Methylmagnesium bromide , addition

On the basis of the methylmagnesium bromide addition reaction to nitrones, an improved synthetic method of fluorinated tert-butyl amines was accomplished (Scheme 2.146) (573). 

One instance has been recorded of methylmagnesium bromide addition to 6 ,7 -epoxy steroids (Eq. 860) which gives 7a-hydroxy-... 

A solution of methylmagnesium bromide in 150 ml of diethyl ether, prepared from 0.5 mol of methyl bromide (see Chapter II, Exp. 5) was subsequently added in 20 min with cooling at about 20°C. After the addition the mixture was warmed for 2 h under reflux (the thermometer and gas outlet were replaced with a reflux condenser), a black slurry being formed on the bottom of the flask. The mixture was cooled in a bath of dry-ice and acetone and a solution of 30 g of ammonium chlori.de in 200 ml of water was added with vigorous stirring. The organic layer and four ethereal extracts were combined, dried over potassium carbonate and subsequently concentrated in a water-pump vacuum. Careful distillation of the residue through a 40-cm... 

Addition of methylmagnesium bromide or methyllithium to 21-acetoxy-3,3 20,20-bisethylenedioxy-17a-hydroxypregn-5-ene-7,l 1-dione and subsequent acid treatment affords 7-methyl-A -cortisone. ... 

The 11-keto group is relatively difficult to attack, due to steric hindrance. However, reaction of 3j -hydroxy-5a-androstane-l 1,17-dione (37) with methylmagnesium bromide at 25° unexpectedly gives a 30% yield of 1 la,17a-dimethyl-5a-androstane-3j5,lljS,17i -triol (38) in addition to the 17-monomethyl product (39). 

The addition of methylmagnesium bromide to 3j -acetoxy-D-homo-androst-5-en-17a-one (52) proceeds with formation of the equatorial 17a/5-methyl carbinol (53), a result which is analogous to the previously described alkylations of 12-keto steroids. 

Alternatively, as described in U.S. Patent 3,341,557, 6-dehydro-17-methyltestosterone may be used as the starting material. A mixture of 0.4 g of cuprous chloride, 20 ml of 4 M methylmagnesium bromide in ether and 60 ml of redistilled tetrahydrofuran was stirred and cooled in an ice bath during the addition of a mixture of 2.0 g of 6-dehydro-l 7-methyl-testosterone, 60 ml of redistilled tetrahydrofuran and 0.2 g of cuprous chloride. The ice bath was removed and stirring was continued for four hours. Ice and water were then carefully added, the solution acidified with 3N hydrochloric acid and extracted several times with ether. The combined ether extracts were washed with a brine-sodium carbonate solution, brine and then dried over anhydrous magnesium sulfate, filtered and then poured over a 75-g column of magnesium silicate (Florisil) packed wet with hexanes (Skellysolve B). The column was eluted with 250 ml of hexanes, 0.5 liter of 2% acetone, two liters of 4% acetone and 3.5 liters of 6% acetone in hexanes. 

Phenyl-2-butanol has a methyl group, an ethyl group, and a phenyl group (—Cgl ) attached to the alcohol carbon atom. Thus, the possibilities arc addition of ethylmagnesium bromide to acetophenone, addition of methylmagnesium bromide to propiophenone, and addition of phenylmagnesimn bromide to 2-butanone. 

Starting from an ester, the only possibility is addition of methylmagnesium bromide to an ester of butanoic acid, such as methyl butanoate. 

Show the products obtained from addition of methylmagnesium bromide to the following compounds ... 

The teal value of the Wittig reaction is that it yields a pure alkene of defined structure. The C=C bond in the product is always exactly where the OO group was in the reactant, and no alkene isomers (except E,Z isomers) are formed. For example, Wittig reaction of cyclohexanone with methylenetriphenyl-phosphorane yields only the single alkene product methylenecyclohexane. By contrast, addition of methylmagnesium bromide to cyclohexanone, followed by dehydration with POCI3, yields a roughly 9 1 mixture of two alkenes. 

When y-lactone 14 is treated with methylmagnesium bromide in THF at -78 °C, a carbonyl addition reaction takes place and gives, after aqueous workup, a hemiketal that is subsequently converted to... 

Ketone 13 possesses the requisite structural features for an a-chelation-controlled carbonyl addition reaction.9-11 Treatment of 13 with 3-methyl-3-butenylmagnesium bromide leads, through the intermediacy of a five-membered chelate, to the formation of intermediate 12 together with a small amount of the C-12 epimer. The degree of stereoselectivity (ca. 50 1 in favor of the desired compound 12) exhibited in this substrate-stereocontrolled addition reaction is exceptional. It is instructive to note that sequential treatment of lactone 14 with 3-methyl-3-butenylmagnesium bromide and tert-butyldimethylsilyl chloride, followed by exposure of the resultant ketone to methylmagnesium bromide, produces the C-12 epimer of intermediate 12 with the same 50 1 stereoselectivity. 

In fact, the highest anti-Cram selectivity reported to date (96% de) was observed with the MAT-mediated addition of methylmagnesium bromide to 2-(l-cyclohexenyl)propanal3 i 36. The stereochemical outcome of this addition reaction can be explained as follows on treatment of the carbonyl compound with the large aluminum reagent, the sterically least hindered complex 9 is formed. Subsequent addition of the nucleophile from the side opposite to the bulky aluminum reagent produces the anti-Cram diastereomer preferentially. 

In contrast to the results obtained with the jS-alkoxy-a-alkyl-y-lactol 16 (vide supra), a chelation-directed, anti-Cram selective nucleophilic addition to the a-methyl-y-lactol 1 was not only observed with methyllithium and methylmagnesium bromide but also with (triisopropoxy)methyl-titanium72. In fact, the highest diastereoselectivity (> 98 % de) was observed with the titanium reagent in dichloromethane as reaction solvent. A seven-membered chelate 3 with the a-methyl substituent in a pscudoequatorial position has been postulated in order to explain the stereochemical outcome. 

On the other hand, addition of methylmagnesium bromide, as well as (triisopropoxy)methyl-titanium, to the O-benzyl-protected analog 4 proceeds with the facial stereoselection predicted by Cram s open-chain model, although the selectivities are very low72. 

As well as the disubstituted C2-symmelrie pyrrolidines E and F, the monosubstituted (f> )-2-(mcthoxymethyl)pyrrolidine G can be used as chiral auxiliary for the diastereoselecti ve addition of organomctallic reagents to a-oxo amides16. As with the phenylglyoxylic acid derivatives derived from amines E and F. methyllithium or methylmagnesium bromide in diethyl ether preferentially attack the (,S)-mms-conformer 11 (R = ( 6H5), leading to predominant formation of the (2 S)-diastercomer by Re-side attack. 

Propargylic acetates, halides, and sulfonates usually react with a double-bond shift to give allenes.34 Some direct substitution product can be formed as well. A high ratio of allenic product is usually found with CH3Cu-LiBr-MgBrI, which is prepared by addition of methylmagnesium bromide to a 1 1 LiBr-Cul mixture.35... 

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