Stereoselective Synthesis of New 4-Aryl-5-indolyl-1,2,4-triazole S- and N-β-Galactosides: Characterizations, X-ray Crystal Structure and Hirshfeld Surface Analysis

Abstract

5-(1H-Indol-2-yl)-4-phenyl-2,4-dihydro-3H-1,2,4-triazole-3-thione 1a and 4-(4-chlorophenyl)-5-(1H-indol-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione 1b were galactosylated in the presence of NaHCO₃ in ethanol to produce S-galactosides 3,4, whereas, in the presence of K₂CO₃ in acetone they produced a mixture of S- and N-galactosides 3-6 with a higher yield of S-galactosides over the respective N-galactosides. Improvement in the yields of N-galactosides was produced by thermal migration of the galactosyl moiety from sulfur to nitrogen using fusion. β-Stereoselectivity of galactosylation was determined using the coupling constant value ³J_1,2, which exceeded 9.0 Hz in all prepared galactosides. The precursors 1a and 1b alkylated with 3-bromopropan-1-ol 7 in K₂CO₃ and acetone produced the S-alkylated products 8 and 9, respectively. Structural determinations of new compounds 5 and 9 are presented. The phenyl and indole moieties were found to be twisted from the triazole ring mean in both compounds. For compound 5, the twist angles were 66.24° and 18.86°, respectively, while the corresponding values for 9 were in the ranges of 73.15–77.29° and 13.96–20.70°, respectively. Hence, the crystal system of 9 is triclinic while the space group is P-1. Detailed analysis of the intermolecular interactions in the crystal structure of 5 is presented using Hirshfeld calculations. The O…H, N…H, C…H, and S…H contacts appeared as red spots in the d_norm Hirshfeld surface indicating short distance intermolecular interactions. Their percentages were estimated based on the decomposition of the fingerprint plot to be 25.6, 2.4, 14.0, and 6.3%, respectively.

1. Introduction

Due to the major role that glycosides, glycoconjugates, and nucleosides play in biological processes, the discovery of such molecules is necessary. These compounds with complex structures, diverse stereochemistry, and numerous linkage possibilities are qualified to fulfill many different functions in biological systems [1]. Indole moiety is one of the most potent pharmacophores, and it constitutes the backbones of serotonin (neurotransmitter) and melatonin (natural hormone), in addition to tryptophan (an essential amino acid). Mitomycin and its analogues are bioactive indole alkaloids gaining great attention because of their use in cancer chemotherapy and in treatment of bacterial infections [2,3]. Moreover, compounds containing an indole nucleus are significant regarding the improvement of various bioactive compounds through derivatization or substitution at the indole ring. These compounds exhibit various biological activities such as antimicrobial, antiviral, anticonvulsant, analgesic, anti-inflammatory, antitubercular, and anticancer effects [4,5,6,7,8].

The 1,2,4-Triazole nucleus also acts as an important pharmacophore, which is characterized by a high affinity for interacting with biological receptors due to its hydrogen bonding capacity, dipole character, solubility, and rigidity [9]. Due to its polar nature, the triazole nucleus could increase the solubility of ligands and considerably improve the pharmacological features of the drug [10]. Many anticancer agents such as tebuconazole, triadimefon, fluconazole, and ribavirin have a 1,2,4-triazole moiety [11]. The 1,2,4-Triazole-3-thiones/thiols show more potency associated to their parent compounds [12]. They have shown interesting biological activities, such as antimicrobial, anticancer, antitubercular, and hypoglycemic properties [13,14,15].

