Synthesis of α-bromocarbonyl compounds: recent advances

Accepted Manuscript Synthesis of α-bromocarbonyl compounds: Recent advances Rajesh H. Vekariya, Hitesh D. Patel PII:

S0040-4020(14)00521-3

DOI:

10.1016/j.tet.2014.04.027

Reference:

TET 25477

To appear in:

Tetrahedron

Received Date: 20 December 2013 Revised Date:

7 April 2014

Accepted Date: 9 April 2014

Please cite this article as: Vekariya RH, Patel HD, Synthesis of α-bromocarbonyl compounds: Recent advances, Tetrahedron (2014), doi: 10.1016/j.tet.2014.04.027. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Synthesis of α-bromocarbonyl compounds: Recent advances

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Rajesh H. Vekariya a and Hitesh D. Patel a, ∗

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Tetrahedron journal homepage: www.elsevier.com

Rajesh H. Vekariya and Hitesh D. Patel∗ Department of Chemistry, School of Sciences, Gujarat University, Ahmedabad-380009, Gujarat, India.

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Synthesis of α-bromocarbonyl compounds: Recent advances

ABSTRACT

Article history: Received Received in revised form Accepted Available online

The α-bromination of carbonyl compounds is one of the most important processes in synthetic organic chemistry. These compounds are important precursors for the production of various biologically important heterocyclic compounds and other industrially important products. Despite the availability of numerous methods for the synthesis of this important class of compounds, the final products usually have impurities of di-brominated or ring brominated products in the reaction mixture. In addition to the inherent efficiency issues, there are also environmental concerns that need to be addressed. In recent years considerable advances have been made for the synthesis of α-bromo carbonyl compounds with high selectivity. In this review, we have summarized various methods for the synthesis of α-bromo carbonyl compounds.

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Content

2014 Elsevier Ltd. All rights reserved.

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Keywords: selectivity α-bromination α-bromo carbonyl compounds synthetic methods

1.

Introduction…………………………………………………………………………………………………………………………....02

2.

Various routes for the synthesis of α-bromo carbonyl compounds…………………………………………………………………..02

I. Synthesis of α-bromo carbonyl compounds using organic brominating agents……………………………………………….........02

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A. Bromination by N-bromosuccinimide (NBS)……………………………………………………………………………………………………..02 B. Bromination by bromo ionic liquids……………………………………………………………………………………………………………....06 C. Bromination by dioxane dibromide………………………………………………………………………………………….................................07

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D. Bromination by pyridinium bromochromate (PBC)……………………………………………………………………………………………..07 E. Bromination by tribromoisocyanuric acid (TBCA)………………………………………………………………………………………….......07 F. Bromination by bromotrimethylsilane (TMSBr)……………………………………………………………………………………………........07 G. Bromination by hexamethylenetetramine-bromine (HMTAB)…………………………………………………………………………….........07 H. Bromination by bromodimethylsulfonium bromide (BDMS)……………………………………………………………………………………08 I. Bromination by 1-butyl-3-methylimidazolium tribromide (TBABr3)…………………………………………………………………………….08

II. Synthesis of α-bromo carbonyl compounds using Inorganic brominating agents……………………………………………........08 A. Bromination by ammonium bromide (NH4Br)…………………………………………………………………………………………………..08 B. Bromination by copper(II) bromide [Cu(Br)2]…………………………………………………………………………………………………..09 C. Bromination by hydrobromic acid (HBr)………………………………………………………………………………………………………..09 D. Bromination by molecular bromine (Br2)…………………………………………………………………………………...................................10

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E. Bromination by potassium bromide (KBr)……………………………………………………………………………………………………....10

∗ Corresponding author. Tel.: +91-079-26300969; fax: +91-07926308545; e-mail: [email protected]

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F. Bromination by magnesium(II) bromide (MgBr2)…………………………………………………………………………………………...10

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Conclusion……………………………………………………………………………………………………………………………...11

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Acknowledgement……………………………………………………………………………………………………………………...11

References………………………………………………………………………………………………………………………………………..11 Biographical sketch……………………………………………………………………………………………………………………………....13

1. Introduction

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were efficiently α-brominated by this method. The best selectivity and yield of the product was obtained in the presence of diethyl ether (Et2O) or carbon tetrachloride (CCl4) compared to the other organic solvents. With toluene a poor conversion to 2-bromotoluene was observed. Ethylacetoacetate, acetyl acetone and acetophenone could also be α-brominated by this method. O

NBS (1.2 mmol), NaHCO3-SiO2 (200 mg)

(1 mmol)

Et2O or CCl4 (10 mL), r.t.

SC

(CH2)n

n = 1,2,3

Br (CH2)n 20-55 %

Scheme 1

Synthesis of α-bromo ketones using NBS and catalytic amount of p-TSA in the presence of ionic liquids, such as [bmim]PF6 and [bmpy]Tf2N or in chloroform at room temperature gave a high yield with high purity as reported by Izumisawa et al. (Scheme 2a-b).88 In this reaction diverse ionic liquids such as 1-butyl-3methylimidazolium hexafluorophosphate ([bmim]PF6), N-butylN-methylpyrrolidinium bis(trifluorome-thanesulfonyl)imidate ([bmpy]Tf2N) and 1-butyl-3-methylimidazolium tetrafluoroborate ([bmim]BF4) were used for a comparative study with chloroform as solvent. In these experiments the best results were obtained using [bmim]PF6 and [bmpy]Tf2N respectively. In case of [bmim]BF4 the α-bromination of ketones did not proceed efficiently, because the proton derived from p-TSA could not promote the formation of enol forms of ketones due to the interaction between the proton of p-TSA and BF4- of [bmim]BF4. Here, the ionic liquid was recovered and reused several times without loss of its activity. Furthermore, cyclohexanone, cycloheptanone, 1-phenylnonan-1-one and 1-(thiophen-2-

