Screening of simple N-aryl and N-heteroaryl pyrrolidine amide organocatalysts for the enantioselective aldol reaction of acetone with isatin

Article abstract of DOI:10.1016/j.tetasy.2011.07.016

We have screened a range of simple N-aryl and N-heteroaryl pyrrolidine amide organocatalysts incorporating N-pyridyl and N-quinolinyl groups in the synthetically useful aldol reaction of isatin with acetone. The 'reverse amide' N-pyridyl pyrrolidinylmethy

Full text of DOI:10.1016/j.tetasy.2011.07.016

Tetrahedron: Asymmetry 22 (2011) 1423–1433
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Screening of simple N-aryl and N-heteroaryl pyrrolidine amide
organocatalysts for the enantioselective aldol reaction of acetone with isatin
⇑
Michael Kinsella, Patrick G. Duggan, Claire M. Lennon
Pharmaceutical and Molecular Biotechnology Research Centre, Department of Chemical and Life Sciences, Waterford Institute of Technology, Waterford, Ireland
a r t i c l e i n f o
a b s t r a c t
Article history:
We have screened a range of simple N-aryl and N-heteroaryl pyrrolidine amide organocatalysts incorpo-
rating N-pyridyl and N-quinolinyl groups in the synthetically useful aldol reaction of isatin with acetone.
The ‘reverse amide’ N-pyridyl pyrrolidinylmethyl amide catalysts proved highly catalytically active but
gave disappointing enantioselectivities. However, an N-3-pyridyl prolinamide catalyst gave the aldol
adduct in high yields and high enantioselectivity with up to 72% ee of the (S)-isomer. Conditions were
optimised for this catalyst and in particular an additive screen identified a link between the pKa of the
acid additive and the yield and enantioselectivity. An N-arylsulfonamide prolinamide was also identified
as a catalyst for this reaction giving the (R)-enantiomer in 68% ee.
Received 21 June 2011
Accepted 20 July 2011
Available online 16 September 2011
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
There has been renewed interest in the organocatalyst pro-
moted aldol reaction,22–27 in particular due to the discovery that
The synthesis of natural products remains a significant chal-
lenge for synthetic organic chemists and is an area which requires
continuing attention. In particular, compounds based on the indole
substructure appear in many natural products and drug molecules.
More specifically, oxindoles, which possess a carbonyl group at the
2-position of the 5 membered ring and a stereogenic quaternary
carbon centre at the 3-position of this ring, are present in a number
of natural products including biologically active alkaloids and
pharmacological agents.1–11 As a result, many techniques have
been used to synthesise compounds bearing the aforementioned
functionality with particular interest in the enantioselective addi-
tion to the 3-position.12–17
The aldol addition of ketones to substituted and unsubstituted
isatins would appear to be a simple and suitable route towards
these important biological compounds (Scheme 1).18–21 In addi-
tion, the biological activity of oxindoles may be linked to the con-
figuration at the stereogenic centre, creating a need to develop
enantioselective methods for their synthesis.19
proline is a successful catalyst for this reaction.28–30 This discovery
has pushed the resurgence of organocatalysis and has allowed pre-
viously difficult reactions to be successfully accomplished in a ster-
eoselective manner.31–35
Some examples of biologically active products generated from
the aldol reaction of ketones to isatins include convolutamydines
A–E and 3-cycloalkanone-3-hydroxy-2-oxindoles36–38 (Fig. 1). An
organocatalyst promoted stereoselective aldol reaction for the syn-
thesis of these compounds is highly attractive and prompted us to
investigate this further.20,38
R
Br
HO
O
HO
HO
R
R
*
*
O
O
*
O
N
H
N
H
Br
N
H
convolutamydines A-E 3-hydroxyindoline-2-ones 3-cycloalkanone-3-hydroxy-
A: R = CH2COCH3
B: R = CH2CH2Cl
C: R = CH3
2-oxindoles
O
O
HO
O
catalyst
D: R = CH=CH2
E: R = CH2CH2OH
O
+
O
additive
-20oC
N
H
N
H
Figure 1. Examples of biologically active 3-hydroxy-indolin-2-ones.
Scheme 1. Aldol reaction of acetone with isatin.
Since 2005 work has been conducted by a number of research
groups with the common aim of designing the successful organo-
catalytic enantioselective reactions of isatin and isatin derivatives
with ketones.16,20,21,39,40 Overall, this work has produced varied
⇑
Corresponding author. Tel.: +353 51 304048; fax: +353 51 302679.
E-mail address: clennon@wit.ie (C.M. Lennon).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.07.016

1424
M. Kinsella et al. / Tetrahedron: Asymmetry 22 (2011) 1423–1433
results and there still exists a strong need to develop new, success-
ful, catalytic systems for this reaction.
could serve to enhance binding effects and improve reaction rate
and enantioselectivity.
In response to this challenge, we designed a library of catalysts
and tested them in the aldol reaction of isatin with acetone. We
chose this reaction as a model for other more complex syntheses
towards larger natural products due to the commercial availability
of the starting materials and also the challenging nature of this
reaction which would give us a good indication of our catalysts
performance; herein we report our results.
2.1. Pyrrolidinylmethyl amide ‘reverse amide’ based catalysts
We initially designed and created a series of pyrrolidinyl methyl
amide based catalysts 1–4 (Fig. 2). Each of these catalysts con-
tained the ‘reverse amide’ group when compared to typical proli-
namide catalysts. The combination of this functionality with the
hydrogen bond accepting pyridine group in a single molecule
was expected to be of a suitable size and shape to bind the reaction
intermediates by hydrogen bonding and thereby impart stereose-
lectivity to the product.44 We postulated that the larger distance
between the amide N–H and the enamine formed at the amine
N–H as well as the inherent increased flexibility of these groups
compared to the pyridine carboxyl group may result in a good
hydrogen bonding fit for isatin.
2. Results and discussion
In order to design potential catalysts for the aldol reaction of
isatin and acetone, we considered natural enzymatic processes.
Many of these processes function through molecular recognition
between enzymes and substrates and many artificial systems have
been developed based on the enzyme–substrate model.41 In 2006,
Gong and co-workers studied an organocatalytic system based on
an artificial molecular recognition system.42 They applied the dis-
covery by Hamilton and co-workers that an N-pyridyl amide was
a suitable group to bind a carboxyl molecule43 and in doing so
developed a successful series of hydrogen bond donating organo-
The ‘reverse amide’ catalysts were synthesised in four steps
with moderate yields starting from commercially available L-pro-
line. We used a borane reduction step originally devised by Brown
and Heim45 and recently used by Wang et al. in the case of the Cbz
protected analogue, to convert the Boc-amide to the Boc-amine.46
A modified work-up procedure, which included the azeodistillation
of the borane salts was employed for the acid-sensitive Boc-amine
product.47 This amine was used without further purification for
ethyl chloroformate coupling with the appropriate pyridine car-
boxylic acid and subsequent purification followed by Boc-depro-
tection to yield the pyrrolidine catalysts 1–4.
The results for catalysts 1–4 are presented in Table 1. In all
cases, the absolute configuration of the aldol product was assigned
through comparison of the specific rotations with the reported va-
lue16 and of our HPLC chromatograms, based on triplicate analysis,
with those in the literature.19–21,39 In general, these catalysts were
highly catalytically active at the expense of enantioselectivity; a
catalysts for the aldol reaction of
a-keto acids with acetone. Our
interest also lies in the application of key artificial receptor motifs
as organocatalysis.
Therefore, we wanted to apply a similar strategy to the aldol
reaction of isatin with acetone by designing a number of chiral
amide based catalysts incorporating N-pyridyl and N-quinolinyl
groups. We hoped to exploit cooperatively the hydrogen bond
donating and accepting properties of such catalysts. We envisioned
that the hydrogen bond donating amide N–H group would bind to
and activate the isatin ketone group while concurrently the hydro-
gen bond accepting pyridine moiety could form hydrogen bonds
with the isatin amide N–H group. A cooperative effect of both
O
O
O
N
H
HN
HN
N
N
H
HN
N
H
N
N
N
1
5
H
10
O
O
O
N
N
H
HN
H
N
H
N
N
N
N
6
H
2
11
O
O
O
O
N
H
HN
N
H
HN
N
N
N
H
N
H
N
N
7
H
H
N
12
O
3
O
N
N
H
HN
N
N
O
N
O
H
N
H
8
13
H
O
O
H
N
O
N
H
N
N
N
H
N
HO
N
H
N
N
H
H
4
9
14
Figure 2. Catalysts examined herein; ‘reverse amide’; N-pyridyl pyrrolidine amide catalysts 1–4, N-pyridyl prolinamide catalysts 5–8 and 12, N-quinolinyl prolinamide
catalysts 9–11, N-pyridyl hydroxy and benzyloxy prolinamide catalysts (13 and 14).

M. Kinsella et al. / Tetrahedron: Asymmetry 22 (2011) 1423–1433
1425
Table 1
Aldol reaction of isatin with acetone catalysed by pyrrolidine catalysts 1–4a
O
O
O
HO
10 mol% 1-4
O
O
20 mol% AcOH or
40 equiv H2O,
temp
+
N
H
N
H
Entry
Catalyst
Additive
Temp (°C)
Time (h)
Yieldb (%)
eec (%)
Config
1
2
3
4
1
1
1
1
—
—
AcOH
AcOH
rt
ꢀ20
rt
ꢀ20
44
63
16.5
15
85
95
70
98
22
26
18
30
(R)
(R)
(R)
(R)
5
6
7
8
2
AcOH
AcOH
TFA
ꢀ20
ꢀ20
rt
18
11
120
95
97
52
32
31
10
8
(R)
(R)
(R)
(R)
2d
2
2
p-TSA
rt
120
<10
9
3 (20)
AcOH
H2O
AcOH
AcOH
AcOH
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
14
6
18
16
135
Quant
92
85
87
31
7
8
18
21
24
(S)
(R)
(S)
(R)
(R)
10
11
12
14
3 (30)
3e (20)
3f (20)
3f,g (20)
15
4
—
rt
44
84
6
(S)
a
All reactions were conducted with 0.3 mmol of isatin and 2 mL of acetone at the temperature specified with 10 mol % catalyst loading unless catalyst loading is specified
in parentheses in the Table. In cases where the additive was employed, 20 mol % acid or 40 equiv H2O were used. TLC and HPLC were used to monitor the progression of the
reaction.
b
Isolated yield.
