Discovery of a Novel Series of Tricyclic Oxadiazine 4a-Methyl Esters Based on Indoxacarb as Potential Sodium Channel Blocker/Modulator Insecticides

Article abstract of DOI:10.1021/acs.jafc.9b00826

Indoxacarb, a commercialized oxadiazine insecticide, nearly irreversibly blocks open/inactivated, but not resting sodium channels. The structure-activity relationships showed that the substituents at the position of the chiral atom in the oxadiazine ring are very important to the biological activity of oxadiazine insecticide. Here we synthesized a series of tricyclic oxadiazine 4a-methyl ester derivatives. The chiral atom in the oxadiazine ring has been epimerized and substituted with either pyrethric acid or cinnamic acid derivatives. Benzene ring in the tricyclic moiety was substituted with a chlorine, fluorine, or bromine atom, and nitrogen-linked benzene ring was substituted with a trifluoromethyl or trifluoromethoxy group. Toxicity of these compounds against Spodoptera litura F. was evaluated. Diastereoisomers of most toxic compounds J7 and J9 with pyrethric acid moiety were separated by flash column chromatography. The more polar diastereoisomers, J7-L-Rf and J9-L-Rf, and compounds J24 and J26 with cinnamic acid moiety exhibited highest insecticidal activities. We further used Monte Carlo energy minimizations to dock compound J7 and J24 in the NavMs-based homology model of the open cockroach sodium channel. In the low-energy binding modes, the compound interacted with residues in the inner pore and domain interfaces, which previously were proposed to contribute to receptors of pyrethroids and sodium channel blocker insecticides. Our results define compound J7 and J24 as a potentially useful optimized hit for the development of multiple sites sodium channel blocker or modulator.

Full text of DOI:10.1021/acs.jafc.9b00826

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Agricultural and Environmental Chemistry
Discovery of a Novel Series of Tricyclic Oxadiazine 4a-Methyl Esters Based
on Indoxacarb as Potential Sodium Channel Blocker/ Modulator insecticides
Jianqiang Zhang, Wenbo Hao, Boris S. Zhorov, Ke Dong, and Dingxin Jiang
J. Agric. Food Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jafc.9b00826 • Publication Date (Web): 25 Jun 2019
Downloaded from http://pubs.acs.org on June 27, 2019
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Discovery of a Novel Series of Tricyclic Oxadiazine 4a-Methyl Esters Based on
Indoxacarb as Potential Sodium Channel Blocker/ Modulator insecticides
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Jianqiang Zhang,† Wenbo Hao,† Boris S. Zhorov,‡,§ Ke Dong,¶ Dingxin Jiang†,*
†Key Laboratory of Natural Pesticide and Chemical Biology, Ministry of Education, Laboratory
of Insect Toxicology, South China Agricultural University, Guangzhou 510642, PR China
‡ Sechenov Institute of Evolutionary Physiology and Biochemistry, RAS, St. Petersburg
§ Department of Biochemistry & Biomedical Sciences, McMaster University, Hamilton, Canada
¶ Department of Entomology, Neuroscience and Genetics Programs, Michigan State University,
East Lansing, MI, USA
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* Corresponding author. E-mail: dxj2005@scau.edu.cn
ABSTRACT: Indoxacarb, a commercialized oxadiazine insecticide, nearly irreversibly blocks
open/inactivated, but not resting sodium channels. The structure-activity relationships showed that
the substituents at the position of the chiral atom in the oxadiazine ring is very important to the
biological activity of oxadiazine insecticide. Here we synthesized a series of tricyclic oxadiazine
4a-methyl ester derivatives. The chiral atom in the oxadiazine ring has been epimerized and
substituted with either pyrethric acid or cinnamic acid derivatives. Benzene ring in the tricyclic
moiety was substituted with a chlorine, fluorine or bromine atom and nitrogen-linked benzene ring
was substituted with a trifluoromethyl or trifluoromethoxy group. Toxicity of these compounds
against Spodoptera litura F. was evaluated. Diastereoisomers of most toxic compounds J7 and J9
with pyrethric acid moiety were separated by flash column chromatography. The more polar
diastereoisomers, J7-L-Rf and J9-L-Rf, and compounds J24 and J26 with cinnamic acid moiety
exhibited highest insecticidal activities. We further used Monte Carlo energy minimizations to
dock compound J7 and J24 in the NavMs-based homology model of the open cockroach sodium
channel. In the low-energy binding modes, the compound interacted with residues in the inner pore
and domain interfaces, which previously were proposed to contribute to receptors of pyrethroids
and sodium channel blocker insecticides. Our results define compound J7 and J24 as a potentially
useful optimized hit for the development of multiple sites sodium channel blocker and/or
modulator.
