Bromination acetophenone

Acetophenone bromination to 3 bromo acetophenone, 40,9 chlorination to 3 chloroacetophenone 40,9... 

Bromine (128 g., 0.80 mole) is added dropwise to the well-stirred mixture over a period of 40 minutes (Note 4). After all the bromine has been added, the molten mixture is stirred at 80-85° on a steam bath for 1 hour, or until it solidifies if that happens first (Note 5). The complex is added in portions to a well-stirred mixture of 1.3 1. of cracked ice and 100 ml. of concentrated hydrochloric acid in a 2-1. beaker (Note 6). Part of the cold aqueous layer is added to the reaction flask to decompose whatever part of the reaction mixture remains there, and the resulting mixture is added to the beaker. The dark oil that settles out is extracted from the mixture with four 150-ml. portions of ether. The extracts are combined, washed consecutively with 100 ml. of water and 100 ml. of 5% aqueous sodium bicarbonate solution, dried with anhydrous sodium sulfate, and transferred to a short-necked distillation flask. The ether is removed by distillation at atmospheric pressure, and crude 3-bromo-acetophenone is stripped from a few grams of heavy dark residue by distillation at reduced pressure. The colorless distillate is carefully fractionated in a column 20 cm. long and 1.5 cm. in diameter that is filled with Carborundum or Heli-Pak filling. 4 hc combined middle fractions of constant refractive index are taken as 3-l)romoaccto])lu iu)nc weight, 94 -100 g. (70-75%) l).p. 75 76°/0.5 mm. tif 1.57,38 1.5742 m.]). 7 8° (Notes 7 and 8). 

Our recent studies on effective bromination and oxidation using benzyltrimethylammonium tribromide (BTMA Br3), stable solid, are described. Those involve electrophilic bromination of aromatic compounds such as phenols, aromatic amines, aromatic ethers, acetanilides, arenes, and thiophene, a-bromination of arenes and acetophenones, and also bromo-addition to alkenes by the use of BTMA Br3. Furthermore, oxidation of alcohols, ethers, 1,4-benzenediols, hindered phenols, primary amines, hydrazo compounds, sulfides, and thiols, haloform reaction of methylketones, N-bromination of amides, Hofmann degradation of amides, and preparation of acylureas and carbamates by the use of BTMA Br3 are also presented. 

Not every excess acidity mechanistic analysis has been an outstanding success. For instance, several enolization studies have used this technique. The enolization of acetophenone was one of the reactions originally studied by Zucker and Hammett 146 their sulfuric acid rate constant data, obtained by iodine scavenging (the reaction is zero-order in halogen), was used in an excess acidity analysis,242 together with additional results obtained for some substituted acetophenones (using bromine scavenging).243... 

The very small p- and m-values observed for the fast bromination of a-methoxystyrenes deserve comment since they are the smallest found for this electrophilic addition. The rates, almost but not quite diffusion-controlled, are amongst the highest. The sensitivity to polar effects of ring substituents is very attenuated but still significant that to resonance is nil. These unusually low p-values for a reaction leading to a benzylic carbocation are accompanied by a very small sensitivity to the solvent. All these data support a very early transition state for this olefin series. Accordingly, for the still more reactive acetophenone enols, the bromination of which is diffusion-controlled, the usual sensitivity to substituents is annulled. 

Under carefully controlled conditions the selective mono bromination of an electronically diverse range of acetophenone derivatives can be realized using the polymer-supported pyridinium perbromide reagent. The resultant a-bromoketone... 

Bromination of acetophenone ketazine followed by reaction with benzylamine gives (491) (710PP289). Halogenation of the product leads to ring contraction probably via an intermediate of type (482) <75H(7)547). 

Acetophenone Al(III) Bromination m, coordination prevents side chain halogenation (57)... 

In the original patent published by Merck in 1995, rofecoxib (2) was synthesized in three steps from the known 4-(methylthio)acetophenone (10), prepared from the Friedel-Crafts acylation of thioanisole. As depicted in Scheme 2, oxidation of sulfide 10 using an excess of magnesium monoperoxyphthalate hexahydrate (MMPP, an inexpensive, safe and commercially available surrogate for w-CPBA) gave rise to sulfone 11, which was subsequently brominated with bromine and AICI3 to afford 2-bromo-l-(4-(methylsulfonyl)phenyl)ethanone (12). After recrystallization from 1 1 EtOAc/hexane, the pure phenylacyl bromide 12 was then cyclo-condensed with phenylacetic acid under the influence of l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) to deliver rofecoxib (2) in... 

One research group has exploited the concept of polymer site-isolation in a multistep/one-chamber solution-phase synthesis in which all the reagents, catalysts, and downstream reactants required for a multistep synthesis were combined in one reaction chamber. For instance, a one-chamber/three-step synthesis of substituted acetophenones has been reported (Scheme 10).84 An a-phenethyl alcohol was introduced into a reaction chamber containing the polymer-supported reagents and reactants necessary to accomplish oxidation by polymer-supported pyridinium dichromate 60 bromination by the A-26 perbromide resin 61 and nucleophilic displacement by the A-26 phenoxide resin 62. Filtration afforded the... 

The synthesis of rofecoxib can be achieved by several different routes (Drugs Fut., 1998). A highly efficient synthesis for rofecoxib was recently described (Therien et al., 2001). As illustrated in Scheme 79, acetophenon (i) is prepared according to the literature, by Friedel-Crafts acylation with thioanisole. Oxidation with MMPP (magnesium monoperoxyphthalate hexahydrate) affords the sulfone (ii), which is reacted with bromine in chloroform in the presence of a trace amount of AICI3, to give (iii). Bromoketone (iii) is than coupled and cyclized in a second step, one-pot procedure with phenylacetic acid. Firstly, the mixture of bromoacetophenone (iii) and phenylacetic acid in acetonitrile is treated with... 

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