Regioselective three-component synthesis and theoretical calculations of new alkane-linked bis(thiazol-2(3H)-imine) hybrids: a DFT-based FMO and local reactivity indices

A three-component approach was conducted to adeptly prepare a new series of (Z)-bis(N-phenylthiazol-2(3H)-imines. The newly synthesized compounds were prepared by refluxing a ternary mixture of phenyl isothiocyanate, the suitable α-bromoketones, and alkane-linked diamines in ethanol. Reaction conditions were optimized by comparing the yield of the final product under various bases, solvents, temperatures, and base-to-starting-materials molar ratios. The intended hybrids were produced with 85–96% yields while using ethanol at 80 °C for 3–5 h in the presence of anhydrous sodium acetate. The ascribed configuration of new products as well as the regioselectivity of the one-pot reaction were confirmed using both spectral data (1D and 2D NMR) and DFT-calculation techniques.


Introduction
In a multicomponent reaction (MCR), at a minimum, three reactants are necessary, and most of the components from the beginning materials are incorporated into the final structures [1,2]. The approach differs from multistep synthesis due to its high efficiency, simplicity, and cost-effectiveness in terms of the atoms and steps needed [3]. Mannich [4], 1 3 Gewald [5], Povarov [6], Ugi [7], and Petasis [8] are only a few of the many multicomponent reactions with names of persons. Lately, similar procedures have been used to create molecular scaffolds with a variety of biological traits [9,10].
We present herein a three-component procedure for the synthesis of various regioisomeric alkane-linked bis(thiazol-2(3H)-imine) hybrids 1 that are attached to arene or chromene units as part of our ongoing efforts to produce azoles (see Fig. 2) [44][45][46][47][48][49][50]. 1D and 2D NMR spectroscopy were used to determine the structures of the resulting products. DFT has proven to be an effective tool for determining chemical reactivity and reaction mechanisms in both organic and inorganic chemistry [51,52]. DFT calculations were also carried out to gain insight into the structures of the target thiazoles and the mechanism of their formation.
The synthetic potential of bis(3-phenylthiourea) 4a was then investigated and evaluated through its reaction with an ethanolic solution of 2-bromo-1-(4-methoxypheny)ethan-1one 5c in the presence of triethylamine (TEA) at 80 °C. TLC analysis revealed that after 3 h of heating, the reaction produced a single product, which was then isolated with an 80% yield. The previous product could be assigned to one of two regioisomeric structures, bis(N-phenylthiazol-2(3H)-imine) derivative 1c or bis(3-phenylthiazol-2(3H)-imine) derivative 6c (see Scheme 2).  Elemental analysis and spectral data were used to deduce the structure of the previous product. The 1 H-NMR spectrum of such a product revealed two broad singlet signals at δ 1.85 and 3.67 corresponding to propane spacer protons, as well as two singlet signals at δ 3.78 and 6.02 corresponding to OMe and thiazole-H protons. It also revealed a multiplet signal at δ 6.93-7.32, which was attributed to 18 aromatic protons. The isolated product's 1 H-1 H NOESY spectrum provided additional evidence for its structure (see Fig. 3).
Compound 1c's 1 H-1 H NOESY spectrum provided additional evidence for its presence in a (Z)-configuration (see Fig. 5). The presence of 1c in an (E)-configuration is ruled out because there are no cross-peaks between NPh-H2 and the propane spacer. This finding is consistent with the previous X-ray single crystal study on (Z)-4-methyl-N,3-diphenylthiazol-2(3H)-imine reported by Murru et al. [54].
