Home Two independent and consecutive Michael addition of 1,3-dimethylbarbituric acid to (2,6-diarylidene)cyclohexanone: Flying-bird-shaped 2D-polymeric structure
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Two independent and consecutive Michael addition of 1,3-dimethylbarbituric acid to (2,6-diarylidene)cyclohexanone: Flying-bird-shaped 2D-polymeric structure

  • Nader Noroozi Pesyan EMAIL logo , Saman Mousavi and Ertan Şahin
Published/Copyright: April 25, 2022
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Heterocyclic Communications
From the journal Heterocyclic Communications Volume 28 Issue 1

Abstract

Two independent and consecutive intermolecular Michael addition of 1,3-dimethylbarbituric acid to 2,6-diarylidenecyclohexanone as an α,β-unsaturated ketone leads to synthesis of a new type of meso form 5,5′-((2-oxocyclohexane-1,3-diyl)bis(arylmethylene))bis(1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione) in good yield. These compounds showed a 2D-polymeric structure via intermolecular H-bonds. Structure elucidation is carried out by 1H NMR, 13C NMR, FT-IR, and X-ray diffraction analyses. A plausible reaction mechanism is discussed.

Graphical abstract

Keywords: crossed-aldol condensation; consecutive Michael addition; 1,3-dimethylbarbituric acid; conformation; bifurcated H-bond

1 Introduction

The crossed-aldol and Claisen–Schmidt reactions are a synthetic procedure for the preparation of α,α′-bis(substituted benzylidene)cycloalkanones as starting compounds for obtaining pyrimidine derivatives with biological properties [1,2,3,4,5]. Owing to their uses as an intermediate in pharmaceutical, agrochemical, and perfume industries, therefore, there is a need for much attention in these cases [6,7,8,9], as a free radical scavenger in biological systems [10], and as polymeric liquid crystal units [11,12,13,14]. The aldol condensation reaction is useful for forming carbon–carbon double bonds in many compounds comprising the carbonyl functional group [15,16,17]. Crossed-aldol condensation can be done in the presence of strong bases or acids [2,18]. Previously, several routes have been reported for catalytic crossed-aldol condensation reactions [4,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36].

The Michael addition is one of the most important and useful reactions in organic synthesis to form C–C and C-heteroatom bonds due to its atom economy [37,38,39]. Thia Michael reaction of thiols with benzylidenecyclohexanone was reported by Mallik et al. [40], and meso structures were obtained. Several double aza-Michael were also reported in the literature, such as the synthesis of pyrrolidine Lobelia alkaloid analogues diastereoselectively under ultrasonic conditions [41], double aza-Michael addition reaction within a Sapphyrin core [42], for the synthesis of hexahydroacridine-1,8(2H,5H)-diones [43], etc. Among these Michael-type reactions, the C–C bond formation is more important than the C-heteroatom due to the formation of the large molecular structure of carbon skeleton.

For the spiro barbiturates based on bis-arylideneacetones, there are some reports in the literature. Instead, according to our search in the literature [44,45], there is no report about the synthesis of spiro barbiturates based on 2,6-bis-arylidenecyclohexanones. Therefore, herein, we would like to report a new method for the synthesis of 5,5′-((2-oxocyclohexane-1,3-diyl)bis(phenylmethylene))bis(1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione) by means of condensation reaction of 1,3-dimethylbarbituric acid with 2,6-dibenzylidenecyclohexanone derivatives.

2 Results and discussion

This article describes two independent and consecutive Michael additions of 1,3-dimethylbarbituric acid (4) to crossed conjugated aldol adducts (2,6-di((E)-arylidene)cyclohexan-1-one, 3) that afforded a new class of 5,5′-((2-oxocyclohexane-1,3-diyl)bis(arylmethylene))bis(1,3-dialkylpyrimidine-2,4,6(1H,3H,5H)-trione) (5) (Scheme 1). In this research, our first aim was focused on the synthesis of spiro bicyclic compounds (6). Expectedly, no 6 was obtained (Scheme 1). However, the synthesis of spiro compounds based on (thio)barbituric acids in the reaction with dibenzalacetones has been reported [44,45]. Reaction conditions, melting points, and yields of compounds 5 are outlined in Table 1.

