Nitriles to tertiary amines
(Rated as: excellent)
I found this very interesting route which I belive can be a great way to make a lot of nice compounds.
CONVERSION OF NITRILES INTO TERTIARY AMINES
Step A. 2-(3,4-Dimethoxyphenyl)-N,N-dimethylacet
An oven-dried, 250-mL, single-necked, round-bottomed flask containing a 3-cm magnetic stirring bar is charged with 7.96 g (0.045 mol) of (3,4-dimethoxyphenyl)acetonitrile (Note 1) and 4.95 g (0.050 mol) of copper(I) chloride (Note 2), fitted with a septum, flushed with argon, and maintained under a static pressure of argon using a gas bubbler. Using a 20-mL gas-tight syringe, 45 mL (0.067 mol) of a 1.5 M ethanolic solution of dimethylamine (Note 3) is added successively in three 15-mL portions at room temperature with vigorous stirring. The heterogeneous pale brown mixture is then heated at 70°C for 24 hr, during which time it becomes brown-red. The mixture is cooled to room temperature and poured with vigorous stirring into a 250-mL Erlenmeyer flask containing 70 mL of aqueous 30% sodium hydroxide and 100 mL of diethyl ether (Note 4); the mixture was stirred vigorously for 3 min. The organic layer is separated, and the aqueous layer is extracted with three 75-mL portions of diethyl ether (Note 5). The combined organic extracts are dried over sodium sulfate and filtered through a sintered glass funnel layered with 2 cm of Celite. The solid residue is washed with diethyl ether (20 mL). The combined filtrate and washings are concentrated by rotary evaporation followed by drying under reduced pressure (0.1 mm) for 1.5 hr to provide 9.1-9.4 g (93-96% yield) of a dark brown oil (Note 6),(Note 7). The compound is stored under argon at −18°C until used in step B.
Step B. N,N-Dimethylhomoveratrylamine.
An oven-dried, 100-mL, Erlenmeyer flask is equipped with a magnetic stir bar, and charged with 9.05 g (0.041 mol) of 2-(3,4-dimethoxyphenyl)-N,N-dimethylacet
1. (3,4-Dimethoxyphenyl)acetonitrile was obtained from Aldrich Chemical Company, Inc., and used without further purification.
2. Copper(I) chloride was obtained as a light green powder from Aldrich Chemical Company, Inc. (ref. Aldrich 21,294-6). The submitters obtained material with the same catalog number as sticks, which were carefully ground immediately before use.
3. The 1.5 M solution of dimethylamine in ethanol was prepared as follows: Aqueous 40% dimethylamine is heated at 65°C under a flow of argon. The gas is passed through potassium hydroxide pellets and blown across a known quantity (100 mL) of absolute ethanol (analytical grade used without purification), then cooled to 0°C in an ice bath, with continuous stirring, for 3 hr. The ethanolic solution is weighed and diluted to 150 mL with absolute alcohol. The ethanolic dimethylamine solution (ca. 1.5 M) is carefully capped and kept under an inert atmosphere at −18°C. The concentration may be measured by pouring a 1-mL aliquot of the ethanolic dimethylamine solution into aqueous 1 N hydrogen chloride. Water and ethanol are removed by rotary evaporation, and the residue is dried over potassium hydroxide pellets under vacuum (0.3 mbar, 2.5 mm) for one night. The weight of residue allows the exact concentration of the ethanolic dimethylamine solution to be measured.
With other less volatile amines (see Table I), the mixture of Cu(I)Cl, nitrile, and amine is simply refluxed in ethanol. In such a case, 1.1 equiv only of amine can be used.
Indole-3-acetonitrile and a N,N-dialkylamine should give a N,N-dialkylated tryptamine is good yields.
Acetonitrile and benzylamine gave 70% overall yield of N-benzyl-N-ethylamine. This leads me to belive that this can be a very nice way to get primary amines as well by the following route:
Ar-CH2-CN + Ar-CH2-NH2 --> Ar-CH2-CH2-NH-CH2-Ar
Ar-CH2-CH2-NH-CH2-Ar (debenzylation by catalytic transfer hydrogenation) --> Ar-CH2-CH2-NH2
Very interesting find Barium! Anyone have an idea of the mechanism behind the first step? CuCl catalyzed hydrolyses and reduction maybe? I wonder what the product would be if the reaction was run in the absence of diethylamine- the phenylacetic acid?
The sodium borohydride reduction of secondary amides is also very interesting. This is the first procedure I have seen using NaBH4/methanol to reduce such an amide. Doesn't conventional organic chem teaching state that NaBH4 is unreactive towards such amides?
|Here is some more info on the addition step: ...||Bookmark|
Here is some more info on the addition step: ../rhodium/pdf /amine.nitrile
|Just figured I'd state the obvious||Bookmark|
This has great potential use for Tryptamine Synthesis.
Will perform sexual favors for females in exchange for 1,2-dimethylaziridine. PM for details.
|nabh4 redn of amides||Bookmark|
nabh4-methanesulphonic acid mixtures in dmso reduce amides to amines in reasonable yields 50%
nabh4-acetic acid mix in dioxane reduces 1o and 2o amides to the amines I dont think this agent reduces tert amides
nabh4-triflouroacetic acid (active reducing agent sodium trifluoroacetoxy borohydride) reduced tert amides to tert amines in reasonable to good yields