Asymmetric organocatalytic direct aldol reactions of cyclohexanone with aldehydes in brine

Article abstract of DOI:10.1139/V07-012

Organocatalytic asymmetric direct aldol reactions in brine with high diastereo- and enantioselectivities, using a readily available bifunctional amide catalyst, were developed.

Full text of DOI:10.1139/V07-012

2
08
Asymmetric organocatalytic direct aldol reactions
of cyclohexanone with aldehydes in brine
Wen-Ping Huang, Jia-Rong Chen, Xin-Yong Li, Yi-Ju Cao, and Wen-Jing Xiao
Abstract: Organocatalytic asymmetric direct aldol reactions in brine with high diastereo- and enantioselectivities, using
a readily available bifunctional amide catalyst, were developed.
Key words: aldol reaction, organocatalyst, asymmetric catalysis, water.
Résumé : Opérant dans de la saumure et faisant appel à un amide bifonctionnel facilement disponible comme cataly-
seur organique, on a développé des réactions aldoliques directes et asymétriques qui se produisent avec des diastéréo-
et énantiosélectivités élevées.
Mots-clés : réaction aldolique, catalyse organique, catalyse asymétrique, eau.
[
Traduit par la Rédaction] Huang et al. 213
Introduction
proline-catalyzed intramolecular aldol reaction presented by
Eder et al. (6a) and Hajos and Parrish (6b), List and co-
workers described fundamental work on proline-catalyzed
asymmetric intermolecular aldol reactions of ketones and al-
dehydes (7). After that, there has been a large amount of re-
search activities in this field (8), which has resulted in the
development of asymmetric organocatalysis. Although water
as an additive has a certain positive effect on organocatalytic
aldol reactions (9), the use of a large amount of water or
aqueous buffer as solvent has been found to be detrimental
in some cases (10). Recently, studies by Mase and co-
workers (11a), Hayashi and co-workers (11b, 11c), Dziedzic
and co-workers (11d), and Wu and co-workers (11e) re-
vealed the possibility to carry out enantioselective direct
aldol reactions in water, along or together with organic sol-
vents, by the design and use of new organocatalysts (Scheme 1).
Part of our ongoing project aimed at developing readily
available bifunctional organocatalysts of broad utility to chemi-
cal transformations and with industrial potential (8j, 9d).
Thus, we were interested in applying our artificial bifunctional
amine catalysts 3 and 4 to aldol reactions in brine.
Water, the essential medium for the construction of chem-
ical bonds in life, was widely accepted as “a contaminant in
organic synthesis”. Unless water is used as a reactant, the
use of water was usually avoided in reaction systems. Never-
theless, Breslow and co-workers investigated Diels–Alder re-
actions in water in 1980s, and it was found that water could
remarkably increase the reaction rate and selectivities (1).
Since then, there has been considerable efforts to develop or-
ganic reactions, using water as an additive or a solvent in-
stead of conventional organic solvents, with respect to
environmental concerns, safety, and cost (2, 3). In contrast,
there have been relatively few investigations using brine as
the reaction media (4), although the reaction efficiency in
brine may be superior to that in water. Herein, we report
organocatalytic direct aldol reactions of cyclohexanone with
aldehydes in brine, using our bifunctional organocatalyst 4e.
The reactions afforded the desired products in high yields
and in excellent diastereo- and enantioselectivities.
Organocatalysis, primarily because of the operational sim-
plicity, the cheap catalyst, and the potential industrial appli-
cations, has received renewed attention and became the
focus of intensive research endeavor (5). In 2000, almost
three decades after the first report of enantioselective
Results and discussion
The efficiency of our bifunctional catalysts was first eval-
uated with the direct asymmetric aldol reaction in water. Re-
action of 4-nitrobenzaldehyde with cyclohexanone was
performed in the presence of 20 mol% of catalyst 3 and
Received 12 December 2006. Accepted 9 February 2007.
Published on the NRC Research Press Web site at
http://canjchem.nrc.ca on 27 March 2007.
