2.3.5- Trisubstituted furans synthesis

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. 

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>. 

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. 

Based upon this one-pot synthesis of iodo furans 158 a sequential Sonogashira-cyclization-Suzuki sequence was developed where the coupling of 156 and 157 followed by deprotection, Michael addition and addition of boronic acid and sodium carbonate leads to the formation of 2,3,5-trisubstituted furans 162 in moderate to good yields (Scheme 62). 

In the total synthesis of (-l-)-citreofuran, the transannular cyclization of a 5-oxoalkene was brought about by acid catalysis (Equation 9) <2003JOC1521>. ra-Toluenesulfonic acid turned out to be optimal for this particular substrate. Mercury triflate is also an effective catalyst for the cyclization of 5-oxoalkynes. Through a protodemercura-tion, 2-methyl-5-substituted- and 2,4,5-trisubstituted furans can be prepared in high yields <2004OL3679>. 

A convenient method for the synthesis of annulated 2-alkylthio-5-aminofurans has been described by Padwa et al. The reaction sequence involves the formation of a thionium group from readily available dithioacetals upon treatment with dimethyl(methylthio)sulfonium tetrafluoroborate (DMTSF). The thionium ion undergoes cyclization with the 7-carbonyl group followed by an elimination step to yield the 2,3,5-trisubstituted furans in good to excellent yields (Equation 29) <2002JOC1595>. The alkylthioaminofuran reaction products can be utilized to constmct polyclic frameworks of natural products in a subsequent Diels-Alder reaction. 

A one-pot synthesis of di- and trisubstituted furans from acyl isocyanates using trimethylsilyldiazomethane has been developed, which improves the synthesis of such oxazole intermediates (Scheme 20) <2004S1359>. 

Scheme 51 Cl-Stetter addition-Paal-Knorr three-component synthesis of 2,3,5-trisubstituted furans 95...

Butene-l,4-diones and 2-butyne-l,4-diones were converted into 2,5-diaryl- and 2,3,5-triarylfurans in high yields in the presence of HCOOH and a catalytic anaount of Pd on carbon under microwave-irradiation conditions <03JOC5392>. This procedure provides a new approach to the starting material used in the Paal-Knorr furan synthesis, as unsaturated diones are reduced to saturated diones in situ by formic acid and palladium. The solid-phase synthesis of 2,3,5-trisubstituted furans from 1,4-diketones was also reported <03SL711>. 

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. 

An impressive alternate approach to the synthesis of furans beginning with alkynols was developed by Balme [160, 161] and subsequently applied in a total synthesis by Morimoto [162]. Balme discovered that a three-component coupling reaction between a propargylic alkoxide, a conjugate addition acceptor, and an unsaturated halide yields a variety of di- and trisubstituted furans. In one example, propargyl alcohol, diethyl ethoxymethylene malonate (193), and iodobenzene combine to furnish disubstituted furan 194 in... 

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. 

Efremov, L, and Paquette, L.A., First synthesis of a rearranged ec>-clerodane diterpenoid. Development of totally regioselective trisubstituted furan ring assembly and medium-ring alkylation tactics for efficient access to (—)-teubrevin G, J. Am. Chem. Soc., 122, 9324, 2000. 

Paterson, I.. Gardner, M., and Banks. B.J.. Studies in marine cembranolide synthesis. A synthesis of 2,3,5-trisubstituted furan intermediates for lophotoxin and pukalide. Tetrahedron. 45. 5283. 1989. 

A one-pot synthesis of furan 2-substituted-3-carboxylic and 2-substituted-3,4-dicarboxylic esters was reported. Thus, reaction of an acyl isocyanate with trimethylsilyldiazomethane, a safe replacement for hazardous diazomethane, gave 2-substituted oxazoles, which were treated with dimethyl acetylenedicarboxylate or ethyl propiolate to afford the corresponding di- and trisubstituted furans in good yields <04S1359>. 

An efficient and atom-economical Au-catalyzed poly substituted furan synthesis was reported <04JA11164>. As can be seen, Au-catalyzed cyclization of 2-(l-alkynyl)-2-alken-l-ones in the presence of MeOH as a nucleophile afforded 2,3,5-trisubstituted furans with high regioselectivity and high yields. A variety of alcohols, 1,3-diketones, some indoles, and amines can serve as nucleophiles. 

Heterocycles. Alkenyl and aryl boronates deliver their organic residues to the opposition of the nitrogen atom of cyclic carbinolamines to replace the hydroxyl group. Synthesis of 2,3,5-trisubstituted furans, from a catalyzed reaction of alkynyl borates and enones, is achieved in one step. 

Rao and co-workers effected cycloaddition of 8 with the propargylic aldehyde 156 to afford the 2,3,4-trisubstituted furan 157 in 90% yield in their regioselective synthesis of the antitumor agent camptothecin (Fig. 3.47). Several steps were required to convert 157 to the butenolide 158, a key synthon for the D- and E-rings of... 

A two-step one-pot synthesis of 2,3,5-trisubstituted furans from epoxyalkynyl esters was reported, in which a facile Sml -mediated reduction was used for the generation of the 2,3,4-trien-l-ols, and the reduction was followed by a Pd(ll)-catalyzed cycloisomerization <01JOC564>. An attractive variant of this reaction was extended to the preparation of tetrasubstituted furans. Thus, when electrophilic Pd(ll) complexes were generated in situ by an oxidative addition of aryl halides or triflates to Pd(0), the oxypalladation process was followed by a reductive elimination and tetrasubstituted furans were formed <01TL3839>. 

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. 

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