Treatment of Olefinic Amides with NBS in Water: Synthesis of Monobromo- A nd Multibromobenzoxazines

Article abstract of DOI:10.1055/s-0037-1610724

Treatment of olefinic amides with N-bromosuccinimide (NBS) in water is reported. Monobromobenzoxazines were mainly formed at room temperature, while at 80? °C multibromobenzoxazines were preferentially generated. Mechanism studies showed that the reaction might proceed via a cascade of electrophilic addition at the C=C bond followed by electrophilic substitution at the aromatic ring. No additives are required in this protocol.

Full text of DOI:10.1055/s-0037-1610724

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–J
paper
A
en
X. Zhang et al.
Paper
Synthesis
Treatment of Olefinic Amides with NBS in Water: Synthesis of
Monobromo- and Multibromobenzoxazines
Xu Zhang
R2
Br
Wen-Bin Cao
Xiao-Ping Xu*
25 °C
O
R2
N
R1
Shun-Jun Ji*
00
0
0-0
0
0
2-0
9
7
7-7
8
8
2
14 examples, 83–92% yield
catalyst free
H2O
+
NBS
Key Laboratory of Organic Synthesis of Jiangsu Province, College of
Chemistry, Chemical Engineering and Materials Science & Collaborative
Innovation Center of Suzhou Nano Science and Technology, Soochow
University, Suzhou 215123, P. R. of China
NH
R2
Br
O
R1
Br
80 °C
O
xuxp@suda.edu.cn
R1
shunjun@suda.edu.cn
N
9 examples, 57–90% yield
Received: 25.04.2019
previous work
Accepted after revision: 09.07.2019
Published online: 01.08.2019
DOI: 10.1055/s-0037-1610724; Art ID: ss-2019-h0244-op
X
O
NH
Abstract Treatment of olefinic amides with N-bromosuccinimide
(NBS) in water is reported. Monobromobenzoxazines were mainly
formed at room temperature, while at 80 °C multibromobenzoxazines
were preferentially generated. Mechanism studies showed that the re-
action might proceed via a cascade of electrophilic addition at the C=C
bond followed by electrophilic substitution at the aromatic ring. No ad-
ditives are required in this protocol.
N
O
X = I, Br, CH2F, CN, SCN, Alkyl, etc.
X
Catalyst/Additive
Solvent
Ref.
-X (I/Br)
-CF2H
-SCN
-Alkyl
-CN
NXS/NaHCO3
fac-Ir(ppy)3/Na2CO3
K2S2O8
CH2Cl2
CH3CN
HOAc
8
10
11
12
13
Key words benzoxazines, water, metal free, bromination, selectivity
Cu2O/Phen/DTBP/K2CO3
Alkane
Cu(OTf)2/Phen/DTBP/K2CO3
R-CH2CN
Br
O
The benzoxazine skeleton widely occurs in natural
products which usually exhibit biopharmaceutical activity
(Figure 1),1 some of which have been used as anticonvul-
sants, fungicides and progesterone receptor agonists.2 Be-
sides, benzoxazine compounds can also serve as important
synthons and intermediates in organic reactions.3 There-
fore, the synthesis of benzoxazines has attracted extensive
attention.4,5 Among the methods available, olefinic amide
based reactions have been widely studied6,7 and many con-
structions of benzoxazines using ionic or radical reagents
with olefinic amides have been disclosed.8–13 However,
these methods always suffer from drawbacks such as or-
ganic solvent dependence, non-readily available raw materi-
als, and the requirement for initiators, additives and some-
times transition-metal catalysts (Scheme 1, previous work).
The structural diversity of products has hardly been realized.
this work
25 °C
N
catalyst free
+
NBS
NH
Br
O
H2O
Br
O
80 °C
N
Scheme 1 Methods for the synthesis of functional benzoxazine derivatives
N-Bromosuccinimide (NBS), a simple halogen source,
has been often used as an oxidant14 or bromination re-
agent15 in organic synthesis. By using NBS, a bromine atom
can be readily introduced to realize functionalization of un-
saturated C–C bonds; selective bromination at benzylic po-
sitions or electrophilic substitution of aromatic rings can
also be performed by using Lewis or Brønsted acids and so
on.15,16 Bromo compounds are involved in organic chemis-
try as multipurpose reagents,17a and while sequential bro-
mination via electrophilic addition or electrophilic substi-
tution, as well as other types of reactions, for access to mul-
tibrominated molecules is also desired,17b such reactions
have not yet been successfully achieved.
CN
Ph Me
O
R
Me Me
O
Cl
S
O
Cl
N
N
N
N
H
Me
H2
N
Etifoxine
Progesterone Receptor Agonist
Fungicides
Figure 1 Representative examples of bioactive benzoxazines
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–J
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
X. Zhang et al.
Paper
Synthesis
As an environmentally friendly and low-cost solvent,
water shows good physical and chemical properties. Its
high dielectric constant, high energy density, and strong
hydrogen-bonding and amphoteric properties have a posi-
tive impact on reaction rates and selectivity.18,19 For exam-
ple, the Knowles group found that the rate of the Claisen re-
arrangement of chorismate is 10 times slower in methanol
than in water, while Breslow’s group found that the Diels–
Alder reaction of diene and dienophile exhibited more ex-
cellent stereoselectivity in water.19 Due to the unique prop-
erties of water, organic reactions in the aqueous phase have
received extensive attention and research.20
In continuation of our work on olefinic amide based
synthesis of heterocycles, as well as reactions in water,13 we
recently found that treatment of olefinic amides with NBS
at room temperature could realize the synthesis of mono-
bromobenzoxazines in water, while at 80 °C there was pref-
erential formation of multibromobenzoxazine compounds
(Scheme 1, this work). The structure of the substrate has a
significant influence on the bromination process and no ex-
tra additives are required in these reactions. Herein, we re-
port our results.
We initiated the study by choosing the reaction of N-(2-
(prop-1-en-2-yl)phenyl)benzamide (1a) with NBS (2a) as
template. The reaction was performed at 80 °C in the pres-
ence of 5 equivalents of NBS in ethanol/water (1:1, v/v); the
products, 3a and 4a, were isolated in 34% and 30% yield, re-
spectively (Table 1, entry 1). When acetonitrile/water (1:1,
v/v) was used as solvent and 5 equivalents of NBS were add-
ed, we obtained compound 4a in 39% isolated yield, and
only a trace amount of 3a was observed. This implied that
the contribution of the different products could be tuned by
solvent. Thus, a series of solvents was investigated. To our
delight, water proved to be the most suitable solvent, in
which product 4a could be obtained in 90% yield (Table 1,
entry 7). When the reaction temperature was lowered to
room temperature (25 °C), and the amount of NBS was re-
duced to 1.2 equivalents, product 3a was obtained in 92%
yield, and no formation of 4a was observed (Table 1, entry
12). Hence, we determined that the optimal reaction condi-
tions were as follows: for the formation of monobromo
products, reaction of 1 equivalent of substrate and 1.2
equivalents of NBS in water (3 mL) at 25 °C; for the forma-
tion of multibromo products, reaction of 1 equivalent of
substrate and 5 equivalents of NBS in water (3 mL) at 80 °C.
