Aminomethylation anhydrous

However, with liquid ammonia or anhydrous methylamine 1,2,4-oxadiazines (88) are formed. 5-(Chloromethyl)-l,2,4-oxadiazoles (e.g., (86) react with urotropin to form salts, which are hydrolyzed with hydrochloric acid to 5-(aminomethyl) compounds (the Delepine reaction). Alternatively, 5-(aminomethyl)-l,2,4-oxadiazoles have been prepared by condensation of amidoximes with a-amino-acids <72JHC435>. 

To a 200-mL, round-bottomed flask equipped with magnetic stirring, 2-(aminomethyl)pyridine (Acros, 8 mL, 80 mmol) is added to a solution of picolyl chloride HCl (25.6 g, 160 mmol) in distilled water (40 mL). Sodium hydroxide (31.0 mL of a 10 M solution, 320 mmol) is added dropwise (approximately 5 drops/min) over a period of 2 h using an addition funnel. The flask is then placed in a 70°C oil bath for 30 min. The solution is removed from the oil bath and is cooled to room temperature. The resulting dark red solution is transferred to a separatory funnel and extracted with three 150-mL portions of CHC13. The combined extracts are dried over anhydrous Na2S04. After filtration, the CHC13 is removed on a rotary evaporator. The... 

The direct addition of nitromethane, in a mixture of anhydrous methanol and sodium methoxide, to 9-(3,5-0-isopropylidene-/ -D-fhreo-hexo-furanosyl-2-ulose)adenine (22) gave 9-(2-C-nitromethyl-/ -D-h/xo-hexo-furanosyl)adenine (94) in 75% yield.38 Reduction of 94 in 5 5 1 methanol-water-acetic acid in the presence of 10% palladium-on-charcoal, followed by N-acetylation of the resulting aminomethyl group, afforded, in 62% yield, 9-(2-C-acetamidomethyl-3,5-0-isopropyIidene-/ -D-h/xo-hexofuranosyl)adenine (95). 

From 4.1 parts DL-4-(aminomethyl)-l-[2-(l,4-benzodioxanyl)methyl]-4-phenylpiperidine dihydrochloride, the free base is liberated in the usual manner and extracted with chloroform. The organic layer is separated, dried and evaporated. The DL-4-(aminomethyl)-l-[2-(l,4-benzodioxanyl)methyl]-4-phenylpiperidine obtained is dissolved in 128 parts anhydrous chloroform. This solution is cooled to 5°C and there is added dropwise a solution of 1.6 parts acetylchloride in 7 parts anhydrous chloroform (exothermic reaction). The reaction mixture is stirred over night at room temperature and then alkalized with about 25 parts sodium hydroxide 20% at a temperature of 20°C. The aqueous layer is separated and extracted twice with chloroform. The combined organic layers are washed with water, dried over magnesium sulfate, filtered and evaporated. The oily residue is dissolved in a mixture of 40 parts acetone and 20 parts diisopropyl ether and evaporated again. The solid residue is triturated in diisopropylether, yielding DL-4-(N-acetylaminomethyl)-l-[2-(l,4-benzodioxanyl)-methyl]-4-phenylpiperidine melting point 140°-141.1°C, as a white microcrystalline powder. 

Aminomethyl-l,4-benzodioxane (17 g) and p-methoxyethoxy ethyl chloride (7 g) were heated at 160°C for 2 hours. The reaction mixture was cooled and chloroform (30 ml) and a solution of potassium carbonate (7 g) in water (20 ml) added thereto.The chloroform layer was removed and the aqueous layer extracted twice with chloroform (10 ml each time). The chloroform extracts were combined and dehydrated over anhydrous sodium sulfate. Filtration, followed by distillation gave 2-(p-methoxyethoxyethyl)amino-methyl-l,4-benzodioxane (yield 7.7 g) as a pale yellow oil boiling at 180-186°C/11.5 mm. 

Set up the second 250 mL flask with a septum cap, stirrer bar and a positive pressure of nitrogen as above. Dissolve 1-(triphenylphosphorylidene-aminomethyl) benzotriazole (5.0 g, 12.2 mmol) in anhydrous tetrahydrofuran (50 mL). 

The silicon-based TL 1.35 (Fig. 1.14) (93) on aminomethyl PS resin has been used in the SP preparation of 1,4-benzodiazepines by decoration of the phenyl ring. Cleavage is effected by protodesilylation using the somewhat harsh anhydrous HE, which releases the unsubstituted phenyl. A more labile TL 1.36 (94) obtained by substituting Ge for Si can be cleaved with TFA-Me2S-water in the ratio 85/10/5. Many other silyl-based TLs have been reported (52-56,92) cleavage conditions where H is replaced by I (ICl) or Br (Br2-pyridine) have been validated. 

