A new chiral primary-tertiary diamine-Bronsted acid salt organocatalyst for the highly enantioselective direct anti-aldol and syn-Mannich reactions

Article abstract of DOI:10.1007/s11164-012-0667-x

A new primary-tertiary diamine catalyst is easily prepared in a few steps from inexpensive, commercially available, enantiopure materials. This organocatalyst can be effective catalyzed the direct asymmetric aldol and Mannich reactions. The anti-aldol products can be obtained with up to a 99:1 anti/syn ratio and >98 % ee, while the syn-Mannich products could be obtained with up to a 99:1 syn/anti ratio and >99 % ee. Catalyst 1c can be used efficiently on a large scale with the enantioselectivities of the anti-aldol and syn-Mannich reactions being maintained at the same level, which offers a great possibility for application in industry.

Full text of DOI:10.1007/s11164-012-0667-x

Res Chem Intermed (2013) 39:1069–1087
DOI 10.1007/s11164-012-0667-x
A new chiral primary–tertiary diamine-Brønsted acid
salt organocatalyst for the highly enantioselective direct
anti-aldol and syn-Mannich reactions
•
Guodong Chen Xiangkai Fu
•
•
Chuanlong Wu Chao Li
Received: 21 April 2012 / Accepted: 28 May 2012 / Published online: 3 July 2012
Ó Springer Science+Business Media B.V. 2012
Abstract A new primary–tertiary diamine catalyst is easily prepared in a few steps
from inexpensive, commercially available, enantiopure materials. This organocata-
lyst can be effective catalyzed the direct asymmetric aldol and Mannich reactions.
The anti-aldol products can be obtained with up to a 99:1 anti/syn ratio and[98 %
ee, while the syn-Mannich products could be obtained with up to a 99:1 syn/anti ratio
and[99 % ee. Catalyst 1c can be used efficiently on a large scale with the enanti-
oselectivities of the anti-aldol and syn-Mannich reactions being maintained at the
same level, which offers a great possibility for application in industry.
Keywords Cyclohexyldiamine Á Aldol reactions Á Mannich reactions Á
Large scale Á Stoichiometric
Introduction
The development of stereoselective and enantioselective aldol and Mannich
reactions have become interesting and challenging topics in modern organic and
medicinal chemistry [1–3], because the resulting chiral b-hydroxy ketones and 1,2-
amino alcohols belong to an extremely important class of biological compounds.
Electronic supplementary material The online version of this article (doi:10.1007/
s11164-012-0667-x) contains supplementary material, which is available to authorized users.
G. Chen Á X. Fu (&) Á C. Wu Á C. Li
College of Chemistry and Chemical Engineering, Research Institute of Applied Chemistry
Southwest University, The Key Laboratory of Applied Chemistry of Chongqing Municipality,
Chongqing, China
e-mail: fxk@swu.edu.cn
C. Wu
Chongqing Unis Chemical Co, Ltd, Chongqing 402161, China
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In fact, b-hydroxy ketones and 1,2-amino alcohols can serve as versatile building
blocks for the asymmetric synthesis of carbohydrates, amino acids, and many other
biomolecules [4–6]. They also provide privileged structural functionalities that exist
in many important natural products [7–12].
During the past few years, the field of asymmetric catalysis has been dominated
by biocatalysts and metal catalysts. The advent of organocatalysis brought the
prospect of a complementary mode of catalysis, with the potential for savings in
cost, time, and energy, an easier experimental procedure, and reductions in chemical
waste. For decades, one of the most difficult challenges has been the design of
sustainable experimental processes, which are not only more economical but also
more benign toward the environment and more practicable both in industry and in
practice. Stimulated by this challenge, a great deal of effort is currently being made
in the search for elegant and practical means for preparing highly stereoselective
b-hydroxy ketones and 1,2-amino alcohols.
Since the pioneering findings by List, Barbas, and their co-workers that L-proline
could work as an active organocatalyst in intermolecular direct aldol reactions,
numerous organocatalysts have been developed for direct asymmetric aldol reactions
[13–23]. Usually, enantioselective organocatalytic processes have typically been
carried out in organic solvents, such as DMSO, DMF, or CHCl3. The necessity to
further reduce sources of pollution, such as the sometimes employed chlorinated
solvents, has prompted scientists to search for organic reactions performed in the
presence of water [24–32] or under solvent-free conditions [33, 34]. At the same
time, the reactions using water as the solvent have attracted a great deal of attention,
because water is an environmentally friendly, safe medium, which avoids the
problems of pollution that are inherent with organic solvents [32–34]. On the other
hand, organocatalyzed reactions under solvent-free conditions usually need shorter
reaction times and result in simple and efficient work-up procedures [35–41]. For
these reasons, organocatalyzed aldol reactions under solvent-free conditions or
employing water as solvent have become a highly pursued goal in green chemistry.
Primary–tertiary diamines [42–48] are a type of important organic catalysts,
which have achieved satisfactory results in the aspect of catalyzing Aldol [45, 49]
and Michael [50, 51] reactions. But until now, they were seldom used in catalytic
asymmetric two-component Mannich reactions. Here, we describe the first asym-
metric syn-selective Mannich reactions of a-hydroxyketones catalyzed by a simple
chiral amine catalyst. Hydroxyacetone is a very useful donor, and its Mannich
reaction can yield synthetically versatile 1,2-amino alcohols. Even so, a-hydrox-
yacetone has seldom been used as a donor in asymmetric catalyzed direct two-
component Mannich reactions [52–62]. Lu et al. reported direct anti-selective
Mannich reactions between O-TBS-hydroxyacetone and various N-tosylimines
derived from aromatic aldehydes in the presence of L-threonine-derived catalyst [63].
However, the result of catalyzing a direct Mannich reaction between hydroxylac-
etone with N-tosylimine is unsatisfactory, and the experimental process of removing
the TBS group is troublesome. Therefore, direct Mannich reaction of catalyzing
hydroxyacetone with N-tosylimine is more meaningful and useful.
Recently, primary–tertiary diamines have been frequently explored in organocatal-
ysis [20, 23]. It has been found that, among the reported asymmetric organocatalysts,
123

