Per-6-amino-β-cyclodextrin as a chiral base catalyst promoting one-pot asymmetric synthesis of 2-Aryl-2,3-dihydro-4-quinolones

Article abstract of DOI:10.1021/jo302173a

A highly efficient one-pot synthesis of enantiomerically enriched 2-aryl-2,3-dihydroquinolin-4(1H)-ones has been carried out for the first time using per-6-ABCD as a supramolecular host, chiral base catalyst, and a reusable promoter to give the corresponding scaffold with high yield (up to 99%) and enantiomeric excess (up to 99%). The catalyst is recovered and reused without loss in its activity.

Full text of DOI:10.1021/jo302173a

Note
pubs.acs.org/joc
Per-6-amino-β-cyclodextrin as a Chiral Base Catalyst Promoting One-
Pot Asymmetric Synthesis of 2‑Aryl-2,3-dihydro-4-quinolones
Kuppusamy Kanagaraj and Kasi Pitchumani*
School of Chemistry, Madurai Kamaraj University, Madurai 625021, India
S
* Supporting Information
ABSTRACT: A highly efficient one-pot synthesis of enantio-
merically enriched 2-aryl-2,3-dihydroquinolin-4(1H)-ones has
been carried out for the first time using per-6-ABCD as a
supramolecular host, chiral base catalyst, and a reusable promoter
to give the corresponding scaffold with high yield (up to 99%)
and enantiomeric excess (up to 99%). The catalyst is recovered
and reused without loss in its activity.
he demand for chiral compounds often as single
enantiomers, which are crucially important to the
Cyclodextrins (CDs) are macrocyclic oligosaccharides
possessing hydrophobic cavities that bind substrates selectively
via noncovalent interactions,7a and this property enables them
to be used in various applications. Native β-CD has been
employed as a catalyst7 for thiol7b and aza-Michael addition7c in
water medium with poor chiral induction. Chemical mod-
ification of cyclodextrins is expected to improve the
enantioselectivity in asymmetric catalysis7d and in chiral
NMR analysis.7e Selectively modified cyclodextrins are used
as sensors as well as catalysts.8 Peramino-CDs are homoge-
neous CD derivatives modified by persubstitution at the
primary face with amino pendant groups, which display
combined hydrophobic and electrostatic binding of guest
molecules relative to native CDs. They have been employed as
catalysts in various organic transformations9 and sensors
applications.10 These features prompted us to exploit this
catalyst in the efficient one-pot asymmetric cyclization route for
the development of quinolone scaffolds starting from o-
aminoacetophenone and substituted aldehydes via o-amino-
chalcone intermediate (Scheme 1). Herein, we report per-6-
ABCD (1b) successfully as a reusable multifunctional base
catalyst and a chiral host for the one-pot synthesis of 2-aryl-2,3-
dihydro-4-quinolones in ethanol/water (1:1,v/v) medium at
−5 °C with good to excellent yield and enantiomeric excess. It
is also interesting to note that per-6-ABCD can be recovered
and reused several times. To the best of our knowledge, this is
the first example of a one-pot asymmetric synthesis of 2-aryl-
2,3-dihydro-4-quinolones using o-aminoacetophenone and
substituted aldehyde. A series of six aminocyclodextrin
derivatives (Figure 1) were also synthesized and assayed as
catalysts for synthesis of 2-aryl-2,3-dihydro-4-quinolones.
Preliminary investigations of the title reaction were carried
out using 1b as the catalyst and o-aminoacetophenone (2) and
benzaldehyde (3a) as model substrates to optimize the reaction
conditions, and the results are summarized in Table 1. All of the
T
development of pharmaceutical, agricultural, and fine chemical
industries, as well as materials science has escalated sharply in
recent years.1 Among the various approaches employed for this
purpose, asymmetric catalysis of organic reactions is one of the
most efficient ways to obtain optically pure compounds by
utilizing chiral catalysts and auxiliaries.2 One-pot synthesis is a
powerful method for assembling a single molecule from
multiple starting materials and for forming several bonds in a
one-step process.3 Consequently, many chiral ligands and their
transition-metal complexes have been developed for the
homogeneous one-pot asymmetric catalysis of various organic
transformations. The main concern in this situation is the need
for reusable chiral catalysts for industrial implementation. Due
to the high cost of both the metal and the chiral ligands,
systems that allow the straightforward separation of expensive
chiral catalysts from reaction mixtures and efficient recycling
are highly desirable.
The quinolone scaffold is present in many natural products
and is regarded as a “privileged building block” for medicinal
chemistry, with simple and flexible synthetic routes that allow
the production of large chemical libraries of potential bioactive
molecules.4 Consequently, numerous synthetic strategies have
been developed to gain access to different varieties of this
scaffold. 2-Aryl-2,3-dihydro-4-quinolones represent a new class
of antimitotic antitumor agents. Since their two enantiomers
were found to display distinctly different activities,5 a highly
enantioselective synthesis of these compounds is desirable.
Only four reports are available to date for enantioenriched
synthesis of 2-aryl-2,3-dihydro-4-quinolones reported from the
groups of Shintani,6a Liu,6b Lei,6c and Feng.6d These reports
make use of transition-metal-mediated catalytic processes and
nonrecoverable chiral catalysts and involve multiple steps for
the activation and removal of activating groups and hazardous
chemicals. Taking all these into account, the use of multifunc-
tional catalysts which not only generates less waste but also
ideally obviates the tedious separation and purification
protocols is desirable.
Received: October 13, 2012
Published: December 17, 2012
© 2012 American Chemical Society
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Note
examined with different molar ratios of host and guest. Though
very good conversions were observed, the ee was excellent only
when the H/G ratio was ≥1 (entries 16−20). These
observations clearly indicate that optimum results are found
(yield 98%, ee 98%) when the reaction is carried out in
ethanol/water (1:1, v/v) at −5 °C with 1b for 15 h (entry 13).
To test the generality of the reaction, various substituted
aldehydes were subjected to the above optimized reaction
conditions, and the results are given in Table 2. Good to
excellent yields and enantioselectivities were obtained for a
wide range of para-substituted aromatic aldehydes. Cyclic and
heterocyclic aldehydes provided products in high yield (81−
99%) with excellent enantioselectivity (82−99%). A variety of
functional groups, including methoxy, nitro, chloro, and methyl
groups, are well-tolerated. Substitution on the aryl ring of the
aldehyde at different positions also influences the reactivity.
Among the ortho-, meta-, and para-substituted aldehydes
examined, para-substituted aldehydes provide excellent yields
(93−99%) with high enantioselectivities (94−99%) when
compared to the ortho- and meta-substituted aldehydes. When
more than one substituent is present in the phenyl ring and the
distance between the carbonyl carbon and phenyl ring increases
(entries 13 and 14), the yield as well as ee decrease
considerably. These results clearly suggest that electronic
factors play a limited role, but the position and size (steric
factors) of substituents play a major role in enhancing the ee.
Para-substituted aldehydes (which ensure a stronger binding
and deeper inclusion into the CD cavity) show higher ee. A
gram scale experiment was also performed using 1b and gave
excellent isolated yield (99%) with high ee (99%) (entry 3),
and the results are comparable to those obtained for a small-
scale reaction.
Per-6-ABCD (1b) was also recovered and reused up to seven
times with only a marginal decrease in yield and ee (Supporting
Information, Table S2). To evaluate in more detail the cavity
size effect of the catalyst’s architecture in this system, we
extended our study with 1a and 1c to selected aliphatic and
highly substituted aromatic aldehydes under optimized reaction
conditions (Supporting Information, Table S3). The reaction
was catalyzed by 1a smoothly for aliphatic aldehydes to afford
the corresponding product (4t and 4u) with good yield and
reasonable enantioselectivities (entries 3 and 4) compared to
aromatic aldehydes (entries 1 and 2). With its large cavity, 1c is
found to be useful for disubstituted (in different positions)-
aldehydes also resulting in excellent yield and enantiopurity
(entries 5−9).
