Amines, a-alkylation

Both the fluorescence and intersystem crossing of lt -amine exciplexes can be quenched by added amine (116). Rate constants for exciplex quenching obtained from fluorescence or t-1 isomerization quantum yield data decrease with amine a-alkylation ... 

Sec- and fert-acyclic and cyclic amines A-Alkyl and N,A-dialkylarylamines Hydrazines Primary amines... 

Enders, D., Schubert, H. Enantioselective synthesis of P-substituted primary amines, a-alkylation/reductive amination of aldehydes via SAMP hydrazones. Arrgew. Chem., Int. Ed. Engl. 1984, 23, 365-366. 

Keywords aryl halide, secondary amine, A-alkylation, microwave irradiation, A-arylamine... 

These amphoteric surfactants may be prepared by reaction of a fatty primary amine with chloroacetic acid. They are also produced by reaction of formaldehyde and HCN with a fatty amine. A -alkyl-P-aminopropionates and A -alkyl- 3-iminodipropionates are usually made by reaction of the alkylamine with methyl acrylate, followed by hydrolysis of the methyl esters (3). 

Progress has been made toward enantioselective and highly regioselective Michael type alkylations of 2-cyclohexen-l -one using alkylcuprates with chiral auxiliary ligands, e. g., anions of either enantiomer of N-[2-(dimethylamino)ethyl]ephedrine (E. J. Corey, 1986), of (S)-2-(methoxymethyl)pyrrolidine (from L-proline R. K. EHeter, 1987) or of chiramt (= (R,R)-N-(l-phenylethyl)-7-[(l-phenylethyl)iinino]-l,3,5-cycloheptatrien-l-amine, a chiral aminotro-ponimine G. M. Villacorta, 1988). Enantioselectivities of up to 95% have been reported. 

A special problem arises in the preparation of secondary amines. These compounds are highly nucleophilic, and alkylation of an amine with alkyl halides cannot be expected to stop at any specifle stage. Secondary amides, however, can be monoalkylated and lydrolyzed or be reduced to secondary amines (p. 11 If.). In the elegant synthesis of phenyl- phrine an intermediate -hydroxy isocyanate (from a hydrazide and nitrous acid) cyclizes to pve an oxazolidinone which is monomethylated. Treatment with strong acid cleaves the cyclic irethan. 

The reaction of amines with alkyl halides was seen earlier (Section 22 7) as a complicat ing factor in the preparation of amines by alkylation of ammonia... 

Ammonia can act as a nucleophile toward primary and some secondary alkyl halides to give primary alkylamines Yields tend to be modest because the primary amine IS itself a nucleophile and undergoes alkylation Alkylation of ammonia can lead to a mixture containing a primary amine a secondary amine a tertiary amine and a quaternary ammonium salt... 

Reductive amination of cyclohexanone using primary and secondary aHphatic amines provides A/-alkylated cyclohexylamines. Dehydration to imine for the primary amines, to endocycHc enamine for the secondary amines is usually performed in situ prior to hydrogenation in batch processing. Alternatively, reduction of the /V-a1ky1ani1ines may be performed, as for /V,/V-dimethy1 cyclohexyl amine from /V, /V- di m e th y1 a n i1 i n e [121 -69-7] (12,13). One-step routes from phenol and the alkylamine (14) have also been practiced. 

A AlI lation. A number of methods are available for preparation of A/-alkyl and A[,A/-dialkyl derivatives of aromatic amines. Passing a mixture of aniline and methanol over a copper—zinc oxide catalyst at 250°C and 101 kPa (1 atm) reportedly gives /V-methylaniline [100-61-8] in 96% yield (1). Heating aniline with methanol under pressure or with excess methanol produces /V, /V-dimethylaniline [121 -69-7] (2,3). 

Nuclear Magnetic Resonance. The nmr spectmm of aromatic amines shows resonance attributable to the N—H protons and the protons of any A/-alkyl substituents that are present. The N—H protons usually absorb in the 5 3.6—4.7 range. The position of the resonance peak varies with the concentration of the amine and the nature of the solvent employed. In aromatic amines, the resonance associated with N—CH protons occurs near 5 3.0, somewhat further downfield than those in the aliphatic amines. 

Ethoxylation of alkyl amine ethoxylates is an economical route to obtain the variety of properties required by numerous and sometimes smaH-volume industrial uses of cationic surfactants. Commercial amine ethoxylates shown in Tables 27 and 28 are derived from linear alkyl amines, ahphatic /-alkyl amines, and rosin (dehydroabietyl) amines. Despite the variety of chemical stmctures, the amine ethoxylates tend to have similar properties. In general, they are yellow or amber Hquids or yellowish low melting soHds. Specific gravity at room temperature ranges from 0.9 to 1.15, and they are soluble in acidic media. Higher ethoxylation promotes solubiUty in neutral and alkaline media. The lower ethoxylates form insoluble salts with fatty acids and other anionic surfactants. Salts of higher ethoxylates are soluble, however. Oil solubiUty decreases with increasing ethylene oxide content but many ethoxylates with a fairly even hydrophilic—hydrophobic balance show appreciable oil solubiUty and are used as solutes in the oil phase. 

