Cooperativity in the counterion catalysis of Morita/Baylis/Hillman reactions promoted by enantioselective trifunctional organocatalysts

Article abstract of DOI:10.1016/j.tet.2010.05.007

New trifunctional organocatalysts with a NHTs Br?nsted acid were prepared and tested in their ability to promote the counterion catalysis of generic and aza-Morita/Baylis/Hillman reactions.The cooperativity between the counterion and the NHTs Br?nsted aci

Full text of DOI:10.1016/j.tet.2010.05.007

Tetrahedron 66 (2010) 5486e5491
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journal homepage: www.elsevier.com/locate/tet
Cooperativity in the counterion catalysis of Morita/Baylis/Hillman reactions
promoted by enantioselective trifunctional organocatalysts
*
Christopher Anstiss, Fei Liu
Department of Chemistry & Biomolecular Sciences, Macquarie University, Sydney, NSW 2109, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
New trifunctional organocatalysts with a NHTs Brønsted acid were prepared and tested in their ability to
promote the counterion catalysis of generic and aza-Morita/Baylis/Hillman reactions. The cooperativity
between the counterion and the NHTs Brønsted acid of the trifunctional catalyst was required for good
enantioselectivity and rate enhancement. Better enantioselectivity was observed for aza-MBH reactions
at relatively low catalyst loading (2e5 mol %) under facile conditions.
Received 26 December 2009
Received in revised form 16 April 2010
Accepted 4 May 2010
Available online 8 May 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
a)
The Morita/Baylis/Hillman (MBH) reaction is an atom-economic
carbonecarbon bond forming reaction between an aldehyde, or im-
ine, and an enone to generate a highly functionalized secondary chiral
alcohol or amine. It has great potential in diversity oriented and con-
vergent synthesis but can be limited by (1) slow reaction rates (often
days) and (2) capricious substrate scope, primarily due to the complex
mechanistic nature of this multi-step reaction.1,2 Many asymmetric
bifunctional organocatalysts have been developed to successfully
catalyze several versions of the MBH reaction with high enantiose-
lectivity, although the rate of conversion is still typically in the days
range with low-temperature reaction conditions as a requirement.3
Extending from the bifunctional approaches that utilize a Lewis
base nucleophile and a Brønsted acid for H-bonding interactions,
we have made the first demonstration of a strategy of trifunctional
organocatalyst induced counterion catalysis4 for facile and asym-
metric aza-MBH reactions with very fast rates (86e96% isolated
yields in 3e24 h) and good enantioselectivity (59e92% ee) even at
ambient temperature (Scheme 1a).5 This trifunctional system,
while catalytically inactive by itself, employs an additional
Brønsted base that serves as the activity switch in response to ac-
tivation by a strong external Brønsted acid. The installation of the
third functionality, nitrogen Brønsted base, effectively changes the
bifunctional pathway (slower and less enantioselective) to the tri-
functional pathway (faster and more enantioselective).5 The acid
activation conferred by the Brønsted base, combined with the
known functions of the Lewis base for initiating the Michael ad-
dition and the Brønsted acid for H-bonding interactions, are the
Counterion catalysis by trifunctional organocatalysts
Bifunctional
catalysis
Brønsted base
Brønsted base
H
Brønsted
N
HA
XH
Brønsted
XH
N
H
Nu
acid
XH
Counterion
Lewis base
activation
acid
Brønsted
H A
Nu
Nu
acid
Lewis base
nucleophile
Lewis base
nucleophile
nucleophile
R
O
X
O
R
O
H
Michael
Aldol
R'
X
H
*
R
bifunctional
catalysis
bifunctional
catalysis
*
R'
Nu
u
N
H
II
I
Nu
Proposed counterion catalysis
counterion
Brønsted
proton
transfer
O
R
H
base
NH
H
A
X
NHX
O
Lewis
base
H
O
R
*
R'
P
Brønsted
H
O
R'
acid
b)
H
N
H
N
N
H
HO
O
O
S
?
HN
HN
HO
S
O
PPh2
PPh2
PPh2
TF-1
Two
New
Brønsted acid
Brønsted acids
CH3
CH3
c)
R:
N
H
N
H
NHR
PPh2
H2N
N
1b
H
HO
1c
NHTs
N
H
1e
NHTs
TsHN
1a
:
R = H
1d
* Corresponding author. Tel.: þ61 2 9850 8312; fax: þ61 2 9850 8313; e-mail
address: fliu@science.mq.edu.au (F. Liu).
Scheme 1. A trifunctional approach to facile asymmetric MBH reactions at ambient
temperature.
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.05.007

C. Anstiss, F. Liu / Tetrahedron 66 (2010) 5486e5491
5487
three required catalytic functions to achieve this rate and enan-
a) Synthesis of aldehydes
tioselectivity enhancement simultaneously. Comprehensive bi-
functional controls of the this system were also constructed and
tested, along with examination of solvent effects, which showed
that each of the three functionalities of 1 was essential for
switching to the trifunctional catalysis, that is, dependent on ion-
pairing.5 Second generation catalysts, in which the acidity of the
Brønsted acid on the catalyst is enhanced, showed further im-
provement in reaction rates (0.5e16 h) and expanded substrate
scope.6 Notably, the trifunctional system is again applicable under
facile conditions without the need to lower the reaction tempera-
ture and raises an interesting prospect of further process-related
improvement using this approach. The rapid assembly strategy
behind the synthesis of this trifunctional series offers the oppor-
tunity to explore the catalytic effect of new types of Brønsted acids
that can be installed onto the catalyst scaffold (Scheme 1b). The
phenolic Brønsted acid in early generations of the trifunctional
catalysts such as TF-1 can be replaced by a NHTs Brønsted acid.
Furthermore, more than one Brønsted acid can be added onto the
catalyst scaffold to create new trifunctional and bivalent organo-
catalysts such as 1e. Herein reported is a new series of such tri-
functional organocatalysts 1bee (Scheme 1c) that demonstrate
further improvement in the rate of conversion in asymmetric aza-
MBH reactions at as low as 2e5 mol % loading under facile condi-
tions with good enantioselectivity. In addition, this system displays
a new counterion catalysis profile unlike that observed with pre-
vious generations of trifunctional catalysts.
