Design, synthesis, crystal structure and fungicidal activity of (E)-5-(methoxyimino)-3,5-dihydrobenzo [e] [1,2]oxazepin-4(1 H)-one analogues

Article abstract of DOI:10.1039/c7md00025a

A practical method of four-step synthesis towards novel (E)-5-(methoxyimino)-3,5-dihydrobenzo[e][1,2]oxazepin-4(1H)-one antifungals is presented, where a commercially available pesticide and pharmacology intermediate, (E)-methyl 2-(2-(bromomethyl)phenyl)-

Full text of DOI:10.1039/c7md00025a

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DOI: 10.1039/C7MD00025A
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ARTICLE
Design, synthesis, crystal structure and fungicidal activity of (E)-5-
(methoxyimino)-3,5-dihydrobenzo[e][1,2]oxazepin-4(1H)-one
analogues†
Received 00th January 20xx,
Accepted 00th January 20xx
Dongyan Yang, Chuan Wan, MengMeng He, Chuanliang Che, Yumei Xiao, Bin Fu, and Zhaohai Qin*
DOI: 10.1039/x0xx00000x
A practical method of four step synthesis towards novel (E)-5-(methoxyimino)-3,5-dihydrobenzo[e][1,2]oxazepin -4(1H)-
one antifungals was presented, where a commercial available intermediate of the pesticide and the pharmacology, (E)-
methyl 2-(2-(bromomethyl)phenyl)-2-(methoxyimino) acetate (1), was used as starting material. These compounds were
confirmed by 1H NMR, 13C NMR, high-resolution mass spectroscopy and X-ray crystal structure. Via in vitro fungicidal
evaluation, the moderate to high activities of several compounds against eight phytopathogenic fungi were demonstrated.
Especially, the fungicidal activity of compound 5-03 and 5-09 were comparable to the control azoxystrobin and
trifloxystrobin in precise virulence measurements to four fungi. These results suggested that
dihydrobenzo[e][1,2]oxazepin-4(1H)-one analogues could be considered as potential fungicidal candidates for crop
protection.
www.rsc.org/
Figure 1 Biologically active compounds containing benzoxazepinone moiety
Introduction
Consequently, the widely practical interest of this important
Among the Oxazepine compounds, benzoxazepinones and
their derivatives have a central place in the pharmaceutical
chemistry.1 For example, GSK’481(I) is a highly potent and
heterocyclic ring system motivates continuous efforts of the
exploitation of both efficient compounds and synthetic
methods, but almost reported benzoxazepinones are 1,4-
6-12
monoselective receptor interacting protein
1
kinase;2
benzoxazepinone.
By comprehensive literature search and
Neochromine S5(II) can inhibit proliferation and increase
apoptosis of activated T cells;3 GDC-0032(III) is a β-sparing
phosphoinositide 3-kinase inhibitor and has been evaluated as
potential treatment for human malignancies;4 Tetrahydro-
pyrazolo-oxazepin-one (IV) derivatives as potential telomerase
inhibitors exhibit high anticancer activity.5 (Figure 1) As such,
all the representative compounds containing benzoxazepinone
analysis, we find that the 1,2-benzoxazepinone skeleton is a
new fragment. The method to synthesize a variety of 1,2-
benzoxazepinone, where N-O bond are adjacent to carbonyl
group, is lacking.
On the basis of the development of fungicides targeting at
cytochrome bc1 complex and prompted by the excellent
biological activity of trifloxystrobin and fluoxastrobin, we
attempted to investigate and optimize the structure of
strobilurins, target compounds were designed and
synthesized. These compounds were evaluated against eight
phytopathogenic fungi. In this work, we present a mild and
convenient synthesis as well as systemically bioactive
investigations of this new variety of (E)-5-(methoxyimino)-3,5-
moiety reportedly show outstanding biological activity.
O
Ph
OH
O
O
O
N
N
NH
N
HO
O
O
O
Me
GSK 481(I)
Neochromine S5(II)
O
’
O
N
N
N
dihydrobenzo[e][1,2]oxazepin-4(1H)-one(
5
),
which
have
N
N
O
O
N
N
N
nearby hetero-atoms (N and O) at the seven members ring.
Meanwhile, the corresponding chemical problems and their
structure–activity relationships are discussed.
H2
N
N
Br
Br
IV
GDC-0032(III)
H3C
H3
C
O
N
O
O
N
O
N
N
O
CH3
O
O
O
N
R
CH3
O
F
Cl
O
O
O
CF3
N
N
R'
N
Target compounds
Fluoxastrobin
trifloxystrobin
Scheme 1 Strategies for the target compound designing
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Journal Name
Results and discussion
Chemistry
O
O
N
O
O
O
O
N
Me
N
Me
N
Me
N
O
O
OMe
Br
O
OMe
O
O
O
OMe
O
i
iii
iv
ii
N
R
NH2
N
NH
O
O
R'
5
O
1
2
3
4
i.:N-Hydroxyphthalimide,Et3N,DMF,rt,8h;ii.85% hydrazine hydrate, MeOH, rt ,2h;iii. NaOMe,MeOH,reflux, 4h;iv.60%NaH,DMF,RX
O
N
O
O
S
N
5-01 R=n-Pr,R'=H
5-07 R=Propargyl,R'=H
Cl
5-15 R=
,R'=H
,R'=H
,R'=H
5-13 R=
5-14 R=
5-02 R=n-Bu,R'=H
5-03 R=n-Pentyl,R'=H
5-04 R=n-Hexyl,R'=H
5-05 R=n-Heptyl,R'=H
5-06 R=Allyl,R'=H
5-08 R=4-MeC6H4CH2,R'=H
5-09 R=4-ClC6H4CH2,R'=H
5-10 R=4-NO2C6H4CH2,R'=H
5-11 R=4-CNC6H4CH2,R'=H
5-12 R=2-ClC6H4CH2,R'=H
5-16 R=Allyl,R'=Allyl
5-17 R=2-ClC6H4CH2,R'=2-ClC6H4CH2
5-18 R=Me,R'=H
N
Cl
5-19 R=Et, R'=H
Scheme 2 Preparation of title compounds
The specific synthetic route to compound
commercial available starting material was depicted in scheme
2. Precursor
was prepared as literature reported.15 Starting
material was reacted with N-Hydroxyphthalimide to give
intermediate the later was hydrazinolated to produce the
key precursor . Initial studies found that substrate reacted
without any additive giving compound only yield 7% at room
temperature (RT) for 4 hours. We began our investigations by
choosing as the exclusive substrate for optimizing the
4 and 5 from the
Table 1 Optimization of the reaction condition for the cyclization of 2 to afford 5
O
3
O
Me
N
N
O
OMe
O
O
1
NH2
NH
2
，
O
3
3
4
3
4
Entry
Base
Temperture
Time (h)
Yield (%)a
3
1
2
3
4
5
6
7
8
-
-
-
RT
4
24
24
8
7
reaction conditions. Firstly, the reactive temperature was
investigated (Table 1, entries 2, 3). It was found that, the yield
of reflux temperature (15%) is a little higher than it of RT (9%)
after as long as 24 hours of reaction, where majority of
substrate remained unconverted at these conditions. Then,
some organic and inorganic bases were screened, and NaOMe
furnished good yield, at reflux for 4 hours, whereas other
bases, such as Et3N, NaOH and K2CO3, gave either low product
yields or more byproduct.
