The development of new amine-amide ligands for application in Cu(II)-catalyzed enantioselective Henry reactions

Article abstract of DOI:10.1016/j.tetasy.2016.05.005

A new type of chiral tertiary amine ligand was designed and derived from l-proline and (R)-BINOL. These new chiral ligands chelated with Cu(II) showed highly catalytic efficiency in enantioselective Henry reactions. Excellent yields (up to 99%) and high enantioselectivities (up to 96% ee) were achieved for aromatic, hetero-aromatic and aliphatic aldehyde substrates, without an additional base additive or the need for air or moisture exclusion.

Full text of DOI:10.1016/j.tetasy.2016.05.005

Tetrahedron: Asymmetry xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
The development of new amine–amide ligands for application
in Cu(II)-catalyzed enantioselective Henry reactions
Chunyan Ao a, Jian Men a, Yang Wang b, Tao Shao a, Yuanyuan Huang a, Junji Huo a, Guowei Gao a,
⇑
a College of Chemistry, Sichuan University, Chengdu 610064, PR China
b Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, 21 Nanyang Link, Singapore 637371, Singapore
a r t i c l e i n f o
a b s t r a c t
Article history:
A new type of chiral tertiary amine ligand was designed and derived from L-proline and (R)-BINOL. These
Received 9 February 2016
Revised 3 May 2016
Accepted 10 May 2016
Available online xxxx
new chiral ligands chelated with Cu(II) showed highly catalytic efficiency in enantioselective Henry reac-
tions. Excellent yields (up to 99%) and high enantioselectivities (up to 96% ee) were achieved for aromatic,
hetero-aromatic and aliphatic aldehyde substrates, without an additional base additive or the need for air
or moisture exclusion.
Ó 2016 Elsevier Ltd. All rights reserved.
1. Introduction
biaryl axis due to the steric hindrance of the aryl group. The modifi-
cation of this binaphthyl moiety would also allow further modifica-
To be a useful chiral catalyst, it must provide the target product
in high yield and excellent enantioselectivity. Moreover, it must
have a simple synthesis from commercially available starting
materials. Many enzymes are remarkable asymmetric catalysts
and show excellent activity and selectivity.1 However, their com-
plicated structures and specific selectivity mean that their applica-
bility can be narrow. Aspiring to imitate the enzymatic synergistic
cooperation of multi-active centers, chemists set out to design and
develop many types of useful multifunctional catalysts for asym-
metric synthesis from a fundamental backbone.2 It is even more
surprising that certain classes of synthetic catalysts are enantiose-
lective over a wide range of different reactions; such catalysts can
be called ‘privileged structures’.3 Among them, (S)-proline, and (R)-
and (S)-BINOL are some of the most interesting catalyst struc-
tures.4 Recently, researchers have been actively pursuing the
design of new ligands by exploiting the concept derived from mul-
tifunctional catalysts. Many homochiral catalysts containing ami-
nes, ethers, alcohol etc. as electron donors have been successfully
developed.5
tion of the catalytic activity. Therefore, the design of a new
multifunctional catalyst integrating the above separated moieties
into one molecule would be attractive. Nájera et al.7 developed
and synthesized new types of prolinamides derived from a binaph-
thalene backbone and (S)-proline, as shown in Scheme 1 (BINAM-
prolinamide). However, this catalyst is still a base-reliant type
organocatalyst. The carboxylic group of proline formed a proli-
namide directly with 2,20-diamino-1,10-binaphthalene, which
would restrict its nature of structural diversity. In terms of economy
and flexibility, modification of (S)-proline would be much easier
than that of binaphthalene. Moreover, the chiral ligand could further
expand upon its application with bonds to different metal centers.
Herein our aim was to find a new type of chiral ligand based on
the idea of integrating binaphthyl and proline moieties into one
molecule connected through a simple linker, as shown in Scheme 1
(L).
The Henry reaction is one of the most atom economical carbon–
carbon bond forming reactions.8 The resulting b-hydroxy nitro
compounds re widely used in synthetic chemistry.9 Over the past
few years, many amine and amide type chiral ligands have been
successfully applied in asymmetric Henry reactions.10 However,
many of these catalytic systems still suffer from limitations such
as high catalyst loading, air- and moisture-sensitivity, and addi-
tional stoichiometric base additives. Herein, we report the synthe-
sis of new chiral tertiary amines and amide type ligands simply
derived from (S)-proline and (R)-BINOL, as well as their successful
application as chiral ligands in Cu(II) catalyzed asymmetric Henry
reactions. Excellent yields (up to 99%) and enantioselectivities (up
to 96%) were obtained for aromatic, hetero-aromatic and aliphatic
(S)-Proline features as a bifunctional organocatalyst.4c,d After
simple modification of proline to prolinamide, similar to some
small peptides catalysts,6 the amide functional group could assist
the reactions efficiently and selectively. Moreover, these systems
permit the enhancement of the structural diversity of the catalysts
and thus the ability to finely tune their reactivity. For the binaph-
thalene fragment, it could provide a restricted rotation around the
⇑
Corresponding author. Tel./fax: +86 28 85412095.
E-mail address: gaoguowei@scu.edu.cn (G. Gao).
http://dx.doi.org/10.1016/j.tetasy.2016.05.005
0957-4166/Ó 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Ao, C.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.05.005

2
C. Ao et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
Table 1
NH
Chiral ligands screening in asymmetric Henry reaction
H
N
N
H
OH
*
CONHR
O
O
Cu(OAc)2 H2O (10 mol%)
N
N
NO2
CHO
ligand
(10 mol%)
CH3NO2
+
EtOH, 25 o
C
O2N
O2N
NH
L
6a
5a
BINAM-prolinamide
our design
Entrya
Ligand
Time [h]
% Yieldb
% eec
9 (R)
13 (R)
10 (R)
77 (R)
80 (R)
17 (R)
31 (R)
Scheme 1. BINAM-prolinamide and a new design of chiral ligands.
1
2
3
4
5
6
7
L1
L2
L3
L4
L5
L6
L7
24
24
24
24
24
24
24
85
90
83
99
98
84
83
aldehyde substrates, without the need for an extra base additive or
the need for air or moisture exclusion.
2. Results and discussion
a
Reactions were carried out on a 0.5 mmol scale of nitrobenzaldehyde with
nitromethane (10 equiv) in EtOH (1 mL) in the presence of ligand (10 mol %) Cu
With the aim of discovering a simple, inexpensive and efficient
route to combine (S)-proline and (R)-BINOL into one molecule, a
series of chiral tertiary amine type ligands L1–L5 were synthesized
from commercially available (S)-Boc-proline and (R)-BINOL via the
pathways outlined in Scheme 2. Our synthesis began by transform-
ing (S)-Boc-proline into the corresponding amides. Cleavage of the
N-Boc protecting group with trifluoroacetic acid in dichloro-
methane gave 1.11 It is known that tertiary diamine ligands have
relatively strong basicity and coordination ability, which would
influence the catalytic activity. Therefore in our design strategy,
the linker between the proline and binaphthyl structure is the
key feature. N-Cbz-2-bromoethylamine was finally chosen to play
the role of bridging linker. After alkylation with amides 1, the
N-Cbz protecting group was removed to obtain 2 by hydrogenoly-
sis under a hydrogen atmosphere at ordinary pressure in the pres-
ence of 10% palladium on a carbon catalyst. Meanwhile, (R)-BINOL
was transferred to a bis-triflate protected species with trifluo-
romethanesulfonic anhydride. Subsequent cross-coupling with
methylmagnesium bromide in the presence of the nickel catalyst
NiCl2(PPh3)2 afforded the (R)-dimethylated compound 3. The route
to obtain bis(bromomethyl)binaphthalene 4 involves the use of
NBS in cyclohexane using benzoyl peroxide as a radical initiator.12
The final step was a double-alkylation between 4 and 2 to achieve
chiral ligands L1–L5.10b,13
(OAc)2ꢀH2O (10 mol %) at room temperature.
b
Isolated yield.
c
Enantiomeric excess were determined by HPLC analysis. The absolute config-
urations were established by comparison of the sign of the specific rotation values
with that in the literature.14
tive yield, but with lower enantioselectivity (Table 1, entry 4).