2
0 mol% of acetic acid (HOAc) (co-catalyst) at room tem-
perature in 1 mL of water, and the aldol product 7a (Fig. 1)
was afforded in 89% yield, with 88% enantiomeric excess
(ee) and a diastereomeric ratio (dr) of 92:8 (Table 1, entry
1). Encouraged by this result, we further examined the cata-
lytic efficiency of the chiral amides 4a–e in the presence of
various acid additives (12). Notably, all the reactions with
bifunctional catalysts 3 and 4a–e proceed smoothly with
good diastereo- and enantioselectivities, and 4e shows the
best catalytic activity with HOAc as the co-catalyst (Table 1,
entries 1–10). Lowering the temperature to 0 °C further im-
W.-P. Huang. Key Laboratory of Pesticide and Chemical
Biology, Ministry of Education, College of Chemistry,
Central China Normal University, 152 Luoyu Road, Wuhan,
Hubei 430079, China; Department of Chemistry, Xianning
College, Xianning, Hubei 437000, China.
1
J.-R. Chen, X.-Y. Li, Y.-J. Cao, and W.-J. Xiao. Key
Laboratory of Pesticide and Chemical Biology, Ministry of
Education, College of Chemistry, Central China Normal
University, 152 Luoyu Road, Wuhan, Hubei 430079, China.
1Corresponding author (e-mail: wxiao@mail.ccnu.edu.cn).
Can. J. Chem. 85: 208–213 (2007)
doi:10.1139/V07-012
© 2007 NRC Canada

Huang et al.
209
Scheme 1. Privileged organocatlaysts examined for aldol reaction in water.
Fig. 1. Proposed transition state.
Table 1. Screening of catalysts in the direct aldol reaction of
cyclohexanone and p-nitrobenzaldehyde.
proves the dr from 89:11 to 92:8, although the product suf-
fered a slight decrease of ee (Table 1, entry 11). The use of
brine as solvent was remarkable in our catalytic system, and
diasteroselectivity reached 95:5 (Table 1, entry 12). There-
fore, brine was chosen as the solvent for further optimiza-
tion. The chiral amide – acid combinations were also
evaluated in different ratios, and the best ratio of catalyst 4e
to HOAc was 1:2 (Table 1, entries 12–15). The superior levels
of asymmetric induction and efficiency, exhibited by the
amide 4e – HOAc in brine affording the aldol adduct 7a in
9
2% yield with 93% ee and 95:5 dr, prompted us to select
these catalytic conditions for further investigation (Table 1,
entry 14).
Using these optimized conditions, reactions of cyclo-
hexanone with various aldehydes, catalyzed by 4e in brine,
were then examined. As summarized in Table 2, the aro-
matic aldehydes 6a–i reacted well with 5, and the aldol ad-
ducts 7a–i formed in high yields with high diastereo- and
enantioselectivities (Table 2, entries 1 and 4–11). The only
exception is the case of benzaldehyde, in which the ee was
Note: Unless otherwise shown, the reaction was conducted with catalyst
0.1 mmol), additive (if used, 0.1 mmol), p-nitrobnezaldehyde (0.5 mmol)
and cyclohexanone (2.5 mmol) in water (1.0 mL).
8
3%, and the dr was 85:15 (Table 2, entry 12). Hetero-
(
aromatic aldehydes, such as 6k, could also be successfully
employed in this reaction with a lower yield of 43%
a
Yield of the isolated product.
Determined by H NMR spectroscopy.
b
c
1
(
Table 2, entry 13). Notably, the reaction can still proceed
Determined by chiral-phase HPLC analysis for anti-product.
well with little loss in selectivity even when the catalyst
loading was reduced to 5 mol%, or only 2 equiv. of ketone
was used (Table 2, entries 2 and 3).
d
D-(+)-10-Camphorsulfonic acid.
e
f
The reaction was peformed at 0 °C.
Brine (1 mL) was used as solvent.
g
The scope of this class of aldol reactions was also ex-
tended to a series of other ketone donors (Table 3). The reac-
tion with the water-miscible ketone 6m affords the aldol
40 mol% HOAc was used.
80 mol% HOAc was used.
h
©
2007 NRC Canada

2
10
Can. J. Chem. Vol. 85, 2007
Table 2. Catalyst (4e–HOAc)-catalyzed direct aldol reactions of
Table 3. Catalyst (4e–HOAc)-catalyzed direct aldol reactions of
5 with aldehydes 6a in brine.
5
a with aldehydes 6 in brine.
Note: The reaction was performed with 4e (0.1 mmol), HOAc
0.2 mmol), aldehyde (0.5 mmol), and cyclohexanone (2.5 mmol) in brine
(
at 0 °C for the indicated time.
a
Yield of the isolated product.
Determined by H NMR spectroscopy.
b
c
1
Determined by chiral-phase HPLC analysis for anti-product.
d
1
0 equiv. of acetone was used.
e
The aldol adduct, occured at the C1 position, was obtained with 19%
yield.
f
The ee of syn-product is 55%.
perspective, this is the real organocatalyzed aldol reaction in
water (In Hayashi’s catalytic system, 300 mol% water was
used as solvent (11b)).