RT
9
reflux
RT
15
57
81
45
67
56
NaOMe
NaOMe
Et3N
reflux
reflux
reflux
reflux
4
4
NaOH
4
Na2CO3
4
a:isolated yield.
The present optimized synthesis of benzoxazepinone
4
structure refinement parameters are summarized in Table (S1-
involved stirring of 3 with NaOMe in methanol at reflux for 4 S7). The molecular structure of compound 5-09 is shown in
hours. The method was amenable to gram scale synthesis Figure 2. The seven ring appears to be twisted and the double
under optimized conditions. NaOMe stimulated the cleavage bonds C(1)=O(2) and C(2)=N(2) in compound 5-09 is pushed in
of a molecule of methanol in the intramolecular cyclization opposite directions. The bond lengths of compound 5-09 are
procedure. Compound 4 was obtained with good yields. Then within the normal range.
compound 4 was reacted with various halides in DMF in the
presence of NaH to afford corresponding compounds 5. Most
of compounds
5 were obtained in moderate to good yields.
However, the synthetic yields of compound 5-06 and 5-12
were only 34% and 24%, the reason was that compound 5-06
and 5-12 could be further alkylated to give double substituted
compound 5-16 and 5-17, respectively. (Scheme 5) In addition,
the structure of
5 was further identified by X-ray diffraction
studies (Figure 2).
Crystal Structure Analysis. To provide more evidence for the
proposed molecular structure and establish the conformation
of the target compounds, the compound 5-09 was
recrystallized
by
a
slow
evaporation
from
a
Figure 2 X-ray crystal structure of 5-09(CCDC-1518111).
dichloromethane/n-hexane (v/v = 1:5) solution. Single-crystal
X-ray diffraction analysis showed that the crystal structure of
compound 5-09 belongs to the orthorhombic system, space
group P212121. The details of the crystallographic data and
Structure-Activity Relationship (SAR)
2 | J. Name., 2012, 00, 1-3
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(E)-methyl
2-(2-(bromomethyl)phenyl)-2-(methoxyimino) in vitro at 50 μg/mL. Compound 5-16 and 5-17 exhibited
acetate (
1), a bromoalkane with the bromobenzyl group and certain fungicidal activities. No obvious difference of fungicidal
the 2-(methoxyimino)acetate group, as the starting material, activity between aliphatic and aromatic series was observed.
which has been mass-produced, is an essential intermediate of For aliphatic series (compound 5-01 to 5-07, 5-18 and 5-19),
agricultural fungicides originating in natural product strobilurin however, the fungicidal activity is determined by the length of
A, becoming an attractive area of research in pharmaceutical aliphatic chain, where title compounds with shorter aliphatic
and agricultural chemistry.16 Furthermore, it is not only been chain exhibited relatively lower bioactivity than that with
widely used as key intermediates in fungicides synthesis but longer chain, i.e. compound: 5-18
also serve as scaffolds to access other pesticides. 17 Fungicides
5-04 5-05 (Figure 3). For the substituent benzene of
with this intermediates have proved broad spectrum, high aromatic series (compound 5-08 to 5-12), a para-substituent
efficiency and low toxicity as through field experiments and all (para-alkyl of compound 5-08, para-Cl of compound 5-09
kind of toxicity tests.18 Compounds
and not only keep the para-nitro of compound 5-10 and para-cyano of compound 5-
< 5-19 < 5-01 < 5-02 < 5-03
≈
≈
,
4
5
important scaffold of methoxyacrylates, including benzene 11), no matter it is electron-withdrawing (-Cl, -nitro and –
ring, methoxyimino and carbonyl, but also combine two cyano) or -donating (-alkyl), was the most important factor to
heteroatoms (N,O) into one molecule which plays important enhance the bioactivity comparing with ortho-substituent
role in biological activity.19,20 Accordingly, fungicidal activity of (ortho-alkyl of compound 5-12). In contrast, for the hetero-
these compounds was tested against eight phyto-pathogenic aromatic series (compound 5-13 and 5-14), the inhibitory rate
fungi.
was relatively lower than that of substituent benzene series. In
The antifungal activities of title compounds (compound 5-01 all, several compounds displayed higher activity than the
to 5-19) were measured in vitro and the corresponding results commercial fungicides (azoxystrobin and trifloxystrobin),
were summarized in Table 2. Byproducts 5-16 and 5-17 were including compounds 5-03
tested under the same conditions as well. In general, most of infestans and compounds 5-03 to 5-05
the compounds displayed considerable to excellent fungicidal Setosphaeria turcica. The inhibitory rates of compounds 5-03
activities against eight phytopathogens except compound 5-07 to 5-05 5-08 to 5-11 were comparable to azoxystrobin and
5-15, 5-18and 5-19. Most of these compounds were highly trifloxystrobin against pyricularia grisea and colletotrichum
active against phytophthora infestans, pythium orbiculare.