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The α-bromination of carbonyl compounds is an important transformation in synthetic organic chemistry. These important classes of compounds are useful synthetic intermediates for various transformations employed in organic and pharmaceutical synthesis.1-4 Especially, α-bromo carbonyl compounds have become an important construction motif for the development of various biologically active compounds such as quinoxalines,5-10 24 triazolothiadiazines,11-15 thiazoles,16-22 pyrroles,23, 25 26 dihydropyrazines, imidazoles, imidazo[2,1b][1,3,4]thiadiazole,27 pyrazolines,28 thiazolo[2,3-c][1,2,4]triazoles,29 thiophene and thiazolidin-4-one,30 imidazo[2,1b]benzothiazoles,31 imidazo[1,2-a][1,3,5]triazin,32 thiazoline, thiazinone and thiazolidinone,33 cyclohexanone derivatives,34 pyrazolo[1,5-a][1,3,5]triazin and thiadiazin,35 triazolo[3,4b][1,3,4]thiadiazine,36 benzofuran,37 imidazo[1,2-a]pyridine,38 furans,39 selenazoles,40 indolizines,41 imidazo[2,1-b]benzothiazole, imidazo[1,2-a]quinazoline and 2-imino-4,5,6,7tetrahydrobenzothiazol-3-yl.42 Furthermore, they are versatile building blocks for the retro-synthesis of natural products.43,44 Particularly, α-bromo acetophenone derivatives are reported to have active participation in the inhibition of protein tyrosine phosphatase such as SHP-1 and PTP1B.45 The α-bromo derivatives of levulinic acid are the building blocks for the synthesis of several biologically active compounds.46-49

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The α-monobromination of carbonyl compounds has been a challenging task, because during the reaction a small amount of disubstituted product as a impurity is always accompanied with monosubstituted product.50, 51 Considerable efforts have been focused on the development of various useful reagents and procedures are reported in the literature for the synthesis of αhalo carbonyl compounds in 19th century.52-86 However, some of these methods suffered from one or more disadvantages such as long reaction times, low selectivity of the products, use of hazardous and toxic chemicals, low yields and tedious workup procedures. Considering these problems, new innovations are warranted that would optimize the method of production of selective α-bromination of carbonyl compounds, for milder reaction conditions, lesser process time, higher product yield and superior product purity. Although over a century has passed, no review articles have been published on synthetic protocols of αbromo carbonyl compounds. Thus, in the present review, we have discussed various methodologies for synthesis of α-bromo carbonyl compounds.

2. Various routes for the synthesis of α-bromo carbonyl compounds I. Synthesis of α-bromo carbonyl compounds using organic brominating agents A. Bromination by N-bromosuccinimide (NBS) A selective, mild and efficient synthetic methodology for αbromination of cyclic ketones that proceeds by employing NBS and silica-supported sodium bicarbonate (NaHCO3-SiO2) at room temperature in high yield have been established by Rahman et al. (Scheme 1).87 The best result was obtained when 15% of bicarbonate loading on silica was used as the catalyst in this reaction. Acetophenone, acetyl acetone and ethyl acetoacetate

yl)ethanone were efficiently α-brominated by this method. Particularly, undecan-6-one was efficiently α-brominated by this method as shown in (scheme 2b). The synthesis of α-bromocarbonyl compounds in high to excellent yield have been investigated by Pravst et al. employing NBS and catalytic amount of p-toluenesulfonic acid (p-TSA) under solvent free condition (Scheme 3a-c).89 Homogenization of the mixture was carried out by grinding or triturating of carbonyl compounds and NBS, in porcelain mortar for 5 minutes, which enhances the yield of the products. Here, the use of p-TSA is the key for high yield of the product because the yield of the product

CH3OBr. Now this can react with the enol form of the ketone to ACCEPTED MANUSCRIPT O Br Scheme 6a, R = H, OCH3

R 73-95 % Scheme 3a

(1 mmol)

O

(CH2)n

R

O

NBS (1 mmol), p-TSA (0.1 mmol) triturating or grinding then 20-80 oC, 2-20 h.

Br (CH2)n

R

75-85 % Scheme 3b

(1 mmol) O

O

Scheme 6b, R = H, OCH3 n = 1,2

(1 mmol)

O

NBS (1.1 mmol), Cu(OTf)2 (5 mol%), CHCl3 (5 mL), reflux, 6-8 h (65-89 % yield) R = H, Cl, NO2, 3,4-diOCH3 Scheme 5

R

NBS (1.2 mmol), Montmorillonite K-10 clay (10% w/w), MeOH (2 mL), 60-65 oC, 11-20 min. (45-95 % yield) R = H, CH3, C2H5, OCH3, Br, Cl, NO2 Scheme 6

Br

80 % Scheme 3c

Scheme 3a-c

is significantly enhanced in its presence. Authors have also described this protocol as a wide range synthetic method because various aryl substituted ketones, cyclic ketones and 1,3-diketones were efficiently α-brominated. 2-acetylcyclohexanone and 3-oxo3,N-diphenylpropionamide could also be efficiently αbrominated by this method without use of catalyst.

Br

R

NBS (1 mmol), p-TSA (0.1 mmol)

Ultrasound, CH3OH (2 mL), 35 oC (99 % yield) R= H Scheme 7

Adhikari et al. have shown that α-bromination of acetophenone by employing NBS and p-TSA in the presence of ultrasound in methanol at 35 oC afforded high yield of the product (scheme 7).93 In the absence of p-TSA, reaction was not completed. However, reaction can take place photochemically without the use of p-TSA. As compared to other solvents, methanol was found to be the best solvent for this reaction.

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Salama et al. have described a method in which the combination of NBS and tetrachlorosilane (SiCl4) was used in the preparation of α-bromocarbonyl compounds in acetonitrile at room temperature that afforded an excellent yield of the products with high regioselectivity (Scheme 4a-b).90 The use of inexpensive and readily available tetrachlorosilane is the advantage of this method. This procedure can also be useful in both α-chlorination and α-iodination of carbonyl compounds employing combinations of SiCl4 and NCS or NIS under the same reaction conditions respectively. This method was also used for α-bromination of various alkyl benzene derivatives. Furthermore, 6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one and 3,4-dihydronaphthalen-1(2H)-one were also efficiently αbrominated using this protocol (Scheme 4b).

1 mmol

O

SC

R

form α-bromo derivative. Various factors such as change in solvents, temperature, and mode of NBS addition were examined by the authors for their effect on the conversion of α-bromo compounds. In the absence of the Montmorillonite K-10 clay, bromination was not observed even up to 24 hours, but in its presence the product was obtained in excellent yield at 60–65oC. Furthermore, portion-wise addition shows best result compared to a one time addition of NBS in this reaction. Here, 1(naphthalen-1-yl)ethanone and 1-(naphthalen-2-yl)ethanone were efficiently α-brominated by this method.

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O

3

NBS(1.4 equiv.), SiCl4 (1.4 equiv.) CH3CN,r.t., 5-7 h

1 mmol

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R = H, Ph, CH2Br, NO2, Cl, biphenyl, 2-nephthyl, 2-thienyl, 4-ClC4H6

R

Scheme 4a

(CH2)n 1 mmol

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Scheme 4a-b O

NBS(1.4 equiv.), SiCl4 (1.4 equiv.)

