Bicyclic cycloadduct

Thiophenes are less reactive than furans and therefore react with very reactive dienophiles. They behave somewhat differently from furans and in many cases the intermediate addition products are unstable and undergo cheleotropic extrusion of sulfur [30]. Thiophenes 30 undergo cycloaddition reactions with DMAD (Equation 2.11) to afford bicyclic cycloadducts which lead to phthal-ates by sulfur extrusion, thus offering a one-pot synthesis of dimethylphthalates [31]. 

High pressure cycloaddition of cytraconic anhydride (140) with 2-substituted furans 142 afforded, cxo-diastereoselectively but unregioselectively, bicyclic cycloadducts 143 and 144 that have been used in straightforward routes to CD-ring fragment of paclitaxel [55] (Scheme 5.22). The cycloadducts were then... 

Whereas electronically activated 2-pyrones can react thermally in both normal and inverse electron-demand Diels-Alder cycloaddition, 2-pyrone by itself requires thermal conditions that are so vigorous that they cause spontaneous extrusion of carbon dioxide from the bicyclic cycloadduct [61]. 

In 1996, the first successful combination of an enzymatic with a nonenzymatic transformation within a domino process was reported by Waldmann and coworkers [6]. These authors described a reaction in which functionalized bicy-clo[2.2.2]octenediones were produced by a tyrosinase (from Agaricus bisporus) -catalyzed oxidation of para-substituted phenols, followed by a Diels-Alder reaction with an alkene or enol ether as dienophile. Hence, treatment of phenols such as 8-1 and an electron-rich alkene 8-4 in chloroform with tyrosinase in the presence of oxygen led to the bicyclic cycloadducts 8-5 and 8-6 in moderate to good yield (Scheme 8.1). It can be assumed that, in the first step, the phenol 8-1 is hydroxylated by tyrosinase, generating the catechol intermediate 8-2, which is then again oxidized enzy-... 

Diazaphospholes are known to undergo facile 1,3-dipolar cycloaddditions with a variety of dipoles [2, 4, 7, 98], During recent years, some interesting [2+3] cycloaddition reactions have been reported. 2-Acyl-[l,2,3]diazaphospholes 6 were reported to undergo [2+3] cycloaddition with diazocumulene 92, the minor equilibrium isomer of a-diazo-a-silyl ketones 91, to form a bicyclic cycloadduct 93 (Scheme 29). Thermolysis of the cycloadduct results in the formation of tricyclic phosphorus heterocycle 94, which can be explained due to the possibility of two parallel reactions of cycloadduct. On the one hand, extrusion of molecular nitrogen from 93... 

In the intermolecular series, Diels-Alder cycloaddition of ethene to the pyrazi-none heterodiene led to the expected bicyclic cycloadduct (Scheme 6.95 b) [195], The details of this transformation, performed in pre-pressurized reaction vessels, are described in Section 4.3.2 [196], Similar cycloaddition reactions have also been studied on a solid phase (Scheme 7.58) [197]. 

A-Acyl AAs could be transformed in situ into the azlactones or if these compounds are used as a starting material, they react with DMAD to give a bicyclic cycloadduct which eliminates carbon dioxide to give the corresponding pyrrole derivative (Scheme 7) (70CB2356, 70CB2611). 

After being converted into the hydroxamic acid, A-protected L-Pro was transformed in situ into the acylnitroso dienophile, which underwent cycloaddition with cyclohexadiene to give the bicyclic cycloadduct 108 (or its mirror image) (89TL7061). 

Reaction with acetylenic dipolarophiles represents an efficient method for the preparation of 2,5-dUiydrothiophenes. These products can be either isolated or directly converted to thiophene derivatives by dehydration procedures. The most frequently used dipolarophile is dimethyl acetylenedicarboxylate (DMAD), which easily combines with thiocarbonyl yhdes generated by the extrusion of nitrogen from 2,5-dihydro-1,3,4-thiadiazoles (8,25,28,36,41,92,94,152). Other methods involve the desUylation (31,53,129) protocol as well as the reaction with 1,3-dithiohum-4-olates and l,3-thiazolium-4-olates (153-158). Cycloaddition of (5)-methylides formed by the N2-extmsion or desilylation method leads to stable 2,5-dUiydrothiophenes of type 98 and 99. In contrast, bicyclic cycloadducts of type 100 usually decompose to give thiophene (101) or pyridine derivatives (102) (Scheme 5.37). 

