Fine-tuning the structures of chiral diamine ligands in the catalytic asymmetric aldol reactions of trifluoromethyl aromatic ketones with linear aliphatic ketones

Article abstract of DOI:10.1021/jo5022103

In this work, we thoroughly investigated the effect of structural differentiation of a series of N,N-disubstituted chiral diamine ligands on the catalytic asymmetric aldol reactions between trifluoromethyl ketones and linear aliphatic ketones for the cons

Full text of DOI:10.1021/jo5022103

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Note
Fine-Tuning the Structures of Chiral Diamine Ligands in the
Catalytic Asymmetric Aldol Reactions of Trifluoromethyl
Aromatic Ketones with Linear Aliphatic Ketones
Hua Zong, Huayin Huang, Guangling Bian, and Ling Song
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo5022103 • Publication Date (Web): 12 Nov 2014
Downloaded from http://pubs.acs.org on November 17, 2014
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Fine-Tuning the Structures of Chiral Diamine Ligands in the
Catalytic Asymmetric Aldol Reactions of Trifluoromethyl Aromatic
Ketones with Linear Aliphatic Ketones
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Hua Zong, Huayin Huang, Guangling Bian, Ling Song*
The Key Laboratory of Coal to Ethylene Glycol and Its Related Technology, the State Key Lab of
Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of
Sciences, Fuzhou, Fujian 350002, China
*Eꢀmail: songling@fjirsm.ac.cn; Phone: + 86ꢀ591ꢀ83720913; Fax: +86ꢀ591ꢀ83722697.
Ph
Ph
N
O
(5 mol%)
NH2
O
O
HO
Ar
TsOH (10 mol%)
R2
+
R2
Ar
Rf
toluene, 0 oC, 24 h
Rf
Rf = CF3 or CF2Cl
R2 = Me, Et or nꢀPr
yield up to 99%
ee up to 94%
Abstract: In this work, we thoroughly investigated the effect of structural
differentiation of a series of N, Nꢀdisubstituted chiral diamine ligands on the catalytic
asymmetric aldol reactions between trifluoromethyl ketones and linear aliphatic
ketones for the construction of chiral trifluoromethyl tertiary alcohols. A highly
efficient
primaryꢀtertiary
diamine
ligand
derived
from
(1R,2R)ꢀ1,2ꢀ
diphenylethylenediamine was developed, which catalyzed the reactions with up to
99% yield and up to 94% enantioselectivity in the presence of pꢀtoluenesulfonic acid
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(TsOH) using toluene as solvent.
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Keywords: organocatalytic asymmetric aldol reaction; primaryꢀtertiary diamine;
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trifluoromethyl aromatic ketone; linear aliphatic ketone; tertiary alcohol
Ever since List,1 Barbas,2 and MacMillan3 reported their pioneering works on
organocatalyzed enantioselective aldol reactions，a lot of effort has been made on the
asymmetric organocatalysis and remarkable progress has been achieved.4,5 Although
many strategies have been developed for the organocatalytic aldol reactions of
aldehydes with ketones, it still remains challenging in the organocatalytic ketoneꢀ
ketone crossꢀaldol reactions because of the steric hindrance and electronic constrain
of ketones.6
Owing to the peculiar properties of the fluorine atom, organofluorine compounds
are widely used in many fields of the modern society.7 More than 20% of medicinal
and agrochemical products contain one or more fluorine atoms.8 In the big family, αꢀ
trifluoromethyl tertiary alcohol compounds play an important role due to their
bioactivities and stereoelectronic properties.9 Therefore, various kinds of
transformations have been developed for the syntheses of αꢀtrifluoromethyl tertiary
alcohols.10 There is no doubt that the crossꢀaldol reactions of ketones with
trifluoromethyl ketones could be considered as one of the most useful approaches for
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the construction of chiral trifluoromethyl tertiary alcohols. However, until recently,
only a few crossꢀaldol reactions of ketones with trifluoromethyl ketones have been
reported. 11ꢀ19
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In 2005, Zhang and coworkers firstly reported the asymmetric aldol reactions
between aliphatic methyl ketones and trifluoromethyl ketones catalyzed by chiral
proline, which afforded only low to moderate enantioselectivities (up to 64%).11 Other
successful catalytic reaction systems with improved enantioselectivities have also
been disclosed by Liu,12 Yuan,13 Nakamura,14 Berkessel15 and Kokotos16 (Figure 1,
) with the use of chiral proline derived ligands. Although chiral diamines as
Iꢀ
V
organocatalysts have been widely explored in the past decade,20,21 examples of
diamineꢀcatalyzed asymmetric aldol reactions of ketones with trifluoromethyl ketones
are few. In 2014, Liu and He reported the asymmetric aldol reactions of α, βꢀ
unsaturated ketones with trifluoroacetophenone catalyzed by diamine VI with good to
excellent yields and enantioselectivities, but no aliphatic ketone was reported.18 In the
same year, Xu and coworkers used quinineꢀderived diamine VII in the catalytic
asymmetric crossꢀaldol reactions between aliphatic ketones and trifluoromethyl
ketones, obtaining the corresponding tertiary alcohol products with 65ꢀ89% ee
values.19
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O
Si(TMS)3
O
O O
S
O
O O
S
O
N
H
Ph
Ph
OH
N
O
NH
N
H
N
H
NH
N
H
NH
OH
II
III
IV
I
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O
Ph
NH2
Ph
N
N
H
NH
HN
HN
O
N
N
NH2
CO2tꢀBu
CO2tꢀBu
Ph
MeO
V
VI
VII
Figure 1. Organocatalysts used in the asymmetric aldol reactions of trifluoromethyl
ketones with ketones.
Inspired by the pioneers’ works, we wondered if it was possible to develop a novel
highly efficient diamineꢀcatalyzed reaction system for the asymmetric aldol reactions
of trifluoromethyl ketones with aliphatic ketones by structure modification of simple
diamines (1R,2R)ꢀ1,2ꢀdiaminocyclohexane, (1R,2R)ꢀ1,2ꢀdiphenylethylenediamine and
(R)ꢀ(+)ꢀ1,1′ꢀbinaphthylꢀ2,2′ꢀdiamine. To start our investigation, we firstly examined
the reaction of 2,2,2ꢀtrifluoroꢀ1ꢀphenylethanone with acetone in the presence of 10
mol% of primaryꢀprimary diamine (1R,2R)ꢀ1,2ꢀdiaminocyclohexane 1a, which
proceeded smoothly to give 90% yield of desired tertiary alcohol product 3a with only
20% ee value (Table 1, entry 1). Using N, Nꢀdimethyl substituted primaryꢀtertiray
diamine 1b as the catalyst, ee value of 3a was improved to 44%. Further increasing
the sizes of N, Nꢀdisubstituents (R1 and R2 groups) enhanced the enantioselectivity
gradually in the order of methyl, ethyl and nꢀbutyl groups (Table 1, entries 2ꢀ5).
