Acetylenedicarboxylates cycloaddition

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). 

Thiophene, 3-pentadeuterophenyl-chemical shifts, 4, 730 Thiophene, 2-phenyl-oxidation, 4, 800 phototranspositions, 4, 743 rearrangement, 4, 42 reduction, 4, 775 synthesis, 4, 865, 914 UV spectrum, 4, 735 Thiophene, 3-phenyl-photochemical rearrangements, 4, 735 phototranspositions, 4, 743 lsmeier formylation, 4, 759 Thiophene, 2-pivaloyl-Birch reduction, 4, 775 Thiophene, polybromo-reactivity, 4, 829 Thiophene, polylithio-synthesis, 4, 831 Thiophene, (propargylthio)-rearrangement, 4, 746 Thiophene, 2-(3-pyridinyl)-synthesis, 4, 781 Thiophene, 2-(5-pyrimidinyl)-synthesis, 4, 781 Thiophene, 3-pyrrolidinyl-cycloaddition reactions, 4, 68 with dimethyl acetylenedicarboxylate, 4, 788-789... 

Dimethyl acetylenedicarboxylate reacts similarly to give 74. Again the cycloaddition is presumed to be the initial step (65b). 

Enamino ketones and esters also react with dimethyl acetylenedicarboxylate (67). Again cycloaddition appears to occur and the unstable cyclobutene intermediates rearrange to give insertion of two carbon atoms. 

Dimethyl acetylenedicarboxylate (80) undergoes initial 1,2 cycloaddition with acyclic enamines to form cyclobutene intermediates which immediately decompose into acyclic dienaminodiesters (94,95). When an acyclic n/c-enediamine is used instead of a simple acyclic enamine, a dienediamino-diester is produced via a cyclobutene intermediate (95a). A cyclization reaction of dimethyl acetylenedicarboxylate with an acyclic enaminoketone... 

The reaction of methyl propiolate (82) with acyclic enamines produces acyclic dienamines (100), as was the case with dimethyl acetylenedicarboxylate, and the treatment of the pyrrolidine enamines of cycloheptanone, cyclooctanone, cycloundecanone, and cyclododecanone with methyl propiolate results in ring enlargement products (100,101). When the enamines of cyclohexanone are allowed to react with methyl propiolate, rather anomalous products are formed (100). The pyrrolidine enamine of cyclopentanone forms stable 1,2-cycloaddition adduct 83 with methyl propiolate (82). Adduct 83 rearranges to the simple alkylation product 84 upon standing at room temperature, and heating 83 to about 90° causes ring expansion to 85 (97,100). 

Vinyl ethers undergo many cycloaddition reactions similar to those which take place with enamines. In general, however, these cycloaddition reactions with vinyl ethers take place less readily than those with enamines. These reactions include cycloaddition of vinyl ethers with ketene (200-205), phenyl isocyanate (206), sulfene (207,208), methyl acrylate (209), diethyl acetylenedicarboxylate (210), and diphenylnitrilimine (183). 

A -Alkyl-l,2-dihydropyridines that are not stabilized by electron-withdrawing groups on the ring could behave as dienophiles towards alkynes. For example, N-methyl-l,2-dihydropyridine 41a reacts with dimethyl acetylenedicarboxylate (32) to give [2 + 2] cycloaddition product 42, which rearranges to give the azocine derivative 43 [74JCS(P1)2496],... 

Cycloaddition of 4-nitrofurylmethylquinolinium bromide 88 with dimethyl acetylenedicarboxylate, nitrostyrene, ethyl 3-(5-nitro-2-furyl)-2-propenoate and l-phenyl-3-(5-nitro-2-furyl)-2-propenone afforded the corresponding furylbenzoindolizine 89 (86CCC412) (Scheme 16). 

The synthesis of monocyclic thiepins from thiophene and dimethyl acetylenedicarboxylate is often accompanied by the loss of sulfur. In particular, in cases where room temperature is required for efficient rates of cycloaddition and rearrangement76 (see Section 2.1.3.3.), the desulfurization reaction proceeds rather quickly with the consequence that thiepin formation can be monitored by low temperature HNMR spectroscopy, but the products cannot be isolated.76 - 78 However, in the case of thiepin 1 where R1 = R2 = C02Me and R3 = H, refluxing toluene is necessary for the extrusion of sulfur.78... 

