Optically active amine derivatives: Ruthenium-catalyzed enantioselective hydrogenation of enamides

Article abstract of DOI:10.1055/s-1999-2937

Enamides have first been prepared by reaction of 5-methoxy-3-chromanone and 2-tetralone with primary amides under acidic conditions. The enantioselectivities observed in the asymmetric hydrogenation of these enamides using ruthenium catalysts strongly dep

Full text of DOI:10.1055/s-1999-2937

1
832
LETTER
Optically Active Amine Derivatives: Ruthenium-Catalyzed Enantioselective
Hydrogenation of Enamides
P. Dupau, P. Le Gendre, C. Bruneau,* P. H. Dixneuf
UMR 6509 : CNRS - Université de Rennes - Organométalliques et Catalyse, Campus de Beaulieu, 35042 Rennes Cedex, France
E-mail: christian.bruneau@univ-rennes1.fr
Received 12 August 1998
Abstract: Enamides have first been prepared by reaction of 5-meth-
oxy-3-chromanone and 2-tetralone with primary amides under acid-
ic conditions. The enantioselectivities observed in the asymmetric
hydrogenation of these enamides using ruthenium catalysts strongly
depended on both the starting ketone and the nature of the amide
group.
Scheme 1
Key words: ketone, enamide, enantioselective hydrogenation, ru-
thenium catalyst
The enamides were directly obtained from the non activat-
ed ketones 1 and 2 by direct reaction with primary amides
Optically active amine derivatives constitute a class of under acidic conditions (Scheme 2).
key intermediates towards human health products and1
may be used as efficient ligands for asymmetric catalysis.
Up to now, one of the most direct routes for the access to
these compounds appears to result from the enantioselec-
tive catalytic hydrogenation of enamides. Since the first
example reported by Kagan and coworkers using rhodi-
2
um-diop catalyst precursor, excellent enantioselectivities
were recently reached in the presence of ruthenium-
3
,4
5
binap and rhodium-duphos or rhodium-pennphos pre-
catalysts.
The transformation of a ketone into an enamide is an effi-
cient way to generate a prochiral amine derivative con-
taining a chelating functional group able to orientate the Scheme 2
enantioselective hydrogenation. According to this strate-
gy, Tschaen and coworkers reported the synthesis of sev-
eral enamides by direct condensation of amides with a The enamides 3 and 4 were thus obtained by treatment of
ketone during the course of asymmetric synthesis of MK- 10 mmol of the 5-methoxy-3-chromanone 1 with 25 mmol
4
5a
0
499. More recently, Burk and coworkers have report- of amide in the presence of 1 mmol of paratoluenesulfonic
ed a two-step method for synthesis of acetyl enamides acid (PTSA) (10 mol% with respect to the ketone) in re-
starting from cyclic and acyclic ketones via acylation on fluxing toluene in a Dean-Stark apparatus for 20 h. The re-
nitrogen of oximes using acetic anhydride in the presence action mixture was then washed with water, dried over
of iron powder and acetic acid.
MgSO and evaporated to dryness. The pure enamide 3
4
was obtain as a white solid in 80% yield after simple
washing with pentane. Purification by chromatography
over silica gel with an ether/pentane mixture as eluent
gave the enamide 4 as a white solid in 52% yield. The
commercially available 2-tetralone 2 (97% from Lancast-
er) was converted into the enamides 5-8 in 80, 75, 98, and
Among optically active amines, 3-aminochromans and 2-
aminotetralins are of great interest, because they are
present in biologically active compounds such as (+)-S
6
4
7
2
0499 , MK-0499 and SR58611A. This provided impe-
tus to study the catalytic hydrogenation of chromanone
and tetralone derivatives to obtain precursors of these two
amines.
8
0% yield, respectively. In these cases the reaction had to
be carried out under inert atmosphere in order to avoid
degradation of the ketone. It is worth noting that, in the
case of monochloroacetamide, the use of 5 equivalents of
this amide and refluxing for 48 hours was necessary to ob-
tain 6 in 75% yield. This is probably due the slight elec-
tron attracting effect of the chloromethyl group which
leads to the deactivation of the amide moiety (in com-
parison to acetamide). The same effect probably explains
We now report:
i) an efficient preparation of various enamides from 5-
methoxy-3-chromanone and 2-tetralone, and
ii) their enantioselective hydrogenation in the presence of
optically active ruthenium catalysts into optically active
amides (Scheme 1).
Synlett 1999, No. 11, 1832–1834 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Ruthenium-Catalyzed Enantioselective Hydrogenation of Enamides
1833
that, under similar conditions, no conversion into the de- Similarly, the 2-tetralone enamide derivatives 5-8 were
sired product was obtained with trichloroacetamide.
hydrogenated under 100 bar of H at 20-60°C in the pres-
2
ence of A or B as catalysts (Scheme 3). The results are
summarized in the Table 1. In most cases the hydrogena-
tion of 1 mmol of enamide went to completion at 20 °C
within 20 h with a substrate/catalyst ratio of 200. The
presence of the monochloroacetyl group in the enamide 6
led to a decrease of reactivity and only 50% of conversion
was observed after 20 h at 20 °C. However, a reaction
temperature of 60 °C or a substrate/catalyst ratio of 100
made possible the total conversion of 1 mmol of 6 in 20 h.
Noyori and coworkers had previously reported that us-
ing a trifluoroacetyl group instead of an acetyl one led to
a dramatic decrease of the reactivity in the asymmetric hy-
drogenation of the carbon-carbon double bond of an ena-
mide substrate with the same type of ruthenium catalysts.
The direct hydrogenation of the enamides was attempted
in the presence of catalytic amounts of optically active
ruthenium complexes containing the atropoisomeric
Binap ligand: ((R)-Binap)Ru(O CCF )
A
9and
2
3 2
8
[
NH Et ][{RuCl((S)-Binap)} (m-Cl) ] B (Scheme 3).
2
2
2
3
3
a
As noticed with the chromanone derivatives, we observed
a difference in enantioselectivity between ((R)-Bi-
nap)Ru(O CCF )
A
and [NH Et ][{RuCl((S)-Bi-
2
3 2
2 2
Scheme 3
nap)} (m-Cl) ] B as catalysts, A always giving the best
2
3
results. The presence of the chloro substituent on the
amide group had a negative effect on the enantioselectiv-
ity of the hydrogenation. Whereas good ee's were ob-
tained from acetyl (5) (90%), propionyl (7) (90%) and
benzoyl (8) (96%) enamides at 20 °C with A as catalyst,
only 71% ee was achieved from the substrate 6 under sim-
ilar hydrogenation conditions. The overall effect of the
exchange of an acetyl group into a monochloroacetyl one
is a decrease of both reactivity and enantioselectivity. The
best result obtained from the benzoyl enamide 8 (96% ee)
was comparable to the enantioselectivities resulting from
the hydrogenation of benzoyl enamides derived from 6-
and 7-substituted 2-tetralone using ruthenium catalysts.4
,7
During the course of hydrogenation of the acetyl enamide
5
, we tried to reduce the quantity of catalyst and were able
to obtain complete conversion into the saturated substrate
in 90% ee at 20 °C in 48 h with a substrate/catalyst ratio
of 1000.
Starting from the same type of structure (fused 6-mem-
bered ring ketones with the carbonyl group in b-position
with respect to the aromatic ring), enamides derived from
the 5-methoxy-3-chromanone 1 and the 2-tetralone 2 gave
quite different results in terms of enantioselectivity. The
possible interaction, with the metal centre, of an ether ox-
ygen atom, either from the pyran ring or the methoxy
group on the aromatic ring or both of them in compounds
The enamides 3 and 4 obtained from the 5-methoxy 3-
chromanone 1 were hydrogenated in methanol under 100
bar of hydrogen. The two enamides showed similar reac-
tivities and complete conversion was obtained within 20 h
under mild conditions at 20-30°C (Table 1).
3
and 4, leads to a dramatic decrease of the enantioselec-
tivity during the hydrogenation reaction.
During the hydrogenation of the ene acetamide 3, an im-
portant difference in enantioselectivity was noticed when
either A or B was used as catalyst (in the best case, 35%
ee were obtained with catalyst A, whereas the precatalyst
B led to 8% ee under similar conditions). Nevertheless,
the utilization of ((R)-Binap))Ru(O CCF ) as catalyst for
The direct hydrogenation of enamides containing an intra-
cyclic C=C bond, in the presence of Binap-ruthenium cat-
alysts leads to a complete conversion into saturated
amides. Both reactivity and enantioselectivity strongly
depend on the presence of an additional coordinating
functionality on the substrate skeleton and on the nature of
the amide. Excellent conversion and enantioselectivity
with high substrate/catalyst ratio have been obtained from
the 2-tetralone enamides.
2
3 2
the hydrogenation of the enamides 3 and 4 afforded very
modest enantioselectivities (35 and 40% ee, respectively).
Synlett 1999, No. 11, 1832–1834 ISSN 0936-5214 © Thieme Stuttgart · New York

