Ethers, enol, addition reagents

Cyclic silyl enol ethers.1 This reagent undergoes 1,2-addition to cyclic a,f3-enones usually in high yield. Brook rearrangement of the adduct results in silyl enol ethers. 

Cyclopropyl ketones can be synthesized directly from silyl enol ethers by addition of acid chlorides to a reaction mixture of Simmons-Smith reagent and the enol ether (Scheme 3). In this reaction, the Znl by-product of the cyclopropanation sequence acts as a Friedel-Crafts type catalyst to activate the acid chloride. In related studies, Grignon-Dubois and co-workers have shown that the Friedel-Crafts acylation of cyclopropyltrimethylsilanes also provides an expeditious route to cyclopropyl ketones. 

Enolates can also be prepared by reaction of enol esters - - or silyl enol ethers with alkyllithium reagents. House has worked out a protocol wherein these enolates are allowed to react with aldehydes to give the corresponding aldols. Higher yields of aldol products are obtained when the lithium enolate is generated in ether or 1,2-dimethoxyethane (DME) by reaction of an enol acetate with methyllithium. Lower yields are obtained if the enolate is produced by reaction of a silyl enol ether with methyllithium. For the aldol reaction, ether or mixtures of ether and DME are superior to THF. Acceptable yields of aldol adducts are obtained in ether at low temperatures (-20 to -50 C). In the more polar solvents DME or THF, the addition of anhydrous ZnCh or MgBra results in higher yields. An example is seen in equation (13). The stereochemistry of this process is discussed in Section 1.6.5. 

Stannyl enol ethers are useful reagents as nucleophiles for mild and selective C-C bond formation. A variety of electrophiles such as aldehydes, ketones, enones, haloalkanes, and -allylpalladium complexes reacts with stannyl enol ethers in the presenee or absence of additives or catalysts. 

The in situ cyanosilylation of p-an1saldehyde is only one example of the reaction which can be applied to aldehydes and ketones in general. - The simplicity of this one-pot procedure coupled with the use of inexpensive reagents are important advantages over previous methods. The silylated cyanohydrins shown in the Table were prepared under conditions similar to those described here. Enolizable ketones and aldehydes have a tendency to produce silyl enol ethers as by-products in addition to the desired cyanohydrins. The... 

Reaction of estrone methyl ether with methyl Grignard reagent followed by Birch reduction and hydrolysis of the intermediate enol ether affords the prototype orally active androgen in the 19-nor series, normethandrolone (69). ° (Note that here again the addition of the methyl group proceeded stereoselectively by approach from the least hindered side.) The preparation of the ethyl homolog starts by catalytic reduction of mestranol treatment of the intermediate, 70, under the conditions of the Birch reduction and subsequent hydrolysis of the intermediate enol ether yields norethandrolone (71). ... 

The synthetic problem is now reduced to cyclopentanone 16. This substance possesses two stereocenters, one of which is quaternary, and its constitution permits a productive retrosynthetic maneuver. Retrosynthetic disassembly of 16 by cleavage of the indicated bond furnishes compounds 17 and 18 as potential precursors. In the synthetic direction, a diastereoselective alkylation of the thermodynamic (more substituted) enolate derived from 18 with alkyl iodide 17 could afford intermediate 16. While trimethylsilyl enol ether 18 could arise through silylation of the enolate oxygen produced by a Michael addition of a divinyl cuprate reagent to 2-methylcyclopentenone (19), iodide 17 can be traced to the simple and readily available building blocks 7 and 20. The application of this basic plan to a synthesis of racemic estrone [( >1] is described below. 

Simple 1,2,4-triazole derivatives played a key role in both the synthesis of functionalized triazoles and in asymmetric synthesis. l-(a-Aminomethyl)-1,2,4-triazoles 4 could be converted into 5 by treatment with enol ethers <96SC357>. The novel C2-symmetric triazole-containing chiral auxiliary (S,S)-4-amino-3,5-bis(l-hydroxyethyl)-l,2,4-triazole, SAT, (6) was prepared firmn (S)-lactic acid and hydrazine hydrate <96TA1621>. This chiral auxiliary was employed to mediate the diastereoselective 1,2-addition of Grignard reagents to the C=N bond of hydrazones. The diastereoselective-alkylation of enolates derived from ethyl ester 7 was mediated by a related auxiliary <96TA1631>. 

The low yields, which are observed among styrenyl adducts, reflect a combination of the poor reactivity of the styrene at the low temperature of the reaction. For example, the combination of t-butyl Grignard with the 2,4-bis-OBoc-benzyl alcohol 15 affords the corresponding benzopyran 50 in only 50% yield even when carried out in the presence of 5-10 equivalents of the styrene (method H, Fig. 4.27).27 Yields for substituted benzopyran styrene adducts are still lower (method G, Fig. 4.27). For example, addition of methyl lithium to 2,4-bis-OBoc-benzylaldehyde 5 followed by the addition of the dienophile and magnesium bromide affords benzopyran 51 in a paltry 27% yield. Method F is entirely ineffective in these cases, because the methyl Grignard reagent competes with the enol ether and with styrene 1,4-addition of methyl supercedes cycloaddition. 

This reaction is extended to the intramolecular ring closure of the intermediate radical 224 with olefinic or trimethylsilylacetylenic side chains [121]. Cu(BF4)2 is also effective as an oxidant (Scheme 89) [122]. Conjugate addition of Grignard reagents to 2-eyclopenten-l-one followed by cyclopropanation of the resulting silyl enol ethers gives the substituted cyclopropyl silyl ethers, which are oxidized to 4-substituted-2-cyclohexen-l-ones according to the above-mentioned method [123]. (Scheme 88 and 89)... 

Schreiber and his coworkers have published extensively over the past decade on the use of this photocycloaddition for the synthesis of complex molecules730 81. Schreiber was the first to recognize that the bicyclic adducts formed in these reactions could be unmasked under acidic conditions to afford threo aldol products of 1,4-dicarbonyl compounds (175 to 176) (Scheme 40). The c -bicyclic system also offers excellent stereocontrol in the addition of various electrophilic reagents (E—X) to the enol ether of these photoadducts on its convex face (175 to 177). This strategy has been exploited in the synthesis of a variety of architecturally novel natural products. 

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