Scheme 1. Proposed Mechanism for One-Pot Asymmetric
Synthesis of 2-Aryl-2,3-dihydro-4-quinolone Catalyzed by 1b
reactions are performed in the optimized experimental
procedure given in the Experimental Section. The correspond-
ing imine is the major product (Figure S1a, Supporting
Information) when the reaction is carried out in β-cyclodextrin
in water (entry 1), which indicates the importance of amino
groups in this reaction. When diethylamine is employed as an
external base along with native β-CD, though moderate
conversion is observed, the enantiomeric excess is very poor
at room temperature (ee 5.2%) and at 4 °C (ee 6.4%) (entry
2). Interestingly, when the reaction is carried out with 1b as the
catalyst in water the reaction becomes faster with 42% yield of
4a and 46% ee (entry 3).
During solvent optimization, the reaction studied in various
solvents such as water, dimethylformamide, dimethyl sulfoxide,
acetonitrile, methanol and ethanol affords only modest yield
and low enantioselectivity (entries 4−8). On the other hand,
the ethanol/water (1:1,v/v) mixture is identified as the most
suitable solvent with respect to both yield and enantioselectivity
(entry 12). Under these optimized conditions, to enhance
enantioselectivity, the effect of temperature is also recorded
(entry 13). At low temperature (−5 °C), the enantioselectivity
in 4a increases drastically (ee up to 98%) with a decrease in the
yield (up to 71%) (entry 13). The absolute configuration of the
predominant enantiomer was assigned as S (Supporting
Information) by comparison with literature data.6a−d
The reaction was studied in the presence of the more
sterically demanding 1a and less sterically demanding 1c under
the optimized conditions, and they display low reactivity and
enantioselectivity compared to 1b (entry 14). The reaction was
also studied with monoamino-CDs under the optimized
conditions. Poor reactivity and enantioselectivity were noticed
with 1d (yield 42%, ee 31%), 1e (yield 75%, ee 84%), and 1f
(yield 67%, ee 62%) (entry 15). The reaction was also
On the basis of the above results based on reactivity and
stereochemical outcome and also in accordance with previous
literature reports,11 a plausible reaction pathway is proposed as
shown in Scheme 1.The first step involves formation of
Figure 1. Aminocyclodextrin catalysts employed in this study.
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Note
a
Table 1. Optimization of Reaction Conditions for the Synthesis of 2-Aryl-2,3-dihydro-4-quinolones
b
c
d
entry
medium
catalyst
T (°C)
yield (%)
imine (78)
ee (%)
1
2
water
water
water
β-CD
rt
e
β-CD:diethylamine
rt (4 °C)
54 (50)
5.2 (6.4)
46
3
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1a
1c
1d
1e
1f
rt
42
4
dimethylformamide
dimethylsulfoxide
acetonitrile
rt
56
31
5
rt
61
37
6
rt
66
52
7
methanol
rt
72
60
8
ethanol
rt
86
71
9
dimethylformamide/water
acetonitrile/water
methanol/water
ethanol/water
ethanol/water
ethanol/water
ethanol/water
ethanol/water
ethanol/water
ethanol/water
ethanol/water
ethanol/water
ethanol/water
ethanol/water
ethanol/water
rt
80
66
10
11
12
13
14
15
16
17
18
19
20
21
22
23
rt
86
71
rt
94
76
rt
99
84
10/0/−5/−10/−15
99/99/98/90/71
86/95/98/98/98
−5
−5
−5
−5
−5
−5
−5
−5
−5
−5
99
89
42
75
67
85
92
96
98
99
62
78
31
84
62
36
67
86
98
99
f
1b(0.25:1)
g
1b(0.50:1)
h
1b(0.75:1)
i
1b(1:1)
j
1b(2:1)
a
All reactions were performed with catalyst 1b (0.1 mmol), o-aminoacetophenone (0.1 mmol), aldehyde (0.1 mmol) in ethanol/water (1:1,v/v)
b
c
d
stirred at −5 °C for 15 h, unless otherwise noted. Catalyst used as mole ratio of 1:1 catalyst/aldehyde, unless otherwise noted. Isolated yield. ee
value was determined by HPLC analysis on a chiral stationary phase (AD-H column). Absolute configurations of products were assigned by
comparison with the HPLC retention time of the corresponding product reported in the literature (ref 6a−d.). β-CD as chiral host, diethylamine as
the external base. Mole ratio of 1b/aldehyde is 0.25:1. Mole ratio of 1b/aldehyde is 0.50:1. Mole ratio of 1b/aldehyde is 0.75:1. Mole ratio of 1b/
e
f
g
h
i
j
aldehyde is 1:1. Mole ratio of 1b/aldehyde is 2:1.
chalcone by the condensation between o-aminoacetophenone
and aldehyde. In the second step, isomerization of chalcone, via
aza-Michael addition12 (nucleophilic attack of the 2′-amino
group to β-carbon) takes place followed by tautomerization to
afford 2-aryl-2,3-dihydro-4-quinolone with high enantioselec-
tivity (ee > 99%). Aza-Michael addition takes place inside the
per-6-ABCD cavity, through its Si face, which is activated by
amino groups of 1b. Thus, it is clear that the mode of binding
of substance plays a crucial role9b,e for the stereochemical
outcome in this study. Control experiments also indicate clearly
that mode of addition of reactants and the amount of catalyst
plays a major role. Upon addition of 3a instead 2 to 1b the
corresponding imine is obtained as sole product and using
catalytic amount of 1b as catalyst and reaction is completed
within 6 h at room temperature in ACN as solvent with higher
yield and less ee (Supporting Information, Table S1).
The phenyl ring along with the olefinic double bond is
deeply penetrating inside the cavity, and the benzoyl moiety of
chalcone stays out/near of the wider rim of 1b (Scheme 1 and
Supporting Information, Figure S5). This type of inclusion
(mode A, Supporting Information, Figure S7) with a lower
complexation energy (ΔE = −42.61 kcal·M−1) is preferred
more than other modes (mode B, Supporting Information,
Figure S8), in which the benzoyl moiety penetrates inside the
cavity and the phenyl group with olefinic double bond of the
chalcone stays outside (ΔE = −38.92 kcal·M−1). Mode A is
stabilized by hydrogen bonding between the carbonyl group
and amino group of chalcone and amino groups of 1b. During
the addition of 3a, a ternary complex of 2 and 3a with 1b is
formed (2328 M−2 with a relative error 1.17% for n = 3), which
is more stable than a binary complex (1635 M−1 with relative
error 1.08% for n = 3) of 1b and 2, which is also evident from
molecular modeling studies. Formation of the binary and
ternary complexes and then the intermediate is also evident
from ESI-MS data. The molecular ion peaks (m/z found
1369.5998, calcd 1369.6012; m/z found 1263.5579, calcd
1263.5798; Supporting Information, Figures S12 and S11,
respectively) correspond to ternary complex of 2 and 3a with
1b and the binary complex of 3a and 1b, respectively. During
the course of reaction, the reaction mixture is also analyzed by
ESI-MS, which shows the molecular ion peak (m/z found
1351.5989, calcd 1351.5892), and it is confirmed that the
reaction proceeds via o-aminochalcone (1H and 13C NMR) as
the intermediate (2651 M−1 with relative error 0.98% for n =
3).
