Highly brominated anthracenes as precursors for the convenient synthesis of 2,9,10-trisubstituted anthracene derivatives

When 9,10-dibromoanthracene was treated with bromine in CCl4 without a catalyst, 1,2,3,4,9,10-hexabromo-1,2,3,4-tetrahydroanthracene (3) was obtained in 95% yield in the absence of other stereoisomers or rearomatization products. We investigated the base-induced elimination reaction of hexabromide 3 under various conditions. Pyridine-induced elimination of hexabromide 3 afforded 2,9,10-tribromoanthracene (12) in 75% yield, and tribromide 12 was transformed to trimethoxy compound 13 and trinitrile 14 by copper-assisted nucleophilic substitution reactions.

Bromoanthracenes have become increasingly important in the synthesis of anthracene derivatives [18]. For example, new anthracene derivatives used as light emitting material in a non- doped organic light-emitting diode (OLED) were synthesized from the corresponding bromo derivatives by substitution [19][20][21][22][23].
Recently we succeeded in the bromination of anthracene to give hexabromides 3 and 4 which were used in the selective and specific preparation of anthracene oxides and anthracene derivatives difficult to prepare by other routes [24]. On the other hand, in a previous study, we isolated stereoisomeric hexabromide 3 from a complex reaction mixture of photobromination of 9,10-dibromoanthracene (2) in which the structure of 3 was established by X-ray analysis [25]. We now wish to report on the successful synthesis of hexabromide 7 as the sole product of the reaction in nearly quantitative yield and its base-induced elimination leading to 2,9,10-tribromoanthracene (12).

Results and Discussion
The starting dibromide 2 was prepared from anthracene according to our previously described method [24]. First, bromination of dibromide 2 was examined at 0 °C in CHCl 3 by irradiation with a sun lamp (Table 1, entry 1). The reaction resulted in the formation of three diastereomers: 3, 4, and 5. After chromatography and fractional crystallization, hexabromides 3, 4, and 5 were isolated in yields of 73%, 8%, and 5%, respectively (Scheme 1). The structure of hexabromide 4 was assigned by comparing with an authentic sample, which is the main product in the polar bromination of dibromide 2 (Scheme 1) [24].
The structural assignments of hexabromides 3 and 5 were based on correct elemental analysis, parent ion peak in the MS, and simple characteristic 1 H NMR spectra that exhibited two AA′BB′ systems. The seven lines in the 13 C NMR spectra also agree with the symmetrical hexabromides 3 and 5. Four symmetrical stereoisomers can be formed in the reaction. However, on the basis of NMR data alone we are not able to distinguish between the four possible hexabromides. X-ray analysis of hexabromide 3 showed a trans,cis,trans relationship of bromine atoms [25]. We also have the crystallographic analysis of hexabromide 5, which is in accord with cis,trans,cis configuration of the bromine atoms in 5, which has the aeea conformation ( Figure 1) [26].
Another photolytic process using methylene chloride (Table 1, entry 2 and entry 3) and silica gel supported bromination (Table  1, entry 4) afforded mainly hexabromide 3, in addition to minor amounts of 4 and 5. However, photobromination of dibromide 2 in CCl 4 is an effective and convenient method to prepare hexabromide 3. Most of the product precipitated during the reaction.

