Catalytic enantioselective synthesis of atropisomeric 2-aryl-4-quinolinone derivatives with an N-C chiral axis

Article abstract of DOI:10.1016/j.tetasy.2012.11.004

In the presence of an (R)-MOP-Pd₂(dba)₃ catalyst, the reaction of ortho-tert-butylaniline with 2-bromophenyl arylethynyl ketone proceeded via a tandem amination (1,4-addition of aniline to an ynone and subsequent intramolecular Buchwald-Hartwig amination) to afford axially chiral N-(2-tert-butylphenyl)-2-aryl-4-quinolinone derivatives with moderate enantioselectivity (up to 72% ee).

Full text of DOI:10.1016/j.tetasy.2012.11.004

Tetrahedron: Asymmetry 23 (2012) 1657–1662
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Tetrahedron: Asymmetry
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Catalytic enantioselective synthesis of atropisomeric 2-aryl-4-quinolinone
derivatives with an N–C chiral axis
Isao Takahashi a, Fumika Morita a, Shunsuke Kusagaya a, Haruhiko Fukaya b, Osamu Kitagawa a,
⇑
a Department of Applied Chemistry, Shibaura Institute of Technology, 3-7-5 Toyosu, Kohto-ku, Tokyo 135-8548, Japan
b School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 26 September 2012
Accepted 6 November 2012
In the presence of an (R)-MOP-Pd2(dba)3 catalyst, the reaction of ortho-tert-butylaniline with
2-bromophenyl arylethynyl ketone proceeded via a tandem amination (1,4-addition of aniline to an
ynone and subsequent intramolecular Buchwald–Hartwig amination) to afford axially chiral N-(2-tert-
butylphenyl)-2-aryl-4-quinolinone derivatives with moderate enantioselectivity (up to 72% ee).
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
ortho-anisidine, although there is no mention of any axial chirality
of the 4-quinolinone products obtained by the reaction with these
Atropisomeric compounds with an N–C chiral axis have received
much attention as novel chiral molecules.1 Noteworthy recent top-
ics in this field include the catalytic asymmetric synthesis of N–C
axially chiral compounds.2 In 2005, we reported the highly enantio-
selective synthesis of axially chiral ortho-tert-butylanilides I and
N-(ortho-tert-butylphenyl)-3,4-dihydroquinolin-2-one II (Fig. 1)
via chiral Pd-catalyzed inter- and intramolecular N-arylation of
achiral NH-anilides.3 These reactions provided the first practical
catalytic asymmetric synthesis of N–C axially chiral compounds.
After publication of this work,3a the catalytic asymmetric synthesis
of similar N–C axially chiral compounds was also reported by many
other groups.2c–n We also succeeded in achieving the catalytic
enantioselective synthesis of N–C axially chiral indoles III (Fig. 1)
through the chiral Pd-catalyzed 5-endo-hydroaminocyclization of
ortho-alkynylanilines.4
aryl amines.
On the basis of these results, we thought that the catalytic enan-
tioselective synthesis of N–C axially chiral 4-quinolinones 1 could
be achieved by using ortho-tert-butylaniline 3 (R = t-Bu) in the
presence of a chiral Pd-catalyst (Scheme 1). In the present reaction,
the chiral axis of 1 should be constructed during the reductive
elimination step of the amide–Pd intermediate, and this step might
proceed in a highly enantioselective manner because the N–C bond
forming reaction occurs near a chiral ligand (L⁄).
It was expected that the N–C chiral axis of N-(ortho-tert-
butylphenyl)-4-quinolinone products
1 would have a high
rotational barrier because of the rigid aromatic structure of the
4-quinolinone.7 In the presence of a Pd2(dba)3 catalyst and various
chiral phosphine ligands, the reaction of ortho-tert-butylaniline 3a
with 2-bromophenyl phenylethynyl ketone 2a was investigated
in refluxing 1,4-dioxane (K2CO3 was used as the base, Table 1).
When bidentate chiral phosphine ligands such as (R)-BINAP, (R)-
SEGPHOS, (R)-DIFLUOROPHOS, (R)-SYNPHOS, (R)-TUNEPHOS, and
(S,S)-Trost ligand were used, the 4-quinolinone product 1a was ob-
tained with poor chemical yields (4–21%) and low enantioselectiv-
ity (2–22% ee, entries 1–7). The use of a monodentate phosphine
ligand such as (+)-MENPHOS led to an increase in the chemical
yield (46%), but the enantioselectivity remained poor (9% ee, entry
8). Using (R)-MOP8 gave the best results for both in terms of chem-
ical yield and enantioselectivity. In this case, the product 1a was
obtained in 51% yield and 53% ee (entry 9).
Herein we report the catalytic enantioselective synthesis of
atropisomeric N-(2-tert-butylphenyl)-2-aryl-4-quinolinone deriva-
tives 1, which are new N–C axially chiral compounds.