Scheme 1 Two independent and consecutive Michael addition of 1,3-dimethylbarbituric acid (4) to 3 for the synthesis of 5.
Scheme 1

Two independent and consecutive Michael addition of 1,3-dimethylbarbituric acid (4) to 3 for the synthesis of 5.

Table 1

Reaction conditions, melting points, and yields of compounds 5

Compd. Solvent Temp. (°C) Time (min) M.P. (°C) Yield (%)
5a Ethylene glycol 110 55 252–250 92
5b Ethylene glycol 110 59 274–276 86
5c Ethylene glycol 110 59 261–263 86
5d Ethylene glycol 110 65 270–272 82
5e Ethylene glycol 110 52 247–249 75

The representative mechanism for the formation of 5a is shown in Scheme 2. The nucleophilic attack of 1,3-dimethylbarbituric acid 4 to the β-position of 3a as an α,β-unsaturated carbonyl compound (intermolecular Michael addition) afforded intermediate A and then Michael addition of the second molecule of 4 to intermediate A formed 5a. Owing to the restricted free rotation in 2,6-arylidene cyclohexanone 3, forced to double intermolecular Michael addition (path b). In comparison with the diarylidene acetone (7), in intermediate A, no path a was happened. Instead, in 7, the second intramolecular Michael addition occurred through path a due to the free rotation of a single bond adjacent to the carbonyl group in 7 [44,45] (Scheme 2 and Figure 1). In comparison, 3 in reaction with 4 gave compounds 5 while diarylidene acetone 7 gave spiro compounds 6 [44,45] (Scheme 3).

Scheme 2 Proposed reaction mechanism for the formation of 5a.
Scheme 2

Proposed reaction mechanism for the formation of 5a.

Figure 1 Possible geometric isomers of 3 and 7 [44].
Figure 1

Possible geometric isomers of 3 and 7 [44].

Scheme 3 Comparison of the reaction products derived from 3 and 7.
Scheme 3

Comparison of the reaction products derived from 3 and 7.

Representatively, the IR spectrum of 5a shows the C═O frequencies at 1,749 and 1,682 cm−1 that correspond to saturated carbonyl groups of cyclohexanone and barbituric acid ring moieties, respectively. The 1H NMR spectrum of this compound shows two singlets for N–CH3 protons at δ 2.86 and 2.78 ppm, four multiplets at δ 0.70–1.54 ppm for diastereotopic protons of cyclohexanone moiety, a multiplet at δ 3.38 ppm (essentially, it is a doublet of doublets) for benzylic proton on chiral stereogenic center, a doublet at δ 3.58 ppm for barbituric acid methylene proton, and at δ 6.88–7.28 ppm for phenyl protons. 13C NMR spectrum of this compound shows 15 distinct peaks. The cyclohexanone carbonyl peak extremely shifted to a low field at δ 213.36 ppm, which confirmed the formation of saturated ketone (substituted cyclohexanone). Two carbonyl peaks at δ 171.41 and 151.34 ppm corresponded to barbituric acid carbonyl peaks. Seven peaks at the aliphatic region confirmed the formation of compound 5a (see supplementary material, experimental section, and crystal structure later).

