Furan, reaction with dimethyl acetylenedicarboxylate

In order to exploit the cycloaddition reactions of 2-vinylbenzofurans for natural product synthesis, the reactions of (E)-2-()S-methoxyvinyI)benzo-furans have been examined. The simplest compound (139, Scheme 36) on reaction with dimethyl acetylenedicarboxylate in boiling toluene gave a mixture of products. The major adduct was not the one expected but was its conjugation product 140. The diene system in 140 is able to react with... 

The combination of two successive [4+2] cycloadditions has already been described by Diels and Alder [la] for the reaction of dimethyl acetylenedicarboxylate with an excess of furan. A beautiful, more modern, example is the synthesis of pagodane (4-5) by Prinzbach [2], in which an intermolecular Diels-Alder reaction of 4-1 and 4-2 to give 4-3 is followed by an intramolecular cycloaddition. The obtained 4-4 is then transformed into 4-5 (Scheme 4.1). 

Slee and LeGoff performed further investigations on the reaction of dimethyl acetylenedicarboxylate 4-20 with an excess of furan 4-21, as first described by Diels and Alder (Scheme 4.5) [la]. At 100 °C, 4-24 and 4-25 were not produced (as proposed), but rather 4-22 and 4-23, since at elevated temperature an equilibrium takes place and the primarily formed 4-24 and 4-25 isomerize to give a 6 1-mixture of the exo-endo and the exo-exo products 4-22 and 4-23, respectively. However, at lower temperature, in the primarily formed [4+2] cycloadduct the double bond substituted with the two carbomethoxy group acts as the dienophile to give the two products 4-24 and 4-25 in a 3 1 ratio with 96% yield within five weeks, as has been shown by Diels and Olsen [la,lc]. For a differentiation of these two types of adducts, Paquette and coworkers [7] used a domino and pincer product . The Cram group [8] described one of the first examples of a reaction of a tethered bisfuran 4-26 with dimethyl acetylenedicarboxylate 4-20a to give 4-27. 

Both of the known oxathiolium systems have been trapped in situ by dipolarophiles. Compound (88) reacts with dimethyl acetylenedicarboxylate (DMAD), but not phenyl isocyanate or isothiocyanate, to yield thiophene (89), following loss of carbon dioxide as shown in Scheme 10 (77CPB1471). Similarly, oxathioliums (90) may be trapped by a variety of alkynic dipolarophiles to give furans (91) as shown in Scheme 11. The reaction, which appears to be regiospecific when unsymmetrical alkynes are used, is a useful way of preparing furans containing amine or thioether functionality (75AG(E)422). 

A one-step synthesis of di- and trisubstituted furans from acyl isocyanates adds to the scope of the cycloaddition methodology <2004S1359>. The reaction proceeded via an intermediate 4-trimethylsilyloxyoxazole 71, generated in situ from an acyl isocyanate and TMS-diazomethane, which reacted with dimethyl acetylenedicarboxylate... 

A mild and simple reaction of dimethyl acetylenedicarboxylate with ammonium ylides produced tri substituted furans in good yields <05S391>. Reaction of acetylenedicarboxylate with a-bromoketones in the presence of DABCO gave similar products in good yields <05JOC8204>. It seems that the intermediate is the same in both reactions. 

A one-pot synthesis of furan 2-substituted-3-carboxylic and 2-substituted-3,4-dicarboxylic esters was reported. Thus, reaction of an acyl isocyanate with trimethylsilyldiazomethane, a safe replacement for hazardous diazomethane, gave 2-substituted oxazoles, which were treated with dimethyl acetylenedicarboxylate or ethyl propiolate to afford the corresponding di- and trisubstituted furans in good yields <04S1359>. 

A fiiran synthesis which cannot easily be deduced from retrosynthetic considerations is the ring transformation of oxazoles by a Diels-Alder reaction with activated alkynes. For example, 4-methyloxazole 20 reacts with dimethyl acetylenedicarboxylate to provide furan-3,4>dicarboxylic ester 22 [6] via a nonisolable adduct 21 ... 

Examples of the exploitation of furan Diels-Alder cycloadditions for the construction of complex systems are many two delightful examples are shown below. In the first, the residual dienophilie double bond of the Diels-Alder adduct between one of the two furan rings and dimethyl acetylenedicarboxylate then enters into cycloaddition with the second furan ring. In the second example, a pentacyclic array related to the skeletons and oxygenation pattern of polypropionate natural products, was assembled from another molecule containing two furan rings and a reaction partner with two dienophilie double bonds. ... 

Aoyama and co-workers used this approach in their synthesis of 2,3,4-trisubstituted furan derivatives. Reaction of 2-cyclohexyl-4-(trimethylsilyl)oxazole with dimethyl acetylenedicarboxylate under thermal conditions gave the corresponding derivative in good yield. 

While the cycloaddition of oxazole with acetylene is a well-established method for furan synthesis [36], the corresponding reaction of 5-amino oxazole was unknown at the outset of this work. As shown in Eq. (3) of Scheme 15.19, the reaction of 24b with 3-phenyl-2-propynoyl chloridephenylpropioloyl chloride (55a) proceeded smoothly to provide the 5,6-dihydro-furo[2,3-c]pyrrol-4-one (56) in greater than 95% yield. A triple domino sequence involving acylation/intramolecular DA cycloaddition/retro DA could explain the reaction outcome. That the domino process was initiated by acylation was evidenced by the fact that 24b failed to react with dimethyl acetylenedicarboxylate (DMAD) under the identical conditions. 

