Syntheses of the Furan Ring

The formation of furfural from pentoses, of 5-methylfurfuraI from methylpentoses, and of 5-hydroxymethylfurfural from hexoses under acidic conditions has long been known.1 There are only a few more recent investigations to be mentioned. 

Acid-catalyzed dehydration of aldoses and ketoses yields furan derivatives in 40-80% yield. Recently the reaction has been carried out in an organic solvent, e.g., dioxan or triethylene glycol,5 or with I2 in dimethylformamide at 100°. Often D-fructose is employed as starting material. This ketose gives glucose via an enediol, which yields 5-hydroxymethylfurfural or its O-acyl derivative by dehydration.7-10 

D-Glucal smoothly yields 2-methoxymethyl-5-hydroxymethyl-furan with methanolic hydrochloric acid11  

It was proved by using labeled compounds that C-l of xylose becomes the formyl group of furfural.12 Further analogous preparative methods have been reported,13 14 and a pyrolytic preparation of furfural from xylose is known.15 

The condensation of monosaccharides with /J-ketoesters and related compounds  

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Some of the transformations of F into furanic monomers are shown in Scheme 1. In recent years renewed interest in these syntheses has produced much progress in terms of yields, simplicity and economy. Thus, for example, very convenient routes leading to 2-vinylfuran (9) and 2-mryl oxirane (10) have been reported. The structures of the monomers in Scheme 1 simulate those of aliphatic and aromatic counterparts which are the basis of most polyaddition reactions and which are prepared in typical petrochemical operations. The only (but major) difference stems from the presence of the furan ring in each of the structures. 

A convenient and recently discovered method for synthesizing pyrazole-5-carboxylic acids involves the easy oxidation of the furan ring of 2-furylpyrazoles (81) with neutral permanganate. Only the furan ring is oxidized, and alkyl or aryl substituents are left untouched.106, 107 By condensing 2-acetylfuran with an aldehyde as the... 

Both 2- and 3-nitrofurans with additional substituents on the available positions of the furan ring have been synthesized by cyclization procedures. The nitro-containing reagents are of type 1 or 2. No type 3 reagent seems to have been used for the synthesis of nitrofurans or condensed nitrofurans. 

Electrophilic substitution of the appropriately functionalized arylamine and subsequent iron-mediated oxidative cyclization with aromatization generates the carbazole skeleton. Annulation of the furan ring by treatment with catalytic amounts of amberlyst 15 affords furostifoline directly. Comparison of the six total syntheses reported so far for furostifoline demonstrates the superiority of the iron-mediated synthesis (Table 1 in ref. [43a]). Starting from the 2-methoxy-substituted tricarbonyliron-coordinated cyclohexadienylium salt this sequence has been applied to the synthesis of furoclausine-A (Scheme 15.12) [45]. 

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... 

Amongst forty-two furan derivatives which were investigated by Dodd and Stillman in 1944 nitrofurazone was found to be highly effective as a topical agent. It contains the azomethine side chain (—CH=N—) in the 2-position of the furan ring. From 1944 to 1960 over 450 similar compounds were synthesized and studied for antimicrobial properties. Seven compounds were selected from these, namely the commercially available compounds nitrofurazone, nifuroxime, guanofuracin hydrochloride, nitrofurantoin, furazolidone and panazone. Recently acetyl- and di-(hydroxymethyl)-derivatives of panfuran have been developed for clinical use in Japan. Some physical and chemical properties of these furan derivatives are shown in Table 6.1. 

A series of anti-inflammatory hydroxy butenolides was synthesized starting from 55. Thus heating 55 with ethyl phenyl-prop-1-ynoate 141 for 16 h at 210°C afforded 3-phenyl-4-furancarboxylic acid ethyl ester 142 (Fig. 3.42). Functionalization of the ester followed by reaction of the furan ring with singlet oxygen gave the biologically active butenolides, 143. 

Poly(hydroxymethyl furfurylidene-acetone) adhesive resins were synthesized and characterized [68-70] through the 5-formaldehyde adduct (19) and its acid-catalyzed polymerization. The catalysts used were sulfuric, phosphoric, or p-toluenesulfonic acid. The authors postulated that the first condensation products resulted from the condensation of two methylol groups of two 19 molecules (adduct 20). They also proposed a hypothetical structure of the network formed after curing (21). It seems, however, difficult to envisage the acid-catalyzed resinification of 19 without the participation of hydrogen atoms at the C5 position of the furanic ring [2]. 

Prakash, Petasis and Olah used this approach to synthesize anti-a-(trifluo-romethyl)-P-amino alcohols (R = CFj) [50], and awti-o-(difluoromethyl)-P-amino alcohols (R = CF2H) (Scheme 7.9) [51, 52). An example application is the single enantiomer synthesis of anti-dif luorothreonine, which was readily obtained following N-deallylation and ozonolytic cleavage of the furan ring in the adduct 37 (R = 2-furyl,... 

By homologation of the furan rings of calix[5]furan 40 and calix[6]furan 41 to pyrrole, Kohnke et al. reported the syntheses of the larger family of calixpyrroles, which otherwise are not readily obtainable, as well as the hybrid systems. In contrast with calix[4]pyrroles such as 77, the larger family of calixpyrroles such as 78 and 79 tend to undergo a facile mitosis reaction to the cyclic tetramer even under mild acidic conditions. Reduction of the calix[5]furan-based enedione 66 followed by Pall-Knorr reaction afforded calix[5]pyrrole 78, which was found not to be so unstable as originally envisaged (Scheme 10) [46]. Similarly, caUx[l]furan[5]pyrrole 80, calix[2]furan[4]pyrrole 81, calix[3]furan[3]pyrrole 82, and calix[6]pyrrole 79 were derived from the cahx[6]furan-based enediones 71, 72, 73, and 67, respectively [42,48]. 

The cross-coupling of aromatic and heteroaromatic rings has been carried out extensively[555]. Tin compounds of heterocycles such as oxazo-lines[556,557], thiophene[558,559], furans[558], pyridines[558], and seleno-phenes [560] can be coupled with aryl halides. The syntheses of the phenylo.xazoline 691[552], dithiophenopyridine 692[56l] and 3-(2-pyridyl)qui-noline 693[562] are typical examples. 

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