Chiral primary–tertiary diamine-Brønsted acid salt organocatalyst
1071
mostwerepreparedwithcomplexproceduresand/orrequiredexpensivereagents, which
added hurdles for industrial production, so these organocatalysts were often only used in
research laboratories. Therefore, the development of a new and effective primary–
tertiary diamine catalyst, easily prepared in a few steps from inexpensive, commercially
available, enantiopure materials, is urgently needed. This efficient catalyst can catalyze
the direct aldol reactions by using stoichiometric amounts of ketones and various aryl
aldehydes in the presence of water or under solvent-free conditions from a green
chemistry and atom-economical perspective. It can also be used to catalyze the reaction
of Mannich with high diastereoselectivity up to a 99:1 and enantioselective up to 99 %
ee. In addition, this catalyst can be used in large-scale aldol and Mannich reactions with
the enantioselectivitybeingmaintainedatthe samelevel, whichoffersagreat possibility
for applications in industry.
Experimental
Materials and instruments
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 atmosphere immediately prior to use. 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, and coupling constants (J) in Hz. IR spectra were recorded on a spectrometer.
Melting points were measured on a digital melting-point apparatus. Mass spectra (MS)
were measured with a spectrometer. Analytical high performance liquid chromatog-
raphy (HPLC) was carried out on an Agilent 1200 instrument using Chiralpak AD-H
(4.6 mm 9 250 mm), Chiralcel OD-H (4.6 mm 9 250 mm) columns. Optical rota-
tions were measured on a JASCO P-1010 Polarimeter at k = 589 nm.
The synthesis of the catalysts (Scheme 1)
See Scheme 1.
Monoprotection of 1,2-diaminocyclohexane
Monoprotection of (1R, 2R)-1,2-diaminocyclohexane or (1S, 2S)-1,2-diaminocy-
clohexane was carried out following the literature procedure [64].
Preparation of catalyst 1b [65]
A mixture of monoprotection of (1R, 2R)-1,2-diaminocyclohexane (3.55 mg,
14.5 mmol), 80 % formic acid (1.2 mL), and 36 % formaldehyde solution (0.5 mL,
123

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G. Chen et al.
O
O
N
NH2
NH2
NH2
NH2
1.p-TsOH¡¤H2O, m-Xylene
reflux
O
O
NH2
2.sat. NaHCO3, DCM
r.t., 12 h
O
+
Step A
O
N
O
NH2
Step B
O
O
NH2
N
O
NRR
NRR
H2N-NH2, EtOH, reflux
Step C
NH2
N
NRR
O
NRR
Scheme 1 The synthesis of the catalysts
6.4 mmol) were stirred under reflux (oil bath 120 °C) for 6 h. The solvents were
removed in vacuo and the product was extracted with dichloromethane and
saturated NaHCO3 solution. The organic solution was dried over MgSO4 and
evaporated to give the crude product. This product was directly purified through
flash column chromatography on a silica gel to afford (1R, 2R)-N,N-Dimethyl-N’-
phthaloyl-1,2-diaminocyclohexane as a white solid, yield 80 %.
A sample of (1R, 2R)-N,N-Dimethyl-N’-phthaloyl-1,2-diaminocyclohexane
(7 mmol) was refluxed with hydrazine hydrate (0.84 mL) in ethanol (14 mL) for
2 h. After cooling, the solution was diluted with diethyl ether to precipitate
phthaloyl hydrazide. The mixture was filtered and the filtrate evaporated to dryness.
The products were purified by extraction into the dilute HCl, followed by
neutralization with saturated NaHCO3 solution, and back extraction with dichlo-
romethane. Product 1b was obtained as a yellow oil, yield 85 %; [a]2D0 = -38.7
(c = 1, CHCl3). 1H NMR (300 MHz, CDCl3): d = 2.59 (dt, J = 3, 9 Hz; 1H), 2.24
(s, 8H), 2.08–1.94 (m, 2H), 1.79–1.65 (m, 3H), 1.25–1.06 (m, 4H) ppm; 13C NMR
(75 MHz, CDCl3): d = 69.5, 51.3, 40.1, 34.8, 25.5, 25.0, 20.6; FT-IR (KBr):
[cm-1] = 2,929, 2,858, 2,825, 2,778, 1,668, 1,593, 1,512, 1,452, 1,358, 1,333,
1,270, 1,203, 1,153, 1,116, 1,089, 1,046, 943, 901, 872, 848, 820, 774, 566, 543. MS
(ESI) m/z calcd. for (C8H18N2) 142.24, found 143.63.
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Chiral primary–tertiary diamine-Brønsted acid salt organocatalyst
1073
Preparation of catalyst 1c [65]
To a solution of (1R, 2R)-N-phthaloyl-1,2-diamino-cyclohexane (2.44 g, 10 mmol)
in acetonitrile (50 mL), K2CO3 (3.20 g, 23 mmol) and benzyl bromide (3 mL,
25 mmol) were added at room temperature. The mixture was refluxed with stirring
for 4 h. The solvent was removed in vacuo and the mixture extracted with
dichloromethane and saturated NaHCO3 solution. The organic solution was dried
over MgSO4 and evaporated. The product was directly purified through flash
column chromatography on a silica gel to afford (1R, 2R)-N,N-dibenzyl-N’-
phthaloyl-1,2-diaminocyclohexane as a white solid, yield 92 %.
A
sample of (1R, 2R)-N,N-dibenzyl-N’-phthaloyl-1,2-diaminocyclohexane
(8 mmol) was refluxed with hydrazine hydrate (0.96 mL) in ethanol (16 mL) for
2 h. After cooling, the solution was diluted with diethyl ether to precipitate
phthaloyl hydrazide. The mixture was filtered and the filtrate evaporated to dryness.
The products were purified by extraction into the dilute HCl, followed by
neutralization with saturated NaHCO3 solution, and back extraction with dichlo-
romethane. Product 1c was obtained as a yellow oil, yield 85 %; [a]2D0 = -79.0
(c = 1, CHCl3). 1H NMR (300 MHz, CDCl3): d = 7.30–7.20 (m, 10H), 3.81
(d, J = 13.5 Hz, 2H), 3.37 (d, J = 13.5 Hz, 2H), 2.67 (dt, J = 3.9, 10.2 Hz; 1H),
13
2.12 (m, 1H), 1.98–1.94 (m, 2H), 1.79–1.58 (m, 4H), 1.27–0.84 (m, 4H) ppm;
C-NMR (75 MHz, CDCl3): d = 140.2, 128.9, 128.3, 126.9, 64.6, 53.7, 51.1, 34.8,
25.7, 25.1, 22.5; FT-IR (KBr): [cm-1] = 3,061, 3,027, 2,922, 2,855, 1,493, 1,451,
748, 699. MS (ESI) m/z calcd. for (C20H26N2) 294.43, found 294.68.
Preparation of catalyst 1d
The general procedure described above was followed on a 4-mmol scale of (1S, 2S)-
N,N-dibenzyl-N’-phthaloyl-1,2-diaminocyclohexane. Product 1d was obtained as a
1
yellow oil, yield 75 %; [a]D20 = ? 62.1 (c = 1, CHCl3). H NMR (300 MHz,
CDCl3): d = 7.30–7.21 (m, 10H), 3.81 (d, J = 13.2 Hz, 2H), 3.37 (d, J = 13.5 Hz,
2H), 2.68 (dt, J = 3.6, 10.2 Hz, 1H), 2.29–2.11 (m, 3H), 2.00–1.96 (m, 2H),
1.80–1.77 (m, 1H), 1.64–1.60 (m, 1H), 1.29–0.99 (m, 3H), 0.96–0.87 (m, 1H) ppm;
13 C NMR (75 MHz, CDCl3): d = 140.1, 128.8, 128.3, 126.9, 64.4, 53.7, 53.7, 51.0,
34.5, 25.6, 25.1, 22.5; FT-IR (KBr): [cm-1] = 3,060, 3,027, 2,928, 2,855, 1,493,
1,451, 747, 699. MS (ESI) m/z calcd. for (C20H26N2) 294.43, found 294.69.
Preparation of catalyst 1e
The general procedure described above was followed on a 10-mmol scale of (1R,
2R)-N,N-Di(4-nitrobenzyl)-N’-phthaloyl-1,2-diaminocyclohexane. Product 1e was
obtained as a yellow oil, yield 65 %; [a]2D0 = ?28.9 (c = 1, CHCl3). H NMR
1
(300 MHz, CDCl3): d = 8.17 (d, J = 9.0 Hz, 2H), 7.50 (d, J = 9.0 Hz, 2H), 3.87
(d, J = 15.0 Hz, 2H), 2.60 (d, J = 15.0 Hz, 2H), 2.79 (dt, J = 3.0, 9.0 Hz, 1H),
2.15 (m, 1H), 2.03–2.00 (m, 2H), 1.86–1.65 (m, 4H), 1.30–0.96 (m, 4H) ppm; 13C
NMR (75 MHz, CDCl3): d = 147.3, 147.2, 129.3, 123.7, 65.5, 35.0, 25.5, 24.8,
22.9; FT-IR (KBr): [cm-1] = 3,367, 3,109, 3,078, 2,930, 2,856, 2,450, 1,734,
123