For the rest L1–L3 with aliphatic R groups, only about 10% ee
was obtained (Table 1, entries 1 to 3).
From the above experimental results, we determined that the
reactivity and enantioselectivity of chiral ligands were closely
dependent on the R substituents of the amide moiety. In order to
determine further information about each fragment’s function for
asymmetric induction, we synthesized two comparison ligands
L6 and L7 and tested them in the model reaction (Scheme 3).
Removing the chiral part of (S)-proline, L6 showed only 17% enan-
tioselectivity. After replacement of the binaphthyl fragment with
iso-indoline, L7 only afforded 31% enantioselectivity. These results
suggest that both the amide moiety of (S)-proline and the binaph-
thyl units in chiral ligand play a pivotal role in the asymmetric
induction, among which the amide moiety is more important than
the binaphthyl units. It is evident that we can modify the aromatic
amide moiety with a priority to improve the activity and enantios-
electivity in the future work.
Encouraged by the initial results in the asymmetric Henry reac-
tion, we continued the optimization of the reaction conditions.
First, a series of metal salts were evaluated in combination with
chiral ligand L5 and in ethanol at 25 °C over 24 h to catalyze the
model reaction. The results are shown in Table 2 (entries 1 to 7).
The other divalent metal salts, such as Zn(OAc)2ꢀ2H2O, Co(OAc)2-
ꢀ4H2O, Ni(OAc)2ꢀ4H2O and Cu(acac)2, gave the same high yield,
but no enantioselectivity (Table 2, entries 2 to 5). Furthermore
With the chiral ligands in hand, we were then able to test their
effectiveness in asymmetric Henry reactions. Copper(II) acetate
monohydrate [Cu(OAc)2ꢀH2O] was chosen for screening the new
chiral ligands in ethanol at room temperature to catalyze the
model reaction between 4-nitrobenzaldehyde 5a and nitro-
methane. The results are listed in Table 1 (entries 1 to 5); L5 was
found to be the best for this reaction, affording the desired product
in near quantitative yield with 80% ee after 24 h (Table 1, entry 5).
Ligand L4 with a phenyl group produced the same near quantita-
a
b
COOH
CONHR
CONHR
N
N
H
N
Boc
1
2
CONHR
e
N
N
NH2
Br
Br
L
c
d
OH
OH
L1 R = n-butyl
L2 R = t-butyl
L3 R = cyclohexyl
L4 R = phenyl
L5 R = 1-naphthyl
3
4
Scheme 2. Synthetic routes to chiral ligands: (a) (i) RNH2, ClCO2iBu, Et3N, 0 °C–rt, (ii) TFA, CH2Cl2, rt; (b) (i) BrC2H4NHCbz, K2CO3, CH3CN, reflux, (ii) Pd/C, H2, MeOH, rt; (c) (i)
Tf2O, Py, CH2Cl2, 0 °C, (ii) MeMgBr, NiCl2(PPh3)2, 0 °C; (d) NBS, (PhCO)2O, cyclohexane, reflux; (e) Et3N, CH2Cl2, reflux.
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C. Ao et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
3
a
b
NHCbz
N
NHCbz
N
N
NH
+
Br
L6
CONHR
CONHR
c
Br
Br
N
N
+
N
2
L7
R = naphthyl
NH2
Scheme 3. Synthetic routes to comparison ligands L6 and L7: (a) K2CO3, CH3CN, reflux; (b) (i) Pd/C, H2, MeOH, rt, (ii) 4, Et3N, DCM, reflux; (c) Et3N, DCM, reflux.
Table 2
Optimization on metal ions and temperature
Table 3
Optimization of the reaction conditions
OH
*
OH
*
metal salts (10 mol%)
Cu(OAc)2 (10 mol%)
L5
NO2
CHO
CHO
NO2
L5 (10 mol%)
(10 mol%)
CH3NO2
CH3NO2
+
+
solvent, 10 o
C
ethanol, T
O2N
O2N
O2N
O2N
5a
6a
5a
6a
Entrya
Metal salts
T (°C)
% Yieldb
% eec
Entrya
Solvent
Time [h]
% Yieldb
% eec
1
2
3
4
5
6
7
8
Cu(OAc)2ꢀH2O
Zn(OAc)2ꢀ2H2O
Co(OAc)2ꢀ4H2O
Ni(OAc)2ꢀ4H2O
Cu(acac)2
Cu(OTf)2
CuI
CuOAc
Cu(OAc)2
Cu(OAc)2
25
25
25
25
25
25
25
25
25
20
10
0
98
95
95
93
92
NR
90
90
98
89
95
60
NR
80 (R)
0
1
2
3
4
5
6
7
8
EtOH
iPrOH
MeOH
THF
36
36
36
36
36
36
36
36
24
24
24
48
48
99
95
90
95
75
70
72
29
95
92
93
65
63
96 (R)
90 (R)
92 (R)
88 (R)
85 (R)
85 (R)
88 (R)
89 (R)
93 (R)
82 (R)
94 (R)
90 (R)
82 (R)
0
0
0
—
Et2O
MeCN
Toluene
CH2Cl2
EtOH
EtOH
EtOH
EtOH
EtOH
16 (R)
36 (R)
84 (R)
87 (R)
93 (R)
87 (R)
—
9
9
10
11
12
13
10d
11e
12f
13g
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
ꢁ10
a
a
Reactions were carried out on a 0.5 mmol scale of nitrobenzaldehyde with
Reactions were carried out on a 0.5 mmol scale of nitrobenzaldehyde with
nitromethane (10 equiv) in EtOH (1 mL) in the presence of L5 (10 mol %) metal salts
nitromethane (10 equiv) in solvent (1 mL) in the presence of L5 (10 mol %) Cu(OAc)2
(10 mol %) for 24 h.
(10 mol %) at room temperature.
b
b
Isolated yield.
Isolated yield.
c
c
Enantiomeric excess was determined by HPLC analysis. The absolute configu-
Enantiomeric excess was determined by HPLC analysis. The absolute configu-
rations were established by comparison of the sign of the specific rotation values
rations were established by comparison of the sign of the specific rotation values
with that in the literature.14
with that in the literature.14
d
Et3N (1.0 equiv) was used.
3 Å MS (0.2 g/mmol) was added.
L5 (5 mol %) and Cu(OAc)2 (5 mol %) were used.
L5 (1 mol %) and Cu(OAc)2 (1 mol %) were used.
e
f
when using Cu(OTf)2, the reaction did not take place (Table 2, entry
6). As well as divalent copper salts, monovalent copper salts CuI
and CuOAc also promoted the reaction with satisfactory yield,
but the enantioselectivities dropped dramatically (Table 2, entries
7 and 8). Similar with Cu(OAc)2ꢀH2O, the Cu(OAc)2 could promote
the reaction smoothly in high yield and with an even higher ee
value of 84% (Table 2, entry 9). In terms of yield and enantioselec-
tivity, Cu(OAc)2 proved to be the preferred catalyst. Next, we opti-
mized the temperature (Table 2, entries 10 to 13). Decreasing the
temperature to 10 °C enhanced the enantioselectivity to 93%, while
still keeping with high yield (Table 2, entry 11).