In the proposed mechanism (Scheme 1), primary amino
groups present in the narrow rim of 1b acting as an internal
base (pKa 6.5−8.9)13activate the acetyl group of 2 by
abstracting a proton (reddish orange color, observed λmax
=
356 nm, Supporting Information, Figure S1b(b)), producing
additional support for inclusion of o-aminoacetophenone
(Supporting Information, binary complex structure Figure
S11). This is followed by nucleophilic attack on the included
aldehyde and subsequent dehydration to generate chalcone
(yellow color). Simultaneously, isomerization of chalcone via
aza-Michael addition12 to the β-carbon of chalcone and
tautomerization afford the 2-aryl-2,3-dihydro-4-quinolones
with high enantioselectivity (ee > 99%). This occurs from the
amino-functionalized narrow rim side of 1b leading to the
formation of the major (S)-isomer, which is confirmed from the
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The Journal of Organic Chemistry
Note
the cooperative binding and tighter fit of guest inside the CD
cavity ensure their proximity to the chiral centers in CD, which
may have contributed to the high enantioselectivities. Though
the bulk of the reaction and induction of ee takes place inside
the cavity of 1b, occurrence of the reaction outside the cavity to
a smaller extent is also likely (particularly at room temperature
and in polar solvents (Table 1, entries 4−6)) in view of the
dynamic equilibrium between the free and complexed guest.
In summary, we have presented a highly efficient and
enantioselective (92−99% ee) one-pot synthesis of 2-aryl-2,3-
dihydro-4-quinolone scaffolds for the first time using 1b, which
simultaneously acts as a multifunctional base to promote the
reaction as well as chiral promoter to provide the enantiomeri-
cally enriched 4a. It is relevant to note here that when evaluated
for interactions with tubulin and for cytotoxic activity against a
panel of various human tumor cell lines the optically pure (S)-
isomer exhibits greater biological activity than the racemates or
(R)-isomer.5 This protocol has provided broad substrate scope
for various substituted aldehydes in the synthesis of 4a under
much simpler experimental conditions to give good yields and
excellent enantiomeric excesses. The catalyst can be easily
recovered by simple filtration and reused several times without
significant loss in its activity.
Table 2. Asymmetric One-Pot Synthesis of 2-Aryl-2,3-
dihydro-4-quinolones Catalyzed by Per-6-ABCD with
Various Substituted Aldehydes
a
b
c
entry
R
product yield (%) ee (%)
1
2
C6H5−
p-NO2C6H4−
p-ClC6H4−
m-ClC6H4−
o-ClC6H4−
p-OCH3C6H4−
m-OCH3C6H4−
p-OHC6H4−
o-OHC6H4−
p-CH3C6H4−
p-i-PrC6H4−
p-NMe2C6H4−
C6H5CHCH−
C6H5CH2−
2′-pyrrolyl−
2′-furanyl−
2′-thiophene-yl−
2′-pyridinyl−
cyclohexyl−
4a
4b
4c
4d
4e
4f
98
97
99
90
86
98
95
20
18
94
93
96
79
85
98
95
91
99
81
59
64
93
98
86
81
82
98
98
99
90
82
97
92
88
72
94
99
99
86
91
98
95
98
99
88
69
74
80
78
87
72
91
d
3
4
5
6
7
4g
4h
4i
e
8
e
9
10
11
12
4j
4k
4l
f
13
f
4m
4n
4o
4p
4q
4r
14
15
16
17
18
19
EXPERIMENTAL SECTION
■
General Procedure for Per-6-ABCD (1b)-Promoted One-Pot
Asymmetric Synthesis of 2-Aryl-2,3-dihydroquinolin-4(1H)-
ones. Aminocyclodextrins (1a−f) were synthesized and purified
according to the procedure described in the literature, and their
characterization data are accordance with the literature.14
4s
4t
f
20
CH3−
21
22
(CH3)2CH-CH2−
m,p-Cl2C6H3−
p-Cl,m-NO2C6H3−
m-OCH3-p-OH-C6H3−
m,m′-(OCH3)2-p-OHC6H2−
6-nitropiperonal
4u
4v
4w
4x
4y
4z
Per-6-ABCD (1b) (0.112 g, 0.1 mmol) was suspended in ethanol/
water (1:1 v/v; 2 mL). o-Aminoacetophenone (2) (13.51 mg, 0.1
mmol) dissolved in ethanol (0.5 mL) was added dropwise to the per-
6-ABCD (1b) suspension with constant stirring and continued for 30
min to complete complexation (appeared as a reddish orange color,
λmax = 365 nm). Then aldehyde 3a−z (0.1 mmol) was added and the
mixture allowed to stir at −5 °C for 10 h. After completion of the
reaction, products were extracted with ethyl acetate, dried with sodium
sulfate, and concentrated under reduced pressure. The resulting crude
product was purified by passing over a column of siliga gel 60−120
mesh using petroleum ether/ethyl acetate (8/2 ratio as an eluent) to
afford 2-aryl-2,3-dihydro-4-quinolones 4a−z as a light yellow−dark
yellow solid which was analyzed by NMR spectroscopy (300 MHz,
CDCl3, T = 300 K, TMS = 0 ppm), ESI-MS and CSP (chiral stationary
phase) HPLC. Percent ee was determined by HPLC at 214 nm using a
Chiralpak AD-H column with n-hexane and 2-propanol mixtures at a
flow rate 0.5−1.0 mL/min (or it otherwise noted). After extraction of
the product, per-6-ABCD (1b) is washed three times with ethyl
acetate, filtered, dried in vacuo, and reused (Supporting Information).
Determination of Absolute Configurations of the Products.
The 1H NMR spectrum of 4a was consistent with the literature data.7
The enantiomers of 4a were analyzed by chiral-phase HPLC using a
Chiralpak AD-H column (80:20 n-hexane−2-propanol, 0.3 mL/min,
214 nm); minor enantiomer tminor = 26.6 min [(R)-enantiomer], major
enantiomer tmajor = 30.0 min [(S)-enantiomer], 98% ee, [α]20D = +27.1
f
23
24
25
26
a
All reactions were performed with 1b (0.1 mmol), o-amino-
acetophenone (0.1 mmol), aldehyde (0.1 mmol) in ethanol/water
b
(1:1,v/v) stirred at −5 °C for 15 h, unless otherwise noted. Isolated
c
yield. ee value was determined by HPLC analysis on a chiral
stationary phase (AD-H column). Absolute configurations of products
were assigned by comparison with the HPLC retention time of the
d
corresponding product reported in literature (ref 6a−d). Gram scale.
e
Reaction carried for 48 h; the other product is the corresponding
f
chalcone. Reaction carried for 24 h.
specific rotation6 of the adduct (4a). If the attack takes place
from the wider rim of CD (a Re face attack), it may lead to
formation of the (R)-enantiomer, which is obtained in small
excess in the β-CD-diethylamine system (Table 1, entry 2) and
not observed with 1b. The complexation energies of two
enantiomers of 2-aryl-2,3-dihydro-4-quinolones 4a with 1b are
also calculated and confirm that the (S)-enantiomer forms a
more stable complex (ΔE = −48.92 kcal·M−1, mode C,
Supporting Information, Figure S9) than the corresponding
(R)-enantiomer (ΔE = −40.28 kcal·M−1, mode D, Supporting
Information, Figure S10).
