Base-Promoted Chemodivergent Formation of 1,4-Benzoxazepin-5(4H)-ones and 1,3-Benzoxazin-4(4H)-ones Switched by Solvents

Article abstract of DOI:10.3390/molecules24203773

The KOH-promoted chemodivergent benzannulation of ortho-fluorobenzamides with 2-propyn-1-ol can afford either 1,4-benzoxazepin-5(4H)-ones or 1,3-benzoxazin-4(4H)-ones in good yields with high selectivity, depending greatly upon the use of solvents. In the

Full text of DOI:10.3390/molecules24203773

molecules
Article
Base-Promoted Chemodivergent Formation of
1,4-Benzoxazepin-5(4H)-ones and
1,3-Benzoxazin-4(4H)-ones Switched by Solvents
Qian Chen, Yunpeng Wang and Ruimao Hua *
Department of Chemistry, Tsinghua University, Key Laboratory of Organic Optoelectronics & Molecular
Engineering of Ministry of Education, Beijing 100084, China; chenqian9482@126.com (Q.C.);
wangyp16@mails.tsinghua.edu.cn (Y.W.)
* Correspondence: ruimao@mail.tsinghua.edu.cn; Tel.: +86-10-6279-2596
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Academic Editor: Alejandro Baeza Carratalá
Received: 12 September 2019; Accepted: 18 October 2019; Published: 19 October 2019
Abstract: The KOH-promoted chemodivergent benzannulation of ortho-fluorobenzamides with
2-propyn-1-ol can afford either 1,4-benzoxazepin-5(4H)-ones or 1,3-benzoxazin-4(4H)-ones in
good yields with high selectivity, depending greatly upon the use of solvents. In the case
of using DMSO, the intermolecular benzannulation produced seven-membered benzo-fused
heterocycles of 1,4-benzoxazepin-5(4H)-ones, whereas in MeCN, the six-membered benzo-fused
heterocycles of 1,3-benzoxazin-4(4H)-ones were formed. The KOH-promoted benzannulation
proceeded most probably through the C–F nucleophilic substitution of ortho-fluorobenzamides
with 2-propyn-1-ol to give the intermediate of ortho-[(2-propynyl)oxy]benzamide, which underwent
the intramolecular hydroamidation in a different manner to afford either seven- or six-membered
benzo-fused heterocycles.
Keywords: base-promoted; chemodivergent formation; solvent-dependent transformation;
1,4-benzoxazepinones; 1,3-benzoxazinones
1. Introduction
Chemodivergent reactions are interesting and efficient protocols that form the structurally
different heterocyclic compounds from the same starting materials through simple change of reaction
conditions [
have been well applied in the synthesis of heterocyclic compounds [11
benzo-fused seven- and six-membered heterocycles containing two heteroatoms of oxygen and
nitrogen such as 1,4-benzoxazepin-5(4H)-ones [22], 3,4-dihydro-1,4-benzoxazepin-5(2H)-ones [23 24],
2,3,4,5-tetrahydro-1,4-benzoxazepines [25 29], and 2,3-dihydro-1,3-benzoxazin-4(4H)-ones [30 32], are
1–
10]. Among them, the solvent-dependent or solvent-controlled chemodivergent reactions
–
21]. On the other hand,
,
–
–
important and interesting heterocyclic compounds due to their wide spectrum of biological activities
(Scheme 1). In addition, as the structures shown in Scheme 1, 1,4-benzoxazepin-5(4H)-one is the
useful and potential precursor for the synthesis of its derivatives by simple transformation. Therefore,
the synthetic approach to 1,4-benzoxazepin-5(4H)-one ring has been well investigated. However,
the known procedures for the formation of the seven-membered benzo-fused heterocycle either
are multi-step with low atom-utilization or using uneasily available starting materials catalyzed by
palladium complexes [33–35].
As part of our continued interest in the development of the application of base/DMSO-promoted
SNAr reaction for the formation of C–N bond under transition-metal-free conditions [36
–38],
and the chemodivergent transformations of alkynes [39 41], as well as the new synthetic
–
methods of heterocyclic compounds [42
–
44], we herein describe an efficient protocol for the
Molecules 2019, 24, 3773; doi:10.3390/molecules24203773
www.mdpi.com/journal/molecules

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formation of 1,4-benzoxazepin-5(4H)-ones and 2-vinyl-1,3-benzoxazin-4(4H)-ones via KOH-promoted
solvent-controlled intermolecular cyclization reaction between substituted ortho-fluorobenzamide and
2-propyn-1-ol [45].
Scheme 1. 1,4-Benzoxazepin-5(4H)-ones, 1,3-benzoxazin-4(4H)-ones, and their derivatives.
2. Results and Discussion
Table 1 concludes the results from the reaction of ortho-fluoro-N-propylbenzamide (1a) with
2-propyn-1-ol. We firstly examined the reaction of 1a with 2-propyn-1-ol (1.2 equivalents) in the presence
of KOH (3.0 equivalents) in DMSO at 50 ◦C for 12 h. Two products could be isolated from the reaction
mixture, and their structures were confirmed to be N-propyl-3-methyl-1,4- benzoxazepin-5(4H)-one
(2a, 45%) and N-propyl-2-vinyl-2,3-dihydro-1,3-benzoxazin-4(4H)-ones (3a, 12%) (entry 1) [46]. When
the same reaction was repeated at 30 ◦C, the yield of 2a was slightly increased (entry 2), and if the
reaction was carried out at 30 ◦C for 12 h firstly and then 50 ◦C for 12 h, 2a was isolated in 54% yield
(entry 3). In this case, 3a was determined only in a small amount (<5%) in the reaction mixture with
the complete conversion of 1a. The use of either 1.0 equivalent or 1.5 equivalents of 2-propyn-1-ol
resulted in the decrease of 2a yield (entries 4 and 5). Increase of the reaction temperature to 70 ◦C for
12 h also led to the lower yield of 2a (entry 6). Decreasing the amount of KOH to 1.0 or 2.0 equivalents
affected the formation of 2a (entries 7 and 8). Other inorganic bases, such as NaOH, K2CO3, Cs2CO3,
and t-BuOK were not efficient in promoting the cyclocondensation (entries 9–12). Very interestingly,
the screening of solvents disclosed that the selective chemodivergent formation of 2a and 3a greatly
depended on the use of solvents (entries 13–18). In the cases of THF, DMF and a mixture solvent of
DMSO/MeCN used, 3a was the major product, and in MeCN, 3a could be isolated in 83% yield with a
small amount of 2a formation. In addition, either increasing the amount of 2-propyn-1-ol or increasing
the reaction temperature did not improve the yield of 3a (entries 19 and 20).
