REACTIVITY OF SUBSTITUENTS ON CARBON

5-Fluoro- and 5-chloro-2-(dimethylamino)-3//-azepine react with i-butyllithium to give a mixture of 4- and 5-r-butyl-2-(dimethylamino)-3//-azepines in high yield 85H(23)27I5 . The ratio of the two products is of the order of 2.5-3.0 1 and is independent of the halogen substituent, an observation supporting the intermediacy of 2-(dimethylamino)-3/f-4,5-didehydroazepine in the reaction. A 

Metalation of the imine (104) with LDA and treatment with a nitrile and regioselective trapping of the resulting diazapentadienyl anion with prop-2-ynyl bromide affords the 4-azaazulene (105) in high yield (Equation (7)) 92CC1419 . 

Many reactions of substituted diazepines and their fused derivatives frequently relate to a study of the functionality rather than being dependent on the presence of the azepine ring system, most particularly with reduced derivatives. Reaction of the unsymmetrical semicarbazones (110) 91JOC5203 gives the two selenodiazoles (111) and (112), the ratios of which show a solvent dependency (Equation (8)). 

Lactim ethers and thioethers are reported to react with imides 93H(35)1055 , amino ketones and acetals 82jhci93 , amino acids 90JHC1973 , active methylene compounds 82JHC193, 82JHC43I, 88T3309), and diethyl ethoxymethylenemalonate 84H(22)2285 . 7,8,9,10-Tetrahydro-6//-l,3,5-tri-azino[l,2-fl]azepine-2,4(3/f)-dione has been prepared from 7-amino-3,4,5,6-tetrahydro-2(//)-azepine and diphenyl imidodicarboxylate 93JHC55l , and caprolactam acetals are reported to react with amino heterocycles 938521 and ureas and urethanes 82KGS1553 . Most of these reactions lead to fused azepines either directly or after subsequent treatment of the isolated intermediate. 

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Further examples of the ease of exchange of substituents on carbon by nucleophiles under mild conditions have been reported. The reactivity of the ring towards nucleophiles is increased in triazolium cations and mesoionic derivatives. 

General Survey of Reactivity of Substituents on Ring Carbon Atoms... 

Bicyclic 5-6 Systems Four Heteroatoms 3 1 7.10.7 REACTIVITY OF SUBSTITUENTS ON RING CARBONS... 

Quite a considerable number of papers deal with the effect of structure of olefinic substrates on their reactivity in the catalytic hydrogenation 65). Lebedev 66) attempted a generalization of the problem. His conclusion that the rate of hydrogenation of olefins decreases in the order monosubstituted - symmetric disubstituted - asymmetric disubstituted - trisubstituted tet-rasubstituted ethylene derivatives is called the Lebedev rule. Campbell 67) supplemented it by demonstrating that the rate of hydrogenation decreases with the number and size of substituents on carbon atoms of the double bond, cis isomers are usually hydrogenated more quickly than trans isomers, and olefins containing the terminal double bond are more reactive than those with the double bond inside the chain. 

The reaction of an alcohol with a hydrogen halide is a substitution A halogen usually chlorine or bromine replaces a hydroxyl group as a substituent on carbon Calling the reaction a substitution tells us the relationship between the organic reactant and its prod uct but does not reveal the mechanism In developing a mechanistic picture for a par ticular reaction we combine some basic principles of chemical reactivity with experi mental observations to deduce the most likely sequence of steps... 

Apeloig and Kami (13) have also studied the effects of substituents on the reactivity of silenes by the frontier molecular orbital (FMO) approach. They have concluded that, concerning electronic factors, the polarity of the carbon-silicon double bond, and thus the coefficients of the frontier orbitals, play a more important role than the energies of these orbitals in controlling the reactivity of silenes. 

Hammond postulate has been used to explain the effect of substituents on the rate of benzilic acid rearrangements, mechanism of electrophillic aromatic substitution reactions and reactions involving highly reactive intermediates such as carbonium ions and carbon ions. 

