Divergent Reactions of 2-Aminophenol with α-Bromoacetate: Asymmetric Synthesis of Two Regioisomeric 1,4-Benzoxazinones

Article abstract of DOI:10.1002/bkcs.12165

2-Aminophenol displays a diverse pattern of reactivity in the substitution reaction of α-bromoacetate. The substitution under neutral or basic conditions results in the formation of 1,4-benzoxazinones, whereas Lewis acid-promoted substitution leads to Friedel–Crafts alkylation of 2-aminophenol. Asymmetric synthesis of two regioisomeric 1,4-benzoxazinones is accomplished from the nucleophilic substitution of highly diastereoenriched α-aryl-α-bromoacetates with N-alkyl-2-aminophenols under varied reaction conditions.

Full text of DOI:10.1002/bkcs.12165

Article
DOI: 10.1002/bkcs.12165
BULLETIN OF THE
S. Y. Kim et al.
KOREAN CHEMICAL SOCIETY
Divergent Reactions of 2-Aminophenol with α-Bromoacetate:
Asymmetric Synthesis of Two Regioisomeric 1,4-Benzoxazinones
*
Seo Yun Kim, Gun Hee Han, Su Kyung Hong, Jieun Park, and Yong Sun Park
Department of Chemistry, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Korea.
*E-mail: parkyong@konkuk.ac.kr
Received October 11, 2020, Accepted November 24, 2020
2-Aminophenol displays a diverse pattern of reactivity in the substitution reaction of α-bromoacetate. The
substitution under neutral or basic conditions results in the formation of 1,4-benzoxazinones, whereas
Lewis acid-promoted substitution leads to Friedel–Crafts alkylation of 2-aminophenol. Asymmetric syn-
thesis of two regioisomeric 1,4-benzoxazinones is accomplished from the nucleophilic substitution of
highly diastereoenriched α-aryl-α-bromoacetates with N-alkyl-2-aminophenols under varied reaction
conditions.
Keywords: Nucleophilic substitution, Asymmetric synthesis, Dynamic resolution, Heterocycles, Chiral
auxiliary
Introduction
developing α-aryl-α-bromoacetate 1 as generally useful plat-
forms for asymmetric organic synthesis.4b–d It is recently
envisaged that a divergent asymmetric synthesis of two reg-
ioisomeric N-alkyl-1,4-benzoxazinones would be possible
through the nucleophilic substitution reaction of nearly
diastereomerically pure α-aryl-α-bromoacetate 1 with N-
alkyl-2-aminophenols and subsequent spontaneous cycliza-
tion. We report herein the convenient divergent asymmetric
synthesis of two regioisomeric 1,4-benzoxazinones such as
4-alkyl-3-aryl-1,4-benzoxazin-2-one 2 and 4-alkyl-2-aryl-1,-
4-benzoxazin-3-one 3 through the nucleophilic substitution of
the configurationally labile α-aryl-α-bromoacetate 1 with
various N-alkyl-2-aminophenol nucleophiles.
Condition-based divergence in organic synthesis can gener-
ate more than one molecular scaffold in a selective manner
from one set of starting materials. As 2-aminophenol has
three nonequivalent nucleophilic sites such as amino,
hydroxyl, and aromatic groups, it can display a diverse pat-
tern of reactivity in the reactions with an electrophile under
varied reaction conditions. In the nucleophilic substitution
reaction of α-aryl-α-bromoacetate 1 with 2-aminophenol
shown in Figure 1, the displacement with the amino group
at the α-bromo carbon and following lactonization with the
hydroxy group (Path A) can provide 1,4-benzoxazin-2-one
2. Next, appropriate tuning of 2-aminophenol reactivity
with a base can lead to the nucleophilic substitution with
the phenoxide group at the α-bromo carbon and following
lactamization with the amino group (Path B) affords reg-
ioisomeric 1,4-benzoxazin-3-one 3. In addition, Lewis acid-
promoted reaction of the highly nucleophilic aromatic ring
of 2-aminophenol with α-aryl-α-bromoacetate (Path C)
leads to Friedel–Crafts alkylation to produce trisubstituted
aromatic compound 4.
Both 1,4-benzoxazin-2-one and 1,4-benzoxazin-3-one
structures are frequently found in important pharmaceuticals
and natural compounds.1 Accordingly, an efficient protocol
for the asymmetric synthesis of these systems has become a
topic of high interest in organic synthesis. While promising
advances have recently been made in developing asymmetric
synthetic methods for these frameworks,2,3 the studies for
asymmetric synthesis of N-alkyl-1,4-benzoxazinones have
rarely been reported. We have formerly reported on the
Results and Discussion
Initial studies were carried out with isopropyl N-benzoyl
L-threoninate-derived α-bromo-α-phenylacetate (1a) and
N-methyl-2-aminophenol as shown in Table 1. When 1a of
50:50 diastereomeric ratio (dr) was treated with N-methyl-
2-aminophenol (2.0 equiv), diisopropylethylamine (1.1
equiv., DIEA) and tetrabutylammonium iodide (1.1 equiv.,
TBAI) in CHCl3 at ambient temperature for 1.5 h, the sub-
stitution with the amino group and spontaneous lacto-
nization produced 2a in 81% yield with 59:41 enantiomeric
ratio (er) along with a small amount of regioisomer 3a as
shown in entry 1. The result suggests that the dynamic
kinetic resolution of two diastereomers of α-bromo-
α-phenylacetate 1a is not considerably operating in the sub-
stitution reaction. The same reaction with highly
diastereoenriched (αR)-1a (99:1 dr) provided 2a in 95%
yield with 89:11 er (entry 2). To obtain the highly enantio-
enriched 2a from the substitution of (αR)-1a, it is essential
to perform the substitution under the reaction conditions
N-benzoyl-L-threonine-mediated
crystallization
induced
dynamic resolution (CIDR) of configurationally labile α-aryl-
α-bromoacetate.4a Continuous interest has been focused on
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Table 1. Reactions of α-bromo-α-phenylacetate (αR)-1a with N-
methyl-2-aminophenol.