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However, the enantioselectivity was decreased with much bigger CH2Bu and/or
CH2Ph groups (Table 1, entries 6ꢀ8). In addition, using Nꢀmonosubstituted primaryꢀ
secondary diamine 1i (R1 = CH2Ph and R2 = H) as the catalyst, racemic product was
obtained (Table 1, entry 9). These results indicate that N, Nꢀdisubstituted groups with
medium sizes are helpful for the improvement of enantioselectivity of this catalytic
aldol reaction. The best result was obtained with the use of Nꢀ(CH2)5ꢀ disubstituted
chiral ligand 1k, giving the desired tertiary alcohol 3a in 95% yield and 68% ee value
(Table 1, entry 11).
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Table 1. Optimization of the Reaction Conditions for the Asymmetric Aldol Reaction
of 2,2,2ꢀTrifluoroacetophenone with Acetone.a
R1
N
R1
N
O
acid (10 mol%)
chiral ligand 1 or 2 (X mol%)
O
O
Ph
Ph
R2
or
R2
HO
Ph
+
Ph
CF3
temperature, time, Solvent
CF3
NH2
NH2
1.0 mmol
10 equiv
1
2
3a
yieldb
(%)
90
eec
(%)
20
44
40
61
62
53
46
24
yieldb
(%)
95
eec
entry ligand
R1
R2
entry ligand
R1
R2
(%)
68
44
48
66
65
66
62
70
1
2
3
4
5
6
7
8
H
Me
Me
Et
H
Me
iꢀPr
Et
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12
13
14
15
16
17
18
ꢀ(CH2)5ꢀ
1a
1b
1c
1d
1e
1f
1k
2a
2b
2c
2d
2e
2f
93
H
H
85
85
Me
Et
Me
Et
94
95
95
nꢀBu
nꢀBu
96
Me
Et
93
CH2Bu CH2Bu
CH2Bu CH2Ph
CH2Ph CH2Ph
87
nꢀPr nꢀPr
ꢀ(CH2)4ꢀ
92
70
96
1g
1h
53
ꢀ(CH2)5ꢀ
97
2g
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CH2Ph
H
93
95
1
19 d
ꢀ(CH2)5ꢀ
ꢀ(CH2)5ꢀ
98
98
83
92
1i
1j
2g
2g
10
ꢀ(CH2)4ꢀ
58
20 d,e
6
7
a
Unless otherwise noted, the reaction was carried out on 1 mmol scale, in the presence of 10
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b
mol% chiral ligand and 10 mol% TFA in dry acetone (2 mL), at 0 C ~ r.t., stirred for 10 h.
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c
d
e
Isolated yield. Determined by chiral HPLC. Toluene (2 mL) was used as solvent. TsOH (10
mol%) was used as acid, chiral ligand 2g (5 mol%), stirred for 24 h at 0 oC.
Using (1R,2R)ꢀ1,2ꢀdiphenylethylenediamine 2a as the chiral ligand, the desired
product was obtained with 44% ee value and 85% yield (Table 1, entry 12), which
indicates that the backbone of (1R,2R)ꢀ1,2ꢀdiphenylethylenediamine is better than that
of (1R,2R)ꢀ1,2ꢀdiaminocyclohexane in this aldol reaction. Then a series of N, Nꢀ
disubstituted (1R,2R)ꢀ1,2ꢀdiphenylethylenediamine ligands 2bꢀ2g were synthesized
and evaluated (Table 1, entries 13ꢀ18). Unfortunately, these ligands did not improve
the enantioselectivity of the aldol reaction dramatically compared with the ligands
derived from (1R,2R)ꢀ1,2ꢀdiaminocyclohexane 1a. The best result was obtained with
chiral ligand 2g, giving the desired product 3a in 97% yield and 70% ee value (Table
1, entry 18). In addition, (R)ꢀ(+)ꢀ2,2'ꢀdiaminoꢀ1,1'ꢀbinaphthalene could not promote
the direct asymmetric aldol reaction of 2,2,2ꢀtrifluoroꢀ1ꢀphenylethanone with acetone
at all. Therefore, by fineꢀtuning the structure of diamine ligands, chiral primaryꢀ
tertiary amine 2g was chosen as the optimum catalyst. To maximize the
enantioselectivity, various reaction conditions including solvent, acid, the loading of
catalyst, reaction time and temperature were further tested (see
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Supporting information for details). Finally, the asymmetric catalytic aldol reaction
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was carried out in toluene with 5 mol% chiral primaryꢀtertiary diamine 2g and 10
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o
mol% TsOH at 0 C for 24 h, giving the tertiary alcohol product 3a with 98% yield
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and 92% ee value as shown in entry 20 of Table 1.
With the optimized reaction conditions in hand, we next evaluated the applicability
of the developed organocatalytic system and the results are summarized in Scheme 1.
To our delighted, the reactions between acetone and various aryl trifluoromethyl
ketones with either electronꢀrich or electronꢀdeficient substituents gave products 3aꢀ
3h in excellent yields (up to 99%) and good to excellent ee values (up to 94%).
However, once the CF3 group (3a) was replaced by less electonꢀwithdrawing CF2Cl
group (3i), lower yield and enantioselectivity were observed (75% yield and 81% ee
value). Using other aliphatic ketones, 2ꢀbutanone and 2ꢀpentanone, the yields and ee
values of the corresponding tertiary alcohol products (3j and 3k) were also excellent.
Scheme 1. Enantioselective aldol reactions of fluoroalkylated ketones and linear
aliphatic ketones.
O
2g (5 mol%)
TsOH (10 mol%)
toluene (2 mL)
0 oC, 24 h
O
O
HO
Ar
R2
+
Ar
Rf
R2
10 equiv
Rf
3a-3k
1 mmol
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O
O
O
HO
HO
HO
6
7
8
9
CF3
3a
CF3
CF3
3b
3c
F
F3C
O
96%, 87% ee
98%, 92% ee
82%, 93% ee
O
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O
HO
HO
HO
CF3
Me
CF3
CF3
Cl
3f
3e
3d
O
95%(48 h), 88% ee
84%, 87% ee
95%, 93% ee
O
O
O
F
HO
HO
HO
F
F
CF3
CF3
CF2Cl
F
MeO
3g
3h
3i
F
97%(48 h), 94% ee
99%, 90% ee 75%(48 h), 81% ee
O
O
HO
HO
CF3
CF3
3k
3j
92%(48 h), 87% ee
95%(48 h), 88% ee
In order to explain the excellent enantioselectivity of the direct asymmetric aldol
reactions of trifluoromethyl ketones with linear aliphatic ketones, a possible reaction
pathway was proposed on the basis of our experimental findings and previously
published works in the field of asymmetric aldol reactions. The amine group of chiral
ligand 2g activated acetone by forming an enamine intermediate, while the
trifluoromethyl carbonyl group was activated via hydrogen bonding interaction with
the quaternary ammonium salt. A transition state, in which the enamine intermediate
situated on the Reꢀface of trifluoroacetophenone was favored because the CF3 group
of trifluoroacetophenone preferred to the opposite position of the Nꢀ(CH2)5ꢀ group of
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chiral diamine 2g for less steric repulsion to give (S)ꢀ product as shown in Figure 2.
