Catalytic Enantioselective Synthesis of N-C Axially Chiral Phenanthridin-6-one Derivatives

Article abstract of DOI:10.1021/acs.joc.5b02387

N-C axially chiral phenanthridin-6-one derivatives bearing various ortho-substituted phenyl groups on the nitrogen atom were enantioselectively prepared through (R)-DTBM-SEGPHOS-Pd(OAc)₂-catalyzed intramolecular Buchwald-Hartwig amination. The enantioselectivity strongly depended on solvents, bases, and reaction temperature as well as on the bulkiness of ortho-substituents.

Full text of DOI:10.1021/acs.joc.5b02387

Note
pubs.acs.org/joc
Catalytic Enantioselective Synthesis of N‑C Axially Chiral
Phenanthridin-6-one Derivatives
Tomoaki Hirata,† Isao Takahashi,† Yuya Suzuki,† Hiroaki Yoshida,† Hiroshi Hasegawa,‡
and Osamu Kitagawa*,†
†Department of Applied Chemistry, Shibaura Institute of Technology, 3-7-5 Toyosu, Kohto-ku, Tokyo, 135-8548, Japan
‡School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1, Horinouchi, Hachioji, Tokyo, 192-0392, Japan
S
* Supporting Information
ABSTRACT: N-C axially chiral phenanthridin-6-one derivatives bearing
various ortho-substituted phenyl groups on the nitrogen atom were
enantioselectively prepared through (R)-DTBM-SEGPHOS-Pd(OAc)2-
catalyzed intramolecular Buchwald−Hartwig amination. The enantiose-
lectivity strongly depended on solvents, bases, and reaction temperature
as well as on the bulkiness of ortho-substituents.
ecently, catalytic enantioselective syntheses of N-C axially
chiral compounds have received considerable attention.
under the present conditions (80 °C, 20 h). Thus, the reaction
of Scheme 1 would be difficult to apply to the synthesis of N-
aryl-3,4-dihydroquinolin-2-one derivatives II bearing ortho-
monosubstituents except for a tert-butyl group.
On the other hand, it has been reported that phenanthridin-
6-one derivatives 2 (Scheme 2) maintain a stable axially chiral
structure even in substrates bearing a small ortho-substituent
such as a methyl group (R = Me, ΔG⧧ = 28.5 kcal/mol);5,6
however, their enantioselective synthesis has not yet been
achieved. We expected that catalytic enantioselective synthesis
of phenanthridin-6-one derivatives bearing various ortho-
substituted phenyl groups could be achieved by applying the
R
Various N-C axially chiral compounds have been prepared with
high enantioselectivity through an original catalytic asymmetric
reaction developed for an each group.1,2 These N-C axially
chiral compounds usually have ortho-tert-butyl- or 2,6-
disubstituted anilide skeletons,1,2 while catalytic enantioselec-
tive synthesis of anilide derivatives bearing an ortho-
monosubstituent except for a tert-butyl group is far less
common.3
We succeeded in the highly enantioselective synthesis of N-
(2-tert-butylphenyl)-3,4-dihydroquinolin-2-one derivative IIa
through chiral palladium-catalyzed intramolecular Buchwald−
Hartwig amination of NH-anilides Ia,b (Scheme 1).1a This
Scheme 2. Synthesis of Biphenyl Amide Substrates 1 and
Attempted Catalytic Asymmetric Synthesis of N-C Axially
Chiral Phenanthridin-6-one Derivatives 2
Scheme 1. Catalytic Enantioselective Synthesis of N-C
Axially Chiral 3,4-Dihydroquinolin-2-one Derivatives II
reaction is the first practical catalytic asymmetric synthesis of
N-C axially chiral compounds. When this reaction was applied
to ortho-iso-propyl derivative Ic, the product IIc was obtained in
racemic form.4 Since the rotational barrier around a chiral axis
in IIc is approximately 25 kcal/mol (the rotational barrier of IIa
= 32.0 kcal/mol), the racemization of IIc should easily occur
Received: October 14, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b02387
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Table 1. Screening of Chiral Ligands, Solvents, and Bases in the Reaction of 1a
2a
a
b
entry
ligand
solvent
base
yield (%)
ee (%)
1
2
(R)-SEGPHOS
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
t-BuOK
NaH
90
6
(R)-BINAP
98
15
0
3
chiral-NHC
91
4
(R)-MOP
97
5
5
(S,R)-PPFA
52−92
94
51−73
63
59
17
31
75
49
65
77
9
6
(R)-DTBM-SEGPHOS
(R)-DTBM-SEGPHOS
(R)-DTBM-SEGPHOS
(R)-DTBM-SEGPHOS
(R)-DTBM-SEGPHOS
(R)-DTBM-SEGPHOS
(R)-DTBM-SEGPHOS
(R)-DTBM-SEGPHOS
(R,R)-CHI-RAPHOS
(R)-SYNPHOS
7
93
8
98
9
39
10
11
12
13
14
15
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
58
1,4-dioxane
96
toluene−1,4-dioxane (1:1)
toluene−1,4-dioxane (9:1)
toluene−1,4-dioxane (9:1)
toluene−1,4-dioxane (9:1)
94
95
96
62
36
a
b
Isolated yields. The ee was determined by HPLC analysis using a chiral column.