O

Br

R

The reaction of various carbonyl compounds with NBS catalyzed by trimethylsilyl trifluoromethanesulfonate (TMSOTf) that afforded high yield of the α-carbonyl compounds have been investigated by Guha and co-workers (Scheme 8).94 For comparison, authors carried out this reaction in different solvents, but the best result was obtained with ACN. The reaction time and solvent play an important role for high selectivity of the product. However, the drawback of this method is the formation of the α,α’-dibrominated product along with the desired monobrominated product. Cycloheptanone, cyclohexanone, 2-methyl cyclohexanone, 3,4-dihydronaphthalen-1(2H)-one, 2-furanyl, 3thiophenyl, 2-naphthyland cyclopent-2-en-1-one were selectively α-brominated by this method in high to excellent yields.

85-92 %

O Br (CH2)n 85-91 %

CH3CN, r.t., 7 h n = 1, 2

Scheme 4b

Jagdale et al. have synthesized α-bromoketones with high product yield by employing NBS as a brominating agent with mild Lewis acid copper(II) triflate as a catalyst in chloroform at reflux temperature (Scheme 5).91 Furthermore, α-tetralone, 2acetyl-naphthalene, cyclohexanone and 2-methyl cyclohexanone were also efficiently α-brominated by this method. Simple and efficient method for regioselective α-bromination of various aryl alkyl ketones by employing N-bromosuccinimide (NBS) in the presence of Montmorillonite K-10 catalyst in methanol at 60–65 oC has been disclosed by Mohan et al. (Scheme 6).92 The mechanism shows that NBS reacts with Montmorillonite K-10 first and forms the bromocation, then it reacts with a nucleophilic solvent such as methanol to form a

Arbuj et al. have discovered a simple, mild and efficient photochemical method (under UV–vis irradiation) for synthesis of α-bromination of ketones using NBS at room temperature without the use of any catalyst, which gives the products in high yield (Scheme 9a-c).95 Different solvents were taken by the authors for a comparative study on the α-bromination of

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1,3-dione and 2-methylcyclohexanone were efficiently αcyclohexanone. Here, selectivity towards α-bromo MANUSCRIPT ACCEPTED brominated by this method. cyclohexanone was obtained efficiently in the presence of DMF, DMSO, carbon tetrachloride, ACN and diethyl ether, while the best conversion of cyclohexanone to α-bromo cyclohexanone was obtained in the presence of Et2O, ACN and CCl4. The stepwise addition of NBS to the reaction mixture generally increase the rate of conversion and selectivity of the product due to controlled formation and release of Br free radicals, that react with the substrate molecules at a constant rate. Similar conversion and selectivity was obtained, when this reaction was carried out under irradiation of sunlight. Also, cyclohexanone, cyclopentanone and 1-cyclopropylethanone were efficiently αbrominated by this method. Particularly, cyclododecanone,1-(6methoxynaphthalen-2-yl)ethanone could also be α-brominated with 99 % yield by this method as shown in (Scheme 9c).

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An efficient regioselective α-bromination of ketones with NBS and a catalytic amount of p-TSA was investigated by Pravst et al. under solvent-free condition, which afforded high yield of the products (Scheme 12).98 While in the presence of water, bromination occurred in the aromatic ring with methoxy substituted aromatic ketones. In the absence of catalyst the rate of reaction was decreased, while in the presence of p-TSA or H2SO4 in catalytic amount the rate of reaction was sharply increased. For comparison authors carried out this reaction under different solvent such as methanol or acetonitrile and more eco-friendly catalysts such as polymer supported analogue or iodine gave comparatively good results.

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An efficient synthetic protocol was developed by Lee et al. for α-bromination of carbonyl compounds by employing NBS and urea–hydrogen peroxide (UHP) in 1-butyl-3-methylimidazolium tetrafluoroborate ([bmim]BF4) at 60 oC that afforded the products in high yield (Scheme 10).96 Here, UHP is a stable, neutral, and nontoxic reagent. The [bmim]BF4 in this reaction was recovered and reused many times without loss of its activity, which makes this method green. 3,4-dihydronaphthalen-1(2H)-one was also efficiently α-brominated by this method.

Meshram et al. have established an efficient method for αbromination of 1,3-diketones, β-keto-esters and cyclic ketones by employing NBS and [bmim]PF6 (Scheme 11a-b).97 Here, [bmim]PF6 plays the dual role of solvent as well as a catalyst, also it was recycled and reused many times without loss of its activity. For comparison, the authors carried out this reaction with [bmim]BF4 in place of [bmim]PF6, however in both cases similar results were obtained. Furthermore, ethyl 2-benzyl-3oxobutanoate, ethyl 2-oxocyclohexanecarboxylate, tetrahydronaphthalene-2-carboxylate, 5,5-dimethylcyclohexane-

Das and co-workers discovered α-bromination of carbonyl compounds such as cyclic and acyclic ketones, 1,3-diketones, βketoesters, lactones, coumaranones and lactams using NBS and sulfonic acid functionalized silica at room temperature in excellent yield (Scheme 13a-c).99 For comparative study, authors attempted this reaction with other solvents such as chloroform, dichloromethane (DCM), tetrahydrofuran (THF), acetonitrile (ACN) and methanol but the yield of the products were much lower in this instance. Here, β-dicarbonyl compounds gave better results in Et2O, while CCl4 was found to be better for acyclic ketones. In case of lactams α-bromination was carried out at 80 o C in CCl4, while for lactones and coumaranones the conversion underwent smoothly at room temperature in the same solvent. An unsymmetrical acyclic ketones form two products, which resulted by monobromination at two α-positions. Here, the use of heterogeneous catalyst makes this method environmentally friendly because it can be recovered and reused three times without loss of its activity. 5-methoxy-1-benzofuran-2(3H)-one, 5,5-dimethylcyclohexane-1,3-dione, pentan-3-one, acetophenone 1-(6-methoxynaphthalen-2-yl)butane-1,3-dione, ethyl 2oxocyclohexanecarboxylate and 6,7-dihydroxy-1-benzofuran3(2H)-one were also efficiently α-brominated by this protocol.

