Methylmagnesium iodide

Cyanopyridazines add ammonia, primary and secondary amines and hydroxylamine to give amidines or amidoximes. Substituted amides, thioamides and carboximidates can be also prepared. With hydrazine, 3-pyridazinylcarbohydrazide imide is formed and addition of methylmagnesium iodide with subsequent hydrolysis of the imine affords the corresponding pyridazinyl methyl ketone. 

The addition of methylmagnesium iodide to 2-phenylpropanal is stereoselective in producing twice as much syn-3-phenyl-2-butanol as the anti isomer (entry 5). The stereoselective formation of a particular configuration at a new stereogenic center in a reaction of a chiral reactant is called asymmetric induction. This particular case is one in which the stereochemistry can be predicted on the basis of an empirical correlation called Cram s rule. The structural and mechanistic basis of Cramls rule will be discussed in Chapter 3. 

The stereochemistry of the 1,4-addition to A -octal-l-one and 1,1-di-methyl-A -octal-2-one has been investigated by House and Marshall, respectively. In summary, steric and stereoelectronic factors play a part in the mechanism of conjugate addition of Grignard compounds. With methylmagnesium iodide, the introduction of an axial methyl group into steroidal 5a-A -3-ketones (3) and 5 -A -3-ketones (6) is favored by stereo-electronic factors in the transition state. 

In the presence of an axial la-hydroxyl group methylmagnesium iodide reacts with 3-keto-5a-steroids from the j5-side exclusively to yield the 3f -methyl isomer. ... 

The action of methylmagnesium iodide on 3-pyrrolidino-A -4-ketones (19) gives the 4a-methyl-4l -hydroxy steroids (20). ... 

Treatment of the 6,11-diketo dioxolane (29) with methylmagnesium iodide in benzene-ether solution at room temperature gives the carbinol (30) in 70% yield. The 11-keto group is not attacked under these conditions. ... 

The 7a-methyl-7 -hydroxy compound (32) was obtained from reaction of (31) with 3 moles of methylmagnesium iodide for 16 hours at room temperature followed by 2 hours reflux. 

The action of Grignard reagents on 20,20-ethylenedioxy-12-ketones and 20a-hydroxy-12-ketones also shows that the attack of methylmagnesium iodide on 12-ketones proceeds mainly from the i -side of the steroid mole-cule. ... 

The orally effective androgen 17a-methyltestosterone (51) is prepared from 3jS-hydroxyandrost-5-en-17-one (49) by treatment with methylmagnesium iodide to give the 17a-methyl compound (50) which is then oxidized to yield... 

Acetoxy-21-nor-5a-cholestan-20-one (73a) as well as the free alcohol (73b) react with methylmagnesium iodide to give a mixture of epimeric diols (74). After treatment with acetic anhydride and subsequent hydrogenation over reduced platinum oxide this mixture alfords 3j5-acetoxy-5oc-cholestane (75) which is identical with the natural product. This synthesis has been used to prepare the 21- C compound (75) in a total yield of 18... 

Cholestane-3,25-diols (77) have been obtained in greater than 80% yield by treatment of 3a-acetoxy-5a-, 3)5-acetoxy-A -, 3j -hydroxy-A - ° and 3 -acetoxy-5a-27-nor-cholestan-25-one ° with methylmagnesium iodide. 

Schaub ° introduced methyl groups at both the 16a- and 17a-positions by 1,4-addition of methylmagnesium iodide to the A -20-ketone (8) followed by methylation of the intermediate 16a-methyl-17-enolate anion (9) with methyl iodide. After hydrolysis of the tetrahydropyranyl ether group a 40% yield of the 16,17-dimethyl derivative (10) was obtained. With the corresponding 3j -acetoxy derivative, the yield of (10) is only 20%. 

Oxime 26 was prepared from 5,ll-dihydro-dibenzo[a,d]cyclohepten-10-one. The Hoch-Campbell reaction of 26 with 3-dimethylaminopropylmagnesium bromide produced aziridine 27 in 46% yield after acidic workup. Extension of the Hoch-Campbell reaction to steroids has also been reported. Thus, treatment of 3(3-hydroxy-5-pregnen-20-one oxime (28) with methylmagnesium iodide furnished a mixture of diastereomers, 20ot/20P,21-imino-20-methyl-5-pregnen-3P-ol (29) in a 50% combined yield and a 3 1 ratio. On the other hand, homo-adamantan-4-one oxime (30) was transformed to homo-adamantano[4,5-b]-2 -ethylaziridine (31) in 76% yield upon the action of... 

Acetylisothiazoles have been prepared by ketonic hydrolysis of the jS-ketoesters derived from the Claisen condensation on 5-ethoxycar-bonylisothiazoles. 5-Acetyl-3-methylisothiazole is also obtained from the reaction of 5-cyano-3-methylisothiazole with methylmagnesium iodide. ... 

By a procedure analogous to that described in the preceding experiment, octalone-2 (12 g, 0.08 mole, Chapter 9, Section III) in ether is added to methylmagnesium iodide in the presence of cuprous bromide (0.2 g). After decomposition with ice-acetic acid, extraction with ether, and washing of the ether extract, the ethereal solution is shaken with an equal volume (50-60 ml) of saturated aqueous sodium bisulfite for 3 hours. The mixture is filtered and the filtrate is reserved. The crystals are washed with ether. The filtrate is separated and the aqueous phase is combined with the filtered solid. The combination is acidified (dilute hydrochloric acid) and heated under reflux for 30 minutes. The product thus liberated is extracted into ether, the ether is washed with bicarbonate, then with saturated aqueous sodium chloride solution, and then dried and evaporated. The residual oil is the desired product, bp 250-254°. 

To a solution of 2 mols of methylmagnesium iodide in 1.5 liters of ether are added with vigorous stirring 107 g (0.5 mol) of ethyl p-chloroatrolactate. The reaction mixture is stirred for about sixteen hours, and is then decomposed by the addition of about 320 ml of saturated aqueous ammonium chloride solution. After standing, the ether layer is decanted from the mixture and the aqueous phase and the precipitated salts are washed with several 500 ml portions of ether. The combined ether solution and washings are washed with successive 500 ml portions of 5% ammonium chloride solution and water, are dried over anhydrous magnesium sulfate, and are evaporated to dryness in vacuo. The crystalline residue consisting of 2-p-chlorophenyl-3-methyl-2,3-butanediol, is recrystallized from a mixture of benzene and petroleum ether. 

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