Determined by chiral HPLC.
0.3 mL Acetone used.
Toluene solvent (2 mL) used with 1 mL acetone.
DMF solvent (2 mL) used with 1 mL acetone.
Two equivalents (0.044 mL) acetone used.
c
d
e
f
g
maximum ee of 32% was obtained for catalyst 2. After testing a
number of acidic additives and also water, we concluded that
AcOH was the most successful additive enhancing both the reac-
tion rate and enantioselectivity. Attempts to improve the enanti-
yield and enantioselectivity. Overall, the 3- and 4-aminopyridinyl
catalysts 7 and 8 and the 3-aminoquinolinyl catalyst 10 provided
the best results (Table 2, entries 3–9, 14 and 15). As with the pre-
vious series, the use of common aldol additives enhanced yield and
enantioselectivity.22,50 In general, the inclusion of 20 mol % AcOH
and a reduction in temperature to ꢀ20 °C resulted in improved
yield and ee values.21,51 The addition of an appropriate quantity
of H2O was also effective at improving the ee (Table 2, entries 8
and 9), but it decreased the reaction rate. This has previously been
observed for proline-based catalysts.18,40,52 The 4-aminopyridine
derivative 8 proved slightly inferior to 7 in terms of both yield
and ee, in particular when H2O was used as an additive. Both 7
and 8 were far superior to the 2-aminopyridine derivatives 5 and
6 and the 2- and 8-aminoquinoline derivatives 9 and 11.
oselectivity of the most reactive catalyst
3 by varying the
temperature, additive, catalyst loading and stoichiometry proved
unsuccessful. However, the solvent was found to have the most
significant effect on the configuration of the product and its enanti-
oselectivity. When the reaction was conducted in non-polar tolu-
ene as a solvent, the (S)-enantiomer was formed preferentially;
however, the (R)-product was obtained when using the polar apro-
tic DMF solvent (Table 1, entries 11–14).
2.2. Prolinamide based catalysts
In the reaction of isatin with acetone catalysed by 7 with H2O
and AcOH, the enantioselectivity of the product increased slightly
as the reaction progressed. This phenomenon has been previously
observed and reported for this aldol reaction using a dipeptide
based catalyst and was ascribed to the formation of diastereomeric
complexes between the catalyst and product.52
With the limited success of our ‘reverse amide’ pyrrolidine
catalysts, we subsequently synthesised and screened a series of
prolinamide catalysts derived from aminopyridines and amino-
quinolines.27,42,43,48 The synthesis was achieved through the cou-
pling of Boc-proline to an aminopyridine or aminoquinoline;
subsequent Boc-deprotection yielded prolinamide catalysts 5–12
in good yields.49
2.3. Hydroxyprolinamide based catalysts
These catalysts were tested in the reaction of isatin with ace-
tone under similar conditions as used for the pyrrolidine catalysts;
however, a 20 mol % catalyst loading was used in this screen due to
a general improvement in results when using this loading for the
previous screen. The 2-aminopyridine derivative 5 and its picoline
derivative 6 yielded disappointing results; 11% and 15% ee of the
(R)-product, respectively, with long reaction times (Table 2, entries
1 and 2). The C2-symmetric bis-prolinamide catalyst 12 gave im-
proved results, however, the ee was still at a moderate level of
47% in favour of the (S)-product. The position of the nitrogen in
the ring proved to have the most pronounced effect on both the
Previous success with hydroxyproline catalysts in aldol reac-
tions motivated us to investigate this functionality.53 We based
our bifunctional hydroxyprolinamide catalysts on our most suc-
cessful catalysts to date (catalyst 7) and examined the effect of
the additional stereogenic centre, a benzyloxy group (catalyst 13)
and the unprotected hydroxyl group (catalyst 14). Catalyst 13
was synthesised in 4 steps with moderate yield starting with N-
Boc-trans-4-hydroxy-L-proline methyl ester and 14 was prepared
in 3 steps in an analogous way to the synthesis of 5–12. The benzyl
protected catalyst 13 produced the (S)-product in 54% ee using

1426
M. Kinsella et al. / Tetrahedron: Asymmetry 22 (2011) 1423–1433
Table 2
Aldol reaction of isatin with acetone catalysed by prolinamide catalysts 5–14a
O
O
O
HO
20 mol% 5-14
O
O
+
20 mol% additive or
40 equiv H2O
temp
N
H
N
H
Entry
Catalyst
Additive
Temp (°C)
Time (h)
168
Yieldb (%)
eec (%)
11
Config
(R)
1
2
5
6
—
—
rt
rt
80
74
168
15
(R)
3
4
5
6
7
8
9
7
7
7
7
7
7
7
—
—
rt
ꢀ20
rt
ꢀ20
ꢀ20
ꢀ20
ꢀ20
17
32
15
30
37
37
37
98
96
92
95
84
76
72
55
57
60
66
66
58
69
(S)
(S)
(S)
(S)
(S)
(S)
(S)
AcOH
AcOH
AcOHd
H2Oe
H2O
10
11
8
8
AcOH
H2O
ꢀ20
ꢀ20
22
24
89
87
65
54
(S)
(S)
12
13
9
9
AcOH
H2O
ꢀ20
ꢀ20
504
312
<20
<20
17
7
(R)
(S)
14
15
10
10
AcOH
H2O
ꢀ20
ꢀ20
50
44
71
89
64
66
(S)
(S)
16
17
11
11
AcOH
H2O
ꢀ20
ꢀ20
44
60
76
75
13
5
(R)
(R)
18
19
20
12(10)
12
12
AcOH
AcOH
H2O
ꢀ20
ꢀ20
ꢀ20
88
88
88
81
99
99
47
39
43
(S)
(S)
(S)
21
22
13
13
AcOH
H2O
ꢀ20
ꢀ20
90
90
77
79
50
54
(S)
(S)
23
24
14
14
AcOH
H2O
ꢀ20
ꢀ20
15
17
85
87
44
58
(S)
(S)
a
All reactions were conducted with 0.3 mmol of isatin and 2 mL of acetone at the temperature specified with 20 mol % catalyst loading unless the catalyst loading is
specified in parentheses in the Table. In cases where the additive was employed, 20 mol % AcOH or 40 equiv H2O was used unless otherwise specified. TLC and HPLC were
used to monitor the progression of the reaction.
b
Isolated yield.
Determined by chiral HPLC.
40 mol % AcOH used.
6.6 equiv H2O used.
c
d
e
20 mol % catalyst loading and 40 equiv H2O at ꢀ20 °C (Table 2, en-
Table 3
try 22). The unprotected hydroxy proline derivative 14 furnished
Variation of the acid additive and relationship between pKa of additive and ee of (S)-
product for 7 catalysed reactiona
product the (S)-product in up to 58% ee, using the same conditions
(Table 2, entry 24). Therefore, the incorporation of a second func-
tional group and stereogenic centre into the prolinamide catalyst
resulted in a slight reduction in ee.
With the screening results in hand, we identified catalyst 7 as
the catalyst with the most potential for the reaction. We subse-
quently undertook a study to optimise the reaction conditions
and hence improve the yield and enantioselectivity further.
O
O
O
HO
20 mol% 7
O
O
+
20 mol% additive,
-20oC
N
H
N
H
Entry
Additive
Additive pKa
Time (h)
Yield (%)
ee (%)
1
2
3
4
5
6
7
8
p-TSA
TFA
ClCH2COOH
HCOOH
PhCOOH
AcOH
4-NO2-phenol
4-Cl-phenol
Phenol
Methanol
Water
ꢀ1.34
0.26
2.85
3.75
4.21
4.76
7.14
9.38
9.94
15
88
12
6
52
97
98
94
90
95
84
85
80
77
96
13
12
37
58
63
66
69
70.5
71
69
57
2.4. Variation of acid additive
Having observed the positive effect of AcOH as an additive on
the yield and enantioselectivity in our preliminary studies we con-
sidered the effect of the strength of the acid additive. We tested a
range of additives across a pKa range of ꢀ2 to 16 (literature values)
and found a correlation between the pKa of the acid additive and
the enantioselectivity (Table 3 and Fig. 3).54,55 Interestingly, a plot
of pKa versus enantioselectivity gave a curve resembling a pH titra-
tion curve. The ee appeared to rise sharply and linearly between
additive pKa 2–6. A plateau was reached at pKa 7 after which an
essentially constant ee value was obtained regardless of the pKa
of the additive; (Fig. 3). A correlation between the pKa of the addi-
14
14
65
78
89
89
89
32
9
10
11
15.7
a
Unless otherwise noted, all reactions for the acid additive study were conducted
using 20 mol % catalyst loading of 7 at ꢀ20 °C with 20 mol % of additive. TLC and
HPLC were used to monitor the progress of the reaction. Literature pKa data, as
measured in water.56

M. Kinsella et al. / Tetrahedron: Asymmetry 22 (2011) 1423–1433
1427
Table 5
Variation of the conditions and additives in the reaction of isatin and acetone
catalysed by 7a
O
O
HO
x mol% 7
O
O
O
+
20 mol% AcOH or
40 equiv H2O,
temp
N
H
N
H
Entry
Loading
Additive
Temp (°C)
Time (h)
Yield (%)
ee (%)
1
2
3
4
5
6
7
30
30
30
20
30
30
40
AcOH
AcOH
AcOHb
H2Oc
H2O
rt
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
15
37
37
37
37
37
33
95
95
84
76
88
87
68
60
63
69
58
72
72
69
H2Od
H2O
a
Figure 3. Relationship between the pKa of the additive and ee of the product using
20 mol % catalyst 7 and 20 mol % additive.
