Application of bis(oxazoline) in asymmetric β-amination of chalcones

Article abstract of DOI:10.1039/c4nj01660b

An effective enantioselective β-amination of chalcones with N-bromosuccinimide into β-imidoketones using a bis(oxazoline) ligand is described. A wide variety of β-imidoketone derivatives containing various functional groups can be obtained with high enantioselectivities. The products are highly valuable molecules regarding their vast applications as building blocks of drugs and biologically active compounds.

Full text of DOI:10.1039/c4nj01660b

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Application of bis(oxazoline) in asymmetric
b-amination of chalcones†
Cite this:DOI: 10.1039/c4nj01660b
Tao Deng, Hongjun Wang and Chun Cai*
Received (in Montpellier, France)
27th September 2014,
Accepted 28th October 2014
DOI: 10.1039/c4nj01660b
www.rsc.org/njc
An effective enantioselective b-amination of chalcones with the use of bis(oxazoline)-containing ligands including C2-symmetric
N-bromosuccinimide into b-imidoketones using a bis(oxazoline) bis(oxazoline) or aza-bis(oxazoline) turned out to be a powerful
ligand is described. A wide variety of b-imidoketone derivatives approach for the asymmetric synthesis of a great variety of highly
containing various functional groups can be obtained with high enantioenriched organic compounds.8
enantioselectivities. The products are highly valuable molecules
With all of these precedents in mind, we were interested in
regarding their vast applications as building blocks of drugs and exploring the enantioselectivity for the asymmetric b-amination
biologically active compounds.
reaction9 when NBS reacted as a nucleophilic nitrogen source
with chalcones. Herein, we report the details of our studies and
Over the past decade, tremendous progress has been achieved disclose improved enantiomeric ratios using an optimized
by employing different nitrogen nucleophiles and new acceptors bis(oxazoline) ligand.
as well as more efficient catalyst systems for carbon–nitrogen
Our initial studies were carried out with chalcone (1a) as the
bond formation.1 Especially in the past several years, the devel- substrate and N-bromosuccinimide (NBS) as the nucleophilic
opment of efficient and conventional approaches2 (for example, nitrogen source under basic conditions. A variety of commonly
the iminium-activated nucleophilic additions to a,b-unsaturated used chiral ligands were examined (Fig. 1). Only modest ee
aldehydes3 and the Mannich-type reaction of bis(dialkylamino)- values were generally obtained except for bis(oxazoline) (L3);
boron enolates with aldehydes4), leading to chiral b-imido- good yield and ee value could be obtained with bis(oxazoline)
ketones and their derivatives has attracted much attention in (L3) (Table 1, entry 4). Decreasing L3 to 5 mol% led to a lower
organic synthesis, as the b-imidoketones obtained are highly yield with obvious loss of ee (Table 1, entry 5).
valuable molecules regarding their vast applications as building
As shown in Table 2, no reaction occurred in MeCN at room
blocks of drugs and biologically active compounds.5 Very temperature upon utilizing NaOH, K2CO3, Et3N, DABCO, and
recently, Han and co-workers developed an acid-functionalized DMAP as bases (Table 2, entries 1–5). The reaction with pyridine
ionic liquid as catalyst for hetero-Michael addition of nitrogen (1.2 equiv.) as the base in MeCN gave 1-(3-oxo-1, 3-diphenyl-
nucleophiles to a,b-unsaturated ketones.6 Brenna et al. reported propyl)-pyrrolidine-2, 5-dione (2a) in 39% yield (Table 2, entry 7).
that Ni(II) and Pd(II) pyridinyloxazolidine-compound catalyzed
aza-Michael addition of aliphatic amines to a,b-unsaturated
ketones7 is an efficient approach toward the synthesis of
b-imidoketones.