Next, the solvent effect on the enantioselectivity was examined
and the results are shown in Table 3. When the alcohol solvents
such as iPrOH, EtOH, and MeOH were used, all of the reactions pro-
ceeded smoothly to afford the desired product 6a with high yields
(up to 99%) and high enantioselectivities (up to 96% ee) (Table 3,
entries 1 to 3). It was worth noting that EtOH still resulted in a
higher ee than any other solvents (Table 3, entry 1). Using THF as
the solvent, the reaction gave the desired Henry product 6a in
95% yield and with 88% ee (Table 3, entry 4). When toluene, Et2O
and MeCN were used as solvents, the reaction resulted in good
yield (70% to 75%) and with high enantioselectivity (up to 88%
ee) (Table 3, entries 5 to 7). Unfortunately, when CH2Cl2 was used
as the solvent, it gave product 6a with only 29% yield and 89% ee
g
(Table 3, entry 8). The above results indicated that ethanol was
the preferred solvent for this Henry reaction. A Lewis base can play
a role in the activation of the substrate.15 Et3N was tested as an
additive, but unfortunately the enantioselectivity dropped to 82%
(Table 3, entry 10). As in previous metal salt screening, Cu(OAc)2
gave higher enantioselectivity than Cu(OAc)2ꢀH2O. Hence we
speculated that the hydrate might have some influence on the
enantioselectivity. The molecular sieves additive was tested in this
reaction (0.2 g/mmol 3 Å MS). However there was no obvious
improvement in the enantioselectivity, which meant that this
reaction was not moisture sensitive (Table 3, entry 11). When
the reaction time was prolonged, it could enhance the yield and
enantioselectivity (Table 3, entry 1, 9). Catalyst loading was also
tested; 5 mol % of Cu(OAc)2 and L5 resulted in high ee (90%) but
the yield decreased dramatically (Table 3, entry 12). Even lower
catalyst loading (1 mol %) was also tested, and comparable enan-
tioselectivity (82%) could still be achieved (Table 3, entry 13).
With the optimized condition in hand, we next studied the
generality of the asymmetric Henry reaction of various aromatic
aldehydes and aliphatic aldehydes with nitromethane in the
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C. Ao et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
Table 5
presence of catalyst L5 with Cu(OAc)2 as shown in Table 4. The
scope of our catalyst system was extended to aromatic aldehydes
(Table 4, entries 1 to 13), which provided high yields (up to 99%)
and excellent enantioselectivities (up to 96% ee). The reactions of
benzaldehydes substituted with electron-donating groups afforded
Henry adducts 6d and 6g in lower yields than 6c (Table 4, entries 4,
7). Conversely, electron-withdrawing substituents made the yield
higher (Table 4, entries 1, 2, and 10). Although the electronic prop-
erties of the substituents on the aromatic ring affected the yield,
they had little influence on the enantioselectivity. In addition, a
variety of 2-, 3-, or 4-substituted benzaldehydes (Table 4, entries
4 to 9) were involved with the corresponding reactions and no sig-
nificant differences in the yields or enantioselectivities of the prod-
ucts related were observed. This indicated that the position of the
substituted groups on the phenyl ring had little influence on the
catalytic effect of our system. Other aromatic aldehydes, 1-naph-
thaldehyde and 2-naphthaldehydes, were found to be suitable sub-
strates, and the reaction afforded the desired Henry products 6k to
6l in high yields (82%, 83%) and enantioselectivities (90%, 88% ee)
(Table 4, entries 11, 12). The heteroaromatic aldehydes also
reacted with nitromethane in our catalytic system to give optically
active nitroaldol adducts 6m in good yield and with good enantios-
electivity (Table 4, entry 13). Under the same reaction conditions, a
variety of aliphatic aldehydes were obtained in good yields (up to
91%) as well as with excellent enantioselectivities ranging from
88% to 93%, which produced their respective b-nitroalcohols. It
should be noted that the length and the size of the alkyl chains
in the substrates, no matter if they were unbranched (Table 4,
entries 14 to 20), branched (Table 4, entry 17) alkyl chain aldehy-
des, they had hardly any influence on the enantioselectivity or the
yield of the resulting product derived from aliphatic aldehydes.
In view to explore the nitroalkane substrate scope, we also
tested some other nitroalkanes. The corresponding nitroaldol
adducts bearing two stereogenic centers were obtained in good
Diastereoselective Henry reactions
OH
OH
Cu(OAc)2 (10 mol%)
L5 (10 mol%)
NO2
NO2
R1CH2NO2
RCHO
+
R
R
+
EtOH, 10 oC, 24 h
R1
syn-8
R1
anti-8
7
5a
R= 4-NO2C6H4
Entrya
R1
% Yieldb
% syn/antic
% eed
1
2
3
Methyl 7a
Ethyl 7b
Benzyl 7c
89
92
75
55/45
71/29
76/24
64/54
77/50
36/25
a
Reactions were carried out with nitrobenzaldehyde (0.5 mmol) and nitroalkane
(10 equiv) in EtOH (1 mL) in the presence of L5 (10 mol %) and Cu(OAc)2 (10 mol %).
b
Isolated yield.
c
Determined by 1H NMR spectroscopy analysis.
d
Enantiomeric excess was determined by HPLC analysis.
yield albeit moderate diastereoselectivities favoring syn-product
and enantioselectivities were observed. Diastereoselectivity was
improved when more sterically hindered aldehyde was used
(Table 5, entries 1 to 3). The limitation was the bad enantioselectiv-
ity of each diastereomer.
On the basis of the preliminary experimental findings and pre-
viously reported steric and electronic considerations,10a,17 we have
proposed
a
reasonable transition state model for the
enantioselective Henry reaction (Fig. 1). The Cu(II) complex with
a plane quadrilateral geometry has four strong coordination sites
at the equatorial positions and two weak coordination sites at
the apical positions due to the Jahn–Teller effect.18 In the transition
state, the two highly coordinative tertiary amine nitrogen atoms of
L5 occupy two neighboring strong coordination sites. Both the
aldehyde and nitromethane are efficiently activated by coordina-
tion to the equatorial and the apical position of the copper atom,
respectively. For maximum activation, the nucleophilic nitronate
would orientate towards the inside position perpendicular to the
ligand plane and be fixed with the hydrogen bonding with the
N–H group of the amide moiety, whereas the electrophilic alde-
hyde should occupy the outside site, thus avoiding the steric hin-
drance of ligand L5. Therefore, the attack of the nitronate from
the Re-face of the carbonyl group is hampered by one of the naph-
thyl structure moieties of the ligand, and so it takes place preferen-
tially from the Si-face to give the nitroaldol with an (R)-
configuration.
