Synthesis and structure-physicochemical properties relationship of thiophene-substituted bis(5,4-d)thiazoles

Abstract Substituted thiophene-2-carbaldehydes 1a-dwere utilized in the synthesis of symmetrically substituted thiazolo[5,4-d]thiazoles 3a-d. Bis(5,4-d)thiazoles with thiophene core at the termini are the most employed in the chemistry of materials but exhibit insufficient solubility in majority of organic solvents with notable impact on the low yields of products. Accordingly, the synthetic approach towards 2,5-dithiophen- 2-yl-thiazolo[5,4-d]thiazole (3a) and its substituted derivatives 3b-d is discussed under the various reaction conditions. Appropriate structural characterisations are included with emphasis on relationship between structure and physicochemical properties highlighting the UV-Vis and fluorescence.


Introduction
Thiazolo [5,4-d]thiazoles are an important class of bicyclic aromatic systems constructed from two [3.3.0]-fusedthiazole rings acting as the electrondeficient moiety due to the presence of imine backbone (C=N, TzTz, Fig. 1) (Smirnova et al. 2006).The parent compound of this class was misstated as 2,2´-diaryl-4,4´-bisthiazethine (TzE, Fig. 1).Later, the 2,5-diaryl-thiazolo [5,4d]thiazoles were established as thermodynamically favoured over bithiazetines (Johnson et al. 1970).Since the thiazoles are generally known as key structural units in a wide variety of natural products (i.e.abafungin, tiazofurin) (Arshadi et al. 2017) the fused bis (5,4-d)thiazoles have been initially screened as inhibitors of central nervous system and antibacterial agents.The high toxicity (LD50 ≥ 0.5 g/Kg) associated with most of pattern TzTz derivatives when tested as CNS depressants, and unsufficient antibacterial activity against various strains of bacteria have excluded thiazolo [5,4-d]thiazoles suitable for further biological applications (Ketcham and Mah 1971).Re-interest in potential biological applications of these compounds was highlighted quite recently.Owing the rigid planar structure in the ground state and upon coordination (Millan et al. 2018) accompanied with the colorimetric change and often also with the fluorescent quenching thiazolo [5,4-d]   variety of cations (Jung et al. 2012;Sivaraman et al. 2018).In some of these compounds the bivalent sulphur atom makes close contact with electrondonating nitrogen/oxygen (Table 1), which is isosteric to the hydrogen-bonding interactions as important features of bioactivity in pharmaceuticals and natural drugs (Beno et al. 2015) what re-opens the possibility of research on the design of bis (5,4d)thiazoles as bioactive compounds.However, these applications have lagged behind the use of TzTz units as monomeric building blocks in photovoltaics (Song et al. 2017) or co-polymers in semiconductors such as organic field emitting transistors (OFETs) (Ando et al. 2005) (Fig. 2).Despite the significant interest in applications of bis (5,4-d)thiazoles the synthetic chemistry has only been explored to a minor extent (Dessi et al. 2014;Dessi et al. 2015;Papernaya et al. 2016).The most of procedures towards (hetero)aryl substituted thiazolo [5,4-d]thiazoles are still based on the condensation of dithioxamide (2) with an excess of aldehyde (Johnson and Ketcham 1960).The reactions are most often performed in high boiling point solvents, such as dimethylformamide (DMF, 153 °C); N,N-dimethylacetamide (DMAc, 165 °C) or under solvent free conditions (≤ 200 °C).In general, the solubility of thiophene-substituted TzTz derivatives is the most supressed affecting the tedious work-up and low yields.Accordingly, in our research the synthesis of a series of thiophene-substituted thiazolo [5,4-d]thiazoles 3a-d is discussed under various reaction conditions (Scheme 1).Compounds 3a-d are important intermediates for design of low molecular mass type chemosensors and building blocks for (opto)electronic materials.In this context, the physicochemical data (UV-Vis and fluorescence) are analyzed.

General
All commercially available chemicals were used as received without further purification.Solvents were purified by standard methods and dried if necessary.Reactions were monitored by thin layer chromatography (TLC) on plates percoated with silica gel (SiGel 60 F254).Melting points were recorded on a Kofler hot plate apparatus and are uncorrected.The infrared spectra were taken on Agilent Cary 630 FTIR spectrometer with diamond ATR.Elemental analyses were obtained using a Flash EA 2000 CHNS/O-OEA analyser. 1H NMR spectra (400 MHz) were measured as solutions in deuterated dimethylsulfoxide (DMSO-d6) on a Bruker Biospin type instrument, products were reported relative to tetramethylsilane (TMS, 0.0 ppm).Absorption spectra (UV-Vis) of solutions (c = 1.10 -5 mol.L -1 ) in dimethylformamide were recorded on a UV 1650PC spectrometer (Schimadzu, Jpn) and the fluorescence on a RF 5301 PC type instrument (Shimadzu, Jpn).