Active participation and catalysis by the amino groups of 1b
are also supported by the fact that per-6-amino-β-cyclodextrin
hydrochloride fails to catalyze the addition of 3a to 2 and aza-
Michael addition of o-aminochalcone. A control experiment
carried out with 1b/adamantanol complex as the catalyst (2248
M−1 with relative error 1.20% for n = 3) gives a good yield of 4a
without any ee, which confirms active participation of the chiral
cavity of 1b in inducing enantiometric excess. We believe that
(c 0.42, CHCl3) [lit.6c [α]20 = +27.3 (c 0.35, CHCl3)], [lit.6a Daicel
D
Chiralpak AD-H column with 50:50 n-hexane−2-propanol, 0.3 mL/
min: major enantiomer tmajor = 14.5 min [(R)-enantiomer], minor
enantiomer tminor = 15.7 min [(S)-enantiomer], 98% ee, [α]20 −28.4
D
(c 0.77, CHCl3)]. The configuration of 4a (S) was assigned
accordingly, and the configurations of other products were assigned
by analogy.6
(S)-2-Phenyl-2,3-dihydroquinolin-4(1H)-one (Table 2, entry 1,
4a): pale yellow solid (21.86 mg, 98% yield); mp 150−152 °C [lit.11m
1
mp 149−150 °C); [α]20 = +27.1 (c 0.42, CHCl3); H NMR (300
D
MHz, CDCl3, δ ppm) 2.72 (dd, J = 4.5, 15.3 Hz, 1H), 2.97 (dd, J =
3.6, 15.3 Hz, 1H), 5.17 (dd, J = 8.4, 3.3 Hz, 1H), 5.57 (br s, 1H),
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Note
6.79−6.83 (m, 2H), 7.26−7.32 (m, 4H), 7.42−7.43 (m, 2H), 7.94−
7.99 (m, 1H); 13C NMR (75 MHz, CDCl3, δ ppm) 45.9, 57.9, 115.5,
117.9, 118.5, 126.2, 127.1, 128.0, 128.5, 135.0, 140.6, 151.2, 192.9;
ESI-MS m/z calcd for C15H13NO [M + H]+ 224.1076, found 224.2500
(rel int 100%). HPLC: enantiomeric excess was determined by HPLC
with a Chiralpak AD-H column (80:20 n-hexane−2-propanol, 0.3 mL/
min, 214 nm); minor enantiomer tminor = 26.6 min, major enantiomer
tmajor = 30.0 min, 98% ee.
214 nm); minor enantiomer tminor = 38.5 min, major enantiomer tmajor
= 46.6 min, 97% ee.
(S)-2-(3-Methoxyphenyl)-2,3-dihydroquinolin-4(1H)-one (Table 2,
entry 7, 4g): brownish yellow solid (24.06 mg, 95% yield); mp 129−
131 °C (lit.11m mp 129−130 °C); H NMR (300 MHz, CDCl3, δ
1
ppm) 2.72−2.83 (m, 1H), 2.96−3.07 (m, 1H), 3.78 (s, 3H), 5.15−
5.18 (m, 1H), 5.70 (br s, 1H), 6.76−6.81 (m, 3H), 6.99−7.06 (m,
2H), 7.20−7.27 (m, 2H), 7.95−7.97 (m, 1H); 13C NMR (75 MHz,
CDCl3, δ ppm) 42.2, 55.6, 55.9, 112.9, 114.4, 116.9, 117.9, 121.3,
123.2, 127.0, 129.5, 130.9, 143.5, 149.6, 159.9, 191.4; ESI-MS m/z
calcd for C16H15NO2 [M + H]+ 254.3037, found 254.3104 (rel int
100%). HPLC: enantiomeric excess was determined by HPLC with a
Chiralpak AD-H column (60:40 n-hexane−2-propanol, 0.5 mL/min,
214 nm); minor enantiomer tminor = 27.3 min, major enantiomer tmajor
= 30.3 min, 92% ee.
(S)-2-(4-Nitrophenyl)-2,3-dihydroquinolin-4(1H)-one (Table 2,
entry 2, 4b): orange solid (26.00 mg, 97% yield); mp 200−202 °C
(lit.11m mp 200−202 °C); H NMR (300 MHz, CDCl3, δ ppm) 2.79
1
(dd, J = 5.4, 15.6 Hz, 1H), 2.96 (dd, J = 3.6, 15.6 Hz, 1H), 5.23 (dd, J
= 9.3, 4.2 Hz, 1H), 5.81 (br s, 1H), 6.78−6.81 (m, 2H), 7.25−7.27 (m,
1H), 7.82−7.84 (m, 2H), 7.95−7.97 (m, 1H), 8.16−8.19 (m, 2H); 13C
NMR (75 MHz, CDCl3, δ ppm) 47.1, 57.2, 115.9, 117.4, 118.4, 123.8,
124.1, 128.6, 134.8, 139.6, 141.5, 151.3, 190.5; ESI-MS m/z calcd for
C15H12N2O3 [M + H]+ 269.0927, found 269.0833 (rel int 100%).
HPLC: enantiomeric excess was determined by HPLC with a
Chiralpak AD-H column (20:80 n-hexane−2-propanol, 0.3 mL/min,
214 nm); minor enantiomer tminor = 32.6 min, major enantiomer tmajor
= 40.0 min, 98% ee.
(S)-2-(4-Hydroxyphenyl)-2,3-dihydroquinolin-4(1H)-one (Table 2,
entry 8, 4h): yellow solid (4.78 mg, 20% yield); mp 158−161 °C; 1H
NMR (300 MHz, CDCl3, δ ppm) 2.82 (dd, J = 3.0, 15.3 Hz, 1H), 3.02
(dd, J = 5.4, 15.0 Hz, 1H), 4.61 (br s, 2H), 5.19 (dd, J = 9.6, 3.3 Hz,
1H), 6.78−6.81 (m, 4H), 7.23−7.27 (m, 3H), 7.95−7.97 (m, 1H); 13C
NMR (75 MHz, CDCl3, δ ppm) 42.5, 55.4, 116.0, 117.0, 117.9, 123.2,
127.0, 127.9, 131.0, 135.5, 149.5, 156.2, 192.3; ESI-MS m/z calcd for
C15H13NO2 [M + H]+ 240.1025, found 240.1106 (rel int 100%). Anal.
Calcd for C15H13NO2: C, 75.30; H, 5.48; N, 5.85; O, 13.37. Found: C,
75.31; H, 5.50; N, 5.86; O, 13.39. HPLC: enantiomeric excess was
determined by HPLC with a Chiralpak AD-H column (80:20 n-
(S)-2-(4-Chlorophenyl)-2,3-dihydroquinolin-4(1H)-one (Table 2,
entry 3, 4c): pale yellow solid (25.44 mg, 99% yield); mp 169−170 °C
(lit.11g mp 168−170 °C); H NMR (300 MHz, CDCl3, δ ppm) 2.80
1
(dd, J = 3.9, 14.7 Hz, 1H), 3.15 (dd, J = 4.8, 14.7 Hz, 1H), 5.17 (dd, J
= 9.0, 3.0 Hz, 1H), 5.81 (br s, 1H), 6.78−6.81 (m, 2H), 7.38−7.39 (m,
1H), 7.43−7.59 (m, 4H), 7.95−7.98 (m, 1H); 13C NMR (75 MHz,
CDCl3, δ ppm) 46.3, 57.8, 116.0, 118.6, 119.0, 127.5, 127.9, 129.1,
134.1, 135.5, 139.5, 151.4, 192.8; ESI-MS m/z calcd for C15H12ClNO
[M + H]+ 258.0686, found 258.1667 (rel int 100%). HPLC:
enantiomeric excess was determined by HPLC with a Chiralpak AD-
H column (80:20 n-hexane−2-propanol, 0.3 mL/min, 214 nm); minor
enantiomer tminor = 29.0 min, major enantiomer tmajor = 33.4 min, 99%
ee.
hexane−2-propanol, 0.4 mL/min, 214 nm); minor enantiomer tminor
28.3 min, major enantiomer tmajor = 30.1 min, 88% ee.