,
5-08
,
5-09 against phytophthora
,
5-08 to 5-11 against
,
aphanidermatum, setosphaeria turcica and pyricularia grisea
Table 2 In vitro fungicidal activity of target copmounds against Phytopathogensa
mycelium growth inhibitory rate (%) at 50 μg/mL
Compd.
SS
22.8
BC
5.0
PI
11.7
PA
2.9
RS
8.6
ST
36.7
PG
14.0
CO
15.3
4
5-01
NA
20.3
27.5
40.6
40.6
40.6
12.8
NA
24.2
35.5
56.5
48.4
37.1
23.3
NA
9.6
22.3
46.2
40.1
35.5
11.0
11.0
40.1
54.7
41.2
42.3
4.7
10.0
20.0
35.0
33.3
25.0
10.9
NA
26.8
45.4
69.2
65.7
70.0
15.3
25.4
56.9
67.7
65.7
62.3
14.4
49.2
42.2
15.8
24.2
27.1
19.8
30.5
49.5
54.9
21.9
35.9
51.6
50.0
53.1
16.1
3.2
19.1
22.1
36.8
38.2
36.8
14.7
5.1
5-02
13.3
60.0
57.3
58.7
15.6
NA
5-03
5-04
5-05
5-06
5-07
5-08
65.3
72.0
22.7
41.3
15.4
41.7
17.3
NA
36.2
40.6
31.9
36.4
5.2
58.1
56.5
46.8
52.5
18.2
30.1
35.5
9.2
28.0
28.3
25.0
35.0
11.7
24.6
16.7
4.6
46.9
62.5
51.6
50.7
13.4
35.5
29.7
14.5
19.4
22.0
5.4
32.4
32.4
25.0
29.4
5.7
5-09
5-10
5-11
5-12
5-13
29.7
34.8
7.3
34.3
23.8
7.6
15.3
17.6
10.2
5.7
5-14
5-15
5-16
5.6
4.4
5.7
4.9
5.7
5-17
14.3
13.6
6.1
15.1
13.0
9.6
25.5
8.9
25.6
9.3
7.4
17.0
5.1
5-18
1.7
5-19
25.2
56.5
53.2
5.2
15.4
43.3
41.7
4.8
6.8
Azoxystrobin
Trifloxystrobin
98.7
99.6
72.5
49.3
57.3
62.5
53.1
50.0
36.8
23.5
SS =Sclerotinia sclerotiorum (Lib.) de Bary; BC =Botrytis cinerea; PI =Phytophthora infestans (Mont.) De Bary; P A
= Pythium aphanidermatum; R S = Rhizoctonia solani; ST = Setosphaeria turcica; PG = Pyricularia grisea ;CO =
Colletotrichum. orbiculare (Berk. & Ment.)
aNA : No activity.
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Journal Name
80
70
60
50
40
30
20
10
0
PI
ST
PG
Figure 3 Inhibitory rates of partial compounds against PI, ST and PG
In order to study the activities of the superior target
compounds further, five compounds were chose for precise
virulence measurements to the four fungi, and their EC50
values were summarized in Table 3. These compounds were
highly effective against setosphaeria turcica and compound 5-
Figure 4 Topomer CoMFA contour maps of compound 5-09. (a) steric field around
03
activity than the control azoxystrobin and trifloxystrobin.
Compound 5-03 was effective to phytophthora infestans
, 5-05 and 5-09 exhibited lower EC50 values antifungal
benzoxazepinone moiety (b) electrostatic field around benzoxazepinone moiety (c)
steric field around
ClC6H4CH2)
R group(4-ClC6H4CH2) (d) electrostatic field around R group(4-
,
pyricularia grisea and setosphaeria turcica with the EC50 values
of 17.8, 26.1 and 9.6, respectively. Compounds 5-09 displayed
In contour maps of aliphatic series, the length of R group of
compounds 5-03 to 5-05 was comparable to aromatic
substituent and compounds 5-03 to 5-05 also exhibited
excellent fungicidal activity. For the substituent benzene of
aromatic series, compounds with a para-substituent showed
better fungicidal activity than with ortho-substituent
compounds. Compound 5-09, which has the highest activity,
was selected as a representative molecule, making it is easier
to explain the contour map. The benzene ring of
benzoxazepinone moiety with small substituent exhibits
stronger bioactivities in the map of the steric field (Figure 4a).
In the electrostatic field, the carbonyl group benzoxazepinone
moiety hovered red blocks (Figure 4b), indicating the
electronegative was beneficial for the antifungal activity. In
Figure 4c, reducing the steric hindrance of benzyl was
beneficial to the activity and a large substituent such as a tert-
butyl group, a cyclohexyl group in the para position of benzene
ring was unfavorable. Para-position of benzene ring hovered
blue blocks in the electrostatic field (Figure 4d), indicating the
introducing of electropositive group was beneficial for the
antifungal activity. The above discussions about SARs are
conducive to further structure optimization of this series of
compounds.
excellent activities
against
sclerotinia sclerotiorum,
phytophthora infestans
, pyricularia grisea and setosphaeria
turcica with the EC50 values of 21.7, 15.0, 16.7 and 7.8,
respectively.
