4- Bromoanisole

Bradfield et al.21g first studied the kinetics of molecular bromination using aromatic ethers in 50% aqueous acetic acid at 18 °C. They showed that the kinetics are complicated by the hydrogen bromide produced in the reaction which reacts with free bromine to give the tribromide in BrJ, a very unreactive electrophile. To avoid this complication, reactions were carried out in the presence of 5-10 molar excess of hydrogen bromide, and under these conditions second-order rate coefficients (believed to be I02k2 by comparison with later data) were obtained as follows after making allowance for the equilibrium Br2 + Br7 Bn, for which K = 50 at 18 °C 4-chloroanisole (1.12), 4-bromoanisole (1.20), 4-... 

Kumada-Corriu Reactions Investigated in Micro Reactors Organic synthesis 47 [OS 47] Reaction between 4-bromoanisole and phenylmagnesium bromide [2]... 

General procedure for Suzuki coupling. 4-Bromoanisole (125 pL, 1 mmol), phenylboronic acid (186 mg, 1.5 mmol), K2CO3 (0.55 g, 4 mmol) and the BaCei.j,Pdj,03.j, catalyst were mixed in a 20 ruL scintillation vial. A preheated 2-propanol/water solution (IPA/H2O, 1 1 v/v, 12 ruL, 80°C) was added, the vial was immediately placed on a hot plate stirrer and its temperature was maintained at (80 1) °C. The reaction mixture was stirred at 1000 rpm for 3 min, then cooled to room temperature. The 4-methoxybiphenyl product was extracted with diethyl ether (3 x 15 ruL). The organic fractions were washed with deionized water and dried with MgS04. After filtration, volatiles were removed under reduced pressure to yield the isolated product. 

Suzuki coupling reactions with aryl halides. Two as-prepared BaCei cPd c03. ( materials (x = 0.05 and 0.10) were successfully utihzed in several Suzuki coupling reactions. Both aryl iodides and aryl bromides react smoothly with 4-phenylboronic acid, eq 1, to yield the corresponding biatyls in high yields (> 95%). For both 4-bromoanisole and 4-iodoanisole, the biatyl yields reached nearly 100% in 3 min with BaCeo 95Pdoo503 5 as the catalyst, corresponding to an effective TON of ca. 2,000 and an effective TOF of nearly 50,000 h. Resnlts are smmnarized in Table 27.1. 

Figure 27.1. Kinetic profiles for the coupling of 4-bromoanisole with phenylboronic acid to yield 4-bromonaphthalene, (a) using as-prepared BaCeo95Pdoo502 95 (open circles) or BaCeo9oPdoio02 9o (filled circles) as the catalyst and (b) using BaCeo95Pdoos02 95 as-prepared (small open circles) reduced (filled circles) and reoxidized (open squares) as the catalyst. Reagents and conditions 3.0 mg catalyst (0.05 mol % Pd, X = 0.05 0.10 mol % Pd, x = 0.10), 1.0 mmol 4-bromoanisole, 1.5 mmol PhB(OH)2, 4.0 mmol K2CO3, 12 mL IPA-H2O (1 1, v/v), 80°C. Lines are drawn only to guide the eye.

Analysis of soluble Pd. To assess the amount of ligand-free soluble Pd present in the reaction mixture, the solution containing 4-bromoanisole/4-... 

Maitlis filtration test. To investigate whether the Pd-doped perovskite is the actual catalyst, or a reservoir of soluble Pd, a Maitlis filtration test (10) was performed. The reaction of 4-bromoanisole with 4-phenylboronic acid, catalyzed by BaCeo 95Pdo os02 95, was intemipted at 20 s and 1 min, corresponding to conversions of 16 and 45%, respectively, by filtering the hot reaction mixture to remove the solid perovskite. The filtrates were allowed to cool to room temperature without stirring. After 3 h, the biatyl yields in both samples were estimated to be 100% by H NMR. 

Solvent effect. Several different solvent systems were investigated for the coupling of 4-bromoanisole with 4-phenylboronic acid catalyzed by BaCeo 95Pdoo50295. The resnlts are summarized in Table 27.2. A phase-transfer catalyst (Aliquat 336) was added in the experiment involving toluene/H20. However, only the IPA/H2O solvent system was effective, resulting in a biaiyl yield of 100% all other solvents gave rather low yields. 

