<P>The design of new catalytic cascade reactions is at the forefront of modern organic
synthesis because such processes can effectively save time, energy, and materials.
[
1 ]
Especially, the modular combination of different organocatalytic reactions into cascades
has recently become a fruitful concept for complex molecule synthesis.
[
2 ]
This approach fundamentally relies on the reaction compatibility, often realized in
organocatalysis.
[
3 ]
</P><P>Amines and their salts are particularly versatile for the design of organocatalytic
cascade reactions because they can trigger reactions either via enamine or iminium
ion formation.
[
4 ]
Combining enamine and iminium catalysis in different sequences paves a facile way
for the creation of new carbon-carbon bonds and stereogenic centers in a highly controlled
fashion from readily available precursors in one-pot operations.
[
5 ]
Meanwhile, Brønsted acid catalysis have already found many applications in organic
synthesis, and been shown to be compatible with amine substrates and products.
[
6 ]
However, the combination of Brønsted acid catalysis with amine catalysis is largely
undeveloped. In this communication, we wish to report a new strategy for organocatalytic
cascade reactions. We found that the amine substrate itself in combination with a
catalytic amount of a Brønsted acid can function as both enamine and iminium catalyst
accomplishing an aldol condensation-conjugate reduction cascade, which terminates
in a Brønsted acid catalyzed reductive amination and the incorporation of the amine
into the final product. This transformation provides a useful access to
trans 3-substituted cyclohexyl amines in good yields and diastereoselectivities (Scheme
[
1 ]
).</P>
Scheme 1
<P>We have previously demonstrated that salts consisting of an achiral or chiral ammonium
cation and a chiral phosphate anion are powerful catalysts of transfer hydrogenations
of α,β-unsaturated aldehydes and ketones with Hantzsch esters.
[
7 ]
[
8 ]
We have also developed Brønsted acid catalyzed imine reductions and reductive aminations
with Hantzsch esters.
[
9 ]
Based on these results, together with the well-established capacity of amine salts
to catalyze aldolizations,
[
10 ]
we designed a new triple organocatalytic cascade process which integrates enamine
catalysis, iminium catalysis, and Brønsted acid catalysis. Accordingly, treating 2,6-heptanediones
with an amine, a catalytic amount of a Brønsted acid, and two equivalents of a Hantzsch
ester (HE), the corresponding saturated amines should be formed via an aldol condensation-conjugate
reduction-reductive amination cascade (Scheme
[
1 ]
). The first two steps of this reaction would be catalyzed by the amine salt via enamine
catalysis and via a combination of iminium and Brønsted acid catalysis. The amine
would finally be incorporated into the product in a Brønsted acid catalyzed reductive
amination.
[
11 ]
</P><P>This concept was realized by treating 2,6-heptanedione (
1a ) with 1.5 equivalents of
p -ethoxy aniline (PEP-NH
2 ,
2 ), 2.2 equivalents of Hantzsch ester
3 , and 5 mol% of PTSA·H
2 O, in toluene at 40 °C. After 48 hours, cyclohexyl amine
4a was isolated in 72% yield (Scheme
[
2 ]
). The relative configuration of
4a was confirmed by NMR analysis, the
trans isomer being the major product (dr = 4:1).
[
12 ]
We have investigated various solvents without significantly affecting the diastereoselectivity.</P>
Scheme 2
<P>The highest reactivity was observed in toluene. The use of 1.5 equivalents of the
amine was found to minimize the amount of byproduct 3-methylcyclohexanone
6a . This intermediate serves as the precursor for the terminating reductive amination.