Table 4
Asymmetric catalysis Henry reactions
Cu(OAc)2 (10 mol%)
OH
L5 (10 mol%)
CH3NO2
RCHO
NO2
+
EtOH, 10 o
C
R
*
6
Entrya
R
Time (h)
% Yieldb
% eec
96 (R)
1
2
3
4
5
6
7
8
4-NO2C6H4 5a
3-NO2C6H4 5b
Phenyl 5c
4-MeOC6H4 5d
2-MeOC6H4 5e
3-MeOC6H4 5f
4-MeC6H4 5g
2-MeC6H4 5h
3-MeC6H4 5i
4-BrC6H4 5j
1-Naphthyl 5k
2-Naphthyl 5l
2-thienyl 5m
CH3CH2 5n
CH3(CH2)2 5o
CH3(CH2)3 5p
(CH3)2CHCH2 5q
CH3(CH2)4 5r
CH3(CH2)5 5s
Cyclohexyl 5t
36
36
36
48
48
48
48
48
48
48
48
48
48
48
48
48
56
48
48
36
99
95
90
85
83
89
83
80
83
92
82
83
80
83
91
85
87
89
84
81
80 (R)
81 (R)
87 (R)
87 (R)
89 (R)
83 (R)
69 (R)
75 (R)
80 (R)
90 (R)
88 (R)
85 (S)
89 (NA)
93 (NA)
90 (R)
88 (R)
89 (R)
90 (R)
90 (R)
O
N
X
N
CuII
O
9
O
R
N
10
11
12
13
14
15
16
17
18
19
20
H
N
O
Si face attack
Figure 1. Proposed transition state for asymmetric Henry reaction.
3. Conclusions
In conclusion, we have designed and developed a series of new
chiral amine ligands, which can be used to combine with copper(II)
acetate as efficient catalysts for asymmetric Henry reactions. The
results showed that most catalysts consisting of L5–Cu(OAc)2 gave
good yields and enantiomeric excess for the desired product. This
catalyst system enables us to prepare b-nitroalcohols with good
a
Reactions were carried out with aldehydes (0.5 mmol) and nitromethane
(10 equiv) in EtOH (1 mL) in the presence of L5 (10 mol %) and Cu(OAc)2 (10 mol %).
b
Isolated yield.
c
Enantiomeric excess was determined by HPLC analysis. The absolute configu-
rations were established by comparison of the sign of the specific rotation values
with that in the literature.14,16
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C. Ao et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
5
enantioselectivities and high yields for a wide range of aldehydes
including aliphatic, aromatic aldehydes, and heteroaromatic alde-
hydes. Further studies focusing on the modification of the ligands
and their use as chiral ligands for other asymmetric reactions are
currently under investigation in our laboratory.
1H), 2.90 (dt, J = 10.3, 6.4 Hz, 1H), 2.62 (d, J = 56.5 Hz, 1H), 2.12 (tt,
J = 18.4, 9.0 Hz, 1H), 1.98–1.82 (m, 1H), 1.79–1.62 (m, 2H), 1.35 (t,
J = 4.3 Hz, 9H) ppm. 13C NMR (100 MHz, CDCl3): d = 174.0, 61.2, 50.2,
47.2, 30.7, 28.8, 26.1 ppm. [a D
]
25 = ꢁ15.6 (c 1, MeOH).
4.1.1.3. (S)-N-Cyclohexylpyrrolidine-2-carboxamide 1c.
Brown
oil (5.38 g, 85.7% yield). 1H NMR (400 MHz, CDCl3): d = 7.46 (d,
J = 51.2 Hz, 1H), 3.81–3.63 (m, 2H), 3.01 (dt, J = 10.1, 6.8 Hz, 1H), 2.89
(dt, J = 10.2, 6.3 Hz, 1H), 2.19–2.04 (m, 2H), 1.95–1.79 (m, 3H), 1.75–
1.65 (m, 4H), 1.64–1.55 (m, 1H), 1.44–1.30 (m, 2H), 1.23–1.09 (m, 3H)
ppm. 13C NMR (100 MHz, CDCl3): d = 174.0, 60.6, 47.3, 47.2, 33.2, 33.1,
4. Experimental
4.1. General
Starting materials, reagents, and dry solvent were purchased
from commercial suppliers and used without further purification.
Et2O and THF were distilled from Na and benzophenone, Et3N
was dried from CaH2. CH2Cl2 was distilled from CaH2. Melting
points (mp) were measured with melting point apparatus and
which were uncorrected. Enantiomeric excesses (ee) were deter-
mined by HPLC using the corresponding commercial chiral column
as stated in the experimental procedures at 23 °C and 25 °C with
UV detector at 220 nm and 210 nm. Optical rotations were mea-
30.8, 26.1, 25.6, 24.8, 24.8 ppm. [a D
]
25 = ꢁ23.7 (c 1, MeOH).
4.1.1.4. (S)-N-Phenylpyrrolidine-2-carboxamide 1d.
Yellow
solid (5.26 g, 86.5% yield), mp = 76–77 °C [lit.19: 72 °C]. 1H NMR
(400 MHz, CDCl3): d = 9.94 (s, 1H), 7.69–7.59 (m, 2H), 7.37–7.27
(m, 2H), 7.1–7.06 (m, 1H), 4.16–4.02 (m, 1H), 3.37 (s, 1H), 3.12
(dtd, J = 12.8, 10.4, 6.7 Hz, 2H), 2.36–2.15 (m, 1H), 2.07 (tt,
J = 12.8, 6.2 Hz, 1H), 1.96–1.69 (m, 2H) ppm. 13C NMR (100 MHz,
CDCl3): d = 172.2, 137.8, 129.0, 124.10, 119.5, 61.0, 47.3, 30.8,
sured on a commercial polarimeter and are reported as follows:
(c g/100 mL, in solvent). 1H NMR spectra were recorded on
T
26.0 ppm. [a]
25 = ꢁ48.7 (c 1, ethanol).
[
a]
D
D
commercial instruments (400 MHz). Chemical shifts are reported
in ppm from tetramethylsilane with the solvent resonance as the
internal standard (CDCl3, d = 7.26). Spectra are reported as follows:
chemical shift (d ppm), multiplicity (s = singlet, d = doublet, t = tri-
plet, q = quartet, m = multiplet), coupling constants (Hz), integra-
tion and assignment. 13C NMR spectra were collected on
commercial instruments (100 MHz) with complete proton decou-
pling. Chemical shifts are reported in ppm from the tetramethylsi-
lane with the solvent resonance as internal standard (CDCl3,
d = 77.0). HRMS was recorded on a commercial apparatus (ESI
Source).
4.1.1.5.
(S)-N-(Naphthalen-1-yl)pyrrolidine-2-carboxamide
Pale brown solid (6.78 g, 88.3% yield), mp = 62–65 °C
1e.
[lit.20: 63–64 °C]. 1H NMR (400 MHz, CDCl3): d = 10.40 (s, 1H), 8.10
(t, J = 10.9 Hz, 1H), 7.67 (dd, J = 16.8, 7.9 Hz, 2H), 7.43 (d, J = 8.2 Hz,
1H), 7.38–7.24 (m, 3H), 3.78–3.65 (m, 1H), 2.93–2.73 (m, 2H), 2.25
(s, 1H), 2.12–1.80 (m, 2H), 1.67–1.42 (m, 2H) ppm. 13C NMR
(100 MHz, CDCl3): d = 173.8, 134.0, 132.7, 128.7, 126.1, 126.0,
126.0, 125.9, 124.5, 120.3, 117.7, 61.5, 47.4, 30.9, 26.5 ppm.
[a
]
D
31 = ꢁ14.6 (c 0.51, CH2Cl2) [lit.19: [
a
]
D
25 = ꢁ7.3 (c 1, ethanol)].