[
1]
Note: The reaction was performed with 4e (0.1 mmol), HOAc
0.2 mmol), aldehyde (0.5 mmol), and cyclohexanone (2.5 mmol) in brine
(
at 0 °C for the indicated time.
a
Yield of the isolated product.
Determined by H NMR spectroscopy.
b
c
1
Determined by chiral-phase HPLC analysis for anti-product.
d
5
mol% of the catalyst was used.
e
Experimental section
2
equiv. of cyclohexanone was used.
General methods
Unless otherwise noted, commercial reagents were used
as received. Hexane and ethyl acetate, for flash column chro-
matography, were distilled before use. Flash column chro-
matography was performed using 200–300 mesh silica gel.
adduct in good yield with high diastereo- and enantio-
selectivity, while moderate results were obtained with ace-
tone as donor (Table 3, entries 1, 2). Significantly, the reaction
preferentially occurred at the C3 position of butanone. To
our surprise, although the reaction of cyclopentanone af-
forded the syn-diastrereomer as maojor product with 55% ee,
the ee for the anti-adduct is still up to 92% (Table 3, entry 3).
Interestingly, the absolute configuration of the major aldol
1
H NMR spectra were recorded on Varian Mercury 400
(
400 MHz) spectrophotometers. Chemical shifts are reported
in ppm from the solvent resonance, as the internal standard
CDCl : 7.26 ppm). Data are reported as follows: chemical
(
3
1
shift, multiplicity (s = single, d = doublet, t = triplet, q =
quartet, br = broad, and m = multiplet), coupling constants
adduct 7a was determined to be (2R,1S) by H NMR spec-
troscopic analysis and comparison of HPLC retention time
with literatures (11). Thus, we proposed that 4e–HOAc cata-
lyzed a Si-face of enamine attack on Si-face of the aryl-
aldehyde. Notably, this result showed completely different
transition-state model from the previously proposed L-proline-
based aldol transition state (13) and recent Barbas and
Hayashi’s experiments (11). This unusual π-facial differenti-
ation of enamine may be affected by the two-hydrogen-bond
bearing chiral diaminocyclohexane backbone. Further stud-
ies on the mechanism are underway.
1
3
(
Hz), and integration. C NMR spectra were recorded on
Varian Mercury 400 (100 MHz) spectrophotometers with
complete proton decoupling (CDCl : 77.0 ppm). Chiral
3
HPLC was performed on Agilent 1100 series with chiral col-
umns (Chirapak AS, AD, OD, and OJ columns; Daicel
Chemical Ind. Ltd.). Catalysts 3 and 4 were prepared by the
previously described methods (8j).
Typical procedure for aldol reaction using the bifunctional
catalyst 4e–HOAc in brine (Table 1, entry 14)
To a mixture of catalyst 4e (33 mg, 0.10 mmol),
cyclohexanone (0.26 mL, 2.5 mmol), and brine (1 mL), ace-
tic acid (11.6 µL, 0.20 mmol) was added at 0 °C. The reac-
We have also found that this process is appropriate for
gram-scale reactions, eventhough the catalyst loading is only
5
mol%, and water is 5500 mol%. The diastereo- and stereo-
selectivities are excellent (see eq. [1]). From a green-chemistry
©
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Huang et al.
211
tion mixture was stirred for 10 min in a closed system, and
then p-nitrobenzaldehyde (76 mg, 0.5 mmol) was added.
The reaction mixture was stirred for 7 h, then the reaction
was quenched by the addition of saturated ammonium chlo-
ride solution and extracted three times with ethyl acetate
CDCl , δ): 1.47–2.08 (m, 6H), 2.33–2.43 (m, 2H), 2.80–2.84
3
(m, 1H), 3.70 (s, 1H), 5.92 (d, J = 2.0 Hz, 1H), 7.38 (t, J =
8.4 Hz, 1H), 7.60 (t, J = 7.2 Hz, 1H), 7.80 (d, J = 7.6 Hz,
1
3
1H), 7.94 (d, J = 8.4 Hz, 1H). C NMR (100 MHz, CDCl3,
δ): 24.7, 26.3, 27.2, 42.3, 54.8, 66.3, 124.5, 127.8, 129.5,
133.0, 137.1, 213.7. HPLC (Chiralcel OD-H, Hexane–i-
(
3 mL). The mixture of combined organic phases was stirred
over anhydr. MgSO , filtered, and concentrated to give pure
PrOH (95:5), 1.0 mL/min, 254 nm, 20 °C): t = 24.7 min
4
R
aldol adduct 7a, as white solid, through column chromatog-
raphy on silica gel (hexane – ethyl acetate (3:1)). The
enantiomeric excess (ee) of 7a was determined by chiral-
phase HPLC analysis.
and t = 27.2 min.
