Phenylmagnesium bromide with methanol

Use curved arrows to show the flow of electrons in the reaction of butyllithium with water and that of phenylmagnesium bromide with methanol J... 

One of the virtues of the Braun reagent is that both enantiomers are available, since the chiral diol is made by reaction of phenylmagnesium bromide with (/ )- or (5)-methylmandelate. An application of the (5)-enantiomer is shown in equation (123). The initial aldol reaction was carried out with the magnesium enolate in THF at -78 C to give the diastereomeric aldols in a ratio of 97 3. Transesterification with methanol gives -hydroxy ester (207) in 94% enantiomeric excess. 

A. Preparation of an ether solution of phenylmagnesium bromide (Note 1). Ether (100 mL) is added to magnesium (Mg) turnings (74.6 g, 3.07 mol) in a dry, S-L flask equipped with an overhead stirrer, reflux condenser, and addition funnel. Iodine (several crystals) is added and the mixture is stirred for several minutes (the color dissipates). Bromobenzene (9.23 mL, 13.76 g, 87.64 mmol) is added and the mixture is heated with a heat gun to initiate the reaction. A solution of bromobenzene (322.8 mL, 481 g, 3.06 mol) in ether (600 mL) is added dropwise over 2.75 hr, maintaining a gentle reflux. The dark brown mixture is stirred an additional 3 hr at ambient temperature under nitrogen and then cooled in an ice/methanol bath to 0°C. 

One notable advance in this chemistry since the publication of CHEC-II(1996) is the use of enantiomerically enriched 3,6-dihydro-l,2-thiazine 1-oxides in the rearrangement sequence. For instance, iV-Cbz-protected bicyclic 1,2-dihydrothiazine 44 undergoes ring opening upon treatment with phenylmagnesium bromide (Scheme 16). The synthesis of allylic amino alcohol 129 is completed in excellent yield upon exposure of the intermediate sulfoxide 130 to trimethyl phosphite and methanol at 80 °C <2002TA2407, 2000TL3743>. 

A solution of phenylmagnesium bromide is prepared from magnesium (0.54 g, 22 mmol) and bromobenzene (2.20 ml, 21 mmol) in diethyl ether (20 ml). The solution is stirred under reflux as a solution of chalcone (1,3-diphenylpropenone) (2.0 g, 10 mmol) in diethyl ether (15 ml) is added dropwise. The mixture is stirred under reflux for 5 min after the addition is complete, and then allowed to cool. 6M-Hydrochloric acid is added dropwise until two clear layers form. The layers are separated and the aqueous layer is extracted with ether (10 ml). The organic layers are combined, dried (MgS04), and the solvent is evaporated. The residue is recrystallized from methanol (20 ml), to give 1,2,2-triphenylpropan-l-one (1.97 g, 69%), m.p. 92-94°. 

When N-sulfinylcarbamate 224 was reacted with ( , )-2,4-hexadiene 225 the formal [4 -I- 2] cycloaddition products (the reaction mechanism is a matter of debate [141-143]) 226 and epi-226 were formed in a 15 1 ratio, respectively. Treatment of this mixture with phenylmagnesium bromide followed by refluxing the resulting mixture with trimethyl phosphite in methanol af-... 

Mandelic acid-derived chiral (a-substituted) acetate enolate addition to aldehydes leading to chiral j5-hydroxycarboxylic acids illustrates the versatility of the readily available ester 63. The addition of phenylmagnesium bromide to methyl (i )-mandelate (63) gives the (i )-diol 152, which is acetylated to (i )-2-acetoxy-l,l,2-triphenylethanol (153) [(/ )-HYTRA]. Deprotonation with LDA at — 78 °C provides an enolate that is then transmetallated with magnesium bromide and further cooled to —115 °C before reaction with an aldehyde to produce 154 as the major diastereomer with a yield of 84-95%. Heating 154 in aqueous methanol containing potassium hydroxide provides the optically active j5-hydroxyacid 156 (Scheme 36) [41- 4]. 

