Dimethylformamide dimethyl acetal is the amide acetal formed by acetalization of dimethylformamide with methanol and carrying two alkoxy groups on the carbonyl group . The compound has as a formylation and methylating agent for carboxylic acids , phenols , amines , thiols and amino acids [5] [6] [7] and as a molecular building block ( building block ), especially for heterocycles, [8] found greater distribution.
Analogously to the first publication on dimethylformamide diethylacetal from the working group of Hellmut Bredereck [9], the dimethylformamide dimethylacetal of the adduct obtained by reacting ( O - methylation ) dimethylformamide with dimethyl sulfate is converted with sodium methoxide in methanol at 0 °C in yields of 72 to 87% % receive. [10] [11]
Because of the decomposition of the DMF-DMA during the distillation under atmospheric pressure, the rapid distillation of the reaction mixture with the addition of methanol as an entraining agent and subsequent fractional distillation of the resulting methanol/DMF-DMA mixture is recommended. This achieves pure yields of 85 to 90% of dimethylformamide dimethylacetal. [12]
Reaction of the Vilsmeier reagent N,N -dimethyl(chloromethylene)iminium chloride in chloroform with sodium methoxide in methanol gives DMF-DMA in 55% yield. [13] [14]
Dimethylformamide dimethylacetal is also formed when the reactants methoxide, DMF and CHCl 3 react . [15] Chloroform reacts with solid sodium methoxide or sodium methoxide in methanol, presumably via the intermediately formed dichlorocarbene :CCl 2 , which converts dimethylformamide to DMF-DMA with elimination of CO. [16]
Crude yields of up to 91% are achieved in millimolar batches.
Dimethylformamide dimethyl acetal is a clear, colorless liquid with an amine-like odor that is miscible with water and many organic solvents. The acetal gradually decomposes in water. [6]
DMF-DMA as a methylating agent
Acidic compounds [17] , such as. B. Carboxylic acids [18] [19] , phenols [18] , thiols [20] are methylated by dimethylformamide dimethylacetal in a smooth reaction,
as well as NH-heterocycles, such as. B. Triazoles . [21]
DMF-DMA as a formylating agent
Dimethylformamide dimethylacetal reacts with primary amines to form N,N-dimethylformamidines [22] and with α- amino acids to form the relatively stable α-formamidinomethyl esters. [23]
The α-Formamidinomethylester can with good yields after deprotonation with strong bases such. B. lithium diisopropylamide LDA or potassium tert-butanolate KOtBu with alkyl halides , such as. B. iodomethane or in a Michael addition with z. B. methyl acrylate can be implemented.
As an alternative to the synthesis of the cyclic polyamine cyclen according to Reed and Weisman [24], which is more suitable as a laboratory method, the reaction of triethylenetetramine TETA with DMF-DMA to form the bis-amidine 1,1'-ethylenedi-2-imidazoline in 85% strength is suitable Yield (1st stage). Its macrocyclization under dilute conditions with 1,2-dibromoethane gives a monoimidazolium compound in a 70% yield, which is then cleaved with boiling potassium hydroxide solution in a yield of 88% for cycling. [25] [26]
The corresponding N -formyl- N,N -dialkylamines are formed by reacting dimethylformamide dimethylacetal with secondary amines . [27]
With CH-acidic compounds with activated methylene groups, such as. B. ketones , DMF-DMA reacts smoothly to vinylogous amides, the so-called enaminones. [28]
Thus, cyclopentanone forms the corresponding enaminone with DMF-DMA in 86% yield, which with lithium aluminum hydride LiAlH 4 gives the corresponding Mannich base in 88% yield. [29]
Bis-enaminones are formed analogously with diketones , from which a large number of heterocycles are accessible. [30]
The bis-enaminone formed practically quantitatively in the reaction of 2,6-diacetylpyridine with DMF-DMA reacts with hydrazine to form the 3-arylpyrazole. [31]
An effective method for preparing substituted indoles is what is known in the English literature as "Leimgruber-Batcho indole synthesis" from 2-nitrotoluene and dimethylformamide dimethylacetal, with pyrrolidine being added to accelerate the reaction. [32]
In the presence of traces of sodium methoxide , 1,3,5-triphenylbenzenes are formed from β-nitrostyrene and two equivalents of DMF-DMA in DMF in moderate yields (up to 40%) . [33]