4.1.2. General synthetic procedures for (2S)-2-(20-ethylamine)-
pyrrolidine carboxamide 2
4.1.1. General synthetic procedures for (2S)-2-(20-ethylamine)-
pyrrolidine carboxamide 1
To a solution of 1 (15.0 mmol) in CH3CN (60 mL) were added
K2CO3 (3.10 g, 22.5 mmol) and N-Cbz-2-bromoethylamine (3.87 g,
15.0 mmol) under stirring. It was then kept at 80 °C, and monitored
by TLC (Hexane/EtOAc = 2/1, v/v). Next, K2CO3 was removed by fil-
tration. The filtrate was concentrated to give a light brown oil. The
oil was dissolved in ethyl acetate (150 mL) and the solution was
washed with water (2 ꢂ 50 mL). The organic phase was dried over
anhydrous Na2SO4 and concentrated under reduced pressure to
afford the crude product. The residue was concentrated and puri-
fied by silica gel column chromatography (Hexane/EtOAc = 4/1, v/
v) to give a white solid.
To a 50 mL three-necked flask was added the above product
(30.00 mmol), which was dissolved in anhydrous MeOH (30 mL),
after which 0.05 g Pd/C (10%, w/w) were added to the solution.
The mixture was stirred at room temperature for 4 h under a
hydrogen atmosphere. The reaction solution was filtered and the
filtrate was concentrated under reduced pressure to afford 2 as a
yellow oil. This compound was used directly in the next step.
To a solution of L-N-Boc-proline (6.88 g, 32.0 mmol) in CH2Cl2
(240 mL) were added triethylamine (3.54 g, 35.2 mmol) and isobu-
tyl chloroformate (4.64 g, 35.2 mmol) at 0 °C with stirring. After
15 min, amine (35.2 mmol) was added. The reaction was allowed
to warm to room temperature and detected by TLC (Hexane/
EtOAc = 4/1, v/v). The mixture was washed with 1 M KHSO4, satu-
rated NaHCO3 and brine, then dried over anhydrous MgSO4 and
concentrated to give a crude product, which was further purified
by silica-gel column chromatography (Hexane/EtOAc = 6/1, v/v).
The above product was dissolved in dry CH2Cl2 (16 mL) and
treated with trifluoroacetic acid (16 mL). It was then stirred at
room temperature for 3 h. The solvent was removed under vac-
uum, after which was added CH2Cl2 (10 mL). The pH value was
brought into the range of 9–10 by the addition of 1 M NaOH. The
aqueous phase was extracted with CH2Cl2 (3 ꢂ 20 mL). The com-
bined organic phase was washed with brine, dried over anhydrous
MgSO4 and concentrated to give pure product 1.
4.1.3. General synthetic procedures for (R)-2,20-dimethyl-1,10-
binaphthyl 3
4.1.1.1. (S)-N-Butylpyrrolidine-2-carboxamide 1a.
Brown
oil (4.85 g, 89.2% yield). 1H NMR (400 MHz, CDCl3): d = 7.73 (s,
1H), 3.82 (dd, J = 27.2, 18.8 Hz, 1H), 3.25 (dd, J = 13.4, 6.8 Hz, 2H),
3.08 (dt, J = 10.2, 6.8 Hz, 1H), 2.96 (dt, J = 10.2, 6.3 Hz, 1H), 2.29–
2.10 (m, 1H), 2.03–1.89 (m, 1H), 1.83–1.70 (m, 2H), 1.56–1.46
(m, 2H), 1.43–1.26 (m, 3H), 0.94 (t, J = 7.2 Hz, 3H) ppm. 13C NMR
(100 MHz, CDCl3): d = 174.3, 61.5, 60.5, 47.2, 38.8, 31.7, 30.8,
To a solution of (R)-BINOL (14.3 g, 50 mmol) in 125 mL of CH2-
Cl2 was added pyridine (15.2 g, 150 mmol) followed by the drop-
wise addition of triflic anhydride (31.0 g, 110 mmol) at 0 °C. The
mixture was then stirred at room temperature for 6 h. After
removal of the solvent, the residue was diluted with EtOAc
(100 mL) and then washed with 5% aqueous HCl (25 mL), saturated
NaHCO3 (50 mL) and brine (50 mL). The organic layer was dried
over anhydrous sodium sulfate, concentrated and passed through
a silica gel plug (Hexane/EtOAc = 10/1, v/v) to give the (R)-2,20-
bistriflate-1,10-binaphthyl.
26.1, 20.1, 13.8 ppm. [
a]
25 = ꢁ20.5 (c 1, MeOH).
D
4.1.1.2. (S)-N-(tert-Butyl)pyrrolidine-2-carboxamide 1b.
White
solid, (4.52 g, 83.1% yield), mp = 79–80 °C. 1H NMR (400 MHz, CDCl3):
d = 7.50 (s, 1H), 3.65 (dd, J = 8.8, 5.6 Hz, 1H), 3.02 (dt, J = 10.1, 6.7 Hz,
Please cite this article in press as: Ao, C.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.05.005

6
C. Ao et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
To a solution of (R)-bistriflate (4.57 g, 8.30 mmol) and NiCl2(-
J = 8.2 Hz, 2H), 7.50–7.42 (m, 4H), 7.27 (d, J = 7.6 Hz, 2H), 3.69 (d,
J = 12.3 Hz, 2H), 3.22 (t, J = 8.9 Hz, 2H), 3.05–2.88 (m, 2H), 2.78–
2.62 (m, 2H), 2.52 (dd, J = 19.1, 9.6 Hz, 1H), 2.37 (td, J = 9.5,
6.6 Hz, 1H), 2.24–2.08 (m, 2H), 1.93–1.60 (m, 4H), 1.38 (s, 9H)
ppm. 13C NMR (100 MHz, CDCl3): d = 174.2, 135.0, 133.2, 131.4,
128.4, 128.3, 127.7, 127.5, 125.8, 125.5, 68.8, 55.9, 54.82, 54.7,
54.7, 50.2, 30.6, 29.7, 28.9, 24.3 ppm. ESI-MS+ m/z calcd. For
PPh3)2 (0.46 g, 0.70 mmol) in ether (80 mL) was added dropwise
methyl magnesiumbromide (3.0 M in ether, 15 mL) at 0 °C. The
reaction mixture was stirred at room temperature for 24 h. The
reaction was quenched by the addition of water (10 mL) slowly
at 0 °C and then diluted with 5% aqueous HCl (20 mL). The aqueous
layer was extracted with ether (3 ꢂ 50 mL). The combined organic
layer was washed with NaHCO3 (20 mL), dried over anhydrous and
concentrated to afford 3 as a light yellow solid (2.14 g, 91.2% yield),
C
33H38N3O 492.3015 [M+H]+; found 492.3025. [
0.5, CH2Cl2).
a
]
D
25 = ꢁ222.8 (c
mp = 66–68 °C [lit.12
:
68–72 °C]. 1H NMR (400 MHz, CDCl3):
d = 7.87 (d, J = 8.5 Hz, 2H), 7.85 (d, J = 8.4 Hz, 2H), 7.36 (d,
J = 8.3 Hz, 2H), 7.35–7.33 (m, 2H), 7.19–7.16 (m, 2H), 7.05 (d,
J = 8.4, 2H), 2.02 (s, 6H) ppm. 13C NMR (100 MHz, CDCl3):
d = 135.1, 134.3, 132.8, 132.2, 128.8, 127.9, 127.4, 126.1, 125.6,
4.2.3. (S)-1-(2-((R)-3H-Dinaphtho[2,1-c:10,20-e]azepin-4(5H)-yl)
ethyl)-N-cyclohexylpyrrolidine-2-carboxamide L3
Light yellow solid (0.57 g, 54.8% yield), mp = 82–84 °C. 1H NMR
(400 MHz, CDCl3): d = 7.99–7.88 (m, 4H), 7.53 (d, J = 8.2 Hz, 2H),
7.47 (dd, J = 7.6, 6.5 Hz, 4H), 7.28 (dd, J = 7.1, 1.5 Hz, 2H), 3.83–
3.73 (m, 1H), 3.70 (d, J = 12.3 Hz, 2H), 3.29–3.19 (m, 3H), 3.11
(dd, J = 10.1, 4.5 Hz, 1H), 2.94 (dt, J = 10.1, 7.2 Hz, 1H), 2.78–2.66
(m, 2H), 2.51 (dd, J = 14.6, 4.7 Hz, 1H), 2.44–2.34 (m, 1H), 2.28–
2.12 (m, 2H), 2.01–1.92 (m, 1H), 1.87 (ddd, J = 12.6, 7.9, 3.5 Hz,
2H), 1.81–1.59 (m, 5H), 1.48–1.32 (m, 2H), 1.22–1.05 (m, 3H)
ppm. 13C NMR (100 MHz, CDCl3): d = 174.0, 135.0, 133.2, 133.0,
131.4, 128.4, 128.3, 127.7, 127.4, 125.9, 125.6, 68.0, 55.8, 54.8,
54.4, 47.5, 33.4, 33.1, 30.7, 25.6, 25.0, 24.9, 24.3 ppm. ESI-MS+ m/
124.9, 20.0 ppm. [
a]
25 = ꢁ40.5 (c 1, CH2Cl2).