R
2
-[Hydroxy-(4-cyano-phenyl)-methyl]-cyclohexanone (7d)
Yield: 86%; anti:syn (91:9). Anti-diastereomer: H NMR
1
(
400 MHz, CDCl , δ): 1.31–2.11 (m, 6H), 2.30–2.48 (m,
3
2
-[Hydroxy-(4-nitro-phenyl)-methyl]-cyclohexanone (7a)
Yield: 92%; anti:syn (95:5). Anti-diastereomer: H NMR
2H), 2.53–2.59 (m, 1H), 4.07 (s, 1H), 4.82 (d, J = 8.4 Hz,
1H), 7.43 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.0 Hz, 2H).
1
13
C
(
2
1
400 MHz, CDCl , δ): 1.29–2.09 (m, 6H), 2.30–2.47 (m,
NMR (100 MHz, CDCl , δ): 24.6, 27.6, 30.6, 42.5, 57.0,
3
3
H), 2.55–2.61 (m, 1H), 4.10 (s, 1H), 4.87 (d, J = 8.4 Hz,
74.0, 111.5, 118.6, 127.7, 132.1, 146.3, 214.7. HPLC
(Chiralcel OD-H, Hexane–i-PrOH (95:5), 1.0 mL/min,
220 nm, 20 °C): t = 47.6 min (minor) and t = 60.8 min
1
3
H), 7.48 (t, J = 8.0 Hz, 1H), 8.16 (d, J = 8.4 Hz, 2H).
C
NMR (100 MHz, CDCl , δ): 24.5, 27.5, 30.6, 42.5, 57.0,
7
3
R
R
1
3.8, 123.4, 127.8, 147.4, 148.4, 214.6. HPLC (Chiralcel
(major), ee: 91%. Syn-diastereomer: H NMR (400 MHz,
AD-H, Hexane–i-PrOH (95:5), 1.0 mL/min, 254 nm, 20 °C):
t = 49.5 min (minor) and t = 67.6 min (major), ee = 93%.
CDCl , δ): 1.52–2.12 (m, 6H), 2.33–2.48 (m, 2H), 2.57–2.61
3
(m, 1H), 3.19 (s, 1H), 5.42 (s, 1H), 7.42 (d, J = 8.0 Hz, 2H),
R
R
1
13
Syn-diastereomer: H NMR (400 MHz, CDCl , δ): 1.50–2.13
(
1
(
2
2
1
4
7.62 (d, J = 8.4 Hz, 2H). C NMR (100 MHz, CDCl , δ):
3
3
m, 6H), 2.39–2.50 (m, 2H), 2.61–2.65 (m, 1H), 3.20 (s,
H), 5.48 (d, J = 2.0 Hz, 1H), 7.48 (d, J = 8.8 Hz, 2H), 8.20
24.7, 25.8, 27.8, 42.5, 56.7, 70.1, 110.7, 118.8, 126.5, 132.0,
147.0, 214.1. HPLC (Chiralcel OD-H, Hexane–i-PrOH
(95:5), 1.0 mL/min, 220 nm, 20 °C): t = 32.6 min and t =
d, J = 8.8 Hz, 2H). 13C NMR (100 MHz, CDCl , δ): 24.7,
3
R
R
5.9, 27.8, 42.6, 56.7, 70.1, 123.4, 126.6, 147.0, 149.1,
40.1 min.
14.1. HPLC (Chiralcel AD-H, Hexane–i-PrOH (95:5),
.0 mL/min, 254 nm, 20 °C): tR = 35.2 min and tR
=
2-[Hydroxy-(4-bromo-phenyl)-methyl]-cyclohexanone
4.3 min.