Unless otherwise noted, all of the reactions for the catalyst optimisation study
were conducted using 30 mol % catalyst loading of 7 with either 20 mol % AcOH or
40 equiv H2O additive to yield an excess of (S)-product. TLC and HPLC were used to
monitor the progress of the reaction.
b
40 mol % AcOH used.
6.6 equiv H2O used.
One millilitre acetone used.
Table 4
c
Variation of solvents in reaction catalysed by 7a
d
O
O
20 mol% 7
HO
1 mL acetone
O
2.5. Variation of solvent
O
20 mol% AcOH or
40 equiv H2O
2mL solvent, -20
O
+
N
N
H
H
We conducted a detailed study to investigate the effects of vary-
ing the reaction solvent (Table 4). Due to the similar performance
of 7 using AcOH or 40 equiv H2O as additive, we conducted the sol-
vent study for both additives independently. We tested a range of
solvents of varying polarities and in the case of the AcOH additive,
found that a marginally higher ee value could be obtained when
the reaction was conducted in non-polar CHCl3 or CH2Cl2 (Table 4,
entries 7 and 8) but this came at the expense of the reaction yield.
However, using H2O as an additive, the reaction in acetone was
found to be marginally superior in terms of ee when compared
to the use of alternative reaction solvents. When relatively non-po-
lar solvents were used, an increase in reaction yield was observed
in hexane and CHCl3, however, significantly longer reaction times
were required (Table 4, entries 9–16).
oC
Entry
Solvent
Additive
Time (h)
Yield (%)
ee (%)
1
2
3
4
5
6
7
8
Acetone
Toluene
DMF
Dioxane
THF
Hexane
CH2Cl2
CHCl3
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
65
22
61
42
48
38
46
40
95
91
78
85
78
96
82
80
66
66
54
64
64
58
68.5
69
9
Acetone
Toluene
DMF
Dioxane
THF
Hexane
CH2Cl2
CHCl3
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
37
108
108
13.5
41
88
108
90
72
72
85
97
92
98
68
85
69
63
61
50
63
68
66
68
10
11
12
13
14
15
16
2.6. Optimisation of the reaction conditions
We finally attempted to further optimise conditions for 7. We
studied the effects of catalyst loading, temperature and additive
loading. Overall, our best results in terms of enantioselectivity
were obtained using 30 mol % loading of catalyst in the presence
of 40 equiv H2O at ꢀ20 °C for 37 h, producing the (S)-product in
a yield of 88% and 72% ee (Table 5, entry 5).52 It was noted that
the reaction with the AcOH additive proceeded with marginally
less enantioselectivity and improved yield; however, reactions
using water were slower but provided higher enantioselectivities.
To compare our catalysts with related organocatalysts, (S)-proline
gave 33% ee while Tomasini et al. obtained 73% ee for their proline
dipeptide catalyst39 and up to 86% ee in the presence of H2O.52 Xiao
et al. obtained up to 88% ee at ꢀ50 °C,21 while Nakamura et al. pro-
duced 3% ee from their N-heteroarylsulfonamide catalyst but 95%
ee for the reaction of acetone with 4,6-dibromoisatin.18 In general,
organocatalysts have been found to give better enantioselectivities
with 4,6-dibromoisatin compared to isatin itself.18,19,40 A highly
efficient enantioselective example of this reaction was reported
by Malkov et al. with up to 94% ee being obtained for an amino
alcohol catalyst.16 Chen et al. obtained a product in up to 67% ee
using a carbohydrate derived alcohol catalyst.57 It is worth noting
that the work reported herein represents an extension of the scope
a
Unless otherwise noted, all of the reactions for the solvent study were con-
ducted using 20 mol % catalyst loading of 7 at ꢀ20 °C with either 20 mol % AcOH or
40 equiv H2O additive to give excess of the (S)-product. TLC and HPLC were used to
monitor the progress of the reaction.
tive and the reaction rate and yield was also observed. It was noted
that the reaction proceeded at a slower rate when using additives
with pKa values >6 (Table 3, entry 6 vs entries 8 and 9). Addition-
ally, an increase in ee was observed at the expense of product yield.
It could, therefore, be said that the optimum acid additive for yield
and enantioselectivity should have a pKa value of approximately
4.0–6.0. Water as an additive at 20 mol % was found to be an
exception to the aforementioned trends resulting in lower ee and
higher yield than expected based on its pKa of 15.7 (Table 3, entry
11). It should be noted, however, that the quantity of water present
in the media has been demonstrated to be critical to the level of
enantioselectivity.52 A quantity of 40 equiv (4000 mol %) has been
found to be optimum by us and also reported in the literature.52
Additionally, above the optimum level, water was shown to have
a negative effect on the enantioselectivity of the reaction.52

1428
M. Kinsella et al. / Tetrahedron: Asymmetry 22 (2011) 1423–1433
of catalyst 7 from the enantioselective aldehyde:ketone to ketone:-
ketone aldol reactions.
2.7. Structural considerations
Our studies identified several key structural design parameters
that were critical with regard to the yield and enantioselectivity.
The results indicate that the position of the pyridyl nitrogen was
important for achieving high yield and enantioselectivity. The loss
of enantioselectivity in the 2-pyridyl catalyst is possibly due to
electron repulsion between the lone pair of electrons in the pyri-
dine nitrogen and the non-hydrogen bonded carbonyl group of
isatin upon hydrogen bonding of the reactive carbonyl with the
amide N–H. This repulsion may not arise when the N lies at the
3- or 4-position in the pyridyl ring. The pKa of the acid additive
was also key with regard to the yield and enantioselectivity. A loss
in enantioselectivity seems to occur when an additive with a pKa
lower than 4 is employed. Using an acid with a lower pKa could
lead to possible protonation of the pyridine nitrogen and/or accel-
eration of the direct reaction of acetone with isatin, which could
account for the loss of selectivity. Water may alternatively be used
as an additive for 7, with 40 equiv at ꢀ20 °C giving the highest
enantioselectivity.
In order to study the effect of the pyridine N in the ring and
hence determine the potential mode of action of 7, catalyst 15
(Fig. 4), in which a phenyl ring was used in place of a pyridine ring,
was prepared. We obtained a relatively high ee of 65% using
30 mol % loading and 40 equiv water additive at ꢀ20 °C; however,
the reaction was considerably slower with catalyst 15 compared to
7 (Table 6, entry 3).
In order to assess the role of the amide N–H proton, prolinamides
16 and 17 (Fig. 4) were synthesised from proline coupled to the
appropriate methylamine. As expected, the 4-methylaminopyridine
prolinamide catalyst 16 failed to catalyse the reaction (Table 6, entry
4). In the case of the methylaniline prolinamide derivative 17, the
product was obtained in good yield while the enantioselectivity
was significantly lower and the opposite enantiomer was obtained
(Table 6, entry 5), indicating a loss of special fit.
Figure 4. Catalysts synthesised and tested for mechanistic investigations.
Therefore, we suggest that in the case of aminopyridine and
aminoquinoline based catalysts, the relative position of the amino
group and the pyridine nitrogen atom has a major impact on the
enantioselectivity of the reaction. The presence of N in the ring is
not crucial, however, as the aniline derived prolinamide 15 also
catalysed the reaction, albeit with lower enantioselectivity. In both
cases the amide N–H was necessary to obtain high yields and
enantioselectivity.
With a relatively high ee obtained using the aniline derived cat-
alysts, we also considered catalysts 18 and 19 (Fig. 4) with en-
hanced N–H acidities compared to 15. Catalyst 18 was derived
from proline coupled to 3,5-bis(trifluoromethyl)aniline and 19 de-
rived from 3,5-bis(trifluoromethyl)benzenesulfonamide.53,58–60
Previously, our group reported acidic amides and N-acyl sulfona-
mides as successful acidic anion receptors and organocatalysts
for the Baylis–Hillman reaction; therefore, we were interested in
studying the effects of increased N–H acidity on this reaction.61
The results for these acidic catalysts, in particular 19, (the acidity
of such a compound would be expected to be similar to carboxylic
acids)62,63 were surprising. Catalyst 18 furnished the aldol product
in high yield and with up to 71% ee of the (S)-product using the
previously determined optimum conditions (Table 6, entry 8). This
result is very similar to the optimum catalyst 7 under the same
conditions, however, the latter catalyst produced a higher yield
Table 6
Aldol reaction of isatin with acetone catalysed by catalysts 15–19a
O
O
HO
x mol% 15-19
O
O
+
O
20 mol% AcOH or
40 equiv H2O,
-20oC
N
H
N
H
Entry
Catalyst
Cat loading (mol %)
Additive
Time (h)
Yieldb (%)
eec (%)
1
2
3
15
15
15
20
20
30
—
AcOH
H2O
91
91
91
90
92
89
58
61
65
4
16
20
AcOH
336
Trace
-
5e
6e
17
17
20
30
AcOH
H2O
12
12
99
96
46e
37e
7
8
18
18
20
30
AcOH
H2O
39
39
85
71
69
71
9e
19
19
19
20
20
20
AcOH
AcOH
H2O
37
37
37
92
87
32
68e
68e
3e
10d,e
11e
a
Unless otherwise noted, all reactions were conducted with 0.3 mmol of isatin and 2 mL of acetone at ꢀ20 °C to yield an excess of (S)-product. Unless otherwise noted,
20 mol % AcOH was used and 40 equiv H2O; TLC and HPLC were used to monitor the progress of the reaction.
b
Isolated yield.
Determined by chiral HPLC.
40 mol % AcOH used.