Entrya Dr of 1a Conditions
2a:3a Yield Erb
1
50:50
Nuc (2.0 euqiv),
TBAI, DIEA
96:4
81
59:41
2
99:1
Nuc (2.0 equiv),
TBAI, DIEA
94:6
95
89:11
3
4
99:1
99:1
Nuc (2.0 equiv)
Nuc (10.0 equiv)
99:1
99:1
53
90
94:6
99:1
a All the reactions were carried out in CHCl3 (0.1 M) at ambient temp.
For 1.5 h.
Figure 1. Divergent pathways for the substitution of
α-bromoacetate with 2-aminophenol.
b The enantiomeric ratios were determined by chiral stationary phases
(CSP) HPLC using a racemic mixture as a standard.
that avoid or at least minimize the unfavorable
epimerization of (αR)-1a, when exposed to the basic reac-
tion conditions. Without both DIEA and TBAI, under
which conditions the epimerization is not activated, the
reaction afforded 2a as an only product with an improved
er of 94:6, while the reaction was slower to provide 2a in
53% yield after 1.5 h (entry 3). We have thus examined to
use more excess amounts of N-methyl-2-aminophenol
nucleophiles to accelerate the substitution rate with respect
to the rate of epimerization of (αR)-1a. The use of 10 equiv.
of N-methyl-2-aminophenol successfully produced (S)-2a
in 90% yield with a satisfactory er of 99:1 (entry 4).5
The highly efficient asymmetric synthesis of N-methyl-
1,4-benzoxazin-2-one (2a) under the conditions shown in
Table 1 (entry 4) encouraged us to investigate the
stereoselective syntheses of 4-alkyl-3-aryl-1,4-benzoxazin-
2-ones 2b-j as shown in Scheme 1. When (αR)-1a of 99:1
dr was treated with seven different N-alkyl-2-aminophenols
(10 equiv) under the reaction conditions optimized in
Table 1, the substitution-lactonizations provided (S)-1,-
4-benzoxazin-2-ones 2b–h in yields of 94–63% with high
ers ranging from 99:1 to 96:4. The N-substituted alkyl
groups such as the allyl, n-propyl, n-pentyl, and benzyl
groups influenced both yield and er of products. The reac-
tions with three different N-benzyl-2-aminophenols pro-
duced 2e, 2g, and 2h with a lowest er of 96:4 among the
seven N-alkyl-2-aminophenol nucleophiles examined
(Scheme 1). Also, the substitution-lactonization of
α-bromo-α-(p-chlorophenyl)acetate 1b and α-bromo-α-(p-
bromophenyl) acetate 1c with N-methyl 2-aminophenol
afforded 3-(p-chlorophenyl) and 3-(p-bromophenyl)
substituted 1,4-benzoxazin-2-ones 2i and 2j with 99:1
er. The limited results show that the variation of the α-aryl
substituent of α-bromoacetate did not affect the er of
1,4-benzoxazin-2-one products. The present er values of
Scheme 1. Asymmetric synthesis of 4-alkyl-3-aryl-1,-
4-benzoxazin-2-ones.
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Asymmetric Synthesis of Two Regioisomeric 1,4-Benzoxazinones
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3-aryl-1,4-benzoxazin-2-ones 2a-j obtained from α-aryl-
α-bromoacetates (αR)-1a-c are much higher than the er
values (about 90:10 er) obtained from our previous work
using the (R)-pantolactone-mediated dynamic kinetic reso-
lution of α-aryl-α-bromoacetates.2h
four different N-alkyl-2-aminophenols to produce enantio-
enriched 2-aryl-1,4-benzoxazin-3-ones as shown in Scheme 2.