Triazole heterocycles, which incorporate exocyclic sulfur as mercapto (thiols) and thiones, reveal more potency compared to their parent compounds [12]. A diversity of biological activities was found for 1,2,4-triazole-3-thione and 1,2,4-triazole-3-thiol, including anticancer, antimicrobial, antitubercular, and hypoglycemic activities [13,14,15]. Carbohydrates possess essential roles in nature by means of being energy sources and structural matter, and because of their molecular recognition in cellular processes [16]. Hence, bringing indole, 1,2,4-triazole, and carbohydrate or alkyl groups into a single heterocyclic framework could result in enhancing biological properties [17,18,19,20,21]. Maftei, et al. combined a pyrazole–pyrimidine unit with 1,2,4-oxadiazole and trifluoromethylpyridine moieties to improve the antitumor activity of the heterocyclic system as whole [22]. A galactosylation reaction means a coupling of a galactcosyl donor with a galactosyl acceptor to form galactoside. A galactosyl donor with a suitable leaving group at the anomeric position is required. Neda, et al. successfully used 2,3,4,6-tetra-O-benzyl-β-D-galactopyranosyl difluorophosphate as a galactosyl donor for the synthesis of highly β-stereoselective galactosylation [23]. Herein, a 2,3,4,6-tetra-O-acetyl-α-D-galactopyranosyl bromide galactosyl donor was used.

In organic and bio-organic chemistry, the determination of structural features such as the site of alkylation (i.e., whether the alkylation is performed on sulfur or nitrogen) and the configuration of the glycosyl moiety (alpha or beta) is very significant for recognizing a structure’s activity relationship and pharmacological action. In this context, S-, N-β-D-galactosides and exocyclic 3-hydroxyproyl derivatives as acyclonucleosides were synthesized. The chemical structures, galactosyl moiety configuration, and site of alkylation were assigned using NMR. In addition, X-ray single crystal analysis was used for studying the crystal features of compounds 5 and 9. Moreover, full analysis of intermolecular interactions that control molecular packing in crystal structures was performed using Hirshfeld surface calculations.

2. Materials and Methods

2.1. Chemicals and Instrumentation

Anhydrous solvents and all reagents were purchased from Sigma-Merck (Haverhill, MA, USA) and Alfa Aesar (Mississauga, ON, Canada). Melting points were measured via a melting-point apparatus (SMP10, Starfire Systems Inc., Schenectady, NY, USA) in open capillaries and were uncorrected. The progress of the reactions was observed using thin layer chromatography (TLC) with pre-coated plates with silica gel 60 F254 with a thickness of 0.25 mm (Merck, Millipore, Burlington, MA, USA). Detections were achieved using UV light illumination and/or treatment with a solution of 10% H₂SO₄ in aqueous methanol. For flash chromatography, commercial alumina or silica was used. Nuclear magnetic resonance (¹H NMR and ¹³C NMR) spectra were determined in CDCl₃ and DMSO-d₆ and were recorded on a Bruker AC 400 MHz spectrometer (Bremen, Germany) in the presence of tetramethylsilane as an internal standard. Chemical shifts were described in δ (ppm), and coupling constants were given in Hz. EI mass spectra were recorded with Finnigan MAT312 and Jeol JMS.600H (Tokyo, Japan) mass spectrometers. HREI mass spectra were recorded with a Finnigan MAT 95XP instrument. ESI-MS spectra were recorded with an Applied BiosystemsQStar XL apparatus (Darmstadt, Germany).

2.2. General Procedures for Galactosylation

2.2.1. Method A

To a solution of the selected 4-aryl-1,2,4-triazole-thione 1a or 1b (1.0 mmol) in dry acetone (10 mL), K₂CO₃ (1.1 mmol), was added. After stirring the previous mixture for one hour, 2,3,4,6-tetra-O-acetyl-α-D-galactopyranosyl bromide (1.1 mmol) was added portion-wise and the reaction mixture kept overnight under continuously stirring. The solvent was evaporated under vacuum; then, cold water was added, and the formed precipitate was collected and dried. Pure products were separated using alumina column chromatography with elution using ethyl acetate/n-hexane 3:7.

