A simple access to hexahydropyrimidine from 1,3-diamine: Synthesis and solid-state characterization

doi:10.21203/rs.3.rs-3210977/v1

Download PDF

Research Article

A simple access to hexahydropyrimidine from 1,3-diamine: Synthesis and solid-state characterization

https://doi.org/10.21203/rs.3.rs-3210977/v1

This work is licensed under a CC BY 4.0 License

Journal Publication

published 09 Oct, 2023

Read the published version in Structural Chemistry →

You are reading this latest preprint version

1,3-bis((1H-1,2,4-triazol-1-yl)methyl)hexahydropyrimidine were readily prepared by cyclocondensation of propane-1,3-diamine with a mixture of (1H-1,2,4-triazol-1-yl)methanol and formaldehyde. The ¹H- and ¹³C-NMR spectroscopic data of this ligand have been fully assigned and are consistent with the molecular structure. The crystalline structure of the compound was fully determined by single crystal X-ray diffraction at 150K and at room temperature, together with the isobaric thermal expansion. Finally, during the first heating, DSC measurements showed no phase transition up to the melting temperature at 385.1 K (111.9°C).

Hexahydropyrimidine

triazole

cyclocondensation

crystalline structure

DSC

The six-membered heterocyclic hexahydropyrimidine derivatives are essential chemicals that have attracted much attention for their applications in many advanced fields of chemistry. The hexahydropyrimidine moiety is found in many natural products [1–3] and also found in a broad spectrum of pharmacological activity [4], like anti-inflammatory, anticancer, fungicide, antibacterial, parasiticide and antivirals [3, 5, 6].

The synthetic organic chemistry of hexahydropyrimidine (Fig. 1) extends to several areas of chemistry, including drug discovery [7], polymer stabilizers [8], and protective groups in selective acylation [9].

Furthermore, hexahydropyrimidine derivatives have been employed in inorganic synthesis as suitable polydentate nitrogen donor complexes for functional metals [10–13] and have been used as precursors for the rhodium(I)-carbene complexes in the catalytic addition of phenylboronic acid to aldehydes [13].

Various methods are reported in the literature for the preparation of hexahydropyrimidine derivatives, the traditional synthetic route leading to these hetero-aliphatic rings mainly built using Biginelli reactions of substituted propane-1,3-diamines with aldehydes and ketones [14], urea or thiourea with aldehydes and 1,3-dicarbonyl compounds [15], or by Mannich condensation of aldehydes with primary amines [16]. Very recently, the direct construction of hexahydropyrimidine heterocyclic has been obtained by the catalytic cycloaddition pathways from alkenes [17].

In the present communication, we suggested simple and efficient access to a derivative compound of N, N′-disubstituted hexahydropyrimidine (named L1) by one-pot synthesis. Furthermore, the X-ray structures of the title compound have been wholly determined at room temperature and 150K; the experimental was then compared to the geometry optimized with DFT calculations. The measurements of the cell parameters as a function of temperature allowed the calculation of the thermal dilatation tensor.

2.1. Materials

High purity of 1H-1,2,4-triazole, propane-1,3-diamine, and formaldehyde (36.5%) were purchased from Sigma-Aldrich. Ethanol, acetonitrile, dichloromethane, and diethyl ether were used as reagent-grade solvents. All the reagents and solvents were directly handled as received.

2.2. Synthesis and NMR data

2.2.1. Synthesis of 1,3-bis((1H-1,2,4-triazole-1-yl)methyl)hexahydropyrimidine

A solution of 1H-1,2,4-triazole (0.99 g; 10 mmol) and excess of formaldehyde (36.5%) (2 equiv.) in 25 mL of ethanol were stirred at reflux for 1 hour and then for 12 hours at room temperature, finally the solvent was removed under vacuum. Then, the residue was dissolved in 25 mL of acetonitrile, and a solution of propane-1,3-diamine (0.185 g; 2.5 mmol) was added dropwise. The reaction mixture was heated to reflux under magnetic stirring for 4 hours; the acetonitrile layer was dried over Na₂SO₄, filtered, and evaporated under reduced pressure. The residue was washed with a mixture of dichloromethane and ether to give a white oil, which was recrystallized in ethanol to yield white crystals. Yield: 77%.

2.2.2. Spectroscopic measurements

The ¹H-NMR (300 MHz) and ¹³C-NMR (75 MHz) spectral data were collected on a Bruker spectrometer. Chemical shifts are reported in parts per million (ppm) downfield from an internal trimethylsilane (s: singulet; q: quadruplet; m: multiplet).

NMR data of both proton and carbon spectra are in good agreement with the assigned structure, signals of aromatic and aliphatic protons and carbon are cited according to their positions.

¹H-NMR (300 MHz, DMSO, δ, ppm): 8.54 (s, 2H, H_11,18); 7.97 (s, 2H, H_13,16); 5.08 (s, 4H, H_7,8); 3.47 (s, 2H, H₁); 2.52 (m, 4H, H_3,5); 1.52 (q, J = 5.50 Hz, 2H, H₄).¹³C-NMR (75 MHz, DMSO, δ, ppm): 151.66 (C_13,16); 145.02 (C_11,18); 70.20 (C₁); 67.78 (C_7,8); 48.69(C_3,5); 22.97 (C₄).