The cyclocondensation of other substrates 1b–k, bearing different substituents on nitrogen or
benzene ring with 2-propyn-1-ol, was then studied under the conditions of entry 3 in Table 1. As
can be seen from Scheme 2, N-alkyl-2-fluorobenzamides (alkyl = Me (1b), isopropyl (1c), t-butyl
(1d), t-amyl (1e), cyclopentyl (1f), cyclohexyl (1g)) showed similar reactivity to 1a affording the
corresponding N-alkyl-3-methyl-1,4-benzoxazepin-5(4H)-ones (2b 2g) in good yields. It was also
–
noted that N-phenyl-2-fluorobenzamide showed unexpectedly sluggish reactivity, and almost all
starting materials could be recovered after the reaction under the same conditions. In addition,
the results from the reactions of 2-fluoro-3-methyl-N-propylbenzamide (1h), 2-fluoro-4-methoxy-N-
propylbenzamide (1i), and 4-chloro-2-fluoro-N-propylbenzamide (1j) with 2-propyn-1-ol apparently
indicated that the electron-withdrawing group in 1j was unfavorable in the formation of
1,4-benzoxazepin-5(4H)-one ring. Moreover, the reaction of 2-fluorobenzamide (1k), bearing an
unprotected NH2 group, afforded the corresponding product (2k) in only 31% yield. It should be
noted that the reaction of ortho-fluorobenzamides bearing a strong electron-withdrawing group, such
as 2-fluoro-5-nitro-N-propylbenzamide (1l) and 2-fluoro-N-propyl-5-trifluoromethyl- benzamide (1m),
resulted in a complex mixture.

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Table 1. Effects of reaction conditions on the chemodivergent formation of 1,4-benzoxazepin-5(4H)-ones
and 1,3-benzoxazin-4(4H)-ones a.
Yield (%) b
Entry
Base (equivalent)
Solvent
Temperature (◦C)/Time (h)
1
2
3
KOH (3)
KOH (3)
KOH (3)
KOH (3)
KOH (3)
KOH (3)
KOH (1)
KOH (2)
NaOH (3)
K2CO3 (3)
Cs2CO3 (3)
t-BuOK (3)
KOH (3)
KOH (3)
KOH (3)
KOH (3)
KOH (3)
KOH (3)
KOH (3)
KOH (3)
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMAc
1,4-dioxane
THF
DMF
MeCN
50/12
30/12
45% (2a) + 12% (3a)
52% (2a) + 7% (3a)
54% (2a)
30/12 + 50/12
30/12 + 50/12
30/12 + 50/12
30/12 + 70/12
30/12 + 50/12
30/12 + 50/12
30/12 + 50/12
30/12 + 50/12
30/12 + 50/12
30/12 + 50/12
30/12 + 50/12
30/12 + 50/12
30/12 + 50/12
30/12 + 50/12
30/12 + 50/12
30/12 + 50/12
30/12 + 50/12
30/12 + 70/12
4 c
5 d
6
45% (2a)
47% (2a)
41% (2a)
44% (2a)
47% (2a)
33% (2a)
~ 10% (2a)
7
8
9
10
11
12
13 e
14
15
16
17
18
19d
20
comlex mixture
complex mixture
52% (2a) + 26% (3a)
35% (2a) + ~10% (3a)
~10% (2a) + 48% (3a)
~10% (2a) + 48% (3a)
trace (2a) + 83% (3a)
12% (2a) + 53% (3a)
trace (2a) + 79% (3a)
trace (2a) + 62% (3a)
MeCN
DMSO/MeCN (1:1 in volume)
MeCN
a
Unless otherwise noted, the reactions were carried out using 0.5 mmol of 1a, 0.6 mmol of 2-propyn-1-ol, and
b
c
d
1.5 mmol of base in 4.0 mL of solvent. Isolated yields. 0.5 mmol of 2-propyn-1-ol was used. 0.75 mmol of
2-propyn-1-ol was used. DMAc: N,N-dimethyl acetamide.
e
O
O
NHR
F
R
R'
N
KOH (3.0 equiv)
OH
+
R'
DMSO
O
30 oC, 12 h and
then 50 oC, 12 h
2
1
O
O
R
2b
2c
R = Me,
57%
60%
N
N
i
Pr,
2d
t-Bu,
59%
O
O
2e
51%
O
O
O
N
N
N
O
O
O
2g
70%
2f
2h
64%
45%
O
O
O
Cl
N
N
NH
MeO
O
O
O
2i
2j
2k
31%
68%
18%
a
The reactions were carried out using 0.5 mmol of 1, 0.6 mmol of 2-propyn-1-ol, and 1.5 mmol of
KOH in anhydrous DMSO (4.0 mL).