2. Results and discussion
Recently, Xu et al. reported a Pd-catalyzed tandem amination
reaction for the synthesis of 1,2-diaryl-4-quinolinones.5 This reac-
tion, which involves aniline and 2-bromophenyl arylethynyl ketone
substrates in the presence of Ph3P-Pd2(dba)3 catalyst, proceeds
smoothly via 1,4-addition of an aniline to an ynone and subsequent
intramolecular Buchwald–Hartwig amination.6 This reaction is not
only applicable to simple aniline, but also to 1-aminonaphthalene
and ortho-substituted anilines such as ortho-toluidine and
Although other solvents (toluene and diglyme), bases (Cs2CO3,
Na2CO3, and NaH), and Pd-catalyst [Pd(OAc)2] were also investi-
gated, no better results than those obtained in entry 9 were
obtained. Subsequently, a survey of arylamines was performed.
The reaction with ortho-iso-propylaniline 3b gave product 1b in
good yield (63%), but the enantioselectivity was lower than that
⇑
Corresponding author. Tel.: +81 3 5859 8161; fax: +81 3 5859 8101.
E-mail address: kitagawa@shibaura-it.ac.jp (O. Kitagawa).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.11.004

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I. Takahashi et al. / Tetrahedron: Asymmetry 23 (2012) 1657–1662
O
N
O
Ar
N
N
Ar
R
N
O
t-Bu
Ar
t-Bu
t-Bu
t-Bu
R'
I (88-96%ee)
R
1
III (60-83%ee)
II (93-98%ee)
Figure 1. Several N–C axially chiral compounds prepared by catalytic asymmetric reactions.
R
O
X
O
X
NH2
L*Pd(0)
base
HN
Ar
R
+
Ar
L*= chiral
ligand
3
2
O
R
O
H
N
Ar
N
R
Pd
Ar
Pd-X
L*
*L
O
N
Ar
stable axial chirality?
enantioselective?
R
1
Scheme 1. Synthetic scheme for preparing axially chiral 1,2-diaryl-4-quinolinones via chiral Pd-catalyzed tandem amination.
of ortho-tert-butylaniline 3a (30% ee, entries 9 and 10). With 2,5-
di-tert-butylaniline 3c, decreases in both yield and enantioselectiv-
ity were observed (27%, 21% ee, entries 9 and 11).
for 18 h in refluxing 1,4-dioxane, the enantiomeric excess of 1g
was almost unchanged (70.4% ee). This result may indicate that
in the reaction of Table 2, any decrease in the ee due to the partial
thermal racemization of products 1 is excluded.
The reactions of ortho-tert-butylaniline 3a with various 2-
bromophenyl arylethynyl ketones 2d–h were investigated further
under the optimized conditions (Table 2). The reaction with 4-
methoxyphenyl and 4-methylphenyl derivatives 2d and 2e gave
products 1d and 1e with yield and enantioselectivities similar to
those of phenyl derivative 2a (1d: 46%, 52% ee, 1e: 48%, 54% ee, en-
tries 2 and 3). While, in the reaction with 4-chlorophenyl and 4-
nitrophenyl derivatives 2f and 2g with an electron-withdrawing
group at the para-position, a decrease in yield was observed (1f:
31%, 1g: 34%), and the enantioselectivity was increased in compar-
ison with the phenyl derivative 2a (1f: 66% ee, 1g: 72% ee, entries 4
and 5). The reaction with ortho-methoxyphenyl derivative 2h led
to a slight increase in the enantioselectivity relative to that of the
para-methoxyphenyl derivative 2d (entry 6).
In addition to the arylethynyl ketones 2a,d–h shown in Table 2,
the reaction with 2-bromophenyl cyclohexylethynyl ketone and 2-
bromophenyl 1-hexynyl ketone was also investigated under the
same conditions. However, in the ethynyl ketones with a non-aro-
matic substituent, the formation of 4-quinolinone products did not
occur.
The absolute configuration of the chiral axis in 1 was deter-
mined in accordance with Scheme 2. Compound 1g (72% ee) was
converted into almost enantiomerically pure form (>99% ee)
through self-disproportionation of the enantiomers (SDE) by MPLC
using an achiral silica gel column,3d,9 that is, the MPLC chart of 1g
(72% ee, 38 mg) showed two distinct peaks and looked like a regu-
lar chart observed for a mixture of two chemically different com-
pounds, and the ee of 1g in the less polar and more polar
fractions were >99% ee (13 mg) and 54% ee (20 mg), respectively.