=
(S)-2-(2-Hydroxyphenyl)-2,3-dihydroquinolin-4(1H)-one (Table 2,
1
entry 9, 4i): yellow solid (4.30 mg, 18% yield); mp 164−168 °C; H
NMR (300 MHz, CDCl3, δ ppm) 2.89 (dd, J = 3.6, 15.6 Hz, 1H), 3.04
(dd, J = 3.6, 15.6 Hz, 1H), 4.97 (br s, 2H), 5.52 (dd, J = 9.3, 3.3 Hz,
1H), 6.79−6.91 (m, 3H), 6.91 (m, 1H), 7.07 (m, 1H), 7.08 (m, 1H),
7.27 (m, 1H), 7.95−7.98 (m, 1H); 13C NMR (75 MHz, CDCl3, δ
ppm) 42.4, 51.8, 116.2, 116.8, 117.5, 122.7, 123.2, 126.3, 126.5, 126.9,
128.2, 131.2, 150.1, 156.6, 192.7; ESI-MS m/z calcd for C15H13NO2
[M + H]+ 240.1025, found 240.1092 (rel int 100%). Anal. Calcd for
C15H13NO2: C, 75.30; H, 5.48; N, 5.85; O, 13.37. Found: C, 75.31; H,
5.51; N, 5.85; O, 13.38. HPLC: enantiomeric excess was determined
by HPLC with a Chiralpak AD-H column (70:30 n-hexane−2-
propanol, 0.3 mL/min, 214 nm); minor enantiomer tminor = 26.2 min,
major enantiomer tminor = 31.3 min, 72% ee.
(S)-2-(3-Chlorophenyl)-2,3-dihydroquinolin-4(1H)-one (Table 2,
entry 4, 4d): pale yellow solid (23.13 mg, 90% yield); mp 143−145
1
°C; H NMR (300 MHz, CDCl3, δ ppm) 2.83 (dd, J = 3.9, 15.0 Hz,
1H), 3.03 (dd, J = 3.3, 15.0 Hz, 1H), 5.13−5.19 (m, 1H), 5.75 (br s,
1H), 6.79−6.81 (m, 2H), 7.27−7.34 (m, 4H), 7.48 (s, 1H), 7.95−7.98
(m, 1H); 13C NMR (75 MHz, CDCl3, δ ppm) 46.1, 57.9, 116.0, 118.6,
119.0, 124.7, 126.7, 127.5, 128.5, 130.2, 134.8, 135.4, 143.1, 151.3,
192.5; ESI-MS m/z calcd for C15H12ClNO [M + H]+ 258.0686, found
258.1660 (rel int 100%). HPLC: enantiomeric excess was determined
by HPLC with a Chiralpak AD-H column (90:10 n-hexane−2-
propanol, 0.2 mL/min, 214 nm); minor enantiomer tminor = 60.1 min,
major enantiomer tminor = 66.0 min, 90% ee.
(S)-2-p-Tolyl-2,3-dihydroquinolin-4(1H)-one (Table 2, Entry 10,
4j): glittering pale yellow solid (22.28 mg, 94% yield); mp 148−149
°C (lit.11g,m mp 148−149 °C); H NMR (300 MHz, CDCl3, δ ppm)
1
2.21 (s, 3H), 2.80 (dd, J = 3.3, 16.2 Hz, 1H), 3.04 (dd, J = 4.2, 16.2
Hz, 1H), 5.11−5.28 (m, 1H), 5.81 (br s, 1H), 6.78−6.81 (m, 2H),
7.12 (d, J = 6.9 Hz, 2H), 7.17−7.38 (m, 3H), 7.95−7.98 (m, 1H); 13C
NMR (75 MHz, CDCl3, δ ppm) 20.7, 46.0, 57.8, 115.5, 117.9, 118.6,
126.1, 127.2, 129.2, 134.9, 137.7, 137.8, 151.3, 193.0; ESI-MS m/z
calcd for C16H15NO [M + H]+ 238.1233, found 238.1695 (rel int
100%). HPLC: enantiomeric excess was determined by HPLC with a
Chiralpak AD-H column (60:40 n-hexane−2-propanol, 0.4 mL/min,
214 nm); minor enantiomer tminor = 14.2 min, major enantiomer tmajor
= 17.7 min, 94% ee.
(S)-2-(2-Chlorophenyl)-2,3-dihydroquinolin-4(1H)-one (Table 2,
entry 5, 4e): pale yellow solid (22.10 mg, 86% yield); mp 146−147 °C
[lit.11m mp 145−147 °C]; H NMR (300 MHz, CDCl3, δ ppm) 3.58
1
(dd, J = 3.9, 13.8 Hz, 1H), 3.02 (dd, J = 4.2, 13.8 Hz, 1H), 5.44−5.59
(m, 1H), 5.95 (br s, 1H), 6.78−6.82 (m, 2H), 7.25−7.27 (m, 3H),
7.52 (d, J = 6.3 Hz, 2H), 7.96−7.98 (m, 1H); 13C NMR (75 MHz,
CDCl3, δ ppm) 37.2, 47.4, 109.2, 111.8, 112.3, 120.7, 122.4, 122.5,
123.2, 123.3, 125.9, 128.6, 131.5, 144.8, 186.0; ESI-MS m/z calcd for
C15H12ClNO [M + H]+ 258.0686, found 258.2250 (rel int 100%).
HPLC: enantiomeric excess was determined by HPLC with a
Chiralpak AD-H column (90:10 n-hexane-2-propanol, 0.3 mL/min,
214 nm); minor enantiomer tminor = 41.9 min, major enantiomer tmajor
= 46.0 min, 82% ee.
(S)-2-(4-Isopropylphenyl)-2,3-dihydroquinolin-4(1H)-one (Table
2, entry 11, 4k): glittering yellow solid (24.65 mg, 93% yield); mp
1
156−158 °C; H NMR (300 MHz, CDCl3, δ ppm) 1.22 (s, 6H),
2.78−2.88 (m, 2H), 2.96−3.00 (m, 1H), 5.14−5.19 (m, 1H), 5.75 (br
s, 1H), 6.78−6.81 (m, 2H), 7.20−7.27 (m, 3H), 7.39 (d, J = 4.8 Hz,
2H), 7.95−7.97 (m, 1H); 13C NMR (75 MHz, CDCl3, δ ppm) 24.3,
34.3, 46.8, 58.6, 116.2, 118.7, 119.5, 127.0, 127.4, 128.0, 135.7, 138.8,
149.7, 152.0, 193.7; ESI-MS m/z calcd for C18H19NO [M + H]+
266.1546, found 266.1673 (rel int 100%). Anal. Calcd for C18H19NO:
C, 81.47; H, 7.22; N, 5.28; O, 6.03. Found: C, 81.48; H, 7.22; N, 5.30;
O, 6.04. HPLC: enantiomeric excess was determined by HPLC with a
Chiralpak AD-H column (70:30 n-hexane-2-propanol, 0.3 mL/min,
214 nm); minor enantiomer tminor = 16.8 min, major enantiomer tmajor
= 19.0 min, 99% ee.
(S)-2-(4-Methoxyphenyl)-2,3-dihydroquinolin-4(1H)-one (Table 2,
entry 6, 4f): yellow solid (24.82 mg, 98% yield); mp 145−146 °C
(lit.11m mp 145−147 °C); H NMR (300 MHz, CDCl3, δ ppm) 2.83
1
(dd, J = 3.0, 15.3 Hz, 1H), 3.03 (dd, J = 3.6, 15.3 Hz, 1H), 3.82 (s,
3H), 5.19 (dd, J = 8.1, 3.3 Hz, 1H), 5.78 (br s, 1H), 6.77−6.88 (m,
4H), 7.26−7.37 (m, 3H), 7.95−7.97 (m, 1H); 13C NMR (75 MHz,
CDCl3, δ ppm) 46.2, 55.0, 57.6, 114.0, 115.7, 117.9, 118.6, 127.5,
129.8, 132.8, 135.1, 151.5, 159.3, 193.3; ESI-MS m/z calcd for
C16H15NO2 [M + H]+ 254.3037, found 254.2562 (rel int 100%).
