2.3.5- Trisubstituted furans, formation

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. 

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. 

Reaction of ketones and a,a-dimethoxyketones in the presence of TiCl4-Bu3N led to the formation of a,p-unsaturated lactones, which were converted to 2,3,4-trisubstituted furans. One of the examples is the preparation of menthofuran, the natural mint perfume <02CC2542>. 

Several related methods for the preparation of differentially substituted 5-thio-2,3-trisubstituted furans were developed, which involved the formation of a thionium ion and the cyclization of this reactive intermediate into the tethered carbonyl group <02JOC1595>. 

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). 

From cyclopropenylketones, either 2,3,4- or 2,3,5-trisubstituted furans are available with high regioselectivities, depending on the choice of the catalyst <2003JA12386>. Pd(ii)-catalysis leads to the formation of the 2,3,5-isomers, whereas with Cul as a catalyst 2,3,4-isomers are obtained (Scheme 8). 

An organophosphine-mediated cyclization of alkyl 3-aroyloxy-2-butynoates gives rise to the formation of 2,3- and 2,4-disubstituted as well as 2,3,5-trisubstituted furans (Equation 25) <2004JA4118>. 3-Alkyne-l,2-diols undergo iodo-cyclization to give 3-iodofurans after subsequent dehydration <2001TL5945>. 

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 novel organophosphine-mediated protocol for the construction of substituted furans with different substitution patterns was disclosed, in which a variety of y-aroyloxy butynoates were converted to 2,3- and 2,4-disubstituted furans as well as 2,3,5-trisubstituted furans as shown below <04JA4118>. Another phosphine-initiated reaction leading to the formation of vinylfurans with substituents on the furan ring using 2-penten-4-ynones and a various aldehydes was also published <04T1913>. 

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). 

Rh( 11)-catalyst at room temperature to provide fused trisubstituted furans 182. Apparently, employment of unsymmetrical diazodiones leads to the formation of mixtures of regioisomeric furan products. 

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. 

Development of the furan formation reaction by mercury-catalyzed 5-endo-dig cyclization dates back to the middle of the twentieth century [112]. For example, a trisubstituted furan 239 was prepared by the HgCb-catalyzed cyclization of an alkynylated diol 238 (Scheme 19.63). The pioneering discovery of 5-exo-dig cyclization by Heilborn et al. in 1947 is described later (Scheme 19.70). 

In 2008, Donohoe and coworkers reported the total synthesis of (—)-(Z)-deoxpukalide (1) [30], a complex marine natural product with an intriguing 14-membered carbon macrocyclic skeleton containing a trisubstituted furan moiety (Fig. 1). The key features in the synthesis involve a selective alkene RCM/aromati-zation protocol to prepare the disubstituted furan methyl ester (3) as well as a late stage RCM to furnish the butenolide moiety. Since the five-membered ring formation is more favored, the marked exomethylene functionality was intact under the alkene RCM conditions. 

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>. 

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>. 

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... 

Various other acetylenic substrates can also be used for the synthesis of furans by intramolecular gold-catalyzed C-O bond formation. Thus, acetylenic diols gave a variety of monosubstituted, disubstituted, or trisubstituted fiirans by dehydrative cyclization in the presence of 2 mol% Au[P(r-Bu)2(o-biphenyl)]Cl/AgOTf or AuCl at 0 °C (Scheme 4-8In the latter case, the catalyst loading can be decreased to 0.05 mol% by scavenging water with activated molecular sieves and conducting the reaction in refluxing THF. 

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