The (R)-product was obtained as the major enantiomer.
c
d
e

M. Kinsella et al. / Tetrahedron: Asymmetry 22 (2011) 1423–1433
1429
Table 7
N-atom, but clearly it is not as important as was shown with
results using the aniline derived catalyst 15, albeit with lower
enantioselectivity and longer reaction time. The relatively high ee
found for N-benzylisatin with 7 also suggests that binding to the
amide N–H of isatin may not play a significant role in the mecha-
nism. Similar interactions to 7 are possible with the structurally re-
lated aminoquinoline based catalyst 10.
Substrate scope of catalyst 7 varying each component of the reactiona
Entry
Isatin
Ketone
Time (h)
Yieldb(%)
eec(%)
1
2
3
4
5
N-benzyl
Isatin
Isatin
Isatin
N-benzyl
Acetone
44
23
>100
48
62
72
—
85
28
61
52
2-Butanone
Cyclohexanone
Acetaldehydee
Acetaldehydee
d
d
—
39
32
48
The suggested interactions above are consistent with the results
for the hydroxyproline derived catalysts 13 and 14 where the
added stereogenic centre had only minor effects as the added
groups point away from the cleft. Furthermore, the importance of
hydrogen bonding to the amide group in 7 is supported by the re-
duced activity and enantioselectivity of the N-methylated catalysts
16 and 17 and the good results found for the activated amide in
catalyst 18.
a
Unless otherwise noted, all reactions for the substrate scope study were con-
ducted using 30 mol % catalyst loading of 7 with 40 equiv H2O additive at ꢀ20 °C to
give excess of the (S)-product.
b
Isolated yield.
Determined by chiral HPLC.
Multiple products formed with product separation impossible.
Reaction conducted using 30 mol % 7, 0.3 mmol isatin/N-benzylisatin, 5 equiv
c
d
e
CH3CHO, 17 mg chloroacetic acid at rt and reduced (NaBH4 reduction) to the alcohol
product prior to analysis with excess of the (R)-product. Absolute configurations
were assigned through comparison of the specific rotations and chiral chromatog-
raphy with literature data.
The sulfonamide catalyst 19 gave high enantioselectivity to-
wards the (R)-product. With this catalyst,
p-stacking of isatin in
the catalyst cleft could allow the formation of two hydrogen bonds,
one between the C@O on isatin and the sulfonamide N–H and the
other binding between the N–H on isatin and the S@O of the cata-
lyst, facilitating an attack on the Si face leading to the (R)-product.
In addition, when catalyst 19 was tested in the reaction of N-ben-
zylisatin with acetone, the (R)-product was formed with a slightly
lower ee compared to the reaction catalysed by 7. It is interesting
to note the low yield and enantioselectivity obtained when water
was used as an additive instead of AcOH; this may be due to the
deprotonation of the highly acidic sulfonamide N–H in this reac-
tion media forming a zwitterionic state which could inhibit enam-
ine formation.
With the ‘reverse amide’ catalysts, while the catalytic activity
was high, the enantioselectivity was poor and more variable be-
tween (R) and (S)-selectivity. With these catalysts, the extra carbon
can be expected to impart greater flexibility to the cleft site and the
high catalytic activity observed may be related to the reduced
steric strain involved during the enamine attack with these more
flexible catalysts. Considering catalyst 3, it is possible to envisage
(Table 5, entry 5 vs Table 6, entry 8). Catalyst 17 was observed to
give the opposite enantiomer [the (R)-product] in 68% ee using
20 mol % catalyst loading with 20 mol % AcOH (Table 6, entry 9).
2.8. Substrate scope
The final study undertaken was a substrate scope of our most
successful catalyst 7. We examined a number of substrates using
catalyst 7 and the optimum catalyst conditions as obtained from
our previous studies. The reaction of N-benzylisatin with acetone
produced the (S)-product in 61% ee after 44 h (Table 7, entry 1).
This result has implications for the binding to the N–H of isatin
which will be discussed below. We tested the reaction of isatin
with 2-butanone and obtained the product in good ee and regiose-
lectivity with 52% ee of the major product, 9:1 regioselectivity in
favour of C–C bond formation at the less substituted methyl group
(Table 7, entry 2).64 We also attempted the reaction of isatin with
cyclohexanone, but were unsuccessful in assessing the perfor-
mance of this difficult substrate due to the formation of many
products, which proved to be inseparable from the desired and bio-
logically active product.38 We also studied the reaction of isatin
and N-benzylisatin with acetaldehyde (Table 7, entries 4 and 5).
We deviated from our prescribed conditions in these cases and fol-
lowed a previously reported method.65 We observed the formation
of the product from both reactions. It has been previously reported
that isatin was inactive with acetaldehyde when the highly suc-
cessful 4-hydroxydiarylprolinol was used as a catalyst.65 We ob-
tained the product (R)-product in 39% ee for the isatin reaction
and in 33% ee for the reaction of the acetaldehyde with N-
benzylisatin.
p-stacking of isatin in the catalyst cleft, which facilitates two
hydrogen bonds between isatin and the amide group of the cata-
lyst. Due to the greater flexibility of the ‘reverse amide’, similar
complexes are possible by a conformational change leading to
either the (R)- or (S)-product. The results for 3 also highlight the
likely importance of the solvation in all these catalytic processes.
3. Conclusions
In conclusion, we have designed and tested a range of simple
organocatalysts for the synthetically useful reaction of isatin to
acetone. Our ‘reverse amide’ N-pyridyl pyrrolidinylmethyl amide
catalysts produced disappointing enantioselectivities but were
highly catalytically active. We achieved more success with our
N-pyridyl prolinamide and N-quinolinyl prolinamide catalysts
obtaining the (S)-isomer product in up to 72% ee. Conditions were
optimised and in particular an additive screen showed a link
between the pKa of the acid additive used and the yield and enanti-
oselectivity. A small substrate screen was carried out. Investiga-
tions into the mode of action of the most successful catalyst 7
also provided interesting results and led to the discovery of two
other catalysts, which may be applied to the reaction; the acidic
prolinamides 16 and 17. Thus one can choose the catalyst to use
based on the desired configuration of the product. Structural mod-
ifications were made to the catalysts and substrates to study the
catalytic action, and mechanisms are proposed for the catalytic
2.9. Mechanistic considerations
We postulate that a combination of hydrogen bonding and p–p
stacking of the aromatic rings of our catalysts with isatin is respon-
sible for the observed catalytic activity and enantioselectivity. Ini-
tially, we suggest that the acid additive promotes the reaction of
the catalyst with acetone to form a reactive enamine intermediate.
In the case of aminopyridine and aminoquinoline based catalysts,
the relative position of the amino group and the pyridine nitrogen
atom had a major impact on the enantioselectivity of the reaction.
With catalyst 7, it is possible to envisage p-stacking of isatin in
the enamine modified catalyst cleft. The hydrogen bonding of isat-
in C@O with the catalyst N–H could facilitate enamine attack on
the Re face of the isatin C@O leading to the (S)-product. An addi-
tional hydrogen bond is possible between isatin and the pyridyl
action based on p-stacking and hydrogen bonding of the substrate
in the catalyst cleft. Work is currently underway to apply these
catalysts to the enantioselective synthesis of biologically active
compounds.

1430
M. Kinsella et al. / Tetrahedron: Asymmetry 22 (2011) 1423–1433
dropwise trifluoroacetic acid (5 mL) and the reaction mixture stir-
4. Experimental section
4.1. General information
red at room temperature for 2 h. After this time, the solvent and
excess TFA were removed in vacuo. The residue was redissolved
in dichloromethane (10 mL), neutralised with 5% NaOH and the
aqueous layer extracted with dichloromethane (5 ꢁ 15 mL). The
combined extracts were washed with saturated NaCl, dried
over MgSO4, filtered and the solvent removed in vacuo to yield cat-
alysts 1–19.
All commercial chemicals were obtained from Sigma and were
used as received unless otherwise stated. Flash chromatography
was conducted using 200–300 mesh silica gel. Nuclear Magnetic
Resonance (NMR) spectra were measured using a Joel ECX-400
spectrometer operating at 400 MHz for 1H NMR and at 100 MHz
for 13C NMR. Chemical shift values (d) are reported in ppm relative
to either TMS at 0.0 ppm or the NMR solvent peak. NMR data are
reported as follows: chemical shift, multiplicity (s = singlet,
d = doublet, t = triplet, q = quartet, m = multiplet, br = broad), cou-
pling constant expressed in Hertz, integration, assignment of peak.
Chiral HPLC was conducted on HP 1050 HPLC using a chiral column
(Chiralpak AD-H or IA columns). Low resolution mass spectra were
performed using an Agilent 1200 series LC-MSD Trap XCT Ultra LC–
MS instrument and Varian Saturn 2000 GC/MS/MS with high reso-
lution mass spectrometry conducted using a Waters Xevo G2 Q-
TOF mass spectrometer. An external reference standard of Leucine
enkephalin was infused in order to confirm mass accuracy of the
HRMS data acquired. Melting points were measured on a Stuart
Scientific Melting point apparatus SMP3 and are uncorrected. Opti-
cal rotations were measured on an AA series polAAr 20 automatic
polarimeter. FTIR spectra were recorded on a Varian 660-IR FTIR
spectrometer and KBr discs were produced using a KBr press; Spe-
cac ATLAS T25.
4.5. Catalysts 1–19
4.5.1. (S)-N-(Pyrrolidin-2-ylmethyl)picolinamide 1
Brown oil; yield: 258 mg, 43%; ½a D21
¼ þ27:6 (c 0.5, CH2Cl2);
ꢂ
mmax (KBr disc) 3379, 2963, 1664, 1529, 1269, 997, 750,
694 cmꢀ1; dH (400 MHz, CDCl3) 8.54–8.57 (m, 1H, H-6), 8.44 (s,
br, 1H, amide N–H), 8.18 (d, J = 8.39 Hz, 1H, H-3), 7.81–7.87 (m,
1H, H-4), 7.39–7.44 (m, 1H, H-5), 3.59–3.66 (m, 1H, H-20), 3.31–
3.49 (m, br, 2H, CONH–CH2), 2.96–3.03 (m, 2H, H-50), 2.66 (s, br,
1H N–H), 1.45–2.0 (m, br, 4H, H-30 and H-40); dC (100 MHz, CDCl3)
166.3 (amide C@O), 149.1 (C-2), 148.5 (C-6), 137.4 (C-4), 126.6 (C-
5), 122.4 (C-3), 59.9 (C-20), 45.2 (C-50), 41.0 (CH2NH), 27.9 (C-30),
24.3 (C-40). m/z 205 (M+); HRMS (ESI): MH+, found 206.1298,
C11H16N3O requires 206.1293.
