Safe Synthesis of 4,7-Dibromo[1,2,5]thiadiazolo[3,4-d]pyridazine and Its SNAr Reactions

A safe and efficient synthesis of 4,7-dibromo[1,2,5]thiadiazolo[3,4-d]pyridazine from the commercial diaminomaleonitrile is reported. Conditions for selective aromatic nucleophilic substitution of one or two bromine atoms by oxygen and nitrogen nucleophiles are found, whereas thiols formed the bis-derivatives only. Buchwald-Hartwig or Ullmann techniques are successful for incorporation of a weak nitrogen base, such as carbazole, into the [1,2,5]thiadiazolo[3,4-d]pyridazine core. The formation of rather stable S…η2-(N=N) bound chains in 4,7-bis(alkylthio)-[1,2,5]thiadiazolo[3,4-d]pyridines makes these compounds promising for the design of liquid crystals.


Introduction
Electron-deficient π-conjugated building blocks have been widely applied for the preparation of functional organic dyes and electronic materials [1][2][3]. Heterocycles with high electron affinity have been recently showed to be some of the best strong and synthetically variable acceptors. The role of acceptors is to tune the energy levels of the frontiers orbitals (the highest occupied molecular orbital (E HOMO ) and the lowest unoccupied molecular orbital (E LUMO )) as well as the difference between these energies and, as a consequence, the absorption of the materials based on these molecules [4]. The choice of the acceptor is important for high performance of the materials. Electron-acceptor building blocks (A) should be linked with an at least one electronodonor (D) either directly or through a π-conjugated bridge (π) in small molecules or polymers. Many applications of these materials can be mentioned: dye-sensitized solar cells (DSSCs) [2,5,6], bulk heterojunction solar cells (BHJ) [7,8], n-type organic field-effect transistors [9,10], near infrared absorption and emissions materials [11,12], electrochromic materials [13,14], and many others.
Herein, we describe the safe and efficient synthesis of 4,7-dibromo [1,2,5]thiadiazolo [3,4-d] pyridazine (1) and its S N Ar reactions as a basis for the preparation of compounds which are of interest as potential photovoltaic materials.
The overall yield of 4,7-dibromo [1,2,5]thiadiazolo [3,4-d]pyridazine (1) was 36% that is almost three times higher than in the method described by us previously [22]. The other advantages are a shorter route, and the safety of the procedures which can be carried out on a larger synthetic scale as the use of the dangerous tetrasulfur tetranitride and chlorine is avoided. [1,2,5]thiadiazolo [3,4-

Sulfur Nucleophiles
Dibromo derivative 1 successfully reacted upon treatment with thiophenol at room temperature in various organic solvents (CHCl 3 , THF, MeCN and DMF) to give dimercapto derivative 10a, even if we used one equivalent of the thiol ( Table 2). The reaction in an aprotic dipolar solvent (DMF) was facilitated and occurred much faster than in a less polar organic solvent (chloroform). The formation of the monosubstituted thiol was detected by TLC monitoring of the reaction mixtures in chloroform, and mono-adducts underwent fast transformation to dithiol 10a. In wet solvents (for example, in chloroform), the reaction occurred much faster (Entries 2, 3, Table 1). This means that for other reactions (nucleophilic substitution and cross-coupling reactions), it is strongly recommended to avoid even traces of water. Surprisingly, dibromothiadiazolopyridazine 1 gave in the reaction with MeOH the same 7-bromo [1,2,5]thiadiazolo [3,4-d]pyridazin-4(5H)-one (7) in high yield (Entry 6, Table 1). Less nucleophilic phenol did not react with dibromide 1 (Entries 10, 11, Table 1). Treatment of dibromide 1 with NaOMe in MeOH led selectively to displacement of one or two bromine atoms, depending on the quantity of the base used (Entries 7, 8, Table 1). Reaction of dibromide 1 with sodium phenoxide in THF gave monosubstituted product 8b in high yields (Entries 12-14, Table 1). To obtain 4,7-diphenoxy [1,2,5]thiadiazolo [3,4-d]pyridazine (9b), it was necessary to use a strong aprotic dipolar solvent, viz., DMF, at 90 °C (Entry 17, Table 1). It is necessary to mention that monobromo derivatives 8 are hydrolytically stable and can be kept at room temperature for months without noticeable changes.

