Synthesis, characterization and RHF/ab initio simulations of 2-amino-1,3,4-thiadiazole and its annulated ring junction pyrimidine derivatives.

Michael addition reaction of the 2-amino-1,3,4-thiadiazole to chalcone as biselectrophile afforded 5,7-diphenyl-6-[1,3-diphenylpropan-1-on-3-yl][1,3,4]thiadiazolo[3,2-a]pyrimidine (3) instead of 5,7-diphenyl-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidine (5) via further Michael addition at C5 in pyrimidine moiety. The structure 3 was established through the aspect of ab initio calculations, elemental analysis and spectral data.

Introduction

The diverse and interesting biological activity of <span class="Chemical">thiadiazoles has been reported [1], [2], [3], [4]. It is well known that these heterocycles are valuable building blocks. Many methods for preparation of these heterocyclic ring systems and their fused analogues have been described in the literature [5], [6]. <span class="Chemical">2-Amino-1,3,4-thiadiazoles as <span class="Chemical">amidine moiety provided a useful method for the synthesis of thiadiazolopyrimidine [7]. Also, the N-alkylation could occur either on the endocyclic or on the exocyclic nitrogen atom [8].

The objective of this work is directed to annulate compound 1 via sequential cycloaddition followed by cyclocondensation reaction with <span class="Chemical">enonesn> as biselectrophile, in order to synthesize <span class="Chemical">5,7-diphenyl-5H-[1,3,4] thiadiazolo[3,2-a]pyrimidine (5). Formation of compound 5 was unsuccessful and instead, we obtained <span class="Chemical">5,7-diphenyl-6-[1,3-diphenylpropan-1-on-3-yl][1,3,4]thiadiazolo[3,2-a]pyrimidine (3), this result persuaded us to use RHF/ab initio calculations with the aim to explore the chemical reactivity of the interacted compounds including the investigation of different reaction processes on the basis of their expected quantum mechanical behavior and to envisage why compound 5 reacted with another equivalent mole of chalcone.

Experimental

The melting point is in degree centigrade (uncorrected) and was determined on Gallenkamp electric melting point apparatus. The IR spectrum (ύ cm−1) was recorded using KBr discs on a Mattson 5000 FTIR <n class="Chemical">span class="Chemical">Spectrophotometer at Microanalytical Center, Faculty of Science, Mansoura University. The 1H NMR spn>ectrum was carried out on a Varian Spectrophotometer at 300 MHz, using TMS as an internal reference and <span class="Chemical">DMSO-d6 as solvent at Chemistry Department, Faculty of Science, Cairo University. High Resolution Mass Spectra (HRMS) were recorded using both a Bruker HCT ultra and a high resolution (Bruker Daltonics micrOTOF) instruments from methanol or dichloromethane solutions using the positive Electrospray Ionization Mode (ESI). The RHF/ab initio quantum mechanical level of computation was employed in all calculations of molecular orbitals and quantum chemical parameters. The 6–31G** basis set was used for carbon, nitrogen, hydrogen atoms, whereas the 6–31++G** diffuse function basis set for Sulfur atom. All calculations were performed in vacuo, and no solvent effect was considered. The HyperChem ver 8.06 software package, accommodated on Core-Due 2 PC was employed.

5,7-Diphenyl-6-[1,3-diphenylpropan-1-on-3-yl][1,3,4]thiadiazolo[3,2-a]pyrimidine (3)

A mixture of <span class="Chemical">2-amino-1,3,4-thiadiazole (1) (0.5 g, 0.5 mmol) and <span class="Chemical">benzalacetophenone (0.5 mmol) in <span class="Chemical">ethanol/glacial acetic acid mixture (1:1, 10 mL) was refluxed for 15 h and then left to cool. The formed precipitate was filtered and recrystallized ethanol/DMF mixture (1:1) to afford the corresponding thiadiazolopyrimdine derivative 3 as yellow crystals; yield (43%); mp 285 °C; R = 0.6 [pet. ether (40–60): ethyl acetate (3:2.5)]; IR (KBr) ύ (cm−1), 3097 (CH, str.), 1666 (CO), 1575 (CC); 1H NMR (300 MHz, DMSO-d6) δ (ppm): at 4.57 (br, 1H), 4.91 (br, 1H), 5.91 (br, 1H), 6.61–7.84 (m, 21H, CH, Ar—H), 8.79 (s, 1H, C—H7, pyrimidothiadiazole); (ESI, −98.7v) (+)-ESI mass spectrum showed three quasi-molecular ion peak at 500 (MH+), 523 (MH++Na) and 539 (MH++K) pointing 399 as the molecular mass of 5; HRMS(micrOTOF): m/z for C32H26N3OS + Na, Calcd.: 523.6320. Found: 523.6479 (MH++Na); Anal. Calcd for C32H25N3OS (499.632): C, 76.93; H, 5.04; N, 8.41%. Found: C, 76.96; H, 5.08; N, 8.39%.