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Ph
Ph
N
Ph
Ph
N
H
H
HN
HN
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O
O
Ph
F3C
CF3
Ph
disfavored Siꢀattack
favored Re-attack
Figure 2. Proposed transition states.
In conclusion, by fineꢀtuning the structure of simple diamines, we have developed a
chiral primaryꢀtertiary diamine ligand 2g from (1R,2R)ꢀ1,2ꢀdiphenylethylenediamine,
which is highly efficient in the catalytic enantioselective crossꢀaldol reaction between
linear aliphatic ketones and trifluromethyl ketones. Under optimized reaction
conditions, excellent yields (up to 99%) and enantioselectivities (up to 94%) of the
desired trifluoromethylꢀβꢀhydroxy ketones were obtained. A possible transition state
was also proposed.
Experimental Section
General Methods
All reactions were carried out under N2 atmosphere in oven dried glassware
with magnetic stirring unless otherwise noted. All solvents were purified prior to
use according to the reported method. 22 1H NMR (400 MHz), C NMR (100 MHz)
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and 19F NMR (376 MHz) spectra were recorded in CDCl3 solution using a 400
MHz spectrometer. Chemical shifts were reported in parts per million (ppm, δ)
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9
1
relative to CDCl3 (δ 7.26 for H NMR), or CDCl3 (δ 77.0 for 13C NMR).
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Multiplicities are indicated as (s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet, br = broad, coupling constants in Hz). All commercially available
reagents were used without further purification unless otherwise noted. Optical
T
D
rotations were measured on a polarimeter and reported as follows:
[
α
]
(c g/100
mL, solvent). HPLC analysis were performed using Chiralcel columns (Chiralcel
ODꢀH, OJꢀH, ADꢀH, and Chiralpak ASꢀH). High resolution mass spectra (HRMS)
were measured on a LTQ FTꢀICR mass spectrometer by using MatrixꢀAssisted Laser
Desorption Ionization (MALDI).
Synthesis of chiral ligands 1b-1h, 1j-1k, 2b-2g.
Chiral ligands 1b, 1dꢀ1e were synthesized according to the reported method. 21b
1
28. 7
D
1b: colorless oil; 298 mg, 70% overall yield;
[
α
]
ꢀ32.1 (1.0, CHCl3), H NMR
(400 MHz, CDCl3): δ 0.48ꢀ0.79 (m, 4H), 1.12ꢀ1.55 (m, 7H), 1.71 (s, 6H), 1.98ꢀ2.13
(m, 1H); 13C NMR (100 MHz, CDCl3): δ 19.5, 24.0, 24.6, 34.1, 39.0, 50.4, 68.7.
30. 1
D
Chiral ligand 1d: colorless oil; 321 mg, 63% overall yield;
[
α
]
ꢀ140.2 (1.0,
1
CHCl3), H NMR (400 MHz, CDCl3): δ 0.90ꢀ1.00 (m, 6H), 1.01ꢀ1.26 (m, 4H), 1.51ꢀ
1.77 (m, 3H), 1.77ꢀ2.13 (m, 4H), 2.18ꢀ2.37 (m, 2H), 2.40ꢀ2.63 (m, 3H); 13C NMR
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(100 MHz, CDCl3): δ 15.0, 23.1, 25.1, 26.0, 35.1, 43.3, 51.2, 66.4.
5
6
7
29. 9
D
Chiral ligand 1e: colorless oil; 352 mg, 52% overall yield;
[
α
]
ꢀ110.5 (1.0,
8
9
1
CHCl3), H NMR (400 MHz, CDCl3): δ 0.75ꢀ0.98 (m, 6H), 1.00ꢀ1.43 (m, 12H), 1.53ꢀ
1.80 (m, 3H), 1.83ꢀ2.07 (m, 4H), 2.15ꢀ2.32 (m, 2H), 2.34ꢀ2.61 (m, 3H); 13C NMR
(100 MHz, CDCl3): δ 14.1, 20.6, 22.8, 25.1, 26.0, 31.7, 35.1, 49.7, 51.3, 66.8.
Chiral ligand 1c was synthesized according to the reported method.23 Colorless oil;
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1
29. 1
D
178 mg, 35% overall yield;
[
α
]
ꢀ45.2 (c 1.00, CH2Cl2); H NMR (400 MHz,
CDCl3): δ 0.95ꢀ1.07 (m, 7H), 1.13ꢀ1.27 (m, 3H), 1.57ꢀ1.78 (m, 5H), 1.87ꢀ2.02 (m,
13
1H), 2.06ꢀ2.21 (m, 4H), 2.44ꢀ2.57 (m, 1H), 2.74ꢀ2.90 (m, 1H); C NMR (100 MHz,
CDCl3): δ 20.7, 21.2, 25.2, 25.8, 26.1, 30.9, 35.2, 51.4, 52.3, 66.8.
Chiral ligand 1f was synthesized according to the reported method.24 Colorless
29. 8
D
1
oil; 365 mg, 48% overall yield;
[
α
]
ꢀ80.5 (1.0, CHCl3), H NMR (400 MHz,
CDCl3): δ 0.73ꢀ0.98 (m, 6H), 1.02ꢀ1.48 (m, 17H), 1.57ꢀ1.87 (m, 3H), 1.93ꢀ2.14 (m,
13
2H), 2.22ꢀ2.60 (m, 6H); C NMR (100 MHz, CDCl3): δ 14.1, 22.6, 22.9, 25.1, 26.0,
29.2, 29.7, 34.9, 50.1, 51.3, 66.8.
Chiral ligand 1g was synthesized according to the reported method.25 Colorless
29. 8
D
1
oil; 354 mg, 43% overall yield;
[
α
]
ꢀ30.5 (1.0, CHCl3), H NMR (400 MHz,
CDCl3): δ 0.85 (t, J = 7.0 Hz, 3H), 1.11ꢀ1.29 (m, 8H), 1.37ꢀ1.51 (m, 2H), 1.61ꢀ1.70
(m, 1H), 1.74ꢀ1.83 (m, 1H), 1.86ꢀ1.94 (m, 1H), 1.95ꢀ2.08 (m, 1H), 2.21ꢀ2.25 (m, 1H),
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2.31ꢀ2.42 (m, 1H), 2.44ꢀ2.54 (m, 1H), 2.60ꢀ2.68 (m, 1H), 2.71 (s, 2H), 3.35 (d, J =
13.8 Hz, 1H), 3.79 (d, J = 13.8 Hz, 1H), 7.17ꢀ7.35 (m, 5H); 13C NMR (100 MHz,
CDCl3): δ 14.1, 22.5, 22.8, 25.0, 25.8, 28.6, 29.6, 34.4, 49.7, 51.3, 54.3, 65.5, 126.7,
128.2, 128.7, 140.8.
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Chiral ligand 1h was synthesized according to the reported method.26 Colorless
1
29. 8
D
oil; 590 mg, 67% overall yield;
[
α
]
ꢀ110.5 (1.0, CHCl3), H NMR (400 MHz,
CDCl3): δ 0.90ꢀ1.31 (m, 4H), 1.63ꢀ1.87 (m, 4H), 1.92ꢀ2.09 (m, 2H), 2.11ꢀ2.25 (m,
1H), 2.61ꢀ2.79 (m, 1H), 3.43 (d, J = 13.3 Hz, 2H), 3.86 (d, J = 13.3 Hz, 2H), 7.11ꢀ
7.53 (m, 10H); 13C NMR (100 MHz, CDCl3): δ 22.6, 25.2, 25.8, 35.0, 51.2, 53.8, 64.8,
126.9, 128.3, 128.9, 140.3.
