Mannich reaction with diethylamine

Alkylquinoxalines undergo Mannich reaction with formaldehyde and diethylamine hydrochloride to afford diethylaminoethyl derivatives. ... 

This ring system was prepared by treatment of quinoline derivative 786 with antimonyl chloride to give 787. Quinoline derivative 786 was prepared by Mannich reaction on 2,8-dihydroxylepidine with diethylamine and formaldehyde to afford the respective diethylaminomethyl derivative that followed by subsequent nitration. The schistosomicidal activity of 787 was studied (80MI66) (Scheme 138). 

Methyl vinyl ketone 2 tends to polymerize, especially in the presence of a strong base the yield of annulation product is therefore often low. A methyl vinyl ketone precursor, e.g. 6, is often employed, from which the Michael acceptor 2 is generated in situ, upon treatment with a base. The quaternary ammonium salt 6 can be obtained by reaction of the tertiary amine 5, which in turn is prepared from acetone, formaldehyde and diethylamine in a Mannich reaction. 

The thioxotetrazinoquinazoline 7 was reacted with paraformaldehyde and secondary amines, namely diethylamine and piperidine (Mannich reaction), to afford the corresponding derivatives (Equation 2) <1999IJB850>. 

In the pyrazine series, the Mannich reaction was applied first to 2,5-dimethyl-pyrazine by Linder and Spoerri (715). Of the amines tried, positive reactions were obtained only with dime thy lamine, piperidine, and morpholine, and it was found that one, or more usually two, of the hydrogen atoms of each of the methyl groups could be substituted. Thus 2,5-dimethylpyrazine, dimethylamine hydrochloride, and formalin in refluxing isopentyl alcohol gave 2,5-bis[bis(dimethylaminomethyl)-methyl]pyrazine and 2,5-bis(j3-dimethylaminoethyl)pyrazine. Reaction of 2-methyl-pyrazine with formalin and diethylamine hydrochloride gave 2- 3-diethylamino-ethylpyrazine (716) similarly dimethylamine hydrochloride gave 2-dimethyl-aminoethylpyrazine (17) and some 2-[bis(dimethylaminomethyl)]methylpyrazine (18) (657). 

As dihydrocodeinone contains the system —CO—CH2— it was expected to undergo the Mannich reaction, and indeed after heating with dimethylamine hydrochloride and formaldehyde no dihydrocodeinone could be recovered, and only 40 per cent, of the product was crystalline. Under the same conditions 1-bromodihydrocodeinone (in which the reactive position of the aromatic nucleus is blocked, thus preventing any nuclear condensation) gave a 90 per cent, yield of crystalline material, also obtained when diethylamine hydrochloride was used in the reaction. The product cannot be sublimed, evidently boing dimolecular, and has been allotted the structure [lxvi, R = Br], i.e. 7 7 -methylenebis-(l-bromodihydrocodeinone). It is converted to 7 7 -methylenebis-(dihydrocodeinone) [lxvi, R = H] by catalytic reduction, and this is identical with the crystalline material obtained from dihydrocodeinone. A 5 5 or 5 7 -linkage is of course also possible, but the 7 7 union was considered to be most likely as it is the least hindered. No reaction occurs if triethylamine is substituted for the secondary amine, so that formation of a complex between the latter and... 

With formaldehyde and amines such as dimethylamine, diethylamine, or pentaethylenehexamine, Mannich reactions have been carried out on poly(sty-rene-co-acrylamide) latex particles. The expected tertiary amines were accompanied by hydrolysis products. Thus both the Hofmann rearrangement and the Mamiich reactions led to amphoteric latex particles. When attempts were made to alkylate the Maimich reaction product, soluble products (presumably quarternary ammoniitm salts) were formed. 

In order to prepare C -labeled d-a-tocopherol we started from natural d-7-tocopherol (Fig. 6) and introduced the C -methyl group into the 5-position by use of the Mannich reaction. Condensation of d-y-tocopherol with radioactive paraformaldehyde in the presence of diethylamine followed by catalytic reduction gave d-a-tocopherol. This was acetylated to methyl-C Mabeled d-a-tocopherol acetate (specific activity 1.7 tc/mg Fig. 6). 

Tritiated formaldehyde is also useful in Mannich reactions. Examples of such applications include the preparation of the topoisomerase-1 inhibitor 364 by condensation of tritiated formaldehyde and dimethylamine with 10-hydroxycamptothecin 1363). the reaction with acetone and diethylamine to give 4-diethylamino-4-[ H2]butan-2-one 365 which was further converted upon heating with thebaine (366) to the morphine derivative 367 (specific activity of 46 Ci/mol). Furthermore, condensation of aqueous deuterated formaldehyde with allyltrimethylsilane to prepare the 2,6-doubly labeled piperidine 368. as indicated , would be expected to work equally well with tritiated formaldehyde. 

Inclusion of the carbon atoms of an aromatic ring in the side chain sequence is apparently quite consistent with antlmalarial activity. Thus, reaction of p-acetamidophenol with formaldehyde and diethylamine affords the Mannich product, 79. This is then converted to the diamine (80) by saponification. Alkylation with the chloroquinoline, 70, affords amidoquine (81). The same sequence starting with the Mannich product in which pyrrolidine has been used as the amine (82) gives amopyroquine (83). 

The inclusion of aromatic rings as part of the side chains results in quite potent agents, possibly because the rigid rings better define the position of the basic nitrogen. Reaction of para-hydroxyacetanilide (19-1) with formaldehyde and diethylamine affords the corresponding Mannich product (19-2) hydrolysis of the acetamide then leads to the aniline (19-3). Treatment of that compound with dichloro-quinoline (17-6) leads to the displacement of chlorine on the heterocyclic ring and the formation of amodiaquine (19-4) [21]. 

On treatment of 1 with equimolar quantities of formaldehyde and piperidine, morpholine or diethylamine in acetic acid, the Mannich bases 182a-c were synthesized in good yield. Their analogue, 182d, was obtained in the reaction of 1 with one equivalent of bis(dimethylamino)methane in AcOH or with A,A-dimethylmethyleneimmonium chloride in dry acetonitrile (yields are 79 and 47%, respectively)193. The introduction of the second dialkylaminomethyl group into compounds 182 is discussed in Section IV.D. 

Compounds capable of forming an enol react with imines from formaldehyde and a primary or secondary amine to yield /3-aminoalkyl carbonyl compounds called Mannich bases. The following reaction of acetone, formaldehyde, and diethylamine is an example ... 

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