1) TsCl, pyridine
OH
O
CH2Cl2, 0 °C to r.t., 3 h
2) MnO2, CH2Cl2, r.t., 1 h
(82 % 2 steps)
6
7
NH2
O
NHTs
1) SOCl2/MeOH
reflux, 3 h
O
O
BBr3, CH2Cl2
-78 °C, 1 h, 82%
2) LAH/THF
HO
-78 °C to r.t., 5 h
3) TsCl, pyridine
CH2Cl2, r.t., 2 h
4) MnO2,CH2Cl2
r.t., 4 h
MeO
MeO
HO
NHTs
9
NH2
O
NHTs
10
8
(23% over 4 steps)
O
OH
1) TsCl, pyridine
CH2Cl2, 0 °C to r.t., 1 h
1) ClCO2Me, K2CO3
THF/water, r.t., 1 h
2) MnO2, CH2Cl2, r.t., 2 h
2) MnO2, CH2Cl2
NHTs
NH2
r.t., 3 h
NH
(91 % 2 steps)
12
13
11
(94 % 2 steps)
COOMe
b) Synthesis of catalyst 1b-1e
1) 12, Si(OEt)4,112 °C, 14 h
NH2
2) NaBH4, EtOH
0 °C to r.t., 6 h
N
NH2
H
3) TMSI, CHCl3
0 °C to 40 °C, 2 h
4) PhSiH3, 112 °C, 14 h
(42 % 4 steps)
PPh2
P(O)Ph2
1b
(S)-MAP Oxide
CHO
X
X
Y
N
Y
1)
H
NH2
PPh2
2. Results and discussion
Si(OEt)4,112 °C, 14 h
PPh2
2) NaBH4, EtOH
0 °C to r.t., 15 min
(81 - 86%)
1c: X= H; Y=NHTs
1d: X=NHTs; Y=H
1e: X=OH; Y=NHTs
The installation of a new NHTs Brønsted acid moiety on the chiral
BINAP backbone to make new trifunctional catalysts required prep-
aration of substituted aryl aldehydes 7, 10, 12, and 13 (Scheme 2).
2-N-Tosylbenzaldehyde 13 and 3-N-tosylbenzaldehyde 7 were pre-
pared from their commercially available amino alcohols, 11 and 6, in
91% and 82% yield over two steps, respectively using a modified
procedure byKonig7 (Scheme2a). Thetosylationof6or11 proceeded
smoothly under the reported conditions. The more stable and envi-
ronmentally friendly manganese dioxide was used for benzylic oxi-
dation instead of the reported PCC.
2-Hydroxy-3-N-tosylbenzaldehyde 10 was prepared from the
commercially available 2-methoxy-3-aminobenzoic acid 8 (Scheme
2a). The amino acid 8 was reduced to the alcohol using a procedure
reported by O’Hare.8 The corresponding amino alcohol was then
N-tosylated and oxidized to furnish aldehyde 9 using the same
reagents as described above. O-Methoxy deprotection with boron
tribromide provided the desired aldehyde 10 in 20% yield over five
steps.
With the required aldehydes in hand, the synthesis of catalysts
1bee proceeded from (S)-MAP as described previously.5,9 Re-
ductive amination of aldehydes 7, 10, and 13 with (S)-MAP yielded
multifunctional catalysts 1c, 1d, and 1e in 84%, 86%, and 81% yield
over two steps from (S)-MAP, respectively (Scheme 2b). The syn-
thesis of 1b was more elaborate as direct reductive amination with
(S)-MAP and 2-amino benzaldehyde gave a complex reaction
mixture, probably due to the instability of this aldehyde at high
temperatures. Alternatively, 2-N-methylcarbamate benzaldehyde
12 was prepared over two steps in 94% yield from 11 as reported by
Yoshiharu10 (Scheme 2a). Aldehyde 12 was then subjected to re-
ductive amination with (S)-MAP oxide, followed by trimethylsilyl
iodide (TMSI) deprotection of the N-methylcarbamate and phos-
phine oxide reduction in neat phenylsilane to give the multifunc-
tional catalyst 1b over four steps in 41% yield (Scheme 2b).
The activity of catalysts 1bee, along with catalysts from earlier
generations (TF-1 and 1a) were then investigated in both the ge-
neric (aldehydes as electrophiles) and aza-MBH (imines as
(S)-MAP
Scheme 2. Catalyst synthesis.
electrophiles) test reactions (Table 1). The effect of acid activation
on these new trifunctional catalysts were also examined.
The first point to note is that all of the new trifunctional catalysts
1cee required acid activation, the lack of which resulted in re-
duction of both rate and enantioselectivity (Table 1, entries 12e27).
This concomitant rise of both the rate and enantioselectivity is the
hallmark of the trifunctional catalytic pathway and consistent with
the observation on early generations of trifunctional catalysts such
as TF-1 that required the Brønsted base functionality for acid ac-
tivation.5 The bifunctional catalyst 1a, which is used as a control
(Table 1, entries 4e7), demonstrates that acid activation is sufficient
for enhancing the rate of catalysis, but the enantioselectivity of this
catalysis is poor without the third NHTs Brønsted functionality.
Catalyst 1b (Table 1, entries 8e11), which is different from 1d by
missing the NHTs Brønsted acid, exhibited poor response to acid
activation with little enantioselectivity and revealed the important
role of the NHTs Brønsted acid in conferring the required cooper-
ativity between the catalyst and the acid additive.
The second point to note is that the new trifunctional organo-
catalysts 1c and 1d have significantly different catalytic profiles
compared to those of earlier generations. Catalyst 1d, compared to
TF-1, is more active, exhibiting a faster rate of catalysis with
a similar level of enantioselectivity in both the generic and aza-
MBH test reactions (Table 1, entries 1 and 3 vs entries 16 and 21).
