Dimethylamine, reaction with aldehydes

Treatment of allyl p-tolyl sulfoxide with LDA followed by addition of HMPA (4.4 mol equiv.) and chiral 2-methylalkanal (3 mol equiv.) at -78 C gave a mixture of readily separable a- and y-adducts, where the a y regioisomer ratios are markedly higher than those obtained in Ae reaction with aromatic aldehydes. Exposure of the a-adduct to an excess of a thiophile (trimethyl phosphite or dimethylamine in MeOH) results in quenching of the allylic sulfoxide-sulfenate equilibrium and affords diastereoisomeric mixtures of the syn- and anti-diols (Scheme 18), for which some yields and product ratios are shown in Table 3. 

The pathway proposed for the reaction of aryl aldehydes and enolizable ketones in DIMCARB involved formation of a putative, transient iminium species that underwent Mannich reaction with the ketone. Subsequent elimination of dimethylamine from the Mannich adduct occurred slowly in situ to afford the 2-arylidene derivative (Scheme 6.1)."... 

Hydrazine (97) is considered to be the parent of substituted hydrazine derivatives, such as 98, which react with aldehydes and ketones to form substituted hydrazone derivatives. An example is the reaction ofi JV-dimethylhydrazme (103) and 2-methylpropanal (isobut3rraldehyde, 102) to give the A JV-dimethylamine hydrazone 104 in 64% 3deld. Two important A Af-disubstituted hydrazine reagents are phenylhydrazine (PhNHNH2) and 2,4-dinitrophenylhydrazine (106), which react with aldehydes or ketones to give the corresponding hydrazone. 

When the additional nitrogen atom is included in one of the aromatic rings, on the other hand, there is obtained a compound with antihistaminic properties. Reaction of the Grignard reagent from 4-chlorobromobenzene with pyridine-2-aldehyde gives the benzhydrol analog (12). The alcohol is then converted to its sodium salt by means of sodium, and this salt is alkylated with W-C2-chloroethyl)dimethylamine. Carbinoxamine (13) is thus obtained. ... 

The Maunich reaction of a ketone, an amine, and an aldehyde is one of the few three-component reactions in organic chemistry. Cyclohexanone, for example, reads with dimethylamine and acetaldehyde to yield an amino ketone. The reaction takes place in two steps, both of which are typical carbonyl-group reactions. 

A recent total synthesis of tubulysin U and V makes use of a one-pot, three-component reaction to form 2-acyloxymethylthiazoles <06AG(E)7235>. Treatment of isonitrile 25, Boc-protected Z-homovaline aldehyde 26, and thioacetic acid with boron trifluoride etherate gives a 3 1 mixture of two diastereomers 30. The reaction pathway involves transacylation of the initial adduct 27 to give thioamide 28. This amide is in equilibrium with its mercaptoimine tautomer 29, which undergoes intramolecular Michael addition followed by elimination of dimethylamine to afford thiazole 30. The major diastereomer serves as an intermediate in the synthesis of tubulysin U and V. 

The Mannich reaction is best discussed via an example. A mixture of dimethylamine, formaldehyde and acetone under mild acidic conditions gives N,N-dimethyl-4-aminobutan-2-one. This is a two-stage process, beginning with the formation of an iminium cation from the amine and the more reactive of the two carbonyl compounds, in this case the aldehyde. This iminium cation then acts as the electrophile for addition of the nucleophile acetone. Now it would be nice if we could use the enolate anion as the nucleophile, as in the other reactions we have looked at, but under the mild acidic conditions we cannot have an anion, and the nucleophile must be portrayed as the enol tautomer of acetone. The addition is then unspectacular, and, after loss of a proton from the carbonyl, we are left with the product. 

The most important reactions of alkyl substituents a and y to the ring heteroatom are those which proceed via base-catalyzed deprotonation. Treatment of 2- and 4-alkyl heterocycles with strong bases such as sodamide and liquid ammonia, alkyllithiums, LDA, etc., results in an essentially quantitative deprotonation and formation of the corresponding carbanions. These then react normally with a wide range of electrophiles such as alkyl halides and tosylates, acyl halides, carbon dioxide, aldehydes, ketones, formal-dehyde/dimethylamine, etc., to give the expected condensation products. Typical examples of these transformations are shown in Scheme 17. Deprotonation of alkyl groups by the use of either aqueous or alcoholic bases can also be readily demonstrated by NMR spectroscopy, and while the amount of deprotonation under these conditions is normally very small, under the appropriate conditions condensations with electrophiles proceed normally (Scheme 18). 

Certain N-alkylamino nitriles have been made by replacing the ammonium chloride with a primary or a secondary amine hydrochloride. An aqueous solution of amine hydrochloride, alkali cyanide, and aldehyde (or ketone) is shaken at room temperature for 2 to 48 hours (39-78%). A variation of this procedure consists in adding concentrated hydrochloric acid to an aqueous solution of amine, aldehyde, and sodium cyanide. In this manner, dimethylaminoacetonitrile is prepared by the condensation of dimethylamine and formaldehyde in 73-83% yield. Acetic acid serves as a solvent for the reaction of less soluble aromatic compounds. °... 

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