Nucleophilic substitutions tetrahydrofuran

Cyclic sulfites. 1,2-Diols form cyclic sulfites very readily. Although there are few important synthetic uses for these compounds, their oxidation to cyclic sulfates provides excellent substrates for nucleophilic substitutions. Tetrahydrofuran ring closure in an intramolecular attack has enormous implication for the synthesis of a family of natural products, because proper design can precipitate a cascade process. 

Reaction of 3,4-bis(phenylsulfonyl)-l,2,5-oxadiazole oxide isomers with ethanol and ethanethiol in basic medium gave the expected alkoxy- and alkylthio-substituted (benzenesulfonyl)furoxans, respectively <1996JHC327, 1997FES405>. Nucleophilic substitution of the sulfonyl group of 3,4-bis-(benzenesulfonyl)furoxan 222 in the presence of aqueous NaOH in tetrahydrofuran (THF) furnished the corresponding 3 -0-(3-benzenesulfonylfur-oxan-4-yl) derivative 223 in 79-92% yield (Equation 44) <2004JME1840>. 

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>. 

GABA HMG-CoA HMPA HT LDA LHMDS LTMP NADH NBH NBS NCS NIS NK NMP PMB PPA RaNi Red-Al RNA SEM SnAt TBAF TBDMS TBS Tf TFA TFP THF TIPS TMEDA TMG TMP TMS Tol-BINAP TTF y-aminobutyric acid hydroxymethylglutaryl coenzyme A hexamethylphosphoric triamide hydroxytryptamine (serotonin) lithium diisopropylamide lithium hexamethyldisilazane lithium 2,2,6,6-tetramethylpiperidine reduced nicotinamide adenine dinucleotide l,3-dibromo-5,5-dimethylhydantoin A-bromosuccinimide A-chlorosuccinimide A-iodosuccinimide neurokinin 1 -methyl-2-pyrrolidinone para-methoxybenzyl polyphosphoric acid Raney Nickel sodium bis(2-methoxyethoxy)aluminum hydride ribonucleic acid 2-(trimethylsilyl)ethoxymethyl nucleophilic substitution on an aromatic ring tetrabutylammonium fluoride tert-butyldimcthyisilyl fert-butyldimethylsilyl trifluoromethanesulfonyl (triflyl) trifluoroacetic acid tri-o-furylphosphine tetrahydrofuran triisopropylsilyl A, N,N ,N -tetramethy lethylenediamine tetramethyl guanidine tetramethylpiperidine trimethylsilyl 2,2 -bis(di-p-tolylphosphino)-l,r-binaphthyl tetrathiafulvalene... 

In contrast to the relative chemical stability of mono-epoxides, diol epoxides of fatty acids (10.52), which are formed from di-epoxides by EH, are subject to a different fate. In such metabolites, intramolecular nucleophilic substitution may occur, such that oxirane opening is accompanied by formation of a tetrahydrofuran ring [134], Such reactions of intramolecular nucleophilic substitution are discussed in detail in Sect. 11.9. In the case of diol epoxides of fatty acids, the resulting tetrahydrofuran-diols (10.53) are part of a much larger ensemble of oxygenated metabolites of fatty acids, the potential cytotoxicities of which are being evaluated [135]. 

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... 

Methoxymethyl derivatives of polysilanes, which cannot be obtained from the corresponding chloromethyl compounds by nucleophilic substitution because of intramolecular rearrangement, are prepared successfully by the reaction of chloropolysilanes with monochloromethyl ether in the presence of magnesium in tetrahydrofuran. 

The kinetics of the reaction between Irons- Ml N2Me)Br(dppe)21 and methyl iodide in tetrahydrofuran exhibit a first-order dependence in the concentration of complex and first-order in the concentration of methyl iodide. When M = W, the reaction with methyl iodide is 38 times faster than the reaction with ethyl iodide, which is typical ofSN2 reactions. Therefore, it is concluded that the secondary alkylation is a bimolecular nucleophilic substitution (Scheme 10) in which nucleophilic attack of the diazenido ligand on the carbon atom of the alkyl halide is the rate-limiting step (93). 

When bis-2,2 -biphenylylenephenylstiborane (150) is treated with lithium aluminum hydride in diethyl ether or better in tetrahydrofurane, a deep red solution results, from which after addition of iodine good yields of 2,2 -biphenylyleneiodo-stibine (175) can be isolated 137). Again a nucleophilic substitution, here by the hydride ion, is involved, leading first to the carbanionic hydridostiborane 172 (or the... 

Ligands 179 and 180 were synthesized by the nucleophilic substitution of the sodium glycolate of TV-methyldiethanol amine on either 2,6-dichloropyridine or 2,6-6 (chloromethyl)pyridine. However, 183 and 184 were synthesized by the qua-temization of 181 or 182 with l,2-6is(P-ethoxy)ethane in acetonitrile. In both instances the resulting diquatemary ammonium salts were demethylated by L-Selec-tride in refluxing tetrahydrofuran to afford the desired pyridino coronand. Com-piexation studies have not been performed on any of these coronands and the physical properties of these compounds do not indicate any unusual characteristics m). 

