Acylfurans

An interesting preparation of substituted o-aminophenols has been developed by Birkofer and Daum (30). 2-Acylfurans (8) plus an aliphatic secondary amine presumably condense to give the eorresponding enamine (9) (not isolated), which undergoes thermal isomerization to the o-amino-phenol (10). 

The formation of enamines from carbonyl compounds and secondary amines usually entails as only questionable structural feature, the possible isomeric position of double bonds in the product. Molecular rearrangements have not presented synthetic limitations. A notable exception is the generation of o-aminophenols on distillation of enamines derived from 2-acylfurans 620,621). 

When forced, reactions with ammonia commonly lead to derivatives of pyrrole or pyridine, e.g., 2-furoic acid at 210r,C gives 2-amino-3-hydroxyri-dine.189 Hydrazine is a better nucleophile and attacks 3-acylfurans in hot ethanol if there is no group to be displaced the ring opens and a pyrazole is formed.190... 

Very many naturally occurring 3-alkyl- or 3-acylfurans are now routinely synthesized by preparing a substrate for treatment with 3-furyllithium, itself made from 3-bromofuran according to Fukuyama, Tokoroyama, and Kubota, who used it to obtain pyroangensolide and fraxinellone.212 Equally, 2-lithiofuran is used for such natural products as the acetylenic furans from Alphonsea ventricosa213 and other compounds.214 For the synthesis of the sesquiterpenoid sponge-metabolite pleraplysillin-2 78, the lithiofuran 79 and therefore the bromofuran 80 was needed to secure the orientation a suitable preparation was devised for 80.215... 

When bromination of the enolizable ketone is conducted in glycol, simultaneous monobromination and acetalization is observed [2]. 1,5-Dicarbonyl compounds react with benzyltrimethylammonium dichloroiodate to yield initially a monochloro derivative, which undergoes ring closure to produce a 2-substituted 5-acylfuran [26],... 

Encouraged by the recent work on the conversion of 3-trimethylstannylfuran or 156 to 3-acylfurans, the palladium-catalyzed reaction was carried out by Yang between 137 and benzoyl chloride, yielding 158 (Scheme 33). This partial acylation therefore provided a direct entry to unsymmetrical 3,4-disubstituted fufans. A fitting example to demonstrate such an application was the conversion of 158 to 159 as shown in Scheme 33. ... 

The presence of at least one electron-withdrawing group in the furan ring makes monobromination a much more viable process. Considerable study has been made of the bromination of 2-acylfurans, especially in the presence of Lewis acid catalysts. A kinetic study of the bromination of 2-formylfuran in aqueous medium showed that the reaction is first order in each reactant and pH-independent, and influenced by bromide ion concentration (83MI1). In contrast to the analogous acylthiophenes and acylselenophenes, 2-acetylfuran was hydrolyzed when treated with bromine in the presence of sodium acetate (81SC29). 

With bromine and excess aluminium chloride, 2-acetylfuran was converted into a mixture of 2-acetyl-4,5-dibromofuran (major product) and about equal quantities of the 4- and 5-bromo derivatives. The swamping catalyst effect is operating here. Coordination of the catalyst with the carbonyl function makes the substituent more electronegative, and in the presence of a large excess of Lewis acid catalyst, positions ortho and para to the substituent are deactivated more than the me/a-position [68AG(E)519 82AHC(30)167]. In terms of a 2-acylfuran, this means that... 

Bailey TR, Diana GD, Mallamo JP, et al. An evaluation of the antirhinoviral activity of acylfuran replacements for 3-methylisoxazoles. Are 2-acetylfurans bioisosteres for 3-methylisoxazoles. J Med Chem 1994 37 4177-4184. 

Aminomethylfurans are converted into 3-hydroxypyridines by acid and an oxidizing agent, e.g. (219) —+ (220). 2-Hydroxymethylfurans with chlorine in aqueous methanol give 3-hydroxy-4-pyrones. 3-Hydroxypyridines can conveniently be prepared by reaction of 2-acylfurans with ammonia (Scheme 75). Pyrrole and dichlorocarbene give some 3-chloropyridine (Section 3.3.1.7.1). 

The reaction of furans with ammonia and its derivatives is of considerable synthetic utility (B-73MI31 too). Substituted furan-2-carbaldehydes and 2-acylfurans on heating with ammonia and ammonium salts, often under pressure, yield 3-hydroxypyridines. The mechanism of this reaction is thought to involve nucleophilic attack of ammonia at the 2-position. Ring opening affords an amino aldehyde or ketone and thence, by reclosure, the 3-hydroxy-pyridine (Scheme 29). A wide range of substitutents is tolerated. Primary amines with furan-2-carbaldehydes yield A-substituted pyrroles, the closure of the intermediate... 