4.5.2. (S)-6-Methyl-N-(pyrrolidin-2-ylmethyl)picolinamide 2
Viscous yellow oil; yield: 330 mg, 32%; ½a D19
¼ þ26:6 (c 0.2,
ꢂ
CH2Cl2); mmax (KBr disc) 3379, 3290, 2959, 1662, 1593, 1406, 994,
761 cmꢀ1; dH (400 MHz, CDCl3) 8.42 (s, br, 1H amide N–H), 7.95
(d, 1H, J = 7.63 Hz, H-3), 7.67 (t, 1H, J = 7.63 Hz, H-4), 7.23 (d, 1H,
J = 7.63 Hz, H-5), 3.52–3.54 (m, 1H, H-20), 3.25–3.42 (m, 2H,
CONH–CH2), 2.88–2.99 (m, 2H, H-50), 2.53 (s, 3H, Ar-CH3), 2.47 (s,
1H, N–H), 1.38–1.95 (m, 4H, H-30 and H-40); dC (100 MHz, CDCl3)
164.8 (amide C@O), 157.2 (C-6), 149.3 (C-2), 137.4 (C-4), 125.8
(C-5), 119.2 (C-3), 58.1 (C-20), 46.6 (C-50), 44.2 (CH2NH), 29.4 (C-
30), 25.8 (C-40), 24.3 (Ar-CH3); m/z 220 (M+); HRMS (ESI): MH+,
found 220.1455, C12H18N3O requires 220.1450.
4.2. General method for the synthesis of catalysts 1–4
To a suspension of the appropriate pyridine-carboxylic acid
(5 mmol) in dichloromethane (30 mL) was added EDCI (0.959 g,
5 mmol) and DMAP (0.611 g, 5 mmol) and this suspension was
stirred for 10 min. Next, Boc-pyrrolidinylmethyl amine (1 g,
5 mmol) was added slowly as a solution in dichloromethane
(20 mL) and the reaction mixture was stirred at room temperature
for 16 h. After this time, the solvent was removed in vacuo and the
product was purified by flash chromatography (hexane:ethyl ace-
tate gradient) eluting the Boc-protected catalysts as oily residues
in moderate yields. The Boc-deprotection was conducted as per
the general method.
4.5.3. (S)-N-(Pyrrolidin-2-ylmethyl)nicotinamide 3
Brown oil; yield: 450 mg, 53%; ½a D21
¼ þ22:6 (c 0.1, CHCl3); mmax
ꢂ
(KBr disc) 3407, 3066, 2968, 1655, 1545, 1420, 1133, 708 cmꢀ1; dH
(400 MHz, CDCl3); 8.99 (d, J = 1.53 Hz, 1H, H-2), 8.61 (dd, J = 3.05
and 1.53 Hz, 1H, H-6), 8.05–8.09 (m, 1H, H-4), 7.89 (s, br, 1H, amide
N–H), 7.27–7.30 (m, 1H, H-5), 4.19 (s, br, 1H, aliphatic N–H), 3.31–
3.72 (m, 3H, H-20 and CONH–CH2), 3.03–3.10 (m, 2H, H-50), 1.50–
2.05 (m, 4H, H-30 and H-40). dC (100 MHz, CDCl3) 166.1 (amide
C@O), 151.9 (C-6), 148.3 (C-2), 135.3 (C-4), 129.6 (C-1), 123.3 (C-
3), 59.0 (C-20), 45.3 (C-50), 42.1 (CH2NH), 28.4 (C-30), 24.7 (C-40);
m/z 206 (MH+), 136, 106, 70; HRMS (ESI): MH+, found 206.1299,
4.3. General method for synthesis of catalysts 5–19
At first, Boc-L-proline (10 mmol, 2.15 g) was dissolved in dry
THF (30 mL) and treated with triethylamine (10 mmol, 1.01 g,
1.38 mL). The stirred reaction mixture was cooled to 0 °C and ethyl
chloroformate (1.09 g, 10 mmol) was added dropwise over 15 min.
After the mixture had been stirred for a further 30 min at 0 °C,
amine (10 mmol) was added slowly over 15 min. This reaction
mixture was stirred for 1 h at 0 °C, 16 h at room temperature and
heated at reflux for 3 h with the reaction monitored by TLC. The
mixture was subsequently diluted with ethyl acetate and the
TEA. HCl removed by filtration and the solvent removed from the
filtrate in vacuo. The resulting residue was dissolved in ethyl ace-
tate, washed with saturated aqueous ammonium chloride, dried
over MgSO4, filtered and evaporated. The crude product was puri-
fied by flash chromatography using ethyl acetate and petroleum
ether mixtures. The Boc-deprotection was conducted as per the
general method.
C11H16N3O requires 206.1293.
4.5.4. (R)-N1-(6-Methylpyridin-2-yl)-N3-(pyrrolidin-2-
ylmethyl)isophthalamide 4
This catalyst was synthesised by first reacting mono-methyl
isophthalate with 2-amino-6-picoline and hydrolysis to produce
the appropriate carboxylic acid. This acid was coupled to previ-
ously synthesized Boc-pyrrolidine amine and Boc-deprotection re-
leased catalyst 4; colourless oil; yield: 500 mg, 38%; ½a D14
¼ þ19:0
ꢂ
(c 0.1, EtOAc); mmax (KBr disc) 3400, 3332, 2932, 1675, 1603,
1538, 1398, 1113 cmꢀ1; dH (400 MHz, CDCl3) 8.89 (s, 1H, N–Hb);
8.34 (s, 1H, H-2), 7.93–7.98 (m, 1H, H-4), 7.87–7.93 (m, 2H, H-6
and H-30), 7.48–7.54 (m, 1H, H-5), 7.29–7.34 (m, 1H, H-40), 6.78–
6.82 (m, 1H, H-50), 6.08 (s, br, 1H, N–Ha), 3.67–3.76 (m, 1H, H-
200), 3.37–3.68, (m, 2H, CONH–CH2), 3.03–3.23 (m, 2H, H-500), 2.30
(s, 3H, Ar-CH3), 1.85–2.12 (m, 1H, H-300), 1.35–1.70 (m, 1H, H-300),
1.70–2.02 (m, 2H, H-400); dC (100 MHz, CDCl3) 167.8 (CONHCH2),
165.3 (CONH–Py), 156.9 (C-20), 150.8 (C-60), 138.8 (C-40), 134.3
4.4. General method for the Boc-deprotection of 1–19
A solution of Boc-protected catalyst (5 mmol) in dichlorometh-
ane (5 mL) was cooled to 0 °C. To this chilled solution was added

M. Kinsella et al. / Tetrahedron: Asymmetry 22 (2011) 1423–1433
1431
(C-3), 133.8 (C-1), 131.2 (C-6), 131.0 (C-4), 129.1 (C-5), 126.0 (C-2),
119.7 (C-50), 111.6 (C-30), 59.9 (C-100), 45.2 (CH2), 41.5 (C-500), 28.1
(C-300), 24.1 (C-400), 23.9 (Ar-CH3). m/z 339 (MH+). HRMS (ESI):
MH+, found 339.1823, C19H23N4O2 requires 339.1821.
1H, H-2), 8.75–8.77 (m, 1H, H-4), 8.0–8.04 (m, 1H, H-5), 7.77–
7.81 (m, 1H, H-7), 7.57–7.62 (m, 1H, H-6), 7.49–7.53 (m, 1H, H-
8), 3.91–3.97 (m, 1H, H-20), 3.0–3.20 (m, 2H, H-50), 2.01–2.31 (m,
2H, H-3’), 2.09 (s, 1H, aliphatic N–H), 1.75–1.85 (m, 2H, H-40); dC
(100 MHz, CDCl3) 174.4 (amide C@O), 145.2 (C-b), 144.0 (C-2),
131.4 (C-3), 128.8 (C-4), 128.2 (C-a), 128.1 (C-6), 127.7 (C-7),
127.1 (C-8), 123.0 (C-5), 61.1 (C-20), 47.5 (C-50), 30.9 (C-30), 26.5
(C-40); m/z 242 (MH+); HRMS (ESI): MH+, found 242.1297,
4.5.5. (S)-N-(Pyridin-2-yl)pyrrolidine-2-carboxamide 542,66
Viscous brown oil; yield: 900 mg, 43%; mp = 48–51 °C;
½
a 2D2
ꢂ
¼ ꢀ56:2 (c 0.4, EtOAc); dH (400 MHz, CDCl3) 10.20 (s, 1H,
amide N–H), 8.20–8.31 (m, 2H, H-6 and H-3), 7.65–7.72 (m, 1H,
H-4), 6.99–7.04 (m, 1H, H-5), 3.86–3.92 (m, 1H, H-20), 2.98–3.12
(m, 2H, H-50), 2.39 (s, br, 1H, aliphatic N–H), 1.98–2.25 (m, 2H,
H-30), 1.71–1.81 (m, 2H, H-40). dC (100 MHz, CDCl3) 174.0 (amide
C@O), 151.2 (C-2), 148.0 (C-6), 138.3 (C-4), 119.7 (C-5), 113.7 (C-
3), 61.0 (C-20), 47.3 (C-50), 30.9 (C-30), 26.1 (C-40); m/z 191 (M+).
C14H16N3O requires 242.1293.