2.2.2. Method B

A mixture of the selected 4-aryl-1,2,4-triazole-thione 1a or 1b (1.0 mmol) and NaHCO₃ (1.1 mmol), in abs. EtOH (10 mL), was stirred for one hour; then, 2,3,4,6-tetra-O-acetyl-α-D-galactopyranosyl bromide (1.1 mmol) was added portion-wise, and the mixture was continuously stirred for 48 h. The workup was performed as in method A.

2.3. General Method for Thermal Transformation of S-Galactosides into N-Glycosides

Method C

The S-galactosides 3,4 (0.1 mmol) were heated on a hotplate at a temperature a little bit higher than the melting point for 5 min; TLC was used to follow up the conversion process. The fused mass was allowed to cool to room temperature once galactosyl migration was finished, and the resulting solid was powdered and recrystallized from EtOH to provide the corresponding N-galactosides 5,6.

5-(1H-Indol-2-yl)-4-phenyl-3-(2,3,4,,6-tetra-O-acetyl-β-D-galactopyranosylsulfanyl)-1,2,4-triazole 3. Yields: (66% method A, 65% method B), m.p. 138–140 °C. ¹H NMR (400 MHz, CDCl₃): δ 1.94, 2.00, 2.05, 2.13 (4s, 12H), 4.08–4.13 (m, 3H), 5.13–5.20 (m, 1H), 5.13 (t, 1H, J = 10.0 Hz), 5.47 (s, 1H), 5.68 (d, 1H, J = 10.20 Hz), 5.74 (s, 1H), 7.03 (dd, 1H, J = 7.6, J = 7.2 Hz), 7.21 (t, 1H, J = 7.6 Hz), 7.35–7.45 (m, 3H), 7.62–7.71 (m, 4H), 11.17 (br.s, 1H); ¹³C NMR (100 MHz, CDCl₃): δ 20.57, 20.59, 20.63, 20.74, 61.24, 67.18, 67.31, 71.71, 74.90, 84.86, 103.37, 112.28, 120.37, 121.21, 123.04, 124.07, 127.68, 127.99, 130.33, 131.00, 133.40, 136.91, 149.58, 150.27, 169.83, 169.90, 170.23, 170.37; HRMS (EI): m/z Calcd for C₃₀H₃₀N₄O₉S (M+): 622.1733 Found: 622.1733.

4-(4-Chlorophenyl)-5-(1H-indol-2-yl)-3-(2,3,4,,6-tetra-O-acetyl-β-D-galactopyranosylsulfanyl)-1,2,4-triazole 4. Yields: (67% method A, 69% method B), m.p. 154–155 °C. ¹H NMR (300 MHz, CDCl₃): δ 1.94, 2.00, 2.07, 2.15 (4s, 12H), 4.08–4.13 (m, 3H), 5.17 (dd, 1H, J = 10.00, J = 3.20 Hz), 5.31 (t, 1H, J = 10.0 Hz), 5.47 (d, 1H, J = 3.20 Hz), 5.64 (d, 1H, J = 10.0 Hz), 5.80 (s, 1H), 7.05 (dd, 1H, J = 7.6, J = 7.2 Hz), 7.22 (dd, 1H, J = 7.20, J = 8.00 Hz), 7.34–7.37 (m, 2H), 7.44 (d, 1H, J = 8.0 Hz), 7.60–7.65 (m, 3H), 10.93 (br.s, 1H); ¹³C NMR (75 MHz, CDCl₃): δ 20.55, 20.61, 20.71, 61.29, 67.24, 67.39, 71.63, 74.98, 85.13, 103.34, 112.24, 120.48, 121.27, 122.83, 124.18, 127.64, 129.44, 130.59, 131.88, 136.91, 137.15, 149.44, 150.16, 169.83, 169.87, 170.19, 170.32; HRMS (ESI +ve mode): m/z Calcd for C₃₀H₂₉N₄O₉SCl (M + 1): 657.1422 Found: 657.1360.