(7e)
1
Yield: 84%; anti:syn (97:3). Anti-diastereomer: H NMR
(400 MHz, CDCl3, δ): 1.24–2.08 (m, 6H), 2.28–2.37 (m,
2H), 2.43–2.57 (m, 1H), 3.40 (s, 1H), 4.73 (d, J = 8.4 Hz,
2
-[Hydroxy-(3-nitro-phenyl)-methyl]-cyclohexanone (7b)
1
Yield: 91%; anti:syn (96:4). Anti-diastereomer: H NMR
1H), 7.18 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H). 13
C
(
2
1
(
(
1
(
2
(
400 MHz, CDCl , δ): 1.33–2.10 (m, 6H), 2.32–2.48 (m,
3
H), 2.58–2.64 (m, 1H), 4.14 (s, 1H), 4.87 (d, J = 8.4 Hz,
H), 7.50 (t, J = 8.0 Hz, 1H), 7.64 (t, J = 7.6 Hz, 1H), 8.12
NMR (100 MHz, CDCl3, δ): 24.6, 27.6, 30.6, 42.5, 57.2,
74.0, 121.6, 128.6, 131.3, 140.0, 215.1. HPLC (Chiralcel
OD-H, Hexane–i-PrOH (95:5), 1.0 mL/min, 220 nm, 20 °C):
tR = 24.0 min (minor) and tR = 28.6 min (major), ee: 93%.
1
3
d, J = 7.6 Hz, 1H), 8.18 (d, J = 1.6 Hz, 1H). C NMR
100 MHz, CDCl , δ): 24.5, 27.5, 30.6, 42.5, 57.0, 73.8,
3
1
21.9, 122.7, 129.2, 133.1, 143.2, 148.1, 214.7. HPLC
Syn-diastereomer: H NMR (400 MHz, CDCl3, δ): 1.46–2.08
Chiralcel AD-H, Hexane–i-PrOH (95:5), 1.0 mL/min,
54 nm, 20 °C): t = 37.3 min (major) and t = 48.4 min
(m, 6H), 2.30–2.45 (m, 2H), 2.50–2.56 (m, 1H), 3.04 (s,
1H), 5.31 (d, J = 2.4 Hz, 1H), 7.12 (d, J = 8.4 Hz, 2H), 7.44
R
R
1
13
minor), ee = 96%. Syn-diastereomer: H NMR (400 MHz,
(d, J = 8.4 Hz, 2H). C NMR (100 MHz, CDCl3, δ): 24.7,
CDCl , δ): 1.48–2.10 (m, 6H), 2.33–2.46 (m, 2H), 2.62–2.66
25.8, 27.8, 42.5, 56.9, 70.0, 120.6, 127.5, 131.1, 140.5,
214.4. HPLC (Chiralcel OD-H, Hexane–i-PrOH (95:5),
1.0 mL/min, 220 nm, 20 °C): tR = 13.7 min and tR =
16.9 min.
3
(
m, 1H), 3.27 (s, 1H), 5.44 (d, J = 2.0 Hz, 1H), 7.48 (t, J =
8
1
2
1
.0 Hz, 1H), 7.64 (t, J = 7.6 Hz, 1H), 8.06 (t, J = 6.0 Hz,
H); 8.15 (s, 1H). 13C NMR (100 MHz, CDCl , δ): 24.6,
3
5.8, 27.7, 42.4, 56.6, 69.7, 120.8, 121.9, 129.0, 131.9,
43.9, 148.1, 214.0. HPLC (Chiralcel AD-H, Hexane–i-
2-[Hydroxy-(3-bromo-phenyl)-methyl]-cyclohexanone (7f)
1
PrOH (95:5), 1.0 mL/min, 254 nm, 20 °C): t = 29.9 min
Yield: 76%; anti:syn (94:6). Anti-diastereomer: H NMR
R
and t = 32.6 min.
(400 MHz, CDCl , δ): 1.35–2.31 (m, 6H), 2.11–2.49 (m,
R
3
2
1
H), 2.54–2.60 (m, 1H), 4.04 (s, 1H), 4.74 (d, J = 8.8 Hz,
H), 7.18–7.24 (m, 2H), 7.41–7.49 (m, 2H). 13C NMR
2
-[Hydroxy-(2-nitro-phenyl)-methyl]-cyclohexanone (7c)
Yield: 85%; anti:syn (99:1). Anti-diastereomer: H NMR
1
(100 MHz, CDCl , δ): 24.6, 27.6, 30.7, 42.6, 57.2, 74.1,
3
1
(
2
22.5, 125.7, 129.8, 129.9, 130.9, 143.3, 215.1. HPLC
Chiralcel OD-H, Hexane–i-PrOH (90:10), 0.5 mL/min,
20 nm, 20 °C): t = 18.1 min (major) and t = 23.5 min
(
2
1
(
(
1
400 MHz, CDCl , δ): 1.51–1.78 (m, 6H), 2.25–2.40 (m,
3
H), 2.69–2.75 (m, 1H), 4.04 (s, 1H), 5.39 (d, J = 7.2 Hz,
H), 7.37 (t, J = 8.0 Hz, 1H), 7.57 (t, J = 7.6 Hz, 1H), 7.70
R
R
d, J = 8.0 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H). 1 C NMR
3
(minor), ee: 90%. Syn-diastereomer: HPLC (Chiralcel OD-
H, Hexane–i-PrOH (90:10), 1.0 mL/min, 220 nm, 20 °C): t =
100 MHz, CDCl , δ): 24.7, 27.6, 30.8, 42.5, 57.1, 69.3,
R
3
1
5.1 min and t = 16.6 min.
