Applications of t-Butoxybis(dimethylamino)methane

- Feb 22, 2018 -

Introductions

  Alkoxybis(dimethylamino)methanes can be obtained in good yields from N,N,N´,N´-tetraalkylformamidinium salts and alcohol-free alkoxides. The reactions have to be conducted in inert, strictly anhydrous solvents like cyclohexane, hexane, ether, or THF, in which unfortunately both reagents are insoluble. As a consequence it is necessary to use relatively large amounts of the solvent and long reaction times (eq 1). In the patent literature it is claimed that by the use of a mixture of DMF and mesitylene as solvent, the yields can be improved to about 95%.

Eq1.png

  In another method, bis(dimethylamino)acetonitrile is used as the starting compound. Alcohol-free alkoxides suspended in absolute ether substitute the cyano group to give the corresponding aminal ester (eq 2). In contrast to the aforementioned method, less solvent and shorter reaction times are needed because the nitrile is soluble in ether and the product yields are normally 5-20% higher.

Eq2.png

  The purity and stability of the product are determined by the quality of the metal alkoxide. Traces of alcohol catalyze the disproportionation of the aminal ester to the corresponding DMF acetal and tris(dimethylamino)methane (eq 3), which may complicate spectroscopic investigations. For preparative purposes the disproportionation reaction can be disregarded; at higher temperatures the orthoamides interconvert very rapidly to the aminal ester, and usually the condensation reactions of aminal esters are not affected by the equilibrium.

Eq3.png

  t-Butoxybis(dimethylamino)methane CAS: 5815-08-7 is also named as Bredereck's reagent, or wrote as t-BAE.

 

Reactions

  The reactivity of aminal esters is very similar to that of Tris(dimethylamino)methane. In the first step of the reaction the compounds dissociate, forming strong basic alkoxide anions which set up an equilibrium with the XH2-acidic compounds (eq 4). The HX- anions thus formed combine with the formamidinium ions. b-Elimination of dimethylamine from the adduct is the final step of the condensation reaction.

Eq4.png

  Because of their high reactivity with XH2-acidic compounds, aminal esters have found widespread application as formylating reagents; especially with CH2-acidic ketones such as simple dialkyl ketones, aryl alkyl ketones, heteroaryl alkyl ketones, 1-alkenyl alkyl ketones, a-dialkylamino ketones, a-glycosyl alkyl ketones, cycloalkanones, 4-piperidinones, and steroidal ketones. If an additional acidic functional group is present (e.g. an NH2 group), this may also be aminomethylenated by the reagent, in some cases accompanied by ring closure.The resulting difunctional compounds formed have been transformed into various types of product. Eqs 5-11 give an overview of these applications.

Eq5.png

 Eq6.png

Eq7-8.png

Eq9.png

Eq10.png

Eq11.png

   This type of condensation reaction of aminal esters may proceed with even weaker CH-acidic compounds (eq 12), such as esters which have in the a-position, amino, alkoxy and heteroaryloxy, thio, phosphonyl, and silyl groups.  Aminomethylenation reactions have also been reported for the following functionalities or compound classes: lactones, a,b-unsaturated esters and lactones, thioesters, imidates, isocyanides and nitriles, amides and lactams, cyclic imides, thioamides and thiolactams, amidines, amidinium and phosphonium salts, phosphonates,ketone hydrazones, cyclopentadienes, xanthene, toluenes, nitroarenes, 2-methyl-1-pyrroline N-oxides, 2-alkyl-5-nitroimidazole, 4-methylpyridine,methylpyrimidines, 3-methylpyridazine, 2-methylpyrazine, 2-pyridones, 1,3,4-thiadiazoles, 1,4-dihydro-4-oxo-1,8-naphthyridine, pyrimidine acids and esters, 3-arylidenebenzothiazines and 3-methyl-1,2,4-triazines.

Eq12.png

  The reaction of t-BAE with Schiff bases of aromatic aldehydes, heteroaromatic aldehydes, and benzalazines at temperatures of about 160 °C represents a valuable synthesis of 1,1,2-triaminoethylenes and 1,1-diaminoethylenes (eq 29). The reaction of t-BAE with aromatic aldehydes affords mixtures which are not easy to separate (eq 30). 1,2-Diaminoethylene derivatives were isolated from reactions with p-tolyl- and anisaldehyde.

Eq29-30.png