Dimethyl acetylenedicarboxylate DMAD

Dimethyl acetylenedicarboxylate (DMAD) (125) is a very special alkyne and undergoes interesting cyclotrimerization and co-cyclization reactions of its own using the poorly soluble polymeric palladacyclopentadiene complex (TCPC) 75 and its diazadiene stabilized complex 123 as precursors of Pd(0) catalysts, Cyclotrimerization of DMAD is catalyzed by 123[60], In addition to the hexa-substituted benzene 126, the cyclooctatetraene derivative 127 was obtained by the co-cyclization of trimethylsilylpropargyl alcohol with an excess of DMAD (125)[6l], Co-cyclization is possible with various alkenes. The naphthalene-tetracarboxylate 129 was obtained by the reaction of methoxyallene (128) with an excess of DMAD using the catalyst 123[62],... 

Dimethyl acetylenedicarboxylate (DMAD) has also been used to catalyse gramine alkylations (see Entry 7). It may function by both activating the dialkylamino leaving group and deprotonating the nucleophile[3]. 

The reactions of pyrroles with dimethyl acetylenedicarboxylate (DMAD) have been extensively investigated. In the presence of a proton donor the Michael adducts (125) and (126) are formed. However, under aprotic conditions the reversible formation of the 1 1 Diels-Alder adduct (127) is an important reaction. In the case of the adduct from 1-methylpyrrole, reaction with a further molecule of DMAD can occur to give a dihydroindole (Scheme 48) (82H(19)1915). 

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). 

The insertion reaction of dimethyl acetylenedicarboxylate (DMAD) into the S-S bond of a cyclic disulfido complex of niobium, Nb(S2)(S2CNEt2)3, takes place to give the corresponding dithiolene complex, Nb S2C2(C02Me)2 (S2CNEt2)3 (Scheme 56) [134]. 

The stereoselective catalyzed addition of water or methanol to dimethyl acetylenedicarboxylate (DMAD) was reported to yield oxalacetic acid dimethylester or dimethyl methoxyfumarate. The catalyst precursor cis-[Pd(PMe2Ph)2(solvent)2] [BFJj was prepared from ds-[PdCl2(PMe2Ph)2] and AgBp4 (Eq. 6.54). The analogous platinum complex was not effective, however [99]. 

Other interesting multicomponent sequences utilizing isocyanides have been elaborated by Nair and coworkers. In a recent example, this group exploited the nucleophilic nature of the isocyanide carbon, which allows addition to the triple bond of dimethyl acetylenedicarboxylate (DMAD) (9-90) in a Michael-type reaction (Scheme 9.19) [59]. As a result, the 1,3-dipole 9-91 is formed, which reacts with N-tosylimines as 9-92 present in the reaction vessel to give the unstable iminolactam 9-93. Subsequently, this undergoes a [1,5] hydride shift to yield the isolable aminopyrroles 9-94. In addition to N-tosylimine 9-92 and cyclohexyl isocyanide (9-89), substituted phenyl tosylimines and tert-butyl isocyanide could also be used here. 

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>. 

Dipolar cycloaddition reaction of thioisomilnchnones 204 with dimethyl acetylenedicarboxylate (DMAD) furnished adducts 205, which underwent extrusion of sulfur to give 2-substituted-7-phenyl-l,8-dioxo-l//,8//-pyrido[l,2-f]pyrimidine-5,6-dicarboxylates 206 (Scheme 14) <20000L581>. 

The treatment of 1,4-di hydro-2 7/-pyrido[ 2,3-< [ 1,2,4]triazine-3-thione 82 with dimethyl acetylenedicarboxylate (DMAD) in methanol at room temperature leads to the formation of 5-oxo-8,8a,9,10-tetrahydro-5//-4,4b,9,10-tetra-azaphenanthrene-7-carboxylic acid methyl ester 83 <1998IJH303> (Equation 5). 

Reaction of dimethyl acetylenedicarboxylate (DMAD) with extremely unstable mesomeric betaine 96, generated in situ from 95, gives in 30-36% yield of a 1 2 adduct, the structure of which was originally determined as 97 <1978CL1093>. However, a more recent reinvestigation based on the H and 13C NMR spectroscopy shows that the actual product is pyrazolo[l,5- ]azepine 98, formed probably by mechanism shown in Scheme 6 <1995JCM338>. 

Triazole-fused pyridopyrimidines can be prepared by reaction of aldehydes with the substituted pyridopyrimidine 309 (Equation 106). The pyrazole-fused derivative 311 can be prepared by the reaction of the sulfonimine 310 with dimethyl acetylenedicarboxylate (DMAD) (Equation 107) <1998H(47)871>. 

Treatment of 6-aminouracils 202 with dimethyl acetylenedicarboxylate (DMAD) affords the tricyclic pyrimidine derivatives 203 in excellent yields (Equation 20) <1998JCM502>. 

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. 

Heating of the sulfoxide 31 causes a Pummerer rearrangement generating the ylide 32, which could be trapped with dimethyl acetylenedicarboxylate (DMAD) giving the dihydrothiophene derivative 33 <06HC648>. 

The chemistry of pentathiepins has been extended to the pyrrolo-fused derivative 155. Reaction of 155 with dimethyl acetylenedicarboxylate (DMAD) and triphenylphosphine at room temperature gave the fused 1,4-dithiin derivative 156 in high yield <06OL4529>. 

