Simple and Regioselective Bromination of 5,6-disubstituted- Indan-1-ones with Br 2 under Acidic and Basic Conditions

Bromination of 5,6-dimethoxyindan-1-one with Br 2 in acetic acid at room temperature produced exclusively the corresponding 2,4-dibromo compound in 95% yield. Reaction of 5,6-dimethoxyindan-1-one with Br 2 in the presence of KOH, K 2 CO 3 or Cs 2 CO 3 at ~0°C gave the monobrominated product 4-bromo-5,6-dimethoxyindan-3-one in 79%, 81% and 67% yield, respectively. 5,6-Dihydroxyindan-1-one was dibrominated on the aromatic ring affording 4,7-dibromo-5,6-dihydroxyindan-1-one both in acetic acid at room temperature and in the presence of KOH at ~0°C. 5,6-Difluoroindan-1-one and 1-indanone were α-monobrominated in acetic acid and α,α-dibrominated under KOH conditions at room temperature.

We report herein our attempts to find a simple, regioselective and high-yielding monobromination method for the aromatic bromination of 5,6-dimethoxy-, 5,6-dihydroxy-, 5,6-difluoroindan-1-one and indan-1-one, which all possess both an aromatic ring and an unprotected carbonyl group.The reaction conditions studied involved the use of Br 2 under neutral, acidic and basic conditions and a variety of well known brominating reagents such as KBr, NH 4 Br and pyridinium bromochromate.