2.3 X-ray diffraction

2.3.1 Single crystal diffraction and crystalline structure

A L1 single crystal was glued to a glass rod (Fig. 3). The crystal data were collected at 150.0(1) K and room temperature on a Bruker-D8 Venture four-axis diffractometer equipped with a Photon2 detector and using monochromated Mo Kα (wavelength λ = 0.71079 Å). Integration of the diffracted intensities was performed using the APEX3 software suite. Details of the X-ray diffraction experimental conditions are given in Table 1.

The crystal structure was solved using the SIR92 program and refined with SHELX implemented in the WinGX package [18, 19].

Table 1

Experimental X-ray data of the L1 compound.
Molecular formula	C₁₀H₁₆N₈
T (K)	150	294
Crystal system	Orthorhombic
Space group	Pnma
Unit cell dimension (Å)	a = 10.0546(4); b = 16.6072(6); c = 7.3647(2)	10.56655(2): 16.7408(3); 7.4127(2)
Volume (Å³)	1229.75(7)	1260.37(5)
Z	4	4
Calculated density (g.cm^− 3)	1.341	1.309
F(000)	528	528
Color, habit	Colorless, prism	Colorless, prism
θ range for data collection (deg)	3.026–34.720	2.433–31.304
Index ranges	-16 < h < 16; -26 < k < 26; -11 < l < 11	-14 < h < 14; -24 < k < 21; -10 < l < 10
Reflections collected/unique	42740/2517	43991/1915
Goodness of fit on F²	1.064	1.046
Final R indices	R1 = 0.03532 R1all = 0.0353	0.0465 0.0503

2.3.1 Thermal expansion tensor

Lattice parameters of the single crystal were recorded at different temperatures (Table 2). The crystal was allowed to equilibrate in the nitrogen flux before starting each isothermal data collection. The anisotropy of the intermolecular interactions can be investigated with the isobaric thermal expansion tensor, which measures how the interactions change with temperature. The tensor was calculated from the temperature-dependent lattice parameters with the program PASCAL [20].

This tensor is a symmetrical second-rank tensor with nonzero eigenvalues on the diagonal α₁₁, α₂₂, α₃₃. A small value for a tensor eigenvalue is commonly referred to as a ‘‘hard’’ direction because it indicates a small deformation, and a significant value as a ‘‘soft’’ direction because it indicates a large deformation. The eigenvectors can be expressed as a function of the cell parameters a, b and c.

The anisotropy of the thermal expansion can be expressed as a single value by the aspherism coefficient [21], comprising the 3 different coefficients of the thermal tensor

\(A\left(T\right)=\frac{2}{3}\sqrt{1-\frac{3({\alpha }_{11}{\alpha }_{22}+{\alpha }_{11}{\alpha }_{33}+{\alpha }_{22}{\alpha }_{33})}{{{\alpha }_{v}}^{2}}}\) with \({\alpha }_{V}=\frac{1}{V}\left(\frac{\partial V}{\partial T}\right)\) and V the unit cell volume. When A = 0, the expansion is totally isotropic, in general, it is only observed in cubic crystals. Higher values of A indicate increased anisotropy of the expansion.

Graphical representations of the tensor at given temperatures have been drawn using Wintensor [22].

Table 2

Cell parameters of L1 as a function of temperature.
T (K)	a (Å)	b (Å)	c (Å)	V (Å³)
296.1	7.4172(16)	10.149(2)	16.713(6)	1257.8(9)
276.0	7.4141(15)	10.142(2)	16.708(6)	1256.4(8)
256.0	7.40604(19)	10.126(3)	16.682(6)	1251.0(10)
236.1	7.3983(18)	10.110(3)	16.664(6)	1246.5(9)
216.1	7.3933(19)	10.102(3)	16.673(6)	1245.3(9)
196.0	7.3917(18)	10.092(3)	16.656(6)	1242.4(5)
174.1	7.3768(18)	10.075(3)	16.629(6)	1235.9(9)
150.1	7.3749(16)	10.065(2)	16.624(5)	1233.9(8)

2.3. DFT calculations

Theoretical calculations on isolated molecules were performed using GAUSSIAN09 [23] with the density functional theory (DFT) method using the hybrid functional B3LYP with 6(31G(d) basis set. This method seems to be the most popular choice for calculations on complexes [24]. The total energies are given in hartrees (1 Ha = 2,625.5 kJ.mol^− 1). The experimental geometry of the ligand L1 was used as input.

