Hantzsch reaction with 6-aminouracil: Synthesis of novel tetrakis(6-aminouracil-5-yl)methanes and bis(decahydropyrido[2,3-d :6,5-d' ]dipyrimidine-tetraones) linked to aliphatic or aromatic cores via ether-amide or ester-amide linkages

One-pot three-component cyclo-condensation reaction of bis(aldehydes) containing ether-amide or ester-amide linkages with 6-aminouracil in boiling acetic acid afforded tetrakis(6-aminopyrimidine-2,4-diones) or bis(tetraoxodecahydropyrido[2,3-d :6,5-d ']dipyrimidines) depending on the reaction conditions


Results and Discussion
Firstly, the bis(2-(2-formylphenoxy)acetamide) 1a was prepared following our reported procedure via the reaction of the potassium salt of salicylaldehyde with N,N'-(ethane-1,2-diyl)bis (2-chloroacetamide) in DMF. 74he reactivity of the bis(aldehyde) 1a towards 6-aminouracil 2 was then investigated aiming at the synthesis of bis(decahydropyrido[2,3-d:6,5-d']dipyrimidin-5-yl)phenoxy)acetamide) 4a.Contrary to our expectation, the reaction did not yield compound 4a, instead it gave the uncyclized tetrakis(6-aminopyrimidine-2,4-dione) 3a in 88% yield (Scheme 1).It worth mentioning that trials to cyclize similar systems in acetic acid at reflux were unsuccessful. 75On the other hand, heating a mixture of the bis(aldehyde) 1a with the aminouracil 2 in acetic acid in the presence of p-TSA for 3 h afforded the target 4a as the sole product.Moreover, we have found that heating of compound 3a in acetic acid /p-TSA for 1 h afforded 4a directly in one step.The structures of compounds 3a and 4a were supported based on the different spectral tools.Thus, the 1 H NMR spectrum of compound 3a revealed a characteristic broad integrated by 4H at δ 3.30 ppm for the two methylene linkage.It also showed two characteristic singlets at δ 4.31 and 5.38 ppm for the -OCH 2 CO-and the bridging CH protons, respectively.In addition, it exhibited four broad singlet signals characteristic for the NH 2 and three NH groups at δ 6.74 and δ 7.48, 10.30 and 10.42, respectively.It also featured aromatic protons at δ 6.83-7.15.On the other hand, the 1 H NMR spectrum of compound 4a, indicated the disappearance of the characteristic broad signals at the range of 6-7 ppm for the amino groups.It also featured in addition to the signals of methylene groups, singlet signal at δ 5.13 ppm for the pyridine-H5.It also indicated three different broad singlets at δ 8.41, 10.64 and 11.18 ppm corresponding to three different NH groups.
A proposed synthetic pathway for the reaction of bisaldehydes with 6-aminouracil is shown in scheme 5. Nucleophilic addition of the enamine β-carbon of 6-aminouracil 2 to the two carbonyl centers of the bis(aldehydes) 1 affords the corresponding adducts 10.Subsequent elimination of water leads to the formation of the corresponding ene-imine intermediate 11.The Michael addition of another two moles of 6aminouracil 2 to the intermediate 11 affords the products 3. Subsequent removal of ammonia using p-TSA led to the formation of 4 (Scheme 6).Scheme 6.A proposed pathway for the synthesis of compounds 3 and 4.

Conclusions
We developed a synthetic approach for the synthesis of novel tetrakis(6-aminopyrimidine-2,4-diones) or bis(tetraoxodecahydropyrido[2,3-d:6,5-d']dipyrimidines) via one-pot three-component cyclo-condensation reaction of bis(aldehydes) containing ether-amide or ester-amide linkages with 6-aminouracil.The reaction products was found to be dependent on the reaction conditions.It is expected that the novel structures prepared in this paper would be useful in the field of medicinal and synthetic organic chemistry.

Experimental Section
General.Melting points were measured with a Stuart melting point apparatus and are uncorrected.The IR spectra were recorded using a FTIR Bruker-vector 22 spectrophotometer as KBr pellets.The 1 H and 13 C NMR spectra were recorded in DMSO-d 6 as solvent on Varian Gemini NMR spectrometer at 400 MHz and 100 MHz, respectively, using TMS as internal standard.Chemical shifts are reported as δ values in ppm.Mass spectra were recorded with a Shimadzu GCMS-QP-1000 EX mass spectrometer in EI (70 eV) model.Elemental analyses were performed on a Perkin-Elmer 240 micoanalyser at the Micro analytical Center of Cairo University.
General procedure for the synthesis of 3a-3g and 8.A solution of each of bisaldehydes 1a-1g and 7 (1 mmol) and 6-aminouracil (4 mmol) in acetic acid (3 ml) was heated at reflux for 1 h.The solid obtained was collected and crystallized from DMF/EtOH to give compounds 3a-g and 8.