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P. Dupau et al.
LETTER
th
Acknowledgement
(6) Usse, S.; Guillaumet, G.; Viaud, M.-C. 10 IUPAC
Symposium on Organo-Metallic Chemistry directed towards
Organic Synthesis, 18-22 July 1999, Versailles (France),
P-495.
(
(
(
The authors are very grateful to Dr. A. Renaud, J.-C. Souvie and J.-
P. Lecouvé from ORIL Industrie Company for fruitful discussions
and financial support.
7) Devocelle, M.; Mortreux A.; Agbossou, F.; Dormoy, J. R.
Tetrahedron Lett., 1999, (in press).
8) Ohta, T.; Tonomura, Y.; Nozaki, K; Takaya, H; Mashima, K.
Organometallics, 1996, 15, 1521-1523.
9) Typical procedure for enantioselective hydrogenation of
enamides 3-8: 1 mmol of enamide and 0.005 mmol of
ruthenium catalyst were placed in a 125 ml autoclave in 8 ml
of methanol. After degassing with hydrogen, a pressure of 100
bar of hydrogen was applied. The autoclave was stirred
mechanically during 20 to 60 h and the conversion was
References and Notes
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(
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1
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(
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Article Identifier:
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Synlett 1999, No. 11, 1832–1834 ISSN 0936-5214 © Thieme Stuttgart · New York