Dimethyl acetylenedicarboxylate, addition

Few isothiazoles undergo simple cycloaddition reactions. 4-Nitroisothiazoles add to alkynes (see Section 4.17.7.4). With 5-thiones (84) and dimethyl acetylenedicarboxylate, addition to both sulfur atoms leads to 1,3-dithioles (85) (77SST(4)339, 80H(14)785, 81H(16)156, 81H(16)595). Isothiazol-3-one 1-oxide and the corresponding 1,1-dioxide give normal adducts with cyclopentadiene and anthracene (80MI41700), and saccharin forms simple 1 1 or 1 2 adducts with dimethyl acetylenedicarboxylate (72IJC(B)881). 

Methyl- and 2,3-dimethylquinoxaline also undergo interesting addition reactions with dimethyl acetylenedicarboxylate. Addition of 2-methylquinoxaline to two molecules of the ester results in the formation of the isomeric azepino[l,2-a]quinoxalines 61 and 62. Addition is accom-... 

An interesting new synthesis of azulenes has been developed that involves the [6 + 4] cycloaddition of NiV-diethyl-l-butadienylamine to fulvenes. The Diels-Alder product of dimethyl acetylenedicarboxylate addition to the azulene formed from dimethylfulvene possesses structure (234), whose n.m.r. spectrum indicated it to be a mixture of conformational isomers. The high barrier (AG ss 18—20 kcal... 

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],... 

Treatment of 192 with dimethyl acetylenedicarboxylate yields a thiophene derivative (195) when R = Ph and a 2-p3Tidone (1S>6) derivative when R = H (Scheme 100). The proposed mechanism involves the formation of a mesoionic derivative (193) initially further dipolar addition yields adduct 194, the decomposition of which is dependent on the R substituent as described for related compounds (435). ... 

Like pyridines (334), thiazoles undergo addition reactions with dimethyl acetylenedicarboxylate leading to 2 1 molar adducts, the structure of which has been a matter of controversy (335-339). 

Both terminal and nonterminal acetylenes have been used. Activating groups oL to the acetylenic bond have included sulfone (131-135), sulfoxide (134), ester (28,133-139), and ketone (134,140). Whether adduct 183 Is designated as cis or trans depends on the investigators and the particular compound. If the addition reaction is carried out in aprotic solvents, the major isomer is 183 formed by cis addition (135,138,139). For example, the addition of aziridine to dimethyl acetylenedicarboxylate (182, X, Y = CO2CH3) in dimethyl sulfoxide (135) gave 75 % of a mixture containing 95 % of the Chester 185. Collapse of the intermediate zwitterion intermediate 186... 

Methyl pyrrole-l-carboxylate (14) and hot dimethyl acetylenedi-carboxylate give trimethyl pyrrole-1,3,4-tricarboxyIate (15) and acetylene, presumably through the addition-elimination sequence shown. Dimethyl acetylenedicarboxylate and 1-methylpyrrole com-... 

Addition o/ a Second Mole of Dimethyl Acetylenedicarboxylate to the Initial Zwitterion... 

Pyridine and dimethyl acetylenedicarboxylate in methanol yield - a mixture of (33) and (34). It is tempting to assume that a zwitterion (30) is first formed and that this then adds a proton followed by a methoxide ion (Michael addition) under the influence of both the positive charge on the ring and the assisting ester group. The resulting structure (31) could then add another molecule of the ester and cyclize, as indicated, to (32). Subsequent aromatization accompanied by loss of one, or the other, substituent at position 3 would lead to the two products, (33) and (34), actually isolated. 

Methylpyrrole and dimethyl acetylenedicarboxylate interact at 0°C to give a 1 2 adduct which is now known " to have structure (48). It is formed by addition of the ester across the 2,5-positions of the pyrrole yielding (47), which was not isolated but combined with a second molecule of the ester across the 2,7-positions accompanied by scission of the 4,7-bond as indicated. This adduct (48) was oxidized by bromine in methanol to trimethyl l-methylindole-2,3,4-tricarboxyl-ate and reacted further with hot dimethyl acetylenedicarboxylate. 

Indole on standing with dimethyl acetylenedicarboxylate for 74 days gave a 63% yield of the carbazole (55) along with 7-8% of each of two 1 3 molar adducts and about 2% of a 2 1 molar adduct for which no structures were suggested. It was proposed that the fumarate (56) was an intermediate, as it gave the carbazole (55) with the ester. However, as the yield in this last reaction, 26%, is much less than that obtained in the direct addition, it is very unlikely that (56) is, in fact, an intermediate, and an alternative reaction scheme as suggested here may be applicable. 

Methyloxindole and dimethyl acetylenedicarboxylate with me-thanolic sodium methoxide gave two addition products which from their ultraviolet absorption spectra are suspected to be the geo-... 

Pyrazole and its 3,5-dimethyl and 3,4,5-trimethyl derivatives combined with two moles of dimethyl acetylenedicarboxylate giving products of similar ultraviolet absorption spectra to the parent pyrazoles. These products [e.g., (69)] do not possess the strong broad absorption at ca. 3.20 /u, characteristic of the bonded N—H group which is present in the parent pyrazoles and are formed by two successive Michael addition reactions. In the case of 3,5-dimethylpyra-zole, the initial fumarate (68) has been isolated and possessed a more conjugated type of absorption spectrum to those of the dipyrazolyl-... 

Diels and Meyer found that the exothermic reaction obtained on dropping pyridine into dimethyl acetylenedicarboxylate in methanol gave a mixture of the indolizine (108) and a methoxymethylindolizine formulated as (109), and some dimethyl fumarate and dimethyl methoxyfumarate. Later workers - obtained only the methoxymethylindolizine in rather poor yield. The indolizine (108) has also been isolated from the products obtained when the addition reaction was carried out in ether, but in this case the course of the reaction was very susceptible to the presence of impurities in the ether, and the results indicated that ethanol was necessary as a reactant. ... 

