Multifaceted Strategy for the Synthesis of Diverse 2,2'-Bithiophene Derivatives

New catalytically or high pressure activated reactions and routes, including coupling, double bond migration in allylic systems, and various types of cycloaddition and dihydroamination have been used for the synthesis of novel bithiophene derivatives. Thanks to the abovementioned reactions and routes combined with non-catalytic ones, new acetylene, butadiyne, isoxazole, 1,2,3-triazole, pyrrole, benzene, and fluoranthene derivatives with one, two or six bithiophenyl moieties have been obtained. Basic sources of crucial substrates which include bithiophene motif for catalytic reactions were 2,2'-bithiophene, gaseous acetylene and 1,3-butadiyne.


Introduction
Compounds containing thiophene, bithiophene or oligothiophene motifs are particularly popular because they are used in various fields of science and technology, ranging from organic chemistry and synthesis to material science, technology, medicine and pharmaceutical science. Therefore, new structures containing the abovementioned motifs are still being synthesized and the possibilities of their practical application intensively tested. Various organic and organometallic systems containing thiophene, bithiophene or oligothiophene moieties (and other essential structural elements, i.e., highly conjugated aromatic and heteroaromatic systems, coordinated metal centers, diimide or triphenylamine moiety and others) are used in organic electronics [1][2][3][4] and are still intensively investigated in OLED [1][2][3][4], organic field-effect transistor [1,5] and solar cell [1,6,7] technology.
However, in many cases such catalytic systems are inactive due to strong coordination of the substrate by a transition metal catalytic center [19]. This fact ought to be taken into consideration when planning catalytic systems to be used for transformations of strongly coordinated reagents, for instance thiophene or oligothiophene [19]. There are a number of stable neutral and cationic transition metal (Cr, Ru, Ir, Rh, Mn, Re, Ti, Cu, Fe etc.) complexes with thiophene. The issue of transition metal complexation with thiophene and oligothiophenes has been intensively studied in view of the hydrodesulfurization (HDS) process [20]. Thiophene coordinates transition metals in many ways, but the most common are the η 1 -S, η 1 -C, and η 5 -coordination modes [21,22], and furthermore, it forms neutral complexes with Re and Mn, involving C-, S-and π-coordinated ligands [23]. Moreover, it forms stable cationic complexes, e.g., [Mn(CO)3(η 5 -thiophene)][BF4], which precursor is [Mn(CO)5Br].
In addition, exchange of CO-ligand to η 5 -thiophene in the reaction of [Cr(CO)6] with various thiophene derivatives [Cr(CO)3(η 5 -substituted-thiophenes)] took place [24]. Furthermore, reaction of [RuCl2(p-cymene)]2 with tetramethylthiophene resulted in a very stable [(tetramethyl-thiophene)RuCl2]2 complex, indicating that thiophene coordinates a Ru atom stronger than p-cymene [25]. The above analysis indicates that strong coordination of a transition metal with thiophene and oligothiophene may interfere with some reactions involving substrates containing a thiophene moiety.
It is worth noting that the reactions leading to new 2,2'-bithiophene derivatives have not been reported so far (or are significantly improved). Since our work is a multifaceted one, i.e., it concerns a series of different reactions, relevant literature is presented in each subsection.
In order to improve the yield of 5 and 6 we applied a cascade consisting of three reactors. The reactions were carried out in acetone due to a high solubility of acetylene and butadiyne therein. Other authors have used MeCN as solvent [32], but MeCN appears to be a much worse solvent (the solubility of acetylene therein is much lower), and in addition it is toxic. Gaseous acetylene (generated from CaC2 [34] or more conveniently supplied from a bottle gas) and butadiyne (generated from 1,4-dichloro-2-butyne) were dried before the introduction into the reaction system and additionally dispersed with a stream of argon. It is of particular importance in the case of butadiyne for safety reasons (high concentrated butadiyne is explosive). Moreover, in the procedure leading to 5 [PdCl2(PPh3)2] was applied, which was much more effective than Pd(OAc)2 + PPh3 catalytic system used by Chuentragool et al. in the synthesis of 1,2-bis(2-thienyl)acetylene [32]. Compound 6 was obtained as yellow crystals and its structure was confirmed using X-ray crystallography ( Table 2 in Supporting Information). The [PdCl2(PPh3)2]/CuI catalytic system appeared to be more effective and convenient (due to its stability and price) than [Pd(PPh3)4] used by McCormick et al., in the synthesis of different ArC≡CC≡CAr from 1,4-bis(trimethylsilyl)-1,3-butadiyne [38].
It was found that the absence of alkyl iodide or bromide resulted in extremely low yield (approximately 10%). In addition, the influence of different alkyl bromides and iodides on the yield of this reaction was tested. It was confirmed that the yield of homocoupling depends on the type of the halide as follows: decyl bromide (60%), ethyl bromide (70%), decyl iodide (80%), and ethyl iodide (97%). Moreover, no heterocoupled products of reaction of alkyl halides with 5-ethynyl-2,2'-bithiophene (to bt-≡-R) were observed.
