Enamine catalysis with low catalyst loadings - High efficiency via kinetic studies

Article abstract of DOI:10.1021/ja9068112

(Chemical Equation Presented) Kinetic studies on enamine catalysis provided insight into the rate determining step(s) of peptide catalyzed conjugate addition reactions between aldehydes and nitroolefins. They demonstrate that not enamine formation but both the reaction of the enamine with the electrophile and hydrolysis of the resulting imine are rate limiting. These results allowed for reducing the catalyst loading by a factor of 10 to as little as 0.1 mol %. This is the lowest catalyst loading that has been achieved so far in enamine catalysis with low molecular weight catalysts for a broad range of substrates.

Full text of DOI:10.1021/ja9068112

Published on Web 09/30/2009
Enamine Catalysis with Low Catalyst Loadings - High Efficiency
via Kinetic Studies
Markus Wiesner, Gre´gory Upert, Gaetano Angelici, and Helma Wennemers*
Department of Chemistry, UniVersity of Basel, St. Johanns-Ring 19, CH-4056 Basel, Switzerland
Received August 11, 2009; E-mail: Helma.Wennemers@unibas.ch
Scheme 2. Catalytic Cycle Proposed for Conjugate Addition
Reactions of Aldehydes to Nitroolefins Catalyzed by Peptide 1
Enamine catalysis with chiral secondary amines of low molecular
weight has become a versatile method to activate aldehydes and ketones
for reactions with different electrophiles.1 A multitude of different
amine-based catalysts has been introduced over the past decade that
provide the products in high stereoselectivities.1 The understanding
of the kinetics and rate determining steps in enamine catalysis is,
however, still limited.2,3 Better insight into the catalytic cycle could
in particular be useful to address a major challenge in enamine catalysis:
typically high catalyst loadings (10-20 mol %) are necessary to obtain
the products in good yields and stereoselectivities.1 Only a few
examples have been presented where enamine catalysis is possible
utilizing 1 mol % or less of the catalyst.4-6 Herein we describe how
kinetic studies provided insight into the catalytic cycle of peptide
catalyzed conjugate addition reactions and allowed for reducing the
catalyst loading by a factor of 10 to as little as 0.1 mol %.
Previously we introduced peptides of the type H-Pro-Pro-Xaa-NH2
as highly active and stereoselective catalysts for enamine catalysis (Xaa
) amino acid with a carboxylic acid in the side chain).5,6 For example,
in the presence of 1 mol % of peptide H-D-Pro-Pro-Glu-NH2 1 a broad
range of different aldehydes and nitroolefins react readily with each
other to provide synthetically useful γ-nitroaldehydes in excellent yields
and stereoselectivities (Scheme 1).6 In contrast to many other examples
in enamine catalysis, essentially no side products form, no catalyst
deactivation takes place, and no additives are necessary for effective
catalysis.7 Thus, these peptide catalyzed conjugate addition reactions
are ideal models to gain insight into the rate determining steps within
enamine catalysis.
that turned into a zero order dependence at higher concentrations
(Figure 1a, green line). This demonstrates that a steady state is reached
at a certain concentration of the aldehyde and suggests that the reaction
of the catalyst with the aldehyde to form the enamine is not rate
limiting. Attempts to detect the enamine were not successful suggesting
that the equilibrium is far on the side of the catalyst and the aldehyde.
