Ortho-monobromination of phenols and polyphenols by 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) is described. A simple addition of commercially available DBDMH to phenols and polyphenols in chloroform at room temperature resulted in a good to excellent yield of corresponding ortho-monobromo derivatives

Alam, Ashraful

Takaguchi, Yutaka

Tsuboi, Sadao

Okayama University Scientific Achievement Repository

Journal of the Faculty of Environmental Science and Technology,Okayama UniversityVol.lO, No.1, pp.l05-109, February 20051,3-Dibromo-5,5-dimethylhydantoin, a useful reagent forortho-monobromination of phenols and polyphenolsAshraful Alam,a,b Yutaka Takaguchia and Sadao Tsuboia,*(Received November 29, 2004)Ortho-monobromination of phenols and polyphenols by 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) is described. A simple addition of commerciallyavailable DBDMH to phenols and polyphenols in chloroform at roomtemperature resulted in a good to excellent yield of correspondingortho-monobromo derivatives.Keywords: ortho-monobromination, phenol, polyphenol, DBDMHIntroductionAromatic bromination with bromine is one of themost widely used and extensively studiedelectrophilic aromatic substitution reactions. 1Owing to low reactivity, highly toxicity, andhandling inconvenience due to the liquidbehavior of bromine, some other alternativebrominating agents such as NBS, I tetrabromo-cyclohexadienone2 have been developed. For thebromination of phenols, bromine in halogenatedhydrocarbons3 or AcOIt is often the reagent ofchoice. However, for many substances, mixturesof mono- and poly-brominated compounds areobtained.s For selective monobromination of*Corresponding author, Phone/Fax: 81-86-251-8898;E-mail: stsuboi6@cc.okayama-u.ac.jpaDepartment of Environmental Chemistry andMaterials, Faculty of Environmental Sciences andTechnology, Okayama University, Okayama, Japan.bOn study leave from Dept. of Chem., Shahjalal Uni.of Sci. and Tee., Sylhet-3114, Bangladesh.105less hazardous reagents like dioxane dibromide,6phenols and other active aromatics, milder andDBD hydrobromide perbromide,7 tetrabromo-cyclohexadienone,2 tetraalkylammoniumtribrom-ides8 have developed. These reagents yieldselectively para-brominated phenols unless thepara-position is substituted. Several methods forortho-bromination of phenols have beenappeared,9 but some of them required low tem-perature or other uses very unstable brominatingagents and most of them suffers from theformation of dibromo derivatives. 1oScheme 1.There are several reports of bromination ofaromatics using N-bromosuccinamide (NBS)1O or106 J. Fac. Environ. Sci. and Tech., Okayama Univ.10 0) 2005by DBDMH in the presence of HBF4'Et2011 orother strong acids such as methyltrifluoroaceticacid. 12 Monobromination of carboxylic acid byDBDMH in aqueous NaOH has been reported, 13but it is not applicable for other aromatics exceptcarboxylic acids. Herein, we report a very simpleand convenient method for the ortho-monobromination of phenols and polyphenolsusing 1,3-dibromo-5,5-dimethylhydantoin(DBDMH) (Scheme I).Results and discussionAll the reactions were carried out in ordinarychloroform at room temperature. The yield inDMF was worst and the starting material wasremained unreacted after long period of time.Results of the bromination of variety of phenolsand polyphenols by DBDMH are summarized inTable 1. Most of the phenols and polyphenolsgave the single bromo- derivative, whereas someof them yielded small amount of dibromoderivatives (entry 8 and 9). Treatment of la withDBDMH yielded the corresponding 2-Brderivative in 92.5% yield and high puritycompared to the reported Br2liso-Pr2NHJtoluenemethod (68% isolated yield, lit. 14 74%). Butunfortunately, similar treatment of 2a withDBDMH yielded the mixture of mono-, dibromoderivative and the unreacted starting material,which was difficult to separate by columnchromatography. Then, the Br2/iso-Pr2NHmethod was examined for 2a and resulted in amixture of mono- and dibromo components in1.5: 1 ratio with only 61 % yield. In the presenceof different organic acids12 such asmethylsulfonic acid, DBDMH also yielded amixture of bromides and some other unknowncompound. Changing the solvent to DMF,treatment with excess DBDMH for short reactiontime was also failed. Then, suddenly it was foundthat if DBDMH is added at once instead of inportion, the reaction goes smoothly and yieldedpure monobromo derivative in surprisingly highyield (98%). Whereas, for all other reactions theDBDMH was added in several portions and itwas not so much sensitive to the mode ofaddition (at once or in portion).Table 1. Bromination of phenols and polyphenols by DBDMH.Entry Phenol/ Polyphenol Condition Product Isolated yield1 ~OMe1a "'=::IMeO .0 OHOMe23~OMe2a "'=::BnO I .0 OHOMe3a~OH~DBDMH (0.52 eq),5 h, rt.DBDMH (0.50 eq)"16h, rt.DBDMH (0.53 eq),15min, rt.