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

Article abstract of DOI:10.24820/ark.5550190.p011.357

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']dipy

Full text of DOI:10.24820/ark.5550190.p011.357

The Free Internet Journal
for Organic Chemistry
Paper
Archive for
Arkivoc 2020, part __, 0-0
Organic Chemistry
to be inserted by editorial office
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
Amr M. Abdelmoniem, Amna M. Abdella, Ahmed H. M. Elwahy,* Ismail A. Abdelhamid*
Department of Chemistry, Faculty of Science, Cairo University,12613 Giza, A. R. Egypt
E-mail: aelwahy@hotmail.com, ismail_shafy@yahoo.com
Received mm-dd-yyyy
Dates to be inserted by editorial office
Abstract
Accepted mm-dd-yyyy
Published on line mm-dd-yyyy
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.
Keywords: Hantzsch reaction, bis(aldehydes), amide linkages, tetrakis(6-aminopyrimidine-2,4-diones),
bis(tetraoxodecahydropyrido[2,3-d:6,5-d']dipyrimidines)
DOI: https://doi.org/10.24820/ark.5550190.p011.357
Page 1
©AUTHOR(S)

Arkivoc 2020, part _, 0-0
Abdelmoniem, A. M. et al.
Introduction
Hantzsch reaction is one of the most common routes for the synthesis of 1,4-dihydropyridines (1,4-DHPs)
having therapeutic and pharmacological properties.1–19 In addition, Uracil is considered to be one of the major
motifs present in the biopolymer RNA20,21 and it plays several roles in our life.22,23 The uracil scaffold and its
derivatives exhibit a wide range of biological activities, including anticancer agents,24–26 antihypertensive
agents,27 antiallergic compounds28 and antiviral agents.29–31 Structures of some FDA-approved uracil drugs are
depicted in figure 1. Moreover, dipyrimidines exhibit a broad range of pharmacological properties, such as
antimicrobial,32,33 antitumor,34 and antiviral.35,36 Furthermore, the multicomponent reactions (MCRs) provide
an easy and rapid access to diversity of heterocycles as they have the advantages of atom-economy and
selectivity.18,37-51
Figure 1. Some selected FDA-approved uracil drugs
In connection with the importance of both 1,4-dihydropyridine and the dipyrimidine moiety and in
continuation to our interest in enamine chemistry,52–56 the synthesis of bis(heterocycles)17,47–60 as well as the
C-C bond formation reactions,52,71–73 we report herein a highly efficient method for the synthesis of
bis(pyrido[2,3-d:6,5-d']dipyrimidinetetraones) linked to aliphatic or aromatic core via ether-amide or ester-
amide linkages through the reaction of bis(aldehydes) with 6-aminouracil.
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.74
The 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.75 On 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.
Page 2
©AUTHOR(S)

Arkivoc 2020, part _, 0-0
Abdelmoniem, A. M. et al.
Scheme 1. Synthesis of tetrakis(6-aminopyrimidine-2,4-dione) 3a and bis(decahydropyrido[2,3-d:6,5-
d']dipyrimidin-5-yl)phenoxy)acetamide) 4a
1
The structures of compounds 3a and 4a were supported based on the different spectral tools. Thus, the 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 -OCH2CO- and the
bridging CH protons, respectively. In addition, it exhibited four broad singlet signals characteristic for the NH2
and three NH groups at δ 6.74 ppm and δ 7.48, 10.30 and 10.42 ppm, respectively. It also featured aromatic
1
protons at δ 6.83-7.15 ppm. On the other hand, the 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.
Stimulated by these noteworthy results, a series of bis(aldehydes) 1b-f were prepared74 and used to
ascertain the generality and the scope of the protocol. The reaction of 6-aminouracil 2 with the appropriate
bis(aldehydes) 1b-f in acetic acid afforded the corresponding tetrakis(uracil) 3b-f (Scheme 2) .
Page 3
©AUTHOR(S)

Arkivoc 2020, part _, 0-0
Abdelmoniem, A. M. et al.
Scheme 2. Multicomponent synthesis of tetrakis(6-aminopyrimidine-2,4-dione) derivatives 3a-f
However, the reaction of 6-aminouracil 2 with the bis(aldehydes) 1a, 1c, 1e in acetic acid / p-TSA resulted
in the formation of bis(decahydropyrido[2,3-d:6,5-d']dipyrimidin-5-yl)phenoxy)acetamides) 4a-c, respectively,
in good yields (Scheme 3). The latter compounds were alternatively obtained in good yields, by heating the
corresponding tetra-uracil 3a, 3c and 3e in acetic acid containing p-TSA at reflux.
Page 4
©AUTHOR(S)

Arkivoc 2020, part _, 0-0
Abdelmoniem, A. M. et al.
Scheme 3. Multicomponent synthesis of bis(decahydropyrido[2,3-d:6,5-d']dipyrimidin-5-yl)phenoxy)-
acetamide) derivatives 4a-c
The scope of the reaction was further extended towards aldehydes which are linked to the benzene core
via ether-amide linkage. It has been found that the reaction of bis(aldehyde) 1g (aldehydic groups in meta
position) with 6-aminouracil in acetic acid failed to give the target cyclized product pyridodipyrimidine even
after prolonged heating in the presence of p-TSA (Scheme 4). The reaction gave instead the tetrakis(6-
aminopyrimidine-2,4-dione) 3g. On the other hand, the reaction of the bis(aldehyde) 1h (aldehydic groups in
ortho position) with 6-aminouracil 2 in acetic acid/p-TSA affords directly, the cyclic aromatized
pyridodipyrimidine product 4d (Scheme 4).
Page 5
©AUTHOR(S)

