An efficient regioselective bromination protocol of activated

ARTICLE

An ef?cient regioselective bromination protocol of activated coumarins using 2,4,4,6-tetrabromo-2,5-cyclohexadienone

Nemai C.Ganguly,Subhasis Nayek,and Sumanta Chandra

Abstract:2,4,4,6-Tetrabromo-2,5-cyclohexadienone mediated bromination of a wide assortment of activated coumarins in acetonitrile has been accomplished with high regioselectivity and good to excellent yields.The selectivity and ef?ciency of bromination were found to be markedly dependent on electronic factors,particularly degree of electron withdrawal from electron-releasing 7-oxygenated substituents to the C-3position of the ?-pyrone moiety by vinylogous resonance and the presence of nucleophilic additives such as water and tetra-n -butylammonium bromide in the reaction medium.The sole by-product of the reaction was converted back to the reagent by oxidation with KBr?KBrO 3,which was recycled three times without signi?cant loss of ef?ciency.

Key words:regioselective bromination,TBCHD,activated coumarins,nucleophilic additives,recyclability of reagent.

Résumé:La bromation d’une grande gamme de coumarines activées a étéeffectuée avec une très haute régiosélectivitéet des

rendements bons a

`excellents par réaction avec de la 2,4,4,6-tétrabromo-2,5-cyclohexadiénone dans l’acéhttps://www.360docs.net/doc/e14609839.html, sélectivitéet l’ef?cacitéde la bromation dépendent fortement de facteurs électroniques,notamment le degréde transfert d’électrons des

substituants donneurs d’électrons oxygénés en position 7a

`la position C-3du groupe ?-pyrone par résonance vinylogue et la présence d’additifs nucléophiles,tels que l’eau et le bromure de tétra-n -butylammonium,dans le milieu réactionnel.Le seul sous-produit de la réaction a étéreconverti par oxydation avec du KBr?KBrO 3en réactif qui a étérecyclétrois fois sans perte appréciable d’ef?cacité.[Traduit par la Rédaction]

Mots-clés :bromation régioselective,TBCHD,coumarines activées,additifs nucléophiles,recyclabilitédu réactif.

Introduction

Regioselective bromination of activated coumarins is an impor-tant synthetic transformation of considerable contemporary interest owing to diverse synthetic and biological utilities of bro-mocoumarins.Bromoheteroarenes and bromocoumarins in par-ticular are useful synthons for transition metal mediated C?C 1and C?N 2bond formations in view of their ready accessibility as compared with iodo derivatives and relatively high reactivity compared with corresponding chloro compounds.The coumarin core is represented in a host of biologically active compounds including anticoagulants,3antitumour agents,4and anti-HIV agents.53-Bromocoumarins serve as building blocks for the syn-thesis of heat-shock protein 90(Hsp 90)inhibitor novobiocin an-alogues 6CK2(casein kinase)inhibitors and antineoplastic drug candidates.6b ,78-Bromo-7-O -allylated coumarins offer facile entries to natural and unnatural linear coumarins by Claisen rearrange-ment where the bromine atom plays crucial role in directing the migrating allyl moiety to the 6position and thereafter acts as a thermolabile group.8They are also synthetic precursors of linear and angular furano-and dihydrofuranocoumarins such as marmesin and psoralin,which are photosensitizers and widely used as an-tipsoriasis agents.9Brominated methylcoumarins also provide ac-cess to several biologically relevant compounds.10Notably,usefulness of these molecules hinges upon the speci?c location of bromine in the coumarin moiety.This prompted several recent initiatives towards development of regioselective bromination protocols of coumarins based on N -bromosuccinimide (NBS),7a ,11including one previously reported by us using NBS in molten tetra-n -butylammonium bromide (TBAB),11c CuBr 2/Al 2O 3,12Et 4N +Br ?in the presence of hypervalent iodine compounds,13and diox-ane dibromide.14However,the existing methods have certain draw-backs such as use of harsh reaction conditions and focus on speci?c target,7a use of halogenated and volatile organic solvents,11a and re-lease of hazardous HBr during bromination.11b ,14In continuation of our interest in development of environmentally friendly synthetic methodologies,15we became interested in developing a selective bro-mination protocol for activated coumarins based on a mild,easily accessible solid brominating agent.To this end,we identi?ed 2,4,4,6-tetrabromo-2,5-cyclohexadienone (TBCHD)that essentially relies on abstraction of Br +by a nucleophile from its sterically encumbered C-4position and concomitant release of corresponding phenolate anion (Scheme 1).The selectivity of bromination by this reagent is dependent on the steric situation in the vicinity of C-4.

