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],... 

The cyclohexadiene derivative 130 was obtained by the co-cyclization of DMAD with strained alkenes such as norbornene catalyzed by 75[63], However, the linear 2 1 adduct 131 of an alkene and DMAD was obtained selectively using bis(maleic anhydride)(norbornene)palladium (124)[64] as a cat-alyst[65], A similar reaction of allyl alcohol with DMAD is catalyzed by the catalyst 123 to give the linear adducts 132 and 133[66], Reaction of a vinyl ether with DMAD gives the cyclopentene derivatives 134 and 135 as 2 I adducts, and a cyclooctadiene derivative, although the selectivity is not high[67]. 

The reaction of l,4-bis(trimethylsilyl)-l,3-butadiyne (174) with disilanes, followed by treatment with methylmagnesium bromide, produces i,l,4,4-tetra(-trimethylsilyl)-l,2,3-butatriene (175) as a major product[96]. The reaction of octaethyltetrasilylane (176) with DMAD proceeds by ring insertion to give the six-membered ring compounds 177 and 178[97], The l-sila-4-stannacyclohexa-2,5-diene 181 was obtained by a two-step reaction of two alkynes with the disilanylstannane 179 via the l-sila-2-stannacyclobutane 180[98],... 

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]. 

Acetylenic aldehydes and ketones or their chloroenone equivalents have been used (58GEP1040040), as have acetylenic esters such as DMAD (e.g. 76JOC1095, 73CPB2014). 

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). 

A -Amino- and A-substituted amino-pyrroles readily undergo Diels-Alder additions and add to activated alkynes at room temperature. The resulting azanorbornadienes extrude A-aminonitrenes and this forms the basis of an unusual synthesis of benzene derivatives (81S753,81TL3347). It has been found that ethyl/3-phenylsulfonylpropiolate (135) is a superior dienophile to DMAD (Scheme 50). 

Aminothiophenes and 3-aminobenzo[Z)]thiophene undergo thermal [2 + 2] cycloaddi-tion reactions with activated alkynes. The reactions are solvent dependent thus in non-polar solvents at -30 °C, 3-pyrrolidinothiophene adds to DMAD to give a [2 + 2] cycloadduct which is ultimately converted into a phthalic ester. In methanol, however, a tricyclic product is formed (Scheme 54) (81JOC424. ... 

The benzo[Z)] fused systems participate in a number of [2 + 2] cycloaddition reactions (81JOC3939, 81TL521). The photocycloaddition products of benzo[Z)]thiophenes and DMAD are dependent on the irradiation wavelength (Scheme 56). 

Pyrrole 1-oxides are known they undergo 1,3-dipolar cycloaddition with DMAD and with A-phenylmaleimide (80TL1833). 

Thermal reactions of 1,4,2-dioxa-, 1,4,2-oxathia- and 1,4,2-dithia-azoles are summarized in Scheme 1. The reactive intermediates generated in these thermolyses can often be trapped, e.g. the nitrile sulfide dipole with DMAD. 

In the alternative approach.the 1,3-dipolar system can be constructed in several ways. Treatment of a-chloroacylhydrazones of diaryl ketones and certain aralkyl and dialkyl ketones (382) with NaH in anhydrous THF gives l-(disubstituted methylene)-3-oxo-l,2-diazetidinium inner salts (383). Reaction of (383) with DMAD in methylene chloride gave (384), a 2 1 adduct with loss of CO. Double bond migration in (384) occurred on heating to give (385). The intermediate in the cycloaddition was found to be (386), which on heating lost CO to form a new ylide system which in turn underwent reaction with more DMAD <81JA7743). 

However, depending on the nature of the initial heterocycle, rearrangements are possible. Alkylation of thiazole to form the thiazolium salt (390) and generation of the ylide (391) with triethylamine in the presence of DMAD gave not (392) but the isomeric product (393) by the rearrangement indicated (76JOC187). Rearrangements of these types are described in Chapters 4.07 and 4.19. 

Reaction of the A-nitrosoglycine (394) with acetic anhydride gave the anhydro-5-hydroxy-l,2,3-oxadiazolium hydroxide (395). Reaction with DMAD resulted in formation of the intermediate 1 1 cycloadduct (396) which was not isolated and which lost CO2 under the thermal reaction conditions to give dimethyl l-phenylpyrazole-3,4-dicarboxylate (397) (83MI40300). This reaction is capable of considerable variation in terms of the substituents... 

A similar product is obtained from the reaction of anhydro-4(5)-hydroxy-l,2,3-triazolium hydroxide (398). In this case reaction with DMAD occurred in 1 hour in boiling benzene. Extrusion of methyl isocyanate from the initial 1 1 cycloadduct (399) occurred during the reaction giving (400). 

Reaction of thiazoles with DMAD illustrates the overall reaction and the rearrangements which may be encountered. Thiazole or 2-methylthiazole (411 R=H and Me, respectively) in DMF reacted with DMAD to give an initial 1,4-dipolar species (412). Reaction with a second DMAD gave the 1 2 molar adduct, presumably (413). Ring opening to (414), followed by cyclization in the alternative mode, resulted in the formation of (415), the structure of which (R = Me) was established by X-ray analysis (78AHC(23)263) (see also Chapter 4.19). 

Solvent has an important influence on the course of this cycloaddition, and in the reaction of 2,5-dimethylthiazole with DMAD in DMF the product analogous to (415) was obtained. However, in DMSO or acetonitrile a thiazolo[3,2-a]azepine was formed in addition to this product, whereas with THF, dichloromethane or nitromethane, only the thiazoloazepine was isolated. 

Dipoles can also be built into heterocyclic systems, and though of limited use, they may also be utilized for the synthesis of [5,6] ring-fused systems. Reaction of 2 3H)-benzothiazolethione with (chlorocarbonyl)phenylketene in warm anhydrous benzene gave the heteroaromatic betaine (416). On heating with DMAD in boiling toluene the tricyclic pyridinone (418) was obtained, presumably by elimination of COS from the intermediate cycloadduct (417) (80JOC2474). 

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