2.5- disubstituted furan

The formation of disubstituted alkynes by coupling of terminal alkynes, followed by intramolecular attack of an alcohol or amine, is used for the preparation of benzofurans and indoles. The benzo[il)]furan 356 can be prepared easily by the reaction of o-iodophenol with a terminal alkyne[262]. The 2-substituted indole 358 is prepared by the coupling of 2-ethynylaniline (357) with aryl and alkenyl halides or triflates, followed by Pd(ll)-catalyzed cycliza-tion[263]. 

Mercury(II) acetate tends to mercurate all the free nuclear positions in pyrrole, furan and thiophene to give derivatives of type (74). The acetoxymercuration of thiophene has been estimated to proceed ca. 10 times faster than that of benzene. Mercuration of rings with deactivating substituents such as ethoxycarbonyl and nitro is still possible with this reagent, as shown by the formation of compounds (75) and (76). Mercury(II) chloride is a milder mercurating agent, as illustrated by the chloromercuration of thiophene to give either the 2- or 2,5-disubstituted product (Scheme 25). 

Acyl-pyrroles, -furans and -thiophenes in general have a similar pattern of reactivity to benzenoid ketones. Acyl groups in 2,5-disubstituted derivatives are sometimes displaced during the course of electrophilic substitution reactions. iV-Alkyl-2-acylpyrroles are converted by strong anhydrous acid to A-alkyl-3-acylpyrroles. Similar treatment of N-unsubstituted 2- or 3-acyIpyrroles yields an equilibrium mixture of 2- and 3-acylpyrroles pyrrolecarbaldehydes also afford isomeric mixtures 81JOC839). The probable mechanism of these rearrangements is shown in Scheme 65. A similar mechanism has been proposed for the isomerization of acetylindoles. 

Cyclotrithiazyl chloride is also a useful reagent in organic chemistry in the fusion of 1,2,5-thiadiazoles to quinones as well as the synthesis of (a) isothiazoles from 2,5-disubstituted furans and (b) bis-1,2,5-thiadiazoles from A-alkylpyrroles (Scheme 8.4). Alkenes and alkynes react readily with (NSC1)3 to give 1,2,5-thiadiazoles, while 1,4-diphenyl-1,3-butadiene gives a variety of heterocyclic products including a bis(l, 2,5-thiadiazole). ... 

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... 

Disubstituted furans are available from the combination of P-dicarbonyl compounds with bromoacetaldehyde diethyl acetal (44). For example, dibenzoylmethane (45) reacts with acetal 44 to furnish 2,3-disubstituted furan 46 in 77% yield. This two-... 

The final variation of the Feist-Benary furan synthesis encompasses reactions of 1,3-dicarbonyls with 1,2-dibromoethyl acetate (52). For example, treatment of ethyl acetoacetate (9) with sodium hydride followed by addition of 52 at 50°C yields dihydrofuran 53. The product can be easily converted into the corresponding 2-methyl-3-furoate upon acid catalyzed elimination of the acetate, thus providing another strategy for the synthesis of 2,3-disubstituted furans. 

In a series of papers in late 1884 and early 1885, Paal and Knorr demonstrated that several 1,4-dicarbonyls could be transformed into furans, pyrroles, and thiophenes. Paal first discovered this transformation and used it to prepare di-, tri-, and tetrasubstituted furans. For example, dicarbonyl 3 yielded disubstituted furan 4 upon treatment with weak acid. 

The most common use of the Paal-Knorr condensation begins with a 1,4-diketone and yields a 2,5-disubstituted furan. This method has been used to produce dialkyl and disilyl furans however, the most popular use of this strategy is for the production of 2,5-diaryl furans. In addition to their utility as synthetic intermediates, these compounds are under investigation for novel electronic and pharmaceutical applications. 

Several other research teams used the Paal-Knorr condensation to prepare 2,5-disubstituted furans that were investigated as potential enzyme inhibitors. Nagai produced furan 17 via treatment of dione 16 with sulfuric acid and subsequently examined the activity of 17 toward a retenoic acid receptor. Perrier discovered that furan 19, derived from dione 18, is a potent PDE4 inhibitor and may have anti-inflammatory activity. ... 