Scheme 2. Formation of 1,4-benzoxazepin-5(4H)-ones in KOH/DMSO a.

Molecules 2019, 24, 3773
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We also examined the substrate scope under the reaction conditions indicated in entry 17 of Table 1
access to 1,3-benzoxazin-4(4H)-ones ( ) by reacting 2-propyn-1-ol with different ortho-fluorobenzamides
in MeCN. As summarized in Scheme 3, the reactions of 1b and 1g afforded the corresponding
2-vinyl-1,3-benzoxazin-4(4H)-one derivatives 3b and 3g in good to high yields. It should be noted
3
–
d
–j
–d
–j
that, compared to KOH/DMSO system, ortho-fluorobenzamides having electron-withdrawing group
displayed a higher reactivity than ones with an electron-donating group (1j vs. 1i) in KOH/MeCN
in undergoing the cyclization reaction to give the expected cyclic products in good yield (3j vs. 2j
and 3i vs. 2i) (vide infra). In addition, both 1l and 1m also showed good reactivity, giving the
corresponding products of 3l and 3m (vide supra). Note that in KOH/MeCN, all the reactions occurred
with excellent chemoselectivity, and only a trace amount of the corresponding product
reaction mixtures.
2 formed in the
However, when substituted propargyl alcohols, such as 1-methyl-2-propyn-1-ol, 1-phenyl-
2-propyn-1-ol, 3-methyl-2-propyn-1-ol, and 3-phenyl-2-propyn-1-ol, were subjected to the similar
reaction conditions, although the formation of the corresponding cyclic compounds 2 and 3 could be
determined by GC-MS, the reactions unfortunately occurred not only with low chemoselectivity in
both DMSO and MeCN solvents, but also with low total yields of 2 and 3.
In order to understand the chemodivergent formation of
2 and 3 switched by solvents, the
observation of real-time reactions of 1a with 2-propyn-1-ol in NMR tube using DMSO-d6 or CD3CN
were introduced. As shown in Scheme 4, in KOH/DMSO-d6, the cyclization reaction occurred fast, and
a 1 h reaction at 30 ◦C resulted in the formation of 2a and 3a in 58% and 10% NMR yields, respectively.
In this case, no considerable amount of intermediates could be observed in 1H-NMR. An additional 1
h reaction led to the yield increase of 2a to 74%, whereas the NMR yield of 3a was decreased to 6%. A
subsequent 2 h reaction at 50 ◦C afforded 2a in 82% NMR yield, and 3a was determined in a small
amount (<5%). In addition, we also examined the conversion of 3a in KOH/DMSO at 50 ◦C for 2 h, and
found that 3a completely disappeared due possibly to its polymerization, as the formation of 2a could
not be observed at all in the reaction mixture. Therefore, it can be concluded that in the KOH/DMSO
system, the excellent regioselectivity for the formation of 2a resulted from the easy formation of 2a and
the side-reaction of 3a.
O
O
NHR
F
R'
R
KOH (3.0 equiv)
N
OH
+
R'
MeCN
O
30 oC, 12 h and
then 50 oC, 12 h
3
1
O
O
O
R
3b
3c
R = Me,
78%
81%
N
N
i
Pr,
O
O
3d
t-Bu,
78%
3g
85%
O
O
R'
N
O
N
N
O
MeO
O
3j
R' = Cl, 61%
3h
3i
3l
NO2, 65%
54%
45%
3m
F3C,
The reactions were carried out using 0.5 mmol of 1, 0.6 mmol of 2-propyn-1-ol, and 1.5 mmol of
KOH in anhydrous MeCN (4.0 mL).
Scheme 3. Formation of 1,3-benzoxazin-4(4H)-ones in KOH/MeCN a.
73%
a

Molecules 2019, 24, 3773
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On the other hand, in KOH/CD3CN, the reaction of 1a with 2-propyn-1-ol in NMR tube without
stirring occurred very slowly, and only small amount of intermediate 4a could be determined from the
SNAr reaction. 1a was almost remained, and neither 2a nor 3a formed at all at 30 ◦C for 12 h. Even a
prolonged reaction time (at 30 ◦C for 36 h) did not result in the formation of considerable amount of 3a
and in this case, 4a was the major product. With the subsequent reaction at 50 ◦C for 12 h, 3a formed in
31% NMR yield, and in the sequent reaction for 36 h, the yield of 3a was increased to 54%.
Taking into consideration of the results shown in Schemes 2–4, it might be concluded that the
,
chemodivergent formation of either 2 or 3 switched by using DMSO or MeCN as solvents resulted from
the base strength of the reaction mixture. KOH/DMSO was well-applied as the superbase medium to
promote the diverse organic transformation due to the high solubility of KOH in DMSO [47], whereas
KOH/MeCN is a medium alkaline condition owing to the low solubility of KOH in MeCN. In fact, the
present reaction mixtures in DMSO were homogeneous to afford
2, but the reaction mixtures in MeCN
were heterogeneous to give . Thus, it is also easy to understand why in NMR tube, without stirring, a
3
very low rate of reaction in CD3CN was observed (Scheme 4 vs. Scheme 3).
a NMR yield using 1,3,5-trimethoxybenzene as an internal standard. b ND: not determined due to the
overlapping of peaks.
Scheme 4. Real-time monitoring of 1a with 2-propyn-1-ol reaction a.