Although a variety of methods have been reported, further
development of asymmetric b-amination reactions still remains
a hot topic. Therefore, the necessity to explore appropriate
conditions to improve the ee is sometimes required. Among
various subareas of the rapidly growing field of organocatalysis,
Chemical Engineering College, Nanjing University of Science & Technology, Nanjing,
Jiangsu 210094, P. R. China. E-mail: c.cai@mail.njust.edu.cn
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
Fig. 1 Selected examples of chiral ligands examined.
c4nj01660b
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Table 1 Screening of ligandsa
Table 3 Optimization of reaction conditionsa
Entry
Ligand
Yieldb (%)
eec (%)
Entry
Solvent
Yieldb (%)
eec (%)
1
2
3
4
5d
6
7
8
9
—
69
64
61
76
73
74
58
60
68
Racemic
1
2
3
4
CH2Cl2
THF
EtOH
MeOH
DMF
57
62
33
29
61
n.r.
76
54
n.r.
51
63
73
57
29
—
90
84
—
L1
L2
L3
L3
L4
L5
L6
L7
19
18
90
64
65
9
5
6d
7
H2O
MeCN
MeCN
MeCN
8e
9 f
13
10
a
a
Reactions were carried out with 1a (1.0 mmol), NBS (1.2 mmol), ligand
Reactions were carried out with 1a (1.0 mmol), NBS (1.2 mmol),
b
(0.1 mmol) and DBU (1.2 mmol) in MeCN (2.0 mL) for 15 h. Deter- L3 (0.1 mmol) and DBU (1.2 mmol) in solvent (2.0 mL) for 15 h.
mined by HPLC analysis. The ee was checked by chiral HPLC using an
Ultron ES-OVM column. With L3 (0.05 mmol).
c
b
c
Determined by HPLC analysis. The ee was checked by chiral HPLC
d
d
using an Ultron ES-OVM column. TBAB (0.05 mmol) was added.
e
f
With NIS (1.2 equiv.). With NCS (1.2 equiv.).
Table 2 Effect of different bases on b-amination of chalconesa
and enantioselectivities (Table 4, entries 1, 12 and 13). When
electron-withdrawing groups (such as para-bromo or trifluoro-
methyl groups) were introduced on the phenyl ring R1, lower
enantioselectivities but higher yields were obtained (Table 4,
entries 1, 14 and 15). However, the electron-donating groups
(such as para-methyl or para-dimethylamino) on the phenyl ring
R2 seemed to be less favorable in this protocol providing the
corresponding products with moderate enantioselectivities
(Table 4, entries 1, 5 and 6). Furthermore, with strong
electron-withdrawing substituents (such as para-fluoro or para-
nitro groups) on the phenyl ring R2, the reactions did not occur
(Table 4, entries 2 and 4). It was notable that para-chloro
substituents gave better ee in this reaction (Table 4, entry 3).
Upon replacing the phenyl ring R2, with 1-naphthyl or other
Entry
Base
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
NaOH
K2CO3
Et3N
DABCO
DMAP
DBU
n.r.
n.r.
n.r.
n.r.
n.r.
76
—
—
—
—
—
90
71
Pyridine
39
a
Reactions were carried out with 1a (1.0 mmol), NBS (1.2 mmol), L3
b
(0.1 mmol) and base (1.2 mmol) in 2.0 mL MeCN for 15 h. Determined
by HPLC analysis. The ee was checked by chiral HPLC using an Ultron
c
ES-OVM column.
Table 4 Scope of substratesa
To our delight, DBU was found to be the most suitable base in
terms of yield and enantioselectivity (Table 2, entry 6).
The reaction was further optimized with respect to solvents
(Table 3). When CH2Cl2, THF, EtOH, MeOH and DMF were
selected as the solvents, the yields decreased (Table 3, entries
1–5). Additionally, no desired product was obtained with H2O
as the solvent in the presence of TBAB (Table 3, entry 6). Among
all the solvents tested, MeCN was the most efficient. 1-(3-Oxo-1,
3-diphenylpropyl)-pyrrolidine-2,5-dione (2a) was obtained in
76% yield with 90% ee using 10 mol% L3 in MeCN at room
temperature (Table 3, entry 7). Other nucleophilic nitrogen
sources were also examined (Table 3, entries 8 and 9). Moderate
yield and ee were obtained with N-iodosuccinimide (NIS). How-
ever, no reaction was observed with N-chlorosuccinimide (NCS).