Based on the established optimal reaction conditions,
the substrate scope for the synthesis of monobromo- and
multibromobenzoxazines was investigated. Firstly, the syn-
thesis of monobromobenzoxazines 3 was examined. As
shown in Scheme 2, a wide range of functional groups was
well tolerated under the reaction conditions. The acyl struc-
ture attached to the N-position in substrate 1 has a weak ef-
fect on the reaction results. The yield decreased slightly
when there was a substituent at the ortho-position of the
benzene ring (Scheme 2; 3d, 3e). Fortunately, both halogen
Table 1 Optimization of the Reaction Conditionsa
Br
Br
Br
O
solvent
O
+
+
NH
NBS
N
N
Temp (°C)
2 h
O
3a
4a
1a
2a
0.3 mmol
Entry
Solvent
NBS (equiv) Temp (°C) Yieldb (%) of 3a/4a
1
H2O/EtOH (1:1)
5
80
80
80
80
80
80
80
80
80
60
100
25
34/30
trace/39
N.D.c
2
H2O/CH3CN (1:1)
5
3
H2O/DMSO (1:1)
5
4
H2O/DMF (1:1)
CH3CN
DMF
5
–/10
5
5
51/18
–/57
6
5
7
H2O
5
trace/90
trace/82
trace/79
53/29
20/34
92/–
8
H2O
4
9
H2O
3
10
11
12
H2O
5
H2O
5
H2O
1.2
a Reaction conditions: 1a (0.30 mmol), 2a, solvent (3 mL).
b Isolated yields.
c N.D. = 0%.
and electron-withdrawing substituents were compatible
with this methodology, affording the desired benzoxazines
in moderate to good yields (Scheme 2; 3f–3j, 3p). When the
aryl group was replaced by an alkyl group or heterocycle
(such as thiophene), the reaction also proceeded smoothly
to give the desired products in good yields (Scheme 2; 3l,
3o). When the methyl group was replaced by a phenyl
group, the reaction gave the desired product in good yield
(Scheme 2, 3q); however, when R2 was H, no target product
could be observed.21 Compared with the same reaction in
an organic phase, we found that the reaction in water was
more effective.8
Although bromination of aromatic rings with NBS has
been achieved,16 multibrominations involving this reaction
have not been reported previously. Moreover, bromination
of aromatic rings with NBS, to a great extent, has relied on
Lewis or Brønsted acid catalysis. Taking this into consider-
ation, we investigated the substrate scope for the synthesis
of multibromobenzoxazines 4. The results are summarized
in Scheme 3. We found that the steric and electronic effects
of substituents on the aroyl fragment in the substrates has
some influence on the reaction. An alkyl or halogen substit-
uent was well tolerated in the reaction (Scheme 3, 4b–4h),
but benzamido bearing a substituent at the ortho-position
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–J

C
X. Zhang et al.
Paper
Synthesis
R2
R2
R2
Br
R2
Br
H2O
r.t.
H2O
Br
+
O
NBS
+
O
NBS
NH
NH
80 °C
R1
N
R1
N
O
R1
O
R1
1
2a
3
1
2a
4
Br
Br
Br
O
Br
O
O
Br
O
N
N
N
N
OMe
3a, 2 h, 92%
3b, 2 h, 92%
3c, 2 h, 91%
4a, 2 h, 90%
Br
Br
O
Br
O
Br
Br
Br
O
OMe
Br
Br
Br
O
O
O
N
N
N
N
N
N
F
OMe
3d, 2 h, 84%
3e, 2 h, 86%
3f, 2 h, 89%
4b, 2 h, 70%
Br
4c, 2 h, 71%
Br
4d, 3 h, 68%
Br
O
Br
O
Br
O
Br
O
Br
Br
Br
O
O
N
N
N
N
N
N
Cl
CF3
NO2
Cl
I
F
3g, 2 h, 90%
3i, 2 h, 88%
3j, 2 h, 87%
4f, 2 h, 85%
4g, 2 h, 64%
Br
4h, 2 h, 57%
Br
O
Br
O
Br
O
Br
Br
Br
Br
Br
O
O
N
O
N
N
N
N
N
S
Cl
NO2
CF3
N
3l, 2 h, 85%
3m, 2 h, 88%
3o, 3 h, 83%
4i, 3 h, 58% (3i, 23%)
4j, 2 h, trace (3j, 85%)
4k, 2 h, trace
Br
Ph
Br
Br
Cl
Br
Br
O
Br
O
O
N
O
N
Br
Br
O
O
N
N
N
N
Br
Br
Br
4m, 2 h, 44%
Cl Br
3r, 2 h, 0%
3q, 2 h, 90%
3p, 2 h, 91%
4l, 2 h, 65%
4n, 2 h, 81%
Scheme 2 Substrate scope for monobromobenzoxazines. Reagents and
conditions: 1 (0.3 mmol), 2a (0.36 mmol), H2O (3 mL), 25 °C; isolated
yields.
Br
O
Ph
Br
Br
Br
O
S
gave only a moderate yield of the benzoxazine product.
However, when an electron-withdrawing group such as tri-
fluoromethyl was attached to the benzene ring, the yield of
the product (4i) decreased to 58% and, at the same time, 3i
was obtained in 23% yield. When a nitro group was intro-
duced into the benzene ring, the reaction was almost com-
pletely hindered; only the monobromination reaction oc-
curred and 3j was isolated in 85% yield (Scheme 3). Disap-
pointingly, when a pyridinoyl skeleton was employed
instead of aroyl in the substrate, the reaction barely worked
under the standard conditions (Scheme 3, 4k). Some inter-
esting reactions were observed when N-isobutyryl- and 4-
(chloromethyl)benzoyl-substituted compounds were uti-
lized: tetrabromo- and a new tribromobenzoxazine were
produced separately, which presumably relates to the tau-
N
N
Br
4o, 2 h, 78%
4q, 2 h, 59%
Scheme 3 Substrate scope for multibromobenzoxazines. Reagents and
conditions: 1 (0.3 mmol), 2a (1.5 mmol), H2O (3 mL), 80 °C; isolated
yields.
tomerism between the imine–enamine structure of ben-
zoxazines22 (Scheme 3; 4l, 4m). Moreover, a new dibromo
product could be obtained when the para-position relative
to benzamido was occupied by an alkyl group such as
methyl (Scheme 3, 4n). When benzamido was replaced by
the thiophenamido skeleton, a tribromination reaction took
place and 4o was obtained in 78% yield (Scheme 3). Product
4q could also be obtained, in 59% yield, by variation of R2
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–J

D
X. Zhang et al.
Paper
Synthesis
from a methyl to a phenyl group. The structures of 4a and
4o were unambiguously identified by X-ray crystallogra-
phy.
(a)
Br
Br
Br
Br
NaOtBu
O
NH
Encouraged by these good results, we next set out to ap-
ply this protocol to fluorination and chlorination reactions
(Scheme 4). We were delighted to find that, under the stan-
dard conditions, the reaction of 1a with Selectfluor gave the
monofluorinated product 5a in 45% yield, but the multifluo-
rinated product could not be obtained even at higher reac-
tion temperature and if more Selectfluor was used. Dichlo-
robenzoxazine 6a could be readily obtained in 65% yield by
the reaction of 1a with N-chlorosuccinimide.
DMSO
r.t.
N
O
4a
(b)
Br
Br
7a, 53%
O
N
Br
O
Cs2CO3
4a
Pd(PPh3)2Cl2
CH3CN
+
OH
N
B
80 °C
Ar
8a, 49%
OH
(a)
F
(c)
Br
H2O
O
Br
Selectfluor
+
NH
80 °C
2 h
N
O
O
5a, 45%
1a
N
Br
Cs2CO3
(b)
4a
Pd(PPh3)2Cl2
S
O
Cl
O
+
Cl
OH
B
CH3CN
H2O
O
N
+
NH
N
Cl
80 °C
Ar
OH
8b, 63%
N
80 °C
2 h
S
O
O
Scheme 5 Conversion reactions of multibromobenzoxazine 4a
1a
6a, 65%
Scheme 4 Synthesis of fluoro- and dichlorobenzoxazines
(a)
Br
Br
O
N
Br
H2O
O
O
In order to show the importance of the protocol, 4a was
selected to undergo conversion reactions (Scheme 5). Thus,
in DMSO, sodium tert-butoxide promoted the ring-opening
reaction of 4a to give the brominated olefin product 7a in
53% yield. With reference to the bioactive benzoxazine skel-
eton, we attempted two Suzuki coupling reactions. To our
delight, 4a reacted with phenylboronic acid and with 2-
thiopheneboronic acid to afford 8a and 8b in 49% and 63%
yield, respectively (Scheme 5). This fully demonstrates the
potential application value of multibrominated benzox-
azine compounds as synthetic intermediates.
+
Br
N
N
80 °C
2 h
O
3a
4a, 92%
2a
(b)
Br
O
N
Br
standard conditions
O
+
NH
Br
in the dark
N
O
O
4a, 86%
1a
2a
(c)
To gain insight into the reaction mechanism, some con-
trol experiments were carried out (Scheme 6). First, the re-
action of compound 3a with 3 equivalents of NBS (2a) at
80 °C was performed, which gave product 4a in 92% yield,
indicating that 3a might be the key intermediate for the for-
mation of 4a, and during the reaction an electrophilic sub-
stitution of 3a occurred (Scheme 6a). Second, under dark
conditions, the reaction of 1a and 2a proceeded smoothly
to produce product 4a in 86% yield (Scheme 6b), implying
that visible light has almost no effect on the reaction. A rad-
ical pathway was also excluded by introducing the radical
scavenger 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO)
into the model reaction (Scheme 6c).