As a conclusion, several compounds displayed comparable
activity to the commercial fungicides (azoxystrobin and
trifloxystrobin) against some fungi. In particularly, the
compound 5-03 and 5-09 showed better bioactivities than the
other compounds against most phytopathogens, suggesting
they might deserve to be developed as potential agricultural
fungicides.
Table 3. EC50 values of target compounds against four fungi
Compd.
EC50 (μg/ml)
PI
SS
PG
ST
5-03
5-04
38.9
47.2
43.0
21.7
75.0
1.8
17.8
35.9
>100
15.0
40.0
12.2
18.0
26.1
35.4
25.3
16.7
55.5
21.0
18.4
9.6
16.1
6.5
5-05
5-09
7.8
5-11
23.5
15.1
16.9
Azoxystrobin
Trifloxystrobin
1.6
Quantitative Structure-Activity Relationship (QSAR) Analyses.
During biological screening, models of the new compounds
were constructed using topomer CoMFA with Sybyl 7.3 to find
the relationship between structure and activity in theory.
Cross-validation q2 value of 0.594 and a non-cross-validation r2
value of 0.899 with an optimized component of 3 were
obtained, which suggested that the model has good predictive
ability (q2 > 0.5). In the sterically favoured and disfavoured
region are shown in green and yellow. For the electrostatic
field, the positively charged favoured regions are shown in
blue, and the negatively charge favoured regions are shown in
red.
Experimental
Intruments and Materials
1H NMR and 13C NMR spectra were obtained at 300 MHz using
a Bruker Avance DPX300 spectrometer in CDCl3 or DMSO-d6
solution with tetramethylsilane as the internal standard.
Chemical shift values (δ) are given in parts per million. High
resolution mass spectrometry data were obtained with an
Accurate-Mass-Q-TOF MS 6520 system equipped with an
electrospray ionization (ESI) source. The single crystal
4 | J. Name., 2012, 00, 1-3
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structure analysis was performed using X-ray diffraction on 7.41 – 7.18 (m, 2H), 7.06 (d,
ARTICLE
J
= 7.5 Hz, 1H), 5.16 (s, 2H), 4.00 (s,
Thermo Fisher ESCALAB 250 diffractometer. The melting 3H), 3.70 – 3.54 (m, 2H), 1.84 – 1.60 (m, 2H), 1.45 – 1.19 (m,
points were determined on a Cole-Parmer microscope melting 4H), 0.88 (t,
= 6.8 Hz, 3H).13C NMR (75 MHz,CDCl3) δ 167.05,
point apparatus and are uncorrected. Intermediate 152.39, 135.29, 130.71, 129.55, 126.13, 124.76, 124.63, 74.16,
J
3
synthesized as literature report.21 All the title compounds were 62.48, 45.76, 28.47, 26.12, 21.91, 13.54. HRMS (ESI) m/z calcd
confirmed by 1H NMR, 13C NMR and HRMS.
Synthetic procedures
for C15H20N2O3 (M+H)+ 277.1547, found 277.1547.
Data for (E)-3-hexyl-5-(methoxyimino)-3,5-
dihydrobenzo[e][1,2]oxazepin-4(1H)-one 5-04 ): yield 75 %;
colorless oil; 1H NMR (300 MHz, CDCl3) δ 7.71 (d,
= 7.6 Hz, 1H),
7.40 – 7.16 (m, 2H), 7.04 (d, = 7.6 Hz, 1H), 5.14 (s, 2H), 3.98 (s,
3H), 3.71 – 3.48 (m, 2H), 1.68 (dd, = 14.2, 7.1 Hz, 2H), 1.39 –
1.20 (m, 6H), 0.86 (t,
= 6.6 Hz, 3H).13C NMR (75 MHz, CDCl3) δ
Optimized Synthetic Procedure for Compound 4
(
J
Compound
3 (50 mmol) and methanol (50 mL) was stirred in
J
an ice bath. Sodium methoxide (2.67 g,50 mmol),was added
slowly then the reaction mixture was heated to reflux for 4 h.
and After cooling, the solid was filtered off, and the filtrate
was concentrated in vacuo. The residue was purified by silica
gel using petroleum ether/ethyl acetate (EtOAc:PE = 3: 1) as
J
J
167.06, 152.38, 135.29, 130.71, 129.54, 126.12, 124.77, 124.62,
74.17, 62.46, 45.79, 31.02, 26.39, 26.00, 22.07, 13.59.HRMS
(ESI) m/z calcd for C16H23N2O3 (M+H)+ 291.1703, found
291.1702.
eluent to give Compound
Data for
dihydrobenzo[e][1,2]oxazepin-4(1H)-one (
4 81%.
(E)-5-(methoxyimino)-3,5-
): yield 81 %; white
; H NMR (300 MHz, DMSO) δ 11.63 (s, 1H),
= 7.8 Hz, 1H), 7.42 (dt, = 7.6, 3.8 Hz, 1H), 7.32 (t,
7.1 Hz, 1H), 7.22 (d,
= 7.7 Hz, 1H), 5.19 (s, 2H), 3.90 (s, 3H).13C
Data
for
(E)-3-heptyl-5-(methoxyimino)-3,5-
5-05 ): yield 73 %;
colorless oil; H NMR (300 MHz, CDCl3) δ 7.82 – 7.60 (m, 1H),
7.41 – 7.15 (m, 2H), 7.03 (d, = 7.6 Hz, 1H), 5.13 (s, 2H), 3.98 (s,
3H), 3.74 – 3.51 (m, 2H), 1.79 – 1.60 (m, 2H), 1.41 – 1.18 (m,
8H), 0.85 (t,
= 6.7 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 167.03,
4
1
dihydrobenzo[e][1,2]oxazepin-4(1H)-one
(
solid; mp 146
7.60 (d,
℃
1
J
J
J =
J
J
NMR (75 MHz, DMSO) δ 168.42, 136.45, 130.44, 130.11,
126.53, 125.92, 124.63, 76.08, 62.52. HRMS (ESI) m/z calcd for
C10H10N2O3 (M+H)+ 207.0764, found 207.0765.
