Diels-Alder furan cycloaddition Intramolecular-

Furans are also useful 4ti components for tandem Ugi condensation/intramolecular Diels-Alder cascade reactions. For example, stirring a methanolic mixture of compounds 131-133 and benzylamine at room temperature gave the Ugi condensation product 134 that underwent a subsequent intramolecular Diels-Alder furan cycloaddition (IMDAF) to furnish 135 in 70-90% yield (Scheme 13.35) [69,70]. This methodology also allowed for a solid-phase synthesis by using an ArgoGel-Rink resin as the amine component, thereby providing cycloadducts 135 (after cleavage from the resin) in 90-95% yields. 

Padwa and co-workers have shown that the amides 55 can be conveniently prepared in high yield by [4 + 2]-cycloaddition of an acetylenic dienophile to the corresponding 2-amino oxazole derivative 54 (Eq. (6)). The reaction was extended to intramolecular reactions (e.g. 56 - 57, Eq. (7)), giving convenient 2-aminofuran precursors for further intramolecular Diels Alder furan (IMDAF) reactions (see Section Il.C.l.e) (99JOC3595, 99TL1645). 

Oxazoles readily undergo Diels-Alder type cycloaddition across the 2,5-positions, in parallel with the behaviour of furans (18.7). Thiazole and imidazole do not show this mode of reactivity, however they do react with highly electrophilic alkynes via initial electrophilic addition to the nitrogen, then nucleophilic intramolecular cyclising addition (cf the comparable reactivity of quinohnes, 9.13). ... 

Keay B. A., Hunt 1. R. Aspects of the Intramolecular Diels-Alder Reaction of Furan Dienes Leading to the Formation of Epoxydecalin Systems Adv. Cycloaddit. 1999 6 173-210... 

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). 

At ambient pressure, 195a did not undergo intramolecular [4 + 2] cycloaddition even at temperatures up to 150°C. The use of Lewis acids to promote the Diels-Alder reactions was of marginal success only. In contrast, on exposing the furan derivatives 195 to high pressure (10kbar) in 0.1-0.5 moll-1 solutions at 60-70°C, a clean cycloaddition took place (Table 18). 

Cycloaddition reactions of furans are still widely used as key steps in the construction of complex molecules including natural products. As an example, the intramolecular Diels-Alder cycloaddition of 2-amido substituted furans provides a useful tool for the synthesis of fused, nitrogen-containing poly-heterocycles. Thus, thermolysis of 3-substituted amidofuran produces tricyclic indolinone 39 as a 2 1 mixture of diastereomers via amidofuran cycloaddition-rearrangement methodology, which serves as a key intermediate in the total synthesis of ( )-dendrobine, a major component of the Chinese ornamental orchid Dendrobium nobile . 

Bicyclopropylidene (1) does not undergo an intermolecular Diels-Alder reaction with furan and 2-methoxyfuran even under high pressure. Intramolecular cycloadditions of compounds 160 with a furan tethered to bicyclopropylidene, however, were easily brought about under high pressure (10 kbar) and gave cycloadducts 161 stereoselectively in yields ranging from 32 to 95% (Scheme 35) [58]. 

Friedrichsen and co-workers (135), along with Padwa, has utilized the carbonyl ylide cycloaddition to generate reactive furan moieties that can be further used in inter- or intramolecular Diels-Alder reactions to prepare aza- and carbocyclic compounds. Friedrichsen conducted a number of synthetic and theoretical studies on the reactivity, regioselectivity, and stereoselectivity of substituted furan formation and subsequent Diels-Alder reaction (Scheme 4.69). 

An interesting one-pot, five-component domino process using an intermolecular Diels-Alder reaction of furans with AT-phenylmaleimide as its final step has been used to construct the central core of indolo[2,3- ]carbazoles (Equation 86) <2002AGE4291>. Thus, aminooxazoles produced from an Ugi three-component reaction undergo acylation/intramolecular Diels-Alder/retro-Diels-Alder cycloreversion with pentafluorophenyl arylprop-2-ynoates to give furan derivatives. Subsequent Diels-Alder cycloaddition at elevated temperatures with A -phenylmaleimide produces carbazoles in good yields (Table 5). 

