Acyclic enol ether

The addition of sulphinyl chlorides to trimethylsilyl enol ether 138 affording a-ketosulphoxides 139 (equation 76) represents an extension of the reaction of sulphinyl chlorides with ketones. This reaction has attracted attention only recently. Sergeev and coworkers192 reported that treatment of sulphinyl chlorides with acyclic enol ethers afforded a-ketosulphoxides 139 in good to excellent yields. Meanwell and Johnson193 observed that in the case of cyclic enol ethers the corresponding sulphoxides were formed only in very low yields. They found, however, that the introduction of an equivalent amount of a Lewis acid into the reaction mixture markedly promotes the desired reaction, whereas the use of catalytic amounts of a Lewis acid led to a substantial reduction in the yield. This is most probably due to the formation of a complex, between the a-ketosulphoxide and the Lewis acid. 

The described approach to this pharmaceutically important class of compounds [324] was also utilized by Bonnet-Delpon and coworkers one year later [325]. Interestingly, these authors employed hexafluoroisopropanol (HFIP) as solvent and were able to perform the domino process without adding any extra Lewis acid catalyst such as InCl3 due to the acidic properties of HFIP (pKa = 9.3) [326]. Besides di-hydrofuran or dihydropyran, they have also used acyclic enol ethers. 

An alternative approach involves a two-step procedure, in which carbonyl olefination, using the Tebbe reagent 93, generates an acyclic enol ether-olefin (Scheme 16). In this case, subsequent RCM using molybdenum alkylidene 1 proceeds to give cyclic enol ethers. An efficient, one-pot carbonyl olefination-RCM approach has been developed by Nicolaou et al. for the formation of cyclic enol... 

Jorgensen s group44a carried out the reaction using the anhydrous form of chiral bis(oxazoline) coordinated copper complex. Complex 106 containing 83 as the chiral ligand was found to be the most effective. As shown in Scheme 5-32, the asymmetric hetero Diels-Alder reaction of //.y-unsaturated a-keto esters with acyclic enol ethers results in products with excellent yield and enantioselectivity. 

Cyclic enol ethers are reductively cleaved to produce a,to-diols using a stoichiometric amount of benzyltriethylammonium borohydride and chlorotrimethylsilane [30] acyclic enol ethers give saturated alcohols. 

A very useful class of chiral auxiliaries has been developed for alkenes substituted with a heteroatom. These auxiliaries, attached to the heteroatom, allow for the preparation of enantiomerically enriched cyclopropanols, cyclopropylamines and cyclopropylboronic acids. Tai and coworkers have developed a method to efficiently generate substituted cyclopropanol derivatives using the cyclopropanation of a chiral enol ether (equation 78) . The reaction proceeds with very high diastereocontrol with five- to eight-membered ring sizes as well as with acyclic enol ethers. The potential problem with the latter is the control of the double bond geometry upon enol ether formation. A detailed mechanistic study involving two zinc centers in the transition structure has been reported. ... 

The cyclofunctionalization of cycloalkenyl systems where the chain containing the nucleophilic functionality is attached at one end of the double bond leads to spirocyclic structures. Cyclizations of cyclic and acyclic enol ethers to generate spiroacetals are shown in equations (66)168 and (67).169 These reactions generate the thermodynamically more stable products based on anomeric and steric factors.170 Spiroacetal products have also been obtained using isoxazolines as the nucleophilic functionality (cf. Table 14).l4lb Studies of steric and stereoelectronic control in selenoetherification reactions which form spirocyclic tetrahydrofurans have been reported.38 An interesting example of stereoelectronic control in the formation of a spirocyclic lactone has been reported in a recent mevinolin synthesis (equation 68).171... 

The yields from aldehyde alkylidenation is somewhat lower due to the reductive dimerization of aldehydes with low-valent Ti. Alkylidenation of esters is possible by the reaction of 1,1 -dibromoalkane. TiCU and Zn in the presence of TMEDA to give (Z) vinyl ethers [60], Cyclic vinyl ethers are prepared from unsaturated esters in two steps. The first step is formation of the acyclic enol ethers using a stoichiometric amount of the Ti reagent, and the second step is ring-closing alkene metathesis catalysed by Mo complex 19. Thus the benzofiiran moiety of sophora compound I (199, R = H) was synthesized by the carbonyl alkenation of ester in 197 with the Ti reagent prepared in situ, and the subsequent catalytic RCM of the resulting enol ether 198 catalysed by 19 [61]. 