23.8, 128.2, 128.9, 132.9, 136.3, 148.6, 214.5. HPLC
R
(
2
(
Chiralcel OD-H, Hexane–i-PrOH (95:5), 1.0 mL/min,
54 nm, 20 °C): t = 37.6 min (major) and t = 45.9 min
minor), ee = 96%. Syn-diastereomer: H NMR (400 MHz,
2-[Hydroxy-(4-chloro-phenyl)-methyl]-cyclohexanone (7g)
Yield: 80%; anti:syn (95:5). Anti-diastereomer: H NMR
R
R
1
1
©
2007 NRC Canada

2
12
Can. J. Chem. Vol. 85, 2007
(
2
1
400 MHz, CDCl , δ): 1.26–2.11 (m, 6H), 2.31–2.49 (m,
(Chiralcel OD-H, Hexane–i-PrOH (90:10), 1.0 mL/min,
220 nm, 20 °C): t = 18.2 min (major) and t = 26.5 min
(minor), ee: 83% Syn-diastereomer: H NMR (400 MHz,
3
H), 2.52–2.59 (m, 1H), 3.61 (s, 1H), 4.76 (d, J = 8.4 Hz,
R
R
1
3
1
H), 7.25 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.8 Hz, 2H).
C
NMR (100 MHz, CDCl , δ): 24.6, 27.2, 30.7, 42.6, 57.3,
CDCl , δ): 1.48–2.10 (m, 6H), 2.32–2.47 (m, 2H), 2.57–2.62
3
3
1
3
7
4.0, 128.3, 128.4, 133.5, 139.5, 215.2. HPLC (Chiralcel
(m, 1H), 5.39 (d, J = 2.4 Hz, 1H), 7.23–7.35 (m, 5H).
C
OD-H, Hexane–i-PrOH (95:5), 1.0 mL/min, 220 nm, 20 °C):
t = 22.1 min (minor) and t = 26.0 min (major), ee: 92%.
NMR (100 MHz, CDCl , δ): 24.8, 26.0, 27.9, 42.6, 57.1,
3
70.6, 125.7, 126.9, 128.1, 141.4, 214.8. HPLC (Chiralcel
OD-H, Hexane–i-PrOH (90:10), 1.0 mL/min, 220 nm,
20 °C): t = 14.7 min and t = 16.2 min.
R
R
1
Syn-diastereomer: H NMR (400 MHz, CDCl , δ): 1.49–2.09
3
(
1
(
2
2
1
1
m, 6H), 2.32–2.46 (m, 2H), 2.53–2.57 (m, 1H), 2.92 (s,
H), 5.34 (d, J = 2.0 Hz, 1H), 7.23 (d, J = 8.4 Hz, 2H), 7.30
R
R
d, J = 8.4 Hz, 2H). 13C NMR (100 MHz, CDCl , δ): 24.8,
3
2
-(Furan-2-yl-hydroxy-methyl)-cyclohexanone (7k)
Yield: 43%; anti/syn (89:11). Anti-diastereomer: H NMR
5.9, 27.8, 42.6, 57.0, 70.0, 127.1, 128.2, 132.6, 140.0,
14.5. HPLC (Chiralcel OD-H, Hexane–i-PrOH (95:5),
1
(
400 MHz, CDCl , δ): 1.30–2.10 (m, 6H), 2.34–2.46 (m,
.0 mL/min, 220 nm, 20 °C): tR = 13.5 min and tR
=
3
2
8
1
H), 2.88–2.90 (m, 1H), 3.90 (d, J = 3.6 Hz, 1H), 4.81 (d, J =
6.6 min.
