Ethers nucleophilicity

Crown Ethers Nucleophilic Substitution Reactions in Relatively Nonpolar Aprotic Solvents by Phase-Transfer Catalysis... 

The thermal decomposition of arenediazonium tetrafluoroborates is slowed down when the salt is complexed by 18-crown-6 (Bartsch et al., 1976). The kinetic data obtained for the 4-t-butylbenzenediazonium salt at 50°C in 1,2-dichloroethane revealed that the rate of complexed to uncomplexed salt is more than 100. Other crown ethers such as dibenzo-18-crown-6 and dicyclohexyl-18-crown-6 exhibited the same effect but smaller molecules such as 15-crown-5 did not influence the rate at all. It is not only the rate of the Schiemann reaction that is affected by the crown ether nucleophilic aromatic substitutions by halide ions (Cl-, Br-) at the 4-positions in arenediazonium salts are retarded or even entirely inhibited when 18-crown-6 is added. This is attributed to the attenuation of the positive charge at the diazonio group in the complex (Gokel et al., 1977). 

Five years later, the same authors reported an improved total synthesis of arcyriaflavin A (345) starting from the TBS enol ether 1490 (for the synthesis see Scheme 5.252). This route involves two indolizations based on silyl enol ether nucleophilic attack and Fischer processes. Using Cadogan s procedure by heating in triethyl phosphite, the TBS enol ether 1490 was transformed into the ketone ( + )-1495, involving silyl enol ether-mediated indolization. Finally, Fischer indolization of (+ )-1495 by reacting with phenylhydrazine (524) led directly to arcyriaflavin A (345) in 57% yield (794) (Scheme 5.253). 

Having defined the types of commonly used carbon nucleophiles and carbon electrophiles, it would seem that if you react any of the carbon nucleophiles (electron donors) with any of the carbon electrophiles (electron acceptors), then a carbon-carbon bond should be formed. While this is theoretically true, it is unworkable from a practical point of view. If, for example, a carbanion nucleophile was reacted with a cationic electrophile, it is unlikely that the desired carbon-carbon bond formation would be detected, even after the smoke cleared. Or if a silyl enol ether nucleophile was reacted with an a, /f-unsaturated ester, no reaction could be observed to take place in any reasonable time frame. 

The concept of the generation of silylenium ion by hydride abstraction with a stable carbenium ion has been explored in designing the synthesis of saturated and unsaturated cyclic silaethers (104). For this purpose the incipient silylenium ion is intramolecularly trapped by a properly located ethereal nucleophile, which leads to cyclization [Eq. (21)]. If the triphenyl-... 

If the anodic oxidation of N-alkylanilines is performed in the presence of nucleophiles like enol ethers, nucleophilic substitution in the of-position to nitrogen by the enol ether can be observed in low yields. The electrophilic intermediate is the N-aryl iminium ion or the N-aryl imine after loss of two electrons and one or two protons. These intermediates add to the enol ether to give acetals (up to 26%) as addition products, or the first addition step is followed by an electrophilic aromatic substitution to form tetrahydroqui-nolines (13-39%) [47]. It should be noted at this point that better results for the nucleophilic a-substitution to nitrogen can be obtained with N,N-dialkylanilines (see next subsection). Optimum results, however, are obtained with N-acylated compounds via the intermediate N-acyl iminium ions (see Ref. 8). 

Acylation of sulfide and ether nucleophiles by protonated acyl derivatives is uncommon in condensed phase but, in the gas phase, ions of composition Ac+XMe2 are readily formed. For example, vinyl and iso-propenyl acetates acylate ethers under ICR conditions (11) ... 

When the thioacetal (128) was treated with allylmagnesium bromide and subsequently with BFs etherate, nucleophilic addition on the carbonyl carbon and a subsequent cationic cyclization took place the product (129) was obtained by aromatization with loss of methanethiol (Scheme 18) <84TL5095>. The reaction of (128) under the Simmons-Smith reaction conditions gave the thienothiepine derivative (130). The proposed mechanism for the formation of (130) involves a nucleophilic attack of the initially formed sulfonium ylide intermediate, intramolecular aldol type condensation, aromatization and demethylation (Scheme 19) <89TL3093>. 