4.5.11. (S)-N-(Quinolin-8-yl)pyrrolidine-2-carboxamide 11
Brown viscous oil; yield: 1.8 g, 84%; ½a D24
¼ þ18:6 (c 0.1, CHCl3);
ꢂ
m
max (KBr disc) 3257, 2965, 1670, 1516, 1382, 1102, 824, 791 cmꢀ1
;
dH (400 MHz, CDCl3) 11.61 (s, br, 1H, amide N–H), 8.81–8.89 (m,
2H, H-2 and H-7), 8.12–8.16 (m, 1H, H-4), 7.48–7.56 (m, 2H, H-5
and H-6), 7.41–7.45 (m, 1H, H-3), 3.98–4.05 (m, 1H, H-20), 3.11–
3.21 (m, 2H, H-50), 2.08–2.33 (m, 2H, H-30), 2.18 (s, br, 1H, aliphatic
N–H), 1.71–1.90 (m, 2H, H-40); dC (100 MHz, CDCl3) 174.3 (amide
C@O), 148.6 (C-2), 139.2 (C-a), 136.1 (C-4), 134.5 (C-8), 128.1 (C-
b), 127.2 (C-6), 121.6 (C-5), 121.4 (C-3), 116.4 (C-7), 61.8 (C-20),
47.5 (C-50), 31.0 (C-30), 26.3 (C-40); m/z 242 (MH+); HRMS (ESI):
MH+, found 242.1296, C14H16N3O requires 242.1293.
4.5.6. (S)-N-(6-Methylpyridin-2-yl)pyrrolidine-2-carboxamide
642
Off-white solid; yield: 1.50 g, 66%; mp = 59–62 °C; ½a D22
¼ ꢀ40:2
ꢂ
(c 0.4, EtOAc); dH (400 MHz, CDCl3) 10.1 (s, br, 1H, N–H), 8.04 (d,
J = 8.2 Hz, 1H, H-3), 7.56 (t, J = 8.2 Hz, 1H, H-4), 6.86–6.89 (m, 1H,
H-5), 3.83–3.88 (m, 1H, H-20), 2.99–3.10 (m, 2H, H-50), 2.46 (s,
3H, Ar-CH3), 1.97–2.26 (m, 2H, H-30), 1.8 (s, br, 1H, aliphatic N–
H) 1.67–1.81 (m, 2H, H-40); dC (100 MHz, CDCl3) 174.4 (amide
C@O), 156.9 (C-6), 150.5 (C-2), 138.5 (C-4), 119.1 (C-5), 110.4 (C-
3), 61.0 (C-20), 47.3 (C-50), 30.9 (C-30), 26.2 (C-40), 24.2 (Ar-CH3);
m/z 205 (M+).
4.5.12. (2S,20S)-N,N0-(Pyridine-2,6-diyl)dipyrrolidine-2-
carboxamide 1267
Off-white solid; yield: 800 mg, 21%; mp = 177.5–177.9 °C;
½
a 2D0
ꢂ
¼ þ10:0 (c 0.1, CHCl3); dH (400 MHz, CDCl3) 9.97 (s, br, 2H,
4.5.7. (S)-N-(Pyridin-3-yl)pyrrolidine-2-carboxamide 742,66
amide N–H), 7.95 (d, J = 7.63 Hz, 2H, H-3), 7.70 (t, J = 7.63 Hz, 1H,
H-4), 3.78–3.87 (m, 2H, H-20), 2.9–3.13 (m, 4H, H-50), 1.62–2.25
(m, 10H, H-30, H-40 and aliphatic N–H); dC (100 MHz, CDCl3)
174.2 (amide C@O), 149.4 (C-2), 140.2 (C-4), 108.9 (C-3), 61.0 (C-
20), 47.3 (C-50), 30.8 (C-30), 26.2 (C-40); m/z 326 (MNa+), 304 (MH+).
Colourless oil; yield: 1.15 g, 40%; ½a D18
¼ ꢀ65:8 (c = 0.1, CHCl3);
ꢂ
dH (400 MHz, CDCl3) 9.87 (s, br, 1H, amide N–H), 8.59 (d,
J = 2.75 Hz, 1H, H-2), 8.28- 8.32 (m, 1H, H-4), 8.21–8.25 (m, 1H,
H-6), 7.20–7.26 (m, 1H, H-5), 3.83–3.89 (m, 1H, H-20), 2.92–3.12
(m, 2H, H-50), 2.25 (s, br, 1H, aliphatic N–H), 1.97–2.25 (m, 2H,
H-30), 1.70–1.81 (m, 2H, H-40); dC (100 MHz, CDCl3) 174.3 (amide
C@O), 145.1 (C-4), 141.0 (C-6), 134.7 (C-2), 126.4 (C-5), 123.7 (C-
3), 61.1 (C-20), 47.5 (C-50), 30.8 (C-30), 26.4 (C-40); m/z 192 (MH+).
4.5.13. (2S,4R)-4-(Benzyloxy)-N-(pyridin-3-yl)pyrrolidine-2-
carboxamide 13
Brown oil; yield: 95 mg, 29%; ½a D14
¼ ꢀ22:5 (c 0.05, CHCl3); mmax
ꢂ
(KBr disc) 3377, 2921, 1670, 1583, 1425, 1259, 806, 741 cmꢀ1; dH
(400 MHz, CDCl3) 9.85 (s, 1H, amide N–H), 8.58–8.61 (m, 1H, H-
2), 8.28–8.31 (m, 1H, H-4), 8.19–8.23 (m, 1H, H-6), 7.20–7.38 (m,
6H, H-5 and aromatic benzyl protons), 4.41–4.52 (m, 2H, OCH2Ph),
4.12 (s, 1H, H-40), 4.03–4.09 (m, 1H, H-20), 3.20–3.25 (m, 1H, H-50),
2.76–2.82 (m, 1H, H-50), 2.55 (s, br, 1H, N–H), 2.47–2.56 (m, 1H, H-
30), 1.93–2.0 (m, 1H, H-30); dC (100 MHz, CDCl3) 173.7 (amide C@O),
145.1 (C-4), 141.0 (C-6), 138.0 (C-100), 134.6 (C-3), 128.6 (C-300),
127.9 (C-400), 127.7 (C-200), 126.5 (C-2), 123.7 (C-5), 80.5 (C-40),
70.8 (O–CH2–Ph), 60.4 (C-20), 52.8 (C-50), 36.3 (C-30); m/z 298
(MH+); HRMS (ESI): MH+, found 298.1559, C17H20N3O2 requires
298.1556.
4.5.8. (S)-N-(Pyridin-4-yl)pyrrolidine-2-carboxamide 866
White solid; yield: 500 mg, 31%; mp = 171–173 °C;
½
a 1D8
ꢂ
¼ ꢀ84:2 (c 0.2, CHCl3); dH (400 MHz, CDCl3) 9.93 (s, br, 1H,
amide N–H), 8.43–8.51 (m, 2H, H-2), 7.49–7.55 (m, 2H, H-3),
3.83–3.89 (m, 1H, H-20), 2.92–3.13 (m, 2H, H-50), 1.98–2.28 (m,
2H, H-30), 1.77 (s, br, 1H, aliphatic N–H), 1.68–1.88 (m, 2H, H-40);
dC (100 MHz, CDCl3) 174.6 (amide C@O), 150.8 (C-4), 144.6 (C-2),
113.4 (C-3), 61.2 (C-20), 47.5 (C-50), 30.8 (C-30), 26.4 (C-40); m/z
191 (M+).
4.5.9. (S)-N-(Quinolin-2-yl)pyrrolidine-2-carboxamide 9
Off-white solid; yield: 1.4 g, 49%; mp = 108.3–109.1 °C;
½
a 1D4
ꢂ
¼ þ7:4 (c 0.1, CHCl3); mmax (KBr disc) 3347, 3213, 2967,
4.5.14. (2S,4R)-4-Hydroxy-N-(pyridin-3-yl)pyrrolidine-2-
carboxamide 14
1678, 1499, 1233, 1105, 828 cmꢀ1; dH (400 MHz, CDCl3) 10.43 (s,
br, 1H, amide N–H), 8.48 (d, J = 8.70 Hz, 1H, H-3), 8.16 (d,
J = 9.16 Hz, 1H, H-4), 7.86 (d, J = 8.70 Hz, 1H, H-8), 7.76 (d,
J = 9.16 Hz, 1H, H-5), 7.61–7.68 (m, 1H, H-7), 7.40–7.46 (m, 1H,
H-6), 3.88–3.95 (m, 1H, H-20), 3.04–3.15 (m, 2H, H-50), 2.01–2.30
(m, 2H, H-30), 2.15 (s, br, 1H, aliphatic N–H), 1.73–1.85 (m, 2H,
H-40); dC (100 MHz, CDCl3) 174.9 (amide C@O), 150.7 (C-2), 146.8
(C-b), 138.4 (C-4), 129.8 (C-7), 127.5 (C-5), 127.4 (C-8), 126.3 (C-
a), 124.9 (C-6), 113.9 (C-3), 61.1 (C-20), 47.4 (C-50), 30.9 (C-30),
26.2 (C-20); m/z 242 (MH+). HRMS (ESI): MH+, found 242.1297,
Orange solid; yield: 200 mg, 42%; mp = 142.5–143.2 °C;
½
a 1D8
ꢂ
¼ ꢀ1:0 (c 0.1, CHCl3); dH (400 MHz, CD3OD) 8.77–8.81 (m,
1H, H-2), 8.26–8.29 (m, 1H, H-4), 8.08–8.14 (m, 1H, H-6), 7.37–
7.42 (m, 1H, H-5), 6.93 (s, 1H, amide N–H), 4.51 (s, 1H, H-40),
4.31–4.37 (m, 1H, H-20), 3.11–3.28 (m, 2H, H-50), 2.36–2.43 (m,
1H, H-30), 2.01–2.10 (m, 1H, H-30); dC (100 MHz, CD3OD) 161.8
(amide C@O), 144.3 (C-4), 140.8 (C-2), 127.8 (C-6), 124.0 (C-5),
118.2 (C-3), 71.1 (C-40), 59.8 (C-20, 54.2 (C-50), 39.0 (C-30); HRMS
(ESI): MH+, found 208.1089, C10H14N3O2 requires 208.1086.