Pravst et al. have discovered α-bromination ofACCEPTED 1,3-diketones and MANUSCRIPT O O β-keto esters with NBS under solvent free condition triturating in Scheme 15a, R = Ph, Pyridinyl a porcelain mortar at room temperature, which afforded high R R' R' = OBn, OEt 100 yield of the products (Scheme 14a-d). Particularly, 1(1 mmol) substituted-2-bromo-4,4,4-trifluoro-3,3-dihydroxybutan-1-ones were α-brominated efficiently by this method. Throughout the NBS (1.05 mmol), Amberlyst-15 (0.75 g) process there is no use of any organic solvent and catalyst which r.t., 10-30 min. O makes this method green and clean. O

R' R''

Scheme 13a, R = Ph, CH3 R' = OEt, OCH3, CH3 R'' = H, Et, CH2Ph

R''

Br

(CH2)n

R'

91- 98 % Scheme 13a

(1 mmol)

O

R

NBS (1.2 mmol), Sulfonic acid functionalized silica (60 mg.)

O Br (CH2)n

R

CCl4 or Et2O (5 mL) r.t. to 80 oC, 0.5-3 h.

91- 99 % Scheme 13b

(1 mmol) Scheme 13b, n = 1, 2, 3 R = H, Ph O R

Scheme 13c, n = 1, 2 R = CH3, Cyclohexyl

N

O R

N

Br (CH2)n

(CH2)n

Scheme 15b, n = 1, 2, 3 R = H, Ph

(1 mmol) Scheme 15a-b

R

R' Br 89-95 % Scheme 15a O

R

Br (CH2)n

86-90 % Scheme 15b

Das et al. have developed α-bromination of carbonyl compounds such as cyclic and acyclic ketones, amides and βketoesters by utilizing NBS and silica-supported sodium hydrogen sulfate (NaHSO4.SiO2) as catalyst in Et2O or CCl4 affording in good to excellent yield of the products (Scheme 16ac).102 Here, α-bromination of cyclic ketones is carried out at room temperature, while acyclic ketones gives reaction at 80 oC. Although, α,α’-dibromo compounds were formed as minor products and unsymmetrical acyclic ketones afforded two products in this reaction, this method was also useful for αbromination of lactams. 5-methyl-2-(propan-2-yl)cyclohexyl 3oxobutanoate, pentan-3-one and acetophenone could also be αbrominated by this method.

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(CH2)n Scheme 13a-c

71-96 % Scheme 13c

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(1 mmol)

R

O

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R

R

O

O

O

SC

O

5

A simple and rapid method has been developed by Meshram et al. for the α-monobromination of 1,3-keto-esters and cyclic ketones by using NBS and Amberlyst-15 at room temperature to produce the corresponding α-brominated products in high to excellent yield (Scheme 15a-b).101 This method is also useful for the α-chlorination and α-iodination of 1,3-keto-esters using Nchlorosuccinimide (NCS) or N-iodosuccinimide (NIS) under similar reaction conditions. For a comparative study authors, employed other solid acid catalysts like heteropoly acid (H3PW12O40) and H-ZSM in this reaction instead of Amberlyst15, but in this case yield of the product decreased. The Amberlyst-15 catalyst can be easily separated by simple filtration after completion of the reaction and it can be recovered and reused in the next batch with gradual decrease in activity. Furthermore, ethyl 2-oxocyclohexanecarboxylate, methyl 5chloro-1-oxo-2,3-dihydro-1H-indene-2-carboxylate and methyl 1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate were αbrominated efficiently by this method.

Tanemura and co-workers have reported an efficient αbromination of ketones by using NBS and ammonium acetate (NH4OAC) in Et2O or CCl4 at 25 to 80 °C which afforded high yield of the products (Scheme 17a-b).103

With the process that they developed, acyclic ketones acyclic ketones were efficiently α-brominated in CCl4 at 80 °C, while in the case of cyclic ketones, α-bromination can take place in Et2O

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employed a mild reagent bis(2-N-methylimidazoliumethyl)ether at 25 °C. It was observed that, in the case of acyclic ketones, α- MANUSCRIPT ACCEPTED dibromochlorate in the presence of dichloromethane (DCM) and bromination occurred at the more substituted positions methanol (MeOH) as a dual solvent system at reflux temperature predominantly. In addition, heptan-2-one, acetophenone, pentan(Scheme 20).106 This reagent was readily prepared from an ionic2-one, 3-methylbutan-2-one and pentan-3-one were also efficiently α-brominated by this method. liquid and molecular bromine in high yield and has a high stability with no loss in activity over long periods of storage. This Lee and co-workers proposed a method for synthesis of αmethod is also efficient for α-chlorination of carbonyl bromocarbonyl compounds using NBS and p-toluenesulfonic compounds and for this purpose bis(2-Nacid (p-TSA) in ACN at reflux temperature, which afforded high methylimidazoliumethyl)ether dichloroiodate was used as a 104 yield of the products (Scheme 18). For comparative study chlorinating agent. These novel halogenating reagents are soluble authors also tested this reaction using various catalyst such as pin water, acetonitrile (ACN) and dimethylsulfoxide (DMSO), but TSA, trifluoroacetic acid (TFA), sulfuric acid (H2SO4), insoluble in DCM. Here, 5,5-dimethylcyclohexane-1 as well as trifluoromethanesulfonic acid (TfOH). However the use of pcyclohexanone could also be brominated efficiently using this TSA proved to be the most efficient. Also, α-chlorination could method (Scheme 20b). The biggest advantage of this system is be carried out efficiently using NCS under same reaction that, after completion of the reaction, ionic liquid can be conditions. Ethyl acetoacetate, ethyl 3-oxo-3-phenylpropanoate recovered and reused for several times without loss of its activity. and ethyl 4-ethoxy-3-oxobutanoate could also be efficiently αbrominated by this method.

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Yang et al. have developed mild and chemoselective αbromination of 1,3-dicarbonyl compounds by employing Mg(ClO4)2 combined with NBS in ACN or ethyl acetate at room temperature (Scheme 19).105 This method is highly selective because of the fact that the bromination occurred only at αposition of carbonyl group even in the presence of olefinic bond and other sensitive functional groups.

Chemoselective α-bromination of 1,3-diketones and βketoesters has been achieved by Hosseinzadeh et al. using ethylene bis(N-methylimidazolium)ditribromide (EBMIDTB) in ACN at 0-5 oC (Scheme 21).107 The use of (EBMIDTB) which is a stable crystalline solid is very advantageous, since it is less hazardous, easy to handle, readily accessible and easily prepared by the reaction of the corresponding dibromide salt with bromine in n-hexane. The same reaction when carried out in alternative solvents such as DCM, CHCl3 and H2O resulted in poor rate of reaction. It also resulted in a poor yield of the final product. Furthermore, 1H-indene-1,3(2H)-dione, cyclohexane-1,3-dione, 5,5-dimethylcyclohexane-1,3-dione, propanedinitrile and 2methylcyclopentane-1,3-dione were efficiently α-brominated by this method.

