Substituents on heterocycles

Best Synthetic Methods is now 10 years old, is a family of 16 volumes and has been well received by the majority of chemists as a valuable aid in their synthetic endeavours, be they academic or commercial. The focus of the series so far has been on special methods, reagents or techniques. This volume is the first of a new sub-series with a focus on heterocycles and their synthesis. It is amazing the extent to which each heterocyclic type has its own specialized synthetic methodology. Whether the chemist is endeavouring to make a heterocycle by ring synthesis or wishes to introduce specific substituents, it is the intention that this new development will serve their needs in a practical, authoritative, fully illustrative and compact manner. Richard Sundberg is an authority on indole chemistry and it is a pleasure to have such a noted heterocyclist to initiate this venture. 

The nature of the substituent on the exocyclic nitrogen also influences the ambident activity of anion 48 in DMF (Scheme 35) when R is an heterocyclic ring, nitrogen alkylation predominates (189) when R is a methylamino group, a mixture of the two isomers is reported (190) when... 

The spectroscopic properties of the /V-nitrosamines, especially the nmr and mass spectra, vary widely depending on the substituents on the amine nitrogen (44—47). The nmr spectra are affected by the E—Z isomerism around the N—N partial double bond and by the axial—equatorial geometry resulting from conformational isomerism in the heterocycles (44,45). Some general spectral characteristics for typical dialkylnitrosamines and simple heterocycHc nitrosamines are given in Table 1. 

The effect of substituents on the reactivity of heterocyclic nuclei is broadly similar to that on benzene. Thus mem-directing groups such as methoxycarbonyl and nitro are deactivating. The effects of strongly activating groups such as amino and hydroxy are difficult to assess since simple amino compounds are unstable and hydroxy compounds exist in an alternative tautomeric form. Comparison of the rates of formylation and trifiuoroacetylation of the parent heterocycle and its 2-methyl derivative indicate the following order of sensitivity to substituent effects furan > tellurophene > selenophene = thiophene... 

Charton has recently examined substituent effects in the ortho position in benzene derivatives and in the a-position in pyridines, quinolines, and isoquinolines. He concludes that, in benzene derivatives, the effects in the ortho position are proportional to the effects in the para position op). However, he finds that effects of a-sub-stituents on reactions involving the sp lone pair of the nitrogen atoms in pyridine, quinoline, and isoquinoline are approximately proportional to CT -values, or possibly to inductive effects (Taft s a ). He also notes that the effects of substituents on proton-deuterium exchange in the ortho position of substituted benzenes are comparable to the effects of the same substituents in the a-position of the heterocycles. 

In this chapter, an attempt has been made to present a total number of 20 QSAR models (12 QSAR models for topo I inhibitors and eight QSAR models for topo II inhibitors) on 11 different heterocyclic compound series (an-thrapyrazoles, benzimidazoles, benzonaphthofurandiones, camptothecins, desoxypodophyllotoxins, isoaurostatins, naphthyridinones, phenanthridines, quinolines, quinolones, and terpenes) as well as on some miscellaneous heterocyclic compounds for their inhibition against topo I and II. They have been found to be well-correlated with a number of physicochemical and structural parameters. The conclusion, from the analysis of these 20 QSAR, has been drawn that the inhibition of topo I is largely dependent on the hydrophobicity of the compounds/substituents. On the other hand, steric parameters (molar refractivity, molar volume, and Verloop s sterimol parameters) are important for topo II inhibition. 

A new series of unfunctionalized (17) and functionalized (18) 3,4-dihydrocoumarins (Fig. 11.11) was synthesized. These new benzopyranones differ from the previous neutral dihydrocoumarins, which are suicide substrates of proteinases (Section 11.4, in that they have a carboxy substituent on their aromatic ring and a side chain phenylacetamido group at the 3-position of the heterocycle instead of a benzyl one in compound 3. 

The limited data available for simple fluoroheterocycles allow one to see how the position of the fluorine substituent on a heterocycle can... 

Cyanine and squaraine dyes with hydrogen substituents on the indolenine-nitrogen in one or both of the heterocyclic end-groups, the so-called norcyanines and norsquaraines, are useful as fluorescent pH-indicators due to the reversible equilibrium between their protonated and deprotonated forms ... 

At the Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, we have been dealing with the synthesis and utilization of P-heterocycles for more than two decades. In this chapter, the synthesis and properties of phospholes with bulky substituent on the phosphorus atom are described. 

More recently, reductive elimination of aryl ethers has been reported from complexes that lack the activating substituent on the palladium-bound aryl group (Equation (55)). These complexes contain sterically hindered phosphine ligands, and these results demonstrate how steric effects of the dative ligand can overcome the electronic constraints of the reaction.112,113 Reductive elimination of oxygen heterocycles upon oxidation of nickel oxametallacycles has also been reported, but yields of the organic product were lower than they were for oxidatively induced reductive eliminations of alkylamines from nickel(II) mentioned above 215-217... 

---