Mannich reaction acetylene

The high reactivity of monosubstituted acetylenes in many reactions (acetylenic condensation, Favorsky reaction, Mannich reaction, oxidative coupling, etc.) is determined by their acidity (7IMI1 83MI1). The literature data on the thermodynamic CH acidity of these compounds are rather scarce. 

A rather more complex amino alcohol side chain is accessible by a variation of the Mannich reaction. Taking advantage of the acidic proton in acetylenes, propargyl acetate (62) is condensed with formaldehyde and dimethylamine to give the acetylated amino... 

Inclusion of an acetylenic linkage as part of the side chain is apparently consistent with antidepressant activity. Reaction of propargyl magnesium bromide with dibenzocycloheptadieneone leads to carbinol 82. A Mannich reaction with formaldehyde and dimethylamine leads to 83 which, upon dehydration... 

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]. 

M. C. Sharma, A. K. Garcia, J. M. Gonzalez, A. Landa, C. Linden, A. a-Oxymethyl ketone enolates for the asymmetric Mannich reaction. From acetylene and N-alkoxycarbonylimines to /J-amino acids. Angew. Chem. Int. Ed. 2000, 39, 1063-1065. 

In the reaction of 3,5-dimethyl-2,6-diphenylpiperid-4-one oxime (10) with acetylene and RbOH-DMSO, migration of the 3a-Me group to the anionic nitrogen atom occurred, leading to 5,7-dimethyl-4,6-diphenyl-4,5,6,7-tetrahydropyrrolo[3,2-c]pyridine (11) (04CHE326). The formation of the N-anion caused aromatization of the tetrahydropyridine ring. Tetrahydropyrrolo[l,2-c]pyrimidine 12 resulted from the decomposition of the intermediate 3H-pyrrole in a retro-Mannich reaction (Scheme 3). 

In addition to the abovementioned macromolecular alkyl ketones, it is worth recalling the Mannich reaction on polymers functionalized with phenol, amide, or acetylene moieties - these last give products 434. 

Fowler, J. S 2-Methyl-3-butyn-2-ol as an acetylene precursor in the Mannich reaction. A new synthesis of suicide inactivators of monoamine oxidase, J. Org. Chem., 42,26.37, 1977. 

For the Mannich reaction, a screw-capped fritted glass reaction vessel was charged with the resin (0.3 g, 0.75 mmol g ), Cu Cl (45 mg, 0.45 mmol), and benzaldehyde (0.16 mL, 1.57 mmol). After shaking for 0.5 h, phenyl-acetylene (0.173 niL, 1.57 mmol) was added to the mixture, and the reaction vessel was heated at 85 °C with shaking for 3 h. The resin was filtered hot and washed thoroughly with dioxane (once), DMF (three times), 20% aqueous AcOH (once), DMF (once), 7 m NH4OH (once), DMF (once), MeOH (three times), THF (three times), and CH2CI2 (three times). 

It might be possible to make (10) by a regioselective Mannich reaction but a more cunning approach comes from the realisation that any jS-substituted compound (11) will do as well If we put X = OMe, symmetry can be introduced by FGI to an acetylene (12) and readily available butyne diol (13) becomes the starting material (see Chapter 16). 

Aminomethylation of propargylic phosphoramides with terminal acetylene groups by the Mannich reaction, followed by hydrolysis, gives unsymmetrical l,4-diaminobut-2-ynes in high yields (e.g. Scheme 116). ... 

Terminal allenes.1 Terminal acetylenes can be converted by a one-step reaction into terminal allenes by treatment with formaldehyde, diisopropylaminc, and copper(l) bromide in refluxing THF or dioxane. The Mannich base is an intermediate, but, surprisingly, preparation of the quaternary base is not necessary. The source of the introduced hydrogen is not clear. The highest yields are obtained with 2-propynylic alcohols, ethers, and esters. 

Fig. 118. Synthesis of allenes by organomcial reaction on g-methoxy acetylenic Mannich bases.

Acetylenic Mannich bases are also used for producing homo- as well as heterocyclic derivatives (Fig. 12.3). For instance, the cyclopentcne ring is formed by cyclization of the bis-Mannich base 319, prepared from heptane-1,6-di-ync with butyllithium. However, the reaction is strongly affected by the steric hindrance of the amino group, as it occurs almost instantaneously with the dimcthylamino compound, whereas the diethyl-amino- and pyrrolidino derivatives do not react. 

N-Alkylation—Secondary Mannich bases can give the corresponding tertiary derivatives by treatment with particular alkylation agents, such as epoxides (affording P-ami-noalcohols) and acrylic derivatives. Tertiary Mannich bases, mostly, are submitted to N-alkylation in order to produce stable quaternary ammonium salts to be subsequently subjected to deamination (Sec. A.2). However, different quaternary ammonium byproducts can be readily given by the reaction. " For instance, a base-catalyzed rearrangement is afforded by allyl ammonium salts 365 (Fig. 144), obtained by N-alkylation of acetylenic Mannich bases with ally] halides. " In the presence of sodium hydride, the compounds 365 yield a wide range of 3-amino-5-hexen-l-yne derivatives 366. 

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