2.4. DSC experiments

Differential scanning calorimetry (DSC) experiments were carried out using a Perkin-Elmer DSC Diamond apparatus purged with N₂ flow (20 mL.min^− 1) and equipped with an Intracooler 2P cooling device and connected to a Pyris Thermal Analysis Software System (Version 13.2.1). Aluminum pans of 50 µL without holes were filled with around 5 mg of the studied compound with a balance sensitive to 0.01 mg and sealed. The samples were first cooled from 20 to -10°C at a constant rate |dT/dt| = 5°C.min^− 1 and allowed to equilibrate for 10 min at this temperature. The samples were then heated from − 10 to 195°C at 5° C.min^− 1 and cooled down to -70°C at the same rate and allowed to equilibrate for 15 h at this temperature. Then the samples were then heated once more from − 70 to 195°C at 5° C.min^− 1 rate. The apparatus was calibrated for temperature and enthalpy under the same analysis conditions with Naphatlene (T_m = 80.23°C; Δ_mH = 147.6 J.g^− 1) and Indium (T_m = 156.60°C; Δ_mH = 28.62 J.g^− 1). The melting temperatures were taken at the onset of the transitions (T_onset). The melting enthalpy Δ_mH was obtained from the area under the corresponding peak and normalized with respect to the mass in the pan.

3.1. Synthesis

The creation of the methylene bridge by condensation of triazole and propane-1,3-diamine using an active carbonyl group of formaldehyde at a molar ratio of 2:1:4, leading to the formation of hetero-aliphatic rings. 1H-1,2,4-triazole in ethanol and excess formaldehyde solution (36.5%) was refluxed for 1 h, and stirring was continued at room temperature for 12 h. After the elimination of the solvent, the obtained residue of (1H-1,2,4-triazol-1-yl)methanol and formaldehyde was dissolved in acetonitrile with propane-1,3-diamine and refluxed for 1 h, 1,3-bis((1H-1,2,4-triazol-1-yl)methyl)hexahydropyrimidine was synthesized by mixing a tri-molecular combination of 1,3-propanediamine, formaldehyde, and (1H-1,2,4-triazol-1-yl)methanol in acetonitrile as solvent, under neutral conditions typically involves a one-pot reaction as shown in Scheme 1. This reaction can be a simple model for synthesizing various dihydropyrimidine derivatives.

One of the possible mechanisms of 1,3-bis((1H-1,2,4-triazol-1-yl)methyl)hexahydropyrimidine formation can be established as follows (Scheme 2); the 1,3-propanediamine contains two primary amine groups (-NH₂) on each end of the molecule, acting as a nucleophile, with formaldehyde (H₂CO).

It would appear that the reaction proceeds through a condensation step where one of the amine groups of 1,3-propanediamine attacks the carbonyl carbon of formaldehyde. This results in the formation of an imine intermediate. This intermediate can undergo intramolecular cyclization; the second nitrogen atom in the amine group attacks the imine's carbon, leading to the formation of a six-membered ring.

As a final step, both secondary amino groups can undergo substitution to introduce various substituents (R groups) by reacting with appropriate reagents such as (1H-1,2,4-triazol-1-yl)methanol, which would give the observed product. This step allows for synthesizing N, N’-substituted hexahydropyrimidine [25–27].

Therefore, the faster reaction rate observed between 1,3-propanediamine and formaldehyde can be attributed to the higher electrophilicity due to the electron-deficient carbonyl group of formaldehyde as compared to the lower electrophilicity and steric hindrance of the electrophilic center of (1H-1,2,4-triazol-1-yl)methanol.

This mechanism can be justified by the fact that we used an excess of (1H-1,2,4-triazol-1-yl)methanol. Nevertheless, the final product shows a monocondensation of the last reactant on each of both amines of the hexahydropyrimidine.

This result opens the way to new and numerous perspectives allowing access to new organic compounds.

3.2 Crystalline structure of L1

The L1 compound crystallizes in the Pnma space group with half a molecule in the asymmetric unit (a mirror passes through the atoms C4-C1). The molecular structure and crystalline packing are given in Fig. 4. No disorder was found at 150K and room temperature in the crystalline structure.

a) Molecular conformation

The molecule is somewhat flexible, with four torsional angles defining the relative orientation of the triazole groups; because of the symmetry of the experimental conformation, only two are reported in Table 3. The two triazole groups are more or less face-to-face (Fig. 4).

In the crystalline structural database, the first crystalline structure of a 1,3-derivative hexahydropyrimidine was found: 1,3-dicyanomethylhexahydropyrimidine (code CSD JULBUN [28] and its crystalline polymorph JULBUN01 [29]). The sole torsional angle comparison possible would be the equivalent of C3 N2 C5 N6, which appears to be -58.60° and 66.07° in JULBUN (and − 65.35° and 57.49° in JULBUN01) and ± 68.70(6)° in L1 at 150K (Table 2), leading to a relatively similar conformation (the -C ≡ N groups being almost parallel in JULBUN whereas the triazole groups are also nearly face to face in L1). Four additional crystalline structures were found in this database, the substituents in positions 1 and 3 on the hexahydropyrimidine ring being 4-bromophenol, phenol, 2-tert-butyl-4-methoxyphenol, 2,4-tert-butylphenol with CSD codes GAQYOO [30], LAQTEE [31], SAGXIJ [32], and XAYRIA [33], respectively. They exhibit, respectively the following torsional angles: (-69.76°, + 170.08°), (-62.63°, + 165.33°), ± 76.78° and ± 71.89. Consequently, GAQYOO and LAQTEE exhibit a similar conformation, but this conformation is different from the one of SAGXIJ and XAYRIA. At last, the conformation of SAGXIJ and XAYRIA is similar to L1 in the sense that the two phenol rings are on the same side of the hexahydropyrimidine ring, but they are not exactly face-to-face as in L1. This is reflected by the second torsional angle equivalent of C10 N6 C5 N2, which is ± 84.44(7)° in L1 at 150K (Table 2), ± 43.06° in SAGXIJ and ± 45.54° in XAYRIA.