2.1 X-ray data for 5a

The ORTEP diagram of 5a is shown in Figure 2 (up). X-ray analysis of molecule 5a was performed to identify the structure and possible interactions. A perspective view of the polymeric interactions is shown in Figure 3. The crystallographic data for hydrogen bonds and interactions of this compound are shown in Table 2. The structure has a racemic form and crystallizes in the triclinic centrosymmetric space group P1 with two enantiomers in the unit cell. There are two molecules in the unit cell, and the circumference of each one is the same. The structure has an internal plane of symmetry and superimposes on its mirror image, so it is a meso compound. A cyclohexanone scaffold has chair conformation. Two 1,3-dimethylbarbituric acid rings have distorted form. Other large units are attached to the ring from the equatorial positions. The C–C (cyclohexane) distances are in the typical single bond range [1.514(3)–1.544(3) Å]. The O4═C13 double bond is 1.215(3) Å, and the C–N pyrimidine bonds are 1.368–1.393(3) Å. Pyrimidine heterocyclic skeletons are not planar. Deviation from the planarity of the heterocycles is due to significant steric effects and intermolecular interactions. The structure contains four asymmetric carbon atoms, and the stereogenic centers are as follows: C7(R,S), C8(R,S), C12(S,R), and C14(S,R). Intermolecular C–H⋯O [H10A⋯O2 = 2.495 Å, H10A⋯O5 = 2.679 Å, H4⋯O6 = 2.594 Å] interactions lead to the formation of 2D-polymeric structure (Figure 2 (bottom) and Table 2). The π–π interactions in the crystal lattice are insignificant, and the distance between the ring centroids is greater than 5.8 Å.

Figure 2 (Top) Crystal structure of the compound 5a with atom labeling scheme. (Bottom) 2D-polymeric structure of enantiomer 5a. Anisotropic displacement ellipsoids are shown at 40% probability level.
Figure 2

(Top) Crystal structure of the compound 5a with atom labeling scheme. (Bottom) 2D-polymeric structure of enantiomer 5a. Anisotropic displacement ellipsoids are shown at 40% probability level.

Figure 3 A perspective view of the polymeric interactions along with a axis (a) in 5a. Dashed red lines indicate H-bonding geometry.
Figure 3

A perspective view of the polymeric interactions along with a axis (a) in 5a. Dashed red lines indicate H-bonding geometry.

Table 2

Hydrogen-bond geometry (Å, °) in 5a

D—H···A D—H H···A D···A D—H···A Directionality
C12—H12···O5 0.98 2.53 3.136 (3) 120 Weak
C8—H8···O2 0.98 2.42 3.080 (3) 125 Weak
C31—H31···O4 0.98 2.55 3.157 (2) 120 Weak
C21—H21···O4 0.98 2.39 3.051 (2) 124 Weak
C27—H27A···O5i 0.96 2.53 3.389 (3) 150 Weak

Symmetry code: (i) −x + 1, −y + 1, −z + 1.

For crystal structure determination, a single crystal of compound 5a was used for data acquisition on a four-circle Rigaku R-AXIS RAPID-S diffraction meter (equipped with a two-dimensional IP detector). Graphite monochromate Mo-Kα radiation (λ = 0.71073 Å) was used for data collection and oscillation scanning technique with Δw = 5° for an image. The lattice parameters were determined by the least-squares method based on all reflections with F 2 > 2σ (F 2). Integration of intensities, correction for Lorentz and polarization effects, and cell refinement were performed using CrystalClear (Rigaku/MSC Inc., 2005) software [46]. The structure was solved by direct methods using SHELXS-97 [47], which allows the position of most of the heaviest atoms. The remaining non-hydrogen atoms are located from different Fourier maps calculated from successive full-matrix least-squares refinement cycles on F 2 using SHELXL-97 [47]. All non-hydrogen atoms were refined using anisotropic displacement parameters. The hydrogens attached to the carbons were placed in their geometric positions using the appropriate HFIX instructions in SHELXL. The final difference Fourier maps showed no peaks of chemical significance. Crystal data for 5a: C32H34N4O7, crystal system, space group: triclinic, P1; (no:2); unit cell dimensions: a = 7.6135(4), b = 14.6821(9), c = 15.2150(10) Å, α = 62.800(2), β = 83.988(3), γ = 75.238(3)°; volume; 1462.6(2) Å3, Z = 2; calculated density: 1.332 g cm−3; absorption coefficient: 0.095 mm−1; F(000): 620; θ-range for data collection 2.8–26.4°; refinement method: full-matrix least-squares on F 2; data/parameters: 4,795/393; goodness-of-fit on F 2: 1.034; final R-indices [I > 2σ(I)]: R 1 = 0.045, wR 2 = 0.120; largest diff. peak and hole: 0.194 and −0.155 e Å−3. CCDC-2008861 number contains the supplementary crystallographic data for this structure (5a, for more information, see supplementary data). These data are provided free of charge via the joint CCDC/FIZ Karlsruhe deposition service (www.ccdc.cam.ac.uk/structures).