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KEYWORDS: indoxacarb derivatives; insecticidal activity; structure activity relationship (SAR);
sodium channel; docking study
INTRODUCTION
With the growing demand for agricultural products for the rising global population, control of
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weeds, pathogens and insect pests remains a constant and critical need. However, increasing
resistance of insect pests to currently used insecticides limits the arsenal of pesticides suitable for
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pest control. Therefore, development of new insecticides with novel modes of action is
desirable.3,4
Indoxacarb (Figure 1), an oxadiazine insecticide, is the first commercialized pyrazoline–type
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sodium-channel blocker. Metaflumizone (Figure 1), a semi–carbazone insecticide, is the first
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sodium channel blocker insecticide in the animal health market. These compounds represent a
class of sodium channel blocker insecticides (SCBIs) with favorable environmental and
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toxicological properties. The molecular mechanisms of action and selective toxicity of these
compounds have been studied.6-9 Indoxacarb and metaflumizone cause a voltage–dependent,
nearly irreversible block in the inactivated channels by selectively targeting recovery from the
slow inactivation, thus preventing transition to the closed state after a prolonged membrane
depolarization.10,11 SCBIs bind at a receptor site in voltage–gated sodium channels, which overlaps
with the binding site for local anesthetic/anticonvulsant and exhibit selective toxicity between pest
insects and mammals.12
Voltage-gated sodium channels are transmembrane proteins that play key roles in the action
potential initiation and propagation in excitable cells, including neurons. Following membrane
depolarization, sodium channels open and permeate sodium ions into the cell, causing membrane
depolarization. A few milliseconds after opening, the channels inactivate, the process playing an
important role in the action potential termination. The pore-forming α1-subunit, which folds from
a single polypeptide, has four homologous repeat domains. Every repeat domain contains six
transmembrane segments (S1–S6) connected by intracellular and extracellular loops, including
large extracellular membrane-reentering P-loops between S5 and S6. A P-loop has membrane-
descending helix P1, membrane-ascending helix P2 and residues between P1-P2 that contribute to
the selectivity filter. In each domain, segments S1–S4 form a voltage-sensing module, while S5,
S6 and P-loop contribute a quarter to the pore module.
Mutational analysis and computational modeling suggest that SCBIs bind in the inner pore and
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extend their trifluoromethoxy-phenyl moiety into the III/IV domain interface, while the common
fragment C=N–NH–C=O chelates a sodium ion at the focus of P1 helices to form the energetically
preferable 5–membered ring.13-15 Another class of sodium-channel targeting insecticides,
pyrethroids, promote the channel activation and inhibit inactivation, resulting in prolonged channel
openings.16,17 Pyrethroids bind to two analogous receptor sites on sodium channels, which are
distinct from the receptor site of SCBIs.18,19 Pyrethroids and SCBIs showed little cross-resistance
in pest insects.20,21
Fragment–based drug discovery (FBDD) revolutionized development of new drugs. Many leads
with dual/multi–target or novel mode of action were developed with FBDD.22-26 Both pyrethroids
and SCBIs affect sodium channel inactivation, but the action details are different. Pyrethroids
inhibit fast inactivation, while SCBIs inhibit recovery from the fast and slow inactivation.