The treatment of (αR)-α-bromo-α-phenylacetate 1a of 99:1 dr
with N-alkyl-2-aminophenols and t-BuO−Na+ under the same
reaction conditions shown in Table 2 (entry 2) successfully
provided N-alkyl-2-phenyl-1,4-benzoxazin-3-ones 3b-e with er
values that ranged from 90:10 to 87:13 in isolated yields of
72–43%.5
Having successfully established a convenient synthetic
method in the asymmetric synthesis of 3-aryl-1,4-benzoxazin-
2-ones 2a-j, we next investigated the stereoselective synthesis
of their regioisomeric 1,4-benzoxazin-3-ones using phenoxide
as a nucleophile. However, the existence of the potentially
unstable stereocenter at 2-position of 2-aryl-1,4-benzoxazin-
3-one makes it particularly challenging to obtain high optical
purity of the product under basic conditions. Our strategy to
minimize both the epimerization of (αR)-α-aryl-α-bromoacetate
and the racemization of 2-aryl-1,4-benzoxazin-3-one is to run
the substitution with preformed phenoxide in shortest possible
reaction time. Preliminary investigations were performed with
the nucleophilic substitution of (αR)-1a of 99:1 dr with N-
methyl-2-aminophenol under basic conditions as shown in
Table 2. The addition of (αR)-1a to the premixed solution of
N-methyl-2-aminophenol (1.5 equiv) and K2CO3 (1.3 equiv) in
DMF produced two regioisomeric benzoxazinones 3a and 2a
at a ratio of 67:33 in 85% yield. The substitution of α-bromo-
α-phenylacetate 1a with the preformed phenoxide and sponta-
neous lactamization afforded 2-phenyl-1,4-benzoxazin-3-one
(3a) as a major product with 84:16 er and a regioisomer 2a as
a minor product (entry 1). The use of t-BuO−Na+ as a base
improved both the regioisomeric ratio to 86:14 and the er of
3a to 93:7 (entry 2). No further significant improvement in
stereoselectivities was achieved in the reaction using t-BuO−K+
or NaH (entries 3–4). The use of 2.0 equiv. of base improved
the regioselectivity of the reaction to give 3a as an only prod-
uct, but the er of 3a was significantly diminished. We next
studied the scope of this asymmetric synthetic strategy with
We have previously studied that both arenes and alcohols
can act as a nucleophile for AgOTf-promoted nucleophilic
substitution of α-aryl-α-bromoacetates.4c,d In order to inves-
tigate the competing reactivity between arene and hydroxyl
group of 2-aminophenol, the reaction of α-bromoacetate
with N-Boc-2-aminophenol was investigated in the pres-
ence of AgOTf as shown in Scheme 3. The substitution of
(αR)-α-bromo-α-phenylacetate 1a (99:1 dr) gave 4-alkyl
substituted 2-aminophenol 4a exclusively in 80% yield
with 99:1 dr through the Friedel-Crafts alkylation at the
para-position to the strong electron donating OH group.
When 4-methyl substituted N-Boc-2-aminophenol was used
as a nucleophile to block the substitution at the 4-position,
the substitution showed interesting results as depicted in
Scheme 3. The AgOTf-promoted substitution of (αR)-1a
with N-Boc-4-methyl-2-aminophenol provided a mixture of
C-alkylation products 4b and O-alkylation product 5 in a
ratio of 2:1. A mixture of regioisomeric dialkyl substituted
2-aminophenols 4b was produced in 38% yield, while
α-aryloxy substituted phenylacetate 5 was isolated in 20%
yield. After simple deprotection of N-Boc group of 5 with
trifluoroacetic acid (TFA), Et3N-promoted lactamization
was completed within 1 h to ultimately afford 6-methyl-
2-phenyl-1,4-benzoxazin-3-one 3f in 59% yield with
93:7 er.
Table 2. Reactions of (αR)-1a with N-methyl-2-aminophenol and
a base.
Entrya
Base
3a:2ab
67:33
86:14
85:15
85:15
Yieldc
85
68
65
Erd
1
2
3
4
K2CO3
t-BuO−Na+
t-BuO−K+
NaH
84:16
93:7
93:7
93:7
37
a All the reactions were carried out in DMF (0.2 M) with 1.3 equiv. of
base and 1.5 equiv. of 2-aminophenol at ambient temp. For 0.5 h.
b The regioisomeric ratios(rr) were determined by 1H-
NMRspectroscopy of the reaction mixture.
c Combined isolated yield of 3a and 2a.
d The enantiomeric ratios were determined by chiral stationary phases
(CSP) HPLC using a racemic mixture as a standard.
Scheme 2. Asymmetric synthesis of 4-alkyl-2-phenyl-1,-
4-benzoxazin-3-ones.
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Asymmetric Synthesis of Two Regioisomeric 1,4-Benzoxazinones
KOREAN CHEMICAL SOCIETY
JMS-700 by using the FAB or ESI technique. Analytical TLC
was performed on silica gel 60F254 plates and visualized by
UV irradiation (254 nm). Flash column chromatography was
performed with 230–400 mesh silica gel and n-hexane-ethyl
acetate mixtures as the eluent. Supporting Information (see
footnote on the first page of this article): The NMR spectra of
new compounds 2d, 2f, 2h, 3b, 3c, 3d, 3e, 4a and 5 and the
CSP-HPLC chromatograms.
General Procedure for the Asymmetric Preparation of
1,4-benzoxazin-2-ones (2a–j). To a solution of (αR)-
α-aryl-α-bromoacetate (1a-c, 1.0 mmol) in CHCl3 (0.1 M)
were added N-alkyl-2-aminophenol (10 equiv) at ambient
temperature. After stirring for 1.5 h, the solution was con-
centrated and purified by column chromatography on silica
gel to afford a 1,4-benzoxazin-2-one.