Sulfur Nucleophiles
Dibromo derivative 1 successfully reacted upon treatment with thiophenol at room temperature in various organic solvents (CHCl3, THF, MeCN and DMF) to give dimercapto derivative 10a, even if we used one equivalent of the thiol ( Table 2). The reaction in an aprotic dipolar solvent (DMF) was facilitated and occurred much faster than in a less polar organic solvent (chloroform). The formation of the monosubstituted thiol was detected by TLC monitoring of the reaction mixtures in chloroform, and mono-adducts underwent fast transformation to dithiol 10a.
Our attempts to isolate mono-substituted derivatives were unsuccessful; the use of one equivalent of a base and thiol led to a mixture of disubstituted derivative 10a and starting material 1. Inverse addition and lowering the concentration of the reagents did not also yield the monosubtituted products. Although the presence of a base did not facilitate the nucleophilic substitution by thiols (compare Entries 3 and 6, Table 2), bis(phenylthio) derivative 10a was formed in a bit higher yield if sodium hydride was used. The reaction was extended to other thiols (hexanethiol and undecanothiol), and bis-thiols 10b, c were isolated in high yields.

Nitrogen Nucleophiles
Treatment of 4,7-dibromo [1,2,5]thiadiazolo [3,4-d]pyridazine (1) with morpholine in MeCN at room temperature for 3 h gave selectively mono-aminated derivative 11a in good yield. This reaction was investigated thoroughly in order to achieve the best yield of this product (Table 3). It was found * The starting dibromo derivative 1 was isolated in 52% yield.
Our attempts to isolate mono-substituted derivatives were unsuccessful; the use of one equivalent of a base and thiol led to a mixture of disubstituted derivative 10a and starting material 1. Inverse addition and lowering the concentration of the reagents did not also yield the monosubtituted products. Although the presence of a base did not facilitate the nucleophilic substitution by thiols (compare Entries 3 and 6, Table 2), bis(phenylthio) derivative 10a was formed in a bit higher yield if sodium hydride was used. The reaction was extended to other thiols (hexanethiol and undecanothiol), and bis-thiols 10b, c were isolated in high yields.  [3,4-d]pyridazine (1) with morpholine in MeCN at room temperature for 3 h gave selectively mono-aminated derivative 11a in good yield. This reaction was investigated thoroughly in order to achieve the best yield of this product (Table 3). It was found that the nature of the solvent did not affect the yield of the final product significantly, changing the reaction velocity only. According to TLC data (Silica), morpholine reacted with dibromo derivative 1 slower in MeOH (completed in 6 h, Table 3, Entry 1), and more rapidly in DMF (0.5 h, Table 3, Entry 9), and in all cases mono-aminated product 11a was formed at room temperature. Disubstituted product 12a was not detected even if an excess of morpholine was used. that the nature of the solvent did not affect the yield of the final product significantly, changing the reaction velocity only. According to TLC data (Silica), morpholine reacted with dibromo derivative 1 slower in MeOH (completed in 6 h, Table 3, Entry 1), and more rapidly in DMF (0.5 h, Table 3, Entry 9), and in all cases mono-aminated product 11a was formed at room temperature. Disubstituted product 12a was not detected even if an excess of morpholine was used. Upon heating the reaction mixtures at 80 °C in DMF or in MeCN with two equivalents of morpholine in the presence of Et3N, diaminated product 12a was formed. To complete the reaction in MeCN, the reaction mixture had to be refluxed for 30 h, whereas in DMF, heating for 20 h was required (Table 3, Entries 13,14). The best yield and most convenient reaction conditions for the synthesis of unsymmetrical compound 11a involved the treatment of dibromo derivative 1 with one equiv. of morpholine and Et3N in CH2Cl2 at room temperature, while for disubstituted compound 12a-heating with two equivalents morpholine and Et3N in MeCN at 80 °C.