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B. Bromination by bromo ionic liquids

Another efficient method for α-bromination of carbonyl compounds was proposed by H. Eshghi et al. in which, they

An efficient and solvent free synthetic method for αbromination of alkanones has been developed by Zhang et al. by employing novel 1-butyl-3-methylimidazolium tribromide ([Bmim]Br3) at room temperature (Scheme 22).108 An added advantage of this ionic liquid is that it can complete the transformation rapidly with high selectivity within a short period of time. It plays a dual role in the reaction as a solvent and reagent and it can be regenerated after the end of this reaction. Using this method ethyl acetoacetate and ethyl cyanoacetate could also be α-brominated in high yield.

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ACCEPTED MANUSCRIPT C. Bromination by dioxane dibromide

R = H, OH, OCH3 R' = H, CH3

(1 mmol)

Br O

R

O

O Br

Dioxane dibromide (1.1 mmol) 60–120 mesh of SiO2 (3 g.)

Dioxane dibromide (2.2 mmol)

MW, 1-13 min.

R

O

Br

R

R = H, CH3, OEt, OCH3 ,NO2, Cl, Br, F, C6H11 Scheme 24

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and also on α-position of the carbonyl group.

AC C

EP

A rapid, economic and environmentally friendly method for αbromination of alkanones have been developed by Paul et al. using dioxane–dibromide and silica gel in solvent-free conditions under microwave irradiation in high to excellent yield (Scheme 24).110 Using this method α,α’-dibromoalkanones were synthesized by employing dioxane-dibromide in twice the amount. The amount of dioxane–dibromide, silica gel and time of microwave irradiation are key elements for the selectivity in this reaction. Solid supports such as silica gel, different aluminas, and montmorillonite K-10 clay are employed in this reaction for comparative study. The best result was obtained in case of silica gel. When the same reaction was carried out in conventional heating, the yield of product is very low.

D. Bromination by pyridinium bromochromate (PBC) An efficient and selective method for α-bromination of 1,3diketones and β-keto-esters has been achieved by Sarrafi et al. using pyridinium bromochromate (PBC) in DCM at room temperature (Scheme 25).111 This reaction does not require a catalyst. Various solvents were used by the authors for a comparative study and it proved that DCM was the most efficient solvent. PBC has some unique features such as ease of handling and storage (in a sealed polyethylene bag) without decomposition for a long time. Also, 5,5-dimethylcyclohexane-1,3-dione, cyclohexane-1,3-dione and 1H-indene-1,3(2H)-dione could also be efficiently α-brominated by this method.

N

O

O R'

R''

Br

N

N Br

O

O

O

R''

Br

TBCA (0.34 mmo l)

H 2O (30 mL), r.t., 0.8-2 0 h

(2 m mol)

75-95 %

(1 mmol)

RI PT

E. Bromination by tribromoisocyanuric acid (TBCA)

O

Br

74 -9 5 %

Sc hem e 2 5

79-85 %

Scheme 23

R' Br

R = CO P h, C OC H 3, C OO E t, CN R ' = P h , C H 3 , OE t

(1 m m ol)

R O

R

CH 2C l2 ( 10 m L ), r .t., 1 5-9 0 m in.

M AN U

O

R'

O

R

r.t., 2-3 h

P B C (1 m m ol),

Br

Dioxane dibromide (1.0-1.2 mmol), O

R

R'

R'

O

O

SC

Chaudhuri et al. have reported an efficient and solvent-free regioselective α-bromination of substituted coumarins by using dioxane dibromide (C4H8O2Br2) as the solid brominating agent at room temperature, which afforded excellent yield of the products (Scheme 23).109 While using chloroform as a solvent gave a low yield of product. The use of dioxane dibromide in this reaction has some significant features such as better accessibility and stability for at least three to four months in a refrigerator. In case of amino substituted coumarine, bromination occurred only in aromatic ring instead of α-position of the carbonyl group. When, an electron withdrawing groups are present on coumarine ring, then no reaction is observed. Furthermore, when double or triple bond containing alkyl groups were present on coumarin ring, the bromination occurred on double or triple bonds of alkyl group

R

B rC r O 3

N H

R

R'

R = CH 3, (C H2 )3 R ' = Ph, (C H2 )4 , OEt R '' = H

54-10 0 %

Sc hem e 26

Mendonça et al. have synthesized various α-bromo carbonyl compounds using tribromoisocyanuric acid (TBCA) at room temperature in water as a solvent, giving high yield of products (Scheme 26).112 Furthermore, α-chloro carbonyl compounds were obtained by using trichloroisocyanuric acids (TCCA) under same reaction condition but in the presence of CHCl3 as a reaction solvent instead of water. In this reaction α,α’-di-bromo carbonyl compound was obtained, when 0.68 mol equiv. of TBCA used. A number of other solvents were studied by the authors in this reaction for comparative study. However, for this reaction water was deemed to be the best solvent in terms of conversion and selectivity. F. Bromination by bromotrimethylsilane (TMSBr)

A mild synthetic protocol was developed by Surya Prakash et al. for chemoselective α-bromination of carbonyl compounds accomplished using bromotrimethylsilane (TMSBr) with potassium nitrate (KNO3) in non-nucleophilic solvents such as dichloromethane at 60 oC affording high yield of the products (Scheme 27).113 Also α-chlorination of various acetophenone occurred under same reaction condition using chlorotrimethylsilane (TMSCl). Here mechanism shows that insitu generation of nitryl bromide (NO2Br) using TMSBr and potassium nitrate, which then reacts with various acetophenone derivatives to give α-brominated products. O

O

Br

(CH 3) 3SiBr (4 m mol), KNO3 (2 mmol) R 1 mmol

CH2 Cl2 (5 mL), r.t. R = CH 3, CF 3 , Cl

R 35-72 %

Scheme 27

G. Bromination (HMTAB)

by

hexamethylenetetramine-bromine

8

Tetrahedron

A novel synthetic method for α-bromination of alkanones MANUSCRIPT ACCEPTED O has been proposed by Paul et al. in the presence of hexamethylenetetramine-bromine complex (HMTAB) and basic Scheme 31a, R = H, CH3, C2H5, OH, Br, alumina in solvent-free conditions under microwave irradiation Cl, F, NO2, CN, NH2 R (Scheme 28).114 HMTAB is a non-hygroscopic homogenous (2 mmol) solid that has a high stability at room temperature, which makes Scheme 31b, R = H, CH3, OCH3 it ideal reagent. Cyclohexan-1-one, cycloheptan-1-one, O cyclooctan-1-one and 1-Tetralone could also be efficiently αbrominated by this method. O

Br

(2 mmol)

1 mmol

O

R R

R = H, CH 3, NO 2, Cl, Br, F, OCH3 , OEt, OH, Cyclohexyl

R'

70-83 %

Scheme 28 O

O

O

O BDMS (1.25 mmol) R'

R

CH2Cl2 (5 mL), 0 oC to r.t.

