Trisubstituted furan

In 1902 Feist first described the combination of chloroacetone (4) and diethyl 3-oxoglutarate (5) in the presence of ammonia to yield trisubstituted furan 6 ... 

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... 

Several variations of the Feist-Benary reaction furnish substituted furans as products. The following three examples provide synthetically useful alternatives to the standard reaction conditions. One method is based on the reaction of a sulfonium salt with a P-dicarbonyl compound. For example, reaction of acetylacetone (39) with sulfonium salt 38 in the presence of sodium ethoxide yields 81% of trisubstituted furan 40. This strategy provides a flexible method for the preparation of 2,3,4-trisubstituted furans. 

A different procedure provides access to 2,3,5-trisubstituted furans. Deslongchamps discovered that simply heating a mixture of glyceraldehyde (41) and methyl acetoacetate (42) in DMF provides a high yield of furan 43. Subsequent transformations enable selective substitution at the 2-position of the product. 

Portella reported the Paal-Knorr condensation of l,4-bis(acylsilanes) 38 in the presenc( of p-toluenesulfonic acid to yield a variety of 2,5-disilylfurans 1)9. Presumably due to steri( constraints, bis(acylsilanes) substituted in the 2-position failed to undergo the Paal-Knor reaction to provide any of the expected trisubstituted furan products. 

A multitude of 2,3,5-trisubstituted furans are available via the Paal-Knorr condensation. As with the synthesis of disubstituted furans, the scope of this version of the reaction is broad and includes incorporation of aryl, alkyl, ester, and phosphonate substituents. 

A recent report demonstrates that trisubstituted furans can be prepared on a solid support using the Paal-Knorr condensation. Raghavan synthesized a variety of triaryl and alkyl diary] furans, one of which is highlighted below. Dione 50 was cyclized using p-toluenesulfonic acid in refluxing toluene followed by cleavage from the solid support to yield furan 51. ... 

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... 

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>. 

Phomactin A is the most challenging family member architecturally. The fragments that are most challenging are highlighted in Fig. 8.4. In Box-A, the highly sensitive hydrated furan is prone to dehydration under acidic or basic conditions, and any total synthesis almost certainly must save introduction of this fragment until the end game. Box-B relates to the strained and somewhat twisted electron-rich double bond. This trisubstituted olefin is extremely reactive toward electrophilic oxidants. 

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. 

Another example of Au-catalyzed was reported using alkynyl cyclopropyl ketones as a starting material. Trisubstituted furans were given in high yields under mild condition via a domino reaction process and an example is given below <06AG(I)6704>. 

Iodonium ylides reacted with electron-deficient alkynes or conjugated Rh-catalyst to form trisubstituted furans in moderate yields as depicted in the... 

Reaction of a tungsten carbene complex with alkynyllithium followed by treatment of aldehyde in the presence of Et3Al afforded trisubstituted furans in good to excellent yields <06AG(I)6874>. Dienes were the products without Ft,AI. 

Allenes as starting materials are still being explored. One example shown below is that the reaction of bromoallene with a 1,3-diketone under PTC condition provided a trisubstituted furan in high yield <060L5061>. 

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>. 

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. 

Disubstituted- and 2,3,4-trisubstituted-furans are provided by oxidation or oxidation/acid-induced cyclization of the corresponding 2-butene-l,4-diols. These methods have been successfully employed for the synthesis of hibiscone C <00SL363> and cristatic acid . 

An intermolecular version of a [4+2] cycloaddition-retrofragmentation of alkyne-oxazoles can be adapted to the synthesis of 2,3,4-trisubstituted furan in high regioselectivity if acetylenic aldehydes are used as starting materials. The product of this reaction is a pivotal intermediate for the synthesis of (-)-teubrevin G <00JA9324>. 

A divergent protocol for a solid-phase synthesis of 3-substituted 2,5-biarylfurans was reported. Thus, reaction of furan zincate A with polymer bound aryl bromide or iodide provides resin intermediates 61. Subsequent bromination-Suzuki coupling reaction followed by further transformations gives rise to structurally diverse 2,3,5-trisubstituted furans 68 in good overall yields and chemical purities <00TL5447>. 

Alkylation of fert-butylacetoacetate with a-haloketones followed by treatment of the intermediate with TFA leads to substituted 2-hydroxy-3-acetylfurans 69 in high yields. A second alkylation of the intermediate followed by treatment with TFA affords trisubstituted furans 70 . 

Trisubstituted furans can be realized from a novel palladium-catalyzed hydrofurylation of alkylidenecyclopropanes 73 <00JA2661>. 

Reaction of propargylic dithioacetals 74 with organocopper reagent followed by treatment with an aldehyde and then with acid provides 2,3,5-trisubstituted furans in moderate to good yields <00JA4992>. 

