Carboxamide substituent, effect

The overall biosynthetic pathway to the tetracychnes has been reviewed (74). Studies (75—78) utilising labeled acetate and malonate and nmr analysis of the isolated oxytetracycline (2), have demonstrated the exclusive malonate origin of the tetracycline carbon skeleton, the carboxamide substituent, and the folding mode of the polyketide chain. Feeding experiments using [1- 02] acetate and analysis of the nmr isotope shift effects, led to the location of... 

The range of action of carboxamides depends partly on the basic skeleton and partly on the substituents. With a few exceptions, carboxamides are effective... 

Winstein showed that carboxamides display a strong syn directing effect, as demonstrated in the epoxidation of amide 21, furnishing cis-epoxide 22 as the only observed diastereomer (Equation 8) [63]. The directing effect of carboxamide substituents was studied by Sable, who found that triol 24 is converted diastereoselectively into epoxide 25 (syn to the amide group), despite the presence of one allylic and two homoallylic hydroxyl substituents on the opposite face (Equation 9) [64],... 

The nature of the carboxamide aryl substituent has a dramatic effect on the pharmacokinetic properties, with the 2-benzothiazolyl group leading to a longer half-life compared to a phenyl group. 

The catalysed two-phase alkylation of carboxamides has the advantages of speed and simplicity over the traditional procedures and provides a valuable route to secondary and tertiary amines by hydrolysis or reduction of the amides, respectively. The procedure appears to be limited, however, to reactions with primary haloalkanes and dialkyl sulphates, as secondary haloalkanes are totally unreactive [6, 7]. The use of iodoalkanes should be avoided, on account of the inhibiting effect of the released iodide ion on the catalyst. Also, the A-alkylation reaction is generally susceptible to steric effects, as seen by the low yields in the A -cthylation of (V-/-butylacetamide and of A-ethylpivalamide [6]. However, the low steric demand of the formyl group permits A,A-dialkylation and it is possible to obtain, after hydrolysis in 60% ethanolic sulphuric acid, the secondary amines having one (or, in some cases, two) bulky substituent(s) [7]. 

From a study of the protonation of various 5-X-substituted thiophene-2-carboxamides in aqueous H2SO4, it has been concluded that the thiophene nucleus is more efficient than the benzene ring in relaying the electronic effects of substituents to the reaction centre (80JCS(P2)172l). This follows from the fact that the p-value for the thiophene series (-1.16) is larger than that for benzamides (-0.956). 

The special, and somewhat complex, role played by a substituent in the 4-position was first observed in the quinazoline series. The carbon atom that received the —OH group during hydration was located by preparing all six C-methylquinazolines. Only when inserted in the 4-position did a methyl group prevent the addition of water.41,23 This inhibition has both an inductive (+1) and a steric component. A kinetic study of quinazoline-4-carboxamide showed that the carbamoyl substituent, because of its steric effect, slowed the attainment of hydration from less than a second to 2-4 hours. However, this substituent has the... 

Dirhodium(II) compounds are reported to be the most suitable catalysts for insertion. Selectivity is higher and yields are greater with dirhodium(II) carboxylates or carboxamidates than with copper catalysts, whereas Ru catalysts are not known to facilitate C-H insertion. As expected by a process that is basically electrophilic, electron-donating substituents that are adjacent to the site of insertion activate that center for C-H insertion ril4]. In addition to electronic influences, however, conformational effects that are basically steric in origin can also control reaction selectivity [115]. 

A most dramatic difference is the case of fluoride [4,129]. In a competition between carboxamide and fluoro substituents arranged ortho on a benzene ligand, LDA rapidly removes the proton ortho to F with complete selectivity [4]. In another example, amide dominates over a m-methoxide but with low selectivity [24]. The collective results suggest that conformational effects are signiflcant (best conformation of the Cr(CO)3 tripod), and that inductive effects are relatively more important than speciflc coordination of the base to a ring ortho substituent (compared to the uncomplexed arene). The high inductive effect of F is critical in directing deprotonation of the fluorobenzene complexes. 

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