Br
Br
O
N
O
standard conditions
+
NH
Br
N
TEMPO
O
1a
O
4a, 82%
2a
Scheme 6 Control experiments
Thus, we supposed the reaction might proceed via a
cascade of electrophilic addition and electrophilic substitu-
tion. To prove this hypothesis, we carried out further con-
trol experiments. NBS was stirred in water at 80 °C, where-
upon the solution gradually turned reddish-brown, and a
reddish-brown gas was generated (when the solution was
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–J

E
X. Zhang et al.
Paper
Synthesis
cooled and a small amount of aniline was added, there was
rapid formation of a white precipitate). All this evidence in-
dicated that molecular bromine might be formed during the
reaction (see Supporting Information, Figure S1).
In summary, we have developed an efficient method for
the synthesis of monobromo- and multibromobenzox-
azines which does not require additional catalysts and ad-
ditives, and has the advantages of simple raw materials,
mild and green reaction conditions, and a controllable mul-
tistep conversion in one pot. At room temperature, mono-
bromobenzoxazines were mainly formed; when the tem-
perature was raised to 80 °C, bromination occurs at multi-
On the basis of these results as well as related reports,23
a plausible mechanism is proposed (Scheme 7). We specu-
late that this reaction might proceed via a cascade of elec-
trophilic addition, cyclization and electrophilic substitu-
tion. Bromide species with a positive charge (mainly exist-
ing as HOBr) are first formed by two possible pathways
(Scheme 7a): 1) Homolysis of the N–Br bond in NBS occurs
on heating, which leads to the formation of molecular bro-
mine via coupling of bromo free radicals. HOBr is thus gen-
erated from the reaction of Br2 with water; 2) NBS reacts
with Brønsted acid (water) to form HOBr.16a Initially, the
C=C bond of 1a is attacked by Br+ to give intermediate A;
then, A undergoes an intramolecular nucleophilic cycliza-
tion reaction to afford intermediate B (Scheme 7b). After
loss of a proton (H+), 3a is formed. Next, the electron-rich
benzene ring in 3a is attacked by Br+ to perform an electro-
philic substitution, with deprotonation producing 4a.
ple
sites.
Dibromo-,
tribromo-
and
even
tetrabromobenzoxazines were synthesized by variation of
the structure of the substrates. The reaction in water might
occur via a cascade of electrophilic addition/cycliza-
tion/electrophilic substitution in which molecular bromine
is involved. This method also provides a greener and more
convenient way for the construction of monobromo- and
multibromobenzoxazines with potential biopharmaceuti-
cal activity.
Unless otherwise stated, all reagents were purchased from commer-
cial suppliers and used without further purification. All reactions
were carried out under an atmosphere of oxygen and using undis-
tilled solvent unless otherwise noted. Melting points were recorded
on an Electrothermal digital melting point apparatus. IR spectra were
recorded on a Bruker ALPHA FT-IR spectrophotometer using KBr op-
tics. 1H, 13C and 19F NMR spectra were recorded in CDCl3 or DMSO-d6
on Bruker AVANCEIII HD-400 400 MHz spectrometers. TMS served as
internal standard for 1H and 13C NMR spectra. High-resolution mass
spectra were obtained using a commercial apparatus (ESI or EI
source). All olefinic amides 1 were synthesized according to the liter-
ature, and the NMR spectra were in full accordance with the literature
data.8–13
+
(a) Generation of Brδ
[O]
O
H2O
H2O
+
2 Br
Br2
HO Brδ
(I)
H+
Br–
+
+
2
N
Br
Br
80 °C
O
O
O
O
H2O
H2O
+
HO Brδ
(II)
+
N
Br
N
N
O
O
OH
H
Monobromobenzoxazines 3; General Procedure
OH
+
(b) Brδ participation in the reaction
N-(2-(Prop-1-en-2-yl)phenyl)benzamide 1 (0.3 mmol) and NBS (2a,
0.36 mmol) in H2O (3 mL) was stirred at 25 °C for 2–3 h. Then, the re-
action mixture was extracted with EtOAc. The organic layer was dried
over anhydrous Na2SO4, and then concentrated in vacuo. The residue
was purified by column chromatography on silica gel (petroleum
ether/EtOAc) to give the desired product 3.
Br
O
N
+
Brδ OH
3a
– H+
Br
Br
H
4-(Bromomethyl)-4-methyl-2-phenyl-4H-benzo[d][1,3]oxazine (3a)
O
Br
O
Yield: 87 mg (92%); white solid; mp 82.9–83.4 °C.
N
H
N
IR (KBr): 1598, 1448, 1320, 1069, 747, 688, 594 cm–1
.
B
C
1H NMR (400 MHz, CDCl3):  = 8.14 (d, J = 8.0 Hz, 2 H), 7.41–7.37 (m, 3
H), 7.27 (s, 2 H), 7.14-7.08 (m, 2 H), 3.69 (d, J = 12.0 Hz, 1 H), 3.47 (d,
J = 12.0 Hz, 1 H), 1.84 (s, 3 H).
– H+
13C NMR (101 MHz, CDCl3):  = 155.8, 138.6, 131.8, 131.1, 129.1,
127.8, 126.6, 126.3, 125.1, 122.8, 77.6, 39.3, 24.4.
HRMS: m/z [M + H]+ calcd for C16H14BrNO: 316.0332; found:
Br
O
Br
Br
O
N
H
316.0375.
N
NH
4a
4-(Bromomethyl)-4-methyl-2-(p-tolyl)-4H-benzo[d][1,3]oxazine(3b)
A
+
Brδ
OH
O
Yield: 92 mg (92%); light yellow oil.
1a
IR (KBr): 2362, 1610, 1568, 1313, 1265, 1068, 754, 546 cm–1
.
Scheme 7 Plausible reaction mechanism
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–J

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X. Zhang et al.
Paper
Synthesis
1H NMR (400 MHz, DMSO-d6):  = 8.02 (d, J = 8.0 Hz, 2 H), 7.42–7.30
(m, 4 H), 7.29–7.19 (m, 2 H), 4.00 (d, J = 12.0 Hz, 1 H), 3.94 (d, J = 12.0
Hz, 1 H), 2.38 (s, 3 H), 1.83 (s, 3 H).
13C NMR (101 MHz, DMSO-d6):  = 155.1, 141.8, 138.5, 129.3, 129.0,
127.7, 127.1, 126.7, 124.7, 124.0, 78.5, 41.1, 25.6, 21.1.
4-(Bromomethyl)-2-(4-chlorophenyl)-4-methyl-4H-ben-
zo[d][1,3]oxazine (3g)
Yield: 95 mg (90%); white solid; mp 109.5–110.5 °C.
IR (KBr): 1621, 1480, 1240, 1069, 831, 749, 582, 492 cm–1
.
1H NMR (400 MHz, DMSO-d6):  = 8.11 (d, J = 8.0 Hz, 2 H), 7.60 (d, J =
8.0 Hz, 2 H), 7.45–7.33 (m, 2 H), 7.33–7.21 (m, 2 H), 4.03 (d, J = 12.0
Hz, 1 H), 3.97 (d, J = 12.0 Hz, 1 H), 1.84 (s, 3 H).
HRMS: m/z [M + H]+ calcd for C17H16BrNO: 330.0488; found:
330.0510.
13C NMR (101 MHz, DMSO-d6):  = 154.1, 138.1, 136.6, 130.7, 129.3,
128.7, 127.2, 127.0, 124.9, 124.1, 79.9, 41.3, 25.8.
HRMS: m/z [M + H]+ calcd for C16H13BrClNO: 349.9942; found:
349.9950.
4-(Bromomethyl)-2-(4-methoxyphenyl)-4-methyl-4H-ben-
zo[d][1,3]oxazine (3c)
Yield: 96 mg (91%); white solid; mp 72.0–72.8 °C.