Furthermore, we explored the application of the optimized reaction conditions to other primary and secondary amines and achieved high yields of mono-and disubstituted thiadiazolopyridazines 11-12a-j (Table 4). Carbazole and diphenylamine did not react with 4,7-dibromo- [1,2,5]thiadiazolo [3,4-d]pyridazine (1). Our attempts to force these reactions by using sodium salts of these amines (prepared in situ from carbazole or diphenylamine and NaH) were also unsuccessfuldibromothiadiazolopyridazine 1 decomposed and did not react with sodium carbazol-9-ide or sodium diphenylamide in THF or DMF even under heating (ca. 60 °C, 3 h). Upon heating the reaction mixtures at 80 • C in DMF or in MeCN with two equivalents of morpholine in the presence of Et 3 N, diaminated product 12a was formed. To complete the reaction in MeCN, the reaction mixture had to be refluxed for 30 h, whereas in DMF, heating for 20 h was required (Table 3, Entries 13,14). The best yield and most convenient reaction conditions for the synthesis of unsymmetrical compound 11a involved the treatment of dibromo derivative 1 with one equiv. of morpholine and Et 3 N in CH 2 Cl 2 at room temperature, while for disubstituted compound 12a-heating with two equivalents morpholine and Et 3 N in MeCN at 80 • C.
Furthermore, we explored the application of the optimized reaction conditions to other primary and secondary amines and achieved high yields of mono-and disubstituted thiadiazolopyridazines 11-12a-j (Table 4). Carbazole and diphenylamine did not react with 4,7-dibromo- [1,2,5]thiadiazolo [3,4-d]pyridazine (1). Our attempts to force these reactions by using sodium salts of these amines (prepared in situ from carbazole or diphenylamine and NaH) were also unsuccessfuldibromothiadiazolopyridazine 1 decomposed and did not react with sodium carbazol-9-ide or sodium diphenylamide in THF or DMF even under heating (ca. 60 • C, 3 h).
Recently it was found that 4,7-di(9H-carbazol-9-yl)benzo[c] [1,2,5]thiadiazole (17) can be considered as an excellent candidate for a highly efficient red thermally activated delayed fluorescence emitter (TADF), and can also act as a high efficiency organic light-emitting diode (OLED) [30], since this compound has a small energy gap which is compatible with a large fluorescence rate. 4,7-di(9H-Carbazol-9-yl) [1,2,5]thiadiazolo [3,4-d]pyridazine (16), which seems to be a promising candidate for a similar application, could not be obtained from dibromo derivative 1 because it did not react either under aromatic nucleophilic substitution conditions or under Buchwald-Hartwig or Ullmann conditions. We have found that this compound can be successfully obtained from its bis(hexahydrocarbazolyl) derivative 12d by dehydrogenation with DDQ by a known procedure (see ref. [28]), affording the target product 16 in high yield (Scheme 4). The fluorescent and photophysical properties of the new OLED are now under investigation. summarized in Table 5. Refluxing of the reaction mixtures and microwave irradiation without any ligand were not successful, the starting material was recovered in high yield. Using XPhos ligand in the Buchwald-Hartwig reaction and DMEDA in the Ullmann reaction gave carbazole derivative 15. In both cases, microwave irradiation gave better results than prolonged heating in the corresponding solvent (Table 5).