The geometry of the isolated L1 molecule has been fully optimized with GAUSSIAN09 software and B3LYP/6-31G(d) method. The input model was obtained from the experimental crystallographic structure of L1. The optimized conformation of L1 remains relatively similar to the conformation in the crystalline structure despite the relative flexibility of the molecule; the internal symmetry is preserved (the mirror passing through C4-C1); see Table 4. The total energy is -828.660855310 Ha.

Several conformations were explored with GAUSSIAN09 by changing the torsion angles C3 N2 C5 N6 and C10 N6 C5 N2 (see Fig. 4a and Table 3) by 180°: the geometry was then fully optimized with the B3LYP/6-31G(d) method. Because of the molecule’s inherent symmetry, only five additional conformations can be found, see Fig. 5 and Table 5. Conformation 2 appears to have lower energy. Consequently, the observed conformation (conformation 1) is probably stabilized by the intermolecular interactions in the crystalline structure.

Table 3

Torsion angles (in °) characterizing the conformation of L1 at 150K and room temperature compared to the optimized torsion angles of conformation 1 (with B3LYP/6-31G(d) method).
Temperature	150 K	RT	optimized
C3 N2 C5 N6	68.70(6)	68.54(10)	63.88
C10 N6 C5 N2	-84.44(7)	-84.30(13)	-95.55

Table 4

Intermolecular close contacts in the L1 crystalline structure at 150K.
D-H‧‧‧A	D-H (Å)	H‧‧‧A (Å)	D‧‧‧A (Å)	DHA (°)
C3 H3A N7	0.981(11)	2.665(11)	3.5049(7)	143.9(8)
C5 H5B N9	0.973(10)	2.686(10)	3.6106(8)	158.9(8)
C10 H10 N9	0.929(12)	2.487(12)	3.3577(8)	156.3(10)
C8 H8 N2	0.964(11)	2.639(11)	3.5323(7)	154.1(8)

Table 5

Energies in Hartrees of different conformations of the L1 molecule.
conformation	Energies in Ha	Relative energies (kJ.mol^− 1)
1	-828.660853631	0.000
2	-828.661419021	-1.484
3	-828.660135490	+ 1.885
4	-828.658518828	+ 6.130
5	-828.658577455	+ 5.976
6	-828.659518836	+ 3.505

b) Crystal Packing and intermolecular interactions

Each molecule is involved in 8 weak intermolecular hydrogen bond networks C-H‧‧‧N with three different molecules (see Fig. 4b): the molecule being donor for four hydrogen bonds (involving the CH₂ of the hexahydropyrimidine and the CH of the triazole groups) and acceptors for four hydrogen bonds (involving the nitrogen atoms of the hexahydropyrimidine and the two triazole groups). Because of the molecule’s symmetry, we must define only four kinds of hydrogen bonds (see Table 4 and Fig. 4b).

The C8H8‧‧‧N2 hydrogen bonds form an infinite chain along c (corresponding to the C¹₁ (6) graph set [34–36]); because of the symmetry of the molecule, the same hydrogen bonds form a cyclic dimer (graph set R²₂(16)). Between these infinite chains of hydrogen bonds are the C10H10‧‧‧N9, forming infinite chains of hydrogen bonds along b (with graph set C11(11)). The C3H3A‧‧‧N7 and the C5H5B‧‧‧N9 hydrogen bonds form an infinite chain along a (corresponding to the C¹₁ (6) graph set). Consequently, the four types of hydrogen bonds form a 3D network linking all the molecules (Fig. 4b).

c) Influence of the temperature

Cell parameters of L1 were followed by single crystal X-ray diffraction from 150K to ambient temperature (Table 2). No phase transition was observed. The volume (in Å³) of L1 as a function of temperature T (in K) can be fitted to a straight line, with r² = 0.98:

V(T) = 0.1714 × T + 1207.6

It demonstrates that the volume increases linearly with temperature in the studied temperature range. It corresponds to an expansivity α_v of 1.42 × 10^− 4 K^− 1 (Table 5), somewhat smaller than the average value 2 ×10^− 4 K^− 1 for small organic molecules [37], and the expansivity of another ligand poly(3,5-dimethylpyrazol-1-ylmethyl)benzene which also comprises C-H‧‧‧N hydrogen bonds (1.91 × 10^− 4 K^− 1) [38] but significantly larger than the one of another ligand with C-H‧‧‧N hydrogen bonds: N, N, N’, N’-tetrakis-[(1H,2,4-triazol-1-yl)methyl)]-ethane-1,2-diamine named TTYED (1.16× 10^− 4 K^− 1) [39].

