Benzo furans intermediates

Furans also undergo cycloadditions with o-benzoquinones. Thus furan, 2-methylfuran, 2,5-diphenylfuran and benzo[ >]furan yield dihydrofurobenzodioxins of type (238) with tetrachloro-l,2-benzoquinone (Scheme 83). The reaction of furan with 1,2-benzoquinone affords only a 1% yield of adduct because most of the quinone undergoes polymerization. The reaction with 2-methylfuran produces a 25% yield of adduct, however. The reactions are thought to involve the electrophilic attack of the quinone on the furan to produce a carbonium ion. In the case of 2-methylfuran the more stable carbonium ion (239) is produced. Evidence for a two-step mechanism is the diversion of the intermediate (239) to the addition product (240) which may be isolated when the reaction is conducted in the presence of ethanol (69JCS(C)1694). 

The reaction of lithiated benzo[ ]furan 93 with sulfur resulted in a novel heterocyclic system, bis(benzo[4,5]-furo)[2,3-< 3. 2 -g][l,2,3,4]tetrathiocine 95, possibly formed via intermediate pentathiepine 94 (Scheme 5) <2002JOC6220>. The assumed mechanism was based on the reported transformation of a pentathiepine into a tetrathiocine induced by Et3N <2001T7185> (cf. Section 14.09.10). 

Photocyclization of A -alkylfuran-2-carboxyanilides conducted in inclusion crystals with optically active tartaric acid-derived hosts led to the formation of tricyclic /ra r-dihydrofuran compounds with up to 99% ee <1996JOC6490, 1999JOC2096>. 2-(/>-Alkoxystyryl)furans underwent photocyclization to give 5-(3-oxo-(/ )-butenyl)benzo[ ]furans as the predominant isomers in undehydrated dichloromethane as shown in Equation (59). The intermediate alkyl enol ether could be obtained by performing the reaction in anhydrous benzene <1999OL1039>. 

Benzo[ ]furan-based diazobutenoates were used as a substrate to make a cyclopropane in 89% yield via a rhodium-catalyzed intramolecular process, as can be seen in Equation (74). Cyclopropane 88 was the key intermediate for the total synthesis of diazonamide A <20000L3521>. 

Chloromercurio-benzo[ ]furans 107 were key intermediates for the syntheses of natural product XH14 and its analogs. The synthesis proceeded by the palladium-catalyzed carbonylation reaction as a pivotal step. The 3-chloromercurio-benzo[ ]furan 107 was also reduced to form its hydride derivative by NaBH4 reduction, as illustrated in Scheme 54 <2002JOC6772>. 

As can be seen in Equation (99), a platinum-catalyzed intramolecular cyclization was also utilized in the formation of benzo[, ]furan-based tricycles. A platinum carbene was proposed as an intermediate in this reaction <2003JA5757>. 

Benzo[/ ]furyl-4-chloromethyl-l,3-oxazole 127, an important intermediate for the synthesis of potent and highly selective D3 receptor ligands, was realized by a direct condensation of benzo[/ ]furan-2-carbamide and 1,3-dichloro-propan-2-one (Equation 108) <2003JME3822>. 

Tetramethyl-la,2,3,4,6,7,8,8a-octahydrobenzofuro[4,3,2-fr,c,d]benzo-furan 604 was obtained in a one-pot reaction of 1 with lithium ethylenediamine(Li/EDA), through the enolization of dimedone in the alkaline medium to give the dienol, which underwent dehydration to the diether 602. The latter formed two free-radical sites at 2,2 -positions upon attack by the nascent hydrogen formed by Li/EDA, which led to the formation of a C-C bond to give the intermediate 603 that on isomerization furnished 604 (92IJC(B)762) (Scheme 128). 

Intramolecular reaction of the vinyl triflate with benzo[ ]furan in 7 is a key step in the preparation of the synthetic intermediate 8 of (—)-frondosin A [5], Intramolecular reaction of the iodide with furan in 9 gave the tetracyclic jS-lactam 10 containing furan ring in the presence of TI2CO3 as a base. The rather unusual C-3 substitution occurs in the reactions of 7 and 9, because the C-2 positions are blocked [6], If the cyclizations of 7 and 9 proceed similar to Heck-type carbopalladation and f-H elimination, direct syn y3-H elimination is not possible, and isomerization from anti to syn, followed by syn y3-H elimination should occur. Therefore, direct electrophilic substitution may be a better explanation. 

Building upon this promising chemistry, Stoltz and coworkers [50] extended the scope of the mild oxidation system to the formation of other cyclic compounds - specifically, benzo-furans and dihydrobenzofurans. Aryl allyl ether 142 was subjected to the Pd(OAc)2/ethyl nicotinate catalyst under a variety of oxidants to provide benzofuran 144. Presumably, this reaction proceeds by initial palladation, followed by alkene insertion and )3-hydride elimination to form vinylic intermediate 143, which then isomerizes to the more thermodynamically stable benzofuran 144. Although molecular oxygen was a suitable oxidant for this reaction (Table 9.2 entry 1), benzoquinone appeared to be the optimal reoxidant (Table 9.2 entry 2), providing the highest overall yields. 

