Directing heteroatoms

Although allylic lithiation by deprotonation of non-heterosubstituted compounds is possible using superbases (see section 2.6), in most cases allylic lithiation requires a directing heteroatom. (Non-heterosubstituted allyllithiums are best produced by reductive lithiation of allyl ethers or allyl sulfides - see section 4.4.) One of the few cases where this heteroatom is not a to the new organolithium is shown below the p-lithiation of a homoallylic amide 137. The reaction is particularly remarkable because of the possibility of competing deprotonation... 

Fig. 8.14. Ensuring Felkin-Anh or Cram chelate selectivity in the addition of hydride donors to a-chiral carbonyl compounds by varying the protecting group on the stereo-directing heteroatom.

Only derivatives of the 1,2-oxathiole series have been obtained by direct heteroatom coupling. The successful bond formation involves some type of activation of the sulfur atom in 3-hydroxypropanethiol or its oxidized derivatives. TTie parent 1,2-oxathiolane system (106) was recently reported (81CC741) to be obtained from the vacuum pyrolysis of (105), as shown in Scheme 23. A cyclic oligomer is believed to be generated first and (106) is formed on standing. Oxidation of (106) yields the mono- and di-oxide which have been known for some time. The monoxide may be obtained by the oxidative coupling of 3-hydroxypropane thiol (equation 22). Chlorine is the most frequently used oxidant and... 

Only one derivative of the 2,1-benzoxathiole system has been reported in its lowest oxidation state (75JA6909), and involves direct heteroatom coupling as indicated in equation (44). Preparative routes to oxidized forms of 3H- 1,2-benzoxathiole (76CJC3012) and 5H- 2,1-benzoxathiole (66HC(21-1)76) are shown in equation (45) and Scheme 45, respectively. 

Allylic alcohols and amines are typical substrates that bear directing heteroatoms within the main substrate structure. Under suitable conditions, oxygen and nitrogen atoms in allylic alcohols and amines participate in the Mizoroki-Heck reaction through O—Pd or N—Pd coordination, bringing about some chelation effect in the outcome of reactions. 

While 3-methylenecephams themselves are completely devoid of antimicrobial activity, the exomethylene function is a distinctive feature of these compounds that many workers recognized could be a key intermediate in a chemical route to novel classes of cephalosporins with direct heteroatom substitution at C-3. Whereas 3-methylenecephams were first employed to produce deacetoxycephalosporins, exploration of their chemistry has led to the preparation of 3-chloro-3-cephems and 3-methoxyl-3-cephems that possess marked antimicrobial activity. These compounds represent a new and different generation of cephalosporin antibiotics. Two members of this class of p-lactams have achieved clinical importance. One bears the D-phenylglycyl side chain Lilly compound 99638, with the generic name cefaclor (Ceclor, Lilly). The other bears the D-cyclohexadienylglycyl side chain Ciba-Geigy Compound 9000. Both compounds are potent broad-spectrum p-lactam antibiotics with oral therapeutic efficacy. 

This chapter reviews the preparations of 3-methylenecephams that led to direct heteroatom substitutions at C-3. The chemistry of 3-hydroxy-3-cephems is detailed as it pertains to syntheses of 3-halo- and 3-methoxy-... 

Chelation itself is sometimes useful in directing the course of synthesis. This is called the template effect (37). The presence of a suitable metal ion facihtates the preparation of the crown ethers, porphyrins, and similar heteroatom macrocycHc compounds. Coordination of the heteroatoms about the metal orients the end groups of the reactants for ring closure. The product is the chelate from which the metal may be removed by a suitable method. In other catalytic effects, reactive centers may be brought into close proximity, charge or bond strain effects may be created, or electron transfers may be made possible. 

Several types of nitrogen substituents occur in known dye stmetures. The most useful are the acid-substituted alkyl N-substituents such as sulfopropyl, which provide desirable solubiUty and adsorption characteristics for practical cyanine and merocyanine sensitizers. Patents in this area are numerous. Other types of substituents include N-aryl groups, heterocycHc substituents, and complexes of dye bases with metal ions (iridium, platinum, zinc, copper, nickel). Heteroatom substituents directly bonded to nitrogen (N—O, N—NR2, N—OR) provide photochemically reactive dyes. 

Alkyl substituents supplement the a-directing effect of the heteroatom and direct the incoming substituent into the 2-position. However, steric effects can result in an increased proportion of 5-substitution. 

The above examples illustrate reactions at an electron-deficient carbon atom. Other 1,1-bielectrophiles allow the direct introduction of a heteroatom into the resultant heterocycle. The most widely applicable and versatile methods for the synthesis of 1,2,5-thiadiazoles and 1,2,5-selenadiazole rely on this approach. 

Table 15 [S 19 56, 59 93 107 108 109, 110, 111, 112 113, 114] contams NMR data for a vanety of tnfluoromethyl compounds that do not fit into the more common categones already covered Most carbon-attached tnfluoromethyl (CF3-C) F-NMR signals fall in the 25 ppm range from -60 to -85 ppm, a notable exception being trifluoromethylacetylenes, with signals at approximately -50 ppm Trifluoromethylated compounds in which the CFj is directly bonded to an atom orlier carton are considered in Table 16 [57 59,95 109,115,116 117 118,119,120 121 122, 123 124, 125] These heteroatom contaming compounds are of interest to both organic and morganic chemists and have been studied by NMR for numerous reasons...

The methodology of heteroatom-directed lithiation has been applied to the synthesis of a variety of organochalcogen compounds, including unstable, low-valent compounds (Section 15.6). ° The Se N interactions in the diselenide 15.4 activate the Se-Se bond toward insertion of a sulfur atom or a methylene group to give the derivatives 15.21a,... 

An ylide can be defined as a compound in which a carb-anion is attached directly to a heteroatom carrying a high degree of positive charge ... 

The direction of primary intermolecular nucleophilic attack at heterosubstituted acetylenes of type HC —X, where X = R2N, RO, RS, is governed by the nature of heteroatom and can be different. 

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