Simple and facile l-prolinamides derived from achiral cycloalkylamines as organocatalysts for the highly efficient large-scale asymmetric direct aldol reactions

Article abstract of DOI:10.1007/s10562-011-0585-3

A series of N-cycloalkylprolinamides have been designed and synthesized from achiral cycloalkylamines in a facile manner. They promoted high stereoselectivity in the cross-aldol reaction. N-cyclopropylprolinamide performed best with a smallest carbocyclic

Full text of DOI:10.1007/s10562-011-0585-3

Catal Lett (2011) 141:1156–1163
DOI 10.1007/s10562-011-0585-3
Simple and Facile L-Prolinamides Derived from Achiral
Cycloalkylamines as Organocatalysts for the Highly Efficient
Large-Scale Asymmetric Direct Aldol Reactions
•
•
•
Jiang-Wei Xu Xiang-Kai Fu Xiao-Yan Hu
Chuan-Long Wu
Received: 22 February 2011 / Accepted: 17 March 2011 / Published online: 7 April 2011
Ó Springer Science+Business Media, LLC 2011
Abstract A series of N-cycloalkylprolinamides have been
designed and synthesized from achiral cycloalkylamines in
a facile manner. They promoted high stereoselectivity in the
cross-aldol reaction. N-cyclopropylprolinamide performed
best with a smallest carbocyclic ring, and the anti-aldol
products could be obtained with up to 99:1 anti/syn and
99% ee. Carbocyclic ring was found to play a significant
role in the formation of the aldol products. This simple
catalyst can be efficiently used in large-scale reactions with
the enantioselectivity being maintained at the same level,
which offers great possibility for applications in industry.
savings in cost, time and energy, an easier experimental
procedure, and reductions in chemical waste [10, 11]. Not
surprisingly, aldol reaction constitutes one of the immen-
sely investigated amongst C–C bond forming reactions in
the realm of organocatalysis [12–15]. Since the pioneering
work of List et al. [16–18] who demonstrated the use of
proline in catalyzing the direct aldol reaction of p-nitro-
benzaldehyde with acetone, a number of organocatalysts
that function based on the principle of the so-called
‘‘enamine catalysis’’ have been reported [15]. Although the
acidic proton of the carboxylic group of proline is
responsible for enantioselectivity in aldol reactions, it is
sufficiently clear that the carboxylic acid group is not
indispensable for catalysis. A variety of pyrrolidine-based
organocatalysts that are devoid of carboxyl groups have
been designed and shown to be efficient. These compounds
are generally prolinamide derivatives that differ in the
nature of the amine component attached to the carboxylic
functionality of proline, and generally contain additional
stereogenic center and hydrogen-bonding site [19–23].
Therefore, these catalysts not only complex but also
expensive as a rule. Barbas, [24–27] Hayashi, [28–31]
Gong, [32–36] Xiao et al. [37, 38] reported the intermo-
lecular aldol reactions of the ketone-aldehyde type and
aldehyde-aldehyde type catalyzed by L-proline or its
derivatives and analogues. However, their shortcomings
have also been realized. One of the major limitations using
organocatalyst catalyzed reactions is the high catalyst
loading (10–30 mol%) generally required to complete the
transformations in large equivalents ketone in reasonable
timescales. This will raise a cost concern when large
amounts of chiral materials are used for a large-scale
synthesis in industrial applications. In spite of significant
efforts devoted to the development of highly active
organocatalysts aimed at lowering catalyst loading, it has
Keywords N-cycloalkylprolinamides Á Stereoselectivity Á
Cross-aldol Á Carbocyclic ring Á Organocatalyst Á Large-
scale
1 Introduction
Asymmetric organocatalysis has emerged as a rapidly
growing and important field in organic chemistry [1–9].