The regioselectivity of the Paterno-Biichi reaction with acyclic enol ethers is substantially higher than with the corresponding unsymmetrically alkyl-substituted olefins. This effect was used for the synthesis of a variety of 3-alkoxyoxetanes and a series of derivatives [55]. The diastereoisomeric cis-and tnms-l-methoxy-l-butenes were used as substrates for the investigation of the spin state influence on reactivity, regio- and stereoselectivity [56]. The use of trimethylsilyloxyethene 62 as electron rich alkene is advantageous and several 1,3-anhydroapiitol derivatives such as 63 could be synthesized via photocycloaddition with l,3-diacetoxy-2-propanone 61 (Sch. 17) [57]. 

Photoinduced [2+2] cycloaddition (the Paterno-Buchi reaction) of 1-acetylisatin with acyclic enol ethers afford the spiro(3f/-indole-3,2 -oxetane)s 43 with moderate regio- and diastereoselectivity via the mi triplet state of the isatin derivative without involvement of single electron transfer <02JCS(P1)345>. 

For the first example, we chose to acylate olefin alcohol la. This was readily accomplished using acetic anhydride and 4-DMAP in pyridine to provide ester 17. Methylenation, using Takai s (10) protocol, yielded the acyclic enol ether 18 which was subsequently cyclized with 15 mol % of the Schrock catalyst 6 in hot toluene to afford the glycal 19 in good yield. Hydroboration and oxidative work-up led to the methyl-C-glycoside 20 (Scheme 4). With this proof of principle in hand, we then set out to prepare a number of additional examples as shown in Table 1 (11). 

Entry Ester/Acyclic Enol Ether Glycal, (% Yield)3, b... 

The reaction was carried out in a few different ways as summarized below in Table 5. We found that material was being lost at the methylenation stage and that purification of the acyclic enol ether was causing a drop in the overall yield. If no purification was carried out until after the hydroboration step, then good overall yields (over 3 steps) of product could be obtained (Table 5) 18). To obtain reproducible yields, each of the individual reactions had to be pushed to completion. 

The acyclic enol ether was purified by flash chromatography. The product glycal was not isolated, but rather the one-pot protocol was employed. cYield is over two steps. dThe acyclic enol ether was not purified by flash chromatography, but the crude reaction mixture filtered through a pad of basic alumina. The glycal was not isolated, but carried on crude to the next step. Yield is over three steps. 

Early investigations dealing with intermolecular arylations of uiisymmetrically donor-substituted alkenes often revealed only poor regioselectivities, especially with acyclic enol ethers. However, suitable conditions have since been developed for both the selective a-... 

A further improvement is achieved by a sterically more demanding auxiliary in enol ethers which are prepared from 2,6-dimethyl-3,5-heptanediol71. In this case, the diastereofacial selectivity is next to perfect. For one acyclic enol ether of this type a similar selectivity is described70. 

It is worth noting that only 1,2-dioxetanes (206) are obtained by photooxygenating 2-(phenoxymethylidene)adamantanes (205) in acetaldehyde as solvent (Equation (30)). However, these dioxetanes can be expanded to trioxanes at a later stage (see Section 6.20.6.4). Acyclic enol ethers behave in the same way. l,l-Di- -butyl-2-methoxyethylene (207), singlet oxygen and acetaldehyde cyclize to the cis and trans trioxanes (208) in 31% yield (Equation (31)). 

Some electron-rich olefins, such as enol ethers 170, react directly with 32 under mild conditions with Lewis acid catalysis. The first product of the reaction results from addition of the S-Cl bond to the olefin, the sulfur atom being attached to the carbon / to the oxygen and the chlorine in the a-position. If the / -carbon carries a hydrogen atom, elimination of HCl can be effected with mild bases such as triethylamine to regenerate a double bond. The reaction works with both cyclic and acyclic enol ethers, the latter case giving ( ) (Z)-mrxtures of products 171 (Equation 13) <2000JHC583>. 