Scheme 1034. The synthesis of (l/ )-l-phenylpropylamine hydrochloride. Beginning with tert-butyl disnlfide, oxidation with hydrogen peroxide in the presence of VO(acac>2 and (5 )-2-(A -3,5-di-f-butylsaIicylidene)amino-3,3-dimethyl-l-butanol prodnces the chiral sulfinate (5 )-f-butyl-f-butanethiosulfinate. Then, addition of the sulfinate in THF (oxocyclopentane, THF) to a suspension of lithium amide (L1NH2) in Uquid ammonia (NHs )) generates K)-t-butanesulfinamide. The optically active sulfinamide reacts with propanal to form the corresponding sulfinimine. Reaction of the latter with phenylmagnesium bromide (CtllsMgBr) in ether yields A -(l-phenylpropyl)-f-butanesulhnamide and hydrolysis in methanolic HCI generates the corresponding (IR)-l-phenylpropylamine hydrochloride. The cartoon drawing of the presumed cyclic transition state is used to account for the stereochemical outcome. But see Hose, D. R. I Mahon, M. E Molloy, K. C. Raynham, T Wills, M. /. Chem. Soc. Perkin Trans. 7,1996, 7, 691.

The first application of the alkyltrifluoroborate salts was the conversion into alkyldihaloboranes by silyl hahdes and subsequent reaction with alkyl azides [77]. An example of a usefid synthesis was the preparation of (S)-2-phenylpyrrolidine (141) (Scheme 8.32). (S)-DICHED (3-bromopropyl)boronate (13S) was converted into the 3-azido derivative 136 at reflux temperature under phase-transfer conditions. The usual reaction with (dichloromethyl)lithium followed by phenylmagnesium bromide to form DICHED ester 137 was followed by treatment with potassium bifluoride in aqueous methanol to provide the alkyltrifluoroborate salt 138. Neither boronic esters nor alkyltrifluoroborate salts react with alkyl azides. Reaction of 138 with trimethylsi-lyl chloride yielded (S)-2-phenylpyrrolidine (141), but reaction with silicon tetrachloride proved much faster and more efficient. At first it was thought that the intermediates 139 and 140 were probably difluoroboranes in accord with literature precedent [76], but careftil reinvestigation has revealed that reaction of alkyltrifluoroborate salts with silicon tetrachloride in coordinating solvents yields alkyldichloroboranes [78]. 

Synthetic Transformations of 2-Pyridyl-substituted Vinyl-silane. 2-Pyridyl-substituted vinylsilanes can be converted into other vinylsilanes. Subjection of 2-pyridyl-substituted vinylsi-lanes to potassium fluoride/methanol leads to the formation of methoxy(vinyl)silanes by pyridyl-silyl bond cleavage (eq 4). The resultant methoxysilanes can be further allowed to react with Grig-nard reagents such as phenylmagnesium bromide to give the corresponding vinylsilanes that are commonly used for various transformations (eq 4). ... 

In a dry reaction vessel, a mixture of l,2-bis[di(4-fluorophenyl)phosphano]benzene (51.8 mg, 0.10 mmol), zinc(II) chloride (a 1.0-M tetrahydrofuran solution, 7.5 mL, 7.5 mmol), and phenylmagnesium bromide (1.17-M tetrahydrofuran solution, 12.8 mL, 15.0 mmol) in toluene (20 mL) is stirred at room temperature for 0.5 h. The resulting suspension is cooled to 0 °C before iron(III) chloride (0.10-M tetrahydrofuran solution, 0.50 mL, 0.050 mmol) and 7-oxabenzonorbomadiene (0.72 g, 5.0 mmol) are added and the reaction is stirred at 0 °C for 2 h. The reaction mixture is quenched with an ice-cooled, degassed solution of 5% acetic acid/methanol and then extracted with n-hexane and 30% diethyl ether/ -hexane, passed through a pad of Florisil, and concentrated in vacuo. The product is obtained as a colorless solid after column chromatography on silica gel (n-hexane/EtOAc, 20 1 Rf = 0.36) 1.02 g (92%). ... 

Methylcyclohexenone 281 upon oxidation with Mn(OAc)3 in benzene under reflux gave 282, which reacted with phenylmagnesium chloride and CuBr-Me2S to form two isomeric ketones 283 and 284. Further, 283 has been transformed to vinylsilane 285 followed by its hydrolysis to form the free alcohol 286, which in turn was alkylated with methoxyallyl bromide to give 287. Oxalic acid-mediated deprotection of 287 led to the formation of the ketone 288. Ozonolysis of 288 in methanol afforded the fused 1,2,5-trioxepine 289 in low yields (Scheme 66) <1997BML2357>. 

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