Arkivoc 2020, part _, 0-0
Abdelmoniem, A. M. et al.
Scheme 4. Synthesis of tetrakis(6-aminopyrimidine-2,4-dione) 3g and bis(tetraoxo-octahydropyrido[2,3-d:6,5-
d']dipyrimidine) 4d which are linked to the benzene core via amide linkage
Interestingly, the same methodology was also applied for the synthesis of the corresponding tetrakis(uracil)
linked to ester-amide core linkage 8 via the direct reaction of the bis(aldehyde) 7 with four equivalents of 6-
aminouracil 2 in acetic acid. Unfortunately, trials to cyclize 8 into bis(decahydropyrido[2,3-d:6,5-
d']dipyrimidin-5-yl)phenoxy)acetamide) 9 upon heating 2 in acetic acid / p-TSA were unsuccessful (Scheme 5).
The aldehyde containing ester-amide linkage 7 was prepared via the reaction of the potassium salt of the p-
formylbenzoic acid 6 with the corresponding bis(2-chloroacetamide) 5 in boiling DMF.74
Scheme 5. Unsuccessful trial to obtain bis(decahydropyrido[2,3-d:6,5-d']dipyrimidin-5-yl)phenoxy)-acetamide)
9. Only tetrakis(6-aminopyrimidine-2,4-dione) 8 was obtained.
Page 6
©AUTHOR(S)

Arkivoc 2020, part _, 0-0
Abdelmoniem, A. M. et al.
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 6-
aminouracil 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
1
13
spectra were recorded using a FTIR Bruker–vector 22 spectrophotometer as KBr pellets. The H and C NMR
spectra were recorded in DMSO–d6 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
Page 7
©AUTHOR(S)

