Electron‐Rich Phenothiazine Congeners and Beyond: Synthesis and Electronic Properties of Isomeric Dithieno[1,4]thiazines

Abstract A series of isomeric dithieno[1,4]thiazines is accessible through an intermolecular–intramolecular Buchwald–Hartwig amination starting from dihalodithienyl sulfides. The electronic properties of dithieno[1,4]thiazine isomers differ conspicuously over a broad range depending on the thiophene–thiazine anellation: a large cathodic (340 mV) or an anodic shift (130 mV) of the redox potentials relative to corresponding phenothiazines is possible. Structure–property relationships of the dithieno[1,4]thiazine constitution derived from DFT calculations and cyclic voltammetry not only reveal increased electron density but also different delocalization of the radical cations that determines the electrochemical properties significantly. In addition, photophysical properties (absorption and emission) qualify dithieno[1,4]thiazines as promising substitutes of phenothiazine and beyond due to increased tunable electron richness.


General Considerations
All reactions were carried out in flame-dried Schlenk tubes by using syringes under nitrogen atmosphere. Dry solvents for reactions and analytics were directly used from a MB-SPS 800 solvent drying system (MBraun) except of toluene, which was refluxed under nitrogen atmosphere over sodium, distilled and stored in a Schlenk flask over molecular sieve 4 Å under nitrogen atmosphere. 10-Phenyl-10H-phenothiazine (1) [1] and 4-phenyl-4Hdithieno [2,3-b:3',2'-e] [1,4]thiazine (2a) [2] and were synthesized according to the literature procedures as indicated. Commercial grade reagents were purchased from Sigma Aldrich, Alfa Aesar, ABCR, Fluorochem and ACROS and used as supplied without further purification. Crude mixtures were adsorbed on Celite® 545 (0.02-0.20 mm) from Carl Roth GmbH Co.KG. The purification of products was performed on silica gel 60 M (0.04-0.063 mm) from Macherey-Nagel by using the flash technique under a pressure of 2 bar. For TLC silica gel coated aluminium plates (60, F 254 ) from Merck were employed and analyzed with UV light at 254 or 365 nm. 1 H, 13 C, and 135-DEPT NMR spectra were recorded at 293 K on 300 MHz (Bruker AVIII 300), 500 MHz (Bruker Avance DRX 500) and the resonances of the residues of nondeuterated CDCl 3 ( 1 H = 7.26 ppm, 13 C = 77.00 ppm), acetone-d 6 ( 1 H = 2.05 ppm, 13 C = 29.84 ppm) or THF-d 8 ( 1 H = 3.58 ppm, 13 C = 67.57 ppm) were locked as internal standards. The multiplicities of signals are abbreviated as follows: d = doublet, dd = doublet of doublets and m = multiplet. The assignments of C quat and CH nuclei are based on DEPT spectra. IR spectra were recorded on a Shimadzu IR Affinity-1 with ATR technique. The intensities of IR signals are abbreviated as s (strong), m (medium) and w (weak).
The elemental analyses were carried out on a Perkin Elmer Series II Analyser 2400 at the Institute for Pharmaceutical and Medicinal Chemistry at Heinrich-Heine-University Düsseldorf.
Melting points (uncorrected) were measured with a Büchi B545 apparatus.
Absorption spectra were recorded in dichloromethane high performance liquid chromatography (HPLC) grade at 293 K on Perkin Elmer UV/vis/NIR Lambda 19 spectrometer. For the determination of the extinction coefficientsεabsorption measurements at five different concentrations were carried out. Emission spectra were recorded in dichloromethane HPLC grade at 293 K on a Perkin Elmer LS55 spectrometer.
Quantum chemical calculations were carried out utilizing the HPC-Cluster Ivybridge of the Zentrum for Informations-und Medientechnologie (ZIM) at the Heinrich-Heine-University Düsseldorf.
Cyclic voltammetry experiments (EG&G Princeton Applied Research Model 263A potentiostat) were performed under argon atmosphere in dry and degassed dichloromethane at 293 K using n-Bu 4 NPF 6 (0.1 M) as electrolyte and at scan rates v of 100, 250, 500 and 1000 mVs -1 . The three-electrode array consists of a working electrode with a 2 mm platinum disk, a platinum wire counter electrode, and an Ag/AgCl (3.0 M NaCl) reference electrode.