Chiral ligand 1j-1k was synthesized according to the reported method.23 1j:
29. 8
D
1
Colorless oil; 302 mg, 60% overall yield;
[
α
]
ꢀ51.2 (1.0, CHCl3), H NMR (400
MHz, CDCl3): 1.05ꢀ1.40 (m, 4H), 1.42ꢀ1.56 (m, 1H), 1.58ꢀ2.00 (m, 6H), 2.10ꢀ2.27 (m,
1H), 2.48ꢀ2.74 (m, 5H), 2.75ꢀ2.91 (m, 1H), 5.16 (s, 2H); 13C NMR (100 MHz,
CDCl3): δ 22.0, 23.6, 24.5, 24.8, 32.1, 47.3, 52.8, 62.6.
29. 8
D
Chiral ligand 1k: colorless oil; 355 mg, 65% overall yield;
[
α
]
ꢀ35.6 (1.0,
1
CHCl3); H NMR (400 MHz, CDCl3): δ 1.01ꢀ1.22 (m, 4H), 1.32ꢀ1.66 (m, 7H),
13
1.68ꢀ1.80 (m, 2H), 1.86ꢀ2.03 (m, 4H), 2.16ꢀ2.34 (m, 2H), 2.48ꢀ2.68 (m, 3H); C
NMR (100 MHz, CDCl3): δ 22.6, 25.06, 25.11, 25.9, 26.9, 35.1, 49.7, 50.7, 71.2.
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Chiral ligand 2b was synthesized according to the reported method.21b Colorless
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1
29. 7
D
oil; 288 mg, 40% overall yield;
[
α
]
ꢀ91.1 (1.0, CHCl3), H NMR (400 MHz,
8
9
CDCl3): δ 2.07 (s, 2H), 2.24 (s, 6H), 3.66 (d, J = 10.5 Hz, 1H), 4.45 (d, J = 10.5 Hz,
1H), 6.98ꢀ7.31 (m, 10H); 13C NMR (100 MHz, CDCl3): δ 40.9, 55.6, 75.3, 126.8,
127.3, 128.0, 129.8, 134.0, 143.3.
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Chiral ligand 2c was synthesized according to the reported method.27 Colorless
1
29. 7
D
oil; 442 mg, 55% overall yield;
[
α
]
ꢀ52.0 (1.0, CHCl3), H NMR (400 MHz,
CDCl3): δ 1.19 (t, J = 7.1 Hz, 6H), 2.14ꢀ2.26 (m, 2H), 2.41 (s, 2H), 2.77ꢀ2.98 (m, 2H),
13
3.89 (d, J = 10.6 Hz, 1H), 4.48 (d, J = 10.6 Hz, 1H), 6.98ꢀ7.36 (m, 10H); C NMR
(100 MHz, CDCl3): δ 14.4, 43.5, 55.8, 70.4, 126.7, 128.8, 127.5, 128.0, 128.1, 129.6,
136.1, 143.5.
Chiral ligand 2d was synthesized according to the reported method.28 Colorless
29. 7
D
1
oil; 365 mg, 48% overall yield;
[
α
]
ꢀ62.0 (1.0, CHCl3), H NMR (400 MHz,
CDCl3): δ 1.16 (t, J = 7.1 Hz, 3H), 2.23 (s, 3H), 2.28ꢀ2.37 (m, 3H), 2.45ꢀ2.59 (m, 1H),
13
3.78 (d, J = 10.6 Hz, 1H), 4.48 (d, J = 10.6 Hz, 1H), 7.00ꢀ7.32 (m, 10H); C NMR
(100 MHz, CDCl3): δ 13.7, 36.6, 47.9, 55.5, 74.3, 126.78, 126.85, 127.4, 128.0, 128.1,
129.7, 134.7, 143.3.
Chiral ligand 2e was synthesized according to the reported method.27
[
α
]
ꢀ42.3
29. 1
D
1
(c 1.00, CH2Cl2); 443 mg, 50% overall yield; H NMR (400 MHz, CDCl3): δ 1.10 (t,
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J = 7.4 Hz, 6H), 1.56ꢀ1.71 (m, 4H), 2.12ꢀ2.22 (m, 2H), 2.42 (br, 2H), 2.59ꢀ2.72 (m,
2H), 3.85 (d, J = 10.6 Hz, 1H), 4.49 (d, J = 10.7 Hz, 1H), 7.03ꢀ7.23 (m, 8H), 7.25ꢀ
7.33 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 12.1, 21.9, 51.9, 55.9, 70.9, 126.7,
126.8, 127.4, 127.9, 128.2, 129.7, 135.9, 143.6.
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Chiral ligand 2f-2g was synthesized according to the reported method.28 Chiral
1
29. 7
D
ligand 2f: Colorless oil; 535 mg, 67% overall yield;
[
α
]
ꢀ23.0 (1.0, CHCl3), H
NMR (400 MHz, CDCl3): δ 1.62ꢀ1.79 (m, 4H), 2.19 (s, 2H), 2.48ꢀ2.66 (m, 4H), 3.88
(d, J = 9.1 Hz, 1H), 4.48 (d, J = 9.1 Hz, 1H), 6.97ꢀ7.32 (m, 10H); 13C NMR (100
MHz, CDCl3): δ 22.9, 49.0, 56.8, 72.5, 126.75, 126.84, 127.3, 127.88, 127.91, 129.9,
135.6, 143.4.
o
29. 7
D
Chiral ligand 2g: white solid, 868 mg, 62% overall yield; Mp 86ꢀ87 C;
[
α
]
ꢀ
1
61.2 (1.0, CHCl3), H NMR (400 MHz, CDCl3): δ 1.30ꢀ1.43 (m, 2H), 1.53ꢀ1.76 (m,
4H), 2.20 (s, 2H), 2.25ꢀ2.43 (m, 2H), 2.44ꢀ2.69 (m, 2H), 3.66 (d, J = 10.7 Hz, 1H),
13
4.51 (d, J = 10.7 Hz, 1H), 7.00ꢀ7.30 (m, 10H); C NMR (100 MHz, CDCl3): δ 24.7,
26.7, 50.5, 55.0, 76.5, 126.8, 127.3, 128.0, 128.1, 129.6, 134.9, 143.4; Elemental
Analysis: Anal. Calcd. for C19H24N2: C 81.38, H 8.63, N 9.99, found: C 81.43, H 8.57,
N 9.90; HRMS (MALDI): (m/z) calcd for C19H25N2 [M+H]+: 281.2014, found:
281.2012.
Synthesis of (1R, 2R)-1-N-benzylcyclohexane-1,2-diamine 1i.