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G. Chen et al.
1,647, 1,603, 1,518, 1,492, 1,449, 1,340, 1,244, 1,175, 1,108, 1,014, 988, 959, 851,
809, 741, 699. MS (ESI) m/z calcd. for (C20H24N4O4) 384.43, found 384.66.
Preparation of catalyst 1f [66]
The general procedure described above was followed on a 10-mmol scale of (1R,
2R)-N,N-Di(4-nitrobenzyl)-N’-phthaloyl-1,2-diaminocyclohexane. Product 1f was
1
obtained as a yellow oil, yield 60 %; [a]2D0 = -58.0 (c = 1, CHCl3). H NMR
(300 MHz, CDCl3): d = 2.65–2.52 (m, 4H), 2.31–2.25 (m, 1H), 2.71–1.84 (m, 4H),
1.77–1.68 (m, 6H), 1.25–1.04 (m, 4H) ppm; 13C NMR (75 MHz, CDCl3): d = 64.1,
52.4, 46.9, 33.8, 25.1, 24.7, 23.5, 21.4; FT-IR (KBr): [cm-1] = 2,928, 2,857, 2,805,
1,665, 1,582, 1,448, 1,357, 1,292, 1,244, 1,204, 1,120, 1,088, 941, 904, 751, 660.
MS (ESI) m/z calcd. for (C10H20N2) 168.16, found 168.54.
General procedure for aldol reaction of ketones with aldehydes
A mixture of organocatalyst 1c/TfOH (10 mol %) and ketone (0.5 mmol) were
stirred in water (0.5 mL) at room temperature. Subsequently, an aldehyde
(0.5 mmol) was added and the reaction mixture was stirred at room temperature.
Until the reaction was judged to be complete based on TLC analysis, the mixture
was partitioned between a saturated solution of ammonium chloride and dichlo-
romethane. The organic layer was separated and dried over anhydrous Na2SO4. It
was purified over silica gel by column chromatography to give the pure product,
then examined by HPLC to determine ee value (Fig. 1).
(2S, 10R)-2-(Hydroxy-(4-nitrophenyl)-methyl)cy-clohexan-1-one (5a) [67]
Isolated yield: 81 %; dr (anti/syn) = 99:1, ee = 98 %. Enantiomeric excess was
determined by HPLC with a Chiralpak AD-H column (hexane/2-propanol = 80/20),
20 °C, 254 nm, 0.5 mL/min; major enantiomer tR = 36.1 min and minor enantio-
1
mer tR = 47.2 min. H NMR (300 MHz, CDCl3): d = 8.21 (d, J = 8.4 Hz, 2H),
7.51 (d, J = 8.5 Hz, 2H), 4.91 (dd, J = 8.3 Hz and J = 3.0 Hz, 1H), 4.09 (d, 1H,
J = 3.0 Hz), 2.40–2.64 (m, 2 H), 2.36 (td, J = 13.2 Hz and J = 5.7 Hz, 1H),
2.09–2.15 (m, 3 H), 1.78–1.85 (m, 1 H), 1.54–1.65 (m, 4H), 1.35–1.44 (m, 1H).
1a-(1R, 2R): R = H
1b-(1R, 2R): R = Me
1c-(1R, 2R): R = Bn
R
N
R
H2N
H2N
N
1d-(1S, 2S): R = Bn
1e-(1R, 2R): R = 4-nitrobenzy
1f-(1R, 2R)
Fig. 1 The structure of the organocatalysts
123