On the basis of the obtained results and above discussion, a proposed mechanism for the formation
of either
2-propyn-1-ol, giving the intermediate of ortho-[(2-propynyl)oxy]benzamide
system, a superbase medium [47], the formation of and the subsequent formation of a nitrogen
anion are very fast and favorable, leading to the quickly intramolecular nucleophilic addition to
alkyne concurrently to construct the seven-membered ring via a 7-exo-dig cyclization, and the final
protonation step afforded . On the other hand, in the KOH/MeCN system, a relatively weak base
medium compared to KOH/DMSO, not only is the formation of slow, but also the isomerization
2
in DMSO or
3
in MeCN is depicted in Scheme 5. It involves the SNAr reaction of
1 with
4
. In the KOH/DMSO
4
5
2
4

Molecules 2019, 24, 3773
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of
4
into allenyl intermediate
6
is possible [48], which undergoes the base-promoted intramolecular
Michael addition of N–H to allene giving 3 [49].
We also examined the conversion of the isolated intermediate 4a under the similar reaction
conditions as shown in Schemes 2 and 3. As expected, 2a and 3a could be isolated in 65% and 41%
yields, respectively (Scheme 6).
R
N
R
N
O
O
H
O
H
F
KOH
+
+ HF
solvent
HO
4
1
KOH/MeCN
KOH/DMSO
HO
R
R
O
N
H2O
H
O
N
O
.
O
5
6
O
7-exo-dig
R
N
base-promoted
Michael addition
CH2
O
O
O
H2O
R
N
R
N
HO
O
O
2
3
Scheme 5. Proposed mechanism for the chemodivergent formation of 1,4-benzoxazepin-5(4H)-ones
and 1,3-benzoxazin-4(4H)-ones.
Scheme 6. Formation of 2a and 3a from intermediate 4a.
3. Materials and Methods
3.1. General Methods
All commercial reagents and metal salts are analytically pure and used directly without further
purification. 1k is commercially available and other ortho-fluoro-N-alkylbenzamides are known
compounds and were prepared by a modified procedure via the reactions of ortho-fluorobenzoyl
chlorides with primary amines (the procedure, yields in both weight and percentage, and 1H-NMR
charts are reported in the Supplementary Information) [50]. KOH (99.99%) was obtained from
Sigma-Aldrich (St. Louis, MO, USA). Nuclear magnetic resonance (NMR) spectra were recorded on
an ECA-400 spectrometer (JEOL, Tokyo, Japan) using CDCl3 as solvent at 298 K. 1H NMR (400 MHz)
chemical shifts (δ δ
) were referenced to internal standard TMS (for 1H, = 0.00). 13C NMR (100 MHz)

Molecules 2019, 24, 3773
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chemical shifts were referenced to internal solvent CDCl3 (for 13C,
δ
= 77.16). The high-resolution mass
spectra (HRMS) with electron spray ionization (ESI) were obtained with a micrOTOF-Q spectrometer
(Agilent, Santa Clara, CA, USA). The melting points were uncorrected. Single crystals of 2g and 3g
were obtained by slow evaporation of their solution in a mixture solvent of acetone and n-hexane.
3.2. Typical Experimental Procedure for the Synthesis of N-Propyl-3-methyl-1,4-benzoxazepin-5(4H)-one (2a
)
A mixture of 2-fluoro-N-propylbenzamide (1a, 90.5 mg, 0.5 mmol), 2-propyl-1-ol (ca. 34.0 mg,
0.6 mmol), KOH (84.0 mg, 1.5 mmol), and DMSO (4.0 mL) in a 25 mL screw-capped thick-walled Pyrex
tube was stirred at 30 ◦C for 12 h, and then at 50 ◦C for 12 h. After the reaction mixture was cooled to
room temperature, water (10 mL) was added with stirring, and the mixture was extracted with ethyl
acetate three times (3
×
10 mL). The combined organic phases were dried over anhydrous mgSO4. The
filtered solution was then concentrated under reduced pressure, and the crude residue was purified by
column chromatography on silica gel with the use of petroleum ether/ethyl acetate (gradient mixture
ratio from 20:1 to 4:1 in volume) to afford 2a as a pale yellow oil in 54% yield (58.5 mg).
When MeCN was used as solvent to replace DMSO, the similar operation afforded N-propyl-2-
vinyl-2,3-dihydro-1,3-benzoxazin-4(4H)-ones (3a) as a pale yellow oil in 83% yield (90.5 mg).
3.3. Characterization Data of Products:
1
N-Propyl-3-methyl-1,4-benzoxazepin-5(4H)-one (2a): Pale yellow oil (58.5 mg, 54%). H NMR (400 MHz,
CDCl3):
δ 7.86 (dd, J = 7.8, 1.6 Hz, 1H), 7.40 (apparent td, J = 7.8, 1.6 Hz, 1H), 7.18 (apparent t, J = 7.8 Hz,
1H), 6.96 (d, J = 7.8 Hz, 1H), 5.43 (s, 1H), 3.57 (t, J = 7.4 Hz, 2H), 1.93 (s, 3H), 1.64–1.73 (m, 2H), 0.96 (t,
J = 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3):
δ 166.6, 160.5, 148.5, 133.1, 132.2, 127.3, 124.8, 120.1, 115.0,
49.8, 21.4, 17.7, 11.2. HRMS (ESI) m/z: [M + H]+ calcd for C13H16NO2, 218.1176; found, 218.1174.
1
N-Methyl-3-methyl-1,4-benzoxazepin-5(4H)-one (2b): Pale yellow oil (54.1 mg, 57%). H NMR (400 MHz,
CDCl3)
1.8 Hz, 1H), 6.97 (dd, J = 7.8, 1.8 Hz, 1H), 5.46 (s, 1H), 3.19 (s, 3H), 1.93 (s, 3H). 13C NMR (100 MHz,
CDCl3)
166.8, 160.4, 147.9, 133.1, 132.1, 126.9, 124.8, 120.1, 115.8, 35.9, 17.5. HRMS (ESI) m/z: [M + H]+
calcd for C11H12NO2, 190.0863; found, 190.0862.