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1. benzaldehyde
o
Ph
NH
NH2
4 A molecular sieves
NH2
NaBH3CN,
O
MeOH, r.t. overnight
N
2. N2H4—H2O, EtOH
reflux, 2 h
O
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4
1i
Compound 4 was prepared according to literature.29
To a solution of 4 (732 mg, 3 mmol) in methanol (30 mL), benzaldehyde (350 mg,
3.3 mmol), molecular sieves (3 g) and three drops of glacial acetic acid were added.
After the reaction mixture was stirred for 3 h, NaBH3CN (473 mg, 7.5 mmol) was
o
added at 0 C, the reaction was allowed to warm to room temperature and stirred
overnight. The molecular sieves were filtered and the solution was concentrated under
reduced pressure to give a residue, which was dissolved in CH2Cl2 (30 mL) and
washed by saturated Na2CO3 solution (30 mL). The organic solution was dried over
anhydrous MgSO4 and the solvent was removed under reduced pressure to afford 822
mg white solid, which was used in the next step without further purification. To the
solution of the white solid in 10 mL ethanol, hydrazine monohydrate (1.21 mL, 25
mmol) was added and the reaction mixture was stirred at reflux (oil bath 70 oC) for 2
h. After the reaction mixture was cooled to room temperature, diethyl ether (30 mL)
and CH2Cl2 (30 mL) were added to form precipitates which were removed by
filtration. The filtrate was dried over anhydrous MgSO4 and the solvent was removed
under reduced pressure to afford a crude product, which was subjected to silica gel
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column chromatography (MeOH/CH2Cl2 = 1/30) affording 373 mg (two steps, 61%)
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of 1i as a colorless oil.
[
α
]
ꢀ22.7 (c 1.00, CH2Cl2); 1H NMR (400 MHz, CDCl3): δ
29. 1
D
8
9
0.95ꢀ1.33 (m, 4H), 1.66ꢀ1.76 (m, 5H), 1.80ꢀ1.94 (m, 1H), 2.04ꢀ2.19 (m, 2H), 2.33ꢀ
2.46 (m, 1H), 3.68 (d, J = 13.0 Hz, 1H), 3.94 (d, J = 13.1 Hz, 1H), 7.13ꢀ7.46 (m, 5H);
13C NMR (100 MHz, CDCl3): δ 25.2, 25.3, 31.4, 35.9, 51.1, 55.4, 63.2, 126.8, 128.1,
128.3, 128.9, 141.1. Elemental Analysis: Anal. Calcd. for C13H20N2: C 76.42, H 9.87,
N 13.71 Found: C 76.38, H 9.89, N 13.73.
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Typical procedure for the catalytic asymmetric aldol reaction between 2,2,2-
Trifluoroacetophenone with acetone catalyzed by ligand 2g.
O
2g (5 mol%)
TsOH (10 mol%)
toluene, 0 oC, 24 h
O
O
HO
Ph
+
Ph
CF3
CF3
To a solution of 2g (14 mg, 0.05 mmol) and TsOH (17 mg, 0.1 mmol) in anhydrous
toluene (2 mL), trifluoroacetophenone (174 mg, 1.0 mmol) and acetone (580 mg, 10.0
o
mmol) were added at 0 C and the resulting mixture was stirred for 24 h at that
temperature. The solvent was removed under reduced pressure. The crude product
was purified by flash column chromatography on silica gel (hexane/EtOAc = 6: 1) to
give 227 mg (98% yield) corresponding product 3a as a colorless oil. The ee value
was determined by chiral HPLC analysis.
(S)ꢀ5,5,5ꢀtrifluoroꢀ4ꢀhydroxyꢀ4ꢀphenylpentanꢀ2ꢀone (3a)16: Colorless oil. 227 mg,
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98% yield; 92% ee value was determined by HPLC Chiralcel ODꢀH column
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(Hexane/2ꢀpropanol = 97: 3, 1.0 mL/min, 210 nm) analysis, minor enantiomer tR =
8
9
31. 1
D
8.579 min, major enantiomer tR = 12.152 min.
[ α]
[Literature 16 +18.8 (c 0.4, CHCl3) for 80% ee (S)]; 1H NMR (400 MHz, CDCl3):
D
[
α
]
+25.0 (c 1.0, CHCl3)
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δ 2.20 (s, 3H), 3.21 (d, J = 17.2 Hz, 1H), 3.36 (d, J = 17.2 Hz, 1H), 5.44 (s, 1H), 7.32ꢀ
13
7.43 (m, 3H), 7.51ꢀ7.61 (m, 2H); C NMR (100 MHz, CDCl3): δ 32.1, 45.1, 76.0 (q,
19
J = 29.1 Hz), 124.5 (q, J = 285.4 Hz), 126.1, 128.4, 128.8, 137.5, 208.9; F NMR
(376 MHz, CDCl3): δ ꢀ80.3 (s).
(S)ꢀ5,5,5ꢀtrifluoroꢀ4ꢀ(4ꢀfluorophenyl)ꢀ4ꢀhydroxypentanꢀ2ꢀone (3b)16: Colorless oil.
240 mg, 96% yield; 87% ee value was determined by HPLC Chiralcel OJꢀH column
(Hexane/2ꢀpropanol = 90: 10, 1.0 mL/min, 210 nm) analysis, minor enantiomer tR =
30. 2
D
7.699 min, major enantiomer tR = 9.960 min.
[Literature16 +15.2 (c 1.0, CH2Cl2) for 74% ee (S)]; 1H NMR (400 MHz, CDCl3):
[ α]
D
[
α
]
+21.6 (c 1.0, CHCl3)
δ 2.20 (s, 3H), 3.22 (d, J = 17.4 Hz, 1H), 3.33 (d, J = 17.4 Hz, 1H), 5.57 (s, 1H), 6.96ꢀ
13
7.15 (m, 2H), 7.45ꢀ7.62 (m, 2H); C NMR (100 MHz, CDCl3): δ 31.8, 45.0, 75.7 (q,
J = 29.2 Hz), 115.4 (d, J = 21.6 Hz), 124.4 (q, J = 285.3 Hz), 128.1 (d, J = 8.4 Hz),
133.4 (d, J = 2.9 Hz), 162.9 (d, J = 247.8 Hz), 208.9; 19F NMR (376 MHz, CDCl3): δ
ꢀ80.5 (s), ꢀ113.4 (s).
(S)ꢀ5,5,5ꢀtrifluoroꢀ4ꢀ(4ꢀ(trifluoromethyl)phenyl)ꢀ4ꢀhydroxypentanꢀ2ꢀone
(3c)16:
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Colorless oil. 246 mg, 82% yield; 93% ee value was determined by HPLC Chiralcel
5
6
7
ASꢀH column (Hexane/2ꢀpropanol = 97: 3, 1.0 mL/min, 210 nm) analysis, minor
8
9
31. 1
D
enantiomer tR = 6.342 min, major enantiomer tR = 7.968 min.
