Asymmetric synthesis of 2,3-dihydroquinolin-4-one derivatives catalyzed by a chiral bisguanidium salt

Article abstract of DOI:10.1002/chem.201203216

Worth its salt: An orgnaocatalytic asymmetric intramolecular aza-Michael reaction and one-pot bromination reaction of activated α,β- unsaturated ketones have been realized using a chiral bisguanidium salt (see scheme). Optically enriched 2-aryl- and 2-alk

Full text of DOI:10.1002/chem.201203216

DOI: 10.1002/chem.201203216
Asymmetric Synthesis of 2,3-Dihydroquinolin-4-one Derivatives Catalyzed
by a Chiral Bisguanidium Salt
Xiao Xiao, Xiaohua Liu,* Shunxi Dong, Yunfei Cai, Lili Lin, and Xiaoming Feng*[a]
Optically active 2,3-dihydroquinolin-4-one scaffolds ex-
hibit intriguing biological activities and have attracted signif-
icant attention.[1] Among the strategies for the construction
of such compounds,[2] asymmetric intramolecular aza-Mi-
chael addition of a,b-unsaturated ketones with aniline is a
straightforward route. The first example of enantioselective
intramolecular aza-Michael addition to afford 2,3-dihydro-
quinolin-4-ones was reported by Youꢀs group with chiral N-
triflyl phosphoramide.[2c] Later, the Lu group developed a
bifunctional thiourea-mediated intramolecular cyclization to
achieve this goal.[2d] One limitation of previous work in this
area is that 2-alkyl-substituted derivatives could not be ob-
tained with high enantioselectivity. Additionally, synthesis of
chiral 2,3-dihydroquinolin-4-one derivatives with vicinal
stereogenic centers has not been reported to date. Recently,
the Ma group developed a one-pot, multistep transformation
to synthesize 3-halo-2,3-dihydroquinolin-4-one derivatives
with high diastereoselectivity.[3] Herein, we report an effi-
cient organocatalytic asymmetric intramolecular aza-Mi-
chael reaction and a one-pot bromination reaction for the
synthesis of optically enriched 2-substituted dihydroqui-
nones and brominated dihydroquinones, respectively
(Scheme 1). In the presence of chiral bisguanidium salt cata-
lyst, both 2-aryl- and 2-alkyl-substituted products could be
generated with excellent outcomes (up to 99% yield and
99% ee for the aza-Michael reaction and up to 95% yield,
96:4 d.r., and 95% ee for the one-pot bromination reaction).
To improve the reactivity of the intramolecular aza-Mi-
chael reaction, an ester function was added to the unsaturat-
ed ketones and a sulfonyl group was attached to the nitro-
gen of the anilines .[2,4] This additional functionality provided
more sites for potential interaction with a catalyst. The
Scheme 1. Intramolecular aza-Michael reaction and one-pot bromination
reaction to obtain 2,3-dihydroquinolin-4-one derivatives.
our previous study relating to guanidine[6,7] promoted reac-
tions of 1,3-dicarbonyl compounds and azlactones, we envi-
sioned that this kind of bifunctional organocatalyst[7h–m]
could also initiate the intramolecular aza-Michael addition
of activated a,b-unsaturated ketone . As shown in Table 1, a
series of guanidines and bisguanidines (1a–e) were used to
promote the asymmetric intramolecular cyclization (Table 1,
entries 1–5). In all cases, the reactions were rapid and com-
plete conversion was achieved within 0.5 hour at 258C.
Chiral bisguanidine 1c derived from (S,S)-1,2-diphenyleth
ACHTUNGTRENNUNGyl-
AHCTUNGTRENNUNG
promising catalyst, affording the product 3a in 99% yield
with 50% ee (Table 1, entry 3). In view of the unique and
helpful role of an achiral counterion which can modify the
catalystꢀs reactivity and structure directly,[8] a bisguanidium
salt was next evaluated. When the corresponding bisguanidi-
um salt[6i–m] 1c·HBArF (HBArF = HB
ACHTUNTRGENNUG[3,5-ACHTUTGNNERN(UNG CF3)2C6H3]4)
4
4
stereo
G
was used, the enantioselectivity improved to 58% ee
(Table 1, entry 6). Catalysts with other counterions were
also tested, but no improvement was observed (see the Sup-
porting Information for details). The use of polar solvents
resulted in a sharp decline in enantioselectivity, which might
be due to the adverse effect on the hydrogen-bonding inter-
actions between the substrate and the catalyst (Table 1, en-
tries 7–9 vs. entry 6). CH2Cl2 was the best solvent, generat-
ing the product with slightly improved enantioselectivity
(Table 1, entry 10). Notably, the ee value of the product in-
creased gradually by lowering the reaction temperature
(Table 1, entries 10–14). The desired quinolone derivative
3a could be obtained in 99% yield with 96% ee at À608C
(Table 1, entry 14). It was worth mentioning that the catalyst
to be E-type by X-ray crystallography analysis.[5] In view of
[a] X. Xiao, Prof. Dr. X. Liu, S. Dong, Y. Cai, Dr. L. Lin,
Prof. Dr. X. Feng
Key Laboratory of Green Chemistry & Technology
Ministry of Education, College of Chemistry
Sichuan University, Chengdu 610064 (P.R. China)
Fax: (+86)28-8541-8249
E-mail: liuxh@scu.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201203216.
15922
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Chem. Eur. J. 2012, 18, 15922 – 15926