The eigenvalues and eigenvectors of the thermal expansion tensor have been compiled in Table 6, while a graphical representation of the tensor at ambient temperature is presented in Fig. 6. Because the cell parameters increase linearly with temperature, the isobaric thermal expansion tensor is constant with temperature.

Table 6

Isobaric thermal tensor coefficients (in MK^− 1) and orientation of the tensor in the unit cell.
eigenvalues		eigenvectors
a_V	142(6)	a	b	c
a₁₁	38(2)	0.00	0.00	1.00
a₂₂	41(2)	-1.00	0.00	0.00
a₃₃	59(2)	0.00	-1.00	0.00

The aspherism coefficient has a value of 0.09, which is very close to zero, at least significantly small than the one of poly(3,5-dimethylpyrazol-1-ylmethyl)benzene (0.31) [38], ascorbic acid (0.47) [40], tienoxolol (0.50) [41] or the molecule N, N, N’, N’-tetrakis-[(1H,2,4-triazol-1-yl)methyl)]-ethane-1,2-diamine (0.58) [39], which indicates that the thermal expansion is more isotropic. And unlike these compounds, the expansivity of L1 is positive in all directions.

The maximum expansion occurs along e₃ (or the b direction in an orthorhombic crystal), which is between 1.4 to 1.6 times larger than the expansion along the two other directions. This relatively high value indicates that e₃ is the “soft direction” in the crystal. The minimum expansion is along e₁ (or c direction); this can be referred to as the “hard direction” in the crystal. These two directions are parallel to a different infinite chain of hydrogen bonds. It can be concluded that the C8H8‧‧‧N2 hydrogen bonds parallel to c are weaker than the other hydrogen bonds in the crystalline structure. In contrast, the C10H10‧‧‧N9 hydrogen bonds parallel to b are the strongest. This is consistent with the experimental geometry of these hydrogen bonds (Table 4): C10H10‧‧‧N9 has the smallest A‧‧‧H distance and the hydrogen bond angle closest to the ideal 180° value.

Differential scanning calorimetry (DSC) was used to complete the thermal behavior of L1. To avoid the degradation of L1 that occurs at around 523 K (250°C), DSC studies were carried out below 473 K (200°C). The melting point of L1 was found to be 385.1 K (111.9°C) with an enthalpy of fusion of 132.6 J.g^− 1 (32.9 kJ.mol^− 1). Cooling the molten sample to 203 K (-70°C) with 5°C.min^− 1 and reheating resulted in a glass transition at 258.1 K (-15.0°C; midpoint) on heating (Fig. 7). Subsequently, a large exothermic peak was observed related to recrystallization, which occurred between 336.3 K and around 368 K. After recrystallization, a melting peak was observed at 371.7 K (98.5°C, Fig. 7). The enthalpy associated with this melting transition was estimated at 39.8 J.g^− 1 (9.9 kJ.mol^− 1). This enthalpy value is probably underestimated because L1 has difficulty recrystallizing and because recrystallization and melting are concomitant. To our knowledge, there are no calorimetric data published on 1,3-disubstituted hexahydropyrimidine. However, analysis of melting point data from the literature [42] shows that the value obtained during the first heating is consistent with the range of values obtained for different N, N’-disubstituted hexahydropyrimidines between 60 and 204°C (average melting point = 130°C, median melting point = 121°C).

A novel molecule of 1,3-bis((1H-1,2,4-triazol-1-yl)methyl)hexahydropyrimidine was obtained from a tri-molecular combination using a one-pot procedure. The simplicity and efficiency of the synthetic procedure make it an optional choice for usage in organic synthesis; This synthetic strategy opens the way to new and numerous perspectives allowing access to many new organic products. Furthermore, crystal structures were determined using single-crystal X-ray diffraction and presented here. The title compound's X-ray structures were fully established at room temperature and 150 K; the experimental results were then compared to the geometry optimized using DFT simulations. The thermal dilatation tensor has been calculated by recording observations of the cell's characteristics as a function of temperature.

Ethical Approval: not applicable.

Competing interests: The authors declare have no competing interests in this work.

Authors' contributions: Z, MT, ZB, SEK : synthesis and NMR measurements; BN, NG : crystallographic measurements ; BN : molecular modelling calculations ; FXL : DSC measurements ; BN, SEG, FXL :initial draft. All authors reviewed the manuscript.

Funding : not applicable.

