2-Substituted tetrahydrofurans

Polymerization of substituted 1,4-epoxides to high molecular weight polymers is not expected on a thermodynamic basis. Indeed high molecular weight polymers have not yet been prepared. However, 3-MeTHF [106] and 2-MeTHF [96] have both been polymerized to give oligomers. 

4-Epoxycyclohexanes, which can be considered to be 2,5-disub-stituted THF s, polymerize quite readily [90, 107—9]. For example, from 

This means that the C-4 carbon atom selectively undergoes inversion of configuration. 

Kinetic analyses of the polymerizations of these exo and endo isomers have been reported by Guisti et al. [112] and by Saegusa et al. [113, 114]. The former made their kinetic analysis on the basis of the initial velocity observed in the conversion—time curve. As usual, the latter group used their phenoxyl end-capping method. The initiator used was the BF3—ECH system. Polymerizations of both isomers were characterized by slow initiation and fairly rapid termination. In contrast to THF polymerizations, the depolymerization reaction was insignificant and the kinetics were analysed on the basis of the kinetic equation 

Kinetic parameters for exo- and endo-2-methyl-7-oxabicyclo[2.2.1 ] heptane [113, 114] 

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Complete chirality transfer has been observed in the intramolecular allyla-tion of an alcohol with the activated allylic ester of 2,6-dichlorobenzoic acid 338 to give the 2-substituted tetrahydrofuran 339[208]. 

Because of the high ring strain of the four-membered ring, even substituted oxetanes polymerize readily, ia contrast to substituted tetrahydrofurans, which have tittle tendency to undergo ring-opening homopolymerization (5). 

Many copolymerization studies have been made. A detailed discussion and critique of the results has been pubHshed (1) and the breadth of the comonomers studied has been summarized (6). Among the comonomers used are oxiranes, oxetanes, 1,3-dioxolane, substituted tetrahydrofurans. 

There are two possible ways for the ring opening of 35 in the polymerization The C1—O7 bond cleavage leads to the formation of a substituted tetrahydropyran ring 36 in the polymer chain, while the C1—O2 bond cleavage produces a substituted tetrahydrofuran ring 37. Product analysis of the acid-catalyzed hydrolysis of the... 

The application of 1,3-dipolar cycloaddition processes to the synthesis of substituted tetrahydrofurans has been investigated, starting from epoxides and alkenes under microwave irradiation. The epoxide 85 was rapidly converted into carbonyl ylide 86 that behaved as a 1,3-dipole toward various alkenes, leading to quantitative yields of tetrahydrofuran derivatives 87 (Scheme 30). The reactions were performed in toluene within 40 min instead of 40 h under classical conditions, without significantly altering the selectivi-ties [64]. 

ISOC reaction was employed to synthesize substituted tetrahydrofurans 172 fused to isoxazolines (Scheme 21) [44b]. The silyl nitronates 170 resulted via the nitro ethers 169 from base-mediated Michael addition of allyl alcohols 168 to nitro olefins 167. Cycloaddition of 170 followed by elimination of silanol provided 172. Reactions were conducted in stepwise and one-pot tandem fashion (see Table 16). A terminal olefinic Me substituent increased the rate of cycloaddition (Entry 3), while an internal olefinic Me substituent decreased it (Entry 4). 

Acetalization or ketalization with silylated glycols or 1,3-propanediols and the formation of thioketals by use of silylated 1,2-ethylenedithiols and silylated 2-mer-captoethylamines have already been discussed in Sections 5.1.1 and 5.1.5. For cyclizations of ketones such as cyclohexanone or of benzaldehyde dimethyl acetal 121 with co-silyl oxyallyltrimethylsilanes 640 to form unsaturated spiro ethers 642 and substituted tetrahydrofurans such as 647, see also Section 5.1.4. (cf. also the reaction of 654 to give 655 in Section 5.2) Likewise, Sila-Pummerer cyclizations have been discussed in Chapter 8 (Schemes 8.17-8.20). 

The catalytic preparation of substituted tetrahydrofurans and pyrrolidines with a number of N-protecting groups has been reported. The use of 1,2-... 

Olefinic iodoethers 52 undergo the Cp2TiCl2-catalyzed reductive cycli-zation in the presence of Mn and Mc3SiCl (Scheme 32) [72]. This protocol provides a versatile method for the selective formation of multi-substituted tetrahydrofurans 53. 