Cinnamic acid and its esters show diverse biological activities such as leishmanicidal, insecticidal,
acaricidal and antimicrobial properties.27-31 The wide ranges of biological applications have
intrigued considerable attention of synthetic chemists to design and synthesize diverse cinnamic
acid derivatives. 27,28
In our previous work, we found that the presence of strong electron-withdrawing group in 5-
position of the indanone ring of indoxacarb derivatives could enhance insecticidal activity and
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cockroach sodium channel variant (BgNav1-1a) inhibitory activity. Based on these reports, a
new series of tricyclic oxadiazine 4a-methyl ester derivatives were designed and synthesized by
introducing the cinnamic or pyrethric acid moiety at the position of the chiral atom in the
oxadiazine ring, and their insecticidal activities against S. litura F. were evaluated. The binding
activities of compounds J7 and J24 into the sodium channel model were also studied by molecular
docking investigations, which proposed structural models of sodium channel complexes with most
potent compounds.
MATERIALS AND METHODS
Chemicals and instruments
Starting materials and reagents were all analytically or chemically pure. All anhydrous solvents
reagents were dried by standard methods in advance. The melting points were determined on an
YRT-3 melting point apparatus (P.I.T TIANJING UNVERSITY) without calibration. Yields were
not optimized. NMR spectra were obtained on Bruker AV-600 instrument. Chemical shifts were
expressed in parts per million (ppm) with TMS as internal standard. High-resolution mass spectra
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(HRMS) of ultimate target compounds were obtain by Bruker maxis 4G ESI-Q-TOF. Data were
reported as m/z. Analytical thin layer chromatography (TLC) was performed on silica gel GF254.
Flash chromatography was performed with silica gel (200–300 mesh and 300–400 mesh).
Preparation of Compounds B–G. Compounds B–G were synthesized referring to the methods
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reported in the literature. The melting point and H NMR data were consistent with the literature.
General Methods for Synthesis of Compounds H1–H6. In an ice bath, a solution of compound
G1-G6 (2 mmol, 1 eq) in anhydrous tetrahydrofuran (THF) (10 mL) was added dropwise to a
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suspension of LiAlH (38 mg, 1 mmol, 1 eq) and anhydrous THF (5 mL) under argon. The TLC
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assay was supplemented with LiAlH (18 mg, 0.5 mmol, 0.25 eq) until the reactant consumption
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was complete. Then, the mixture was stirred at room temperature for 2 h and adjusted pH to 2–3
with 1 M HCl. The organic layers were collected and washed with brine (3 × 30 mL), dried over
MgSO , filtered and concentrated in vacuum for silica gel (200–300 mesh) column
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chromatography (petroleum ether/ethyl acetate= 2:1, v/v) to give the desired products H1–H6.
7-chloro-4a-(hydroxymethyl)-N-(4-(trifluoromethyl)phenyl)-4a,5-dihydroindeno[1,2-
1
e][1,3,4]oxadiazine-2(3H)-carboxamide (H1). H NMR (600 MHz, Chloroform-d) δ 8.53 (s, 1H,
NH), 7.68 (s, 1H, phenyl), 7.65 (d, J = 8.4 Hz, 2H, phenyl), 7.60 (d, J = 8.6 Hz, 2H, phenyl), 7.38
(d, J = 11.2 Hz, 2H, phenyl), 5.57 (d, J = 9.2 Hz, 1H, oxadiazine), 5.25 (d, J = 9.1 Hz, 1H,
oxadiazine), 3.82 (d, J = 13.2 Hz, 1H, cyclopentane), 3.62 (d, J = 12.1 Hz, 1H, cyclopentane), 3.34
1
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(d, J = 15.8 Hz, 1H, CH ), 3.06 (d, J = 15.6 Hz, 1H, CH ). C NMR (151 MHz, Chloroform-d) δ
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156.16 (CONH), 151.70 (oxadiazine-CN), 144.72 (phenyl-C), 140.99 (phenyl-C), 137.76 (phenyl-
C), 132.35 (phenyl-C), 128.74 (phenyl-C), 126.55 (phenyl-C), 126.27 (phenyl-C), 125.42 (phenyl-
C), 125.20 (CF ), 123.30 (phenyl-C), 118.84 (phenyl-C), 81.45 (oxadiazine-C), 69.83 (oxadiazine-
3
CH ), 64.67 (CH OH), 38.46 (cyclopentane-CH ).
