fact, the cyclization methods discussed in Chapter II lead to thiazoles possessing functional groups on the alkyl chain if the aliphatic compounds to be cyclized, carrying the substituent on what will become the alkyl side chain, are available. If this is not the case, another functional substituent can be introduced on the side-chain by cyclization and can then be converted to the desired substituent by a classical reaction. 

Aromatization of paraffins can occur through a dehydrocyclization reaction. Olefinic compounds formed by the beta scission can form a carbocation intermediate with the configuration conducive to cyclization. For example, if a carbocation such as that shown below is formed (by any of the methods mentioned earlier), cyclization is likely to occur. 

Alkyl radicals generated efficiently from allylsulfones in 80% aqueous formic acid induced a cyclization reaction on aromatic and heteroaromatic compounds to provide polycyclic aromatic and heteroaromatic derivatives (Eq. 7.17).37... 

PET reactions [2] can be considered as versatile methods for generating radical cations from electron-rich olefins and aromatic compounds [3], which then can undergo an intramolecular cationic cyclization. Niwa and coworkers [4] reported on a photochemical reaction of l,l-diphenyl-l, -alkadienes in the presence of phenanthrene (Phen) and 1,4-dicyanobenzene (DCNB) as sensitizer and electron acceptor to construct 5/6/6- and 6/6/6-fused ring systems with high stereoselectivity. 

The reduction of polymers can be carried out by using a diimide, generated in situ. The precursor for diimide can be p-toluenesulfonyl hydrazide (TSH), the reaction temperature is between 110-160 °C and the solvents are high boiling aromatic compounds. Possible side-reactions are cis-trans isomerization of 1,4-dienes, attachment of hydrazide fragments to the polymer, degradation and cyclization of the polymer. 

A common feature of any cyclization reaction is that a new intramolecular C—C bond is produced that would not have been formed in the absence of the catalyst. Those reactions in which one ring closure step is sufficient to explain the formation of a given cyclic product will be called simple cyclization processes, although their mechanism is, as a rule, complex. We shall distinguish those cases in which any additional skeletal rearrangement step(s) is (are) required to explain the process. Some specific varieties of hydrocarbon ring closure processes are not included. A recent excellent review deals with the formation of a second ring in an alkyl-substituted aromatic compound (12). Dehydrocyclodimerization reactions have also to be omitted—all the more since it is doubtful whether a metallic function itself is able to catalyze this process (13). 

The alkylation of benzene by alkylpotassium compounds has been reported by Bryce-Smith (S9) and is probably due to the increased base strength of organopotassium compounds over organosodium compounds. The potassium hydride eliminated in the cyclization reaction may add to ethylene to form ethylpotassium, which then may react with the aromatic to yield ethane and a benzylic carbanion [Reactions (16) and (17)]. 

Many natural aromatic compounds are produced from the cyclization of poly- -keto chains by enzymic aldol and Claisen reactions. Examples include simple structures like orsellinic acid and phloracetophenone, and more complex highly modified structures of medicinal interest, such as mycophenolic acid, used as an immunosuppressant drug, the antifungal agent griseofulvin, and antibiotics of the tetracycline group, e.g. tetracycline itself. 

As noted earlier, most classical antidepressant agents consist of propylamine derivatives of tricyclic aromatic compounds. The antidepressant molecule tametraline is thus notable in that it is built on a bicyclic nucleus that directly carries the amine substituent. Reaction of 4-phenyl-l-tetralone (18) (obtainable by Friedel-Crafts cyclization of 4,4-diphenyl butyric acid) with methyl amine in the presence of titanium chloride gives the corresponding Schiff base. Reduction by means of sodium borohydride affords the secondary amine as a mixture of cis (21) and trans (20) isomers. The latter is separated to afford the more active antidepressant of the pair, tametraline (20). 

Formation of aromatic compounds involves either the dehydrogenation (by way of reaction with carbonium ions) of the cyclohexane compounds or, less likely, the cyclization of a triolefinic carbonium ion. 

As seen in Figure 2.2 and from the corresponding discussion, dehydrocyclization is a key reaction in forming aromatic compounds.307 A study comparing dehydrocyclization over mono- and bifiinctional catalysts at atmospheric pressure and high pressure representative of naphtha reforming conditions concludes that primary aromatic products at all pressures are formed by direct six-carbon ring formation.313 Over bifunctional catalysts the acid-catalyzed cyclization is more rapid... 

The major classes of photochemical reaction for aromatic compounds are nucleophilic substitution and a range of processes that lead to non-aromatic products—valence isomerization, addition or cycloaddition reactions, and cyclization involving 6-electron systems. These five general categories of reaction will be described in the following sections, together with a few examples of more specific processes. 

Further extensions of the slilbene photocydizatinn are seen in analogous reactions of compounds containing the imine chro-mophore (e.g. 3,71 or an amide group (3.72). The amide reaction can be considered formally as giving a zwitterion intermediate, which undergoes proton shifts and oxidation to form the observed product. Non-oxidative cyclizations that start with either JV-vinyl aromatic carboxamides (C=C—N—CO—Ar) or N-aryl a. -unsaturated carboxamides (Ar—N—CO—C—C) have been extensively used to make quinoline or isoquinoline alkaloids and their derivatives a fairly simple example is given in (3.73). 

The cyclopropanation of alkenes, alkynes, and aromatic compounds by carbenoids generated in the metal-catalyzed decomposition of diazo ketones has found widespread use as a method for carbon-carbon bond construction for many years, and intramolecular applications of these reactions have provided a useful cyclization strategy. Historically, copper metal, cuprous chloride, cupric sulfate, and other copper salts were used most commonly as catalysts for such reactions however, the superior catalytic activity of rhodium(ll) acetate dimer has recently become well-established.3 This commercially available rhodium salt exhibits high catalytic activity for the decomposition of diazo ketones even at very low catalyst substrate ratios (< 1%) and is less capricious than the old copper catalysts. We recommend the use of rhodium(ll) acetate dimer in preference to copper catalysts in all diazo ketone decomposition reactions. The present synthesis describes a typical cyclization procedure. 

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