Catalyst 1c is also a more active catalyst compared to TF-1 (Table 1,
entries 1 and 3 vs entries 12 and 14). For catalysts 1c and 1d, ether,
not dichloromethane, was found to be the best solvent for the ge-
neric MBH reaction. Catalyst 1e is a trifunctional catalyst with two
Brønsted acid interaction sites (Table 1, entries 24e27). It has
a comparable catalytic profile to that of 1c and 1d but is a slower
catalyst. This suggests that the position of the Brønsted acid

5488
C. Anstiss, F. Liu / Tetrahedron 66 (2010) 5486e5491
Table 1
Table 2
Initial catalysis examination of catalysts 1 in test MBH reactions
The effect of catalyst loading using 1d
X
XH
XH
X
10 mol% catalyst
1d
benzoic acid
benzoic acid
O
O
+
O
+
O
solvent, RT
CH2Cl2, RT
O2N
O2N
O2N
O2N
3a: X = NTs
5a: X = O
2a: X = NTs
4a: X = O
2a: X = NTs
4a: X = O
3a: X = NTs
5a: X = O
Entry Cat.
Loading PhCOOH
[mol %] [mol %]
X
Solvent Time [h] Conv(ee)a,b [%]
Entry
X
1d (mol %)
Acid (mol %)
Time [h]
Conv.a [%]
eeb [%]
1
2
3
4
5
6
7
8
TF-1 10
TF-1 10
TF-1 10
10
NTs CH2Cl2
NTs CH2Cl2
3
3
24
3
3
6
>95(80)c
16(0)c
no conversion
60(10)
14(0)
81(33)
6(n.d.)
28(40)
9(32)
38(24)
33(24)
>95(40)
34(0)
1
2
3
4
5
6
7
8
NTs
NTs
NTs
NTs
NTs
NTs
NTs
NTs
NTs
NTs
NTs
Oc
10
10
10
10
10
5
5
2
2
2
50
20
10
1
0.5
5
1
2
2
0.4
1
20
10
5
1
1
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
3
3
3
3
24
3
29
48
71
76
82
88
85
88
91
90
90
88
n.d.
52
47
44
n.d.
41
54
48
0
10
10
0
10
0
10
0
10
0
5
0
10
0
10
0
10
10
10
10
0
10
5
0
O
CH2Cl2
>95
>95
>95
>95
75
1a
1a
1a
1a
1b
1b
1b
1b
1c
1c
1c
1c
1d
1d
1d
1d
1d
1d
1d
1d
1e
1e
1e
1e
10
10
10
10
10
10
10
10
5
NTs CH2Cl2
NTs CH2Cl2
O
O
Ether
Ether
6
NTs CH2Cl2
NTs CH2Cl2
0.5
0.5
24
24
0.5
0.5
6
6
0.5
0.5
0.5
0.5
3
36c
89
34
0
31
71
77
11
89
9
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
O
O
Ether
Ether
10
11
12
13
14
15
16
17
18
1
NTs CH2Cl2
NTs CH2Cl2
10
10
10
10
10
5
5
Oc
10
10
10
10
10
10
10
10
10
10
5
O
O
Ether
Ether
95(54)
30(0)
Oc
Oc
NTs CH2Cl2
NTs CH2Cl2
NTs Ether
>95(82)
37(51)
>81(76)
>95(66)
<5(n.d.)
73(47)
9(n.d.)
43(50)
40(88)
17(0)
Oc
Oc
5
10
21
65
Oc
5
3
NTs Toluene
O
O
O
O
CH2Cl2
Ether
Ether
a
Calculated by 1H NMR spectroscopy after 30 min of reaction.
Determined by chiral HPLC analysis.
Reaction performed in ether.
3
3
3
0.5
0.5
b
c
Toluene
NTs CH2Cl2
NTs CH2Cl2
Table 3
5
10
10
The effect of the counterion using catalyst 1d
10
0
O
O
Ether
Ether
24
24
75(48)
36(21)
X
XH
2 mol% 1d
2 mol% acid
a
Calculated by 1H NMR spectroscopy.
Determined by chiral HPLC analysis.
Data from Ref. 5.
O
+
O
b
c
CH2Cl2, RT
O2N
O2N
2a: X = NTs
4a: X = O
3a: X = NTs
5a: X = O
functionality ortho to the Brønsted base functionality is crucial for
catalysis with minimal enhancement from the functionality at the
meta position.
Entry
X
Acid
Conv.a [%]
eeb [%]
1
2
3
4
5
6
7
8
9
NTs
Acetic acid
Acetic acid
20
21
82
20
34
36
33
0
ꢀ60d
The loading effect of the most effective catalyst 1d in response to
acid activation was investigated next (Table 2). In both the generic
and aza-MBH test reactions, excess amount of acid additive resul-
ted in reduction of the rate of catalysis (Table 2, entries 1, 2, and 12),
although the enantioselectivity was reduced only in the aza-MBH
test reaction (Table 2, entries 1 and 2). In both test reactions,
a lower catalyst loading with correspondingly lower amount of acid
additive improved the enantioselectivity of the catalysis up to
a limit (Table 2, entries 9 and 17). For the aza-MBH test reaction,
a lower catalyst loading did not affect the rate of catalysis signifi-
cantly (Table 2, entries 4e7), while for the generic MBH test re-
action, the rate of catalysis was faster at a higher catalyst loading
(Table 2, entries 13e18). In general, the ratio of 1:1 catalyst to acid
additive provided the best balanced outcomes in rate improvement
and enantioselectivity.
NTs
NTs
NTs
NTs
NTs
Oc
78
Phenylphosphinic acide
2-Naphtholic acid
2-Fluorobenzoic acid
Benzoic acid
60
89
88
90
49
n.d.
46
Acetic acid
Oc
Phenylphosphinic acid
2-Naphtholic acid
Benzoic acid
Oc
42
21
10
Oc
54
a
Calculated by 1H NMR spectroscopy after 30 min of reaction.
Determined by chiral HPLC analysis.
The loading of the catalyst was 5 mol % with 5 mol % acid additive in ether
b
c
for 3 h.
d
Reaction time was 3 h with TF-1 as the catalyst at 10 mol % with 10 mol % acid
additive.
e
Reaction time was 24 h.
With the earlier generations of trifunctional catalysts such as
TF-1, the counterion from the acid additive was found to control the
sense of the asymmetric induction.5 The counterion effect of this
new type of trifunctional catalysts was therefore examined using
catalyst 1d (Table 3). Contrary to the varying counterion effect
observed with TF-1,1d exhibited a higher level of consistency in the
sense of asymmetric induction. No reversal of the sense of asym-
metric induction was observed with different counterions tested,
and benzoic acid was again identified as the best additive for
enantioselectivity with more generality (Table 3, entries 6 and 10).