This procedure illustrates a fundamentally new method for constructing substituted tetrahydrofurans.5-10 This practical method assembles the tetrahydrofuran ring from allylic diol and carbonyl components and in the process forms three ring bonds C(2)-C(3), C(4)-C(5) and 0-C(5). Both aldehydes (eq 1) and ketones (illustrated in the present procedure) can be employed as the carbonyl component. Although it is often convenient to isolate the acetal intermediate, conversion to the 3-acyltstrahydrofuran can also be accomplished in many cases by the direct reaction of the diol and carbonyl components.8 High ds stereoselectivity (at least 20 1) is observed in the preparation of tetrahydrofurans that contain single side chains at carbons 2 and 5 (eq 1). The kinetically controlled product also has the cis relationship of these side chains and the 3-acyl substituent. 

A definitive feature of this highly stereoselective new route to substituted tetrahydrofurans is that both syn and anti allylic diol stereoisomers typically afford identical tetrahydrofuran products. Thus, there is no need for stereoselective... 

CARBOETHOXY-2,3-DIMETHYL-1-OXA-8-AZASPIRO[4-5]DECANE, a procedure that exemplifies a new stereocontrolled method for constructing substituted tetrahydrofurans. 

Very simple compounds such as alkyl-substituted tetrahydrofurans can be dehydrogenated by chlorosulfonic acid or by oleum, these reagents having some capacity for oxidation, and furylium ions are produced (Section III,B), but the technique has not been exploited synthetically.19 The presence of an easily eliminated group helps indeed, the terpenoid furan solidagenone might well be an artefact formed during isolation from an unstable hydrofuran... 

These sequential steps generate the intermediate substituted tetrahydrofuran-2-ol, which is converted in the second sequence into the final product shown. 

The products arising from such condensations of the hexoses readily lose the elements of water in a way similar to the dehydration of 7-hydroxy acids, when heated in aqueous solution the hydroxyl groups corresponding to those at C3 and C6 of the original sugar are involved, and a substituted tetrahydrofuran ring results. 

The Williamson ether synthesis remains the most practical method for the preparation of tetrahydrofurans, as can be exemplified by the two examples shown in the following schemes. A simple synthesis of 2-substituted tetrahydrofuran-3-carbonitriles 84 is achieved by generating the alkoxide under a phase transfer condition via reaction between 4-chlorobutyronitrile and non-enolizable aldehydes <00SL1773>. A synthesis of 2-alkylidene-tetrahydrofuran 85 was recorded, in which a dianion can be generated through treatment of the amide shown below with an excess of LDA, and is followed by addition of l-bromo-2-chloroethane. In this way, the more basic y-carbon is alkylated and leads eventually to the nucleophilic cyclization <00SL743>. 

Viewed in a much broader context, C-aldopentofuranosyl derivatives may also be regarded as highly functionalized, chiral derivatives of substituted tetrahydrofuran. As such, they may be useful intermediates in the synthesis of a variety of compounds that contain a chiral, substituted tetrahydrofuran ring. 

The intramolecular cyclization of the open chain glucose derivative 143 leading to substituted tetrahydrofuran 146 was observed by Cumpstey (Fig. 46).62... 

Compounds 561/562 were transformed into substituted tetrahydrofurans 563 in 23-51% yield by reaction with silicon-containing nucleophiles in the presence of On the... 

Intramolecular displacement by a benzyloxy group to form a tetrahydrofuran ring with concomitant debenzylation has been recognized as an undesired side reaction [111, 112] but is also useful in stereocontrolled formation of poly-substituted tetrahydrofurans [111, 113]. 

Sulfonyl-substituted homoallylic alcohols tmdergo 5-endo-trig cyclization reactiorrs on treatment with base, with cyclization stereoselectively depending on double bond geometry, to give substituted tetrahydrofurans <99T13471>. 

A very interesting application of the above methodology is the synthesis of hetero-cycles60. Thus, substituted tetrahydrofurans 121-123 are obtained easily with perfect diastereoselectivities (equation 57)60a. 

Bis(2-oxolanyl)propane and other compounds with substituted tetrahydrofuran moieties have been suggested as modifiers (12,13). 2,2-Bis(2-oxolanyl)propane is shown in Figure 9.2. 

Hydroxymethyltetrahydrofuran is converted into 5,6-dihydrcM-//-pyran and the acid catalyzed rearrangement of other 2-substituted tetrahydrofurans forms 3-hydroxytetrahydropyrans (Scheme 27). Thiepan-4-one results from ring expansion of tetrahydrothiopyran-4-one (Scheme 28). 

In a 2- (5-) substituted tetrahydrofuran loss of the 2-substituent is nearly always important because it leaves behind an oxygen-stabilized cation. Scheme 14 displays the fissions that allow a ready identification of the position of the tetrahydrofuran residue in a long chain but not the stereochemistry, the cis and trans isomers having nearly identical spectra (72MI31000). The series designated in that scheme was produced by the oxygenation of lipids... 

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