TBCHD and its derivatives have been utilized for selective bro-mination for activated aromatic and heteroaromatic compounds including phenols,16anilines,16b and ?avones 17as well as for ?-bromination of aldehydes,ketones,18and acid chlorides.19It is inexpensive,readily accessible from phenol,16a and compatible with several common organic solvents.TBCHD is more selective than NBS in bromination reactions 20and this motivated us to evaluate its hitherto unexplored ef?cacy for selective bromina-tion of activated coumarins.Herein,we reveal the results of TBCHD-mediated bromination of a wide variety of activated cou-marins in acetonitrile (Table 1).

Results and discussion

Initially,coumarin was treated with TBCHD to assess the sus-ceptibility of the ?-pyrone double bond towards bromination.It was thoroughly resistant even under forcing reaction conditions (TBCHD (2mol equiv.),acetonitrile,re?ux,15h).This result is in

Received 23May 2013.Accepted 16July 2013.

N.C.Ganguly,S.Nayek,and S.Chandra.Department of Chemistry,University of Kalyani,Kalyani-741235,India.Corresponding author:Nemai C.Ganguly (e-mail:nemai_g@yahoo.co.in ).

1155

C a n . J . C h e m .

D o w n l o a d e d f r o m w w w .n r c r e s e a r c h p r e s s .c o m b y C h i n e s e A c a d e m y o f M e d i c a l S c i e n c e & P e k i n g U n i o n M e d i c a l C o l l e g e o n 03/05/15F o r p e r s o n a l u s e o n l y .

sharp contrast with the reported ease of formation of coumarin-3,4-dibromide with dioxane dibromide 14that acts as a surrogate of bromine.It is also slowly formed in low yield (23%,10h)by the reaction of coumarin with NH 4Br (4mmol)and Oxone in acetoni-trile under re?ux that proceeds via bromonium ion intermedi-ate.21These results suggest a different mechanistic paradigm for TBCHD-mediated bromination.Inasmuch as bromination of acti-vated aromatics by TBCHD is a nucleophile-driven process,we felt that the activation of the coumarin moiety was imperative for bromination,and therefore,we explored the feasibility of bromi-nation of 4,7-dimethylcoumarin (1)that represents a substrate with modest activation in both benzene and pyrone ring.Bromi-nation of 1with TBCHD (1mol equiv.)in acetonitrile under re?ux cleanly delivered 3-bromo-4,7-dimethylcoumarin (1a )in 85%yield (entry 1).Notably,side-chain bromination and nuclear bromina-tion of the benzene did not occur.Encouraged by this result,we proceeded to explore the bromination of 7-hydroxycoumarin (2),a naturally occurring coumarin of immense importance in the bio-genetic map of coumarins and precursor of several coumarin mo-tifs.It is endowed with substantial nucleophilic activity due to ionization to its oxyanion and three nucleophilic sites at the C-3,C-6,and C-8positions.Gratifyingly,it underwent selective mono-bromination to 8-bromo-7-hydroxycoumarin (2a ),albeit slowly,in 68%yield (entry 28h).This presumably stems from its sparing solubility in acetonitrile and also partly due to unfavourable steric factor associated with ortho nucleophilic attack at C-4of the re-agent.Interestingly,bromination of 2with NBS (1.1mol equiv.,CH 3CN,room temperature,3h)was found to be unselective,pro-viding 3,6,8-tribromo-7-hydroxycoumarin in 26%yield.In fact,one-pot selective bromination at C-8is unprecedented and 2a was previously accessed by a multistep sequence in low overall yield.13We reasoned that water might act as a nucleophilic activator to generate a more potent bromonium ion equivalent,H 2OBr +from TBCHD 22(Scheme 1).Coupled with substrate activation by facili-tating ionization,bromination in aqueous acetonitrile was antic-ipated to be faster and more ef?cient.Treatment of 2in aqueous acetonitrile (CH 3CN?H 2O,90:10)for 6h afforded 2a as the major product (50%)together with a substantial amount of its regioiso-mer,3-bromo-7-hydroxycoumarin 2b (32%).Thus,the selectivity was compromised to attain higher overall yield (entry 26h).In contrast,7-methoxycoumarin (3)underwent surprisingly expedi-tious and selective monobromination at C-3to give 3a (entry 33h).Higher solubility in CH 3CN and less steric hindrance involved in C?Br bond formation at C-3account for this observation.The marginally higher yield of 3a and its increased rate of formation (85%,1h,entry 31h)in aqueous acetonitrile suggested the implica-tion of a more potent bromonium ion equivalent,presumably H 2OBr +,as substrate activation by acid ionization is precluded here.Similar bias towards selective vinylogous bromination was a persistent feature of 7-allyloxy and 7-acetoxycoumarin (entries 4and 5).This feature can be explained by substantial electron with-drawal from these substituents to C-3and consequent depletion of electron density at ortho positions,discouraging bromination at these positions.In fact,the electron withdrawal by the ?-pyrone moiety from the benzene ring in the case of 7-acetoxycoumarin (5)activates its carbonyl towards nucleophilic attack by water,result-ing in hydrolytic cleavage.Absence of ortho -brominated products,