We continued our efforts, inspired by the findings, to prepare the target bis(N-phenylthiazol-2-(3H)-imines) 1 using a one-pot protocol. The synthesis of 1c was taken as a model. A ternary mixture of propane-1,3-diamine 2a, phenyl isothiocyanate 3, and 2-bromo-1-(4-methoxyphenyl)ethan-1-one 5c was reacted in various solvents and bases (see Scheme 3 and Table 1). All reactions were monitored by TLC analyses. The potential of TEA or diethylamine (DEA) was investigated. As a result, using two equivalents of each base, TEA and DEA were tested in various solvents, such as ethanol at 80 °C, dioxane at 100 °C, and toluene at 80 °C (Table 1, Entries 1-6). The previous conditions produced the target 1c in 52-80% yields.
It is worth of mention that our first attempt to start the one-pot synthesis of 1c in the presence of DEA resulted in the formation of a mixture of several products, as detected by TLC analysis. This could be due to the side reaction of DEA with phenyl isothiocyanate 3, which interferes with the formation of the bis(3-phenylthiourea) 4a. To avoid this, propane-1,3-diamine 2a was reacted first with two equivalents of phenyl isothiocyanate 3 at rt in the respective solvent. After 10 min of stirring, the intermediate 4a was completely formed, and then two equivalents of both 5c and DEA were added to the reaction mixture to complete the formation of target 1c.
Moreover, the use of two equivalents of sodium bicarbonate, sodium carbonate, potassium carbonate, or cesium carbonate to mediate such three-component reactions in ethanol at 80 °C or dioxane at 100 °C was investigated. These inorganic bases produced 1c in yields ranging from 58 to 81% ( Following that, the amount of anhydrous sodium acetate required to mediate the three-component synthesis of 1c was investigated (see Table 2). All reactions were carried out in ethanol for 2-4 h at 80 °C with sodium acetate amounts ranging from 2 to 2.5 equivalents. For the one-pot protocol, the best reaction conditions were 2.2 equivalents of sodium acetate for 3 h. It yielded 1c with a 95% yield (Table 2 and Entry 4).  The research was then expanded to produce a series of alkane-linked bis(N-phenylthiazol-2(3H)-imines) 1a-1f. The desired hybrids were created with minor modifications to the optimized one-pot protocol. After heating the respective reaction mixture at 80 °C for 3-4 h, the appropriate alkanelinked diamines 2a,b, and p-substituted phenacyl bromides 5a-5c were used to produce the target products 1a-1f in 89-96% yields (see Scheme 4) [31].
In addition, we conducted a screening of the nucleophilicity and electrophilicity of both reactants and found that intermediates 7 act as nucleophilic species, while α-bromoketones 5 act as electrophilic species. For instance, 7a exhibits a nucleophilicity of 4.504, which is higher than 5a's value of 2.034. In contrast, the electrophilicity of 7a is 1.149, which is lower than 5a's value of 2.554. This indicates that 7a will attack 5a during the reaction, with electrons moving from 7a to 5a.
FMO calculations for the possible products (Z/E)-1 DFT at (B3LYP/6-31G) level was used to shed more light on the correct configuration of the regioisomeric products 1 [56][57][58]. Table 6 shows the visualized optimized structures, HOMO, and LUMO of products (Z/E)-1a, as well as their energies in three different media, namely gas, water, and ethanol. All findings are presented in Tables S1 and S2 in the electronic supplementary file.
Global reactivity indices of regioisomeric products (Z/E)-1 Theoretical calculations of the total energy (RB3LYP) [59] derived from conceptual DFT provide additional evidence for the superiority of (Z)-1 over (E)-1. Global reactivity indices of (Z/E)-1a as a typical example are presented in Table 7 in three different media, namely gas, water, and ethanol. The findings of all products are presented in Tables S3-S5 in the electronic supplementary file.