In the case of the cycloaddition reactions activated by high pressure, it is very important to take into consideration the stability and reactivity of ArCNO, and in addition the solubility of ArCNO in organic solvents (Scheme 5). In the case of terephthaloyldinitrile dioxide, which is a low reactivity oxide, performance of the cycloaddition under high pressure gave a good result, i.e., with practically quantitative conversion (Scheme 5). It was very important to reach such a conversion since it facilitated the separation of the pure product, which would have been difficult if the product had been a mixture of mono-and diisoxazoline. At room temperature the reaction between p-(ONC)2C6H4 and 10 practically did not occur, whereas at 80 °C in a steel reactor (under equilibrium pressure) the yield of isoxazolines was 60%, while 10% was the product of monoaddition. There is no doubt that considerable enhancement of yield is caused by high pressure activation. The reaction shown in Scheme 5 leading to 14 was the first 1,3-DC of nitrile oxide to alkenes under high pressure. In the literature, there are many examples reporting the beneficial, spectacular influence of high pressure on chemical reactions, cycloaddition reactions in particular, due to their highly negative activation volume [60][61][62][63]. There are many papers on diene-ene [4 + 2] cycloadditions but the number of papers on dipolar [3 + 2] cycloaddition is limited, furthermore, most of them concern the cycloaddition of nitrones to alkenes [62], and azides to alkynes [61,63]. There are no reports on the beneficial effects of high pressure on the cycloaddition reaction of nitrile oxide to alkenes. All five 1,3-DC reactions shown in Scheme 5 were concerted, since the trans/cis ratio for the isoxazolines obtained was the same as the E/Z ratio for the dipolarophile (9/1). On the other hand, the regioselectivity of the cycloaddition presented in Scheme 5 was slightly different. In the case of dipolarophiles of MeCH=CHQ type (as 10), the regioselectivity was very high or complete when Q was a strong donor, as it has been shown in our previous papers [46][47][48]. The content of the second regioisomer, i.e., 3-Ar, 4-bithienyl-5-methylisoxazolines depended on the type of Ar is 5%, 2%, 2% 1% and 1% for 2,6-Cl2C6H3, p-Me2NC6H4, bt, C6H4, 2-Py, respectively. It means that the reactions are highly regioselective, allowing one to obtain pure 5-bithienyl isoxazolines. In the case of the reaction with 2-pyridinecarbonitrile oxide, a side product, i.e., oxide dimer was isolated, which structure was confirmed by X-ray spectroscopy (Table S1 in Supporting Information). This dimer is a known compound [64], however, its X-ray structure is not known.
The alternative route for the synthesis of isoxazoles via addition nitrile oxide to double bond and then aromatization can be the direct addition of RCNO into triple bond-see Scheme 7.
According to us, the reaction shown in Scheme 7 is a particularly spectacular example of the beneficial influence of high pressure on 1,3-DC. The conversion and the selectivity were practically quantitative, whereas under atmospheric or equilibrium pressure, in a steel reactor, this reaction does not take place even at 100 °C (in CH2Cl2 or DMF). [RhCl(PPh3)3] was applied as a catalyst since, together with [Co2(CO)8], it is the most frequently applied and effective catalyst for both inter-and intramolecular [2 + 2 + 2] cycloadditions [67][68][69]. In the literature there are only a few papers devoted to the synthesis of 7,8,9,10-tetrasubstituted fluoranthenes from derivatives of 1,8-diethynylnaphthalene and alkynes, except for conjugated diynes, or NBD which can act as an acetylene equivalent catalyzed by various rhodium complexes [67][68][69]. To date, fluoranthenes with alkyl or phenyl substituents, except for the ones with heteroaryl substituent, have been obtained in this way. Recently, several fluoranthenes with substituted thiophene motifs (except for the ones with a bithiophene one) and two fluoranthenes with a 6H-indolo[2,3-b]quinazoline chromophore [70] have been obtained. The compounds were obtained via [4 + 2], but not via [2 + 2 + 2] cycloaddition. The novel compounds 19 and 20 are the first bithiophene derivatives of the bt-A-bt type, where the fluoroanthene fragment plays a role of a spacer. The polymers obtained from them are expected to have interesting conducting and luminescence properties.