Hydrolase-catalyzed domino reactions incorporating a resolution and a subsequent cycloaddition reaction have been described [95-97]. This constitutes an attractive approach to complex synthetic intermediates. For example, the l-(3-methyl-2-furyl)]propanol roc-93 reacts with ethoxyvinyl methyl fumarate (94) catalyzed by Lipase LIP (from Pseudomonas aeruginosa) to furnish a dienophilic fumarate ester, which spontaneously undergoes an intramolecular Diels-Alder reaction with the furan moiety furnishing exclusively the syn-adduct, the oxabicy-clohexene 95 in excellent along with the remaining alcohol S-96 (Scheme 4.31) [95]. A similar approach has been used for a procedure that includes a series of domino reactions that includes dynamic kinetic resolution of the 3-vinylcyclohex-... 

The first example of a tandem Ugi-4CR/intramolecular Diels-Alder reaction was reported by Paulvannan at Affimax [95], who obtained precursors for intramolecular Diels-Alder cycloadditions by an Ugi-4CR between furan-2-carboxaldehydes, monoamides or monoesters of fumaric or maleic acids, benzylamine, and benzyl isocyanide. The Ugi-4CR adducts 172 were never isolated since they underwent... 

Several additional examples of the intramolecular cycloaddition of unactivated acetylenes with isomiinchnones were reported by Maier [30]. This cycloaddition approach represents an efficient method for providing rapid access to annulated furans present in several sesqui- and diterpenes, such as the panicu-lides [51],furanonaphthoquinones [52],furodysin,andfurodysinin [53,54].The decomposition of acyclic acetylenic diazoimides 102 and 103 with Rh2(OAc)4 resulted in cycloaddition and retro-Diels-Alder extrusion of methyl isocyanate to give annulated furans 104 and 105 in good yield. The overall transformation is closely related to the intramolecular Diels-Alder reactions of acetylenic oxa-zoles extensively studied by Jacobi and coworkers [55]. 

M4604>. The synthesis of a fullerene embedded with a furan motif was reported, which was confirmed by a single crystal X-ray analysis <07OL1741>. Tandem Wittig reaction-intramolecular Diels-Alder cycloaddition of 2-furfural provided tricyclic furans, which may serve as precursors in the synthesis of furanosesquiterpenes <07TL3517>. 

A slightly modified synthesis of dihydrobenzo[c]furan was achieved, in which the key reaction involved the exposure of a dibromide to dry alumina and one equivalent of water in toluene instead of in hexanes <07TL3039>. Another synthesis of dihydrobenzo[c]furans was reported by Hashmi and Teles <07SL1747> and an example is depicted below. Base-promoted cycloaddition of 1-aryl- or l-aryl-7-substituted-4-oxahepta-1,6-diynes in DMSO were found to involve an anionic intramolecular Diels-Alder reaction, and also resulted in the formation of dihydrobenzo[c]furans <07JA4939>. 

A multi-gram enantioselective synthesis of (+)-37, a key precursor to the tetracycline antibiotics, has been performed from simple heterocyclic compounds. Key steps in the route involve enantioselective addition of divinylzinc to 3-benzyloxy-5-isoxazolecarboxaldehyde (with 93% ee) for the preparation of 36 and, after its nucleophilic addition to 35, an intramolecular furan Diels-Alder cycloaddition <07OL3523>. 

The inter- and intramolecular Diels-Alder reactions of furans, and their applications to the synthesis of natural products as well as synthetic materials, were reviewed <1997T14179>. HfCU promoted the endo-seXccuve. inter-molecular Diels-Alder cycloadditions of furans with a,/3-unsaturated esters <2002AGE4079>. The cycloaddition between furan and methacrylate was also achieved under these conditions, providing, however the o-isomer as the major cycloadduct. A catalytic enantioselective Diels-Alder reaction between furan and acryloyl oxazolidinone to provide the < 46i-adduct in 97% ee was achieved by using the cationic bis(4-fer7-butyloxazoline)copper(ll) complex 55, as shown in Equation (41) <1997TL57>. 

A complexation-induced intramolecular Diels-Alder cycloaddition of furan is depicted in Scheme 34. Upon exposure to silica gel, the alkyne-Co2(CO)6 complex 61 was transformed to the cycloadduct that contained a seven-membered ring <20000L871>. This facile process was supposed to be arisen from the bending of the linear triple bond to a structure with a 140° angle between the two carbon substituents in the cobalt complex 61. 

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