Scheme 2:
Configuration isomerization mechanism of the hexabromides. After the reaction, a rapid and simple recrystallization gave the pure hexabromide 3 in 95% yield. As hexabromide 4 is quite sensitive to daylight and temperature, aromatization and epimerization occur to give a product mixture, and compound 3 is more stable. Its strain energy [27] (SE) is the lowest (SE = 23.81 kJ/mol total strain energy, Scheme 2) among the possible stereoisomers, which may explain why compound 3 is selectively formed.
When the pure hexabromide 4 was subjected to daylight at room temperature in solvent (CDCl 3 ), an equilibrium was established with the other hexabromides 3 and 5 ( Table 2). A similar distribution was observed in the case of pure 5. In the case of the direct irradiation of 4 with a projector lamp (150 W), equilibrium was established in a short time (15 min). The configurational isomerization stopped in the dark, which strongly supports a radical mechanism for interconversion of the bromides. We assume that the visible light initiates formation of radicals at C-1 and C-3 positions (Scheme 2), while recombination of the radicals (9 and 10) causes configuration isomerization to give hexabromides 3 and 5.
Isomerization of compound 4 may lead to 3 and 5. In order to evaluate the relative stabilities of the diastereomeric hexabromides 3, 4, and 5, we carried out molecular mechanistic calculations with MM2 relative steric energies [27]. These calculations demonstrate that hexabromide 3 is more stable than the other three (4, 5, and 7). The fact that hexabromide 5 is the major product instead of the thermodynamically more stable  Hexabromide 3 was subjected to aromatization with various bases. Treatment of hexabromide 3 with sodium methoxide or DBU led to a mixture of tetrabromide 11 [24], tribromide 12, and dibromide 2, while NaOH produced dibromide 2 (Scheme 3). Lastly, the reaction with pyridine efficiently and selectively afforded 2,9,10-tribromoanthracene (12) in high yield (75%, Scheme 4).
Preparation of 2,9,10-tribromoanthracene (12) was previously tedious and unsatisfactory [28][29][30]. Our results show that the bromination and elimination conditions are crucial for selective preparation in high yield. Having obtained tribromide 12 in a high yield, we investigated its value as a precursor of other useful compounds. For this purpose, tribromide 12 was treated with sodium methoxide in the presence of CuI in DMF at ca. 100 °C. The expected trimethoxy compound 13 was isolated as the sole product in 70% yield. The structure of 13 was proved by its 1 H NMR spectrum. Compound 13 gave a mass spectrum (M + ) at 268 corresponding to the molecular formula C 17 H 16 O 3 .
Methoxyanthracenes have great synthetic importance in several ways, i.e. in the synthesis of other substituted anthracene derivatives, which can be easily converted to hydroxyanthracenes, and also in the synthesis of anthraquinones. In addition, there are many naturally occurring methoxyanthracene derivatives [31,32].
Copper-assisted nucleophilic substitution of tribromide 12 by cyanide ions easily afforded a cyano derivative of anthracene (14) as the sole product (Scheme 4). The IR spectrum exhibited nitrile bands and the correct elemental analysis substantiates the structure of 14 as a trinitrile. The molecular ion at m/z 253.0 (base peak, [M + ]) accompanied with fragment peaks suggest that the structure is a trinitrile. The downfield shift in the proton NMR and seventeen lines in 13 C NMR are in accord with a trinitrile structure.

Conclusion
Specific and selective bromination is important in both intermediate and product synthesis. Aromatic bromination generally requires the use of a catalyst and often gives a mixture of products [33]. Therefore, the synthesis of polybromo-substituted anthracenes is restricted because reactivity towards bromine is reduced as bromination proceeds [34]. However, our study achieved efficient bromination without a catalyst under mild conditions.
We have described an efficient and convenient synthesis of the hexabromide 3 and the tribromide 12, which was produced via base-mediated elimination of 3. These two compounds are often the starting points for the polyfunctionalization to other anthracene derivatives and as such our methodology offers a new way to prepare a variety of anthracene derivatives in an efficient manner. We demonstrated that the bromination conditions of 9,10-dibromoanthracene dramatically affect the nature of the stereoisomeric hexabromide product and ratio. The studies also revealed that aromatization of hexabromide 3 depends strongly on the choice of base.  cis,trans,cis-1,2,3,4,9,10-hexabromo-1,2,3,4-

Entry 2.
The bromination was carried out in a borosilicate glass cylindrical vessel with two necks, in which a tube was immersed (immersion-well type reactor). For irradiation, this tube contained a 150 W projector lamp, surrounded by a glass tube, and cooled by water circulation. Dibromide 2 (1 g, 2.97 mmol) was dissolved in CH 2 Cl 2 (70 mL) in the reaction apparatus and cooled to 0 °C. To the solution, which was being irradiated with stirring, was added dropwise Br 2 (1.19 g, 7.44 mmol) in CH 2 Cl 2 (10 mL) over 30 min. After completion of the reaction (2 h), the solvent was removed and the residue was filtered from a short silica gel column (15 g) eluting with hexane (45 mL). The product ratio was established as 88:5:3:2 by 1 H NMR for 3, 4, 5, and 2, respectively. Hexabromide 3 was obtained in 85% yield (1.68 g) after crystallization of the mixture (CHCl 3 , 70 mL, rt, in the dark).

Entry 3.
To the solution of dibromide 2 (1 g, 2.95 mmol) in CH 2 Cl 2 (80 mL) was added bromine (1.9 g, 9.83 mmol) in CH 2 Cl 2 (10 mL) dropwise over 1 h. The mixture was stirred in daylight at room temperature for 5 d. After removal of the solvent, the residue (2.02 g) was filtered through a short silica gel column (15 g) eluting with hexane (40 mL), and the product ratio was established by NMR as 91:4:4:1 for 3, 4, 5, and 2, respectively. The mixture was recrystallized from benzene (50 mL, rt in the dark) to give hexabromide 3 in 1.67 g (86%) yield.