Chiral primary–tertiary diamine-Brønsted acid salt organocatalyst
1075
(2S, 10R)-2-(Hydroxy-(2-nitrophenyl)-methyl)cy-clohexan-1-one (5b) [67]
Isolated yield: 73 %; dr (anti/syn) = 94:6, ee = 98 %. Enantiomeric excess was
determined by HPLC with a Chiralpak OD-H column (hexane/2-propanol = 95/5),
20 °C, 254 nm, 0.5 mL/min; major enantiomer tR = 47.2 min and minor enantio-
1
mer tR = 40.8 min. H NMR (300 MHz, CDCl3): d = 7.84 (d, J = 8.1 Hz, 1H),
7.77 (d, J = 7.8 Hz, 1H), 7.63 (t, J = 7.5 Hz, 1H), 7.43 (t, J = 7.8 Hz, 1H), 5.45
(d, J = 6.6 Hz, 1H), 3.90 (br, 1H), 2.82–2.70 (m, 1H), 2.50–2.40 (m, 1H), 2.34 (td,
J = 12.3 Hz and J = 5.7 Hz, 1H), 2.15–2.06 (m, 1H), 1.90–1.55 (m, 4H).
(2S, 10R)-2-(Hydroxy-(3-nitrophenyl)-methyl)cyc-cyclohexan-1-one (5c) [67]
Isolated yield: 85 %; dr (anti/syn) = 98:2, ee = 97 %. Enantiomeric excess was
determined by HPLC with a Chiralpak AD-H column (hexane/2-propanol = 80/20),
20 °C, 254 nm, 0.5 mL/min; major enantiomer tR = 30.6 min and minor enantio-
1
mer tR = 25.1 min. H NMR (300 MHz, CDCl3): d = 8.21 (d, J = 8.7 Hz, 2H),
7.51 (d, J = 8.7 Hz, 2H), 4.90 (dd, J = 8.4 Hz and J = 3.0 Hz, 1H), 4.09 (d,
J = 3.0 Hz, 1H), 2.65–2.45 (m, 2H), 2.36 (td, J = 13.2 Hz and J = 5.7 Hz, 1H),
2.17–2.06 (m, 1H), 1.87–1.78 (m, 1H), 1.67–1.51 (m, 3H), 1.45–1.31 (m, 1H).
(2S, 10R)-2-(Hydroxy-(2,4-dinitro-phenyl)-methyl- yl)-cyclohexan-1-one (5d) [67]
Isolated yield: 75 %; dr (anti/syn) = 95:5, ee = 97 %. Enantiomeric excess was
determined by HPLC with a Chiralpak AD-H column (hexane/2-propanol = 85/15),
25 °C, 254 nm, 1.0 mL/min; major enantiomer tR = 26.3 min and minor enantiomer
tR = 29.8 min. 1H NMR (300 MHz, CDCl3): d = 8.75 (d, J = 2.4 Hz, 1H), 8.48 (dd,
J = 8.4, 2.0 Hz, 1H), 8.09 (d, J = 8.8 Hz, 1H), 7.25 (d, J = 6.0 Hz, 2H), 5.06–4.90
(d, J = 8.4 Hz, 1H), 2.82–2.31 (m, 3H), 2.16–2.11 (m, 1H), 1.94–1.63 (m, 5H).
(2S, 10R)-2-(Hydroxy-(4-(trifluoromethyl)phenyl) methyl)cyclohexan-1-one (5e)
[67]
Isolated yield: 63 %; dr (anti/syn) = 98:2, ee = 97 %. Enantiomeric excess was
determined by HPLC with a Chiralpak AD-H column (hexane/2-propanol = 90/10),
21 °C, 254 nm, 0.5 mL/min; major enantiomer tR = 27.3 min and minor enantio-
1
mer tR = 35.1 min. H NMR (300 MHz, CDCl3): d = 7.74–7.55 (m, 3H), 7.40
(t, J = 7.2 Hz, 1H), 5.30 (d, J = 9.3 Hz, 1H), 4.03 (t, J = 3.0 Hz, 1H), 2.81–2.69
(m, 1H), 2.55–2.45 (m, 1H), 2.37 (td, J = 12.9 Hz and J = 4.8 Hz, 1H), 2.15–2.03
(m, 1H), 1.81–149 (m, 3H), 1.48–1.23 (m, 1H).
(2S, 10R)-2-(Hydroxyl(2-chlorophenyl)-methyl)cy- clohexan-1-one (5f) [67]
Isolated yield: 70 %; dr (anti/syn) = 98:2, ee = 94 %. Enantiomeric excess was
determined by HPLC with Chiralcel OD-H (hexane/i-PrOH = 95/5), 20 °C, 220 nm,
flow rate 1.0 mL/min, major anti enantiomer tR = 12.9 min and minor anti
1
enantiomer tR = 10.9 min. H NMR (300 MHz, CDCl3): d = 7.56 (d, J = 8.4 Hz,
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G. Chen et al.
1H), 7.20–7.34 (m, 3H), 5.35 (d, J = 8.0 Hz, 1H), 3.88 (s, 1H), 2.65–2.71 (m, 1H),
2.46–2.49 (m, 1H), 2.31–2.39 (m, 1H), 2.05– 2.13 (m, 1H), 1.53–1.84 (m, 5H).
(2S, 10R)-2-(Hydroxy-(4-chlorophenyl)-methyl)cy-clohexan-1-one (5g) [67]
Isolated yield: 55 %; dr (anti/syn) = 95:5, ee = 95 %. Enantiomeric excess was
determined by HPLC with a Chiralpak AD-H column (hexane/2-propanol = 90/10),
21 °C, 220 nm, 0.5 mL/min; major enantiomer tR = 34.2 min and minor enantio-
1
mer tR = 40.7 min. H NMR (300 MHz, CDCl3): d = 7.29 (dd, J = 20.4 Hz and
J = 8.4 Hz, 4H), 4.76 (dd, J = 8.7 Hz and J = 2.7 Hz, 1H), 3.99 (d, J = 3.0 Hz,
1H), 2.61–2.44 (m, 2H), 2.35 (td, J = 12.9 Hz and J = 5.4 Hz, 1H), 2.15–2.05 (m,
1H), 1.85–1.75 (m, 1H), 1.70–1.50 (m, 3H), 1.37–1.20 (m, 1H).
(2S, 10R)-2-(Hydroxy-(4-cyanophenyl)-methyl)cy-clohexan-1-one (5h) [67]
Isolated yield: 75 %; dr (anti/syn) = 99:1, ee = 97 %. Enantiomeric excess was
determined by HPLC with a Chiralpak AD-H column (hexane/2-propanol = 80/20),
20 °C, 254 nm, 0.5 mL/min; major enantiomer tR = 36.7 min and minor enantio-
1
mer tR = 46.5 min. H NMR (300 MHz, CDCl3): d = 7.65 (d, J = 8.1 Hz, 2H),
7.45 (d, J = 8.1 Hz, 2H), 4.85 (dd, J = 8.1 Hz and J = 3.0 Hz, 1H), 4.11
(d, J = 3.0 Hz, 1H), 2.65–2.44 (m, 2H), 2.37 (td, J = 12.9 Hz and J = 6.0 Hz,
1H), 2.17–2.06 (m, 1H), 1.88–1.77 (m, 1H), 1.72–1.47 (m, 3H), 1.44–1.31 (m, 1H).
(2S, 10R)-2-(Hydroxy-(4-bromophenyl)-methyl)c-yclohexan-1-one (5i) [67]
Isolated yield: 62 %; dr (anti/syn) = 94:6, ee = 94 %. Enantiomeric excess was
determined by HPLC with a Chiralpak AD-H column (hexane/2-propanol = 90/10),
20 °C, 220 nm, 0.8 mL/min; major anti enantiomer tR = 21.1 min and minor anti
1
enantiomer tR = 25.4 min. H NMR (300 MHz, CDCl3): d = 7.47 (d, J = 8.1 Hz,
2H), 7.20 (d, J = 8.7 Hz, 2H), 4.75 (dd, J = 8.7 Hz and J = 2.7 Hz, 1H), 3.99 (d,
J = 3.0 Hz, 1H), 2.61–2.44 (m, 2H), 2.35 (td, J = 12.9 Hz and J = 6.3 Hz, 1H),
2.15–2.04 (m, 1H), 1.85–1.75 (m, 1H), 1.70–1.50 (m, 3H), 1.37–1.20 (m, 1H).
(2S, 10R)-2-(Hydroxy-(4-fluor-phenyl)-methyl)-cy-clohexan-1-one (5j) [67]
Isolated yield: 50 %; dr (anti/syn) = 95:5, ee = 97 %. Enantiomeric excess was
determined by HPLC with a Chiralpak AD-H column (hexane/2-propanol = 95/5),
20 °C, 220 nm, 1.0 mL/min; major enantiomer tR = 25.3 min and minor enantio-
1
mer tR = 29.2 min. H NMR (300 MHz, CDCl3): d = 7.55–7.45 (d, J = 8.4 Hz,
2H), 7.20–7.15 (d, J = 8.4 Hz, 2H), 4.85–4.75 (d, J = 8.7 Hz, 1H), 2.60–2.30 (m,
3H), 2.20–2.00 (m, 1H), 1.85–1.50 (m, 5H), 1.40–1.20 (m, 1H).
(2S, 10R)-2-(Hydroxy-(3-methoxy-phenyl)-methy-l)-cyclohexan-1-one (5k) [67]
Isolated yield: 55 %; dr (anti/syn) = 95:5, ee = 98 %. Enantiomeric excess was
determined by HPLC with a Chiralpak AD-H column (hexane/2-propanol = 90/10),
123