Also, in the case of 1d, the generic MBH and aza-MBH reactions
showed disparate levels of sensitivity to the counterion variation.
The counterion variation displayed less effect on enantioselectivity
in the generic MBH reaction than its aza counterpart. This obser-
vation suggests that for this trifunctional approach, the coopera-
tivity between the catalyst and the counterion is crucial for
enantioselectivity and highly dependent on the nature of the
Brønsted acid of the trifunctional catalyst.
The substrate scope of catalyst 1d was investigated last using
a representative set of aryl imines and aryl aldehydes (Table 4).
These electrophiles 2 and 4 bear both electron rich and deficient
substituents at ortho, meta, and para positions of the aromatic ring.

C. Anstiss, F. Liu / Tetrahedron 66 (2010) 5486e5491
5489
Table 4
without further purification. Reactions were performed under
a nitrogen atmosphere. Reactions were magnetically stirred and
monitored by thin-layer chromatography (TLC) using silica gel 60
F254 aluminum pre-coated plates from Merck (0.25 mm). Flash
column chromatography was performed on silica gel (60 Å,
0.06e0.2 mm, 400 mesh from Scharlau). 1H NMR and 13C NMR
spectra were obtained in dry CDCl3 on a Bruker Avance DPX
400 MHz spectrometer. Chemical shifts were reported in parts per
million using chloroform as the internal reference (1H, 7.26 ppm,
13C, 77.09 ppm for CDCl3). All spectra were processed using Bruker
TOPSPIN (1.4) and MestRec 4.9.9.6. Infrared spectra were taken on
a PerkineElmer paragon 1000PC FTIR spectrometer. Optical rota-
tions were measured at 21 ꢁC on a P1010 digital polarimeter (Jasco,
Japan). High resolution mass analysis was provided by University of
Illinois, Urban-Champaign USA.
The substrate scope of catalyst 1d at 2e10 mol % loading
X
XH
R
R
1d
benzoic acid
O
O
+
CH2Cl2, RT
2: X = NTs
4: X = O
3: X = NTs
5: X = O
Entry
R
X
Cat. [mol %]
Time [h]
Yielda [%]
eeb [%]
1
2
3
4
5
6
7
8
p-NO2 (2a)
p-Br (2b)
o-Cl (2c)
p-Me (2d)
m-NO2 (2e)
o-OMe (2f)
p-NO2 (4a)
p-Me (4b)
NTs
NTs
NTs
NTs
NTs
NTs
O
2
2
5
5
2
5
10
10
2
12
12
36
2
36
6
24
92 (3a)
92 (3b)
96 (3c)
93 (3d)
97 (3e)
91 (3f)
73d (5a)
de
86c
81
54
70c
86
60
47
d
O
4.2. General procedure for the preparation of N-tosyl
aldehydes 7 and 13
a
Isolated yield.
b
c
Determined by chiral HPLC analysis.
Scale-up reaction at 1 mmol of imine.
Calculated by 1H NMR spectroscopy.
No conversion by 1H NMR spectroscopy.
d
e
To a solution of amino alcohol (500 mg, 4.06 mmol) and pyri-
dine (401 mL) in CHCl3 (15 mL) was slowly added a solution of
4-toluenesulfonyl chloride (860 mg, 4.51 mmol) in CHCl3 (4.3 mL).
After stirring at room temperature for 2 h the reaction was con-
centrated in vacuo, redissolved in EtOAc, and washed with satu-
rated aqueous NH4Cl. The organic layer was dried over Na2SO4,
filtered, and concentrated in vacuo to give the crude (N)-sulfon-
amide alcohol, which was used immediately without further pu-
rification. To a solution of crude alcohol in CH2Cl2 (20 mL) was
added manganese dioxide (2.82 g, 32.5 mmol). After stirring at
room temperature for 1 h, the reaction was filtered through a pad of
Celite and the filtrate was concentrated in vacuo. The crude product
was purified by flash chromatography on silica gel (petroleum
ether/EtOAc, 3:1) to afford purified aldehydes 7 and 13.
As 1d is a very active catalyst, the reactions were performed at
2e5 mol % loading for the aza-MBH reactions and 10 mol % for the
generic MBH reactions. In some cases (Table 4, entries 1 and 4), the
reactions were performed at a relatively large scale to investigate
the process utility of this system. Comparable to the observations
made with TF-1 in the aza-MBH reactions, catalyst 1d is generally
tolerant of substituted aryl imines except the ortho-substituted
ones (Table 4, entries 3 and 6). The catalyst is robust in scaled-up
reactions with excellent isolated yields. However, the enantiose-
lectivity of the scaled up reaction is slightly lower (86% ee vs 90%
ee) compared to that in the small-scale test reaction. For the generic
MBH reaction, the activity of catalyst 1d is limited by the reactivity
of the aryl aldehyde, as the more electron rich aryl aldehyde did not
result in any conversion. It is worth noting that while ineffective,1d
did not lead to formation of side products, which is markedly more
chemospecific compared to other bifunctional catalysts that lead to
complex reaction mixtures with electron rich aryl aldehydes.11
4.2.1. 3-N-Tosylbenzaldehyde (7). Yield: 916 mg, 82% over two
steps; 1H NMR (400 MHz, CDCl3)
d
2.37 (s, 3H), 7.23 (d, J¼8.1 Hz,
2H), 7.36 (br s, 1H), 7.42 (m, 2H), 7.57 (m, 1H), 7.61 (t, J¼4.3 Hz, 1H),
7.70 (d, J¼8.1 Hz, 2H), 9.91 (s,1H); 13C NMR (100 MHz, CDCl3)
d 22.0,
121.8, 126.8, 127.1, 127.7, 130.3, 130.5, 136.1, 137.8, 138.2, 144.8, 192.0;
IR (KBr, cmꢀ1) 3454, 3167, 3064, 2975, 2924, 2854,1673,1586,1504;
HRMS (ESI) [MþHþ]: 276.0693, calcd for (C14H14NO3S)þ: 276.0694.