A further strong bathochromic shift is observed as the basicity of the primary amines is increased by A/-alkylation, eg, malachite green [569-64-2] Cl Basic Green 4, =621 nm (5). 

Commercial Antioxidants Table 4 includes the main classes of antioxidants sold in the United States and the suppHer s suggested apphcations. Some of these are mixtures rather than single substrates. This is especially tme of alkylated amines and alkylated phenols. The extent of alkylation and the olefins used for alkylation can vary among manufacturers. Table 4 is not a complete listing of available antioxidants in the United States. 

A nitrogen atom at X results in a variable downfield shift of the a carbons, depending in its extent on what else is attached to the nitrogen. In piperidine (45 X = NH) the a carbon signal is shifted by about 20 p.p.m., to ca. S 47.7, while in A-methylpiperidine (45 X = Me) it appears at S 56.7. Quaternization at nitrogen produces further effects similar to replacement of NH by A-alkyl, but simple protonation has only a small effect. A-Acylpiperidines show two distinct a carbon atoms, because of restricted rotation about the amide bond. The chemical shift separation is about 6 p.p.m., and the mean shift is close to that of the unsubstituted amine (45 X=NH). The nitroso compound (45 X = N—NO) is similar, but the shift separation of the two a carbons is somewhat greater (ca. 12 p.p.m.). The (3 and y carbon atoms of piperidines. A- acylpiperidines and piperidinium salts are all upfield of the cyclohexane resonance, by 0-7 p.p.m. 

The imine, prepared from an amine and (C5H4N)(Me3C JH2)CO (TiC, toluene, reflux, 12 h NaOH, 80% yield), can be cleaved with coned. HCl (reflux). The protective group was used to direct a-alkylation of amines. 

The reaction of aliphatic primary amines with alkyl a-hydrogenoperfluorocar-boxylates leads to the corresponding P-alkyl iminoesters as the major or the sole tautomers, depending on the length of the perfluoroalkyl chain [ 103] (equation 89). 

Nitrosation (Section 22.15) Nitrosation of amines occurs when sodium nitrite is added to a solution containing an amine and an acid. Primary amines yield alkyl diazonium salts. Alkyl diazonium salts are very unstable and yield carbo-cation-derived products. Aryl diazonium salts are exceedingly useful synthetic intermediates. Their reactions are described in Table 22.7. 

A -Nitroso derivatives, prepared from secondary amines and nitrous acid, are cleaved by reduction (H2/Raney Ni, EtOH, 28°, 3.5 h CuCl/concd. HCF). Since many A -nitroso compounds are carcinogens, and because some racemiza-tion and cyclodehydration of A -nitroso derivatives of A -alkyl amino acids occur during peptide syntheses, A -nitroso derivatives are of limited value as protective groups. 

Coe et al. reported an efficient modification for the preparation of /-substituted indole analogs for biology screening in good yield. The intermediate P-nitrostyrene 44, prepared from the condensation of 43 with DMFDMA, underwent methanolysis and reduction to provide the aniline acetal intermediate 45. Alkylation of amine 45 was carried out employing standard conditions of reductive alkylation to provide A-alkyl analogs represented by 46. The indole 47 was generated by formation of the oxonium ion (from 46) under acidic conditions, followed by cyclization, accompanied by loss of methanol. 

The well-known reaction of a-alkyl-/3-ketoaldehydes and hydroxyl-amine has been applied to the elucidation of the structure of formyl-ation products of ketones the conclusions are, however, open to question. Some workers attempted to overcome the ambiguity of the reaction of j8-ketoaldehydes and hydroxylamine, which results in a mixture of 3- and 5-monosubstituted isoxazoles and thus considerably lowers the preparative value of the method, by using various derivatives of yS-ketoaldehydes, especially those of their enolic forms (jS-substituted vinylketones) investigated by Kochetkov et al. The use of readily available /3-chlorovinylketones (12) in the reaction with hydroxylamine represents a rather useful preparative method to synthesize monoalkylisoxazoles but again gives rise to a mixture of 3- (13) and 5-alkylisoxazoles (14). This is due to the attack... 

The hydrolytic cleavage is usually slow, and requires drastic reaction conditions. A more elegant method is presented by the Ing-Manske procedure, where the A-alkylated imide is treated with hydrazine under milder conditions. In addition to the desired amine 5, the cyclic phthalic hydrazide 6 is then formed ... 

Reaction of dibenzylamine with ethylene oxide affords the amino alcohol, 82. Treatment of that product with thionyl chloride gives the a-sympathetic blocking agent, dibenamine (83). (Condensation of phenol with propylene chlorohydrin (84) gives the alcohol, 85. Reaction with thionyl chloride affords the chloride (86). Use of the halide to alkylate ethanolamine affords the secondary amine (87). Alkylation of this last with benzyl chloride... 

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