Ethers from nucleophilic substitution reaction

Recall that p-toluenesul Innate (tosylate) is a good leaving group in nucleophilic substitution reactions. The nucleophile that displaces tosylate from carbon is the alkoxide ion derived from the hydroxyl group within the molecule. The product is a cyclic ether, and the nature of the union of the two rings is that they are spirocyclic. 

A convenient and efficient synthetic route to a new class of macrocyclic aryl ether ether sulfide oligomers was reported. The process is shown in Fig. 28. This new class of cyclic oligomers is prepared in excellent yield by quantitative chemical reduction of macrocyclic aryl ether ether sulfoxide oligomers with oxalyl chloride and tetrabutylammonium iodide. The cyclic sulfoxide oligomeric precursors are prepared in high yields by an aromatic nucleophilic substitution reaction from bis(4-fluorophenyl) sulfoxide with potassium salts of bisphenols under high-dilution conditions [99]. 

Trimethylsilyl ethers of several steroidal ketones were a-fluorinated by 4-(difluoroiodo)toluene, in moderate yield because of concomitant elimination, accompanied by the formation of other by-products from nucleophilic substitution to a phenyliodonium intermediate. The analogous reaction with xenon difluoride resulted in much better yields but different stereochemistry [50],... 

A similar approach was described by Kim et al. <01MI1403> to build the Furstner synthon from the vinylogous amide 9, previously described, and the commercially available dimethyl aminomalonate hydrochloride as building block for pyrrole systems. The cyclocondensation reaction between the vinylogous amide 9 and dimethyl aminomalonate hydrochloride was performed in acetic acid at room temperature to yield the presumed Intermediate 12 via an acid-catalyzed nucleophilic substitution reaction. The mixture was then diluted with additional acetic acid and heated under reflux to facilitate the intramolecular ring closure and the loss of the methoxycarbonyl moiety to produce the desired pyrrole. Formation of lamellarin O dimethyl ether was achieved as in the Furstner approach <95JOC6637>. 

An example of using sonication and PTC to improve an aromatic nucleophilic substitution reaction has been provided by Wu et al. [56]. Nine diphenyl ether compounds were synthesized from chloronitrobenzene and alkyl-substituted phenols with higher yields and shorter reaction period (Equation 7). 

The indan-based a-amino acid derivatives can be synthesized by PTC. Kotha and Brahmachary [11] indicated that solid-liquid PTC is an attractive method that offered an effective way of preparing optically active products by chiral PTC. They found that ethyl isocyanoacetate can be easily bisalkylated in the presence of K2CO3 as the base and tetrabutylammonium hydrogen sulfate as the catalyst. The advantage of isolating water from the reaction medium is to avoid the formation of unwanted hydroxy compounds in the nucleophilic substitution reaction. If liquid-liquid PTC is applied in the system with the strong base NaOH and dichloromethane as the organic solvent, the formation of dihydroxy or cyclic ether can be observed. 

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. 

The reagents (such as SOCI2, PCI3, or TsCl) used to activate alcohols so they can undergo nucleophilic substitution reactions cannot be used to activate ethers. When an alcohol reacts with one of these activating agents, a proton dissociates from the intermediate in the second step of the reaction and a stable product results. 

Scheme 10.10 outlines the synthesis of polyfaryl ether ketone) s copolymers derived from different molar ratio of TFPOPH and hydroquinone with 4,4 -difluorobenzophenone by the nucleophilic substitution reaction method. 

Gas-liquid phase-transfer catalysis (GL-PTC) is a new synthetic organic method that has similarities both with phase-transfer catalysis (PTC) and with gas-liquid chromatography (GLC) in that anion transfer processes and partition equilibria between gaseous and liquid phases both take place and affect the synthesis. Using GL-PTC, nucleophilic substitution reactions have been so far carried out under operative conditions and with synthetic results, making this method different from the well known liquid-liquid (LL-) and solid-liquid (SL-) phase-transfer catalysis. As regards these latter, phase-transfer catalysts (onium salts, crown ethers and cryptands) transfer the reactive anion from an aqueous liquid (LL-PTC) or a solid salt (SL-PTC) phase into the organic one in which the substitution reaction occurs. In the case of GL-PTC, where no solvent is used, the catalyst always acts as an anion transfer (between solid and liquid phases) but, as it works in the molten state it also constitutes the medium in which the reaction proceeds. 

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