Amines monomethylation

B) Secondary amines, (i) Aromatic amines. Monomethyl and monoethylaniline, diphenylamine. (ii) Aliphatic and other amines. Diethyhmine, di-n-propylamine, di-isopropylamine. Also piperidine piperazine diethylene-diamine). 

SYNS P-(METHYLAMINO)ETHANOL N-METHYL-AMINOETHANOL N-METHYXETHANOLAMINE METHYLETHYLOL.AMINE METHYL(P-HYDROXY-ETHYL)AMINE MONOMETHYL-AMINOAETHANOL (GERMAN) MONOMETHYLAMINOETHANOL N-MONOMETHYLAMINOETHANOL USAF DO-50... 

Synonyms Ethanol, 2-(methylamino)- (2-Hydroxyethyl) methylamine N-(2-Hydroxyethyl)-N-methylamine 2-(Methylamino) ethanol p-(Methylamino) ethanol N-Methylaminoethanol Methylethanolamine (INCI) Methyl (2-hydroxyethyl) amine Methyl (P-hydroxyethyl) amine Monomethyl ami noethanol Monomethylethanolamine Classification Organic compd. amino alcohol Empihcal C3H9NO Formula CH3NHCH2CH2OH Properties Colorless vise, liq. fishy odor sol. in water, ethanol, diethyl ether, acetone, benzene, oxygenated soivs. insol. in aliphatic soivs. m.w. 75.11 dens. 0.9414 (20 C) vapor pressure 0.5 mm Hg (20 C) m.p. -4.5 C b.p. 158 C flash pt. (OC) 74 C ref. index 1.439 pH strong base surf, tens. 34.4 mN/m (22 C)... 

Tertiary amines containing one alkyl and two aryl groups, such as mono-I ncthyldiphenyhiniir.e, Cl l3(C, l l.diX , arc rarely encountered and arc unimportant. They usually react with nitrous acid with the insertion of a nitroso group into only one of the two available para positions monomethyl-diphenylamine thus gives monomethyl-mono - pnitroso-diphenylamine. Cl hj(C.ill .)N C l 1 jXO, or V-nicthyl-p-nitrosodiphcnylaniine. 

The desired pyridylamine was obtained in 69 % overall yield by monomethylation of 2-(aminomethyl)pyridine following a literature procedure (Scheme 4.14). First amine 4.48 was converted into formamide 4.49, through reaction with the in situ prepared mixed anhydride of acetic acid and formic acid. Reduction of 4.49 with borane dimethyl sulfide complex produced diamine 4.50. This compound could be used successfully in the Mannich reaction with 4.39, affording crude 4.51 in 92 % yield (Scheme 4.15). Analogous to 4.44, 4.51 also coordinates to copper(II) in water, as indicated by a shift of the UV-absorption maximum from 296 nm to 308 nm. 

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. 

Acrylonitrile will polymerize violendy in the absence of oxygen if initiated by heat, light, pressure, peroxide, or strong acids and bases. It is unstable in the presence of bromine, ammonia, amines, and copper or copper alloys. Neat acrylonitrile is generally stabilized against polymerization with trace levels of hydroquinone monomethyl ether and water. 

The reduction oFvapor pressure by diluting ammonia, monomethyl-amine, and hydrochloric acid with water is shown in Table 26-9. 

FIG. 26-28 Relative hazard zones for anhydrous and aqueous monomethyl-amine releases—relative distance within which there is a specified atmospheric concentration of monomethylamine and aqueous monomethylamine. Hender-shot, 1988, hy permission. )... 

O. 016 mole of the amine and then 3.6 g of formaldehyde (ca. 10 ml of formalin) and reflux for 5 hours. Cool to room temperature, add 7 ml concentrated HCI and evaporate in vacuum. The resulting oily dimethylamine can be purified by dissolving in 25 ml water, extracting with 2X25 ml CHCI3. Basify the aqueous layer with 2N NaOH and extract with 3X25 ml ether, and proceed as described above for the N-methylamines. This procedure should work for both phenethylamines and phenylisopropylamines, and should affect the trip similarly to N-monomethylation. 