3. Conclusions
4.2.2. 2-N-Tosylbenzaldehyde (13)7. Yield: 1.016 g, 91% over two
In summary, new enantioselective trifunctional catalysts 1bee
were synthesized and investigated in generic and aza-MBH re-
actions. The activity of these catalysts requires acid activation, as
seen with previous trifunctional systems.5,6 In the case of 1d,
a lower loading of catalyst and acid additive unexpectedly im-
proved enantioselectivity for both the generic and aza-MBH test
reactions. More importantly, the counterion effect of this new se-
ries was found to differ significantly from that in previous series of
trifunctional catalyst, suggesting that the counterion effect requires
cooperativity from the Brønsted acid functionality for asymmetric
induction. This will serve as an important design principle in the
development of next generation catalysts. Catalyst 1d was also
amenable to reaction processes on larger scales with low loading
levels at 2e5 mol % for the aza-MBH reactions with good enantio-
selectivity. While its activity for the generic MBH reactions is lim-
ited in scope, 1d exhibited a high level of catalytic chemospecificity
without converting the starting material to unwanted products.
steps; 1H NMR (400 MHz, CDCl3)
d
2.36 (s, 3H), 7.16 (t, J¼7.6 Hz, 1H),
7.24 (d, J¼8.5 Hz, 2H), 7.51 (t, J¼7.7 Hz, 1H), 7.59 (d, J¼7.7 Hz, 1H),
7.69 (d, J¼8.4 Hz, 1H), 7.76 (d, J¼8.5 Hz, 2H), 9.83 (s, 1H), 10.78 (br s,
1H); 13C NMR (100 MHz, CDCl3)
d 22.0, 118.2, 122.4, 123.3, 125.6,
127.7, 130.2, 136.2, 136.5, 140.4, 144.6, 195.4; APCI [MþHþ]: 276,
calcd for (C14H14NO3S)þ: 276.
4.3. Preparation of 2-hydroxy-3-N-tosyl benzaldehyde 10
To a solution of 3-amino-2-methoxybenzoic acid 8 (1.0 g,
5.98 mmol) in MeOH (10 mL) was added thionyl chloride (1.74 mL)
slowly at to 0 ꢁC. After refluxing for 3 h, the reaction was cooled to
room temperature, quenched with saturated aqueous NaHCO3, and
extracted three times with EtOAc. The organic layer was dried over
MgSO4, filtered, and concentrated in vacuo. The resulting oil was
dissolved in THF (20 mL) and was added to a suspension of lithium
aluminum hydride (241 mg, 6.3 mmol) in THF (23 mL) at ꢀ78 ꢁC.
The reaction was allowed to come to room temperature and left to
stir for 4 h. The reaction was quenched with saturated aqueous
Na2SO4 (1.5 mL) and dried over solid Na2SO4 (1 g). The mixture was
filtered through a pad of Celite and washed with MeOH (50 mL).
The filtrate was concentrated to yield the crude amino alcohol,
which was used immediately without further purification of
4. Experimental section
4.1. General
Unless otherwise stated, all chemicals and reagents were re-
ceived from SigmaeAldrich, Castle Hill, NSW Australia and used

5490
C. Anstiss, F. Liu / Tetrahedron 66 (2010) 5486e5491
characterization. This crude amino alcohol was transformed into 3-
N-tosyl-2-methoxybenzaldehyde 9 as described for the preparation
of aldehydes 7 and 13.
sulfate, and concentrated under vacuum. This crude product was
redissolved in chloroform (1 mL), cooled to 0 ꢁC, and treated with
dropwise addition of TMSI (0.1 mmol). The reaction was warmed to
40 ꢁC and stirred for 2 h, quenched with methanol (1 mL), and di-
luted with dichloromethane (5 mL). The organic phase was washed
with water and brine, dried over anhydrous magnesium sulfate, and
concentrated under vacuum. This crude phosphine oxide was re-
duced as previously reported5 to give catalyst 1b as a white foam.
4.3.1. 3-N-Tosyl-2-methoxybenzaldehyde (9). Yield: 420 mg, 23%
over four steps; 1H NMR (400 MHz, CDCl3)
d 2.35 (s, 3H), 3.62 (s,
3H), 7.17 (t, J¼8.0 Hz, 1H), 7.23 (d, J¼8.4 Hz, 2H), 7.51 (dd, J1¼7.8,
J2¼1.6 Hz,1H), 7.71 (d, J¼8.4 Hz, 2H), 7.81 (dd, J1¼8.0, J2¼1.6 Hz,1H),
10.15 (s, 1H); 13C NMR (100 MHz, CDCl3)
d 21.9, 64.9, 125.4, 125.8,
126.0, 127.6, 129.3, 130.3, 131.8, 136.4, 144.9, 152.4, 189.2; IR (KBr,
cmꢀ1) 3455, 3267,1686, 1592, 1538; HRMS (ESI) [MþHþ]: 306.0789,
calcd for (C15H16NO4S)þ: 306.0800.
To a solution of 3-N-tosyl-2-methoxybenzaldehyde 9 (100 mg,
0.326 mmol) in CH2Cl2 (8 mL) was added boron tribromide (307 mL,
4.5.1. Catalyst 1b. Yield: 25 mg, 42% over four steps; 1H NMR
(400 MHz, CDCl3)
d
3.27 (t, J¼5.4 Hz, 1H), 3.74 (br s, 2H), 4.02 (d,
J¼13.5 Hz, 2H), 6.49 (d, J¼8.0 Hz, 1H), 6.57 (d, J¼8.5 Hz, 1H), 6.62 (t,
J¼7.5 Hz, 2H), 6.89 (d, J¼7.4 Hz, 1H), 6.94 (t, J¼7.7 Hz, 1H),
6.98e7.05 (m, 3H), 7.09e7.19 (m, 5H), 7.23e7.36 (m, 6H), 7.43 (d,
J¼8.5 Hz, 1H), 7.48 (t, J¼7.3 Hz, 1H), 7.77 (d, J¼8.0 Hz, 1H), 7.83e7.93
3.26 mmol) dropwise at ꢀ78 ꢁC. After stirring at ꢀ78 ꢁC for 1 h, the
reaction was diluted with ether, warmed to room temperature, and
quenched with H2O. The product was extracted with EtOAc. The
organic layer was dried over MgSO4, filtered, and concentrated in
vacuo. The residue was purified by flash chromatography on silica
gel (petroleum ether/EtOAc, 2:1) to afford 3-N-tosyl-2-hydroxy-
benzaldehyde 10.