reaction of Scheme 1 to biphenyl amide substrates 1.7 In this
paper, we report catalytic asymmetric synthesis of N-C axially
chiral phenanthridin-6-one derivatives bearing various ortho-
substituted phenyl groups on the nitrogen atom through (R)-
DTBM-SEGPHOS-Pd(OAc)2-catalyzed intramolecular Buch-
wald−Hartwig amination.8 The mechanistic consideration of
the present reaction and the stereochemical assignment of a
chiral axis are also described.
The biphenylamide substrates 1 were easily prepared through
the condensation of methyl 2′-bromo-(1,1′-biphenyl)-2-carbox-
ylate7,9 (commercially available) with ortho-substituted-aniline
in the presence of Me3Al (Scheme 2). Initially, the reaction of
biphenylamide 1a bearing an ortho-iso-propyl group was
conducted under the conditions shown in Scheme 1 (Scheme
2). Although the reaction proceeded smoothly to give
phenanthridin-6-one 2a in a good yield (90%), little
enantioselectivity was observed (6% ee). Moreover, in the
reaction with ortho-tert-butyl derivative 1b, the enantioselectiv-
ity was unexpectedly poor (96%, 11% ee).
Thus, since the reaction with biphenyl amides 1 was found to
be very different from the reaction in Scheme 1, we reexamined
the screening of chiral ligands, bases, and solvents in the
reaction of 1a.
The results are shown in Table 1. As a chiral ligand (entries
1−6), the use of (R)-DTBM-SEGPHOS10 gave the best
result.11 In this case, an N-C axially chiral phenanthridinone 2a
was obtained in 94% yield and 63% ee (entry 6). With (S,R)-
PPFA, good reproducibility for both the chemical yield and the
enantioselectivity was not obtained (entry 5).
In the presence of (R)-DTBM-SEGPHOS-Pd(OAc)2 cata-
lyst, bases and solvents were investigated next. When t-BuOK
and NaH were used as the base, the enantioselectivity
decreased significantly (17% ee and 31% ee, entries 8 and 9).
The use of K3PO4 gave the best enantioselectivity (75% ee),
but a decrease in the chemical yield was also observed (58%,
entry 10). To improve the chemical yield, a survey of solvents
was conducted. Although the reaction in 1,4-dioxane gave the
product 2a in an excellent yield (96%), the enantioselectivity
was significantly lower (49% ee, entry 11). A relatively good
result was obtained when a mixed solvent of toluene and 1,4-
dioxane was used: in particular, the reaction in toluene:1,4-
dioxane = 9:1 gave the best chemical yield and enantiose-
lectivity (95%, 77% ee, entry 13). Under the conditions of entry
13, although the other chiral phosphine ligands such as (R,R)-
CHIRAPHOS and (R)-SYNPHOS were further investigated,
good results were not obtained (entry 14: 96%, 9% ee; entry
15: 62%, 36% ee).
Since a detectable change in the ee for the product 2a was
not observed under the present reaction conditions (for 20 h at
B
DOI: 10.1021/acs.joc.5b02387
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The Journal of Organic Chemistry
Note
Table 2. Reaction of Substrates Bearing Various ortho-Substituted Phenyl Groups
2
a
b
entry
1
R1, R2
heating time (h)
2
yield (%)
ee (%)
1
2
3
4
5
1a
1c
1d
1e
1b
1b
R1 = i-Pr, R2 = H
17
17
9
2a
2c
2d
2e
2b
2b
95
77
R1 = R2 = CHCH-CHCH
94
70
R1 = Et, R2 = H
R1 = Me, R2 = H
R1 = t-Bu, R2 = H
R1 = t-Bu, R2 = H
68
68
9
71−92
26
25−42
44
17
c
6
7
90
69
a
b
c
Isolated yields. The ee was determined by HPLC analysis using a chiral column. The reaction was performed at 130 °C.
80 °C in toluene), the ee in Table 1 reflects the actual
enantioselectivity of the reaction.
Under optimized conditions [7.5 mol % (R)-DTBM-
SEGPHOS, 5 mol % Pd(OAc)2, 2 equiv of K3PO4 in
toluene-1,4-dioxane (9:1) at 80 °C], the reactions of biphenyl
amides 2 bearing various ortho-substituted phenyl groups were
further examined (Table 2). The reaction of 1c bearing the
naphthyl-1-yl group gave the product 2c in an excellent yield
(94%) and in 70% ee (entry 2). Under the same conditions (for
17 h at 80 °C), the reaction of ortho-ethyl derivative 1d resulted
in a significant decrease in the ee of 2d (98%, 40% ee).