3 Experimental

3.1 General

The drawing and nomenclature of compounds were done by ChemDraw Professional 15.0 version software. Melting points were measured with a digital melting point apparatus (Electrothermal) and were uncorrected. The 1H and 13C NMR spectra were recorded on Bruker 300 FT-NMR at 300 and 75 MHz, respectively (Urmia University, Urmia, Iran). 1H and 13C NMR spectra were obtained on the solution in DMSO-d 6 and/or in CDCl3 as solvents using TMS as the internal standard. The spectral data are reported as: (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet or unresolved, bs = broad singlet and coupling constant(s) in Hz). IR spectra were determined in the region 4,000–400 cm−1 on a NEXUS 670 FT IR spectrometer by preparing KBr pellets (Urmia University, Urmia, Iran). All reactions were monitored by TLC with silica gel-coated plates (EtOAc: cyclohexane/8:10/v:v). Compounds 3 were synthesized based on reported literature [25,44]. Compounds 1a–e, 2, 4 and solvents used were purchased from Merck and Across Companies without further purification.

3.2 Synthesis

3.2.1 General procedures for the preparation of 5

To a 50 mL round bottom flask equipped with a magnetical stirrer, the mixture of 1,3-dimethylbarbituric acid (1.3 mmol, 0.21 g), 2,6-dibenzylidenecyclohexanone (1.3 mmol, 0.36 g), and triethylamine (2.1 mmol, 0.22 g, 0.3 mL) in 10 mL ethylene glycol was added and refluxed for 1 h. The yellow color disappeared and consequently white crystalline solid precipitated, filtered off, washed with few milliliters of cold ethanol and then dried (0.35 g, 92%).

3.2.1.1 5,5′-((2-Oxocyclohexane-1,3-diyl)bis(phenylmethylene))bis(1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione) (5a)

IR (KBr): 3,061, 3,028, 2,986, 2,862, 1,749, 1,682, 1,429, 1,379, 1,118, 751 cm−1; 1H NMR (250 MHz, CDCl3) δ 7.28 (s, 1H), 7.13 (t, J = 11.7 Hz, 2H), 7.02–6.88 (m, 1H), 3.58 (d, J = 5.3 Hz, 1H), 3.38 (t, J = 11.2 Hz, 1H), 2.86 (s, 3H), 2.78 (s, 3H), 2.51 (dq, J = 19.7, 9.0 Hz, 1H), 1.86 (d, J = 14.9 Hz, 1H), 1.54 (q, J = 17.4, 15.5 Hz, 1H), 0.79 (dt, J = 23.6, 13.0 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 213.36, 171.41, 151.34, 134.37, 134.31, 134.27, 129.43, 129.13, 128.74, 128.43, 128.36, 128.17, 50.25, 50.03, 49.62, 48.92, 40.31, 28.39, 27.21, 20.08.

3.2.1.2 5,5′-((2-Oxocyclohexane-1,3-diyl)bis((3-nitrophenyl)methylene))bis(1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione) (5b)

IR (KBr): 3,097, 3,045, 3,005, 1,747, 1,682, 1,531, 1,382, 1,343, 1,244, 702 cm−1; 1H NMR (250 MHz, CDCl3) δ 7.46 (d, J = 9.8 Hz, 1H), 7.29 (s, 1H), 7.20–7.05 (m, 1H), 6.97 (dd, J = 19.8, 10.3 Hz, 1H), 3.59 (d, J = 4.9 Hz, 1H), 3.38 (t, J = 11.1 Hz, 1H), 2.86 (s, 3H), 2.79 (s, 3H), 2.52 (dq, J = 19.6, 9.0 Hz, 1H), 1.87 (d, J = 14.5 Hz, 1H), 1.54 (q, J = 16.6, 15.2 Hz, 1H), 0.79 (dt, J = 23.4, 13.1 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 213.43, 171.40, 151.33, 141.29, 140.48, 127.89, 127.34, 117.12, 116.16, 50.29, 50.03, 49.52, 48.85, 40.19, 28.45, 27.13, 20.30.

