Friedel-Crafts acylation of furan

Furyl ketones can be easily obtained by Friedel-Crafts acylation of furans. They can also be obtained from derivatives of furan-2-carboxylic acid such as the amides, nitriles and chlorides by literature reactions. The 3-furyl ketones are also obtained by similar methods. 

A -Butylpyridinium tetrafluoroborate, containing dissolved phosphorus pentachloride, allows catalytic Beckmann rearrangement of cyclohexanone oxime giving e-caprolactam with good conversion and selectivity <2001TL403>. The same ionic liquid containing dissolved ytterbium(m) trifluoromethanesulfonate was used to perform Friedel-Crafts acylation of furan and thiophene <2005JIG398>. 

Iodine in trace amounts has been used as catalyst in Friedel-Crafts acylations of furane and thiophene and of more active members of the benzene series such as anisole and acetanilide. " Oddly enough, it is not effective for benzoylation of anthracene.""... 

Carboxylic acid anhydrides or halides normally require the presence of a Lewis acid (often boron trifluoride) for Friedel-Crafts acylation of furans, though trifluoroacetic anhydride will react alone. Aluminium-chloride-catalysed acetylation of furan proceeds 7 x lO times faster at the a-position than at the P-position. 3-Alkyl-furans substitute mainly at C-2 2,5-dialkyl-furans can be acylated at a P-position, but generally with more difficulty. 3-Bromofuran is efficiently acetylated at C-2 using aluminium chloride catalysis. ... 

Friedel-Crafts acylation of furan gives 2-acylfurans. A complementary photochemical procedure has been published for the preparation of 3-acylfurans which involves irradiation of a furan in the presence of a thioamide. The reaction is proposed to occur by regioselective Paterno-BUchi addition of the thioamide to the furan the thietane produced then eliminates and hydrolyses to the observed product. 

Friedel-Crafts Acylation. The Friedel-Crafts acylation of furan was achieved using antimony triflate as catalyst (eq 1). The desired acylated product was afforded in good yield using 5 mol % of the catalyst. 

Since acylated heteroaromatics are active intermediates for the synthesis of various pharmaceuticals, catalytic acylation of heteroaromatics using safe and reusable catalysts is important in pharmaceutical industry. It is found that gallium triflate can act as an efficient catalyst for Friedel-Crafts acylation of furan, pyrrole, and indole derivatives (eq 3-5). Friedel-Crafts acylation of acyl anilides using AICI3 requires a stoichiometric amount of the catalyst and the yields are low. Studies showed that catalytic acylation of aniline derivatives can be achieved in high yields using Ga(OTf)3 (10 mol%) in the presence of LiClOa (eq 6). ... 

Almost every major structural class discussed to date has featured at least one nonsteroidal antiinflammatory carboxylic acid. It is thus perhaps not surprising to find a dibenzoheterocycle serving as the nucleus for one of these agents, furobufen (34). Straightforward Friedel-Crafts acylation of dibenzo-furan (33) with succinic anhydride affords a mixture of 2- and 3-acylated products, with the latter predominating. The mixture is esterified with methanol, and the methyl ester of the 3-isomer is separated by fractional crystallization. Hydrolysis back to the... 

Intramolecular Friedel-Crafts acylation of the furan ring of 403, which reacted at the 2-position, led to efficient formation of the linear 5 6 5 tricyclic system 404 in good yield (Equation 109) <1998JHC1371>. 

A recent halogen-free benzofuran that shares many structural features with its predecessor shows activity in controlling arrythmias. The synthesis starts with an unusual scheme for building the furan ring. Reaction of the benzyl bromide (2-1) with triphenylphosphine leads to phosphonium salt (2-2). Treatment of the salt with valeryl chloride in the presence of pyridine results in acylation on the now highly activated benzylic carbon (2-3). That product cyclizes to the benzofuran (2-4) on heating with expulsion of triphenylphosphine. Friedel-Crafts acylation of (2-4) with anisoyl chloride in the presence of stannic chloride proceeds on the... 