CHCl3) [Literature16
[
α
]
+25.6 (c 1.0,
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1
[
α
]
D +7.5 (c 1.0, CH2Cl2) for 71% ee (S)]; H NMR (400 MHz,
CDCl3): δ 2.25 (s, 3H), 3.26 (d, J = 17.5 Hz, 1H), 3.33 (d, J = 17.5 Hz, 1H), 5.59 (s,
1H), 7.66 (d, J = 8.5 Hz, 2H), 7.70 (d, J = 8.5 Hz, 2H); 13C NMR (100 MHz, CDCl3):
δ 31.9, 45.0, 75.9 (q, J = 29.6 Hz), 123.8 (q, J = 272.0 Hz), 124.2 (q, J = 285.0 Hz),
125.5 (q, J = 3.8 Hz), 126.7, 131.1 (q, J = 33.0 Hz), 141.5, 208.6; 19F NMR (376 MHz,
CDCl3): δ ꢀ62.8 (s), ꢀ80.1 (s).
(S)ꢀ4ꢀ(4ꢀchlorophenyl)ꢀ5,5,5ꢀtrifluoroꢀ4ꢀhydroxypentanꢀ2ꢀone (3d)15: Colorless oil.
253 mg, 95% yield; 93% ee value was determined by HPLC Chiralcel OJꢀH column
(Hexane/2ꢀpropanol = 90: 10, 1.0 mL/min, 210 nm) analysis, minor enantiomer tR =
30. 9
D
7.146 min, major enantiomer tR = 9.126 min.
[
α
]
+27.7 (c 1.0, CHCl3)
[Literature15
[
α
]
+22.8 (c 1.0, CHCl3) for 92% ee (S)]; 1H NMR (400 MHz, CDCl3):
20
D
δ 2.24 (s, 3H), 3.23 (d, J = 17.3 Hz, 1H), 3.32 (d, J = 17.3 Hz, 1H), 5.51 (s, 1H), 7.39
13
(d, J = 8.7 Hz, 2H), 7.52 (d, J = 8.5 Hz, 2H); C NMR (100 MHz, CDCl3): δ 32.0,
45.0, 75.8 (q, J = 29.5 Hz), 124.3 (q, J = 285.9 Hz), 127.7, 128.7, 135.0, 136.1, 208.7;
19F NMR (376 MHz, CDCl3): δ ꢀ80.4 (s).
(S)ꢀ4ꢀ(4ꢀacetylphenyl)ꢀ5,5,5ꢀtrifluoroꢀ4ꢀhydroxypentanꢀ2ꢀone (3e): Colorless oil.
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230 mg, 84% yield; 87% ee value was determined by HPLC Chiralcel ASꢀH column
(Hexane/2ꢀpropanol = 90: 10, 1.0 mL/min, 210 nm) analysis, minor enantiomer tR =
7
8
9
1
30. 8
D
13.607 min, major enantiomer tR = 16.745 min.
[
α
]
+22.4 (c 1.0, CHCl3); H
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NMR (400 MHz, CDCl3): δ 2.20 (s, 3H), 2.58 (s, 3H), 3.24 (d, J = 17.3 Hz, 1H), 3.36
(d, J = 17.3 Hz, 1H), 5.53 (s, 1H), 7.66 (d, J = 7.9 Hz, 2H), 7.95 (d, J = 7.9 Hz, 2H);
13C NMR (100 MHz, CDCl3): δ 26.6, 31.9, 45.1, 76.0 (q, J = 29.3 Hz), 122.8, 125.7,
126.6, 128.4, 137.3, 142.5, 197.6, 208.6; 19F NMR (376 MHz, CDCl3): δ ꢀ80.0 (s).
Elemental Analysis: Anal. Calcd. for C13H13F3O3: C 56.94, H 4.78 Found: C 56.96, H
4.81.
(S)ꢀ5,5,5ꢀtrifluoroꢀ4ꢀhydroxyꢀ4ꢀpꢀtolylpentanꢀ2ꢀone (3f)16: White solid; Mp = 60ꢀ
62 ºC; 234 mg, 95% yield; 88% ee value was determined by HPLC Chiralcel ODꢀH
column (Hexane/2ꢀpropanol = 97: 3, 1.0 mL/min, 210 nm) analysis, minor enantiomer
31. 1
D
tR = 6.793 min, major enantiomer tR = 7.765 min.
[Literature16 +9.6 (c 0.5, CHCl3) for 64% ee (S)]; 1H NMR (400 MHz, CDCl3): δ
[ α]
D
[
α
]
+20.8 (c 1.0, CHCl3)
2.21 (s, 3H), 2.37 (s, 3H), 3.18 (d, J = 17.1 Hz, 1H), 3.38 (d, J = 17.1 Hz, 1H), 5.41 (s,
1H), 7.22 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3):
δ 21.0, 32.1, 45.1, 76.0 (q, J = 29.2 Hz), 124.5 (q, J = 286.9 Hz), 126.1, 129.2, 134.5,
138.7, 209.0; 19F NMR (376 MHz, CDCl3): δ ꢀ80.5 (s).
(S)ꢀ5,5,5ꢀtrifluoroꢀ4ꢀhydroxyꢀ4ꢀ(4ꢀmethoxyphenyl)pentanꢀ2ꢀone (3g)15: Colorless
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oil. 254 mg, 97% yield; 94% ee value was determined by HPLC Chiralcel ODꢀH
5
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column (Hexane/2ꢀpropanol = 97: 3, 1.0 mL/min, 210 nm) analysis, minor enantiomer
8
9
30. 8
D
tR = 10.574 min, major enantiomer tR = 10.917 min.
[
α
]
+24.2 (c 1.0, CHCl3)
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[Literature15
[
α
]
+23.6 (c 1.0, CHCl3) for 95% ee (S)]; 1H NMR (400 MHz, CDCl3):
20
D
δ 2.18 (s, 3H), 3.16 (d, J = 17.0 Hz, 1H), 3.33 (d, J = 17.0 Hz, 1H), 3.80 (s, 3H), 5.39
13
(s, 1H), 6.75ꢀ6.95 (m, 2H), 7.39ꢀ7.52 (m, 2H); C NMR (100 MHz, CDCl3): δ 32.1,
45.1, 55.2, 75.4, 75.8 (q, J = 29.3 Hz), 113.8, 124.6 (q, J = 284.3 Hz), 127.5, 129.4,
159.9, 209.0; 19F NMR (376 MHz, CDCl3): δ ꢀ80.7 (s).
(S)ꢀ5,5,5ꢀtrifluoroꢀ4ꢀhydroxyꢀ4ꢀ(perfluorophenyl)pentanꢀ2ꢀone (3h)16: Colorless
oil. 319 mg, 99% yield; 90% ee value was determined by HPLC Chiralcel ASꢀH
column (Hexane/2ꢀpropanol = 97: 3, 1.0 mL/min, 210 nm) analysis, minor enantiomer
30. 6
D
tR = 4.743 min, major enantiomer tR = 5.981 min.