IR (KBr): 1567, 1512, 1480, 1269, 1248, 1067, 835, 770, 551 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.08 (d, J = 12.0 Hz, 2 H), 7.22 (s, 2 H),
7.12–7.00 (m, 2 H), 6.85 (d, J = 8.0 Hz, 2 H), 3.74 (s, 3 H), 3.65 (d, J =
12.0 Hz, 1 H), 3.41 (d, J = 8.0 Hz, 1 H), 1.80 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 162.5, 156.2, 139.4, 130.2, 129.6,
127.0, 126.4, 125.3, 124.7, 123.3, 113.7, 77.9, 55.4, 39.8, 24.7.
4-(Bromomethyl)-4-methyl-2-(4-(trifluoromethyl)phenyl)-4H-
benzo[d][1,3]oxazine (3i)
Yield: 101 mg (88%); white solid; mp 71.1–71.9 °C.
IR (KBr): 3177, 3067, 2904, 1669, 1630, 1595, 1266, 1160, 759, 690
cm–1
.
HRMS: m/z [M + H]+ calcd for C17H16BrNO2: 346.0437; found:
346.0470.
1H NMR (400 MHz, DMSO-d6):  = 8.32 (d, J = 8.0 Hz, 2 H), 7.90 (d, J =
8.0 Hz, 2 H), 7.48–7.27 (m, 4 H), 4.06 (d, J = 12.0 Hz, 1 H), 4.01 (d, J =
12.0 Hz, 1 H), 1.88 (s, 3 H).
4-(Bromomethyl)-4-methyl-2-(o-tolyl)-4H-benzo[d][1,3]oxazine (3d)
13C NMR (101 MHz, DMSO-d6):  = 154.2, 138.4, 136.2, 132.0, 131.7,
129.9, 128.7 (q, J = 70.7 Hz), 127.5, 125.9, 125.6, 124.6, 123.1, 79.7,
41.8, 26.3.
HRMS: m/z [M + H]+ calcd for C17H13BrF3NO: 384.0205; found:
384.0224.
Yield: 84 mg (84%); light yellow oil.
IR (KBr): 2925, 1717, 1612, 1473, 1240, 1023, 824, 726, 478 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.86 (d, J = 8.0 Hz, 1 H), 7.28–7.11 (m, 6
H), 7.04 (d, J = 8.0 Hz, 1 H), 3.70 (d, J = 12.0 Hz, 1 H), 3.52 (d, J = 12.0
Hz, 1 H), 2.58 (s, 3 H), 1.80 (s, 3 H).
4-(Bromomethyl)-4-methyl-2-(4-nitrophenyl)-4H-ben-
zo[d][1,3]oxazine (3j)
13C NMR (101 MHz, CDCl3):  = 157.6, 138.6, 132.2, 131.5, 130.6,
130.1, 129.6, 127.0, 126.5, 125.8, 123.3, 78.8, 40.1, 25.7, 21.8.
Yield: 94 mg (87%); yellow solid; mp 134.0–135.0 °C.
IR (KBr): 1589, 1518, 1349, 1268, 1068, 850, 752, 706 cm–1
HRMS: m/z [M + H]+ calcd for C17H16BrNO: 330.0488; found:
330.0456.
.
1H NMR (400 MHz, CDCl3):  = 8.37 (d, J = 12.0 Hz, 2 H), 8.28 (d, J = 8.0
Hz, 2 H), 7.42–7.31 (m, 2 H), 7.30–7.26 (m, 1 H), 7.19 (d, J = 8.0 Hz, 1
H), 3.76 (d, J = 12.0 Hz, 1 H), 3.56 (d, J = 12.0 Hz, 1 H), 1.94 (s, 3 H).
4-(Bromomethyl)-2-(2-methoxyphenyl)-4-methyl-4H-ben-
zo[d][1,3]oxazine (3e)
13C NMR (101 MHz, CDCl3):  = 154.0, 149.6, 138.4, 138.1, 129.9,
Yield: 89 mg (86%); light yellow oil.
IR (KBr): 1597, 1461, 1247, 1021, 751, 597, 495 cm–1
.
129.1, 127.9, 126.9, 126.1, 123.4, 123.3, 78.8, 39.9, 25.1.
HRMS: m/z [M + H]+ calcd for C16H13BrN2O3: 361.0182; found:
361.0201.
1H NMR (400 MHz, DMSO-d6):  = 7.64–7.62 (m, 1 H), 7.53–7.45 (m, 1
H), 7.38–7.32 (m, 2 H), 7.28–7.24 (m, 1 H), 7.19–7.17 (m, 1 H), 7.12 (d,
J = 8.0 Hz, 1 H), 7.07–6.99 (m, 1 H), 4.11 (d, J = 12.0 Hz, 1 H), 3.93 (d,
J = 12.0 Hz, 1 H), 3.83 (s, 3 H), 1.78 (s, 3 H).
4-(Bromomethyl)-2-isopropyl-4-methyl-4H-benzo[d][1,3]oxazine
(3l)
13C NMR (101 MHz, DMSO-d6):  = 158.5, 156.8, 139.0, 132.6, 130.9,
Yield: 72 mg (85%); light yellow oil.
129.5, 127.3, 125.1, 124.4, 123.1, 120.5, 112.8, 79.7, 56.3, 41.3, 26.7.
IR (KBr): 1770, 1692, 1383, 1369, 1503, 1208, 802, 748, 510 cm–1
.
HRMS: m/z [M + H]+ calcd for C17H16BrNO2: 346.0437; found:
1H NMR (400 MHz, CDCl3):  = 7.34–7.27 (m, 1 H), 7.24–7.14 (m, 2 H),
7.09 (d, J = 8.0 Hz, 1 H), 3.66 (d, J = 8.0 Hz, 1 H), 3.51 (d, J = 12.0 Hz, 1
H), 2.69–2.62 (m, 1 H), 1.81 (s, 3 H), 1.30–1.27 (m, 6 H).
346.0461.
4-(Bromomethyl)-2-(4-fluorophenyl)-4-methyl-4H-ben-
zo[d][1,3]oxazine (3f)
13C NMR (101 MHz, CDCl3):  = 165.8, 138.6, 129.4, 126.5, 124.9,
Yield: 89 mg (89%); white solid; mp 128.7–129.2 °C.
123.2, 77.5, 39.9, 34.4, 25.3, 19.6.
IR (KBr): 1575, 1481, 1319, 1069, 839, 747, 590, 501 cm–1
.
HRMS: m/z [M + H]+ calcd for C13H16BrNO: 282.0488; found:
1H NMR (400 MHz, DMSO-d6):  = 8.25–8.09 (m, 2 H), 7.43–7.34 (m, 4
H), 7.33–7.20 (m, 2 H), 4.03 (d, J = 12.0 Hz, 1 H), 3.97 (d, J = 8.0 Hz, 1
H), 1.84 (s, 3 H).
13C NMR (101 MHz, DMSO-d6):  = 166.0, 163.5, 154.6, 138.7, 130.7
(d, J = 10.1 Hz), 129.8, 128.9, 127.4, 125.3 (d, J = 80.8 Hz), 116.2 (d, J =
30.3 Hz), 79.3, 41.7, 26.2.
282.0475.
4-(Bromomethyl)-2-(4-(chloromethyl)phenyl)-4-methyl-4H-ben-
zo[d][1,3]oxazine (3m)
Yield: 96 mg (88%); white solid; mp 85.4–86.1 °C.
IR (KBr): 2356, 1595, 1456, 1245, 1064, 749, 689, 592, 498 cm–1
.
HRMS: m/z [M + H]+ calcd for C16H13BrFNO: 334.0237; found:
334.0270.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–J

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X. Zhang et al.
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Synthesis
1H NMR (400 MHz, CDCl3):  = 8.20 (d, J = 8.0 Hz, 2 H), 7.46 (d, J = 8.0
Hz, 2 H), 7.37–7.30 (m, 2 H), 7.25–7.19 (m, 1 H), 7.15 (d, J = 8.0 Hz, 1
H), 4.61 (s, 2 H), 3.74 (d, J = 12.0 Hz, 1 H), 3.53 (d, J = 12.0 Hz, 1 H),
1.91 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 155.6, 140.8, 139.0, 132.4, 129.7,
128.7, 128.5, 127.0, 125.6, 123.3, 78.2, 45.7, 39.8, 24.9.
IR (KBr): 1615, 1470, 1447, 1318, 1069, 1024, 828, 639, 556 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.11 (d, J = 8.0 Hz, 2 H), 7.44–7.36 (m, 4
H), 7.17–7.12 (m, 2 H), 3.64 (d, J = 8.0 Hz, 1 H), 3.46 (d, J = 12.0 Hz, 1
H), 1.82 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 156.0, 137.8, 132.2, 131.4, 128.4,
127.9, 126.7, 125.9, 119.0, 38.9, 24.5.
HRMS: m/z [M + H]+ calcd for C17H15BrClNO: 364.0098; found:
364.0109.
HRMS: m/z [M + H]+ calcd for C16H13Br2NO: 393.9437; found:
393.9452.
4-(Bromomethyl)-4-methyl-2-(thiophen-2-yl)-4H-ben-
zo[d][1,3]oxazine (3o)
6-Bromo-4-(bromomethyl)-4-methyl-2-(p-tolyl)-4H-ben-
zo[d][1,3]oxazine (4b)
Yield: 80 mg (83%); white solid; mp 66.5–67.4 °C.
IR (KBr): 1572, 1426, 1270, 1032, 747, 694, 593 cm–1
1H NMR (400 MHz, CDCl3):  = 7.86 (d, J = 4.0 Hz, 1 H), 7.53 (d, J = 4.0
Hz, 1 H), 7.37–7.33 (m, 2 H), 7.26–7.12 (m, 3 H), 3.79 (d, J = 8.0 Hz, 1
H), 3.56 (d, J = 12.0 Hz, 1 H), 1.94 (s, 3 H).
Yield: 86 mg (70%); light yellow solid; mp 164.8–165.8 °C.
IR (KBr): 2357, 1618, 1472, 1318, 1253, 1066, 1025, 822, 686, 553 cm–1
1H NMR (400 MHz, DMSO-d6):  = 7.99 (d, J = 8.0 Hz, 2 H), 7.64 (d, J =
4.0 Hz, 1 H), 7.52–7.50 (m, 1 H), 7.32 (d, J = 8.0 Hz, 2 H), 7.15 (d, J = 8.0
Hz, 1 H), 4.07 (d, J = 12.0 Hz, 1 H), 3.98 (d, J = 12.0 Hz, 1 H), 2.37 (s, 3
H), 1.80 (s, 3 H).
.
.
13C NMR (101 MHz, CDCl3):  = 152.8, 139.0, 136.6, 130.7, 129.7,
127.8, 127.0, 126.7, 125.3, 123.3, 78.5, 39.6, 24.8.
HRMS: m/z [M + H]+ calcd for C14H12BrNOS: 321.9896; found:
13C NMR (101 MHz, DMSO-d6):  = 156.0, 142.6, 138.4, 132.6, 129.7,
129.6, 129.3, 128.2, 127.3, 127.2, 119.2, 79.1, 41.5, 26.4, 21.6.
321.9879.
HRMS: m/z [M + H]+ calcd for C17H15Br2NO: 407.9593; found:
407.9574.
4-(Bromomethyl)-6-chloro-4-methyl-2-phenyl-4H-ben-
zo[d][1,3]oxazine (3p)
6-Bromo-4-(bromomethyl)-2-(4-methoxyphenyl)-4-methyl-4H-
benzo[d][1,3]oxazine (4c)
Yield: 96 mg (91%); white solid; mp 119.3–120.0 °C.
IR (KBr): 1616, 1576, 1448, 1260, 1013, 796, 693, 560 cm–1
.
Yield: 91 mg (71%); white solid; mp 155.9–156.7 °C.
1H NMR (400 MHz, CDCl3):  = 8.19 (d, J = 8.0 Hz, 2 H), 7.48 (m, 3 H),
7.33–7.24 (m, 2 H), 7.14 (s, 1 H), 3.72 (d, J = 12.0 Hz, 1 H), 3.53 (d, J =
12.0 Hz, 1 H), 1.90 (s, 3 H).
IR (KBr): 1617, 1509, 1321, 1241, 1023, 825, 649, 553 cm–1
.
1H NMR (400 MHz, DMSO-d6):  = 8.05 (d, J = 8.0 Hz, 2 H), 7.64 (s, 1
H), 7.52 (d, J = 12.0 Hz, 1 H), 7.15–7.05 (m, 3 H), 4.07 (d, J = 12.0 Hz, 1
H), 3.98 (d, J = 12.0 Hz, 1 H), 3.84 (s, 3 H), 1.81 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 155.3, 136.8, 130.9, 130.8, 130.7,
128.6, 127.4, 127.3, 127.3, 125.8, 122.5, 76.9, 38.3, 23.9.
HRMS: m/z [M + H]+ calcd for C16H13BrClNO: 349.9942; found:
13C NMR (101 MHz, DMSO-d6):  = 162.3, 155.4, 138.1, 132.1, 129.6,
129.1, 126.8, 126.6, 123.8, 118.3, 113.9, 78.4, 55.4, 40.9, 25.7.
349.9929.
HRMS: m/z [M + H]+ calcd for C17H15Br2NO2: 423.9542; found:
423.9556.
4-(Bromomethyl)-2,4-diphenyl-4H-benzo[d][1,3]oxazine (3q)
Yield: 102 mg (90%); light yellow oil.
IR (KBr): 1733, 1594, 1571, 1448, 1239, 1088, 978 cm–1
6-Bromo-4-(bromomethyl)-4-methyl-2-(o-tolyl)-4H-ben-
zo[d][1,3]oxazine (4d)
.
Yield: 83 mg (68%); light yellow oil.
IR (KBr): 3010, 1790, 1738, 1189, 1027, 740, 717, 588, 487 cm–1
1H NMR (400 MHz, DMSO-d6):  = 7.86 (d, J = 8.0 Hz, 1 H), 7.67 (s, 1
H), 7.53–7.50 (m, 1 H), 7.42 (t, J = 16.0 Hz, 1 H), 7.32 (t, J = 12.0 Hz, 2
H), 7.14 (d, J = 8.0 Hz, 1 H), 4.18 (d, J = 12.0 Hz, 1 H), 4.02 (d, J = 8.0 Hz,
1 H), 2.60 (s, 3 H), 1.82 (s, 3 H).
1H NMR (400 MHz, DMSO-d6):  = 8.23 (d, J = 4.0 Hz, 2 H), 7.63–7.53
(m, 4 H), 7.46–7.40 (m, 3 H), 7.38–7.28 (m, 5 H), 4.62 (d, J = 12.0 Hz, 1
H), 4.56 (d, J = 12.0 Hz, 1 H).
13C NMR (101 MHz, DMSO-d6):  = 155.5, 141.2, 139.3, 132.5, 132.0,
130.0, 129.1, 129.1, 129.0, 128.1, 127.3, 126.4, 126.3, 125.9, 125.5,
82.9, 39.5.
.
HRMS: m/z [M + H]+ calcd for C21H16BrNO: 378.0488; found:
13C NMR (101 MHz, DMSO-d6):  = 157.5, 138.4, 138.2, 132.6, 132.1,
378.0497.
131.9, 131.2, 129.2, 127.3, 127.2, 126.2, 79.7, 41.9, 27.0, 21.9.
HRMS: m/z [M + H]+ calcd for C17H15Br2NO: 407.9593; found:
407.9609.
Multibromobenzoxazines 4; General Procedure
N-(2-(Prop-1-en-2-yl)phenyl)benzamide 1 (0.3 mmol) and NBS (2a,
1.5 mmol) in H2O (3 mL) was stirred at 80 °C for 2–3 h. After cooling
to room temperature, the reaction mixture was extracted with EtOAc.
The organic layer was dried over anhydrous Na2SO4, and then concen-
trated in vacuo. The residue was purified by column chromatography
on silica gel (petroleum ether/EtOAc) to deliver the desired product 4.
6-Bromo-4-(bromomethyl)-2-(4-fluorophenyl)-4-methyl-4H-ben-
zo[d][1,3]oxazine (4f)
Yield: 105 mg (85%); white solid; mp 130.5–131.2 °C.
IR (KBr): 1621, 1472, 1229, 1151, 1078, 827, 732, 652, 554 cm–1
.
1H NMR (400 MHz, DMSO-d6):  = 8.19–8.11 (m, 2 H), 7.67 (s, 1 H),
7.55–7.52 (m, 1 H), 7.37 (t, J = 16.0 Hz, 2 H), 7.17 (d, J = 8.0 Hz, 1 H),
4.11 (d, J = 12.0 Hz, 1 H), 4.01 (d, J = 12.0 Hz, 1 H), 1.83 (s, 3 H).
6-Bromo-4-(bromomethyl)-4-methyl-2-phenyl-4H-ben-
zo[d][1,3]oxazine (4a)
Yield: 106 mg (90%); light yellow solid; mp 120.2–121.2 °C.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–J

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X. Zhang et al.
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Synthesis
13C NMR (101 MHz, DMSO-d6):  = 165.7, 163.2, 154.6, 137.7, 132.2,
130.3, 129.1, 128.1, 126.8, 118.9, 115.8 (d, J = 30.3 Hz), 78.9, 41.1,
26.0.
HRMS: m/z [M + H]+ calcd for C16H12Br2FNO: 411.9342; found:
411.9357.
6,8-Dibromo-4-(bromomethyl)-2-(4-(chloromethyl)phenyl)-4-
methyl-4H-benzo[d][1,3]oxazine (4m)
Yield: 69 mg (44%); white solid; mp 129.7–130.2 °C.
IR (KBr): 2357, 2076, 1608, 1268, 1211, 1069, 826, 667, 601 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.22 (t, J = 20.0 Hz, 2 H), 7.77 (d, J = 4.0
Hz, 1 H), 7.48 (d, J = 8.0 Hz, 2 H), 7.24 (s, 1 H), 4.63 (s, 1 H), 4.52 (s, 1
H), 3.71 (d, J = 12.0 Hz, 1 H), 3.53 (d, J = 12.0 Hz, 1 H), 1.90 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 156.4, 141.1, 136.1, 135.4, 131.1,
129.5, 128.1, 126.0, 125.3, 121.6, 118.9, 77.8, 45.1, 38.3, 32.1.
6-Bromo-4-(bromomethyl)-2-(4-chlorophenyl)-4-methyl-4H-
benzo[d][1,3]oxazine (4g)
Yield: 82 mg (64%); white solid; mp 145.5–146.5 °C.
IR (KBr): 1618, 1088, 825, 727, 639, 611, 555, 497 cm–1
.
HRMS: m/z [M + H]+ calcd for C17H13Br3ClNO: 519.8309; found:
519.8318.
1H NMR (400 MHz, CDCl3):  = 8.13 (d, J = 8.0 Hz, 2 H), 7.51–7.39 (m, 3
H), 7.29 (d, J = 4.0 Hz, 1 H), 7.20 (d, J = 8.0 Hz, 1 H), 3.71 (d, J = 12.0 Hz,
1 H), 3.53 (d, J = 12.0 Hz, 1 H), 1.91 (s, 3 H).
8-Bromo-4-(bromomethyl)-4,6-dimethyl-2-phenyl-4H-ben-
zo[d][1,3]oxazine (4n)
13C NMR (101 MHz, CDCl3):  = 155.6, 138.1, 138.0, 132.8, 130.4,
129.6, 128.7, 128.7, 127.2, 126.4, 119.8, 78.0, 39.4, 24.9.
HRMS: m/z [M + H]+ calcd for C16H12Br2ClNO: 427.9047; found:
427.9030.
Yield: 99 mg (81%); white solid; mp 145.9–146.7 °C.
IR (KBr): 1475, 1447, 1316, 1171, 1057, 889, 692, 498 cm–1
1H NMR (400 MHz, CDCl3):  = 8.23–8.20 (m, 2 H), 7.53 (m, 3 H), 7.34
(s, 1 H), 7.26 (s, 1 H), 3.74 (d, J = 12.0 Hz, 1 H), 3.56 (d, J = 12.0 Hz, 1 H),
2.44 (s, 3 H), 1.92 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 156.6, 139.4, 138.3, 132.1, 131.8,
128.3, 128.3, 127.7, 127.0, 126.2, 122.0, 77.7, 39.6, 25.0, 22.8.
HRMS: m/z [M + H]+ calcd for C17H15Br2NO: 407.9593; found:
407.9582.
.
6-Bromo-4-(bromomethyl)-2-(4-iodophenyl)-4-methyl-4H-ben-
zo[d][1,3]oxazine (4h)
Yield: 89 mg (57%); white solid; mp 140.6–141.0 °C.
IR (KBr): 1616, 1468, 1316, 1078, 1004, 821, 722, 627, 553 cm–1
1H NMR (400 MHz, CDCl3):  = 7.90 (d, J = 8.0 Hz, 2 H), 7.80 (d, J = 8.0
Hz, 2 H), 7.47 (d, J = 8.0 Hz, 1 H), 7.28 (s, 1 H), 7.19 (d, J = 8.0 Hz, 1 H),
3.70 (d, J = 12.0 Hz, 1 H), 3.52 (d, J = 12.0 Hz, 1 H), 1.90 (s, 3 H).
.
6-Bromo-4-(bromomethyl)-2-(5-bromothiophen-2-yl)-4-methyl-
4H-benzo[d][1,3]oxazine (4o)
13C NMR (101 MHz, CDCl3):  = 155.4, 137.5, 137.1, 132.3, 131.1,
131.0, 129.3, 128.3, 126.7, 125.9, 119.3, 98.7, 77.5, 38.9, 24.5.
HRMS: m/z [M + H]+ calcd for C16H12Br2INO: 519.8403; found:
519.8422.
Yield: 112 mg (78%); white solid; mp 126.0–127.0 °C.
IR (KBr): 1611, 1261, 1077, 1037, 802, 654, 558, 491 cm–1
1H NMR (400 MHz, DMSO-d6):  = 7.70 (d, J = 4.0 Hz, 1 H), 7.63–7.53
(m, 2 H), 7.40 (d, J = 4.0 Hz, 1 H), 7.16 (d, J = 8.0 Hz, 1 H), 4.14 (d, J =
12.0 Hz, 1 H), 4.00 (d, J = 12.0 Hz, 1 H), 1.86 (s, 3 H).
13C NMR (101 MHz, DMSO-d6):  = 151.1, 137.4, 137.1, 132.3, 131.8,
131.2, 129.1, 127.0, 126.5, 119.0, 117.8, 79.5, 40.9, 25.8.
HRMS: m/z [M + H]+ calcd for C14H10Br3NOS: 477.8106; found:
477.8113.
.
6-Bromo-4-(bromomethyl)-4-methyl-2-(4-(trifluoromethyl)phe-
nyl)-4H-benzo[d][1,3]oxazine (4i)
Yield: 81 mg (58%); white solid; mp 111.2–111.9 °C.
IR (KBr): 2362, 1615, 1314, 1108, 1015, 660, 591 cm–1
.
1H NMR (400 MHz, DMSO-d6):  = 8.35–8.30 (m, 2 H), 7.99–7.90 (m, 2
H), 7.77–7.73 (m, 1 H), 7.63–7.18 (m, 2 H), 4.23–4.15 (m, 1 H), 4.11–
4.01 (m, 1 H), 1.89 (s, 3 H).
13C NMR (101 MHz, DMSO-d6):  = 154.1, 137.3, 132.3, 130.5, 129.2,
128.6, 128.3, 127.1 (q, J = 3.0 Hz), 127.0, 125.5, 119.6, 79.3, 41.3, 26.2.
6-Bromo-4-(bromomethyl)-2,4-diphenyl-4H-benzo[d][1,3]ox-
azine (4q)
Yield: 81 mg (59%); light yellow oil.
IR (KBr): 1615, 1574, 1468, 1447, 1256, 1069, 827, 692 cm–1
1H NMR (400 MHz, DMSO-d6):  = 8.18 (d, J = 8.0 Hz, 2 H), 7.80 (d, J =
4.0 Hz, 1 H), 7.59–7.50 (m, 4 H), 7.40 (d, J = 8.0 Hz, 2 H), 7.31 (m, 3 H),
7.19 (d, J = 8.0 Hz, 1 H), 4.69 (d, J = 12.0 Hz, 1 H), 4.52 (d, J = 12.0 Hz, 1
H).
HRMS: m/z [M + H]+ calcd for C17H12Br2F3NO: 461.9311; found:
461.9302.
.
6,8-Dibromo-4-(bromomethyl)-2-(2-bromopropan-2-yl)-4-meth-
yl-4H-benzo[d][1,3]oxazine (4l)
Yield: 101 mg (65%); light yellow oil.
IR (KBr): 1593, 1390, 1379, 1184, 1030, 740, 565 cm–1
1H NMR (400 MHz, CDCl3):  = 7.65 (s, 1 H), 7.11 (s, 1 H), 3.58 (d, J =
12.0 Hz, 1 H), 3.54 (d, J = 12.0 Hz, 1 H), 1.99 (d, J = 8.0 Hz, 6 H), 1.74 (s,
3 H).
13C NMR (101 MHz, DMSO-d6):  = 156.1, 140.7, 138.7, 133.0, 132.7,
131.7, 129.3, 129.2, 129.1, 128.6, 128.4, 128.2, 127.5, 126.2, 119.4,
82.8.
HRMS: m/z [M + H]+ calcd for C21H15Br2NO: 455.9593; found:
455.9602.
.
13C NMR (101 MHz, CDCl3):  = 161.5, 135.3, 128.9, 125.6, 122.0,
119.6, 58.3, 37.8, 30.6, 30.2, 25.2.
4-(Fluoromethyl)-4-methyl-2-phenyl-4H-benzo[d][1,3]oxazine (5a)
HRMS: m/z [M + H]+ calcd for C13H13Br4NO: 515.7803; found:
Yield: 34 mg (45%); light yellow oil.
IR (KBr): 1520, 1447, 1317, 1075, 757, 687, 646, 547 cm–1
.
515.7814.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–J

I
X. Zhang et al.
Paper
Synthesis
1H NMR (400 MHz, CDCl3):  = 8.19 (d, J = 8.0 Hz, 2 H), 7.50 (m, 3 H),
7.38 (d, J = 8.0 Hz, 2 H), 7.29–7.23 (m, 1 H), 7.19 (d, J = 8.0 Hz, 1 H),
4.64 (m, 1 H), 4.46 (m, 1 H), 1.85 (d, J = 4.0 Hz, 3 H).
HRMS: m/z [M + H]+ calcd for C20H16BrNOS: 398.0209; found:
398.0218.
13C NMR (101 MHz, CDCl3):  = 156.3, 139.5, 132.5, 131.5, 129.6,
128.3, 128.1, 126.8, 125.5, 123.4, 87.0, 85.1, 78.9, 22.4.
Funding Information
19F NMR (376 MHz, CDCl3):  = –225.10.
HRMS: m/z [M + H]+ calcd for C16H14FNO: 256.1132; found: 256.1114.
We gratefully acknowledge the National Natural Science Foundation
of China (21772138 and 21672157), the Priority Academic Program
Development of Jiangsu Higher Education Institutions (PAPD), the
Project of Scientific and Technologic Infrastructure of Suzhou
6-Chloro-4-(chloromethyl)-4-methyl-2-phenyl-4H-ben-
zo[d][1,3]oxazine (6a)
(SZS201708) and Soochow University.
N
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o
n
a
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i
e
n
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o
u
n
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ati
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i
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a
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C
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i
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a
(2
1
6
7
2
1
5
7)
Yield: 60 mg (65%); light yellow solid; mp 102.9–103.8 °C.
IR (KBr): 1688, 1615, 1448, 1313, 1066, 756, 690, 512 cm–1
.
Acknowledgment
1H NMR (400 MHz, DMSO-d6):  = 8.15–8.13 (m, 2 H), 7.65–7.61 (m, 3
H), 7.58–7.54 (m, 3 H), 4.26 (d, J = 12.0 Hz, 1 H), 4.13 (d, J = 12.0 Hz, 1
H), 1.81 (s, 3 H).
We thank Can Liu in our group for reproducing the results of 3b, 3o,
4a, 4n and 4o.
13C NMR (101 MHz, DMSO-d6):  = 156.9, 135.2, 132.9, 131.8, 131.1,
130.3, 130.2, 129.8, 129.1, 128.4, 123.8, 80.6, 51.8, 26.0.
HRMS: m/z [M + H]+ calcd for C16H13Cl2NO: 306.0447; found:
Supporting Information
306.0430.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610724.
S
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n
N-(4-Bromo-2-((E)-1-bromoprop-1-en-2-yl)phenyl)benzamide (7a)
Yield: 63 mg (53%); yellow oil.
IR (KBr): 1739, 1646, 1313, 1220, 1092, 780, 563, 423 cm–1
References
.
1H NMR (400 MHz, CDCl3):  = 8.29 (d, J = 8.0 Hz, 1 H), 7.94 (s, 1 H),
7.86–7.79 (m, 2 H), 7.60–7.54 (m, 1 H), 7.50 (m, 3 H), 7.26 (d, J = 4.0
Hz, 1 H), 6.51 (s, 1 H), 2.08 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 139.2, 134.6, 132.2, 131.8, 130.3,
129.0, 127.0, 124.5, 123.4, 121.5, 117.4, 112.5, 106.2, 24.9, 9.6.
(1) (a) Krantz, A.; Spencer, R. W.; Tam, T. F.; Liak, T. J.; Copp, L. J.;
Thomas, E. M.; Rafferty, S. P. J. Med. Chem. 1990, 33, 464.
(b) Hays, S. J.; Caprathe, B. W.; Gilmore, J. L.; Amin, N.;
Emmerling, M. R.; Michael, W.; Nadimpalli, R.; Nath, R.; Raser,
K. J.; Stafford, D.; Watson, D.; Wang, K.; Jaen, J. C. J. Med. Chem.
1998, 41, 1060. (c) Zhang, P.-W.; Terefenko, T. A.; Fensome, A.;
Zhang, Z.-M.; Zhu, Y.; Cohen, J.; Winneker, R.; Wrobel, J.;
Yardley, J. Bioorg. Med. Chem. Lett. 2002, 12, 787.
HRMS: m/z [M + H]+ calcd for C16H13Br2NO: 393.9437; found:
393.9427.
(2) (a) Djabrouhou, N.; Guermouche, M. H. J. Pharm. Biomed. Anal.
2014, 100, 11. (b) Zhang, P.; Terefenko, T. A.; Fensome, A.;
Wrobel, J.; Winneker, R.; Lundeen, S.; Marschke, K. B.; Zhang, Z.
J. Med. Chem. 2002, 45, 4379.
4-(Bromomethyl)-4-methyl-2,6-diphenyl-4H-benzo[d][1,3]ox-
azine (8a)
Yield: 58 mg (49%); white solid; mp 167.1–168.0 °C.
(3) (a) Wang, Z.; Ran, Q.-C.; Zhu, R.-Q.; Gu, Y. RSC Adv. 2013, 3,
1350. (b) Wang, H.; Wang, J.; He, X.-Y.; Feng, T.-T.; Ramdani, N.;
Luan, M.-J.; Liu, W.-B.; Xu, X.-D. RSC Adv. 2014, 4, 64798.
(4) Recent examples, see: (a) Lee, W.-C.; Shen, H.-C.; Hu, W.-P.; Lo,
W.-S.; Murali, C.; Vandavasi, J. K.; Wang, J.-J. Adv. Synth. Catal.
2012, 354, 2218. (b) Liu, Q.-L.; Chen, P.-H.; Liu, G.-S. ACS Catal.
2013, 3, 178. (c) Reddy, B. V. S.; Babu, R. A.; Reddy, M. R.; Reddy,
B. J. M.; Sridhar, B. RSC Adv. 2014, 4, 44629. (d) Munusamy, S.;
Venkatesan, S.; Sathiyanarayanan, K. I. Tetrahedron Lett. 2015,
56, 203.
IR (KBr): 1622, 1595, 1319, 1268, 1164, 1091, 1065, 765, 695, 570 cm–1
.
1H NMR (400 MHz, DMSO-d6):  = 8.15 (d, J = 8.0 Hz, 2 H), 7.75 (d, J =
8.0 Hz, 3 H), 7.67 (d, J = 8.0 Hz, 1 H), 7.60–7.50 (m, 5 H), 7.38–7.32 (m,
2 H), 4.16 (d, J = 8.0 Hz, 1 H), 4.07 (d, J = 12.0 Hz, 1 H), 1.91 (s, 3 H).
13C NMR (101 MHz, DMSO-d6):  = 155.5, 139.9, 139.2, 138.3, 132.4,
132.3, 129.4, 129.0, 128.1, 128.0, 127.9, 127.1, 125.9, 122.9, 79.5, 41.9,
26.4.
HRMS: m/z [M + H]+ calcd for C22H18BrNO: 392.0645; found:
392.0629.