Results and Discussion
A number of different bromination methods were examined using as a model compound 5,6dimethoxyindan-1-one (1), which was synthesized according to the previously reported procedure [22].The results are summarized in Table 1.
When compound 1 was reacted with Br 2 in CCl 4 (entry I) or in CHCl 3 (entry III) for 2 hrs at room temperature, 2,2-dibromo-5,6-dimethoxyindan-1-one (2) was obtained in 44% or 22% yield as the major product and 2,2,4-tribromo-5,6-dimethoxyindan-1-one (3) was obtained in 5% or 2% yield, respectively, along with recovered starting material.In the 1 H-NMR spectrum of 2 the two C 3 proton peaks were identified as a singlet at 4.22 ppm and the two aromatic hydrogens were observed at 6.79 and 7.30 ppm.The molecular ion peak at m/z 350 corresponding to the dibrominated product was also observed in its mass spectrum.In the 1 H-NMR spectrum of 3, the two proton peaks of C 3 appeared as a singlet at 4.16 ppm and one aromatic hydrogen was seen at 7.37 ppm.The Br-substituted position of the aromatic ring was identified from the NOESY spectrum.If the C 4 hydrogen were not substituted with bromine, a correlation should be observed between the C 4 and C 3 hydrogens in the NOESY spectrum, but we did not observe such a cross peak, therefore we conclude that the 4-bromo derivative was synthesized.The molecular ion peak at m/z 428 which confirmed the formation of a tribrominated product was noted in the mass spectrum of compound 3.
Under ice bath conditions, 2-bromo-5,6-dimethoxyindan-1-one (4) and 4-bromo-5,6-dimethoxyindan-1-one (5) were formed in 35% and 14% yield using CCl 4 as solvent, and in 14% and 5% yield in CHCl 3 (entries II, IV).No reaction a When Br 2 was used the reaction was carried out with exclusion of light; b Yields refer to pure isolated products.The recovered starting material and traces of other product(s) are not listed.
In the 1 H-NMR spectrum of 4, the single C 2 proton appeared as two double doublets at 4.66 ppm, two C 3 proton peaks were observed as double doublets at 3.34 and 3.77 ppm and two aromatic hydrogens were seen at 6.85 and 7.23 ppm.The molecular ion peak at m/z 271 in the mass spectrum of compound 4 indicated the formation of a monobrominated product.In the 1 H-NMR spectrum of 5, two proton peaks of C 2 and C 3 were identified as triplets at 2.71 and 3.01 ppm and an aromatic proton was observed at 7.21 ppm.The mass spectrum of 5 was similar to that of compound 4.
The reaction of Br 2 , I 2 and Fe with 1 in CCl 4 for 6 hrs in an ice bath gave compound 4 (entry V), while in the presence of AlCl 3 , the reaction of 1 and Br 2 in CH 2 Cl 2 for 2 hrs in an ice bath afforded 2,4-dibromo-5,6-dimethoxyindan-1-one ( 6) and 5 in yields of 25% and 9 %, respectively (entry VI).In the 1 H-NMR spectrum of 6, the one proton peak of C 2 was observed as a multiplet at 4.62-4.69ppm and the two proton peaks of C 3 were observed as a double triplet at 3.29 ppm and as two double doublets at 3.72 ppm.One aromatic proton was observed at 7.28 ppm.The molecular ion peak at m/z 350 in the mass spectrum of 6 confirmed the dibrominated nature of the product.
Bromination of 1 in the presence of acetic acid at room temperature formed 6 exclusively in 95% yield (entry XI).Under acidic conditions, the carbonyl group is easily converted to the corresponding enol form, which reacts preferentially with molecular bromine affording the α-brominated product.
We next examined the use of solid K 2 CO 3 , KOH or Cs 2 CO 3 as bases.The reaction of 1 and Br 2 / K 2 CO 3 in CH 2 Cl 2 at room temperature for 1 hr gave compound 6 as the major product and 5 as a minor one (entry XII), but under ice bath condition, 5 and 4,7-dibromo-5,6-dimethoxyindan-1-one (7) were obtained in 79% and 9% yields (entry XIII).In the 1 H-NMR spectrum of 7, no aromatic proton could be seen and the molecular ion peak at m/z 350 in the mass spectrum indicated formation of a dibrominated product.When KOH or Cs 2 CO 3 were used as base, compounds 5 and 7 were obtained in 81% and 7% yield with the former (entry XIV) and 67% and 20% yield with Cs 2 CO 3 (entry XV), respectively.Under basic and cold conditions, the rate of electrophilic aromatic substitution of Br 2 can be assumed to be faster than that of the enolate formation in 1, but if the reaction time is extended beyond 1 hr, then the dibrominated derivative 7 is formed as the major product and the aromatic and αbrominated product 6 is a minor product.
The bromination of compound 8, which possesses a strong activating group, showed exclusively aromatic direction under acidic conditions at room temperature and KOH conditions at 0°C, and the bromination of compound 1, with a moderately activating group, led to α-mono-and monoaromatic substitution under acidic conditions at room temperature and monoaromatic direction under basic conditions at 0°C, respectively.Compounds 10 and 13, having deactivating groups, were αmonobrominated in acetic acid and α,α-dibrominated under KOH conditions at room temperature.

Conclusions
We have presented a simple and regioselective method for the aromatic monobromination without the protection of the carbonyl group of 5,6-dimethoxyindan-1-one (1), using Br 2 under acidic or basic conditions.An aromatic monobrominated product, 4-bromo-5,6-dimethoxy-indan-1-one ( 5) was regioselectively obtained in 81% yield under KOH conditions at 0°C.Compound 8, having the strong OH activating group produced the aromatic dibrominated compound 9 under both acidic and basic (KOH) conditions at 0°C.The aromatic bromination of 10 and 13 did not occur under acidic and KOH conditions at 0°C, but α-monobromo derivatives were obtained under acidic conditions and α,αdibromo derivatives were obtained under KOH conditions at room temperature, respectively.

General
All non-aqueous reactions were performed under a dry atmosphere of nitrogen.Commercial reagents, including 1-indanone, were purchased from Aldrich, Fluka, or Sigma.5,6-Dimethoxy-1indanone [22], 5,6-dihydroxy- [23] and 5,6-difluoro-1-indanone [24] were synthesized according to known procedures.Solvents were purified and dried prior to use.Melting points were measured on a Thomas-Hoover melting point apparatus and are not corrected.Unless stated otherwise 1 H-(400 MHz), 13 C-NMR (100 MHz), and NOESY spectra were recorded in CDCl 3 on a Varian 400 MHz spectrometer.Chemical shifts (δ) are in parts per million (ppm) relative to tetramethylsilane, and coupling constants (J) are given in Hertz.IR spectra were recorded on a Jasco FT-IR 300E spectrometer as KBr pellets.Low FAB mass spectra were obtained on a Tandem mass spectrometer.Analytical TLC was performed on pre-coated silica gel 60 F 254 plates (Merck).Solvent systems used for TLC were ethyl acetate/n-hexane mixtures and 10% MeOH in methylene chloride.Column chromatography was carried out on Merck silica gel 9385 (230-400 mesh), eluting with ethyl acetate/n-hexane mixtures.