5-(1H-Indol-2-yl)-4-phenyl-2-(2,3,4,,6-tetra-O-acetyl-β-D-galactopyranosyl)-3-thioxo-1,2,4-triazole 5. Yields: (15% method A, 63% method C), m.p. > 300 °C. ¹H NMR (300 MHz, CDCl₃): δ 2.00, 2.05, 2.08, 2.29 (4s, 12H), 4.22–4.32 (m, 2H), 5.31–5.35 (m, 1H), 5.56–5.62 (m, 1H), 5.71–5.76 (m, 1H), 5.98–6.05 (m, 1H), 6.28–6.32 (m, 1H), 7.04–7.12 (m, 1H), 7.26–7.29 (m, 3H), 7.39–7.45 (m, 3H), 7.65–7.75 (m, 3H), 9.12 (br.s, 1H); ¹³C NMR (75 MHz, CDCl₃): δ 20.50, 20.59, 20.68, 20.81, 61.19, 67.06, 67.33, 71.57, 73.71, 83.33, 105.80, 111.35, 120.83, 121.585, 121.73, 125.12, 127.43, 128.485, 130.23, 130.81, 134.48, 136.35, 144.73, 169.35, 169.797, 170.21, 170.36, 171.62; HRMS (EI): m/z Calcd for C₃₀H₃₀N₄O₉S (M+): 622.1733. Found: 622.1723.

4-(4-Chlorophenyl)-5-(1H-indol-2-yl)-2-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl)-3-thioxo-1,2,4-triazole 6. Yields: (18% method A, 59% method C), m.p. > 300 °C. ¹H NMR (300 MHz, CDCl₃): δ 2.00, 2.05, 2.09, 2.30 (4s, 12H), 4.22–4.29 (m, 2H), 5.32–5.35 (m, 1H), 5.58–5.62 (m, 1H), 5.81–5.84 (m, 1H), 5.96–6.02 (m, 1H), 6.24–6.27 (m, 1H), 7.09–7.13 (m, 1H), 7.28–7.30 (m, 2H), 7.43–7.48 (m, 4H), 7.62–7.68 (m, 2H), 9.15 (br.s, 1H); ¹³C NMR (75 MHz, CDCl₃): δ 20.55, 20.73, 20.85, 20.89, 61.18, 66.98, 67.29, 71.51, 73.71, 83.34, 105.82, 111.40, 121.00, 121.29, 121.83, 125.33, 127.37, 129.91, 130.62, 132.85, 136.38, 137.02, 144.52, 169.42, 169.85, 170.24, 170.42, 171.52; HRMS (ESI +ve mode): m/z Calcd for C₃₀H₂₉N₄O₉SCl (M + 1): 657.1422 Found 657.1330.

Alkylation with 3-bromo-1-propanol. To a solution of compound 1a or 1b (1.0 mmol) in dry acetone (10 mL), K₂CO₃ (1.1 mmol), was added under stirring. After one hour 3-bromo-1-propanol (1.1 mmol) was added, and the entire mixture was continuously stirred overnight. The solvent was evaporated under vacuum; then, cold water was added, and the formed precipitate was filtered, dried, and crystallized from EtOH.

3-(3-Hydroxyprop-1-ylsulfanyl)-5-(1H-indol-2-yl)-4-phenyl-1,2,4-triazole 8. Yield: 81%, m.p. 201–203 °C. ¹H NMR (DMSO-d₆, 400 MHz) δ 1.80–1.85 (m, 2H), 3.19 (t, 2H, J = 7.2 Hz), 3.46–3.49 (m, 2H), 4.57 (t, 1H, J = 5.2 Hz), 5.60 (s, 1H), 6.93 (dd, 1H, J = 7.6, J = 6.8 Hz), 7.12 (dd, 1H, J = 6.8, J = 8.0 Hz), 7.34 (d, 1H, J = 7.6 Hz), 7.42 (d, 1H, J = 8.0 Hz), 7.53–7.58 (m, 2H), 7.65–7.71 (m, 3H), 11.94 (br.s, 1H); ¹³C NMR (DMSO-d₆, 100 MHz) δ 29.70, 32.59, 59.46, 101.77, 112.30, 120.17, 121.15, 123.54, 124.42, 127.64, 128.49, 130.70, 131.15, 134.27, 136.95, 149.55, 152.38; HRMS (EI) calcd for C₁₉H₁₈N₄OS (M+): 350.1200 Found: 350.1203.