J
152.38, 135.29, 130.69, 129.51, 126.10, 124.77, 124.61, 74.16,
62.43, 45.76, 31.23, 28.49, 26.43, 26.28, 22.13, 13.64. HRMS
(ESI) m/z calcd for C17H25N2O3 (M+H)+ 305.1860, found
305.1864.
General procedure for the preparation of title compounds 5
Intermediate 4(3 mmol) was dissolved in DMF (10 mL), and a
catalytic amount of KI was added to the mixture, followed by
the addition of 60% NaH(0.18 g, 4.5 mmol) at 10 °C. The
reaction was allowed to stir for 1 h at this temperature. A
solution of halides (3.3 mmol) in 2 mL of DMF was then added
dropwise to the mixture, and the progress of the reaction was
monitored by thin-layer chromatography. Upon completion,
30ml H2O was added to the mixture, then extracted by ethyl
acetate (3×60mL) and concentrated the organic layer to an oil.
Data
dihydrobenzo[e][1,2]oxazepin-4(1H)-one (5-06): yield 34 %;
white solid; mp 62-63
; 1H NMR (300 MHz, CDCl3) δ 7.79 (d,
= 7.6 Hz, 1H), 7.38 (dq, = 14.2, 6.4 Hz, 2H), 7.13 (d, = 7.5 Hz,
1H), 5.96 (ddt, = 16.5, 10.1, 6.3 Hz, 1H), 5.38 (ddd, = 13.6,
11.1, 1.1 Hz, 2H), 5.24 (s, 2H), 4.34 (d, = 6.2 Hz, 2H), 4.09 (s,
for
(E)-3-allyl-5-(methoxyimino)-3,5-
℃
J
J
J
J
J
J
3H).13C NMR (75 MHz, CDCl3) δ 167.35, 152.22, 135.36, 130.80,
130.63, 129.66, 126.22, 124.75, 124.69, 119.43, 74.79, 62.65,
48.80. HRMS (ESI) m/z calcd for C13H14N2O3 (M+H)+ 247.1077,
found 247.1078.
The pure compounds
chromatography (EtOAc:PE = 4:1) purification.
Data for (E)-5-(methoxyimino)-3-propyl-3,5-
dihydrobenzo[e][1,2]oxazepin-4(1H)-one (5-01). White crystal;
5
was obtained by column
Data
dihydrobenzo[e][1,2]oxazepin-4(1H)-one (5-07): yield 52.5 %;
yellowish solid; mp 82-83
; 1H NMR (300 MHz, CDCl3) δ 8.67
– 8.55 (m, 1H), 7.96 (s, 1H), 7.55 – 7.34 (m, 2H), 7.22 (d, = 6.8
Hz, 1H), 5.26 (d, = 15.0 Hz, 1H), 5.06 (d, = 15.0 Hz, 1H), 4.77
(dd, = 61.2, 2.6 Hz, 2H), 4.08 (d,
= 12.2 Hz, 3H).13C NMR (75
for
(E)-5-(methoxyimino)-3-(prop-2-yn-1-yl)-3,5-
1
yield, 52%; mp: 83-85°C. H NMR (300 MHz, CDCl3) δ 7.80 (d,
= 7.6 Hz, 1H), 7.46 – 7.31 (m, 2H), 7.13 (d, = 7.7 Hz, 1H), 5.23
(s, 2H), 4.08 (s, 3H), 3.84 – 3.53 (m, 2H), 1.80 (tt, = 14.3, 7.1
Hz, 2H), 1.01 (t,
= 7.4 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ
J
℃
J
J
J
J
J
J
J
J
167.27, 152.38, 135.28, 130.84, 129.60, 126.24, 124.86, 124.60,
74.26, 62.62, 47.50, 19.90, 10.93. HRMS (ESI) m/z calcd for
C13H16N2O3 (M+H)+ 249.1234, found 249.1234.
MHz, CDCl3) δ 159.64, 157.22, 143.08, 135.42, 131.15, 129.91,
126.97, 124.23, 123.79, 123.01, 89.08, 65.23, 62.98. HRMS (ESI)
m/z calcd for C13H12N2O3 (M+H)+ 245.0921, found 245.0921.
Data
for
(E)-3-butyl-5-(methoxyimino)-3,5-
Data
dihydrobenzo[e][1,2]oxazepin-4(1H)-one
5-08 ): yield 50.9 %; white solid; mp 72-74
MHz, CDCl3) δ 7.90 – 7.70 (m, 1H), 7.42 – 7.31 (m, 4H), 7.21 (d,
= 7.9 Hz, 2H), 7.01 (d, = 7.1 Hz, 1H), 4.98 (s, 2H), 4.84 (s, 2H),
4.09 (s, 3H), 2.40 (s, 3H).13C NMR (75 MHz, CDCl3) δ 167.47,
152.28, 137.54, 135.42, 131.63, 130.89, 129.56, 129.07, 128.65,
126.20, 124.82, 124.57, 74.80, 62.70, 49.64, 20.84. HRMS (ESI)
m/z calcd for C18H18N2O3 (M+H)+ 311.1390, found 311.1390.
for
(E)-5-(methoxyimino)-3-(4-methylbenzyl)-3,5-
dihydrobenzo[e][1,2]oxazepin-4(1H)-one (5-02 ): yield 57 %;
1
white solid; mp 54-55
7.71 (m, 1H), 7.40 (ddd,
7.7 Hz, 1H), 5.24 (s, 2H), 4.09 (s, 3H), 3.81 – 3.62 (m, 2H), 1.77
(dt, = 15.0, 7.6 Hz, 2H), 1.44 (dq, = 14.7, 7.3 Hz, 2H), 1.00 (t,
= 7.3 Hz, 3H).13C NMR (75 MHz, CDCl3) δ 167.23, 152.38,
℃; H NMR (300 MHz, CDCl3) δ 7.88 –
1
(
℃; H NMR (300
J
= 20.1, 9.9, 3.9 Hz, 2H), 7.13 (d,
J =
J
J
J
J
J
135.28, 130.86, 129.59, 126.24, 124.88, 124.59, 74.28, 62.62,
45.69, 28.59, 19.68, 13.40. HRMS (ESI) m/z calcd for
C14H18N2O3 (M+H)+ 263.1390, found 263.1391.
