Trifunctional organocatalyst-promoted counterion catalysis for fast and enantioselective aza-Morita-Baylis-Hillman reactions at ambient temperature

Article abstract of DOI:10.1039/b901781j

Fast and enantioselective aza-Morita-Baylis-Hillman reactions between electron-deficient or electron-rich aromatic N-tosyl imines and methyl vinyl ketone were achieved at ambient temperature using asymmetric counterion-directed catalysis promoted by trifu

Full text of DOI:10.1039/b901781j

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Trifunctional organocatalyst-promoted counterion catalysis for
fast and enantioselective aza-Morita–Baylis–Hillman reactions
at ambient temperature†
Jean-Marc Garnier and Fei Liu*
Received 27th January 2009, Accepted 3rd February 2009
First published as an Advance Article on the web 18th February 2009
DOI: 10.1039/b901781j
Fast and enantioselective aza-Morita–Baylis–Hillman reac-
tions between electron-deficient or electron-rich aromatic
N-tosyl imines and methyl vinyl ketone were achieved at
ambient temperature using asymmetric counterion-directed
catalysis promoted by trifunctional organocatalysts with a
Brønsted base as the activity switch after protonation with
benzoic acid.
the proton transfer as the generally accepted rate-limiting step,7
which augur well for new asymmetric catalytic strategies targeting
the rate-limiting step in order to improve the catalytic proficiency
with faster rates and more facile reaction conditions.
We have initiated a new trifunctional organocatalyst-induced
counterion catalysis approach using the azaMBH reaction be-
tween electron-rich and electron-deficient aromatic N-tosyl imines
and methyl vinyl ketone (MVK).8 This led to enhanced rates
in these reactions (86–96% isolated yields in 3–24 h) with good
enantioselectivity (59–92% ee) without the need to lower the
reaction temperature (Scheme 1). Extending from the bifunctional
approach that utilises a Lewis base nucleophile and a Brønsted
acid for H-bonding interactions, this trifunctional system employs
an additional Brønsted base that serves as the activity switch in
response to protonation by a strong Brønsted acid (Scheme 1a).
The resulting chiral ion-pair becomes catalytically active, with
the counterion of the acid additive controlling the ee and the
sense of asymmetric induction by selectively “gating” the rate-
limiting proton transfer step (Scheme 1b). Unlike bifunctional
catalysis where the rate and enantioselectivity vary independently,
this counterion strategy has resulted in enantioselective azaMBH
reactions where the rate of reaction and enantioselectivity arise in
a coordinated fashion.
In the past decade asymmetric organocatalysis has received
renewed interest since its initial conceptual demonstration in the
last century.1 Efforts thus far have firmly established this approach
as a viable counterpart to existing metal- or enzyme-based catalytic
systems.2 While in scope they have verified advantages, in the sense
of catalysis, where rates and enantioselectivity jointly define the
catalytic proficiency, organocatalysts still require much improve-
ment to emulate that seen with metal or enzyme catalysts. One
strategy is to develop enzyme-mimicking bifunctional or trifunc-
tional organocatalysts,3 and recently, a biomimetic trifunctional
organocatalyst, although without enantioselectivity, has shown
remarkable catalytic rates reminiscent of enzyme catalysis in trans-
esterification reactions.3b Reported herein is a rational and system-
atic approach to developing asymmetric trifunctional organocata-
lysts for fast and facile aza-Morita–Baylis–Hillman reactions in or-
ganic solvents using the strategy of counterion-directed catalysis.4
The MBH and azaMBH reactions are multi-step carbon–
carbon bond-forming reactions with recognized synthetic utility
but hampered by the problems of slow rates and limited scope.5
Enantioselective bifunctional organocatalysts have been devel-
oped, with impressive substrate scope, for catalyzing the MBH
or azaMBH reactions in nonpolar aprotic solvents with high
ee values, although the rate of reaction is generally slow – in
the range of hours to days even at 10–20% catalyst loading.6
However, nonpolar aprotic solvents are necessary for asymmetric
catalytic approaches that require preservation of key H-bonding
interactions. In selected cases, bifunctional catalysts with multi-
valent H-bonding donors can achieve higher catalytic turnover
without compromising the enantioselectivity, although the rate
of reaction is difficult to control due to the typical requirement of
low temperatures to maintain high ee.6e–g Recently, key mechanistic
experiments on the MBH or azaMBH reactions have pointed to
Scheme 1 Counterion catalysis of the azaMBH reaction. (a) Extension
from bifunctional catalysis to a trifunctional framework for counterion
catalysis. (b) Promoting the proton-transfer step in the azaMBH reaction
by counterion catalysis.
