Bifunctional activation and racemization in the catalytic asymmetric Aza-Baylis-Hillman reaction

Article abstract of DOI:10.1021/ja0550024

The mechanism of bifunctional activation in the asymmetric aza-Baylis-Hillman (aza-BH) reaction was studied using NMR spectroscopic techniques. The reaction involves rate-limiting proton transfer in the absence of added protic species, but exhibits no aut

Full text of DOI:10.1021/ja0550024

Published on Web 11/12/2005
Bifunctional Activation and Racemization in the Catalytic Asymmetric
Aza-Baylis-Hillman Reaction
Pascal Buskens, J u¨ rgen Klankermayer, and Walter Leitner*
Institute of Technical and Macromolecular Chemistry, RWTH Aachen, Worringerweg 1, D-52074 Aachen, Germany
Received July 25, 2005; E-mail: leitner@itmc.rwth-aachen.de
The aza-Baylis-Hillman (aza-BH) reaction is a versatile C-C
bond forming reaction of activated alkenes with imines to form
1
highly functionalized allylic amines. It was not until most recently
that chiral catalysts providing high levels of enantioselectivity in
2
the asymmetric aza-BH reaction have been reported. As a common
theme, these organocatalysts are based on bifunctional chiral BINOL
and phosphinyl BINOL compounds.2 So far, however, no detailed
mechanistic information on the aza-BH reaction is available, and
the factors responsible for enantiocontrol are not understood. In
the present communication, we report conclusive evidence for the
mechanism of bifunctional activation and demonstrate that race-
mization of the product under turnover conditions is a crucial aspect
c-e
for future catalyst design.8
Figure 1. Conversion time profiles for the aza-BH reaction of 2 (0.090
In accordance with the generally accepted mechanism of the
Baylis-Hillman (BH) reaction, it is reasonable to assume a catalytic
cycle for the aza-BH reaction where the initial step is the reversible
conjugate addition of the phosphine catalyst 1 to the activated alkene
mmol) with imine 4 (0.075 mmol) using catalyst 1 (0.0075 mmol), and
various additives (0.103 mmol) in THF-d8 (0.6 mL).
2
to generate the corresponding enolate 3. Mannich-type addition
of 3 to the imine 4 forms the zwitterion 5 followed by elimination
to generate the product 6 liberating the catalyst (Scheme 1).3
Scheme 1. Proposed Mechanism of the Aza-BH Reaction
Figure 2. Relative initial reaction rates (k′obs/kobs) for the aza-BH reaction
as a function of the pKa of the additive.
law shown in eq 1 was derived by analyzing the initial rates as a
function of concentration for the individual components. No
evidence for autocatalysis was observed, and the broken order of
0.5 in imine 4 indicates that the rate-determining step (RDS) is
For the BH reaction of acrylate esters with pyridinecarboxalde-
hydes, Kaye reported that the reaction is first order in aldehyde,
partly influenced by proton transfer.
1
1
0.5
3
b
amine, and acrylate. In a later investigation, McQuade observed
that the reaction is second order in aldehyde and proposed the
formation of a hemiacetal intermediate for the reaction in aprotic
rate ) kobs [1] [2] [4]
(1)
We then conducted experiments to assess the influence of
Brønsted acidic additives (1 equiv per 4) with different pK values
(Figure 1). A maximum was observed with 3,5-bis(CF )phenol at
pK
4
solvents. Several groups noted large rate enhancements caused by
a
5
water and other protic additives. Aggarwal and Lloyd-Jones
3
concluded that proton transfer is rate-limiting in the initial stage of
the reaction, but becomes increasingly efficient at higher conversion
causing the aldol-type coupling to become rate-limiting and making
the reaction autocatalytic.6
In a first set of experiments, we performed kinetic studies on
the aza-BH reaction of methyl vinyl ketone (2) with N-(3-
fluorobenzylidene)-4-methylbenzenesulfonamide (4, Ar ) m-F-
a
≈ 8 corresponding to a 14-fold rate enhancement as compared
to the reaction without additive (Figure 2). Less acidic compounds
show a smaller effect, but additives such as water still give a
significant rate enhancement. If the additive is more acidic, the
enhancement is also reduced owing to formation of the protonated
form of enolate 3, which could be detected and characterized by
multinuclear NMR.
C
6
H
4
) in the presence of PPh
3
(1) in THF at room temperature.
Examination of the kinetics in the presence of phenol as
prototypical additive revealed that the rate law of the reaction
19
The reactions were monitored by F NMR spectroscopy. The rate
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J. AM. CHEM. SOC. 2005, 127, 16762-16763
10.1021/ja0550024 CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. Transition State for the Brønsted Acid-Assisted Proton
Transfer in the Aza-BH Reaction
changes in the presence of the Brønsted acid, showing first-order
dependence in imine 4 (eq 2). This clearly demonstrates that the
elimination step is not involved in the RDS anymore, and that the
proton transfer must be accelerated by these additives. Scheme 2
shows the most likely transition state for the assisted proton transfer
in this step.
Figure 3. Racemization of the aza-BH product 6 in the presence of various
catalytic systems.
1
1
1
rate ) k′obs [1] [2] [4]
(2)
Acknowledgment. This work was supported by the Deutsche
Forschungsgemeinschaft (SPP 1179) and Fonds der Chemischen
Industrie. P.B. thanks the Max-Buchner-Stiftung and the
Graduiertenkolleg 440 for their financial support. We thank
Dr. Lasse Greiner for helpful discussions.
The results obtained so far substantiate that bifunctional activation
using a basic and a protic center is a viable strategy for catalyst
design in the asymmetric aza-BH reaction. However, as the
individual steps of the catalytic cycle are potentially reversible, we
investigated also the influence of the catalyst components on
possible racemization pathways. Whereas Brønsted acids alone did
not lead to racemization of 6, complete and rapid racemization
Supporting Information Available: A complete description of
experimental details, kinetics data, rate law derivation, and product
characterization. This material is available free of charge via the Internet
at http://pubs.acs.org.
occurred by 1 either alone or in the presence of 3,5-bis(CF
3
)phenol
(
Figure 3).
References
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reactivity (Ar ) m-FC
6
4
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3
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In summary, these studies show that the aza-BH reaction involves
rate-limiting proton transfer in the absence of added protic species,
but exhibits no autocatalysis. Brønsted acidic additives lead to
substantial rate enhancements through acceleration of the elimina-
tion step. Furthermore, it was found that phosphine catalysts either
alone or in combination with protic additives can cause racemization
of the aza-BH product by proton exchange at the stereogenic center.
This indicates that the spatial arrangement of a bifunctional chiral
catalyst for the asymmetric aza-BH is crucial not only for the
stereodifferentiation within the catalytic cycle but also for the
prevention of subsequent racemization.
7
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(
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