Substitution ring side-chain

One procedure for the synthesis of these title ring systems appeared recently <2003S1079>. Yadav and Kapoor described that the transformation of some oxadiazole and thiadiazole derivatives bearing specially substituted methylsulfinyl side chain 131, when reacted with thionyl chloride, give ring-closed compounds 134. The reaction was carried out in pyridine under reflux conditions in 74-79% yield. As shown in Scheme 25, the authors assume that the first step is the formation of the sulfonium salt 132 which undergoes cyclization with hydrogen chloride and sulfur dioxide elimination to 133 and, finally, demethylation of this intermediate leads to the final product 134. 

The most common Hj antihistamine drugs are structurally similar to histamine with a substituted ethylamine side chain however, they have two aromatic rings and can be formally represented by the general formula ... 

A fused tricyclic ring system based on an indole provides yet another NSAID. Michael addition of the anion from diethyl methylmalonate to cyclohexanone followed by acid hydrolysis of the product gives cyclohexanone (21-3), which incorporates the characteristic profen 2-substituted carboxylic side chain. Sequential reaction with para-chlorophenylhydrazine and a strong acid gives the fused indole... 

R = amino-substituted C3 side chain A - six— or seven—membcred ring... 

Swindell, C. S. Krauss, N. Horwitz, S. B. Ringel, I. Biologically active taxol analogues with deleted A-ring side chain substitutents and variable C-2 configurations. J. Med. Chem., 1991, 34 1176-1184. 

Aromatic hydrocarbons are of special commercial importance. The benzene ring structure, with six carbons and three double bonds, is the fundamental aromatic unit. This molecule can have one or more hydrogen substitutions with side chains, resulting in alkyl benzenes (e.g. the TEX in BTEX [benzene, toluene, ethylbenzene and xylene]) or two or more aromatic rings may be fused together to form polycyclic aromatic hydrocarbons (PAHs). 

The best-known equation of the type mentioned is, of course, Hammett s equation. It correlates, with considerable precision, rate and equilibrium constants for a large number of reactions occurring in the side chains of m- and p-substituted aromatic compounds, but fails badly for electrophilic substitution into the aromatic ring (except at wi-positions) and for certain reactions in side chains in which there is considerable mesomeric interaction between the side chain and the ring during the course of reaction. This failure arises because Hammett s original model reaction (the ionization of substituted benzoic acids) does not take account of the direct resonance interactions between a substituent and the site of reaction. This sort of interaction in the electrophilic substitutions of anisole is depicted in the following resonance structures, which show the transition state to be stabilized by direct resonance with the substituent ... 

Chapters 9, 10 and 11 describe methods for substitution directly on the ring with successive attention to Nl, C2 and C3. Chapters 12 and 13 are devoted to substituent modification as C3. Chapter 12 is a general discussion of these methods, while Chapter 13 covers the important special cases of the synthesis of 2-aminoethyl (tryptaminc) and 2-aminopropanoic acid (tryptophan) side-chains. Chapter 14 deals with methods for effecting carbo cyclic substitution. Chapter 15 describes synthetically important oxidation and reduction reactions which are characteristic of indoles. Chapter 16 illustrates methods for elaboration of indoles via cycloaddition reactions. 

Radicals derived from monocyclic substituted aromatic hydrocarbons and having the free valence at a ring atom (numbered 1) are named phenyl (for benzene as parent, since benzyl is used for the radical C5H5CH2—), cumenyl, mesityl, tolyl, and xylyl. All other radicals are named as substituted phenyl radicals. For radicals having a single free valence in the side chain, these trivial names are retained ... 

The steric bulk of the three iodine atoms in the 2,4,6-triiodoben2ene system and the amide nature of the 1,3,5-substituents yield rotational isomers of the 5-A/-acyl-substituted 2,4,6-triiodoisophthalamides. Rotational motion in the bonds connecting the side chains and the aromatic ring is restricted. These compounds also exhibit stereoisomerism when chiral carbon atoms are present on side chains. (R,5)-3-Amino-l,2-propanediol is incorporated in the synthesis of iohexol (11) and ioversol (12) and an (3)-2-hydroxypropanoyl group is used in the synthesis of iopamidol (10). Consequendy, the resulting products contain a mixture of stereoisomers, ie, meso-isomers, or an optical isomer. 

Steroids (1) are members of a large class of lipid compounds called terpenes that are biogenicaHy derived from the same parent compound, isoprene, C Hg Steroids contain or are derived from the perhydro-l,2-cyclopentenophenanthrene ring system (1) and are found in a variety of different marine, terrestrial, and synthetic sources. The vast diversity of the natural and synthetic members of this class depends on variations in side-chain substitution (primarily at C17), degree of unsaturation, degree and nature of oxidation, and the stereochemical relationships at the ring junctions. 

OC-Methylstyrene. This compound is not a styrenic monomer in the strict sense. The methyl substitution on the side chain, rather than the aromatic ring, moderates its reactivity in polymerization. It is used as a specialty monomer in ABS resins, coatings, polyester resins, and hot-melt adhesives. As a copolymer in ABS and polystyrene, it increases the heat-distortion resistance of the product. In coatings and resins, it moderates reaction rates and improves clarity. Physical properties of a-methylstyrene [98-83-9] are shown in Table 12. 

The chlorination of toluene in the absence of catalysts that promote nuclear substitution occurs preferentially in the side chain. The reaction is promoted by free-radical initiators such as ultraviolet light or peroxides. Chlorination takes place in a stepwise manner and can be controlled to give good yields of the intermediate chlorination products. Small amounts of sequestering agents are sometimes used to remove trace amounts of heavy-metal ions that cause ring chlorination. 

Ring-Substituted Derivatives The ring-chlorinated derivatives of benzyl chloride, benzal chloride, and benzotrichloride are produced by the direct side-chain chlorination of the corresponding chlorinated toluenes or by one of several indirect routes if the required chlorotoluene is not readily available. Physical constants of the main ring-chlorinated derivatives of benzyl chloride, benzal chloride, and benzotrichloride are given in Table 4. 

This interesting conversion of a five- into a six-membered heterocyclic ring was proven by the isolation of the enzyme GTP-cyclohydrolase from E. coli (71MI21600) and a similar one from Lactobacillus platarum (B-71MI21601) which catalyzes the reaction (300)(303). Dephosphorylation leads to 7,8-dihydro-D-neopterin (304), which is then cleaved in the side-chain to 6-hydroxymethyl-7,8-dihydropterin (305), the direct precursor of 7,8-dihy-dropteroic acid and 7,8-dihydrofolic acid (224). The alcohol (305) requires ATP and Mg " for the condensation with p-aminobenzoic and p-aminobenzoylglutamic acid, indicating pyrophosphate formation to (306) prior to the substitution step. 

Substitution at C(5) of the penicillanic ring system has been relatively little explored. The 5a-phenyl analog has been prepared by total synthesis as shown in Scheme 26 75JMC486). It was interesting that epimerization (step iv) occurs without side chain silylation (cf. Section 5.11.3.8.4). 

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