4-(4-Chlorophenyl)-3-(3-hydroxyprop-1-ylsulfanyl)-5-(1H-indol-2-yl)-1,2,4-triazole 9. Yield: 85 %, m.p. 214–216 °C. 1H NMR (DMSO-d₆, 400 MHz) δ 1.80–1.87 (m, 2H), 3.19 (t, 2H, J = 7.2 Hz), 3.46–3.50 (m, 2H), 4.58 (t, 1H, J = 5.2 Hz), 5.70 (s, 1H), 6.94 (dd, 1H, J = 7.6, J = 7.2 Hz), 7.13 (t, 1H, J = 7.6 Hz), 7.41–7.46 (m, 2H), 7.63 (d, 2H, J = 8.8 Hz), 7.75 (d, 2H, J = 8.8 Hz), 11.94 (br.s, 1H); ¹³C NMR (DMSO-d₆, 100 MHz) δ 29.88, 32.58, 59.44, 101.96, 112.30, 120.20, 121.30, 123.61, 124.24, 127.69, 130.51, 130.79, 133.19, 135.78, 137.00, 149.48, 152.31; HRMS (EI) calcd for C₁₉H₁₇N₄OSCl (M+): 384.0812 Found: 384.0838.

2.4. Crystal Structure Determination

The crystals of 5 and 9 were immersed in cryo-oil, mounted in a loop, and measured at a temperature of 120 K. The X-ray diffraction data were collected on a Rigaku Oxford Diffraction Supernova diffractometer using Cu Kα radiation. The CrysAlisPro [24] software package was used for cell refinements and data reductions. Gaussian absorption correction (CrysAlisPro [24]) was applied to the intensities before structure solutions. Structures were solved using the intrinsic phasing (SHELXT [25]) method. Structural refinements were carried out using SHELXL [26] software with the SHELXLE [27] graphical user interface. In 9, the S(CH₂)₃OH moieties were disordered over two sites with an occupancy ratio of 0.87/0.13. A series of geometric and displacement constraints and restraints were applied to the disordered moieties. The crystal of 9 contained solvent-containing voids. These solvent molecules could not be refined satisfactorily. Therefore, the solvent was omitted from the final refinement cycle. The contribution of the missing solvent to the calculated structure factors was taken into account by using the SOLVENT MASK routine of OLEX2 [28]. The solvent mask was calculated, and 25 electrons were found in a volume of 153 ų in 1 void per unit cell. This was consistent with the presence of 2.5 H₂O per unit cell and 0.625 H₂O per formula unit, which accounted for 25 electrons per unit cell. The missing solvent was taken into account in the unit cell content. The NH hydrogen atoms were located from the difference in the Fourier map and were refined isotropically in both structures. Other hydrogen atoms were positioned geometrically and constrained to ride on their parent atoms, with C-H = 0.95–1.00 Å, O-H = 0.84 Å, and U_iso = 1.2–1.5^.U_eq (parent atom). The crystallographic details are summarized in

Table 1. Crystal data and structure refinement for the target crystals.