Treatment of lithiated (41) with aldehydes (42a-c) at -78 °C and then at room temperature gives the corresponding alcohols (43a-c) in yields up to 80%. When (43a-c) were refluxed in benzene containing a catalytic amount of p-toluenesulfonic acid the 2-substituted furans (44a-c) were formed in good yields. Various 2,3-disubstituted furans were readily prepared by combination of the synthetic methods for 2- and 3-substituted furans (Scheme 9). The synthetic utility of this route is illustrated by the preparation of 2-(3,7-dimethyl-2,6-heptadienyl-3-methylfuran (47), which is a typical 2,3-disubstituted furan occurring in nature, starting from the aldehyde (46) and the acetal (45) (Scheme 10). Table 1 summarizes the 2,3-disubstituted furans synthesized by this route. However, attempts to extend the method to the preparation of 3-acylfurans (48) was unsuccessful because of the formation of the vinyl sulfone (49) via deacylation. 

It was found that 3-phenylthiopropanal ethylene acetal (50) is a useful starting material for the preparation of 3-acylfurans (79CL709). Several 3-acylfurans have been discovered in nature (B-59MI31200) but few syntheses have been reported (77JOC1089) except those starting from a 3-substituted furan. Some 3-acylfurans, including perilla ketone, 3-(4-methylpentanoyl)furan, have now been prepared from the acetal (50) and an N-acylaziridine, or an aldehyde and subsequent oxidation. Deacylation reactions are suppressed by the use of 3-phenylthiopropanal ethylene acetal (50), and it affords the desired... 

The reaction of a-bromoacetals with trimethylsilylenolates catalyzed by titanium tetrachloride provides /3-alkoxy-y-bromoketones, which are useful furan precursors (Scheme 33) (75CL527). A new synthesis of acylfurans is exemplified by the formation of the 3-acetyl derivative (146) by heating the brdmoalkene (145) (78JOC4596). 2,2-Dimethyl-3(2//)-furanone (148) has been synthesized from 3-hydroxy-3-methylbutan-2-one treatment with sodium hydride and ethyl formate gave the hydroxymethylene derivative (147), which was cyclized and dehydrated to the furanone (148) with hydrochloric acid (Scheme 34) (71TL4891). O... 

A ring transformation similar to the oxidative conversion of the pyrylium salts to the acylfurans is the formation of 5-alkyl-3,4-dichlorofuran-2-carbonyl chlorides from tetra-chloro-2//-pyrans by oxygen at room temperature. A hyperoxide is proposed as an inter-... 

Cis Dimethylfuranoid esters such as (29) have been isolated from the lipid extracts of some fish species (81CC1110). A naturally occurring 3-acylfuran named perilla ketone (53 R = /-CsHn) has been isolated from Perilla frutescens Brit. (79CL709), while 9,10-dehydrofuranoeremophilane (56) is one of the furanoeremophilanoid constituents isolated from Senecio teretifolins DC (80JCS(P1)963). 

Several rearrangement products (e.g. pyran-2-ones and 2-acylfurans) are obtained when substituted 4-hydroxypyrylium sulfates are irradiated in acid solution. Mechanisms involving many intermediate species as, for example, in the irradiation of (6) and (7) have been advanced to explain the observations (73JA7914,79JA7510). 

Simple 3-acylfurans are not accessible by direct Friedel-Crafts-type substitution of furan, but a most unusual route to these compounds has been discovered. Thus, reaction of the stannylated cyclopropane derivative 1 with acid chlorides (RCOC1) in refluxing toluene for 5 hours gave the dihydrofurans 2 in 64-83% yield. Treatment of 2 with 1.2 equivalents of BF3,OEt2 in dichloromethane at -78°C followed by slow wanning of the reaction mixture to room temperature gave the 3-acylfurans 3 in 30-62% yield. 

Many other reactions of pyrylium salts have been described, converting this readily accessible conjugated C5-synthon into monocyclic aromatic systems with five-membered rings (2-acylfurans, isoxazoles, pyrazoles), or aromatic bicyclic systems (naphthalenes, indolizines),... 

A DFT study of the polar Diels-Alder reaction of 4-aza-6-nitrobenzofuroxan with cyclopentadiene found only one highly asynchronous transition state structure associated with the formation of the 4 + 2-adduct.178 4-Nitrobenzodifuroxan has been shown to be a highly reactive nitroalkene in Diels-Alder reactions with common dienes (cyclopentadiene) to produce stable NED adducts and with ethyl vinyl ether to produce IED adducts.179 Unlike a-acylfuran, 2-nitrofurans have been shown to be active dienophiles in thermal NED Diels-Alder reactions with a variety of buta-1,3-dienes, including Danishefsky s diene.180... 

Enamines obtained from secondary amines and 2-acylfurans undergo the acylfuran-enamine rearrangement with the formation of N-substituted o-aminophenols 297 (Scheme 11). 

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