Meanwhile when the reaction of 1d was finished in a shorter
time (for 9 h at 80 °C), the ee of 2d increased to 68%, while
the chemical yield was lower at 68% (entry 3). This result
indicates that partial racemization of the N-(ortho-ethylphenyl)-
phenanthridinone 2d occurs under the present reaction
conditions. In the reaction of amide 1e bearing the ortho-
methyl group, not only was there a further decrease in the ee
but also the dispersion of the ee was also observed (25−42% ee,
entry 4). With substrates bearing a small ortho-substituent, the
products 2 with high ee may be difficult to obtain because of
the racemization of the product as well as the decrease in the
enantioselectivity of the reaction.
Figure 1. Possible mechanism for the present reaction.
On the basis of these results, we expected that the reaction of
ortho-tert-butyl substrate 1b would give the product 2b with
high ee. However, the reaction with 1b gave 2b in a poor
chemical yield (26%) and lower ee (44% ee) than those of 2a,
2c, 2d (entry 5). Interestingly, when the reaction temperature
was increased from 80 to 130 °C (oil bath), an increase in the
enantioselectivity as well as the chemical yield was observed
(90%, 69% ee, entry 6).
These results may be explained as follows (Figure 1). The
present reaction proceeds via the pathway shown in Figure 1,
and the enantioselectivity may be determined by diastereomeric
Pd-amide intermediates 1C and 1C′ formed from 1B by ligand
exchange. When the interconversion between 1C and 1C′
proceeds smoothly and their thermodynamic stability (or the
rate of reductive elimination) is very different, the reaction may
proceed with high enantioselectivity. In the reaction of 1b
bearing a bulky ortho-tert-butyl group, since the interconversion
between 1C and 1C′ does not occur efficiently because of the
high rotational barrier around the chiral axis, the enantiose-
lectivity may be lower in comparison with those of 1a and 1c
that bear less bulky iso-propyl and naphthyl-1-yl groups (Table
2, entry 5).
On the other hand, the increase in the reaction temperature
leads to relatively efficient interconversion between 1C and
1C′, which leads to an increase in the enantioselectivity (entry
6). As mentioned above, the enantioselectivity was also
significantly influenced by which bases and solvents were
used (Table 1, entries 6−13). This result may indicate that the
interconversion between 1C and 1C′ occurs not only by the
rotation about the chiral axis but also by reversible conversion
between 1C (or 1C′) and 1B.
The optical purification and the determination of absolute
stereochemistry in axially chiral phenanthridinone derivative 2
were achieved in accordance with Schemes 3 and 4,
respectively. 2a (82% ee) and 2b (72% ee) were converted
into an almost enantiomerically pure form (>99% ee) through
self-disproportionation of enantiomers (SDE) by medium-
pressure liquid chromatography (MPLC) using an achiral silica
gel column (Scheme 3).12 That is, the MPLC chart of 2a (82%
ee, 42 mg) and 2b (72% ee, 90 mg) gave two distinct peaks and
C
DOI: 10.1021/acs.joc.5b02387
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The Journal of Organic Chemistry
Note
2′-Bromo-N-(2-iso-propylphenyl)-[1,1′-biphenyl]-2-carboxa-
mide (1a). Under an Ar atmosphere, to 2-iso-propylaniline (0.481 g,
3.56 mmol) in toluene (10.0 mL) was added a 1.1 M hexane solution
of Me3Al (4.9 mL, 5.4 mmol) at 0 °C. After being stirred for 10 min at
0 °C, methyl 2′-bromo-[1,1′-biphenyl]-2-carboxylate7 (commercially
available, 1.036 g, 3.6 mmol) was added to the mixture, and then the
reaction mixture was stirred for 16 h at 70 °C. The mixture was poured
into 2% HCl 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
= 15−5) gave 1a (1.30 g, 93%). 1a: white solid; mp 87−89 °C; IR
Scheme 3. Optical Purification through SDE of 2a and 2b
Using MPLC
1
(neat) 3275, 1651 cm−1; H NMR (CDCl3) δ: 7.85−7.90 (1H, m),
7.67 (1H, d, J = 8.4 Hz), 7.48−7.56 (3H, m), 7.29−7.42 (3H, m), 7.23
(1H, dt, J = 2.0, 7.6 Hz), 7.17−7.20 (1H, m), 7.10−7.15 (2H, m), 7.02
(1H, brs), 2.39 (1H, sept, J = 6.8 Hz), 1.05 (3H, d, J = 6.8 Hz), 1.03
(3H, d, J = 6.8 Hz); 13C NMR (CDCl3) δ: 167.2, 141.0, 140.9, 138.2,
136.0, 133.6, 133.0, 131.2, 131.0, 130.1, 129.7, 128.8, 128.4, 127.7,
126.2, 125.5, 124.7, 123.1, 27.3, 23.4, 23.1; MS (m/z) 416 (MNa+,
79Br), 418 (MNa+, 81Br); HRMS. Calcd for C22H2079BrNONa (MNa+)
416.06260. Found: 416.06280. Anal. Calcd for C22H20BrNO: C, 67.01;
H, 5.11; N, 3.55. Found: C, 67.04; H, 4.90; N, 3.66.