[Literature16 +10.8 (c 1.0, CHCl3) for 54% ee (S)]; 1H NMR (400 MHz, CDCl3):
[ α]
D
[
α
]
+64.2 (c 1.0, CHCl3)
δ 2.27 (s, 3H), 3.12 (dt, J = 3.6 Hz, J = 18.3 Hz, 1H), 3.79 (dt, J = 2.6 Hz, J = 18.3 Hz,
1H), 4.82 (s, 1H); 13C NMR (100 MHz, CDCl3): δ 30.5, 46.5 (t, J = 6.0 Hz), 76.5 (q, J
= 31.0 Hz), 110.0ꢀ148.0 (m), 206.8; 19F NMR (376 MHz, CDCl3): δ ꢀ161.1 (m), ꢀ
152.0 (tt, J = 4.1 Hz, 21.5 Hz), ꢀ138.3 (m), ꢀ81.8 (t, J = 8.2 Hz).
(S)ꢀ5ꢀchloroꢀ5,5ꢀdifluoroꢀ4ꢀhydroxyꢀ4ꢀphenylpentanꢀ2ꢀone (3i)16: Colorless oil.
186 mg, 75% yield; 81% ee value was determined by HPLC Chiralcel ODꢀH column
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(Hexane/2ꢀpropanol = 95: 5, 1.0 mL/min, 210 nm) analysis, minor enantiomer tR =
5
6
7
7.096 min, major enantiomer tR = 9.869 min.
[
α
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+9.5 (c 1.0, CHCl3) [Literature16
31. 1
D
8
9
[ α]
+6.2 (c 1.0, CHCl3) for 72% ee (S)]; 1H NMR (400 MHz, CDCl3): δ 2.18 (s, 3H),
D
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3.25 (d, J = 17.0 Hz, 1H), 3.45 (d, J = 17.0 Hz, 1H), 5.55 (s, 1H), 7.32ꢀ7.47 (m, 3H),
13
7.54ꢀ7.65 (m, 2H); C NMR (100 MHz, CDCl3): δ 32.1, 45.6, 79.5 (t, J = 25.5 Hz),
126.6, 128.3, 128.8, 130.2 (t, J = 299.1 Hz), 138.0, 209.1; 19F NMR (376 MHz,
CDCl3): δ ꢀ65.1 (d, J = 166.3 Hz), ꢀ64.3 (d, J = 166.3 Hz).
(S)ꢀ6,6,6ꢀtrifluoroꢀ5ꢀhydroxyꢀ5ꢀphenylhexanꢀ3ꢀone (3j)16: Colorless oil. 226 mg,
92% yield; 87% ee value was determined by HPLC Chiralcel ODꢀH column
(Hexane/2ꢀpropanol = 97: 3, 1.0 mL/min, 210 nm) analysis, minor enantiomer tR =
30. 4
D
6.243 min, major enantiomer tR = 7.292 min.
[Literature16 +5.7 (c 1.0, CHCl3) for 67% ee (S)]; 1H NMR (400 MHz, CDCl3): δ
[ α]
D
[
α
]
+18.5 (c 1.0, CHCl3)
1.00 (t, J = 7.3 Hz, 3H), 2.33ꢀ2.48 (m, 1H), 2.49ꢀ2.65 (m, 1H), 3.18 (d, J = 16.9 Hz,
1H), 3.30 (d, J = 16.9 Hz, 1H), 5.59 (s, 1H), 7.31ꢀ7.46 (m, 3H), 7.50ꢀ7.65 (m, 2H);
13C NMR (100 MHz, CDCl3): δ 7.1, 38.2, 44.1, 75.9 (q, J = 29.0 Hz), 124.5 (q, J =
284.9 Hz), 126.1, 128.4, 128.8, 137.5, 211.8; 19F NMR (376 MHz, CDCl3): δ ꢀ80.2 (s).
(S)ꢀ1,1,1ꢀtrifluoroꢀ2ꢀhydroxyꢀ2ꢀphenylheptanꢀ4ꢀone (3k)30: Colorless oil. 247 mg,
95% yield; 88% ee value was determined by HPLC Chiralcel ODꢀH column
(Hexane/2ꢀpropanol = 99.5: 0.5, 1.0 mL/min, 210 nm) analysis, minor enantiomer tR
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31. 1
D
= 10.735 min, major enantiomer tR = 14.227 min.
[
α
]
+12.3 (c 1.0, CHCl3); H
6
7
8
9
NMR (400 MHz, CDCl3): δ 0.83 (t, J = 7.4 Hz, 3H), 1.47ꢀ1.60 (m, 2H), 2.30ꢀ2.42 (m,
1H), 2.43ꢀ2.55 (m, 1H), 3.17 (d, J = 17.0 Hz, 1H), 3.31 (d, J = 17.0 Hz, 1H), 5.65 (s,
1H), 7.31ꢀ7.43 (m, 3H), 7.51ꢀ7.63 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 13.3, 16.5,
44.3, 46.7, 76.1 (q, J = 29.1 Hz), 124.6 (q, J = 285.5 Hz), 126.1, 128.4, 128.8, 137.6,
211.5; 19F NMR (376 MHz, CDCl3): δ ꢀ80.2 (s).
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Acknowledgment
The authors would like to thank The Key Laboratory of Coal to Ethylene Glycol
and Its Related Technology, The State Key Lab of Structural Chemistry, Fujian
Institute of Research on the Structure of Matter, Chinese Academy of Sciences for
financial support.
Supporting Information
The detailed conditions for optimization of the catalytic asymmetric aldol reaction;
copies of NMR spectra (1H, 13C and 19F) of chiral ligands and asymmetric aldol
reaction products; copies of HPLC data of chiral aldol reaction products. This
material is available free of charge via the Internet at http://pubs.acs.org.
References
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1. (a) List, B.; Lerner, R. A.; Barbas, C. F. J. Am. Chem. Soc. 2000, 122, 2395ꢀ2396.
(b) Notz, W.; List, B. J. Am. Chem. Soc. 2000, 122, 7386ꢀ7387.
7
8
9
2. (a) Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F. J. Am. Chem. Soc. 2001, 123,
5260ꢀ5267. (b) Cordova, A.; Notz, W.; Barbas, C. F. J. Org. Chem. 2002, 67, 301ꢀ
303.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3. Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 6798ꢀ6799.
4. For selected recent reviews, see: (a) Mahrwald, R. Modern Methods in
Stereoselective Aldol Reactions; WileyꢀVCH: Weinheim, 2013. (b) Trost, B. M.;
Brindle, C. S. Chem. Soc. Rev. 2010, 39, 1600ꢀ1632.
5. For selected recent papers, see: (a) Torii, H.; Nakadai, M.; Ishihara, K.; Saito, S.;
Yamamoto, H. Angew. Chem., Int. Ed. 2004, 43, 1983ꢀ1986. (b) Franzen, J.;
Marigo, M.; Fielenbach, D.; Wabnitz, T. C.; Kjaersgaard, A.; Jorgensen, K. A. J.
Am. Chem. Soc. 2005, 127, 18296ꢀ18304. (c) Liu, K.; Cui, H. F.; Nie, J.; Dong, K.
