Tethered Diels-Alder reactions

Keywords intramolecular Diels-Alder reaction, tether-controlled, synthetic studies direct toward various classes of natural products, alkadienes... 

Carbene complexes which have an all-carbon tether between the diene and the dienophile react via intramolecular Diels-Alder reaction to give the corresponding bicyclic compound. The stereoselectivities of these reactions are comparable to those observed for the Lewis acid-catalysed reactions of the corresponding methyl esters and much higher than those of the thermal reactions of the methyl esters which are completely unselective. Moreover, the ris-sub-stituted complexes undergo endo-selective reactions where the corresponding reaction of the ester fails [109] (Scheme 61). 

The selectivity for two-alkyne annulation can be increased by involving an intramolecular tethering of the carbene complex to both alkynes. This was accomplished by the synthesis of aryl-diynecarbene complexes 115 and 116 from the triynylcarbene complexes 113 and 114, respectively, and Danishefsky s diene in a Diels-Alder reaction [70a]. The diene adds chemoselectively to the triple bond next to the electrophilic carbene carbon. The thermally induced two-alkyne annulation of the complexes 115 and 116 was performed in benzene and yielded the steroid ring systems 117 and 118 (Scheme 51). This tandem Diels-Alder/two-alkyne annulation, which could also be applied in a one-pot procedure, offers new strategies for steroid synthesis in the class O—>ABCD. 

Anomalous products from the thermal Diels-Alder reaction of a (E)-2-thiophenylbuta-diene tethered to 3-methallylcyclohexenone [157]... 

Among special chemical methods that facilitate the Diels-Alder reaction can be included the temporary metal connection strategy [101] that is illustrated in Table 4.27. Si, Mg and A1 are used as temporary connectors of diene and dienophile moieties. The cycloaddition occurs easily due to its intramolecular nature and because the dienophilic component of reagent is now formally a vinyl carbon ion (i.e. a vinyl carbanion in 154 with M = AlEt ). Thus the metal-tethered 154, prepared from lithium alkoxide of 153 with the suitable metal vinyl halide, gives, by heating, the cycloadducts 156 and 157, through the... 

High-pressure and thermally induced intramolecular Diels-Alder reactions of furfuryl fumarates. Influence of tether substituents on diastereoselectivity [74]... 

The inverse electron demand Diels-Alder reaction has also been used to provide expedient access to unnatural 6-carboline alkaloids from 1,2,4-triazines, prepared by microwave-assisted MCR [92]. One-pot reaction of an acyl hydrazide-tethered indole 73, 1,2-diketone and ammonium acetate in acetic acid provided triazines 74 (see Sect. 3.2, Scheme 22), bearing an electron-rich dienophilic indole moiety (Scheme 31). By carrying out the... 

Scheme 23 Microwave-enhanced Diels-Alder reactions of alkene-tethered 2(lff)-pyra-zinones in ionic liquid doped solvents...

To avoid problems with the separation of regiomers, dimethyl acetylene dicarboxylate (DMAD) was chosen as a dienophile. The intermolecular Diels-Alder reactions were performed in refluxing dichlorobenzene (bp 132 °C), while the intramolecular reaction of alkyne tethered pyrazinone required a solvent with a higher boiling point (bromobenzene, bp 156 °C). In the case of 3-methoxy or 3-phenyl pyrazinones a mixture of pyridinones and pyridines was obtained, while for the alkyne tethered analogue only the di-hydrofuropyridinone was isolated as the single reaction product. 

For the microwave-assisted experiments, both solvents were replaced by 1,2-dichlorobenzene, as it couples very effectively with microwaves (loss-tangent (tan 5) at 20 °C 1,2-dichlorobenzene 0.280 as compared to 0.101 for chlorobenzene). Diels-Alder reactions of 3-methoxy or 3-phenyl pyrazinones with DMAD were performed at a pre-selected maximum temperature of 200 °C, whereas the intramolecular reaction of alkyne tethered pyrazinone required a higher temperature (220 °C). The yields obtained under microwave irradiation are comparable with those obtained under conventional conditions, while for the dihydrofuropyridinone the yield was improved from... 

The inverse electron demand Diels-Alder reaction of 3-substituted indoles with 1,2,4-triazines and 1,2,4,5-tetrazines proceeds in excellent yields both inter- and intramolecularly. The cycloaddition of tryptophan 124 with a tethered 1,2,4-triazine produced a diastereomerically pure cycloadduct 125 <96TL5061>. 

Bicyclopropylidene derivatives with fiiran moieties on tethers of various length and nature all undergo clean intramolecular Diels-Alder reactions with complete em/odiastereoselectivities when heated to 70-130 °C under 10 kbar pressure (Scheme 5, <96T12185>). 

The intramolecular inverse electron demand Diels-Alder reaction between the azadiene and the tethered alkene of compound 176 gives the corresponding benzoxazolo- and benzothiazolopyranopyridines. Terminal alkenes (RZ = H) give the tvr-products 177, whereas 1,2-disubstituted alkenes (R2 = Me or Ph) give the /ram-products 178 (Equation 46) <1995J(P1)1759>. 

Azacanthines, 374, like their deaza analogues (cf. Equation 128), can be prepared by inverse electron demand aza-Diels-Alder reactions of the appropriately tethered amidoalkyl-l,2,4-triazinylindoles 373 (Equation 135) <1995TL6591>. The sulfonyl-substituted derivatives 375 can be prepared similarly in high yield, although the conditions for each individual reaction are important, since an appreciable amount of the desulfonated product 376 may also be formed (Equation 136) <1998TL2487>. 

