Synthesis of 3-[(2-Ethylhexyl)amino]-5-phenyl-4H-1,2,6-thiadiazin-4-one and 3-[(2-Ethylhexyl)amino]-5-[(4-oxo-5-phenyl-4H-1,2,6-thiadiazin-3-yl)amino]-4H-1,2,6-thiadiazin-4-one

Abstract

Suzuki–Miyaura coupling of 3-chloro-5-[(2-ethylhexyl)amino]-4H-1,2,6-thiadiazin-4-one with phenylboronic acid, at ca. 100 °C, gave 3-[(2-ethylhexyl)amino]-5-phenyl-4H-1,2,6-thiadiazin-4-one in 69% yield. Another nucleophilic substitution reaction of 3-chloro-5-[(4-oxo-5-phenyl-4H-1,2,6-thiadiazin-3-yl)amino]-4H-1,2,6-thiadiazin-4-one with 2-ethylhexan-1-amine at ca. 100 °C gave 3-[(2-ethylhexyl)amino]-5-[(4-oxo-5-phenyl-4H-1,2,6-thiadiazin-3-yl)amino]-4H-1,2,6-thiadiazin-4-one in 93% yield.

1. Introduction

Heterocyclic oligomers are short, discrete chains composed of repeating heterocyclic units. Owing to their tunable electronic properties, they have found extensive application in materials science, including in organic field-effect transistors (OFETs) [1,2], organic photovoltaics (OPVs) [1,3], and as photosensitizers [4,5]. Syntheses of oligomers often suffer from limited solubility of both substrates and products, particularly as chain length increases. This issue is commonly addressed through the introduction of solubilizing alkyl chains, as demonstrated for oligothiophenes [6], macrocyclic oligofurans [7], and fused pyrrolothiophenes [8].

Our work on heterocyclic oligomers originates from efforts to prepare short-chain 4H-1,2,6-thiadiazine derivatives [9]. This line of research is part of a broader objective aimed at developing π-conjugated materials that mirror the structural and electronic features of the superconducting polymer poly(sulfur nitride) [10], a concept first envisioned in the foundational studies of Woodward (structures I and II, Figure 1) [11] and Rees (structure III, Figure 1) [12]. It is noted that these polymers require alternating S(II)/S(IV) oxidation states in the sulfur atoms to enable the electron transfer in the polymer.

In our previous work [9], 1,2,6-thiadiazin-4-one oligomers containing up to four thiadiazine units (compound 2, Scheme 1) were prepared from 3-aminothiadiazinone 1; however, further chain extension was limited by aggregation-induced insolubility. To address this, alkyl substitution at the nitrogen linkers was explored as a solubilizing strategy, targeting oligomers 3 and 4 bearing 2-ethylhexyl groups and incorporating two or three thiadiazine units, respectively (Scheme 1). While N-substitution is expected to hinder access to alternating S(II)/S(IV) thiadiazine sulfur oxidation states, the present study was confined to assessing solubility. Subsequent derivatives will consider relocating the solubilizing chains to the para-phenyl site.

2. Results and Discussion

For the preparation of oligomer 3 (Scheme 1), we started from aminothiadiazine 5, which undergoes a Suzuki–Miyaura coupling with phenylboronic acid, catalyzed by Pd(Ph₃P)₄, in the presence of Na₂CO₃, which gave phenylthiadiazine 6 in 69% yield (Scheme 2). The preparation of oligomer 4 required access to phenylthiadiazine 8, which was prepared by reaction of chlorothiadiazine 7 with 2-ethylhexan-1-amine in MeCN, at ca. 100 °C, giving the product 8 in 93% yield (Scheme 2).

The two products 6 and 8 were isolated as yellow needles [mp 62–63 °C and 153–154 °C, respectively], and their UV absorption in solution [λ_max (DCM) 400 nm, log ε 4.02 and 432 nm, log ε 4.43, respectively] indicated the presence of the thiadiazine chromophore. The FTIR spectrum showed absorptions corresponding to an amine [ν(N-H) 3333 cm⁻¹, in both spectra], while the ¹³C NMR spectra confirmed the presence of 4 and 7 quaternary carbon atoms, respectively (see Supplementary Materials).

Following the synthesis of phenylthiadiazines 6 and 8, we attempted to further extend the oligomeric framework by introducing an additional thiadiazine unit via the exocyclic alkylamine. However, reaction of both compounds with 3,5-dichloro-4H-1,2,6-thiadiazin-4-one (9) under the previously employed C-N coupling conditions [9] failed to afford the desired products 10 and 11 (Scheme 3). In all cases, treatment of the aminothiadiazines with dichlorothiadiazine 9 (2–10 equiv) resulted in gradual degradation of 9 over prolonged reaction times (up to 5 d), while no new product formation was detected.