δ 7.87 (dd, J = 7.8, 1.8 Hz, 1H), 7.41 (apparent td, J = 7.8, 1.8 Hz, 1H), 7.19 (apparent td, J = 7.8,
δ
1
N-Isopropyl-3-methyl-1,4-benzoxazepin-5(4H)-one (2c): Pale yellow oil (64.7 mg, 60%). H NMR (400 MHz,
CDCl3): 7.88 (dd, J = 7.8, 1.6 Hz, 1H), 7.39 (apparent td, J = 7.8, 1.6 Hz, 1H), 7.18 (apparent td, J = 7.8,
1.6 Hz, 1H), 6.96 (dd, J = 7.8, 1.6 Hz, 1H), 5.49 (s, 1H), 5.04 (hept, J = 6.8 Hz, 1H), 1.95 (s, 3H), 1.23 (d,
δ
J = 6.8 Hz, 6H). 13C NMR (100 MHz, CDCl3):
δ 166.2, 160.5, 149.8, 132.9, 132.4, 127.3, 124.7, 112.0, 109.9,
45.7, 20.3, 17.7. HRMS (ESI) m/z: [M + H]+ calcd for C13H16NO2, 218.1176; found, 218.1173.
1
N-t-Butyl-3-methyl-1,4-benzoxazepin-5(4H)-one (2d): Pale yellow oil (68.2 mg, 59%). H NMR (400 MHz,
CDCl3):
1.6 Hz, 1H), 6.96 (dd, J = 7.8, 1.6 Hz, 1H), 5.59 (q, J = 0.8 Hz, 1H), 1.90 (d, J = 0.8 Hz, 3H), 1.54 (s,
9H). 13C NMR (100 MHz, CDCl3):
166.7, 161.2, 150.0, 132.5, 128.2, 124.5, 119.7, 113.7, 58.9, 28.7, 17.2.
HRMS (ESI) m/z: [M + H]+ calcd for C14H18NO2, 232.1332; found, 232.1332.
δ 7.92 (dd, J = 7.8, 1.6 Hz, 1H), 7.37 (apparent td, J = 7.8, 1.6 Hz, 1H), 7.17 (apparent td, J = 7.8,
δ
1
N-t-Amyl-3-methyl-1,4-benzoxazepin-5(4H)-one (2e): Pale yellow oil (62.1 mg, 51%). H NMR (400 MHz,
CDCl3): 7.90 (dd, J = 7.8, 1.6 Hz, 1H), 7.36 (apparent td, J = 7.8, 1.6 Hz, 1H), 7.16 (apparent td, J = 7.8,
1.6 Hz, 1H), 6.96 (dd, J = 7.8, 1.6 Hz, 1H), 5.56 (s, 1H), 2.02 (q, J = 7.5 Hz, 2H), 1.89 (s, 3H), 1.48 (s, 6H),
δ
0.89 (t, J = 7.5 Hz, 3H). 13C NMR (100 MHz, CDCl3):
δ 166.8, 161.3, 150.2, 132.5, 128.3, 124.6, 119.7, 114.3,
62.0, 32.4, 27.0, 17.2, 8.6. HRMS (ESI) m/z: [M + H]+ calcd for C15H20NO2, 246.1489; found, 246.1487.
N-Cyclopentyl-3-methyl-1,4-benzoxazepin-5(4H)-one (2f): Pale yellow oil (78.1 mg, 64%). 1H NMR
(400 MHz, CDCl3):
td, J = 7.8, 1.6 Hz, 1H), 6.94 (dd, J = 7.8, 1.6 Hz, 1H), 5.44 (s, 1H), 5.10 (pent, J = 8.2 Hz, 1H), 2.00–1.95
(m, 2H), 1.93 (s, 3H), 1.74–1.53 (m, 6H). 13C NMR (100 MHz, CDCl3):
166.7, 160.5, 149.8, 132.9, 132.5,
δ 7.86 (dd, J = 7.8, 1.6 Hz, 1H), 7.37 (apparent td, J = 7.8, 1.6 Hz, 1H), 7.16 (apparent
δ

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127.3, 124.7, 112.0, 110.8, 55.6, 29.6, 24.6, 17.8. HRMS (ESI) m/z: [M + H]+ calcd for C15H18NO2, 244.1332;
found, 244.1331.
N-Cyclohexyl-3-methyl-1,4-benzoxazepin-5(4H)-one (2g): Pale yellow solid (89.4 mg, 70%). mp 63–65 ◦C.
1H NMR (400 MHz, CDCl3):
δ 7.87 (dd, J = 7.8, 1.6 Hz, 1H), 7.40 (apparent td, J = 7.8, 1.6 Hz, 1H), 7.19
(apparent td, J = 7.8, 1.6 Hz, 1H), 6.96 (dd, J = 7.8, 1.6 Hz, 1H), 5.51 (q, J = 0.9 Hz, 1H), 4.67–4.55 (m, 1H),
1.94 (d, J = 0.9 Hz, 3H), 1.91–1.78 (m, 4H), 1.73–1.62 (m, 2H), 1.50–1.40 (m, 4H). 13C NMR (100 MHz,
CDCl3):
δ 166.2, 160.5, 149.3, 132.8, 132.4, 127.4, 124.7, 119.9, 110.9, 53.9, 30.7, 25.8, 25.6, 17.7. HRMS
(ESI) m/z: [M + H]+ calcd for C16H20NO2, 258.1489; found, 258.1488.