(S)-4-Methyl-2-oxo-3-phenyl-3,4-dihydro-2H-
1,4-benzoxazine (2a). A pale yellow oil, 90% yield from
1
1a; Known compound, ref. 2g; H NMR (400 MHz, CDCl3)
Scheme 3. Friedel–Crafts alkylation of N-Boc-2-aminophenols.
7.33–7.03 (m, 7H), 6.86–6.74 (m, 2H), 5.05 (s, 1H), 2.84 (s,
3H); 13C NMR (100 MHz, CDCl3) 164.6, 140.8, 134.6,
133.9, 129.1, 128.9, 127.3, 125.7, 119.2, 116.5, 112.3, 65.6,
35.3; CSP-HPLC (Chiralcel OD column; 20% isopropanol in
n-hexane; 0.5 mL/min): 99:1 er, tR (S-enantiomer) = 14.9 min;
tR (R-enantiomer) = 18.4 min.
Conclusion
We have described the condition-based divergence in asym-
metric synthesis of two regioisomeric 1,4-benzoxazinones
from the substitution of highly diastereoenriched α-aryl-
α-bromoacetates with N-alkyl-2-aminophenols. If no base is
employed in CHCl3, the nucleophilic substitution at α-bromo
carbon with the amine nucleophile and spontaneous lacto-
nization affords 3-aryl-1,4-benzoxazin-2-ones 2a-j with up to
99:1 er. If t-BuO−Na+ is used as a base in DMF, reg-
ioisomeric 2-aryl-1,4-benzoxazin-3-ones 3a-e are produced
with ers up to 93:7 by the substitution with phenoxide and
following spontaneous lactamization. In addition, AgOTf-
promoted reactions with N-Boc-2-aminophenol afforded
highly substituted aromatic compounds by Friedel–Crafts
alkylation. While the er values of 3a-f are not high compared
to 2a-j, the results are worth noting as it is the first example
of asymmetric synthesis of N-alkyl substituted 2-aryl-1,-
4-benzoxazin-3-ones. The condition-based skeletal divergence
in substitutions of α-aryl-α-bromoacetate with 2-aminophenol
should facilitate the asymmetric synthesis of highly
functionalized 1,4-benzoxazinones that could be used
for further transformations.
4-Allyl-2-oxo-3-phenyl-3,4-dihydro-2H-1,4-benzoxazine
(2b). A yellow oil, 94% yield from 1a; Known compound,
1
ref. 2g; H NMR (400 MHz, CDCl3) 7.19–6.82 (m, 9H),
5.86–5.76 (m, 1H), 5.27–5.20 (m, 3H), 4.11–4.06 (m, 1H),
3.64–3.58 (m, 1H); 13C NMR (100 MHz, CDCl3) 164.7,
141.0, 135.1, 133.1, 132.4, 129.0, 128.8, 127.3, 125.5,
119.5, 119.1, 116.8, 113.2, 62.8, 50.7; CSP-HPLC
(Chiralcel OJ-H column; 10% isopropanol in n-hexane;
0.5 mL/min): 97:3 er, tR (S-enantiomer) = 34.5 min; tR (R-
enantiomer) = 24.6 min.
2-Oxo-3-phenyl-4-n-propyl-3,4-dihydro-2H-
1,4-benzoxazine (2c). A colorless oil, 88% yield from 1a;
1
Known compound, ref. 2g; H NMR (400 MHz, CDCl3)
7.28–6.78 (m, 9H), 5.19 (s, 1H), 3.46–3.43 (m, 1H),
3.03–2.99 (m, 1H), 1.69–1.61 (m, 2H), 0.96–0.91 (m, 3H);
13C NMR (100 MHz, CDCl3) 164.5, 140.8, 135.5, 133.1,
129.0, 128.7, 127.0, 125.6, 118.9, 116.8, 112.6, 63.6, 50.4,
20.2, 11.4; CSP-HPLC (Chiralcel OD column; 20% iso-
propanol in n-hexane; 0.5 mL/min): 99:1 er, tR (S-
enantiomer) = 10.3 min; tR (R-enantiomer) = 13.1 min.
2-Oxo-3-phenyl-4-n-pentyl-3,4-dihydro-2H-
Experimental Section
1,4-benzoxazine (2d). A colorless oil, 78% yield from 1a;
1H NMR (400 MHz, CDCl3) 7.27–6.78 (m, 9H), 5.19 (s,
1H), 3.50–3.43 (m, 1H), 3.05–2.97 (m, 1H), 1.66–1.59 (m,
2H), 1.32–1.28 (m, 4H), 0.90–0.86 (m, 3H); 13C NMR
(100 MHz, CDCl3) 164.5, 140.8, 135.5, 133.1, 129.0,
128.7, 127.0, 125.6, 118.9, 116.8, 112.5, 63.6, 48.6, 29.2,
26.6, 22.5, 14.1; CSP-HPLC (Chiralcel OD column; 10%
isopropanol in n-hexane; 0.5 mL/min): 97:3 er, tR (S-
enantiomer) = 10.8 min; tR (R-enantiomer) = 13.2 min;
HRMS: calcd. for C19H22NO2 [M++1] 296.1651; found
296.1649.
