Furan-2 -ones 5-substituted

The synthesis of benzo[Z>]furan derivatives has become a very active field because these molecules have been recently identified as having a variety of biological activities. For example, they can function as inhibitors of protein tyrosine phosphatase IB with antihyperglycemic properties <00JMC1293>, as well as potent and short-acting p-blockers in the treatment of various cardiovascular diseases . An inexpensive, reusable clay has been utilized to catalyze a facile cyclodehydration under microwave without solvent to form 3-substituted benzo[2>]furans from substituted a-phenoxy acetophenones 104. One of the important features of this procedure is that all the selected cyclodehydration reactions are complete in less than 10 minutes <00SL1273>. 

When furan or substituted furans were subjected to the classic oxidative coupling conditions [Pd(OAc)2 in refluxing HOAc], 2,2 -bifuran was the major product, whereas 2,3 -bifuran was a minor product [12,13]. Similar results were observed for the arylation of furans using Pd(OAc)2 [14]. The oxidative couplings of furan or benzo[i]furan with olefins also suffered from inefficiency [15]. These reactions consume at least one equivalent of palladium acetate, and therefore have limited synthetic utility. 

Synthetically even more versatile trifunctional intermediates result from the addition of carbonyl compounds onto methyl 2-siloxycyclopropanecarboxylates 92). Benzo-phenone, titanium tetrachloride, and 162, for instance, provide an excellent yield of the a-hydroxyalkylated y-oxoester 174, which predominates in the equilibrium with its cyclic hemiacetal 176 (y-lactol). It can undergo elimination to the unsaturated ester 175, but as Scheme 7 illustrates, 174/176 can also serve as the starting material to several highly substituted furan(one) derivatives. 

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>. 

Aromatic ethers and furans undergo alkoxylation by addition upon electrolysis in an alcohol containing a suitable electrolyte.Other compounds such as aromatic hydrocarbons, alkenes, A -alkyl amides, and ethers lead to alkoxylated products by substitution. Two mechanisms for these electrochemical alkoxylations are currently discussed. The first one consists of direct oxidation of the substrate to give the radical cation which reacts with the alcohol, followed by reoxidation of the intermediate radical and either alcoholysis or elimination of a proton to the final product. In the second mechanism the primary step is the oxidation of the alcoholate to give an alkoxyl radical which then reacts with the substrate, the consequent steps then being the same as above. The formation of quinone acetals in particular seems to proceed via the second mechanism. ... 

Alkynes substituted with one or two trifluoromethyl groups are also highly reactive dienophiles [9] Indeed, hexafluoro-2-butyne is used increasingly as a definitive acetylenic dienophile in "difficult Diels-Alder reactions. It was used, for example, to prepare novel inside-outside bicycloalkanes via its reaction with cir,trnns -l,3-undecadiene [74] (equation 67) and to do a tandem Diels-Alder reaction with a l,l-bis(pyrrole)methane [75] (equation 68) Indeed, its reactions with pyrrole derivatives and furan have been used in the syntheses of 3,4-bis(tri-fluoromethyl)pyrrole [76, 77] (equation 69) and ],4-bis(trifluoromethyl)benzene-2,3-oxide [78] (equation 70), respectively. 

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. 

Elementary considerations indicate that with appropriate substitutions some of the reactions mentioned above can be eliminated. Indeed, when 5-methyl-2-vinyl-furan was used, no alkylation was observed, the positions C-3 and C-4 being rather unreactive16, and the polymer was a mixture of linear chains with polyunsaturations and linear saturated chains, i.e. only structures like 21, 23 and 26 were present, with a 5-methyl ring instead of the 5-unsubstituted one. When 2-isopropenylfuran was used, no hydride transfer took place since this requires a hydrogen atom in the a-position to the ring, which this monomer does not have the polymers were white and gave electronic spectra transparent down to 280 nm. Alkylation at C-5, how-... 

The first group consists of monocyclic heteroaromatic compounds with one heteroatom and without strongly electron-donating substitutents (OH, NH2). Pyrrole, furan, and thiophene are better electron donors than benzene. The order of their reactivities in azo coupling is thiophene > pyrrole > furan > benzene. 

Benzo[c]furans (isobenzofurans) are very reactive but generally unstable dienes which are prepared in situ and trapped. The in ihu-generated isobenzo-furan 33 was trapped by cycloaddition reaction with bis(methyl (S)-lactyl) ester 34 to afford [32] optically active naphthols (Equation 2.12). The cycloaddition was carried out in the presence of a catalytic amount of glacial acetic acid and represents a facile one-pot procedure to synthesize substituted naphthols. 

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>. 

Slee and LeGoff performed further investigations on the reaction of dimethyl acetylenedicarboxylate 4-20 with an excess of furan 4-21, as first described by Diels and Alder (Scheme 4.5) [la]. At 100 °C, 4-24 and 4-25 were not produced (as proposed), but rather 4-22 and 4-23, since at elevated temperature an equilibrium takes place and the primarily formed 4-24 and 4-25 isomerize to give a 6 1-mixture of the exo-endo and the exo-exo products 4-22 and 4-23, respectively. However, at lower temperature, in the primarily formed [4+2] cycloadduct the double bond substituted with the two carbomethoxy group acts as the dienophile to give the two products 4-24 and 4-25 in a 3 1 ratio with 96% yield within five weeks, as has been shown by Diels and Olsen [la,lc]. For a differentiation of these two types of adducts, Paquette and coworkers [7] used a domino and pincer product . The Cram group [8] described one of the first examples of a reaction of a tethered bisfuran 4-26 with dimethyl acetylenedicarboxylate 4-20a to give 4-27. 

This gives tautomeric mixtures119 when the tert-butyl group is removed. The methyl ether has been used to obtain 3-hydroxy-2-carbonyl derivatives in the selenophene series.120 The unsubstituted 2-hydroxyselenophene system has been prepared by hydrogen peroxide oxidation of 2-selenophene-boronic acid.121 However, in the 5-methyl-substituted system deboronation became such an important side reaction that 5-methyl-2-hydroxyselenophene had to be prepared by acid-catalyzed dealkylation of 5-methyl-2-fert-butoxy-selenophene. Both 2-hydroxy- and 5-methyl-2-hydroxyselenophene exist mainly as 3-selenolene-2-ones (93) and for the 5-methyl derivative it was possible to isolate the / ,y-unsaturated form (92) and follow the tautomeric isomerization. The activation parameters thus obtained were compared with those for the corresponding furan and thiophene systems. 

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