One-pot synthesis of bis(4-bromothiophen-3-yl)sulfane (3a)
Afterwards, while the temperature was raised to 0 °C, the stirring was continued for another 15 min. In the next step, 654 mg (3.43 mmol, 1.00 equiv) p-toluenesulfonyl chloride was added slowly. It was stirred vigorously for 10 min at 0 °C and then for 2 h at 40 °C.
Simultaneously, 580 µL (4.12 mmol, 1.20 equivs) diisopropyl amine and 4 mL dry diethyl ether were charged into another flame-dried Schlenk vessel under nitrogen atmosphere and were cooled down to 0 °C. Then, 2.58 mL (4.12 mmol, 1.20 equivs, 1.6  in hexane) n-butyllithium was added dropwise slowly to the diisopropyl amine solution. It was stirred for 10 min at 0 °C and for 10 min at ambient temperature after that. In the meantime, 671 mg (4.12 mmol, 1.20 equivs) 3-bromothiophene (5a) and 4 mL dry diethyl were filled into a third flame-dried Schlenk vessel under nitrogen atmosphere and were cooled down to -78 °C. The previously prepared lithium diisopropylamide solution was dropped into the 3-bromo-thiophene solution and it was stirred at -78 °C for 30 min. This lithiated 3-bromothiophene was added to the vigorously stirred reaction solution, which had been cooled down to -78 °C before. Then, the reaction solution was stirred at -78 °C for 1.5 h. Finally, the reaction was quenched by the addition of 10 mL water. The organic layer was separated, the aqueous layer was extracted with diethyl ether three times and the combined organic layers were died with dry magnesium sulfate. The volatiles were removed by evaporation and the crude product was purified chromatographically on silica gel (n-hexane) to give 488 mg (1.37 mmol, 40%) of 3a in form of a light-yellow oil.

General procedure 1 (GP1) for the one-pot synthesis of dithienyl sulfides 3b and 3c
In a flame-dried Schlenk vessel under nitrogen atmosphere were filled 1.00 equiv of a bromo thiophene 5 and 0.4 mL/mmol dry diethyl ether. The reaction solution was cooled down to -78 °C (isopropanol/dry ice bath). Then, 1.00 equiv n-butyllithium (1.6  in hexane) was added dropwise slowly and the reaction solution was stirred for 30 min at -78 °C. The temperature was raised to 0 °C (water/ice bath) and the volatiles were removed in vacuo carefully (approx. 1 h). The remaining colorless to light yellow solid was dissolved in 0.4 mL/mmol dry diethyl ether and cooled down to -78 °C again. Next, 1.00 equiv fine mortared sulfur was added. The reaction solution had been stirred for 30 min at -78 °C and for 30 min at 0 °C afterwards. To the reaction solution was added 1.00 equivs ptoluenesulfonyl chloride slowly. It was stirred for 30 min at 0 °C and then for 3 h at 40 °C.
Simultaneously, another portion of a bromo thiophene 5 was lithiated: In a flame-dried Schlenk vessel under nitrogen atmosphere were filled 1.20 equivs of bromo thiophene 5 and 0.4 mL/mmol dry diethyl ether. The reaction solution was cooled down to -78 °C. Then, 1.20 equivs n-butyllithium (1.6  in hexane) were added dropwise slowly and the reaction solution was stirred for 30 min at -78 °C. Likewise, the volatiles were removed and the remaining colorless to light yellow solid was dissolved in 0.4 mL/mmol dry diethyl ether and cooled down to -78 °C again. The resulting second portion of thienyl lithium was dropped to the reaction solution, which had been cooled down to -78 °C after the completion of the tosylation. The reaction solution was stirred overnight and was allowed to come to ambient temperature slowly meanwhile. The reaction was quenched by the addition of 50 mL water.
The organic layer was separated, the aqueous layer was extracted with diethyl ether three times and the combined organic layers were died with dry magnesium sulfate. The volatiles were removed by evaporation and the crude product was purified by column chromatography. For experimental details see table 1.

Bis(2-iodothiophen-3-yl)sulfane (3e)
In a Schlenk vessel under nitrogen atmosphere were charged 191 mg (0.960 mmol, 1.00 equiv) di(thiophen-3-yl)sulfane (5b) and 6 mL dry DMF and cooled down to 0 °C (water/ice bath). Then, 432 mg (1.92 mmol, 2.00 equivs) N-iodosuccinimide was added in one portion. The reaction solution was stirred for 46 h, while the temperature was raised to ambient temperature slowly by thawing. The reaction was quenched by the addition of 10 mL of a saturated sodium sulfite solution. The organic layer was separated, the aqueous layer was extracted with diethyl ether three times and the combined organic layers were died with dry magnesium sulfate. The volatiles were removed by evaporation and the crude product was purified chromatographically on silica gel (n-hexane) to give 371 mg (0.820 mmol, 86%) of 3e in form of a light-yellow oil.