General. All reactions were carried out under an atmosphere
of nitrogen and those not involving aqueous reagents were
carried out in oven-dried glassware. Solvents were purified
and dried using standard methods. Unless otherwise stated, all
compounds were purchased from commercial sources and
were used without further purification. 1H and 13C NMR spec-
troscopy were performed on Bruker spectrometer (400 MHz
1H, 100.6 MHz 13C) using CDCl3 as the internal standard.
The HRMS spectroscopic data were obtained using a JEOL
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Asymmetric Synthesis of Two Regioisomeric 1,4-Benzoxazinones
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4-Benzyl-2-oxo-3-phenyl-3,4-dihydro-2H-
7.47–6.75 (m, 8H), 5.01 (s, 1H), 2.84 (s, 3H); 13C NMR
(100 MHz, CDCl3) 164.0, 140.7, 133.5, 132.3, 128.9, 125.9,
123.2, 119.5, 116.6, 112.4, 65.0, 35.4; CSP-HPLC (Chiralcel
OJ-H column; 20% isopropanol in n-hexane; 0.5 mL/min): 99:1
er, tR (S-enantiomer) = 39.3 min; tR (R-enantiomer) = 27.7 min.
General Procedure for the Asymmetric Preparation of
1,4-benzoxazine (2e). A pale yellow, 63% yield from 1a;
1
Known compound, ref. 2g; H NMR (400 MHz, CDCl3)
7.35–6.82 (m, 14H), 5.10 (s, 1H), 4.66 (d, J = 15.2 Hz,
1H), 4.10 (d, J = 15.2 Hz, 1H); 13C NMR (100 MHz,
CDCl3) 164.7, 141.1, 135.7, 134.7, 133.3, 129.1, 129.0,
128.9, 128.0, 127.8, 127.3, 125.6, 119.7, 116.8, 113.4, 62.7,
51.7; CSP-HPLC (Chiralcel OD column; 20% isopropanol in
n-hexane; 0.5 mL/min): 96:4 er, tR (S-enantiomer) = 14.3 min;
tR (R-enantiomer) = 17.5 min.
4-Allyl-6-methyl-2-oxo-3-phenyl-3,4-dihydro-2H-
1,4-benzoxazine (2f). A yellow oil, 83% yield from 1a;
1H NMR (400 MHz, CDCl3) 7.27–7.18 (m, 5H), 6.92–6.90
(m, 1H), 6.64–6.62 (m, 2H), 5.84–5.76 (m, 1H), 5.26–5.21
(m, 2H), 5.17 (s, 1H), 4.10–4.05 (m, 1H), 3.60–3.54 (m,
1H), 2.31 (s, 3H); 13C NMR (100 MHz, CDCl3) 164.8,
139.1, 135.3, 135.1, 132.7, 132.5, 129.0, 128.8, 127.4,
120.0, 119.0, 116.4, 113.8, 62.7, 50.6, 21.5; CSP-HPLC
(Chiralcel OJ-H column; 10% isopropanol in n-hexane;
0.5 mL/min): 98:2 er, tR (S-enantiomer) = 30.4 min; tR (R-
enantiomer) = 24.4 min; HRMS: calcd. for C18H18NO2
[M++1] 280.1338; found 280.1339.
4-Benzyl-7-methyl-2-oxo-3-phenyl-3,4-dihydro-2H-
1,4-benzoxazine (2g). A colorless oil, 67% yield from 1a;
Known compound, ref. 2g; 1H NMR (400 MHz, CDCl3)
7.23–6.60 (m, 13H), 4.97 (s, 1H), 4.50 (d, J = 14.8 Hz, 1H),
3.97 (d, J = 14.8 Hz, 1H), 2.17 (s, 3H); 13C NMR (100 MHz,
CDCl3) 165.0, 141.2, 136.0, 134.8, 130.9, 129.8, 129.0, 128.9,
128.8, 127.9, 127.8, 127.4, 126.0, 117.3, 113.5, 62.9, 52.1,
20.5; CSP-HPLC (Chiralcel OD column; 20% isopropanol in
n-hexane; 0.5 mL/min): 96:4 er, tR (S-enantiomer) = 14.3 min;
tR (R-enantiomer) = 17.5 min.
1,4-benzoxazine-3-ones (3a–e).
Sodium tert-butoxide
(t-BuO−Na+, 1.3 equiv) was added to a solution of N-alkyl-
2-aminophenol phenol (1.5 equiv) in DMF (ca. 0.1 M) at ambi-
ent temperature and the resulting reaction mixture was stirred at
45ꢀC for 10 min. To the above solution was added α-bromo-
α-phenylacetate (1a, 1.0 mmol) at ambient temperature. After
stiiring for 20 min. Under a nitrogen atmosphere, the mixture
was treated with extractive work up and the solvent was evapo-
rated. The crude mixture was purified by column chromatogra-
phy on silica gel to afford a 1,4-benzoxazin-3-one.