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7-chloro-4a-(hydroxymethyl)-N-(4-(trifluoromethoxy)phenyl)-4a,5-dihydroindeno[1,2-
1
e][1,3,4]oxadiazine-2(3H)-carboxamide (H2). H NMR (600 MHz, Chloroform-d) δ 8.40 (s, 1H,
NH), 7.60 (d, J = 8.2 Hz, 1H, phenyl), 7.52 (d, J = 9.0 Hz, 2H, phenyl), 7.33 (d, J = 8.2 Hz, 1H,
phenyl), 7.31 (s, 1H, phenyl), 7.16 (d, J = 8.4 Hz, 2H, phenyl), 5.52 (d, J = 9.1 Hz, 1H, oxadiazine),
5.22 (dd, J = 9.1, 1.5 Hz, 1H, oxadiazine), 3.77 (d, J = 12.1 Hz, 1H, cyclopentane), 3.57 (d, J =
12.1 Hz, 1H, cyclopentane), 3.28 (dd, J = 15.8, 2.8 Hz, 1H, CH ), 3.00 (d, J = 15.8 Hz, 1H, CH ).
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13C NMR (151 MHz, Chloroform-d) δ 156.21 (CONH), 151.70 (oxadiazine-CN), 144.90 (phenyl-
C), 137.72 (phenyl-C), 136.63 (phenyl-C), 132.60 (phenyl-C), 128.84 (phenyl-C), 126.63 (phenyl-
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C), 122.81(phenyl-C), 121.90 (OCF ), 120.82 (phenyl-C), 120.84 (phenyl-C), 81.62 (oxadiazine-
3
C), 69.91 (oxadiazine-CH ), 64.50 (CH OH), 38.52 (cyclopentane-CH )
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7-bromo-4a-(hydroxymethyl)-N-(4-(trifluoromethyl)phenyl)-4a,5-dihydroindeno[1,2-
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e][1,3,4]oxadiazine-2(3H)-carboxamide (H3). H NMR (600 MHz, Chloroform-d) δ 8.39 (s, 1H,
NH), 7.58 (d, J = 9.2 Hz, 2H, phenyl), 7.55 (s, 1H, phenyl), 7.53 (d, J = 3.5 Hz, 2H, phenyl), 7.20
(d, J = 8.7 Hz, 2H, phenyl), 5.55 (d, J = 9.1 Hz, 1H, oxadiazine), 5.23 (d, J = 9.1 Hz, 1H,
oxadiazine), 3.81 (d, J = 13.1 Hz, 1H, cyclopentane), 3.61 (d, J = 12.1 Hz, 1H, cyclopentane), 3.34
1
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(d, J = 15.8 Hz, 1H, CH ), 3.06 (d, J = 15.7 Hz, 1H, CH ). C NMR (151 MHz, Chloroform-d) δ
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156.05 (CONH), 151.44 (oxadiazine-CN), 144.88 (phenyl-C), 136.48 (phenyl-C), 132.89 (phenyl-
C), 131.55 (phenyl-C), 129.51 (phenyl-C), 125.95 (phenyl-C), 122.94 (phenyl-C), 121.79 (phenyl-
C), 121.36 (CF ), 120.59 (phenyl-C), 119.66 (phenyl-C), 81.38 (oxadiazine-C), 69.87 (oxadiazine-
3
CH ), 64.65 (CH OH), 38.39 (cyclopentane-CH ).