COMMUNICATION
Table 1. Optimization of the reaction conditions in the asymmetric intra-
molecular aza-Michael reaction.
Table 2. Substrate scope in the asymmetric intramolecular aza-Michael
reaction.
Entry[a]
R
Prod.
t
Yield
[%][b]
ee
[h]
[%][c]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Ph
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
10
99
98
99
99
99
99
99
99
99
99
99
99
99
99
96(R)
94(S)
96(R)
95(R)
93(R)
93(R)
94(R)
93(R)
95(R)
96(R)
98(R)
95(R)
94(R)
99(R)
2-FC6H4
3-FC6H4
4-FC6H4
3-ClC6H4
4-ClC6H4
3-BrC6H4
4-BrC6H4
4-MeC6H4
2-naphthyl
iPr
116
16
28
28
18
24
24
34
14
18
52
20
24
Entry[a]
Cat.
Solvent
t
T
[8C]
Yield
[%][b]
ee
[h]
[%][c]
1
2
3
4
1a
1b
1c
1d
toluene
toluene
toluene
toluene
toluene
toluene
THF
0.5
25
25
25
25
25
25
25
25
25
99
99
99
99
99
99
99
99
99
99
99
99
99
99
99
99
17
8
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
2
50
12
12
58
28
28
0
60
84
86
91
96
96
97
nPr
n-pentyl
c-hexyl
5
1e
6[d]
7[d]
8[d]
9[d]
10[d]
11[d]
12[d]
13[d]
14[d]
15[d,e]
16[d,f]
1c·HBArF
1c·HBArF
1c·HBArF
1c·HBArF
1c·HBArF
1c·HBArF
1c·HBArF
1c·HBArF
1c·HBArF
1c·HBArF
1c·HBArF
4
4
4
4
4
4
4
4
4
4
4
Et2O
DMF
[a] Unless otherwise noted, all reactions were carried out with
1c·HBArF (5 mol%) and 2a (0.05 mmol) in CH2Cl2 (0.5 mL) at À608C.
4
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
25
0
[b] Isolated yield. [c] Determined by HPLC.
À20
À45
À60
À60
À60
8
10
72
Alkenes 2k–2n with either linear or branched alkyl substitu-
ents were also well tolerated , giving excellent yields and
enantioselectivities (93–99% ee). Upon treatment with tol-
uene sulfonic acid (TsOH), decarboxylation occured readily
to give the corresponding 2,3-dihydro-4-quinolone. The ab-
solute configuration of 3a was confirmed to be R by com-
parison with the reported value of optical rotation.[2d] The
stereochemical arrangement of the products 3b–3n was de-
termined to be identical through the assay of the Cotton
effect in the circular dichroism (CD) spectra (see the Sup-
porting Information for details).
[a] Unless otherwise noted, all reactions were carried out with
1c·HBArF (10 mol%) and 2a (0.05 mmol) in solvent (0.5 mL) at the
4
temperature specified. [b] Isolated yield. [c] Determined by HPLC.
[d] HBArF4 =HB
G
(CF3)2C6H3]4. [e] 5 mol% 1c·HBArF was used.
4
loading could be decreased to 1 mol% without any loss in
the yield and enantioselectivity (Table 1, entry 16) although
a longer reaction time was required.
Next, we turned our attention to investigate the one-pot
synthesis of brominated dihydroquinones.[9] Initially, the re-
action between activated a,b-unsaturated ketone 2a and N-
bromosuccinimide (NBS) was performed with chiral bisgua-
Under the optimized reaction conditions (Table 1,
entry 15), various alkylidene b-ketoesters 2 were explored to
examine the generality of the reaction. In the presence of
chiral bisguanidium salt 1c·HBArF , a wide range of 2,3-di-
nidium salt 1c·HBArF at À208C in CH2Cl2. The desired
4
4
hydroquinolin-4-one derivatives 3 were generated with high
yields (up to >99%) and excellent ee values (93–99%). As
shown in Table 2, the electronic property and position of the
substituent on the aromatic ring of substrate 2 have no sig-
nificant influence on the enantioselectivity (Table 2, en-
tries 1–9). Substrate 2b bearing an ortho-fluoride substituent
led to the cyclized product in good yields and high enatiose-
lectivity, although a significantly longer reaction time was
required (98% yield, 94% ee; Table 2, entry 2). The 2-naph-
thyl substituted substrate 2j was also suitable substrate for
the reaction, affording the product 3j with 99% yield and
96% ee (Table 2, entry 10). It is worth noting that substrates
containing aliphatic groups delivered the desired 2-alkyl-2,3-
dihydroquinones with superior yields and enantioselectivi-
ties compared to previous reports[2] (Table 2, entries 11–14).
product 4a was generated in 94% ee and 88:12 d.r., al-
though the reaction time was significantly increased in com-
parison with the aza-Michael reaction (Table 3, entry 1). In-
creasing the reaction temperature had no positive effect on
the yield or enantioselectivity (Table 3, entry 2). Increasing
the concentration had minimal effect on the observed
stereoACTHNURTGNEUsGN electivity (Table 3, entry 3). To our delight, the addi-
tion of 4 ꢂ molecular sieves (MS) notably increased the re-
action rate and allowed the reaction to reach completion
within 1 day with 88% yield, 93% ee, and 91:9 d.r. (Table 3,
entry 4). The absolute configuration of the major product 4a
was determined to be (2R,3R) by X-ray crystallography
analysis (Figure 1a).[5] The decreased isolated yield resulted
from the generation of byproduct 5a, which was formed
from the bromination at the C6-position of dihydroquinone
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15923