Occasionally, these thermally induced reactions give rise to complex mixtures of products and hence are not of any great preparative value. For example, 1-mcthylindolc with dimethyl acetylenedicarboxylate in acetonitrile yields seven products including the 1-benzazepine 8 (14%), the 1-methyl derivatives of the cis- and /rwK-indolylacrylates 3. a [4 + 2] cycloadduct of the 1-benzazcpinc with the alkyne dicster (see Section 3.2.2.5.3.), and dimethyl l-mcthyl-2-(l-methylindol-3-yl)-2,3-dihydro-l //-l-benzazepinc-3,4-dicarboxylate (9).21 This last product, which is the major product if the cycloaddition is carried out in acetonitrile containing trace amounts of water,21 has been obtained earlier.143 but was incorrectly formulated. 

The diazepines 13 react with dimethyl acetylenedicarboxylate to yield mixtures of the pyrazole 19 and the benzene derivatives 18. The reaction proceeds by cycloaddition to yield 14, followed by valence isomerization to the 1,2-diazonines 15, a further valence isomerization to 16, a Second cycloaddition to give 17 and, finally, fragmentation."... 

It is well-known that cycloaddition of dimethyl acetylenedicarboxylate with six-membered en-... 

In numerous synthetic studies,9" 6 100 it has been demonstrated that porphyrins react at the chromophore periphery in cycloaddition reactions, rearrangements, conjugative additions and substitution reactions to yield interesting porphyrin derivatives. Thus, metal-free protoporphyrin IX dimethyl ester reacts in Diels-Alder reactions108a b with dienophilcs like ethenetetra-carbonitrile and acetylenedicarboxylates at the diene structural parts to yield, according to the reaction conditions, the corresponding monoadducts 2 and 3 (see also Section 1.2.) and bisadducts 1 (see also Section 1.4.), respectively. 

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). 

Thiazolotriazines 636 (R = CO,Me) were prepared [84JCS(P1)2707] by cycloaddition of dimethyl acetylenedicarboxylate with triazine derivative 632. Derivatives of thiazolo[3,2-b][l,2,4]triazin-3,7-diones 637 have been formed (74JPR163) on reaction with aromatic aldehydes and diazonium salts to give 636 (R = Ar) and 638, respectively. Regioselective catalyzed... 

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... 

Pyrroles can also be prepared by 1,3-dipolar cycloaddition of C-trimethylsilyl amides such as 1497 with dimethyl acetylenedicarboxylate in boihng toluene to give, via the azomethinimide 1498, 78% 1499 [45]. On employing a threefold excess of dimethyl acetylenedicarboxylate the cycloadduct 1499 is obtained in nearly quantitative yield [45] (Scheme 9.26). 

Krapcho and Vivelo have described a new formal total synthesis of tropinone (124) and ( )-cocaine (98) (94). Cycloaddition of IV-methylpyrrole (182) and acetylenedicarboxylic acid leads to 183, which is hydrogenated to 184. The diacid mixture 184 is refluxed in MeOH/HCl to yield the diester mixture 185. Addition of this to an excess of metallic sodium in liquid ammonia at — 78°C leads to the N-methylpyrrolidine derivative 186 (cf. 95), whose diethyl analog 147 has earlier been converted to tropinone (124) and (+)-cocaine (98) (78-80) (Scheme 13). 

Reinhoudt et al.53) have reported the first synthesis of a monocyclic thiepin stabilized by electronic effects of the substituents. This synthesis utilizes the idea described in Section 2.3.3. 3-Methyl-4-pyrrolidinothiophene (85a) was treated in deuteriochloroform at —30 °C with dimethyl acetylenedicarboxylate. H-NMR monitoring of the reaction indicated that a [2 + 2]cycloaddition proceeded slowly at this temperature giving the 2-thiabicyclo[3.2.0]heptadiene (86a) which rearranged via ring opening of the cyclobutene moiety to the 4-pyrrolydinylthiepin (87a). At the... 

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). 

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>. 

---