Arkivoc 2020, part _, 0-0
Abdelmoniem, A. M. et al.
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.
N,N'-(Ethane-1,2-diyl)bis(2-(2-(bis(6-amino-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)methyl)phenoxy)-
acetamide) (3a). Pale yellow powder (88%). mp 270-272 °C. IR (KBr): ν 3344, 3155 (NH and NH2), 1708 (CO).
1H NMR (300 MHz, DMSO-d6): δ 3.30 (br, 4H, CH2N), 4.31 (s, 4H, CH2O), 5.38 (s, 2H, CH), 6.47 (br, 8H, NH2),
6.83-7.15 (m, 8H, Ar-H), 7.48 (br, 2H, NH), 10.30 (br, 4H, NH), 10.42 (br, 4H, NH). 13C NMR (100 MHz, DMSO-
d6): δ 29.7, 36.3, 68.1, 112.8, 121.3, 127.2, 128.4, 129.2, 150.2, 153.9, 156.0, 162.8, 165.6, 168.4. MS (EI, 70
eV): m/z (%) 856 [M+]. Anal. Calcd for C36H36N14O12: C, 50.47; H, 4.24; N, 22.89 found C, 50.73; H, 4.43; N,
23.13.
N,N'-(Ethane-1,2-diyl)bis(2-(3-(bis(6-amino-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)methyl)phenoxy)-
acetamide) (3b). Pale yellow powder (85%). mp 288-290 °C. IR (KBr): ν 3325, 3147 (NH and NH2), 1712 (CO). 1H
NMR (400 MHz, DMSO-d6): δ 3.24 (br, 4H, CH2N), 4.36 (s, 4H, CH2O), 5.30 (s, 2H, CH), 6.70-7.15 (m, 16H,
NH2+Ar-H), 8.19 (br, 2H, NH), 10.32 (br, 4H, NH), 10.51 (br, 4H, NH). MS (EI, 70 eV): m/z (%) 856 [M+]. Anal.
Calcd for C36H36N14O12: C, 50.47; H, 4.24; N, 22.89 found C, 50.69; H, 4.07; N, 23.14.
N,N'-(Propane-1,3-diyl)bis(2-(2-(bis(6-amino-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)methyl)phenoxy)-
acetamide) (3c). Pale yellow powder (90%). mp 242-244 °C. IR (KBr): ν 3348, 3171 (NH and NH2), 2978 (NH),
2850 (NH2), 1712 (CO). 1H NMR (300 MHz, DMSO-d6): δ 1.60-1.62 (m,2H, CH2), 3.14-3.17 (m, 4H, CH2N), 4.34
(s, 4H, CH2O), 5.34 (s, 2H, CH), 6.50 (br, 8H, NH2), 6.81-7.11 (m, 8H, Ar-H), 7.14 (br, 2H, NH), 10.45 (br, 8H, NH).
13C NMR (75 MHz, DMSO-d6): δ 20.9, 29.2, 36.1, 67.2, 86.5, 111.8, 120.6, 120.7, 126.6, 128.6, 149.6, 153.4,
155.3, 165.0, 167.5. MS (EI, 70 eV): m/z (%) 870 [M+]. Anal. Calcd for C37H38N14O12: C, 51.03; H, 4.40; N, 22.52
found C, 51.31; H, 4.66; N, 22.25.
N,N'-(Propane-1,3-diyl)bis(2-(3-(bis(6-amino-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)methyl)phenoxy)-
acetamide) (3d). Pale yellow powder (87%). mp > 300 °C. IR (KBr): ν 3325, 3178 (NH and NH2), 1724 (CO). 1H
NMR (300 MHz, DMSO-d6): δ 1.57-1.64 (m, 2H, CH2), 3.11-3.13 (m, 4H, CH2N), 4.37 (s, 4H, CH2O), 5.30 (s, 2H,
CH), 6.69 (br, 8H, NH2), 6.72-7.13 (m, 8H, Ar-H), 8.08 (br, 2H, NH), 10.28 (br, 4H, NH), 10.47 (br, 4H, NH). 13C
NMR (100 MHz, DMSO-d6): δ 29.7, 32.9, 36.2, 67.5, 110.8, 114.6, 120.4, 129.1, 138.0, 142.0, 150.2, 158.0,
167.8, 168.2, 172.7. MS (EI, 70 eV): m/z (%) 870 [M+]. Anal. Calcd for C37H38N14O12: .C, 51.03; H, 4.40; N, 22.52
found C, 51.32; H, 4.60; N, 22.20.
N,N'-(Butane-1,4-diyl)bis(2-(2-(bis(6-amino-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)methyl)phenoxy)-
acetamide) (3e). Pale yellow powder (91%). mp 242-244 °C. IR (KBr): ν 3429, 3367, 3179 (NH and NH2), 1724
(CO). 1H NMR (300 MHz, DMSO-d6): ): δ 1.42 (br, 4H, CH2), ), 3.16 (br, 4H, CH2N), 4.34 (s, 4H, CH2O), ), 5.34 (s,
2H, CH), 6.46 (br, 8H, NH2), 6.83-7.11 (m, 8H, Ar-H), 7.12 (br, 2H, NH), 10.33 (br, 4H, NH), 10.42 (br, 4H, NH) ).
MS (EI, 70 eV): m/z (%) 884 [M+]. Anal. Calcd for C38H40N14O12: C, 51.58; H, 4.56; N, 22.16 found C, 51.84; H,
4.75; N, 22.45.
N,N'-(Butane-1,4-diyl)bis(2-(3-(bis(6-amino-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)methyl)phenoxy)-
acetamide)(3f). Pale yellow powder (88%). mp 284-286 °C. IR (KBr): ν 3379, 3125 (NH and NH2), 1708 (CO). 1H
NMR (300 MHz, DMSO-d6): ): δ 1.41 (br, 4H, CH2), 3.12 (br, 4H, CH2N), 4.35 (s, 4H, CH2O), 5.29 (s, 2H, CH), 6.68
13
(br, 8H, NH2), 6.70-7.13 (m, 8H, Ar-H), 8.03 (br, 2H, NH), 10.28 (br, 4H, NH), 10.47 (br, 4H, NH). C NMR (100
MHz, DMSO-d6): δ 27.1, 32.8, 38.5, 67.4, 110.7, 114.5, 120.3, 129.0, 142.0, 150.2, 158.0, 158.9, 165.1, 168.0,
Page 8
©AUTHOR(S)