X. Liu, X. Feng et al.
Table 3. Optimization of the reaction conditions in the asymmetric one-
pot bromination reaction.
Table 4. Substrate scope in the asymmetric one-pot bromination reac-
tion.
Entry[a]
R
Prod.
t
Yield
[%][b]
ee
trans/cis[d]
Entry[a]
T [oC]
t [d]
Yield [%][b]
ee [%][c]
trans/cis[d]
[d]
[%][c]
1
2
À20
0
4
3
2
1
86
82
79
88
94
90
88:12
85:15
90:10
91:9
1
2
3
4
5
6
7
8
9
Ph
4a
4b
4c
4d
4e
4f
4g
4h
4i
1
2
1
1
1
1
1
1
1
1
1
1
88
78[e]
82
85
92
95
89
91
92
95
94
80
93
92
94
91
92
92
88
90
90
92
95
94
91:9
3[f]
4[f,g]
À20
93
2-FC6H4
3-FC6H4
4-FC6H4
3-ClC6H4
4-ClC6H4
3-BrC6H4
4-BrC6H4
3-MeC6H4
4-MeC6H4
2-naphthyl
nPr
78:22
90:10
87:13
91:9
89:11
90:10
93:7
92:8
92:8
96:4
86:14
À20
93[e]
[a] Unless otherwise noted, all reactions were carried out with
1c·HBArF (5 mol%), NBS (0.06 mmol) and 2a (0.05 mmol) in CH2Cl2
4
(0.5 mL) at the temperature specified. [b] Isolated yield. [c] Determined
by HPLC. [d] Determined by 1H NMR spectroscopy and HPLC analysis.
[e] Absolute configuration of the major product was determined to be
(2R,3R) by X-ray crystallography. [f] The reaction was carried out with
10
11
12
4j
4k
4l
1c·HBArF (5 mol%), NBS (0.11 mmol) and 2a (0.1 mmol) in CH2Cl2
4
(0.15 mL ) at À208C. [g] 4 ꢂ molecular sieves (20.0 mg) were added.
[a] Unless otherwise noted, all reactions were carried out with
1c·HBArF (5 mol%), 4 ꢂ MS (20 mg), NBS (0.11 mmol) and
2
4
(0.1 mmol) in CH2Cl2 (0.15 mL) at À208C. [b] Isolated yield. [c] Deter-
mined by HPLC. [d] Determined by 1H NMR spectroscopy and HPLC
analysis. [e] Trace amount of aza-Michael product was observed.
resolution.[11] It is interesting to note that this process could
be accelerated by strong inorganic and organic bases, such
as KOH, NaOH, KOtBu, and tetramethyl guanidine
(TMG). The cis isomer (2R,3S)-4a was obtained in 89%
yield, 93% ee, and 95:5 d.r. after treatment with KOH in tol-
uene for 1 h (Scheme 2). The nature of the solvent had a sig-
nificant effect on the epimerization (see the Supporting In-
formation for details).[12] The stereochemistry at the 2-posi-
tion of 4a was maintained. We postulate that the transfor-
mation proceeds through an SE1 mechanism with the cis dia-
stereomer being the most thermodynamically stable
product.
Figure 1. X-ray crystallographic structures of trans-4a and cis-5a.
4a. The structure of 5a was confirmed by X-ray crystallogra-
phy analysis (Figure 1b).
The general applicability of the one-pot bromination reac-
tion of activated a,b-unsaturated ketones 2 was examined
using bisguanidium salt 1c·HBArF at À208C. As shown in
4
Table 4, in the presence of NBS, a variety of 3-bromo-2,3-di-
hydroquinolin-4-ones 4 could be obtained in 78–95% yields,
88–95% ee, and 78:22–96:4 d.r.. The reaction was unbiased
toward both the substitution pattern and electronic proper-
ties of the aromatic moiety (Table 4, entries 1–10). but the
ortho-substituted alkene 2b exhibited a slightly low reactivi-
ty (Table 4, entry 2). Gratifyingly, the fused-ring and aliphat-
ic substrates were successfully employed in the reaction
(Table 4, entries 11 and 12). No aza-Michael products 3
were isolated with the exception of the reaction of 2b.[10]
Interestingly, the trans isomer of 4a could be gradually
transformed into the cis isomer in toluene which might lead
to spontaneous epimerization and crystallization-induced
Scheme 2. The epimerization of trans-3-bromo-2,3-dihydroquinolin-4-one
4a.
These results improve upon the existing substrate scope
of enantioselective aza-Michael reaction and utilizes a one-
pot protocol to access to 3-bromo-2,3-dihydroquinolin-4-one
derivatives under mild reaction conditions. However, it is
premature to advance a discrete model to rationalize the ob-
served trends in stereoselectivity and the effect of tempera-
ture effects in the two processes. Nevertheless, we propose
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Chem. Eur. J. 2012, 18, 15922 – 15926