(S)-4-Methyl-3-oxo-2-phenyl-3,4-dihydro-2H-
1,4-benzoxazine (3a). A yellow oil, 55% yield from 1a;
Known compound, ref. 6; 1H NMR (400 MHz, CDCl3)
7.41–7.29 (m, 5H), 7.06–6.93 (m, 4H), 5.72 (s, 1H), 3.39
(s, 3H); 13C NMR (100 MHz, CDCl3) 164.7, 144.0, 135.4,
129.3, 128.7, 128.6, 126.9, 124.1, 122.7, 117.5, 114.8, 78.6,
28.5; CSP-HPLC (Chiralcel OJ-H column; 40% isopropanol in
n-hexane; 0.5 mL/min): 93:7 er, tR (S-enantiomer) = 55.5 min;
tR (R-enantiomer) = 48.0 min.
4-Allyl-3-oxo-2-phenyl-3,4-dihydro-2H-1,4-benzoxazine
(3b). A pale yellow oil, 53% yield from 1a; 1H NMR
(400 MHz, CDCl3) 7.49–7.23 (m, 5H), 7.11–6.92 (m, 4H),
5.93–5.83 (m, 1H), 5.76 (s, 1H), 5.21–5.12 (m, 2H),
4.76–4.70 (m, 1H), 4.47–4.42 (m, 1H); 13C NMR (100 MHz,
CDCl3) 164.4, 144.1, 135.2, 131.6, 128.7, 128.6, 128.5,
126.8, 124.1, 122.7, 117.7, 117.2, 115.4, 78.5, 44.1; CSP-
HPLC (Chiralcel OD column; 10% isopropanol in n-hexane;
0.5 mL/min): 90:10 er, tR (S-enantiomer) = 14.5 min; tR
(R-enantiomer) = 17.9 min; HRMS: calcd. for C17H16NO2
[M++1] 266.1181; found 266.1181.
7-Methyl-4-(m-methylbenzyl)-2-oxo-3-phenyl-
3,4-dihydro-2H-1,4-benzoxazine (2h). A colorless oil,
76% yield from 1a; 1H NMR (400 MHz, CDCl3)
7.28–6.64 (m, 12H), 5.05 (s, 1H), 4.64 (d, J = 14.4 Hz,
1H), 4.00 (d, J = 14.4 Hz, 1H), 2.33 (s, 3H), 2.29 (s, 3H);
13C NMR (100 MHz, CDCl3) 164.9, 139.1, 138.7, 135.7,
135.4, 134.8, 133.1, 129.0, 128.8, 128.7, 128.6, 127.3,
125.1, 120.1, 116.5, 113.7, 62.2, 51.4, 21.5; CSP-HPLC
(Chiralcel OD column; 20% isopropanol in n-hexane;
0.5 mL/min): 96:4 er, tR (S-enantiomer) = 13.3 min; tR (R-
enantiomer) = 15.8 min; HRMS: calcd. for C23H22NO2
[M++1] 344.1651; found 344.1649.
3-Oxo-2-phenyl-4-n-propyl-3,4-dihydro-2H-
1,4-benzoxazine (3c). A colorless oil, 72% yield from 1a;
1H NMR (400 MHz, CDCl3) 7.41–7.27 (m, 5H), 7.05–6.94
(m, 4H), 5.71 (s, 1H), 4.00–3.89 (m, 2H), 1.75–1.68 (m,
2H), 0.98 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
164.4, 144.2, 135.4, 128.6, 128.5, 128.3, 126.9, 123.9,
122.7, 117.8, 114.8, 78.4, 43.2, 20.5, 11.2; CSP-HPLC
(Chiralcel OJ-H column; 40% isopropanol in n-hexane;
0.5 mL/min): 87:13 er, tR (S-enantiomer) = 39.0 min; tR (R-
enantiomer) = 55.0 min; HRMS: calcd. for C17H18NO2
[M++1] 268.1338; found 268.1337.
3-(p-Chlorophenyl)-4-methyl-2-oxo-3,4-dihydro-2H-
1,4-benzoxazine (2i). A pale yellow, 96% yield from 1b;
1
Known compound, ref. 2g; H NMR (400 MHz, CDCl3)
7.26–6.75 (m, 8H), 5.03 (s, 1H), 2.84 (s, 3H); 13C NMR
(100 MHz, CDCl3) 164.1, 140.7, 135.0, 133.5, 133.0,
129.3, 128.7, 125.9, 119.5, 116.6, 112.4, 64.9, 35.4; CSP-
HPLC (Chiralcel OJ-H column; 10% isopropanol in n-hex-
ane; 0.5 mL/min): 99:1 er, tR (S-enantiomer) = 58.2 min; tR
(R-enantiomer) = 36.8 min.