	5	9
CCDC	2243221	2243222
empirical formula	C30H30N4O9S	C19H18.25ClN4O1.625S
fw	622.64	396.13
temp (K)	120(2) K	120(2) K
λ (Å)	1.54184 Å	1.54184 Å
cryst syst	orthorhombic	triclinic
space group	P212121	P $\stackrel{-}{1}$
a (Å)	a = 6.8865(3) Å	a = 11.0384(5) Å
b (Å)	b = 13.8302(6) Å	b = 13.6634(8) Å
c (Å)	c = 32.4134(19) Å	c = 14.0630(6) Å
α (deg)	90	74.579(4)°
β (deg)	90	74.477(4)°
γ(deg)	90	72.100(5)°
V (Å3)	3087.1(3) Å3	1905.31(18) Å3
Z	4	4
ρcalc (Mg/m3)	1.340 Mg/m3	1.381 Mg/m3
μ(Mo Kα) (mm−1)	1.440 mm−1	2.964 mm−1
no. reflns.	12175	33118
unique reflns.	6313	7107
completeness to θ=67.684°	100%	99.9%
GOOF (F2)	1.029	1.057
Rint	0.0633	0.0402
R1a (I ≥ 2σ)	0.0563	0.0489
wR2b (I ≥ 2σ)	0.1123	0.1378

^a R₁ = Σ||F_o| − |F_c||/Σ|F_o|. ^b wR₂ = {Σ[w(F_o² − F_c²)²]/ Σ[w(F_o²)²]}^1/2.

.

2.5. Hirshfeld Surface Analysis

The topology analyses were performed using the Crystal Explorer 17.5 program [29].

3. Results and Discussion

3.1. Chemistry

The starting indolyl-triazole-thiones 1a and 1b were synthesized as reported in [18]. Galactosylation of the indolyl triazolethiones 1a, 1b with 2,3,4,6-tetra-O-acetyl-α-D-galactopyranosyl bromide 2 in acetone, and in presence of anhydrous K₂CO₃, afforded a mixture of two products that were separated using alumina column chromatography and characterized as S-galactosides 3,4 (yields > 65%) and the respective N-galactoside analogues 5,6 (yields < 18%). The selectivity of S-galactosylation was achieved using NaHCO₃ as a base in ethanol. The yields of N-galactosides 5,6 were improved with thermal galactosyl moiety migration from sulfur to nitrogen using simple fusion on a hotplate for few minutes without the need for a catalyst (Scheme 1). The ¹H NMR of the S-galactosides 3 and 4 showed anomeric protons around 5.64 ppm with a ³J value of 10.2 Hz. The proton H-4 of the galactose moiety was found as a doublet near 5.47 ppm with a ³J value of 3.2 Hz. The NH of the indole ring appeared at 10.39 and 11.17 ppm. The anomeric carbons of the S-galactosides 3,4 appeared at 84.86 and 85.13 ppm, respectively.

The ¹H NMR of the N-galactosides 5 and 6 displayed the anomeric protons at 6.28, 6.24 ppm, respectively. H-4 of galactose appeared at 5.56 and 5.58 ppm, respectively. The indole NH was found at 9.12 and 9.15 ppm. The anomeric carbons appeared at 83.33 and 83.34 ppm.

Alkylation of the 4-aryl-indolyl-triazoles 1a, 1b with 3-bromopropan-1-ol 7 in the presence of K₂CO₃ produced the respective S-alkylated products 8,9 (Scheme 2). The NMR of 3-hydroxypropyl-sulfanyl-triazoles 8 and 9 revealed the relative positions of three methylene group protons (-S-CH₂-CH₂-CH₂-OH) as multiplet, triplet, and multiplet at 1.80–1.85, 3.19, and 3.46–3.49 ppm, respectively. The respective methylene carbons appeared around 29.70, 32.58, and 59.44 ppm. The indole NH was found at 11.94 ppm.

3.2. Crystal Structure Description

Galactosyslation using a protected (acetylated) galctosyl subunit successfully afforded a good quality crystal suitable for X-ray single structure analysis. The structure of 5 was further confirmed using X-ray diffraction of a single crystal. The structure of the asymmetric unit is shown in Figure 1. As seen in this figure, there is one molecule of 5 as an asymmetric formula while four molecules are present in the unit cell. It crystallized in the orthorhombic crystal system and P2₁2₁2₁ space group. The unit cell parameters were a = 13.8302(6) Å, b = 13.8302(6) Å, and c = and 32.4134(19) Å (Table 1). The unit cell volume was 3087.1(3) ų, and the crystal density was 1.340 Mg/m³. A summary of bond distances and angles is depicted in

Table 2. Bond lengths (Å) for 5 and 9 ^a.