A special focus of modem research in Pd-catalyzed Heck-coupling reactions is to investigate the ligand-free reaction in ionic liquids using Pd(OAc)2, PdQz or Pd/C as catalyst precursors [210]. In these examples the role of the ionic liquid is as either solvent, ligand or both. Of special interest for these studies is the regioselectivity of the Heck products when electron-rich olefins, such as acyclic enol ethers, silanes, and enol amides are applied as substrates. Possible products are the branched olefin (a. Scheme 5.3-24) and the linear olefin (P, Scheme 5.3-24). 

The group of Grubbs utilized RCM of acyclic enol ethers 36 to generate 2-substituted benzofurans 37 (94JOC4029). The enol ethers were readily available from the corresponding esters via olefination, and the RCM reaction was carried out using molybdenum alkyhdene catalyst 6 (Scheme 10). 

For Heck reactions catalysed by Pd(OAc)2 associated with dppp, see Ref. [Ig] and (a) Cabri, W., Candiani, I. and Bedeshi, A. (1990) Ligand-controlled a-regioselectivity in palladium-catalyzed arylation of butyl vinyl ether. J. Org. Chem., 55, 3654-5 (b) Cabri, W., Candiani, L, De-Bernardinis, S. et al. (1991) Heck reaction on anthraquinone derivatives ligand, solvent, and salts effects. J. Org. Chem., 56, 5796-800 (c) Cabri, W., Candiani, L, Bedeshi, A. and Santi, R. (1991) Palladium-catalyzed a-arylation of vinyl butyl ether with aryl halides. Tetrahedron Lett., 32, 1753-6 (d) Cabri, W., Candiani, L, Bedeshi, A. et al. (1992) a-Regioselectivity in palladium-catalyzed arylation of acyclic enol ethers. J. Org. Chem., 57, 1481-6 (e) Cabri, W.,... 

Cabri, W., Candiani, L, Bedeschi, A. et al. (1992) Alpha-regioselectivity in palladium-catalyzed arylation of acyclic enol ethers. J. Org. Chem., 57,1481-6. 

Shibasaki and co-workers used a ring-closing metathesis approach to prepare a number of five-, six-, and seven-membered rings from electron-deficient olefins. Treatment of acyclic enol ether 18 with 7 mol % of 3 in refluxing benzene provided the corresponding cyclic enol ether 19 in 94% yield. Deprotection of the silyl ether 19 (not shown) resulted in the corresponding cyclic ketone, a valuable synthetic intermediate in natural products synthesis and a number of industrial processes. The authors reported additional examples of the synthesis of five-membered ring carbocycles as part of this study. 

Shibasaki and co-workers used a ring-closing metathesis approach to prepare seven-membered rings from electron-deficient olefins. Reaction of acyclic enol ethers 226 and 228 with 7 mol % of 3 in benzene provided cyclic enol ethers 227 and 229 in 88 and 93% yield, respectively. 

Enol ethers are more reactive toward formaldehyde and MesAl than simple alkenes. Reaction with dihydropyran gives a 75% yield of a 92 8 mixture of 33 and 34 (See Figure 10). The major product is again formed by cis addition of hydroxymethyl and methyl groups. Quite different results are obtained with acyclic enol ethers. 20 Reaction of ethyl propenyl ether, as a 78 22 cis-trans mixture, with 2 equivalents of paraformaldehyde and 2 equivalents of MesAl at 0 in CH2CI2 gives a 65% yield of an 18 1 mixture of threo- and c yr/ir< -3-ethoxy-2-meAyl-l-butanol (37 and 38). Identical results are obtained from either pure stereoisomer of ethyl propenyl ether. 

Scheme 38. Electrophile-mediated intramolecular cyclization of an acyclic enol ether.

As an extension of this work, photoinduced [2-1-2]-cycloadditions of 1-acetyKsatin 13 with cyclic enol ethers (furan, benzofuran, 2-phenylfuran, 8-methoxypsoralen) and acyclic enol ethers (n-butyl vinyl ether and vinyl acetate) were investigated which afforded the spirooxetanes in high yields (82 to 96%)... 

Entry Acyclic enol ether Product(s) Yield %)... 

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