(1 mmol)

R = alkyl, Ph R' = CH3, Ph, OX X = alkyl Scheme 29

R'

Br

81-99 %

TE D

R

O

I. Bromination by 1-butyl-3-methylimidazolium tribromide (TBABr3)

EP

An efficient α-bromination of 3,4-dihydronaphthalen-1(2H)one have been achieved by Voets et al. using TBABr3 and DCM Bu N

AC C

(C H 2 ) n

(1 e q u iv . )

Br

O

O

R''

Br

R

R'

r.t. = 70-94 % Scheme 31d

Scheme 31a-d

d).117 An oxone has attractive properties including stability, water solubility, nontoxicity, cost-effectiveness and easy availability. This reaction was undertaken in various organic solvents, which produced the best result when methanol was used. Also α,α’dibromination of 1,3-diketones and β-keto esters was obtained by employing 2 equivalent of brominating reagent. For unsymmetrical ketones bromination takes place predominantly at the less substituted α-position, which is considered as an advance application of this system. In the case of tetralone, α-brominated product was obtained in methanol, while the corresponding dehydrogenated product, 1-naphthol was formed in DCM. Cycloheptanone, 1-(naphthalen-1-yl)ethanone and 1-(naphthalen2-yl)ethanone could also be α-monobrominated efficiently by this method in good to excellent yield. Furthermore, 1-(6methoxynaphthalen-2-yl)ethanone was brominated at 5th position of aromatic ring instead of α-position of acetyl group. By this method 2-hydroxynaphthalene-1,4-dione and 5-methoxy-3,4dihydronaphthalen-1(2H)-one could be brominated efficiently into 2-hydroxy-3-bromonaphthalene-1,4-dione and 8-bromo-5methoxy-3,4-dihydronaphthalen-1(2H)-one respectively.

O

O

O Br

D C M /M eO H r. t ., 0 . 5 - 1 h

n = 0, 1 R = H , 6 -O C H 3 , 7 -O C H

R

(C H 2 ) n 95 %

Br

Scheme 32a R = H, Cl, CH3, OCH3 , OH, NO2

T B A B r 3 (1 . 1 e q u iv . )

R

R'

r.t. = 62-90 % reflux = 55-85 % Scheme 31c

SC

(2 mmol)

O R

Scheme 31d, R = CH3, Ph, R'' = H, Et, CH2Ph R' = Et, OEt, OCH2Ph

R' R''

r.t. = 77-92 % reflux = 77-98 % Scheme 31b

B r3

N

O

O

R

R

M AN U

Khan and co-workers have discovered regioselective αmonobromination of β-keto esters and 1,3-diketones employing bromodimethylsulfonium bromide (BDMS) in DCM at 0 oC to room temperature (Scheme 29).115 Since no catalyst is used makes this method is environment friendly. The notable advantage of this protocol was that various β-keto esters and 1,3diketones brominated efficiently.

Br

Scheme 31c, R = CH3, CH(CH3) 2, CH2Ph, C4H9, C6H13 R' = H, CH3

(2 mmol)

H. Bromination by bromodimethylsulfonium bromide (BDMS)

O

RI PT

Grinding then MW, 300 W

R

R

MeOH (10 mL) r.t. or reflux

HMTAB (2.5 mmol), Basic alumina (2.5 g)

Br

r.t. = 24-85 % reflux = 27-97 % Scheme 31a

NH4Br (2.2 mmol), Oxone (2.2 mmol)

R

O

O

R

R

1 mmol

83-91 % O

O

3

Br

Scheme 32b

Sc h em e 3 0

and methanol as a dual solvent system at room temperature affording products in good yields (Scheme 30).116

O

O

O NH4Br (2 mmol), (NH4 )2 S2 O8 (2.5 mmol)

1 mmol O

O

90 % O

6 to 10 drops of H2O, Grinding, 15 min.

Br

II. Synthesis of α-bromo carbonyl compounds by using Inorganic brominating agents

N

N

Scheme 32c

92 %

1 mmol

A. Bromination by ammonium bromide (NH4Br)

O Scheme 32d

Macharla and co-workers have developed highly efficient and environmentally friendly method for selective αmonobromination of aryl alkyl ketones, cyclic and acyclic ketones, 1,3-diketones and β-keto esters utilizing ammonium bromide (NH4Br) and oxone (2KHSO5 . KHSO4 . K2SO4) as an oxidant in methanol at reflux or room temperature (Scheme 31a-

N

N

Br

O

O

O

1 mmol Scheme 32a-d

88 %

9

M AN U

SC

RI PT

Jakhar et al. have formulated an alternative method for MANUSCRIPT Synthesis of α-bromo acetophenones have been reported by ACCEPTED synthesis of α-bromoalkanones from alkanones using ammonium Zbancioc et al. using copper(II) bromide (CuBr2) in chloroform bromide (NH4Br) and ammonium persulfate [(NH4)2S2O8)] by an under ultrasound irradiation or conventional method afforded aqueous grinding technique (Scheme 32a-d).118 Here, the use of high yield of the products (Scheme 35).121 As compared to the organic solvent free protocol makes this method green. Also, as conventional method, ultrasound irradiation significantly compared to other brominating agents NH4Br is relatively increases the rate of reaction and yield of the products. inexpensive, easily accessible and environment friendly, which is the additional advantage of this method. Also, 3-bromoacetyl coumarin, 2-bromoacetyl benzofuran and 3-bromoacetyl cinnoline could be efficiently α-brominated by this method in high yield as shown in (Scheme 32b-d).

AC C

EP

TE D

A mild and environmentally benign synthetic protocol was developed by Khan et al. for chemoselective α-bromination of βketo esters and 1,3-diketones using a combination of vanadium pentoxide (V2O5), H2O2 and NH4Br in dichloromethane and water as a dual solvent system at 0–5 oC (Scheme 33).119 When the ratio of V2O5–H2O2–NH4Br was increased the reaction was completed in shorter time. However, high ratio of V2O5–H2O2– NH4Br can result in di-brominated products. Here, vanadium pentoxide plays a role both in formation of peroxo complexes and oxidizing bromide ion into the bromonium ions which are involved in the promotion of enol formation by chelating with the two carbonyl groups of the β-keto ester or 1,3-diketone.