Bond	Length/Å	Bond	Length/Å
5		9
S(1)-C(16)	1.654(5)	Cl(1)–C(13)	1.741(3)
O(1)-C(19)	1.357(6)	N(15)–C(1)	1.371(3)
O(1)-C(18)	1.442(6)	N(15)–C(8)	1.382(3)
N(1)-C(7)	1.380(7)	N(16)–C(16)	1.370(3)
N(1)-C(8)	1.385(7)	N(16)–C(9)	1.377(3)
O(2)-C(19)	1.188(7)	N(16)–C(10)	1.444(3)
N(2)-C(9)	1.311(7)	N(17)–C(16)	1.315(3)
N(2)-N(3)	1.393(6)	N(17)–N(18)	1.399(3)
O(3)-C(22)	1.367(7)	N(18)–C(9)	1.311(3)
O(3)-C(21)	1.429(6)	C(16)–S(1)	1.732(3)

^a List of bond angles are given in Table S1 (Supplementary Data).

and Table S1 (Supplementary Data). The phenyl and indole moieties were found to be twisted from the triazole ring mean plane by 66.24° and 18.86°, respectively. For the structurally related compound deposited as CCDC number 826844, the corresponding twist angles were 83.67° and 2.17°, respectively. In addition, the indole moiety was found rotated about 180° compared to that found in compound 5, which could be attributed to the presence of a strong H-bonding interaction between the indole N-H and crystal water in the previously published structure.

The molecular units of 5 were connected by the O…H, N…H, and S…H interactions shown in Figure 2A. Details of these non-covalent forces are depicted in

Table 3. Hydrogen bonds for 5 [Å and °].

D-H...A	d(D-H)	d(H...A)	d(D...A)	<(DHA)	Symm. Code
N(1)-H(1)...O(7)	0.85(6)	2.48(6)	3.238(6)	149(5)	x − 1, y, z
C(23)-H(23B)...S(1)	0.98	2.98	3.821(6)	144.8	x − 1/2, −y + 1/2, −z + 1
C(24)-H(24)...O(6)	1.00	2.47	3.416(6)	157.1	x + 1/2, −y + 3/2, −z + 1
C(26)-H(26A)...O(6)	0.98	2.56	3.290(7)	131	x − 1/2, −y + 3/2, −z + 1
C(27)-H(27)...O(2)	1.00	2.21	3.177(7)	163.4	x + 1, y, z
C(30)-H(30C)...N(2)	0.98	2.61	3.531(8)	156.2	x + 1, y, z

. The shortest O...H interaction was C(27)-H(27)...O(2) where the H-acceptor and donor(D)–acceptor(A) distances were 2.21 and 3.177(7) Å, respectively, while the donor–hydrogen–acceptor angle was 163.4°. In addition, the molecules’ packing was controlled by C(23)-H(23B)...S(1) and C(30)-H(30C)...N(2) interactions where the D–A distances were 3.821(6) and 3.531(8) Å, respectively. The packing scheme of the molecular units is shown in Figure 2B.

The X-ray structure of 9 is shown in Figure 3 while the detailed crystal data are given in Table 1. This compound crystallized in the less symmetric triclinic crystal system and p-1 space group with unit cell parameters of a = 11.0384(5) Å, b = 13.6634(8) Å, c = 14.0630(6) Å, α = 74.579(4)°, β = 74.477(4), and γ = 72.100(5)°. There were two molecules as an asymmetric unit, and z = 4. The crystal density was 1.381 Mg/m³, and the unit cell volume was 1905.31(18) ų. In this case, the twist angles between the triazole moiety and the phenyl or indole moieties were 73.15° and 20.70°, respectively. The respective values for the molecular unit with letter B in atom numbering were 77.29° and 13.96°, respectively. The most important bond distances and angles are depicted in Table 2 and Table S1 (Supplementary Data). For the structurally related compound reported by Dalimba et al. (CCDC No.: 913951), the corresponding twist angles are 73.38° and 81.53°, respectively [30].