Scheme 4. Regioselective Bromination of 2b and X-ray
Crystal Structure of 3b
2′-Bromo-N-(2-tert-butylphenyl)-[1,1′-biphenyl]-2-carboxa-
mide (1b). 1b was prepared from 2-tert-butylaniline (0.298 g, 2.0
mmol) in accordance with the procedure described in the preparation
of 1a. Purification of the residue by column chromatography (hexane/
AcOEt = 10) gave 1b (0.72 g, 86%). 1b: pale yellow liquid; IR (neat)
3291, 1667 cm−1; 1H NMR (CDCl3) δ: 7.82 (1H, d, J = 6.8 Hz), 7.62
(1H, d, J = 8.4 Hz), 7.49−7.55 (2H, m), 7.44 (1H, dd, J = 1.6, 7.6 Hz),
7.38 (1H, t, J = 7.2 Hz), 7.31−7.35 (2H, m), 7.20 (1H, dt, J = 1.6, 7.6
Hz), 7.07−7.15 (4H, m), 1.27 (9H, s); 13C NMR (CDCl3) δ: 167.3,
143.8, 140.9, 138.7, 136.2, 134.8, 132.9, 131.3, 130.9, 130.1, 129.7,
128.5, 128.4, 128.1, 127.5, 126.7, 126.6, 126.4, 123.1, 34.5, 30.6; MS
(m/z) 430 (MNa+, 79Br), 432 (MNa+, 81Br); HRMS. Calcd for
C23H2279BrNONa (MNa+) 430.07825. Found: 430.08011.
2′-Bromo-N-(naphthalen-1-yl)-[1,1′-biphenyl]-2-carboxa-
mide (1c). 1c was prepared from 1-naphthylamine (0.73 g, 5.11
mmol) in accordance with the procedure described in the preparation
of 1a. Purification of the residue by column chromatography (hexane/
AcOEt = 5) gave 1c (1.82 g, 90%). 1c: white solid; mp 134−136 °C;
IR (neat) 3256, 1645 cm−1; 1H NMR (CDCl3) δ: 7.97 (1H, d, J = 7.6
Hz), 7.82 (1H, d, J = 7.2 Hz), 7.79 (1H, d, J = 8.8 Hz), 7.68 (1H, d, J
= 8.4 Hz), 7.64 (1H, d, J = 8.4 Hz), 7.53−7.60 (3H, m), 7.31−7.47
(6H, m), 7.24 (1H, t, J = 7.6 Hz), 7.13 (1H, d, J = 8.4 Hz); 13C NMR
(CDCl3) δ: 167.2, 141.0, 138.4, 135.8, 133.8, 133.1, 132.1, 131.3,
131.0, 130.3, 129.8, 129.0, 128.5, 128.5, 127.9, 127.0, 126.0, 125.8,
125.6, 123.2, 120.5, 120.5; MS (m/z) 424 (MNa+, 79Br), 426 (MNa+,
81Br); HRMS. Calcd for C23H1679BrNONa (MNa+) 424.03130.
looked like the usual chart that is seen for a mixture of two
different compounds. The ee of 2a and 2b obtained from the
less polar fraction was >99% ee.13
Subsequently, optically pure 2b was treated with NBS in
DMF to be converted to mono-bromo derivative 3b with
complete regioselectivity and a high yield (89%, Scheme 4).
The X-ray crystal structure of 3b indicates that the absolute
stereochemistry of the major enantiomer in 2b has an (S)-
configuration14 and bromination of 2b occurs selectively at the
C2-position (Scheme 4).15 The absolute stereochemistries of
other phenanthridinones 2a,c,d,e, which have large positive
[α]D values as in 2b, also had the (S)-configuration tentatively
assigned to them.
In conclusion, we succeeded in the catalytic enantioselective
synthesis of N-C axially chiral phenanthridin-6-one derivatives
bearing various ortho-substituted phenyl groups on the nitrogen
atom through (R)-DTBM-SEGPHOS-Pd(OAc)2-catalyzed in-
tramolecular Buchwald−Hartwig amination. The enantioselec-
tivity was found to strongly depend on solvents, bases, and
reaction temperature as well as on the bulkiness of ortho-
substituents.
Found: 424.02954. Anal. Calcd for C23H16BrNO: C, 68.67; H, 4.01;
N, 3.48. Found: C, 68.50; H, 3.91; N, 3.73.
