Cyclodehydration of 1,2-diols

The pioneering work of Denney et ai19 on the synthetic utility of oxyphosphoranes has been thoroughly exploited by Evans et al. in demonstrating that diethoxytriphenylphosphorane promotes mild and efficient cyclodehydration of diols (e.g. 11) to cyclic ethers (e.g. 13) via the cyclic phosphorane (12)20>21. Simple 1,2-, 1,4-, and 1,5- diols afford good yields of the cyclic ethers but 1,3-propanediol and 1,6-hexandiol give mainly 3-ethoxy-l-pro-panol and 6-ethoxy-l-hexanol respectively whereas tri- and tetra-substituted 1,2-diols afford the relatively stable 1,3,2- diox-phospholanes. In some instances (e.g. 14), ketones (e.g. 16) are formed by a synchronous 1,2-hydride shift within (15). The synthetic utility has been extended to diethoxyphosphoranes supported on a polystyrene backbone22. 

Table I. Stereochemistry of Cyclodehydration of Diols with DTPP...

Increasing interest is being shown in the use of solid acid catalysts in potentially more environmentally acceptable syntheses. In this context the use of metal (IV) phosphates has been investigated for the cyclodehydration of diols to give cyclic ethers, including the conversion of the diol 125 to oxepane 126 (32% yield) [01GC143],... 

A Proposed Mechanistic Rationale for Dioxaphospholane-Promoted Cyclodehydration of Diols. 

Cyclodehydration of diols in which one of the hydroxyl groups is allylic shows another reaction pattern. When 2-alkenyl-6-alk yltetrahydropyrans are produced it favors the cis-... 

The cyclopropenium activation approach has been employed in a number of elimination reactions, such as nucleophilic substitution of alcohol, nucleophilic acyl substitution of carboxylic acid, cyclodehydration of diol, and the Beckmann rearrangement (Scheme 6.17) [45]. 

Robinson, P.L., Barry, C.N., Kelly, J.W., and Evans, S.A., Diethoxytriphe-nylphosphorane a mild, regioselective cyclodehydrating reagent for conversion of diols to cyclic ethers. Stereochemistry, synthetic utility, and scope, /. Am. Chem. Soc., 107, 5210, 1985. 

Diethoxytriphenylphosphorane, (C6H5),P(OC2H5)2 (1). The phosphorane is obtained by reaction of diethyl peroxide (caution) with triphenylphosphine at 0-70°. Cyclodehydration of dioIs to ethers. 1,3-, 1,4-, and 1,5-Diols react with 1 to... 

Cyclodehydration of the 1,5-diol in the presence of zinc chloride, however, leads to inversion of configuration, presumably by an 2 displacement at the tertiary centre (Scheme... 

Cyclodehydration of 1,4- and 1,5-diols These diols are converted into tet-rahydrofurans and tetrahydropyrans, respectively, when heated with HMPT (0.3 equiv.). 

Leonard and Elkin s08 cyclodehydration of 4-(/3-hydro xyethyl)-piperidine (43) in the gas phase can be considered as an intramolecular alkylation. The same method was used for synthesis of 3-hydroxy-quinuclidine (44) from 4-piperidylethane-l,2-diol (45).00... 

Cyclodehydration of hexane-1,6-diol with tin phosphate as a catalyst (230°C) gives oxepane in 32% yield <2001GC143>. Acid-catalyzed dehydration of 2,2 -bis(hydroxydiphenylmethyl)biphenyl by an ion-exchange resin allows one to prepare a sterically hindered 2,2,7,7-tetraphenyldibenzo[c, ]oxepine in 70% yield under mild conditions (CH2C12, rt) <2002J(P1)2673>. 

We have systematically examined the facility with which DTPP promotes the cyclodehydration of simple diols to cyclic ethers 1,3-propanediol (1) - oxetane (2) (2-5%) 1,4-butanediol (3) te-trahydrofuran (4) (85%) 1,5-pentanediol (5) - tetrahydropyran (6) (72%) 1,6-hexanediol (7) - oxepane (8) (55-68%). Increased alkyl substitution at the carbinol carbon s gnificantly diminishes the facility for cyclic ether formation. For example, a mixture of meso- and d, 1 —2, 6-heptanediol gave only 6-10% of the cis- and trans-2,6-dimethyltetrahydropyrans when treated with DTPP. While diol 1 resists cyclodehydration with DTPP to oxetane, some 2,2-di-substituted 1,3-propanediols are readily converted to the appropriate oxetanes [e.g., 2-ethyl-2-phenyl-l,3-propanediol -> 3-ethyl-3-phenyloxetane (78%)]. 

