Reductive Amination of Ketones to Primary Amines with Ammonium Chloride/Titanium(IV)Isopropoxide/Sodium Borohydride

The reductive amination of carbonyl compounds that allows an expedient access to diverse amines is one of the most widely applied reactions in synthetic organic chemistry. The synthesis involves the formation of an imine or iminium intermediate upon exposure of a carbonyl compound to an amine followed by in situ reduction to an alkylated amine. Though many of the reported protocols for reductive amination reactions work well for the preparation of tertiary and secondary amines, synthesis of primary amines by reductive alkylation of ammonia is mostly compromised by overalkylation reactions. The formation of variable amounts of secondary and tertiary amines along with the desired primary amines is common. In connection with our ongoing investigations on reductive amination reactions, we have recently used a combination of titanium(IV)isopropoxide and sodium borohydride in the reductive alkylations of primary and secondary amines. Encouraged by our success, we envisaged that selective monoalkylation of ammonia with carbonyl compounds may be achieved with this one-pot reagent system. Indeed, this has been the case. We explored the application of this one-pot reagent system in the selective monoalkylation of ammonia with a variety of ketones to provide primary amines in good to excellent yields and the results are reported herein. A mixture of ammonium chloride and triethylamine has been employed as the ammonia equivalent; this requires no special handling techniques and alleviates the use of excess gaseous ammonia. In this reagent system, both alkyl and aryl ketones were converted to the desired primary amines in high yields; no over-alkylation of the product primary amines was observed. The relevance of this protocol has been demonstrated on a structurally varied set of ketonic8 substrates. The ketones were allowed to react with a mixture of ammonium chloride, triethylamine and titanium(IV)isopropoxide, followed by the treatment with sodium borohydride at room temperature.

Typically, the intermediate aminocarbinolatotitanium(IV) complex was first allowed to form by stirring a mixture of the ketone, ammonium chloride- triethylamine and titanium(IV) isopropoxide in absolute ethanol at ambient temperature for 9-11 h. Sodium borohydride was then added and the resulting mixture was stirred for another 7-8 h at ambient temperature. Finally, the reaction mixture was quenched with aqueous ammonia (2 M) and then extracted with Et2O. The product amines were isolated in their pure forms by simple extraction of the organic solution with hydrochloric acid (1 M), basification of the aqueous layer and subsequent extraction with Et2O. Under these reaction conditions, only primary amines are formed – the traditional problem of over-alkylation of the product amines was not observed.

In conclusion, an efficient one-pot reagent system has been developed for the synthesis of primary amines by selective monoalkylation of ammonia with alkyl and aryl ketones using titanium(IV) isopropoxide and sodium borohydride. Because this method allows easy, direct access to diverse primary amines, it should find widespread application.

General Experimental Procedure

A mixture of the ketone (10 mmol), titanium(IV)isopropoxide (5.9 mL, 20 mmol), ammonium chloride (1.07 g, 20 mmol) and triethylamine (2.79 mL, 20 mmol) in absolute ethanol (20 mL) was stirred in a capped flask at ambient temperature for 9-11 h. Sodium borohydride (0.57 g, 15 mmol) and was then added and the resulting mixture was stirred for an additional 7-8 h at ambient temperature. The reaction was then quenched by pouring into aqueous ammonia (30 mL, 2M), and the inorganic precipitate was filtered and washed with diethyl ether (50 mL). The organic layer was separated and the aqueous layer was extracted once with diethyl ether (50 mL). The combined organic extracts were next extracted with hydrochloric acid (20 mL x 2.1 M) to separate the non-basic materials. The acidic aqueous solution was washed once with diethyl ether (20 mL), then treated with aqueous sodium hydroxide (2 M) to pH 10-12, and extracted with diethyl ether (25 mL x 3). The combined organic extracts were washed with brine (30 mL), dried (MgSO4) and the solvent was removed to afford the primary amine in 62-92% yield. The products were typically more than 90% pure after work-up.

Facile preparation of N-methyl secondary amines by titanium(IV)isopropoxide-mediated reductive amination of carbonyl compounds

A simple, mild and efficient procedure for obtaining N-methyl secondary amines from aldehydes and ketones is reported. Treatment of carbonyl compounds with methylamine hydrochloride, triethylamine and titanium(IV) isopropoxide, followed by in situ sodium borohydride reduction and straightforward aqueous work-up, affords clean products in good to excellent yields.

Reductive amination of MDP2P with MeNH2.HCl, Ti(iPrO)4, NaBH4 and Et3N [2]

A mixture of 3,4-Methylenedioxyphenyl-2-propanone (1.78g, 10 mmol), titanium(IV)isopropoxide (5.9ml, 20 mmol), methylamine hydrochloride (1.35 g, 20 mmol) and triethylamine (2.79ml, 20 mmol) in 15ml absolute ethanol (or methanol) was stirred (preferably under inert atmosphere) room temp for 8–10 h. Sodium borohydride (0.57g, 15 mmol) was then added and the resulting mixture was stirred for an additional 7–8 h at ambient temperature. The reaction was then quenched by pouring into 30ml 2M aqueous ammonia, the resulting inorganic precipitate was filtered off, and washed with 50ml dichloromethane. The organic layer was separated and the remaining aqueous layer was extracted once with 50ml dichloromethane. The combined organic extracts were next extracted once with hydrochloric acid (1 M, 25ml) to separate the neutral materials. The acidic aqueous extracts were washed once with 50ml dichloromethane, then treated with dilute aqueous sodium hydroxide to pH 10–12, and extracted with 3x50ml dichloromethane. The combined organic extracts were washed with 50ml brine, dried over MgSO4 and concentrated in vacuo to afford N-Methyl-3,4-Methylenedioxyphenyl-2-aminopropane in good yield.

[1] Synlett 1781–1783 (1999)

[2] JCS Perkin Trans 1, 2527-31 (1998)