2.5- Dihydrofurans, synthesis from

Heterocycles.—The phosphonium salt (59) is an effective three-carbon synthon, as demonstrated by its reaction with enolates of /9-keto-esters (Scheme 20) to give cyclopentenyl sulphides via an intramolecular Wittig reaction.63 Ylides are also intermediates in the synthesis of dihydrofurans (60) from the cyclopropylphos-phonium salt (61) and sodium carboxylates (Scheme 21).64 Cumulated ylides are very useful for the synthesis of heterocyclic compounds, e.g. (62), from molecules which contain both an acidic Y—H bond and a carbonyl or nitroso-function, as shown in Scheme 22.65... 

Stannyl cuprates couple with vinyl halides or triflates [16c-d, 85], and a vinyl stannane produced this way has been used in the synthesis of 7-[( )-alkylidene]-cephalosporins [117]. Vinyl substitution reactions starting from dihydrofurans are... 

A surprising synthesis of 1,2-fused pyridinium salts (type 230) is exemplified by the formation of derivative 252 from dihydrofuran 251 (83CL21). Amide 253 undergoes, in analogy with homoberbine syntheses, twofold cyclization to achieve enamine 254 (03WO84963). 

The synthesis of dihydrofurans from propargyl esters is another reaction in which both gold and silver have been employed. In early work, Shigemasa et al.37 reported the efficient chirality transfer in the cycloisomerization of monoesters of butynediols. They used 8-15 mol% of AgBF4 as catalyst in benzene at 80°C in the dark. 

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... 

A multicomponent reaction of a species generated from addition of dimethoxycarbene onto the triple bond in DMAD in the presence of aldehydes or quinones has been described, affording a facile synthesis of dihydrofuran derivatives (Equation 70) <2001TL2043>. 

The synthesis of dihydrofurans with an additional ester moiety and one or two quaternary centers are prepared from titanium enolates formed by reactions of 3,4-dienoates with Cp2TiCl2. Titanium enolate derivatives TiCl3[CH2CH2C(=0)0Et] and the Tebbe reagent compound have been applied in the synthesis of pumilio-toxin.1915 Chiral allyl and mono-Gp chloro enolato titanium compounds add with high enantioface discrimination to aldehyde.973... 

A recent synthesis of this building block has been published by Eastham et al. in 2006 (48). Their key step is a Dotz benzannulation reaction and is shown in Scheme 2.10. The bromohydrin 66 was formed from dihydrofuran (50). Cobalt-mediated cyclization, followed by ozonolysis with reductive work-up yielded 68 after hydrazine formation. Reductive removal of the hydrazine function, followed by chromium-carbonyl formation gave the Dotz reaction precursor 69. This reacted with an alkyne in the Dotz reaction, and was then oxidized and hydrogenated 70). Pyrolysis gave the protected alcohol and the remaining free alcohol was protected as a triflate (—> 71). Reductive removal of the triflate and deprotection of the silyl ether yielded the desired 33 in 1.2% overall yield. 

More efficient in terms of the number of steps (six) and overall yield (41%) was a later synthesis from Boukouvalas and co-workers (Scheme 7.2) (302). Bis-silyl-protected 3-hydroxymethyl 2,4-dihydrofuran-2-one (359) was selectively deprotected/condensed with benzyloxyacetaldehyde to give the alcohol, which was protected as a pivalate ester and subjected to selective desilylation then TEMPO-mediated oxidation. The resulting aldehyde 361 was then cyclized with a Lewis acid. Elimination of pivalic acid from ester 362 gave mainly the desired ylidenebutenolide regioisomer and the natural product (348). 

V. Nair, S. Bindu, V. Sreekumar, L. Balagopal, Synthesis 2003, 1446-1456. Novel dipolar cycloaddition reactions of zwitterionic species generated from dimethoxycarbene and dimethyl acetylenedicarhoxylate with carhonyl compounds facile synthesis of dihydrofuran derivatives. 

Boyer, A. Rhodium(lI)-catalyzed stereocontroUed synthesis of dihydrofuran-3-imines from l-Tosyl-l,2,3-triazoles. Org. Lett. 2014, 16, 1660-1663. 

The 7, i5-unsaturated alcohol 99 is cyclized to 2-vinyl-5-phenyltetrahydro-furan (100) by exo cyclization in aqueous alcohol[124]. On the other hand, the dihydropyran 101 is formed by endo cyclization from a 7, (5-unsaturated alcohol substituted by two methyl groups at the i5-position. The direction of elimination of /3-hydrogen to give either enol ethers or allylic ethers can be controlled by using DMSO as a solvent and utilized in the synthesis of the tetronomycin precursor 102[125], The oxidation of the optically active 3-alkene-l,2-diol 103 affords the 2,5-dihydrofuran 104 in high ee. It should be noted that /3-OH is eliminated rather than /3-H at the end of the reac-tion[126]. 

Polysubstituted 3-thiofiirans which are receiving a great interest as flavour and odour chemicals have been obtained by mono-//J5osubstitution and ortho-metallation from 3,4-dibromofuran <96T4065>. Dihydrofuran is used in a new synthesis of ketones from acids via acyl hemiacetals (Scheme 8, <96JOC6071>). 

Cyclopropane 87, obtained from n-butyl vinyl ether, rearranges to dihydrofuran 88 only at elevated temperature, and also partly during work-up on silica gel113). The complete conversion of 87 into veratrole by the action of HCl/CH3OH gave rise to the analogous two-step synthesis of hydrourushiol monomethyl ether from l-diazo-3,3-dimethoxy-2-nonadecanone 89113). Ether cleavage of the product yields hydrourushiol, one of the vesicant components of, inter alia, poison ivy. 

An interesting example of a triple electrophilic aromatic substitution between an oxonium ion, generated from a trisubstituted dihydrofuran, and phloroglucinol was exploited for the total synthesis of the C3-symmetric xyloketal A, as depicted in the scheme below C06OL1427 06JOC1620>. 

A short five-step synthesis of a bifuran, namely ( )-2,2 -bis(diphenylphosphino)-3,3 -binaphtho[2,l-I>]furan (BINAPFu) from naphthofuranone via a low-valent titanium-mediated dimerization was reported. The newly developed resolution procedure for phosphines was utilized to provide the optically active bidentate phosphine ligands (BINAPFu), which consistently outperforms BINAP in the asymmetric Heck reaction between 2,3-dihydrofuran and phenyl triflate . Another way in which a benzofuranone can be converted into benzo[7 ]furan is by treatment of the former with 1-BU2AIH at -78°C followed by an acidic work up <00TL5803>. 

In a synthesis of furanomycin, this reaction was a stereospecific key step for the construction of the dihydrofuran ring 77 from the chiral non-racemic precursor 76 (Scheme 15.18) [41]. 

Complex [RuCl(=C=C=CPh2)( 7 -p-cymene)(PCy3)][PF6] (or its triflate salt) was also effective in the RCM of enynes. Thus, as shown in Scheme 38, the straightforward synthesis of 3-vinyl-2,5-dihydrofurans 104 from enynes 103... 

Mai et al. also reported a formal synthesis of murrayaquinone A (107) starting from murrayafoline A (7). However, the required murrayafoline A (7) was obtained by the benzannulation of furoindolone, which was prepared by Fischer indolization of 3-(2-phenylhydrazono)dihydrofuran-2(3H)-one (648) (see Scheme 5.46) (584) (Scheme 5.113). 

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