D
4.1.4. General synthetic procedures for (R)-2,20-dibromomethyl-
1,10-binaphthyl 4
To
a
solution of (R)-2,20-dimethyl-1,10-binaphthyl (2.8 g,
10.0 mmol) in cyclohexane (60 mL) was added N-bromosuccin-
imide (3.56 g, 20.0 mmol) and benzoyl peroxide (0.24 g, 1.0 mmol).
The reaction mixture was heated at reflux and irradiated under a
250 W infrared lamp for 8 h. The reaction mixture was cooled to
room temperature and filtered. The filtrate was concentrated
under reduced pressure. After removal of the solvent, the residue
was recrystallized from EtOAc to afford 4 as a white solid (2.64 g,
z
calcd. for C
35H40N3O 518.3171 [M+H]+; found 518.3168.
[a
]
25 = ꢁ229.4 (c 0.5, CH2Cl2).
D
60.0% yield), mp = 184–186 °C [lit.21
:
185–187 °C]. 1H NMR
4.2.4. (S)-1-(2-((R)-3H-Dinaphtho[2,1-c:10,20-e]azepin-4(5H)-yl)
ethyl)-N-phenylpyrrolidine-2-carboxamide L4
(400 MHz, CDCl3): d = 8.02 (d, J = 8.0 Hz, 2H), 7.92 (d, J = 8.0 Hz,
2H), 7.75 (d, J = 8.0 Hz, 2H), 7.46–7.44 (m, 2H), 7.25–7.23 (m,
2H), 7.06 (d, J = 8.0 Hz, 2H), 4.26 (s, 4H) ppm. 13C NMR (100 MHz,
CDCl3): d = 134.2, 134.1, 133.3, 132.5, 129.4, 128.0, 127.8, 127.6,
Light yellow solid (0.62 g, 60.3% yield), mp = 165–168 °C. 1H
NMR (400 MHz, CDCl3): d = 10.01 (s, 1H), 7.92 (d, J = 8.1 Hz, 2H),
7.79 (d, J = 8.2 Hz, 2H), 7.63 (d, J = 7.9 Hz, 2H), 7.44 (dd, J = 14.3,
7.5 Hz, 4H), 7.30 (t, J = 7.9 Hz, 3H), 7.24 (dd, J = 8.4, 1.8 Hz, 3H),
7.15 (t, J = 7.4 Hz, 1H), 4.12 (q, J = 7.1 Hz, 2H), 3.70 (d, J = 12.3 Hz,
2H), 3.33–3.19 (m, 3H), 3.04–2.90 (m, 1H), 2.48 (dt, J = 14.3,
7.4 Hz, 2H), 2.33–2.18 (m, 1H), 2.14–2.06 (m, 1H), 1.93–1.68 (m,
3H) ppm. 13C NMR (100 MHz, CDCl3): d = 178.0, 138.1, 135.0,
133.1, 131.3, 129.0, 128.3, 128.2, 127.8, 127.4, 125.8, 125.6,
124.0, 119.9, 68.4, 60.4, 55.8, 54.8, 54.1, 30.7, 29.6, 24.6, 21.1,
14.2 ppm. ESI-MS+ m/z calcd. for C35H34N3O 512.2702 [M+H]+;
126.8, 32.6 ppm. [
a]
25 = ꢁ89.3 (c 1, CH2Cl2).
D
4.2. General synthetic procedures for ligand L
A solution of 2 (2.0 mmol), 4 (0.97 g, 2.2 mmol), and triethy-
lamine (0.44 g, 4.4 mmol) in anhydrous CH2Cl2 (30 ml) was heated
at reflux for 24 h under Ar. The reaction was cooled to room tem-
perature and quenched by the addition of distilled water (15 ml),
and the aqueous layer was extracted with CH2Cl2. The combined
organic phase was washed with brine, and dried over Na2SO4. After
removal of the solvent under reduced pressure, the residue was
purified by column chromatography using silica gel (Hexane/
EtOAc = 3/1, v/v) to give product L.
found 512.2715. [
a]
25 = ꢁ297.4 (c 0.5, CH2Cl2).
D
4.2.5. (S)-1-(2-((R)-3H-Dinaphtho[2,1-c:10,20-e]azepin-4(5H)-yl)
ethyl)-N-(naphthalen-1-yl)pyrrolidine-2-carboxamide L5
Light yellow solid (0.65 g, 55.2% yield), mp = 200–202 °C. 1H
NMR (400 MHz, CDCl3): d = 10.47 (s, 1H), 8.17–8.10 (m, 1H),
7.95–7.90 (m, 2H), 7.89–7.84 (m, 2H), 7.84–7.80 (m, 1H), 7.74–
7.68 (m, 1H), 7.57–7.50 (m, 1H), 7.49–7.42 (m, 4H), 7.42–7.35
(m, 3H), 7.25–7.16 (m, 3H), 7.00 (s, 1H), 3.65 (s, 2H), 3.56–3.48
(m, 1H), 3.44 (dd, J = 10.2, 4.0 Hz, 1H), 3.23–3.04 (m, 3H), 3.00–
2.88 (m, 2H), 2.70–2.58 (m, 2H), 2.33 (ddd, J = 18.9, 12.9, 9.6 Hz,
4.2.1. (S)-1-(2-((R)-3H-Dinaphtho[2,1-c:10,20-e]azepin-4(5H)-yl)
ethyl)-N-butylpyrrolidine-2-carboxamide L1
Yellow colloidal solid (0.49 g, 50.3% yield), mp = 56–60 °C. 1H
NMR (400 MHz, CDCl3): d = 7.95 (d, J = 8.4 Hz, 4H), 7.51 (d,
J = 8.2 Hz, 2H), 7.47 (dd, J = 7.4, 5.8 Hz, 4H), 7.28 (d, J = 7.8 Hz,
2H), 3.68 (d, J = 12.3 Hz, 2H), 3.39 (td, J = 13.9, 7.1 Hz, 1H), 3.28–
3.18 (m, 4H), 3.15 (dd, J = 10.0, 4.2 Hz, 1H), 2.98–2.85 (m, 1H),
2.81–2.66 (m, 2H), 2.52–2.34 (m, 2H), 2.29–2.10 (m, 2H), 1.98–
1.87 (m, 1H), 1.84–1.66 (m, 2H), 1.52–1.42 (m, 2H), 1.34 (dq,
J = 14.1, 7.0 Hz, 2H), 0.88 (t, J = 7.3 Hz, 3H) ppm. 13C NMR
(100 MHz, CDCl3): d = 175.1, 135.1, 135.0, 133.3, 133.2, 133.1,
132.6, 131.4, 128.6, 128.4, 128.3, 128.3, 127.6, 127.5, 127.4,
126.0, 125.9, 125.7, 125.6, 68.0, 58.4, 56.5, 55.9, 55.1, 54.7, 54.4,
38.8, 31.9, 30.7, 29.7, 29.4, 24.5, 22.7, 20.2, 14.1, 13.8 ppm. ESI-
MS+ m/z calcd. for C33H38N3O 492.3015 [M+H]+; found 492.3014.