Attack by the halide nucleophile always occurs at the 5/ -hybridized carbon of the alkyl group and is analogous to what takes place in the cleavage of dialkyl ethers. Nucleophilic aromatic substitution does not occur under these conditions. 

The four most common methods for the synthesis of late transition metal enolates are oxidative addition to halocarbonyl compoxmds, ligand metathesis with main group enolates or silyl enol ethers, nucleophilic addition of anionic metal complexes to halocarbonyl electrophiles, and insertion of an a,3-imsaturated carbonyl compoimd into a metal hydride. Examples of these synthetic routes are shown in Equation 3.47-Equation 3.50. Equation 3.47 shows the synthesis of a palladium enolate complex by oxidative addition of ClCHjC(0)CHj to Pd(PPh3), Equation 3.48 shows the synthesis of a palladium enolate complex by the addition of a potassium enolate to an aryl Pd(II) halide complex, and Equation 3.49 shows the synthesis of the C-bound W(II) enolate complex in Figure 3.7 by the addition of Na[( n -C5R5)(CO)jW] to the a-halocarbonyl compound. Finally, Equation 3.50 shows the synthesis of a rhodium enolate complex by insertion of but-l-en-3-one into a rhodium hydride. This last route has also been used to prepare enolates as intermediates in reductive aldol processes. - ... 

In N-acyliminium ion-mediated functionalization of 2- or 6-alkoxy-substituted piperidines, Sc(OTf)3 was found to be an excellent Lewis acid with a silyl enol ether nucleophile, and moderate diastereoselectivities were obtained (trans/cis = 26/74 and 78/22, respectively) [158]. Sc(OTf)3 was found to be a more efficient metal tri-flate in the nucleophilic substitution of N-benzyloxycarbonyl-2-methoxypiperidine and 3-substituted-2-acyloxy-N-benzyloxy-carbonylpiperidine with silylicon enolates [159]. 2-Acetoxy-3-benzyloxy-N-benzyloxycarbonylpiperidine afforded the 2-alkylat-ed adducts in high cis selectivity (cis/trans = 71/29), while 2,3-diacyloxy-N-benzyl-oxycarbonylpiperidines showed trans selectivity (trans/cis = 80/20-100/0). Febri-fugine, a potent malarial alkaloid, was successfully synthesized from 2,3-diacetoxy car bony Ipiperidine on the basis of these diastereoselective nucleophilic substitution reactions. 

TMSLi adds to cyclohexenone in THF-HMPA to give exclusively the 1,4-addition product (eq 3). The intermediate enolate may be stereoselectively alkylated at carbon with alkyl halides, or 0-silylated with chlorotrimethylsilane to provide the enol ether. Nucleophilic 1,4-addition to cyclohexenones is quite stereoselective. Reaction of 5-methylcyclohex-2-enone with TMSLi occurs predominantly by axial attack, resulting in a 92 8 ratio of axial to equatorial products. TMSLi also undergoes diastereoselec-tive nucleophilic addition to 1-naphthyloxazolines (eq 4) however, the addition of the silyl nucleophile is not as selective as the... 

Scheme 74 Complex alkylations of a-acetoxy ethers employing silyl enol ether nucleophiles in the context of leucascandrolide A [76, 117, 131]...

A different class of C-N electrophiles was developed by Livinghouse in the total synthesis of the Orchidaceae alkaloid dendrobine (144, Scheme 11.23) [122]. Dendrobine is the principle component of the Chinese folk medicine Chin-Shin-Hu" and has been shown to exhibit antipyretic and hypotensive activity. In this study, it was found that silver-mediated abstraction of the chloride in 141 affords an intermediate acylnitrilium ion 142. This is trapped by the silyl enol ether nucleophile to give bicycle 143 in 88% yield. 

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