DMFDMA dimethyl acetal

In 1971, Batcho and Leimgruber introduced a new method for the synthesis of indoles. For example, condensation of o-nitrotoluene (5) with N,N-dimethylformamide dimethyl acetal (6) (DMFDMA) was followed by reduction of the rrans-P-dimethylamino-2-nitrostyrene (7) which resulted to provide the indole (8). ... 

The condensation between enaminones and cyanoacetamide is a well-established method for the synthesis of 2-pyridones (see c, Scheme 2, Sect. 2.1), and the use of malonodinitrile instead of the amide component has also been shown to yield 2-pyridones [39-41]. Recently, Gorobets et al. developed a microwave-assisted modification of this reaction suitable for combinatorial synthesis, as they set out to synthesize a small library of compounds containing a 2-pyridone scaffold substituted at the 3, 5, and 6-positions [42]. The 2-pyridones were prepared by a three-component, two-step reaction where eight different carbonyl building blocks were reacted with N,N-dimethylformamide dimethyl acetal (DMFDMA) to yield enaminones 7 (Fig. 2). The reactions were performed under solvent-free conditions at el-... 

We also investigated reaction of 4-hydroxycoumarin with an excess of Ar,Ar-dimethylformamide dimethyl acetal (DMFDMA) which afforded the corresponding 3-(dimethylaminomethylene)-chromane-2,4-dione derivative 72. The structure was again confirmed by IR, NMR, and MS analyses. 

The groups of Giacomelli and Taddei have developed a rapid solution-phase protocol for the synthesis of 1,4,5-trisubstituted pyrazole libraries (Scheme 6.194) [356]. The transformations involved the cyclization of a monosubstituted hydrazine with an enamino-/8-ketoester derived from a /8-ketoester and N,N-dimethylformamide dimethyl acetal (DMFDMA). The sites for molecular diversity in this approach are the substituents on the hydrazine (R3) and on the starting j3-keto ester (R1, R2). Subjecting a solution of the /8-keto ester in DMFDMA as solvent to 5 min of microwave irradiation (domestic oven) led to full and clean conversion to the corresponding enamine. After evaporation of the excess DMFDMA, ethanol was added to the crude reaction mixture followed by 1 equivalent of the hydrazine hydrochloride and 1.5 equivalents of triethylamine base. Further microwave irradiation for 8 min provided - after purification by filtration through a short silica gel column - the desired pyrazoles in >90% purity. 

In Scheme 6.230, the multistep synthesis of 2,3-dihydro-4-pyridones is highlighted [411]. The pathway described by Panunzio and coworkers starts from a dioxin-4-one precursor, which is readed with 2 equivalents of benzyl alcohol under solvent-free microwave conditions to furnish the corresponding /1-diketo benzyl esters. Subsequent treatment with 1 equivalent of N,N-dimethylformamide dimethyl acetal (DMFDMA), again under solvent-free conditions, produces an enamine, which is then cyclized with an amine building block (1.1 equivalents) to produce the desired 4-pyridinone produds. All microwave protocols were conducted under open-vessel conditions using power control. 

In the first reported syntheses <92T1039> of either of the fused indole heterocycles shown in Equation (26), dihydropyrano[3,2-ej- and [2,3-/]indoles (53) and (54) were prepared from a mixture of nitrodihydrobenzopyrans via condensation with DMFDMA (DMF dimethyl acetal) followed by reductive cyclization of the resulting /f-aminostyrene derivatives. The isomers were separated by flash chromatography. 

Diethyl acetone-l,3-dicarboxylate (1) reacts with N,N-dimethylforma-mide dimethyl acetal (DMFDMA) in ethanol at room temperature to give diethyl l-dimethylamino-3-oxobut-l-ene-2,4-dicarboxylate (2), which was used without isolation and purification. To this mixture 1 equivalent of a monosubstituted hydrazine was added and then stirred at room temperature or heated under reflux for several hours to form intermediates 3, which were, without isolation, cyclized into 1-substituted 4-ethoxycarbonyl-5-(ethoxycarbonylmethyl)pyrazoles 4 in 24-71% yield (08ACSil019) (Scheme 1). 

Diphenyl-l,3,5-pentanetrione (45) with 1 equivalent of N,N-dimethylacetamide dimethyl acetal (DMADMA) yielded 5-benzoyl-2-phenil-6-methyl-4-pyranone (49). Pyranone 49 with DMFDMA yielded 50, which was converted to 2,5-diphenyl-lH,4H-pyrido[4,3- 7]pyrane-4-one (51) by cyclization of compound 50 with aqueous ammonia. This reaction was performed in DMF at 80 °C and the product precipitated from the mixture (Scheme 19). 

There are no detailed reports on the mechanism of the Bateho-Leimgruber process, but it is proposed below. In the presence of the base, o-nitrotoluene is coupled with iV.A dimethylformamide dimethyl acetal [DMFDMA, Me2NCH(OMe)2] to offer the dimethylamino imine. Hydrogenation then reduces the nitro group to aniline. When workup with an acid, cyclization and re-aromatization then delivered the indole. 

Two pathways for the preparation of 1,4-dihydropyridazine derivatives were envisaged. According to the first, dimethyl 3-oxopentane-l,5-dioate (dimethyl acetone-1,3-dicarboxylate) (1) was treated in ethanol and sodium acetate at 0 °C with acidic aqueous diazonium salts, prepared from aromatic or heteroaromatic amines, to give hydrazones 69 in 35-94% yields. They were next treated with DMFDMA in dichloromethane at room temperature to form the (dimethylamino) methylidene derivatives 70 as intermediates, which immediately cyclized into dimethyl 1 -(hetero)aryl-4-oxo-l, 4-dihydropyridazine-3,5-dicarboxy-lates 71 in 72-94% yields, except for 71 (R=lH-l,2,4-triazol-3-yl), which was obtained in 35% yield (08ZN(63b)407) (Scheme 23). 

Dimethyl acetone-l,3-dicarboxylate (1) reacts with benzamidine to form methyl 2-(6-hydroxy-2-phenylpyrimidin-4-yl)acetate (72). With DMFDMA in refluxing toluene the reactive methylene group of 72 was transformed into an N,N-dimethylaminomethylidene derivative. While methylation of the hydroxyl group was taking place to give methyl (E)-3-(dimethylamino)-2-(6-methoxy-2-phenylpyrimidin-4-yl)propenoate (73) (Scheme 24). 

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