as in the case of 2,entails that vinylogous bromination occurred prior to its hydrolysis or these are concomitant events.Notably,the allylic double bond was generally well tolerated under the conditions of the present method (entries 4,8,9,11,14,and 15),further attesting to the absence of free bromine or bromonium ion in the reaction medium.In an attempt to control hydrolytic cleavage of the acetoxy group of 7-acetoxy-8-allylcoumarin (6),the reaction was performed in dry acetonitrile under mild warming conditions (50–60°C).Under these conditions,the hydrolysis of the acetoxy group was totally suppressed and it was recovered unchanged,demonstrating that the 7-AcO group neither partici-pated in heterocyclization nor was activating enough to ensure ring bromination.However,when it was submitted to reaction with TBCHD (1.2mol equiv.)in dry acetonitrile in the presence of TBAB (1.5mol equiv.),addition of bromine occurred in the allylic side chain (entry 66h).This is reminiscent of nucleophilic activa-tion of NBS by the unsolvated bromide ion provided by TBAB,as previously reported by us.11c

However,the juxtaposition of 7-oxyanion and pendant epoxi-dized allyl moiety of complementary reactivities triggered facile heterocyclization of 7to hydroxypyranocoumarin and its bromi-nation to 7a in aqueous acetonitrile.The rate and selectivity of bromination were comparable with those of 7-methoxycoumarin (3),suggesting heterocyclization occurred as a prelude to C-3bro-mination.There was substantial erosion of selectivity for bromination of 8-allyl-7-hydroxycoumarin (8)and 6-allyl-7-hydroxycoumarin (9).In-stallation of the allyl moiety adjacent to 7-OH made bromination at the vacant ortho position further sterically demanding,thereby prolonging reaction time and allowing competing C-3bromina-tion (entries 8and 9).The presence of an activating 4-Me group invariably promoted C-3bromination in the ?-pyrone ring.Dibromi-nation of 7-hydroxy-4-methylcoumarin (10)afforded 3,8-dibromo-4-methyl-7-hydroxycoumarin (10a )(12h,40%)(entry1012h),which exhibits speci?c ATP site directed inhibitory activity to-wards protein kinases,particularly CK2,in the low micromolar range and is a potential antineoplastic drug candidate.6b ,7The yield of 10a was substantially improved by using 2.1mol equiv.of the reagent in aqueous acetonitrile (entry 107h).3,6,8-Tribromo-4-methyl-7-hydroxycoumarin (10b ),a potent pesticide used to con-trol vectors Culex quinquefasciatus and Aedes aegypti 23responsible for tropical diseases such as malaria and dengue,could also be accessed with ease and ef?ciency employing further excess of the reagent (3.4mol equiv.)in aqueous acetonitrile (entry 108.5h).Surprisingly,7-acetoxy-4-methylcoumarin (13)was less prone to hydrolysis than its hydroxy counterpart and delivered 7-acetoxy-3-bromo-4-methylcoumarin (13a )(entry 13).This is a re?ection of reduced electron demand from 7-OAc to C-3due to the presence of electron-releasing 4-Me,making it less susceptible to hydrolytic cleavage.Unlike 7-oxygenated coumarins,there is no signi?cant electron withdrawal from electron-releasing substituents at C-6by vinylogous resonance.This difference in electronic situation for 6-methoxy/-aminocoumarin allowed faster and predominant,if not exclusive,ortho bromination at C-5(entries 16and 17).This was also revealed by the unfavourable effect of water on rate and yield of bromination for 6-methoxycoumarin (16).Addition of 10mol%of water to a solution of 16in nonpolar dichloromethane considerably slowed down the reaction to give 16a (60%,1.5h).The mechanistic scenario of aromatic bromination generally involves late transition state with predominant carbocation character.24The stabilization of the incipient carbocation intermediate is expected to be strongly in?uenced by the electron releasing of the 6-OMe group.It acts as a hydrogen bond base and its oxygen lone pairs of electrons become engaged in hydrogen bonding in the presence of water and,there-fore,less available for stabilizing the carbocation-like transition state with resultant decrease in reaction rate and ef?ciency.As ex-pected,4-hydroxycoumarin (18)underwent exclusive bromina-tion at C-3(entry 18).In the absence of this ring bromination site,as for the 3-allyl derivative 19,prompt heterocyclization to

Scheme 1.Nucleophile-induced bromination by

TBCHD.