Three reactions of 1 successively with diethyl fumarate, maleic anhydride, and dimethyl acetylenedicarboxylate (DMAD) are highly representative of the variety of experimental conditions used in the GS/MW process [26, 27]. Continuous MW irradiation (CMWI) with an incident power of 120 W for 1 min led to a high increase in temperature (Tmax> 300 °C). Adduct 4 was obtained almost quantitatively (Tab. 7.1, entry 1), whereas only traces of adducts 5 and 6 were detected. When the incident power was reduced (30 W) and sequential MW irradiation (SMWI) was used, adducts 5 and 6 were obtained in good yield (Tab. 7.1, entries 3 and 4). This controlled irradiation enabled the temperature to be limited (Tmax < 200 °C) and avoided the retro-DA reaction. In the reaction between 1 and diethyl fumarate similar SMWI conditions also gave the adduct 4 in high yield (Tab. 7.1, entry 2). 

Ylides forming from the thermolysis of compound 59 (R1, R2 = Me, R3 = Ar, R4 = OMe) reacted also with dimethyl acetylenedicarboxylate (DMAD) or diethyl azodicarboxylate (DEAD) <2003TL5029> in the presence of aldehydes, quinones <2001TL2043>, or ketones <20020L2821, 20000L3501> to give 2,5-dihydrofuran derivatives, for example, 67 (Rs = Me, Et). 

The cycloaddition reactions of [(thioacyl)methylene]thiadiazoles 83 with dimethyl acetylenedicarboxylate (DMAD) under UV irradiation at room temperature gave the spiro[3/7-l,3,4-thiadiazoline-2,4 -477-thiopyrans] 84 in 50-60% yields (Equation 23) <2003EJ02480>. 

When the C=S bond is conjugated with double or triple bonds, thioketones can also behave as heterodienes93 104 towards dienophiles. If thioketone contains an aromatic ring, the [4+2] cycloaddition can be followed by 1,3-protot-ropy to restore the ring aromaticity,105 108 forming lH-2-benzothiopyrans as shown in Scheme 13, where 4,4 dimethoxythiobenzophenone reacts with the dienophile dimethyl acetylenedicarboxylate (DMAD).105... 

Intermolecular Reactions Dimethyl acetylenedicarboxylate (DMAD) is frequently used as an alkyne dipolarophile (23, 24, 126b, 152, 241, 333). 

For example, it was reported (223) that unstable acyl nitronate (172) was detected by its trapping with dimethyl acetylenedicarboxylate (DMAD) (Scheme... 

Reactions of zirconacyclopentadienes with dimethyl acetylenedicarboxylate (DMAD) proceed to give benzene derivatives in high yields, as shown in Eq. 2.48 [7b,7k],... 

This route relies on 1,3-dipolar cycloaddition reactions a series of dihydropyrrolizines 213 were synthesized by heating the proline derivatives 211 with dimethyl acetylenedicarboxylate (DMAD) at 130-140 °C in the presence of acetic anhydride. Reaction between 211 and AczO provides the mesoionic oxazalone intermediate 212 which adds to dimethyl acetylenedicarboxylate, giving a cycloadduct, which undergoes spontaneous decarboxylation leading to 213 (Scheme 50) <1998JME4744, 1977JME812>. 

The reaction of nitrone 99 with dimethyl acetylenedicarboxylate (DMAD) at room temperature in CH2CI2 gave a colorless crystalline product that has been identified as trimethyl 3,3-dimethyl-l-phenyl-377-pyrrolo[l,2-f]imidazole-5,6,7-tricarboxylate 100. A mechanism explaining this transformation has been reported (Equation 13) <2001RCB882>. 

The Michael addition of ylide 132 with dimethyl acetylenedicarboxylate (DMAD) has been investigated < 1998T3913>. Depending on the solvent, different adducts are isolated. Using acetonitrile, 3-methylthiazolo[3,2-f][l,2,3]triazole 105... 

Quaternarization of 43 with phenacyl bromide produced the corresponding salt 51 that was reacted with several triple-bond-containing dipolarophiles (Scheme 4), such as dimethyl acetylenedicarboxylate (DMAD) or alkyl propiolates to give tricyclic compounds 52, 53 and 54, 55. Compound 51 reacted also with acrylonitrile as dipolaro-phile in MeCN/K2C03 to give the cycloadduct 56 as a mixture of diasteroisomers. 

Cycloaddition of 113 with two molecules of dimethyl acetylenedicarboxylate (DMAD) gives 114 in 47% yield (Equation 9) <1996H(42)53>. 

Thus, derivatives of structure 84 were treated with iV-methylmaleinide to give the cycloadducts 85 in high yields. In accordance with the concerted nature of this process, the pyrazoles and pyrrolidine-dione had a rxr-fusion. Similar cycloaddition was also experienced with dimethyl acetylenedicarboxylate (DMAD) to afford 86 containing the partially unsaturated pyrazole ring. 

As substrates, pyrrolotetrazoles 12 and 13 have been used in a variety of electrophilic substitutions. It has been observed that with the exception of bromination, monosubstitution (acetylation, benzoylation, carbamoylation, formylation, azo coupling, nitrosation, and reaction with dimethyl acetylenedicarboxylate (DMAD)) occurs preferentially at C-5, if the 5- and 7-positions are both available. Upon bromination, double substitution occurs at C-5 and C-7 with the same substrates. It has further been observed that substitution at C-7 occurs only if C-5 is occupied <2001J(P1)729>. 

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. 

The salt 2 reacts with dimethyl acetylenedicarboxylate (DMAD) in the presence of CsF (or NaH) to form an isoxazolidine (4), which is formally derived from N-methyl-C-phenylnitrone. This reaction is believed to involve removal of the proton from the OH group of 2 to give b, which cycloadds with DMAD to provide c, the immediate precursor to 4. 

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