Small molecules as organocatalysis brought the prospect of
a complementary mode of catalysis, with the potential for
J.-W. Xu Á X.-K. Fu (&) Á X.-Y. Hu Á C.-L. Wu
College of Chemistry and Chemical Engineering, Southwest
University, Institute of Applied Chemistry Southwest University,
The Key Laboratory of Applied Chemistry of Chongqing
Municipality, Chongqing 400715, People’s Republic of China
e-mail: fxk@swu.edu.cn
J.-W. Xu Á X.-K. Fu Á X.-Y. Hu Á C.-L. Wu
The Key Laboratory of Ecoenvironments in Three Gorges
Reservoir Region Ministry of Education, Chongqing 400715,
People’s Republic of China
123

Simple and Facile L-Prolinamides Derived from Achiral Cycloalkylamines
1157
proved to be a significant challenging task, and only lim-
ited success has been achieved so far.
rotations were measured on a JASCO P-1010 Polarimeter
at k = 589 nm.
In this context, a series of simple organocatalysts
1a–e with different carbocyclic rings were synthesized
from achiral cycloalkylamine [39–41], and their catalytic
properties were studied in depth for the first time. Our
initial purpose was to discuss the influence of different
ring strain and steric hindrance on the asymmetric aldol
reaction. It is shown that all prolinamides 1a–e exhibited
great catalytic activity in the asymmetric aldol reaction in
m-xylene at -20 °C with only 5 mol% catalyst loading. In
particular, the reactions proceed with catalyst 1a afforded
aldol products in a high diastereoselectivity (up to 99:1)
and enantioselectivity (up to 99%) and significantly
enhanced reaction yield (up to 99%). However, the com-
pound 1f synthesized by alkylamine demonstrated lower
catalytic activity. The result indicates that carbocyclic ring
of N-cycloalkyl-L-prolinamide could be anticipated in
some way to enhance the enantioselectivity in m-xylene at
low temperature. Organocatalyst 1a not only simple and
easily prepared in a facile manner, but the enantioselec-
tivities are maintained at the same level for the large-scale
aldol reactions, which offers great possibilities for appli-
cations in industry.
2.2 General Procedure for the Preparation of Catalysts
1a–1f
All prolinamides 1a–1f were synthesized starting from N-
Boc-L-proline, under a dry Ar atmosphere, to a stirred
solution of N-Boc-L-proline (215 mg, 1 mmol, 1 equiv),
DMAP (42 mg, 0.3 equiv), EDCI (244 mg, 1.1 equiv), and
Cycloalkyl amine (0.8 equiv) were dissolved in dichloro-
methane (10 ml). The resulting mixture was stirred at room
temperature for 2 days. Then the mixture was concentrated
to half of the volume in vacuo and the resulting mixture
was partitioned between EtOAc (100 ml) and 0.5 M
aqueous HCl (50 ml). The organic layer was washed with
half-saturated brine (25 ml), dried (Na2SO4), filtered, and
concentrated followed by flash column chromatogra-
phy (AcOEt/petroleum ether = 1:3) to give N-Boc-L-
prolinamide.
Compound 1a is referred to as an example: To a stirred
solution of N-Boc-L-proline Cyclopropylamine (255 mg,
1 mmol) in dichloromethane (10 ml), TFA (4.3 ml) was
added and stirred at room temperature for 5 h. After
evaporation of the solvent, the resulting residue was neu-
tralized with 10% NaOH aqueous solution, and extracted
with EtOAc. The organic layer was dried over Na2SO4,
filtered, and concentrated followed by flash column chro-
matography on silica gel (MeOH/CHCl3 = 1:10, v/v) to
give 1a as a pale yellow oil.
2 Experimental
2.1 General Information
The starting reagents used during the course of preparing
organocatalysts 1a–1f were purchased from the Aldrich
Company. All chemicals were used as received unless
otherwise noted. Reagent grade solvents were distilled
prior to use. Reactions were monitored by thin-layer
chromatography (TLC) carried out on 0.25 mm silica gel
plates visualized with UV light and/or by staining with
ethanolic phosphomolybdic acid (PMA) and/or ninhydrin
both in ethanol stain. THF was freshly distilled from
sodium-benzophenone ketyl radical under an argon atmo-
sphere immediately prior to use, CH2Cl2 was distilled after
2.3 (S)-N-Cyclopropyl-Pyrrolidine-2-Carboxamide
(1a)
Light yellow oil. Yield: 80%; [a]2D0 = -66.2 (c = 1,
CHCl3); FT-IR mmax (neat)/cm-1: 3263.89, 2969.65,
2871.12, 1658.18, 1520.43, 1265.88, 1182.73, 1099.52,
1
731.42 and 697.50 cm-1; H NMR (300 MHz, CDCl3):
d = 0.43–0.64 (m, 2H), 0.70–0.90 (m, 2H), 1.73–1.87 (m,
2H), 1.86–2.00 (m, 1H), 2.11–2.34 (m, 1H), 2.65–2.87 (s,
1H), 2.98–3.21 (m, 2H), 3.86–4.06 (dd, J1 = 8.7 Hz,
J2 = 5.7 Hz, 1H), 7.92–8.22 (s, 1H); 13C NMR (75 MHz,
CDCl3): d = 5.93, 6.05, 22.24, 25.55, 30.51, 46.81, 60.03,
174.99; MS (ESI) m/z: calcd. for C8H14N2O 154.21, found
154.60.