The reduction of the nitro group in 1g (>99% ee) obtained from
the less polar fraction followed by condensation with (S)-2-acet-
oxypropionyl chloride gave compound 4g. The X-ray crystal struc-
ture of 4g indicates that the absolute stereochemistry of the major
enantiomer in 1g is an (S)-configuration (Scheme 2).10
3. Conclusion
We have explored the catalytic asymmetric synthesis of axially
chiral N-(ortho-tert-butylphenyl)-2-aryl-4-quinolinone derivatives
through the chiral Pd-catalyzed tandem amination with ortho-
The axially chiral 4-quinolinone products 1 were also found to
have a high rotational barrier. When 1g (71.6% ee) was heated

I. Takahashi et al. / Tetrahedron: Asymmetry 23 (2012) 1657–1662
1659
Table 1
Optimization of the conditions for the catalytic asymmetric tandem amination of 2a and 3a
O
N
O
NH2
10 mol% chiral ligand
5 mol% Pd2(dba)3
2 eq K2CO3
R
Ph
+
R
Ph
1,4-dioxane
reflux, 12 h
R'
Br
2a
3a
(R = t-Bu, R' = H)
1
R'
3b (R = i-Pr, R' =H)
3c (R = R' = t-Bu)
Entry
3a
Chiral ligand
1a
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
3c
(R)-BINAP
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
4
7
21
4
9
14
5
46
51
63
27
16
18
2
17
7
22
20
9
53
30
21
(R)-SEGPHOS
(R)-DTBM-SEGPHOS
(R)-DIFLUOROPHOS
(R)-SYNPHOS
(R)-C3-TUNEPHOS
(S,S)-Trost ligand
(+)-MENPHOS
(R)-MOP
10
11
(R)-MOP
(R)-MOP
a
b
c
Reaction conditions: 2a (0.3 mmol), 3 (0.6 mmol), ligand (0.03 mmol), Pd (0.015 mmol), K2CO3 (0.6 mmol), dioxane (3 mL), reflux 12 h.
Isolated yield.
The ee was determined by HPLC using a chiral column.
Table 2
Catalytic asymmetric tandem amination with various arylethynyl ketone substrates 2aa
O
N
O
NH2
10 mol% (R)-MOP
5 mol% Pd2(dba)3
2 eq K2CO3
t-Bu
Ar
+
t-Bu
Ar
1,4-dioxane
reflux, 12 h
Br
2
3a
1
Entry
2a
Ar
Ph
1a
Yieldb (%)
eec (%)
1
2
3
4
5
6
2a
2d
2e
2f
2g
2h
1a
1d
1e
1f
1g
1h
51
46
48
31
34
45
53
52
54
66
72
60
4-MeOC6H4
4-MeC6H4
4-ClC6H4
4-NO2C6H4
2-MeOC6H4
a
b
c
Reaction conditions: 2 (0.3 mmol), 3a (0.6 mmol), (R)-MOP (0.03 mmol), Pd (0.015 mmol), K2CO3 (0.6 mmol), dioxane (3 mL), reflux 12 h.
Isolated yield.
The ee was determined by HPLC using a chiral column.
tert-butylaniline and 2-bromophenyl arylethynyl ketones. This
reaction proceeded with moderate yields and enantioselectivity
through the 1,4-addition of aniline to ynones and subsequent
intramolecular Buchwald–Hartwig amination in the presence of
the (R)-MOP-Pd2(dba)3 catalyst. The absolute configuration of the
major enantiomer in the N–C axially chiral 4-quinolinone product
was determined on the basis of X-ray crystal structural analysis.
chemical shifts are expressed in d (ppm) downfield from CHCl3
(7.26 ppm) and CDCl3 (77.0 ppm), respectively. Mass spectra were
recorded by electrospray ionization. Column chromatography was
performed on silica gel (75–150 mm). Medium-pressure liquid
chromatography (MPLC) was performed on
a
25 ꢀ 4 cm i.d.
prepacked column (silica gel, 10 m) with a UV detector. High-
l
performance liquid chromatography (HPLC) was performed on a
25 ꢀ 0.4 cm i.d. chiral column with a UV detector.
4. Experimental
4.2. Synthesis of 2-bromophenyl arylethynyl ketones 2
4.1. General techniques
Ketones 2a,d,f are known compounds and were prepared in
accordance with the literature.5 Ketones 2e,g,h were prepared in
accordance with the following procedures.
Melting points are uncorrected. 1H and 13C NMR spectra were
recorded on a 400 MHz spectrometer. In 1H and 13C NMR spectra,

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I. Takahashi et al. / Tetrahedron: Asymmetry 23 (2012) 1657–1662
O
N
1) 5% H2/Pd-C
2) (S)-2-acetoxy-
propionyl chloride
MPLC
less polar
Ar
"Self-disproportionation
of enantiomers"
1g (>99%ee, 13 mg)
t-Bu
+
more polar
1g (54%ee, 20 mg)
1g (Ar = 4-NO2C6H4, 72%ee, 38 mg)
O
N
O
t-Bu
OAc
N
H
(X-ray crystal structure of 4g)
4g
Scheme 2. Stereochemical assignment of the chiral axis in 1g.
4.2.1. 1-(2-Bromophenyl)-3-(p-tolyl)prop-2-yn-1-one 2e
Under an N2 atmosphere, to (Ph3P)2PdCl2 (43 mg, 0.06 mmol)
and CuI (23 mg, 0.12 mmol) in THF (3 mL) were added 2-
bromobenzoyl chloride (658 mg, 3.0 mmol) in THF (1.5 mL) and
4-methylphenylacetylene (348 mg, 3.0 mmol) in Et3N (1.5 mL).