Y.; Li, X. J.; Ma, J. A. Org. Lett. 2007, 9, 923ꢀ925. (d) Hayashi, Y.; Itoh, T.;
Aratake, S.; Ishikawa, H. Angew. Chem. Int. Edit. 2008, 47, 2082ꢀ2084. (e)
Nakayama, K.; Maruoka, K. J. Am. Chem. Soc. 2008, 130, 17666ꢀ17667. (f) Ma,
X.; Da, C. S.; Yi, L.; Jia, Y. N.; Guo, Q. P.; Che, L. P.; Wu, F. C.; Wang, J. R.; Li,
W. P. Tetrahedron Asymmetry 2009, 20, 1419ꢀ1424. (g) Lin, J. H.; Zhang, C. P.;
Xiao, J. C. Green Chem. 2009, 11, 1750ꢀ1753. (h) Chen, W. B.; Du, X. L.; Cun, L.
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2
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5
6
7
8
9
F.; Zhang, X. M.; Yuan, W. C. Tetrahedron 2010, 66, 1441ꢀ1446.
6. (a) Kumar, A.; Chimni, S. S. Tetrahedron 2013, 69, 5197ꢀ5204. (b) Adachi, S.;
Herada, T. Eur. J. Org. Chem. 2009, 3661ꢀ3671. (c) Guillena, G.; Najera, C.;
Ramon, D. J. Tetrahedron Asymmetry 2007, 18, 2249ꢀ2293.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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29
30
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32
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42
43
44
45
46
47
48
49
50
51
52
53
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55
56
57
58
59
60
7. (a) Banks, R. E.; Smart, B. E.; Tatlow, J. C. Organofluorine Chemistry: Principles
and Commercial Applications; Plenum Press: New York, 1994. (b) Hiyama, T.
Organofluorine Compounds: Chemistry and Applications; Springer: New York,
2000. (c) Begue, J. P.; Bonnetdelpon, D. Bioorganic and Medicinal Chemistry of
Fluorine; John Wiley & Sons: Hoboken, N.J., 2008. (d) Purser, S.; Moore, P. R.;
Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320ꢀ330.
8. (a) Ritter, K. S. Chem. Eng. News 2012, 90, 10ꢀ17. (b) Zhang, P.; Wolf, C. J. Org.
Chem. 2012, 77, 8840ꢀ8844. (c) Muller, K.; Faeh, C.; Diederich, F. Science 2007,
317, 1881ꢀ1886.
9. Nie, J.; Guo, H. C.; Cahard, D.; Ma, J. A. Chem. Rev. 2011, 111, 455ꢀ529.
10. For selected recent reviews, see: (a) Ma, J. A.; Cahard, D. Chem. Rev. 2004, 104,
6119ꢀ6146. (b) Ma, J. A.; Cahard, D. Chem. Rev. 2008, 108, PR1ꢀPR43.
11. Qiu, L. H.; Shen, Z. X.; Shi, C. Q.; Liu, Y. H.; Zhang, Y. W. Chin. J. Chem. 2005,
23, 584ꢀ588.
12. (a) Wang, X. J.; Zhao, Y.; Liu J. T. Org. Lett. 2007, 9, 1343ꢀ1345. (b) Wang, X. J.;
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Zhao, Y.; Liu J. T. Synthesis 2008, 24, 3967ꢀ3973.
5
6
7
8
9
13. Zhang, D. H.; Yuan, C. Y. Tetrahedron 2008, 64, 2480ꢀ2488.
14. Hara, N.; Tamura, R.; Funahashi, Y.; Nakamura, S. Org. Lett. 2011, 13, 1662ꢀ
1665.
10
11
12
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14
15
16
17
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19
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23
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57
58
59
60
15. Duangdee, N.; Harnying, W.; Rulli, G.; Neudorfl, J. M.; Groger, H.; Berkessel, A.
J. Am. Chem. Soc. 2012, 134, 11196ꢀ11205.
16. Kokotos, C. G. J. Org. Chem. 2012, 77, 1131ꢀ1135.
17. Zheng, Y.; Xiong, H.Y.; Nie, J.; Hua, M. Q.; Ma, J. A. Chem. Commun. 2012, 48,
4308ꢀ4310.
18. Lin, J.; Kang, T. R.; Liu, Q. Z.; He, L. Tetrahedron Asymmetry 2014, 25, 949ꢀ955.
19. Yang, W.; Cui, Y. M.; Zhou, W.; Li, L.; Yang, K. F.; Zheng, Z. J.; Lu, Y. X.; Xu,
L. W. Synlett 2014, 25, 1461ꢀ1465.
20. Review: Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107,
5471ꢀ5569.
21. For selected recent papers on reactions use chiral diamines as organocatalysts, see:
(a) Luo, S. Z.; Xu, H.; Chen, L. J.; Cheng, J. P. Org. Lett. 2008, 10, 1775ꢀ1778. (b)
Luo, S. Z.; Xu, H.; Li, J. Y.; Zhang, L.; Cheng, J. P. J. Am. Chem. Soc. 2007, 129,
3074ꢀ3075. (c) Saito, S.; Yamamoto, H. Acc. Chem. Res. 2004, 37, 570ꢀ579. (d)
Nakadai, M.; Saito, S.; Yamamoto, H. Tetrahedron 2002, 58, 8167ꢀ8177.
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22. Armarego, W. L. F.; Chai, C. L. L. Purification of Laboratory Chemicals, 5th Ed.,
Butterworth Heinemann: Oxford, 2003.
7
8
9
23. (a) GonzalezꢀSabin, J.; Gotor, V.; Rebolledo, F. A. Tetrahedron: Asymmetry 2006,
17, 449ꢀ454. (b) GonzalezꢀSabin, J.; Gotor, V.; Rebolledo, F. Chem. Eur. J. 2004,
10, 5788ꢀ5794.
10
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50
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53
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55
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24. (a) Veitch, G. E.; Jacobsen, E. N. Angew. Chem. Int. Edit. 2010, 49, 7332ꢀ7335. (b)
Fuerst, D. E.; Jacobsen, E. N. J. Am. Chem. Soc. 2005, 127, 8964ꢀ8965.
25. Xu, B.; Li, L.; Gou, S. H. Tetrahedron: Asymmetry 2013, 24, 1556ꢀ1561.
26. Berkessel, A.; Mukherjee, S.; Muller, T. N.; Cleemann, F.; Roland, K.;
Brandenburg, M.; Neudorfl, J. M.; Lex, J. Org. Biomol. Chem. 2006, 4, 4319ꢀ
4330.
27. Li, J. Y.; Fu, N. K.; Zhang, L.; Zhou, P. X.; Luo, S. Z.; Cheng, J. P. Eur. J. Org.
Chem. 2010, 35, 6840ꢀ6849.
28. (a) Huang, H. Y.; Zong, H.; Shen, B.; Yue, H. F.; Bian, G. L.; Song, L.
Tetrahedron 2014, 70, 1289ꢀ1297. (b) Yue, H. F.; Huang, H. Y.; Bian, G. L.;
Zong, H.; Li, F. L.; Song, L. Tetrahedron: Asymmetry 2014, 25, 170ꢀ180.
29. Huang, H. Y.; Zong, H.; Bian, G. L.; Song, L. J. Org. Chem. 2012, 77, 10427ꢀ
10434.
30. Sasaki, S.; Kikuchi, K.; Yamauchi, T.; Higashiyama, K. Synlett 2011, 10, 1431ꢀ
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