1H), 2.22–2.12 (m, 1H), 1.99–1.90 (m, 2H) ppm.13
C NMR
(100 MHz, CDCl3): d = 173.7, 134.9, 134.0, 133.1, 132.7, 131.3,
128.5, 128.3, 127.7, 127.4, 126.4, 125.9, 125.8, 125.6, 125.5,
124.6, 120.5, 118.5, 68.9, 55.8, 55.0, 54.7, 54.3, 31.0, 24.9 ppm.
ESI-MS+ m/z calcd. for
C
39H36N3O 562.2858 [M+H]+; found
562.2819. [
a
]
D
31 = +239.0 (c 0.5, CH2Cl2).
4.2.6. (R)-4-(2-(Pyrrolidin-1-yl)ethyl)-4,5-dihydro-3H-dinaphtho
[2,1-c:10,20-e]azepine L6
To a solution of pyrrolidine (15.0 mmol) in CH3CN (60 mL) was
added K2CO3 (3.10 g, 22.5 mmol) and N-Cbz-2-bromoethylamine
(3.87 g, 15.0 mmol) under stirring and kept at 80 °C, and monitored
by TLC (Hexane/EtOAc = 2/1, v/v), after which K2CO3 was removed
by filtration. The filtrate was concentrated to give a light brown oil.
The oil was dissolved in ethyl acetate (150 mL) and the solution
was washed with water (2 ꢂ 50 mL). The organic phase was dried
[a
]
25 = ꢁ248.0 (c 0.5, CH2Cl2).
D
4.2.2. (S)-1-(2-((R)-3H-Dinaphtho[2,1-c:10,20-e]azepin-4(5H)-yl)
ethyl)-N-(tert-butyl)pyrrolidine-2-carboxamide L2
Light yellow solid (0.53 g, 53.7% yield), mp = 168–170 °C. 1H
NMR (400 MHz, CDCl3): d = 7.95 (d, J = 8.4 Hz, 4H), 7.53 (d,
Please cite this article in press as: Ao, C.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.05.005

C. Ao et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
7
over anhydrous Na2SO4 and concentrated under reduced pressure
to afford the crude product benzyl (2-(pyrrolidin-1-yl)ethyl)carba-
mate (2.54 g, 68.3% yield) as a light yellow oil. 1H NMR (400 MHz,
CDCl3): d = 7.37–7.34 (m, 4H), 7.34–7.28 (m, 1H), 5.09 (s, 2H),
3.40–3.19 (m, 2H), 2.58 (t, J = 6.0 Hz, 2H), 2.49 (s, 4H), 1.77–1.73
(m, 4H), 1.26 (t, J = 7.1 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3):
d = 156.5, 136.7, 128.5, 128.2, 128.1, 66.6, 60.4, 54.9, 53.8, 39.7,
23.5, 21.1 ppm. ESI-MS+ m/z calcd. for C14H21N2O2 249.1603 [M
the resulting mixture was cooled to 10 °C and the corresponding
aldehyde (0.5 mmol) was added. The reaction mixture was stirred
at 10 °C until the reaction was decided to be complete based on TLC
(Hexane/EtOAc = 3/1, v/v) analysis. The reaction mixture was
directly purified by column chromatography on silica gel eluted
to afford the nitroaldol product 6.
Acknowledgments
+H]+; found 249.1580. [
a]
31 = ꢁ79.4 (c 0.51, CH2Cl2).
D
To a 50 mL three-necked flask was added the above compound
(1.24 g), and then dissolved in anhydrous MeOH (30 mL), after
which 0.05 g Pd/C (10%, w/w) were added to the solution. The mix-
ture was stirred at room temperature for 4 h under a hydrogen
atmosphere. The reaction solution was filtered and the filtrate
was concentrated under reduced pressure to afford a light yellow
oil 2-(pyrrolidin-1-yl)ethanamine. This compound was used
directly in the next step.
This work was supported by the Ministry of Education Project
Combining the Industry and Teaching with Research of Guangdong
Province (No. 2011B090400062).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetasy.2016.05.
005.
A solution of 2-(pyrrolidin-1-yl)ethanamine (0.23 g), 4 (0.97 g,
2.2 mmol), and triethylamine (0.44 g, 4.4 mmol) in anhydrous CH2-
Cl2 (30 mL) was heated at reflux for 24 h under Ar. The reaction
was cooled to room temperature and quenched by the addition
of distilled water (15 mL). The aqueous layer was extracted with
CH2Cl2. The combined organic phase was washed with brine, and
dried over Na2SO4. After removal of the solvent under reduced
pressure, the residue was purified by column chromatography
using silica gel (Hexane/CH3OH = 10/1, v/v) to give the product
L6 as a light yellow solid (0.24 g, 41.6% yield), mp = 230–234 °C.
1H NMR (400 MHz, CDCl3): d = 7.95 (dd, J = 8.0, 5.6 Hz, 4H), 7.60
(d, J = 8.3 Hz, 2H), 7.50–7.42 (m, 4H), 7.29 (d, J = 1.1 Hz, 1H), 7.25
(d, J = 1.1 Hz, 1H), 4.21 (s, 4H), 3.78 (d, J = 12.3 Hz, 2H), 3.29–3.20
(m, 6H), 2.07 (t, J = 6.6 Hz, 4H) ppm. 13C NMR (100 MHz, CDCl3):
d = 135.1, 133.3, 132.4, 131.4, 128.7, 128.4, 127.6, 127.4, 126.0,
125.7, 55.3, 54.3, 53.1, 51.3, 29.7, 23.3 ppm. ESI-MS+ m/z calcd.
References and notes
1. (a) Pàmies, O.; Bäckvall, J.-E. Chem. Rev. 2003, 103, 3247–3262; (b) Knowles, R.
R.; Jacobsen, E. N. PNAS 2010, 107, 20678–20685.
2. (a) Shibasaki, M.; Kanai, M. Chem. Pharm. Bull. 2001, 49, 511–524; (b) Shibasaki,
M.; Yoshikawa, N. Chem. Rev. 2002, 102, 2187–2210; (c) Paull, D. H.; Abraham,
C. J.; Scerba, M. T.; Alden-Danforth, E.; Lectka, T. Acc. Chem. Res. 2008, 41, 655–
663.
3. Yoon, T. P.; Jacobsen, E. N. Science 2003, 299, 1691–1693.
4. (a) Chen, Y.; Yekta, S.; Yudin, A. K. Chem. Rev. 2003, 103, 3155–3212; (b)
Matsunaga, S.; Ohshima, T.; Shibasaki, M. Adv. Synth. Catal. 2002, 344, 3–15; (c)
Seayad, J.; List, B. Org. Biomol. Chem. 2005, 3, 719–724; (d) Mukherjee, S.; Yang,
J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471–5569.