Results and discussion

Initially, we have theoretically investigated the expected tautomeric behavior of compound 1, to determine if it is acting either as <span class="Chemical">amine [2-amino-1,3,4-thiadiazole]n> (1a) or as semicyclic <span class="Chemical">amidine [<span class="Chemical">1,3,4-thiadiazol-2(3H)imine] (1b) (Fig. 1).

Fig. 1

Possible tautomeric forms of 2-amino-1,3,4-thiadiazole and the transition state for their conversion (1a → 1c).

Possible tautomeric forms of <span class="Chemical">2-amino-1,3,4-thiadiazole and the transition state for their conversion (1a → 1c).

Results of geometry optimization for the different forms showed that, total energy value of the <span class="Chemical">amine toutomer is that which has the lowest negative value (−400542.16 kcal/mol) when compared with the other two expected isomers of the semicyclic <span class="Chemical">amidine toutomer <span class="Chemical">1b and 1c (−400535.93 and −400537.22 kcal/mol). Optimization job was confirmed in each case by calculating the normal vibrations and realizing the absence of the imaginary frequencies. These energy values mean that the amine toutomer is more stable than the semicyclic amidine (at least by about 4.94 kcal/mol). Moreover, we have also investigated the possible conversion process between the two toutomers, amine and amidine, by studying the expected transition state may formed as a result of the transfer of one of the amine-hydrogen atoms to the ring-imine-nitrogen (N3 atom, see atomic numbering order in Fig. 1). The optimized geometrical parameters of the transition state were determined using the same method of computation. Results indicated that it has a total energy of (−400473.34 kcal/mol) higher than that of the amine form 1a with (68.82 kcal/mol) (Table 1). This high energy barrier indicates that at the normal conditions the structure prevalence is for the amine form and not the amidine.

Table 1

Calculated energies of the toutomeric forms of 2-amino-1,3,4-thiadiazoles (1a–c, Fig. 1).

Character	Amine 1a	Amidine 1b	Amidine 1c	Transition State (1a → 1c)
Total energy (kcal/mol)	−400542.16	−400535.93	−400537.22	−400373.34
E (HOMO) (eV)	−9.595	−8.922	−8.891	−8.8.760
E (LUMO) (eV)	2.333	2.506	3.395	2.292
Dipole moment (debye)	3.737	2.436	1.979	2.596

Calculated energies of the toutomeric forms of <span class="Chemical">2-amino-1,3,4-thiadiazoles (1a–c, Fig. 1).

The <span class="Chemical">amine molecule 1a is expected to act as electron <span class="Species">donor when interacted with an electrophile. Such interaction should take place between its highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) of the electrophile. Calculated atomic charge densities of 1a, as obtained from ab initio calculations are depicted in Table 2. These values indicated that N3 (the <span class="Chemical">imine nitrogen) and N6 (the amino nitrogen) atoms in 1a possess the highest negative charge values (−0.363 and −0.7227, respectively). Moreover, the calculated atomic orbital coefficients of HOMO of 1a, as given in Table 2, indicated that, the 2s and 2pz-atomic orbitals have the highest contribution. 2s- and 2pz-orbitals of the N3 atom contribute the HOMO with the same phase (−0.0661 and −0.2289, respectively) which indicate that they reinforce each other generating an active space for interaction. On the other hand, the highest atomic orbital coefficients of N6 atom in the HOMO were found to be mainly from 2pz-orbital (+0.3055) and have an opposite phase relative to that of the N3 atom. According to these values, it is obvious that 1a is available for interaction with an electrophile through its HOMO via N3 and N6 atoms (Table 2).

Table 2

Calculated atomic charge densities and the HOMO atomic orbital coefficients for the amine 1a.

Atom	Charge	Atomic orbital coefficients
		2s	pz	py	px
S	+0.2163	0.0060	−0.1101	0.0018	0.0044
N3	−0.3633	−0.0661	−0.2289	0.0022	0.0199
N4	−0.2274	−0.0030	0.1776	0.0098	−0.0265
N6	−0.7227	−0.0499	0.3055	0.0239	0.0566

Calculated atomic charge densities and the HOMO atomic orbital coefficients for the <span class="Chemical">aminen> 1a.

On the other hand, the <span class="Chemical">chalcone 2 is expected to act as bis-electrophile, and interact with the <span class="Chemical">amine 1a as electron acceptor. Its interaction should take place through its LUMO via the highest positive centers of the molecule. The Molecular geometry of <span class="Chemical">chalcone 2 was optimized and the molecular orbitals were calculated employing the same level of computation used in case of the amine 1a. The calculated atomic charges and the atomic orbital coefficients of its LUMO for the expected reacting atoms are depicted in Table 3 and shown in Fig. 2. The ease of accepting electronic charge can be easily revealed from the low energy value of this LUMO (+3.347 eV). The Calculated charge densities on the different atoms showed that the C1 and C3 atoms have the highest positive (+0.852 and +0.328, respectively). This indicates that these two atoms are the centers of interaction. Moreover, the calculated atomic orbital coefficients showed that it is mainly contributed from the pz-atomic orbitals of C3 and C1 atoms with opposite phases (+0.519 and −0.242, respectively). This indicates that the electrophile molecule will interact with the amine 1a via its LUMO and through the C3 and C1 atoms (Table 3).