The 7V-monomethylation of primary amines RNH2 (R = CsHn, Ci2H25, Ph, PhCH2CH2 etc.) has been accomplished in high yield by condensation with 3-methyl-2-(methylthio)benzothiazolium iodide, followed by treatment of the resulting imine with methyl iodide or methyl tosylate to give the salts 49. The latter yield the products RNHMe by the action of butylamine (equation 29)76. 

In order to clarify the different behavior of anion 2 and 3 (Scheme 4.10) toward DMC, various anions with different soft/hard character (aliphatic and aromatic amines, alcohoxydes, phenoxides, thiolates) were compared with regard to nucleophilic substitutions on DMC, using different reaction conditions. Results were in good agreement with the hard-soft acid-base (HSAB) theory. Accordingly, the high selectivity of monomethylation of CH2 acidic compounds and primary aromatic amines with DMC can be explained by two different subsequent reactions, which are due to the double electrophilic character of DMC. The first... 

Methyl 6-oxodecanoate Decanoic acid, 6-oxo-, methyl ester (10) (61820-00-6) 1-Chloro-N, N, 2-t rimethylprogeny1 amine Progeny amine, 1-chloro-N, N, 2-trimethyl- (8) 1-Progen-l-aniine, 1-chloro-N,N,2-tr1methyl- (9) (25189-59-3) Adigic acid monomethyl ester (8) Hexanedioic acid, monomethyl ester (9) (627-91-8)... 

Partly reduced counterparts of the indole nucleus provide the basis for several agents with varied biological activities. A pair of closely related A-phenyl derivatives have both shown antidepressant activity in test systems. The apparent preference for the monomethyl amine suggests that these act by the same mechanism as the classical tricyclic antidepressants, where the secondary amine is the more active species. The first step in the preparation of the common intermediate (27-3) to these compounds consists of acylation of diphenylamine (27-1) with chloroacetyl chloride. 

The hydroxyquinoline (39-2) provides the starting material for a quinolone that incorporates a hydrazine function. Reaction of (39-2) with 2,4-dintrophenyl O-hydroxylamine ether (41-1) in the presence of potassium carbonate leads to a scission of the weak N-O hydroxylamine bond by the transient anion from the quinolone the excellent leaving character of 2,4-dinitrophenoxide adds the driving force for the overall reaction, resulting in alkylation on nitrogen to form the hydrazine (41-2). The primary amine is then converted to the formamide (41-3) by reaction with the mixed acetic-formic anhydride. Alkylation of that intermediate with methyl iodide followed by removal of the formamide affords the monomethylated derivative (41-4). Chlorine at the 7 position is then displaced by A-methylpiperazine and the product saponified. There is thus obtained amifloxacin (41-6) [48]. 

Reductive amination of benzaldehyde with (R)-81 provided the corresponding benzyl amine, which was reductively alkylated with formaldehyde to give 82 (Scheme H) " Compound 82 was debenzylated by hydrogenation in the presence of Pearlman s catalyst to afford frovatriptan ((/J)-6). Alternatively, monomethylation of amine (/ )-81 was affected by treatment with carbon disulfide and dicyclohexylcarbodiimide in pyridine to provide isothiocyanate 83, which was reduced with sodium borohydride to give (l )-6. 

Figures 3 and 4 therefore represent our best understanding to date of the reaction pathway for PMMA and dimethyl- or monomethyl- amine respectively. Currently, molecular modeling work is underway (in conjunction with Dr. S. Fitzwater) to help understand these reactions in additional detail.

Diethylene glycol monomethyl ether Diethylenetriamine Diethylformamide Di(2-ethylhexyl)amine Diisobutyl ketone Diisopropylamine Di-n.-propyl aniline Dipropylene glycol Ethyl alcohol Ethyl benzoate Ethyl chloroacetate Ethyl cinnamate Ethylene diacetate Ethylene glycol... 

Monoalkylation of support-bound amines can also be realized by a three-step protocol involving initial protection/activation of the amine (e.g. as 2-nitrobenzenesulfon-amide [132,133], trifluoroacetamide [102], or 4,4 -dimethoxybenzhydrylamine [66]) followed by N-alkylation and deprotection. In particular, if monomethylations (see, e.g., Entry 7, Table 10.7) or allylations are to be performed, this three-step strategy will generally give the best results. 

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