Varying the amount of water present in the reaction mixture had a
significant effect on the overall rate of the reaction.12 When the reaction
was performed with dried solvents and reagents, product formation
was much faster.13 Conversely, addition of water (10 mol %) slowed
the reaction down (Figure 1b). These observations are most likely due
to the influence of water on the enamine formation step. In fact, under
“dry conditions”,13 the steady state was reached already at a lower
aldehyde concentration (Figure 1a, red). In contrast, in the presence
of 10 mol % of water, no steady state was observed even at higher
concentrations of the aldehyde (Figure 1a, blue). The dependence of
the reaction on the nitroolefin was not influenced by the concentration
of the aldehyde, and the rate orders are identical under steady state
and nonsteady state conditions.10 In contrast, the rate order of the
nitroolefin depends on the amount of water. With dried solvents and
reagents, a 0.4 order dependence of the reaction on the nitroolefin was
observed, whereas 0.5 and 0.7 order dependences on the nitroolefin
were observed under standard conditions and with 10 mol % of water,
respectively. These results demonstrate that both the C-C bond
formation step and the hydrolysis of the iminium ion are rate limiting
for the reaction.
Scheme 1. Conjugate Addition Reactions Catalyzed by Peptide 1
The proposed generally accepted catalytic cycle of this reaction
involves enamine formation (A) followed by reaction with the
nitroolefin and hydrolysis of the resulting imine (B) (Scheme 2).3,8
To analyze which of these steps is rate determining, we performed
kinetic studies utilizing in situ IR spectroscopy as a noninvasive method
to monitor the reaction progress.9,10 The 1,4-addition reaction between
butanal and nitrostyrene catalyzed by 1 mol % of 1 was utilized as
the model reaction. Reaction orders of the catalyst, aldehyde, and
nitroolefin were determined by performing at least five reactions in
which only the concentration of the component in question was
varied.11 The slope of the straight line within a log/log plot of the
initial reaction rates versus the concentrations of the component in
question provided then the reaction order of the varied reaction
component.10,11 These experiments revealed as expected a first order
dependence of the reaction on catalyst 1. Interestingly, for the aldehyde
a 0.3 order dependence was observed at low aldehyde concentrations
Figure 1. Influence of water on (a) the rate order of the aldehyde and (b)
product formation (standard conditions, green line; “dry” conditions,13 red line;
and 10 mol % excess of water, blue line).
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J. AM. CHEM. SOC. 2010, 132, 6–7
10.1021/ja9068112  2010 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Conjugate Addition Reactions between n-Butanal and
Nitrostyrene Catalyzed by Peptide 1 under Different Conditions
In conclusion, kinetic studies provided insight into the rate determin-
ing step of peptide catalyzed conjugate addition reactions between
aldehydes and nitroolefins. They revealed that not enamine formation
but both the reaction of the enamine with the electrophile and
hydrolysis of the resulting imine are rate limiting. These findings
allowed for reducing the catalyst loading by a factor of 10 to as little
as 0.1 mol % for a broad range of substrates. This is the lowest catalyst
loading achieved so far in enamine catalysis with organocatalysts of
low molecular weight. The work also highlights the value of
mechanistic insight based on kinetic studies for optimizing organo-
catalytic reactions.
mol %
1
ratio
2:3
time
(h)
convb
(%)
eec
(%)
entry
conda
syn/antib
1
2
3
4
5
6
7
1
1
1
1
1
1
0.1
1.5:1
1:1.5
1.5:1
1:1.5
1:1.2
1:1.5
1:1.5
std
std
dry
dry
dry
16
7
4
3
5
quant.
>95
98:2
98:2
97:3
97:3
95:5
>99:1
94:6
97
97
97
97
97
98
97
>95
>95
>95
Acknowledgment. This work was supported by Bachem, the
Swiss National Science Foundation and the RTN REVCAT. H.W. is
grateful to Bachem for an endowed professorship. We thank Professors
B. Giese and A. Pfaltz for stimulating discussions.
dry, 0 °C
dry
20
48
>95
∼90
a Under “dry conditions” anhydrous reagents and solvents were used
whereas regular solvents and reagents were utilized under “standard
(std) conditions”. b Determined by 1H NMR spectroscopic analysis of
the crude reaction mixture. c Determined by chiral phase HPLC analysis.
