mild regioselective monobromination of activated aromatics ......paper 1103 mild regioselective...

PAPER 1103

Mild Regioselective Monobromination of Activated Aromatics and Hetero-aromatics with N-Bromosuccinimide in Tetrabutylammonium BromideBromination with N-Bromosuccinimide in Tetrabutylammonium BromideNemai C. Ganguly,* Prithwiraj De, Sanjoy DuttaDepartment of Chemistry, University of Kalyani, Kalyani- 741 235, IndiaFax +91(33)25828282; E-mail: [email protected] 19 November 2004; revised 11 January 2005

SYNTHESIS 2005, No. 7, pp 1103–1108xx.xx.2005Advanced online publication: 10.03.2005DOI: 10.1055/s-2005-861866; Art ID: Z22004SS© Georg Thieme Verlag Stuttgart · New York

Abstract: Highly regioselective nuclear bromination of activatedaromatic and heteroaromatic compounds has been accomplished us-ing N-bromosuccinimide in tetrabutylammonium bromide. Pre-dominant para-selective monobromination of activated aromaticssuch as phenols and anilines, rate acceleration of bromination formoderately activated and less reactive substrates on addition ofacidic montmorillonite K-10 clay, with or without microwave assis-tance, are the notable features of this protocol.

Key words: bromination, ionic liquid , tetrabutylammonium bro-mide, N-bromosuccinimide, aromatics, heteroaromatics, regiose-lectivity

Bromination of aromatics and heteroaromatics is an elec-trophilic substitution reaction of immense synthetic andindustrial importance. Brominated arenes and hetero-arenes are useful as pharmaceuticals, flame retardants,agrochemicals, specialty chemicals1 and synthetic inter-mediates capable of undergoing carbon–carbon bond for-mation via transmetalation reactions such as Heck, Stille,Suzuki, Sonogashira and Tamao–Kumada reactions.2 Ingeneral, ring brominated aromatics and heteroaromaticsexhibit interesting biological activities.3 Halogen substi-tuted pyrimidines and purines are particularly importantfor their chemotherapeutic, biochemical and biophysicalproperties.4 Apart from their usefulness as fluorophoresand potential intermediates for photophysical probes,5a

bromocoumarins are also important as synthetic precur-sors of furocoumarins and dihydrofurocoumarins that arewidely used as photosensitizers and chemotherapeuticagents to combat skin diseases,5b–d and naturally abundantlinear coumarins.5e Despite their usefulness, scanty workis documented for regiospecific monobromination of cou-marins.5f,g Bromination of activated arenes and hetero-arenes is often an unselective reaction resulting in amixture of mono- and polybrominated derivatives withconsequent tedious separation problems and poor atomeconomy. Therefore, the search for new regioselectivemethods of bromination has evoked great contemporaryinterest. Use of NBS for nuclear bromination in polar me-dia such as DMF,6a MeCN,6b,c aqueous NaOH,6d in thepresence of acids,6e,f,g silica gel,6h zeolite,6i HZSM-56j andisopropylamine7a is well-documented. These protocols of-fer different levels of selectivity depending primarily on

the extent of activation of N–Br bond in NBS,6e,f,7a actualbrominating species involved6d and control exhibited bythe heterocyclic ring and oxygenated function, ifpresent.7b,c The increasing use of room temperature ionicliquids as alternative green solvents and catalysts8 for or-ganic transformations prompted us to evaluate the effica-cy of NBS for nuclear brominations of arenes andheteroarenes in tetrabutylammonium bromide(TBAB).8a,9 Herein we reveal our results in Table 1.

Activated aromatic substrates represented by phenols andanilines undergo monobromination at 100 °C with para-selectivity in a clean fast process. Gratifyingly, this meth-od gives monobrominated products uncontaminated withdi- or tribromo derivatives with these substrates, whichare otherwise difficult to obtain. It is also significant thatexclusive para-substitution is observed without any spe-cial para-directing additives, such as zeolites7d orcyclodextrins7e and protection-deprotection sequence.Bromination by this method was also much faster thansimilar bromination in DMF,6a which took 24 hours evenfor activated aromatics (entries 1,3, and 5). The free bro-mide ion of TBAB acts as a strong hydrogen bond base10

with phenolic hydroxy group thereby enhancing its nu-cleophilicity. Coupled with the activation of NBS by wayof promoting nucleophilic cleavage of N–Br bond by un-solvated bromide ion (Scheme 1) this factor enhances therate of bromination substantially.

