2,3,4-trisubstituted furan derivatives

In analogy to the Paal-Knorr pyrrole synthesis described by Taddei and coworkers [342] (Scheme 6.181), similar reaction conditions were used by these authors to cyclize 1,4-dicarbonyl compounds to give furans (Scheme 6.190). Thus, heating a solution of a 1,4-dicarbonyl compound in ethanol/water in the presence of a catalytic amount of hydrochloric acid at 140 °C for 3 min provided an excellent yield of the corresponding trisubstituted furan derivative. 

The regioisomers of 3,3,4-trisubstituted l,2,4-dioxazolidine-3-ones 149 were obtained by the [3+2] reactions of carbonyl oxides 144 with phenylisocyanate, where the latter was used as a solvent. Initial carbonyl oxides 144 were generated by photooxygenation of furan derivatives 147 through peroxide intermediate 148 (Scheme 42) <1994J(P1)3295>. 

Adduct 180 can be transformed to various furan derivatives (Scheme 9)61). Dehydration is accompanied by cis/trans isomerization giving tra/w-dihydrofuran 186, and oxidation to ketone 187 followed by condensation provides the trisubstituted furan 188. Cyano and allyl trimethylsilane, respectively, lead to tetrahydrofuran derivatives 189 and 190 with high stereoselection, which carry new substituents suitable for further manipulation. These reactions work equally well for the ketone adduct 176 and a bicyclic y-lactol affording 191-193 93). 

Fischer-type chromium carbene complexes of furans underwent Dotz benzannulation with alkynes to provide trisubstituted benzo [, ]furan derivatives. An example used in the synthesis of isodityrosine is depicted in Equation (39) <2005JOC7422>. The efficiency of the reaction could be improved by ultrasound sonication <19990L1721>. 

Full details for the synthesis of 2,3,5-trisubstituted furans via an oxypalladation-reductive elimination domino reaction were given <03T4661>. Under an atmosphere of CO, the reaction afforded furan derivatives widi incorporation of a carbonyl group. 

Aoyama and co-workers used this approach in their synthesis of 2,3,4-trisubstituted furan derivatives. Reaction of 2-cyclohexyl-4-(trimethylsilyl)oxazole with dimethyl acetylenedicarboxylate under thermal conditions gave the corresponding derivative in good yield. 

Nano-Cu20 can be used as a heterogeneous and recyclable catalyst for the domino synthesis of a-carbonyl furan derivatives (Cao et al., 2010, 2011). A variety of a-carbonyl furans can be efficiently and regioselectively obtained in moderate to good yields from electron-deficient alkynes and 2-yn-l-ols under air atmosphere (Scheme 4.40). Notably, a novel 2,4,5-trisubstituted 3-ynyl-furan was simply generated without tedious procedures. 

Syntheses of trisubstituted furans are much less common than the disubstituted derivatives only one 2,4-disubstituted 3-furoate has been prepared using the Feist-Benary reaction. Combination of chloroacetone (4) with ethyl acetoacetate (9) provides ethyl 2,4-dimethyl-3-furoate (28) in 54-57% yield. The procedure for this... 

A less obvious method for the preparation of 2,4-disubstituted furans involves th< treatment of epoxyketones like 81 with eatalytie p-toluenesulfonie aeid and their rearrangemen to furans (for example 82). Cormier developed this method, whieh presumably involves a 1,4 diketone intermediate, and works for a variety of epoxyketone derivatives to yield othe disubstituted furan isomers as well as 2,3,5-trisubstituted furans. ... 

Another variation of the Paal-Knorr eondensation involves starting with a derivative 0 2-butene-1,4-dione and performing a reduetion prior to the eyelization reaetion. For exampk Rao has reeently reported that trisubstituted furans 84 ean be produeed in high yield upo treatment of diones 83 with formic acid, catalytic sulfuric acid, catalytic palladium on carbor... 

The addition of trithiazyl trichloride (NSC1)3 to 2,5-disubstituted furans and to N-2,5-trisubstituted pyrroles has led to the formation of isothiazole derivatives <96JHC1419>. 

A three-component, one-pot reaction of acyl chloride, propargylic alcohol derivatives and Nal using palladium as catalyst provided trisubstituted furans as depicted in the following scheme <06EJOC2991>. 3-Chloro-4-iodofurans can also be produced when IC1 and NaCl are used in the second step. 

In another variation, the intermediate aldol product 64, with an extra hydroxy group in the y-position, was used to construct the furan ring of rosefuran (65), a trace component of rose oil (Scheme 6.56) (285). Here, the reaction of the nitropentene derivative 61 with crotyl acetate (62) afforded the 3,4,5-trisubstituted isoxazoline (63) in moderate yield. Removal of the acetyl group by saponification of the cycloadduct, subsequent demasking of the aldol moiety using Mo(CO)6, and exposure of the ketodiol (64) to acid gave the target compound 65 (285). 