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7-bromo-4a-(hydroxymethyl)-N-(4-(trifluoromethoxy)phenyl)-4a,5-dihydroindeno[1,2-
1
e][1,3,4]oxadiazine-2(3H)-carboxamide (H4). H NMR (600 MHz, Chloroform-d) δ 8.42 (s, 1H,
NH), 7.54 (d, J = 9.3 Hz, 2H, phenyl), 7.52 (s, 1H, phenyl), 7.50 (s, 2H, phenyl), 7.17 (d, J = 8.7
Hz, 2H, phenyl), 5.51 (d, J = 9.1 Hz, 1H, oxadiazine), 5.25 (d, J = 9.2 Hz, 1H, oxadiazine), 3.78
(d, J = 12.1 Hz, 1H, cyclopentane), 3.58 (d, J = 11.8 Hz, 1H, cyclopentane), 3.29 (d, J = 15.8 Hz,
1
3
1H, CH ), 3.00 (d, J = 15.7 Hz, 1H, CH ). C NMR (151 MHz, Chloroform-d) δ 155.99 (CONH),
2
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151.59 (oxadiazine-CN), 144.95 (phenyl-C), 136.43 (phenyl-C), 132.95 (phenyl-C), 131.49
(phenyl-C), 129.46 (phenyl-C), 125.87 (phenyl-C), 122.92 (phenyl-C), 121.75 (phenyl-C),
121.36(OCF ), 121.09 (phenyl-C), 120.70 (phenyl-C), 81.43 (oxadiazine-C), 69.77 (oxadiazine-
3
CH ), 64.30 (CH OH), 38.38 (cyclopentane-CH ).
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7-fluoro-4a-(hydroxymethyl)-N-(4-(trifluoromethyl)phenyl)-4a,5-dihydroindeno-[1,2-
1
e][1,3,4]oxadiazine-2(3H)-carboxamide (H5). H NMR (600 MHz, Chloroform-d) δ 8.53 (s, 1H,
NH), 7.68 (dd, J = 8.4, 5.1 Hz, 1H, phenyl), 7.64 (d, J = 8.6 Hz, 2H, phenyl), 7.57 (d, J = 8.6 Hz,
2H, phenyl), 7.08 (dt, J = 8.8, 2.0 Hz, 1H, phenyl), 7.04 (d, J = 8.3 Hz, 1H, phenyl), 5.55 (d, J =
9.1 Hz, 1H, oxadiazine 5.19 (d, J = 9.1 Hz, 1H, oxadiazine), 3.78 (dd, J = 12.1, 1.0 Hz, 1H,
cyclopentane), 3.60 (d, J = 12.1 Hz, 1H, cyclopentane), 3.32 (d, J = 15.8 Hz, 1H, CH ), 3.04 (d, J
2
1
3
= 15.8 Hz, 1H, CH ). C NMR (151 MHz, Chloroform-d) δ 166.11 (CONH), 164.43 (oxadiazine-
2
CN), 156.72 (phenyl-C), 151.50 (phenyl-C), 145.81 (phenyl-C), 141.22 (phenyl-C), 126.43
(phenyl-C), 125.50 (phenyl-C), 123.73 (phenyl-C), 123.41 (phenyl-C), 119.00 (CF ), 116.13
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(phenyl-C), 113.60 (phenyl-C), 81.71 (oxadiazine-C), 69.97 (oxadiazine-CH ), 64.91 (CH OH),
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38.73 (cyclopentane-CH2).
7-fluoro-4a-(hydroxymethyl)-N-(4-(trifluoromethoxy)phenyl)-4a,5-dihydroindeno[1,2-
1
e][1,3,4]oxadiazine-2(3H)-carboxamide (H6). H NMR (600 MHz, Chloroform-d) δ 8.44 (s, 1H,
NH), 7.65 (dd, J = 8.5, 5.0 Hz, 1H, phenyl), 7.51 (d, J = 8.9 Hz, 2H, phenyl), 7.14 (d, J = 8.6 Hz,
2H, phenyl), 7.04 (t, J = 8.7 Hz, 1H, phenyl), 7.00 (d, J = 8.1 Hz, 1H, phenyl), 5.51 (d, J = 9.1 Hz,
1H, oxadiazine), 5.21 (d, J = 9.1 Hz, 1H, oxadiazine), 3.76 (d, J = 12.0 Hz, 1H, cyclopentane),
3.55 (dd, J = 11.9, 6.3 Hz, 1H, cyclopentane), 3.28 (d, J = 15.8 Hz, 1H, CH ), 2.98 (d, J = 15.8 Hz,
2
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3
1H, CH ). C NMR (151 MHz, Chloroform-d) δ 165.81 (CONH), 164.14 (oxadiazine-CN),
2
156.27 (phenyl-C), 151.73 (phenyl-C), 145.77 (phenyl-C), 144.83 (phenyl-C), 136.52 (phenyl-C),
130.00 (phenyl-C), 123.45 (phenyl-C), 121.69 (phenyl-C), 120.68 (OCF ), 115.89 (phenyl-C),
3
113.46 (phenyl-C), 81.60 (oxadiazine-C), 69.73 (oxadiazine-CH ), 64.22 (CH OH), 38.80
2
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(cyclopentane-CH2).
