Furan tetrasubstituted

The only tetrasubstituted furans that have been prepared using the Feist-Benary reaction are substituted tetrahydrobenzofurans and octahydrodibenzofurans. This strategy was pioneered by Stetter and Chatterjea and applied in a series of total syntheses by Magnus. Stetter demonstrated that 1,3-cyclohexanedione (30) can act as the P-dicarbonyl component and readily combines with either 3-bromo-2-ketobutyric (29) acid or ethyl 2-chloroacetoacetate (32) in the presence of potassium hydroxide to yield tetrahydrobenzofuran derivatives 31 and 33, respectively. ... 

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. ... 

In a series of papers in late 1884 and early 1885, Paal and Knorr demonstrated that several 1,4-dicarbonyls could be transformed into furans, pyrroles, and thiophenes. Paal first discovered this transformation and used it to prepare di-, tri-, and tetrasubstituted furans. For example, dicarbonyl 3 yielded disubstituted furan 4 upon treatment with weak acid. 

Although nearly all Paal-Knorr condensations produce di-, tri-, or tetrasubstituted furans, it is possible to use this reaction to generate monosubstituted furans. Molander demonstrated the utility of this method with his synthesis of 2-(methyldiphenylsilyl)furan (11) from dicarbonyl 10. ... 

The Paal-Knorr reaction offers an excellent method for the preparation of tetrasubstituted furans however, it does not work for some sterically congested substrates. Similar to di- and trisubstituted furans mentioned previously, tetrasubstituted furans have been investigated for biological acitivity. Katzenellenbogen has prepared numerous alkyl triarylfurans by the Paal-Knorr condensation (e.g. 65 to 66) and investigated their activity toward the estrogen... 

Silylfiirans are available from acylsilane dicarbonyl confounds <96JOC1140>. Fhotocycloaddition of 35 with aUcenes leads cleanly to tetrasubstituted furans 38 in yields of 85%. A mechanism is proposed involving an alkyl propargyl biradical (as 36) that closes first to a vinyl carbene (as 37) and than to 38 <96JOC3388>. 

A stmple and general synthesis of 2,2,4,5-tetrasubstituted furan-3(2//)-ones from 4-hydroxyalk-2-ynones and alkyl halides via tandem CO, addition-elimination protocol is described <96S 1431>. Palladiuni-mediated intramolecular cyclization of substituted pentynoic adds offers a new route to y-arylidenebutyrolactones <96TL1429>. The first total synthesis of (-)-goniofupyrone 39 was reported. Constmction of the dioxabicyclo[4.3.0]nonenone skeleton was achieved by tosylation of an allylic hydroxy group, followed by exposure to TBAF-HF <96TL5389>. 

One of the best-known and highly useful photochemical synthetic procedures is the Paterno-Biichi reaction [17]. This transformation has also been adapted as basic principle for domino processes by different research groups. Agosta and coworkers published a procedure by which tetrasubstituted furans such as 5-65 can be built up from 5-61 and 5-62 (Scheme 5.13) [18],... 

Fully substituted furan as depicted below was prepared from a Baylis-Hillman adduct in the presence of sulfuric acid in a moderate yield. Intermolecular Friedel-Crafts reaction is one of steps to give rise to the final tetrasubstituted furan <06T8798>. 

The usefulness of allene derivatives has also been revealed in other examples. Thus, the annulated tetrasubstituted furan illustrated in the following scheme was delivered in a moderate yield using the diazoallene as precursor by a two-step reaction in the presence of Rh-catalyst <06S3605>. 

Propargylic dithioacetals have been shown to be good starting materials for the synthesis of trisubstituted furans. Recently, a modification appeared, which demonstrated that these compounds could also be used to prepare tetrasubstituted furans in good yields <06SL1209>. 

As can be seen, the reaction between the anisyl derivative and the acetoacetate provided also tetrasubstituted furans. A subsequent demethylation cyclization delivered furo[3,4-c]coumarins in a moderate yield <06JHC 1699>. 

Deprotection of 2,2-disubstituted-l,3-dithiolanes to give carbonyl compounds can be achieved using Oxone with KBr in aq. MeCN <06TL8559> and a review of silylated heterocycles as formyl anion equivalents includes reference to 64 <06CC4881>. A method for transformation of propargylic dithiolanes 43 into tetrasubstituted furans has been reported <06SL1209> and Michael addition of enolates to the chiral dithiolane dioxide 65 takes place... 

Interestingly, if the cyclization was carried out in the presence of an aryl or allyl halide and a palladium(O) catalyst, an additional C-C coupling step via presumed intermediate 210 led to the formation of tetrasubstituted furans of type 211 (Scheme 2.64) [101]. 

Scheme 2.64 Samarium-mediated synthesis of tetrasubstituted furan 211 (L= PPh3).