(m, 3H); 13C NMR (100 MHz, CDCl3)
d 47.4, 114.3, 116.2, 117.7, 118.5,
122.4, 123.4, 124.7, 126.5, 126.6, 127.2, 127.5, 127.9, 128.2, 128.5,
128.6, 128.7, 128.9, 129.0, 129.1, 130.1, 130.2, 130.9, 133.4, 133.7,
134.0, 134.1, 134.4, 134.6, 137.7, 138.4, 142.0, 144.1; 31P NMR
(162 MHz, CDCl3)
d
ꢀ11.7; IR (KBr, cmꢀ1) 3428, 3370, 3049, 2852,
1619, 1596; ESI [MþHþ]: 588.2081, calcd for (C39H31N2P)þ:
21
588.2092; [
a
]
ꢀ6.8 (c 1.0; CHCl3).
D
4.3.2. 2-Hydroxy-3-N-tosyl benzaldehyde (10). Yield: 77.8 mg, 82%;
1H NMR (400 MHz, CDCl3)
d
2.34 (s, 3H), 6.96 (t, J¼7.7 Hz, 1H), 7.04
4.6. General procedure for the preparation of catalysts 1cee
To a mixture of (S)-MAP (0.1 mmol) and aldehyde (0.1 mmol)
(br s, 1H), 7.18 (d, J¼8.2 Hz, 2H), 7.29 (d, J¼8.0 Hz, 1H), 7.66 (d,
J¼8.2 Hz, 2H), 7.82 (d, J¼8.2 Hz, 2H), 9.78 (s, 1H), 11.12 (s, 1H); 13C
NMR (100 MHz, CDCl3)
d
21.9, 120.5, 120.6, 126.2, 127.6, 127.9, 130.0,
was added tetraethylortho silicate (200 mL) at room temperature.
136.4, 144.5, 151.7, 196.8; IR (KBr, cmꢀ1) 3339, 3258, 3050, 1666,
1594; HRMS (ESI) [MþHþ]: 292.0634, calcd for (C14H14NO4S)þ:
292.0644.
The reaction mixture was refluxed overnight (14 h), cooled, and
diluted with absolute ethanol/acetonitrile (1 mL; 1:1). The solution
was cooled to 0 ꢁC and then NaBH4 (0.15 mmol) was added in one
portion and stirred at room temperature for 1 h. The mixture was
quenched with dropwise addition of water, and the organic phase
was extracted with ethyl acetate (three times). The combined or-
ganic phases were washed with brine, dried over anhydrous mag-
nesium sulfate, and concentrated under vacuum. Catalysts 1c and
1d were subject to flash chromatography on silica gel (eluent pe-
troleum ether/ethyl acetate) and catalyst 1e preparative TLC to af-
ford purified catalysts 1cee as off-white solids.
4.4. Preparation of 2-N-methylcarbamate benzaldehyde 12
To a solution of 2-aminobenzyl alcohol 11 (500 mg, 4.06 mmol)
and potassium carbonate (5.6 g, 40.6 mmol) in THF/H2O (20 mL, 2:1
v/v) was added methyl chloroformate (470 mL, 6.09 mmol) drop-
wise at 0 ꢁC. After stirring at room temperature for 1 h, the reaction
was quenched with H2O, extracted with EtOAc, and washed with
brine. The organic layer was dried over MgSO4, filtered, and con-
centrated in vacuo to give the crude N-protected alcohol, which was
used without further purification. To a solution of crude alcohol in
CH2Cl2 (20 mL) was added manganese dioxide (2.82 g, 32.5 mmol).
After stirring at room temperature for 2 h, the reaction was filtered
through a pad of Celite, washed with EtOAc. The filtrate was con-
centrated in vacuo and the crude aldehyde was purified by flash
chromatography on silica gel (petroleum ether/EtOAc, 1:2) to afford
2-N-methylcarbamate benzaldehyde 12.
4.6.1. Catalyst 1c. Yield: 60 mg, 84%; 1H NMR (400 MHz, CDCl3)
d
2.22 (s, 3H), 3.65 (t, J¼5.9 Hz,1H), 3.96 (d, J¼16.5 Hz, 2H), 6.16 (br s,
1H), 6.59 (s, 1H), 6.65 (d, J¼8.4 Hz, 1H), 6.81 (t, J¼9.1 Hz, 2H),
6.93e7.33 (m, 18H), 7.44e7.55 (m, 4H), 7.73 (d, J¼8.7 Hz, 2H), 7.90
(dd, J¼8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d 21.8, 47.5, 113.8,
116.7,116.8,119.7,120.3,122.2,123.8,124.6,126.6,126.8,126.9,127.3,
127.5,127.7,128.2,128.5,128.6,128.7,128.8,128.9,129.0,129.8,129.9,
130.0,131.2,133.2 133.3,133.7,133.8,133.9,134.0,134.5,134.6,134.7,
136.5,137.2,137.8,137.9,138.0,138.5,138.6,142.0,142.3,143.7,144.1;
4.4.1. 2-N-Methylcarbamate benzaldehyde (12)10. Yield: 669 mg,
31P NMR (162 MHz, CDCl3)
d
ꢀ12.0; IR (KBr, cmꢀ1) 3424, 3050, 2923,
92%; 1H NMR (400 MHz, CDCl3)
d
3.80 (s, 3H), 7.16 (t, J¼7.7 Hz, 1H),
2854, 2284, 1597, 1511; ESI [MþHþ]: 713.2393, calcd for
7.59 (t, J¼8.3, 1H), 7.64 (d, J¼7.4 Hz, 1H), 8.45 (d, J¼8.5 Hz, 1H), 9.90
(C46H37N2O2PS)þ: 712.2392; [
a
]
21 ꢀ31.9 (c 1.0; CHCl3).