HPLC: enantiomeric excess was determined by HPLC with a
Chiralpak AD-H column (80:20 n-hexane−2-propanol, 0.3 mL/min,
748
dx.doi.org/10.1021/jo302173a | J. Org. Chem. 2013, 78, 744−751

The Journal of Organic Chemistry
Note
(S)-2-(4-(Dimethylamino)phenyl)-2,3-dihydroquinolin-4(1H)-one
135−137 °C (lit.11m mp 135−137 °C); 1H NMR (300 MHz, CDCl3, δ
ppm) 2.83 (dd, J = 7.5, 16.2 Hz, 1H), 3.07 (dd, J = 7.2, 16.2 Hz, 1H),
5.25 (br s, 1H), 5.48−5.53 (m, 1H), 6.78−6.81 (m, 2H), 6.82−6.98
(m, 2H), 7.18−7.27 (m, 2H), 7.95−7.97 (m, 1H); 13C NMR (75
MHz, CDCl3, δ ppm) 46.9, 53.6, 116.0, 118.7, 119.2, 126.8, 127.5,
128.9, 130.5, 132.5, 135.4, 150.8, 192.6; ESI-MS m/z calcd for
C13H11NOS [M + H]+ 230.0640, found 230.1657 (rel int 100%).
HPLC: enantiomeric excess was determined by HPLC with a
Chiralpak AD-H column (50:50 n-hexane−2-propanol, 0.3 mL/min,
214 nm); minor enantiomer tminor = 15.5 min, major enantiomer tmajor
= 17.4 min, 98% ee.
(Table 2, entry 12, 4l): glittering yellow solid (25.54 mg, 96% yield);
mp 183−184 °C (lit.11m mp 182−184 °C); H NMR (300 MHz,
1
CDCl3, δ ppm) 2.80 (dd, J = 3.3, 15.3 Hz, 1H), 3.02 (dd, J = 3.6, 15.6
Hz, 1H), 3.52 (s, 6H), 5.15 (dd, J = 9.6, 3.9 Hz, 1H), 5.78 (br s, 1H),
6.606−6.63 (m, 2H), 6.78−6.81 (m, 2H), 7.17 (d, J = 4.2 Hz, 2H),
7.25−7.28 (m, 1H), 7.95−7.97 (m, 1H); 13C NMR (75 MHz, CDCl3,
δ ppm) 40.5, 46.4, 57.9, 112.5, 115.9, 118.0, 118.9, 127.48, 127.51,
128.4, 135.2, 150.6, 151.8, 193.9; ESI-MS m/z calcd for C17H18N2O
[M + H]+ 267.1498, found 267.3333 (rel int 100%). HPLC:
enantiomeric excess was determined by HPLC with a Chiralpak AD-
H column (50:50 n-hexane−2-propanol, 0.2 mL/min, 214 nm); minor
enantiomer tminor = 27.5 min, major enantiomer tmajor = 34.1 min, 99%
ee.
(S)-2-(Pyridin-2-yl)-2,3-dihydroquinolin-4(1H)-one (Table 2, entry
18, 4r): brownish yellow solid (22.18 mg, 99% yield); mp 128−130
1
°C; H NMR (300 MHz, CDCl3, δ ppm) 2.75 (dd, J = 3.9, 15.6 Hz,
(S,E)-2-Styryl-2,3-dihydroquinolin-4(1H)-one (Table 2, entry 13,
4m): brownish yellow solid (19.68 mg, 79% yield); mp 117−118 °C;
1H NMR (300 MHz, CDCl3, δ ppm) 2.49 (dd, J = 5.1, 14.7 Hz, 1H),
1H), 3.14 (dd, J = 4.2, 15.3 Hz, 1H), 4.46 (br s, 1H), 5.14 (dd, J = 9.0,
3.3 Hz, 1H), 6.78−6.88 (m, 2H), 7.16−7.35 (m, 3H), 7.62 (m, 1H),
7.86−7.88 (m, 1H), 8.58 (d, J = 3.9 Hz, 1H); 13C NMR (75 MHz,
CDCl3, δ ppm) 46.2, 52.1, 115.8, 117.1, 124.0, 125.0, 126.9, 131.5,
134.5, 136.8, 140.9, 150.0, 153.5, 191.6; ESI-MS m/z calcd for
C14H12N2O [M + H]+ 225.1029, found 225.1381 (rel int 100%). Anal.
Calcd for C14H12N2O: C, 74.98; H, 5.39; N, 12.49; O, 7.13. Found: C,
74.99; H, 5.42; N, 12.51; O, 7.13. HPLC: enantiomeric excess was
determined by HPLC with a Chiralpak AD-H column (80:20 n-
2.63 (dd, J = 4.8, 14.7 Hz, 1H), 4.67−4.72 (m, 1H), 5.47 (br s, 1H),
6.36−6.40 (m, 1H), 6.51−6.54 (m, 1H), 6.78−6.81 (m, 2H), 7.20−
7.28 (m, 6H), 7.94−7.96 (m, 1H); 13C NMR (75 MHz, CDCl3, δ
ppm) 47.3, 52.0, 113.6, 115.7, 117.2, 128.2, 128.7, 128.8, 128.9, 129.2,
129.6, 130.4, 132.0, 134.4, 137.3, 150.3, 196.2; ESI-MS m/z calcd for
C17H15NO [M + H]+ 250.1233, found 250.1253 (rel int 100%). Anal.
Calcd for C17H15NO: C, 81.90; H, 6.06; N, 5.62; O, 6.42. Found: C,
81.90; H, 6.07; N, 5.63; O, 6.44. HPLC: enantiomeric excess was
determined by HPLC with a Chiralpak AD-H column (70:30 n-
hexane−2-propanol, 0.4 mL/min, 214 nm); minor enantiomer tminor
26.4 min, major enantiomer tmajor = 32.2 min, 99% ee.
=
(S)-2-Cyclohexyl-2,3-dihydroquinolin-4(1H)-one (Table 2, entry
1
19, 4s): brown solid (18.56 mg, 81% yield); mp 140−141 °C; H
hexane−2-propanol, 0.3 mL/min, 214 nm); minor enantiomer tminor
19.8 min, major enantiomer tmajor = 21.6 min, 86% ee.
=
NMR (300 MHz, CDCl3, δ ppm) 1.31−1.62 (m, 11H), 2.25−2.29 (m,
1H), 2.64−2.69 (m, 1H), 3.65−3.70 (m, 1H), 5.28 (br s, 1H), 6.75−
6.81 (m, 2H), 7.25−7.27 (m, 1H), 7.92−7.94 (m, 1H); 13C NMR (75
MHz, CDCl3, δ ppm) 25.4, 27.6, 31.8, 43.1, 46.3, 53.0, 115.4, 117.1,
117.9, 131.8, 134.2, 150.4, 194.7; ESI-MS m/z calcd for C15H19NO [M
+ H]+ 230.1546, found 230.1467 (rel int 100%). Anal. Calcd for
C15H19NO: C, 78.56; H, 8.35; N, 6.11; O, 6.98. Found: C, 78.58; H,
8.37; N, 6.11; O, 6.99. HPLC: enantiomeric excess was determined by
HPLC with a Chiralpak AD-H column (40:60 n-hexane−2-propanol,
0.3 mL/min, 214 nm); minor enantiomer tminor = 34.5 min, major
enantiomer tmajor = 37.7 min, 88% ee.