3-(p-Bromophenyl)-4-methyl-2-oxo-3,4-dihydro-2H-
1,4-benzoxazine (2j). A pale yellow, 89% yield from 1c;
Known compound, ref. 2g; 1H NMR (400 MHz, CDCl3)
3-Oxo-4-n-pentyl-2-phenyl-3,4-dihydro-2H-
1,4-benzoxazine (3d). A colorless oil, 43% yield from 1a;
1H NMR (400 MHz, CDCl3) 7.41–7.28 (m, 5H), 7.06–6.94
(m, 4H), 5.70 (s, 1H), 4.01–3.92 (m, 2H), 1.71–1.67 (m, 2H),
1.38–1.35 (m, 4H), 0.92–0.87 (m, 3H); 13C NMR (100 MHz,
CDCl3) 164.3, 144.2, 135.4, 128.6, 128.5, 128.3, 126.9,
123.9, 122.7, 117.8, 114.7, 78.4, 41.7, 29.0, 26.9, 22.4, 14.0;
CSP-HPLC (Chiralcel OJ-H column; 40% isopropanol in n-
hexane; 0.5 mL/min): 90:10 er, tR (S-enantiomer) = 17.7 min;
Bull. Korean Chem. Soc. 2020
© 2020 Korean Chemical Society, Seoul & Wiley-VCH GmbH
www.bkcs.wiley-vch.de
5

BULLETIN OF THE
Article
Asymmetric Synthesis of Two Regioisomeric 1,4-Benzoxazinones
KOREAN CHEMICAL SOCIETY
tR (R-enantiomer) = 20.1 min; HRMS: calcd. for C19H22NO2
[M+ + 1] 296.1651; found 296.1651.
Acknowledgments.
This work was supported by
Basic Science Research Program funded by the National
Research Foundation of Korea under Grant No. NRF-
2020R1F1A1049676.
4-Allyl-6-methyl-3-Oxo-2-phenyl-3,4-dihydro-2H-
1,4-benzoxazine (3e). A pale yellow oil, 68% yield from 1a;
1H NMR (400 MHz, CDCl3) 7.34–7.28 (m, 5H), 6.96–6.72 (m,
3H), 5.94–5.84 (m, 1H), 5.73 (s, 1H), 5,21–5.12 (m, 2H),
4.76–4.70 (m, 1H), 4.45–4.40 (m, 1H), 2.27 (s, 3H); 13C NMR
(100 MHz, CDCl3) 164.6, 141.8, 135.3, 132.3, 131.6, 128.6,
128.5, 128.2, 126.7, 124.5, 117.3, 117.1, 115.9, 78.4, 44.1,
21.1; CSP-HPLC (Chiralcel OD column; 10% isopropanol in n-
hexane; 0.5 mL/min): 90:10 er, tR (S-enantiomer) = 13.0 min; tR
(R-enantiomer) = 15.1 min; HRMS: calcd. for C18H18NO2
[M++1] 280.1338; found 280.1341.
Conflict of interest. The authors declare no conflict of
interest.
Supporting Information. Additional supporting informa-
tion is available in the online version of this article. The
NMR spectra of new compounds 2d, 2f, 2h, 3b, 3c, 3d, 3e,
4a and 5 and the CSP-HPLC chromatograms.
6-Methyl-3-oxo-2-phenyl-3,4-dihydro-2H-
References
1,4-benzoxazine (3f). A colorless oil, 59% yield from 5;
1
Known compound, ref. 3b,7a; H NMR (400 MHz, CDCl3)
1. (a) F. A. Macías, D. Marín, A. Oliveros-Bastidasab, J. M. G.
Molinillo, Nat. Prod. Rep. 2009, 26, 478.(b) J. Ilaš, P. Š.
Anderluh, M. S. Dolenc, D. Kikelj, Tetrahedron 2005, 61,
7325. (c) D. A. Dudley, A. M. Bunker, L. Chi, W. L. Cody,
D. R. Holland, D. P. Ignasiak, N. Janiczek-Dolphin, T. B.
McClanahan, T. E. Mertz, L. S. Narasimhan, S. T. Rapundalo,
J. A. Trautschold, C. A. Van Huis, J. J. Edmunds, J. Med.
Chem. 2000, 43, 4063. (d) A. N. Matralis, M. G. Katselou, A.
Nikitakis, A. P. Kourounakis, J. Med. Chem. 2011, 54, 5583.
2. For asymmetric synthesis of 1,4-benzoxazin-2-ones, see (a) J. L.
Núñez-Rico, A. Vidal-Ferran, Org. Lett 2013, 15, 2066. (b) Q.-A.
Chen, K. Gao, Y. Duan, Z.-S. Ye, L. Shi, Y. Yang, Y. G. Zhou,
J. Am. Chem. Soc. 2012, 134, 2442. (c) Z.-Y. Xue, Y. Jiang, X.-Z.
Peng, W.-C. Yuan, X.-M. Zhang, Adv. Synth. Catal. 2010, 352,
2132. (d) A. V. Malkov, K. Vranková, S. Stoncˇius, P. Kocˇovský,
J. Org. Chem. 2009, 74, 5839. (e) X. Zhang, B. Xu, M.-H. Xu,
Org. Chem. Front. 2016, 3, 944. (f) C. Huo, J. Dong, Y. Su, J.
Tang, F. Chen, Chem. Comm. 2016, 52, 13341. (g) L. Zhao, J. Wei,
J. Lu, C. He, C. Duan, Angew. Chem. Int. Ed. 2017, 56, 8692. (h)
E. Youk, W. Park, Y. S. Park, Synth. Commun. 2018, 48, 1131.
3. For asymmetric synthesis of 2,2-disubstituted 1,4-benzoxazin-
3-ones, see (a) M. Breznik, V. Hrast, A. Mrcina, D. Kikelj, Tet-
rahedron 1999, 10, 153. (b) M. Pawliczek, Y. Shimazaki, H.
Kimura, K. M. Oberg, S. Zakpur, T. Hashimoto, K. Maruoka,
Chem. Commun. 2018, 54, 7078.