D
(s, 1H), 10.60 (br s, 1H); 13C NMR (100 MHz, CDCl3)
d 52.8, 118.7,
121.8, 122.4, 136.4, 141.7, 154.6, 195.5; APCI [MþHþ]: 180, calcd for
4.6.2. Catalyst 1d. Yield: 61 mg, 86%; 1H NMR (400 MHz, CDCl3)
(C9H10NO3)þ: 180.
d
2.40 (s, 3H), 3.26 (t, J¼4.3 Hz,1H), 3.58 (dd, J1¼13.4, J2¼4.3 Hz, 2H),
6.68 (d, J¼8.5 Hz, 1H), 6.82 (d, J¼7.5 Hz, 1H), 6.94e7.07 (m, 5H),
7.10e7.45 (m, 18H), 7.54 (t, J¼8.3 Hz, 1H), 7.78 (d, J¼8.3 Hz 1H),
4.5. Preparation of catalyst 1b
7.86e7.98 (m, 3H); 13C NMR (100 MHz, CDCl3)
d 22.0, 47.8, 114.7,
To a mixture of (S)-MAP oxide (0.1 mmol) and 12 (0.1 mmol) was
added tetraethylortho silicate (200 mL) at room temperature. The
119.5,119.6,123.2,124.0,125.0,125.6,126.4,127.0,127.3,127.8,128.1,
128.3,128.6,129.0,129.1,129.2,129.8,130.0,130.3,130.6,133.3,133.4,
133.7,133.9,134.0,134.2,134.3,134.5,136.8,137.4,137.5,137.7,137.8;
reaction mixture was refluxed overnight (14 h), cooled, and diluted
with absolute ethanol/acetonitrile (1 mL; 1:1). The solution was
cooled to 0 ꢁC and then NaBH4 (1 mmol) was added in three portions
and stirred at room temperature for 6 h. The mixture was quenched
with dropwise addition of water, and the organic phase was
extracted with ethyl acetate (three times). The combined organic
phases were washed with brine, dried over anhydrous magnesium
31P NMR (162 MHz, CDCl3)
d
ꢀ12.1; IR (KBr, cmꢀ1) 3419, 3052, 2923,
2854, 1620, 1597, 1512; ESI [MþHþ]: 713.2388, calcd for
(C46H37N2O2PS)þ: 713.2392; [
a
]
D
21 ꢀ15.6 (c 1.0; CHCl3).
4.6.3. Catalyst 1e. Yield: 59 mg, 81%; 1H NMR (400 MHz, CDCl3)
2.00 (s, 3H), 3.35 (br s, 1H), 3.71, (s, 2H), 6.67 (d, J¼7.8 Hz,1H), 6.75
d

C. Anstiss, F. Liu / Tetrahedron 66 (2010) 5486e5491
5491
(t, J¼7.8 Hz, 1H), 6.81 (d, J¼8.5 Hz, 1H), 6.94e7.02 (m, 6H),
7.09e7.40 (m, 13H), 7.42 (dd, J1¼8.5, J2¼2.7 Hz, 1H), 7.49e7.57 (m,
3H), 7.83 (t, J¼7.8 Hz, 2H), 7.93 (d, J¼8.2 Hz, 2H), 8.84 (br s, 1H); 13C
1H), 6.02 (s, 2H), 6.96 (d, J¼8.1 Hz, 2H), 7.01 (d, J¼8.2 Hz, 2H), 7.23
(d, J¼8.1 Hz, 2H), 7.65 (d, J¼8.2 Hz, 2H); ESI [MþNaþ]: 366, calcd for
(C19H21NO3SNa)þ: 366; HPLC: Chiralpak AD column;
l¼254 nm;
NMR (100 MHz, CDCl3)
d
21.3, 48.8, 115.1, 120.0, 121.3, 123.0, 123.8,
eluent: hexane/isopropanol¼80:20. Flow rate: 0.7 mL/min; tmi-
124.4, 125.0, 125.3, 125.5, 125.6, 126.9, 127.0, 127.1, 127.5, 127.6,
128.0, 128.4, 128.5, 128.6, 128.7, 129.0, 129.1, 129.2, 129.3, 129.5,
129.6, 130.1, 130.3, 132.9, 133.0, 133.2, 133.4, 133.5, 134.1, 134.2,
136.5, 142.7, 143.6, 147.5, 147.8, 153.7, 157.9, 165.5; 31P NMR
¼16.5 min, tmajor¼18.1 min; ee%¼70%.
nor
4.7.5. 3-((3-Nitrophenyl)(tosylamino)methyl)but-3-en-2-one (3e)5.
Yield: 75 mg, 97%; 1H NMR (400 MHz, CDCl3)
d 2.17 (s, 3H), 2.40 (s,
(162 MHz, CDCl3)
d
ꢀ12.5; IR (KBr, cmꢀ1) 3424, 3050, 2922, 2853,
3H), 5.33 (d, J¼9.4 Hz,1H), 5.93 (d, J¼9.4 Hz,1H), 6.11 (s, 1H), 6.16 (s,
1H), 7.23 (d, J¼8.2 Hz, 2H), 7.40 (t, J¼8.0 Hz, 1H), 7.57 (d, J¼8.0 Hz,
2H), 7.64 (d, J¼8.2 Hz, 2H), 7.87 (m, 1H), 8.03 (d, J¼8.2 Hz, 1H); ESI
[MþNaþ]: 397, calcd for (C18H18N2O5SNa)þ: 397; HPLC: Whelk-O1
2284, 1618, 1596, 1512; ESI [MþHþ]: 729.2342, calcd for
(C46H37N2O3PS)þ: 729.2341; [
a
]
2D1þ2.4 (c 1.0; CHCl3).
4.7. General procedure for the Morita/Baylis/Hillman reaction
column;
l
¼230 nm; eluent: hexane/isopropanol¼80:20. Flow rate:
0.7 mL/min; tminor¼41.5 min, tmajor¼45.4 min; ee%¼86%.
Scale-up aza-MBH reactions for 3a and 3d: N-Tosylimine
(1.0 mmol), phosphine (2 mol %, 0.02 mmol for 3a or 5 mol %,
0.05 mmol for 3d) benzoic acid (1 equiv to phosphine), and MS 3 Å
(200 mg) were combined under N2. DCM (3.5 mL) was added fol-
lowed by distilled methyl vinyl ketone (MVK) (3.0 mmol) dropwise.