N-Propyl-3,9-dimethyl-1,4-benzoxazepin-5(4H)-one (2h): Pale yellow oil (52.3 mg, 45%). 1H NMR
(400 MHz, CDCl3):
1H), 5.45 (s, 1H), 3.57 (t, J = 7.4 Hz, 2H), 2.32 (s, 3H), 1.97 (s, 3H), 1.76–1.65 (m, 2H), 0.96 (t, J = 7.4 Hz,
3H). 13C NMR (100 MHz, CDCl3):
167.0, 159.3, 148.7, 134.3, 129.9, 129.0, 127.4, 124.3, 115.5, 49.9, 21.5,
18.3, 16.1, 11.3. HRMS (ESI) m/z: [M + H]+ calcd for C14H18NO2, 232.1332; found, 232.1331.
δ 7.67 (dd, J = 7.8, 1.5 Hz, 1H), 7.27 (d, J = 7.8 Hz, 1H), 7.07 (apparent t, J = 7.8 Hz,
δ
1
8-Methoxyl-N-propyl-3-methyl-1,4-benzoxazepin-5(4H)-one (2i): Pale yellow oil (84.1 mg, 68%). H NMR
(400 MHz, CDCl3): 7.81 (d, J = 8.7 Hz, 1H), 6.73 (dd, J = 8.7, 2.8 Hz 1H), 6.48 (d, J = 2.8 Hz, 1H), 5.43
(s, 1H), 3.83 (s, 3H), 3.55 (t, J = 7.4 Hz, 2H), 1.94 (s, 3H), 1.75–1.62 (m, 2H), 0.96 (td, J = 7.4, 3.5 Hz, 3H).
13C NMR (100 MHz, CDCl3):
166.2, 163.7, 161.6, 147.7, 133.5, 119.5, 115.1, 111.0, 105.1, 55.7, 49.8, 21.5,
17.8, 11.3. HRMS (ESI) m/z: [M + H]+ calcd for C14H18NO3, 248.1281; found, 248.1279.
δ
δ
1
7-Chloro-N-propyl-3-methyl-1,4-benzoxazepin-5(4H)-one (2j): Pale yellow oil (22.3 mg, 18%). H NMR
(400 MHz, CDCl3): 7.83 (d, J = 2.8 Hz, 1H), 7.34 (dd, J = 8.0, 2.8 Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H),
5.43 (s, 1H), 3.56 (t, J = 7.4 Hz, 2H), 1.93 (s, 3H), 1.70–1.62 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H). 13C NMR
δ
(100 MHz, CDCl3):
δ 165.3, 159.0, 148.8, 132.9, 131.9, 130.2, 128.6, 121.6, 115.0, 50.0, 21.4, 17.7, 11.3.
HRMS (ESI) m/z: [M + H]+ calcd for C13H15ClNO2, 252.0786; found, 252.0786.
3-Methyl-1,4-benzoxazepin-5(4H)-one (2k) [23]: Pale yellow oil (26.9 mg, 31%). 1H NMR (400 MHz,
CDCl3):
δ 11.18 (s, 1H), 7.71 (dd, J = 7.8, 1.6 Hz, 1H), 7.24 (ddd, J = 8.3, 7.8, 1.6 Hz, 1H), 6.97 (dd, J = 7.8,
1.6 Hz, 1H), 6.88 (ddd, J = 8.3, 7.8, 1.6 Hz, 1H), 6.75 (q, J = 1.2 Hz, 1H), 2.33 (d, J = 1.2 Hz, 3H). 13
NMR (100 MHz, CDCl3): δ 160.6, 157.1, 147.9, 131.9, 125.7, 122.1, 119.4, 117.2, 111.5, 11.0.
C
1
N-Propyl-2-vinyl-2,3-dihydro-1,3-benzoxazin-4(4H)-one (3a): Pale yellow oil (90.5 mg, 83%). H NMR
(400 MHz, CDCl3):
δ 7.93 (dd, J = 7.8, 1.8 Hz, 1H), 7.41 (apparent td, J = 7.8, 1.6 Hz, 1H), 7.07 (apparent
td, J = 7.8, 1.6 Hz, 1H), 6.91 (dd, J = 7.8, 1.8 Hz, 1H), 5.97 (ddd, J = 16.8, 10.2, 5.8 Hz, 1H), 5.64 (d,
J = 5.8 Hz, 1H), 5.40 (d, J = 16.8 Hz, 1H), 5.36 (d, J = 10.2 Hz, 1H), 3.93 (ddd, J = 14.0, 8.0, 6.8 Hz, 1H),
2.97 (ddd, J = 14.0, 8.0, 6.8 Hz, 1H), 1.77–1.62 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz,
CDCl3):
δ 161.4, 155.4, 134.1, 132.6, 128.0, 122.4, 120.9, 118.7, 116.8, 87.7, 45.8, 21.7, 11.4. HRMS (ESI)
m/z: [M + H]+ calcd for C13H16NO2, 218.1176; found, 218.1175.
N-Methyl-2-vinyl-2,3-dihydro-1,3-benzoxazin-4(4H)-one (3b) [45]: Pale yellow oil (73.7 mg, 78%). 1H
NMR (400 MHz, CDCl3):
δ 7.93 (dd, J = 7.8, 1.7 Hz, 1H), 7.41 (apparent td, J = 7.8, 1.7 Hz, 1H), 7.07
(apparent td, J = 7.8, 1.7 Hz, 1H), 6.92 (dd, J = 7.8, 1.7 Hz, 1H), 5.97 (ddd, J = 16.8, 10.2, 6.0 Hz, 1H),
5.61 (d, J = 6.0 Hz, 1H), 5.45–5.34 (m, 2H), 3.07 (s, 3H). 13C NMR (100 MHz, CDCl3):
δ 161.8, 155.5,
134.2, 131.9, 128.0, 122.4, 121.1, 118.3, 116.8, 89.2, 31.1. HRMS (ESI) m/z: [M + H]+ calcd for C11H12NO2,
190.0863; found, 190.0861.