Synthesis
Method A. To the mixture of dithioxamide (2, 10.0 mmol; 1.10 g) in N,N-dimethylformamide (25 mL) solution of appropriate thiophene-2carbaldehyde 1a-d (40.0 mmol) in DMF (15 mL) was added at room temperature.The reaction mixture was stirred at the boiling point of DMF (153 °C) for 6 hours.The colour of the reaction changed to dark after the substrates became completely dissolved.After the reaction was stated as completed (TLC control), the reaction mixture was cooled to room temperature and diluted with water (15 mL).Crude mixture was extracted with chloroform (3 x 25 mL).Combined organic layers were dried with MgSO4, filtered and the solvent was evaporated.The dark crude product was analyzed ( 1 H NMR) and then purified by flash column chromatography with chloroform as eluent.Note.In the crude residue the traces of the appropriate product were identified according to 1 H NMR Only the substrates were retrieved in majority.Method C. To the mixture of dithioxamide (2, 10.0 mmol; 1.10 g) in nitrobenzene (25 mL) the solution of appropriate thiophene-2-carbaldehyde 1a-d (40.0 mmol) in nitrobenzene (15 mL) was added at room temperature.The reaction mixture was stirred at the boiling point of nitrobenzene (211 °C) for 5 hours.The colour of the reaction changed to dark after the substrates became completely dissolved.After the reaction was stated as completed (TLC control), the mixture was cooled to room temperature and diethylether was added to precipitate the product (15 mL).The precipitate was filtered, washed with diethylether (2x25 mL) to get rid of unreacted dithioxamide.The crude residue was crystallized from methanol with 15 -25 % addition of N,N-dimethylformamide to increase the solubility.Note.Finally, pure products 3a-d (Fig. 3) were isolated from the crude mixture after crystallization (methanol/DMF).2).

Synthesis
Thiophene-substituted thiazolo [5,4-d]thiazoles are among all TzTz-based the most utilized in the optoelectronic materials, but in the same time are one of the most difficult for synthesis.Designed compounds 3a-d were synthesized by initial onestep condensation reaction of appropriate thiophene-based substrate 1a-d with dithioxamide (2, Scheme 1).The carbonyl substrate/dithioxamide ratio 4/1 was used as the optimal for successful reaction proceeding.The aldehyde primarily undergo the condensation reaction (-HC=O → -C=NH) followed by subsequent cyclization but, in the same is essential for final aromatization as oxidizing agent (Scheme 1).Our initial approaches using DMF (Method A, 153 °C, 6 hours) and o-dichlorobenzene (Method B, 180 °C, 12 hours) have failed in products formation.Nitrobenzene was found to be optimal (Method C, 211 °C, 5 hours) and the target thiophene-substituted thiazolo [5,4-d]thiazoles 3a-d were isolated in moderate yields (22 -33 %) and satisfactory purity upon crystallization.In practice, nitrobenzene aside allows the better maintenance of the reaction temperature has few limitations.As the solvent is highly toxic and the products are usually not easily precipitable from the reaction mixture.This can be avoided by the use of n-butanol or performance of the reaction under microwave irradiation (MWO).Still, the solubility of carbonyl substrates in n-butanol could be insufficient and not all of the substrates are liquids as is required for MWO assisted reactions.
On the other hand, the protons of TzTz bearing the unsubstituted thiophene ring for compound 3a and with ethyl group in C5´ for compound 3c, respectively, appear in the range of 6.99 -6.40 ppm in accordance with the similar thiophenesubstituted derivatives.
The complete structural characterisations are part of our subsequent research and herein are presented as the complementary statement supported by the elemental analysis (with deviation max.0.4 %).Compounds 3a-d were prepared as useful tools for the design of (opto)electronic materials when taking in account the further possibilities of the substitution and functionalization arising from the electronic effects in the structure of parent compounds (Fig. 4).Accordingly, the uncommon nucleophilic substitutions (SNAr, Tokárová et al. 2017) are expected to the C4´of thiophene core, but with certainty this position will stay unaffected and 3-substituted thiophene-2-carbaldehyde have to be used when C3´-substituted TzTz products are required (Papernaya et al. 2016).The electrophilic substitutions (ArSE) are predicted to occur at the adjacent β-position (C4´) (Dessi et al. 2013).On the C-α (= C5´) the radical substitutions (SR) are quite common offering the possibility of ubsequent alkylation via the cross-coupling manner (Jung et al. 2010).

Conclusions
The synthesis and optical properties of a series of thiazolo [5,4-d]thiazoles bearing the substituted thiophene ring at the termini have been investigated.Thiophene core in the target bis (5,4d)thiazoles 3a-d offers the possibility of subsequent functionalization according to suggested substitution pattern (Fig. 2) as one of the key requisites in materials design.Exchange of hydrogen to bromo-or other halo-substituent seems to play an important role in blue-shifted UV-Vis and hindered fluorescence.On the other hand, the alkyl-substitution along with position on which  recognized and further managed according to requirements on these compounds as building blocks for (opto)electronical materials (i.e. as monomers for copolymers of different n-or p-type semiconductors, π-spacers or electron-withdrawing moieties for dye sensitised solar cells, ligands).
Method B.To the mixture of dithioxamide (2, 10.0 mmol; 1.10 g) in o-dichlorobenzene (25 mL) the solution of appropriate thiophene-2carbaldehyde 1a-d (40.0 mmol) in o-dichlorobenzene (15 mL) was added at room temperature.The reaction mixture was stirred at the boiling point of o-dichlorobenzene (180 °C) for 12 hours.The colour of the reaction changed to dark after the substrates became completely dissolved.After the reaction was stated as completed (TLC control), the mixture was cooled to room temperature and washed with water (25 mL) afterwards the slow precipitation of crude product occurred.The immiscible mixture was left to cool down to 0 °C overnight and the precipitate was filtered.The crude product was crystalized from methanol.Note.The mixture of products 3a-d and the substrate 1a-d was achieved with the ratio ¼ (aldehyde in majority).

Fig. 4 .
Fig. 4. General structure of thiophene-substituted thiazolo[5,4-d]thiazoles 3a-d presented herein, showing the electronic effects in the structure with prediction of possible substitution patterns.

Table 1 .
Coordination of TzTz-based frameworks with variety of cations and their applications as chemosensors and other coordination compounds with miscellaneous utilizations.