Scheme 1

Addition of 10 mol% water to the reaction mixture dra-matically slowed down the bromination in the case of 1-naphthol (entry 4, ii). This observation suggests that thepresence of unsolvated bromide ion is crucial to brominat-ing ability of this reagent system and solvation of bromideion in the presence of water makes it a poorer nucleophileimpeding its function. Exclusive para-bromination of ar-omatics is consistent with generation of molecular bro-mine at low concentration in a slow rate-determining step

1104 N. C. Ganguly et al. PAPER

Synthesis 2005, No. 7, 1103–1108 © Thieme Stuttgart · New York

and its fast consumption by the substrate in a kineticallycontrolled reaction. This obviously suggests short lifetimeof the ionic intermediate for bromination and similar sug-gestion has been made to explain the stereochemical out-come of bromine addition to alkenes and alkynes in ionicliquid.11 The possibility of molecular bromine forming ad-duct of tetrabutylammonium tribromide (TBATB) withTBAB12 cannot be ruled out at this stage. Significantly,para-monobromination of phenols and anilines employ-ing TBATB12a–c has been reported. The presence of Br3

–

can be ascertained from its characteristic UV absorptionband in the vicinity of 267 nm (ethylene dichloride).13 Infact, TBATB, separately prepared, displayed lmax at 263nm in TBAB-CHCl3 mixture. On the other hand, a mix-ture of NBS in TBAB exhibited a quite different lmax at278 nm. The intermediacy of TBATB seems unlikely inview of this observation. It seems plausible that attain-ment of a reasonable concentration of TBATB in the vis-cous medium by a diffusion controlled process is slow orthe liberated bromine is rapidly consumed by the substrateby an ionic mechanism before it engages itself in an equi-librium with TBAB. Attempted bromination of cinnamicacid with NBS in TBAB led to facile decarboxylation re-sulting in formation of b-bromostyrene (entry 19) byHunsdiecker reaction. In contrast, TBATB is reported13 toyield the 2,3-dibromo-3-phenylpropionic acid thereby re-vealing further the different nature of the brominating spe-cies with NBS in TBAB. The formation of a mixture of E-and Z-bromoalkene is consistent with the intermediacy ofbenzylic b-bromocarbonium ion supported by the ionicnature TBAB rather than rigid cyclic bromonium ion(Scheme 2).

Scheme 2

No decarboxylation was observed when cinnamic acidwas allowed to react with TBATB (1 mol equiv) in TBABor NBS in dichloromethane suggesting the special catalyt-ic role of TBAB in the Hunsdiecker reaction.14 Absence ofside-chain bromination at the methyl groups of 4,6- and4,7-dimethylcoumarins (entries 17, 18) despite prolongedexposure (6 h, 100 °C) is another notable feature of thisprotocol. For moderately activated substrates (entries7,8), addition of boron trifluoride etherate (1 mol equiv)(entry 6) or solid acid montmorillonite K-10 clay to the re-action mixture substantially accelerates bromination,which can be further expedited with microwave assis-tance. This is an obvious synthetic advantage over bromi-nations based on TBATB, which does not work withacetanilides. Exclusive bromination at C-3 of 7-hydroxy-coumarin in preference to nucleophilic sites at C-6 andC-8 ortho to hydroxy group further demonstrates the ab-sence of directive effect of hydroxy group through its as-sociation with NBS promoting delivery of bromine atortho-positions. This protocol is efficient for brominationof nucleoside bases uracil and cytosine in terms of reac-tion time and yield. However, purine bases adenine andguanine are resistant to this reagent system (36 h, r.t./8min, MW, 300 W) due to the strong deactivating nature ofpurine bases.

Table 1 Bromination of Aromatics and Heteroaromatics with NBS in TBAB

Entry Substrate Product Reaction Time Yield (%)a

1 2 h 90

2 2 h 84

3 2.5 h 86

4 i. 4 hii. 8 h

7573b

PAPER Bromination with N-Bromosuccinimide in Tetrabutylammonium Bromide 1105


5 4 h 88

6 i 10 hii. 6 h

8487c

7 i. 10 hii. 2 hiii. 5 min

8085d

92e

8 i. 48 hii. 4 hiii. 8 min

7882d

90e

9 i. 3 hii. 6 min

7882e

10 4 h 60

11 3 h 76

12 4 h 68

13 4 h 75

14 i. 45 minii. 2.5 min

8592e

15 i. 1 hii. 4 min

8290e

16 i. 2 hii. 4 min

7896e

Table 1 Bromination of Aromatics and Heteroaromatics with NBS in TBAB (continued)




In conclusion, a mild efficient protocol for monobromina-tion of activated aromatics and heteroaromatics has beendeveloped employing NBS in TBAB. Para selectivity foraromatics, use of non-excess stoichiometry leading tomonobromination and consequent less demanding purifi-cation procedures are the advantageous features of thismethod.