3.2.1.3 5,5′-((2-Oxocyclohexane-1,3-diyl)bis((4-nitrophenyl)methylene))bis(1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione) (5c)

IR (KBr): 3,061, 3,031, 3,048, 3,006, 1,747, 1,682, 1,529, 1,429, 1,382, 1,343, 1,244, 703 cm−1; 1H NMR (250 MHz, CDCl3) δ 7.64 (dd, J = 30.5, 14.7 Hz, 2H), 6.67 (dd, J = 19.2, 9.7 Hz, 2H), 3.58 (s, 1H), 3.38 (t, J = 10.6 Hz, 1H), 2.86 (s, 3H), 2.79 (s, 3H), 2.52 (dq, J = 19.4, 8.8 Hz, 1H), 1.95 (s, 1H), 1.86 (d, J = 13.2 Hz, 1H), 1.61–1.48 (m, 2H), 0.88–0.71 (m, 1H). 13C NMR (75 MHz, CDCl3) δ 213.32, 171.49, 151.27, 140.57, 134.61, 129.11, 128.49, 118.15, 117.43, 50.28, 49.94, 49.45, 48.78, 40.21, 28.49, 27.24, 20.43.

3.2.1.4 5,5′-((2-Oxocyclohexane-1,3-diyl)bis((2,4-dichlorophenyl)methylene))bis(1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione) (5d)

IR (KBr): 3,068, 3,032, 2,967, 2,901, 1,745, 1,681, 1,756, 1,429, 1,382, 885, 785, 699 cm−1; 1H NMR (250 MHz, CDCl3) δ 7.54 (s, 1H), 7.47 (d, J = 6.1 Hz, 1H), 7.33 (d, J = 9.7 Hz, 1H), 3.78 (d, J = 5.6 Hz, 1H), 3.58 (t, J = 11.3 Hz, 1H), 3.06 (s, 3H), 2.99 (s, 3H), 2.72 (dq, J = 19.8, 9.0 Hz, 1H), 2.06 (d, J = 15.2 Hz, 1H), 1.80–1.63 (m, 1H), 0.99 (dt, J = 23.8, 13.0 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 213.04, 171.62, 151.29, 148.45, 135.71, 133.44, 129.25, 128.59, 127.24, 50.29, 49.89, 49.43, 48.70, 40.14, 28.45, 27.17, 20.34.

3.2.1.5 5,5′-((2-Oxocyclohexane-1,3-diyl)bis((2-hydroxyphenyl)methylene))bis(1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione) (5e)

IR (KBr): 3,427, 3,098, 3,045, 3,005, 1,745, 1,680, 1,574, 1,431, 1,382, 1,244, 751 cm−1; 1H NMR (250 MHz, CDCl3) δ 9.53 (s, 1H), 7.46 (d, J = 11.8 Hz, 1H), 7.29 (d, 1H), 7.20–7.04 (q, J = 10.7 ,8.9 Hz, 1H), 6.96 (q, J = 11.5, 8.5 Hz, 1H), 3.58 (d, J = 4.0 Hz, 1H), 3.38 (t, J = 10.9 Hz, 1H), 2.86 (s, 3H), 2.79 (s, 3H), 2.52 (dq, J = 19.5, 8.9 Hz, 1H), 1.86 (d, J = 14.0 Hz, 1H), 1.54 (q, J = 15.5, 14.7 Hz, 1H), 0.79 (dt, J = 23.2, 13.1 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 213.26, 171.59, 153.27, 151.17, 131.90, 129.24, 126.84, 122.78, 115.31, 50.28, 49.89, 49.43, 48.70, 40.10, 28.45, 27.16, 20.45.

