Functionalized furans, access

R. Spina, E. Colacino, B. Gabriele, G. Salerno, J. Martinez, F. Lamaty, Electrophilic iodo-mediated cycUzation in PEG under microwave irradiation easy access to highly functionalized furans and pyrroles, Synlett 23 (2012) 1481-1484. 

Heterocycles are highly important building blocks, and many approaches have been presented. For example, domino Sonogashira heterocyclization reactions of acids chlorides, terminal alkynes, and hydrazines lead to pyrazoles. " Highly functionalized furans are accessible via a Sonogashira-addition-cyclocondensation-Suzuki reaction. " ... 

To investigate the feasibility of employing 3-oxidopyridinium betaines as stabilized 1,3-dipoles in an intramolecular dipolar cycloaddition to construct the hetisine alkaloid core (Scheme 1.8, 77 78), a series of model cycloaddition substrates were prepared. In the first (Scheme 1.9a), an ene-nitrile substrate (i.e., 83) was selected as an activated dipolarophile functionality. Nitrile 66 was subjected to reduction with DIBAL-H, affording aldehyde 79 in 79 % yield. This was followed by reductive amination of aldehyde x with furfurylamine (80) to afford the furan amine 81 in 80 % yield. The ene-nitrile was then readily accessed via palladium-catalyzed cyanation of the enol triflate with KCN, 18-crown-6, and Pd(PPh3)4 in refluxing benzene to provide ene-nitrile 82 in 75 % yield. Finally, bromine-mediated aza-Achmatowicz reaction [44] of 82 then delivered oxidopyridinium betaine 83 in 65 % yield. 

A flexible means of access to functionalized supports for solid-phase synthesis is based on metallated, cross-linked polystyrene, which reacts smoothly with a wide range of electrophiles. Cross-linked polystyrene can be lithiated directly by treatment with n-butyllithium and TMEDA in cyclohexane at 60-70 °C [1-3] to yield a product containing mainly meta- and para-Iithiated phenyl groups [4], Metallation of noncross-linked polystyrene with potassium ferf-amylate/3-(lithiomethyl)heptane has also been reported [5], The latter type of base can, unlike butyllithium/TMEDA [6], also lead to benzylic metallation [7]. The C-Iithiation of more acidic arenes or heteroar-enes, such as imidazoles [8], thiophenes [9], and furans [9], has also been performed on insoluble supports (Figure 4.1). These reactions proceed, like those in solution, with high regioselectivity. 

Carreira has reported that the aldol addition reaction to fiiran 2-carboxaldehyde may be performed on preparative scale (0.5 mol) with as little as 0.5 mol % catalyst (Scheme 8B2.12) [30], The adduct is isolated as a crystalline solid with 94% ee a single recrystallization allows access to 122 with >99% ee. Ozonolytic cleavage of the furan unmasks a carboxyl function, providing acid 124. This acid has been used in a convergent synthesis of the amphotericin C ]-C3 polyol portion. Moreover, 124 has been utilized in the synthesis of a number of pharmacologically important structures such as HMG CoA reductase inhibitors for the treatment of hypercholesterolemia [34],... 

For fiirther reactions of this type see <95CC2025>. The synthesis of l,4-dihydrofurano[3,4-d]-3,2-oxathiine-2-oxides, precursors for nonclassical heteroaromatic o-quinodimethanes, and their application in the Diels-Alder reaction were reported <95CC2537>. The intramolecular Diels-Alder reaction with furans (e. g., 47) offers a rapid access to highly functionalized isoquinolines <95 JCS(P 1)2393>. 

Sequential treatment of 2-alkynal tetramethylethylene acetals with a divalent titanium reagent Ti(OPr )4/2Pr MgX and aldehydes gives furans in good to excellent yields after acidic workup. This procedure is tolerating various functional groups and provides an efficient one-pot access to a variety of 2-substituted and 2,3-disubstituted furans (Scheme 25) <2001TL5501>. 

A few 2-alkoxyfurans are accessible from the cycloaddition of ynes to ester carbonyl functions.8(7 Replacement reactions at the furan nucleus do give alkoxyfurans but are variable in their ability to yield aryloxyfurans.8fta... 

The Suzuki reaction is an excellent method for the functionalization of furans and benzofurans. The aromatic groups have served as both the boron component [60] and the halide partner in a large number of reactions. A variety of furan and benzofuran substitution patterns are accessible via Suzuki couplings [1, 34]. 

Davies reported that trisubstituted furans could be obtained via the Rh(II)-catalyzed formal [3 + 2] cycloaddition reaction between diazo-1,3-dicarbonyl compounds 173 and terminal alkynes 174 (Scheme 8.67) [189]. This protocol provided access to 2,3,5-trisubstituted furans 175 possessing various functional groups under relatively mild reaction conditions and low catalyst loading, albeit with generally moderate yields. 

Many research groups further investigated the scope of the Rh(II)-catalyzed synthesis of furans from alkynes and a-diazocarbonyl compounds [194, 209-221]. Some representative results are summarized in Scheme 8.70. Tri- and tetra-substi-tuted furans possessing a vast array of functional groups and diverse substitution patterns could be efficiently accessed via this methodology. 

Synthesis of C3 functionalized 2-unsubstituted benzo[l ]furans has been developed by a cyclocarbopalladation/cross-coupHng/aromatization sequence (13JOC4490). Substituted benzo[f>]furans were formed via the hydroxylation of2-haloalkynylarenes (130L5032).Palladium(0)-catalyzed insertion of C—C bonds into benzylic C(sp )-H bonds provided access to 2-methylene-2,3-dihydrobenzo[l ]furans, which transformed into... 

Functionalized benzofurans have been prepared from ort/io-hydroxyphenones and 1,1-dichloroethylene via a chloromethylene furan which rearranges into a benzofuran carbaldehyde under acidic conditions. A synthesis of 3-(but-2-enylidene)quinolin-4(3//)-ones has been described via a triflic acid-mediated Fries rearrangement of 3-butadienyl-2-azetidinones, a protocol that provides access to C(3)-functionalized quinolin-4(3//)-ones. °... 

The furan annelation reaction represents a new method for the preparation of this important class of compounds. Furans are widely found in nature, and highly functionalised furans are desirable targets in total synthesis work, either as products themselves, or as intermediates. Commercially available or readily accessible furans are usually limited to substitution at the more reactive 2- and 5-positions of the ring. The need for the preparation of furans with substitution at other positions on the ring, or with sensitive functional groups present, led to the development in 1987 of a palladium-catalysed method for their preparation. ... 

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