Diphenylamine was found to be inert to the treatment with 4-(7-bromo-[1,2,5]thiadiazolo[3,4d]pyridazin-4-yl)morpholine (11a) even under these conditions.
Recently it was found that 4,7-di(9H-carbazol-9-yl)benzo[c] [1,2,5]thiadiazole (17) can be considered as an excellent candidate for a highly efficient red thermally activated delayed fluorescence emitter (TADF), and can also act as a high efficiency organic light-emitting diode (OLED) [30], since this compound has a small energy gap which is compatible with a large fluorescence rate. 4,7-di(9H-Carbazol-9-yl) [1,2,5]thiadiazolo [3,4-d]pyridazine (16), which seems to be a promising candidate for a similar application, could not be obtained from dibromo derivative 1 because it did not react either under aromatic nucleophilic substitution conditions or under Buchwald-Hartwig or Ullmann conditions. We have found that this compound can be successfully obtained from its bis(hexahydrocarbazolyl) derivative 12d by dehydrogenation with DDQ by a known procedure (see ref. [28]), affording the target product 16 in high yield (Scheme 4). The fluorescent and photophysical properties of the new OLED are now under investigation.

X-Ray Analysis
The geometry of the [1,2,5]thiadiazolo [3,4-d]pyridazine moiety in 10b and 16 is rather close to the expected one (see ref. [31]) with the only exception concerning some shortening of the C(3A)-C(7A) bond. It should be noted that in [1,2,5]thiadiazolo [3,4- (2)3) with the 6-membered carbazole ring (Figure 1). In turn, these A…A and A….B dimers are assembled into chains of the (A…A)…(B….B) type by stacking interactions between pyridazine (interplane distance 3.1 Å) and carbazole rings (3.2 and 3.4 Å). Finally, one of the pyridazine nitrogen atoms participates only in the weak C-H…N interaction (H…N 2.32 Å, CHN 148°) with a CH2Cl2 solvent molecule.   To analyse the character of the shortened contacts in 10b and 16, we used the topological analysis of electron density function (ρ(r)) within Bader's "atom in molecule theory" [38]. The ρ(r) function was obtained from the PBE/6-311++G* single point calculations (see Supplementary Materials) for the above mentioned dimers in the crystals of 10b and 16. According to the critical point (CP), search To analyse the character of the shortened contacts in 10b and 16, we used the topological analysis of electron density function (ρ(r)) within Bader's "atom in molecule theory" [38]. The ρ(r) function was obtained from the PBE/6-311++G* single point calculations (see Supplementary Materials) for the above mentioned dimers in the crystals of 10b and 16. According to the critical point (CP), search both S . . . N interaction are characterized by the presence of CP (3,−1) of ρ(r) and thus may be considered as attractive interactions ( Figure S1) [38]. Their energies estimated by Espinosa et al. using the CEML method [39,40] are equal to~3.0 kcal/mol each. Based on the analysis of the ELF function, we can consider them in terms of n-σ* interactions as the transfer from the nitrogen electron lone pairs to the S-N σ*-orbital.
In contrast, the same procedure for 16 revealed that only the N(3) . . . N(3) interaction is characterized by CP(3,−1). Furthermore, despite the η 6 -type of interaction of S(2) with the carbazole ring, only one S(2) . . . C(14) contact (3.340(2) Å) is characterized by the presence of CP(3,−1). According to the analysis of ELF, we can assume that this contact is the only one for which the electron lone pair of the S(2) atom has the appropriate orientation with respect to the carbons of the aromatic ring ( Figure  S4). The energies of N . . . N and S . . . C interactions are equal to 2.2 and 1.5 kcal/mol, respectively.

General Information
Powdered anhydrous Na 2 SO 4 was used for drying organic extracts and all volatiles were removed under reduced pressure. All reaction mixtures and column eluents were monitored by TLC using commercial aluminium backed thin layer chromatography (TLC) plates (Kieselgel 60 F 254 Merck, Kenilworth, NJ, USA). The plates were observed under UV light at 254 nm. Melting points were determined on a Kofler hot-stage apparatus and are uncorrected. Solvents used for recrystallization are indicated after the melting point. 1 H and 13 C-NMR spectra were taken with a Bruker AM-300 machine (at 300.1 and 75.5 MHz) or Bruker DRX500 machine (at 500.1 and 125.8 MHz) or Bruker AV600 machine (at 600.1 and 150.9 MHz) with TMS as the standard (Bruker, Billerica, MA, USA). J values are given in Hz. MS spectra (EI, 70 eV) were obtained with a MAT INCOS 50 instrument (Thermo Finnigan LLC, San Jose, CA, USA). High-resolution MS spectra were measured on a Bruker MICROTOF II instrument using electrospray ionization (ESI, Bruker). The measurement was operated in a positive ion mode (interface capillary voltage −4500 V) or in a negative ion mode (3200 V); mass range was from m/z 50 to 3000 Da; external or internal calibration was done with Electrospray Calibrant Solution (Fluka Chemicals Ltd., Gillingham, UK). A syringe injection was used for solutions in acetonitrile, methanol, or water (flow rate 3 µL/min). Nitrogen was applied as a dry gas; interface temperature was set at 180 • C. IR spectra were measured with a Bruker "Alpha-T" instrument (Bruker) in KBr pellets. The reagents were purchased from commercial sources and used as received. All synthetic operations were performed under a dry argon atmosphere. Solvents were purified by distillation from the appropriate drying agents.

General Procedure for the Preparation of Mono-Aminated Products 11
Amine (0.17 mmol) and Et 3 N (17mg, 0.17 mmol) were added to a solution of 4,7-dibromo [1,2,5]thiadiazolo [3,4-d]pyridazine (1, 50 mg, 0.17 mmol) in dry CH 2 Cl 2 (10 mL) at room temperature with stirring. The mixture was stirred at room temperature for 4 h. Then the mixture was poured into water (10 mL) and extracted with CH 2 Cl 2 (3 × 35 mL). The combined organic layers were washed with brine, dried over MgSO 4 , filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography.