Transition-Metal-Free Alkylation and Acylation of Benzoxazinones with 1,4-Dihydropyridines

Article abstract of DOI:10.1021/acs.joc.1c01558

The direct functionalization of N-heterocycles is a vital transformation for the development of pharmaceuticals, functional materials, and other chemical entities. Herein, the transition-metal-free alkylation and acylation of C(sp2)-H bonds in biologically relevant 2-benzoxazinones with 1,4-dihydropyridines as readily accessible radical surrogates is described. Excellent functional group compatibility and a broad substrate scope were attained. Gram-scale reaction and transformations of the synthesized adducts via Suzuki coupling with heteroaryl boronic acids demonstrated the synthetic potential of the developed protocol.

Full text of DOI:10.1021/acs.joc.1c01558

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Article
Transition-Metal-Free Alkylation and Acylation of Benzoxazinones
with 1,4-Dihydropyridines
Youjung Byun,‡ Junghyea Moon,‡ Won An, Neeraj Kumar Mishra, Hyung Sik Kim, Prithwish Ghosh,*
and In Su Kim*
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ABSTRACT: The direct functionalization of N-heterocycles is a
vital transformation for the development of pharmaceuticals,
functional materials, and other chemical entities. Herein, the
transition-metal-free alkylation and acylation of C(sp2)−H bonds
in biologically relevant 2-benzoxazinones with 1,4-dihydropyr-
idines as readily accessible radical surrogates is described. Excellent
functional group compatibility and a broad substrate scope were
attained. Gram-scale reaction and transformations of the
synthesized adducts via Suzuki coupling with heteroaryl boronic acids demonstrated the synthetic potential of the developed
protocol.
and investigations of C−H functionalization have been limited
to arylation, amidation, phosphonation, and silylation (Scheme
1).8 Regarding C−H alkylation, few examples for the
photocatalyzed difluoromethylation9 and cyanoalkylation10 of
2-benzoxazinones have been demonstrated. In addition, one
example of the transition-metal-free decarboxylative fluoroal-
kylation of 2-benzoxazinone has been described.11 Further-
more, a methylated benzoxazinone has been prepared by
Minisci-type C−H methylation in the presence of MeSO2Na
and PhI(CO2Me)2 as an oxidant.12 Moreover, the transition-
metal-free C−H trifluoromethylation of 2-benzoxazinone with
CF3SO2Na was also reported.13
Aldehydes are attractive alkyl radical surrogates that operate
through oxidative hydrogen-atom transfer and subsequent
deformylation reactions.14 However, the deformylation process
is usually slow, which can result in mixtures of alkylated and
acylated adducts, leading to regioselectvity and chemo-
selectivity issues under harsh reaction conditions. To overcome
these intrinsic drawbacks, 1,4-dihydropyridines have been
employed as aldehyde surrogates.15 Generally, 1,4-dihydropyr-
idines, known as Hantzsch esters, are bench-stable species that
can be easily prepared from aldehydes. On the basis of these
advantages, a number of radical-mediated synthetic trans-
formations using 1,4-dihydropyridines have been reported.16
For example, Molander and co-workers revealed the role of
INTRODUCTION
■
As an important class of C−C bond formation reactions, the
direct alkylation and acylation of C−H bonds in heterocyclic
molecules can facilitate the rapid generation of structural
diversity.1 Moreover, the selective alkylation of complex N-
heterocycles is of interest because of the biological significance
of such structures and their extensive utility as synthetic
building blocks.2 To address the challenge of incorporating
alkyl groups into N-heterocycles, a number of synthetic
approaches have been reported. In particular, Minisci-type
reactions have been established as the conventional method,3
with alternative routes including transition-metal-catalyzed C−
H alkylations.4 In complementary protocols, transition-metal-
free C−H alkylations have been realized using preactivated N-
heterocycles.5
The 2-benzoxazine scaffold is among the interesting
discoveries in the field of natural products and pharmaceut-
icals.6 In particular, 2-benzoxazinone derivatives have attracted
considerable attention owing to their interesting biological
activities (Figure 1).7 Considerable advances have been made
in the C−H functionalization of various N-heterocycles;
however, for 2-benzoxazinones, acylation remains unexplored
Received: July 2, 2021
Figure 1. Selected Bioactive 2-Benzoxazinones.
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© XXXX American Chemical Society
A

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a
Scheme 1. C−H Functionalzation of 2-Benzoxazinones
Table 1. Optimization of Reaction Conditions
b
entry
2a (equiv)
oxidant (equiv)
solvent
yield (%)
1
2
3
4
5
6
7
8
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.5
1.5
1.5
Na2S2O8 (1.2)
Na2S2O8 (1.2)
Na2S2O8 (1.2)
Na2S2O8 (1.2)
Na2S2O8 (1.2)
Na2S2O8 (1.2)
Na2S2O8 (1.2)
K2S2O8 (1.2)
(NH4)2S2O8 (1.2)
Oxone (1.2)
THF
40
60
NR
42
NR
NR
NR
25
55
40
NR
82
81
MeCN
MeOH
TFE
EtOAc
DMF
DMSO
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
9
10
11
12
13
14
TBHP (1.2)
Na2S2O8 (1.2)
Na2S2O8 (1.2)
Na2S2O8 (1.2)
c
d
24
a
Reaction conditions: 1a (0.2 mmol), 2a (quantity noted), oxidant
(quantity noted), solvent (2 mL) at 50 °C for 7 h under N2
b
atmosphere in pressure tubes. Isolated yield by flash column
c
d
chromatography. The reaction was carried out at 80 °C for 3 h. The
reaction was carried out at room temperature for 18 h. TFE = 2,2,2-
trifluoroethanol.
1,4-dihydropyridines as alkyl radical precursors in coupling
reactions with (hetero)aryl halides under Ni/photoredox dual
catalysis.17 Subsequently, the oxidative C−H alkylation of N-
heterocycles and 1,4-quinones with 1,4-dihydropyridines was
described under transition-metal-free conditions.18 Owing to
the broad relevance of 2-benzoxazinones, we herein describe
the transition metal-free and site-selective C−H alkylation and
acylation of 2-benzoxazinones with 1,4-dihydropyridines.
Notably, the mild reaction conditions and excellent functional
group tolerance highlight the applicability of the developed
methodology to highly functionalized 2-benzoxazinone de-
rivatives.
position resulted in decreased reactivity under the optimized
reaction conditions. To our pleasure, the yields of 3c−3e were
improved at an elevated temperature (80 °C) for 3 h.
Increased reactivity was also observed for C8-substituted and
C6,C8-disubstituted 2-benzoxazinones 1f and 1g, furnishing 3f
(65%) and 3g (68%), respectively. This transformation was
also found to tolerate C5-substituted benzoxazinone 1h,
providing 3h in a high yield (75%). In addition, a variety of
C6-aryl-substituted 2-benzoxazinones were evaluated under
the standard reaction conditions. C6-Aryl-substituted 2-
benzoxazinones 1i−1o, derived from Suzuki cross-coupling
reactions of 1e with corresponding aryl boronic acids, were
found to be viable substrates in this transformation, giving 3i−
3o in moderate to good yields. It is noteworthy that various
functional groups, such as CN (1i), CO2Et (1k), OH (1n),
and OTBS (1o), were found to be tolerable in this
transformation. Furthermore, benzyl halide, epoxide, and
sulfonamide groups were also compatible to provide the
corresponding adducts 3p−3r.
With the successful results of 2-benzoxazinones, the reaction
of 1,4-dihydropyridines 2b−2k with 1a was also investigated,
as shown in Scheme 3. The branched alkyl groups in 2b−2e
readily participated in the C−H alkylation reaction to generate
corresponding products 4b−4e in good to high yields. It
should be noted that the olefin functionality in 4e was
compatible with this coupling reaction. It is noted that 4-
benzyl- and 4-(p-MeO)benzyl-1,4-dihydropyridines were un-
reactive under the current reaction conditions (data not
shown). Furthermore, the site-selective acylation reaction of 2-
benzoxazinones with 1,4-dihydropyridines was also inves-
tigated. Gratifyingly, the coupling of benzoyl and heteroaroyl
dihydropyridines 2f and 2g with 1a proceeded to give C3-
acylated 2-benzoxazinones 4f and 4g. Acylation was also
achieved using aroyl and naphthoyl substrates 2h−2j, albeit in
RESULTS AND DISCUSSION
■
The reaction conditions were optimized using the reaction of
2H-benzo[b][1,4]oxazin-2-one (1a) and 1,4-dihydropyridine
2a with Na2S2O8 as a commercially available oxidant (Table
1). To our delight, C3-isopropylated product 3a was isolated in
40% yield (Table 1, entry 1). Solvent screening revealed
MeCN to be most effective for this transformation, affording
3a in 60% yield (Table 1, entries 2−7). However, oxidants
commonly used in radical-mediated cross-coupling reactions,
such as K2S2O8, (NH4)2S2O8, Oxone, and TBHP, were less
reactive (Table 1, entries 8−11). The best result was obtained
by using an increased amount (1.5 equiv) of 2a, which
furnished 3a in 82% yield (Table 1, entry 12). A higher
temperature (80 °C) for 3 h gave 3a in a comparable isolated
yield of 81% (Table 1, entry 13). However, the reactivity of 1a
was significantly decreased at room temperature for 18 h, with
3a isolated in 24% yield (Table 1, entry 14).
Under the optimized reaction conditions, the scope of the
reaction was evaluated using various 2-benzoxazinones 1a−1r
withC4-isopropylated 1,4-dihydropyridine 2a, as shown in
Scheme 2.
The reaction of C6-OMe-substituted 2-benzoxazinone 1b
with 2a proceeded smoothly to afford the desired product 3b
t
in 75% yield. However, Bu, Ph, and Br substituents at the C6
B
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a
a
Scheme 2. Scope of 2-Benzoxazinones
Scheme 3. Scope of 1,4-Dihydropyridines
a
Reaction conditions: 1a (0.2 mmol), 2b−2k (0.3 mmol, 1.5 equiv),
Na2S2O8 (0.24 mmol, 1.2 equiv), and MeCN (2 mL) at 50 °C for 7 h
b
under N2 atmosphere in pressure tubes. Isolated yield by flash
c
column chromatography. The reaction was carried out at 80 °C for 3
h.
a
Scheme 4. Heteroarylation of Product 3e
a
Reaction conditions: 1a−1r (0.2 mmol), 2a (0.3 mmol, 1.5 equiv),
Na2S2O8 (0.24 mmol, 1.2 equiv), MeCN (2 mL) at 50 °C for 7 h
b
under N2 atmosphere in pressure tubes. Isolated yield by flash
column chromatography. The reaction was carried out at 80 °C for 3
h.
c
a
Reaction conditions: 3e (0.2 mmol), 5a−5c (0.24 mmol, 1.2 equiv),
Pd(OAc)2 (10 mol %), P(o-tol)3 (20 mol %), Na2CO3 (0.4 mmol, 2
equiv), CuCl (0.2 mmol, 1 equiv), and 1,4-dioxane (2 mL) at 120 °C
for 14 h under air in pressure tubes. Yields were not optimized and
b
were isolated by flash column chromatography.
relatively lower yields. However, alkyl acyl 1,4-dihydropyridine
2k was unsuccessful in this reaction.
Scheme 5. Gram-Scale Experiments
To illustrate the synthetic utility of the synthesized 2-
benzoxazinone adducts, Suzuki coupling reactions of 3e with
aryl boronate 5a or aryl boronic acids 5b and 5c were
performed, as shown in Scheme 4. The Pd(II)-catalyzed
heteroarylation between 3e and 1-methylpyrazole-4-boronic
acid pinacol ester (5a) afforded 6a in 43% yield. In addition,
thiophene- and pyridine-incorporated 2-benzoxazinone prod-
ucts 6b and 6c were obtained using boronic acids 5b and 5c,
respectively.
Furthermore, gram-scale experiments were performed, as
shown in Scheme 5. The reaction of 1a (1 g, 6.8 mmol) with
2a was successfully scaled up, affording 1.03 g of 3a in 80%
yield. In addition, the gram-scale reaction of 1a with 2f
furnished the C3-benzolated product 4f in 73% yield.
C
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nones 1a−1h were prepared according to the reported procedur-
es.8a,19 General procedures for the synthesis of 1i−1r are given as
below. 4-Alkyl-1,4-dihydropyridines 2a−2e and 4-acyl-1,4-dihydro-
pyridines 2f−2k were prepared according to the reported
procedures.16d,20 Sealed tubes (13 × 100 mm2) were purchased
from Fischer Scientific, dried in an oven overnight, and cooled at
room temperature prior to use. Thin-layer chromatography was
carried out using plates coated with Kieselgel 60F254 (Merck). For
flash column chromatography, E. Merck Kieselgel 60 (230−400
mesh) was used. Nuclear magnetic resonance spectra (1H and 13C
NMR) were recorded on JEOL 500, Varian 500, and Bruker 400 and
700 spectrometers in CDCl3 solution, and chemical shifts are reported
as parts per million (ppm). Resonance patterns are reported with the
notations s (singlet), d (doublet), t (triplet), q (quartet), sext (sextet),
sept (septet), and m (multiplet). In addition, the notation br is used
to indicate a broad signal. Coupling constants (J) are reported in hertz
(Hz). IR spectra were recorded on a Varian 2000 Infrared
spectrophotometer and are reported as cm−1. High-resolution mass
spectra (HRMS) were recorded on a JEOL JMS-600 spectrometer.
General Procedure and Characterization Data for the
Synthesis of 6-Aryl-2-benzoxazinones (1i−1o). To an oven-
dried sealed tube charged with 6-bromo-2-benzoxazinone (1e) (452.1
mg, 2.0 mmol, 1.0 equiv), Pd(OAc)2 (22.5 mg, 0.1 mmol, 0.05 equiv),
P(o-tol)3 (60.9 mg, 0.2 mmol, 0.1 equiv), 4-methoxybenzeneboronic
acid (364.7 mg, 2.4 mmol, 1.2 equiv), and Na2CO3 (424.0 mg, 4.0
mmol, 2.0 equiv) was added degassed 1,4-dioxane (10 mL). The
reaction mixture was allowed to stir in oil bath at 100 °C for 16 h in
Ar atmosphere. The reaction mixture was cooled to room temperature
and filtered through Celite pad. The filtrate was concentrated under
reduced pressure. The residue was purified by column chromatog-
raphy (n-hexane/EtOAc = 10:1) to afford 380 mg of 1m in 75% yield.
3-(2-Oxo-2H-benzo[b][1,4]oxazin-6-yl)benzonitrile (1i): 377.2 mg
(76%); column eluent (n-hexanes/EtOAc = 1:1); orange solid; mp =
To support the mechanistic pathway for this reaction, the
alkylation reaction of 1a and 2d was performed in the presence
of the radical scavenger TEMPO (Scheme 6). The NMR
Scheme 6. Mechanistic Investigations
analysis revealed the formation of 7a instead of C3-alkylated 2-
benzoxazinone 4d, indicating that a radical pathway is involved
in this process. The radical pathway was further supported by
the reaction of 2d with TEMPO in the absence of 1a, which
provided 7a and pyridine byproduct 8a.
Based on the experimental data and literature precedent,15,17
a plausible reaction mechanism is proposed, as outlined in
Scheme 7. Both alkyl radical species A and pyridine 8a are
Scheme 7. Plausible Reaction Mechanism
1
220.5−222.2 °C; H NMR (400 MHz, DMSO-d6) δ 8.30 (t, J = 1.6
Hz, 1H), 8.24 (s, 1H), 8.20 (d, J = 2.0 Hz, 1H), 8.14 (ddd, J = 7.9,
2.1, 1.1 Hz, 1H), 8.02 (dd, J = 8.4, 2.0 Hz, 1H), 7.87 (d, J = 7.6 Hz,
1H), 7.70 (t, J = 7.6 Hz, 1H), 7.55 (d, J = 8.8 Hz, 1H); 13C{1H}
NMR (100 MHz, DMSO-d6) δ 152.1, 148.5, 146.2, 139.4, 135.2,
131.6, 131.5, 131.3, 130.5, 130.3, 130.1, 127.1, 118.7, 117.3, 112.2; IR
(KBr) υ 2229 (CN), 1743 (CO), 1608 (CN), 1236 (C−O)
cm−1; HRMS (quadrupole, EI) m/z [M]+ Calcd for C15H8N2O2
248.0586; Found 248.0584.
6-(3-Fluorophenyl)-2H-benzo[b][1,4]oxazin-2-one (1j): 144.7 mg
(30%); column eluent (n-hexanes/CH2Cl2 = 1:4); Orange solid; mp
= 118.3−120.8 °C; 1H NMR (700 MHz, CDCl3) δ 8.15 (s, 1H), 7.99
(d, J = 2.8 Hz, 1H), 7.75 (dd, J = 9.1, 2.8 Hz, 1H), 7.46−7.43 (m,
1H), 7.40−7.38 (m, 2H), 7.31−7.29 (m, 1H), 7.11−7.09 (m, 1H);
13C{1H} NMR (175 MHz, CDCl3) δ 163.4 (d, JC−F = 245.0 Hz),
152.2, 147.1, 146.0, 141.2 (d, JC−F = 8.8 Hz), 137.9 (d, JC−F = 3.5
generated from 1,4-dihydropyridine 2a by the homolytic
cleavage of Na2S2O8. Radical addition to 1a provides
intermediate B, which is subsequently oxidized to give nitrogen
cation intermediate C. Finally, desired product 3a is generated
by the elimination of a proton from C.
Hz), 131.5, 130.8, 130.7 (d, JC−F = 8.8 Hz), 128.0, 122.8 (d, JC−F
=
3.5 Hz), 117.42, 115.1 (d, JC−F = 22 Hz), 114.2 (d, JC−F = 22 Hz); IR
(KBr) υ 1747 (CO), 1620 (CN), 1242 (C−O) cm−1; HRMS
(quadrupole, EI) m/z [M]+ Calcd for C14H8FNO2 241.0539; Found
241.0535.
CONCLUSION
■
Ethyl 3-(2-oxo-2H-benzo[b][1,4]oxazin-6-yl)benzoate (1k): 354.4
In conclusion, we have described the transition-metal-free
alkylation and acylation of 2-benzoxazinones with 1,4-
dihydropyridines as radical surrogates. From a mechanistic
perspective, the alkyl radical species generated from 1,4-
dihydropyridines in the presence of Na2S2O8 underwent site-
selective alkylation reactions. A wide substrate scope and broad
functional group tolerance were observed for this reaction.
Furthermore, gram-scale reactions and heteroarylation of the
synthesized adducts demonstrated the synthetic utility of the
developed method.
mg (60%); column eluent (CH2Cl2/EtOAc = 1:1); brown solid; mp =
1
94.5−96.0 °C; H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 1.6 Hz,
1H), 8.17 (s, 1H), 8.10−8.07 (m, 1H), 8.06 (d, J = 2.4 Hz, 1H),
7.83−7.79 (m, 2H), 7.57 (d, J = 7.6 Hz, 1H), 7.41 (d, J = 8.4 Hz,
1H), 4.43 (q, J = 7.2 Hz, 2H), 1.43 (t, J = 7.2 Hz, 3H); 13C{1H}
NMR (100 MHz, CDCl3) δ 166.4, 147.0, 146.0, 139.8, 138.3, 131.6,
131.5, 131.4, 131.0, 129.4, 129.2, 128.8, 128.3, 128.1, 117.5, 61.4,
14.5; IR (KBr) υ 1747 (CO), 1612 (CN), 1242 (C−O) cm−1;
HRMS (quadrupole, EI) m/z [M]+ Calcd for C17H13NO4 295.0845;
Found 295.0841.
6-(Naphthalen-2-yl)-2H-benzo[b][1,4]oxazin-2-one (1l): 295.2
mg (54%); column eluent (n-hexanes/EtOAc = 10:1); yellow solid;
mp = 205.0−207.0 °C; 1H NMR (500 MHz, CDCl3) δ 8.17 (s, 1H),
8.14 (d, J = 2.0 Hz, 1H), 8.07 (d, J = 1.5 Hz, 1H), 7.96 (d, J = 8.5 Hz,
1H), 7.93−7.88 (m, 3H), 7.75 (dd, J = 8.5, 2.0 Hz, 1H), 7.57−7.51
EXPERIMENTAL SECTION
General Information. Commercially available reagents were used
without additional purification, unless otherwise stated. Benzoxazi-
■
D
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(m, 2H), 7.43 (d, J = 8.5 Hz, 1H); 13C{1H} NMR (125 MHz,
CDCl3) δ 152.5, 146.9, 145.7, 139.3, 136.3, 133.8, 133.0, 131.6, 131.2,
129.1, 128.4, 128.2, 127.9, 126.9, 126.7, 126.2, 125.2, 117.4; IR (KBr)
υ 1743 (CO), 1613 (CN), 1267 (C−O) cm−1; HRMS
(quadrupole, EI) m/z [M]+ Calcd for C18H11NO2 273.0790; Found
273.0787.
6-(4-Methoxyphenyl)-2H-benzo[b][1,4]oxazin-2-one (1m): 380.0
mg (75%); column eluent (n-hexanes/EtOAc = 9:1); brown solid; mp
= 131.8−134.4 °C; 1H NMR (700 MHz, CDCl3) δ 8.14 (s, 1H), 7.96
(d, J = 2.8 Hz, 1H), 7.73 (dd, J = 8.4, 2.1 Hz, 1H), 7.56−7.54 (m,
2H), 7.36 (d, J = 8.4 Hz, 1H), 7.03−7.01 (m, 2H), 3.87 (s, 3H);
13C{1H} NMR (175 MHz, CDCl3) δ 159.9, 152.5, 146.8, 145.2,
139.0, 131.5, 131.4, 130.6, 128.3, 127.3, 117.2, 114.7, 55.6; IR (KBr)
υ 1747 (CO), 1608 (CN), 1242 (C−O) cm−1; HRMS
(quadrupole, EI) m/z [M]+ Calcd for C15H11NO3 253.0739; Found
253.0735.
concentrated under reduced pressure. The residue was triturated with
(n-pentane/Et2O = 49:1) to afford 1q in 79% yield. Analytical sample
was collected by preparative TLC.
4-(2-Oxo-2H-benzo[b][1,4]oxazin-6-yl)phenyl 4-(oxiran-2-
ylmethoxy)benzoate (1q): 98.4 mg (79%); preparative TLC (n-
hexane/EtOAc = 3:2, Rf = 0.6); pale brown solid; mp = 114.5−116.1
1
°C; H NMR (500 MHz, CDCl3) 8.18 (d, J = 9.0 Hz, 2H), 8.16 (s,
1H), 8.01 (d, J = 2.5 Hz, 1H), 7.77 (dd, J = 8.5, 2.5 Hz, 1H), 7.66 (d,
J = 8.5 Hz, 1H), 7.40 (d, J = 8.5 Hz, 1H), 7.33 (d, J = 8.5 Hz, 2H),
7.03 (d, J = 8.5 Hz, 2H), 4.36 (dd, J = 11.0, 3.0 Hz, 2H), 4.04 (dd, J =
11.0, 6.0 Hz, 2H), 3.43−3.39 (m, 1H), 2.96 (t, J = 4.5 Hz, 1H), 2.80
(dd, J = 5.0, 2.5 Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 164.9,
163.0, 151.2, 146.9, 145.7, 143.3, 138.6, 136.7, 132.6, 131.5, 130.9,
128.3, 127.9, 122.7, 122.3, 117.3, 114.7, 69.1, 50.0, 44.8; IR (KBr) υ
1730 (CO), 1728 (CO), 1603 (CN), 1257 (C−O), 1167
(C−O), 1068 (C−O) cm−1; HRMS (quadrupole, EI) m/z [M]+
Calcd for C24H17NO6 415.1056; Found 415.1053.
6-(4-Hydroxyphenyl)-2H-benzo[b][1,4]oxazin-2-one (1n): 120.2
mg (25%); column eluent (CH2Cl2/acetone = 49:1); yellow solid;
4-(2-Oxo-2H-benzo[b][1, 4]oxazin-6-yl)phenyl 4-
(phenylsulfonamido)benzoate (1r): 112.2 mg (75%); preparative
TLC (CH2Cl2/acetone = 97:3, Rf = 0.7); pale brown solid; mp =
1
mp = 207.0−208.7 °C; H NMR (400 MHz, CDCl3/MeOD) δ 7.98
(s, 1H), 7.79 (d, J = 2.0 Hz, 1H), 7.60 (dd, J = 8.4, 2.0 Hz, 1H), 7.33
(d, J = 8.4 Hz, 2H), 7.21 (d, J = 8.4 Hz, 1H), 6.78 (d, J = 8.4 Hz, 2H);
13C{1H} NMR (100 MHz, CDCl3/MeOD) δ 157.1, 152.7, 146.3,
1
216.7−218.0 °C; H NMR (500 MHz, CDCl3/MeOD) δ 7.97 (s,
1H), 7.88 (d, J = 8.5 Hz, 2H), 7.83 (d, J = 2.0 Hz, 2H), 7.70 (d, J =
2.0 Hz, 2H), 7.63 (dd, J = 8.5, 2.0 Hz, 1H), 7.49 (d, J = 8.5 Hz, 2H),
7.41−7.37 (m, 1H), 7.32 (t, J = 8.0 Hz, 2H), 7.24 (d, J = 8.5 Hz, 1H),
7.11 (d, J = 9.0 Hz, 2H), 7.09 (t, J = 9.0 Hz, 2H); 13C{1H} NMR
(125 MHz, DMSO-d6) δ 173.4, 161.6, 160.0, 157.7, 155.0, 152.9,
148.8, 146.1, 145.4, 142.7, 140.9, 140.7, 139.3, 138.9, 137.4, 136.2,
136.0, 132.7, 132.0, 127.7, 126.6; IR (KBr) υ 3243 (N−H), 1751
(CO), 1712 (CO), 1602 (CN), 1344 (S = O), 1278 (C−O),
1155 (S = O), 1079 (C−O) cm−1; HRMS (quadrupole, EI) m/z
[M]+ Calcd for C27H18N2O6S 498.0886; Found 498.0885.
144.7, 139.2, 131.1, 130.3, 130.1, 128.0, 126.6, 116.8, 115.8; IR (KBr)
υ 3625 (O−H), 3386 (O−H), 1747 (CO), 1604 (CN), 1083
(C−O) cm−1; HRMS (quadrupole, EI) m/z [M]+ Calcd for
C14H9NO3 239.0582; Found 239.0578.
6-(4-((tert-Butyldimethylsilyl)oxy)phenyl)-2H-benzo[b][1,4]-
oxazin-2-one (1o). 219.2 mg (31%); preparative TLC (n-hexanes/
1
EtOAc = 9:1, Rf = 0.7); pale brown solid; mp = 96.4−97.7 °C; H
NMR (700 MHz, CDCl3) δ 8.14 (s, 1H), 7.96 (d, J = 2.1 Hz, 1H),
7.73 (dd, J = 8.4, 2.1 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.36 (d, J =
8.4 Hz, 1H), 6.94 (d, J = 8.4 Hz, 2H), 1.01 (s, 9H), 0.24 (s, 6H);
13C{1H} NMR (175 MHz, CDCl3) δ 156.1, 152.6, 146.7, 145.2,
General Procedure and Characterization Data for the
Alkylation of 2-Benzoxazinones (3a−3m). To an oven-dried
sealed tube charged with 2H-benzo[b][1,4]oxazin-2-one (1a) (29.4
mg, 0.2 mmol, 1.0 equiv), Na2S2O8 (57.1 mg, 0.24 mmol, 1.2 equiv),
and 4-isopropyldihydropyridine (2a) (80.2 mg, 0.3 mmol, 1.5 equiv)
was added MeCN (2 mL). The air in the tube was displaced with N2
gas, and the reaction mixture was allowed to stir in an oil bath at 50
°C for 7 h under N2 atmosphere. The reaction mixture was cooled to
room temperature, diluted with H2O, and extracted with EtOAc. The
combined organic layer was dried over Na2SO4, filtered, and
concentrated under reduced pressure. The residue was purified by
column chromatography (n-hexane/EtOAc = 49:1) to afford 31.0 mg
of 3a in 82% yield.
139.1, 132.1, 131.5, 130.6, 128.3, 127.3, 120.8, 117.1, 25.8, 18.4, −4.2;
IR (KBr) υ 1757 (CO), 1604 (CN), 1263 (C−O) cm−1; HRMS
(quadrupole, EI) m/z [M]+ Calcd for C20H23NO3Si 353.1447; Found
353.1448.
General Procedure and Characterization Data for the
Synthesis of 1p. To an oven-dried sealed tube charged with 6-
methyl-2H-benzo[b][1,4]oxazin-2-one (322.3 mg, 2.0 mmol, 1.0
equiv), N-bromosuccinimide (391.8 mg, 2.2 mmol, 1.1 equiv), and
dimethyl carbonate (7 mL) was added benzoyl peroxide (24.2 mg, 0.1
mmol, 0.05 equiv). The reaction mixture was allowed to stir in an oil
bath at 80 °C for 4 h. The reaction mixture was cooled to room
temperature, diluted with EtOAc, and evaporated under reduced
pressure. The residue was dissolved in EtOAc, and the organic layer
was washed with 5% Na2S2O3 solution, dried over Na2SO4, filtered,
and concentrated under reduced pressure. The residue was triturated
with (n-pentane/Et2O = 49:1) to afford 1p in 71% yield. Analytical
sample was collected by preparative TLC.
3-Isopropyl-2H-benzo[b][1,4]oxazin-2-one (3a): 31.0 mg (82%);
column eluent (n-hexanes/EtOAc = 49:1); brown solid; mp = 52.3−
1
55.0 °C; H NMR (700 MHz, CDCl3) δ 7.75 (dd, J = 7.7, 1.4 Hz,
1H), 7.46−7.45 (m, 1H), 7.35−7.33 (m, 1H), 7.27 (dd, J = 8.4, 1.4
Hz, 1H), 3.45 (sept, J = 7.0 Hz, 1H), 1.33 (d, J = 7.0 Hz, 6H);
13C{1H} NMR (175 MHz, CDCl3) δ 162.1, 152.7, 146.5, 131.4,
130.5, 129.1, 125.4, 116.4, 32.1, 20.0; IR (KBr) υ 1741 (CO), 1612
(CN), 1213 (C−O) cm−1; HRMS (quadrupole, EI) m/z [M]+
Calcd for C11H11NO2 189.0790; Found 189.0787.
3-Isopropyl-6-methoxy-2H-benzo[b][1,4]oxazin-2-one (3b): 32.9
mg (75%); column eluent (n-hexanes/EtOAc = 49:1); light brown
solid; mp = 105.7−107.2 °C; 1H NMR (400 MHz, CDCl3) δ 7.21 (d,
J = 3.2 Hz, 1H), 7.20 (d, J = 8.8 Hz, 1H), 7.04 (dd, J = 8.8, 3.2 Hz,
1H), 3.87 (s, 3H), 3.46 (sept, J = 6.8 Hz, 1H), 1.32 (d, J = 6.8 Hz,
6H); 13C{1H} NMR (100 MHz, CDCl3) δ 162.5, 157.0, 152.9, 140.6,
131.7, 118.6, 117.0, 111.0, 56.0, 32.1, 20.0; IR (KBr) υ 1738 (CO),
1604 (CN), 1200 (C−O) cm−1; HRMS (quadrupole, EI) m/z
[M]+ Calcd for C12H13NO3 219.0895; Found 219.0892.
6-tert-Butyl-3-isopropyl-2H-benzo[b][1,4]oxazin-2-one (3c): 46.1
mg (94%); column eluent (n-hexanes/EtOAc = 49:1); light brown
solid; mp = 107.3−108.6 °C; 1H NMR (700 MHz, CDCl3) δ 7.74 (d,
J = 2.1 Hz, 1H), 7.49 (dd, J = 8.4, 2.1 Hz, 1H), 7.20 (d, J = 8.4 Hz,
1H), 3.45 (sept, J = 7.0 Hz, 1H), 1.37 (s, 9H), 1.32 (d, J = 7.0 Hz,
6H); 13C{1H} NMR (175 MHz, CDCl3) δ 161.9, 153.0, 148.9, 144.2,
130.9, 128.0, 125.6, 115.8, 34.8, 32.1, 31.5, 20.0; IR (KBr) υ 1738
6-(Bromomethyl)-2H-benzo[b][1,4]oxazin-2-one (1p): 340.8 mg
(71%); preparative TLC (n-hexane/EtOAc = 4:1, Rf = 0.5); pale red
1
solid; mp = 71.4−73.1 °C; H NMR (700 MHz, CDCl3/MeOD) δ
8.08 (s, 1H), 7.78 (d, J = 6.3 Hz, 1H), 7.55 (t, J = 6.3 Hz, 1H), 7.27−
7.26 (m, 1H), 4.52 (s, 2H); 13C{1H} NMR (175 MHz, CDCl3/
MeOD) δ 152.2, 146.9, 146.0, 135.9, 132.9, 131.0, 129.8, 117.4, 31.5;
IR (KBr) υ 1747 (CO), 1615 (CN), 1192 (C−O) cm−1; HRMS
(quadrupole, EI) m/z [M]+ Calcd for C9H6BrNO2 238.9582; Found
238.9579.
General Procedure and Characterization Data for the
Synthesis of 1q and 1r. To an oven-dried sealed tube charged
with 2-benzoxazinone 1n (71.8 mg, 0.3 mmol, 1.0 equiv), 4-(oxiran-2-
ylmethoxy)benzoic acid (64.2 mg, 0.33 mmol, 1.1 equiv), a catalytic
amount of DMAP (3.0 mg), and DMF (1.2 mL) was added 1-ethyl-3-
(3-(dimethylamino)propyl)carbodiimide hydrochloride (EDC·HCl,
63.4 mg, 0.33 mmol, 1.1 equiv) in one portion at 0 °C. The reaction
mixture was allowed to stir at 0 °C for 5 min and further stirred at
room temperature for 4 h. The reaction mixture was diluted with H2O
and extracted with EtOAc. The organic layer was washed with
NaHCO3 solution and brine, dried over Na2SO4, filtered, and
E
https://doi.org/10.1021/acs.joc.1c01558
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(CO), 1612 (CN), 1227 (C−O) cm−1; HRMS (quadrupole, EI)
m/z [M]+ Calcd for C15H19NO2 245.1416; Found 245.1413.
3-Isopropyl-6-phenyl-2H-benzo[b][1,4]oxazin-2-one (3d): 37.1
mg (70%); column eluent (n-hexanes/EtOAc = 49:1); light yellow
solid; mp = 92.0−92.6 °C; 1H NMR (500 MHz, CDCl3) δ 7.97 (d, J
= 2.5 Hz, 1H), 7.68 (dd, J = 8.5, 2.5 Hz, 1H), 7.63−7.61 (m, 2H),
7.49−7.45 (m, 2H), 7.41−7.37 (m, 1H), 7.33 (d, J = 8.5 Hz, 1H),
3.48 (sept, J = 7.0 Hz, 1H), 1.35 (d, J = 7.0 Hz, 6H); 13C{1H} NMR
(125 MHz, CDCl3) δ 162.5, 152.6, 145.7, 139.4, 138.8, 131.5, 129.2,
129.1, 127.9, 127.2, 127.1, 116.6, 32.2, 20.0; IR (KBr) υ 1738 (C
O), 1612 (CN), 1215 (C−O) cm−1; HRMS (quadrupole, EI) m/z
[M]+ Calcd for C17H15NO2 265.1103; Found 265.1102.
6-Bromo-3-isopropyl-2H-benzo[b][1,4]oxazin-2-one (3e): 40.8
mg (76%); column eluent (n-hexanes/EtOAc = 49:1); light yellow
solid; mp = 81.5−82.9 °C; 1H NMR (700 MHz, CDCl3) δ 7.91 (d, J
= 2.5 Hz, 1H), 7.55 (dd, J = 9.1, 2.5 Hz, 1H), 7.16 (d, J = 9.1 Hz,
1H), 3.45 (sept, J = 7.0 Hz, 1H), 1.31 (d, J = 7.0 Hz, 6H); 13C{1H}
NMR (175 MHz, CDCl3) δ 163.4, 152.1, 145.6, 133.3, 132.3, 131.7,
117.9, 117.7, 32.3, 20.0; IR (KBr) υ 1738 (CO), 1610 (CN),
1227 (C−O) cm−1; HRMS (quadrupole, EI) m/z [M]+ Calcd for
C11H10BrNO2 266.9895; Found 266.9893.
8-Bromo-3-isopropyl-2H-benzo[b][1,4]oxazin-2-one (3f): 34.9
mg (65%); column eluent (n-hexanes/EtOAc = 49:1); light brown
solid; mp = 87.2−89.5 °C; 1H NMR (700 MHz, CDCl3) δ 7.70 (dd, J
= 7.7, 1.4 Hz, 1H), 7.67 (dd, J = 7.7, 1.4 Hz, 1H), 7.23 (dd, J = 7.7
Hz, 1H), 3.47 (sept, J = 7.0 Hz, 1H), 1.33 (d, J = 7.0 Hz, 6H);
13C{1H} NMR (175 MHz, CDCl3) δ 162.8, 151.9, 143.9, 133.9,
132.3, 128.3, 125.9, 109.5, 32.2, 20.0; IR (KBr) υ 1728 (CO), 1606
(CN), 1216 (C−O) cm−1; HRMS (quadrupole, EI) m/z [M]+
Calcd for C11H10BrNO2 266.9895; Found 266.9893.
(CN), 1228 (C−O) cm−1; HRMS (quadrupole, EI) m/z [M]+
Calcd for C17H14FNO2 283.1009; Found 283.1007.
Ethyl 3-(3-isopropyl-2-oxo-2H-benzo[b][1,4]oxazin-6-yl)-
benzoate (3k): 39.1 mg (58%); column eluent (n-hexanes/EtOAc
1
= 47:3); light yellow solid; mp = 115.1−116.8 °C; H NMR (400
MHz, CDCl3) δ 8.31−8.30 (m, 1H), 8.08−8.05 (m, 1H), 8.02 (d, J =
2.4 Hz, 1H), 7.82−7.79 (m, 1H), 7.72 (dd, J = 8.4, 2.4 Hz, 1H),
7.56−7.52 (m, 1H), 7.36 (d, J = 8.4 Hz, 1H), 4.42 (q, J = 7.2 Hz,
2H), 3.48 (sept, J = 6.8 Hz, 1H), 1.43 (t, J = 7.2 Hz, 3H), 1.35 (d, J =
6.8 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 166.5, 162.8,
152.5, 146.0, 139.7, 137.8, 131.6, 131.5, 131.4, 129.3, 129.2, 129.0,
128.2, 127.4, 116.9, 61.4, 32.2, 20.0, 14.5; IR (KBr) υ 1743 (CO),
1610 (CN), 1215 (C−O) cm−1; HRMS (quadrupole, EI) m/z
[M]+ Calcd for C20H19NO4 337.1314; Found 337.1313.
3-Isopropyl-6-(naphthalen-2-yl)-2H-benzo[b][1,4]oxazin-2-one
(3l): 35.3 mg (56%); column eluent (n-hexanes/CH2Cl2 = 10:1); light
1
yellow solid; mp = 167.0−168.7 °C; H NMR (700 MHz, CDCl3) δ
8.11 (d, J = 2.1 Hz, 1H), 8.08 (d, J = 0.7 Hz, 1H), 7.95 (d, J = 8.4 Hz,
1H), 7.92−7.90 (m, 1H), 7.89−7.87 (m, 1H), 7.81 (dd, J = 8.4, 2.1
Hz, 1H), 7.77 (dd, J = 8.4, 1.4 Hz, 1H), 7.55−7.50 (m, 2H), 7.38 (d, J
= 8.4 Hz, 1 H), 3.50 (sept, J = 7.0 Hz, 1H), 1.37 (d, J = 7.0 Hz, 6H);
13C{1H} NMR (175 MHz, CDCl3) δ 162.6, 152.6, 145.8, 138.7,
136.7, 133.8, 132.9, 131.6, 129.4, 128.9, 128.4, 127.8, 127.5, 126.7,
126.5, 126.1, 125.2, 116.8, 32.2, 20.0; IR (KBr) υ 1741 (CO), 1612
(CN), 1215 (C−O) cm−1; HRMS (quadrupole, EI) m/z [M]+
Calcd for C21H17NO2 315.1259; Found 315.1254.
3-Isopropyl-6-(4-methoxyphenyl)-2H-benzo[b][1,4]oxazin-2-one
(3m): 32.5 mg (55%); column eluent (n-hexanes/EtOAc = 9:1); light
1
yellow solid; mp = 113.5−115.8 °C; H NMR (700 MHz, CDCl3) δ
7.92 (d, J = 2.8 Hz, 1H), 7.64 (dd, J = 8.4, 2.1 Hz, 1H), 7.57−7.54
(m, 2H), 7.31 (d, J = 8.4 Hz, 1H), 7.01−6.99 (m, 2H), 3.87 (s, 3H),
3.48 (sept, J = 7.0 Hz, 1H), 1.35 (d, J = 6.3 Hz, 6H); 13C{1H} NMR
(175 MHz, CDCl3) δ 162.4, 159.7, 152.4, 145.3, 138.5, 132.0, 131.5,
128.9, 128.3, 126.7, 116.6, 114.6, 55.5, 32.2, 20.0; IR (KBr) υ 1736
(CO), 1608 (CN), 1219 (C−O) cm−1; HRMS (quadrupole, EI)
m/z [M]+ Calcd for C18H17NO3 295.1208; Found 295.1208.
3-Isopropyl-6,8-dimethyl-2H-benzo[b][1,4]oxazin-2-one (3g):
29.5 mg (68%); column eluent (n-hexanes/EtOAc = 49:1); white
1
solid; mp = 99.8−100.7 °C; H NMR (400 MHz, CDCl3) δ 7.38 (s,
1H), 7.12 (s, 1H), 3.44 (sept, J = 6.8 Hz, 1H), 2.38 (s, 6H), 1.31 (d, J
= 6.8 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 161.4, 153.2,
142.7, 134.6, 132.9, 131.0, 126.6, 125.4, 31.9, 20.9, 20.0, 14.9; IR
(KBr) υ 1732 (CO), 1612 (CN) cm−1; HRMS (quadrupole, EI)
m/z [M]+ Calcd for C13H15NO2 217.1103; Found 217.1100.
3-Isopropyl-5-methyl-2H-benzo[b][1,4]oxazin-2-one (3h): 30.5
mg (75%); column eluent (n-hexanes/EtOAc = 49:1); yellow solid;
mp = 61.9−63.0 °C; 1H NMR (500 MHz, CDCl3) δ 7.33 (dd, J = 8.0
Hz, 1H), 7.19−7.17 (m, 1H), 7.10−7.08 (m, 1H), 3.45 (sept, J = 6.5
Hz, 1H), 2.62 (s, 3H), 1.33 (d, J = 6.5 Hz, 6H); 13C{1H} NMR (100
MHz, CDCl3) δ 160.2, 152.9, 146.7, 138.4, 130.1, 129.8, 126.5, 113.9,
32.2, 20.1, 16.8; IR (KBr) υ 1738 (CO), 1610 (CN), 1227 (C−
O) cm−1; HRMS (quadrupole, EI) m/z [M]+ Calcd for C12H13NO2
203.0946; Found 203.0943.
6-(4-Hydroxyphenyl)-3-isopropyl-2H-benzo[b][1,4]oxazin-2-one
(3n): 28.7 mg (51%); column eluent (n-hexanes/EtOAc = 43:7);
1
yellow solid; mp = 187.1−189.7 °C; H NMR (400 MHz, CDCl3/
MeOD) δ 7.80 (d, J = 2.0 Hz, 1H), 7.53 (dd J = 8.4, 2.0 Hz, 1H),
7.36 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 8.4 Hz, 1H), 6.78 (d, J = 8.4 Hz,
2H), 3.31 (sept, J = 6.8 Hz, 1H), 1.22 (d, J = 6.8 Hz, 6H); 13C{1H}
NMR (100 MHz, CDCl3/MeOD) δ 162.0, 156.9, 152.9, 144.8, 138.8,
131.2, 130.7, 128.7, 128.1, 126.2, 116.3, 115.8, 31.9, 19.7; IR (KBr) υ
3626 (O−H), 3385 (O−H), 1745 (CO), 1602 (CN), 1085 (C−
O) cm−1; HRMS (quadrupole, EI) m/z [M]+ Calcd for C17H15NO3
281.1052; Found 281.1052.
6-(4-((tert-Butyldimethylsilyl)oxy)phenyl)-3-isopropyl-2H-benzo-
[b][1,4]oxazin-2-one (3o): 30.0 mg (38%); preparative TLC (n-
hexane/EtOAc = 17:3, Rf = 0.6); pale brown solid; mp = 66.1−67.8
3-(3-Isopropyl-2-oxo-2H-benzo[b][1,4]oxazin-6-yl)benzonitrile
(3i): 33.9 mg (58%); column eluent (n-hexanes/Et2O = 6:1); light
1
1
yellow solid; mp = 124.1−126.4 °C; H NMR (700 MHz, CDCl3) δ
°C; H NMR (700 MHz, CDCl3) δ 7.92 (d, J = 2.1 Hz, 1H), 7.63
7.97 (d, J = 2.8 Hz, 1H), 7.91−7.90 (m, 1H), 7.86−7.85 (m, 1H),
7.69−7.67 (m, 1H), 7.66 (dd, J = 8.4, 2.1 Hz, 1H), 7.60−7.58 (m,
1H), 7.39 (d, J = 9.1 Hz, 1H), 3.49 (sept, J = 7.0 Hz, 1H), 1.35 (d, J =
7.0 Hz, 6H); 13C{1H} NMR (175 MHz, CDCl3) δ 163.2, 152.3,
146.5, 140.8, 136.4, 131.7, 131.5, 131.4, 130.7, 130.0, 129.0, 127.5,
118.7, 117.2, 113.5, 32.3, 20.0; IR (KBr) υ 2231 (C ≡ N), 1743 (C
O), 1612 (CN), 1225 (C−O) cm−1; HRMS (quadrupole, EI) m/z
[M]+ Calcd for C18H14N2O2 290.1055; Found 290.1053.
(dd, J = 8.4, 2.1 Hz, 1H), 7.49 (d, J = 9.1 Hz, 1H), 7.31 (d, J = 8.4 Hz,
1H), 6.93 (d, J = 9.1 Hz, 2H), 3.47 (sept, J = 7.0 Hz, 1H), 1.34 (d, J =
7.0 Hz, 6H), 1.01 (s, 9H), 0.24 (s, 6H); 13C{1H} NMR (175 MHz,
CDCl3) δ 162.4, 155.9, 152.8, 145.3, 138.6, 132.5, 131.5, 128.9, 128.2,
126.8, 120.7, 116.5, 32.2, 25.9, 20.1, 18.4, −4.2; IR (KBr) υ 1756
(CO), 1604 (CN), 1263 (C−O) cm−1; HRMS (quadrupole, EI)
m/z [M]+ Calcd for C23H29NO3Si 395.1917; Found 395.1917.
6-(Bromomethyl)-3-isopropyl-2H-benzo[b][1,4]oxazin-2-one
(3p): 30.0 mg (38%); preparative TLC (n-hexane/EtOAc = 17:3, Rf =
6-(3-Fluorophenyl)-3-isopropyl-2H-benzo[b][1,4]oxazin-2-one
1
(3j): 29.5 mg (52%); column eluent (n-hexanes/EtOAc = 19:1);
0.6); pale brown solid; mp = 56.4−58.2 °C; H NMR (700 MHz,
1
yellow solid; mp = 81.5−83.5 °C; H NMR (700 MHz, CDCl3) δ
CDCl3) δ 7.80 (d, J = 2.1 Hz, 1H), 7.50 (dd, J = 8.4, 2.1 Hz, 1H),
7.27−7.26 (m, 1H), 4.56 (s, 2H), 3.46 (sept, J = 6.3 Hz, 1H), 1.33 (d,
J = 6.3 Hz, 6H); 13C{1H} NMR (175 MHz, CDCl3) δ 162.8, 152.4,
146.2, 135.4, 131.3, 131.2, 129.5, 116.9, 32.2, 32.1, 20.0; IR (KBr) υ
1745 (CO), 1614 (CN), 1192 (C−O) cm−1; HRMS (quadru-
pole, EI) m/z [M]+ Calcd for C12H12BrNO2 281.0051; Found
281.0047.
7.96 (d, J = 2.1 Hz, 1H), 7.66 (dd, J = 8.4, 2.1 Hz, 1H), 7.45−7.39
(m, 2H), 7.35 (d, J = 9.1 Hz, 1H), 7.33−7.31 (m, 1H), 7.10−7.07 (m,
1H), 3.48 (sept, J = 7.0 Hz, 1H), 1.35 (d, J = 6.3 Hz, 6H); 13C{1H}
NMR (175 MHz, CDCl3) δ 163.4 (d, JC−F = 245.0 Hz), 162.8, 152.5,
146.1, 141.7 (d, JC−F = 7.7 Hz), 137.5 (d, JC−F = 2.6 Hz), 131.6, 130.6
(d, JC−F = 8.2 Hz), 129.1, 127.4, 122.8 (d, JC−F = 3.0 Hz), 116.9,
114.8 (d, JC−F = 21.0 Hz), 114.2 (d, JC−F = 22.1 Hz), 32.2, 20.0; 19F
NMR (470 MHz, CDCl3) δ − 112.4; IR (KBr) υ 1743 (CO), 1614
4-(3-Isopropyl-2-oxo-2H-benzo[b][1,4]oxazin-6-yl)phenyl 4-(ox-
iran-2-ylmethoxy)benzoate (3q): 20.0 mg (22%); preparative TLC
F
https://doi.org/10.1021/acs.joc.1c01558
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(n-hexane/acetone = 4:1, Rf = 0.4); brown solid; mp = 96.9−98.5 °C;
1H NMR (500 MHz, CDCl3) δ 8.18 (d, J = 9.0 Hz, 2H), 7.98 (d, J =
125.4, 116.4, 42.6, 19.4; IR (KBr) υ 1743 (CO), 1610 (CN),
1209 (C−O) cm−1; HRMS (quadrupole, EI) m/z [M]+ Calcd for
C16H13NO2 251.0946; Found 251.0946.
2.5 Hz, 1H), 7.77 (dd, J = 8.5, 2.5 Hz, 1H), 7.66 (d, J = 8.5 Hz, 1H),
7.98 (d, J = 8.5 Hz, 1H), 7.69 (dd, J = 8.5, 2.0 Hz, 1H), 7.67 (d, J =
9.0 Hz, 2H), 7.35 (d, J = 8.5 Hz, 1H), 7.32 (d, J = 9.0 Hz, 2H), 7.03
(d, J = 9.0 Hz, 2H), 4.36 (dd, J = 11.0, 3.0 Hz, 2H), 4.04 (dd, J =
11.0, 5.5 Hz, 2H), 3.48 (sept, J = 7.0 Hz, 1H), 3.43−3.39 (m, 1H),
2.95 (dd, J = 4.5, 4.0 Hz, 1H), 2.80 (dd, J = 5.0, 3.0 Hz, 1H), 1.35 (d,
J = 7.0 Hz, 6H); 13C{1H} NMR (125 MHz, CDCl3) δ 164.9, 162.9,
162.6, 152.6, 151.0, 145.8, 138.1, 137.1, 132.5, 131.5, 129.3, 128.3,
127.3, 122.5, 122.4, 116.8, 114.6, 69.1, 50.0, 44.7, 32.2, 20.0; IR (KBr)
υ 1732 (CO), 1730 (CO), 1604 (CN), 1261 (C−O), 1169
(C−O), 1069 (C−O) cm−1; HRMS (quadrupole, EI) m/z [M]+
Calcd for C27H23NO6 457.1525; Found 457.1525.
3-(Cyclohex-3-en-1-yl)-2H-benzo[b][1,4]oxazin-2-one (4e): 30.0
mg (66%); column eluent (n-hexanes/EtOAc = 19:1); light yellow
solid; mp = 99.4−100.8 °C; 1H NMR (500 MHz, CDCl3) δ 7.74 (dd,
J = 8.0, 1.5 Hz, 1H), 7.48−7.44 (m, 1H), 7.36−7.33 (m, 1H), 7.28
(dd, J = 8.5, 1.5 Hz, 1H), 5.80−5.74 (m, 2H), 3.44−3.38 (m, 1H),
2.48−2.40 (m, 1H), 2.36−2.30 (m, 1H), 2.27−2.17 (m, 2H), 2.11−
2.06 (m, 1H), 1.80−1.72 (m, 1H); 13C{1H} NMR (125 MHz,
CDCl3) δ 160.9, 152.8, 146.4, 131.4, 130.6, 129.1, 126.7, 125.8, 125.4,
116.4, 37.7, 28.7, 26.7, 25.5; IR (KBr) υ 1743 (CO), 1610 (C
N), 1217 (C−O) cm−1; HRMS (quadrupole, EI) m/z [M]+ Calcd for
C14H13NO2 227.0946; Found 227.0948.
3-Benzoyl-2H-benzo[b][1,4]oxazin-2-one (4f): 39.2 mg (78%);
column eluent (n-hexanes/EtOAc = 9:1); yellow solid; mp = 133.8−
4-(3-Isopropyl-2-oxo-2H-benzo[b][1,4]oxazin-6-yl)phenyl 4-
(phenylsulfonamido)benzoate (3r): 26.9 mg (25%); preparative
TLC (n-hexane/acetone = 3:2, Rf = 0.4); pale brown solid; mp =
198.6−200.5 °C; 1H NMR (500 MHz, CDCl3/MeOD) δ 7.88 (d, J =
9.5 Hz, 2H), 7.80 (d, J = 3.5 Hz, 1H), 7.70 (d, J = 7.5 Hz, 2H), 7.53
(d, J = 9.0 Hz, 1H), 7.49 (d, J = 8.0 Hz, 2H), 7.41−7.35 (m, 1H),
7.32 (t, J = 8.5 Hz, 2H), 7.18 (d, J = 9.5 Hz, 1H), 7.11−7.07 (m, 4H),
3.31−3.23 (m, 1H), 1.16 (d, J = 6.5 Hz, 6H); 13C{1H} NMR (125
MHz, CDCl3/MeOD) δ 174.4, 164.8, 162.3, 152.6, 145.4, 142.8,
139.2, 137.8, 136.9, 133.0, 131.5, 131.4, 131.2, 129.0, 129.0, 128.0,
126.8, 126.8, 124.1, 122.1, 118.4, 116.5, 31.9, 19.5; IR (KBr) υ 3245
(N−H), 1749 (CO), 1714 (CO), 1602 (CN), 1344 (S = O),
1271 (C−O), 1157 (S = O), 1078 (C−O) cm−1; HRMS
(quadrupole, EI) m/z [M]+ Calcd for C30H24N2O6S 540.1355;
Found 540.1356.
General Procedure and Characterization Data for the
Alkylation of 2-Benzoxazinones (4b−4k). To an oven-dried
sealed tube charged with 2H-benzo[b][1,4]oxazin-2-one (1a) (29.4
mg, 0.2 mmol, 1.0 equiv), Na2S2O8 (57.1 mg, 0.24 mmol, 1.2 equiv),
and 4-benzoyl dihydropyridine (2f) (107.2 mg, 0.3 mmol, 1.5 equiv)
was added MeCN (2 mL). The air in the tube was displaced with N2
gas, and the reaction mixture was allowed to stir in an oil bath at 80
°C for 3 h under N2 atmosphere. The reaction mixture was cooled to
room temperature, diluted with H2O, and extracted with EtOAc. The
combined organic layer was dried over Na2SO4, filtered, and
concentrated under reduced pressure. The residue was purified by
column chromatography (n-hexane/EtOAc = 13:1) to afford 39.2 mg
of 4f in 78% yield.
1
135.7 °C; H NMR (700 MHz, CDCl3) δ 8.04−8.02 (m, 2H), 7.85
(dd, J = 7.7, 1.4 Hz, 1H), 7.69−7.67 (m, 1H), 7.66−7.63 (m, 1H),
7.54−7.52 (m, 2H), 7.46−7.44 (m, 1H), 7.40 (dd, J = 8.4, 1.4 Hz,
1H); 13C{1H} NMR (175 MHz, CDCl3) δ 189.2, 151.1, 150.7, 147.2,
134.9, 134.3, 133.3, 130.5, 130.4, 130.3, 129.0, 126.2, 117.1; IR (KBr)
1745 (CO), 1674 (CO), 1603 (CN), 1227 (C−O) cm−1;
HRMS (quadrupole, EI) m/z [M]+ Calcd for C16H11NO4 251.0582;
Found 251.0582.
3-(Thiophene-2-carbonyl)-2H-benzo[b][1,4]oxazin-2-one (4g):
20.6 mg (40%); column eluent (n-hexanes/EtOAc = 11:1); yellow
1
solid; mp = 140.9−142.3 °C; H NMR (400 MHz, CDCl3) δ 7.92
(dd, J = 4.0, 1.2 Hz, 1H), 7.88 (dd, J = 8.0, 1.6 Hz, 1H), 7.84 (dd, J =
4.8, 1.2 Hz, 1H), 7.68−7.64 (m, 1H), 7.48−7.44 (m, 1H), 7.39 (dd, J
= 8.4, 1.2 Hz, 1H), 7.20 (dd, J = 4.8, 4.0 Hz, 1H); 13C{1H} NMR
(100 MHz, CDCl3) δ 180.5, 150.1, 149.0, 147.4, 140.7, 137.1, 136.7,
133.8, 130.4, 130.3, 128.7, 126.3, 117.0; IR (KBr) υ 1747 (CO),
1643 (CO), 1608 (CN), 1230 (C−O) cm−1; HRMS (quadru-
pole, EI) m/z [M]+ Calcd for C13H7NO3S 257.0147; Found
257.0145.
3-(3-Methoxybenzoyl)-2H-benzo[b][1,4]oxazin-2-one (4h): 25.3
mg (45%); column eluent (n-hexanes/EtOAc = 11:1); yellow solid;
mp = 107.2−109.1 °C; 1H NMR (700 MHz, CDCl3) δ 7.85 (dd, J =
7.7, 1.4 Hz, 1H), 7.65−7.63 (m, 1H), 7.60−7.59 (m, 1H), 7.54−7.52
(m, 1H), 7.46−7.43 (m, 1H), 7.42−7.39 (m, 2H), 7.22 (ddd, J = 8.4,
2.8, 1.4 Hz, 1H), 3.88 (s, 3H); 13C{1H} NMR (175 MHz, CDCl3) δ
189.6, 160.2, 151.1, 150.7, 147.1, 135.5, 133.3, 130.5, 130.3, 130.0,
126.2, 123.5, 121.8, 117.0, 113.7, 55.7; IR (KBr) υ 1745 (CO),
1642 (CO), 1608 (CN), 1234 (C−O) cm−1; HRMS (quadru-
pole, EI) m/z [M]+ Calcd for C16H11NO4 281.0688; Found 281.0687.
3-(3-Bromobenzoyl)-2H-benzo[b][1,4]oxazin-2-one (4i): 19.8 mg
(30%); column eluent (n-hexanes/EtOAc = 17:3); yellow solid; mp =
106.9−109.0 °C; 1H NMR (700 MHz, CDCl3) δ 8.16 (dd, J = 2.1 Hz,
1H), 7.96−7.94 (m, 1H), 7.86 (dd, J = 7.7, 1.4 Hz, 1H), 7.81−7.79
(m, 1H), 7.68−7.65 (m, 1H), 7.47−7.45 (m, 1H), 7.42−7.40 (m,
2H); 13C{1H} NMR (175 MHz, CDCl3) δ 187.7, 150.5, 150.0, 147.2,
137.6, 136.1, 133.7, 133.0, 130.6, 130.5, 130.4, 128.9, 126.3, 123.3,
117.1; IR (KBr) υ 1745 (CO), 1680 (CO), 1267 (C−O) cm−1;
HRMS (quadrupole, EI) m/z [M]+ Calcd for C15H8BrNO3 328.9688;
Found 328.9684.
3-(Pentan-2-yl)-2H-benzo[b][1,4]oxazin-2-one (4b): 41.7 mg
(96%); column eluent (n-hexanes/EtOAc = 49:1); yellow liquid;
1H NMR (400 MHz, CDCl3) δ 7.75 (dd, J = 8.2, 1.4 Hz, 1H), 7.47−
7.43 (m, 1H), 7.36−7.32 (m, 1H), 7.27 (dd, J = 8.2, 1.4 Hz, 1H), 3.36
(sext, J = 6.8 Hz, 1 H), 1.90−1.81 (m, 1H), 1.59−1.50 (m, 1H),
1.44−1.33 (m, 2H), 1.29 (d, J = 6.8 Hz, 3H), 0.93 (t, J = 7.2 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 161.9, 152.8, 146.4, 131.4,
130.5, 129.0, 125.34, 116.4, 36.9, 36.7, 20.7, 18.0, 14.2; IR (KBr) υ
1740 (CO), 1610 (CN) cm−1; HRMS (quadrupole, EI) m/z
[M]+ Calcd for C13H15NO2 217.1103; Found 217.1102.
3-Cyclohexyl-2H-benzo[b][1,4]oxazin-2-one (4c): 38.5 mg (84%);
column eluent (n-hexanes/EtOAc = 19:1); light brown solid; mp =
1
86.7−88.0 °C; H NMR (500 MHz, CDCl3) δ 7.73 (dd, J = 8.0, 1.5
Hz, 1H), 7.46−7.43 (m, 1H), 7.35−7.32 (m, 1H), 7.26 (dd, J = 8.0,
1.5 Hz, 1H), 3.18−3.12 (m, 1H), 2.01−1.97 (m, 2H), 1.90−1.85 (m,
2H), 1.79−1.74 (m, 1H), 1.59−1.51 (m, 2H), 1.48−1.39 (m, 2H),
1.34−1.27 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 161.4,
152.8, 146.3, 131.5, 130.4, 129.0, 125.4, 116.4, 41.5, 30.4, 26.2, 26.1;
IR (KBr) υ 1738 (CO), 1610 (CN), 1206 (C−O) cm−1; HRMS
(quadrupole, EI) m/z [M]+ Calcd for C14H15NO2 229.1103; Found
229.1103.
3-(1-Phenylethyl)-2H-benzo[b][1,4]oxazin-2-one (4d): 32.1 mg
(64%); column eluent (n-hexanes/EtOAc = 19:1); light yellow solid;
mp = 65.0−66.5 °C; 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 8.0
Hz, 1H), 7.53−7.49 (m, 1H), 7.47−7.45 (m, 2H), 7.43−7.39 (m,
1H), 7.38−7.34 (m, 2H), 7.31−7.23 (m, 2H), 4.70 (q, J = 7.2 Hz,
1H), 1.74 (d, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
159.1, 152.6, 146.5, 141.6, 131.3, 130.8, 129.3, 128.7, 128.2, 127.2,
3-(2-Naphthoyl)-2H-benzo[b][1,4]oxazin-2-one (4j): 25.9 mg
(43%); column eluent (n-hexanes/EtOAc = 18:1); yellow solid; mp
= 134.4−136.9 °C; 1H NMR (400 MHz, CDCl3) δ 8.47 (s, 1H), 8.14
(dd, J = 8.8, 2.0 Hz, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.95−7.89 (m,
2H), 7.88 (dd, J = 8.0, 1.6 Hz, 1H), 7.69−7.63 (m, 2H), 7.59−7.55
(m, 1H), 7.46 (dd, J = 8.0, 1.6 Hz, 1H), 7.43 (dd, J = 8.4, 1.2 Hz,
1H); 13C{1H} NMR (100 MHz, CDCl3) δ 189.2, 151.2, 150.8, 147.2,
136.5, 133.6, 133.3, 132.4, 131.6, 130.6, 130.4, 130.1, 129.6, 129.2,
128.1, 127.3, 126.3, 124.4, 117.1; IR (KBr) υ 1747 (CO), 1666
(CO), 1624 (CN), 1265 (C−O) cm−1; HRMS (quadrupole, EI)
m/z [M]+ Calcd for C19H11NO3 301.0739; Found 301.0737.
General Procedure and Characterization Data for Hetero-
arylation of Product 3e. To an oven-dried sealed tube charged with
6-bromo-3-isopropyl-2-benzoxazinone (3e) (53.6 mg, 0.2 mmol, 1.0
equiv), Pd(OAc)2 (4.5 mg, 0.02 mmol, 0.1 equiv), P(o-tol)3 (12.2 mg,
G
https://doi.org/10.1021/acs.joc.1c01558
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
0.04 mmol, 0.2 equiv), CuCl (19.8 mg, 0.2 mmol, 1.0 equiv), Na2CO3
(42.4 mg, 0.4 mmol, 2.0 equiv), and (1-methyl-1H-pyrazol-4-
yl)boronic acid (63.0 mg, 0.5 mmol, 2.5 equiv) was added degassed
1,4-dioxane (2 mL). The reaction mixture was allowed to stir in an oil
bath at 100 °C for 18 h in Ar atmosphere. The reaction mixture was
cooled to room temperature and filtered through Celite. The filtrate
was concentrated under reduced pressure. The residue was purified by
column chromatography (n-hexane/EtOAc = 3:1) to afford 23.2 mg
of 6a in 43% yield.
(29.4 mg, 0.2 mmol, 1.0 equiv), Na2S2O8 (57.1 mg, 0.24 mmol, 1.2
equiv), 4-(1-phenylethyl)dihydropyridine (2d) (98.8 mg, 0.3 mmol,
1.5 equiv), and MeCN (2 mL) was added TEMPO (156.0 mg, 1.0
mmol, 5.0 equiv). The air in the tube was displaced with N2 gas, and
the reaction mixture was allowed to stir in oil bath at 80 °C for 3 h
under N2 atmosphere. The reaction mixture was cooled to room
temperature, diluted with H2O, and extracted with EtOAc. The
combined organic layer was dried over Na2SO4, filtered, and
concentrated under reduced pressure at 35 °C. The residue was
purified by column chromatography (n-hexane/EtOAc = 50:1) to
afford 51.8 mg of 7a in 99% yield.
2,2,6,6-Tetramethyl-1-(1-phenylethoxy)piperidine (7a): 51.8 mg
(99%); column eluent (n-hexanes/EtOAc = 99:1); red sticky solid;
1H NMR (400 MHz, CDCl3) δ 7.48−7.36 (m, 5H), 4.94 (q, J = 6.4
Hz, 1H), 1.65 (s, 3H), 1.63 (s, 3H), 1.53−1.45 (m, 6H), 1.33 (s, 3H),
1.19 (s, 3H), 0.82 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
143.2, 125.4, 124.2, 124.0, 80.4, 57.0, 37.7, 21.0, 17.7, 14.6; HRMS
(quadrupole, EI) m/z [M]+ Calcd for C17H27NO 261.2093; Found
261.2091.
3-Isopropyl-6-(1-methyl-1H-pyrazol-4-yl)-2H-benzo[b][1,4]-
oxazin-2-one (6a): 23.2 mg (43%); column eluent (n-hexanes/
1
EtOAc = 3:1); yellow solid; mp = 161.3−162.5 °C; H NMR (700
MHz, CDCl3) δ 7.82 (d, J = 2.1 Hz, 1H), 7.79 (s, 1H), 7.65 (s, 1H),
7.54 (dd, J = 8.4, 2.1 Hz, 1H), 7.25 (d, J = 8.4 Hz, 1H), 3.96 (s, 3H),
3.46 (sept, J = 6.3 Hz, 1H), 1.33 (d, J = 6.3 Hz, 6H); 13C{1H} NMR
(175 MHz, CDCl3) δ 162.6, 152.7, 144.9, 136.9, 131.6, 130.5, 127.7,
127.2, 125.3, 121.8, 116.7, 39.3, 32.1, 20.0; IR (KBr) υ 1741 (CO),
1267 (C−O) cm−1; HRMS (quadrupole, EI) m/z [M]+ Calcd for
C15H15N3O2 269.1164; Found 269.1161.
3-Isopropyl-6-(thiophene-2-yl)-2H-benzo[b][1,4]oxazin-2-one
Experimental Procedure and Characterization Data for
Reaction of 2d with TEMPO in the Absence of 1a. To an oven-
dried sealed tube charged with 4-(1-phenylethyl) dihydropyridine
(2d) (98.8 mg, 0.3 mmol, 1.0 equiv), Na2S2O8 (57.1 mg, 0.24 mmol,
0.8 equiv), and MeCN (2 mL) was added TEMPO (140.4 mg, 0.9
mmol, 3.0 equiv). The air in the tube was displaced with N2 gas, and
the reaction mixture was allowed to stir in oil bath at 80 °C for 3 h
under N2 atmosphere. The reaction mixture was cooled to room
temperature, diluted with H2O, and extracted with EtOAc. The
combined organic layer was dried over Na2SO4, filtered, and
concentrated under reduced pressure at 35 °C. The residue was
purified by column chromatography (n-hexane/EtOAc = 50:1 to 7:1)
to afford 76.1 mg of 7a in 97% yield and 62.3 mg of 8a in 93% yield.
Dimethyl 2,6-Dimethylpyridine-3,5-dicarboxylate (8a). 62.3 mg
(93%); column eluent (n-hexanes/EtOAc = 7:1); pale yellow solid;
1H NMR (400 MHz, CDCl3) δ 8.71 (s, 1H), 3.93 (s, 6H), 2.85 (s,
(6b): 13.6 mg (25%); column eluent (n-hexanes/EtOAc = 15:1); dark
1
brown solid; mp = 97.5−99.8 °C; H NMR (500 MHz, CDCl3) δ
7.98 (d, J = 2.0 Hz, 1H), 7.70 (dd, J = 8.5, 2.5 Hz, 1H), 7.36 (dd, J =
3.5, 1.0 Hz, 1H), 7.33 (dd, J = 5.0, 1.0 Hz, 1H), 7.28 (d, J = 8.5 Hz,
1H), 7.11 (dd, J = 5.0, 3.5 Hz, 1H), 3.48 (sept, J = 7.0 Hz, 1H), 1.34
(d, J = 7.0 Hz, 6H); 13C{1H} NMR (125 MHz, CDCl3) δ 162.9,
152.5, 145.6, 142.5, 132.3, 131.6, 128.4, 128.1, 125.9, 125.7, 123.9,
116.9, 32.2, 20.0; IR (KBr) υ 1745 (CO), 1267 (C−O) cm−1;
HRMS (quadrupole, EI) m/z [M]+ Calcd for C15H13NO2S 271.0667;
Found 271.0663.
6-(2-Fluoropyridin-3-yl)-3-isopropyl-2H-benzo[b][1,4]oxazin-2-
one (6c): 14.8 mg (26%); column eluent (n-hexanes/EtOAc = 10:1);
light brown solid; mp = 147.5−149.9 °C; 1H NMR (500 MHz,
CDCl3) δ 8.25 (d, J = 5.0 Hz, 1H), 7.95−7.91 (m, 1H), 7.69−7.67
(m, 1H), 7.37 (d, J = 8.5 Hz, 1H), 7.34−7.31 (m, 1H), 3.47 (sept, J =
6.5 Hz, 1H), 1.34 (d, J = 6.5 Hz, 6H); 13C{1H} NMR (125 MHz,
6H); 13C{1H} NMR (100 MHz, CDCl3) δ 166.4, 162.8, 141.2, 122.7,
CDCl3) δ 163.0, 160.4 (d, JC−F = 238.4 Hz), 152.4, 147.2 (d, JC−F
=
52.5, 25.1.
15.0 Hz), 146.4, 140.7 (d, JC−F = 4.5 Hz), 131.5, 131.4 (d, JC−F = 5.0
Hz), 130.8 (d, JC−F = 3.5 Hz), 129.3, 122.3 (d, JC−F = 28.9 Hz), 122.1
(d, JC−F = 4.4 Hz), 116.8, 31.7, 17.1; 19F NMR (470 MHz, CDCl3) δ
− 70.7; IR (KBr) υ 1743 (CO), 1604 (CN), 1211 (C−O) cm−1;
HRMS (quadrupole, EI) m/z [M]+ Calcd for C16H13FN2O2
284.0961; Found 284.0960.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c01558.
Experimental Procedures for Gram-Scale Experiment of 3a.
To an oven-dried sealed tube charged with 2H-benzo[b][1,4]oxazin-
2-one (1a) (1.0 g, 6.8 mmol, 1.0 equiv), Na2S2O8 (1.94 g, 8.16 mmol,
1.2 equiv), and 4-isopropyl dihydropyridine (2a) (2.73 g, 10.2 mmol,
1.5 equiv) was added MeCN (68 mL). The air in the tube was
displaced with N2 gas, and the reaction mixture was allowed to stir in
oil bath at 50 °C for 7 h under N2 atmosphere. The reaction mixture
was cooled to room temperature, diluted with H2O, and extracted
with EtOAc. The combined organic layer was dried over Na2SO4,
filtered, and concentrated under reduced pressure. The residue was
purified by column chromatography (n-hexane/EtOAc = 49:1) to
afford 1.03 g of 3a in 80% yield.
Experimental Procedures for Gram-Scale Experiment of 4f.
To an oven-dried sealed tube charged with 2H-benzo[b][1,4]oxazin-
2-one (1a) (1.0 g, 6.8 mmol, 1.0 equiv), Na2S2O8 (1.94 g, 8.16 mmol,
1.2 equiv), and 4-benzoyldihydropyridine (2f) (3.65 g, 10.2 mmol, 1.5
equiv) was added MeCN (68 mL). The air in the tube was displaced
with N2 gas, and the reaction mixture was allowed to stir in oil bath at
80 °C for 3 h under N2 atmosphere. The reaction mixture was cooled
to room temperature, diluted with H2O, and extracted with EtOAc.
The combined organic layer was dried over Na2SO4, filtered and
concentrated under reduced pressure. The residue was purified by
column chromatography (n-hexane/EtOAc = 13:1) to afford 1.25 g of
4f in 73% yield.
Optimization table for the synthesis of 6-aryl 2-
benzoxazinones (1i−1o), 1H, 13C, 19F NMR spectra
and HRMS data copy for all products (PDF)
FAIR data, including the primary NMR FID files, for
compounds 1a−1r, 3a−3r, 4b−4r, 6a−6c, 7a, and 8a
(ZIP)
AUTHOR INFORMATION
■
Corresponding Authors
Prithwish Ghosh − School of Pharmacy, Sungkyunkwan
University, Suwon 16419, Republic of Korea;
Email: prithwish_ghosh2001@yahoo.com
In Su Kim − School of Pharmacy, Sungkyunkwan University,
Suwon 16419, Republic of Korea; orcid.org/0000-0002-
2665-9431; Email: insukim@skku.edu
Authors
Youjung Byun − School of Pharmacy, Sungkyunkwan
University, Suwon 16419, Republic of Korea
Junghyea Moon − School of Pharmacy, Sungkyunkwan
University, Suwon 16419, Republic of Korea
Won An − School of Pharmacy, Sungkyunkwan University,
Suwon 16419, Republic of Korea
Experimental Procedure and Characterization Data for
Reaction of 1a with 2d in the Presence of TEMPO. To an oven-
dried sealed tube charged with 2H-benzo[b][1,4]oxazin-2-one (1a)
H
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Neeraj Kumar Mishra − School of Pharmacy, Sungkyunkwan
University, Suwon 16419, Republic of Korea
Hyung Sik Kim − School of Pharmacy, Sungkyunkwan
University, Suwon 16419, Republic of Korea
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c01558
Author Contributions
‡Y.B. and J.M. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Research
Foundation of Korea (NRF) grant funded by the Korea
government (MSIT) (Nos. 2019R1A4A2001451 and
2020R1A2C3005357).
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