Brominated Thiophenes as Precursors in the Preparation of Brominated and Arylated Anthraquinones

Brominated anthraquinones can be synthesized directly from bromothiophenes when these are reacted with 1,4-naphthoquinones in the presence of meta-chloroperoxy-benzoic acid. The bromoanthraquinones are versatile building blocks in the preparation of arylated anthraquinones and of extended π-systems with interspersed anthraquinone units.

Coupling reactions have also been carried out with 1-diazoanthraquinone, which was prepared from the corresponding 1-aminoanthraquinone [10]. In order to have a versatile strategy to prepare aryl substituted anthraquinones in hand, we wanted to use haloanthraquinones as key intermediates, which we could subsequently transform into the target compounds by Suzuki cross coupling reactions. Again, preparative routes to haloanthraquinones are known. Thus, Battegay and Claudin prepared a number of dibromoanthraquinones from the corresponding diaminoanthraquinones by Sandmeyer reactions [11] and sulfonic acid functionalities could also be transformed to bromo substituents at elevated temperatures [11]. Scheme 2. 1,4-Diphenylanthraquinone by Suzuki-type coupling with aryl triflates [2].
From our understanding, in halogenated thiophenes, the sulfur is more difficult to oxidize with peracids or with hydrogen peroxide than in the corresponding donor substituted thiophenes. On the other hand, oxidized halothiophenes -halothiophene S-oxides and halothiophene S,S-dioxidesshould be more reactive dienes than their electron-donor substituted counterparts. Therefore, in all likelihood, halothiophene S-oxides would have to be used in situ. In fact, Torssell has reported on one example of a successful oxidative cycloaddition of a monobrominated thiophene with 1,4naphthoquinone (3a), where the cycloadduct was produced in poor yield [29]. Our own work [30] on the oxidative cycloaddition of brominated and chlorinated thiophenes (eg, 8a) to maleimides (eg, to 9) indicated that halothiophene S-oxides can be produced in situ and can be reacted with electron poor dienophiles (Scheme 4).

