Mannich reaction methyl ketone

Methyl vinyl ketone can be produced by the reactions of acetone and formaldehyde to form 4-hydroxy-2-butanone, followed by dehydration to the product (267,268). Methyl vinyl ketone can also be produced by the Mannich reaction of acetone, formaldehyde, and diethylamine (269). Preparation via the oxidation of saturated alcohols or ketones such as 2-butanol and methyl ethyl ketone is also known (270), and older patents report the synthesis of methyl vinyl ketone by the hydration of vinylacetylene (271,272). 

Methyl vinyl ketone 2 tends to polymerize, especially in the presence of a strong base the yield of annulation product is therefore often low. A methyl vinyl ketone precursor, e.g. 6, is often employed, from which the Michael acceptor 2 is generated in situ, upon treatment with a base. The quaternary ammonium salt 6 can be obtained by reaction of the tertiary amine 5, which in turn is prepared from acetone, formaldehyde and diethylamine in a Mannich reaction. 

Scheme 2.12 shows some representative Mannich reactions. Entries 1 and 2 show the preparation of typical Mannich bases from a ketone, formaldehyde, and a dialkylamine following the classical procedure. Alternatively, formaldehyde equivalents may be used, such as l>is-(di methyl ami no)methane in Entry 3. On treatment with trifluoroacetic acid, this aminal generates the iminium trifluoroacetate as a reactive electrophile. lV,A-(Dimethyl)methylene ammonium iodide is commercially available and is known as Eschenmoser s salt.192 This compound is sufficiently electrophilic to react directly with silyl enol ethers in neutral solution.183 The reagent can be added to a solution of an enolate or enolate precursor, which permits the reaction to be carried out under nonacidic conditions. Entries 4 and 5 illustrate the preparation of Mannich bases using Eschenmoser s salt in reactions with preformed enolates. 

The addition product of ethyl acetoacetate and methyl a-methoxyacrylate was hydrolyzed, and the resulting dicarboxylic acid was treated with dimethylamine hydrochloride and aqueous formaldehyde. The product of the Mannich reaction was decarboxylated, reesterifed, and finally treated with methyl iodide to supply quaternary salt 469 as the main product. During the above one-pot process, elimination also took place, yielding unsaturated ketone 470, which was later utilized as its hydrogen bromide adduct 471. Reaction of 3,4-dihydro- 3-car-boline either with 469 or 471 furnished the desired indolo[2,3-a]quinolizine derivative 467 as a mixture of two diastereomeric racemates. 

L-metilionine to -adenosylmethionine. In this process a positively charged sulphur is produced and facilitates the nucleophilic reaction. By the activity of diamine oxidase, the A -methyl-A -pyrrolinium cation is formed and after that the first alkaloid, hygrine. From hygrine, by way of acetyl CoA, hydrolysis and intramolecular Mannich reactions, other pyrrolidine and tropane alkaloids are synthesized cuscohygrine, hyoscyamine or tropinone, tropine and cocaine. The Mannich reaction involves the combination of an amine, an aldehyde or a ketone with a nucleophilic carbon. This reaction is typical in alkaloid synthesis, and can be written as follows ... 

Attachment of a base-bearing side chain to the carbocyclic ring of a benzodioxan gives another compound that acts as an a-adrenergic blocker. Mannich reaction of the methyl ketone in (61-2), obtainable by acetylation of the benzodioxan proper (61-1), with phenylpyrrolidine (61-3) and formaldehyde leads directly to proroxan (61-4) [71]. 

Treatment of the reduced intermediate (23-6) with butyl hthium leads to the anion from the removal of a proton on the methylene group reaction of that with methyl acetate affords the methyl ketone (24-1), which contains two of the three required side chain carbon atoms. The additional carbon atom and the basic function are incorporated by means of a Mannich condensation. Thus, reaction of (24-1) with A-methylpiperazine and formaldehyde leads to the aminoketone (24-2). The carbonyl group is then reduced with sodium borohydride and the resulting alcohol is dehydrated by reaction with phosphoms oxychloride in pyridine. In this case, too, the Z isomer is responsible for most of the activity. This is isolated from the resulting mixture of olefins to afford thiothixene (24-3) [25]. 