White and his co-workers (14) used a Friedel-Crafts acylation of l-(2-furyl)-2-propanol 45, prepared using the same chemistry as Schmidt s (13a), gave the 2,5-disubstituted furan 46 (Scheme 5). Hydrogenation of the furan 46 over rhodium resulted in the c/s-fused tetrahydrofuran alcohol... 

Hafnium triflate has been used for catalytic Friedel-Crafts acylation of aromatic rings [25]. The same catalyst has been found to be effective for heteroaromatics such as furan and pyrrole (58) (Equations 19 and 20) [26]. The reaction of furan with acetic anhydride gave 2-acetylfuran exclusively, whereas that of pyrrole (58) gave a mixture of 2- and 3-acetylpyrroles. 

Furan can also be acylated by the Vilsmeier-Haack method. Acylation of furans can also be carried out with acid anhydrides and acyl halides in the presence of Friedel-Crafts catalysts (BF3-Et20, SnCU or H3PO4). Reactive anhydrides such as trifluoroacetic anhydride, however, require no catalyst. Acetylation with acetyl p-toluenesulfonate gives high yields. 

Reaction of the potassium salt of salicylaldehyde with chlo-roacetone affords first the corresponding phenolic ether aldol cyclization of the aldehyde with the ketonic side chain affords the benzofuran (1). Reduction of the carbonyl group by means of the Wolf-Kischner reaction affords 2-ethyl-benzofuran. Friedel-Crafts acylation with anisoyl chloride proceeds on the remaining unsubstituted position on the furan ring (2). The methyl ether is then cleaved by means of pyridine hydrochloride (3). lodina-tion of the phenol is accomplished by means of an alkaline solution of iodine and potassium iodide. There is thus obtained benziodarone (4)... 

Nevertheless, we can interpret the reactions of furan and thiophene by logical consideration as we did for pyrrole. In electrophilic substitutions, there is again a preference for 2- rather than 3-substitution, and typical electrophilic reactions carried out under acidic conditions are difficult to control. However, because of lower reactivity compared with pyrrole, it is possible to exploit Friedel-Crafts acylations, though using less-reactive anhydrides rather than... 

An approach to the synthesis of a prostaglandin intermediate began with 2-furanacetonitrile (71JOC3191). Friedel-Crafts acylation with pimelic half-ester acid chloride and Wolff-Kishner reduction of the product with concomitant hydrolysis of the nitrile group to acid yielded the diester (78) on diazomethane treatment. Ring opening of the furan by a standard procedure yielded a diketo diester (79) which on refluxing in aqueous methanolic potassium carbonate underwent hydrolysis and cyclization to the diacid (80 Scheme 19). 

Dioxacorroles are 18-7r-electron aromatic systems like corroles. They exhibit basicity intermediate between that of porphyrin and corrole, and require 1 h at 100 °C in TFA for complete deuteration of the meso positions. The furan protons are also substituted by deuterium under the same conditions after lOOh. Friedel-Crafts acylation occurs at C-5 while alkyl halides attack on the pyrrolic nitrogens to give a mixture of mono- and di-alkyl derivatives. 

In the case of 1,3-diphenylfuro[3,2-c]pyrazole (58) most electrophilic substitutions, e.g., Vilsmeier formylation, Friedel-Crafts acylation, and monobromination, take place in the furan ring. Excess bromine gives the second bromination in the 4-position of the 1-phenyl group, but nitration gives the l-(4-nitrophenyl) derivative and a second, uncharacterized, product (78YZ204). 

If the reduction follows two Friedel-Crafts reactions on thiophene the product is a 1,6-diketone instead of the 1,4-diketones from furan. Thiophene is well behaved in Friedel-Crafts acylations, and reaction occurs at the 2- and 5-positions unless these are blocked. 