Availability of data and materials: Supplementary crystallographic data can be found in the CCDC (CCDC numbers 2285205 and 2285206) and obtained free of charge from Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif/

Suzuki, T.; Kubota, T.; Kobayashi, J. Eudistomidins H–K, New β-Carboline Alkaloids from the Okinawan Marine Tunicate Eudistoma Glaucus. Bioorganic & Medicinal Chemistry Letters 2011, 21, 4220–4223, doi:10.1016/j.bmcl.2011.05.072.
Guggisberg, A.; Drandarov, K.; Hesse, M. Protoverbine, the Parent Member of a Class of Macrocyclic Spermine Alkaloids. HCA 2000, 83, 3035–3042, doi:10.1002/1522-2675(20001108)83:11<3035::AID-HLCA3035>3.0.CO;2-P.
Drandarov, K.; Guggisberg, A.; Hesse, M. Macrocyclic Spermine Alkaloids FromVerbascum: The (E/Z)-Isomeric Pairs (−)-(S)-Verbasitrine/(−)-(S)-Isoverbasitrine and (+)-(S)-Verbametrine/(+)-(S)-Isoverbametrine: Isolation, Structure Elucidation, and Synthesis. HCA 1999, 82, 229–237, doi:10.1002/(SICI)1522-2675(19990210)82:2<229::AID-HLCA229>3.0.CO;2-H.
Perillo, I.A.; García, M.B.; Bisceglia, J.Á.; Orelli, L.R. N -Arylhexahydropyrimidines. Part 1. Synthesis and ¹ H NMR Characterization of 1,3-Di and 1,2,3-Trisubstituted Derivatives. Journal of Heterocyclic Chemistry 2002, 39, 655–661, doi:10.1002/jhet.5570390409.
Verma, S.; Kumar, S.; Jain, S.L.; Sain, B. Thiourea Dioxide Promoted Efficient Organocatalytic One-Pot Synthesis of a Library of Novel Heterocyclic Compounds. Org. Biomol. Chem. 2011, 9, 6943, doi:10.1039/c1ob05818e.
Misra, M.; Pandey, S.K.; Pandey, V.P.; Pandey, J.; Tripathi, R.; Tripathi, R.P. Organocatalyzed Highly Atom Economic One Pot Synthesis of Tetrahydropyridines as Antimalarials. Bioorganic & Medicinal Chemistry 2009, 17, 625–633, doi:10.1016/j.bmc.2008.11.062.
Mayr, M.; Wurst, K.; Ongania, K.-H.; Buchmeiser, M.R. 1,3-Dialkyl- and 1,3-Diaryl-3,4,5,6-Tetrahydropyrimidin-2-Ylidene Rhodium(i) and Palladium(II) Complexes: Synthesis, Structure, and Reactivity. Chem. Eur. J. 2004, 10, 1256–1266, doi:10.1002/chem.200305437.
Mayr, M.; Buchmeiser, M.R. Rapid Screening of New Polymer-Supported Palladium(II) Bis(3,4,5,6-Tetrahydropyrimidin-2-Ylidenes). Macromol. Rapid Commun. 2004, 25, 231–236, doi:10.1002/marc.200300173.
Katritzky, A.R.; Singh, S.K.; He, H.-Y. Novel Syntheses of Hexahydropyrimidines and Tetrahydroquinazolines. J. Org. Chem. 2002, 67, 3115–3117, doi:10.1021/jo010927x.
Ren, C.-X.; Ye, B.-H.; Zhu, H.-L.; Shi, J.-X.; Chen, X.-M. Syntheses, Structures and Photoluminescent Properties of Silver(I) Complexes with in Situ Generated Hexahydropyrimidine Derivatives. Inorganica Chimica Acta 2004, 357, 443–450, doi:10.1016/j.ica.2003.06.003.
Schmidt, M.; Wiedemann, D.; Grohmann, A. First-Row Transition Metal Complexes of a Novel Pentadentate Amine/Imine Ligand Containing a Hexahydropyrimidine Core. Inorganica Chimica Acta 2011, 374, 514–520, doi:10.1016/j.ica.2011.02.066.
Bréfuel, N.; Lepetit, C.; Shova, S.; Dahan, F.; Tuchagues, J.-P. Complexation to Fe ^II , Ni ^II , and Zn ^II of Multidentate Ligands Resulting from Condensation of 2-Pyridinecarboxaldehyde with α,ω-Triamines: Selective Imidazolidine/Hexahydropyrimidine Ring Opening Revisited. Inorg. Chem. 2005, 44, 8916–8928, doi:10.1021/ic050791b.
Özdemir, I.; Demir, S.; Çetinkaya, B.; Çetinkaya, E. Novel Rhodium-1,3-Dialkyl-3,4,5,6-Tetrahydropyrimidin-2-Ylidene Complexes as Catalysts for Arylation of Aromatic Aldehydes. Journal of Organometallic Chemistry 2005, 690, 5849–5855, doi:10.1016/j.jorganchem.2005.07.085.
Hwang, J.Y.; Kim, H.-Y.; Jo, S.; Park, E.; Choi, J.; Kong, S.; Park, D.-S.; Heo, J.M.; Lee, J.S.; Ko, Y.; et al. Synthesis and Evaluation of Hexahydropyrimidines and Diamines as Novel Hepatitis C Virus Inhibitors. European Journal of Medicinal Chemistry 2013, 70, 315–325, doi:10.1016/j.ejmech.2013.09.055.
Agbaje, O.C.; Fadeyi, O.O.; Fadeyi, S.A.; Myles, Lewis.E.; Okoro, C.O. Synthesis and in Vitro Cytotoxicity Evaluation of Some Fluorinated Hexahydropyrimidine Derivatives. Bioorganic & Medicinal Chemistry Letters 2011, 21, 989–992, doi:10.1016/j.bmcl.2010.12.022.
Latypova, D.R.; Badamshin, A.G.; Lobov, A.N.; Dokichev, V.A. Reaction of Ethyl Acetoacetate with Formaldehyde and Primary Amines. Russ J Org Chem 2013, 49, 843–848, doi:10.1134/S1070428013060079.
Zhou, H.; Chaminda Lakmal, H.H.; Baine, J.M.; Valle, H.U.; Xu, X.; Cui, X. Catalytic [2 + 2 + 2] Cycloaddition with Indium( iii )-Activated Formaldimines: A Practical and Selective Access to Hexahydropyrimidines and 1,3-Diamines from Alkenes. Chem. Sci. 2017, 8, 6520–6524, doi:10.1039/C7SC02576A.