~OMe1b I "'=:: BrMeO .0 OHOMe~OMe2b I "'=:: BrBnO .0 OHOMe3b Br~OHINSingle product,92.5%;lit. 15 74%Single product,98%Single product,91%(Continued)Alam et al. / 1,3-Dibromo- 5. 5-dimethylhydalltoill. a IIsef,,1 reagellt for ortho- mOllobromillatioll of phenols alld polyphenolsTable 1 (Continued)107Entry45678910Phenol/ Polyphenol4a~0OMe["::o h OH'-0qo OMeSa "::Io h OHPh--\--OPh6a nOyOHMe--\--oMe~o OMe7a I"::RO h OHOHR=Me, BnHo-o-Me8aHo-o-OMe9a?:MeHO¥OH10a OMeConditionDBDMH (0.51 eq),1011, rt.DBDMH (0.51 eq),2 h, rt.DBDMH (0.51 eq),1.5 h, rtDBDMH (0.51 eq),24 h, rt,DBDMH (0.52 eq),30 min, rt.DBDMH (0.52 eq),12 h, rt.DBDMH (1.20 eq),2 h, rt,Productqo OMe4b I ":: Bro h OH'-05b 0;C::O¥OHPh--\--OPh6bq BrI"::o h OHMe--\--OMe~o OMe7b I ":: BrRO h OHOHR=Me, BnHoQMeBr 8b~o OMeBr 1 ":: BrHO h OH10b OMeIsolated yieldSingle product,95%Single product,97%Single product,77%Single productR=Me,98%R=Bn,95%Mono-Br, 85%di-Br (15%)Mono-Br,75%di-Br, traceDi-bromo, 98%Phenols that have two identical positions forbromination (8a, 9a and lOa), getting the puremonobromo derivative is somewhat difficult.For example, a mixture of mono- and dibromoester of lOa was obtained (85:15) upontreatment of lOa with 0.58 mole equivalent ofDBDMH. Thus the suitability of the reagent forthe dibromination was also checked. Forinstance, treatment of lOa with 1.20 equiv. ofDBDMH yielded the corresponding dibromoester lOb in excellent yield (entry 10). So,DBDMD is also an excellent reagent for thepreparation of dibromo derivative of compoundslike lOa,108 1. Fac. Environ. Sci. and Tech., Okayama Univ.lO (1) 2005In conclusion, we can say that DBDMH is anexcellent reagent for the monobromination ofphenols and polyphenols at the ortho-position tothe hydroxy group because of its stable solidstate, commercial availability, simplicity of thereaction, clean reaction product, easy workup,and of course the high yield and purity ofproduct.ExperimentalGeneral: 1,3-Dibromo-5,5-dimethylhydantoin(DBDMH) was purchased from TCI, Japan andwas used as it was. All the reactions werecarried out in the ordinary chloroform and inertatmosphere was not maintained. Reaction wasmonitored by GC-MS and flash chromatographywas performed on silica gel (Merck, 60N,spherical, neutral, 40-50 mash). IR was recordedon a Thermo Nicolet Avatar 360T2 instrumentusing either ATR IH NMR (300 MHz) and BCNMR (75 MHz) were recorded by JEOL AL 300instrument. GC-MS was studied in aSHIMADZU GCMS-QP5000 instrument.The starting materials phenols 1-3a, 5a,7a andlOa were prepared from gallic acid. IS Compound6a was also prepared form pyrogallol by treatingit with acetone and montmorrilonite KIO inCH3CN at room temperature.16General procedure for the bromination byDBDMH:Solid DBDMH (0.50-0.52 mole equiv.) wasadded in part into the solution of startingmaterial (Ar-OH) in CHCh (5-7 mIl mmol) atroom temperature. Upon addition of theDBDMH, the solution became red or deepbrown colored, the next portion of DBDMH wasadded after the disappearance of color and so on.The progress of the reaction was monitored byGC-MS, and sometimes can easily beunderstood by observing the persistence of thecolor of the reaction mixture (in case of slightexcess DBDMH was used). After completion ofthe reaction, removal of the solvent followed bythe separation of the solid byproduct (derivedfrom DBDMH) by simple filtration provided thealmost pure bromide. For the compounds withlow solubility, 10% aq. sodium hydrosulfite(Na2S204) solution was added into the reactionmixture, stirred for 5 min. Organic layer wasseparated, dried over MeS04 and concentrated inevaporator yielded the almost pure product.Passing through a small chromatographiccolumn, it gave the pure products.References1. Larock, R C. Comprehensive OrganicTransformation; Wiley-YCH: New York,1999, 2nd ed., 619; Smith, M. 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1,3-Dibromo-5,5-dimethylhydantoin, a useful reagent for ortho-monobromination of phenols and polyphenols

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