General synthetic procedure for compounds J1–J34. In an ice bath, acyl chloride (3 mmol, 3
eq) was added to a solution of compound H (1 mmol, 1 eq), dimethylaminopyridine (DMAP), dry
diisopropylethylamine (DIPEA) (0.42 mL, 3 mmol, 3 eq) in anhydrous THF (5 mL) under an argon
atmosphere. After 2 h, the organic layers were collected and washed with ice-cold sodium
hydroxide solution (3 × 30 mL), collected with ethyl acetate (3 × 15 mL) and dried over MgSO4,
filtered and concentrated in vacuum for silica gel (300–400 mesh) column chromatography
(petroleum ether/ethyl acetate = 8:1, v/v) to give the desired products J1-J34.
(7-chloro-2-((4-(trifluoromethyl)phenyl)carbamoyl)-2,5-tetrahydroindeno[1,2-
e][1,3,4]oxadiazin-4a-yl)methyl
3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate
1
(J1). J1-H-Rf(Higher Rf value compd) Yield: 37.5%; white solid: mp 87–88 °C; H NMR (600
MHz, Chloroform-d) δ 8.54 (s, 1H, NH), 7.68 (d, J = 8.6 Hz, 2H, phenyl), 7.64 – 7.58 (m, 3H,
phenyl), 7.39 (d, J = 8.2 Hz, 1H, phenyl), 7.37 (s, 1H, phenyl), 6.16 (d, J = 9.0 Hz, 1H, vinyl),
5.58 (d, J = 9.5 Hz, 1H, oxadiazine), 5.43 (d, J = 9.5 Hz, 1H, oxadiazine), 4.52 (d, J = 13.2 Hz,
1H, cyclopentane), 4.10 (d, J = 12.3 Hz, 1H, cyclopentane), 3.33 (d, J = 15.8 Hz, 1H, CH ), 3.12
2
(d, J = 15.8 Hz, 1H, CH ), 2.05 (t, J = 8.7 Hz, 1H, cyclopropane), 1.78 (d, J = 8.5 Hz, 1H,
2
1
3
cyclopropane), 1.24 (s, 3H, CH ), 1.21 (s, 3H, CH ). C NMR (151 MHz, Chloroform-d) δ 169.75
3
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(O=C-O), 152.87 (CONH), 151.14 (oxadiazine-CN), 144.85 (phenyl-C), 144.07 (phenyl-C),
137.46 (C=C), 132.77 (phenyl-C), 128.83 (C=C), 126.33 (phenyl-C), 124.39 (CF ), 122.60
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(phenyl-C), 121.82 (phenyl-C), 121.37 (phenyl-C), 121.14 (phenyl-C), 120.50 (phenyl-C), 119.66
(phenyl-C), 79.14 (oxadiazine-CN), 69.36 (oxadiazine-CH ), 63.68 (CH OH), 39.33
2
2
(cyclopentane-CH ), 33.03 (cyclopropane-C), 31.41 (cyclopropane-C), 29.70 (cyclopropane-
2
C(Me) ), 28.23 (CH ), 28.09 (CH ), 14.81. J1-L-Rf (Lower Rf value compd) Yield: 45.8%;
2
3
3
1
white solid: mp 104–106 °C; H NMR (600 MHz, Chloroform-d) δ 8.39 (d, J = 6.3 Hz, 1H, NH),
7.61 (dd, J = 12.1, 8.1 Hz, 1H, phenyl), 7.57 (dd, J = 9.0, 3.6 Hz, 2H, phenyl), 7.40 – 7.33 (m, 2H,