The Cu(I)-catalyzed cyclization for the formation of ethyl ( )-tetrahydro-4-methylene-2-phenyl-3-(phenylsulfonyl)furan-3-carboxylate 82 has been accomplished starting from propargyl alcohol and ethyl 2-phenylsulfonyl cinnamate. Upon treatment with Pd(0) and phenylvinyl zinc chloride as shown in the following scheme, the methylenetetrahydrofuran 82 can be converted to a 2,3,4-trisubstituted 2,5-dihydrofuran. In this manner, a number of substituents (aryl, vinyl and alkyl) can be introduced to C4 <00EJO1711>. Moderate yields of 2-(a-substituted N-tosyIaminomethyl)-2,5-dihydrofurans can be realized when N-tosylimines are treated with a 4-hydroxy-cis-butenyl arsonium salt or a sulfonium salt in the presence of KOH in acetonitrile. The mechanism is believed to involve a new ylide cyclization process <00T2967>. 

Furthermore, intercepting the furylpalladium(II) species 130 with an electrophile would result in a carbodepalladation in place of protodepalladation. Therefore, a tandem intramolecular alkoxylation of p.y-acetylenic ketone 127 was realized to afford trisubstituted furan 131 when allyl chloride was added to the original recipe [103]. 2,2-Dimethyloxirane was used as a proton scavenger, ensuring exclusive formation of 3-allylated 2,5-disubstituted furan 131 without contamination by protonated furans. 

Timethylsilyl-substituted allenylcarbinols also react in the presence of AgN03, the trisubstituted allenes 59 deliver dihydrofurans 60, which are sensitive towards air oxidation to the furans, as reported by Wang et al. (Scheme 15.13) [29],... 

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 new stereoselective synthesis of 1,2,3-trisubstituted cyclopentanes based on the Wag-ner-Meerwein rearrangement of a 7-oxabicyclo[2.2.1]heptyl 2-cation starts with the Diels-Alder product of maleic anhydride and a furan (78TL2165, 79TL1691). The cycloadduct was hydrogenated and subjected to methanolysis. The half acid ester (47) was then electrolyzed at 0 °C to generate a cationic intermediate via the abnormal Kolbe reaction (Hofer-Moest reaction). Work-up under the usual conditions provided the 2-oxabicyclo[2.2.1]heptane (48) in 83% yield. Treatment of this compound in turn with perchloric acid effected hydrolysis of the ketal with formation of the trisubstituted cyclopentane (49) in nearly quantitative yield (Scheme 11). Cyclopentanes available from this route constitute useful... 

Monosaccharides react with a variety of 1,3-dicarbonyl compounds in the presence of zinc chloride in ethanolic or aqueous solution to yield substituted furans (Scheme 69) (56MI31200). The reaction of ethyl acetoacetate with D-glucose and D-mannose yielded the trisubstituted furan (252) in 20% yield, while D-fructose under similar conditions yielded (253 7%). These products have been used for the synthesis of dehydromuscarones (63HCA1259). Oxidation of the tetrahydroxybutyl side chains with lead tetraacetate gives the aldehyde, which can be converted to the corresponding acid with alkaline silver oxide. 

When an a-chloroaldehyde or an a-chloroketone is condensed with a /3-ketoester, in the presence of aqueous base, a furan is produced bearing an ester substituent at the /3-position. It is thought that the reaction is of the aldol type intermediate dihydrofurans (256) have been isolated in certain cases (Scheme 70) (74BSF519). The condensation of ethyl bromopyru-vate and sodium oxaloacetate follows a similar mechanism (54JOC1671). The one-pot synthesis of 2,4,5-trisubstituted furans (257) from ketones and ethyl 3,4-dibromo-2-butenoate is a useful addition to a well known route (80S52). The analogous reaction of cyclic /3-diketones, i.e. cyclohexane-1,3-dione and 5,5-dimethylcyclohexane-l,3-dione, results in the formation of the condensed furans (258) and (259). These reactions are preformed either in ethanol with sodium ethoxide or in DMF with potassium carbonate. 

Direct treatment of propargyl halides with /3-dicarbonyl compounds and subsequent treatment of the products with zinc carbonate yields 2,3,5-trisubstituted furans. ... 

Bromochromone reacts readily at room temperature with acetylacetone in chloroform in the presence of two equivalents of DBU. The product, isolated in 83% yield in the usual manner after quenching of the reaction mixture with 5% HC1, is 3-acetyl-5-(2-hydroxybenzoyl)-2-methylfuran. A variety of (3-diketones and P-keto esters react similarly to give moderate to excellent yields of highly functionalised trisubstituted furans. 

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>. 

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