After stirring for 3 h at rt, the mixture was poured into NH4Cl aq
and extracted with AcOEt. The AcOEt extracts were washed with
brine, dried over MgSO4, and evaporated to dryness. Purification
of the residue by column chromatography (hexane/AcOEt = 50)
gave 2e (747 mg, 83%). 2e: pale yellow solid; mp 90–92 °C; 1H
NMR (400 MHz, CDCl3, TMS) d = 8.06 (1H, dd, J = 1.4, 7.3 Hz), 7.70
(1H, dd, J = 0.9, 7.8 Hz), 7.54 (2H, d, J = 7.9 Hz), 7.45 (1H, dt,
J = 0.9, 7.3 Hz), 7.37 (1H, dt, J = 1.8, 7.9 Hz), 7.22 (2H, d,
J = 7.9 Hz), 2.40 (3H, s); 13C NMR (100 MHz, CDCl3, TMS)
d = 177.6, 141.8, 137.7, 134.9, 133.2, 133.1, 132.6, 129.5, 127.3,
121.1, 116.9, 95.0, 87.9, 21.8; IR (CH2Cl2) 2192, 1644 cmꢁ1; MS
(ESI, m/z) 301, 299 (MH+); Anal. Calcd for C16H11BrO: C, 64.24; H,
3.71. Found: C, 64.27; H, 3.93.
J = 1.8, 7.8 Hz), 7.68 (1H, dd, J = 1.4, 7.8 Hz), 7.57 (1H, dd, J = 1.4,
7.3 Hz), 7.41–7.47 (2H, m), 7.36 (1H, dt, J = 1.8, 7.8 Hz), 6.96 (1H,
dt, J = 0.9, 7.3 Hz), 6.92 (1H, d, J = 8.2 Hz), 3.91 (3H, s); 13C NMR
(100 MHz, CDCl3, TMS) d = 177.2, 161.8, 137.2, 134.9, 133.5,
133.2, 132.7, 127.2, 121.2, 120.6, 110.9, 109.2, 92.0, 91.3, 55.8; IR
(CH2Cl2) 2189, 1645 cmꢁ1; MS (ESI, m/z) 315, 317 (MH+); Anal.
Calcd for C16H11BrO2: C, 60.98; H, 3.52. Found: C, 60.95; H, 3.65.
4.3. General procedure for the synthesis of axially chiral
4-quionolinone derivatives 1
Under an N2 atmosphere, to (R)-MOP (15 mg, 0.03 mmol) in 1,
4-dioxane (1.0 mL) was added Pd2(dba)2 (14 mg, 0.015 mmol),
and the mixture was stirred for 10 min. Next K2CO3 (83 mg,
0.6 mmol), and then 2a (86 mg, 0.3 mmol) and ortho-tert-butylan-
iline 3a (90 mg, 0.6 mmol) in 1,4-dioxane (2.0 mL) were added to
the mixture. After being stirred for 12 h in refluxing 1,4-dioxane,
the reaction mixture was poured into a saturated NaHCO3 solution
and extracted with AcOEt. The AcOEt extracts were washed with
brine, dried over Na2SO4, and evaporated to dryness. Purification
of the residue by column chromatography (hexane/AcOEt = 1) gave
1a (54 mg, 51%). The ee (53% ee) of 1a was determined by HPLC
analysis using a CHIRALPACK OD-3 column [25 ꢀ 0.46 cm i.d.;
10% i-PrOH in hexane; flow rate, 1.5 mL/min; (ꢁ)-1a (major);
tR = 11.1 min, (+)-1a (minor); tR = 19.7 min].
4.2.2. 1-(2-Bromophenyl)-3-(4-nitrophenyl)prop-2-yn-1-one 2g
Compound 2g was prepared from 2-bromobenzoyl chloride
(342 mg, 1.56 mmol) and 4-nitrophenylacetylene (294 mg,
1.56 mmol) in accordance with the procedure for the synthesis of
2e. Purification of the residue by column chromatography (hex-
ane/AcOEt = 30) gave 2g (110 mg, 21%). 2g: pale yellow solid; mp
149–151 °C; 1H NMR (400 MHz, CDCl3, TMS) d = 8.28 (2H, td,
J = 1.8, 9.2 Hz), 8.05 (1H, dd, J = 1.8, 7.3 Hz), 7.80 (2H, td, J = 1.8,
9.2 Hz), 7.73 (1H, dd, J = 1.4, 7.8 Hz), 7.48 (1H, dt, J = 1.4, 7.3 Hz),
7.42 (1H, dt, J = 1.8, 7.8 Hz); 13C NMR (100 MHz, CDCl3, TMS)
d = 176.8, 148.6, 136.9, 135.1, 133.8, 133.6, 132.8, 127.5, 126.6,
123.8, 121.5, 90.6, 90.2; IR (CH2Cl2) 2205, 1650 cmꢁ1; MS (ESI, m/
z) 330, 332 (MH+); Anal. Calcd for C15H8BrNO3: C, 54.57; H, 2.44;
N, 4.24. Found: C, 54.79; H, 2.51; N, 4.02.