phenyl), 7.20 (d, J = 8.6 Hz, 2H, phenyl), 5.57 – 5.52 (m, 1H, vinyl), 5.52 – 5.46 (m, 1H,
oxadiazine), 5.46 – 5.40 (m, 1H, oxadiazine), 4.54 – 4.46 (m, 1H, cyclopentane), 4.19 – 4.10 (m,
1H, cyclopentane), 3.37 – 3.23 (m, 1H, CH ), 3.12 (dd, J = 15.8, 4.0 Hz, 1H, CH ), 2.19 (dt, J =
2
2
8.5, 4.9 Hz, 1H, cyclopropane), 1.53 (dd, J = 16.8, 5.3 Hz, 1H, cyclopropane), 1.25 (d, J = 3.7 Hz,
1
3
2H, CH ), 1.21 (s, 1H, CH ), 1.20 (s, 1H, CH ), 1.15 (d, J = 3.0 Hz, 2H, CH ). C NMR (151
3
3
3
3
MHz, Chloroform-d) δ 169.64 (O=C-O), 153.00 (CONH), 151.13 (oxadiazine-CN), 144.83
(phenyl-C), 143.93 (phenyl-C), 136.53 (C=C), 132.77 (phenyl-C), 132.66 (phenyl-C), 128.86
(C=C), 126.47 (phenyl-C), 126.27 (phenyl-C, 124.48 (CF ), 122.73 (phenyl-C), 122.69 (phenyl-
3
C), 122.59 (phenyl-C), 121.81 (phenyl-C), 120.50 (phenyl-C), 79.15 (oxadiazine-CN), 69.53
(oxadiazine-CH2), 64.43 (CH O), 39.35 (cyclopentane-CH2), 33.37(cyclopropane-C),
2
33.01(cyclopropane-C), 29.48 (cyclopropane-C(Me) ), 28.20 (CH ), 22.43 (CH ), 19.97. HRMS
2
3
3
+
(ESI-TOF) m/z: calcd for C H F Cl N O [M + CH CN] 654.0782; found 654.0763.
2
7
23
3
3
3
4
3
7-chloro-2-((4-(trifluoromethoxy)phenyl)carbamoyl-2,5-tetrahydroindeno
[1,2-
e][1,3,4]oxadiazin-4a-yl)methyl 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylate
1
(J2). J2-H-Rf (Higher Rf value compd) Yield: 35.5%; white solid: mp 130–131 °C; H NMR
(600 MHz, Chloroform-d) δ 8.37 (s, 1H, NH), 7.58 (d, J = 8.1 Hz, 1H, phenyl), 7.57–7.54 (m, 2H,
phenyl), 7.36 (d, J = 8.2 Hz, 1H, phenyl), 7.35 (s, 1H, phenyl), 7.19 (d, J = 8.4 Hz, 2H, phenyl),
6.15 (d, J = 9.0 Hz, 1H, vinyl), 5.53 (d, J = 9.5 Hz, 1H, oxadiazine), 5.41 (d, J = 9.5 Hz, 1H,
oxadiazine), 4.49 (dd, J = 12.3, 1.3 Hz, 1H, cyclopentane), 4.08 (d, J = 12.3 Hz, 1H, cyclopentane),
3.31 (d, J = 15.8 Hz, 1H, CH ), 3.10 (d, J = 16.3 Hz, 1H, CH ), 2.03 (t, J = 8.7 Hz, 1H,
2
2
1
3
cyclopropane), 1.76 (d, J = 8.5 Hz, 1H, cyclopropane), 1.22 (s, 3H, CH ), 1.20 (s, 3H, CH ). C
3
3
NMR (151 MHz, Chloroform-d) δ 169.92 (O=C-O), 152.99 (CONH), 151.29 (oxadiazine-CN),
145.00 (phenyl-C), 144.99 (phenyl-C), 144.23 (phenyl-C), 137.62 (C=C), 136.69 (phenyl-C),
132.92 (phenyl-C), 128.99 (C=C), 126.49 (phenyl-C), 124.54 (CF ), 122.77 (phenyl-C), 121.99
3
