Synthesis of tetrahydrofuran derivative

The synthesis of tetrahydrofuran derivatives from unsaturated alcohols via hydroformylation intermediates was developed many years ago. Moderate yields are obtained from but-2-en-l,4-diol (Scheme 54)94 but hydroformylation is not the major pathway when coniferyl alcohol is subjected to the oxo process (Scheme 55).9S A more complicated reaction is involved... 

An efficient synthesis of tetrahydrofuran-derived spiro-p-lactams has been reported to be performed by a Staudinger-type reaction of either 2- or 3-tetra-hydrofuroyl chloride with imines [66]. The reaction was carried out by adding Et3N... 

Scheme 16 Synthesis of tetrahydrofuran-derived spiro-J3-lactams...

An efficient and operationally simple synthesis of tetrahydrofuran-derived spiro-P-lactams 15 and 16 using the Staudinger reaction of unsymmetrical cyclic ketones has been described <02JCS(P1)571 02SL69>. Similarly, spiro-P-lactams 17 were synthesized via Staudinger reaction of imines derived from 7-oxanorbomenone with alkoxyacetyl chlorides <02TL6405>. 

Nakada, M., Iwata, Y., Takano, M. Reaction of dianions of acetoacetic esters with epibromohydrin derivatives a novel synthesis of tetrahydrofuran derivatives and tetrahydropyran derivatives. Tetrahedron Lett. 1999,40, 9077-9080. 

Zhao C, Lu J, Yan J et al (2003) One-pot four-component synthesis of tetrahydrofuran derivatives involving an alkyne an ethylene and two aldehydes via CuQ-mediated reactions of oxazireonacyclopentenes with aldehydes. Tetrahedron Lett 44 6895-6898... 

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]. 

The 10 OC route was followed for the synthesis of tetrahydrofurans possessing a y-amino alcohol moiety 247 (Eq. 29) 118]. Aldoximes 21a-f (see also Eq. 3 and Table 2), when heated in benzene in a sealed tube at 110 -120 °C for 6 h, underwent smooth intramolecular cycloaddition to the tetrahydrofuranoisoxazo-lidines 246a-f in 70-83% yield (Eq. 29). This ring closure proceeded stereo-specifically to generate three adjacent stereogenic centers. LAH reduction of 246 b resulted in isolation of stereospecifically functionalized tetrahydrofuran derivative 247b in 75% yield. 

While the notion that the alkoxides derived from aliphatic alcohols are poor nucleophiles toward 7r-allylmetal complexes has prevailed over the years, much progress made in the recent past has rendered the transition metal-catalyzed allylic alkylation a powerful method for the O-allylation of aliphatic alcohols. In particular, owing to the facility of five- and six-membered ring formation, this process has found extensive utility in the synthesis of tetrahydrofurans (THFs) (Equation (29))150-156 and tetrahydropyrans (THPs).157-159 Of note was the simultaneous formation of two THP rings with high diastereoselectivity via a Pd-catalyzed double allylic etherification using 35 in a bidirectional synthetic approach to halichondrin B (Equation (30)).157 The related ligand 36 was used in the enantioselective cyclization of a Baylis-Hillman adduct with a primary alcohol (Equation (31)).159... 

Numerous papers have been devoted to the synthesis of various derivatives of 2-pyridone, 4-pyridone, and aminopyridines based on enamines, di-enamines, dienediamines, and related compounds. For example, enamin-odiketones (153) can react with cyanoacetamide in tetrahydrofuran in the presence of sodium hydride with the formation of a substituted 3-cyano-2-... 

Samarium(II) iodide in the synthesis of tetrahydrofuran and dihy-drobenzofuran derivatives 92SL943. 

The synthesis of dihydrofuran derivatives such as 177 has been performed to explore scope and limitations of the Lewis acid promoted hydroxyalkylation of siloxycyclopropanes. Table 6 shows that aromatic as well as aliphatic ketones can efficiently be incorporated. Enolization of ketones does not occur and a 1-methyl group at the cyclopropane is no obstacle for the reaction, which now binds the carbonyl compound to a quartemary center with surprisingly high efficiency (entry 5). Albeit there are some restrictions with regard to the substitution pattern of the cyclopropanes, bicyclic siloxycyclopropanes also give good yields (e.g. entry 6 and Eq. 76). Further examples of the tetrahydrofuran synthesis from intermediate y-lactols with... 