TBAB and NBS were procured from Spectrochem, India and E.Merck, Germany respectively. Solvents used for extraction andchromatography were distilled prior to use. A domestic microwaveoven (BPL India, 2450 MHz) was used for microwave experiments.

Bromination with NBS in TBAB; 5-Bromo-6-aminocoumarin; Typical Procedure (Table 1, Entry 13)6-Aminocoumarin (342 mg, 2.12 mmol) was added to solid TBAB(0.4 g) with stirring and when the resulting mixture became a cleanmelt, NBS (380 mg, 2.13 mmol) was added. This was heated to100 °C in a closed glass vial and then kept at that temperature for 4h (TLC monitoring). H2O (4 mL) was then added to remove succin-imide followed by extraction with a minimum amount of EtOAc.The organic extract, after washing with brine, drying (Na2SO4) andcareful removal of solvent, gave one product exclusively along withTBAB. The crude product was purified by filtration through a shortpad of silica gel using CH2Cl2–light petroleum ether mixture (1:1)as the eluent. Shining bright yellow crystals of 5-bromo-6-ami-nocoumarin (380 mg, 75%) were obtained; mp 168–169 °C. TBABwas recovered almost quantitatively from later fractions as shiningwhite crystals, which was reused without any decrease of yield ofbromo products.

Microwave-Assisted Bromination of Acetanilide with NBS-TBAB in the Presence of Montmorillonite K-10 Clay; 4-Bro-moacetanilide; Typical Procedure (Table 1, Entry 7, ii) To an intimate mixture of acetanilide (280 mg, 2.07 mmol) andTBAB (0.4 g) in an Erlenmeyer flask was added NBS (370 mg, 2.08mmol) followed by montmorillonite K-10 clay (1 g). The mixture,after thorough stirring, was irradiated with microwave at 300 W for2 × 2.5 min cycles with 30 s in between to allow TLC monitoring.

The reaction mixture was cooled to r.t., diluted with EtOAc (4 mL)and directly charged into a silica gel column for chromatographicpurification. 4-Bromoacetanilide was obtained as a crystalline solid(400 mg, 91%) using CH2Cl2 as eluent; mp 166–167 °C. TBAB wasalso recovered as before from later fractions of CH2Cl2 eluates andwas reused.

Bromination of Aromatics with NBS-TBAB in the Presence of Boron Trifluoride Etherate; 2-Bromo-4-nitroaniline; Typical Procedure (Table 1, Entry 6, i)An intimate mixture of 4-nitroaniline (148 mg, 1.08 mmol) andTBAB (0.22 g) was heated at 100 °C. The mixture was cooled tor.t., and to it was added NBS (195 mg, 1.09 mmol) and finallyBF3·OEt2 (155 mg, 1.07 mmol) in a glass vial. The closed glass vialwas kept at r.t. for 6 h and it was then quenched with sat. aqNaHCO3 (3 mL). This was followed by extraction with EtOAc (2 ×4 mL) and chromatographic filtration over silica gel to afford 2-bro-mo-4-nitroaniline (200 mg, 87%); mp 103–104 °C (Lit.15 mp104.5 °C) and TBAB.

Characterization Data of Some Selected Products3-Bromo-7-hydroxycoumarinMp 214–216 °C.

FTIR (KBr): 3257, 3048, 1695, 1621, 1591, 1441, 1362, 1260,1232, 1148, 1120, 1007, 838, 751 cm–1.1H NMR (300 MHz, DMSO-d6): d = 6.74 (1 H, d, J = 2.1 Hz, H-8),6.82 (1 H, dd, J = 2.1, 8.7 Hz, H-6), 7.53 (1 H, d, J = 8.7 Hz, H-5),8.48 (1 H, s, H-4), 10.76 (1 H, s, 7-OH).

EIMS (70 eV): m/z (%) = 242, 240 (89.0, 84.3, M+), 214, 212 (19.3,24.2), 186, 184 (7.5, 8.0), 161 (23.2).

Anal. Calcd for C9H5O3Br: C, 44.83; H, 2.07. Found: C, 44.89; H,2.01.

Note: This compound has been reported5f as an oil with 1H NMRspectrum (90 MHz, DMSO-d6) exhibiting H-4 at d = 7.8 and 7-OHat d = 5.5; both values seem unusual in view of the fact that 3-Br willcertainly cause substantial low-field shift of H-4 which usually ap-pears at d = 7.8. Hydroxy proton of 7-hydroxycoumarins usually ap-pears in the region d = 10–11 in DMSO-d6. However, no supportivemass spectral and elemental analysis data were reported for the oil.