The lack of reactivity was tentatively attributed to the diminished coupling competence of the exocyclic secondary amine, consistent with related observations reported in the literature [13]. To further probe this hypothesis and to exclude steric effects, 3-chloro-5-(methylamino)-4H-1,2,6-thiadiazin-4-one (12) was subjected to the same coupling conditions with dichlorothiadiazine 9 (2 equiv). This reaction likewise led to complete decomposition of 9 within 24 h, and no formation of the expected bisthiadiazine 13 (Scheme 3).

As primary 3-amino-4H-1,2,6-thiadiazin-4-ones undergo efficient C–N coupling with dichlorothiadiazine 9 under identical conditions [9], the present results demonstrate a marked suppression of reactivity for secondary 3-alkylamino-4H-1,2,6-thiadiazin-4-ones. The analogous behavior observed for the methyl-substituted derivative suggests that simple steric effects are unlikely to be the sole cause. These findings are consistent with a decrease in the effective nucleophilicity of the secondary amine under the coupling conditions [14]; however, definitive mechanistic conclusions cannot be drawn at this stage.

The two thiadiazine products 6 and 8 may serve as useful synthetic scaffolds due to the presence of the readily functionalizable amino group, which could enable their incorporation into biologically active molecules, although such applications are not currently the focus of our work.

3. Materials and Methods

The reaction mixture was monitored by TLC using commercial glass-backed thin-layer chromatography (TLC) plates (Merck Kieselgel 60 F₂₅₄, Darmstadt, Germany). The plates were observed under UV light at 254 and 365 nm. The melting point was determined using a PolyTherm-A, Wagner & Munz, Kofler—Hotstage Microscope apparatus (Wagner & Munz, Munich, Germany). The solvent used for recrystallization is indicated after the melting point. The UV-vis spectrum was obtained using a Perkin-Elmer Lambda-25 UV/vis spectrophotometer (Perkin-Elmer, Waltham, MA, USA), and inflections are identified by the abbreviation “inf”. The IR spectrum was recorded on a Shimadzu FTIR-NIR Prestige-21 spectrometer (Shimadzu, Kyoto, Japan) with Pike Miracle Ge ATR accessory (Pike Miracle, Madison, WI, USA), and strong, medium, and weak peaks are represented by s, m, and w, respectively. ¹H and ¹³C NMR spectra were recorded on a Bruker Avance 500 machine [at 500 and 125 MHz, respectively, (Bruker, Billerica, MA, USA)]. Deuterated solvents were used for homonuclear lock, and the signals are referenced to the deuterated solvent peaks. Attached proton test (APT) NMR studies were used for the assignment of the ¹³C peaks as CH₃, CH₂, CH, and Cq (quaternary). GC-MS analysis (EI) was performed on an Agilent 5973 Inert Mass Selective Detector (Agilent Technologies, Santa Clara, CA, USA) coupled to an Agilent 6890N GC system equipped with a HP-5MS capillary column (30 m × 0.25 mm, 0.25 μm) (Agilent Technologies, Santa Clara, CA, USA). Helium was used as a carrier gas at a flow rate of 0.9 mL/min. The injector was heated to 285 °C, and the oven temperature increased from 50 to 120 °C at the rate of 6 °C/min, and then further increased to 260 °C at 30 °C/min. The MALDI-TOF mass spectrum (+ve mode) was recorded on a Bruker Autoflex III Smartbeam instrument (Bruker). 3-Chloro-5-[(2-ethylhexyl)amino]-4H-1,2,6-thiadiazin-4-one (5) and 3-chloro-5-[(4-oxo-5-phenyl-4H-1,2,6-thiadiazin-3-yl)amino]-4H-1,2,6-thiadiazin-4-one (7) were prepared according to the literature procedure [9].

3.1. 3-[(2-Ethylhexyl)amino]-5-phenyl-4H-1,2,6-thiadiazin-4-one (6)