The selective intramolecular nucleophilic addition of a hydroxy group at Cyof a ruthenium allenylidene generated by activation of propargylic alcohol by RuCl(Cp)(PPh3)2/NH4PF6 provides a ruthenium vinylidene species, which reacts with allylic alcohols as previously described in the section Formation of Unsaturated Ketones (Eq. 11, Scheme 18) [79]. This unprecedented tandem reaction makes possible the construction of tetrahydrofuran derivatives in good yields and has been used as a key step in the synthesis of (-)calyculin A [80]. 

Although less commonly used, Raney Ni cleavage of the C—S bond of sulfoxides and sulfones is also of interest. For example, the removal of sulfoxides is one of the steps in the synthesis of spiroketals and of tetrahydrofuran derivatives (Scheme 2). Exceptionally, the desulfurization is not accompanied by the hydrogenolysis of a benzyl ether group. 

M. Nakada and co-workers developed a novel synthesis of tetrahydrofuran and tetrahydropyran derivatives by... 

Five-membered Rings. - Tetrahydrofurans. Several methods for the synthesis of tetrahydrofurans by acid-catalysed cyclization have been described this year. Noda et al. have shown that the enediol derivatives (3) or (4) can be cyclized in the presence of acid for 1... 

Both syntheses (see Chapter 5.3.3) and reactions of tetrahydrofuran derivatives have been reported last year e.g., the synthesis of 2 ,3 -dideoxy-3 hydroxymethylcytidine (a unique antiviral nucleoside) <97T8085>, cyclic dinucleotides <97T11033>, 7-... 

A stereoselective synthesis of five- to seven-membered cyclic ethers has been achieved by de-iodonative ring-enlargement of cyclic ethers having an iodoalkyl substituent. For example, the reaction of tetrahydrofuran derivative 360 with (diacetoxyiodo)toluene proceeds under mild conditions to afford ring-expanded product 361 (Scheme 3.144). The use of hexafiuoroisopropanol (HFIP) as solvent in this reaction is critical [462]. 

Walkup and co-workers developed new methodologies for the efficient synthesis of tetrahydrofurans 111 and y-butyrolactone derivatives 112, respectively, using the Pd(0)-catalyzed cyclization of organyl halides with 4,5-dienols and 4,5-dienoic acids, respectively (Scheme... 

Cycloaddition of cyclopropanes to aldehydes leads to the formation of tetrahydrofurans derivatives, whose enantiomeric form can be obtained either by using enantioenriched cyclopropane substrates or by a dynamic kinetic asymmetric transformation. In this regard, Johnson et al. reported a dynamic kinetic asymmetric [3 -I- 2] cycloaddition of racemic cyclopropanes 63 for the enantioselective synthesis of tetrahydrofurans 64. In this study, the magnesium catalyst can promote the ring opening of the racemic cyclopropane and catalyses the reaction of one of the ring-opened enantiomers with the aldehydes (Scheme 3.19). 

The stereoselective construction of substituted tetrahydrofurans as enantiomerically pure form is of great interest because many biologically active compounds have such oxygen heterocycles. Fujita et al. developed the synthesis of tetrahydrofuran-3-yl carboxylates 26 via intramolecular oxygenatirm of but-3-enyl carboxylates using lactic acid-derived chiral X -iodanes 25 (Scheme 11) [49, 50]. The enr o-selectivity achieved in this case contrasts with the cxo-selectivity observed in the reaction with conventional oxidizing reagents. The products 26 are obtained in up to 64% ee. 

Heptylmagnesium chloride in ether or tetrahydrofuran added at -5 to some CuBr in a soln. of acrolein diethyl acetal in tetrahydrofuran, and the product isolated after 2 hrs. product (mixture of cis- and trans-isomtrs), Y 89%. F. e. and limitations s. J. F. Normant et al., Tetrah. Let. 1975, 3833 synthesis of ethylene derivs. from alkoxy-2-ethylenes cf. ibid. 1975, 3837. 

SCHEME 27 Synthesis of quinazoline derivatives. DIB, (diacetoxy)iodobenzene. THF, tetrahydrofuran. 

Scheme 12.47 Au-cataiyzed synthesis of tetrahydrofuran or pyrrolidine derivatives.

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