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nium formate as nitrogen and hydrogen source.† Pre-
liminary attempts to perform the reaction in methanol
led to the desired product with low yield but very high
stereoselectivity. This result prompted us to investigate
the solvent effects and we observed that water addition
(10%) to the alcoholic medium surprisingly increased
the reaction yield, still maintaining a very high stereose-
lectivity. Therefore we worked to improve the reaction
conditions in the advantageous aqueous medium.
Table 1. Reductive amination of several ketones
The method reported in the general procedure is opti-
mised for the 3-endo-tropanamine synthesis and
allowed us to obtain the product in very high yield and
stereoselectivity. Nevertheless this procedure was ver-
ified with other carbonyl compounds and shown to be
a general route for the synthesis of primary amines
from ketones under mild reaction conditions and with
high yields (Table 1).
Our new method has the use of ammonium formate as
the hydrogen source in common with the well-known
Leuckart reaction,7 but the palladium catalyst avoids
harsh conditions (high temperatures, lack of solvent
and undesired side reactions) inappropriate for indus-
trial use. In addition we obtained unexpected results in
terms of yield and stereoselectivity; the 3-exo-
tropanamine isomer is practically undetectable (<0.1%
determined on the crude residue using common analyti-
cal GC methods).
tion replacing ammonium formate with ammonium
acetate and bubbling through hydrogen gas as the
hydrogen source; as expected no product formation was
observed.
Looking at the hypothetical imine intermediate 2b, it is
not obvious what effect water has on the reaction yield
.
because of the instability of the imine species in the
aqueous medium. In our opinion water addition disfa-
vours imine formation from the hemiaminal intermedi-
ate which, under the reaction conditions, is directly
reduced to the endo-amine 3. This hypothesis is in line
with the observed stereoselectivity because the endo-
aminal 2a is the favoured one according to Alder’s rule8
(Scheme 1).
In summary, we have found a simple, high yielding,
one-pot, convenient procedure for the transformation
of ketones into primary amines. This method, opti-
mised for the synthesis of 3-endo-tropanamine from
tropanone, gives useful results with several ketones.
Our reaction conditions allow the desired products to
be obtained in high yield and stereoselectivity. This
procedure is an improved choice to Borch and Leuck-
art’s methods commonly used for the synthesis of pri-
mary amines by reductive amination.
We think that the aminal reduction occurs by a direct
transfer of the formate hydrogen mediated by the cata-
lyst. To support this hypothesis we carried out a reac-
† General procedure for the synthesis of 3-endo-tropanamine 3: A
solution of 8-methyl-8-azabicyclo[3.2.1]octan-3-one (1) (6 g, 43
mmol) in MeOH (112 mL) was treated, with vigorous stirring, with
ammonium formate (25 g, 0.40 mol) and water (12.5 mL). After
complete dissolution, 10% Pd/C (5.1 g, 4.8 mmol) was added and
the reaction mixture was stirred overnight at room temperature. On
completion of the reaction (TLC, eluent: EtOH/NH4OH, 8:2), the
catalyst was filtered off on Celite and the solution was concentrated
under reduced pressure; the oily residue obtained was dissolved in
EtOH (100 mL) and to the solution 37% HCl (7.5 mL) was added
dropwise. The solution was seeded and left stirring at room temper-
ature for 1 h and at 4°C for 5 h. The resulting white precipitate was
filtered and dried at 40°C under vacuum to give endo-8-methyl-8-
azabicyclo[3.2.1]octane bis hydrochloride (7.6 g, 35.6 mmol) in 83%
yield; mp >360°C. 1H NMR (300 MHz, DMSO-d6) l 11.2–11.0 (bs,
1H), 8.7–8.2 (bs, 3H), 4.0–3.8 (bs, 2H), 3.7–3.5 (m, 1H), 2.8–2.55
(m, 5H), 2.4–2.05 (m, 6H). Anal. calcd for C8H18N2Cl2 (213.48).
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