Chiral primary–tertiary diamine-Brønsted acid salt organocatalyst
1077
25 °C, 220 nm, 0.5 mL/min; major enantiomer tR = 58.1 min and minor enantio-
mer tR = 52.5 min. 1H NMR (300 MHz, CDCl3): d = 7.28–7.33 (m, 1H),
6.80–7.00 (m, 3H), 4.75–4.85 (d, J = 8.7 Hz, 1H), 3.85 (s, 3H), 2.30–2.75 (m,
3H), 2.00–2.15 (m, 1H), 1.55–1.90 (m, 4H), 1.20–1.40 (m, 1H).
(2S, 10R)-2-(Hydroxy-(1-naphthyl)-methyl)cycloh-exan-1-one (5l) [67]
Isolated yield: 42 %; dr (anti/syn) = 97:3, ee = 96 %. Enantiomeric excess was
determined by HPLC with a Chiralpak AD-H column (hexane/2-propanol = 95/5),
20 °C, 254 nm, 1.0 mL/min; major enantiomer tR = 45.0 min and minor enantio-
mer tR = 36.7 min. 1H NMR (300 MHz, CDCl3): d = 7.70–7.90 (m, 4H),
7.40–7.55 (m, 2H), 4.90–5.05 (d, J = 8.7 Hz, 1H), 2.65–2.75 (m, 1H), 2.30–2.60
(m, 2H), 2.00–2.20 (m, 1H), 1.20–1.80 (m, 5H).
(2S, 10R)-2-(Hydroxy-(phenyl)-methyl)cyclohexa-n-1-one (5m) [67]
Isolated yield: 65 %; dr (anti/syn) = 92:8, ee = 97 %. Enantiomeric excess was
determined by HPLC with a Chiralpak OD-H column (hexane/2-propanol = 90/10),
20 °C, 220 nm, 0.5 mL/min; major enantiomer tR = 29.3 min and minor enantiomer
1
tR = 21.1 min. H NMR (300 MHz, CDCl3): d = 7.50–7.24 (m, 5H), 4.80 (d, J =
9.0 Hz, 1H), 4.00 (m, 1H), 2.70–2.56 (m, 1H), 2.55–2.44 (m, 1H), 2.34 (td, J = 12.3,
5.4 Hz, 1H), 2.16–2.03 (m, 1H), 1.87–1.73 (m, 1H), 1.72–1.50 (m, 3H), 1.40–1.22 (m, 1H).
(2S, 10R)-2-(Hydroxy-(4-nitrophenyl)-methyl)-cyc-lopentan-1-one (5n) [67]
Isolated yield: 50 %; dr (anti/syn) = 89:11, ee = 88 %. Enantiomeric excess was
determined by HPLC with a Chiralpak AD-H column (hexane/2-propanol = 95/5),
20 °C, 254 nm, 1.0 mL/min; major enantiomer tR = 63.2 min, minor enantiomer
1
tR = 67.2 min. H NMR (300 MHz, CDCl3): d = 8.21 (d, J = 8.7 Hz, 2H), 7.54
(d, J = 9.0 Hz, 2H), 4.85 (d, J = 9.0 Hz, 1H), 4.74 (s, 1H), 2.54–2.18 (m, 3H),
2.08–1.95 (m, 1H), 1.81–1.48 (m, 3H).
(2S, 10R)-2-(Hydroxy(4-nitrophenyl)methyl)-4-methylcyclohexan-1-one (5o) [67]
Isolated yield: 60 %; dr (anti/syn) = 99:1, ee (anti) = 94 %, Enantiomeric excess
was determined by HPLC with a Chiralpak AD-H column (hexane/2-propa-
nol = 90/10), 20 °C, 254 nm, 1.0 mL/min; major enantiomer tR = 24.1 min, minor
enantiomer tR = 23.2 min. 1H NMR (300 MHz, CDCl3): d 8.18–8.23 (m, 2H),
7.47–7.52 (m, 2H), 4.92 (d, J = 8.6 Hz, 1H), 3.82 (br, 1H), 2.72–2.78 (m, 1H),
2.48–2.50 (m, 1H), 2.36–2.43 (m, 1H), 2.07–2.09 (m, 1H), 1.89–1.93 (m, 1H),
1.78–1.81 (m, 1H), 1.54–1.60 (m, 1H), 1.33 (m, 1H), 1.05 (d, J = 6.9 Hz, 3H).
The characterizations of Mannich product [68]
Compound: a white solid; tr (major) = 10 min, tr (minor) = 11 min (Chiralcel AD-
H, k = 254 nm, i-PrOH/Hexanes = 20:80, flow rate = 1 mL/min); 1H NMR
123

