Diels-Alder reactions dimethyl acetylenedicarboxylate

Most examples of Diels-Alder reactions reported for both 2-vinyl and 3-vinylindoles involve typical electrophilic dienophiles such as benzoquinone, A"-phenylmaleimide and dimethyl acetylenedicarboxylate (see Table 16.1). T hese symmetrical dienophiles raise no issues of rcgiosclectivity. While there arc fewer examples of use of mono-substituted dienophiles, they appear to react... 

Dicyanoacetylene, 2-hiitynedinitri1e, is obtained from dimethyl acetylenedicarboxylate by ammonolysis to the diamide, which is dehydrated with phosphoms pentoxide (44). It bums in oxygen to give a flame with a temperature of 5260 K, the hottest flame temperature known (45). Alcohols and amines add readily to its acetylenic bond (46). It is a powerhil dienophile in the Diels-Alder reaction it adds to many dienes at room temperature, and at 180°C actually adds 1,4- to benzene to give the bicyclo adduct (7) [18341 -68-9] C QHgN2 (47). 

A convenient alternative to LP-DE is lithium trifluoromethanesulfonimide (LiNTf2) in acetone or diethyl ether (LT-AC, LT-DE). Representative examples are the Diels-Alder reactions of citraconic anhydride with cyclopen-tadiene and of dimethyl acetylenedicarboxylate with isoprene [47] (Scheme 6.26). 

In another paper, the same authors investigated the 1,3-dipolar cycloaddition on 2-(lH)-pyrazine scaffolds 72 and electron-rich azides, using Cu(0) and CUSO4 as pre-catalysts. To demonstrate the versatility of this approach, they reported the generation of different templates (73 in Scheme 25) as an application of cUck chemistry . They also investigated the Diels-Alder reaction of the so obtained triazoles with dimethyl acetylenedicarboxylate (DMAD), under microwave irradiation. The latter reaction allowed obtaining various pyridinones in good yields (74 and 75 in Scheme 25) [57]. 

However, most of the reactions are reported to be slow, taking up to 12 h for complete conversion of the starting materials. A Diels-Alder reaction of the pyrazinone scaffold with dimethyl acetylenedicarboxylate (DMAD) [57] has been studied in view of investigating the swiftness of this cycloaddition-fragmentation protocol (Scheme 20). The authors investigated the reaction with DMAD (lOequiv) under microwave irradiation at an elevated temperature of 190 °C, using small amounts of ionic liquid (bmimPFe) in... 

As the Diels-Alder reactions of 2( lff)-pyrazinones with richly substituted acetylenes can be used to generate diversely substituted pyridines and pyridi-nones, these cyclo additions were investigated under microwave irradiation conditions on the 1,2,3-triazole decorated pyrazinone scaffold. As a proof of concept, the pyrazinones bearing a 1,4-disubstituted-1,2,3-triazole unit, linked via a C-0 bond, were reacted with the symmetrical dienophile dimethyl acetylenedicarboxylate (DMAD), in view of minimizing regioselect-ivity problems (Scheme 28). 

Trimethylsilylketene and acyl isocyanates generate 4-trimethylsiloxy-l,3-oxazin-6-ones 12 in situ, which smoothly react with the enamines of cycloalkanones to give bicyclic 2-pyridones 13 <96TL(37)4977>. The heterocycles 12 also undergo the Diels-Alder reaction with dimethyl acetylenedicarboxylate or methyl propiolate to furnish substituted 2-pyridones <96TL(37)4973>. 

N-silylated imines 509 react with the Li salts of tosylmethylisonitriles to give 4,5-disubstituted imidazoles in moderate yields [93]. Acetylation of N-trimethylsilyl imines 509 with acetyl chloride and triethylamine affords 72-80% of the aza-dienes 510 these undergo readily Diels-Alder reactions, e.g. with maleic anhydride at 24 °C to give 511 [94] or with dimethyl acetylenedicarboxylate to give dimethyl pyridine-3,4-dicarboxylates [94] (Scheme 5.29). 

Roskamp reported29 a similar intramolecular Diels-Alder reaction accelerated by silica gel saturated with water. The reaction led to the ready construction of the 11-oxabicyclo [6,2,1] ring systems (Eq. 12.4). The intramolecular Diels-Alder reaction has also been investigated by Keay.30 The Diels-Alder reaction of 2,5-dimethylpyrrole derivatives with dimethyl acetylenedicarboxylate in water generated the corresponding cyclization products.31... 

