Author Topic: 1-Methyl-4-cyano-4-phenylpiperidine (1h, 95%)  (Read 1546 times)

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1-Methyl-4-cyano-4-phenylpiperidine (1h, 95%)
« on: November 27, 2003, 12:01:00 AM »
An Improved Preparation of 1-Methyl-4-Cyano-4-Phenylpiperidine
D. Gnecco, J. L. Teran, R. G. Enríquez, W. F. Reynolds, C. Marazano
Org. Prep. Proced. Int. 28(4), 478-480 (1996)

Several synthetic approaches are available for the preparation of 1-methyl-4-cyano-4-phenylpiperidine (1). These methods all involve refluxing the starting material in toluene or benzene for several hours which results in the formation of polymeric residues, making the purification process difficult and leading to low overall yields1. Since 1 is a key intermediate for the synthesis of derivatives which exhibit potent narcotic-analgesic or antihypertensive effects2, it would be highly desirable to have a better method for the synthesis of 1. The present work describes modifications that significantly improve its preparation.

Reaction of phenylacetonitrile and bis-(-chloroethyl)methylamine hydrochloride in anhydrous ether with sodium amide at -5°C afforded 1 in yields which were on average 30-40% higher than those previously reported1.

1-Methyl-3-keto-4-phenylquinuclidinium bromide (4) and intermediates 2 and 3 were prepared from 1 according to Perrine's method3.


Caution: Care should be exercised when preparing compound 1 due to the toxicity of bis-(-chloroethyl)methylamine hydrochloride and derivatives.

1-Methyl-4-cyano-4-phenylpiperidine (1)

To bis-(-chloroethyl)methylamine hydrochloride (4.0g, 20.8 mmol) and sodium amide (3.3 g, 83.2 mmol) in a 250 mL round bottom flask in 50 mL of anhydrous ether with magnetic stirring and an inert atmosphere of Argon at -5°C, was added dropwise a solution of phenylacetonitrile (5 mL, 43.4 mmol) in 50 mL of anhydrous ether. After 50 min at room temperature, the reaction was complete. The mixture was cooled to 0°C and upon addition of 15 mL of H2O, two phases separated. The organic phase was washed with a saturated solution of ammonium chloride until neutral. After drying over anhydrous sodium sulfate and removal of solvent in vacuo, a yellowish oil (7.90 g, 95%) consisting of a mixture of the free base of 1 with unreacted phenylacetonitrile was obtained. The crude product was dissolved in 10 mL of ethanol and 2 mL of concentrated HCl were added which afforded the hydrochloride of 1 (4 g, 80% based on reacted phenylacetonitrile) as colorless needles, mp 223-225°C. The hydrochloride of 1 (1 g) could be converted quantitatively into the free base (yellow oil).

Compound 1·HCl 1H NMR (DMSO-d6): 2.49 (m, 4H), 3.31 (s, 3H), 3.30 (br, t, 2H), 3.60 (d, Jgem=12.3 Hz, 2H), 7.60 (m, 5H).


1. a) H. R. Le Sueur and P. Haas. J. Chem. Soc., 97, 967 (1910); b) O. Eisleb and O. Schaumann, Deut. Med. Worrsch., 65, 967, Chem. Abstr., 36, 54653 (1939); c) O. Eisleb, Ber., 74, 1443 (1941); d) A. T. Nielsen, J. Org Chem., 31, 1053 (1966); e) J. Carrol, A. N. Fergusson and J. B. Lewis, J. Org Chem., 31, 2957 (1966); f) D. S. Watt, Tetrahedron, 24, 175 (1968).

2. a) E. Hong,

Patent US3860717

; Chem. Abstr., 82, 149531z (1975); b) L. E. Mather and P. J. Meffin., Clin. Pharmacokinet., 3, 352 (1978); Chem. Abstr., 90, 40w (1979).

3. T. D. Perrine, J. Org. Chem., 22, 1484 (1957).


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« Reply #1 on: November 29, 2003, 06:22:00 AM »
Doug Thompson and Perry C. Reeves, Facile Synthesis of N-Substituted-4-cyano-4-phenylpiperidines via Phase-Transfer Catalysis : J. Heterocyclic Chem., 20, 771 (1983)

The recent advent of phase-transfer catalysis has provided attractive alternatives to the use of hazardous bases such as sodium amide and anhydrous aprotic solvents. It has been demonstrated that phenylacetonitrile can be alkylated under phase-transfer conditions with 1,5-di-bromopentane and bis(2-chloroethyl)ether to yield the corresponding six-membered rings (4). Attempts to extend this technique to the synthesis of nitrogen heterocycles have been plagued by very low yields (5,6).
While attempting to prepare some piperidine derivatives by phase-transfer methods, we compared the activity of a number of catalysts including benzyltriethyl-ammonium chloride, tricaprylmethylammonium chloride (Aliquat 336), trialkyl(C8 —C10)methylammonium chloride (Adogen 464), dicyclohexyl-18-crown-6, and hexadecyltri-butylphosphonium bromide. All of these catalysts are active, but the phosphonium catalyst is vastly superior to the others for this specific application. It produces high yields of the desired compounds in a short reaction time with only trace amounts of undesired byproducts being formed. Typically a mixture of phenylacetonitrile, an N-substituted-bis(2-chloroethyl)-amine, 50% aqueous sodium hydroxide solution, and a catalytic amount of hexadecyltributyl-phosphonium bromide is stirred and heated at 100° for one hour. Isolated yields of the Ar-substituted-4-cyano-4-phenylpiperidines range from 60-88% (Table I). A variety of substituents can be tolerated on the nitrogen atom including those (phenyl, tert-butyl) which could not have been incorporated into the molecule by direct alkylation reactions.
In summary, this method provides an attractive alternative to the reactions utilizing sodium amide in that sodium hydroxide is the base and water is the reaction medium. Reaction conditions are mild, times are short, and yields are generally higher than those reported when sodium amide is used.


Into a three-necked, 100-ml round bottom flask equipped with a mechanical stirrer and a reflux condenser was placed 3.00 g (25.6 mmoles) of phenylacetonitrile, 5.58 g (25.6 mmoles) of N-phenyl-bis-(2-chloroethyl)-amine (or an equivalent amount of the hydrochloride salt), 0.67 g (1.3 mmoles) of hexadecyltributylphosphonium bromide and 30 ml of 50% aqueous sodium hydroxide. The mixture was stirred vigorously while being heated at 100° for one hour. The cooled mixture was transferred to a separatory funnel, diluted with 100 ml water and extracted with ether (3 X 50 ml). The ether extracts were washed with water (2 X 50 ml) and extracted with three 50 ml portions of a 1:1 mixture of concentrated hydrochloric acid and water. The acid extracts were neutralized with solid sodium carbonate and extracted with ether (3 X 50 ml). The ether extracts were dried over anhydrous magnesium sulfate and evaporated to yield 5.92 g (88%) of the desired compound, mp 94-95° (lit (8) 97°).


SWIM used N-benzyl-bis-(2-chloroethyl)-amine hydrochloride, and TBAB (tetrabutylammonium bromide) as PTC catalyst. Yields was around 80% - beautiful white cryst. solid with sharp mp at 75 C.