C14H16N3O requires 242.1293.
4.5.15. (S)-N-Phenylpyrrolidine-2-carboxamide 1559
4.5.10. (S)-N-(Quinolin-3-yl)pyrrolidine-2-carboxamide 10
Off-white solid; yield: 250 mg, 29%; mp = 115.5–116.2 °C;
Brown paste; yield: 400 mg, 22%; ½a D17
ꢂ
¼ ꢀ20:0- (c 0.05, CHCl3);
½
a 1D9
ꢂ
¼ ꢀ62:0 (c 0.1, CHCl3); dH (400 MHz, CDCl3) 9.72 (s, br, 1H,
m
max (KBr disc) 3354, 2969, 1686, 1523, 1490, 1369, 902, 751 cmꢀ1
;
N–H), 7.59 (d, J = 7.79 Hz, 2H, H-2), 7.30 (t, J = 7.79 Hz, 2H, H-3),
dH (400 MHz, CDCl3) 10.11 (s, br, 1H, amide N–H), 8.83–8.85 (m,
7.04–7.10 (m, 1H, H-4), 3.80–3.85 (m, 1H, H-20), 2.92–3.10 (m,

1432
M. Kinsella et al. / Tetrahedron: Asymmetry 22 (2011) 1423–1433
2H, H-50), 1.97–2.23 (m, 3H, H-30 and aliphatic N–H), 1.69–1.80 (m,
2H, H-40); dC (100 MHz, CDCl3) 173.6 (amide C@O), 138.0 (C-1),
129.0 (C-3), 124.0 (C-4), 119.3 (C-2), 61.1 (C-20), 47.4 (C-50), 30.8
(C-30), 26.4 (C-40); m/z 191 (MH+).
4.5.21. (S)-3-Hydroxy-3-(2-oxopropyl)indolin-2-one 2021
The ee was determined on the crude reaction mixture using chi-
ral HPLC–Chiralpak ADH column, hexane/i-PrOH 70/30, flow rate
1 mL/min; tR = 7.0 min [(S)-isomer]; tR = 9.0 min [(R)-isomer],
k = 254 nm. Off-white solid; yield: see Tables; ½a D18
¼ ꢀ20:0 (c
ꢂ
0.03, CH3OH); mmax (KBr disc) 3359, 3258, 2359, 1718, 1620,
1470, 1362, 1057 cmꢀ1; dH (400 MHz, CD3OD) 7.29 (d, J = 7.33 Hz,
1H, Ar-H), 7.21 (dt, J = 7.63 and 1.53 Hz, 1H, Ar-H), 6.98 (t,
J = 7.63 Hz, 1H, Ar-H), 6.86 (m, 1H, Ar-H), 3.36 (d, J = 16.78 Hz,
1H, CH2), 3.15 (d, J = 16.78 Hz, 1H, CH2), 2.04 (s, 3H, CH3); dC
(100 MHz, CD3OD) 206.1 (CH3–CO–CH2), 179.8 (amide C@O),
142.3 (C-7a), 130.9 (C-3a), 129.4 (C-6), 123.5 (C-4), 122.1 (C-5),
109.9 (C-7), 73.4 (C-3), 49.8 (CH2), 29.3 (CH3); m/z 228 (MNa+);
HRMS (ESI): MNa+, found 228.0637, C11H11NO3Na requires
228.0637.
4.5.16. (S)-N-Methyl-N-(pyridin-4-yl)pyrrolidine-2-carboxamide
1666
Colourless oil; yield: 120 mg, 29%; ½a D14
¼ ꢀ90:0 (c 0.05, CHCl3);
ꢂ
dH (400 MHz, CDCl3) 8.07–8.10 (m, 2H, H-3), 6.75 (s, br, 1H, ali-
phatic N–H), 6.31–6.34 (m, 2H, H-2), 3.99–4.02 (m, 1H, H-20),
3.50–3.56 (m, 1H, H-50), 3.16–3.23 (m, 1H, H-50), 2.68–2.71 (m,
3H, N–CH3), 2.14–2.21 (m, 2H, H-30), 1.87–2.03 (m, 2H, H-40); dC
(100 MHz, CDCl3) 172.9 (C@O), 152.0 (C-1), 149.8 (C-3), 108.1 (C-
2), 63.1 (C-20), 48.6 (C-50), 31.3 (C-30), 26.3 (N–CH3), 23.8 (C-40);
m/z 206 (MH+).
4.5.22. (S)-1-Benzyl-3-hydroxy-3-(2-oxopropyl)indolin-2-one
2121
4.5.17. (S)-N-methyl-N-phenylpyrrolidine-2-carboxamide 1768
Colourless oil; yield: 500 mg, 22%; ½a D14
¼ þ18:2 (c 0.1, CHCl3);
ꢂ
The ee was determined on the crude reaction mixture using chi-
ral HPLC–Chiralpak ADH column, hexane/i-PrOH 90/10, flow rate
0.7 mL/min; tR = 39.5 min (minor isomer); tR = 42.3 min (major iso-
dH (400 MHz, CDCl3) 7.62 (s, br, 1H, aliphatic N–H), 7.28–7.34 (m,
2H, H-3), 7.21–7.27 (m, 1H, H-4), 7.13–7.18 (m, 2H, H-2), 3.86–
3.93 (m, 1H, H-20), 2.90–3.29 (m, 2H, H-50), 3.15 (s, 3H, N–CH3),
1.50–1.78 (m, 4H, H-30 and H-40); dC (100 MHz, CDCl3) 170.8
(C@O), 141.9 (C-1), 130.1 (C-3), 128.7 (C-4), 127.7 (C-2), 58.4 (C-
20), 46.7 (C-50), 38.0 (N–CH3), 30.4 (C-30), 25.4 (C-40); m/z 204 (M+).
mer), k = 254 nm; Off-white solid; yield: see Tables; ½a D19
¼ ꢀ4:0 (c
ꢂ
0.05, CH3OH); mmax (KBr disc) 3315, 3060, 2359, 1698, 1616, 1467,
1360, 1079 cmꢀ1; dH (400 MHz, CD3CN) 7.37–7.41 (m, 2H, Bz pro-
tons), 7.29–7.35 (m, 3H, Bz protons), 7.25–7.28 (m, 1H, Ar-H),
7.14–7.19 (m, 1H, Ar-H), 6.96–7.01 (m, 1H, Ar-H), 6.70 (d,
J = 7.79 Hz, 1H, Ar-H), 4.77–4.91 (m, 2H, Bz-CH2), 4.25 (s, br, 1H,
OH), 3.40 (d, J = 17.0 Hz, 1H, CH2), 3.20 (d, J = 17.0 Hz, 1H, CH2),
2.0 (s, 3H, CH3); dC (100 MHz, CD3CN) 206.9 (CH3–CO–CH2), 177.4
(amide C@O), 144.3 (C-7a), 137.4 (C-10), 130.4 (C-30), 129.6 (C-
3a), 128.4 (C-6), 128.2 (C-20), 124.4 (C-40), 123.4 (C-5 and C-6),
110.1 (C-7), 74.0 (C-3), 50.5 (N-CH2-Ph), 44.1 (CH2C@O), 30.9
(CH3); m/z 296 (MH+); HRMS (ESI): MH+, found 296.1294,
4.5.18. (S)-N-(3,5-Bis(trifluoromethyl)phenyl)pyrrolidine-2-
carboxamide 1859
Pale yellow oil; yield: 230 mg, 17%; ½a D18
¼ ꢀ37:0 (c 0.05,
ꢂ
CHCl3); dH (400 MHz, CDCl3) 10.10 (s, br, 1H, amide N–H), 8.10
(s, 2H, H-2), 7.54 (s, 1H, H-4), 3.84–3.90 (m, 1H, H-20), 2.94–3.13
(m, 2H, H-50), 1.95–2.27 (m, 3H, H-30 and aliphatic N–H), 1.71–
1.79 (m, 2H, H-40); dC (100 MHz, CDCl3) 174.3 (amide C@O),
139.3 (C-1), 132.4 (C-3), 127.3, 124.6 (CF3), 121.9, 119.2 (C-2),
117.1 (C-4), 61.0 (C-20), 47.4 (C-50), 30.8 (C-30), 26.4 (C-40); m/z
327 (MH+).
C18H18NO3 requires 296.1287.