˚
drying over anhydrous CaH2 and stored over 4 A molecular
sieves. Flash column chromatography was performed on
silica gel (200–300 mesh). NMR spectra were recorded on
a 300 MHz instrument. Chemical shifts (d) are given in
ppm relative to TMS as the internal reference, coupling
constants (J) in Hz. IR spectra were recorded on a spec-
trometer. Melting points were measured on a digital
melting point apparatus. Mass spectra (MS) were measured
with a spectrometer. Analytical high performance liquid
chromatography (HPLC) was carried out on Agilent 1200
instrument using Chiralpak AD (4.6 mm 9 250 mm),
Chiralcel OD-H (4.6 mm 9 250 mm) columns. Optical
2.4 (S)-N-Cyclopentyl-Pyrrolidine-2-Carboxamide
(1b)
Light yellow oil. Yield: 72%; [a]2D0 = -53.9 (c = 1,
CHCl3); FT-IR mmax (neat)/cm-1
2872.69, 1668.11, 1567.18, 1200.84, 1130.41, 831.70,
: 3251.5, 2957.33,
1
798.92 and 720.43 cm-1; H NMR (300 MHz, CDCl3):
123

1158
J.-W. Xu et al.
2.7 (S)-N-Cyclooctyl-Pyrrolidine-2-Carboxamide (1e)
d = 1.36–1.50 (m, 2H), 1.52–1.60 (m, 2H), 1.63–1.75 (m,
2H), 1.81–2.01 (m, 5H), 2.20–2.34 (m, 1H), 3.07–3.25
(t, J = 6.15 Hz, 2H), 4.03–4.21 (m, 2H), 7.87–8.16 (d,
J = 7.5 Hz, 1H); 13C NMR (75 MHz, CDCl3): d = 23.66,
25.23, 32.65, 46.66, 51.08, 59.94, 171.40; MS (ESI) m/z:
calcd. for C10H18N2O 182.26, found 182.43.
Light yellow oil. Yield: 68%; [a]2D0 = -48.3 (c = 1,
CHCl3); FT-IR mmax (neat)/cm-1: 3254.25, 3072.09,
2923.47, 2855.61, 1561.35, 1200.86, 1176.73, 1131.33 and
701.36 cm-1; 1H NMR (300 MHz, CDCl3): d = 1.38–1.69
(m, 13H), 1.71–1.81 (m, 2H), 1.83–1.99 (m, 3H), 2.20–2.39
(m, 1H), 3.14–3.26 (t, J = 6.6 Hz, 2H), 3.82–3.99 (m, 1H),
4.08–4.25 (dd, J1 = 7.8 Hz, J2 = 5.7 Hz, 1H), 7.89–8.07
(d, J = 7.8 Hz, 1H); 13C NMR (75 MHz, CDCl3):
d = 23.55, 25.29, 26.98, 30.46, 31.72, 46.58, 49.65, 59.84,
169.89; MS (ESI) m/z: calcd. for C13H24N2O 224.34, found
224.50.