Other cationic structures have been proposed for the aminomethylating species. In the reactions of N,0-acetals catalyzed by trimethylsilyl derivatives MejSiX, the reactive agent is claimed to be the oxonium cation 50 (sec also Refs. 210 and 211). Moreover, the intermediate hydrochloride 51 could be formed by the action of anhydrous hydrogen chloride " on hexahydrotriazines 32b, although more recent studies suggest the formation, under the same conditions, of equimolecular amounts of methyleneimmonium chloride and the halogenatcd salt 52. 

Heterocyclic substrates, such as pyrrole and imidazole derivatives 68, may undergo selective Mannich reactions. C-Aminomethylation is favored by acidic conditions, whereas N-Mannich bases are produced when free amine and formaldehyde, or N,0-acetals in anhydrous solvents, are employed. Heterocyclic N-Mannich bases, however, are not particularly stable and may therefore behave as aminomethylation agents (see,... 

A solution of 2.57 g. (0.01 mole) of anhydrous bis(2,4-pentane-dionato)cobalt(II) in 40 ml. of benzene is boiled for 5 minutes, after which 2.5 g. (0.023 mole) of 2-(aminomethyl)pyridine-(2-picolylamine) is added. The solution is boiled until the volume has been reduced to 10-15 ml., during which time some reddish crystals appear. The slurry is cooled in ice, and the crystals are filtered with suction, washed with four 5-ml. portions of cold benzene, sucked dry, and air-dried to constant weight (one day). The yield of brick-red platelets is 2.92 g., 80%. The product darkens above 150° and melts with decomposition at 174-175°. Anal. Calcd. for Ci6H2204N2Co C, 52.60 H, 6.03 N, 7.67 Co, 16.16. Found C, 52.40 H, 6.11 N, 7.75 Co, 16.05. 

Difficulties associated with the preparation and purification of anhydrous, soluble iminium salts (44) suitable for organometallic additions can in certain instances be avoided by an in situ generation of these reactive molecules. A -(Disubstituted)aminomethyl ethers (or acetates) (69), sulfides (70) and nitriles (71) are frequently utilized in the generation of these salts. In addition, A -(disubstituted)aminomethyl-amides (72), -sulfonates (73) and halides (74) have been employed (Scheme 12). 

Solid-phase synthesis was initialed with acylation of 170 onto (aminomethyl)polystyrene resin using DMAP and DIEA to give 171. A synthetic sequence analogous to the one described in Scheme 4.1.7 afforded 1,4-benzodiazepines 172 linked to the solid support. The aryl-silicon bond was then cleaved in the final step with anhydrous HF, delivering benzodiazepines 173 in good yields (Scheme 4.2.2). 

Sodium acetate anhydrous Sodium diacetate buffer, pharmaceutical supplements Calcium citrate buffer, pharmaceutical tablets Calcium citrate buffer, pharmaceuticals Acetic acid, glacial Adipic acid Albumin Aminomethyl propanediol Aminomethyl propanol... 

A soln. of m-(hydroxymethyl) phenoxyacetic acid in thionyl chloride refluxed 3 hrs., evaporated in vacuo, the residue dissolved in ethylene dichloride, and again evaporated in vacuo —crude m-(chloromethyl) phenoxyacetyl chloride (Y 96%) dissolved in methylene chloride, a soln. of 2 moles of m-nitraniline in the same solvent added with stirring during ca. 15 min., stirring continued for 10 min., treated with anhydrous HCl until the yellow color of free m-nitraniline has disappeared, filtered, crude 2-[(m-chloromethyl)phenoxy]-3 -nitro-acetanilide isolated from the filtrate, dissolved in chloroform containing diethanolamine, and refluxed 6 hrs. 2-(m-[bis-(2-hydroxyethyl) aminomethyl]-... 

Anhydrous HCl introduced at -30° into a soln. of 1,3,5-tri-n-propylhexahydro-triazine in anhydrous acetonitrile, then a soln. of phenol in acetonitrile added, and allowed to stand 24 hrs. at room temp. p-(n-propylaminomethyl)phenol. Y 56%. - p-Substitution is favored by this method in contrast to conventional aminomethylating agents, whidi favor o-substitution. F. e. s. D. D. Reynolds and B.C. Cossar, J. Heterocyclic Chem.5,605(1971) 3,4-dihydro-2H-l,3-benzoxazmes cf. ibid. 8, 611. 

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