Thermal cracking at 150°C of the dimer (mixed isomers) of the silole in presence of reactive dienophiles (maleic anhydride, tetracyanoethylene or dimethyl acetylenedicarboxylate) inevitably produced violent explosions arising from exothermic Diels-Alder reactions. 

A warning was given that the 5 molar solution in ether used as a solvent for Diels-Alder reactions would lead to explosions [1], Such a reaction of dimethyl acetylenedicarboxylate and cyclooctatetraene in this solvent exploded very violently on heating. The cyclooctatetraene was blamed, with no supporting evidence [2], It would appear desirable to find the detonability limits of the mixture with ether before any attempt is made to scale up. A safe alternative to lithium perchlorate/ether as a solvent for Diels-Alder reactions is proposed [3],... 

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). 

As already described for the all-carbon-Diels-Alder reaction, a hetero-Diels-Alder reaction can also be followed by a retro-hetero-Diels-Alder reaction. This type of process, which has long been known, is especially useful for the synthesis of heterocyclic compounds. Sanchez and coworkers described the synthesis of 2-aminopyridines [48] and 2-glycosylaminopyridines 4-144 [49] by a hetero-Diels-Alder reaction of pyrimidines as 4-143 with dimethyl acetylenedicarboxylate followed by extrusion of methyl isocyanate to give the desired compounds (Scheme 4.30). This approach represents a new method for the synthesis of 2-aminopyridine nucleoside analogues. In addition to the pyridines 4-144, small amounts of pyrimidine derivatives are formed by a Michael-type addition. 

The reaction of the same ylide 63 with dimethyl acetylenedicarboxylate (DMAD) in chloroform afforded the cyclazine 67, through aromatization of monoadduct 66 the azocine 69, which is formed through a second nucleophilic attack with ring expansion in the bis-adduct 68 and the pyrrolo derivative 71, which is formed by evolution of the bis-adduct 70 through a retro-Diels-Alder reaction (Scheme 3) <2001JOC1638>. 

Typically, the synthesis of block B involves the Diels-Alder reaction of 1,4-naphthoquinone with cyclopentadiene, followed by reduction and OH methylation to give 92 (Scheme 33). The next step involves a Ru-catalysed [2+2] cycloaddition of 92 with dimethyl acetylenedicarboxylate (DMAD), followed by epoxidation (MeLi, BuOOH) to give 94 as block B. 

Giguere performed tandem ene-intramolecular Diels-Alder reactions between 1,4-cyclohexadiene (29) and dimethyl acetylenedicarboxylate (26b) in sealed tubes in a commercial microwave oven (Scheme 9.6) [47]. 

In the course of investigation of reactivity of the mesoionic compound 44 (Scheme 2) the question arose if this bicyclic system participates in Diels-Alder reactions as an electron-rich or an electron-poor component <1999T13703>. The energy level of the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) orbitals were calculated by PM3 method. Comparison of these values with those of two different dienophiles (dimethyl acetylenedicarboxylate (DMAD) and 1,1-diethylamino-l-propyne) suggested that a faster cycloaddition can be expected with the electron-rich ynamine, that is, the Diels-Alder reaction of inverse electron demand is preferred. The experimental results seemed to support this assumption. 

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. 

At higher temperatures retro-Diels-Alder reaction may also occur in the opposite sense to addition, as in the reaction of methyl pyrrole-1-carhoxylate with dimethyl acetylenedicarboxylate at 200°, which affords acetylene and the pyrrole triester (56). The decomposition of the suspected intermediate Diels-Alder adduct (11) at 170° has been separately established. Compounds 19 and 20 are intermediates in similar addition-elimination reactions leading to pyrrole-l,3,4-triesters, in which removal of acetylene from the system makes the reaction sequence effectively irreversible. 

Norbornadiene adds typical dienophiles in a homo-Diels-Alder reaction whereby, for example, the adduct 86 is obtained with tetra-cyanoethylene. Dimethyl acetylenedicarboxylate and dicyanoacetyl-ene add to barrelene (bicyclo[2.2.2]octa-2,5,7-triene) in a similar way. °... 