2.5 (S)-N-Cyclohexyl-Pyrrolidine-2-Carboxamide (1c)
Light yellow oil. Yield: 71%; [a]2D0 = -60.5 (c = 1,
CHCl3); FT-IR mmax (neat)/cm-1: 3256.03, 3070.10,
2937.53, 2855.39, 1664.46, 1557.65, 1523.33, 1451.18,
1
1201.24, 1176.27, 1132.25, 733.74 and 699.76 cm-1; H
NMR (300 MHz, CDCl3): d = 1.11–1.27(m, 3H),
1.27–1.44 (m, 1H), 1.55–1.65 (m, 1H), 1.65–1.79 (m, 4H),
2.09–2.25 (m, 3H), 2.93–3.14 (m, 2H), 3.63–3.77 (m, 2H),
3.79–3.91 (dd, J1 = 8.7 Hz, J2 = 5.7 Hz), 7.55–7.82 (d,
J = 7.8 Hz, 1H); 13C NMR (75 MHz, CDCl3): d = 24.71,
25.43, 30.69, 32.79, 46.94, 47.70, 60.27, 172.75; MS (ESI)
m/z: calcd. for C11H20N2O 196.29, found 196.51.
2.8 (S)-N–n-Hexyl-Pyrrolidine-2-Carboxamide (1f)
Light yellow oil. Yield: 70%; [a]2D0 = -48.6 (c = 1,
CHCl3); FT-IR mmax (neat)/cm-1: 3312.34, 3065.68,
2957.45, 2928.14, 2857.83, 1658.13, 1523.91, 1462.12,
1
1245.87, 1103.97 and 731.94 cm-1; H NMR (300 MHz,
CDCl3): d = 0.85–0.91 (t, J = 6.6 Hz, 3H), 1.24–1.35 (m,
8H), 1.65–1.76 (m, 2H), 1.84–1.98 (m, 1H), 2.07–2.22 (m,
1H), 2.83-2.95 (m, 1H), 2.97–3.07 (m, 1H), 3.16–3.27 (dd,
J1 = 6.6 Hz, J2 = 6.9 Hz, 2H), 3.68–3.84 (dd, J1 = 8.4
Hz, J2 = 3.6 Hz, 1H); 7.54–7.83 (br.s, 1H). 13C NMR
(75 MHz, CDCl3): d = 13.63, 22.18, 25.76, 26.22, 29.24,
30.42, 31.11, 38.54, 46.87, 60.20, 174.41; MS (ESI) m/z:
calcd. for C11H22N2O 198.31, found 198.42.
2.6 (S)-N-Cycloheptyl-Pyrrolidine-2-Carboxamide
(1d)
Light yellow oil. Yield: 68%; [a]2D0 = -45.6 (c = 1,
CHCl3); FT-IR mmax (neat)/cm-1: 3418.01, 3254.27,
3074.07, 2929.91, 2858.93, 1664.58, 1557.74, 1459.27,
1
1200.98, 1132.43 and 701.77 cm-1; H NMR (300 MHz,
CDCl3): d = 1.39–1.68 (m, 11H), 1.75–1.89 (m, 2H),
1.93–2.07 (m, 3H), 2.32–2.52 (m, 1H), 3.31–3.46 (m, 2H),
3.74–3.93 (dd, J1 = 9.0 Hz, J2 = 5.4 Hz, 1H), 8.12–
8.35(d, J = 7.8 Hz, 1H); 13C NMR (75 MHz, CDCl3):
d = 23.99, 24.92, 27.87, 31.17, 34.41, 34.58, 38.08, 46.72,
51.39, 59.64, 170.69; MS (ESI) m/z: calcd. for C12H22N2O
210.32, found 210.54.
2.9 General Procedure for the Preparation of Aldol
Products
A mixture of catalyst (0.025 mmol), ketone (2 mmol) and
AcOH (0.025 mmol) contained in 1.0 ml of m-xylene was
stirred at room temp for 10 min. Subsequently, the
Scheme 1 Synthesis of
catalysts 1a–1f
O
HN R
O
O
HN R
N
TFA/DCM
amine, EDCI, DMAP
CH2Cl2, rt.