(R)-2-Benzyl-2,3-dihydroquinolin-4(1H)-one (Table 2, entry 14,
1
4n): brown solid (20.15 mg, 85% yield); mp 105−108 °C; H NMR
(300 MHz, CDCl3, δ ppm) 2.30−2.37 (m, 1H), 2.61−2.66 (m, 1H),
2.89−2.92 (m, 1H), 3.02−3.08 (m, 1H), 4.33−4.39 (m, 1H), 5.54 (br
s, 1H), 6.70−6.82 (m, 2H), 7.25−7.28 (m, 6H), 7.92−7.97 (m, 1H);
13C NMR (75 MHz, CDCl3, δ ppm) 39.5, 42.0, 48.8, 116.5, 116.8,
121.9, 126.4, 127.2, 128.4, 129.6, 130.7, 136.9, 150.8, 192.2; ESI-MS
m/z calcd for C16H15NO [M + H]+ 238.1233, found 238.2603 (rel int
100%). Anal. Calcd for C16H15NO: C, 80.98; H, 6.37; N, 5.90; O, 6.74.
Found: C, 80.98; H, 6.38; N, 5.91; O, 6.74. HPLC: enantiomeric
excess was determined by HPLC with a Chiralpak AD-H column
(40:60 n-hexane−2-propanol, 0.4 mL/min, 214 nm); major
enantiomer tmajor = 19.9 min, minor enantiomer tminor = 22.9 min,
91% ee.
(R)-2-Methyl-2,3-dihydroquinolin-4(1H)-one (Table 2, entry 20,
4t): brownish yellow semisolid (9.50 mg, 59% yield); mp 49−50 °C
(lit.11l mp 49−51 °C); 1H NMR (300 MHz, CDCl3, δ ppm) 1.28 (d, J
= 3.6 Hz, 3H), 2.28−2.35 (m, 1H), 2.56−2.65 (m, 1H), 4.04−4.10 (m,
1H), 5.58 (br s, 1H), 6.73−6.82 (m, 2H), 7.25−7.28 (m, 1H), 7.92−
7.94 (m, 1H); 13C NMR (75 MHz, CDCl3, δ ppm) 18.6, 44.6, 46.9,
116.9, 119.9, 121.6, 127.3, 130.5, 151.8, 192.7; ESI-MS m/z calcd for
C10H11NO [M + H]+ 162.0919, found 162.0992 (rel int 100%).
HPLC: enantiomeric excess was determined by HPLC with a
Chiralpak AD-H column (80:20 n-hexane−2-propanol, 0.4 mL/min,
214 nm); major enantiomer tmajor = 18.5 min, minor enantiomer tminor
= 20.7 min, 69% ee.
(S)-2-(1H-Pyrrol-2-yl)-2,3-dihydroquinolin-4(1H)-one (Table 2,
1
entry 15, 4o): pale yellow sticky liquid (20.78 mg, 98% yield); H
NMR (300 MHz, CDCl3, δ ppm) 2.89 (dd, J = 3.0, 13.8 Hz, 1H), 3.02
(dd, J = 3.3, 13.8 Hz, 1H), 5.00 (br s, 2H), 5.31 (dd, J = 10.2, 3.6 Hz,
1H), 6.06−6.08 (m, 1H), 6.16−6,19 (m, 1H), 6.65−6.67 (m, 1H),
6.79−6.81 (m, 2H), 7.25−7.28 (m, 1H), 7.94−8.16 (m, 1H); 13C
NMR (75 MHz, CDCl3, δ ppm) 44.0, 48.5, 102.5, 107.6, 117.0, 117.9,
118.1, 123.2, 127.2, 128.9, 131.2, 149.9, 192.0; ESI-MS m/z calcd for
C13H12N2O [M + H]+ 213.1028, found 213.1012 (rel int 100%). Anal.
Calcd for C13H12N2O: C, 73.56; H, 5.70; N, 13.20; O, 7.54. Found: C,
73.57; H, 5.72; N, 13.21; O, 7.54. HPLC: enantiomeric excess was
determined by HPLC with a Chiralpak AD-H column (70:30 n-
(R)-2-Isobutyl-2,3-dihydroquinolin-4(1H)-one (Table 2, entry 21,
1
4u): brownish yellow sticky liquid (13.00 mg, 64% yield); H NMR
(300 MHz, CDCl3, δ ppm) 0.86 (s, 6H), 1.34−1.54 (m, 3H), 2.81−
2.32 (m, 1H), 2.55−2.28 (m, 1H), 3.95−4.04 (m, 1H), 5.47 (br s,
1H), 6.74−6.81 (m, 2H), 7.25−7.27 (m, 1H), 7.92−7.94 (m, 1H); 13C
NMR (75 MHz, CDCl3, δ ppm) 22.1, 24.9, 43.0, 43.9, 46.4, 116.4,
116.7, 121.9, 127.2, 131.7, 150.8, 192.3; ESI-MS m/z calcd for
C13H17NO [M + H]+ 204.1388, found 204.1402 (rel int 100%). Anal.
Calcd for C13H17NO: C, 76.81; H, 8.43; N, 6.89; O, 7.87. Found: C,
76.81; H, 8.44; N, 6.89; O, 7.88. HPLC: enantiomeric excess was
determined by HPLC with a Chiralpak AD-H column (70:30 n-
hexane−2-propanol, 0.3 mL/min, 214 nm); minor enantiomer tminor
17.5 min, major enantiomer tmajor = 20.8 min, 98% ee.
=
(S)-2-(Furan-2-yl)-2,3-dihydroquinolin-4(1H)-one (Table 2, entry
16, 4p): pale yellow semisolid (20.24 mg, 95% yield); mp 92−93 °C
(lit.11d mp 92 °C); H NMR (300 MHz, CDCl3, δ ppm) 2.81−2.89
1
(m, 1H), 3.01−3.06 (m, 1H), 5.45−5.56 (m, 1H), 5.87 (br s, 1H),
6.36−6.50 (m, 2H), 6.78−6.86 (m, 2H), 7.25−7.27 (m, 1H), 7.55−
7.58 (m, 1H), 7.94−7.97 (m, 1H); 13C NMR (75 MHz, CDCl3, δ
ppm) 39.3, 47.5, 104.8, 111.4, 117.0, 117.9, 123.2, 127.0, 131.0, 142.1,
149.6, 152.4, 192.4; ESI-MS m/z calcd for C13H11NO2 [M + H]+
214.0869, found 214.0988 (rel int 100%). HPLC: enantiomeric excess
was determined by HPLC with a Chiralpak AD-H column (80:20 n-
hexane−2-propanol, 0.3 mL/min, 214 nm); major enantiomer tmajor
26.8 min, minor enantiomer tminor = 29.9 min, 74% ee.
=
(S)-2-(3,4-Dichlorophenyl)-2,3-dihydroquinolin-4(1H)-one (Table
2, entry 22, 4v): yellow semisolid (27.06 mg, 93% yield); mp 205−208
1
°C; H NMR (300 MHz, CDCl3, δ ppm) 2.86 (dd, J = 7.8, 16.2 Hz,
1H), 3.05 (dd, J = 7.2, 16.2 Hz, 1H), 5.15 (dd, J = 9.9, 3.3 Hz, 1H),
5.76 (br s, 1H), 6.78−6.81 (m, 2H), 7.25−7.27 (m, 2H), 7.40−7.42
(m, 1H), 7.52 (s, 1H), 7.95−7.97 (m, 1H); 13C NMR (75 MHz,
CDCl3, δ ppm) 43.2, 56.9, 117.0, 117.9, 123.1, 126.7, 126.9, 127.0,
hexane−2-propanol, 0.4 mL/min, 214 nm); minor enantiomer tminor
=
20.5 min, major enantiomer tmajor = 23.7 min, 95% ee.
(S)-2-(Thiophene-2-yl)-2,3-dihydroquinolin-4(1H)-one (Table 2,
entry 17, 4q): brownish yellow solid (20.84 mg, 91% yield); mp
749
dx.doi.org/10.1021/jo302173a | J. Org. Chem. 2013, 78, 744−751

The Journal of Organic Chemistry
Note
129.3, 129.8, 130.3, 130.9, 143.0, 149.6, 191.4; ESI-MS m/z calcd for
C15H11Cl2NO [M + H]+ 292.0297, found 292.0357 (rel int 100%).