An example of an acetylenic furan cycloaddition reaction was reported by Ho and Wong [14]. While in some cases, the reaction of furans with dimethyl acetylenedicarboxylate (DMAD) leads to ring opening and aromatization (see below), the addition of 3,4-bis(trimethylsilyl)furan to DMAD at 75 °C gave furan-3,4-dicarboxylate 13, presumably by extrusion of bis(trimethylsilyl)acetylene from the initially formed cycloadduct 12. Stable [47t-l-27i] furan cycloadducts were also obtained using the highly reactive bis(terf-butylsulfonyl)acetylene [15], as well as nitro(trime thylsilyl)acetylene (Scheme 13.5) [16]. 

Dimethyl acetylenedicarboxylate gave first a similar adduct (2) which then added further molecules of furan yielding (3) and subsequently (4). Between 1931 and 1940 the reactions of acetylenedi-carboxylic acid and its dimethyl ester with a number of nitrogen containing heterocyclic compounds were examined, and structures were proposed for the products. Apart from an unpublished investigation of the products from pyridine and dimethyl acetylenedicar-... 

Acetylenedicarboxylic acid, dimethyl ester, 50, 25, 36 Acetylenes, reaction with tri-methylsilyl azide, 50, 109 Acetylenic sulfonium salts, furans from, 53, 3 2-Acetylindane-l,3-dione, 52, 4 2-ACETYL-6-METHOXYNAPHTHALENE, 53, 5... 

Intramolecular Diels—Alder reactions without prior 1,4-addition of oxygen (cf. previous section) have similarly been postulated for a number of [2.2]paracyclophane analogs. When [2](2,5)furano[2](l,4)naphthalen-ophane (42) is heated in excess dimethyl acetylenedicarboxylate at 100 °C, a polycyclic compound of structure 134 is formed. The mechanism of formation of 134 is most probably as follows 101> the furan moiety reacts as active diene component in an intermolecular Diels—Alder reaction to give 135. This is followed by further intramolecular 1,4-addition with the unsubstituted naphthalene ring as diene component to give the product 133, which has been isolated. 

Thermal decomposition of the diazo compounds 116a,b in methanol or ethanol, in the presence of Cu(acac)2 as catalyst, resulted in an intramolecular carbene reaction the benzo[c]furans 117a,b were not isolated, but 117b could be trapped with A-phenylmaleimide and dimethyl acetylenedicarboxylate, to give compounds 118 (endo exo =1 1, 90%) and 121 (92%). Dimethyl fumarate yielded adduct 119 (15%) and supposedly 120 (83%) concerning this structure the same objections can be raised as in the case of... 

When the diazoesters (240) and (241) were thermally decomposed in the presence of copper(II) acetoacetate ester as catalyst, an intermolecular carbene reaction occurred, the resulting benzo[c]furans (242) and (243) were not isolated but were trapped as the Diels-Alder adducts with N- methylmaleimide and dimethyl acetylenedicarboxylate (76CL287). 

Dimethyl acetylenedicarboxylate (DMAD) reacts with a-chloro carbonyl compounds to form 2//-pyrans as the major products and furans 19 as minor components (Equation 11) <2005JOC8204>. Under the same reaction conditions the equivalent a-bromo carbonyl compounds and DMAD react to form only the furans 19 <2005JOC8204>. 

Theoretical and experimental studies revealed a mechanistic twist of the concerted [8+2] cycloaddition between dienylbenzo[c]furans and dimethyl acetylenedicarboxylate (DMAD). Thus, DFT calculation at the (U)-B3LYP/6-31+G(d) level had suggested a stepwise mechanism involving the formation of a zwitterionic intermediate for the [8+2] cycloaddition between DMAD and dienylbenzo[c]furans with electron-donating methoxy groups in the diene moiety. When no electron-donating substituents are present in the diene moiety of the dienylbenzo[c]furan, computational results indicated an alternative mechanism in which a [4+2] reaction occurs between the furan moiety and DMAD, and was followed by a [l,5]-vinyl shift <07JA10773>. 

Methylbenzophenone gives, on photochemical bromination (refluxing CCI4), 2-bromomethylbenzophenone in 80% yield. When the bromination was conducted at room temperature and the crude product treated in refluxing CHCI3 with iV-phenylmaleimide, dimethyl maleate, diethyl fu-marate, methyl vinyl ketone, dimethyl acetylenedicarboxylate, and 1,4-naphthoquinone adducts 92 (mp 227-228°C, 75%), 93 (mp 120-121°C, 65%), 94 (mp 129-130°C, 51%), 95 (mp 81-82 C, 23% an unidentified product was also isolated), 96 (mp 149-150°C, 62%) and 97 (mp 315-316°C, 19%) were obtained. l-Phenylbenzo[c]furan is assumed to be an intermediate in these reactions. Whereas the formation of 92-96 can be simply... 

Similarly, reaction of a thiazolium salt with aldehydes and dimethyl acetylenedicarboxylate provided 3-amino tetrasubstituted furans in moderate to good yields. The substitution pattern differs from the reactions illustrated above <05JOC8919 05OL1343>. 

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