Entry 4.
To dibromide 2 (1 g, 2.95 mmol) in benzene (60 mL) was added silica gel (2.23 g) and bromine (1.87 g, 11.70 mmol) in benzene (10 mL). The reaction mixture was stirred for 4 d at room temperature. After completion of the reaction, the resulting material was extracted with saturated Na 2 S 2 O 3 solution and combined organic layers were washed with water, and dried over anhyd MgSO 4 . After evaporation of the solvent, the residue consisted of compounds 3, 4, 5, and 2 in the ratio of 80:6:4:10, respectively, as assigned by 1 H NMR. Recrystallization of the residue from CHCl 3 (40 mL) gave hexabromide 3 (1.43 g, 74%).

Entry 5.
To the solution of dibromide 2 (1 g, 2.98 mmol) in CCl 4 (30 mL) in a cylindrical flask (35 mL) was added bromine (1.2 g, 7.44 mmol). The stirred solution was irradiated with a sun lamp (projector lamp, 150 W) for 1 h at room temperature. After decantation of the precipitated product (1.57 g) during the reaction, the mother liquor was allowed to crystallize in a freezer. After the reaction, the investigation of the reaction mixture by 1 H NMR indicated that compounds 3, 4, and 5 were in the ratio of 98:1:1, respectively. Precipitated materials (hexabromide 3) were combined and recrystallized from CH 2 Cl 2 (yield: 1.84 g, 95%). Hexabromide 3 is sensitive to daylight and slowly aromatizes to 9,10-dibromoanthracene (2) while the product is stable in the dark in the freezer.

Irradiation of hexabromide 4 in daylight
A solution of hexabromide 4 (50 mg, mmol) in CDCl 3 was placed in an NMR tube (0.5 mL). The solution was allowed to stand at room temperature in daylight for 1 d. 1 H NMR analysis indicated the formation of a mixture consisting of 4, 5, 3, and 2 in a ratio of 51:41:5:3. Product ratios were 43:42:6:9 after 3 d and 43:41:7:9 after 22 d for the same compounds (4, 5, 3, and 2, respectively) as assigned by 1 H NMR spectra. When a solution of hexabromide 3 was left to stand in the dark for 3 d in the same conditions, no conversion occurred.

Irradiation of hexabromide 4 with a projector lamp
A solution of hexabromide 4 (50 mg) in CDCl 3 was placed in an NMR tube (0.5 mL). When hexabromide 4 was subjected to direct irradiation with a projector lamp (150 W), the equilibrium mixture formed in a short time (15 min). Product distributions are shown in Table 2.

Base-induced elimination of hexabromide 3
NaOCH 3 . NaOCH 3 (0.2 g, 3.8 mmol) in dry and freshly distilled THF (20 mL) was added dropwise to a solution of hexabromide 3 (1 g, 1.52 mmol) in dry and freshly distilled THF (20 mL). The mixture was stirred at room temperature overnight under argon atmosphere. After the reaction was complete (TLC control), the reaction material was diluted with diethyl ether (50 mL), washed with H 2 O (3 × 25 mL) and dried over CaCl 2 . After removal of the solvent, the residue was filtered through a short silica gel column (10 g, eluting with hexane). Then the relative percentages of the products were determined by 1 H NMR as 40:57:3 for tetrabromide 11 [24], tribromide 12, and dibromide 2, respectively. Fractional and chromatographic attempts to separate the mixture failed.

DBU.
To a stirred solution of hexabromide 3 (1.4 g, 2.12 mmol) in dry and freshly distilled THF (80 mL) was added 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU, 0.81 g, 5.33 mmol) dropwise in THF (15 mL) over 15 min. The reaction mixture was stirred at room temperature for 5 h. After completion of the reaction, the reaction mixture was diluted with diethyl ether (50 mL). The organic layer was washed with H 2 O (3 × 40 mL) and dried over CaCl 2 . After removal of the solvent, the residue (0.84 g) was filtered through a short silica gel column (10 g, hexane). Fractional and chromatographic attempts to separate the residue failed. Relative percentages of the products were 22:66:3 for tetrabromide 11, tribromide 12, and dibromide 2, respectively (from 1 H NMR).

NaOH.
To the solution of hexabromide 3 (1.0 g, 1.52 mmol) in THF (70 mL) at 0 °C was added NaOH (1.38 g, 34.5 mmol) in THF (20 mL THF + 5 mL H 2 O) over 10 min. The reaction mixture was stirred at 0 °C in the dark for 3 h. After the reaction was complete, the reaction material was diluted with CH 2 Cl 2 (60 mL) and washed with H 2 O (40 × 4 mL). After drying with CaCl 2 and removing the solvent, dibromide 2 was obtained in 95% (0.64 g) yield.