Catalyst recycling. The solid Pd-doped perovskite catalysts are easily filtered from the reaction mixtnre for reuse. The activity of the recycled BaCco 95Pdo.o502 95 catalyst was investigated in the coupling of 4-bromoanisole with 4-phenylboronic acid. The results in Table 27.3 show that high activity was retained even after seven cycles of catalyst use. 

Bromoanisole Anisole, p-bromo- (8) Benzene, 1-bromo-4-methoxy- (9) (104-92-7) Methyl iodide Methane, iodo- (8,9) (74-88-4)... 

Bromoanisole is purchased from the Aldrich Chemical Company, Inc., and used as received. 

Bromoanisole. The competition between ortho and ipso attack (83) is also pertinent to the simultaneous nitration and transbromination of 4-bromoani-sole (Perrin and Skimer, 1971). Charge-transfer nitration leads to mixture of 2-nitro-4-bromoanisole and 2,4-dibromoanisole (and 4-nitroanisole), the relative amounts of which are equivalent to those obtained in the electrophilic nitration of 4-bromoanisole. 

It is noteworthy that, although 4-bromoanisole produces anisic acid in high yield, 4-hydroxybenzoic acid is isolated in only 17% yield from the corresponding reaction of 4-bromophenol. Also, 4-bromoacetophenone, which may react by a normal SN reaction, is readily converted into 4-acetylbenzoic acid, whereas 4-bromonitro-benzene produces 4-nitrobenzoic acid in only 17% yield, together with nitrobenzene (17%). 

Two steps are critical the cross-coupling itself, and making the Grignard of 4-bromoanisole. Zambon has spent 10 man-year on the optimisation of the cross-coupling reaction In the following we summarise the results. 

The Grignard is made from 4-bromoanisole, Mg (3 % excess), I2 catalyst, in tetrahydrofuran (3 M), at 70 °C. The major problem is the formation of the homo coupled product during the Grignard synthesis. Up to 6% of 4,4 -dimethoxybiphenyl may be formed. The amount depends on the type of... 

Some aryl iodides are known to generate the diaryImercury at a mercury cathode. In the case of 4-iodoaniso e, reduction at more negative potentials in dimeth-ylfonnamide leads to the formation of less di(4-methoxyphenyl)mercury. At glassy carbon, anisole is the only reduction product. 4-Bromoanisole gives only anisole at either mercury or carbon [143]. Mercur> has been used as cathode material for many preparative experiments with aryl halides but glassy carbon and also stainless steel are very satisfactory alternatives. 

One year later, we extended the aforementioned palladium(II)-catalyzed approach to a series of 6-oxygenated carbazole alkaloids, glycozoline (86), glycozolinine (glycozolinol) (91), glycomaurrol (92), micromeline (100), and methyl 6-methoxycarbazole-3-carboxylate (104) (547). The palladium(0)-catalyzed coupling of 4-bromoanisole (670) and p-toluidine (1028), followed by palladium(II)-catalyzed oxidative cyclization, afforded directly glycozoline (86). 

To a suspension of magnesium (1.64 g, 67.5 mmol in 30 ml of THF, there is added a solution of 1.4 g (4.5 mmol) of 2-(l-adamantyl)-4-bromoanisole and 0.39 ml of dibromoethane in 10 ml of THF. The mixture is stirred until the reaction is initiated and then there is slowly added a solution of (40.8 mmol) of 2-(l-adamantyl)-4-bromoanisole in 90 ml of THF. The mixture is refluxed for 2 hours, and then cooled to 20°C. After that 6.2 g (45 mmol) of anhydrous ZnCI2 are added. The mixture is stirred for 1 hour at 20°C at which point 7.95 g (30 mmol) of methyl 6-bromo-2-naphthoate are added followed by addition of 300 g of NiCI2/l,2-(diphenylphosphino)ethane-complex as the catalyst. The mixture is stirred again for 2 hours at 20°C, poured into water, extracted with CH2CI2 dried and evaporated. The product is isolated by column... 

Examples of the one-pot method are given in Table 1 [13]. The coupling works not only with aryl bromides that are electronically non-activated with regard to oxidative addition, for example bromobenzene and 3-bromotoluene, but also for the deactivated substrate 4-bromoanisole. When 3-bromotoluene is used as the substrate, in principle, two isomers can form. This indeed occurs and both the 2- and... 

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