Mannich—Grignard reaction

Synthesis (Pohland, 1953 1955 1963 janssen and Karel (Janssen)1956 Sullivan et al., 1963) In the Grignard reaction of 3-dimethylamino-2-methyl-1-phenyl-propan-lone with benzylmagnesium chloride 4-dimethylamino-3-methyl-1,2-diphenyl-butan-2-ol is formed. The preferred product is the a-diastereomer(75 % a-form, 15 % p-form). The a-form crystallizes and the diastereomeric p-form remains in solution, because of its better solubility. Racemic resolution to obtain the analgetically (+) enantiomer can be achieved on the pure a-Grignard product via fractional crystallization of the salts with D-camphorsulfonic acid. Alternatively the resolution can be achieved by treating the racemic mannich product 3-dimethylamino-2-methyl-1-phenyl-propan-1-one with (-)-dibenzoyltartaric acid in acetone as solvent. 

Reaction of the Mannich product (112) from acetophenone itself with the Grignard reagent from p-chlorobcnzyl chloride gives the carbinol, 113. Dehydration in this case gives the antihistamine pyrrobutamine (114). It is not immediately clear why dehydration does not occur in the other sense so as to afford the energetically more favored stilbene. 

Answer Ester disconnection gives a tertiary alcohol (4S), Of the three possible Grignard disconnections, (a) is most helpful as it requires the Mannich product (49) of an aryl ketone (50) available by the Friedel-Crafts reaction. 

Example The lactone (8>, needed for a natural product synthesis, might be made from (6) via epoxide (7) and so a synthesis for (6) was required. Wittlg disconnection reveals a 1,5-dicarbonyl compound (9), best made by Michael addition of a substituted malonate (11) to enone (10). The enone was made by the simple but reliable Grignard route rather than risking a Mannich reaction of unknown regloselectivity. 

The Mannich reaction of secondary amines R NH (dibenzylamine, piperidine, morpholine, etc.), aldehydes R2CHO (R2 = alkyl, Ph or 2-furyl) and thiols R3SH (R3 = alkyl, Ph or benzyl) results in a-amino sulphides, which react with Grignard compounds to give tertiary amines in good yields (equation 47)136. 

Dibenzocycloheptenone (24-6) also serves as a starting material for the preparation of one of the few medicinal products that contains an acetylenic linkage. Reaction of (24-6) with the Grignard reagent from propargyl bromide leads to the alcohol (27-1). The free proton acetylene is sufficiently acidic for that center to take part in a Mannich reaction. Thus, reaction of (27-1) with formaldehyde and dimethylamine gives the adduct (27-2). Dehydration by means of thionyl chloride completes the synthesis of intriptyline (27-3) [28]. 

Preparation of Monomers. Methyl vinyl ketone (MVK) was obtained from Pfizer Chemical Division, New York, and distilled to remove the inhibitor. Methyl isopropenyl ketone (MIPK) was prepared by the aldol condensation of methyl ethyl ketone and formaldehyde, according to the method of Landau and Irany 0. The major impurity in this monomer is ethyl vinyl ketone (5. The monomer was redistilled before use. 3 Ethyl 3 buten 2 one (EB) was prepared by the aldol condensation of methyl propyl ketone and formaldehyde. Ethyl vinyl ketone (EVK) was prepared by a Grignard synthesis of the alcohol, followed by oxidation to the ketone. t-Butyl vinyl ketone (tBVK) was prepared from pinacolone and formaldehyde by the method of Cologne (9). Phenyl vinyl ketone (PVK) was prepared fay the dehydrochlorlnatlon of 0 cbloro propiophenone (Eastman Kodak). Phenyl isopropenyl ketone (PPK) was prepared by the Mannich reaction using propiophenone, formaldehyde and dimethylamine HCl. 

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