Scheme 9 A three-component reaction to yield tetrasubstituted furans [25]...

A reaction mechanism was proposed to explain the formation of tetrasubstituted furans when R4 or R5 are H (Scheme 8.16). 

The course of the reaction of furan and DMAD is temperature dependent (73CJC4125). The initially formed monoadduct (118) acts as a dienophile and further addition of furan can occur at the di- or tetra-substituted double bonds. In such additions to norbornene-type dienophiles the diene is subject to steric approach control and approach to the exo face is preferred. At 25 °C the tetrasubstituted double bond acts as a dienophile and the endo,exo... 

The selenium ylides (140) with dimethyl acetylenedicarboxylate afford moderate yields of tetrasubstituted furans (Scheme 31) (73KGS1447). 

The enedione (283) is a useful starting material for a two-step synthesis of 2,3,4,5-tetrasubstituted furans which are not otherwise readily accessible (81JCS(P1)2398). Michael addition of an active methylene compound, e.g. (284), to the enedione (283) led to the two regioisomeric adducts (285) and (286) which could then be cyclized to furans (287) and (288) under mild conditions (Scheme 75). The formation of Michael adducts was successful with both j8-ketoesters (284) and cyclic 1,3-diones. Normal routes to furans require much more drastic conditions the Michael addition allowed the preparation of 1,4-diones particularly activated by the presence of an easily enolizable group. This is a useful synthetic pathway because alternative routes for the preparation of complex furans are not at present available. 

A phenolic oxygen participates in facile oxypalladation. 2-Allylphenol (55) undergoes clean cyclization to 2H-l-benzopyran (56) in DMSO under air with a catalytic amount of Pd(OAc)2 without a reoxidant. 2-Methylbenzofuran (57) is obtained when PdCl2 is used [50]. But different chemoselectivity with the Pd(II) salts was also reported [51]. Catalytic asymmetric cyclization of the tetrasubstituted 2-allylic phenol 58 using the binaphthyl-type chiral ligand 60, called (.S, .S )-ip-borax, afforded the furan 59 with 96% ee. Use of Pd(CF3 002)2 as a catalyst is essential in the presence of benzoquinone [52]. Formation of the benzofuran 62 from 61 has been utilized in the synthesis of aklavinione [53]. The intramolecular reaction of 2-hydroxychalcone (63) produces the flavone 64 [54]. 

Attempted annulation of 3-iodoflavones, for example 428, by internal alkynes catalyzed by Pd(OAc)2 in the presence of NaOAc and LiCl yielded a mixture of two compounds (Scheme 73) <1998JOC2002>. While the expected benzoxanthenes (e.g., 429) were isolated as the minor compound, tetrasubstituted furans (e.g., 430) resulting from the electrophilic attack on the carbonyl oxygen atom by the vinylpalladium intermediate followed by pyrone ring opening were the major product. 

Yavari reported a procedure to prepare tetrasubstituted furans through the reaction of dibenzoylacetylene and enol systems in the presence of triphenylphosphine <02TL4503>. 

Tetrasubstituted furans were obtained by a simple and efficient protocol starting from propargylic alcohols and 1,3-dicarbonyl compounds in the presence of a ruthenium-catalyst and CF3CO2H <07ASC382>. 

Indium-catalyzed Michael addition of 1,3-dicarbonyl compounds to but-2-ene-1,4-diones, followed by cyclization and dehydration gave rise to the formation of tetrasubstituted furans in high yields. An example is shown below <07TL2573>. 

The cycloisomerization of allenyl ketones can be exploited for the synthesis of 2,3,4- or 2,3,5-trisubstituted and tetrasubstituted furans, when the Pd(0)-catalyzed cyclization of a,7-disubstituted substrates is combined with the coupling of an aryl halide or substituted allyl halide, as has been reported by Ma et al. (Equation 14) <20000L941, 2000CC117, 2003CEJ2447>. 

Oxy-tetrasubstituted furans are obtained in a silver-catalyzed isomerization sequence involving an initial [3,3]-sigmatropic rearrangement (Scheme 7). Phosphatyloxy and sulfonyloxy groups can be employed as well <2004AGE2280>. 

In much the same way, but with improved yields, a gold(l)-catalyzed propargyl Claisen rearrangement affords tri-and tetrasubstituted furans in good to excellent yields (Equation 32) <2005OL3925>. 

The reaction of dibenzoylacetylene and enol systems, such as acetylacetone, 5,5-dimethylcyclohexane-l,3-dione, 1-naphthol, 2-naphthol, 2,7-dihydroxynaphthalene, or 8-hydroxyquinoline in the presence of triphenylphosphine, leads to tetrasubstituted furans in 65-83% yield (Equation 115) <2002TL4503>. DABCO-catalyzed reaction of a-bromocarbonyl compounds with DMAD also yields highly substituted furans <2005JOC8204>. 

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