The reaction mixture was stirred until completion. The solvent was
evaporated and the crude mixture was purified by silica gel flash
chromatography (petroleum ether/ethyl acetate) and subjected to
chiral HPLC for the ee analysis.
4.7.6. 3-((2-Methoxyphenyl)(tosylamino)methyl)but-3-en-2-one
(3f)5. Yield: 65 mg, 91%; 1H NMR (400 MHz, CDCl3)
d 2.18 (s, 3H),
2.34 (s, 3H), 5.59 (d, J¼9.3 Hz, 1H), 5.91 (d, J¼9.3 Hz, 1H), 6.09 (s,
1H), 6.13 (s, 1H), 6.67 (d, J¼8.4 Hz, 1H), 6.73 (t, J¼7.4 Hz, 1H), 7.08 (d,
J¼7.4 Hz, 2H), 7.12 (d, J¼8.4 Hz, 2H), 7.58 (d, J¼8.4 Hz, 2H); ESI
[MþNaþ]: 382, calcd for (C19H21NO4SNa)þ: 382; HPLC: Whelk-O1
column;
l
¼230 nm; eluent: hexane/isopropanol¼80:20. Flow rate:
0.7 mL/min; tminor¼64.5 min, tmajor¼72.6 min; ee%¼60%.
Smaller scale aza-MBH reactions3b, 3c, 3e, and 3f: N-Tosylimine
(0.2 mmol), phosphine (5 mol %, 0.01 mmol or 2 mol %,
0.004 mmol) benzoic acid (1 equiv to phosphine), and MS 3 Å
(40 mg) were combined under N2. DCM (0.7 mL) was added fol-
lowed by distilled methyl vinyl ketone (MVK) (0.6 mmol) dropwise.
The reaction mixture was stirred until completion. The solvent was
evaporated and the crude mixture was purified by silica gel flash
chromatography (petroleum ether/ethyl acetate) and subjected to
chiral HPLC for the ee analysis.
Acknowledgements
C.A. is the recipient of an Australian Postgraduate Award
scholarship.
Supplementary data
Supplementary data for this article (NMR spectra of aldehydes 7,
10, 12, and 13 and catalysts 1be1e) can be found. Supplementary
data associated with this article can be found, in the online version,
at doi:10.1016/j.tet.2010.05.007. This data include MOL files and
InChIKeys of the most important compounds described in this
article.
4.7.1. 3-((4-Nitrophenyl)(tosylamino)methyl)but-3-en-2-one (3a)5.
Yield: 344 mg, 92%; 1H NMR (400 MHz, CDCl3)
d 2.14 (s, 3H), 2.39 (s,
3H), 5.34 (d, J¼9.3 Hz, 1H), 6.05 (d, J¼9.4 Hz, 1H), 6.08 (s, 1H), 6.12
(s, 1H), 7.22 (d, J¼8.0 Hz, 2H), 7.32 (d, J¼8.6 Hz, 2H), 7.63 (d,
J¼8.1 Hz, 2H), 8.02 (d, J¼8.7 Hz, 2H); ESI [MþNaþ]: 397, calcd for
(C18H18N2O5SNa)þ: 397; HPLC: Chiralpak AD column;
l
¼254 nm;
eluent: hexane/isopropanol¼80:20. Flow rate: 1.0 mL/min; tmi-
References and notes
¼22.3 min, tmajor¼28.5 min; ee%¼86%.
nor
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4.7.2. 3-((4-Bromophenyl)(tosylamino)methyl)but-3-en-2-one
(3b)5. Yield: 75 mg, 92%; 1H NMR (400 MHz, CDCl3)
d 2.15 (s, 3H),
2.41 (s, 3H), 5.21 (d, J¼9.0 Hz, 1H), 5.73 (d, J¼9.0 Hz, 1H), 6.05 (s,
2H), 6.09 (s, 1H), 6.98 (d, J¼8.5 Hz, 2H), 7.23 (d, J¼8.2 Hz, 2H), 7.31
(d, J¼8.5 Hz, 2H), 7.62 (d, J¼8.5 Hz, 2H); ESI [MþNaþ]: 430, calcd for
(C18H18 BrNO3SNa)þ: 430; HPLC: Chiralpak AD column;
l
¼254 nm;
eluent: hexane/isopropanol¼80:20. Flow rate: 0.7 mL/min; tmi-
¼16.7 min, tmajor¼18.8 min; ee%¼81%.
nor
4.7.3. 3-((2-Chlorophenyl)(tosylamino)methyl)but-3-en-2-one
(3c)5. Yield: 70 mg, 96%; 1H NMR (400 MHz, CDCl3)
d 2.19 (s, 3H),
3. (a) Shi, Y.-L.; Shi, M. Eur. J. Org. Chem. 2007, 18, 2905e2916; (b) Masson, G.;
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2.36 (s, 3H), 5.70 (d, J¼8.7 Hz, 1H), 5.85 (d, J¼8.7 Hz, 1H), 6.12 (s,
1H), 6.14 (s, 1H), 7.04e7.13 (m, 2H), 7.16 (d, J¼8.2 Hz, 2H), 7.21 (m,
1H), 7.29e7.33 (m, 1H), 7.62 (d, J¼8.2 Hz, 2H); ESI [MþNaþ]: 386,
calcd for (C18H18ClN2O3SNa)þ: 386; HPLC: Chiralpak AD column;
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63, 7738e7748.
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6262e6263.
l
¼230 nm; eluent: hexane/isopropanol¼80:20. Flow rate: 0.7 mL/
min; tminor¼18.1 min, tmajor¼20.6 min; ee%¼54%.
4.7.4. 3-((4-Methylphenyl)(tosylamino)methyl)but-3-en-2-one
(3d)5. Yield: 319 mg, 93%; 1H NMR (400 MHz, CDCl3)
d
2.15 (s, 3H),
2.26 (s, 3H), 2.41 (s, 3H), 5.23 (d, J¼8.4 Hz, 1H), 5.57 (d, J¼8.4 Hz,