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         Reductive amination with Titanium(IV)Isopropoxide - by Cesium
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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 hihg
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 presumablz functioning as a Lewis acid catalyst as
well as an excellent water scavenger to generate imines which are reduced bz
sodium borohzdride. Another possible mechamism is formation of stable
intermediate aminocarbinolatotitanium complexes, that are reduced either
directlz 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 Ethanole (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

and finally somthing for those lowing cyano:
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. 20°C, b.p. 232 °C,
97% 100 ml = 23 DM, 2 L = 175 DM Aldrich
Triethylamine 99+% 100 ml 10 DM, 1 L 49 DM Sigma