4.3.1. 1-(2-(tert-Butyl)phenyl)-2-phenylquinolin-4(1H)-one 1a
Compound 1a (57% ee): white solid; ½a D25
¼ ꢁ36:1 (c 0.41,
ꢂ
CHCl3); mp 221–223 °C; 1H NMR (400 MHz, CDCl3, TMS) d = 8.51
(1H, dd, J = 1.8, 8.2 Hz), 7.46–7.51 (2H, m), 7.33–7.40 (2H, m),
7.16–7.25 (6H, m), 7.12 (1H, dd, J = 1.8, 8.2 Hz), 6.77 (1H, d,
J = 8.7 Hz), 6,47 (1H, s), 0.98 (9H, s); 13C NMR (100 MHz, CDCl3,
TMS) d = 178.1, 154.2, 147.5, 143.7, 135.5, 135.2, 133.0, 131.9,
131.3, 129.9, 129.5, 128.8, 127.7, 126.6, 126.2, 125.9, 123.6,
118.7, 113.1, 36.3, 31.5; IR (neat) 1624 cmꢁ1; MS (ESI, m/z) 354
(MH+); Anal. Calcd for C25H23NO: C, 84.95; H, 6.56; N, 3.96. Found:
C, 84.70; H, 6.38; N, 3.83.
4.2.3. 1-(2-Bromophenyl)-3-(2-methoxyphenyl)prop-2-yn-
1-one 2h
Compound 2h was prepared from 2-bromobenzoyl chloride
(1.097 g, 5.0 mmol) and 2-methoxyphenylacetylene (661 mg,
5.0 mmol) in accordance with the procedure for the synthesis of
2h. Purification of the residue by column chromatography (hex-
ane/AcOEt = 30) gave 2h (1.167 g, 74%). 2h: pale brown solid; mp
45–46 °C; 1H NMR (400 MHz, CDCl3, TMS) d = 8.25 (1H, dd,
4.3.2. 1-(2-(iso-Propyl)phenyl)-2-phenylquinolin-4(1H)-one 1b
Compound 1b was prepared from 2a (86 mg, 0.3 mmol) and
ortho-iso-propylaniline 3b (86 mg, 0.6 mmol) in accordance with
the general procedure for the synthesis of 1. Purification of the res-

I. Takahashi et al. / Tetrahedron: Asymmetry 23 (2012) 1657–1662
1661
idue by column chromatography (hexane/AcOEt = 1) gave 1b
(64 mg, 63%). The ee (30% ee) of 1b was determined by HPLC anal-
ysis using a CHIRALPACK OD-3 column [25 ꢀ 0.46 cm i.d.; 10% i-
PrOH in hexane; flow rate, 1.5 mL/min; (ꢁ)-1b (major);
tR = 9.8 min, (+)-1b (minor); tR = 19.3 min]. Compound 1b (30%
9.2 min, (+)-1e (minor); tR = 15.7 min]. Compound 1e (55% ee):
white solid; ½a 2D5
ꢂ
¼ ꢁ35:1 (c 0.42, CHCl3); mp 174–177 °C; 1H
NMR (400 MHz, CDCl3, TMS) d = 8.51 (1H, dd, J = 1.4, 7.8 Hz),
7.45–7.50 (2H, m), 7.35–7.39 (2H, m), 7.24 (1H, dt, J = 1.8,
8.2 Hz), 7.09–7.13 (3H, m), 6.98 (2H, d, J = 8.2 Hz), 6.75 (1H, d,
J = 8.2 Hz), 6,46 (1H, s), 2.26 (3H, s), 0.97 (9H, s); 13C NMR
(100 MHz, CDCl3, TMS) d = 178.1, 154.4, 147.5, 143.7, 138.8,
135.4, 133.0, 132.6, 131.8, 131.3, 129.8, 129.5, 128.4, 126.6,
126.2, 125.9, 123.6, 118.7, 113.1, 36.3, 31.5, 21.1; IR (neat)
1621 cmꢁ1; MS (ESI, m/z) 368 (MH+); HRMS (ESI). Calcd for
ee): white solid; ½a D25
¼ ꢁ29:9 (c 0.40, CHCl3); mp 228–230 °C;
ꢂ
1H NMR (400 MHz, CDCl3, TMS) d = 8.52 (1H, dd, J = 1.4, 7.8 Hz),
7.46 (1H, ddd, J = 1.8, 6.9, 8.7 Hz), 7.28–7.39 (4H, m), 7.16–7.25
(6H, m), 6.79 (1H, d, J = 8.7 Hz), 6,50 (1H, s), 2.46 (1H, sept,
J = 6.9 Hz), 0.84 (3H, d, J = 6.9 Hz), 0.78 (3H, d, J = 6.9 Hz); 13C
NMR (100 MHz, CDCl3, TMS) d = 178.0, 154.1, 146.8, 142.7, 136.2,
135.1, 131.7, 130.8, 130.1, 129.5, 128.8, 127.65, 127.56, 126.3,
126.2, 126.1, 123.8, 118.3, 112.6, 27.7, 24.9, 22.0; IR (neat)
1625 cmꢁ1; MS (ESI, m/z) 340 (MH+); Anal. Calcd for C24H21NO:
C, 84.92; H, 6.24; N, 4.13. Found: C, 84.93; H, 6.31; N, 4.03.