N
OH
N
O
O
H
0°C to rt, 5 h
O
O
O
O
O
N
N
HN
N
H
HN
HN
1b
H
H
1a
1c
O
O
O
N
H
N
H
N
H
N
HN
HN
H
1e
1d
1f
123

Simple and Facile L-Prolinamides Derived from Achiral Cycloalkylamines
1159
temperature was brought down to -20 °C and the aldehyde
(0.5 mmol) was introduced. The reaction mixture was
stirred at -20 °C until the reaction was judged to be
complete based on TLC analysis. The reaction was quen-
ched by adding saturated NH4Cl solution, and the organic
material was extracted with ethyl acetate (2 9 20 ml). The
combined organic extract was dried with Na2SO4 and
concentrated in vacuo. The crude product was purified by
silica gel column chromatography to give the pure aldol
adduct.
3 Results and Discussion
With the aim to discover a simple and efficient route to
obtain highly enantiomerically enriched anti-aldol products
and offer great possibility for applications in industry, we
prepared proline derivatives 1a–1f. All the compounds 1a–
1f were easily prepared from the commercially available
Boc-protected L-proline and the corresponding amine com-
ponent according to the synthetic route shown in Scheme 1.
Products were obtained in 68–80% overall yields.
The product after SiO2 chromatography was analyzed
by HPLC to determine the enantiomeric as well as the
diastereomeric ratios; the latter matched, within allowable
limits, the values determined by 1HNMR analysis. The syn
and anti diastereomers of the aldols were readily distin-
These were evaluated for direct aldol reaction between
benzaldehyde and cyclohexanone in m-xylene. The com-
pounds 1a–1e with different carbocyclic rings were syn-
thesized from achiral cycloalkylamine, and compound 1f
have been prepared from alkylamine. These organic cata-
lysts were used in 5 mol%, and the reactions were studied
with 5 mol% AcOH at different temperatures. As can be
seen from the summarized results in Table 1, when the
1
guished in HNMR spectroscopy by the diagnostic chem-
ical shifts of –CHOH– proton, cf. SI for the chemical shift
data.
Table 1 Direct aldol reaction of cyclohexanone and p-nitrobenaldehyde catalyzed by 1a–1f and proline
O
O
OH
CHO
Catalyst 5 mol%
AcOH 5 mol%, m-xylene
NO2
NO2
Entry
1
Catalyst
Temperature (°C)
Time (h)
Yielda (%)
anti/synb
eec (%)
1a
RT
5
5
99
99
95
90
99
78
99
55
99
75
99
80
99
83
72
80
86:14
88:12
97:3
82
90
97
97
68
94
66
93
79
95
74
94
80
78
68
75
0
-20
-40
RT
24
36
5
93:7
2
3
4
5
6
7
1b
1c
1d
1e
1f
80:20
93:7
-20
RT
24
5
75:25
94:6
-20
RT
24
5
85:15
94:6
-20
RT
24
5
82:18
95:5
-20
RT
24
8
73:27
89:11
79:21
84:16
-20
RT
24
24
36
L-Prolined
-20
The reaction was performed with p-nitrobenzaldehyde (0.5 mmol), cyclohexanone (4equiv.), catalyst (5 mol %), acetic acid (5 mol %) in the
specified solvent (1.0 ml)
a
Isolated yield after chromatography on silica gel
b
Determined by chiral HPLC analysis, major product is anti
c
Determined by chiral HPLC
d
Catalyst 20 mol %
123

1160
J.-W. Xu et al.
reaction temperature was lowered from room temperature
to -20 °C, catalysts 1a–e given the product in diastere-
oselectivities and enantioselectivities increased greatly, in
particular, the reactions proceed with catalyst 1a afforded
aldol products in a high diastereoselectivity (97:3) and
enantioselectivity (97%) and significantly enhanced reac-
tion yield (95%). But the catalyst 1f synthesized by
alkylamine demonstrated lower catalytic activity. More-
over, other tested of L-proline only gave moderate enanti-
oselectivities (68–75% ee). So, the carbocyclic ring of
N-cycloalkyl-L-prolinamide could be anticipated in some
way to enhance the enantioselectivity in m-xylene at low
temperature. Therefore, we chose 1a as a representative
catalyst for the aldol reaction.