In work reminiscent of earlier studies by van der Plas <89T803, 89T5611>, Dehaen and co-workers illustrated how the electron deficient pyrimidine ring can be exploited in the intramolecular inverse electron demand Diels-Alder reactions of pyrimidine-tethered alkynes 102 <00SL625>. Under thermal conditions, pyridines 103 were produced in modest to excellent yields. 

Allenes as versatile synthons including Diels-Alder reactions and especially intramolecular cycloadditions of this type were reviewed by Aso and Kanematsu [338], In some cases of intramolecular Diels-Alder reactions of open-chain starting materials such as 340 [339], 342 [339] and similar acceptor-substituted allenes [156], the formation of two new six-membered rings seems to be favorable if possible (Scheme 7.48). The non-activated cumulated C=C bond of 340 takes part in the [4+ 2]-cycloaddition and hence the necessary reaction temperature is high. On the other hand, the progressive truncation of the tether and the electron deficiency of the allenic C=C bond involved give rise to a remarkable Diels-Alder reactivity of the sulfone 346 generated in situ from sulfoxide 345 [339]. 

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]. 

The cross-conjugated trienes have potential in many different types of diversification strategies. For example, the triene clearly lends itself to inter- and intramolecular Diels-Alder reactions. Incorporation of the hydroxymethyl group on the tether allows attachment of functionality suitable for reactions subsequent to the Alder-ene reactions. As depicted in Scheme 8.5, propargyl tosylamides A, alkynyl silanes B, acrylate esters C, and propargyl ethers D can all be readily prepared from 39... 

Over the past several years, Mascarenas and co-workers (150-153) utilized the oxidopyrylium ion with variously hetero-substituted olefin tethers. Mascarenas has used this methodology in tandem with a Diels-Alder reaction to prepare tricyclic cycloheptanoid substrates. Further, Mascarenas and co-workers (154—156) achieved the synthesis of optically active oxabicyclic[3.2.1]octane derivatives through the addition of a homochiral p-tolylsulfinyl group substituted at the olefin tether. The Mascarenas group has also used this methodology to prepare the THF portion of ( )-nemorensic acid via oxidative cleavage of the substituted a-hydroxyketone moiety (157) (Scheme 4.78). 

The presence or absence of the dioxolane protecting group in dienes dictates whether they participate in normal or inverse-electron-demand Diels-Alder reactions.257 The intramolecular inverse-electron-demand Diels-Alder cycloaddition of 1,2,4-triazines tethered with imidazoles produce tetrahydro-l,5-naphthyridines following the loss of N2 and CH3CN.258 The inverse-electron-demand Diels-Alder reaction of 4,6-dinitrobenzofuroxan (137) with ethyl vinyl ether yields two diastereoisomeric dihydrooxazine /V-oxide adducts (138) and (139) together with a bis(dihydrooxazine A -oxide) product (140) in die presence of excess ethyl vinyl ether (Scheme 52).259 The inverse-electron-demand Diels-Alder reaction of 2,4,6-tris(ethoxycarbonyl)-l,3,5-triazine with 5-aminopyrazoles provides a one-step synthesis of pyrazolo[3,4-djpyrimidines.260 The intermolecular inverse-electron-demand Diels-Alder reactions of trialkyl l,2,4-triazine-4,5,6-tricarboxylates with protected 2-aminoimidazole produced li/-imidazo[4,5-c]pyridines and die rearranged 3//-pyrido[3,2-[Pg.460]

Optically pure c/.v-2-azetidi none-tethered dienes have been reported to undergo intermolecular Diels-Alder reaction with a variety of symmetric and unsymmetric dienophiles [257] providing a synthetic entry to various types of racemic and homochiral 1,3,4-trisubstituted 2-azetidinones (I, Fig. 7). 

The use of isopropylidine acetals (112) as tethers in the intramolecular Diels-Alder reactions of dienes with alkenes facilitates the formation of civ-fused cycloadducts (113) from an endo transition state (Scheme 41).218 The intramolecular Diels-Alder reaction of 4-[tris-(2-mcthylcthyl)silyl]oxy-2//-thiopyran derivatives with potential dienophiles tethered at C(2), C(3), C(5), and C(6) positions yielded cycloadducts when the dienophiles were activated with a carbomethoxy group.219 By the substitution of a phenylsulfonyl group on the dienophile of 2-benzopyran-3-ones, it is possible to enhance exo addition during intramolecular Diels-Alder cyclizations to yield a predominance of trans-fused hexaphenanthrenes related to natural products.220 The intramolecular Diels-Alder reaction of 2-furfuryl fumarates has been investigated by molecular mechanics (SIBFA)/continuum reaction field computations.221 The intramolecular 4 + 2-photo-cycloaddition of A-benzylcinnamamides (114) in the presence of C(,H6 gives 3-azatricyclo[5.2.2.01,5]undeca-8,10-dien-4-ones (115) with high stereoselectivity (Scheme 42).222... 

The first use of /3-hydroxysu I lone-based tethers in an intramolecular Diels-Alder reaction provides a novel route to fused 1,4-oxathiepinone sulfone derivatives the endo-adduct is favored (Equation 7) <20050L3203>. 

A review cataloging intramolecular Diels-Alder reactions as key steps in the total synthesis of natural products has been published.78 A key step in the total synthesis (g) of (+)-dihydrocompactin (66) is the intramolecular ionic Diels-Alder reaction of the trienone (63) to yield the (+)-compactin core compound (65) via the intermediate cyclic vinyloxocarbenium ion (64) (Scheme 17).79 The intramolecular Diels-Alder reaction of the Asp-Thr tethered compound (67) produced the cycloadduct (68) with high regio- and stereo-selectivity (Scheme 18).80 Mixed quantum and molec- (g) ular mechanics (QM/MM) combined with Monte Carlo simulations and free-energy perturbation (FEP) calculations have been used to show that macrophomate synthase... 

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