The [Rh(NHC)Cl(COD)]/AgSbF6-catalysed intramolecular 4 + 2-cycloaddition of dienynes and the intramolecular 5 + 2-cycloaddition of alkyne vinylcyclopropanes formed the corresponding bicyclic cycloadducts in 91-99% yields within 10 min.8... 

The reaction of the 2,3-dihydroazetium-l-anilide 44 with DMAD comes with an unexpected result. Instead of the anticipated fused bicyclic cycloadduct, two products are detected in the mixture by... 

When an aziridine ring is fused at the 2,3-bond to another ring system, the only ring opening structurally allowed is a disrotatory rotation, which must be photolytically performed as discussed above. Thus, the fused aziridine 8 on irradiation generates syn-azomethine ylide 9, which is captured by an acetylene to give a bicyclic cycloadduct (68CPB764). 

When the above reaction sequence is applied to an N-allylaldimine, the substituted azomethine ylide 71, a transient intermediate, can be trapped intramolecularly to give a bicyclic cycloadduct (77TL3437). 

From a synthetic viewpoint, iV-arylvinylamines are not appropriate as azomethine ylide precursors because the hydrogen shift from the intermediary ylides must be extremely accelerated by the rearomatization of the fused dihydro benzo moiety. Zaima and Mitsuhashi were the first to succeed with synthetic applications of the above photochemical generation method of cyclic azomethine ylides (83JHC1). The substrate employed in their work is bis(l-methoxycarbonylvinyl)amine. Irradiation of this divinylamine in carbon tetrachloride at 18°C in the presence of acetylenedicarboxylates produces excellent yields of 7-azabicyclo[2.2.1]hept-2-ene-l,2,3,4-tetracarboxylates 172, which correspond to the cycloadducts of the expected azomethine ylide intermediate 171. Heating the bicyclic cycloadducts 172 at 90-120°C induces a smooth cycloreversion eliminating a molecule of ethene to give pyrrole-2,3,4,5-tetracarboxylates in quantitative yields. The azomethine ylide 171 can be trapped also with olehnic dipolarophiles, such as maleates and fuma-rates, to furnish stereospecifically 7-azabicyclo [2.2.1] heptane-1,2,3,4-tetra-carboxylates 173 and 174, respectively (84JHC445). 

A highly exo-selective asymmetric hetero Diels-Alder reaction was the key step in D.A. Evans total synthesis of (-)-epibatidine. The bicyclic cycloadduct was then subjected to a fluoride-promoted fragmentation that afforded a (f-keto ester, which was isolated exclusively as its enol tautomer. The removal of the ethoxycarbonyl functionality was achieved using the Krapcho decarboxylation. Interestingly, the presence of a metal salt was not necessary in this transformation. Simply heating the substrate in wet DMSO gave rise to the decarboxylated product in quantitative yield. 

Alkenylcarbenes can also be produced by photolysis of 3tf-pyrazoles. Generated via this route, cyano-(2-methyl-l-propenyl)carbene adds to cyclopentadiene and provides two bicyclic cycloadducts, with moderate preference for the e.to-product (see Vol. E 19b, pp 701 - 705)6. 

Cyclization studies were carried out in sealed tubes in toluene solutions at 165 °C and provided excellent yields of the corresponding bicyclic cycloadducts in 5-9 h. Reactions of tertiary alkyl ethers showed moderate to complete trans selectivity. This selectivity was observed even for inherently cw-directing systems and may be attributed to the gem-dimethyl group in the ether tether comparison of the reacting conformations leading to cis- and rrans-fused decalins reveals, in the cis case, an unfavorable non-bonding interaction between the axial methyl group and H-C(3) of the diene (Scheme 10-15). 

Peri-, regio-, and stereoselectivity of cycloaddition reactions of substituted mesomeric betaines (106) have been studied with different alkynic and alkenic dipolarophiles. High periselectivity has been observed in cycloaddition with both series of dipolarophiles, with the dipolarophile adding exclusively across the 1,3-azomethine ylide dipole (106a). The formation of 2,2 -bipyrroles (108) could be explained by a rearrangement of initial bicyclic cycloadduct (107) <90JOC910>. All these reactions are shown in Scheme 18. 

