Mono-substituted furans

The effect of acids on 2-alkylfurans was discussed in Section III-A-l-c). It was remarked that 2,5-disubstituted furans are less reactive in this context than mono-substituted derivatives. This observation again points to the important role played by a free C-5 position in resinification processes. 

Similar correlations have been observed (75CS(7)2ll) between the 13C NMR spectra of mono-substituted furans, thiophenes, selenophenes and tellurophenes as with their H NMR spectra (cf. Section 2.3.3.3). Thus, for the 2-substituted compounds the A(C-3)/A(C-5) ratios decrease systematically in the series furan (2.58) > thiophene (1.34) = selenophene (1.34) > tellurophene (0.91). Extensive quantitative correlations have been established between the shifts of the corresponding carbon atoms in the different heterocycles (75CS(7)21l). In most cases Tsubstituted heterocycles can be linearly correlated with the electronegativity of the heteroatom, with the couplings being largest for the furans. 

Pyridine (Figure 2.35) shows four bands in this region and, in this respect, closely resembles a mono-substituted benzene. Furans, pyrroles, and thiophenes display two to four bands in this region. 

Achmatowicz and Wrobel sought to settle the question by IR- and NMR-studies. The former revealed the frajis-quinolizidine system, mono-substituted furan ring, methyl groups, and the system —CH2—S—C unconjugated with fiiran. 

Reactions of 2-trialkylsilyl- and trialkylstannyl-substituted furans with benzhydryl cations provided 2,5-disubstituted furans and ipso-substituted furans. Kinetic investigations of the reactions revealed that the monosubstituted product was produced from the protonolysis of the 2,5-disubstituted furylstannane, while the 2,5-disubstituted furan was derived from an electrophilic substitution of the mono-substituted furan. Introduction of a trialkylsilyl and a trialkylstannyl group to the 2-position of furan hardly affected the reactivity of this position towards carbenium ions ipso attack), while the 5-position is somewhat activated <01OL1629,01OL1633>. 

Only a single example employing the Paal-Knorr synthesis for the generation of mono-substituted furans has been reported to date. Molander demonstrated that 2-(methyldiphenylsilyl)furan could be prepared in good yield via treatment of 4-(methyldiphenylsilyl)-4-oxobutanal with hydrochloric acid in THF. ... 

Previously, only a handftil of reports have demonstrated asymmetric hydrogenation of mono-substituted furans, with limited scope and enantioselectivities. In a new study (14AGE8751), a Ru(II) complex bearing the chiral N-heterocyclic carbene ligand SINpEt was employed to successfully hydrogenate disubstituted furans to chiral tetrahydrofu-rans. In the case of 2,4-disubstituted furans, products were obtained with excellent enantio- and diastereoselectivity.The cis isomer was the major product. 

The synthesis of non-peripherally substituted octa(alkoxymethyl)phthalocyanines is outlined in Seheme 57 [213, 214]. 2,5-fcij(Alkoxymethyl)furan can be prepared by lithiation of furan followed by quenching the anion with (bromomethyl)alkyl ether to give the mono-substituted furan, and repetition of the procedure to give the required product [213]. A more simple synthesis involves chlorination of 2,5-furan dimethanol with thionyl chloride, followed by nucleophilic displacement of chloride with sodium alkoxide [214]. The furan is equilibrated with fumaronitrile for about a week and the Diels-Alder adduct aromatized by treatment with lithium fcwftrimethylsilyl)-amide (a non-nucleophilic base), followed by an acidic work-up. The 3,6-/7i5(alkoxy-methyl)phthalonitrile is cyclized under standard conditions (lithium/pentanol). 

Treatment of 1,4-dicarbonyls (1) with catalytic acid yields substituted furans (2) and is called the Paal-Knorr furan synthesis. This method is used extensively to produce a variety of mono-, di-, tri-, and tetrasubstituted furans. ... 