(5) (a) Okuma, K.; Yasuda, T.; Takeshita, I.; Shioji, K.; Yokomori, Y.
Tetrahedron 2007, 63, 8250. (b) Jaganathan, A.; Garzan, A.;
Whitehead, D. C.; Staples, R. J.; Borhan, B. Angew. Chem. Int. Ed.
2011, 50, 2593. (c) Cahard, E.; Bremeyer, N.; Gaunt, M. J. Angew.
Chem. Int. Ed. 2013, 52, 9284. (d) Yin, Q.; You, S.-L. Org. Lett.
2014, 16, 2426. (e) Deng, Q.-H.; Chen, J.-R.; Wei, Q.; Zhao, Q.-Q.;
Lu, L.-Q.; Xiao, W.-J. Chem. Commun. 2015, 51, 3537.
(6) Li, B.; Park, Y.; Chang, S. J. Am. Chem. Soc. 2014, 136, 1125.
(7) (a) Kobayashi, K.; Miyamoto, K.; Morikaea, O.; Konishi, H. Bull.
Chem. Soc. Jpn. 2005, 78, 886. (b) Yu, Y.-J.; Zhang, F.-L.; Cheng, J.;
Hei, J.-H.; Deng, W.-T.; Wang, Y.-F. Org. Lett. 2018, 20, 24.
(c) Cortés González, M. A.; Nordeman, P.; Gómez, A. B.; Meyer,
D. N.; Antoni, G.; Schou, M.; Szabó, K. J. Chem. Commun. 2018,
54, 4286.
4-(Bromomethyl)-4-methyl-2-phenyl-6-(thiophen-2-yl)-4H-ben-
zo[d][1,3]oxazine (8b)
Yield: 75 mg (63%); yellow solid; mp 116.0–117.0 °C.
IR (KBr): 1623, 1570, 1449, 1269, 1069, 829, 696, 563 cm–1
.
1H NMR (400 MHz, DMSO-d6):  = 8.17–8.11 (m, 2 H), 7.74 (d, J = 4.0
Hz, 1 H), 7.64–7.51 (m, 6 H), 7.28 (d, J = 8.0 Hz, 1 H), 7.17 (m, 1 H),
4.14 (d, J = 12.0 Hz, 1 H), 4.06 (d, J = 8.0 Hz, 1 H), 1.90 (s, 3 H).
13C NMR (101 MHz, DMSO-d6):  = 155.5, 143.3, 138.3, 133.0, 132.3,
132.3, 129.0, 128.3, 128.1, 126.8, 126.3, 126.0, 124.5, 121.5, 79.4, 41.8,
26.4.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–J

J
X. Zhang et al.
Paper
Synthesis
(8) Okuma, K.; Yasuda, T.; Takeshita, I.; Shioji, K.; Yokomori, Y. Bull.
Chem. Soc. Jpn. 2007, 80, 1824.
(9) (a) Wang, Y.-M.; Wu, J.; Hoong, C.; Rauniyar, V.; Toste, F. D.
J. Am. Chem. Soc. 2012, 134, 12928. (b) Zhao, J.-F.; Duan, X.-H.;
Yang, H.; Guo, L.-N. J. Org. Chem. 2015, 80, 11149.
(10) Fu, W.-J.; Han, X.; Zhu, M.; Xu, C.; Wang, Z.-Q.; Ji, B.-M.; Hao, X.-
Q.; Song, M.-P. Chem. Commun. 2016, 52, 13413.
(11) Yang, H.; Duan, X.-H.; Zhao, J.-F.; Guo, L.-N. Org. Lett. 2015, 17,
1998.
(g) Butler, R. N.; Coyne, A. G. Chem. Rev. 2010, 110, 6302.
(h) Gawande, M. B.; Bonifacio, V. D. B.; Luque, R.; Branco, P. S.;
Varma, R. S. Chem. Soc. Rev. 2013, 42, 5522.
(19) (a) Copley, S. D.; Knowles, J. R. J. Am. Chem. Soc. 1987, 109, 5008.
(b) Breslow, R.; Maitra, U.; Rideout, D. Tetrahedron Lett. 1983,
24, 1901.
(20) (a) Xie, P.-Z.; Wang, J.-Y.; Liu, Y.-N.; Fan, J.; Wo, X.-Y.; Fu, W.-S.;
Sun, Z.-L.; Loh, T.-P. Nat. Commun. 2018, 9, 1321. (b) Wang, B.;
Tang, L.; Liu, L.-Y.; Li, Y.-N.; Yang, Y.; Wang, Z.-Y. Green Chem.
2017, 19, 5794.
(12) Wang, J.; Sang, R.-Y.; Chong, X.-L.; Zhao, Y.-N.; Fan, W.-J.; Li, Z.-
J.; Zhao, J.-C. Chem. Commun. 2017, 53, 7961.
(21) When R2 = H, only N-(2-(2-bromoacetyl)phenyl)benzamide
could be obtained, and when we employed the corresponding
alkynyl amide, the reaction gave N-(2-(2,2-dibromoacetyl)phe-
nyl)benzamide as product (Scheme 8).
(13) (a) Chu, X.-Q.; Xu, X.-P.; Meng, H.; Ji, S.-J. RSC Adv. 2015, 5,
67829. (b) Zhu, S.-L.; Ji, S.-J.; Zhang, Y. Tetrahedron 2007, 63,
9365. (c) Jiang, R.; Wu, X.-J.; Zhu, X.; Xu, X.-P.; Ji, S.-J. Eur. J. Org.
Chem. 2010, 5946. (d) Jiang, R.; Xu, H.-Y.; Xu, X.-P.; Chu, X.-Q.; Ji,
S.-J. Org. Biomol. Chem. 2011, 9, 5659.
O
Br
(14) Filler, R. Chem. Rev. 1963, 63, 21.
H2O
NH
+
NBS
(15) Recent examples, see: (a) Chun, S.; Chung, Y. K. Org. Lett. 2018,
20, 5583. (b) Zhou, J.; Yeung, Y.-Y. Org. Biomol. Chem. 2014, 12,
7482. (c) Zhou, L.; Tan, C. K.; Jiang, X.-J.; Chen, F.; Yeung, Y.-Y.
J. Am. Chem. Soc. 2010, 132, 15474. (d) Yu, W. Z.; Chen, F.;
Cheng, Y. A.; Yeung, Y.-Y. J. Org. Chem. 2015, 80, 2815. (e) Chen,
J.; Chng, S.; Zhou, L.; Yeung, Y.-Y. Org. Lett. 2011, 13, 6456.
(16) (a) Ross, S. D.; Finkelstein, M.; Petersen, R. C. J. Am. Chem. Soc.
1958, 80, 4327. (b) Ni, S.; El Remaily, M. A. E. A. A. A.; Franzén, J.
Adv. Synth. Catal. 2018, 360, 4197. (c) Shibatomi, K.; Zhang, Y.;
Yamamoto, H. Chem. Asian J. 2008, 3, 1581.
(17) (a) Saikia, I.; Borah, A. J.; Phukan, P. Chem. Rev. 2016, 116, 6837.
(b) Huang, Z.; Zhan, M.; Zhang, S.-G.; Luo, Q.; Zhang, W.-Z.; Xi,
Z.-F. Org. Chem. Front. 2017, 4, 1785.
(18) (a) Lindström, U. M. Chem. Rev. 2002, 102, 2751. (b) Kobayashi,
S.; Manabe, K. Acc. Chem. Res. 2002, 35, 209. (c) Breslow, R. Acc.
Chem. Res. 2004, 37, 471. (d) Li, C.-J.; Chen, L. Chem. Soc. Rev.
2006, 35, 68. (e) Chen, L.; Li, C.-J. Adv. Synth. Catal. 2006, 348,
1459. (f) Chanda, A.; Fokin, V. V. Chem. Rev. 2009, 109, 725.
r.t.
NH
O
O
O
Br
H2O
r.t.
+
NBS
NH
Br
NH
O
O
Scheme 8
(22) See Supporting Information, Figure S2.
(23) (a) Zhang, M.-Z.; Sheng, W.-B.; Jiang, Q.; Tian, M.; Yin, Y.; Guo,
C.-C. J. Org. Chem. 2014, 79, 10829. (b) Podgorsek, A.; Stavber, S.;
Zupan, M.; Iskra, J. Tetrahedron 2009, 65, 4429.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–J