Amidation steric course

This section mainly deals with the practical applications of amide enolate alkylations, although a short discussion of some mechanistic aspects is necessary in order to understand the steric course of these reactions. 

In contrast to the many examples dealing with esters (see Section 1.1.1.3.2.), there are few examples in the literature of alkylations of amide enolates where the steric course is governed by the configuration of chiral units on the carbon side of the starting amide, i.e., substrate control by C-chirality. It is likely, however, that amide alkylations of this type will emerge as a very useful procedure since amide enolates are easy to prepare and usually, in contrast to some esters, provide very high ratios of syn- to a / -enolate. 

Chiral auxiliaries are capable of controlling the absolute steric course of radical reactions. 8-Phenylmenthyl ester or an amide derived from Oppolzer s camphor sultam can be utilized for enantioselective ring closure to cyclopentane, the chiral auxiliary directing the addition to the alkene. The reductive radical cyclization of 8-phenylmenthyl 2-phenylthio-6-heplenoale at 80 °C gives four isomeric cyclopentane derivatives in an overall yield of 90 % 3. The reaction proceeds with modest cis irons ratio, but a considerably higher RiS selectivity of 80 20. 

The chelation hypothesis could also be applied to the catalytic hydrogenation of a-keto acid amides carried out initially by Hiskey et al., who explained the steric course assuming intermediate structure V (11) (Scheme 6). 

The mesitylylene-bridged tris(NAH) derivative of 5-prolin-amide and the p-xylylene-bridged bis(NAH) derivative of 5-prolinol switched the steric course of reduction so as to give the enantiomeric 5-mandelate in lower e.e. 

Anionic polymerization of o-divinylbenzene was examined by Aso et al. [294]. The authors used n-BuLi, phenyllithium, and naphthalene/alkali metal in THF, ether, dioxane, and toluene at temperatures between —78 and 20 °C. Generally, it was found that as with radical and cationic initiators, a competition between cyclopolymerization and conventional 1,2-polymerization occurs, with the tendency for cyclization to be lower than with the other mechanisms. The polymerization initiated with the lithium organic compounds resulted in polymers with up to 92% double bonds per monomer unit (THF, 20 °C). Polymerization with lithium, potassium, and sodium naphthalene also showed a rather weak tendency for cyclization. In THF at 0°C and 20 °C the cyclization tendency increased with decreasing ionic radii of the counter cation, while in dioxane the reverse effect was observed, and in ether still another dependence was found (K > Li > Na). Nitadori and Tsuruta [299] used lithium diisopropyl amide in THF at 20 °C to polymerize m- and p-divinylbenzene. The authors obtained soluble products with molecular weight up to 100 000 g/mol (GPC) and showed the polymers to contain pendant double bonds by IR and NMR spectra. It seemed to be important that a rather large excess of free amine (the initiator was formed by reaction of -BuLi with excess diisopropylamine) was present in the polymerization mixture. In later studies [300,301] a closer view was taken on polymerization kinetics and the steric course of the polymerization reaction. 

Chlorpromazine (33) can probably be considered the prototype of the phenothiazine major tranquilizers. The antipsychotic potential of the phenothiazines was in fact discovered in the course of research with this agent. It is of note that, despite the great number of alternate analogs now available to clinicians, the original agent still finds considerable use. The first recorded preparation of this compound relies on the sulfuration reaction. Thus, heating 3-chlorodiphenylamine (30) with sulfur and iodine affords the desired phenothiazine (31) as well as a lesser amount of the isomeric product (32) produced by reaction at the 2 position. The predominance of reaction at 6 is perhaps due to the sterically hindered nature of the 2 position. Alkylation with w-C3-chloropropyl)dimethylamine by means of sodium amide affords chlorpromazine (33). ... 

All shifts are negative, downfield from external trifluoroacelic acid, b An S configuration would mean that the CF3 signal of the (R)-MTPA amide with the (S)-primary amine appears at lower field than the (R.R)-diastereomer (no example presented in this table). The consequence is that in such a case one has to assume that the relative steric effects of a certain pair of substituents are different to that expected, since each example in the table is of known configuration. An unknown example of this type would of course get a wrong assignment. 

A very recent slick investigation by Majewski and Nowak also supports Collum s theoretical and experimental results. They measured decreases in optical purity of (l )-6, originally in the optically pure form, during the course of deprotonation and provided the rate of the enolization (Sch. 7) [31]. Lithiation of bulky ketone 6 with LDA is first-order in the ketone and 0.5-order in the base. This result is consistent with a spectroscopically invisible dimer-monomer pre-equilibrium of LDA which is also suggested by Collum s results. Fractional order in LDA suggests a pathway involving the monomer of the amide and rate-determining proton transfer. Most notably, a combination of both monomer and dimer pathways is possible, especially for substrates less sterically hindered. 

Bioisosteric interchanges, of course, are not limited to univalent functions. In fact, divalent atoms and groups add the additional factor of steric similarity to the equation since the bond angles between the valencies are very similar. The angles for/CH2 (l 11.5°),/NHv(l 11°) /S (l 12°), and/Q(108°) illustrate this point. When a deviation of 3 degrees, depending on the full structural features of the compound, are taken into consideration, it becomes apparent how identical these features can be. A rather convincing example is seen when the bioactivity relationship between the isosteric ester and amide moieties is examined (Fig. 1-4). 

In sum, the course of heteroatom oxidation appears to be sensitive to the oxidation potential of the heteroatom, the acidity of hydrogens on the adjacent carbon, and steric factors. The bulk of the evidence suggests that oxidation of the nitrogen in amines generally involves electron abstraction followed primarily by A-dealkylation if a labile proton is present, or nitrogen oxidation if it is not. As the nitrogen oxidation potential increases, there is a shift toward direct insertion into the C-H bond, as is thought to occur in the A-dealkylation of amides. 

---