Arkivoc 2020, part _, 0-0
Abdelmoniem, A. M. et al.
172.8. MS (EI, 70 eV): m/z (%) 884[M+]. Anal. Calcd for C38H40N14O12: C, 51.58; H, 4.56; N, 22.16 found C,
51.35; H, 4.35; N, 22.42.
N,N'-(1,3-Phenylenebis(methylene))bis(2-(3-(bis(6-amino-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-
methyl)phenoxy)acetamide) (3g). Pale yellow powder (89%). mp 296-298 °C. IR (KBr): ν 3356, 3152 (NH and
NH2), 1716 (CO). 1H NMR (300 MHz, DMSO-d6): 4.30-4.32 (d, J = 5.7 Hz, 4H, CH2N), 4.44 (s, 4H, CH2O), 5.30 (s,
2H, CH), 6.70 (br, 8H, NH2), 6.73-7.15 (m, 12H, Ar-H), 8.59-8.62 (t, J = 6.6 Hz, 2H, NH), 10.29 (br, 4H, NH), 10.47
(br, 4H, NH). 13C NMR (100 MHz, DMSO-d6): δ 33.1, 42.2, 67.4, 110.7, 114.6, 120.3, 126.2, 126.8, 128.7, 129.0,
139.8, 139.9, 142.0, 150.2, 158.0, 167.9, 168.2, 172.8. MS (EI, 70 eV): m/z (%) 932[M+]. Anal. Calcd for
C42H40N14O12: C, 54.08; H, 4.32; N, 21.02 found C, 53.89; H, 4.12; N, 21.22.
((1,3-Phenylenebis(methylene))bis(azanediyl))bis(2-oxoethane-2,1-diyl)bis(4-(bis(6-amino-2,4-dioxo-1,2,3,4-
tetrahydropyrimidin-5-yl)methyl)benzoate) (8). Pale yellow powder (86%). mp 294-296 °C. IR (KBr): ν 3368,
3151 (NH and NH2), 1713 (CO), 1624 (CO). 1H NMR (300 MHz, DMSO-d6): 4.30-4.32 (d, J = 5.4 Hz, 4H, CH2N),
4.75 (s, 4H, CH2O), 5.36 (s, 2H, CH), 6.71 (br, 8H, NH2), 7.14-7.16 (m, 4H, Ar-H),7.23-7.26 (d, J = 8.7 Hz, 4H, Ar-
13
H), 7.87-7.90 (d, J = 8.7Hz, 4H, Ar-H), 8.60-8.62 (t, J = 6 Hz, 2H, NH), 10.33 (br, 4H, NH), 10.52 (br, 4H, NH). C
NMR (100 MHz, DMSO-d6): δ 33.3, 42.3, 63.3, 126.1, 126.6, 127.4, 128.8, 129.6, 130.0, 130.7, 139.7, 146.7,
150.2, 164.7, 165.9, 167.3, 172.5. MS (EI, 70 eV): m/z (%) 988[M+]. Anal. Calcd for C44H40N14O14: C, 53.44; H,
4.08; N, 19.83 found C, 53.70; H, 3.86; N, 19.64.
General procedure for the synthesis of 4a-d. A solution of each of bisaldehydes (1a, 1c, 1e and 1h) (1 mmol)
and 6-aminouracil (4 mmol) in acetic acid (3 ml) in the presence of p-TSA was heated at reflux for 1 h. The solid
obtained was collected and crystallized from DMF/EtOH to give compounds 4a-d.
N,N'-(Ethane-1,2-diyl)bis(2-(2-(2,4,6,8-tetraoxo-1,2,3,4,5,6,7,8,9,10-decahydropyrido[2,3-d:6,5-d']-
dipyrimidin-5-yl)phenoxy)acetamide) (4a). Pale yellow powder (93%). mp >300 °C. IR (KBr): ν 3070 (NH), 1690
(CO). 1H NMR (300 MHz, DMSO-d6): 3.24 (br, 4H, CH2N), 4.46 (s, 4H, CH2O), 5.13 (s, 2H, Pyridine-H), 6.72-7.10
(m,10H, Ar-H+NH), 8.41 (br, 2H, NHCO), 10.64 (br, 4H, NH), 11.18 (br, 4H, NH). 13C NMR (100 MHz, DMSO-d6):
δ 26.3, 38.3, 67.5, 90.2, 111.5, 121.5, 127.6, 130.0, 136.1, 144.1, 150.2, 154.7, 163.1, 170.0. MS (EI, 70 eV):
m/z (%) 822[M+]. Anal. Calcd for C36H30N12O12: C, 52.56; H, 3.68; N, 20.43 found C, 52.77; H, 3.44; N, 20.61.
N,N'-(Propane-1,3-diyl)bis(2-(2-(2,4,6,8-tetraoxo-1,2,3,4,5,6,7,8,9,10-decahydropyrido[2,3-d:6,5-d']-
dipyrimidin-5-yl)phenoxy)acetamide) (4b). Pale yellow powder (91%). mp >300 °C. IR (KBr): ν 3035 (br, NH),
1690 (CO). 1H NMR (300 MHz, DMSO-d6): 1.50-1.60 (m, 2H, CH2), 3.04-3.10 (m, 4H, CH2N), 4.49 (s, 4H, CH2O),
5.14 (s, 2H, Pyridine-H), 6.72-7.12 (m, 10H, Ar-H+NH), 8.34 (br, 4H, NHCO), 10.65 (br, 4H, NH), 11.18 (br, 4H,
NH). 13C NMR (100 MHz, DMSO-d6): δ 29.2, 36.6, 38.3, 67.6, 90.2, 111.5, 121.6, 127.7, 130.2, 135.8, 144.3,
150.3, 154.6, 163.2, 168.7. MS (EI, 70 eV): m/z (%) 836 [M+]. Anal. Calcd for C37H32N12O12: C, 53.11; H, 3.85; N,
20.09 found C, 52.89; H, 4.10; N, 20.30.
N,N'-(Butane-1,4-diyl)bis(2-(2-(2,4,6,8-tetraoxo-1,2,3,4,5,6,7,8,9,10-decahydropyrido[2,3-d:6,5-d']-
dipyrimidin-5-yl)phenoxy)acetamide) (4c). Pale yellow powder (94%). mp 294-296 °C. IR (KBr): ν 3032 (br,
NH), 1690 (CO). 1H NMR (300 MHz, DMSO-d6): δ 1.26 (br, 4H, CH2), 3.05 (br, 4H, CH2N), 4.50 (s, 4H, CH2O),
5.15 (s, 2H, Pyridine -H), 6.70-7.10 ( m, 10H, Ar-H+NH), 8.35 (br, 2H, NH), 10.72 (br, 4H, NH), 11.15 (br, 4H,
NH). 13C NMR (75 MHz, DMSO-d6): 26.6, 37.8, 38.6, 67.0, 89.6, 110.9, 120.2, 121.0, 127.0, 129.4, 135.4, 143.8,
153.9, 162.5, 168.0. MS (EI, 70 eV): m/z (%) 850 [M+]. Anal. Calcd for C38H34N12O12: C, 53.65; H, 4.03; N, 19.76
found C, 53.84; H, 3.79; N, 20.02.
N,N'-(1,3-Phenylenebis(methylene))bis(2-(2-(2,4,6,8-tetraoxo-1,2,3,4,6,7,8,9-octahydropyrido[2,3-d:6,5-
d']dipyrimidin-5-yl)phenoxy)acetamide) (4d). Pale yellow powder (89%). mp >300 °C. IR (KBr): ν 3201 (NH),
3070 (br, NH), 1705 (CO). 1H NMR (300 MHz, DMSO-d6): δ 4.19-4.21(d, J = 6.3 Hz, 4H, CH2N), 4.78 (s, 4H, CH2O),
Page 9
©AUTHOR(S)