.4 Hz, 1H), 6.26 (d, J = 3.2 Hz, 1H), 6.30 (q, J = 2.8 Hz,
1
3
H), 7.36 (d, J = 1.2 Hz, 1H). C NMR (100 MHz, CDCl3,
2
-[Hydroxy-(2-chloro-phenyl)-methyl]-cyclohexanone (7h)
Yield: 82%; anti:syn (99:1). Anti-diastereomer: H NMR
1
δ): 24.6, 27.7, 30.5, 42.5, 54.8, 68.1, 107.9, 110.0, 142.2,
53.5, 214.9. HPLC (Chiralcel AD-H, Hexane–i-PrOH
95:5), 1.0 mL/min, 220 nm, 20 °C): t = 25.8 min (major)
1
(
2
1
(
(
1
400 MHz, CDCl , δ): 1.51–2.09 (m, 6H), 2.28–2.46 (m,
3
(
R
H), 2.63–2.70 (m, 1H), 3.92 (s, 1H), 5.34 (d, J = 8.0 Hz,
H), 7.19 (t, J = 7.6 Hz, 1H), 7.28 (d, J = 7.6 Hz, 1H), 7.31
1
and t = 28.6 min (minor), ee: 86%. Syn-diastereomer: H
R
1
3
NMR (400 MHz, CDCl3, δ): 1.61–2.10 (m, 6H), 2.34–2.45
d, J = 8.0 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H). C NMR
(
(
2
m, 2H), 2.78–2.82 (m, 1H), 3.11 (d, J = 4.8 Hz, 1H), 5.26
t, J = 3.6 Hz, 1H), 6.26 (d, J = 2.8 Hz, 1H), 6.30 (q, J =
.8 Hz, 1H), 7.33 (d, J = 1.6 Hz, 1H). C NMR (100 MHz,
100 MHz, CDCl , δ): 24.8, 27.7, 30.3, 42.6, 57.5, 70.3,
3
27.1, 128.2, 128.6, 129.1, 132.8, 139.0, 215.1. HPLC
1
3
(
2
(
Chiralcel AD-H, Hexane–i-PrOH (95:5), 1.0 mL/min,
20 nm, 20 °C): t = 17.2 min (major) and t = 19.7 min
minor), ee: 91%. Syn-diastereomer: H NMR (400 MHz,
CDCl , δ): 24.7, 27.2, 27.5, 42.4, 54.5, 66.5, 106.5, 110.2,
3
R
R
1
141.4, 154.6, 213.6. HPLC (Chiralcel AD-H, Hexane–i-
PrOH (95:5), 1.0 mL/min, 220 nm, 20 °C): t = 17.8 min
R
CDCl , δ): 1.49–2.10 (m, 6H), 2.35–2.48 (m, 2H), 2.78–2.83
3
and t = 19.5 min.
R
(
m, 1H), 3.16 (s, 1H), 5.71 (d, J = 1.2 Hz, 1H), 7.19 (t, J =
8
1
.0 Hz, 1H), 7.27 (d, J = 4.4 Hz, 1H), 7.31 (d, J = 8.0 Hz,
H), 7.56 (d, J = 8.0 Hz, 1H). 1 C NMR (100 MHz, CDCl3,
3
4-Hydroxy-3-methyl-4-(4-nitro-phenyl)-butan-2-one (7m)
δ): 24.7, 25.8, 27.8, 42.5, 53.5, 67.5, 126.5, 128.1, 128.4,
29.1, 130.7, 138.6, 214.5. HPLC (Chiralcel AD-H,
Hexane–i-PrOH (95:5), 1.0 mL/min, 220 nm, 20 °C): t =
1
Yield: 55%; anti/syn (97:3). Anti-diastereomer: H NMR
1
(
400 MHz, CDCl , δ): 1.01 (d, J = 7.6 Hz, 3H), 2.21 (s, 3H),
3
R
2.87–2.94 (m, 1H), 3.34 (d, J = 4.8 Hz, 1H), 4.87 (d, J =
8.0 Hz, 1H), 7.51 (d, J = 8.4 Hz, 2H), 8.21 (d, J = 8.8 Hz,
9
.0 min and t = 10.2 min.