2,3-Dihydroquinolin-4-one Derivatives
COMMUNICATION
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through hydrogen-bonding interactions, and the other guani-
dium functional group, in conjuction with the counterion,
provides a steric variation that is crucial in defining the size
and shape of the substrate binding pocket.
In summary, we have developed a highly efficient bisgua-
nidium organocatalyst for an intramolecular aza-Michael re-
action and a one-pot bromination reaction, affording a
series of optically enriched, 2-substituted dihydroquinones
and brominated dihydroquinones (up to 99% yield and
99% ee for the aza-Michael reaction; and up to 95% yield,
96:4 d.r., and 95% ee for the one-pot bromination reaction).
Both 2-aryl- and 2-alkyl-substituted products could be gen-
erated with excellent outcomes. Further studies into the re-
action mechanism are currently in progress.
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Experimental Section
Typical procedure for the asymmetric intramolecular aza-Michael reac-
tion: Bisguanidium salt catalyst 1c·HBArF (5 mol%, 4.3 mg) and sub-
4
strate 2a (23.8 mg, 0.05 mmol) were stirred in a dry reaction tube at
À608C for 0.5 h. Subsequently, CH2Cl2(0.5 mL; cooled at À608C) was
added. The reaction was stirred at À608C and monitored by TLC. After
complete consumption of the starting materials, the mixture was directly
purified by column chromatography on silica gel (petroleum ether/ethyl
acetate=8:1) to afford 3a (23.6 mg, 99% yield) as a light yellow solid.
Typical procedure for the asymmetric one-pot bromination reaction: Bis-
guanidium salt catalyst 1c·HBArF (5 mol%, 8.6 mg), 4 ꢂ molecular
4
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strate 2a (47.7 mg, 0.1 mmol) were stirred in a dry reaction tube at
À208C for 0.5 h. Subsequently, CH2Cl2 (0.15 mL; cooled at À208C) was
added. The reaction was stirred at À208C for 24 h. The mixture was di-
rectly purified by column chromatography on silica gel (petroleum ether/
ethyl acetate=8:1) to afford 4a (48.8 mg, 88% yield) as a white solid.
Acknowledgements
We thank the National Natural Science Foundation of China (Nos.
21021001, 21072133, and 21222206), National Basic Research Program of
China (973 Program: No. 2010CB833300), and the Ministry of Education
of China (NCET-11-0345) for financial support.
Keywords: asymmetric
synthesis
·
bromination
·
dihydroquinolones · guanidines · Michael addition
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[12] The aza-Michael product 3a was detected when CH3CN was used as
the solvent. Complicated side products were generated when 4a was
treated with KOH in methanol.
Received: September 10, 2012
Published online: November 14, 2012
15926
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Chem. Eur. J. 2012, 18, 15922 – 15926