Arkivoc 2020, part _, 0-0
Abdelmoniem, A. M. et al.
6.90-7.31 (m, 14H, Ar-H+NH), 7.76-7.78 (t, J = 6.3 Hz, 2H, NHCO), 11.15 (br, 4H, NH), 11.84 (br, 4H, NH). MS (EI,
70 eV): m/z (%) 894 [M+]. Anal. Calcd for C42H30N12O12: C, 56.38; H, 3.38; N, 18.78 found C, 56.17; H, 3.56; N,
19.04.
Supplementary Material
Supplementary material related to this article, including Nuclear Magnetic Resonance (1H and 13C NMR) figures
for all new compounds are available in the online version of the text.
References
1. Shamim, T.; Gupta, M.; Paul, S. J. Mol. Catal. A Chem. 2009, 302, 15–19.
https://doi.org/10.1016/j.molcata.2008.11.024
2. Gómez-Pliego, R.; Gómez-Zamudio, J.; Velasco-Bejarano, B.; Ibarra-Barajas, M.; Villalobos-Molina, R. J.
Pharmacol. Sci. 2013, 122, 184–192.
https://doi.org/10.1254/jphs.12248FP
3. Ibrahim, N.S.; Mohamed, M.F.; Elwahy, A.H.M.; Abdelhamid, I.A. Lett. Drug Des. Discov. 2018, 15, 1036–
1045.
https://doi.org/10.2174/1570180815666180105162323
4. Sridhar, R.; Perumal, P.T. Tetrahedron 2005, 61, 2465–2470.
https://doi.org/10.1016/j.tet.2005.01.008
5. Paul, S.; Sharma, S.; Gupta, M.; Choudhary, D.; Gupta, R. Bull. Korean Chem. Soc. 2007, 28, 336–338.
https://doi.org/10.5012/bkcs.2007.28.2.336
6. Saikh, F.; De, R.; Ghosh, S. Tetrahedron Lett. 2014, 55, 6171–6174.
https://doi.org/10.1016/j.tetlet.2014.09.025
7. Sridharan, V.; Perumal, P.T.; Avendaño, C.; Menéndez, J.C. Tetrahedron 2007, 63, 4407–4413.
https://doi.org/10.1016/j.tet.2007.03.092
8. Navidpour, L.; Shafaroodi, H.; Miri, R.; Dehpour, A.R.; Shafiee, A. Farmaco 2004, 59, 261–269.
https://doi.org/10.1016/j.farmac.2003.11.013
9. Debache, A.; Ghalem, W.; Boulcina, R.; Belfaitah, A.; Rhouati, S.; Carboni, B. Tetrahedron Lett. 2009, 50,
5248–5250.
https://doi.org/10.1016/j.tetlet.2009.07.018
10. Miri, R.; Javidnia, K.; Hemmateenejad, B.; Tabarzad, M.; Jafarpour, M. Chem. Biol. Drug Des. 2009, 73,
225–235.
https://doi.org/10.1111/j.1747-0285.2008.00770.x
11. Abbas, H.A.S.; El Sayed, W.A.; Fathy, N.M. Eur. J. Med. Chem. 2010, 45, 973–982.
https://doi.org/10.1016/j.ejmech.2009.11.039
12. Safak, C.; Simsek, R. Mini-Reviews Med. Chem. 2006, 6, 747–755.
https://doi.org/10.2174/138955706777698606
13. Murthy, Y.L.N.; Rajack, A.; Taraka Ramji, M.; Jeson Babu, J.; Praveen, C.; Aruna Lakshmi, K. Bioorganic
Med. Chem. Lett. 2012, 22, 6016–6023.
https://doi.org/10.1016/j.bmcl.2012.05.003
Page 10
©AUTHOR(S)