1
N-Isopropyl-2-vinyl-2,3-dihydro-1,3-benzoxazin-4(4H)-one (3c): Pale yellow oil (89.0 mg, 81%). H NMR
(400 MHz, CDCl3):
δ 7.92 (dd, J = 7.8, 1.6 Hz, 1H), 7.40 (apparent td, J = 7.8, 1.6 Hz, 1H), 7.05 (apparent
td, J = 7.8, 1.6 Hz, 1H), 6.88 (dd, J = 7.8, 1.6 Hz, 1H), 5.97 (ddd, J = 16.8, 10.0, 6.0 Hz, 1H), 5.78 (d,
J = 6.0 Hz, 1H), 5.40 (d, J = 16.8 Hz, 1H), 5.29 (d, J = 10.0 Hz, 1H), 4.85 (hept, J = 6.8 Hz, 1H), 1.33
(d, J = 6.8 Hz, 3H), 1.21 (d, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3):
δ 160.7, 154.9, 134.6, 133.9,
128.0, 122.2, 120.5, 119.5, 116.7, 82.9, 45.0, 20.9, 20.7. HRMS (ESI) m/z: [M + H]+ calcd for C13H16NO2,
218.1176; found, 218.1175.

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1
N-t-Butyl-2-vinyl-2,3-dihydro-1,3-benzoxazin-4(4H)-one (3d): Pale yellow oil (89.9 mg, 78%). H NMR
(400 MHz, CDCl3): 7.90 (dd, J = 7.8, 1.6 Hz, 1H), 7.38 (apparent td, J = 7.8, 1.6 Hz, 1H), 7.03 (apparent
td, J = 7.8, 1.6 Hz, 1H), 6.86 (dd, J = 7.8, 1.6 Hz, 1H), 6.05–5.92 (m, 2H), 5.41 (d, J = 16.8 Hz, 1H), 5.29 (d,
δ
J = 10.0 Hz, 1H), 1.56 (s, 9H). 13C NMR (100 MHz, CDCl3):
δ 162.1, 154.7, 134.9, 133.8, 127.9, 122.1, 120.5,
120.4, 116.4, 84.6, 57.4, 28.8. HRMS (ESI) m/z: [M + H]+ calcd for C14H18NO2, 232.1332; found, 232.1331.
N-Cyclohexyl-2-vinyl-2,3-dihydro-1,3-benzoxazin-4(4H)-one (3g): White solid (109.6 mg, 85%). mp
84–86 ◦C. 1H NMR (400 MHz, CDCl3):
δ 7.91 (d, J = 7.8 Hz, 1H), 7.39 (apparent t, J = 7.8 Hz, 1H),
7.05 (apparent t, J = 7.8 Hz, 1H), 6.88 (d, J = 7.8 Hz, 1H), 5.95 (ddd, J = 16.8, 10.6, 5.7 Hz, 1H), 5.80
(d, J = 5.7 Hz, 1H), 5.40 (d, J = 16.8 Hz, 1H), 5.28 (d, J = 10.6 Hz, 1H), 4.48 (tt, J = 12.2, 3.4 Hz, 1H),
1.98–1.01 (m, 10H). 13C NMR (100 MHz, CDCl3):
δ 160.8, 155.0, 134.7, 134.0, 128.1, 122.3, 120.1, 119.7,
116.8, 83.2, 52.9, 31.4, 31.2, 26.0, 25.9, 25.6. HRMS (ESI) m/z: [M + H]+ calcd for C16H20NO2, 258.1489;
found, 258.1487.
1
N-Propyl-2-vinyl-8-methyl-2,3-dihydro-1,3-benzoxazin-4(4H)-one (3h): Pale yellow oil (65.8 mg, 54%). H
NMR (400 MHz, CDCl3):
δ 7.77 (dd, J = 7.8, 1.5 Hz, 1H), 7.25 (dd, J = 7.8, 1.5 Hz, 1H), 6.95 (apparent t,
J = 7.8 Hz, 1H), 5.95 (ddd, J = 17.0, 10.6, 6.4 Hz, 1H), 5.67 (d, J = 6.4 Hz, 1H), 5.38 (d, J = 17.0 Hz, 1H),
5.32 (d, J = 10.6 Hz, 1H), 3.94 (ddd, J = 14.0, 8.0, 6.4 Hz, 1H), 2.97 (ddd, J = 14.0, 8.0, 6.4 Hz, 1H), 2.21
(s, 3H), 1.78–1.59 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3):
δ 161.6, 153.5, 135.0,
132.7, 126.0, 125.4, 121.8, 120.4, 118.3, 87.4, 45.7, 21.6, 15.2, 11.4. HRMS (ESI) m/z: [M + H]+ calcd for
C14H18NO2, 232.1332; found, 232.1331.
7-Methoxyl-N-propyl-2-vinyl-2,3-dihydro-1,3-benzoxazin-4(4H)-one (3i): Pale yellow oil (55.5 mg, 45%).
1H NMR (400 MHz, CDCl3):
δ 7.84 (d, J = 8.8 Hz, 1H), 6.62 (dd, J = 8.8, 2.4 Hz, 1H), 6.40 (d, J = 2.4 Hz,
1H), 5.98 (ddd, J = 16.8, 10.4, 5.9 Hz, 1H), 5.61 (d, J = 5.9 Hz, 1H), 5.40 (d, J = 16.8 Hz, 1H), 5.35 (d,
J = 10.4 Hz, 1H), 3.91 (ddd, J = 14.0, 8.0, 6.8 Hz, 1H), 3.81 (s, 3H), 2.95 (ddd, J = 14.0, 8.0, 6.8 Hz, 1H),
1.72–1.58 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3):
δ 164.5, 161.5, 157.1, 132.6, 129.5,
120.8, 111.8, 109.4, 101.1, 88.0, 55.7, 45.6, 21.7, 11.4. HRMS (ESI) m/z: [M + H]+ calcd for C14H18NO3,
248.1281; found, 248.1279.