The scope of this reaction was then evaluated with respect to
substituted chalcones under the optimized conditions to form
the corresponding b-imidoketones in 52–85% yield with 40–94%
ee using 10 mol% L3 (Table 4, entries 1–15). The introduction of
strong electron-donating groups (such as methoxy and methyl)
Entry R1
R2
Product Yieldb (%) eec (%)
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
2a
—
2b
—
2c
76
n.r.
83
n.r.
73
62
90
—
94
—
80
40
—
—
—
—
64
80
76
66
92
4-FC6H4
4-ClC6H4
4-NO2C6H4
4-MeC6H4
4-NMe2C6H4 2d
1-Naphthyl
2-ClC6H4
2-BrC6H4
Me
—
—
—
—
2e
2f
2g
2h
2i
n.r.
n.r.
n.r.
n.r.
67
52
71
9
10
11
12
13
14
15
4-Pyridinyl
4-MeOC6H4 Ph
4-MeC6H4
4-CF3C6H4
4-BrC6H4
Ph
Ph
Ph
79
85
a
Reactions were carried out with 1 (1.0 mmol), NBS (1.2 mmol),
L3 (0.1 mmol) and DBU (1.2 mmol) in MeCN (2.0 mL) for 15 h.
b
c
Determined by HPLC analysis. The ee was checked by chiral HPLC
at the para-position on the phenyl ring R1, led to a drop in yields using an Ultron ES-OVM column.
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temperature for 5 min. Then, NaOH (3 equiv.) was added. The
reaction mixture was stirred at room temperature overnight
until aldehyde consumption. After that, HCl (10%) was added
until neutrality. Then dichloromethane was added to dilute the
reaction mixture. The organic layer was dried over anhydrous
Na2SO4 and concentrated on Rotavapor under reduced pressure.
Finally, the residue was purified by silica gel column chromato-
graphy to give 1a.
A typical procedure for the b-amination of chalcones
A general procedure for the preparation of 2 (2a as an example): a
mixture of chalcone 1a (208 mg, 1.0 mmol), L3 (30.6 mg,
0.1 mmol), and DBU (0.18 mL, 1.2 mmol) in MeCN (2.0 mL) was
stirred at room temperature. NBS (213 mg, 1.2 mmol) was then
added to the mixture. After starting material 1a was consumed as
indicated by TLC, the reaction mixture was poured into water and
then extracted with CH2Cl2 (3 Â 10 mL). The combined organic
phase was washed with water (3 Â 10 mL), dried over anhydrous
MgSO4, filtered and concentrated under reduced pressure. The
crude product was purified by flash chromatography.
Scheme 1 Plausible mechanism for the formation of b-aminoketones.
ortho-substituted phenyl on the phenyl ring R2, no desired
products were obtained (Table 4, entries 7–9). This may be
attributed to the effect of steric hindrance. Besides, this protocol
could also be applied to heterocyclic chalcones as exemplified by
(E)-1-phenyl-3-(pyridin-4-yl)prop-2-en-1-one in 67% yield and 64%
ee (Table 4, entry 11). We further expanded the scope of this
reaction to aliphatic chalcones. Unfortunately, we found that no
desired product was obtained when a methyl substituent was
introduced (R2 = Me) due to side reactions (Table 4, entry 10).
The reaction begins with the formation of intermediate
A from NBS and DBU via halogen bond interaction. Then A
transforms into a more electrophilic species B. Although the
precise reaction mechanism is not clear, we proposed a possible
plausible mechanism based on our work and on pertinent
literature9 (Scheme 1).
In summary, we have developed an efficient enantioselective
b-amination reaction of chalcones into b-imidoketones using NBS
as nucleophilic nitrogen source and bis(oxazoline) as ligand. A
wide variety of b-imidoketone derivatives with various functional
groups were obtained in generally good yields with high enantio-
selectivities. Further transformations of these compounds provide
access to useful intermediates with diverse functionality, such as
building blocks of drugs and biologically active compounds.
Notes and references
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Experimental section
General remarks
All reagents were purchased from commercial sources and used
without treatment, unless otherwise indicated. The products
were purified by column chromatography over silica gel. NMR 3 R. Appel, S. Chelli, T. Tokuyasu, K. Troshin and H. Mayr,
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