Arkivoc 2020, part _, 0-0
Abdelmoniem, A. M. et al.
14. Samzadeh-Kermani, A.; Shafaroodi, H.; Miri, R.; Mirkhani, H.; Vosooghi, M.; Shafiee, A. Med. Chem. Res.
2009, 18, 112–126.
https://doi.org/10.1007/s00044-008-9112-5
15. Huber, I.; Wappl, E.; Herzog, A. Biochem. J. 2000, 836, 829–836.
https://doi.org/10.1042/bj3470829
16. Ghozlan, S.A.S.; Ramadan, M.A.; Abdelmoniem, A.M.; Elwahy, A.H.M.; Abdelhamid, I.A. Turkish J. Chem.
2017, 41, 410 – 419.
https://doi.org/10.3906/kim-1609-42
17. Kassab, R.M.; Elwahy, A.H.M.; Abdelhamid, I.A. Monat. Chem. 2016, 147, 1227–1232.
https://doi.org/10.1007/s00706-015-1644-z
18. Mohamed, M.F.; Darweesh, A.F.; Elwahy, A.H.M.; Abdelhamid, I.A. RSC Adv. 2016, 6, 40900–40910.
https://doi.org/10.1039/c6ra04974e
19. Abdelhamid, I.A.; Darweesh, A.F.; Elwahy, A.H.M. Tetrahedron Lett. 2015, 56, 7085–7088.
https://doi.org/10.1016/j.tetlet.2015.11.015
20. Fathalla, M.; Lawrence, C.M.; Zhang, N.; Sessler, J.L.; Jayawickramarajah, J. Chem. Soc. Rev. 2009, 38,
1608–1620.
https://doi.org/10.1039/b806484a
21. Sivakova, S.; Rowan, S.J. Chem. Soc. Rev. 2005, 34, 9–21.
https://doi.org/10.1039/b304608g
22. Dinner, A.R.; Blackburn, G.M.; Karplus, M. Nature 2001, 413, 752–755.
https://doi.org/10.1038/35099587
23. Di Noia, J.; Neuberger, M.S. Nature 2002, 419, 43–48.
https://doi.org/10.1038/nature00981
24. Tucci, F.C.; Zhu, Y.F.; Guo, Z.; Gross, T.D.; Connors Jr., P.J.; Gao, Y.; Rowbottom, M.W.; Struthers, R.S.;
Reinhart, G.J.; Xie, Q.; et al. J Med Chem 2004, 47, 3483–3486.
https://doi.org/10.1021/jm049791w
25. Sutherlin, D.P.; Sampath, D.; Berry, M.; Castanedo, G.; Chang, Z.; Chuckowree, I.; Dotson, J.; Folkes, A.;
Friedman, L.; Goldsmith, R.; Heffron, T.; Lee, L.; Lesnick, J.; Lewis, C.; Mathieu, S.; Nonomiya, J.;
Olivero, A.; Pang, J.; Prior, W. W.; Salphati, L.; Sideris, S.; Tian, Q.; Tsui, V.; Wan, N. C.; Wang, S.;
Wiesmann, C.; Wong, S.; Zhu, B. Y. J. Med. Chem. 2010, 53, 1086–1097.
https://doi.org/10.1021/jm901284w
26. Brognara, E.; Lampronti, I.; Breveglieri, G.; Accetta, A.; Corradini, R.; Manicardi, A.; Borgatti, M.; Canella,
A.; Multineddu, C.; Marchelli, R.; et al. Eur. J. Pharmacol. 2011, 672, 30–37.
https://doi.org/10.1016/j.ejphar.2011.09.024
27. Liu, Y.Y.; Zeng, S.Y.; Leu, Y.L.; Tsai, T.Y. J. Agric. Food Chem. 2015, 63, 7333–7342.
https://doi.org/10.1021/acs.jafc.5b01649
28. Tobe, M.; Isobe, Y.; Goto, Y.; Obara, F.; Tsuchiya, M.; Matsui, J.; Hirota, K.; Hayashi, H. Bioorganic Med.
Chem. 2000, 8, 2037–2047.
https://doi.org/10.1016/S0968-0896(00)00126-7
29. Sapozhnikova, K.A.; Slesarchuk, N.A.; Orlov, A.A.; Khvatov, E. V.; Radchenko, E. V.; Chistov, A.A.; Ustinov,
A. V.; Palyulin, V.A.; Kozlovskaya, L.I.; Osolodkin, D.I.; et al. RSC Adv. 2019, 9, 26014–26023.
https://doi.org/10.1039/c9ra06313g
30. Geant, P.Y.; Uttaro, J.P.; Périgaud, C.; Mathé, C. Molecules 2020, 25, 3708.
https://doi.org/10.3390/molecules25163708
Page 11
©AUTHOR(S)