Theoretical energy differences calculations for the interaction of α-haloketone 5 and (Z)-bis(carbamimidothioates)
7 FMO analysis was used as an important step in understanding the mechanism of the regioselective reaction between α-haloketones 5 and (Z)-bis(carbamimidothioates) 7. Therefore, the calculation of the two possible relative   Table 8) [60]. Generally, we found that ΔE 2 is smaller than ΔE 1 . This implies that HOMO of (Z)-7 interacts with LUMO of 5 to initiate the reaction. This result offers significant support for the hypothesis that electrons move from the more nucleophilic (Z)-bis(carbamimidothioates) 7 to the more electrophilic α-haloketones 5. The FMO diagram for the interaction between α-haloketone 5a and (Z)-bis(carbamimidothioates) 7a,b is shown in Fig. 6. The ΔE 1 and ΔE 2 of the 5a/7a interaction are 5.659 and 2.352 eV, respectively, whereas the ΔE 1 and ΔE 2 of the 5a/7b interaction are 5.112 and 2.236 eV, respectively.

Theoretical calculations of Parr indexes and local nucleophilicity and electrophilicity
Using local reactivity indices [61][62][63][64][65][66][67], the next step involves determining which of the nucleophilic centers from (Z)-7 will be the most effective in attacking the highly electrophilic center in 5. Recent advancements have turned the Parr, local nucleophilic, and local electrophilic indices into powerful tools for site selectivity [63,68]. To compute the Parr function, the atomic spin density was analyzed under unrestricted formalization (UB3LYP) using the Gaussian 09 program and the 6-31 + G(d,p) basis set [64]. The preferred attack site can be identified by utilizing the Parr, local nucleophilic, and local electrophilic indices [69]. Tables 9 and 10 summarize the information obtained from these indices for both 5 and (Z)-7.
Based on data collected on Parr [64], and local nucleophilicity [65], as well as dual descriptors [63] for (Z)-7a,b, we have found that the sulfur site is more nucleophilic than the NH site. As an example, in 7a, the local nucleophilicity (NP − ) of the sulfur site is 0.721, which is higher than that of the NH site, which is only 0.027. Similarly, the Parr nucleophilicity (P r − ) of the sulfur site is higher with a value of 0.160 compared to the NH site with a value of 0.006. Moreover, the dual descriptor (Δƒ r ) on the sulfur site is more negative than that on the NH site with values of − 0.012 and + 0.028, respectively. Additionally, the local Fukui nucleophilicity (Nƒ r − ) of the sulfur site is more positive, with a value of + 0.014, whereas the NH site has a value of − 0.140.
We have determined that, based on our analysis of Parr [64], local electrophilicity [65], and dual descriptors [63] of compounds 5a-5f, the CH 2 -site adjacent to the bromine atom in the molecule is more electrophilic than the carbonsite of the carbonyl group. For instance, in 5a, the local electrophilicity of the CH 2 -site (ωP + ) is + 1.540, which is higher than that of the CO-site (− 0.158), and the Parr electrophilicity (P + ) of the CH 2 -site (+ 0.603) is also higher than that of the CO-site (− 0.062). Additionally, the dual descriptor (Δƒ r ) value on the CH 2 -site (+ 0.134) is more positive than that on the CO-site (− 0.144), while the local Fukui electrophilicity (ωƒ + ) of the CH 2 -site (+ 1.540) is more positive than that of the CO-site (− 0.158). These findings demonstrate that the attack of the more nucleophilic sulfur site in (Z)-7 on the more electrophilic CH 2 -site in 5 will initiate the reaction (see Fig. 7).       Table 9 Dual descriptor and Parr and local nucleophilicity indices of (Z)-7a, b Site

Theoretical calculations for the proposed intermediates 9-11
Further study of the reaction between 5 and (Z)-7 was performed by computing global descriptors of the proposed intermediates [56-58, 70, 71]. The previous calculations were used to predict the plausible mechanism of the formation of the target hybrids 1. As previously discussed, the reaction between 5 and (Z)-7 can be triggered by the nucleophilic substitution reaction between the sulfur-site in (Z)-7 and the electrophilic CH 2 adjacent to the bromine atom in 5, resulting in the corresponding (Z)-bis(S-alkyl) derivative 9. This intermediate may then be converted into three possible intermediates: (Z,Z)-10, (Z,E)-10 or (Z)-11. The compound (Z)-9 can tautomerize to either (Z,Z)-10 or (Z,E)-10 in their enol-forms. Furthermore, (Z)-9 can undergo cyclization via the acyl nucleophilic addition of the two spacer-NH sites to the carbonyl functions, forming the adduct (Z)-11 (see Fig. 8).
Calculating the energy of compounds (Z,Z)-10, (Z,E)-10, and (Z)-11 leads us to anticipate which route compound (Z)-9 will take. Taking the reaction between 5a and (Z)-7a as a model, the theoretical parameters for the intermediates 9-11 are listed in Table 11. All calculations are listed in Table S6 in the electronic supplementary file. It is evident from the data gathered for 10 and 11 that cyclization is preferable than tautomerization in all derivatives.
Based on the aforementioned findings, the mechanism for the current three-component reaction can be summarized in Scheme 7. First, alkane-linked diamines 2 were reacted with phenyl isothiocyanate 3 to yield bis(3-phenylthiourea) derivatives 4. The previous intermediate produces the most stable (Z)-bis(carbamimidothioates) 7 in the presence of sodium acetate, which then reacted with α-haloketones 5 via a nucleophilic substitution reaction to give the corresponding (Z)-bis(S-alkyl) derivative 9. The acyl nucleophilic additions of the two spacer-NH sites to the carbonyl functions produced the adduct (Z)-11. Next, two molecules of water were removed from (Z)-11 to yield the regioisomeric (Z)-1 as a final isolable product.

Conclusion
A new series of (Z)-bis(N-phenylthiazol-2(3H)-imines) was efficiently prepared using a three-component protocol. For this purpose, a one-pot reaction was conducted between alkane-linked diamines, phenyl isothiocyanate, and the appropriate α-bromoketones in ethanol in the presence of anhydrous sodium acetate. Both 1D and 2D NMR techniques were used to investigate the regioselectivity of the one-pot reaction as well as the assigned structure of new products. Additional support for the aforementioned findings was obtained by DFT-based calculations at the computational level B3LYP/6-31 + G(d,p). The current study demonstrated that the favored mechanism and experimental regioselectivity of the applied reaction protocol, as well as the assigned configuration of new products, could be correctly predicted using previous computational tools.

Materials
All solvents unless otherwise noted, were purchased from commercial sources and utilized directly as received. The other substances were purchased from Merck or Aldrich and utilized directly. The melting points are uncorrected and determined using Stuart's melting point equipment. IR spectra were recorded using the Nicolet iS10 FT-IR spectrometer's Smart iTR, Chemical shifts were represented as ppm units, and NMR spectra were captured on a Bruker Avance III 400 MHz spectrophotometer (400 MHz for 1 H and 100 MHz for 13 C) using TMS as an internal standard and DMSO-d 6 as a solvent. Elemental analyses were performed on a EuroVector instrument C, H, N analyzer EA3000 Series. For detailed synthetic protocol and characterization data of all newly synthesized products, see the Electronic supplementary file.

Computational screening
The theoretical calculations were carried out using the Gaussian 09W software [56,57]. Using the widely accepted 6-31 + G(d,p) basis set, the molecular geometry of the investigated compounds was optimized using the density functional theory B3LYP approach. The optimized structure was visualized with GaussView 6.0.1 [58,70,71].

Frontier molecular orbitals and global reactivity indices
The HOMO (highest-occupied molecular orbital) and LUMO (lowest-unoccupied molecular orbital) were estimated at the same computational level. Measurements are performed to define a system's reactivity and stability using widely applied chemical principles generated from conceptual DFT (see Electronic supplementary file) [72][73][74][75][76][77][78].

Local reactivity indexes
To describe the regioselectivity of an atom 'r' in a molecule, several local reactivity indices are computed, including the condensed Fukui functions ( f + r and f − r ) [61,62], the dual descriptor ( Δf r ) [63], Parr functions (P r ) [64,65], and Domingo-related work (see Electronic supplementary file) [66,67]. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/.