Although it is far more common to synthesize these substrates using the Feist-Benary reaction (Section 4.1), the Paal-Knorr reaction can also be used to prepare 2,3-disubstituted furans. In a recent example, Castagnoli converted 1,4-ketoaldehyde 40 into furan 41 in 97% yield upon exposure to hot sulfuric acid. ... 

Other less common products of the Paal-Knorr condensation include 2,4-disubstituted furans. An example of such a reaction is Molander s combination of dicarbonyl 42 with hydrochloric acid to furnish 4-methyl-2-(methyldiphenylsilyl)furan (43) in 87% yield.It is important to note that this methodology can also be used to produce 2,5- and 2,3-disubstituted furans. ... 

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 eommon approaeh starts with a proteeted 1,4-diearbonyl and unmasks the requisite earbonyl using aeid, thus faeilitating the Paal-Knorr reaetion immediately upon deproteetion. For example, Nagai used sulfurie aeid to eonvert aeetal 77 into 2,4-disubstituted furan 78 albeit in low yield.Molander produeed a different 2,4-disubstituted furan by a similar strategy. Thioketal aeetal 79 was treated with mereury(II) ehloride and furnished furan 80 in 71% yield. Thus this strategy provides a useful approaeh for the synthesis of a variety of 2,4-disubsituted furans. 

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. ... 

Regiospecific synthesis of 3,4-disubstituted furans and thiophenes 97LA459. 

The effect of acids on 2-alkylfurans was discussed in Section III-A-l-c). It was remarked that 2,5-disubstituted furans are less reactive in this context than mono-substituted derivatives. This observation again points to the important role played by a free C-5 position in resinification processes. 

PhsSnflV)] carboxylates and of some 1 1 addition compounds of PhsSnCl and 2,3-disubstituted thiazolidin-4-ones indicate that the carboxylates in the solid state are monomeric with a Sn atom = 2.14—2.54 mm s the only exception being the furan-2-carboxylic acid derivative, which is polymeric. The PhsSnCl adducts are Thp (I Ag p I = 2.97-3.08 mm s ) with the three Ph groups in a not coplanar eq plane. These complexes are effective inhibitors of C. The 2,3-disubstituted... 

The diastereoselective hydrogenation of 2,5-disubstituted furans on a Raney nickel contact provides an easy access to tetrahydroilirylcarbinols. Due to the alcohol used as the solvent it is possible to influence the direction of the stereo selection process (erythro vs. threo). The highest diastereoselectivities reached till now are in the range of 70% <96S349>. The (ij-Cij-Cjj portion of the venturicidins was synthesized stereo selectively in 17 steps from 2-furaldehyde in an overall yield of 7% <96SL135>. 

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 reaction of crotonaldehyde and methyl vinyl ketone with thiophenol in the presence of anhydrous hydrogen chloride effects conjugate addition of thiophenol as well as acetal formation. The resulting j3-phenylthio thioacetals are converted to 1-phenylthio-and 2-phenylthio-1,3-butadiene, respectively, upon reaction with 2 equivalents of copper(I) trifluoromethanesulfonate (Table I). The copper(I)-induced heterolysis of carbon-sulfur bonds has also been used to effect pinacol-type rearrangements of bis(phenyl-thio)methyl carbinols. Thus the addition of bis(phenyl-thio)methyllithium to ketones and aldehydes followed by copper(I)-induced rearrangement results in a one-carbon ring expansion or chain-insertion transformation which gives a-phenylthio ketones. Monothioketals of 1,4-diketones are cyclized to 2,5-disubstituted furans by the action of copper(I) trifluoromethanesulfonate. ... 

Disubstituted benzo[fo]furans were also prepared by intramolecular cyclisation in the presence of a [Pd(thiourea)4]l2 catalyst (thiourea = H2NCS NH2). No Pd precipitation occurred with this very stable thiourea complex (Scheme 31) [120]. 

A number of the bicyclic ozonides 12 were prepared in good yield (45-65 %) by diimide reduction of furan singlet oxygenates (Eq. 9) 23>. Again, low temperature were essential because the furan endoperoxides readily transform into 1,2-diacyl-ethylenes. Of course, the bicyclic ozonides 12 can alternatively be prepared via ozonolysis of the appropriate 1,2-disubstituted cyclobutene 24). 

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