Data
for
(E)-3-(4-chlorobenzyl)-5-(methoxyimino)-3,5-
Data
for
(E)-5-(methoxyimino)-3-pentyl-3,5-
dihydrobenzo[e][1,2]oxazepin-4(1H)-one (5-09 ): yield 75 %;
1
; H NMR (300 MHz, CDCl3) δ 7.84 –
dihydrobenzo[e][1,2]oxazepin-4(1H)-one (5-03): yield 69 %;
1
colorless oil; H NMR (300 MHz, CDCl3) δ 7.77 – 7.66 (m, 1H),
white solid; mp 93-94
℃
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Journal Name
7.64 (m, 1H), 7.37 – 7.25 (m, 6H), 6.98 (d,
J
= 6.4 Hz, 1H), 4.95 (m, 2H), 7.19 (dd, J = 5.4, 3.6 Hz, 1H), 6.94 (d, J = 7.7 Hz, 1H),
(s, 2H), 4.77 (s, 2H), 4.03 (s, 3H).13C NMR (75 MHz, CDCl3) δ 4.77 (s, 2H), 4.68 (s, 2H), 4.04 (s, 3H), 3.95 (s, 3H), 3.64 (s,
167.66, 152.02, 135.14, 133.78, 133.24, 130.92, 130.03, 129.68, 3H).13C NMR (75 MHz, CDCl3) δ 167.76, 162.98, 152.13, 148.36,
128.60, 126.31, 124.72, 124.60, 74.83, 62.76, 49.27. HRMS 135.70, 133.15, 130.79, 130.49, 129.82, 129.47, 129.36, 128.45,
(ESI) m/z calcd for C17H15ClN2O3 (M+H)+ 331.0844, found 127.79, 126.03, 124.77, 124.62, 75.01, 63.46, 62.71, 52.48,
331.0847.
48.45. HRMS (ESI) m/z calcd for C21H21N3O6 (M+H)+ 412.1503,
(E)-5-(methoxyimino)-3-(4-nitrobenzyl)-3,5- found 412.1503.
for
; 1H NMR (300 MHz, DMSO) δ 8.39 dihydrobenzo[e][1,2]oxazepin-4(1H)-one (5-16 ): yield 42%;
= 12.7, 4.9 Hz, 3H), 7.49 (td, = 7.6, white solid; mp 52
; 1H NMR (300 MHz, CDCl3) δ 7.61 (dd,
= 7.8 Hz, 1H), 5.33 6.3, 2.8 Hz, 1H), 7.35 (ddd, = 3.9, 3.2, 1.1 Hz, 2H), 7.22 – 7.06
(s, 2H), 5.06 (s, 2H), 3.95 (s, 3H).13C NMR (75 MHz, DMSO) δ (m, 1H), 6.13 (ddd,
= 17.2, 10.2, 7.0 Hz, 1H), 5.96 – 5.66 (m,
166.11, 152.38, 147.24, 143.36, 135.97, 130.49, 130.28, 129.47, 1H), 5.54 – 5.36 (m, 2H), 5.36 – 5.17 (m, 2H), 5.11 (d, = 7.0 Hz,
126.65, 125.86, 124.37, 123.92, 74.00, 62.68, 48.10. HRMS (ESI) 1H), 5.00 (d, = 14.9 Hz, 1H), 4.82 (d, = 14.9 Hz, 1H), 4.61 (dd,
m/z calcd for C17H15N3O5 (M+H)+ 342.1086, found 342.1084.
= 15.1, 4.7 Hz, 1H), 3.96 (d, = 1.0 Hz, 3H), 3.44 (dd, = 15.1,
Data for
(E)-4-((5-(methoxyimino)-4-oxo-4,5- 8.2 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 162.86, 154.10, 136.19,
Data
for
dihydrobenzo[e][1,2]oxazepin-4(1H)-one (5-10 ): yield 56 %; Data
(E)-1,3-diallyl-5-(methoxyimino)-3,5-
yellowish solid; mp 92-93
– 8.20 (m, 2H), 7.66 (dd,
℃
J
J
℃
J =
1.4 Hz, 1H), 7.38 (t,
J
= 6.9 Hz, 1H), 7.27 (d,
J
J
J
J
J
J
J
J
J
dihydrobenzo[e][1,2]oxazepin-3(1H)-yl)methyl)benzonitrile (5- 133.16, 131.77, 130.73, 129.02, 127.25, 125.41, 119.11, 119.06,
1
11). Yellowish oil; yield, 26%. H NMR (300 MHz, CDCl3) δ 7.89 90.77, 69.03, 62.06, 46.37. HRMS (ESI) m/z calcd for
– 7.75 (m, 1H), 7.70 (d,
7.46 – 7.33 (m, 2H), 7.07 (d,
J = 8.4 Hz, 2H), 7.54 (d, J
= 8.4 Hz, 2H), C16H18N2O3 (M+H)+ 287.1390, found 287.1391.