This route is especially valuable for the transformation of electron-rich heteroaromatic compounds into their fluorinated analogues, which are not suitable for the nucleophilic exchange route. The method has been extended by addition of fluorinated olefins. The fluoroolefins add in a radical process to the 2-position of tetrahydrofuran, followed by perfluori-nation to give the perfluorinated 2-alkyl-substituted tetrahydrofurans in excellent yields [84JFC(25)523 85JFC(29)323] (Scheme 3). 

Allylic alcohols can serve as 7t-allyl cation precursors to act as electrophiles in Sn reactions with a tethered O-nucleophile giving rise to the formation of spiroannulated tetrahydrofurans <2000TL3411>. Michael acceptors are also suitable electrophiles for the cyclization to tetrahydrofuran rings <2003T1613>. The Tsuji-Trost allylation has found widespread application in the synthesis of carbo- and heterocyclic compounds. Allylic substitution has been employed in the stereoselective synthesis of 2-vinyl-5-substituted tetrahydrofurans <2001H(54)419>. A formal total synthesis of uvaricin makes twofold use of the Tsuji-Trost reaction in a double cyclization to bis-tetrahydrofurans (Equation 73) <20010L1953>. 

On the other hand, treatment of the benzenesulfonate depicted below with 3 equivalents of LDA gave an intermediate propargyl alkoxide through a double elimination. Then a concomitant intramolecular nucleophilic substitution led to the formation of the tetrahydrofuran ring <03TA1363>. 

An approach to enantiomerically pure (R)- and (S)-2-(alkenyl)tetrahydrofurans has been devised via a nucleophilic substitution on an allylic complex of palladium(O). This substitution proceeds with chirality transfer from a preexisting stereogenic center to the newly formed center. Thus, starting from (/ )-(,E)-7-methyI-4-octene-l,6-dioI (1), an efficient transfer is realized by treatment with a catalytic amount of tetrakis(triphenylphosphane)palladium in the presence of triethylamine in acetonitrile66. After 30-45 min at 35-37 °C, (5)-tetrahydro-2-f( )-3-methyl-l-butenyl]furan (2) is obtained in 95% yield and 80% ee. The absolute stereochemistry and the optical purity [a]D —10.7 (c = 2.279, CH2C12) are conveniently determined by conversion to the known (S)-tetrahydro-2-furanmethanol. 

Cyclic ethers have an O atom in a ring. A common cyclic ether is tetrahydrofuran (THF), a somewhat polar aprotic solvent used in nucleophilic substitution (Section 7.8C) and many other organic reactions. 

Solvent is another key parameter that can have an effect on the course of the reaction. Nonpolar solvents, such as toluene or heptane, facilitate nucleophilic substitution, and these are typically added to the etheral solutions [tetrahydrofuran (THF) or diethyl ether]. These solvents do not effectively solubilize MgCl2, thereby minimizing the Lewis acid-catalyzed reactions as well as some exchange reactions. Note that these solvents were initially added to improve phase splits, especially with THF. 

An efficient method for the preparation of mono-heterocyclic compounds such as substituted tetrahydrofurans with high stereoselectivity via intramolecular SN2 O-cyclization of alkoxides has been reported. This is a nucleophilic displacement with a simultaneous allylic rearrangement (Scheme 321).1114... 

Selectivity in the epoxidation of dienes where the two alkene residues are a widely differing nucleophilicities is not difficult to achieve and we will return to this point later in this review. However, it is worth pointing out that quite good diastereofacial selectivity was reported in the epoxidation shown in Eq. (12), part of a total synthesis of (+ )-altholactone. The epoxidation using MCPB A proceeded with poor selectivity whereas MMPP gave predominant attack on the P-face and a 3.5 1 mixture of the substituted tetrahydrofuran derivatives was obtained after acid catalysed cyclisation [26]. 

These nucleophilic substitution reactions can in theory proceed intra- or intermolecularly (4). The structure of the repeating unit of the cellulose macromolecule is such that in an intramolecular reaction, two types of anhydro derivatives may form mixed polysaccharides, whose repeating units contain a-oxide rings (2,3-anhydro rings), and anhydro rings of the tetrahydrofuran type (3,6-anhydro rings). 

Compounds of the type [(Me3Si)2N]3M have been prepared for all of the lanthanide elements except Pm, Tb, Dy, Tm, and Er (4). The synthetic method used in their preparation is nucleophilic substitution with three molar equivalents of lithium -or sodium - bis(trimethylsilyl)amide on the metal trichlorides in tetrahydrofuran. The compounds are rather high melting solids (145-170°C) which can be isolated by crystallization from pentane as long needles or by vacuum sublimation (80-100°C). The binary silylamides are monomeric in refluxing benzene solution, in the gas phase (by mass spectrometry), and in the solid state (by x-ray crystallography, see below). Thus, these compounds are three-coordinate, a unique coordination number for the lanthanide elements. 

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