A solvent-free synthesis of benzo[b]furan derivatives 10-79, a class of compounds which is often found in physiologically active natural products, was described by Shanthan Rao and coworkers. These authors heated phosphorane 10-71 for 8 min in a microwave oven and obtained the benzo[b]furan 10-74 in 73% yield (Scheme 10.18) [25]. The sequence is initiated by an intramolecular Wittig reaction, providing alkyne 10-72 this underwent a subsequent Claisen rearrangement to give the intermediate 10-73. Also in this case, normal oil-bath heating gave much lower yields (5%) of the desired product the authors hypothesize that the micro-... 

The asymmetric synthesis of a galanthamine alkaloid relies also on the intramolecular Heck reaction for the preparation of the benzo[h]furan-based key intermediate with a crucial chiral quaternary center, which eventually leads to the synthesis of (-)-galanthamine <00JA11262>. A similar approach towards the construction of galanthamine ring system via an intramolecular Heck reaction has also been investigated <00SL1163>. 

The synthetic approach to the benzo[fo]furan is similar to that of the thiophenes described in Scheme 39. The synthetic approach was described by Flynn et al. [73], and an example synthesis is given in Scheme 40. The appropriate iodophenol 104 is coupled to the aryl alkyne 111. The intermediate 155 is subsequently cyclized in the presence of an appropriately substituted aryl iodide, e.g., 107 under an atmosphere of carbon monoxide gas, to give the benzo[fr]furan chalcone derivative 156. Deprotection of the hydroxyl produces the target compound 157. 

These compounds are less common than indole (benzo[ ]pyrrole). In the case of benzo[i>]furan the aromaticity of the heterocycle is weaker than in indole, and this ring is easily cleaved by reduction or oxidation. Electrophilic reagents tend to react with benzo[Z ]furan at C-2 in preference to C-3 (Scheme 7.21), reflecting the reduced ability of the heteroatom to stabilize the intermediate for 3-substitution. Attack in the heterocycle is often accompanied by substitution in the benzenoid ring. Nitration with nitric acid in acetic acid gives mainly 2-nitrobenzo[Z ]furan, plus the 4-, 6- and 7-isomers. When the reagent is in benzene maintained at 10 °C, both 3- and 2-nitro[ ]furans are formed in the ratio 4 1. Under Vilsmeier reaction conditions (see Section 6.1.2), benzo[Z ]furan gives 2-formylbenzo[6]furan in ca. 40% yield. 

Substituted benzo[ ]thiophene derivatives have been prepared in excellent yields by a tandem Pummer rearrange-ment/Diels-Alder reaction of the intermediate furan with maleic anhydride or A -phenylmaleimide (Equation 87) <1996JOC6166>. 

Synthesis of benzo[c]furans and isoindoles (181) is also possible by the addition of benzyne to the respective monocycles (178), followed by reduction (179 — 180) and pyrolysis. In an alternative procedure, (179) is reacted with 3,6-bis(2-pyridyl)-l,2,4,5-tetrazine, which affords (181) under far less vigorous conditions via a retro Diels-Alder reaction of the intermediate (182). 4-Phenyl-1,2,4-triazoles pyrolyze to form isoindoles (Section 3.4.3.12.2). 

Preparation of addition polymers having the oxolene (dihydrofuran) functionality can be envisioned to occur in two possible ways (Scheme 13). Both, in fact, have been observed (77MI11102). Whereas furan (53) or its derivatives do not homopolymerize under free radical conditions, 1 1 alternating copolymers possessing the 1,4-structure are produced with maleic anhydride (50). Intermediate formation of a CT complex between monomers (50) and (53) is believed to be necessary before polymerization can occur. On the other hand, cationic polymerization is quite facile. The outcome is straightforward with benzo[f>]furan derivatives, producing 1,2-polymers. Optically active poly(benzofurans) are formed when the cationic polymerizations are conducted in the presence of a chiral anion. 

The photoaddition of benzo[c]furan to a variety of alkenes has been described. With cycloheptatriene the [4 +4] adducts (320) and (321) and the [4 + 6] adducts (322) and (323) are obtained in addition to the photodimer (301) and the photooxidation product 1,2-dibenzoylbenzene. The [4 + 4] adducts may be formed in a concerted manner via an exciplex intermediate in a 7r-7r singlet state. The [4+6] adducts, formally symmetry forbidden,... 

Benzofuran-3(2/f)-ones (396) exist in the keto form but undergo ready enolization. Acetylation with acetic anhydride and sodium acetate affords 3-acetoxybenzo[6]furans, but reaction under acidic conditions usually supplies these products admixed with 3-acetoxy-2-acetylbenzo[6]furans. Alkylation usually furnishes a mixture of O- and C-alkylated products. 3-Acetoxy-6-methoxy-4-methylbenzo[6]furan, on Vilsmeier reaction, supplies the 3-chlorobenzo[6]furan-2-carbaldehyde, the product expected from an enolizable ketone (72AJC545). Benzofuran-3(2//)-ones react normally with carbonyl reagents. Grignard reagents react in the expected way and dehydration of the intermediate affords a 3-substituted benzo[6]furan. The methylene group is reactive so that self condensation, condensation with aldehydes and ketones and reaction with Michael acceptors all occur readily. 

AHC(18)337>. The 3-alkylbenzo[6 ]furans result from cyclodehydration of aryloxyacetones the most common dehydrating agents are sulfuric acid, phosphorus oxychloride and poly-phosphoric acid. The allyl ethers of phenols can be converted to 2-alkyl-2,3-dihydro-benzo[6]furan by heating with polyphosphoric acid, pyridine hydrochloride or magnesium chloride at 180 °C the intermediate o-allylphenol is not isolated. 

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