B. Bromination by copper(II) bromide [Cu(Br)2] Shirinian et al. have reported an efficient method for αbromination of 2,3-diarylcyclopent-2-en-1-ones using copper(II) bromide in methanol at room temperature (Scheme 34).120 Here, 5-bromocyclopentenone was obtained by the reaction with copper(II) bromide in methanol, while reaction in n-propyl acetate yielded 4-bromocyclopentenone. Here the selectivity and conversion of the products depends on the brominating reagent, solvent, as well as on the aryl moieties. When a mixture of copper(II) bromide and copper(II) acetate was used as brominating reagent in ethyl acetate, bromination takes place only on aromatic rings.

Synthesis of α-bromo carbonyl compounds by employing CuBr2 supported alumina (Al2O3) in CCl4 at reflux temperature for 3 hours afforded high yield of the products as established by Park et al. (Scheme 36).122 In this method dibrominated product was also formed along with α-brominated product. Also, indanone was efficiently α-brominated by this method. O

O

Br C uB r2 (2 e quiv . ) E tO A c /C H C l 3 R eflu x, 5 h 95 %

(1 e q u iv.) Sc h em e 3 7

Fitzgerald et al. have reported α-bromination of 3,4dihydronaphthalen-1(2H)-one using copper (II) bromide in a mixture of ethyl acetate and chloroform in reflux condition which afforded excellent yield of the product (Scheme 37).123 C. Bromination by hydrobromic acid [HBr] Moghimi et al. have introduced a mild and solvent-free method for α-bromination of several ketones using aqueous H2O2–HBr system in presence of LiCl as a natural catalyst at room temperature (Scheme 38a-b).124 Here, the use of LiCl is the key factor that significantly increased the yield of the products and reduced the reaction time. For a comparative study authors employed this reaction under various brominating systems such as NBS/ Ammonium acetate and NBS/ Ammonium acetate-SiO2, but the best result was obtained in the case of HBr (47%) /H2O2 (30%) system in terms of conversion and isolated yield of the

10

Tetrahedron

products. Also cycloheptanone, cyclopentanone and MANUSCRIPT O ACCEPTED acetophenone could be efficiently α-brominated by this method. 70% aq. TBHP (1 mmol), 48% aq. HBr (1 mmol) The mild, solvent-free and organic waste free condition makes this method green and clean. Dioxane (2.5 mL), Reflux, 20 h.

Br

47 % of HBr (1 mL), CH3CN (2.5 mL) 10 oC, Electrochemical Process R 1 mmol

R = H, F, Cl, Br, CH3, NO2, OH, OCH3, Cyclohexyl

R 74-92 %

, 75-95 %

R = H, CH3, NO2, Cl, OH Scheme 41

Zavozin and co-workers have found that ionic liquids strongly influence on the regioselective α-bromination of methyl ketones such as levulinic acid and its esters by using Br2 as brominating agent in high to excellent yield (Scheme 42).128 This reaction was carried out a variety of organic solvents and in various ILs such as 1-ethyl-3-methylimidazolium (emim), 1-butyl-3methylimidazolium (bmim), 1-n-octyl-3-methylimidazolium (omim) and 1-butyl-1-methylpyrrolidinium (bmpl) with anions such as bromide (Br), tetrafluoroborate (BF4), hexafluorophosphate (PF6), hydrosulfate (HSO4) and bis(triflyl)imide (NTf2). The best regioselectivity was obtained in the ILs with anions such as HSO4-, PF6- and NTf2-. The major advantage of this method is that the ionic liquids are easily recovered and reused many times.

RI PT

O

O

R

R

1 mmol

Br

SC

Kumar et al. have proposed a method for the α-bromination of alkyl aryl ketones in the presence of 47% of HBr and acetonitrile at 10 oC by electrochemical procedure (Scheme 39).125 Here, a charge of 2F current is passed galvanostatically with a current density of 50 mA cm-2. This reaction was carried out with various solvents for comparative study, and the highest yield of monobrominated product was obtained in ACN, while highest yield of dibrominated product was obtained in THF. Also, 1-(6methoxynaphthalen-2-yl)ethanone was efficiently α-brominated by this method. This method is environment friendly and has a superb synthetic utility owing to its high selectivity.

O

Scheme 39

M AN U

Podgorsek and co-workers developed an efficient and highly selective α-bromination for various 1,3-diketones, β-ketoesters, cyclic ketones, aryl alkyl and dialkyl ketones by employing hydrobromic acid (HBr) and hydrogen peroxide (H2O2) in water (Scheme 40a-b).126 This method is green and clean because no catalyst and organic solvent are required. In this method dilution

EP

TE D

E. Bromination by potassium bromide (KBr)

AC C

by aqueous solutions of H2O2 and HBr also increases selectivity towards ring bromination instead of α-bromination of aryl ketones. Furthermore, way of addition of H2O2 and HBr either in one portion or portion-wise affected the selectivity and yield of the products. Water in this case is an excellent reaction media for α-bromination of carbonyl compounds and plays an important role in the activation of the ketone group for α-bromination. Chloroform was also tested as an alternative to water but the product was obtained in very low yield. Acetophenone, 4-methyl acetophenone, cyclooctanol, 2-methylcyclopentane-1,3-dione, 5,5-dimethylcyclohexane-1,3-dione and ethyl 2oxocyclopentanecarboxylate could also be efficiently αbrominated by this method. Regioselective α-bromination of carbonyl compounds employing a mixture of H2O2 or tert-butylhydroperoxide (TBHP) and hydrobromic acid (HBr) afforded high to excellent yield of the products (Scheme 41).127 In case of 1-(5-chloro-2-hydroxy-4methylphenyl)ethanone bromination occurred in the phenyl ring instead of α-position of the carbonyl group. Also, 2,3-dihydro1H-inden-1-one, 3,4-dihydronaphthalen-1(2H)-one and ethyl acetoacetate could be efficiently α-brominated by this method. D. Bromination by molecular bromine [Br2]

Nath et al. have reported another environmentally friendly protocol for the regioselective α-bromination of acetophenone by employing boric acid (H3BO3) as a recyclable catalyst, potassium bromide (KBr) as a brominating agent and hydrogen peroxide (H2O2) as the oxidant which afforded good yield of product (Scheme 43).129

O

O K B r ( 1.2 m m ol) , 30 % H 2O 2 (3 m m o l), H 3 B O 3 ( 0.05 m m o l)

Br

5 M H 2 S O 4 ( 0.7m m o l) , H 2 O (2 .5 m L ), r.t., 2 4 h 1 mmol

76 % S che m e 43

F. Bromination by magnesium(II) bromide (MgBr2) Lee et al. have investigated the rapid synthesis of αbromocarbonyl compounds by using [hydroxy(tosyloxy)iodo]benzene (HTIB) (Koser’s reagent) followed by magnesium bromide (MgBr2) under solvent-free microwave irradiation (Scheme 44a-b).130 When sodium, potassium, and zinc halides were used in place of magnesium halide, the yield of product was significantly reduced due to increased impurities. This method also describes α-chlorination and α-iodination of ketones under same reaction condition using magnesium chloride or magnesium iodide respectively. Various aryl methyl ketones, aryl methylene ketones and cyclic ketones could also be efficiently α-brominated by this method in good to excellent yield. Also, 2-acetylthiophene, cyclopentanone, cyclohexanone and indanone cloud be efficiently α-brominated by this method.