Three reactions, which were known from the literature to be catalyzed by Lewis acids were selected as test reactions. A, was the Reetz alkylation of silyl enol ethers with -butyl chloride for which titanium tetrachloride is known to be useful [52]. B, was the Diels-Alder reaction between furan and acetylenedicarboxylic ester for which aluminium trichloride is a good catalyst [53]. C, was a Friedel-Crafts acylation for which aluminium trichloride is the preferred catalyst [54]. The reactions are summarized in Scheme 6. 

The tanshinones are diterpenoid furanoquinones which occur in the roots of Salvia miltiorrhiza. The syntheses of tanshinone II and cryptotanshinone were accomplished from 1,2,4-trimethoxybenzene. This was converted by a Friedel-Crafts acylation to 2,4,5-trimethoxybenzoylpropionic acid and thence to the tetralone (125). The tetralone was condensed with ethyl y-bromocrotonate and the product converted directly to a naphthylbutyric ester. Curiously, an aromatic methoxy-group was displaced in this reaction. Reaction of the ethyl ester with methyl magnesium iodide and cyclodehydration afforded the tetra-hydrodimethoxyphenanthrene (126). The furan ring was added via the derivative (127) which underwent cyclization and decarboxylation to afford (128). Hydrolysis and oxidation gave the tanshinone (129). 

Instead, these heterocycles and their derivatives most commonly undergo electrophilic substitution nitration, sulfonation, halogenation. Friedel-Crafts acylation, even the Reimer-Tiemann reaction and coupling with diazonium salts. Heats of combustion indicate resonance stabilization to the extent of 22-28 kcal/ mole somewhat less than the resonance energy of benzene (36 kcal/mde), but much greater than that of most conjugateci dienes (about Tlccal/mole). On the basis of these properties, pyrrole, furan, and thiophene must be considered aromatic. Clearly, formulas I, II, and III do not adequately represent the structures of these compounds. 

White has also completed two syntheses of racemic methyl nonactate (154). The first approach controlled the C-8 alcohol stereochemistry, and the second provided a rapid entry into the ring system. The first sequence, outlined in Scheme 4.28, began with the opening of propylene oxide by 2-lithiofuran. The Friedel-Crafts acylation that followed also resulted in protection of the alcohol as the acetate to give 175 in 81% overall yield. Hydrogenation of the furan ring over rhodium on charcoal gave a 96% yield of tetrahydrofuran diastereomers... 

As illustrated in the following scheme, in the first total synthesis of (5)-(+)-cacalol, the benzo[b]furan ring was assembled by a base-mediated condensation reaction <05H(65)319>. Other similar scaffolds were made by a procedure featuring an intramolecular Friedel-Crafts acylation and a subsequent methylation <05OL1765>. A... 

Kinetic studies of acylation reactions are somewhat limited by the insolubility of the acyl halide-Lewis acid complexes in many of the solvent systems that are used. However, useful results have been obtained and, as far as we are concerned, relative rates of reactions are of greater importance than absolute values. In any case it is not possible to distinguish between the two mechanistic extremes on the basis of the observed kinetics." Friedel-Crafts acylations are generally characterized by high substrate selectivity and frequently by high positional selectivity. Relative rate data show, as expected, that toluene is more reactive than benzene and that /n-xylene is the most reactive of the dimethylbenzenes. Values, relative to benzene, for benzoylation catalyzed by aluminum chloride were r-butylbenzene (72), toluene (1.1 X 10 ), p-xylene (1.4 x 10 ), o-xylene (1.12 x 10 ), and m-xylene (3.94 x 10- ). Competition data for the trifluoroacetylation of a number of heterocycles using trifluoroacetic anhydride at 75 "C gave the relative rates thiophene (1.0), furan (1.4 x lO ), 2-methylfuran (1.2 x 10 ) and pyrrole (5.3 x 10 ). ... 

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