C
26H26NO (MH+) 368.2014. Found: 368.2006.
4.3.6. 1-(2-(tert-Butyl)phenyl)-2-(4-chlorophenyl)quinolin-
4(1H)-one 1f
Compound 1f was prepared from 2f (96 mg, 0.3 mmol) and
ortho-tert-butylaniline 3a (90 mg, 0.6 mmol) in accordance with
the general procedure for the synthesis of 1. Purification of the res-
idue by column chromatography (hexane/AcOEt = 1) gave 1f
(36 mg, 31%). The ee (66% ee) of 1f was determined by HPLC anal-
ysis using a CHIRALPACK OD-3 column [25 ꢀ 0.46 cm i.d.; 10%
i-PrOH in hexane; flow rate, 1.5 mL/min; (ꢁ)-1f (major);
tR = 9.8 min, (+)-1f (minor); tR = 26.2 min]. Compound 1f (66%
4.3.3. 1-(2,5-(Di-tert-butyl)phenyl)-2-phenylquinolin-4(1H)-one
1c
Compound 1c was prepared from 2a (86 mg, 0.3 mmol) and 2,
5-di-tert-butylaniline 3c (74 mg, 0.36 mmol) in accordance with
the general procedure for the synthesis of 1. Purification of the res-
idue by column chromatography (hexane/AcOEt = 1) gave 1c
(33 mg, 27%). The ee (21% ee) of 1c was determined by HPLC
analysis using a CHIRALPACK OD-3 column [25 ꢀ 0.46 cm i.d.;
10% i-PrOH in hexane; flow rate, 1.0 mL/min; (+)-1c (minor);
tR = 6.8 min, (ꢁ)-1c (major); tR = 9.1 min]. Compound 1c (21% ee):
ee): white solid; ½a D25
¼ ꢁ38:3 (c 0.41, CHCl3); mp 196–198 °C;
ꢂ
1H NMR (400 MHz, CDCl3, TMS) d = 8.49 (1H, dd, J = 1.4, 7.8 Hz),
7.46–7.52 (2H, m), 7.34–7.40 (2H, m), 7.25 (1H, dt, J = 2.7,
7.8 Hz), 7.16–7.17 (4H, m), 7.10 (1H, dd, J = 1.4, 7.8 Hz), 6.75 (1H,
d, J = 8.7 Hz), 6,41 (1H, s), 0.97 (9H, s); 13C NMR (100 MHz, CDCl3,
TMS) d = 178.0, 152.9, 147.6, 143.6, 135.1, 135.0, 134.0, 132.9,
132.0, 131.5, 131.2, 129.8, 128.0, 126.8, 126.3, 126.0, 123.8,
118.7, 113.2, 36.3, 31.6; IR (neat) 1622 cmꢁ1; MS (ESI, m/z) 388
(MH+); HRMS (ESI). Calcd for C25H23ClNO (MH+) 388.1468. Found:
388.1458.
white solid; ½a 2D5
ꢂ
¼ ꢁ14:9 (c 0.40, CHCl3); mp 216–218 °C; 1H
NMR (400 MHz, CDCl3, TMS) d = 8.52 (1H, dd, J = 1.4, 7.8 Hz), 7.50
(1H, ddd, J = 1.4, 7.3, 8.7 Hz), 7.36–7.40 (2H, m), 7.32 (1H, dd,
J = 1.8, 8.7 Hz), 7.14–7.23 (5H, m), 7.03 (1H, d, J = 1.8 Hz), 6.82
(1H, d, J = 8.7 Hz), 6,49 (1H, s), 1.25 (9H, m), 0.98 (9H, s); 13C
NMR (100 MHz, CDCl3, TMS) d = 178.1, 154.4, 149.8, 144.2, 143.7,
135.6, 134.7, 131.9, 130.8, 129.9, 129.8, 128.7, 127.6, 126.4,
126.3, 125.9, 123.6, 118.8, 113.0, 35.8, 34.1, 31.5, 30,9; IR (neat)
1623 cmꢁ1; MS (ESI, m/z) 410 (MH+); HRMS (ESI). Calcd for
4.3.7. (S)-1-(2-(tert-Butyl)phenyl)-2-(4-nitrophenyl)quinolin-
4(1H)-one 1g
C
29H32NO (MH+) 410.2484. Found: 410.2481.
