Formation of Cyclic Ethers

Cyclic ethers can be prepared by the intramolecular Sj j2 reaction of a halogen-substituted alcohol such as a bromo alcohol. Proton transfer to a base such as sodium hydroxide gives a bromo alkoxide. If the solution is dilute, the alkoxide acts as a nucleophile, and an intramolecular reaction displaces a bromide ion. This process is shown below for 5-bromo-l-penten-l-ol. 

In more concentrated solutions, an intermolecular WUhamson reaction occurs to give a bromo alkoxy ether. Continued reactions of this type yield long-chain ethers. 

The intramolecular reaction is favored in dilute solution because it is first order. The competing intermolecular reaction is second order, and the rate of the reaction decreases as the square of the concentration. Thus, in a chime solution of the bromoalkoxide, the rate of the intermolecular reaction decreases more rapidly than the rate of the intramolecular reaction. 

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A variety of cyclic ethers, 410, have been obtained via both, solution-phase and polymer-supported methods in the [3 + 2] cycloadditions of nitrile oxides to alkenes and dienes to give isoxazolines (Scheme 1.50). Both simple and substituted dienes have been found suitable for polymer-supported formation of cyclic ethers of ring sizes five through seven (449). 

An alternative method for benzoxepine ring assembly uses the formation of cyclic ethers. Thus, benzoxepino[4,3-f>]indole 130 can be synthesized by the treatment of the keto-alcohol 129 with hot alcoholic base to produce the product in 90% yield as a result of intramolecular nucleophilic substitution (Equation (19) (1993AX(C)2126)). 

The possibility of obtaining real improvements in the industrial production of perfluorooctanoic acid by using perfluorohexyl acetyl chloride in place of octanoyl chloride as starting material has been investigated [136]. In particular, the effect of blocking the formation of cyclic ethers on the yield of the perfluoro-acid was examined this was, however, less than expected due to the increased formation of perfluoro- -heptane. 

While the precise role of metal coordination in the formation of cyclic ethers is open to some doubt, such is not the case where there is good supporting coordination from nitrogen donor atoms. This is illustrated by the macrocyclization on a salicylaldimine complex (equation 39).161... 

The intramolecular alkoxy- or phenoxy-mercuration of unsaturated alcohols or phenols, respectively, provides an exceptionally useful process for the formation of cyclic ethers, particularly those bearing a five- or six-membered ring (equation 263).415... 

We have observed that diol 3, cis-2-butene-l,4-diol, and cis-1,2-bis(hydroxymethyl)cyclohexane react smoothly with TPP-CClq to afford 4 (78%), 2,5-dihydrofuran (65%), and cis-8-oxabicyclo[4.3.0]-nonane 84%). Reaction of diol 5 with TPP-CCli in CH3 CN gives 52% of 5-chloropentanol, 6 (11%), and 1,5-dichloropentane (25%) while diol 7 affords 6-chlorohexanol (48%) and 1,6-dichlorohexane (39%). Comparisons of the ether chlorohydrin dichloride product distributions arising from these simple diols reveal a trend for efficiency of chain closure to 3 - 7 membered rings where the formation of cyclic ethers appear to decrease in order of the following ring size 3-5>6>4-7. 

Finally, it is worth noting that the formation of cyclic ethers by intramolecular nucleophilic substitutions is quite favorable if the resulting ring is three, five, or six mem-bered, as shown in the following reactions ... 

Cyclodehydration. The reaction of this reagent with 1,4-diols results mainly in cyclodehydration to tetrahydrofuranes. Extent of formation of cyclic ethers decreases in order of the ring sizes 5 > 6 > 4 = 7. The reaction with 1,2-diols or 1,3-diols results in chlorohydrins as the major products. If the reaction is conducted in the presence of solid K,CO, in CCI4 (reflux), epoxides become the major products formed from 1,2-diols. 

When the olefin has a hydroxyl group in a y- or (5-position to the double bond, the addition of the tellurinyl acetate is accompanied by the formation of cyclic ethers. The cyclization reactions compete with the formation of the linear addition products shown in the preceding equation. 