2′-Bromo-N-(2-ethylphenyl)-[1,1′-biphenyl]-2-carboxamide
(1d). 1d was prepared from 2-ethylaniline (0.30 g, 2.5 mmol) in
accordance with the procedure described in the preparation of 1a.
Purification of the residue by column chromatography (hexane/AcOEt
= 10) gave 1d (0.89 mg, 94%). 1d: white solid; mp 102−104 °C; IR
1
(neat) 3250, 1653 cm−1; H NMR (CDCl3) δ: 7.88 (1H, dd, J = 2.8,
6.4 Hz), 7.66 (1H, d, J = 8.4 Hz), 7.63 (1H, d, J = 8.0 Hz), 7.50−7.56
(2H, m), 7.29−7.41 (3H, m), 7.23 (1H, m), 7.05−7.17 (3H, m), 7.03
(1H, brs), 2.16 (2H, q, J = 7.6 Hz), 1.04 (3H, d, J = 7.6 Hz); 13C NMR
(CDCl3) δ: 166.9, 140.9, 138.3, 135.9, 135.3, 134.6, 133.0, 131.2,
131.0, 130.1, 129.7, 128.8, 128.4, 128.2, 127.8, 126.4, 125.6, 123.6,
123.1, 23.5, 14.0; MS (m/z) 402 (MNa+, 79Br), 404 (MNa+, 81Br);
HRMS. Calcd for C21H1879BrNONa (MNa+) 402.04695. Found:
402.04844. Anal. Calcd for C21H18BrNO: C, 66.33; H, 4.77; N, 3.68.
Found: C, 66.30; H, 4.69; N, 3.75.
EXPERIMENTAL SECTION
■
Melting points were uncorrected. 1H and 13C NMR spectra were
recorded on a 400 and 100 MHz spectrometer, respectively. In 1H and
13C NMR spectra, chemical shifts were expressed in δ (ppm)
downfield from CHCl3 (7.26 ppm) and CDCl3 (77.0 ppm),
respectively. High-resolution mass spectra (HRMS) were obtained
using the electron spray ionization technique (ESI) and TOF mass
analyzer. 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 μm)
with a UV detector. High-performance liquid chromatography
(HPLC) was performed on a 25 × 0.4 cm i.d. chiral column with a
UV detector.
2′-Bromo-N-(2-methylphenyl)-[1,1′-biphenyl]-2-carboxa-
mide (1e). 1e was prepared from 2-methylaniline (0.268 g, 2.5 mmol)
in accordance with the procedure described in the preparation of 1a.
Purification of the residue by column chromatography (hexane/AcOEt
= 10−4) gave 1e (0.732 g, 80%). 1e: white solid; mp 112−114 °C; IR
1
(neat) 3237, 1651 cm−1; H NMR (CDCl3) δ: 7.89−7.92 (1H, m),
D
DOI: 10.1021/acs.joc.5b02387
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The Journal of Organic Chemistry
Note
7.72 (1H, d, J = 7.6 Hz), 7.68 (1H, d, J = 7.6 Hz), 7.50−7.57 (2H, m),
7.32−7.42 (3H, m), 7.24 (1H, dt, J = 2.4, 7.8 Hz), 7.16 (1H, t, J = 7.6
Hz), 7.09 (1H, d, J = 6.8 Hz), 7.00−7.05 (2H, m), 1.90 (3H, s); 13C
NMR (CDCl3) δ: 166.6, 141.0, 138.3, 135.9, 135.5, 133.0, 131.3,
131.0, 130.3, 130.2, 129.7, 129.0, 128.9, 128.4, 127.8, 126.6, 125.1,
123.1, 122.6, 17.3; MS (m/z) 366 (MH+, 79Br), 368 (MH+, 81Br);
HRMS. Calcd for C20H1779BrNO (MH+) 366.04935. Found:
366.04628. Anal. Calcd for C20H16BrNO: C, 65.59; H, 4.40; N,
3.82. Found: C, 65.33; H, 4.37; N, 3.78.
(MNa+); HRMS. Calcd for C23H15NONa (MNa+) 344.10513. Found:
344.10539.