Molecular sieves (5 Å) accelerated the reaction. The substrate scope was then examined
under the optimized reaction conditions (Table
[
1 ]
).</P>
Table 1 Substrate Scope
[13 ]
<TD VALIGN="TOP" COLSPAN="5">
</TD>
<TD VALIGN="TOP">
Entry
</TD><TD VALIGN="TOP">
R1
</TD><TD VALIGN="TOP">
Product 4
</TD><TD VALIGN="TOP">
Yield (%)
</TD><TD VALIGN="TOP">
dra
</TD>
<TD VALIGN="TOP">
1
</TD><TD VALIGN="TOP">
Me
</TD><TD VALIGN="TOP">
4a
</TD><TD VALIGN="TOP">
72
</TD><TD VALIGN="TOP">
4:1
</TD>
<TD VALIGN="TOP">
2
</TD><TD VALIGN="TOP">
</TD><TD VALIGN="TOP">
4b
</TD><TD VALIGN="TOP">
65
</TD><TD VALIGN="TOP">
4:1
</TD>
<TD VALIGN="TOP">
3
</TD><TD VALIGN="TOP">
</TD><TD VALIGN="TOP">
4c
</TD><TD VALIGN="TOP">
72
</TD><TD VALIGN="TOP">
3:1
</TD>
<TD VALIGN="TOP">
4
</TD><TD VALIGN="TOP">
</TD><TD VALIGN="TOP">
4d
</TD><TD VALIGN="TOP">
73
</TD><TD VALIGN="TOP">
6:1
</TD>
<TD VALIGN="TOP">
5
</TD><TD VALIGN="TOP">
</TD><TD VALIGN="TOP">
4e
</TD><TD VALIGN="TOP">
86
</TD><TD VALIGN="TOP">
5:1
</TD>
<TD VALIGN="TOP">
6
</TD><TD VALIGN="TOP">
</TD><TD VALIGN="TOP">
4f
</TD><TD VALIGN="TOP">
75
</TD><TD VALIGN="TOP">
4:1
</TD>
<TD VALIGN="TOP">
7
</TD><TD VALIGN="TOP">
</TD><TD VALIGN="TOP">
4g
</TD><TD VALIGN="TOP">
68
</TD><TD VALIGN="TOP">
5:1
</TD>
<TD VALIGN="TOP">
8
</TD><TD VALIGN="TOP">
</TD><TD VALIGN="TOP">
4h
</TD><TD VALIGN="TOP">
83
</TD><TD VALIGN="TOP">
4:1
</TD>
<TD VALIGN="TOP">
9
</TD><TD VALIGN="TOP">
</TD><TD VALIGN="TOP">
4i
</TD><TD VALIGN="TOP">
63
</TD><TD VALIGN="TOP">
8:1
</TD>
<TD VALIGN="TOP">
10
</TD><TD VALIGN="TOP">
Ph
</TD><TD VALIGN="TOP">
4j
</TD><TD VALIGN="TOP">
60
</TD><TD VALIGN="TOP">
5:1
</TD>
<TD VALIGN="TOP">
11
</TD><TD VALIGN="TOP">
</TD><TD VALIGN="TOP">
4k
</TD><TD VALIGN="TOP">
66
</TD><TD VALIGN="TOP">
5:1
</TD>
<TD COLSPAN="20">
</TD></TR><TR><TD VALIGN="TOP" COLSPAN="5">
a Determined by GC-MS or 1 H NMR analysis.
</TD>
<P>Several substituted 2,6-diones (
1a -
k ) react smoothly to the desired products
4 (Table
[
1 ]
). All the substrates afforded good to high yield and the
trans -diastereomer was the major product with selectivities of up to 8:1.</P><P>The initial
aldol condensation is fast and seems to be kinetically controlled. This reaction
almost exclusively takes place between the 1-methyl- and the 6-carbonyl group of the
substrate.
[
14 ]
Even in the case of substrate
1b and
1c , apt to give regioisomeric mixtures, less than 5% of the regioisomers could be detected
in a careful GC-MS study. The aldolization is catalyzed by the amine substrate and
the acid catalyst; either reagent alone is inefficient in catalyzing the reaction.
The formation of 2,6-disubstituted piperidines, which may have been expected from
a double reductive amination, was not observed.</P><P>The conjugate reduction step
is Brønsted acid and amine co-catalyzed and in the absence of either catalyst, no
further conversion of the enone intermediate is observed. That the amine is a true
catalyst of at least the initial two steps of the cascade reaction is revealed when
the reaction is carried out in the presence of only one equivalent of the Hantzsch
ester and a substoichiometric amount of the amine. Under these conditions the product
of the aldol-conjugate reduction sequence is observed as the major product after passing
the crude mixture through a short pad of silica gel. The regioselectivity in the
conjugate reduction step (1,4- vs. 1,2-reduction) is excellent. Only when R
1 is aromatic (entries 9-11), small amounts of the 1,2-reduction products
7i -
k (Figure
[
1 ]
) are formed as byproducts in 10-15% yield. Similar electronic effects have been observed
in reductions of preformed α,β-unsaturated iminium ions.
[
15 ]
</P>
Figure 1
<P>Interestingly, with
t -Bu-substituted diketone
1l , the desired product
4l could be obtained in only 10% (Scheme
[
3 ]
). In this case, compound
8 was formed as major product. Presumably reductive amination is faster than aldol
condensation in this case.</P>
Scheme 3
<P>This method can also be used for the synthesis of heterocyclic compounds. For
example, thiodiketone
1m could be transformed to the corresponding heterocyclic compound
4m in excellent diastereoselecitivity (92:8) and in moderate yield (Scheme
[
4 ]
).</P>
Scheme 4
<P>The PEP group can be readily removed in high yield using H
5 IO
6 , a method recently reported by researchers at DSM (Scheme
[
5 ]
).
[
17 ]
</P>
Scheme 5
<P>In conclusion, we demonstrate that combining enamine catalysis and iminium catalysis
with Brønsted acid catalysis constitutes a powerful strategy for developing organocatalytic
cascade reactions. Based on this strategy, we have developed a new triple organocatalytic
cascade reaction for preparing
trans -3-substituted (hetero) cyclohexyl amines from 2,6-diones, which are constituents
in several pharmaceutically active compounds.
[
17 ]
The use of a catalytic amount of Brønsted acid in combination with a stoichiometric
amount of an achiral amine as self-sacrificing aminocatalyst is a new concept for
organocatalysis. Further extensions of this strategy are under investigation in our
laboratory.</P>