1078
G. Chen et al.
(300 MHz, CDCl3) d = 2.17 (s, 3H), 2.36 (s, 3H), 4.57 (s, 1H), 4.90–4.93 (d, 1H),
5.73–5.76 (d, 1H), 7.08–7.15 (m, 4H), 7.38–7.41 (d, 2H), 7.46–7.49 (d, 2H), 13C
NMR (75 MHz, CDCl3): d = 21.25, 26.10, 58.97, 79.87, 126.85, 127.79, 129.41,
130.37, 132.16, 138.55, 142.64, 209.63. MS (ESI) m/z: calcd. for: C17H18N2O6S
378.09, found 378.40.
General procedure for large-scale aldol reactions
Method A: A mixture of organocatalyst 1c/TfOH (10 mol %) and ketone (20 mmol)
was stirred in the presence of water (20 mL) at room temperature. Method B: A mixture
of organocatalyst 1c (10 mol %), ketone (40 mL), and TfOH (10 mol %) was stirred
without solvent at room temperature. To this, an aldehyde (20 mmol) was added after
30 min and the reaction mixture was stirred and the progress of the reaction was
monitored by TLC. After completion of the reaction, the reaction mixture was
partitioned between a saturated solution of ammonium chloride and dichloromethane.
The organic layer was separated and dried over anhydrous Na2SO4. It was purified over
silica gel by column chromatography to obtain the pure product. The chromatography
purified aldol products were then examined by HPLC to determine ee value.
General procedure for Mannich reaction of hydroxyacetone with N-tosylimine
A mixture of organocatalyst 1c/TfOH (10 mol%) and N-tosylimine (0.25 mmol) was
stirred in MeOH (1 mL) at room temperature. To this, a hydroxyacetone (1 mmol) was
added after 30 min and the reaction mixture was stirred and the progress of the reaction
was monitored by TLC. After completion of the reaction, an amount of ethyl acetate
and a few drops of dilute hydrochloric acid were added. It was purified over silica gel
by column chromatography to obtain the pure product. The chromatography purified
Mannich products were then examined by HPLC to determine ee value.
General procedure for large-scale Mannich reactions
A mixture of organocatalyst 1c/TfOH (10 mol%) and N-tosylimine (20 mmol) was
stirred in CH3OH (80 mL) at room temperature. To this, a hydroxyacetone
(80 mmol) was added after 30 min and the reaction mixture was stirred and the
progress of the reaction was monitored by TLC. After completion of the reaction,
the reaction mixture was partitioned between a saturated solution of ammonium
chloride and dichloromethane. The organic layer was separated and dried over
anhydrous Na2SO4. It was purified over silica gel by column chromatography to
obtain the pure product. The chromatography purified aldol products were then
examined by HPLC to determine ee value.
Results and discussion
In this work, a series of novel diamines (1c–f) and a known diamine (1b) were
synthesized by coupling of bromides and phthalic anhydride monoprotected (1S,
123

Chiral primary–tertiary diamine-Brønsted acid salt organocatalyst
1079
2S)- and (1R, 2R)-cyclohexyldiamine followed by deprotection with NH2NH2/
EtOH, easily prepared in a few steps from inexpensive, commercially available,
enantiopure materials.
The catalytic activities for the asymmetric direct aldol reaction were investigated
by performing a model reaction using 4-nitrobenzaldehyde with cyclohexanone in
the presence of water (Method A) and under solvent-free conditions with
conventional magnetic stirring (Method B) at room temperature (Table 1).
As depicted in Table 1 (entries 5, 6), catalyst 1c exhibited high catalytic efficiency,
whereas the different steric configuration 1a–b and 1d–f showed lower diastereose-
lectivities, which suggested that the steric property is essential to maximize the
diastereoselectivities. The catalyst 1e, having an electron-withdrawing group in the
aromatic ring, afforded 5a with good enantioselectivity on the one hand, but low
yield and moderate diastereoselectivity on the other hand (Table 1, entries 9 and 10).
Therefore, we chose 1c as a catalyst for the aldol reaction. Using 1c as catalyst, the
effects of catalyst loading on the reaction of 4-nitrobenzaldehyde and cyclohexanone
were investigated (Table 1, entries 13 and 16). When 5 mol% 1c was used in the
presence of water (Methods A and B), the aldol product could be obtained in low
yield and moderate diastereoselectivities. When 1 equiv of cyclohexanone was used,
the diastereoselectivity and enantioselectivity were not changed in the presence of
water (Method A) or under solvent-free conditions (Method B) (Table 1, entries 15
and 17). The amount of solvent was also investigated: when 1 mL of water was used,
the poor dr and ee value were obtained (entry 14). When 1 mL of cyclohexanone was
used, the aldol product could be obtained in high yield with good stereoselectivity
under solvent-free conditions (entry 18).
Considerations of stereoselectivity and reaction time led us to focus our next
study under the optimal reaction conditions for Methods A and B, as follows:
Method A: ketone (0.5 mmol), aldehyde (0.5 mmol), 1c/TfOH (10 mol %) and H2O
(0.5 mL) at room temperature; Method B: ketone (1 mL), aldehyde (0.5 mmol),
1c/TfOH (10 mol %) at room temperature. Under these conditions, the direct cross-
aldol reaction of other several acceptor aromatic aldehydes with cyclohexanone was
examined in order to study the reaction scope using water as solvent and under
solvent-free conditions (Table 2). It can be seen that a wide range of aromatic
aldehydes can effectively participate in the aldol reactions. From Table 2, we were
able to access aldol adducts 5a–l derived from their corresponding aromatic
aldehydes and cyclohexanone. In general, the reactions between cyclohexanone and
aromatic aldehydes bearing electron-withdrawing substituents furnished b-hydroxy
carbonyl aldol products in good yields (63–98 %) and enantioselectivities (96–98 %
ee for anti-isomer) within 15–80 h (Table 2, entries 1–10, 15, 16). In contrast,
longer reaction times were required for aromatic aldehydes containing an electron-
donating group to give comparatively lower yields (42–87 %), but without decrease
of enantioselectivities. This can be explained in that electron-withdrawing groups
enhance the electrophilicity of carbonyl carbons in aldehydes which facilitates the
reaction, while electron-donating groups lessen the electrophilicity.
We also checked the aldol reactions of other ketones (4-methylcyclohexanone,
cycloheptanone) with aromatic aldehydes using catalyst 1c (10 mol%) (Table 3).
The 4-methylcyclohexanone gave high diastereoselective and good enantioselective
123