The addition of dimethyl acetylenedicarboxylate to 5-/er/-butyl-Ar,Ar,Ar, Ar -tetramethyl-2-aza-pentalene-1,3-diamine (20) is frontier orbital rather than charge controlled, and results initially in attack at the 3a-position to give, via a dipolar intermediate, tricycle 21, which undergoes valence isomerization to the cyclopent[c]azepine 22.107... 

In contrast, addition of dimethyl acetylenedicarboxylate to cyclopent[6]azepine (6) is slow and furnishes, in 53% yield, a mixture of the dimeric 1 2 adduct 7 (red crystals), the 1 3 adduct 8 (yellow oil), and an unidentified purple oil.2 Surprisingly, cyclopent[6]azcpine fails to react with other common dienophiles such as ethenetetracarbonitrile, diethyl maleate and chlorosulfonyl isocyanate. 

The thermal addition of dimethyl acetylenedicarboxylate to indoles, unlike the photocycloaddition (see Section 3.2.1.4.1.1.), proceeds via a polar stepwise process to yield, initially, 3,4-benzo-2-azabicyclo[3.2.0]hepta-3,6-dienes which in some cases are isolable,13 141 but which, in general, ring open in situ to give the indolylacrylates 3 and/or undergo electrocyclic ring expansion to 1-benzazepines.21... 

Indole and dimethyl acetylenedicarboxylate yield 2-(indol-3-yl)-2,3-dihydro-l//-l-ben-zazepine (mp 240-242 C) by addition of indole to the initially formed l//-l-benzazepinc,21 whereas 1,3-dimethylindole (10, R = H) fails to react with the diester under a variety of conditions.145 However, in the presence of boron trifluoride-diethyl ether complex at room tem-... 

In the presence of a catalytic amount of concentrated hydrochloric acid, dimethyl 1 -methyl-1 H-l-benzazepine-3,4-dicarboxylate (1) undergoes addition of 1-methylindole, probably via initial protonation of the enaminic 3-position of the benzazepine ring, to give the indolyldihydrobenz-azepine 2.21 In fact, adduct 2 is the major product from the reaction of 1-mcthylindole with dimethyl acetylenedicarboxylate in acetonitrile. Similar adducts are obtained with indole. 

The sodium salt of tropone tosylhydrazone (14.8 g, 50 mmol) and dimethyl acetylenedicarboxylate (14.6 g, 100 mmol) in bis(2-methoxyethyl) ether (70 mL) was heated at 120 C for 15 min. The solution was poured into H20 and the mixture extracted with Et20. The extract was washed with H20, followed by brine, and dried (Na2S04). The solution was evaporated to yield the crystalline product (4.01 g), together with an oil. The latter was chromatographed (silica gel) to give additional product (0.405 g) total yield 4.415 g (34%) mp 153-154°C (cyclohexane). 

The addition of two molecules of dimethyl acetylenedicarboxylate to the imidazole 1 results in the ring-expanded product 2.154... 

Treatment of 1,2,4-triazines 91a-91e with the electron-deficient die-nophile dimethyl acetylenedicarboxylate gave products, depending on the substituents [77LA( 10) 1718]. Pyrrolo-[2, -/][ ,2,4]triazines 92 were obtained via [4 + 2]-cycloaddition [77LA(9)1413, 77LA( 10)1718] with 91, but interaction with 91b in the absence of solvent gave, in addition to 92, the pyrido[2,l-/][l,2,4]triazine 93 and [l,3]oxazino[2,3-/][l,2,4]-triazine 94. In case of 91a pyridine and benzene derivatives were also formed in addition to 92 (Scheme 23). 

Examples of this ring system were synthesized by nucleophillic addition of 613 to dimethyl acetylenedicarboxylate in moist solvents to afford the ylidene-substituted oxazolo[3,2-rf][l,2,4]triazine 614. Its X-ray crystal structure has been described [90JCR(S)354] (Scheme 126). 

It has been shown that, on treatment with base, 1-aminopy-ridinium iodide undergoes 1,3-dipolar addition with ethyl propiolate or dimethyl acetylenedicarboxylate thus the N-aminoheterocycles may serve as convenient starting materials for the synthesis of a variety of unusual fused heterocycles.8... 

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 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]. 

In a manner similar to OsH(OH)(CO)(P Pr3)2, the hydride-metallothiol complex OsH(SH)(CO)(P Pr3)2 adds Lewis bases that are not bulky such as CO and P(OMe)3 to give the corresponding six-coordinate hydride-metallothiol derivatives OsH(SH)(CO)L(P Pr3)2 (L = CO, P(OMe)3). OsH(OH)(CO)(PiPr3)2 and OsH(SH)(CO)(P Pr3 also show a similar behavior toward dimethyl acetylenedi-carboxylate. Treatment of OsH(SH)(CO)(P Pr3)2 with this alkyne affords 6sH SC(C02Me)CHC(OMe)6 (CO)P Pr3)2, which is the result of the tram addition of the S—H bond to the carbon-carbon triple bond of the alkyne. Phenyl-acetylene, in contrast to dimethyl acetylenedicarboxylate, reacts with OsH(SH) (CO)(P Pr3)2 by insertion of the carbon-carbon triple bond into the Os—H bond to give the unsaturated alkenyl-metallothiol derivative Os ( )-CH=CHPh (SH) (CO)(P Pr3 )2, the inorganic counterpart of the organic a, (3-unsaturated mercaptans (Scheme 46).92... 

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. 

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. 

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