In a study described by Kappe et al. (Section 11.4.1) [58], the intermolecular Diels-Alder cycloaddition reaction of the pyrazinone heterodiene 52 with ethylene led to the bicyclic cycloadduct S3 (Scheme 11.15). Under conventional conditions these cycloaddition reactions must be conducted in an autoclave at an ethylene pressure of 25 bar at 110 °C for 12 h. In contrast, under the action of microwaves, he Diels-Alder addition of pyrazinone precursor 52 to ethylene in a sealed vessel flushed with ethylene before sealing was complete after 140 min at 190 °C. It was not, however, possible to further increase the reaction rate by increasing the temperature. At temperatures above 200 °C an equilibrium between the cycloaddition 52 S3 and the competing retro Diels-Alder fragmentation process was observed (Scheme 11.15) [58]. By use of a microwave reactor enabling pre-pressurization of the reaction vessel with 10 bar ethylene, however, the Diels-Alder addition 52 S3 was definitely more efficient at 190 °C 85% yield of adduct 53 was obtained within 20 min [65b]. 

Diels-Alder cycloaddition of pyrazinone 687 with ethene in the presence of 1,2-dichlorobenzene (DCB) under MWI gave the bicyclic cycloadducts 688 in 86-89% yields within 40-140 min (Scheme 132). Under conventional heating, these reactions were carried out in an autoclave for 12 h (02JOC7904). 

Hashimoto has reported the enantioselective domino carbonyl yUde formation/l,3-dipolar cycloaddition reaction of a range of a-diazo ketones 185 with various aromatic aldehydes 92, promoted by the chiral Rh(II)-tetrakis[N-benzene-fused-phthaloyl-(S)-valinate] complex (184). The present reaction afforded the corresponding bicyclic cycloadducts 186 in good yields and enantioselectivities. The exo diastereomer 186 was diastereoselectively generated as a single product in almost all the cases (Scheme 11.40) [61]. 

A one-step Lewis acid-catalysed intermolecular 4- -3-cycloaddition of aromatic a,)3-unsaturated aldehyde and ketones (105) with epoxides (106) formed seven-membered oxacycles (107) under mild conditions (Scheme 34).The effect of oxygen-, sulfur-, and halogen-substituents on the reactivity of nitrogen-stabilized oxyallyl cations in 4- -3-cycloaddition reactions has been extensively investigated. Aza-oxyallyl cationic intermediates react with cyclopentadiene and furan via an aza-4 -I- 3-cycloaddition reaction to form bicyclic cycloadducts in moderate yields. The intramolecular formal 4- -4-cycloaddition of conjugated enynes with an e-deflcient cyclobutene (108) yielded a strained six-membered cyclic allene (109) that isomerized to a 1,3-cyclohexadiene (110). This intermediate underwent a thermal or acid-promoted six-electron electrocyclic ring opening to yield a 2,4,6-cyclooctatrienone (111) (Scheme 35). ... 

The cobalt-mediated 6-I-2-cycloaddition of cycloheptatriene and allenes formed bicyclic cycloadducts in high yields and with an excellent E Z selectivity. Rh(I)- (g) catalysed formal intramolecular 6- -2-cycloaddition of the allenal (116) readily produced 5-8- and 6-8-fused bicyclic ketone cycloadducts (118) in excellent yields. A key intermediate in this cycloaddition is the rhodacycle (117) (Scheme 38). The TiCl4-Et2AlCl-catalysed 6-1-2-cycloaddition of 1,2-dienes and 1,3,5-cycloheptatrienes produced endo-bicyclo[4.2.1]nona-2,4-dienes in high yields (80%). ... 

The most commonly employed dienophiles in DA reactions with normal electron demand are maleimide derivatives. These electron-poor alkenes react smoothly with various conjugated dienes to form the respective bicyclic cycloadducts under mild conditions (Fig. 14a). One drawback of maleimides that limits their widespread use in bioconjugation is their ability to react with naturally occurring nucleophiles,... 

A) and (B) = Diasteroisomeric Tetrahydrofuro [3, 4-df] isoxazoles derived bicyclic cycloadducts... 

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