A stirred solution of 3-chloro-5-[(2-ethylhexyl)amino]-4H-1,2,6-thiadiazin-4-one (5) (55.2 mg, 0.200 mmol) in dioxane (1 mL) and H₂O (0.6 mL) at ca. 20 °C were added phenylboronic acid (36.3 mg, 0.300 mmol), Pd(Ph₃P)₄ (11.6 mg, 0.010 mmol, 5 mol%) and Na₂CO₃ (21.2 mg, 0.200 mmol). The solution was then deaerated by bubbling Ar into the reaction mixture for 10 min. The reaction mixture was then heated to ca. 100 °C under Ar until no starting material remained (TLC, 3 h). On cooling to ca. 20 °C, the reaction mixture was adsorbed onto silica and chromatographed (n-hexane/DCM, 70:30) to give the title compound 6 (43.8 mg, 69%) as yellow needles, mp 62–63 °C (from n-hexane/−20 °C); R_f = 0.38 (n-hexane/DCM, 70:30); (found: C, 64.58; H, 7.14; N, 13.08. C₁₇H₂₃N₃OS requires C, 64.32; H, 7.30; N, 13.24%); λ_max(CH₂Cl₂)/nm 229 (log ε 4.20), 249 inf (3.73), 323 (4.19), 400 (4.02); ν_max/cm⁻¹ 3333 m (N-H), 2955 w, 2932 w and 2862 w (C-H aliph.), 1589 m, 1566 s, 1528 w, 1512 w, 1474 m, 1458 w, 1435 w, 1412 w, 1381 w, 1343 w, 1304 w, 1273 w, 1234 w, 1165 w, 1080 w, 1057 w, 1034 w, 964 w, 941 w, 887 w, 864 w, 833 m, 748 m; δ_H[500 MHz; (CD₃)₂CO] 8.16 (2H, d, J = 7.3 Hz, Ar CH), 7.49 (1H, br. s, NH), 7.47–7.40 (3H, m, Ar CH), 3.38 (2H, dd, J = 6.4, 6.4 Hz, NCH₂CH), 1.74 (1H, br. s, CH), 1.45–1.32 (8H, m, CH₂), 0.93 (3H, t, J = 7.5 Hz, CH₂CH₃), 0.90 (3H, t, J = 6.9 Hz, CH₂CH₃); δ_C[125 MHz; (CD₃)₂CO] 160.6 (Cq), 156.6 (Cq), 150.4 (Cq), 136.7 (Cq), 130.1 (CH), 129.1 (CH), 128.8 (CH), 44.4 (CH₂), 39.7 (CH), 31.7 (CH₂), 24.9 (CH₂), 23.7 (CH₂), 14.3 (CH₃), 11.1 (CH₃), one CH₂ peak missing due to overlap with solvent; m/z (GC-MS) 317 (M⁺, 89%), 218 (M⁺-C₇H₁₅, 100), 205 (32), 162 (15), 135 (21).

3.2. 3-[(2-Ethylhexyl)amino]-5-[(4-oxo-5-phenyl-4H-1,2,6-thiadiazin-3-yl)amino]-4H-1,2,6-thiadiazin-4-one (8)

A stirred suspension of 3-chloro-5-[(4-oxo-5-phenyl-4H-1,2,6-thiadiazin-3-yl)amino]-4H-1,2,6-thiadiazin-4-one (7) (70.4 mg, 0.20 mmol) in MeCN (2 mL) at ca. 20 °C was added 2-ethylhexan-1-amine (66 µL, 0.40 mmol). The tube was then sealed and the mixture heated to ca. 100 °C until no starting material remained (TLC, 4 h). The mixture was then adsorbed onto silica and chromatographed (n-hexane/DCM, 50:50) to give the title compound 8 (82.8 mg, 93%) as yellow needles, mp 153–154 °C (from EtOH); R_f = 0.30 (n-hexane/DCM, 50:50); (found: C, 54.18; H, 5.22; N, 18.71. C₂₀H₂₄N₆O₂S₂ requires C, 54.03; H, 5.44; N, 18.90%); λ_max(CH₂Cl₂)/nm 268 (log ε 4.18), 336 inf (4.34), 365 (4.52), 432 (4.43); ν_max/cm⁻¹ 3333 m (N-H), 2955 w, 2924 w and 2870 w (C-H aliph.), 1605 m, 1566 m, 1505 s, 1451 m, 1373 w, 1327 m, 1304 m, 1265 m, 1219 w, 1165 m, 1103 w, 1034 w, 880 w, 864 w, 802 w, 779 w, 756 m, 733 m, 718 m; δ_H[500 MHz; (CD₃)₂CO] 8.21–8.18 (2H, m, Ar CH), 7.52–7.49 (3H, m, Ar CH), 7.45–7.41 (1H, m, NH), 3.38 (2H, dd, J = 6.5, 6.5 Hz, NCH₂), 1.73–1.72 (1H, m, CH), 1.47–1.32 (8H, m, CH₂), 0.93 (3H, t, J = 7.4 Hz, CH₂CH₃), 0.89 (3H, t, J = 7.1 Hz, CH₂CH₃); δ_C(125 MHz; DMSO-d₆) 159.2 (Cq), 154.4 (Cq), 153.8 (Cq), 152.3 (Cq), 149.9 (Cq), 141.6 (Cq), 134.8 (Cq), 130.3 (CH), 128.4 (CH), 128.3 (CH), 43.5 (CH₂), 37.9 (CH), 30.3 (CH₂), 28.2 (CH₂), 23.7 (CH₂), 22.6 (CH₃), 14.0 (CH₃), 10.6 (CH₃); m/z (MALDI-TOF) 445 (M + H⁺, 81%), 345 (M⁺-C₇H₁₅, 49), 333 (36), 325 (40), 258 (72), 232 (40), 212 (44), 156 (C₉H₅N₂O⁺, 100).