J
= 6.6 Hz, 1H), 5.08 (s, 2H), 4.92 (s, Data for (E)-1,3-bis(2-chlorobenzyl)-5-(methoxyimino)-3,5-
2H), 4.09 (s, 3H).13C NMR (75 MHz, CDCl3) δ 167.80, 151.71, dihydrobenzo[e][1,2]oxazepin-4(1H)-one (5-17 ): yield 54 %;
1
; H NMR (300 MHz, CDCl3) δ 7.85 –
140.07, 134.84, 132.22, 130.96, 129.80, 129.05, 126.46, 124.63, white solid; mp 96-97
124.60, 118.14, 111.79, 74.73, 62.84, 49.48. HRMS (ESI) m/z 7.74 (m, 1H), 7.68 (dd,
℃
J
= 5.8, 3.3 Hz, 1H), 7.42 – 7.23 (m, 7H),
calcd for C18H16N3O3 (M+H)+ 322.1186, found 322.1185.
Data for (E)-3-(2-chlorobenzyl)-5-(methoxyimino)-3,5- = 14.9 Hz, 1H), 4.31 (d,
dihydrobenzo[e][1,2]oxazepin-4(1H)-one (5-12): yield 24 %; (75 MHz, CDCl3) δ164.96, 154.11, 135.48, 133.75, 133.23,
white solid; mp 69-70 133.19, 133.14, 130.61, 130.19, 129.89, 129.34, 129.28, 129.02,
. 1H NMR (300 MHz, CDCl3) δ 7.90 (d,
= 8.0 Hz, 1H), 7.60 – 7.50 (m, 1H), 7.41 (dd,
7.32 (t, = 6.4 Hz, 2H), 7.29 (s, 1H), 7.15 (d,
7.22 – 7.09 (m, 3H), 6.24 (s, 1H), 5.19 – 5.01 (m, 2H), 4.80 (d,
J
J
= 15.5 Hz, 1H), 3.91 (s, 3H). 13C NMR
℃
J
J
= 8.1, 5.6 Hz, 2H), 128.63, 128.30, 127.62, 127.49, 126.71, 126.55, 125.89, 89.11,
J
J
= 7.6 Hz, 1H), 5.38 72.15, 62.17, 44.21. . HRMS (ESI) m/z calcd for C24H20Cl2N2O3
(s, 2H), 5.23 (s, 2H), 4.09 (s, 3H).13C NMR (75 MHz, CDCl3) δ (M+H)+ 455.0924, found 455.0930.
171.17, 147.18, 137.83, 133.12, 132.63, 130.31, 129.92, 129.34, Data
129.23, 129.15, 126.49, 125.88, 125.07, 71.84, 67.44, 62.82. dihydrobenzo[e][1,2]oxazepin-4(1H)-one (5-18): yield 83 %;
HRMS (ESI) m/z calcd for C17H15ClN2O3 (M+H)+ 331.0844, found white solid; mp 106-107 ; 1H NMR (300 MHz, CDCl3)
7.85
7.70 (m, 1H), 7.39 (ddd, J = 15.3, 10.5, 4.3 Hz, 2H), 7.13 (d, J
(E)-3-((2-chlorothiazol-5-yl)methyl)-5- = 7.6 Hz, 1H), 5.24 (s, 2H), 4.08 (s, 3H), 3.32 (s, 3H). 13C NMR
(75 MHz, CDCl3) δ 167.36, 152.08, 135.24, 130.88, 129.63,
; H NMR 126.27, 124.82, 124.65, 73.65, 62.69, 32.44. HRMS (ESI) m/z
= 7.7 Hz, 1H), 7.58 (s, 1H), 7.36 (dt, calcd for C11H12N2O3 (M+H)+ 221.0921, found 221.0919.
= 7.5 Hz, 1H), 5.19 (s, 2H), 4.92 (s, Data for (E)-3-ethyl-5-(methoxyimino)-3,5-
2H), 4.05 (s, 3H).13C NMR (75 MHz, CDCl3) δ 168.12, 152.45, dihydrobenzo[e][1,2]oxazepin-4(1H)-one (5-19): yield 63 %;
151.55, 141.23, 134.91, 133.22, 130.89, 129.82, 126.37, 124.73, white solid; mp 61-62 7.79 (d,
; 1H NMR (300 MHz, CDCl3)
124.50, 75.08, 62.83, 42.28. HRMS (ESI) m/z calcd for J = 6.8 Hz, 1H), 7.45 7.31 (m, 2H), 7.13 (d, J = 7.7 Hz, 1H),
C14H12ClN3O3S (M+H)+ 338.0361, found 338.0367.
5.25 (s, 2H), 4.08 (s, 3H), 3.77 (q, J = 7.1 Hz, 2H), 1.36 (t, J = 7.1
Data for
(E)-3-((6-chloropyridin-3-yl)methyl)-5- Hz, 3H).13C NMR (75 MHz, CDCl3) δ 167.38, 152.40, 135.34,
(methoxyimino)-3,5-dihydrobenzo[e][1,2]oxazepin-4(1H)-one 130.89, 129.59, 126.23, 124.94, 124.58, 74.57, 62.65, 40.94,
; H NMR 11.68. HRMS (ESI) m/z calcd for C12H14N2O3 (M+H)+ 235.1070,
for
(E)-5-(methoxyimino)-3-methyl-3,5-
℃
δ
331.0843.
–
Data
for
(methoxyimino)-3,5-dihydrobenzo[e][1,2]oxazepin-4(1H)-one
1
(
5-13 ): yield 66 %; yellowish solid; mp 109-111
(300 MHz, CDCl3) δ 7.75 (d,
= 20.5, 6.7 Hz, 2H), 7.09 (d,
℃
J
J
J
℃
δ
–
1
(
5-14): yield 68 %; yellowish solid; mp 109-111 ℃
(300 MHz, CDCl3) δ 8.45 (d,
J
= 2.4 Hz, 1H), 7.84 – 7.71 (m, 2H), found 235.1070.
