Magnesium methyl- bromide

Medroxyprogesterone acetate (74) is stmcturaHy related to and has been prepared from hydroxyprogesterone (39) (Fig. 10). Formation of the bis-ketal accomplishes the protection of the ketones and the required migration of the double bond. Epoxidation with peracetic acid produces a mixture of epoxides (75), with a predominating. Treatment of the a-epoxide with methyl magnesium bromide results in diaxial opening of the epoxide. Deprotection of the ketones provides (76), which is dehydrated to (77) by treatment with dilute sodium hydroxide in pyridine. Upon treatment with gaseous hydrochloric... 

A slow stream of purified and dried acetylene is passed for 3 hr through a solution containing 25 ml (75 mmoles) of a 3 TV solution of methyl magnesium bromide and 100 ml of anhydrous tetrahydrofuran. A solution consisting of 5 g (17 mmoles) of 3)5-hydroxyandrost-5-en-17-one and 50 ml of anhydrous tetrahydrofuran is then added and the mixture is boiled at reflux for 15 min, during which time a heavy precipitate forms. The reaction mixture is cooled and poured into 1 liter of water containing 20 ml of concentrated sulfuric acid. The crude product is obtained as a precipitate, which is filtered, washed with water and dried to yield 5.2 g of 17a-ethynylandrost-5-ene-3, 17 -diol mp 228-232°. One crystallization from chloroform-hexane yields 4.5 g (83%) mp 238-240° [[Pg.73]

J/3,5a,6(3- Trihydroxy-6oi, 17a-Dimethyl-17 -Carbometboxyandrostane (IV) 3(3-Acetoxy-5a-hydroxy-17a-methyl-17/3-carbomethoxyandrostan-6-one (III, 1.004 g) is dissolved in dry benzene (25 ml) and methyl magnesium bromide solution in ether (3M, 10 ml) is added. 

Alternatively, 25.0 g of either 3j3,5a-dihydroxy-17a-methyl-17j3-carbomethoxyandrostan-6-one (Ilia) or 25.0 g of its 3)3-acetate (Hlb), are dissolved in dry tetrahydrofuran (1,250 ml, freshly distilled over lithium aluminum hydride) and dry benzene (2,000 ml) is added. Methyl magnesium bromide in ether solution (3 M, 750 ml) is added to the stirred solution and the resulting mixture is stirred at room temperature for 16 hours. An additional quantity of methyl magnesium bromide solution in ether (2M, 375 ml) is added, and 1,250 ml of the solvent mixture are distilled off. The resulting mixture is refluxed for 5 hours and worked up as described above, yielding compound (V) as a colorless oil. 

Hydroxyprogesterone Methyl magnesium bromide Sulfuric acid... 

Preparation of 5a,17a-Dihydroxy-6 -Methylallopregnane-3,20-dione 3,20-Bis-fEthylene Ketal) To a solution of 91.6 g of 5a,6a-oxido-17a-hydroxyallopregnane-3,20-dione 3,20-bis-(ethylene ketal) in 3,500 ml of freshly distilled tetrahydrofuran was added 1,170 ml of commercial 3 molar methyl magnesium bromide in ether solution. The reaction mixture was boiled to remove 1,800 ml of solvent by distillation and thereafter 1,000 ml of freshly distilled tetrahydrofuran was added. 

In the present instance, the product is a tertiary alcohol with two methyl groups and one props7 group. Starting from a ketone, the possibilities are addition of methyl-magnesium bromide to 2-pentanone and addition of propylmagnesium bromide to acetone. 

A synthetically useful diastereoselectivity (90% dc) was observed with the addition of methyl-magnesium bromide to a-epoxy aldehyde 25 in the presence of titanium(IV) chloride60. After treatment of the crude product with sodium hydride, the yy -epoxy alcohol 26 was obtained in 40% yield. The yyn-product corresponds to a chelation-controlled attack of 25 by the nucleophile. Isolation of compound 28, however, reveals that the addition reaction proceeds via a regioselective ring-opening of the epoxide, which affords the titanium-complexed chloro-hydrin 27. Chelation-controlled attack of 27 by the nucleophile leads to the -syn-diastereomer 28, which is converted to the epoxy alcohol 26 by treatment with sodium hydride. 

Similar results are found with the threose derivatives 11 and 13. Both aldehydes can be readily synthesized in either enantiomeric form from l- and D-tartaric acid. The open-chain aldehyde 11 with Grignard reagents affords predominantly the all-.v> n(xj/o)-diastereomer 12. The steric demand of the nucleophile apparently does not affect the diastereoselectivity, and the extremely high selectivity observed with [(l,3-dioxolan-2-yl)methyl]magnesium bromide is attributed to the presence of the dioxolane moiety, which is thought to stabilize the a-chelated transition state. 

Several enamines also participate in these cycloaddition reactions. For example, the addition of methyl lithium to benzaldehyde 5 and the sequential introduction of the vinylogous amide and magnesium bromide results in the cycloaddition elimination product chromene 63 (method G, Fig. 4.33).27 The introduction of methyl magnesium bromide to a solution of the benzaldehyde 5 and two equivalents of the morpholine enamine produces the cycloadduct 64 in 70% yield with better than 50 1 diastereoselectivity (method F). Less reactive enamides, such as that used by Ohwada in Fig. 4.4, however, fail to participate in these conditions. 

Imines, on the contrary, proved particularly reactive under these conditions (Fig. 4.34). For example, Jones and Selenski report that the introduction of one equivalent of methyl magnesium bromide to benzaldehyde 5 stirring at —78 °C in the presence of one and half equivalents of the imine that is derived from the condensation of benzyl amine and benzaldehyde proceeds immediately to the aminal 65 in 94% yield.27 Only the trans isomer is observed from this low-temperature cycloaddition. While the relative stereochemistry appears to be result of an exo transition state, we suspect that initial cis adduct from and endo addition may epimerize under these conditions. 

Grignard reaction, addition of methyl-magnesium bromide to thiophos-phoryl chloride, 45,102 Grignard reagents, synthesis and utility of unsolvated, 47, 116 titration of, 48, 48... 

If the action of methyl magnesium bromide on acetaldehyde be taken as example, the following equation holds ... 

Tryptamine from Indole. CA, 54, 13018 (1960). To 15.5 g of most any indole in 40 ml of dry ether, under a nitrogen atmosphere, add 50 ml of methyl magnesium bromide in 2% moles of dry ether and reflux for 15 min. Cool on ice bath and add 68 ml of ethyleneimine in 30 ml of dry xylene. Stir for IVi hours at 65-70° F (room temp) adding dry xylene, as needed, to maintain starting volume. Reflux for 1 hour and cool to room temp. Add 75 ml of water dropwise and add HCl acid slowly to give a pH of 1. Filter off the precipitate, wash with ether (cold) and then dissolve in 150 ml of hot water. Cool to 1(F C for 15 min and decolorize in the usual... 

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