Results and Discussion
In the present case, a variety of brominated thiophenes 8 were submitted to oxidative cycloaddition reactions with 1,4-naphthoquinones 3. Heated solutions of thiophene 8 and 1,4-naphthoquinone (3a) were treated with meta-chloroperbenzoic acid in small portions over 48 h. Under these conditions, cycloaddition between intermediately formed thiophene S-oxides and 1,4-naphthoquinone 3 takes place, where the formulated, primary sulfoxy-bridged cycloadduct 11 loses the SO-bridge with concomitant aromatization (Scheme 5). The bromoanthraquinones 7 can be obtained, albeit in very moderate yield (Table 1). A number of more polar side products formed, depending on the substrate. One important type of side product are hydroxyanthraquinones 12 ( Figure 2). That bromothiophene Soxides are involved here, has been shown in the reaction under analogous conditions of 2,5dibromothiophene (8a), 2,3,4,5-tetrabromothiophene (8e) and 2,5-dichlorothiophene with Nphenylmaleimide (9), where halogenated 7-thiabicyclo[2.2.1]heptene S-oxides 10 could be isolated (Scheme 4) [30]. Nevertheless, even in cases where halothiophene S-oxides are oxidized further to halothiophene S,S-dioxides, cycloaddition reactions may be expected to proceed as electron poor thiophene S,S-dioxides have been found to undergo cycloaddition reactions readily [31][32][33], so that under the present conditions, halothiophene S,S-dioxides can also contribute to the reaction.  The brominated anthraquinones obtained were subjected to Suzuki-Miyaura cross coupling reactions with a variety of arylboronic acids. Either Pd(PPh 3 ) 4 /PPh 3 or Pd(PPh 3 ) 2 Cl 2 /PPh 3 was used as catalyst in a biphasic reaction medium of DME and aq. Na 2 CO 3 . The corresponding arylated anthraquinones were obtained in good yield. In the case of the 1-aryl-2,4-dibromoanthraquinones, the first aryl group enters selectively into the 4-position, ie., away from the aryl function already present in the anthraquinone system ( Figure 3). Prolonged reaction times and an excess of arylboronic acid make the 2-position accessible, also. In this manner it is possible to provide anthraquinones with three different aryl substituents in positions 1, 2 and 4. Equally interesting is the fact that chlorinated anthraquinones exchange the chloro-substituent readily, and thus they undergo Suzuki-Miyaura cross coupling reactions with ease, too, even when using a common catalyst such as Pd(PPh 3 ) 4 . Thus, 1,4-dibromo-5,8-dichloroanthraquinone (7c) can be converted to the 1,4,5,8-tetra-arylanthraquinone 4t (see continued Table 2), using Pd(PPh 3 ) 4 as a catalyst, as can be 1-bromo-5,8-dichloro-4-hydroxyanthraquinone (12b) to 13 (Scheme 7). Scheme 6. Arylated anthraquinones by Suzuki-Miyaura coupling of dibromoanthraquinones. Ar The anthraquinones obtained show spectral data typical for this species of compounds. Thus, in the mass spectra, many of the anthraquinones prepared above have [M + -CO] and [M + -2CO] fragmentation peaks that are typical for anthraquinones [34,35]. In their carbon NMR spectra, the carbonyl functions resonate at 184 -185 ppm. In 1,2-aryl-substituted anthraquinones, the influence of the proximity of the π-system of one aryl group on the protons of the other can be noted by a high-field shift.
The UV-VIS spectra of most of the solutions of the arylated anthraquinones in acetonitrile show at least three distinct bands, usually associated with π-π* transitions [36,37]. The strongest band, normally called a 'benzoid band' [37], is located at around λ = 250 nm for most of the compounds, which is in accordance to data gathered from other substituted anthraquinones. It could be shown that the substitution pattern of the aryl substituent in the anthraquinone has little influence on the wavelength of this absorption band. Methylation of the C6/C7 positions in the anthraquinone core leads to a shift of Δλ = 10 nm, where λ max = 263 nm. A longer-wave π-π*-transition (often called a 'quinoid band' [37]) can be found as a shoulder at λ = 265 -270 nm for the 1,4-diarylated anthraquinones. Again, there is very little influence of the substitution pattern of the aryl groups at C1 and C4 on the wavelength of this band. Also, 1,2,4-triarylated anthraquinones show this band within the same wavelength region. Where identifiable, this transition is shifted to lower energy for 6,7methylated anthraquinones (eg., for 4k, λ = 279 nm). A shift to higher wavelength is also found for the β-bromo substituted anthraquinone 4n (λ = 275 nm). Two further π-π* transitions can be noted, although they cannot be identified for all compounds measured. The first is found at around λ = 300 nm. The π-π* transition with the longest wavelength can be noted at λ = 350 -380 nm for the compounds measured. Substituent dependence of this transition has been reported for monosubstituted anthraquinones [36,37], and also in our case a substituent-dependence can be noted.

Experimental Section
Warning: Working with meta-chloroperoxybenzoic acid at elevated temperatures is hazardous. The reactions should be carried out in a well-ventilated hood. Protections against an explosion should be set up. (The authors themselves have not experienced any difficulties with these reactions. The above measures may be seen as protective precautions).

Conclusions
Bromoanthraquinones can be synthesized by an oxidative cycloaddition to suitably substituted naphthoquinones. Bromoanthraquinones can be reacted further to arylated anthraquinones via Suzuki-Miyaura coupling. Initial results show that also chloro substituted anthraquinones undergo Suzuki reactions in presence of the commercially available Pd(PPh 3 ) 4 . The UV-VIS spectra of most of the solutions of the arylated anthraquinones in acetonitrile show at least three distinct bands associated with π-π* transitions. Substituent dependence of the longest wavelength transition of the three bands can be noted.