7.46 – 7.31 (m, 3H), 7.07 (d,
J
= 7.3 Hz, 1H), 5.09 (s, 2H), 4.84 (s, X-ray Diffraction. Compound 5-09 was recrystallized by a slow
2H), 4.07 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 168.01, 151.67, evaporation from a dichloromethane/n-hexane (v/v = 1:5)
151.10, 149.71, 139.17, 134.82, 130.93, 129.79, 129.41, 126.43, solution to afford
124.66, 124.56, 124.14, 74.84, 62.84, 46.73.HRMS (ESI) m/z crystallography and mounted in inert oil and transferred to the
calcd for C16H15ClN3O3 (M+H)+ 332.0796, found 332.0792.
cold gas stream of the diffractometer. Cell dimensions and
Data for (E)-methyl 2-(methoxyimino)-2-(2-(((E)-5- intensities were measured using a Thermo Fisher ESCALAB 250
a single crystal suitable for X-ray
(methoxyimino)-4-oxo-4,5-dihydrobenzo[e][1,2]oxazepin-
diffractometer with graphite monochromated Mo Kα radiation.
Compound 5-09 orthorhombic, =8.7758(3) Å,
=16.7996(6) Å, =104.8,
=1529.75(10) Å3,
CDCl3) δ 7.79 – 7.66 (m, 1H), 7.55 – 7.37 (m, 3H), 7.35 – 7.25 space group P212121 (no. 19), = 4, μ(Mo Kα) =0.267. A total of
3(1H)-yl)methyl)phenyl)acetate
:
a
b =
(
5-15 ): yield 63 %; white solid; mp 147
℃
; 1H NMR (300 MHz, 10.3761(4) Å,
c
U
T
Z
6 | J. Name., 2012, 00, 1-3
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6446 reflections were measured, of which 3009 were unique In summary, we provid a novel and scalable method to
Rint = 0.0255) in the range of 6.54 <2Θ< 52°(-10 ≤ h ≤ 10, -12 ≤ prepare (E)-5-(methoxyimino)-3,5-
k ≤ 10, -20 ≤ l ≤ 20), and 3009 observed reflections with I > 2σ dihydrobenzo[e][1,2]oxazepin-4(1H)-one through
(I) were used in the refinement on F2. The structure was commercial available intermediate as raw material. Compound
solved by direct method with the SHELXTL-97 program. All of underwent an efficient intramolecular cyclization and
the non-H atoms were refined anisotropically by fullmatrix provided good isolated yields of under optimized reacting
(
a
3
4
least-squares to give the final wR(F2)= 0.0675. The atomic condition. Interestingly, some of these compounds displayed
coordinates for 5-09 have been deposited at the Cambridge excellent agricultural fungicidal activities, even comparing with
Crystallographic Data Centre. CCDC-1518111 contains the recently commercial products. Overall, we report a practical
supplementary crystallographic data for this paper. These data way to access these benzoxazepinones for their novel
can be obtained free of charge from The Cambridge structure and fungicidal activities that could be of great utility
Crystallographic Data Centre via CCDC CIF Depository Request for pharmacist as new scaffolds for SAR studies of their
Form for data published from 1994.Crystallographic data in CIF nitrogen and oxygen containing heterocycles and clearly point
format are in the Supporting Information.
Biological Assays
out the direction of the optimization of better fungicide
candidate. Thus, it is significantly important for new pestcide
design and development.
Fungicidal Activity. The test fungi, Sclerotinia sclerotiorum
(Lib.) de Bary, Botrytis cinerea, Phytophthora infestans (Mont.)
De Bary, Pythium aphanidermatum, Rhizoctonia solani
,
Acknowledgements
Setosphaeria turcica, Pyricularia grisea and Colletotrichum.
orbiculare (Berk. & Ment.) were provided by the Laboratory of
Institute of Plant Protection, Chinese Academy of Agricultural
Sciences. After retrieval from the storage tube, the strains
were incubated in PDA at 25 °C for several days to get new
This work was supported by the National Natural Science
Foundation of China (Grants 31272076).
mycelia for the antifungal assay.22 Azoxystrobin and Notes and references
trifloxystrobin, gifts from Jiangsu Frey Chemicals Co. were used
The authors declare no competing financial interest.
1 (a) V. G. Noskov, L. N. Kalinina, M. N. Noskova, Y. L. Kruglyak,
O. G. Strukov and A. P. Bezrukovet, Pharm.Chem.J. ,1997, 31
as control. The synthesized compounds and controls were
dissolved in DMSO to prepare the 20 mg·mL-1 stock solution
before mixing with molten agar. The media containing
compounds at a concentration of 50 μg·mL-1 for initial
screening were then poured into sterilized Petri dishes for the
initial screening. Their relative inhibition ratio (%) was
calculated as following equation:
,
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Commun., 2016,52, 6280-6283; (b) V.Psarra,M. A.Fousteris,
L.Hennig, M.Bantzi, A.Giannis and S. S. Nikolaropoulos, 2016
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,
2724-2726; (f) M.Ozeki,A.Muroyama,T.
(colony diameter of control − colony diameter of treatment) /
(colony diameter of control − mycelial disks diameter) × 100%.
This experiment was conducted twice with three replicates.
The fungicidal activity is listed in table 2.
,
,
The 20 mg·mL-1 stock solution was diluted diluted with PDA
to obtain a series of concentrations, repeat the experiments
above, and calculated the inhibition rate separately. The EC50
was calculated by spss statistics v17.0 and listed in table 3.
QSAR Analyses. Topomer CoMFA (in the SYBYL X 7.3 program)
was performed to analysis the relationship between structure
and activity. Topomer CoMFA is an alignment-independent 3D-
QSAR method that combines the topomer search method23
with the conventional CoMFA method. Besides the core of the
molecule, we split the functional of compound into two R-
groups that refer to the R1 (benzoxazepinone moiety) and R2(R
substituent) groups. In total, 20 compounds obtained from
synthesis were used to create a data set in which the inhibition
rate of all compounds was determined (Table 1) against
2
3
4
5
6
7
8
(a) K.Woydowski, and J.Liebscher, Tetrahedron,1999, 55,
setosphaeria turcica
.
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