Compound 1g was prepared from 2g (70 mg, 0.3 mmol) and
ortho-tert-butylaniline 3a (90 mg, 0.6 mmol) in accordance with
the general procedure for the synthesis of 1. Purification of the res-
idue by column chromatography (hexane/AcOEt = 1) gave 1g
(41 mg, 34%). The ee (72% ee) of 1g was determined by HPLC anal-
ysis using a CHIRALPACK OD-3 column [25 ꢀ 0.46 cm i.d.; 50% i-
PrOH in hexane; flow rate, 1.0 mL/min; (ꢁ)-1g (major);
tR = 8.8 min, (+)-1g (minor); tR = 17.1 min]. Compound 1g (72%
4.3.4. 1-(2-(tert-Butyl)phenyl)-2-(4-methoxyphenyl)quinolin-
4(1H)-one 1d
Compound 1d was prepared from 2d (95 mg, 0.3 mmol) and
ortho-tert-butylaniline 3a (90 mg, 0.6 mmol) in accordance with
the general procedure for the synthesis of 1. Purification of the res-
idue by column chromatography (hexane/AcOEt = 1) gave 1d
(53 mg, 46%). The ee (52% ee) of 1d was determined by HPLC anal-
ysis using a CHIRALPACK OD-3 column [25 ꢀ 0.46 cm i.d.; 10% i-
PrOH in hexane; flow rate, 1.5 mL/min; (ꢁ)-1d (major); tR =
16.0 min, (+)-1d (minor); tR = 26.3 min]. 1d (52% ee): white solid;
ee): white solid; ½a D
ꢂ
¼ ꢁ49:1 (c 0.40, CHCl3); mp 261–264 °C; 1H
NMR (400 MHz, CDCl3, TMS) d = 8.50 (1H, dd, J = 1.4, 8.2 Hz), 8.07
(2H, td, J = 2.2, 8.7 Hz), 7.50–7.55 (2H, m), 7.37–7.46 (4H, m),
7.26 (1H, dt, J = 1.4, 7.8 Hz), 7.13 (1H, dd, J = 1.4, 7.8 Hz), 6.78
(1H, d, J = 8.2 Hz), 6,42 (1H, s), 1.01 (9H, s); 13C NMR (100 MHz,
CDCl3, TMS) d = 177.8, 151.6, 147.7, 147.6, 143.6, 141.7, 134.7,
132.8, 132.4, 131.6, 130.9, 130.1, 127.0, 126.4, 126.1, 124.1,
122.9, 118.7, 113.2, 36.3, 31.7; IR (neat) 1625 cmꢁ1; MS (ESI, m/z)
399 (MH+); HRMS (ESI). Calcd for C25H23N2O3 (MH+) 399.1709.
Found: 399.1697.
½
a 2D5
ꢂ
¼ ꢁ42:3 (c 0.41, CHCl3); mp 173–176 °C; 1H NMR (400 MHz,
CDCl3, TMS) d = 8.50 (1H, dd, J = 1.4, 7.8 Hz), 7.45–7.51 (2H, m),
7.33–7.40 (2H, m), 7.25 (1H, dt, J = 1.4, 7.9 Hz), 7.10–7.16 (3H,
m), 6.75 (1H, d, J = 8.7 Hz), 6.70 (2H, dt, J = 2.7, 9.2 Hz), 6,46 (1H,
s), 3.74 (3H, s), 0.96 (9H, s); 13C NMR (100 MHz, CDCl3, TMS)
d = 178.1, 159.7, 154.1, 147.5, 143.7, 135.4, 133.0, 131.8, 131.4,
131.3, 129.5, 127.8, 126.6, 126.2, 125.9, 123.5, 118.7, 113.1, 55.2,
36.3, 31.5; IR (neat) 1620 cmꢁ1; MS (ESI, m/z) 384 (MH+); HRMS
(ESI). Calcd for C26H26NO2 (MH+) 384.1964. Found: 384.1963.
4.3.8. 1-(2-(tert-Butyl)phenyl)-2-(2-methoxyphenyl)quinolin-
4(1H)-one 1h
Compound 1h was prepared from 2h (95 mg, 0.3 mmol) and
ortho-tert-butylaniline 3a (90 mg, 0.6 mmol) in accordance with
the general procedure for the synthesis of 1. Purification of the res-
idue by column chromatography (hexane/AcOEt = 1) gave 1h
(51 mg, 45%). The ee (60% ee) of 1h was determined by HPLC anal-
ysis using a CHIRALPACK AD column [25 ꢀ 0.46 cm i.d.; 10% i-PrOH
in hexane; flow rate, 2.0 mL/min; (+)-1h (minor); tR = 12.5 min,
(ꢁ)-1h (major); tR = 16.1 min]. Compound 1h (60% ee): white solid;
4.3.5. 1-(2-(tert-Butyl)phenyl)-2-(4-methylphenyl)quinolin-
4(1H)-one 1e
Compound 1e was prepared from 2e (90 mg, 0.3 mmol) and
ortho-tert-butylaniline 3a (90 mg, 0.6 mmol) in accordance with
the general procedure for the synthesis of 1. Purification of the
residue by column chromatography (hexane/AcOEt = 1) gave 1e
(53 mg, 48%). The ee (54% ee) of 1e was determined by HPLC anal-
ysis using a CHIRALPACK OD-3 column [25 ꢀ 0.46 cm i.d.; 10%
i-PrOH in hexane; flow rate, 1.5 mL/min; (ꢁ)-1e (major); tR =
½
a 2D5
ꢂ
¼ þ19:4 (c 0.40, CHCl3); mp 236–238 °C; 1H NMR (400 MHz,
CDCl3, TMS) d = 8.51 (1H, dd, J = 1.8, 8.2 Hz), 7.47 (1H, ddd,

1662
I. Takahashi et al. / Tetrahedron: Asymmetry 23 (2012) 1657–1662
Brandes, S.; Niess, B.; Bella, M.; Prieto, A.; Overgaard, J.; Jorgensen, K. A. Chem.