Arkivoc 2020, part _, 0-0
Abdelmoniem, A. M. et al.
31. Maslova, A.A.; Matyugina, E.S.; Snoeck, R.; Andrei, G.; Kochetkov, S.N.; Khandazhinskaya, A.L.; Novikov,
M.S. Molecules 2020, 25.
https://doi.org/10.3390/molecules25153350
32. Fatma, S.; Bishnoi, A.; Singh, V.; Al-Omary, F.A.M.; El-Emam, A.A.; Pathak, S.; Srivastava, R.; Prasad, O.;
Sinha, L. J. Mol. Struct. 2016, 1110, 128–137.
https://doi.org/10.1016/j.molstruc.2016.01.054
33. Suresh, T.; Nandha Kumar, R.; Mohan, P.S. Heterocycl. Commun. 2003, 9, 203–208.
https://doi.org/10.1515/HC.2003.9.2.203
34. Maddila, S.; Naicker, K.; Gorle, S.; Rana, S.; Yalagala, K.; N. Maddila, S.; Singh, M.; Singh, P.; B.
Jonnalagadda, S. Anticancer. Agents Med. Chem. 2016, 16, 1031–1037.
https://doi.org/10.2174/1871520616666151123095932
35. Neamati, N. Expert Opin. Investig. Drugs 2003, 12, 289–292.
https://doi.org/10.1517/13543784.12.2.289
36. Pannecouque, C.; Pluymers, W.; Van Maele, B.; Tetz, V.; Cherepanov, P.; De Clercq, E.; Witvrouw, M.;
Debyser, Z. Curr. Biol. 2002, 12, 1169–1177.
https://doi.org/10.1016/S0960-9822(02)00952-1
37. Elwahy, A.H.M.; Shaaban, M.R. Curr. Org. Synth. 2015, 11, 835–873.
https://doi.org/10.2174/157017941106141023114039
38. Zhu, J.; Bienaymé, H. Multicomponent Reactions; Zhu, J., Bienaymé, H., Eds.; Wiley-VCH: Weinheim,
Germany, 2005; ISBN 3527308067.
39. Elwahy, A.; Shaaban, M. Curr. Org. Synth. 2010, 7, 433–454.
https://doi.org/10.2174/157017910792246117
40. Elwahy, A.H.M.; Shaaban, M.R. Curr. Org. Synth. 2015, 10, 425–466.
https://doi.org/10.2174/1570179411310030007
41. Shaaban, M.R.; Elwahy, A.H.M. Curr. Org. Synth. 2015, 11, 471–525.
https://doi.org/10.2174/15701794113106660076
42. Khoobi, M.; Ramazani, A.; Foroumadi, A.; Souldozi, A.; Ślepokura, K.; Lis, T.; Mahyari, A.; Shafiee, A.; Joo,
S.W. Helv. Chim. Acta 2013, 96, 906–918.
https://doi.org/10.1002/hlca.201200187
43. Zareai, Z.; Khoobi, M.; Ramazani, A.; Foroumadi, A.; Souldozi, A.; Ślepokura, K.; Lis, T.; Shafiee, A.
Tetrahedron 2012, 68, 6721–6726.
https://doi.org/10.1016/j.tet.2012.05.112
44. Khoobi, M.; Ramazani, A.; Mahdavi, M.; Foroumadi, A.; Emami, S.; Joo, S.W.; Ślepokura, K.; Lis, T.;
Shafiee, A. Helv. Chim. Acta 2014, 97, 847–853.
https://doi.org/10.1002/hlca.201300310
45. Ramazani, A.; Khoobi, M.; Torkaman, A.; Zeinali Nasrabadi, F.; Forootanfar, H.; Shakibaie, M.; Jafari, M.;
Ameri, A.; Emami, S.; Faramarzi, M.A.; et al. Eur. J. Med. Chem. 2014, 78, 151–156.
https://doi.org/10.1016/j.ejmech.2014.03.049
46. Sanad, S.M.H.; Kassab, R.M.; Abdelhamid, I.A.; Elwahy, A.H.M. Heterocycles 2016, 92, 910–924.
https://doi.org/10.3987/COM-16-13441
47. Sharma, M.G.; Rajani, D.P.; Patel, H.M. R. Soc. Open Sci. 2017, 4, 170006.
https://doi.org/10.1098/rsos.170006
48. Patel, D.M.; Patel, H.J.; Padrón, J.M.; Patel, H.M. RSC Adv. 2020, 10, 19600–19609.
https://doi.org/10.1039/D0RA02990D
Page 12
©AUTHOR(S)