Department of Chemistry & Biomolecular Sciences, Macquarie University,
Sydney, NSW 2109, Australia. E-mail: fliu@alchemist.chem.mq.edu.au;
Fax: +61-2-9850-8313; Tel: +61-2-9850-8312
† Electronic supplementary information (ESI) available: Spectra and
characterisation data of catalysts 1b–1f and MBH/azaMBH reaction
adducts 3 and 6. See DOI: 10.1039/b901781j
The modular nature of this catalytic system presented an
opportunity to systematically and rapidly adjust the apparent
acidity of the phenolic Brønsted acid group by adding substituents
on the phenol ring to investigate its potential effect on further
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Table 2 AzaMBH reactions of N-(arylmethylidene)arylsulfonamide 2b
(1.0 equiv.) with MVK (2.0 equiv.) in the presence of 1d or 1f (10 mol%)
and benzoic acid (10 mol%) in various solvents
promoting the catalytic proficiency of this counterion strategy
(Scheme 2). This acidity tuning of the phenolic Brønsted acid
could have a variety of effects for and against the counterion
catalysis. A more acidic phenolic Brønsted acid could facilitate
the protonation of the Brønsted base and provide a stronger ionic
H-bonding network to position the counterion better for catalysis.
However, as this trifunctional system contains the bifunctional
themes and is capable of bifunctional catalysis in its unprotonated
form, the bifunctional catalysis may also escalate, interfering with
the counterion catalysis that requires acid activation. Nonetheless,
an iterative process was followed to construct catalysts 1b–f related
to the root catalyst 1a. All catalysts 1a–f were readily procured with
the reductive amination method, followed by silane reduction,
starting from MAP oxide9 and, as triaryl phosphines, displayed
good air stability.
1d
1f
Entry
Solvent
Conv. (%)a
ee (%)b
Conv. (%)c
ee (%)b
1
2
3
4
5
THF
Toluene
Et2O
CHCl3
CH2Cl2
>95
>95
>95
>95
>95
80
86
87
86
90
70
>95
87
>95
>95
79
87
86
88
92
a Calculated by 1H NMR spectroscopy after 30 min of reaction.
b Determined by chiral HPLC analysis. c Calculated by 1H NMR spec-
troscopy after 60 min of reaction.
enhancement of about 4-fold with comparable ee (entry 3). This
suggested that increasing the acidity of the phenolic Brønsted acid
might have an overall positive effect on promoting the counterion
catalysis. The addition of a second electron-withdrawing bromo
group in the para position, as seen in catalysts 1d and 1e (entries
4 and 5), improved the conversion to 87–91% in 15 min with
improved enantioselectivity. An even more electron-withdrawing
nitro group at the para position, however, resulted in slight
reduction of catalytic proficiency. In summary, a more acidic
phenolic Brønsted acid improved the catalytic proficiency of the
counterion catalysis, up to a limit.
Catalysts 1d and 1f were next examined in various solvents
using a test azaMBH reaction (Table 2). As expected, nonpolar
aprotic solvents generally preserved the required tight-ion pairing
for catalysis, with dichloromethane providing the best ee values
for both 1d and 1f.
Scheme 2 Acidity tuning of the trifunctional organocatalysts. (a) A
general synthesis of 1 from MAP oxide. (b) Acidity tuning from the root
catalyst 1a.
Catalysts 1a–f were tested using the azaMBH reaction between
an N-tosyl imine and MVK (Table 1).‡ Compared to the root
catalyst 1a, the addition of an electron-rich tert-butyl substituent
ortho to the phenolic Brønsted acid reduced slightly the rate of
conversion and ee (entry 2). On the other hand, the addition of an
electron–withdrawing fluorine substituent resulted in an initial rate
The substrate scope was also investigated using 1d and 1f
(Table 3). In general, 1d delivered faster rates (for both electron-
deficient and electron-rich aromatic N-tosyl imine substrates) with
slightly lower ee. It is possible that, in 1f, the bulky tert-butyl
group ortho to the phenolic Brønsted acid may provide some
barrier to the competing monofunctional or bifunctional catalysis
of the acidified phenolic proton, resulting in a more consistent
enantioselectivity range (87–94% ee), compared to that of 1d (72–
93% ee), without the need to lower the reaction temperature.
The scope of this trifunctional organocatalyst-promoted coun-
terion strategy was further tested in the more difficult generic
MBH reaction or the azaMBH reaction with acrylate esters
(Table 4). Triaryl phosphines are generally poor catalysts for these
reactions with little activity, although attempts have been made
to use more nucleophilic chiral alkyl phosphines to catalyse these
reactions with moderate ee.10 Upon acid activation, 1f exhibited
good rates of reaction for these test cases, while 1a showed no
activity even with benzoic acid activation. In the generic MBH
reaction between an aldehyde and MVK (entry 1, Table 4), the
rate of conversion and ee were both reduced compared to those
seen with the its aza counterpart (entry 6, Table 3). For the
azaMBH reaction between electron-deficient N-tosyl imines and
phenyl acrylate (entries 2–4, Table 4), the rate of conversion is
also significantly slower compared to those with MVK. For these
Table 1 AzaMBH reactions of N-(arylmethylidene)arylsulfonamide 2a
(1.0 equiv.) with MVK (2.0 equiv.) in the presence of 1a–f (10 mol%) and
benzoic acid (10 mol%) in DCM
Entry
Catalyst
Time/min
Conv. (%)a
ee (%)b
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
15
15
15
15
15
15
15 (>95c)
85c
80
73
81
82
88
87
57 (87)d
91 (>95)d
87 (>95)d
57 (91)d
a Calculated by 1H NMR spectroscopy. b Determined by chiral HPLC
analysis. c Conversion after 180 min. d Conversion after 30 min in
parentheses.