4. (a) K. J. Park, Y. Kim, M. Lee, Y. S. Park, Eur. J. Org. Chem.
2014, 2014, 1645. (b) Y. S. Choi, S. Park, Y. S. Park, Eur.
J. Org. Chem. 2016, 2016, 2539. (c) Y. Kim, Y. S. Choi, S. K.
Hong, Y. S. Park, Org. Biomol. Chem. 2019, 17, 4554. (d) W.
Park, Y. Kim, Y. S. Park, Eur. J. Org. Chem. 2019, 2019, 2671.
5. In references 4, it has been established that (αS)-products were
provided in the substitution of (αR)-1a-c with various nucleo-
philes via SN2 (like) mechanism. The absolute configuration of
2a, 2b, 2c, 2e, 2g, 2i, 2j and 3a is confirmed to be (S) by com-
parison of CSP-HPLC retention time with previously reported
data (refs. 2h and 6). The absolute configuration of 2d, 2f, 2h
and 3b-f is assigned by analogy.
7.47–7.33 (m, 5H), 6.91–6.65 (m, 3H), 5.68 (s, 1H), 2.24
(s, 3H); 13C NMR (100 MHz, CDCl3) 166.9, 140.5, 135.1,
132.5, 129.0, 128.8, 127.1, 125.5, 125.0, 117.0, 116.6,
78.4, 20.8; CSP-HPLC (Chiralcel OJ-H column; 40%
isopropanol in n-hexane; 0.5 mL/min): 93:7 er, tR
(S-enantiomer) = 19.8 min; tR (R-enantiomer) = 17.3 min.
General Procedure for the Preparation of 4a and 5. To
a solution of α-bromo-α-phenylacetate 1a of 99:1 dr (1.0
equiv) at ambient temperature were added N-Boc-
2-aminophenol (10 equiv) and AgOTf (1.0 equiv). After
the reaction mixture was stirred for 3 h, the resulting mix-
ture was treated with extractive work up and the solvent
was evaporated. The crude mixture was purified by column
chromatography on silica gel to afford the product.
N-Benzoyl-O-[α-(N-Boc-3-amino-4-hydroxyphenyl)
phenylacetyl]-L-threonine Isopropyl Ester (4a). A yellow
1
oil, 99:1 dr, 80% yield from 1a; H NMR (400 MHz, CDCl3)
7.53–7.34 (m, 10H), 7.09–7.07 (m, 1H), 7.01–6.97 (m, 2H),
6.74–6.70 (m, 1H), 6.49–6.47 (m, 1H), 5.52–5.47 (m, 1H),
5.09–4.93 (m, 4H), 1.52 (s, 9H), 1.23 (d, J = 6.0 Hz, 3H), 1.11 (d,
J = 6.4 Hz, 3H), 1.04 (d, J = 6.4 Hz, 3H); 13C NMR (100 MHz,
CDCl3) 170.4, 169.0, 168.1, 151.6, 138.4, 138.0, 136.9, 133.7,
132.0, 129.1, 128.5, 127.4, 127.2, 121.9, 118.0, 112.7, 84.2, 73.1,
70.0, 60.8, 55.7, 27.6, 21.8, 21.5, 16.3; HRMS: calcd. for
C33H39N2O8 [M++1] 591.2706; found 591.2705.
N-Benzoyl-O-[α-(N-Boc-2-amino-4-methylphenoxy)
phenylacetyl]-L-threonine Isopropyl Ester (5). A yellow
1
oil, 20% yield from 1a; H NMR (400 MHz, CDCl3) 7.94
(br, 1H), 7.72–7.70 (m, 2H), 7.55–7.20 (m, 8H), 6.86–6.82
(m, 1H), 6.67–6.57 (m, 2H), 5.57 (s, 1H), 5.54–5.48 (m,
1H), 5.00–4.86 (m, 2H), 2.24 (s, 3H), 1.50 (s, 9H), 1.22 (d,
J = 6.0 Hz, 3H), 1.18 (d, J = 6.4 Hz, 3H), 0.97 (d,
J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) 169.0,
168.9, 167.8, 152.9, 143.6, 134.9, 133.5, 132.5, 132.1,
129.4, 129.0, 128.7, 128.6, 128.5, 127.2, 127.1, 127.0,
122.8, 119.7, 113.0, 80.5, 79.9, 72.8, 70.2, 55.8, 28.3,
21.8, 21.3, 21.1, 16.6; HRMS: calcd. For C34H41N2O8
[M++1] 605.2863; found 605.2866.
6. K. E. O. Ylijoki, E. P. Kündig, Chem. Commun. 2011, 47, 10608.
7. (a) J. W. Park, S. Jang, M. H. Choo, D. Y. Kim, Bull. Korean.
Chem.Soc. 2020, 41, 570. (b) M. Pawliczek, Y. Shimazaki, H.
Kimura, K. M. Oberg, S. Zakpur, T. Hashimoto, K. Maruoka,
Chem. Comm. 2018, 54, 7078.
Bull. Korean Chem. Soc. 2020
© 2020 Korean Chemical Society, Seoul & Wiley-VCH GmbH
www.bkcs.wiley-vch.de
6