1156Can.J.Chem.Vol.91,2013

C a n . J . C h e m .

Table1.Bromination of coumarins with TBCHD in acetonitrile.

Entry Substrate Products Time(h)a Yield(%)b

1985

2(i)82a,68

(ii)62a,50;2b,32c

3(i)380

(ii)185c

4880

51055c

6(i)4No reaction

(ii)645

70.590c

8138a,40;8b,15

91246

10(i)1210a,40

(ii)710a,82d

(iii)8.510b,75e

11778

12250

13960

141545

151040

16(i)0.7582

(ii)1.560

17117a,70;17b,10 Ganguly et al.1157 C

brominated pyranocoumarin was the only course of the reaction

(entry19).TBCHD was recovered from2,4,6-tribromophenol by a

simple green procedure using KBr?KBrO3as a source of electro-

philic bromine.Exploratory bromination of7-methoxycoumarin

(3)recycling-recovered TBCHD gave yields comparable with the orig-

inal one(entry33h)for three successive runs(66%,65%,and62%,

respectively).

Density functional theory calculations were performed at the

B3LYP level(Gaussian-09software)for estimation of electron den-

sity at different ring carbons of activated coumarins.It was re-

vealed that C-8of7-hydroxycoumarin(2)clearly surpasses other

ring carbons,C-3in particular,in electron density.On the other

hand,in the case of7-methoxycoumarin(3),this difference in

electron density is signi?cantly reduced in favour of C-3,suggest-

ing a greater degree of electron withdrawal from electron-

releasing7-MeO to electron-de?cient C-3.The7-oxyanion of2

exhibits a highly delocalized structure where substantial deple-

tion of negative charge results in its almost even distribution at

all possible nucleophilic sites.7-Hydroxy-4-methylcoumarin(10),

as expected,possesses C-3and C-8of comparable activation

levels and,therefore,both qualify as bromination sites.For

6-methoxycoumarin(16),the ambiphilic nature of the coumarin

ring system is evident,with the electron-rich benzene ring being

segregated from the electron-withdrawing pyrone ring.The C-5is

decidedly the seat of highest electron density in this case and,

therefore,the exclusive bromination site.These data corroborate

the contention that nucleophilicity is the de?ning element of

selectivity of bromination of these coumarins with TBCHD. Conclusion

To summarize,bromination of activated coumarins has been

achieved with high selectivity and good to excellent yields in

acetonitrile under re?uxing conditions.The reaction time and

selectivity of bromination exhibited marked dependence on nu-

cleophilicity of the bromination site that is related to electron

withdrawal from electron-releasing substituents in the benzene

ring to C-3of the?-pyrone ring by vinylogous resonance.The ?-pyrone double bond as well as the allyl moiety were generally tolerated under the conditions of the current method.The selec-

tivity,yield,and reaction time could be effectively tuned by addi-

tion of nucleophilic additives such as water and TBAB.The sole

by-product of bromination viz.2,4,6-tribromophenol could be

converted back to TBCHD for recycling,adding to the synthetic

utility of the method.

Supplementary data

Supplementary material is available with the article through

the journal Web site at https://www.360docs.net/doc/e14609839.html,/doi/suppl/

10.1139/cjc-2013-0230.Supplementary data include full experi-

mental procedures,characterization data for all new compounds,

and Mulliken charges calculated for some representative cases.Acknowledgements

S.C.thanks the Council of Scienti?c and Industrial Research (SRF-NET),New Delhi,for?nancial assistance by way of a research fellowship.Facilities provided by the DST-FIST programme and UGC-SAP programmes,Government of India,are also acknowl-edged.

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Entry Substrate Products Time(h)a Yield(%)b

18375

19 1.585

a Reaction conditions:substrate(1mmol),TBCHD(1.1mol equiv.),acetonitrile(4mL),re?ux,unless otherwise stated.

b Yields refer to chromatographically pure products characterized by spectroscopi

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d Reaction conditions:substrate:TBCHD(1:2.1mol equiv.),acetonitrile(4mL),re?ux.

e Reaction conditions:substrate:TBCHD(1:3.4mol equiv.),acetonitrile?water(9:1)(4mL),re?ux.

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