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Table 3 Aza-Morita–Baylis–Hillman reactions of N-(arylmethylidene)arylsulfonamide 2 (1.0 equiv.) with MVK (2.0 equiv.) in DCM with catalyst 1d
or 1f (10 mol%) and benzoic acid (10 mol%)
1d
1f
Entry
R
Time/min
Conv. (%)a
ee (%)b
Time/min
Conv. (%)a
ee (%)b
1
2
3
4
5
6
7
8
9
m-NO2 2a
p-Br 2b
30
60
60
180
60
30
>95
>95
91
>95
71
>95
59
78
84
90
90
72
88
82
78
93
76
91
60
60
120
180
180
30
89
87
92
94
89
90
87
88
93
88
94
41 (>95)c
71
p-Cl 2c
o-Cl, 2d
p-F, 2e
p-NO2 2f
o-NO2 2g
p-Me 2h
o-OMe 2i
m-OMe 2j
39 (72)d
87
>95
30
60
42 (>95)c
62
180
180
150
900
900
120
43 (82)d
93
64
10
31 (81)d
a Calculated by 1H NMR spectroscopy. b Determined by chiral HPLC analysis. c Conversion after 180 min. d Conversion after 360 min.
Table 4 Generic or azaMBH reactions of an electrophile 4 (1.0 equiv.)
with an enone 5 (2.0 equiv.) in DCM with catalyst 1f (10 mol%) and benzoic
acid (10 mol%)
organocatalyst-promoted counterion strategy here (Fig. 1) offers
a different avenue by promoting the rate-limiting proton-transfer
step, which can be combined with the steric-based strategies to
afford a catalytic system with improved scope by expediting a
particular proton-transfer pathway while hindering spatially the
competing pathways without the low temperature prerequisite.
Effort towards a generally proficient system using this trifunctional
organocatalyst-promoted counterion strategy for fast and enan-
tioselective MBH reactions under facile conditions is currently
underway and will be reported in due course.
Entry
R
Z
X
Time/h
Conv. (%)a
ee (%)b
1
2
3
4
p-NO2
p-NO2
p-Br
O
Me
24
16
16
60
95 (6a)
53 (6b)
41 (6c)
48 (6d)
52
40
77
70
NTs
NTs
NTs
OPh
OPh
OPh
p-Cl
a Calculated by 1H NMR spectroscopy. b Determined by chiral HPLC
analysis.
less reactive substrates, the proton-transfer step is, as expected,
slower compared to that of more reactive substrates such as
N-tosyl imines with MVK. This would lead to retardation of
the counterion-catalysed proton-transfer pathway, resulting in
leakage of enantioselectivity to competing pathways. A variable
due to the significantly different enolate geometry, in addition to
a slower proton-transfer step, was also introduced in the azaMBH
reactions with the use of an acrylate ester. This may also be part
of the basis to the significantly reduced rates observed in these
cases, as the position of the counterion could also be significantly
altered.
Fig. 1 Proposed transition structure for the counterion catalysis pro-
moted by a trifunctional organocatalyst.
Acknowledgements
This work is supported by an Australian Research Council
Discovery Grant (ARC-DP055068).
Notes and references
The persistent scope issue of the MBH reaction has limited
the development of a generally effective catalytic system. This
is attributed to the complex nature of this reaction, where the
geometry of the highly unstable Michael adduct, the reversibility
of the Michael-aldol step, and the autocatalysis by the adduct
itself all converge to render the rate and enantioselectivity difficult
to attain concurrently with generality.7b–d While bifunctional
organocatalysts for the MBH or azaMBH reaction will continue
to improve in scope, the rates for these systems tend to be
slower, as lower temperatures are generally required to maintain
enantioselectivity by conformational locking. The trifunctional
‡ Typical reaction procedure for generic or azaMBH reaction catalyzed by
phosphines 1a–e: An imine or aldehyde (0.5 mmol), phosphine catalyst
(10 mol%, 0.05 mmol) and benzoic acid (10 mol%, 0.05 mmol) were
combined under N2. DCM (0.1 mL per mg of catalyst) was added, followed
by the purified enone (2 equiv.) dropwise. The reaction was stirred at room
temperature until completion. The solvent was evaporated and the crude
mixture was immediately subjected to the chiral HPLC for the ee analysis.
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