4.5.23. (S)-3-Hydroxy-3-(2-oxobutyl)indolin-2-one 2221
The ee was determined on the crude reaction mixture using chi-
ral HPLC–Chiralpak ADH column, hexane/i-PrOH 70/30, flow rate
0.7 mL/min; tR = 10.0 min (major isomer); tR = 11.0 min (minor iso-
mer), k = 254 nm. 91% regioselectivity of reaction, C–C bond forma-
tion at the less substituted methyl group of the ketone (as
determined by NMR). Off-white solid; yield: see Tables;
4.5.19. (S)-N-(3,5-Bis(trifluoromethyl)phenylsulfonyl)-pyrrolid-
ine-2-carboxamide 19
A deviation from the general procedure was used to synthesise
this catalyst. The synthesis was achieved through EDCI coupling of
Boc-L-proline with the previously synthesized 3,5-bis(trifluoro-
methyl)benzylsulfonamide61 to give Boc-19; subsequent Boc-
deprotection produced 19; white solid; yield: 200 mg, 27%;
mp = 222.3–223.1 °C; mmax (KBr disc) 3447, 3187, 1622, 1361,
1310, 1279, 1128, 852 cmꢀ1; dH (400 MHz, DMSO-d6) 8.30 (s, 2H,
H-2), 8.24 (s, 1H, H-4), 3.86 (t, J = 6.9 Hz, 1H, H-20), 2.94–3.14 (m,
2H, H-50), 2.06–2.12 (m, 1H, H-30), 1.62–1.83 (m, 2H, H-40), 1.62–
1.83 (m, 1H, H-30); dC (100 MHz, DMSO-d6) 13C NMR (100 MHz,
DMSO-d6) d = 173.0 (amide C@O), 148.3 (C-1), 130.7 (C-3), 128.2
(C-2), 124.9 (C-4), 122.1 (CF3), 62.4 (C-20), 45.8 (C-50), 29.4 (C-30),
23.7 (C-40); m/z 389 (MꢀH); HRMS (ESI): MH+, found 391.0551,
½
a 1D4
ꢂ
¼ ꢀ40:0 (c 0.01, CH3OH); mmax (KBr disc) 3356, 2972, 2360,
1723, 1621, 1473, 1180, 777 cmꢀ1; dH (400 MHz, DMSO-d6) 10.20
(s, br, 1H, N–H), 7.22 (d, J = 7.2 Hz, 1H, H-3), 7.15 (t, J = 8.0 Hz,
1H, H-4), 6.88 (t, J = 7.6 Hz, 1H, H-5), 6.76 (d, J = 7.6 Hz, 1H, H-6),
5.96 (s, 1H, OH), 3.25 (d, J = 16.4 Hz, 1H, CH2-a), 2.97 (d,
J = 16.4 Hz, 1H, CH2-a), 2.24–2.42 (m, 2H, CH2-b), 0.74 (t,
J = 7.2 Hz, 3H, CH3); dC (100 MHz, DMSO-d6) 207.4 (CH2–CO–
CH2), 178.2 (amide C@O), 142.5 (C-7a), 131.5 (C-3a), 128.9 (C-6),
123.7 (C-4), 121.2 (C-5), 109.4 (C-7), 72.7 (C-3), 49.1 (C–CH2-CO),
35.6 (CH3CH2–CO), 7.3 (CH3); m/z 242 (MNa+); HRMS (ESI):
MNa+, found 242.0797, C12H13NO3Na requires 242.0793.
C13H13N2O3F6S requires 391.0551.
4.5.20. General procedure for the aldol reaction of isatin with
acetone21
4.6. General procedure for aldol reaction of isatins with
acetaldehyde followed by reduction65
The organocatalyst 20 mol % (0.06 mmol) and additive (either
40 equiv H2O or 20 mol % acid additive) were stirred in 2 mL anhy-
drous acetone for 10 min at the specified temperature. Isatin
(0.3 mmol, 44 mg) was subsequently added and the mixture was
stirred at the desired temperature for the specified time. The pro-
gression of the reaction was monitored by TLC and HPLC. Acetone
was subsequently removed in vacuo and the mixture was purified
by flash chromatography (petroleum ether:ethyl acetate 2:1). The
ee of the product was determined by chiral HPLC on the crude
reaction mixture.
To a solution of optimum catalyst 7 (30 mol %, 0.09 mmol,
17.2 mg), chloroacetic acid (60 mol %, 17 mg, 0.18 mmol) and isatin
(0.3 mmol) in DMF (0.3 mL) was added acetaldehyde (84 lL,
1.50 mmol). This reaction mixture was stirred at room temperature
under N2 for 48 h, followed by the addition of methanol (0.5 mL)
and NaBH4 (56 mg, 1.5 mmol and the mixture was stirred for 1 h
at ꢀ20 °C. The resulting mixture was quenched with pH 7.0 phos-
phate buffer solution, extracted with ethyl acetate (3 ꢁ 25 mL),
dried over anhydrous Na2SO4, filtered and the solvent removed in

M. Kinsella et al. / Tetrahedron: Asymmetry 22 (2011) 1423–1433
1433
14. Nakamura, T.; Shirokawa, S.; Hosokawa, S.; Nakazaki, A.; Kobayashi, S. Org. Lett.
2006, 8, 677–679.
vacuo. The product was isolated by flash chromatography (80:20
ethyl acetate:petroleum ether for the isatin derivative and 50:50
ethyl acetate:petroleum ether for the benzylisatin product).
15. Guo, X.; Huang, H. X.; Yang, L. P.; Hu, W. H. Org. Lett. 2007, 9, 4721–4723.
16. Malkov, A. V.; Kabeshov, M. A.; Bella, M.; Kysilka, O.; Malyshev, D. A.;
Pluhackova, K.; Kocovsky, P. Org. Lett. 2007, 9, 5473–5476.
17. Adachi, S.; Harada, T. Eur. J. Org. Chem. 2009, 2009, 3661–3671.
18. Nakamura, S.; Hara, N.; Nakashima, H.; Kubo, K.; Shibata, N.; Toru, T. Chem.-A
European J. 2008, 14, 8079–8081.
19. Luppi, G.; Monari, M.; Correa, R. J.; Violante, F. D.; Pinto, A. C.; Kaptein, B.;
Broxterman, Q. B.; Garden, S. J.; Tomasini, C. Tetrahedron 2006, 62, 12017–
12024.
20. Chen, G.; Wang, Y.; He, H. P.; Gao, S.; Yang, X. S.; Hao, X. J. Heterocycles 2006, 68,
2327–2333.
21. Chen, J. R.; Liu, X. P.; Zhu, X. Y.; Li, L.; Qiao, Y. F.; Zhang, J. M.; Xiao, W. J.
Tetrahedron 2007, 63, 10437–10444.
22. Trost, B. M.; Brindle, C. S. Chem. Soc. Rev. 2010, 39, 1600–1632.
23. Pellissier, H. Tetrahedron 2007, 63, 9267–9331.
24. Guillena, G.; Najera, C.; Ramon, D. J. Tetrahedron: Asymmetry 2007, 18, 2249–
2293.
25. Russo, A.; Botta, G.; Lattanzi, A. Tetrahedron 2007, 63, 11886–11892.
26. Chimni, S. S.; Singh, S.; Mahajan, D. Tetrahedron: Asymmetry 2008, 19, 2276–
2284.
27. Chimni, S. S.; Mahajan, D. Tetrahedron: Asymmetry 2006, 17, 2108–2119.
28. List, B.; Lerner, R. A.; Barbas, C. F. J. Am. Chem. Soc. 2000, 122, 2395–2396.
29. List, B.; Pojarliev, P.; Castello, C. Org. Lett. 2001, 3, 573–575.
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5267.
4.6.1. (R)-3-Hydroxy-3-(2-hydroxyethyl)indolin-2-one 2336
The ee was determined on the purified reaction mixture (flash
chromatography) using chiral HPLC (Chiralpak IA column, 10:1
hexane:i-PrOH, flow rate 0.7 mL/min; tR = 30.9 min (minor enan-
tiomer); tR = 44.1 min (major enantiomer), k = 254 nm). White so-
lid; yield: see Tables; ½a D14
¼ þ19:1 (c 0.01, CHCl3); mmax (KBr
ꢂ
disc) 3379, 2963, 1664, 1529, 1269, 997, 750, 694 cmꢀ1; dH
(400 MHz, CD3CN) 8.35 (s, br, 1H, N–H), 7.30 (d, J = 6.87 Hz, 1H,
Ar-H), 7.22 (t, J = 6.87, 1H, Ar-H), 7.0 (t, J = 7.63, 1H, Ar-H), 6.85
(d, J = 7.63 Hz, 1H, Ar-H), 4.30 (s, br, 1H, OH), 3.53–3.59 (m, 2H,
CH2OH), 2.98 (s, br, 1H, OH), 1.95–2.09 (m, 2H, CH2CH2OH); dC
(100 MHz, CD3CN) 180.0 (amide C@O), 142.0 (C-7a), 132.4 (C-3a),
130.3 (C-6), 125.1 (C-4), 123.2 (C-5), 110.8 (C-7), 76.2 (C-3), 58.3
(CH2OH), 40.5 (C–CH2); m/z 216 (MNa+); HRMS (ESI): MNa+, found
216.0638, C10H11NO3Na requires 216.0637.
4.6.2. (R)-1-Benzyl-3-hydroxy-3-(2-hydroxyethyl)indolin-2-one
2436
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The ee was determined on the purified reaction mixture (after
flash chromatography) using chiral HPLC (Chiralpak IA column,
10:1 hexane:i-PrOH, flow rate 0.7 mL/min; tR = 36.2 min (minor
enantiomer); tR = 40.2 min (major enantiomer), k = 254 nm). Col-
ourless oil; yield: see Tables; ½a D14
¼ þ14:0 (c 0.01, CHCl3); mmax
ꢂ
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(KBr disc) 3395, 2924, 1705, 1613, 1269, 1468, 1174, 753 cmꢀ1
;
dH (400 MHz, CDCl3) 7.38–7.42 (m, 1H, H-5), 7.24–7.33 (m, 5H,
Bz protons), 7.17–7.22 (m, 1H, H-4), 7.03–7.09 (m, 1H, H-3),
6.68–6.72 (m, 1H, H-6), 4.96 (d, J = 16.0 Hz, 1H, CH2–Ph), 4.77 (d,
J = 16.0 Hz, 1H, CH2–Ph), 4.43 (s, br, 1H, OH), 3.92–4.04 (m, 2H,
CH2–OH), 2.99 (s, br, 1H, OH), 2.26–2.34 (m, 1H, CH2–C(OH)),
2.03–2.12 (m, 1H, CH2–C(OH)); dC (100 MHz, CDCl3) 178.4 (amide
C@O), 141.9 (C-7a), 135.3(C-10), 130.6 (C-3a), 129.6 (C-30), 128.8
(C-20), 127.7 (C-40), 127.2 (C-6), 123.9 (C-4), 123.3 (C-3), 109.6
(C-7), 58.6 (CH2OH), 43.8 (N–CH2-Ph), 39.3 (C–CH2); m/z 306
(MNa+); HRMS (ESI): MNa+, found 306.1107, C17H17NO3Na requires
306.1106.
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Acknowledgements
We would like to thank the Irish Research Council for Science,
Engineering and Technology and Waterford Institute of Technology
for funding provided.
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