Dimethylformamide Dimethyl Acetal ( DMFDMA ) in Heterocyclic Synthesis : Synthesis of Polysubstituted Pyridines , Pyrimidines , Pyridazine and Their Fused Derivatives

Reaction of N,N’-dimethylformamide dimethyl acetal (DMFDMA) with malononitrile dimer 8 (1:1) mole afforded 9 while, this reaction when carried out in (2:1) mole to give amidine 11 which can be used for the preparation of pyrimidine 13, amidine 14 and pyridine 19 when reacted with 4-nitroaniline, 4-methylaniline and alkoxide respectively. Malononitrile dimer reacted with diazonium chloride to give pyridazine 21, which can be reacted with DMFDMA, AcOH/HCl and cyanoacetamide to give pyridazine 22, 23 and pyrido[4,3-c] pyridazine 24 respectively. The latter reacted with DMFDMA to afford tricyclic compound 25.


Introduction
Formamide acetals are useful reagents in organic synthesis; [1,2] their main application has been used for functional group transformations [3], but they may also be regarded as one-carbon synthons in the construction of carbon skeletons.One type of reaction, which is potentially valuable for the future purpose, is the reaction of N,N'dimethylformamide dimethyl acetal (DMFDMA) with 1, 3-dicarbonyl compounds 1 to give enamines 2 [2,4].

Results and Discussion
In conjunction with this work we report here the reaction of malononitrile dimer 8 [11] with one mole of N,N'-dimethylformamide dimethyl acetal (DMFDMA) in dry dioxane afforded only one product that could be formulated as 9 or 10 as result of condensation on either the amino or active methylene group.The structure of the isolated product was elucidated based on the spectral analysis.The 1 H-NMR spectrum shows two singlet signals at δ H = 3.2 and 3.25 ppm corresponding to the two methyl groups of NMe 2 moiety, singlet signal at δ H = 7.59 ppm corresponding to methylene group or amino group and singlet signal at δ H = 7.99 ppm corresponding to methine proton.While we could not differentiate between 9 and 10 by 1 H-NMR, DEPT-135 of 13 C-NMR shows a methylene group at -66.78 ppm which indicates that the isolated product is 9 and not 10.This can be attributed to the fact that the nucleophilicity of the amino group is greater than that of methylene group.
The treatment of malononitrile dimer 8 with two moles of N,N'-dimethylformamide dimethyl acetal (DM-FDMA) afforded amidine 11 in which N,N'-dimethylformamide dimethyl acetal (DMFDMA) reacted with both the amino group and the active methylene.The mass spectrum of this compound shows molecular weight at m/z 242 which corresponds to structure 11.Amidine 11 can also be obtained by treatment of amidine 9 with another one mole of DMFDMA.
The reaction of amidine 11 with one mole of aromatic amines (1:1) afforded the corresponding pyrimidine derivative 13. while the treatment of amidine 11 with two moles of aromatic amines (1:2) afforded formamidine 14 (Scheme 1).This suggests that the isolated pyrimidine 13 was formed through the intermediate 12.The structure of these compounds was confirmed by elemental analysis as well as spectral analysis.The IR spectrum of compound 14 shows the appearance of two bands of υ max at 3286.3 cm -1 , 3208.2 cm -1 corresponding to two (NH) groups, while the IR spectrum of compound 13 shows the disappearance of NH groups.The mass spectrum of compound 14 shows the molecular ion peak at m/z 366 which is in agreement with the proposed structure 14.
We expected that the treatment of amidine 11 with sodium alkoxide (sodium ethoxide, sodium methoxide, sodium n-propoxide or sodium isopropoxide) in the corresponding alcohol would afford pyrido [4,3-d]pyrimidine derivatives 16 [12] through the cyclization of the intermediate 15 in which, two molecules of alcohol were added on the two cyano groups.However, the mass spectra of the isolated products shows a molecular weight which does not agree with the expected structure 16.Also the 1 H-NMR spectra shows three exchangeable protons corresponding to NH and NH 2 groups as well as only one aromatic proton.This means that the isolated product is not 16 and the reaction takes place by another pathway in which the intermediate 15 is attacked by the alkoxide to give intermediate 17 in which N,N'-dimethylformamidine moiety is replaced by alkoxide group followed by hydrolysis and cyclization to give 4-alkoxy-5-cyanopyridine-2(1H)-one-3-carboxylic acid amide 19.The structure of the isolated product was confirmed by elemental analysis as well as spectral data in which the IR spectra show the presence of NH, NH 2 and cyano group.Also 1 H-NMR spectra show two exchangeable protons for NH & NH 2 and one aromatic proton.Sodium isopropoxide cannot react with amidine 11.This is due to the fact that the isopropoxide group is a bulkynucleophile.Since it does not replace the N,N'-dimethylamidine moiety because of the steric hindrance, we could not isolate pyridine isopropoxide derivative (19d) (Scheme 2).
The reaction of malononitrile dimer 8 with diazonium salts of aromatic amines 20a-e furnished the corresponding pyridazine derivatives 21a-e.The structure of the isolated products was confirmed by elemental analysis as well as spectral data.The IR spectra of these compounds show the appearance of amino and imino groups.Also the 1 H-NMR spectra of these compounds 21a-e show the appearance of aromatic protons and two exchangeable broad singlet signals corresponding to NH 2 and NH groups.
The pyridazine derivatives 21a-e were found to be a good intermediate for the formation of fused heterocyclic compounds.Reaction of pyridazine derivatives 21a-e with N,N'dimethylformamide dimethyl acetal (DMFDMA) afforded  Further treatment of pyridazine derivatives 21b,c,e with acetic acid in the presence of small amounts of hydrochloric acid afforded the corresponding pyridazinone derivatives 23a-c.The IR spectra of these compounds show disappearance of cyano groups and the appearance of amide carbonyl groups.

N'-(2,2-Dicyano-1-cyanomethyl-vinyl)-N,N-dimethyl -formamidine (9)
Also, the treatment of pyridazine derivatives 21a,b,e with cyanoacetamide afforded pyrido [4,3-c]pyridazine derivatives 24a-c.Consequently, pyridopyridazine derivatives 24a-c were treated with N,N'-dimethylformamide dimethyl acetal (DMFDMA) to afford the tricyclic heterocycle 25a-c (Scheme 3).The IR spectra of compounds 25a-c show the disappearance of amino group.Also, 1 H-NMR spectra of compounds 25a-c show the disappearance of amino group and the appearance of (NH) group and methine protons at δ H = 7.45 and 8.71 ppm respectively. 1H-NMR Spectra of these compounds also show two exchangeable broad signals at δ H = 7.45 and 10.50 ppm The sum of the two integrations of both signals is equivalent to one proton which indicates that these compounds 25a-c may exist as a mixture of three tautomers 25A,B,C.

The treatment of amidine 11 with sodium alkoxide. 3. Experimental
the corresponding amidine 22a-e.IR spectra of these compounds show the disappearance of the amino group, and the 1 H-NMR spectrum of compound 22b (as an example) shows two singlet signals for 6 protons at δ