Table 3

Charge densities and LUMOa atomic orbital coefficients of the chalcone 2.

Atom	Charge	LUMO coefficients
		2s	2pz	2py	2px
O	−0.630	−0.0001	0.2462	−0.12781	−0.1249
C1	+0.852	−0.0014	−0.2428	0.1246	−0.2428
C2	−0.548	−0.0013	−0.3357	0.1729	0.1692
C3	+0.328	0.0104	0.5196	−0.2679	−0.2652

Orbital energy = +3.437 eV.

Fig. 2

(a) Orbital representation of LUMO of the chalcone (2) at a contour level of 0.12; (b) the calculated atomic charge densities.

Charge densities and LUMOa atomic orbital coefficients of the <span class="Chemical">chalcone 2.

(a) Orbital representation of LUMO of the <span class="Chemical">chalcone (2) at a contour level of 0.12; (b) the calculated atomic charge densities.

Interaction of HOMO of 1a with LUMO of <span class="Chemical">chalconen> 2 was investigated on the basis of their atomic orbital coefficients. Calculated data showed that the sp hybrid orbital of N3 atom of 1a has the same orbital phase as the pz-orbital of <span class="Chemical">chalcone 2. Also the pz-orbital coefficient of N6 of 1a has the same orbital phase as pz-orbital of C1 of chalcone 2 (see Fig. 3). Therefore, the interaction of the two molecules will take place first through the interaction of N3 of 1a with C3 of <span class="Chemical">chalcone 2, then the N6 atom of 1a with the carbonyl C1 of chalcone 2 to form the intermediate compounds 4 and 5 (Scheme 2).

Fig. 3

The HOMO–LUMO interaction of 1b with chalcone 2.

Scheme 2

The plausible reaction mechanism for the formation of 3via intermediates 4 and 5.

The HOMO–LUMO interaction of <span class="Chemical">1b with <span class="Chemical">chalcone 2.

The intermediate 5 will be reacted with another molecule 2. In this case 5 will behave as electron <span class="Species">donorn>, (as <span class="Chemical">enamine) attacking the electrophillic center of 2 (Scheme 1). Therefore, their interaction will take place through the HOMO of 5 and the LUMO of compound 2. The calculated atomic charge densities for 5 (Fig. 4) indicated that the C2 atom is that one carrying the highest −ve value (−0.308). On the other hand, the calculated atomic orbital coefficients of its HOMO showed that, it is highly contributed from the pz-atomic orbital of the <span class="Disease">C2-atom. These results strongly indicated that molecule 5 is adapted as a nucleophile to be attacked by another molecule of compound 2. The chalcone 2 as discussed before will interact via its LUMO through its positively charged C3-atom in a similar manner as before with the amine molecule (Table 4).

Scheme 1

Synthesis of 5,7-diphenyl-6-[1,3-diphenylpropan-1-on-3-yl][1,3,4]thiadiazolo[3,2-a]pyrimidine (3).

Fig. 4

(a) prospective representation of the HOMO of compounds 1a and 5; (b) atomic charges at the active positions.

Table 4

Charge densities and HOMO atomic orbital coefficients of compound 5.

Atom	Charge	HOMO coefficients
		2s	2pz	2py	2px
C1	+0.7108	−0.0052	−0.1546	−0.0061	0.0141
C2	−0.3076	0.0115	−0.3835	−0.0089	0.0298
C3	+0.3621	−0.0567	−0.0126	−0.0147	0.0014
N8	−0.7672	0.0032	0.2660	0.0233	−0.0477

Synthesis of <span class="Chemical">5,7-diphenyl-6-[1,3-diphenylpropan-1-on-3-yl][1,3,4]thiadiazolo[3,2-a]pyrimidine (3).

Regarding the reaction of 1 [9] with <span class="Chemical">chalcone 2 in a mixture of <span class="Chemical">ethanol/<span class="Chemical">acetic acid, it give 5,7-diphenyl-6-[1,3-diphenylpropan-1-on-3-yl][1,3,4]thiadiazolo[3,2-a]pyrimidine (3) instead of 5,7-diphenyl-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidine (5), similar behavior has been reported [10].

The structure 3 was established on the basis of elemental analysis and spectral data. The plausible reaction mechanism for the formation of 3 via intermediates 4 and 5 is illustrated in the sequence of Scheme 2. The reaction mechanism is din class="Chemical">splayed via sequential cycloaddition followed by cyclocondensation reaction with <span class="Chemical">enone as biselectrophile.