4 Conclusion

In summary, two independent and consecutive Michael addition reactions of 1,3-dimethylbarbituric acid with 2,6-di-arylidenecyclohexan-1-ones bearing electron-donating and electron-withdrawing substituents afforded a new type of flying-bird-shaped 2D-polymeric structure of 5,5′-((2-oxocyclohexane-1,3-diyl)bis(arylmethylene))bis(1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione). Crystal structure revealed that these compounds have 2D-polymeric interactions.

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Acknowledgments

We gratefully acknowledge financial support from the Research Council of Urmia University. The authors acknowledge crystallography laboratory management at Atatürk University, Erzurum, Turkey.

  1. Funding information: The study was supported by Research Council of Urmia University.

  2. Conflict of interest: Authors state no conflict of interest.

  3. Data availability statement: The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Received: 2021-12-27
Revised: 2022-01-31
Accepted: 2022-02-23
Published Online: 2022-04-25

© 2022 Nader Noroozi Pesyan et al., published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

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https://doi.org/10.1515/hc-2022-0009
Keywords for this article
crossed-aldol condensation; consecutive Michael addition; 1,3-dimethylbarbituric acid; conformation; bifurcated H-bond
Creative Commons
BY 4.0

Articles in the same Issue

  1. Research Articles
  2. Sono and nano: A perfect synergy for eco-compatible Biginelli reaction
  3. Study of the reactivity of aminocyanopyrazoles and evaluation of the mitochondrial reductive function of some products
  4. “Click” assembly of novel dual inhibitors of AChE and MAO-B from pyridoxine derivatives for the treatment of Alzheimer’s disease
  5. Synthesis of 2,2-difluoro-2-arylethylamines as fluorinated analogs of octopamine and noradrenaline
  6. Cyclization of N-acetyl derivative: Novel synthesis – azoles and azines, antimicrobial activities, and computational studies
  7. Two independent and consecutive Michael addition of 1,3-dimethylbarbituric acid to (2,6-diarylidene)cyclohexanone: Flying-bird-shaped 2D-polymeric structure
  8. Ionic liquid-catalyzed synthesis of (1,4-benzoxazin-3-yl) malonate derivatives via cross-dehydrogenative-coupling reactions
  9. Synthesis of novel triiodide ionic liquid based on quaternary ammonium cation and its use as a solvent reagent under mild and solvent-free conditions
  10. Eelectrosynthesis of benzothiazole derivatives via C–H thiolation
  11. Synthesis of fluoro-rich pyrimidine-5-carbonitriles as antitubercular agents against H37Rv receptor
  12. Syntheses, crystal structure, thermal behavior, and anti-tumor activity of three ternary metal complexes with 2-chloro-5-nitrobenzoic acid and heterocyclic compounds
  13. Synthesis of enhanced lipid solubility of indomethacin derivatives for topical formulations
  14. Synthesis of newer substituted chalcone linked 1,2,3-triazole analogs and evaluation of their cytotoxic activities
  15. Novel benzodioxatriaza and dibenzodioxadiazacrown compounds carrying 1,2,4-oxadiazole moiety
  16. Synthesis of rhodium catalysts with amino acid or triazine as a ligand, as well as its polymerization property of phenylacetylene
  17. DABCO-based ionic liquid-promoted synthesis of indeno-benzofurans derivatives: Investigation of antioxidant and antidiabetic activities
  18. Design, synthesis, and biological activity of novel pomalidomide linked with diphenylcarbamide derivatives
  19. Study on effective synthesis of 7-hydroxy-4-substituted coumarins
  20. Review Article
  21. Chemical constituents of plants from the genus Carpesium
  22. Communication
  23. Reactions of 3-amino-1,2,4-triazine with coupling reagents and electrophiles
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