Reactivity of substituents attached to ring heteroatoms 5.2.2.7 Alkyl groups and further carbon functional groups. The N-2-nitrobenzoyl derivative of indolo benzazepine 384a can be easily deprotected on the indole nitrogen by treatment with N,N-diethylaminoethylamine in DMF at room temperature (Scheme 79, Section 5.1.2 (1991JHC379)). 

Condensation of the 5-methyl group in (80) (R = Me, Et, Ph, SMe) with aromatic aldehydes leads to 5-styrylthiadiazoles (79). The action of carboxylic acid esters gives ethoxalyl derivatives (81) and that of isoamyl nitrite produces the oxime (82) (Scheme 20) <82AHC(32)285>. These reactions are restricted exclusively to the 5-methyl group in (80) (R = Me), reflecting the greater reactivity of substituents in the 5-position compared to the 3-position in 1,2,4-thiadiazoles. This point is further illustrated when (80) (R = Me) is selectively converted into the carboxylic acid (83) on treatment with n-butyllithium and carbon dioxide (Scheme 20) <84CHEC-I(6)463). 

Non-stabilized ylides lack any substituent on carbon that can conjugate with the P=C double bond. In other terms, the substituents attached to the carbanion cannot assist in delocalizing the anion. Although these types of ylides are reactive, a large number of examples have been prepared and their single-crystal X-ray structures determined. We... 

In six-membered rings containing three or more heteroatoms, any substituent must necessarily be close to, or on, a heteroatom. In this respect the reactivity of substituents in these systems is controlled by the adjacent heteroatoms. For example, halogens on carbon atoms or to a heteroatom are readily displaced. For the most part, the reactivity of substituents is fairly easy to predict on the basis of the chemistry of the functional groups of which they are part, and of the generalizations outlined in Chapter 2.02. 

This chapter begins with an introduction to the basic principles that are required to apply radical reactions in synthesis, with references to more detailed treatments. After a discussion of the effect of substituents on the rates of radical addition reactions, a new method to notate radical reactions in retrosynthetic analysis will be introduced. A summary of synthetically useful radical addition reactions will then follow. Emphasis will be placed on how the selection of an available method, either chain or non-chain, may affect the outcome of an addition reaction. The addition reactions of carbon radicals to multiple bonds and aromatic rings will be the major focus of the presentation, with a shorter section on the addition reactions of heteroatom-centered radicals. Intramolecular addition reactions, that is radical cyclizations, will be covered in the following chapter with a similar organizational pattern. This second chapter will also cover the use of sequential radical reactions. Reactions of diradicals (and related reactive intermediates) will not be discussed in either chapter. Photochemical [2 + 2] cycloadditions are covered in Volume 5, Chapter 3.1 and diyl cycloadditions are covered in Volume 5, Chapter 3.1. Related functional group transformations of radicals (that do not involve ir-bond additions) are treated in Volume 8, Chapter 4.2. 

There has been considerable effort directed towards obtaining a fundamental understanding of the factors that govern the reactivities of carbon-centered radicals in bimolecular reactions, particularly with respect to their addition to alkenes [84]. From early liquid and gas phase studies, reactivity in such addition reactions was concluded to derive from a complex interplay of polar, steric, and bond-strength terms [85], which is much influenced by the nature and position of substituents on both the radical and the alkene. 

The boron atom dominates the reactivity of the boracyclic compounds because of its inherent Lewis acidity. Consequently, there have been very few reports on the reactivity of substituents attached to the ring carbon atoms in the five-membered boronated cyclic systems. Singaram and co-workers developed a novel catalyst 31 based on dicarboxylic acid derivative of 1,3,2-dioxaborolane for the asymmetric reduction of prochiral ketones 32. This catalyst reduces a wide variety of ketones enantioselectively in the presence of a co-reductant such as LiBH4. The mechanism involves the coordination of ketone 32 with the chiral boronate 31 and the conjugation of borohydride with carboxylic acid to furnish the chiral borohydride complex 34. Subsequent transfer of hydride from the least hindered face of the ketone yields the corresponding alcohol 35 in high ee (Scheme 3) <20060PD949>. 

Considering the lack of research being performed on 1,2- and 1,3-oxathietanes and their oxidized forms, it is not surprising that there are no reports in the last decade on the reactivity of substituents attached to ring carbon atoms. 

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