1
6-Chloro-N-propyl-2-vinyl-2,3-dihydro-1,3-benzoxazin-4(4H)-one (3j): Pale yellow oil (76.2 mg, 61%). H
NMR (400 MHz, CDCl3):
δ 7.89 (d, J = 2.7 Hz, 1H), 7.35 (dd, J = 8.7, 2.7 Hz, 1H), 6.86 (d, J = 8.7 Hz, 1H),
5.94 (ddd, J = 17.0, 10.3, 5.5 Hz, 1H), 5.65 (d, J = 5.5 Hz, 1H), 5.40 (d, J = 17.0 Hz, 1H), 5.38 (d, J = 10.3 Hz,
1H), 3.92 (ddd, J = 14.0, 8.4, 7.2 Hz, 1H), 2.96 (ddd, J = 14.0, 8.4, 7.2 Hz, 1H), 1.72–1.63 (m, 2H), 0.97 (t,
J = 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3):
δ
160.3, 153.9, 133.9, 132.2, 127.8, 127.7, 121.3, 119.9, 118.4,
87.7, 46.0, 21.6, 11.4. HRMS (ESI) m/z: [M + H]+ calcd for C13H15ClNO2, 252.0786; found, 252.0785.
1
6-Nitro-N-propyl-2-vinyl-2,3-dihydro-1,3-benzoxazin-4(4H)-one (3l): Pale yellow oil (85.4 mg, 65%). H
NMR (400 MHz, CDCl3): 8.83 (d, J = 2.8 Hz, 1H), 8.30 (dd, J = 8.9, 2.8 Hz, 1H), 7.05 (d, J = 8.9 Hz, 1H),
δ
5.94 (ddd, J = 17.0, 10.3, 5.4 Hz, 1H), 5.78 (dd, J = 5.4, 0.8 Hz, 1H), 5.44 (dd, J = 17.0, 0.8 Hz, 1H), 5.44 (d,
J = 10.3 Hz, 1H), 3.97 (ddd, J = 14.0, 8.2, 6.8 Hz, 1H), 3.01 (ddd, J = 14.0, 8.2, 6.8 Hz, 1H), 1.83–1.67
(m, 2H), 0.98 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3):
δ 159.9, 159.5, 143.0, 131.6, 129.2, 124.5,
121.9, 118.8, 118.0, 88.2, 46.2, 21.5, 11.4. HRMS (ESI) m/z: [M + H]+ calcd for C13H15N2O4, 263.1026;
found, 263.1023.
6-Trifluoromethyl-N-propyl-2-vinyl-2,3-dihydro-1,3-benzoxazin-4(4H)-one (3m): Pale yellow oil (103.8 mg,
1
73%). H NMR (400 MHz, CDCl3):
δ 8.22 (d, J = 2.1 Hz, 1H), 7.63 (dd, J = 8.6, 2.1 Hz, 1H), 7.01 (d,
J = 8.6 Hz, 1H), 5.94 (ddd, J = 16.4, 10.4, 5.5 Hz, 1H), 5.71 (d, J = 5.5 Hz, 1H), 5.40 (d, J = 16.4 Hz,
1H), 5.40 (d, J = 10.4 Hz, 1H), 3.95 (ddd, J = 14.1, 8.0, 6.5 Hz, 1H), 2.98 (ddd, J = 14.1, 8.0, 6.5 Hz, 1H),
1.72–1.62 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3):
δ 160.2, 157.7, 132.0, 130.84 (q,
J = 13.0 Hz), 125.8 (q, J = 13.0 Hz), 124.9 (q, J = 34.0 Hz), 123.9 (q, J = 270.0 Hz), 121.5, 118.7, 117.6,
87.90, 46.02, 21.55, 11.36. HRMS (ESI) m/z: [M + H]+ calcd for C14H15F3NO2, 286.1049; found, 286.1046.

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4. Conclusions
In summary, a facile and efficient solvent-controlled chemodivergent synthesis of
1,4-benzoxazepin-5(4H)-ones and 1,3-benzoxazin-4(4H)-ones via the KOH-promoted cyclization of
ortho-fluorobenzamides with 2-propyn-1-ol was developed. The cyclization reaction was proposed to
involve the SNAr reaction of C–F bond with 2-propyn-1-ol to give ortho-[(2-propynyl)oxy]benzamide
intermediates, which underwent the intramolecular either 7-exo-dig cyclization in a superbase medium
of KOH/DMSO or a Michael addition of N–H to allenyl intermediate in KOH/MeCN medium to give
different benzo-fused cyclic compounds. The present protocol had the significant advantages of high
atom-utilization and high selectivity of product output controlled by simple changing the solvents.
Supplementary Materials: The following are available online: Synthesis of known compound
1
, copies of 1H
NMR spectra of the prepared 1, copies of NMR spectra of 2, copies of NMR spectra of 3, X-ray structural details of
2g and 3g, results from the reactions of 1a with propargyl alcohol in either KOD/D2O/DMSO or KOD/D2O/MeCN.
Author Contributions: Investigation, writing—original draft preparation, Q.C.; investigation, Y.W.;
conceptualization, supervision, writing—review and editing, R.H.
Funding: Financial support from the National Natural Science Foundation of China (No. 21473097 and
No. 21673124).
Conflicts of Interest: The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds 2 and 3 are not available from the authors.
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