Substitution trisubstituted enol ethers

The fluorination of 12, easily prepared from the corresponding triketo steroid, with an equimolar amount of 1 (Scheme 2) shows the remarkable ability of 1 to distinguish di-substituted from tri-substituted enol silyl ethers. The 9a-fluoro steroid 13 is produced in 51% yield (78% based on recovered triketo steroid) and the combined yield of the other fluorinated products is only 4.6%.17 it thus is apparent that 1 reacts almost exclusively with the trisubstituted enol ether moiety. The new, selective direct fluorination at the 9a-position holds considerable promise as a means to prepare biologically important 9a-fiuoro steroids.18... 

Cycloaddition with nitrile oxides is also efficient with trisubstituted enol ethers and enolates. With fluoro-substituted chiral vinyl sulfoxides 10. cycloadditions performed with aryl chloroaldoximes, at room temperature in carbon tetrachloride in the presence of triethylaminc, are slow but give the homochiral dihydroisoxazoles 11 with high regio- and diastereoselectivity. ... 

The silyl enol ether 83 represents an exception from the 6-endo cyclization rule. The reason for this differing behavior can be seen in the stability of the tertiary radical intermediate and the bulkiness of the trisubstituted double bond. The alkyne substituted silyl enol ether 85 resulted in the formation of the isomeric olehns 86 and 87 in a 1 1 ratio. 

The phthalazide bis(cinchona) derivatives [(DHQD)2-PHAL] are the best ligands for the asymmetric dihydroxyla-tion of trans, 1,1-disubstituted, and trisubstituted alkenes, enol ethers, a,p-unsaturated ketones, and a,p- and p,y-unsaturated esters, whereas the DHQD-IND ligand turns out to be superior for c/j -alkenes (Table 1). The bis(cinchona) alkaloid-substituted pyrimidine ligand was found to be the best for monosubstituted terminal alkenes. The addition of Methanesulfonamide to enhance the rate of osmate(VI) ester hydrolysis is recommended for all nonterminal alkenes. 

The main deficiencies with the preceding approaches are that only arylene-amines give good yields (and there are other routes to 5-arylimidazolcs), and since unsubstituted vinylamines (R = H Scheme 4.3.3) are not available this means that 4- and 5-unsubstituted imidazoles are not accessible. An alternative route involving silyl enol ethers (6) has been reported to overcome these deficiencies (Scheme 4.3.4). Silyl enol ethers can be made either by treating a ketone with chlorotrimethylsilane and triethylamine in DMF solution, or by sequential reactions of the ketone with LDA and chlorotrimethylsilane in 1,2-dimethoxyethane. This normally gives a mixture in which the less highly substituted enol ether is the major product (enolate formation is kinetically controlled) [25], When (6) is heated with an At-chloroamidine for 12-24h in chloroform solution in the presence of an equimolar amount of dry pyridine 1,2-disubstituted (5) (R = H) or 1,2,5-trisubstituted (5) imidazoles are... 

The example depicted below indicates preferential cleavage of the electron-rich enol ether double bond over the trisubstituted one by the electrophilic ozone. Thus, Birch reduction of methoxy-substituted benzenes followed by ozonolysis of the resultant enol ethers provides a powerful route to functionally substituted (Z)... 

Nucleophilic displacement of chlorine, in a stepwise manner, from cyanuric chloride leads to triazines with heteroatom substituents (see Section 6.12.5.2.4) in symmetrical or unsymmetrical substitution patterns. New reactions for introduction of carbon nucleophiles are useful for the preparation of unsymmetrical 2,4,6-trisubstituted 1,3,5-triazines. The reaction of silyl enol ethers with cyanuric chloride replaces only one of the chlorine atoms and the remaining chlorines can be subjected to further nucleophilic substitution, but the ketone produced from the silyl enol ether reaction may need protection or transformation first. Palladium-catalyzed cross-coupling of 2-substituted 4,6-dichloro-l,3,5-triazine with phenylboronic acid gives 2,4-diaryl-6-substituted 1,3,5-triazines <93S33>. Cyanuric fluoride can be used in a similar manner to cyanuric chloride but has the added advantage of the reactions with aromatic amines, which react as carbon nucleophiles. New 2,4,6-trisubstituted 1,3,5-triazines are therefore available with aryl or heteroaryl and fluoro substituents (see Section 6.12.5.2.4). 

This section covers cyclizations to the pyrrole nucleus catalyzed by other metals (Ti, Mn, Ru, Pd, Pt, Zn, In). Dembinski and co-workers used zinc(II) chloride as ligand-free catalyst for the microwave-assisted cyclization of homopropargyl azides 26 to afford substituted pyrroles 27 (Scheme 8) [62]. A similar methodology for the synthesis of 2,4,5-trisubstituted pyrroles was described by Driver et al. employing substituted 1-azidobuta-l,3-dienes in a cyclization reaction using catalytic amounts of zinc(ll) iodide [63]. A three-component zinc-catalyzed one-pot cyclization of aromatic and aliphatic propargylic acetates, silyl enol ethers, and primary amines to substituted pyrroles has been described by Zhan et al. The reaction sequence includes propargylation of the silyl enol ether, amination, 5-exo-(7ig-cyclization, and isomerization [64]. Hiroya and co-workers have shown... 

An intermediate dienylketene 149 is also generated in the reaction of the trisubstituted vinyl ketene 148 with lithium enolates, and subsequent 6 jr-electrocyclization followed by tautomerization to give the highly substituted resorcinol monosilyl ethers 150 in good yields . ... 

When substituted silanes are used instead of hydrogen, the process is referred to as silylformylation or silylcarbonylation. Only rhodium complexes catalyze the transformation of unsaturated compounds to silylaldehydes via the silylformylation reaction. Iridium complexes also are able to catalyze the simultaneous incorporation of substituted silanes and CO into unsaturated compounds, although during the reaction other types of product are formed. In the presence of [ IrCl(C03) ] and [Ir4(CO)i2]) the alkenes react with trisubstituted silanes and CO to give enol silyl ethers of acyl silanes [58] according to Scheme 14.10. 

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