participate in the reaction. In general, the reaction between
cyclohexanone and aromatic aldehydes bearing electron-
withdrawing substituents furnished b-hydroxy carbonyl
aldol products in excellent yields (90–99%) within 36 h
(entries 1–9). In contrast, longer reaction times were
required for aromatic aldehydes containing an electron-
donating group to give comparatively lower yields
(65–80%) (entries 10–12). This can be explained that
electron-withdrawing groups enhance the electrophilicity
of carbonyl carbons in aldehydes which facilitate the
reaction, while electron-donating groups lessen the elec-
trophilicity. Moreover, the neutral aromatic aldehydes and
the heteroaromatic aldehydes 2-thiophenaldehyde both
reacted smoothly with cyclohexanone under optimal con-
ditions to give the corresponding aldol products in mod-
erate yields of 79–88% (entries 13–16). When 2-substituted
benzaldehydes were used as the aldol acceptor, the aldol
products exhibited excellent stereoselectivity (entries 2 and
8, up to anti/syn 99:1 and up to 99% ee). The results
showed that the aldol reactions of ortho-substituted and
electron-deficient aromatic aldehydes exhibited higher
In order to increase the scope of the methodology, we
carried out several aldol reactions using the catalyst 1a in
order to demonstrate their catalytic activity, the reactions
of various aromatic aldehydes with cyclohexanone were
studied under the optimized conditions. The results are
summarized in Table 2. It can be seen that a wide range of
aromatic and heteroaromatic aldehydes can effectively
Table 2 Catalytic aldol reactions between cyclohexanone and aldehydes catalyzed by 1a
O
O
OH
O
Catalyst 1a (5 mol%)
R
AcOH (5 mol%)
H
R
m
-xylene,-20 °C
4
Entry
Product
Time (h)
Yielda (%)
anti/synb
eec (%)
1
4a(R = p-NO2–C6H4)
4b(R = o-NO2–C6H4)
4c(R = m-NO2–C6H4)
4d(R = p-CN–C6H4)
4e(R = p-Br–C6H4)
4f(R = p-Cl–C6H4)
24
24
24
24
36
36
36
36
36
48
48
48
36
36
48
36
95
99
99
99
98
95
93
92
90
65
65
68
79
86
82
85
97:3
97:3
97
99
97
95
97
97
98
98
96
99
96
97
96
94
97
95
2
3
95:5
4
91:9
5
94:6
6
93:7
7
4 g(R = m-Cl–C6H4)
4 h(R = o-Cl–C6H4)
4i(R = p-F–C6H4)
95:5
8
99:1
9
91:9
10
11
12
13
14
15
16
4j(R = p-CH3–C6H4)
4 k(R = p-OMe–C6H4)
4 l(R = m-OMe–C6H4)
4 m(R = 2-naphthyl)
4n(R = 1-naphthyl)
4o(R = C6H5)
84:16
90:10
90:10
90:10
92:8
84:16
80:20
4p(R = 2-Thiophenecarboxaldehyde)
The reaction was performed with p-nitrobenzaldehyde (0.5 mmol), cyclohexanone (4 equiv.), catalyst 1a (5 mol %), acetic acid (5 mol %) in m-
xylene (1.0 ml)
a
Isolated yield after chromatography on silica gel
b
Determined by chiral HPLC analysis, major product is anti
c
Determined by chiral HPLC
123

Simple and Facile L-Prolinamides Derived from Achiral Cycloalkylamines
1161
enantioselectivities than those of meta- and para-substi-
tuted aldehydes. In fact, catalyst 1a could efficiently cat-
alyze the direct aldol reactions of cyclohexanone with
aldehydes generating the products with high diastereose-
lectivity and excellent enantioselectivity on electron-with-
drawing or electron-rich systems.
required in comparison with cyclic ketones, satisfactory
results were obtained. The organocatalyst 1a also catalyzed
direct aldol reactions of hydroxyacetone (Table 3, entire
3), and the aldol products were obtained with excellent
enantioselectivities (96% ee for anti-isomer). Furthermore,
when the aldol reaction of chlorobenzaldehyde with ace-
tone was conducted in the presence of 5 mol% organo-
catalyst 1a, the aldol product was obtained with high
enantioselectivities (95% ee). All the reactions of other
cyclic and acyclic ketones with aromatic aldehydes pro-
vided the corresponding aldol products with excellent
enantioselectivities.