Treatment of cyclopropyl sulfides bearing a hydroxy group in the side chain with ceric ammonium nitrate (CAN) in methanol gives five- and six-membered cyclic ethers.In this reaction, the formation of cyclic ethers is understood by assuming a single electron transfer mechanism, which involves ring opening of the cation intermediate followed by intramolecular nucleophilic addition. 

Sibi and coworkers examined some of the factors that control the radical addition/cyclization reactions for the formation of cyclic ethers in terms of the stereoselectivity of the reaction as well as the size of the cyclic ether that is formed. 

The formation of cyclic ethers (701 e.g. 6/5,19-ether ) by Ag" -catalysed reaction of a hypobromite (699) is strongly catalysed by tetrahydrofuran, which... 

Phenylselenoetherificalion. The reaction of certain unsaturated alcohols with this reagent results in formation of cyclic ethers under very mild conditions. ... 

Alkylation of mesitylene by 2-propanol gives 100% selectivity for 1-isopropyl-2,4,6-trimethylbenzene 22 at a conversion of 50% (Scheme 37). Compared with liquid-phase or gas-phase reactions, SCCO2 reduces the mass transport restrictions at the catalytic surface, which increases the residence time of the substrate and reduces coking of the catalysts. This reaction method is also successful in the formation of cyclic ethers, acetals, linear alkyl ethers and aryl ethers. For example, when synthesizing THF from 1,4-butanediol in SCCO2 at 100°C, increasing the pressure from 100 to 200 bar increases the yield from 63 to 87% (Scheme 38). 

If fragmentation involves only the urethane group, one would expect sets of peaks for various combinations of n and nt. The smallest of these should be due to cleavage of the PPG units alone from either end of the molecule tiiese would correspond to m = 0. This is observed in the region below 500 Da where three sets of peaks occur, all due to PPG species cationized with Na. The peaks labeled (o) are due to PPG oligomers with n = 4-17 and n ax = 7. The original PPG also had = 7. The most intense set of peaks ( ) is for n = 4 -13 and n = 7 and corresponds to PPG minus two hydrogens. Because the spectra were run under low resolution, no additional structural information is available. The third set ( ) is presumably due to formation of cyclic ethers and has n = 5-12 and n = 7. 

This reaction is especially useful for the formation of cyclic ethers, and macrocycles. ... 

Another possibility for the formation of cyclic ethers during the transesterification of H-phosphonate diesters with 1,4-butanediol or 1,5-pentadiol is the intramolecular cyclization of the monotransesterificated product. This cyclization occurs by the attack of the oxygen atom of the remaining hydroxyl group from the diol on the a-carbon atom of the same sub-stitutent [28]. 

TABLE 2. Termination of Pd-Catalyzed Formation of Cyclic Ethers by Carbonylative Lactonization... 

P. Poplau, S. Frank, B.l. Morinaka, J. Piel, An Enzymatic domain for the formation of cyclic ethers in complex polyketides. Angew. Chem. Int. Ed. 50,13215-13218 (2013)... 

In contrast, operating in the presence of palladium catalysts at 250°C under 80 bar hydrogen pressure cyclodehydration reactions of sorbitol and mannitol occurred with formation of cyclic ethers (isosorbide 5, 2,5-anhydromannitol, 2,5-anhydroiditol, and 1,4-anhydrosorbitol) (6), Up to 50% and 90% yield of isosorbide were obtained from sorbitol and mannitol, respectively. These... 

Formation of Cyclic Ethers. Alcohols that have a hydrogen in the 5-position can be cyclized with silver acetate and bromine (eq 1). The ring closure occurs via an intermediate hy-pobromite. The reaction can be run under a variety of conditions (presence/absence of light, acidity, solvent, temperature). Because of this variety and the products formed, there has been some disagreement about the role silver plays in the hypobromite decomposition. ... 

The presence of neighboring pairs of hydroxy groups in the sugars allows for the formation of cyclic ether derivatives. For example, it is possible to synthesize five- or six-membered cyclic sugar acetals from the vicinal (and also from some jS-diol) units by treating them with carbonyl compounds (Section 17-8). 

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