17 no reaction 6 h –

18 no reaction 6 h –

19

(E:Z = 2:1)

40 min 96

a Yields refer to those of pure isolated products characterized by spectroscopic data (IR, 1H and 13C NMR and EIMS). b Reaction conditions: substrate (1 mmol), NBS (1 mol equiv), TBAB (0.2 g), 10 mol% H2O, 100 °C.c Reaction conditions: substrate, NBS and BF3·Et2O (each 1 mol equiv), TBAB (0.2 g).d Reaction conditions: substrate (1 mmol), NBS (1 mol equiv), TBAB (0.2 g), K-10 clay (0.5 g/mol equiv of substrate), 100 °C. e Reaction conditions: substrate (1 mmol), NBS (1 mol equiv), TBAB (0.2 g), substrate separately adsorbed on K-10 clay (0.5/mmol each), MW, 300 W.

Table 1 Bromination of Aromatics and Heteroaromatics with NBS in TBAB (continued)


PAPER Bromination with N-Bromosuccinimide in Tetrabutylammonium Bromide 1107


3-Bromo-4-methyl-7-methoxycoumarinMp 130–133 °C.

IR (KBr): 2940, 1700, 1590, 1530, 1500, 1370, 1350, 1280, 1240,1200, 1060, 1010, 990, 820, 740 cm–1.1H NMR (300 MHz, CDCl3): d = 2.58 (3 H, s, 4-CH3), 3.87 (3 H, s,7-OCH3), 6.81 (1 H, d, J = 2.4 Hz, H-8), 6.88 (1 H, dd, J = 9.0, 2.4Hz, H-6), 7.55 (1 H, d, J = 9.0 Hz, H-5).13C NMR (75.5 MHz, CDCl3): d = 162.83 (C-7), 153.70 (C-2),152.60 (C-8a), 150.96 (C-4), 126.00 (C-5), 113.48 (C-6), 112.93(C-3), 109.78 (C-4a), 100.83 (C-8), 55.82 (7-OCH3), 19.40 (4-CH3).

DEPT-135: d = 126.06 (C-5), 113.00 (C-6), 100.78 (C-8), 55.86 (7-OCH3), 19.49 (4-CH3).

EIMS (70 eV): m/z (%) = 270, 268 (74.6, 100.0, M+), 242, 240(29.4, 38.6), 227, 225 (34.7, 45.1), 214, 212 (12.7, 10.1), 189 (27.7),162 (30.1), 133 (50.6).

5-Bromo-6-hydroxycoumarinMp 210–211 °C.

IR (KBr): 3180, 3120, 1660, 1600, 1540, 1455, 1380, 1290, 1270,1240, 1220, 1120, 990, 940, 890 cm–1. 1H NMR (300 MHz, DMSO-d6): d = 6.51 (1 H, d, J = 9.6 Hz, H-3),7.16 (1 H, d, J = 9.0 Hz, H-7), 7.26 (1 H, d, J = 9.0 Hz, H-8), 8.55(1 H, d, J = 9.6 Hz, H-4), 10.57 (1 H, s, 6-OH).13C NMR (75.5 MHz, DMSO-d6): d = 162.20 (C-2), 151.36 (C-6),147.47 (C-8a), 142.41 (C-4), 119.76 (C-8), 118.91 (C-4a), 118.54(C-7), 117.81 (C-3), 107.39 (C-5).

EIMS (70 eV): m/z (%) = 242, 240 (68.0, 100.0, M+), 214, 212(74.7, 86.8), 161 (40.0), 133 (44.1).

Anal. Calcd for C9H5BrO3: C, 44.83, H, 2.07. Found: C, 44.73; H,2.10.

5-Bromo-6-aminocoumarinMp 168–169 °C.

FTIR (KBr): 3456, 3331, 1708, 1623,1559, 813 cm–1. 1H NMR (300 MHz, CDCl3): d = 3.97 (2 H, br s, 6-NH2), 6.46 (1 H,d, J = 9.6 Hz, H-3), 6.97 (1 H, d, J = 8.7 Hz, H-7), 7.14 (1 H, d,J = 8.7 Hz, H-8), 8.03 (1 H, d, J = 9.6 Hz, H-4).

Anal. Calcd for C9H7BrNO2: C, 45.18; H, 2.51; N, 5.85. Found: C,45.21; H, 2.49; N, 5.86.

Acknowledgment

One of the authors (PD) sincerely thanks University of Kalyani forfinancial assistance by way of UGC Minor Research Grant. The fa-cility provided by DST-FIST Grant to the Department of Chemistryis also acknowledged.

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mild regioselective monobromination of activated aromatics ......paper 1103 mild regioselective...

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