Carbon aminomethylations

Olefins can be aminomethylated with carbon monoxide [630-08-0] (CO) and amines in the presence of rhodium-based catalysts. Eor example, pipera2ine reacts with cyclohexene [110-83-8] to form W,Af-di-(l-cyclohexylmethyl)-pipera2ine [79952-94-6] (55). 

The original Demjanov reaction is the conversion of an aminomethyl-cycloalkane into a cycloalkanol consisting of a carbocyclic ring that is expanded by one carbon center e.g. the reaction of aminomethylcyclohexane 8 with nitrous acid leads to formation of cycloheptanol 9 ... 

A solution of 192 g of 1 -phenethyl-4-hydroxy-4-aminomethyl piperidine in BOO cc of diethyi-carbonate is heated for 1 /i hours to refiux at about B0°C in the presence of sodium methylate (prepared for immediate use from 2 g of sodium). After this time, the ethyl alcohol formed during the reaction is slowly distilled while the maximum temperature is reached. The excess ethyl carbonate is distilled under reduced pressure. A crystallized residue Is then obtained, which is stirred with 400 cc of water and 400 cc of ether. The solution is filtered and 125 g (77.6%) of practically pure product melting at 232°C to 233°C, are obtained. 

The Mannich condensation has traditionally been carried out in the presence of water as a three-component condensation involving a carbonyl compound (or related carbon nucleophile), formaldehyde, and a primary or secondary amine. The initial step is a condensation between the latter two reactants to form a mono- or dialkyl(methylene)ammonium ion which subsequently serves as the electrophilic partner in the reaction. With unsymmetrical ketones aminomethylation generally occurs at both positions to give mixtures of isomeric 3-amino ketones. The ratio of the isomers depends strongly on the structure of the ketone, and the more highly branched (3-amino ketone usually predominates. 

Formation, transamination, and mutual transitions of aminomethyl derivatives of phosphines, representing nucleophilic substitution at the carbon atom in the P—C—O(N) fragment, take place under milder conditions than similar reactions of alcohols and amines. The reason is likely the participation of a phosphino group in intramolecular interactions (86MI1). 

The intramolecular photochemistry of 9-[2-(7V-substituted aminomethyl)-l-naph-thyl]phenanthrenes has also been studied101 (equation 40). The pyrroline derivatives are obtained by the addition of the N—H to the C-9 carbon atom of phenanthrene ring. Reasonable yields for the highly regioselective products are obtained by irradiation in benzene solution. 

Pliotolytic. Bussacchini et al. (1985) studied the photolysis (7, = 254 nm) of phenmedipham in ethanol, ethanol/water, and hexane as solvents. In their proposed free radical mechanism, homolysis of the carbon-oxygen bond of the carbamate linkage gave the following photoproducts 3-(hydroxylphenyl)carbamic acid methyl ester, m-toluidine, 2-hydroxy-4-aminomethyl benzoate, 3-hydroxy-5-aminomethyl benzoate, 2-amino-4-hydroxymethyl benzoate, and 2-amino-6-hydroxymethyl benzoate. 

Thiadiazole, the 2-amino, 2-aminomethyl, 2-aminomethyl-5-methyl, and 2,5-dimethyl derivatives are all soluble in water. Generally, as the size of the substituents on carbon increases, the aqueous solubility decreases and the solubility in organic solvents increases. 

Reduction of cycloalkane-condensed 2-phenyl-5,6-dihydro-4//-l,3-benzoxazines 144 with lithium aluminium hydride (LAH) afforded A -benzyl-substituted 2-(aminomethyl)cycloalkanols 145 in a reductive ring opening via the ring-chain tautomeric tetrahydro-l,3-oxazine intermediates. Catalytic reduction of 1,3-oxazines 144 under mild conditions in the presence of palladium-on-carbon catalyst similarly resulted in formation of the A -benzyl-1,3-amino alcohols 145. When the catalytic reduction was performed at elevated temperature at hydrogen pressure of 7.1 MPa, the N-unsubstituted 2-(aminomethyl)cycloalkanols 146 were formed in good yields (Scheme 22) <1998SC2303>. 

As a further illustration of the reactivity of the 3 position toward electrophiles, the methoxyindole (25-1) readily undergoes Mannich reaction with formaldehyde and dimethylamine to afford the aminomethylated derivative (25-2). Treatment of that intermediate with potassium cyanide leads to the displacement of dimethylamine and the formation of the nitrile (25-3), possibly by an elimination-addition sequence involving a 3-exomethylene-indolenine intermediate. The protons on the methylene group adjacent to the nitrile are quite acidic and readily removed. Reaction of (25-3) with methyl carbonate in the presence of sodium methoxide gives the carbo-methoxylated derivative (25-4). Catalytic hydrogenation leads to reduction of the nitrile to a primary amine. There is thus obtained the antihypertensive agent indorenate (25-5) [26]. 

Aminomethylated polystyrene (DVB I %, 1.07 mmol Trifluoroacetic acid / dichloromethane (I/I, v/v), 10mL 3-Bromopropionic acid (97 %) (158 mg, I mmol) Cesium carbonate (99.9%) (652 mg, 2 mmol) Triethylamine Benzene Acetone... 

Nondestructive reactions of trisacetylacetonates of chromium(lll), cobalt(lll), and rhodium(lll) are reviewed. Halogenation, nitration, thiocyanation, acylation, formylation, chloromethylation, and aminomethylation take place at the central carbon of the chelate rings. Trisubstituted chelates were obtained in all cases except acylation and formylation. Unsymmetrically and partially substituted chelates have been prepared. Substitutions on partially resolved acetylacetonates yielded optically active products. NMR spectra of unsymmetrically substituted, diamagnetic chelates were interpreted as evidence for aromatic ring currents. Several groups were displaced from the chelate rings under electrophilic conditions. The synthesis of the chromium(lll) chelate of mal-onaldehyde is outlined. 

Support-bound indoles can be modified in several ways. N-Alkylation of polystyrene-bound indoles has been achieved by treatment with reactive alkylating agents (Mel, BnBr, BrCH2C02R) in conjunction with NaH or KOrBu as a base in DMF at room temperature (Entries 1 and 2, Table 15.7). The aminomethylation of indole at C-3 proceeds smoothly on cross-linked polystyrene. The resulting (aminomethyl)in-doles are thermally unstable and undergo substitution reactions with various carbon nucleophiles (e.g. cyanide or nitroacetates) at higher temperatures (Entry 4, Table... 

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