5-(2-Ethylphenyl)phenanthridin-6(5H)-one (2d). 2d was pre-
pared from 1d (74 mg, 0.2 mmol) in accordance with the procedure
described in the preparation of 2a. Purification of the residue by
column chromatography (hexane/AcOEt = 5) gave 2d (40 mg, 68%,
68% ee). The enantiomers of 2d were separated by HPLC using a
CHIRALCEL OD-3 column [25 cm × 0.46 cm i.d.; 17% i-PrOH in
hexane; flow rate, 1.5 mL/min; (+)-2d (major); tR = 8.7 min, (−)-2d
(minor); tR = 12.5 min]. 2d: colorless liquid; [α]D = +55.1 (c = 0.38,
5-(2-iso-Propylphenyl)phenanthridin-6(5H)-one (2a). Under
an Ar atmosphere, to the suspension of Pd(OAc)2 (3.4 mg, 0.015
mmol) and (R)-DTBM-SEGPHOS (26.5 mg, 0.0225 mmol) in
toluene-1,4-dioxane (1.35−0.15 mL) were added 1a (118 mg, 0.30
mmol) in toluene-1,4-dioxane (1.35 mL-0.15 mL) and subsequently
K3PO4 (127 mg, 0.6 mmol). After being stirred for 10 min at rt, the
reaction mixture was stirred for 17 h at 80 °C. The mixture was poured
into 2% HCl solution 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
= 10) gave 2a (91 mg, 96%, 77% ee). The enantiomers of 2a were
separated by HPLC using a CHIRALCEL OD-3 column [25 cm ×
0.46 cm i.d.; 17% i-PrOH in hexane; flow rate, 1.5 mL/min; (+)-2a
(major); tR = 4.6 min, (−)-2a (minor); tR = 17.1 min]. 2a: white solid;
mp 57−59 °C (77% ee); [α]D = +49.8 (c = 0.40, CHCl3, 80% ee); IR
1
CHCl3, 70% ee); IR (neat) 1653 cm−1; H NMR (CDCl3) δ: 8.57
(1H, d, J = 8.4 Hz), 8.34 (1H, d, J = 8.4 Hz), 8.29−8.32 (1H, m), 7.81
(1H, dt, J = 1.2, 7.2, Hz), 7.61 (1H, t, J = 7.6 Hz), 7.46−7.52 (2H, m),
7.41 (1H, dt, J = 2.0, 7.2 Hz), 7.26−7.30 (2H, m), 7.19 (1H, d, J = 7.2
Hz), 6.59−6.63 (1H, m), 2.42 (1H, qd, J = 7.6, 15.2 Hz), 2.32 (1H,
qd, J = 7.6, 15.2 Hz), 1.07 (3H, t, J = 7.6 Hz); 13C NMR (CDCl3) δ:
161.3, 141.9, 138.9, 136.6, 134.1, 132.8, 129.5, 129.2, 129.1, 128.0,
127.7, 125.9, 123.0, 122.6, 121.8, 119.0, 116.7, 23.6, 13.6; MS (m/z)
322 (MNa+); HRMS. Calcd for C21H17NONa (MNa+) 322.12078.
Found: 322.12061.
5-(2-Methylphenyl)phenanthridin-6(5H)-one (2e). 2e was
prepared from 1e (72 mg, 0.2 mmol) in accordance with the
procedure described in the preparation of 2a. Purification of the
residue by column chromatography (hexane/AcOEt = 5) gave 2e (42
mg, 74%, 42% ee). The enantiomers of 2e were separated by HPLC
using a CHIRALCEL OD-3 column [25 cm × 0.46 cm i.d.; 9% i-
PrOH in hexane; flow rate, 1.0 mL/min; (+)-2e (major enantiomer);
tR = 25.7 min, (−)-2e (minor enantiomer); tR = 30.4 min]. 2e: white
solid; mp 102−104 °C (42% ee); [α]D = +26.3 (c = 0.26, CHCl3, 42%
ee); IR (neat) 1651 cm−1; 1H NMR (CDCl3) δ: 8.58 (1H, dd, J = 1.2,
7.6 Hz), 8.34 (1H, d, J = 8.4 Hz), 8.29−8.32 (1H, m), 7.81 (1H, dt, J =
1.2, 7.8 Hz), 7.61 (1H, dt, J = 1.0, 7.8 Hz), 7.38−7.47 (3H, m), 7.26−
7.31 (2H, m), 7.21 (1H, dd, J = 2.4, 6.4 Hz), 6.60 (1H, m), 2.05 (3H,
s); 13C NMR (CDCl3) δ: 161.0, 138.4, 137.1, 136.5, 134.1, 132.8,
131.5, 129.3, 129.0, 128.9, 128.0, 127.7, 125.9, 123.1, 122.7, 121.8,
119.0, 116.3, 17.4; MS (m/z) 308 (MNa+); HRMS. Calcd for
C20H15NONa (MNa+) 308.10513. Found: 308.10504.
1
(neat) 1657 cm−1; H NMR (CDCl3) δ: 8.56 (1H, dd, J = 0.8, 7.6
Hz), 8.34 (1H, d, J = 8.0 Hz), 8.30 (1H, m), 7.81 (1H, ddd, J = 2.0,
7.6, 8.8 Hz), 7.61 (1H, ddd, J = 1.2, 7.6, 8.8 Hz), 7.55 (1H, dd, J = 1.6,
8.0 Hz), 7.50 (1H, dt, J = 1.2, 7.6 Hz), 7.38 (1H, dt, J = 1.6, 7.6 Hz),
7.24−7.31 (2H, m), 7.15 (1H, dd, J = 1.2, 7.8 Hz), 6.57−6.62 (1H,
m), 2.64 (1H, sept, J = 6.8 Hz), 1.16 (3H, d, J = 6.8 Hz), 1.01 (3H, d, J
= 6.8 Hz); 13C NMR (CDCl3) δ: 161.4, 146.7, 139.0, 135.6, 134.0,
132.7, 129.4, 129.1 129.0, 128.8, 128.0, 127.5, 127.2, 125.8, 122.9,
122.6, 121.7, 118.8, 116.8, 28.0, 23.8, 23.4; MS (m/z) 336 (MNa+);
HRMS. Calcd for C22H19NONa (MNa+) 336.13643. Found:
336.13928.