General procedure 2 (GP2) for the preparation of dithieno[1,4]thiazines 2
In a flame-dried Schlenk vessel under nitrogen atmosphere were charged 1.00 equiv dithienyl sulfide 3, 1.20 equivs aniline (6), 3.00 equivs sodium tert-butoxide, 7.5 mol% bis(dibenzylideneacetone)palladium(0), 15 mol% 1,1′-bis(diphenylphosphino)ferrocene and 6 mL/mmol dry toluene. After degassing with nitrogen for 5 min, the reaction solution was stirred at 100 °C until full conversion of the dithienyl sulfide 3 was observed via TLC. The volatiles were removed by evaporation and the crude product was purified by column chromatography and by recrystallization. For experimental details see table 2. The crude product was synthesized following GP2 and purified chromatographically on silica gel (n-hexane with 1% triethyl amine) and by recrystallization from n-hexane to give 245 mg (0.850 mmol, 71%) of 2b in form of a beige solid.

Computed xyz-coordinates, excitations of compounds 1 and 2 and selected properties derived from the DFT calculations
The ground state geometries of both the intra and the extra conformation of compounds 1 and 2 were optimized using the Gaussian09 program package, [5] the B3LYP functional [6] and the 6-311G* basis set. [7] The ground state geometries of the radical cations were optimized using the Gaussian09 program package, [5] the uB3LYP functional [6] and the 6-311G* basis set. [7] Excitation energies and the excited state geometry (S 1 ) of 2d were calculated with TDDFT [8] methods implemented in the Gaussian09 program package using the same functional and basis set, that were used for the ground state optimizations. All optimized geometries were confirmed as minima by analytical frequency analyses. The polarizable continuum model (PCM) with dichloromethane as a solvent was applied for the calculations each. [9] For the calculation of redox potentials (see chapter 6.2) the optimized ground state geometries of the intra conformations and the radical cations were reoptimized using the Gaussian09 program package, [5] the uB3LYP functional [6] and the 6-311G* basis set. [7] The reoptimizations were performed in the gas phase and all optimized geometries were confirmed as minima by analytical frequency analyses again. The SMD solvation model with dichloromethane as a solvent was applied afterwards to determine the solvation enthalpies. [10] Bond orders (Wiberg , Tables 3 and 4) and HOMO compositions (Mulliken, Figure 24) were extracted from the Gaussian09 calculation outputs by the help of the Multiwfn software. [11] Figure 24. HOMO composition of dithienothiazines 2a, 2c and 2d and phenothiazine 1 (B3LYP/6-311G*). [11] DFT-calculated properties derived from the geometry optimizations of compounds 1 and 2 (S,N-folding angles , free enthalpies of switching from extra to intra conformation G extra→intra and the HOMO-and LUMO-energies E HOMO and E LUMO ) are listed in table 5. Table 3. Change of the Wiberg bond-orders from neutral ground-state to the oxidized species (radical cation) (D0-S0) in the dithienothiazine core of compounds 2a, 2c and 2d (uB3LYP/6-311G*). [11]
G     Sum of electronic and thermal Free Energies= -1788.060351
Total Energy, E(TD-HF/TD-KS) = -1788.23977339 Copying the excited state density for this state as the 1-particle RhoCI density. Thermal correction to Gibbs Free Energy= 0.146321

DFT calculation of the redox potentials of compounds 1 and 2
The calculation of the redox potentials (Table 6)  G solv (gas), G solv (solv) and G redox (gas) were calculated from the values of the free enthalpies obtained from the geometry optimizations given in chapter 6.1 (uB3LYP/6-311G*).
The SMD solvation model [10] with dichloromethane as a solvent was applied to determine the solvation enthalpies, since all experimental determined oxidation potentials were measured in dichloromethane solutions. For a linear correlation of the measured first oxidation potential E 0/+1 exp with the calculated first oxidation potential E 0/+1 cal of the compounds 1 and 2 in their intra conformations in the gas-phase, see figure 45. The redox potentials were also calculated for the extra conformers revealing a poorer correlation with the experimental results (Table 7, Figure 46), which indicates that the redox behavior of the dithienothiazines 2 is dominated by the intra conformations respectively.