The methods known from the literature were applied for the synthesis of diiodonaphthalene [71], was obtained from commercially available 1,8-diaminonaphthalene, which was further used to obtain a phenyl derivative via Sonogashira coupling [72]. The trimerization of the acetylene derivative 5, both in the reaction shown in Scheme 9 and during heating of 5 in xylene at 130 °C in the presence of 10 mol% [RhCl(PPh3)3] was observed. The latter reaction allowed to obtain pure hexa(2,2'-bithiophen-5-yl)benzene (21) with 40% yield (Scheme 9). In the literature, there is only one work devoted to the trimerization of ArC≡CAr (Ar is alkyl-substituted-thienyl, bithienyl or terthienyl) to hexakis(alkylthienyl-, bithienyl and terthienyl)benzenes catalyzed by [Co2(CO)8] [73].
Our result, i.e., the trimerization of 5, corresponds to the results of other authors, who used [RhCl(PPh3)3] with very good results for fully intermolecular [2 + 2 + 2] cycloaddition [67]. However, trimerization of 1,4-bis(2,2'-bithiophen-5-yl)-1,3-butadiyne was not observed despite the fact that such a reaction is known for 1,4-diphenyl-1,3-butadiyne [67]. It probably results from the steric effects being greater for the 2,2-bitihophen-5-yl substituent than for the phenyl one, which have a major influence on the course of the studied cycloaddition reactions. One should remember that this reaction probably proceeds via a metalacyclopentadiene intermediate and steric hindrance plays a crucial role in this transformation [67].

Catalytically or High Pressure Activated 1,3-DC of Azides to Triple Bond for Synthesis of Triazoles with bt Moiety
Using 5-iodobithiophene (3), 5-ethynylbithiophene (4), 1,2-bis(2,2'-bithiophen-5-yl)acetylene (5) and Cu-catalyst or Ru-catalyst or high pressure mediated 1,3-dipolar cycloaddition of azides to alkynes, four novel triazole derivatives 22-25 containing one or two bt moieties were obtained (Scheme 10). In these syntheses, typical catalytic systems, i.e., CuSO4/sodium ascorbate [75][76][77] or [RuClcp(PPh3)2] [78,79] or high pressure activation were used. The use of high pressure in the 1,3-DC of azides to alkynes has already been described [63,80], although not for heteroaryl-substituted alkynes. Decyl, benzyl, and bithienyl azides [13] were synthesized using the methods known from the literature (the latter was generated in situ). It should be noted that the reaction carried out under high pressure is fully regioselective-only 4-(2,2'-bithiophen-5-yl)triazole is formed. The obtained triazoles may play the role as cyclometalating ligands or monomers for the synthesis of polythiophenes, where the triazole ring is the linker connecting tetrathiophene fragments. Up till now, this type of conducting polythiophenes has not been known. Moreover, there are a lot of triazoles which play a vital role of ligands in the molecular catalysis described in the literature [75]. Additionally, a triazole motif is present in the structure of many pharmaceuticals, in particular antifungal ones [81].

General Methods
All starting materials and reagents were purchased from commercial sources and were used as received, unless otherwise stated. All reactions were carried out under argon atmospheres undernhydrous conditions. Solvents were dried and purified using usual methods before use. Thin layer chromatography was performed on silica gel (TLC silica gel 60, Merck, Darmstadt, Germany). NMR spectra were recorded on an Avance 400 instrument (400 MHz for 1 H and 100 MHz for 13 C) or Ascend 500 instrument (500 MHz for 1 H and 125 MHz for 13  Limited Group, Staffordshire, United Kingdom). Low resolution mass spectra were recorded in methanol on a Varian LC-920 instrument (Varian, Palo Alto, CA, USA). HRMS-ESI spectra were recorded in methanol on a Synapt G2-S HDMS mass spectrometer (Waters Inc., Milford, MA, USA) equipped with an electrospray ion source and q-TOF type mass analyzer. HRMS-EI spectra were recorded on an AutoSpec Premier magnetic sector mass spectrometer (Waters Inc.) equipped with an electron impact (EI) ion source and the EBE double focusing geometry mass analyzer. The setup for reactions under high pressure conditions was built for high pressure dielectric measurements by UNIPRESS (Warsaw, Poland) and described by Paluch et al. [91].
The crystals of compounds were mounted in turn on a Gemini Ultra Oxford Diffraction automatic diffractometer (Agilent, Santa Clara, CA, USA) equipped with a CCD detector, and used for data collection. X-ray intensity data was collected with graphite monochromated MoKα radiation (λ = 0.71073 Å) at a temperature of 295.0(2) K, with ω scan mode. Ewald sphere reflections were collected up to 2θ 50.10. Details concerning crystal data and refinement is gathered in Tables S1-S3. Lorentz, polarization and empirical absorption corrections using spherical harmonics implemented in SCALE3 ABSPACK scaling algorithm [92]. The structures were solved by the direct method and subsequently completed by difference Fourier recycling. All the non-hydrogen atoms were refined anisotropically using full-matrix, least-squares techniques. The Olex2 [93] and SHELXS97, SHELXL97 [94] programs were used for all the calculations. Atomic scattering factors were incorporated in the computer programs.