3.3. Hirshfeld Surface Analysis

In the light of the importance of non-covalent interactions on crystal stability, the different contacts among molecular units were analyzed using Hirshfeld calculations. With the aid of Hirshfeld analysis, one can determine all possible non-covalent interactions and their percentages. The results presented in Figure 4 indicate that the H…H, O…H, C…H, and S…H intermolecular interactions were the most dominant. Their percentages were calculated to be 46.8%, 25.6%, 14.0%, and 6.3%, respectively.

Hirshfeld surfaces such as d_norm, shape index, and curvedness maps are presented in Figure 5. In the d_norm map, there were many red spots indicating the presence of intermolecular contacts shorter than the vdWs radii sum of the interacting atoms. These red spots were found corresponding to the O…H, N…H, C…H, and S…H contacts, which are designated by letters A to D, respectively. Their percentages are depicted in Figure 4. Among these interactions, the O…H interactions were the most dominant. A summary of all short non-covalent interactions detected in the crystal structure of this compound with the aid of Hirshfeld analysis is listed in

Table 4. Short contacts and the corresponding interaction distances.

Contact	Distance	Contact	Distance
H1…O7	2.607	H14…C7	2.784
H6…O7	2.348	H14…C6	2.737
H24…O6	2.396	H14…C5	2.733
H26A…O6	2.497	H15…C3	2.685
H26C…O8	2.606	H24…C25	2.767
H27…O2	2.126	H23A…C25	2.666
H30C…N2	2.518	H23A…C26	2.771
H11…S1	3.025	H24…C25	2.767

.

Careful inspection of the shape index and curvedness maps leaves no doubt about the absence of π–π stacking interactions. This observation agreed very well with the small contributions of the C…C (1.3%) and C…N (1.1%) interactions. Other interesting illustrations, which offer not only the weight of each contact in the crystal structure but also shed light on the strength of each contact, are the fingerprint plots shown in Figure 6. The area of the fingerprint gives the percentages of all contacts detected in the crystal structure. Hence, decomposition of the fingerprint gives the percentage of each contact in the crystal structure (Figure 4). In addition, the sharp spikes in the fingerprint plot indicate interactions with short distances and hence are important in molecular packing. This feature is clearly evident in the decomposed fingerprint plots of the H…S, H…O, H…C, and H…N interactions.

4. Conclusions

Base-dependent stereoselective β-galactosylation of 4-aryl-5-indolyl-1,2,4-triazole-3-thiones 1a and 1b were performed in the presence of NaHCO₃ to produce the S-galactosides 3,4 whereas the use of K₂CO₃ afforded a mixture of S- and N-galactosides 3-6. Thermal migration of the galactosyl moiety from sulfur to nitrogen was successful using fusion, which was used to improve the yields of the N-galactosides. In addition, alkylation of 1a and 1b with 3-bromopropan-1-ol 7 in K₂CO₃ afforded the S-alkylated products 8 and 9, respectively. NMR and single crystal analysis were used for structure determinations; two single crystals from compounds 5 and 9 were obtained, and their structural analyses were presented. The X-ray structure of 5 was used for analysis of molecular packing with the aid of Hirshfeld calculations. The supramolecular structure of 5 was found to depend on short O…H, N…H, C…H, and S…H contacts. Among these interactions, the O...H (25.6%) contacts were the most dominant while the N…H (2.4%), C…H (14.0), and S…H (6.3%) contributed less to molecular packing.