Aminomethylation from ketones

A synthesis of ( )-pilosinine (32) via aminomethyl homopilosinyl ketone, starting from ethyl [Pg.299]

Six-membered heterocycles have been prepared from cyclopropanes by a diverse selection of methods. Thermolysis of an acetonitrile solution of the hydrobromide of the aminomethyl cyclopropyl ketone 32 in a sealed tube caused cleavage of the cyclopropane ring, which was followed by cyclization to afford the piperidone derivative 33. The non-narcotic analgesic pentazocine was obtained from 33 in several steps. ... 

An improved preparation of p-aminomethyl alcohols from ketones has been developed using trimethylsilyl cyanide followed by lithium aluminium hydride reduction. It is particularly useful for ocp-unsaturated ketones and for relatively hindered ketones, and should make the Tiffeneau-Demjanov ring-expansion procedure more attractive. ... 

Via intermediates l-(Aminomethyl)alcohols from ketones via a-siloxynitriles... 

Pyridyl)hydrazine (Aldrich), 4-acetylpyridine (Acros), N,N,N -trimethylethylenediamine (Aldrich), methylrhenium trioxide (Aldrich), InQj (Aldrich), Cu(N0j)2-3H20 (Merck), Ni(N03)2-6Il20 (Merck), Yb(OTf)3(Fluka), Sc(OTf)3 (Fluka), 2-(aminomethyl)pyridine (Acros), benzylideneacetone (Aldrich), and chalcone (Aldrich) were of the highest purity available. Borane dimethyl sulfide (2M solution in THE) was obtained from Aldrich. Methyl vinyl ketone was distilled prior to use. Cyclopentadiene was prepared from its dimer immediately before use. (R)-l-acetyl-5-isopropoxy-3-pyrrolin-2-one (4.15) has been kindly provided by Prof H. Hiemstra (University of Amsterdam). 

Goldberg and Wydler have shown that the 17a-ketone is not the only product of the Tiffeneau ring enlargement sequence. Careful examination of the products derived from nitrous acid deamination of 17a-aminomethyl-5a-androstane-3/l,17j6-diol 3-acetate (91) showed the presence of a minor amount of isomeric D-homo-17-one (98). 

While studying the conversion of the adducts, obtained from aldehydes, it was discovered that upon thermolysis they lose diphenyl-phosphine oxide (Ph2P0H) to form a-aminomethyl ketones 7. The overall reaction thus results in a-aminomethylation of the parent al-... 

Little is known so far about a-ketoenamines, probably because they are sometimes not directly accessible from the corresponding diketones. Nevertheless, they are useful synthones, especially for heterocyclic synthesis. Compared with / -ketoenamines, the chemical behaviour of the a-keto-derivatives is somewhat different. They react as enamines, as well as a,/ -unsaturated ketones, which means that they act either as an electrophile or as a nucleophile in the -position. For example, protonation usually occurs at the fi-C atom with subsequent enolization308. Aminomethylation according to Mannich takes place in the -position as well309. The alkylation with alkyl halide, however, is reported to occur at nitrogen310,311. In addition to electrophilic and nucleophilic chemistry, a-ketoenamines are useful synthons in photochemistry and electrocyclic reactions. 

Thus many compounds arc obtained (250, Table 24), which may be considered to be derived from C-alkylation of the nucleophilic reagent by the Mannich base. Alkyl ketonic and phenolic bases arc mostly involved in this reaction, which exhibits many analogies with aminomethylation, particularly concerning chemo- and regioselectivity on aromatic and heteroaromatic derivatives. Ring activation by means of hydroxy and amino substituents in the alkylation of pyridine and pyrimidine derivatives is also required. 

Terpenoids are subjected to aminomethylation in order to intrtxiuce a basic moiety into the molecule. The reactive site of the substrate is usually an alkene or alkyl ketone group however, unsaturated derivatives of type 490 arc obtained from terpenes suitably functionalized by the alkyne moiety. ... 

Further examples reported in Table 40 arc given by the alkyl ketone moieties deriving from oxidation of polyenes, which arc subjected to Mannich aminomethylation in order to produce compounds 559 having dispersant properties for lubricating oils, by benzotriazoles 557, capable of forming, due to physical adsorption, thin layers over the surfaces subjected to friction, and by S-Mannich bases 558, combining antifriction and antioxidant properties. 

Preparation. [(i )-a-(2-Naphthyl)aminomethyl]ferrocene was prepared in three steps from ferrocenyl 2-naphthyl ketone featuring an asymmetric CBS reduction with >99% ee (eq 1). After protection of the secondary hydroxyl group with an acetyl group, a nucleophilic displacement of the acetoxy group with an amino group proceeded with retention of stereochemistry. A range of different variations of [(i )-a-(2-naphthyl)aminomethyl]ferro-cene could be prepared using this sequence with similar efficiency. 

Summary (Aminomethyl)silanes have been prepared by new synthetic routes starting from lithiosilanes or (lithiomethyl)amines. (Lithiomethyl)(aminomethyl)silanes were formed by metallation with lithioalkyls. A sulfur-substituted (lithiomethyl)(aminomethyl)silane and a THF adduct are characterized by single crystal X-ray diffraction. In reactions of (lithiomethyl)(aminomethyl)silanes with aldehydes or ketones no clear addition/depro-tonation profile was observed. 

The original Mannich reaction is the acid-catalyzed aminomethylation of enohz-able ketones with non-enolizable aldehydes and ammonia, primary amines, or secondary amines, which involves nucleophilic addition of ketone enols to iminium salts generated in situ from the aldehydes and the nitrogen compounds [183]. This three-component coupling reaction provides a powerful tool for carbon-carbon bond formation and introduction of nitrogen functionality. The classical Mannich reaction has some drawbacks in reaction efficiency, regioselectivity, and appli-... 

Preparation of the chiral oxazolidine-aldehyde 64 from D-serine 59 required various steps, including conversion into the silyl ether 60, reaction with ketone 61 to provide oxazolidine silyl ether 62 and subsequent desilylation of the tert-butyldiphenylsiloxy group. Oxidation of the hydroxy functionality and hydrogeno-lytic cleavage of the benzyl ester then gave the corresponding aldehyde 63. The acid functionality of 63 was then coupled to aminomethylated Merrifield resin (Scheme 12.26). 

In addition to the side reactions mentioned above, deamination of Mannich bases can occur, especially at elevated temperature, to give a,p-unsaturated derivatives. This route of decomposition of Mannich bases has been exploited as a means of in situ generation of a,p-unsaturated ketones in the Michael reaction and for the direct synthesis of a,3-unsaturated ketones several reviews of the Mannich reaction have discussed aspects of these applications.Recently, a direct one-pot synthesis of a-methylene ketones has been reported involving condensation of ketones with formaldehyde and A -methylaniline tri-fluoroacetate in aptotic solvents. Also, a less direct method has been described in which Mannich bases prepared from 3-keto esters, formaldehyde and dimethylamine are subjected to quatemarization and thermal fragmentation to yield a-methylene ketones.This method is particularly useful for the regios-pecific synthesis of a-methylene ketones because the aminomethylation reaction always takes place at the most activated position flanked by the ketone and ester groups. 

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