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Reductive amination with Titanium(IV)Isopropoxide

by Cesium

Facile, high-yielding method, using safe and inexpensive reagents, does not require the use od gaseous ammonia or methylamine with simple work-up is given here. The reaction has been successfully applied to carbonyl compounds containing sensitive functional groups (such as acetals, carbamate, benzyloxy-, methoxy-, nitro-, cyano-, bromo- groups.) attached to carbonyl without destruction of these groups.


Synlett 11, 1781-83, 1999: Selective monoalkylation of ammonia: A high throughput synthesis of primary amines:

The ketone is allowed to react with a mixture of ammonium chloride, triethylamine and titanium(IV)isopropoxide in absolute EtOH. Titanium(IV)isopropoxide is presumably functioning as a Lewis acid catalyst as well as an excellent water scavenger to generate imines which are reduced by sodium borohydride. Another possible mechamism is formation of stable intermediate aminocarbinolatotitanium complexes, that are reduced either directly or via transient iminium species.

General procedure:

10 mmol of Ketone, 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 room temp. for 10 h. Sodium borohydride (0.57 g, 15 mmol) was added and the mixture stirred for additional 7 h at room temp. The reaction was quenched by pouring into aq. ammonia (30 ml, 2M), organic layer separated, A/B extraction, drying over MgSO4. Yield of primary amine after isolation purification for acetophenone was 83%.


J. Chem. Soc., Perkin Trans. 1, (16), 2527-2532 : 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-Me secondary amines from aldehydes and ketones is reported. Treatment of carbonyl compds with methylamine hydrochloride, NEt3 and Ti(IV) isopropoxide, followed by in situ Na borohydride redn. and straightforward aq. work-up, affords clean products in good to excellent yields. An equimolar mixture of methylamine hydrochloride and triethylamine is used as the mathylamine equivalent. This alleviates the use of excess gaseous methylamine. The reaction may proceed through an intermediate methylaminoalcoholatotitanium complex which is than reduced. Only N-monomethylated secondary amines are formed.

General procedure: 10 mmol of Ketone, titanium(IV)isopropoxide (5.9 ml, 20 mmol), methylamine hydrochloride (1.35 g, 20 mmol) and triethylamine (2.79 ml, 20 mmol) in absolute Ethanole (15 ml) was stirred in a capped flask at room temp. for 8-10 h. Sodium borohydride (0.57 g, 15 mmol) was added and the mixture stirred for additional 7-8 h at room temp. The reaction was quenched by pouring into aq. ammonia (30 ml, 2M), resulting inorganic precipitate filtered off, organic layer separated, A/B extraction, drying. Yield of primary amine after isolation purification for acetophenone was 86 % of N-methyl-phenethylamine.

Further reading:

Synlett, (10), 1079-80 (English) 1995: An efficient, safe and convenient one-step synthesis of beta-phenethylamines via reductive amination reactions utilizing Ti(OCHMe2)4 and NaBH4

Tetrahedron Lett., 35(15), 2401-4 (English) 1994: Titanium(IV) isopropoxide and sodium borohydride: a reagent of choice for reductive amination

J. Org. Chem., 60(15), 4928-9 (English) 1995: Reductive alkylation of dimethylamine using titanium(IV) isopropoxide and sodium borohydride: an efficient, safe, and convenient method for the synthesis of N,N-dimethylated tertiary amines

J. Org. Chem., 55(8), 2552-4 (English) 1990: An improved method for reductive alkylation of amines using titanium(IV) isopropoxide and sodium cyanoborohydride

Titanium isopropoxide = Ti(O-i-C3H7)4, m.p. 20C, b.p. 232 C