HPLC: enantiomeric excess was determined by HPLC with a
Chiralpak AD-H column (70:30 n-hexane−2-propanol, 0.3 mL/min,
214 nm); minor enantiomer tminor = 28.6 min, major enantiomer tmajor
= 30.8 min, 80% ee.
C22H19NO3S [M + H]+ 378.1164, found 378.1321 (rel int 100%).
HPLC: enantiomeric excess was determined by HPLC with a
Chiralpak AD-H column (90:10 n-hexane−2-propanol, 0.4 mL/min,
214 nm); minor enantiomer tminor = 38.9 min, major enantiomer tmajor
= 44.6 min, 97% ee.
(S)-2-(4-Chloro-3-nitrophenyl)-2,3-dihydroquinolin-4(1H)-one
ASSOCIATED CONTENT
■
(Table 2, entry 23, 4w): brownish yellow soild (29.60 mg, 98% yield);
S
* Supporting Information
1
mp 186−188 °C; H NMR (300 MHz, CDCl3, δ ppm) 2.87 (dd, J =
1
General methods, experimental procedures, copies of H and
7.2, 15.3 Hz, 1H), 3.03 (dd, J = 7.8, 15.3 Hz, 1H), 5.21 (dd, J = 9.9, 4.8
Hz, 1H), 5.59 (br s, 1H), 6.77−6.81 (m, 2H), 7.25−7.27 (m, 1H),
7.60−7.72 (m, 2H), 7.91−7.97 (m, 2H); 13C NMR (75 MHz, CDCl3,
δ ppm) 42.2, 56.0, 117.0, 117.9, 121.0, 123.2, 127.0, 128.1, 131.2,
131.5, 131.9, 143.5, 148.2, 149.9, 192.3; ESI-MS m/z calcd for
C15H11ClN2O3 [M + H]+ 303.0536, found 303.0612 (rel int 100%).
Anal. Calcd for C15H11ClN2O3: C, 59.52; H, 3.66; Cl, 11.71; N, 9.25;
O, 15.86. Found: C, 59.52; H, 3.68; Cl, 11.72; N, 9.25; O, 15.87.
HPLC: enantiomeric excess was determined by HPLC with a
Chiralpak AD-H column (80:20 n-hexane−2-propanol, 0.4 mL/min,
214 nm); minor enantiomer tminor = 27.5 min, major enantiomer tmajor
= 32.1 min, 78% ee.
13C NMR, HPLC trace, and ESI-MS. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: pit12399@yahoo.com.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(S)-2-(4-Hydroxy-3-methoxyphenyl)-2,3-dihydroquinolin-4(1H)-
We gratefully acknowledge the financial assistance from UGC-
BSR and Department of Science and Technology (DST), New
Delhi, India, and K.K. thanks the Council of Scientific and
Industrial Research (CSIR), New Delhi, for the award of a
Senior Research Fellowship.
one (Table 2, entry 24, 4x): yellow solid (23.14 mg, 86% yield); mp
1
143−144 °C; H NMR (300 MHz, CDCl3, δ ppm) 2.83 (dd, J = 5.4,
16.2 Hz, 1H), 3.01 (dd, J = 6.0, 16.2 Hz, 1H), 3.84 (s, 3H), 5.15−5.20
(m, 1H), 5.52 (br s, 2H), 6.78−6.86 (m, 5H), 7.25−7.28 (m, 1H),
7.95−7.97 (m, 1H); 13C NMR (75 MHz, CDCl3, δ ppm) 46.2, 55.5,
57.9, 108.4, 114.1, 115.4, 117.9, 118.5, 119.2, 127.1, 132.5, 134.9,
145.3, 146.4, 151.1, 193.0; ESI-MS m/z calcd for C16H15NO3 [M +
H]+ 270.1131, found 270.1667 (rel int 100%). HPLC: enantiomeric
excess was determined by HPLC with a Chiralpak AD-H column
(80:20 n-hexane−2-propanol, 0.5 mL/min, 214 nm); minor
enantiomer tminor = 27.1 min, major enantiomer tmajor = 29.1 min,
87% ee.
REFERENCES
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(S)-2-(4-Hydroxy-3,5-dimethoxyphenyl)-2,3-dihydroquinolin-
4(1H)-one (Table 2, entry 25, 4y): yellow solid (24.22 mg, 81% yield);
mp 167−168 °C; 1H NMR (300 MHz, CDCl3, δ ppm) 2.78−2.83 (m,
1H), 2.98−3.05 (m, 1H), 3.73 (s, 6H), 5.12−5.29 (m, 1H), 5.57 (br s,
2H), 6.53 (s, 2H), 6.78−6.81 (m, 2H), 7.25−7.27 (m, 1H), 7.95−7.97
(m, 1H); 13C NMR (75 MHz, CDCl3, δ ppm) 46.5, 56.0, 58.5, 103.0,
115.6, 118.1, 118.7, 127.2, 131.9, 134.4, 135.0, 146.9, 151.2, 192.9;
ESI-MS m/z calcd for C17H17NO4 [M + H]+ 300.1237, found
300.1608 (rel int 100%). Anal. Calcd for C17H17NO4: C, 68.21; H,
5.72; N, 4.68; O, 21.38. Found: C, 68.24; H, 5.73; N, 4.69; O, 21.39.
HPLC: enantiomeric excess was determined by HPLC with a
Chiralpak AD-H column (50:50 n-hexane−2-propanol, 0.3 mL/min,
214 nm); minor enantiomer tminor = 24.1 min, major enantiomer tmajor
= 27.3 min, 72% ee.
(S)-2-(6-Nitrobenzo[d][1,3]dioxol-5-yl)-2,3-dihydroquinolin-
4(1H)-one (Table 2, entry 26, 4z): yellow solid (25.59 mg, 82% yield);
1
mp 179−180 °C; H NMR (300 MHz, CDCl3, δ ppm) 2.87 (dd, J =
7.2, 16.5 Hz, 1H), 3.31 (dd, J = 6.9, 16.5 Hz, 1H), 5.24 (dd, J = 10.2,
6.0 Hz, 1H), 5.76 (br s, 1H), 6.12 (s, 2H), 6.26−6.82 (m, 2H), 7.14 (s,
1H), 7.26−7.29 (m, 2H), 7.93−7.95 (m, 1H); 13C NMR (75 MHz,
CDCl3, δ ppm) 39.1, 47.4, 100.1, 110.5, 111.8, 113.3, 121.9, 125.6,
129.1, 130.0, 132.9, 142.0, 146.7, 151.7, 154.9, 193.7; ESI-MS m/z
calcd for C16H12N2O5 [M + H]+ 313.0825, found 313.2591 (rel int
100%). Anal. Calcd for C16H12N2O5: C, 61.54; H, 3.87; N, 8.97; O,
25.62. Found: C, 61.54; H, 3.90; N, 8.98; O, 25.64. HPLC:
enantiomeric excess was determined by HPLC with a Chiralpak AD-
H column (50:50 n-hexane−2-propanol, 0.2 mL/min, 214 nm); minor
enantiomer tminor = 51.6 min, major enantiomer tmajor = 42.1 min, 91%
ee.
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1
Supporting Information): H NMR (300 MHz, CDCl3, δ ppm) 2.51
(s, 3H), 2.72 (dd, J = 3.3, 15.6 Hz, 1H), 3.14 (dd, J = 3.6, 15.6 Hz,
1H), 5.98 (dd, J = 9.6, 3.3 Hz, 1H), 7.24−7.36 (m, 8H), 7.61−7.70
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