Sheldrick, G.M. Crystal Structure Refinement with SHELXL. Acta Crystallogr C Struct Chem 2015, 71, 3–8, doi:10.1107/S2053229614024218.
Sheldrick, G.M. A Short History of SHELX. Acta Crystallogr A Found Crystallogr 2008, 64, 112–122, doi:10.1107/S0108767307043930.
Cliffe, M.J.; Goodwin, A.L. PASCal : A Principal Axis Strain Calculator for Thermal Expansion and Compressibility Determination. J Appl Crystallogr 2012, 45, 1321–1329, doi:10.1107/S0021889812043026.
Weigel, D.; Beguemsi, T.; Garnier, P.; Berar, J.F. Evolution des tenseurs de dilatation thermique en fonction de la temperature. I. Loi generale d’evolution de la symetrie du tenseur. Journal of Solid State Chemistry 1978, 23, 241–251, doi:10.1016/0022-4596(78)90071-3.
Kaminski, W. WinTensor.
Gaussian 09, Revision C.01.
Hopmann, K.H. How To Make Your Computational Paper Interesting and Have It Published. Organometallics 2019, 38, 603–605, doi:10.1021/acs.organomet.8b00942.
Muthusaravanan, S.; Perumal, S.; Almansour, A.I. Facile Catalyst-Free Pseudo Five-Component Domino Reactions in the Expedient Synthesis of 5-Aroyl-1,3-Diarylhexahydropyrimidines. Tetrahedron Letters 2012, 53, 1144–1148, doi:10.1016/j.tetlet.2011.12.097.
Mukhopadhyay, C.; Rana, S.; Butcher, R.J. FeCl3 Catalysed Two Consecutive Aminomethylation at the α-Position of the β-Dicarbonyl Compounds: An Easy Access to Hexahydropyrimidines and Its Spiro Analogues. Tetrahedron Letters 2011, 52, 4153–4157, doi:10.1016/j.tetlet.2011.05.144.
Dandia, A.; Jain, A.K.; Sharma, S. Indium Triflate Catalyzed One-Pot Multicomponent Synthesis of Spiro-Hexahydropyrimidines Explained by Multiple Covalent Bond Formation. Tetrahedron Letters 2012, 53, 5270–5274, doi:10.1016/j.tetlet.2012.07.079.
Shoja, M.; Saba, S. 1,3-Dicyanomethylhexahydropyrimidine. Acta Crystallogr C Cryst Struct Commun 1993, 49, 354–355, doi:10.1107/S0108270192005614.
Rivera, A.; Maldonado, M.; Ríos-Motta, J.; Fejfarová, K.; Dušek, M. 2,2′-(1,3-Diazinane-1,3-Diyl)Diacetonitrile: A Second Monoclinic Polymorph. Acta Crystallogr E Struct Rep Online 2011, 67, o2734–o2734, doi:10.1107/S1600536811038013.
Rivera, A.; Trujillo, G.P.; Ríos-Motta, J.; Fejfarová, K.; Dušek, M. 2,2′-[1,3-Diazinane-1,3-Diylbis(Methylene)]Bis(4-Bromophenol). Acta Crystallogr E Struct Rep Online 2012, 68, o498–o498, doi:10.1107/S1600536812001985.
Rivera, A.; González, D.M.; Ríos-Motta, J.; Fejfarová, K.; Dušek, M. 6,6′-Dimethyl-2,2′-[1,3-Diazinane-1,3-Diylbis(Methylene)]Diphenol. Acta Crystallogr E Struct Rep Online 2012, 68, o698–o699, doi:10.1107/S1600536812005284.
Rivera, A.; González, D.M.; Ríos-Motta, J.; Fejfarová, K.; Dušek, M. 6,6′-Di- Tert -Butyl-4,4′-Dimethoxy-2,2′-[1,3-Diazinane-1,3-Diylbis(Methylene)]Diphenol 0.19-Hydrate. Acta Crystallogr E Struct Rep Online 2012, 68, o191–o192, doi:10.1107/S1600536811053542.
Zhang, M.; Li, L.; Yuan, F.; Qian, H. 4,4′,6,6′-Tetra- Tert -Butyl-2,2′-[1,3-Diazinane-1,3-Diylbis(Methylene)]Diphenol 0.25-Hydrate. Acta Crystallogr E Struct Rep Online 2012, 68, o2123–o2123, doi:10.1107/S1600536812026505.
Etter, M.C.; MacDonald, J.C.; Bernstein, J. Graph-Set Analysis of Hydrogen-Bond Patterns in Organic Crystals. Acta Crystallographica Section B Structural Science 1990, 46, 256–262, doi:10.1107/S0108768189012929.
Etter, M.C. Encoding and Decoding Hydrogen-Bond Patterns of Organic Compounds. Accounts of Chemical Research 1990, 23, 120–126, doi:10.1021/ar00172a005.
Etter, M.C. Hydrogen Bonds as Design Elements in Organic Chemistry. J. Phys. Chem. 1991, 95, 4601–4610, doi:10.1021/j100165a007.
Gavezzotti, A. The “Sceptical Chymist”: Intermolecular Doubts and Paradoxes. CrystEngComm 2013, 15, 4027, doi:10.1039/c3ce00051f.
Zerrouki, A.; Nicolaï, B.; Taleb, M.; Guiblin, N.; Bahari, Z.; Kadiri, S.E. Poly((3,5-Dimethylpyrazol-1-Yl)Methyl)Benzene Ligands: Synthesis, Crystal Structure and Catecholase Activities. Struct Chem 2023, 34, 681–694, doi:10.1007/s11224-022-02014-x.
Zerrouki, A.; Allouchi, H.; Nicolaï, B.; El Kadiri, S.; Bahari, Z.; Céolin, R.; Rietveld, I.B. Crystal Structure and Thermal Expansion of N,N,N′,N′-Tetrakis-[(1H,2,4-Triazol-1-Yl)Methyl]-Ethane-1,2-Diamine. Struct Chem 2016, 27, 697–704, doi:10.1007/s11224-015-0611-y.
Nicolaï, B.; Barrio, M.; Tamarit, J.-Ll.; Céolin, R.; Rietveld, I.B. Thermal Expansion of L-Ascorbic Acid. Eur. Phys. J. Spec. Top. 2017, 226, 905–912, doi:10.1140/epjst/e2016-60232-6.
Nicolaï, B.; Rietveld, I.B.; Barrio, M.; Mahé, N.; Tamarit, J.-L.; Céolin, R.; Guéchot, C.; Teulon, J.-M. Uniaxial Negative Thermal Expansion in Crystals of Tienoxolol. Struct Chem 2013, 24, 279–283, doi:10.1007/s11224-012-0078-z.
CAS SCifinder 2008.