Bicyclopropylidenes with two larger rings annelated at both cyclopropyl moieties are sufficiently well documented (Table 1). But compounds in which the larger ring bridges the two ends of a bicyclopropylidene are usually more highly strained and, as a consequence, not as easily accessible. The first such compounds 89 and 91 were obtained by Diels-Alder reaction of the bis(cyclo-propenyl) derivative 90 with dimethyl acetylenedicarboxylate (DMAD) and te-... 

Reaction of dimethyl acetylenedicarboxylate with A " -compounds in boiling xylene gave the unstable Diels-Alder adducts (65) which rearranged by a retro-Diels-Alder reaction to the aromatic seco-compound (67). Using dicyanoacety-lene at lower temperature, the adducts (66) have been isolated and these were converted, in boiling xylene, into the analogous aromatic seco-compound (68). No... 

As can be seen in the intramolecular cycloaddition (Section 8.03.5.1), the intermolecular Diels-Alder reactions between functionalized 2(l/f)-pyrazinones 83 and dimethyl acetylenedicarboxylate (DMAD) forming bicyclo adducts 84 has been shown to be significantly rate enhanced and increased in yields by using controlled microwave irradiation compared to the conventional thermal protocols (Scheme 21) <2002JOC7904>. The microwave-assisted Diels-Alder reactions of substituted 2(l//)-pyrazinones with ethene are significantly more effective utilizing prepressurized (up to 10 bar) reaction vessels <20040BC154>. 

Furthermore, the synthetic utility of 2,6-divinyl-l,4-dithiin 68 as a reactive diene in Diels-Alder reactions was reported with tetracyanoethylene, maleic anhydride, A -phenylmaleimide, and dimethyl acetylenedicarboxylate (DMAD) and allowed the preparation of various dihydrothianthrene derivatives (Equation 9) <2003S849>. 

The cycloaddition reactions of 368 (X = CO) with 7V-phenylmaleimide, p-benzoquinone, dimethyl acetylenedicarboxylate, and tetracyanoethylene afforded [4 + 2]-cycloadducts with endo-stereochemistry ethyl acrylate gave two isomers (probably endo and exo). l,4-Dihydro-l,4-oxidonaph-thalene (19) yielded the endo-exo isomer. The Diels-Alder reaction of 368 (X = SO2) with ethyl acrylate gave a mixture of isomers, from which the higher melting product could be isolated in pure form. ... 

The Wittig reaction of 6-methoxy-4-methylbenzofuran-2-carbaldehyde with methoxy-methylenephosphorane gave a 2 1 mixture of (E)- and (Z)-6-methoxy-2-(/3-methoxyvinyl)-4-methylbenzofuran, which was used directly in a Diels-Alder reaction with dimethyl acetylenedicarboxylate, a key step in the route to polyfunctional dibenzofurans (70AJC2119). The di-O-methyl derivative (397) of the lichen natural product strepsilin was synthesized by this route (Scheme 106) (72AJC545). 

Diphenylfuro[3,4-6 ]quinoxaline (207) has been obtained (70TL1409) from the phthalide (206) as a green crystalline, quite stable solid (m.p. 244-246 °C). In DMSO (deep blue solution), (207) reacts instantaneously with such dienophiles as maleic anhydride, maleimide, dimethyl acetylenedicarboxylate and others to give crystalline adducts which, when heated to or above their melting points, decompose giving a blue color presumably due to reversal of the Diels-Alder reactions. 

Although chromenes are not sufficiently reactive, 2/f-naphtho[ 1,2-6]pyrans (202) add reactive dienophiles such as dimethyl acetylenedicarboxylate in a Diels-Alder reaction. 

Nitrodienes undergo intermolecular Diels-Alder reactions with appropriate dienophiles. The resulting nitro compounds can then be cyclized via a nitrile oxide intermediate.49 Thus, the 2-chloroacrylonitrile Diels-Alder adduct of 8-nitro-l,3-octadiene was prepared and cyclized to give (105) as a 3 1 mixture of diastereomers (Scheme 30). The Diels-Alder adduct of dimethyl acetylenedicarboxylate and 8-nitro-l,3-octadiene cyclized exclusively at the conjugated double bond, activated by the ester groups. Similarly, the quinone Diels-Alder adduct (106) cyclized at the conjugated double bond reduction of the conjugated double bond permitted cyclization on the cycloalkenyl double bond. 

Compound B arises by way of a Diels-Alder reaction between compound A and dimethyl acetylenedicarboxylate. Compound A must therefore have a conjugated diene system. 

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