Arkivoc 2020, part _, 0-0
Abdelmoniem, A. M. et al.
49. Patel, D.M.; Sharma, M.G.; Vala, R.M.; Lagunes, I.; Puerta, A.; Padrón, J.M.; Rajani, D.P.; Patel, H.M.
Bioorg. Chem. 2019, 86, 137–150.
https://doi.org/10.1016/j.bioorg.2019.01.029
50. Patel, D.M.; Patel, H.M. ACS Sustain. Chem. Eng. 2019, 7, 18667–18676.
https://doi.org/10.1021/acssuschemeng.9b05184
51. Santosh, R.; Paul, P.; Selvam, M.K.; Raril, C.; Krishna, P.M.; Manjunatha, J.G.; Nagaraja, G.K.
ChemistrySelect 2019, 4, 990–996.
https://doi.org/https://doi.org/10.1002/slct.201803416
52. Darwish, E.S.; Abdelhamid, I.A.; Nasra, M.A.; Abdel-Gallil, F.M.; Fleita, D.H. Helv. Chim. Acta 2010, 93,
1204–1208.
https://doi.org/10.1002/hlca.200900355
53. Abdelhamid, I.A.; Ghozlan, S.A.S.; Kolshorn, H.; Meier, H.; Elnagdi, M.H. Heterocycles 2007, 71, 2627–
2637.
https://doi.org/10.3987/com-07-11141
54. Ghozlan, S.A.S.; Abdelhamid, I.A.; Gaber, H.M.; Elnagdi, M.H. J. Heterocycl. Chem. 2005, 42, 1185–1189.
https://doi.org/10.1002/jhet.5570420623
55. Ghozlan, S.A.S.; Ahmed, A.G.; Abdelhamid, I.A. J. Heterocycl. Chem. 2016, 53, 817–823.
https://doi.org/10.1002/jhet.2341
56. Abdelhamid, I.A.; Darwish, E.S.; Nasra, M.A.; Abdel-Gallil, F.M.; Fleita, D.H. Synthesis (Stuttg). 2010,
1107–1112.
https://doi.org/10.1055/s-0029-1219235
57. Abdella, A.M.; Moatasim, Y.; Ali, M.A.; Elwahy, A.H.M.; Abdelhamid, I.A. J. Heterocycl. Chem. 2017, 54,
1854–1862.
https://doi.org/10.1002/jhet.2776
58. Abdelmoniem, A.M.; Ghozlan, S.A.S.; Abdelmoniem, D.M.; Elwahy, A.H.M.; Abdelhamid, I.A. J. Heterocycl.
Chem. 2017, 54, 2844–2849.
https://doi.org/10.1002/jhet.2890
59. Abdelmoniem, A.M.; Salaheldin, T.A.; Abdelhamid, I.A.; Elwahy, A.H.M. J. Heterocycl. Chem. 2017, 54,
2670–2677.
https://doi.org/10.1002/jhet.2867
60. Darweesh, A.F.; Abd El-Fatah, N.A.; Abdelhamid, I.A.; Elwahy, A.H.M.; Salem, M.E. Synth. Commun. 2020,
50, 2531–2544.
https://doi.org/10.1080/00397911.2020.1784436
61. Eid, E.M.; Hassaneen, H.M.E.; Abdelhamid, I.A.; Elwahy, A.H.M. J. Heterocycl. Chem. 2020, 57, 2243–
2255.
https://doi.org/10.1002/jhet.3945
62. Abdella, A.M.; Abdelmoniem, A.M.; Abdelhamid, I.A.; Elwahy, A.H.M. J. Heterocycl. Chem. 2020, 57,
1476–1523.
https://doi.org/10.1002/jhet.3883
63. Abdella, A.M.; Mohamed, M.F.; Mohamed, A.F.; Elwahy, A.H.M.; Abdelhamid, I.A. J. Heterocycl. Chem.
2018, 55, 498–507.
https://doi.org/10.1002/jhet.3072
64. Salama, S.K.; Mohamed, M.F.; Darweesh, A.F.; Elwahy, A.H.M.; Abdelhamid, I.A. Bioorg. Chem. 2017, 71,
19–29.
Page 13
©AUTHOR(S)

Arkivoc 2020, part _, 0-0
Abdelmoniem, A. M. et al.
https://doi.org/10.1016/j.bioorg.2017.01.009
65. Salama, S.K.; Darweesh, A.F.; Abdelhamid, I.A.; Elwahy, A.H.M. J. Heterocycl. Chem. 2017, 54, 305–312.
https://doi.org/10.1002/jhet.2584
66. Salem, M.E.; Darweesh, A.F.; Mekky, A.E.M.; Ahmad M. Farag, A.; Elwahy, and A.H.M. J. Heterocycl.
Chem. 2017, 54, 226–234.
https://doi.org/10.1002/jhet.2571
67. El-Fatah, N.A.A.; Darweesh, A.F.; Mohamed, A.A.; Abdelhamid, I.A.; Elwahy, A.H.M. Monatshefte fur
Chemie 2017, 148, 2107–2122.
https://doi.org/10.1007/s00706-017-2040-7
68. Abd El-Fatah, N.A.; Darweesh, A.F.; Mohamed, A.A.; Abdelhamid, I.A.; Elwahy, A.H.M. Tetrahedron 2017,
73, 1436–1450.
https://doi.org/10.1016/j.tet.2017.01.047
69. Diab, H.M.; Abdelhamid, I.A.; Elwahy, A.H.M. Synlett 2018, 29, 1627–1633.
https://doi.org/10.1055/s-0037-1609967
70. M. Abdella, A.; H. M. Elwahy, A.; A. Abdelhamid, I. Curr. Org. Synth. 2016, 13, 601–610.
https://doi.org/10.2174/1570179413999151211115100
71. Al-Awadi, N.A.; Abdelhamid, I.A.; Al-Etaibi, A.M.; Elnagdi, M.H. Synlett 2007, 2205–2208.
https://doi.org/10.1055/s-2007-985573
72. Abdelhamid, I.A.; Darwish, E.S.; Nasra, M.A.; Abdel-Gallil, F.M.; Fleita, D.H. Arkivoc 2008, 2008, 117–121.
https://doi.org/10.3998/ark.5550190.0009.h11
73. Al-Awadi, N.A.; Ibrahim, M.R.; Abdelhamid, I.A.; Elnagdi, M.H. Tetrahedron 2008, 64, 8202–8205.
https://doi.org/10.1016/j.tet.2008.06.026
74. Abdella, A.M.; Abdelmoniem, A.M.; Ibrahim, N.S.; El-Hallouty, S.M.; Abdelhamid, I.A.; Elwahy, A.H.M.
Mini-Reviews Med. Chem. 2019, 20, 801–816.
https://doi.org/10.2174/1389557519666190919160019
75. Abdelmoniem, A.M.; Ghozlan, S.A.S.; Butenschön, H.; Abdelmoniem, D.M.; Elwahy, A.H.M.; Abdelhamid,
I.A. Arkivoc 2019, 2019, 163–177.
https://doi.org/10.24820/ark.5550190.p010.875
This paper is an open access article distributed under the terms of the Creative Commons Attribution (CC BY)
license (http://creativecommons.org/licenses/by/4.0/
Page 14
©AUTHOR(S)