The interesting work of Martin and coworkers " on oxygen-substituted sul-furanes(VI) lO-S-4 and 12-S-6 species made available for the first time quasi mono-and bis-acetals of sulfones (1 and 2). Proton-catalyzed fragmentation of lb led to the sulfone isomer 3 the corresponding fragmentation of 2a gave, depending on reaction conditions, the isomeric sulfone 4 or a mixture of the sulfone isomers 4 and 5 . 

Hanssen, and Nair,127 and by Chadwick et a/.128 All deal with mono-, di-tri-, and sometimes tetra-substituted furans where the substituents are variously selected from halogen, ester, acid, aldehyde, and ketonic functions. Here we consider only some more special situations. 

An example of electrophilic substitution on position C2 of the fused furan has been reported for 8H-furo[3,4-d]dibenz[ 7,/]azepine, which reacts with f-butyl hypochlorite to afford a mono chlorinated furan ring product (1995H431). 

Mono- and di-alkylated furans were synthesized in a one-pot preparation from 2-propynyl-2-tetrahydropyranyl ether (106), butyllithium and formaldehyde. The intermediate allenyl ether (107) presumably cyclizes via a 2-(2-tetrapyranyloxy)-2,5-dihydrofuran (108) to afford the heterocycle (109) (79AG(E)875). In a similar manner, singly and doubly branched tetrahydropyranyloxybutynolates afforded the substituted furans (110) (Scheme 20). The thermocatalytic isomerization of ethyl l-methyl-2-phenylcyclopropene-3-carboxylate yielded the furan, possibly by a 1,3-sigmatropic displacement step or by a non-concerted biradical intermediate (75T2495). 

Dioxacorroles are 18-7r-electron aromatic systems like corroles. They exhibit basicity intermediate between that of porphyrin and corrole, and require 1 h at 100 °C in TFA for complete deuteration of the meso positions. The furan protons are also substituted by deuterium under the same conditions after lOOh. Friedel-Crafts acylation occurs at C-5 while alkyl halides attack on the pyrrolic nitrogens to give a mixture of mono- and di-alkyl derivatives. 

Mono-alkyl-fnrans nndergo Mannich substitution under normal conditions," bnt fnran itself reqnires a preformed imininm salt for 2-substitution." iV-Tosyl-imines, generated in situ from iV-snlhnyl-p-tolnenesnlfonamide and aldehydes, bring about tosylaminoalkylation at C-2." The use of furan boronic acids allows Mannich snbstitntions at both a- and P-positions, with primary or secondary amine components." " ... 

Methoxy- and 2-acetoxy-furans are available from 2,5-dimethoxy- and 2,5-diacetoxy-2,5-dihydro-furans (18.1.1.4) via acid-catalysed elimination. They undergo Diels-Alder cycloadditions the adducts can be further transformed into benzenoid compounds by acid-catalysed opening. 3,4-Dihydroxyfuran is undetectable in tautomeric equilibria between mono-enol and dicarbonyl forms the dimethyl ether behaves as a normal furan, undergoing easy a-electrophilic substitution, mono- or dilithiation at the a-position(s), and Diels-Alder cycloadditions. 2,5-Bis(trimethylsilyloxy)furan is synthesised from succinic anhydride it too undergoes Diels-Alder additions readily. Both furan-2- and -3-thiols can be obtained by reaction of lithiated furans with sulfur in each case the predominant tautomer is the thiol form. ... 

It seems that the creation of polychlorophenoxyphenols, polychlorodibenzo-furans or polychlorodibenzodioxins is closely related to the varying degrees of chlorination. During the mono and dichlorination of phenol, no parasite chemistry appears. But if we introduce a third and especially a fourth or fifth chlorine atom within the aromatic core then a problem is created. This is problably linked to the high activating quality of the OH group which tends to orientate an electrophilic substitution - in an ortho or para positioning (Fig. 1). 

Early attempts to effect Mannich reactions with furan itself failed, though mono-alkylfurans undergo the reaction normally, but by reaction with preformed iminium salt normal 2-substitution of furan itself occurs at room temperature. ... 

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