Bromination with bromine/CHCl 3 in an ice bath.
The experimental method described in 1.2 was followed, using CHCl 3 as solvent, to give 4 in 14% yield and 5 in 5% yield, respectively.

Bromination with bromine/I 2 , Fe in an ice bath.
A crystal of iodine and a pinch of iron powder were added to a solution of 1 (100 mg, 0.52 mmol) in CCl 4 (7 mL) and the reaction mixture was cooled to 0°C.Light was excluded from the flask and bromine (0.26 mL, 0.52 mmol) was added with stirring over a period of 6 hrs, without allowing the temperature to rise above 5°C.Bromine and CCl 4 were removed by distillation and the residue was washed thoroughly with 10 % NaOH solution, extracted with CH 2 Cl 2 and the organic phase was dried over anhydrous MgSO 4 , filtered and concentrated.The residue was purified by column chromatography to give 4 in 32% yield.

Bromination with bromine/AlCl 3 in an ice bath.
A dried flask was loaded with AlCl 3 (693.2mg, 5.20 mmol) in anhydrous CH 2 Cl 2 (60 mL).A solution of 1 (500 mg, 2.60 mmol) in anhydrous CH 2 Cl 2 (20 mL) was then added dropwise to the reaction mixture, which was cooled in an ice bath and bromine (1.95 mL, 1.14 mmol) was then added with exclusion of light.After 2 hrs, the reaction mixture was poured into water, treated with 10 % NaOH, and extracted with CH 2 Cl 2 .The organic extract was dried over anhydrous MgSO 4 and the solvent evaporated under reduced pressure.The products were purified by column chromatography over silica gel to give 2,4-dibromo-5,6-dimethoxyindan-1-one (6)  Oxone ® (703.3 mg, 1.14 mmol) was added to a stirred solution of KBr (136.1 mg, 1.14 mmol) and 1 (200 mg, 1.04 mmol) in methanol (10 mL) and the reaction mixture was stirred 2 hrs at room temperature, then the mixture was filtered and the solvent evaporated under reduced pressure.The products were purified by column chromatography over silica gel to give 4 in 46% yield.
Bromine (1.43 mL, 2.86 mmol) was added dropwise to solution of 1 (500 mg, 2.60 mmol) in acetic acid (40 mL).The solution was stirred 2 hrs at room temperature.The reaction mixture was poured into water and treated with 5 % sodium bisulfite solution to remove the excess bromine.The solid was filtered, washed with water and recrystallized from methanol to give compound 6 in 95% yield.
Bromine (1.52 mL, 1.04 mmol) was added with exclusion of light to a solution of 1 (100 mg, 0.52 mmol) and K 2 CO 3 (215 mg, 1.56 mmol) in CH 2 Cl 2 (20 mL) at room temperature.After 1 hr the reaction was quenched with 1 M Na 2 S 2 O 3 and extracted with CH 2 Cl 2 , dried over anhydrous MgSO 4 and evaporated.The products were purified by column chromatography over silica gel to give 6 in 44% yield and 5 in 23% yield, respectively.1.10.Bromination with bromine/K 2 CO 3 in an ice bath.

Bromination with bromine/KOH in an ice bath
The experimental method described in 1.9 was followed to yield 5 in 81% yield and 7 in 7% yield.
a When Br 2 was used, the reactions were carried out with exclusion of light.bYields refer to pure isolated products.The recovered starting material and traces of other product(s) are not listed.