A simple procedure to prepare 5-aryl- and 5-pyridyl-2-furaldehydes from inexpensive, commercially available 2-furaldehyde diethyl acetal was reported. The reaction proceeded in a four-step, one-pot procedure and the yield of coupling step was usually between 58-91% <02OL375>. A facile route to 3,4-furandicarboxylic acids was developed. DDQ-oxidation of 2,5-dihydrofuran derivatives, which were produced from dimethyl maleic anhydride, furnished the desired esters of furan-3,4-dicarboxylic acid <02S1010>. The furan-fused tetracyclic core of halenaquinol and halenaquinone possessing antibiotic, cardiotonic, and protein tyrosine kinase inhibitory activities was synthesized. Intramolecular cycloaddition of an o-quinodimethane with furan gave the adduct as a single isomer via an enrfo-transition state, which was converted to trisubstituted furan by oxidation-elimination reactions <02T6097>. 

The research team of E.-S. Lee synthesized and evaiuated severai 2,4,6-trisubstituted pyridine derivatives as potential topoisomerase I inhibitors. One of these compounds, 4-furan-2-yl-2-(2-furan-2-yl-vinyl)-6-thiophen-2-yl-pyridine, was prepared by the Krohnke pyridine synthesis and showed strong topoisomerase I inhibitory activity. 

Morimoto successfully used this strategy as a key step in his synthesis of nordehydro-cacalohastine derivates 203 [162]. Trisubstituted furan 202 is available upon the three-component coupling of enynol 201, Michael acceptor 193, and o-iodotohicnc. The desired product, 203, can then be prepared in five to six steps from 202. 

Tetrathianes. (1) Oxidative dimerization of a,a-disuhstituted alkanedithioic acid dianions (Scheme 38) or 1,1-dithiols (Equation 17) - very limited examples and a-monosuhstituted alkanedithioic acids decompose (2) reductive or pyrolytic dimerization of gi OT-disulfenyl dichlorides (Equation 18) - only malonate-derived examples (3) reaction of a-chloro sulfenyl chlorides with sodium trithiocarhonate (Equation 19) - only malonate-derived examples (4) sodium thiophenoxide-catalyzed reaction of thioketones with elemental sulfur (5) reaction of benzo-furan-3(2//)-one with S2CI2" (6) UV irradiation of a CS2 solution of a diazirine (7) reaction of a 2,2,4-trisubstituted-1,3-dithietane with Oxone (Scheme 54)". Method (4) is the most convenient and general of these. 

In the vertical mode [88], constructing a trisubstituted furan (102) was considered a suitable starting point. Subsequent cyclo-addition reaction with the allene derivative 103 gave the Diels-Alder adduct which with lithiumaluminiumhydride-titanium trichloride complex and triethyl amine opened up to form the penta substituted benzene derivative 104. This was converted into 86a in five steps as depicted in Scheme 21. 

In continuation of our efforts in the development of new synthetic routes for the synthesis of heterocyclic compounds using nanocatalysts, we have recently reported a novel synthesis of 3,4,5-trisubstituted furan-2(5H)-one derivatives by the one-pot three-component condensation of aldehydes, amines, and dimethyl acetylenedicar-boxylate (DMAD) by nsing nanoparticulate ZnO as a catalyst in Et0H H20 (1 1) at 90°C (Scheme 9.30) (Tekale et al. 2013). Almost all the employed aldehydes and amines reacted smoothly to afford excellent yields of the prodncts, irrespective of the natnre of the snbstitnent present on the aldehyde or amine. The plausible mechanism for the synthesis of furan-2(5 f)-ones using nano-ZnO is depicted in Figure 9.3. The catalyst promotes the formation of enamines (99) from amines (97) and DMAD (96). ZnO polarizes the carbonyl group of aldehydes to form a polarized adduct (100) which reacts with the enamines, followed by cyclization with the elimination of methanol molecules to afford the corresponding trisubstituted furanone derivatives (98). 

B.i.b. Alkynes Containing Proximate 1,3-Dicarbonyl Groups. 2-Propargyl-1,3-dicarbonyl compounds react with alkenyl triflates or alkenyl/aryl/heteroaryl halides to give 2,3,5-trisubstituted-furans (Scheme 4). The process probably proceeds through an oxypalladation step that involves a nucleophilic attack of a stabilized enolate across the activated carbon-carbon triple bond, reductive elimination of a palladium(0) species from the resultant oxypalladation adduct, and isomerization of the initially formed alkylidene derivative. 

When 2-propargyl-l,3-dicarbonyl compounds are treated with aryl iodides under a balloon of carbon monoxide 2,3,5-trisubstituted-furans containing a 5-acylmethyl group (Scheme 7a) or its enol ester (Scheme 7b) can be obtained. Formation of the acyhnethyl derivative or its enol ester depends on the aryl iodide to alkyne ratio. Excess alkyne affords the acyhnethyl derivative as the main product whereas employment of an excess of the aryl iodide favors the formation of the enol ester. The enol ester product is very likely formed from the acyhnethyl product via trapping of the corresponding enolate with an acylpalladium complex. 

Inokuchi, T., and Kawafuchi, H. (2006). E- orZ-selective Knoevenagel condensation of acetoacetic derivatives Effect of acylated substituent, that is, TEMPO and amines, as an auxiliary, and new accesses to trisubstituted E- and Z-2-aDcraials and furans. 7. Org. Chem., 71, 947-953. 

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