A second method of producing polyamines starting with the QH4—CO copolymer involves the following reaction, Eq. (20)67). The Mannich reaction has also been carried out on CO—C2Ht—C3H6 and CO—C2H4—C3H6—methyl vinyl ketone ter-polymers 47 ... 

Aube and co-workers have found that enolizable ketones react with benzyl azide in triflic acid to yield /V-(phenylamino)-methylated products [Eq. (5.354)]. The transformation is an aza-Mannich reaction interpreted with the involvement of the Mannich reagent A -phenyl iminium ion 295 formed in situ in a Schmidt rearrangement. Cyclic tertiary alcohols react with alkyl azides in triflic acid to yield N-alkylamines (296, 297)983 [Eq. (5.355)]. The Schmidt rearrangement was used to transform Merrifield resin into amino-polystyrene resin by reacting the azido derivative in excess triflic acid (CH2CI2, 0°C).984... 

Aryl methyl ketones can only give a single enol (or enolate ion) and subsequent reactions are therefore entirely regioselective. These include halogenation (cf. Section 5.11.1, p. 667), and the Mannich reaction (cf. Section 5.18.2, p. 801). 

Most reports in this category deal with asymmetric processes. For example, classic Mannich reaction of unmodified ketones, aqueous formaldehyde, and aromatic amines produces a-aminomethylation of the ketones in >99% ee, using L-proline as catalyst. 24 Methyl ketones regioselectively reacted on the methylene carbon. The method is simple, using wet solvents in the presence of air. 

Cyclic ketone with exo cyclic methylenes can be prepared in just the same way and used in situ. Morpholine is often used as a convenient secondary amine for the Mannich reaction and the resulting amino-ketones can be methylated and undergo elimination-addition reactions with stabilized enoUtes such as that derived from ethyl acetoacetate. This starting material wias prepared from natural menthone and the mixture of diastereoisomers produced is unimportant because the product is to be used in a Robinson annelation (see below). 

The 1,3 relationship between C-N and C-O suggests a Mannich reaction to add the imidazole ling (Chapter 27), and that disconnection reveals an indole with an unsymmetrical right-hand side, having an extra ketone group. Fischer disconnection will reveal a diketone as partner for phenylhy-drazine. We shall leave aside for the moment when to add the methyl group to the indole nitrogen. 

Mndzhoyan, O. L. and Gevorkyan, O. A., Derivatives of aminokelones. IX. Products of the Mannich reaction using methyl ether ketones, Ann. Khim. Zh.. 26, 220, 1973 Chem. 

Two types of substituents linked to the steroid rings arc involved in the Mannich reaction, namely, methyl ketone and alkyne residues. The former react on the methyl group, and the latter react chemo.selectivcly on the alkyne hydrogen atom when copper salts are employed as a catalyst. ... 

Reactions at the active a-methyl or a-methylene group have also been investigated. Under Mannich reaction conditions 10-methyl-phenothiazinyl 2- and 3-ketones yielded the expected products. ... 

The methylene group of methyl ethyl ketone is active in the condensation to give, upon pyrolysis, only methyl isopropenyl ketone (92%). Olefinic aldehydes, acids, esters, and nitro compounds have been prepared in a similar manner. The literature of the Mannich reaction has been reviewed. ... 

A total synthesis of adaline (550) has been performed (73BSB699). The vinyl ketone 547 was submitted to hetero Diels-Alder reaction with methyl vinyl ether to yield the dihydropyran derivative 548 in 60% yield. Acid hydrolysis of 548 produced the keto aldehyde 549. Finally, a Mannich reaction involving... 

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