The feasibility of using other cyclic and acyclic ketones
as aldol donors was then examined. As shown in Table 3,
when 4-methylclohexanone were used as aldol donors,
good yield of 95% with excellent stereoselectivity (anti/syn
97:3 and 96% ee) for the anti isomer were received.
However, when cyclopentanone was used as an aldol
donor, only were excellent enantioselectivities obtained,
but low diastereoselectivities were achieved (anti/syn
75:25 and 93% ee). We also examined the feasibility of
using acyclic ketones, such as hydroxyacetone and acetone,
as aldol donors. Although longer reaction times were
Large-scale asymmetric aldol reactions were then per-
formed with 25 mmol of aromatic aldehydes and 4 equiv.
of ketones. The same catalyst loading of 5 mol% as used in
the experimental scale was used. The large-scale experi-
ments proceeded smoothly using the same procedure as for
Table 3 Direct asymmetric aldol reactions between cyclic ketones and p-nitrobenzaldehydes catalyzed by 1a
O
O
O
OH
Catalyst 1a (5 mol%)
H
AcOH (5 mol%)
NO2
NO2
m
-xylene, -20 °C
4
Entry
1
Product
No.
Time (h)
24
Yielda (%)
anti/synb
eec (%)
4q
95
97:3
96
O
OH
NO2
2
4r
36
72
75:25
93
OH
O
NO2
3
4
4s
4t
48
48
70
68
80:20
96
95
O
OH
OH
NO2
–
O
OH Cl
The reaction was performed with p-nitrobenzaldehyde (0.5 mmol), cyclohexanone (4 equiv.), catalyst 1a (5 mol %), acetic acid (5 mol %) in m-
xylene (1.0 ml)
a
Isolated yield after chromatography on silica gel
b
Determined by chiral HPLC analysis
c
Determined by chiral HPLC
123

1162
J.-W. Xu et al.
Table 4 Large-scale asymmetric aldol reactions
O
O
OH
O
Catalyst 1a (5 mol%)
R
AcOH (5 mol%)
m-xylene,-20 °C
H
R
4
Entry
1
Product
No.
Time (h)
30
Yielda (%)
90
anti/synb
eec (%)
4a
94:6
96
O
OH
NO2
OH NO2
2
3
4
4b
4c
4f
30
30
40
92
90
85
95:5
91:9
98
96
96
O
O
O
OH
NO2
88:12
OH
Cl
5
4o
48
70
80:20
95
O
OH
The reaction was performed with p-nitrobenzaldehyde (25 mmol), cyclohexanone (4 equiv.), catalyst 1a (5 mol %), acetic acid (5 mol %) in m-
xylene (50.0 ml)
a
Isolated yield after chromatography on silica gel
b
Determined by chiral HPLC analysis, major product is anti
c
Determined by chiral HPLC
the experimental-scale reactions. As can be seen from the
results summarized in Table 4, the enantioselectivities
were maintained at the same level for the large-scale
reactions. This offers great possibilities for applications in
industry.
99%) and significantly enhanced reaction yield (99%). The
results observed for 1a surpass those reported so far for
simple prolinamide derivatives and are comparable to those
for organocatalysts of much more structural complexity.
However, the compound 1f synthesized by alkylamine
demonstrated lower catalytic activity. The result indicated
that carbocyclic rings could be anticipated in some way to
enhance the enantioselectivity in m-xylene at low temper-
ature. Furthermore, catalyst 1a can be efficiently used in
large-scale reactions with the enantioselectivity being
maintained at the same level. Thus, this catalyst is not only
simple and easily prepared in a facile manner, but the e-
nantioselectivities are maintained at the same level for the
large-scale aldol reactions, which offers great possibility
for applications in industry.
4 Conclusion
In conclusion, all prolinamides 1a–e exhibited great cata-
lytic activity in the asymmetric aldol reaction in m-xylene
at -20 °C with only 5 mol% catalyst loading in 4 equiv-
alents ketone. In particular, the reactions proceed with
catalysts 1a afforded aldol products in a high diastereose-
lectivity (up to anti/syn 99:1) and enantioselectivity (up to
123

Simple and Facile L-Prolinamides Derived from Achiral Cycloalkylamines
1163
Acknowledgments Authors are grateful to Southwest University of
China for financial support.
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