t-Butoxybis(dimethylamino)methane1

(1; R = t-Bu) (t-BAE)

[5815-08-7]  · C9H22N2O  · t-Butoxybis(dimethylamino)methane  · (MW 174.33) (2; R = Me) (MAE)

[1186-70-5]  · C6H16N2O  · Methoxybis(dimethylamino)methane  · (MW 132.24)

(aminal esters reactive as aminomethylenating reagents (formylating reagents) for CH2- and NH2-acidic compounds. The t-butyl analog is somewhat more reactive than the methyl derivative; bis(dimethylamino)carbene can be generated from both compounds)

Alternate Name: Bredereck's reagent.

Physical Data: (1) bp 50-52 °C/12 mmHg; n20D = 1.4250. (2) bp 128 °C/760 mmHg; 32-33 °C/25 mmHg; n20D = 1.4158.

Solubility: miscible with nonpolar aprotic waterfree solvents (benzene, toluene, cyclohexane, diethyl ether, etc.); react with protic solvents like water (hydrolysis to DMF) or alcohols (alcoholysis affords DMF acetals). Even common solvents like acetonitrile or acetone which are weakly CH-acidic react with the aminal esters on heating.

Form Supplied in: colorless to weak yellow, strong amine-smelling liquids.

Analysis of Reagent Purity: the best method is 1H NMR spectroscopic examination of a neat sample.

Handling, Storage, and Precautions: both compounds should be handled in a fume hood, with strict exclusion of atmospheric moisture. They should be stored in tightly sealed containers in a refrigerator under an atmosphere of dry nitrogen or argon.

Introduction.

Alkoxybis(dimethylamino)methanes can be obtained in good yields from N,N,N,N-tetraalkylformamidinium salts and alcohol-free alkoxides.2 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%.3

In another method,4 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.

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),5 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.

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.

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,6-9 aryl alkyl ketones,6,10-16 heteroaryl alkyl ketones,17-19 1-alkenyl alkyl ketones,20 a-dialkylamino ketones,21 a-glycosyl alkyl ketones,22 cycloalkanones,10,11,16,20,23 -28 4-piperidinones,29 and steroidal ketones.30,31 If an additional acidic functional group is present (e.g. an NH2 group), this may also be aminomethylenated by the reagent,10 in some cases accompanied by ring closure.32 The resulting difunctional compounds formed have been transformed into various types of product. Eqs 5-11 give an overview of these applications.6-27,32

This type of condensation reaction of aminal esters may proceed with even weaker CH-acidic compounds (eq 12), such as esters33-35 which have in the a-position, amino,21,36-39 alkoxy21,40 and heteroaryloxy,39 thio,21,39 phosphonyl,41 and silyl groups.41 Aminomethylenation reactions have also been reported for the following functionalities or compound classes: lactones,33,42-51 a,b-unsaturated esters38,52 and lactones,53 thioesters,33 imidates,41 isocyanides41 and nitriles,6,21,41 amides33 and lactams,27,33,54-58 cyclic imides,55,59 thioamides33 and thiolactams,33,60 amidines,41 amidinium41 and phosphonium salts,61,62 phosphonates,41,62 ketone hydrazones,63,64 cyclopentadienes,60-67 xanthene,68 toluenes,68-73 nitroarenes,74 2-methyl-1-pyrroline N-oxides,75 2-alkyl-5-nitroimidazole,17 4-methylpyridine,68,73,76,77 methylpyrimidines,68,77-79 3-methylpyridazine,78,80 2-methylpyrazine,78 2-pyridones,81 1,3,4-thiadiazoles,82 1,4-dihydro-4-oxo-1,8-naphthyridine,83 pyrimidine acids84 and esters,85 3-arylidenebenzothiazines86 and 3-methyl-1,2,4-triazines.87

The condensation products thus available can be transformed into various types of compounds. Eqs 13-17 give some examples.34,35,43,46,70,73,79,81

Compounds containing two acidic CH2 groups can be formylated once or twice; examples of this type of reaction have been demonstrated with dinitriles,59,88 1,2-bis(phenylsulfonyl)ethane,21 2,2-dimethyl-1,3-cyclopentanedione,59 5,10-dihydroindeno[2,1-a]indene,67 ethyl 4-oxoglutarate,59 diethyl succinate,59 diethyl adipate,59 diethyl tetrathioadipate,59 N-alkylsuccinimides,59 and N-alkylglutarimides.59 NH2-Acidic compounds react with aminal esters analogously to CH2-acidic compounds, i.e. the nitrogen atom is aminomethylenated. A few amides have been converted to the corresponding acylamidines (eq 18).33,89 This condensation reaction is of less importance, because the same results can be achieved with the more accessible DMF acetals.

Since the primary condensation products from amides still contain an acidic methylene group, further formylation can occur (eq 19).33 Similar results were obtained in the formylation of diethyl aminomethylphosphonate (eq 20).90

If two acidic functions of the type XH2 and XH are present in suitable positions, the condensation reaction can be used for ring closure (eq 21).91 In some cases the desired condensation reaction is accompanied by transformations of other functional groups present in the molecule (eqs 22 and 23).77,92

Weakly acidic heteronucleophiles substitute for the alkoxy group in aminal esters. Thus hydrocyanic acid,83 terminal alkynes,93 and thiols94 afford cyano, alkynyl, and alkylthio aminals (eq 24). With secondary amines the substitution of the alkoxy group is accompanied by a transamination to give tris(dialkylamino)methanes (eq 25).95 The alcoholysis of aminal esters proceeds very similarly, giving rise to the formation of DMF acetals,4,84 whereas phenols are formylated in the 4-position. N-Monosubstituted formamides are converted by t-BAE to N,N,N-trisubstituted formamidines (eq 26).38,43

With stronger CH-, NH-, or OH-acidic compounds such as phenols bearing electron-attracting groups,1c imides of dicarboxylic acids,59 tertiary CH-acidic acids,93 and extremely strong CH2-acidic compounds,96 as well as mineral acids, the aminal esters act as a base to give formamidinium salts (eq 27).

The strong basicity of t-BAE is exploited in the synthesis of methylenedioxybenzenes from catechols and dichloromethane.97 Electrophilic reagents such as acyl cyanides,98 acyl azides,99 CS2,1c isothiocyanates,100 and N-chloroamides101 undergo a variety of unusual reactions with aminal esters. Although the mechanisms of these interesting reactions have been investigated thoroughly, they are - with a few exceptions - of less importance in the preparative sense because the resulting products are often obtainable with better yields from DMF acetals. Eq 28 gives three examples.

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).102 The reaction of t-BAE with aromatic aldehydes affords mixtures which are not easy to separate (eq 30).103 1,2-Diaminoethylene derivatives were isolated from reactions with p-tolyl- and anisaldehyde.104

Heating selenium and t-BAE produces N,N,N,N-tetramethylselenourea.105 Oxidation of MAE with peroxides affords N,N,N,N-tetramethylurea,106,107 whereas with dibutyldiborane N,N,N,N-tetramethylformaldehydaminal is formed.108 Formamidinium (dimethylcarbamoyltetracarbonyl)ferrate is obtained from Pentacarbonyliron and aminal esters (eq 31).108

Related Reagents.

N,N-Dimethylformamide; N,N-Dimethylformamide Diethyl Acetal; Tris(dimethylamino)methane; Tris(formylamino)methane; Dimethylchloromethyleneammonium Chloride.


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Willi Kantlehner

Universität Stuttgart, Germany



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