1080
G. Chen et al.
Table 1 Aldol reaction of cyclohexanone with 4-nitrobenzaldehyde catalyzed by 1 in the presence of
water (Method A) and under solvent-free conditions (Method B)
CHO
O
O
OH
Catalyst (10 mol%)
TfOH (10 mol%), rt
+
NO2
NO2
3a
4a
5a
Entry
Catalyst
Method
Yield (%)a
Anti/synb
eec
91
1
1a
1a
1b
1b
1c
1c
1d
1d
1e
1e
1f
A
B
A
B
A
B
A
B
A
B
A
B
A
A
A
B
B
B
84
55
60
87
83
75
81
85
17
34
60
65
50
72
81
55
70
93
75:25
77:23
88:12
83:17
99:1
2
85
94
3
4
95
5
98
6
94:6
95
7
78:22
83:17
83:17
81:19
97:3
-96
-95
94
8
9
10
11
12
13d
14f
15e
16d
17e
18g
92
94
1f
82:18
93:7
96
1c
1c
1c
1c
1c
1c
98
98:2
97
99:1
98
93:7
92
95:5
95
99:1
98
Method A: cyclohexanone (1 mmol), aldehyde (0.5 mmol), catalyst/TfOH (0.05 mmol), solvent (0.5 mL)
at room temperature. Method B: cyclohexanone (1 mmol), aldehyde (0.5 mmol), catalyst/TfOH
(0.05 mmol) at room temperature
a
The combined isolated yield of the diastereomers
b
Determined by chiral HPLC analysis, major product is anti
c
Determined by HPLC analysis of the anti product
d
5 mmol% 1c/TfOH was used
e
Cyclohexanone(0.5 mmol) was used
f
1 mL H2O was used
g
Cyclohexanone(1 mL) was used
(Table 3, entries 3 and 4). When cyclopentanone was used as an aldol donor, a good
yield of (58–97 %) with moderate ee (84–90 %) for the anti-isomer was received;
however, the diastereomeric ratio obtained was only (85/15–89/11) anti/syn
(Table 3, entries 1 and 2).
We also investigated the asymmetric direct two-component Mannich reactions of
hydroxyacetone to N-tosylimine in toluene (Table 4). A solvent screening (entries
1–7) was then performed to identify the best reaction conditions. Among the various
123

Chiral primary–tertiary diamine-Brønsted acid salt organocatalyst
1081
Table 2 Results of reaction of various aldehydes with cyclohexanone catalyzed by 1c in the presence of
water (Method A) and under solvent-free conditions (Method B)
O
O
OH
O
Catalyst 1c/TfOH (10 mol%)
R
+
H
R
water or solvent-free , rt
3
4a
5
Entry
R
Product
Method
Time (h)
Yield (%)a
Anti/synb
ee (%)c
1
4-NO2-C6H4
4-NO2-C6H4
2- NO2-C6H4
2- NO2-C6H4
3- NO2-C6H4
3- NO2-C6H4
5a
5a
5b
5b
5c
5c
5d
5d
5e
5e
5f
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
50
35
50
46
55
46
55
15
80
64
90
84
96
84
72
72
96
96
96
96
96
96
96
72
81
93
73
89
85
93
75
98
63
83
70
78
55
71
75
87
62
87
50
68
55
70
42
78
99/1
99/1
94/6
98/2
98/2
98/2
95/5
98/2
98/2
98/2
98/2
99/1
95/5
80/20
99/1
93/7
94/6
93/7
95/5
96/4
95:5
89:11
97/3
95/5
98
98
98
98
97
97
97
96
97
98
94
97
95
94
97
98
94
94
97
95
98
90
96
90
2
3
4
5
6
7
2,4-(NO2)2-C6H4
2,4-(NO2)2-C6H4
4-CF3-C6H4
4-CF3-C6H4
2-Cl-C6H4
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
2-Cl-C6H4
5f
4-Cl-C6H4
5g
5g
5h
5h
5i
4-Cl-C6H4
4-CN-C6H4
4-CN-C6H4
4-Br-C6H4
4-Br-C6H4
4-F-C6H4
5i
5j
4-F-C6H4
5j
3-MeO-C6H4
3-MeO-C6H4
1-naphthyl
1-naphthyl
5k
5k
5l
5l
Method A: cyclohexanone (0.5 mmol), aldehyde (0.5 mmol), catalyst/TfOH (0.05 mmol), water (0.5 mL)
at room temperature. Method B: cyclohexanone (1 mL), aldehyde (0.5 mmol), catalyst/TfOH
(0.05 mmol) at room temperature
a
The combined isolated yield of the diastereomers
Determined by 1H NMR of the crude product and by HPLC
b
c
Determined by chiral HPLC
organic solvents tested, the aprotic solvent obtained satisfactory results, CH3OH
was found to be the best solvent with good yield (up to 95 %), diastereoselectivities
(up to 93:7), and enantioselectivity (up to 97 %) (entry 3). Then, we investigated the
effects of catalyst loading on the reactions of hydroxyacetone with N-tosylimine.
While the use of a relatively large amount (20 mol%) of inexpensive catalyst 1c in
123

1082
G. Chen et al.
Table 3 Reactions of cyclopentanone and 4-methylcyclohexanone with p-nitrobenzaldehyde by 1c
CHO
O
OH
O
Catalyst 1c/TfOH (10 mol%)
R1
+
R1
water or solvent-free , rt
R2
R2
NO2
NO2
5
3a
4
Entry
1
Product
No.
Method
A
Yield (%)a
58
drb
ee (%)c
88
5m
89:11
O
O
O
OH
OH
OH
NO2
2
3
5m
5n
B
A
97
60
85:15
99:1
90
94
NO2
NO2
4
5n
B
89
98:2
96
O
OH
NO2
Method A: ketones (0.5 mmol), aldehyde (0.5 mmol), catalyst/TfOH (0.05 mmol), solvent (0.5 mL) at
room temperature. Method B: ketones (1 mL), aldehyde (0.5 mmol), catalyst/TfOH (0.05 mmol) at room
temperature
a
The combined isolated yield of the diastereomers
b
Determined by chiral HPLC analysis, major product is anti
c
Determined by HPLC analysis of the anti product
our original study may be justified, reducing catalyst loading would certainly
constitute an improvement. Noticeably, when using 10–20 mol% of catalyst 1c, the
reaction was faster but the diastereoselectivity was lower than in the other cases
(entries 3, 8). When the loading of catalyst 1c was reduced to 2 mol% and the
amount of CH3OH was reduced to 1 mL, a good yield (85 %) and a high
diastereoselective (up to 99:1) and enantioselective (up to 99 %) were obtained.
Asymmetric synthesis is dedicated to the preparation of chiral compounds with
defined three-dimensional molecular structures. Its importance is probably best
appreciated in the context of drug–receptor interactions, because most biological
targets are chiral entities. Because of the synthetic versatility of amino carbonyl
compounds, it is of great interest to generate Mannich products with either syn- or
anti-selectivity. In the process of screening solvents, we found an interesting
phenomenon: when using CH3OH as a solvent, the absolute configuration of the
syn-Mannich product was determined to be (3S, 4R), then the use of CH3CN or
n-butanol instead of CH3OH, the absolute configuration of the anti-Mannich product
was determined to be (3R,4R) (Table 5) (See Supplementary Material).
123