5. (a) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138–5175; (b) Taylor,
M. S.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 1520–1543.
6. (a) Kofoed, J.; Nielsen, J.; Reymond, J.-L. Bioorg. Med. Chem. Lett. 2003, 13, 2445–
2447; (b) Tang, Z.; Yang, Z.-H.; Cun, L.-F.; Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-Z. Org.
Lett. 2004, 6, 2285–2287; (c) Akagawa, K.; Sakamoto, S.; Kudo, K. Tetrahedron
Lett. 2005, 46, 8185–8187; (d) Luppi, G.; Cozzi, P. G.; Monari, M.; Kaptein, B.;
Broxterman, Q. B.; Tomasini, C. J. Org. Chem. 2005, 70, 7418–7421; (e) Krattiger,
P.; Kovasy, R.; Revell, J. D.; Ivan, S.; Wennemers, H. Org. Lett. 2005, 7, 1101–
1103.
for C28H29N2 393.2331 [M+H]+; found 393.2326. [
0.19, CH2Cl2).
a]
25 = +63.7 (c
D
4.2.7. (S)-1-(2-(Isoindolin-2-yl)ethyl)-N-(naphthalen-1-yl)
pyrrolidine-2-carboxamide L7
7. (a) Guillena, G.; del Carmen Hita, M.; Nájera, C. Tetrahedron: Asymmetry 2006,
17, 729–733; (b) Bañón-Caballero, A.; Guillena, G.; Nájera, C. J. Org. Chem. 2013,
78, 5349–5356; (c) Bañn-Caballero, A.; Flores-Ferrándiz, J.; Guillena, G.; Nájera,
C. Molecules 2015, 20, 12901–12912.
A solution of 2e (2.0 mmol), 1,2-bis(bromomethyl)benzene
(0.97 g, 2.2 mmol), and triethylamine (0.44 g, 4.4 mmol) in anhy-
drous CH2Cl2 (30 mL) was refluxed for 24 h under Ar. The reaction
was cooled to room temperature and quenched by the addition of
distilled water (15 mL). The aqueous layer was extracted with CH2-
Cl2. The combined organic phase was washed with brine, and dried
over Na2SO4. After removal of the solvent under reduced pressure,
the residue was purified by column chromatography using silica
gel (Hexane/EtOAc = 4/1, v/v) to give product L7 (0.61 g, 43.5%
yield), mp = 70–74 °C. 1H NMR (400 MHz, CDCl3): d = 10.78 (s,
1H), 8.28 (dd, J = 7.5, 0.6 Hz, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.68 (d,
J = 8.2 Hz, 1H), 7.53 (d, J = 8.2 Hz, 1H), 7.41 (t, J = 7.9 Hz, 1H),
7.24–7.21 (m, 1H), 7.03–6.91 (m, 3H), 6.90–6.81 (m, 2H), 3.89 (d,
J = 10.9 Hz, 2H), 3.77 (d, J = 10.9 Hz, 2H), 3.52–3.38 (m, 2H), 3.04–
2.87 (m, 4H), 2.62 (ddd, J = 15.8, 9.0, 7.2 Hz, 1H), 2.38–2.24 (m,
1H), 2.21–2.11 (m, 1H), 1.88 (tt, J = 8.9, 4.9 Hz, 2H) ppm. 13C
NMR (100 MHz, CDCl3): d = 173.8, 139.5, 133.8, 132.9, 128.1,
126.4, 125.9, 125.6, 125.5, 124.3, 121.8, 120.4, 117.4, 68.6, 59.0,
55.1, 31.0, 24.8 ppm. ESI-MS+ m/z calcd. for C25H28N3O 386.2232
8. Henry, L. C. R. Hebd. Seances Acad. Sci. 1895, 1265.
9. (a) Noland, W. E. Chem. Rev. 1955, 55, 137–155; (b) Varma, R. S.; Dahiya, R.;
Kumar, S. Tetrahedron Lett. 1997, 38, 5131–5134; (c) Luzzio, F. A. Tetrahedron
2001, 57, 915–945; (d) Ono, N. The Nitro Group in Organic Synthesis; Wiley-VCH:
New York, 2001. pp 30–69.
10. (a) Evans, D. A.; Seidel, D.; Rueping, M.; Lam, H. W.; Shaw, J. T.; Downey, C. W. J.
Am. Chem. Soc. 2003, 125, 12692–12693; (b) Jin, W.; Li, X.; Wan, B. Org. Lett.
2007, 9, 3595–3597; (c) Arai, T.; Watanabe, M.; Yanagisawa, A. J. Org. Chem.
2011, 76, 484–491; (d) White, J. D.; Shaw, S. Org. Lett. 2012, 14, 6270–6273; (e)
Arai, T.; Joko, A.; Sato, K. Synlett 2015, 209–214.
11. Qin, B.; Liu, X.; Shi, J.; Zheng, K.; Zhao, H.; Feng, X. J. Org. Chem. 2007, 72, 2374–
2378.
12. Xiao, D.; Zhang, Z.; Zhang, X. Org. Lett. 1999, 1, 1679–1681.
13. Arai, T.; Takashita, R.; Endo, Y.; Watanabe, M.; Yanagisawa, A. J. Org. Chem.
2008, 73, 4903–4906.
14. Boobalan, R.; Lee, G.-H.; Chen, C. Adv. Synth. Catal. 2012, 354, 2511–2520.
15. Shi, Y.; Mao, Z.; Xue, Q.; Zhu, C.; Hu, H.; Cheng, Y. Inorg. Chem. Commun. 2012,
20, 259–262.
16. Wolin´ ska, E. Tetrahedron 2013, 69, 7269–7278.
17. (a) Kodama, K.; Sugawara, K.; Hirose, T. Chem. Eur. J. 2011, 17, 13584–13592;
(b) Chunhong, Z.; Liu, F.; Gou, S. Tetrahedron: Asymmetry 2014, 25, 278–283; (c)
Holmquist, M.; Blay, G.; Muñoz, M. C.; Pedro, J. R. Org. Lett. 2014, 16, 1204–
1207.
18. (a) Hathaway, B. J.; Billing, D. E. Coord. Chem. Rev. 1970, 5, 143–207; (b) Reinen,
D.; Atanasov, M.; Köhler, P. J. Mol. Struct. 2007, 838, 151–156; (c) Naumov, P.;
Pejov, L.; Jovanovski, G.; Stafilov, T.; Taseska, M.; Stojanovska, E. Cryst. Growth
Des. 2008, 8, 1319–1326; (d) Reinen, D.; Atanasov, M.; Köhler, P.; Babel, D.
Coord. Chem. Rev. 2010, 254, 2703–2754.
[M+H]+; found 386.2230. [
a
]
D
31 = ꢁ79.4 (c 0.51, CH2Cl2).
4.3. General procedure for the asymmetric Henry reaction
19. Moorthy, J. N.; Saha, S. Eur. J. Org. Chem. 2009, 2009, 739–748.
20. Carmona, A.; Corma, A.; Iglesias, M.; San José, A.; Sánchez, F. J. Organomet.
Chem. 1995, 492, 11–21.
21. Das, A.; Kureshy, R. I.; Subramanian, P. S.; Khan, N.-U. H.; Abdi, S. H. R.; Bajaj, H.
C. Catal. Sci. Technol. 2014, 4, 411–418.
A mixture of ligand L5 (28 mg, 0.05 mmol, 10 mol %) and Cu
(OAc)2 (9 mg, 0.05 mmol, 10 mol %) was stirred in EtOH (1 mL) at
room temperature for 30 min to form the complex catalyst. Then
nitroalkane (5 mmol) was added to the mixture. After the addition,
Please cite this article in press as: Ao, C.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.05.005