Reactions Involving Side Chains

In general, the side chain derivatives of azaindoles undergo reactions analogous to those with indoles. The azagramines and 3-carboxaldehydes are the most useful, leading to many other azalogs of indole derivatives of biological importance. Unfortunately, most of the reactions and compounds involve the more accessible 7-azaindoles, so few comparisons in reactivity differences can be made. 

112 For further discussion of the quaternization, see G. F. Duffin, Advan, Heterocyclic Chem. 3, 38 (1964). 

Treatment of the azagramine (126) with sodium cyanide led to resins, but use of hydrogen cyanide (formed in situ with NaCN/HCl) in water with refluxing gave the 3-acetonitrile (129) in 49%yield. This has been prepared in better yield (76 %) by treatment of 126 with dimethyl sulfate followed by potassium cyanide. The nitrile (129) 

Velluz, G. Muller, and A. Allais, French Patent 1,261,179 (1961) Chem. 

Frydman et al. condensed ethyl 5-methoxy-6-azagramine-2-carboxylate (135) with diethyl sodiomalonate to give the triester (136) (80%), which was hydrolyzed with hydrochloric acid to the diacid (137) (95%). Treating this with hydrobromic acid gave the 5-hydroxy-6-azaindole, which exists in the lactam form (138). Reduction to the tetrahydrolactam (93, R = C02H), followed by decarboxylation and hydrolysis, provided a novel route to porphobilinogen (92,R = H). 

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Reactions involving side chain and complex groups... 

The introduction of conformational restrictions into flexible active molecules is a well-known strategy for trying to increase their potency and/or selectivity toward their biological targets.1 Several methods have been used for constraining flexible molecules. Cyclic derivatives of hnear peptides or peptidomimetics can thus be prepared by reactions involving side-chain... 

The ability of side chains to become coplanar with the heteroaromatic ring will be greater than in benzene, so that for reactions involving side-chain carbocations, the heterocycle may appear to be a better transmitter than benzene. 

For reactions involving side-chain carbocations, the order of transmission of substituent effects is quite different to the electrophilic substitutions, being furan > pyrrole > thiophene > benzene > tellurophene. 

Brief reports of many other reactions involving side chains are scattered in the literature (115, 182, 327, 364, 367, 414). 

Among the phenolic compounds, phenol vjhich is absent in oil 5 is foiond as a major component in residua. Cracking reactions involving side chains like propenyl and methoxy groups on phenolic compounds have therefore occurred. 

Special reactions of side-chain substituents rearrangements involving three-atom side chains... 

Beyond the well-defined substitutions of the heterocyclic ring systems, numerous other transformations have been carried out that cannot be simply classified into the substitution category. These transformations involve side chain alkylations, exchange of substituents by more sophisticated methods, or ring closures carried out on the side chains. A set of such reactions are summarized in Table 3. 

Aromatic compounds undergo many reactions, but relatively few reactions that affect the bonds to the aromatic ring itself. Most of these reactions are unique to aromatic compounds. A large part of this chapter is devoted to electrophilic aromatic substitution, the most important mechanism involved in the reactions of aromatic compounds. Many reactions of benzene and its derivatives are explained by minor variations of electrophilic aromatic substitution. We will study several of these reactions and then consider how substituents on the ring influence its reactivity toward electrophilic aromatic substitution and the regiochemistry seen in the products. We will also study other reactions of aromatic compounds, including nucleophilic aromatic substitution, addition reactions, reactions of side chains, and special reactions of phenols. 

Side Reaction of Dehydration Involving Side Chains of Activated Residues... 

Tocopherol can be isolated from plant oils, but purification is tedious. Several total syntheses, including a few industrial ones, are similar to carotene syntheses involving the repeated application of the Wittig reaction. The side chain of ubiquinones and vitamins E and K has been introduced by using vinylketones and benzyl chlorides as educts in the presence of a Ni(0) catalyst. Pd(0) does not work Electron-rich and electron-poor aromatics react with equal facility. 

Additional metabolism, involving side-chain degradation, proceeds by transamination, oxidative deamination, and decarboxylation to yield thyroacetic acid and thyroethanediol cleavage of the diphenyl ether linkage has been detected as well, both in vitro and in vivo. The reactions through which thyroid hormone is metabolized are summarized in Figure 34.5. 

Cycloadditions involving side-chain n-systems in addition to the thiophene double bond. 9.3 Photocycloadditions. 9.4 Cycloadditions of 3,4-dimethylenethiophene Reactions of Strained Thiophenes... 

Reactions can be accelerated by the formation of intermediates, provided that such intermediates are rapidly formed and broken down. This then provides a new reaction pathway of lower activation energy. Many enzyme-catalyzed reactions proceed via covalent catalysis, involving side chains such as Cys, Ser, Eys. or His acting as nucleophiles in the formation of intermediates such as acyl-enzymes or Schiff bases. Changes in environment... 

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