11

19. Potewar, T. M.; Ingale, S. A.; Srinivasan, K. V. Tetrahedron ACCEPTED MANUSCRIPT 2008, 64, 5019. Br

Sche m e 44a , R = H, CH 3 , B r, NO 2 R ' = H, CH 3, C2 H5 R

R H TIB (1.2 mm ol), MgBr 2 (2 mmo l)

(1 m mol)

MW O

8 2-9 5 % Sc hem e 4 4a

O

R

O R'

Sche m e 44b , R = Ph , C H3 , O Et R ' = OEt, O t Bu

O

R

R' Br

(1 m mol)

7 6-9 2 % Sch em e 44b

Sche m e 44a -b

3. Conclusion

M AN U

This review reveals that the development of various convenient methods for the selective synthesis of α-bromo carbonyl compounds in recent years. Many new brominating reagents have been explored for improving selectivity, purity and high yield of the α-bromo carbonyl compounds. Particularly, NBS is widely used for α-bromination of carbonyl compounds efficiently. It should be noted that though great progress has been achieved in this field over the last few years. This research area has still further possibilities for growth and with no doubt, we will see an increasing number of new and novel procedures for αbromination of carbonyl compounds. 4. Acknowledgement

3. 4. 5. 6. 7. 8. 9. 10.

11. 12. 13. 14. 15. 16. 17. 18.

EP

2.

Larock, R. C. In Comprehensive Organic Transformations; Wiley, 1999, pp 717. House, H. O. In Modern synthetic reactions; W. A. Benjamin, 1972, pp 459. Erian, A. W.; Sherif, S. M.; Gaber, H. M. Molecules 2003, 8, 793. Veisi, H. Curr. Org. Chem. 2011, 15, 2438. Meshram, H. M.; Santosh Kumar, G.; Ramesh, P.; Chennakesava Reddy, B. Tetrahedron Lett. 2010, 51, 2580. Haldar, P.; Dutta, B.; Guin, J.; Ray, J. K. Tetrahedron Lett. 2007, 48, 5855. Madhav, B.; Narayana Murthy, S.; Prakash Reddy, V.; Rama Rao, K.; Nageswar, Y. Tetrahedron Lett. 2009, 50, 6025. Meshram, H. M.; Ramesh, P.; Santosh Kumar, G.; Chennakesava Reddy, B. Tetrahedron Lett. 2010, 51, 4313. Ghosh, P.; Mandal, A. Tetrahedron Lett. 2012, 53, 6483. Ishida, J.; Yamamoto, H.; Kido, Y.; Kamijo, K.; Murano, K.; Miyake, H.; Ohkubo, M.; Kinoshita, T.; Warizaya, M.; Iwashita, A.; Mihara, K.; Matsuoka, N.; Hattori, K. Bioorg. Med. Chem. 2006, 14, 1378. Aytac, S. P.; Tozkoparan, B.; Kaynak, F. B.; Aktay, G.; Goktas, O.; Unuvar, S. Eur. J. Med. Chem. 2009, 44, 4528. Khanum, S. A.; Shashikanth, S.; Umesha, S.; Kavitha, R. Eur. J. Med. Chem. 2005, 40, 1156. Karabasanagouda, T.; Adhikari, A. V.; Shetty, N. S. Eur. J. Med. Chem. 2007, 42, 521. Kaplancikli, Z. A.; Turan-Zitouni, G.; Ozdemir, A.; Revial, G. Eur. J. Med. Chem. 2008, 43, 155. Karegoudar, P.; Prasad, D. J.; Ashok, M.; Mahalinga, M.; Poojary, B.; Holla, B. S. Eur. J. Med Chem. 2008, 43, 808. Potewar, T. M.; Ingale, S. A.; Srinivasan, K. V. Tetrahedron 2007, 63, 11066. Goff, D.; Fernandez, J. Tetrahedron Lett. 1999, 40, 423. Holla, B. S.; Malini, K. V.; Rao, B. S.; Sarojini, B. K.; Kumari, N. S. Eur. J. Med. Chem. 2003, 38, 313.

AC C

1.

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The authors are thankful to the Department of Chemistry, Gujarat University Ahmedabad, for providing the necessary facilities. UGC-Info net & INFLIBNET Gujarat University are acknowledged for providing the e-source facilities. Hinaben Patel, helped with the editing of this manuscript. Rajesh H. Vekariya is thankful to UGC-BSR for financial assistance. References

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ACCEPTED MANUSCRIPT Biographical sketch

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Dr. Hitesh D Patel was born in 1973 and received his Ph.D in Organic Chemistry from the South Gujarat University, Surat, Gujarat, India in 2005 under the supervision of Dr. B. D. Mistry of B .K. M. Science College, Valsad, Gujarat, India. He is working on synthesis of biologically active heterocyclic compounds, their characterization by various analytical techniques and their testing for activities. He joined as a lecturer at St. Xavier’s College, Ahmedabad Gujarat, India and had been associated with Xavier Research Foundation, Ahmedabad, India, during the period of 1998 to 2005. Since then he joined as an Associate Professor at Department of Chemistry, Gujarat University, Ahmedabad, Gujarat, India.

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Rajesh H. Vekariya was born in Ahmedabad (Gujarat) India in 1989. He obtained his B.Sc. degree in Chemistry in 2010 and his M.Sc. degree in organic chemistry in 2012 both from the Gujarat University, Ahmedabad (India). Currently, he is pursuing his Ph.D. under the guidance of Dr. Hitesh D. Patel at the Chemistry Department of the Gujarat University, Ahmedabad. His research focuses on synthesis of organic intermediates via green chemistry and their utilization in synthesis of biologically active compounds. Mainly, he is working on highly important and basic industrial process such as nitration, bromination and oxidation reactions.