Chiral primary–tertiary diamine-Brønsted acid salt organocatalyst
1083
Table 4 Screening of the asymmetric Mannich reactions between hydroxyacetone and N-tosylimine
Ts
Ts
N
O
O
HN
Catalyst 1c/TfOH
CH3OH, r.t.
OH
OH
O2N
NO2
Entry
Catalyst
Solvent
Yield (%)a
dr (syn/anti)b
ee (syn)c
1
10
10
10
10
10
10
20
5
m-xylene
Dioxane
CH3OH
CHCl3
75
95
95
70
94
90
98
90
80
85
52:48
52:48
93:7
63:37
92:8
97:3
91:9
95:5
98:2
99:1
66
53
97
61
97
96
95
97
99
99
2
3
4
6
DMF
7
EtOH
8
CH3OH
CH3OH
CH3OH
CH3OH
9
10
11d
2
2
The reactions were performed with hydroxyacetone (1 mmol), N-tosylimine (0.25 mmol) and catalyst
1c (0.025 mmol) in solvent (2 ml) at room temperature
a
Isolated yield
The syn to anti ratio was determined by 1H NMR analysis of the crude products and by HPLC
b
c
The ee value of the syn-isomer was determined by chiral HPLC analysis
d
1 mL CH3OH was used
Such a switch of the diastereoselectivities of a given catalyst by changes in the
solvent is unusual. It suggests that the conformation of the chiral amine catalyst is
significantly different in the solvents leading to the formation of different chiral
products, which offers a great possibility for obtaining different chiral amino
alcohols.
We first performed a large-scale asymmetric direct two-component syn-Mannich
reaction with 25 mmol of N-tosylimine, and 4 equiv of hydroxyacetone (Fig. 2)
using a 250-mL round-bottomed flask. Although the diastereoselectivity and
enantioselectivity (83 % yield, 99 % ee, 99:1 dr) were maintained at the same level
for the large-scale reaction, the main limitation associated with syn-Mannich
reaction is the requirement of a low catalyst loading of 1c/TfOH (0.44 g, 2 mol%).
This will raise a cost concern when large amounts of chiral materials are used for a
large-scale synthesis in practical applications.
We further performed large-scale asymmetric aldol reactions, as follows: Method
A: ketone (20 mmol), aldehyde (20 mmol), 1c/TfOH (10 mol%) and H2O (20 mL)
at room temperature; Method B: ketone (40 mL), aldehyde (20 mmol), 1c/TfOH
(10 mol%) at room temperature. The large-scale experiments can be readily carried
out using the same procedure as for the experimental scale reactions. As can be seen
from the results summarized in Table 6, delightfully, the enantioselectivity was
maintained at the same level for the large-scale reactions.
123

1084
G. Chen et al.
Table 5 Direct asymmetric Mannich reactions hydroxyacetone and N-tosylimine in various solvents,
catalyzed by 1c
Ts
Ts
N
O
O
HN
catalyst 1c, 2 mol%
CH3OH, r.t.
OH
OH
O2N
NO2
Entry
1
Product
Solvent
CH3OH
Yield (%)a
85
dr (anti/syn)b
1:99
ee (%)c
99
Ts
O
O
O
HN
OH
NO2
2
3
CH3CN
70
80
68:32
65:35
72
70
Ts
Ts
HN
OH
NO2
n-Butanol
HN
OH
NO2
The reactions were performed with hydroxyacetone (1 mmol), N-tosylimine (0.25 mmol) and catalyst
1c (0.005 mmol) in the solvent (1 ml) at room temperature
a
Isolated yield
The anti to syn ratio was determined by 1H NMR analysis of the crude products and by HPLC
b
c
The ee value was determined by chiral HPLC analysis
Ts
Ts
O
N
O
HN
cat. 1c 2 mol-% 0.44g
OH
CH3OH(100mL), r.t. 36h
OH
O2N
NO2
6.9 mL
7.6 g
7.852 grams prepared.
(4 equiv.)
(1 equiv.)
83 % yield, 99% ee, 99:1 dr
Fig. 2 Large-scale example of enantioselective syn-Mannich reaction
Conclusion
In summary, the catalysts can be easily prepared in a few steps from inexpensive,
commercially available, enantiopure materials. The diamine 1c is a robust and
effective catalyst for direct aldol reactions with high diastereo- and enantioselec-
tivities in the presence of water and under solvent-free conditions, which meet the
demand of atom-economical and green chemistry. It was also used to catalytic
123

Chiral primary–tertiary diamine-Brønsted acid salt organocatalyst
1085
Table 6 Large-scale asymmetric aldol reactions
CHO
O
O
OH
Catalyst 1c/TfOH (10 mol%)
R1
+
R1
water or solvent-free , rt
R2
R2
NO2
NO2
5
3a
4
Entry
1
Product
Method
Time (h)
50
Yield (%)a
78
Anti/synb
ee (%)c
A
B
A
[99:1
[98
O
OH
OH
OH
NO2
NO2
2
3
50
50
83
51
92:8
93:7
98
88
O
O
NO2
NO2
4
B
50
85
80:20
89
O
OH
Method A: ketones (20 mmol), aldehyde (20 mmol),catalyst 1c/TfOH (2 mmol), solvent (20 mL) at room
temperature. Method B: ketones (40 mL), aldehyde (20 mmol), catalyst 1c/TfOH (2 mmol) at room
temperature
a
The combined isolated yield of the diastereomers
b
Determined by chiral HPLC analysis, major product is anti
c
Determined by HPLC analysis of the anti product
asymmetric two-component syn-Mannich reaction with good results. Notably, these
organocatalyzed direct asymmetric anti-aldol and syn-Mannich reactions can be
performed on a large scale with the enantioselectivity being maintained at the same
level, which offers a great possibility for application in industry.
Acknowledgment Authors are grateful to Southwest University of China for financial support.
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