Eur. J. 2006, 12, 6039; (f) Duan, W.; Imazaki, Y.; Shintani, R.; Hayashi, T.
Tetrahedron 2007, 63, 8529; (g) Oppenheimer, J.; Hsung, R. P.; Figueroa, R.;
Johnson, W. L. Org. Lett. 2007, 9, 3969; (h) Tanaka, K.; Takeishi, K. Synthesis
2007, 2920; (i) Tanaka, K.; Takahashi, Y.; Suda, T.; Hirano, M. Synlett 2008,
1724; (j) Clayden, J.; Turner, H. Tetrahedron Lett. 2009, 50, 3216; (k)
Oppenheimer, J.; Johnson, W. L.; Figueroa, R.; Hayashi, R.; Hsung, R. P.
Tetrahedron 2009, 65, 5001; (l) Lin, S.; Leow, D.; Huang, K.-W.; Tan, C-H.
Chem. Asian J. 2009, 4, 1741; (m) Onodera, G.; Suto, M.; Takeuchi, R. J. Org.
Chem. 2012, 77, 908; (n) Shirakawa, S.; Liu, K.; Maruoka, K. J. Am. Chem. Soc.
2012, 134, 916.
J = 1,8, 7.3, 8.7 Hz), 7.42 (1H, d, J = 8.2 Hz), 7.36 (1H, dt, J = 0.9,
7,8 Hz), 7.23–7.30 (3H, m), 7.20 (1H, dt, J = 1.4, 8.7 Hz), 7.10 (1H,
m), 6.84 (1H, m), 6.71 (1H, d, J = 8.2 Hz), 6.67 (1H, d, J = 7.8 Hz),
6,37 (1H, s), 3.70 (3H, s), 1.06 (9H, s); 13C NMR (100 MHz, CDCl3,
TMS) d = 178.2, 155.8, 151.9, 146.9, 144.0, 135.4, 131.7, 131.1,
130.8, 130.6, 129.9, 129.4, 126.3, 125.9, 125.8, 124.8, 123.3,
119.7, 118.4, 113.2, 110.4, 54.8, 36.3, 31.7; IR (neat) 1623 cmꢁ1
;
MS (ESI, m/z) 384 (MH+); HRMS (ESI). Calcd for C26H26NO2 (MH+)
384.1964. Found: 384.1957.
3. (a) Kitagawa, O.; Takahashi, M.; Yoshikawa, M.; Taguchi, T. J. Am. Chem. Soc.
2005, 127, 3676; (b) Kitagawa, O.; Yoshikawa, M.; Tanabe, H.; Morita, T.;
Takahashi, M.; Dobashi, Y.; Taguchi, T. J. Am. Chem. Soc. 2006, 128, 12923; (c)
Kitagawa, O.; Kurihara, D.; Tanabe, H.; Shibuya, T.; Taguchi, T. Tetrahedron Lett.
2008, 49, 471; (d) Takahashi, M.; Tanabe, H.; Nakamura, T.; Kuribara, D.;
Acknowledgments
This work was partly supported by a Grant-in-Aid (C22590015)
for Scientific Research and the Ministry of Education, Science,
Sports and Culture of Japan.
Yamazaki, T.; Kitagawa, O. Tetrahedron 2010, 66, 288; For
a review: (e)
Takahashi, M.; Kitagawa, O. Yuki Gosei Kagaku Kyokaishi 2011, 69, 985.
4. Ototake, N.; Morimoto, Y.; Mokuya, A.; Fukaya, H.; Shida, Y.; Kitagawa, O. Chem.
Eur. J. 2010, 16, 6752.
5. Zhao, T.; Xu, B. Org. Lett. 2010, 12, 212.
6. (a) Guram, A. S.; Rennels, R. A.; Buchwald, S. L. Angew. Chem., Int. Ed. Engl. 1995,
34, 1348; (b) Hartwig, J. F.; Loue, J. Tetrahedron Lett. 1995, 36, 3609; (c) Yin, J.;
Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 6043; (d) Shen, Q.; Shashank, S.;
Stambuli, J. P.; Hartwig, J. F. Angew. Chem., Int. Ed. 2005, 44, 1371.
7. Recently we found that the rotational barrier of N-(ortho-tert-butylphenyl)-2-
quinolinone is higher than 10 kcal/mol in comparison to that of N-(ortho-tert-
butylphenyl)-3,4-dihydro-2-quinolinone. The high rotational barrier of N-
(ortho-tert-butylphenyl)-2-quinolinone was disclosed to be due to the rigid
aromatic structure: Suzumura, N.; Kageyama, M.; Kamimura, D.; Inagaki, T.;
Dobashi, Y.; Hasegawa, H.; Fukaya, H.; Kitagawa, O. Tetrahedron Lett. 2012, 53,
4332.
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