Scheme 1 and 2 are available in the Supplementary Files section.

No competing interests reported.

Scheme1.png
Scheme 1. Synthesis of 1,3-bis((1H-1,2,4-triazol-1-yl)methyl)hexahydropyrimidine.
SCheme2.png
Scheme 2. A possible mechanism for the reaction of 1,3-propanediamine with formaldehyde and (1H-1,2,4-triazol-1-yl)methanol.

Download PDF

Journal Publication

published 09 Oct, 2023

Read the published version in Structural Chemistry →

Editorial decision: Major revision
04 Aug, 2023
Reviews received at journal
04 Aug, 2023
Reviews received at journal
03 Aug, 2023
Reviewers agreed at journal
01 Aug, 2023
Reviewers invited by journal
31 Jul, 2023
Editor assigned by journal
31 Jul, 2023
Submission checks completed at journal
31 Jul, 2023
First submitted to journal
27 Jul, 2023

You are reading this latest preprint version

A simple access to hexahydropyrimidine from 1,3-diamine: Synthesis and solid-state characterization

Status:

Journal Publication

Version 1

Abstract

Figures

1. Introduction

2. Experimental

2.1. Materials

2.2. Synthesis and NMR data

2.2.1. Synthesis of 1,3-bis((1H-1,2,4-triazole-1-yl)methyl)hexahydropyrimidine

2.2.2. Spectroscopic measurements

2.3 X-ray diffraction

2.3.1 Single crystal diffraction and crystalline structure

2.3.1 Thermal expansion tensor

2.3. DFT calculations

2.4. DSC experiments

3. Results and discussion

3.1. Synthesis

3.2 Crystalline structure of L1

Conclusion

Declarations

References

Scheme

Additional Declarations

Supplementary Files

Status:

Journal Publication

Version 1