Supporting Information Available: Experimental details on the
kinetic studies and presented compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
These insights into the kinetics of the conjugate addition reaction
provided a guide for improving the reaction conditions. Clearly a
reduction of the water amount accelerates the reaction (Figure 1b). In
addition, the fact that the nitroolefin and not the aldehyde is involved
in the rate limiting step suggests that an excess of nitrolefin with respect
to the aldehyde should lead to a faster reaction. Indeed, when the
conjugate addition reaction was performed utilizing 1.5 equiv of
nitrostyrene and 1.0 equiv of butanal, the γ-nitroaldehyde was obtained
within a significantly shorter time compared to the originally used
conditions utilizing an excess of the aldehyde (Table 1, entries 1 and
2). Combined with the use of dried solvents and reagents, the original
reaction time of 16 h was reduced to 3 h (Table 1, entry 4). Under
those conditions, the γ-nitroaldehyde was isolated with the same high
enantioselectivity and only slightly reduced diastereoselectivity utilizing
1 mol % of the peptidic catalyst. Essentially perfect stereoselectivities
were obtained when the reaction was performed at reduced temperature
(Table 1, entry 6). Most remarkably, under these improved reaction
conditions a catalyst loading of as little as 0.1 mol % is still sufficient
for excellent catalytic activity and stereoselectivity within 48 h (Table
1, entry 7).
References
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These low catalyst loadings proved to be broadly applicable. A wide
range of aldehyde and nitroolefin combinations react in the presence
of 0.1 mol % of peptide H-D-Pro-Pro-Glu-NH2 1 readily to γ-nitroal-
dehydes (Table 2). All products were isolated in high to excellent yields
and stereoselectivities. Only the less reactive substrates required a
slightly higher quantity of the catalyst (0.2 and 0.4 mol %, respectively)
to allow for high product yields (Table 2, entries 2, 5, 9, and 10).
Table 2. Conjugate addition reactions between aldehydes and
nitroolefins catalyzed by peptide 1
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chem.200901021.
yielda
(%)
eec
(%)
entry
R1
R2
mol %
syn/antib
(7) Reactions catalyzed by peptide 1 proceed equally as well in the presence
or absence of salts such as TFA•NMM; see ref 6c for details.
(8) For an initial report and proposed mechanism of this 1,4-addition reaction,
see: Betancort, J. M.; Barbas, C. F., III. Org. Lett. 2001, 3, 3737–3740.
(9) Cabot, R.; Lledo, A.; Reves, M.; Riera, A.; Verdaguer, X. Organometallics
2007, 26, 1134–1142.
1
2
3
4
5
6
7
8
9
Et
Ph
Ph
Ph
Ph
Ph
0.1
0.2
0.1
0.1
0.4
0.1
0.1
0.1
0.4
0.2
87
92
98
87
93
95
96
92
96
92
94:6
95:5
95:5
94:6
95:5
95:5
97:3
98:2
93:7
91:9
97
96
96
98
94
96
97
99
95
98
Me
nPr
Bn
iPr
Et
Et
Bn
Et
(10) For experimental details see Supporting Information.
(11) (a) Birk, J. P. J. Chem. Educ. 1976, 53, 704–707. (b) Casado, J.; Lo´pez-
Quintela, M. A.; Lorenzo-Barral, F. M. J. Chem. Educ. 1986, 63, 450.
(12) For other kinetic studies on the influence of water on enamine catalysis
see ref 2e-2i.
C6H3-2,4-Cl2
C6H4-2-CF3
C6H4-2-CF3
C6H4-4-OMe
CH2CH(CH3)2
(13) “Dry” conditions refer to the use of dried solvents, reagents, and glassware.
Water generated in the course of the reaction is allowed to be present and
is in fact crucial. Reactions performed in the presence of molecular sieves
do not allow for product formation.
10
Et
a Isolated yield. b Determined by 1H NMR spectroscopic analysis of
the crude material. c Determined by chiral phase HPLC analysis.
JA9068112
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