5-(2-tert-Butylphenyl)phenanthridin-6(5H)-one (2b). 2b was
prepared from 1b (119 mg, 0.3 mmol) in accordance with the
procedure described in the preparation of 2a. Purification of the
residue by column chromatography (hexane/AcOEt = 10) gave 2b
(92.6 mg, 97%, 73% ee). The enantiomers of 2b were separated by
HPLC using a CHIRALCEL OD-3 column [25 cm × 0.46 cm i.d.; 9%
i-PrOH in hexane; flow rate, 1.5 mL/min; (+)-2b (major); tR = 6.9
min, (−)-2b (minor); tR = 11.3 min]. 2b: white solid; mp 61−63 °C
(>99% ee); [α]D = +97.7 (c = 0.40, CHCl3, 70% ee); IR (neat) 1655
Optical Purification through SDE by MPLC of 2a. Medium-
pressure liquid chromatography (MPLC, eluent: hexane/AcOEt = 30)
of 2a (82% ee, 42 mg) was performed on a 25 × 4 cm i.d. prepacked
column (silica gel, 10 μm) with a UV detector. The eluted substrate 2a
was collected in two fractions across the boundary point, and >99% ee
(21 mg) and 56% ee (14 mg) of 2a were obtained from less polar and
more polar fractions, respectively.
1
cm−1; H NMR (CDCl3) δ: 8.57 (1H, dd, J = 0.8, 7.6 Hz), 8.33 (1H,
Optical Purification through SDE by MPLC of 2b. Medium-
pressure liquid chromatography (MPLC, eluent: hexane/AcOEt = 30)
of 2b (73% ee, 90 mg) was performed on a 25 × 4 cm i.d. prepacked
column (silica gel, 10 μm) with a UV detector. The eluted substrate 2b
was collected in two fractions across the boundary point, and >99% ee
(27 mg) and 62% ee (59 mg) of 2b were obtained from less polar and
more polar fractions, respectively.
d, J = 8.0 Hz), 8.29 (1H, dd, J = 1.6, 7.6 Hz), 7.80 (1H, t, J = 7.2 Hz),
7.72 (1H, dd, J = 1.4, 8.0 Hz), 7.60 (1H, t, J = 7.6 Hz), 7.47 (1H, dt, J
= 1.2, 8.0 Hz), 7.37 (1H, dt, J = 1.2, 7.4 Hz), 7.24−7.32 (2H, m), 7.02
(1H, dd, J = 1.4, 7.8 Hz), 6.57 (1H, dd, J = 1.2, 8.0 Hz), 1.16 (9H, s);
13C NMR (CDCl3) δ: 162.4, 147.5, 140.0, 135.7, 134.0, 132.8, 131.3,
130.0, 129.1, 129.0, 128.9, 128.0, 128.0, 126.0, 123.0, 122.5, 121.8,
119.0, 118.0, 36.1, 31.6; MS (m/z) 350 (MNa+); HRMS. Calcd for
C23H21NONa (MNa+) 350.15208. Found: 350.15242.