R
1
3
2
H). C NMR (100 MHz, CDCl , δ): 14.1, 29.7, 53.2, 75.4,
3
2
-[Hydroxy-(2,4-dichloro-phenyl)-methyl]-cyclohexanone
123.7, 127.5, 147.5, 149.3, 212.8. HPLC (Chiralcel AS-H,
(
7i)
Hexane–i-PrOH (93:7), 1.0 mL/min, 254 nm, 20 °C): t =
R
1
Yield: 88%; anti:syn (99:1). Anti-diastereomer: H NMR
51.1 min (major) and tR = 75.9 min (minor). Syn-
diastereomer: HPLC (Chiralcel AS-H, Hexane–i-PrOH
(93:7), 1.0 mL/min, 254 nm, 20 °C): t = 47.6 min and t =
(
2
400 MHz, CDCl , δ): 1.53–2.11 (m, 6H), 2.33–2.48 (m,
3
H), 2.61–2.64 (m, 1H), 4.09 (d, J = 4.0 Hz, 1H), 5.28 (d,
R
R
2
J = 8.0 Hz, 1H), 7.27–7.35 (d, J = 8.0 Hz, 2H), 7.49 (d, J =
66.8 min.
1
3
8
3
1
.8 Hz, 1H). C NMR (100 MHz, CDCl , δ): 24.8, 27.7,
3
0.3, 42.6, 57.5, 70.0, 127.5, 128.8, 129.2, 133.4, 133.7,
37.8, 215.0. HPLC (Chiralcel OD-H, Hexane–i-PrOH
(
90:10), 0.5 mL/min, 220 nm, 20 °C): t = 14.9 min (major)
R
Conclusions
and tR = 18.4 min (minor), ee: 94%. Syn-diastereomer:
HPLC (Chiralcel OD-H, Hexane–i-PrOH (90:10),
In summary, we have developed an organocatalytic asym-
metric direct aldol reaction in brine with high diastereo- and
enantioselectivities, using a readily available bifunctional
amide catalyst. From a green-chemistry view, employing
brine or water as the reaction medium is environment-
friendly and safe, regardless of performing the reaction un-
der truly aqueous conditions or not (14). Further studies that
focus on the application of this catalyst system to other
types of transformations are under investigation in our labo-
ratory.
0
1
.5 mL/min, 220 nm, 20 °C): tR = 10.8 min and tR
=
1.4 min.
2
-(Hydroxy-phenyl-methyl)-cyclohexanone (7j)
Yield: 72%; anti:syn (85:15). Anti-diastereomer: H NMR
1
(
2
400 MHz, CDCl , δ): 1.25–2.10 (m, 6H), 2.32–2.49 (m,
3
H), 2.58–2.65 (m, 1H), 4.78 (d, J = 6.0 Hz, 1H), 7.29–7.36
1
3
(
4
m, 5H). C NMR (100 MHz, CDCl , δ): 24.7, 27.8, 30.8,
3
2.6, 57.4, 74.7, 127.0, 127.9, 128.3, 140.9, 215.5. HPLC
2
Supplementary data for this article are available on the journal Web site (http://canjchem.nrc.ca) or may be purchased from the Depository
of Unpublished Data, Document Delivery, CISTI, National Research Council Canada, Ottawa, ON K1A 0S2, Canada. DUD 5138. For more
information on obtaining material, refer to http://cisti-icist.nrc-cnrc.gc.ca/irm/unpub_e.shtml.
©
2007 NRC Canada

Huang et al.
213
Shimomoto, S. Fujioka, and H. Kotsuki. Synlett, 11, 1655
Acknowledgement
(
2003); (h) A.B. Northrup and D.W.C. MacMillan. Science
We are grateful for the financial support from the National
Natural Science Foundation of China (20672040), the Na-
tional Basic Research Program of China (2004CCA00100),
the program for New Century Excellent Talents in Univer-
sity (NCET-05–0672), and the Hubei Province Science Fund
for Distinguished Young Scholar (2004ABBC011).
(Washington, D.C.), 305, 1752 (2004); (i) Z. Tang, F.
Jiang, L.-T. Yu, L.-Z. Gong, A.-Q. Mi, Y.-Z. Jiang, and Y.-D.
Wu. J. Am. Chem. Soc. 125, 5262 (2003); (j) J.-R. Chen, H.-
H. Lu, X.-Y. Li, L. Cheng, J. Wan, and W.-J. Xiao. Org. Lett.
7
, 4543 (2005); (k) Y.-J. Cao, H.-H. Lu, Y.–Y. Lai, L.–Q. Lu,
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Notz, and C.F. Barbas, III. Chem. Commun. 6, 3024 (2002);
(
m) Y.-S. Wu, Y. Chen, D.-S. Deng, and J. Cai. Synlett, 1627
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©
2007 NRC Canada