Stereochemical information on the mode of cyclodehydration of unsymmetrical diols to cyclic ethers could obviously have important consequences regarding useful, preparative routes to chiral cyclic ethers of high enantiomeric purity. For example, dioxyphos-phorane promoted cyclodehydration of a chiral diol can, in principle, give the enantiomeric ethers by either of two stereochemi-cally distinct routes. Separate stepwise decomposition of oxy-phosphonium betaines, A and B, although proceeded by a number of equilibria could ultimately afford a nonracemic mixture of cyclic ethers. 

Diols are directly converted into oxiranes with Ph3P or other phosphines in the presence of diisopropyl azodicarboxylate (Mitsunobu reaction). Simple alkenes can be converted into nonracemic epoxides in high yields and with excellent ee values via a two-step sequence of asymmetric dihydroxylation and Mitsunobu cyclodehydration of the intermediate diol (Scheme 18) <20010L2513>. These reactions give best results using electron-poor alkenes . 

Of the alkylation systems described in Section 1.1.2.5.1, the DEAD-PhsP procedure cannot be used in the preparation of acyclic dialkyl ethers, but alkyl aryl ethers and cyclic ethers have been synthesized. The PhaP-CCU system is also effective for the cyclodehydration of 1,4- and 1,2-diols to tetrahydrofurans and epoxides, respectively. ... 

Hauser and co-workers effected cyclodehydration of the diol (7) to the ether diphenane (8) by heating an intimate mixture with potassium bisulfate, cooling. 

Regio- and Stereochemical Features of the Dioxaphosphorane-Promoted Cyclodehydration of 1,2-Diols. 

Oxyphosphorane-promoted cyclodehydration of an unsymmetrical chiral diol can, in principle, give enantiomeric ethers by either of two stereoisomerically-distinct routes... 

Consequently, cyclodehydration of unsymmetrical chiral 1,2-diols should afford predominantly the cyclic chiral ether with retained configuration at the C-2 stereogenic carbon, and (b) as the steric bulk of the attached R group increases, the percent of regioselection or stereospecificity of substitution should also increase. 

An interesting synthetic target related to triptindane is the tris(naph-tho)[3.3.3]propellane 86 (Schemes 16 and 17). Alder et al. [84] reported on first attempts to construct this two-fold triptindane bearing a highly strained C - C bond. Cyclodehydration of acenaphthenediol 85, prepared previously from acenaphthene quinone (84) [85], or the corresponding pinacolone formed as an intermediate in the acidic medium, did not occur in the desired way (Scheme 16). Attempts to utilize the corresponding bis(dihydro) derivative (i.e. the diol derived from 87) resulted in the formation of the C2-symmetrical polycycle 88, possibly by di-oxy Cope rearrangement followed by a criss-cross [2 + 2] cycloaddition [84]. 

Table 2. Cyclodehydration of higher diol homologs to the corresponding cyclic ethers.

Nucleophilic Attack at Halogen. Further studies have been reported of the reactions of diols with the triphenylphosphine-carbon tetrachloride reagent. It has now been applied to 1,2-diols (in the presence of potassium carbonate) to form epoxides and to the trans-6 o (84), the nature of the product depending on the relative amounts of phosphine and diol present. The major product of reactions involving equimolar quantities of phosphine and diol is (85). The cyclodehydration product (86) is formed in only poor yield. In the presence of carboxylic acids, the triphenylphosphine-carbon tetrachloride system causes ring-opening of epoxides with the formation of c -enol esters, the reaction presumably proceeding via nucleophilic attack by the oxirane at an acyloxyphos-phonium intermediate. ... 

The simplest method for obtaining tetrahydrofurans is by cyclodehydration of 1,4-diols ... 

Tetrahydrofuran is produced industrially by catalytic cyclodehydration of butane-1,4-diol. 

Simple alkenes can also provide non-raccmic epoxides via a two-step sequence of asymmetric dihydroxylation (AD) and Mitsunobu cyclodehydration of the intermediate diol. For example, the styrene derivative 26 was converted to the corresponding (S)-epoxide in excellent yield and enantiomeric excess by standard AD conditions, followed by a combination of tricyclohexylphosphinc l(C6Hi])3PJ and diisopropyl azodicarboxylale (DIAD). The best optical yields were obtained with electron-poor alkenes, presumably due to the stabilization of the secondary alkoxidc intermediate (Scheme 2) <01OL2513>. 

Dehydration and Cydization. Amberlyst 15 has been used in the cyclodehydration of pentane 1,5 diol to tetrahydropyran and in the synthesis of a library of substituted benzofurans (eq 7)... 

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