2-Bromo-5-(2-(tert-butyl)phenyl)phenanthridin-6(5H)-one
(3b). To the solution of 2b (>99% ee, 44 mg, 0.134 mmol) in DMF
(2.0 mL) was added N-bromosuccinimide (48 mg, 0.272 mmol). After
being stirred for 24 h at 50 °C, the mixture was poured into 2% HCl
solution 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 = 15) gave
3b (50.4 mg, 89%). 3b: white solid; mp 159−161 °C; [α]D = +108.7
5-(Naphthalen-1-yl)phenanthridin-6(5H)-one (2c). 2c was
prepared from 1c (80 mg, 0.2 mmol) in accordance with the
procedure described in the preparation of 2a. Purification of the
residue by column chromatography (hexane/AcOEt = 5) gave 2c (60
mg, 94%, 70% ee). The enantiomers of 2c were separated by HPLC
using a CHIRALCEL OD-3 column [25 cm × 0.46 cm i.d.; 33% i-
PrOH in hexane; flow rate, 1.0 mL/min; (+)-2c (major); tR = 8.0 min,
(−)-2c (minor); tR = 14.9 min]. 2c: white solid; mp 229−231 °C
(70% ee); [α]D = +131.1 (c = 0.40, CHCl3, 70% ee); IR (neat) 1653
1
(c = 0.40, CHCl3); IR (neat) 1659 cm−1; H NMR (CDCl3) δ: 8.56
(1H, d, J = 8.0 Hz), 8.38 (1H, d, J = 2.0 Hz), 8.24 (1H, d, J = 8.0 Hz),
7.81 (1H, dt, J = 1.2, 7.8 Hz), 7.71 (1H, dd, J = 1.4, 8.2 Hz), 7.63 (1H,
t, J = 7.6 Hz), 7.47 (1H, dt, J = 1.2, 8.0 Hz), 7.34−7.39 (2H, m), 6.99
(1H, dd, J = 1.2, 7.6 Hz), 6.45 (1H, d, J = 8.4 Hz), 1.16 (9H, s); 13C
NMR (CDCl3) δ: 162.1, 147.6, 139.0, 135.3, 133.0, 132.7, 131.7,
131.2, 130.1, 129.2, 129.2, 128.8, 128.1, 126.1, 125.7, 121.9, 120.7,
119.6, 115.7, 36.1, 31.6; MS (m/z) 428 (MNa+, 79Br), 430 (MNa+,
81Br); HRMS. Calcd for C23H2079BrNONa (MNa+) 428.06260.
Found: 428.05948.
1
cm−1; H NMR (CDCl3) δ: 8.63 (1H, dd, J = 1.2, 8.0 Hz), 8.42 (1H,
d, J = 8.4 Hz), 8.37 (1H, dd, J = 1.2, 8.0 Hz), 8.07 (1H, d, J = 8.4 Hz),
8.01 (1H, d, J = 8.0 Hz), 7.87 (1H, dt, J = 1.2, 7.8 Hz), 7.64−7.72 (2H,
m), 7.50−7.55 (2H, m), 7.46 (1H, d, J = 8.4 Hz), 7.38 (1H, t, J = 7.6
Hz), 7.29 (1H, t, J = 7.2 Hz), 7.21 (1H, dt, J = 1.2, 8.0 Hz), 6.54 (1H,
d, J = 8.4 Hz); 13C NMR (CDCl3) δ: 161.7, 139.1, 134.9, 134.8, 134.2,
133.0, 130.2, 129.4, 129.3, 129.2, 128.6, 128.1, 127.4, 127.1, 126.6,
126.1, 125.8, 123.0, 122.7, 122.4, 121.8, 119.0, 117.2; MS (m/z) 344
E
DOI: 10.1021/acs.joc.5b02387
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
M.; Joseph, D.; Andrioletti, B. Tetrahedron 2002, 58, 2041.
(g) Hartwig, J. F. In Handbook of Organopalladium Chemistry for
Organic Synthesis; Negishi, E., Ed.; Wiley-Interscience: New York,
2002; p 1051. (h) Jiang, L.; Buchwald, S. L. In Metal-Catalyzed Cross-
Coupling Reactions, 2nd ed.; De Meijere, A., Diederich, F., Eds.; Wiley-
VCH: Weinheim, Germany, 2004; p 699.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b02387.
■
S
Copies of 1H NMR and 13C NMR spectra of compounds
1a−e, 2a−e, 3b, and chiral HPLC data of 2a−e (PDF)
Crystallographic data for compound 3b (CIF)
(9) Wang, Y.; Gulevich, A. V.; Gevorgyan, V. Chem.Eur. J. 2013,
19, 15836.
(10) (a) Saito, T.; Yokozawa, T.; Ishizaki, T.; Moroi, T.; Sayo, N.;
Miura, T.; Kumobayashi, H. Adv. Synth. Catal. 2001, 343, 264.
(b) Sumi, K.; Kumobayashi, H. Top. Organomet. Chem. 2004, 6, 63.
(11) With the reaction of Ia and Ib in Scheme 1, the use of (R)-
DTBM-SEGPHOS was not effective. In these cases, the racemic
products Ia were obtained in poor yields.
AUTHOR INFORMATION
Corresponding Author
*E-mail: kitagawa@shibaura-it.ac.jp.
■
Notes
(12) For reviews on SDE via achiral chromatography: (a) Solo-
shonok, V. A.; Berbasov, D. O. Chim. Oggi 2006, 24, 44.
(b) Soloshonok, V. A.; Roussel, C.; Kitagawa, O.; Sorochinsky, A. E.
The authors declare no competing financial interest.
Chem. Soc. Rev. 2012, 41, 4180. (c) Sorochinsky, A. E.; Acena, J. L.;
Soloshonok, V. A. Synthesis 2013, 45, 141.
̃
REFERENCES
■
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(15) The crystal structure of 3b was deposited at the Cambridge
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F
DOI: 10.1021/acs.joc.5b02387
J. Org. Chem. XXXX, XXX, XXX−XXX