(phenyl-C), 121.28 (phenyl-C), 79.29 (oxadiazine-CN), 69.50 (oxadiazine-CH ), 63.82 (CH O),
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39.48 (cyclopentane-CH2), 33.19 (cyclopropane-C), 31.56 (cyclopropane-C), 33.53
(cyclopropane-C(Me) ), 28.38 (CH ), 28.26 (CH ), 14.95. J2-L-Rf (Lower Rf value compd)
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3
3
1
Yield: 53.6%; white solid: mp 85–86 °C; H NMR (600 MHz, Chloroform-d) δ 8.37 (d, J = 6.2
Hz, 1H, NH), 7.59 (dd, J = 12.4, 8.1 Hz, 1H, phenyl), 7.56 (dd, J = 9.0, 3.7 Hz, 2H, phenyl), 7.38
– 7.33 (m, 2H, phenyl), 7.19 (d, J = 8.7 Hz, 2H, phenyl), 5.54 (dd, J = 8.2, 5.8 Hz, 1H, vinyl), 5.50
(dd, J = 15.2, 9.5 Hz, 1H, oxadiazine), 5.42 (dd, J = 11.9, 9.5 Hz, 1H, oxadiazine), 4.49 (dd, J =
14.8, 12.8 Hz, 1H, cyclopentane), 4.14 (dd, J = 12.3, 5.4 Hz, 1H, cyclopentane), 3.35 – 3.24 (m,
1H, CH ), 3.11 (dd, J = 15.8, 3.9 Hz, 1H, CH ), 2.17 (td, J = 8.8, 5.4 Hz, 1H, cyclopropane), 1.52
2
2
(dd, J = 16.4, 5.3 Hz, 1H, cyclopropane), 1.24 (d, J = 3.8 Hz, 3H, CH ), 1.14 (d, J = 3.0 Hz, 3H,
3
CH3). 13C NMR (151 MHz, Chloroform-d) δ 170.60 (O=C-O), 153.29 (CONH), 153.10
(oxadiazine-CN), 144.96 (phenyl-C), 144.26 (phenyl-C), 137.63 (C=C), 132.91 (phenyl-C),
132.80 (phenyl-C), 129.00 (phenyl-C), 128.95 (phenyl-C), 126.65 (CF ), 126.61 (phenyl-C),
3
122.83 (phenyl-C), 122.73 (phenyl-C), 122.52 (phenyl-C), 121.96 (phenyl-C), 120.62 (phenyl-C),
79.38 (oxadiazine-CN), 69.54 (oxadiazine-CH ), 64.13 (CH O), 39.51 (cyclopentane-CH ), 34.36
2
2
2
(cyclopropane-C), 33.51 (cyclopropane-C), 33.50 (cyclopropane-C(Me) ), 29.66 (CH ), 29.61
2
3
+
(CH ). HRMS (ESI-TOF) m/z: calcd for C H F N O [M + Na] 654.0548; found 654.0546.
3
22 20
3
3
7
(7-bromo-2-((4-(trifluoromethyl)phenyl)carbamoyl)-2,5-tetrahydroindeno[1,2-
e][1,3,4]oxadiazin-4a-yl)methyl 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate
1
(J3). J3-H-Rf (Higher Rf value compd) Yield: 45.6%; white solid: mp 80–81 °C; H NMR (600
MHz, Chloroform-d) δ 8.53 (d, J = 8.5 Hz, 1H, NH), 7.68 (dd, J = 8.7, 3.3 Hz, 2H, phenyl), 7.60
(d, J = 8.5 Hz, 2H, phenyl), 7.57 – 7.50 (m, 3H, phenyl), 6.15 (dd, J = 17.1, 9.0 Hz, 1H, vinyl),
5.58 (d, J = 9.8 Hz, 1H, oxadiazine), 5.57 – 5.52 (m, 1H, oxadiazine), 5.48 – 5.40 (m, 1H,
cyclopentane), 4.52 (ddd, J = 12.4, 5.0, 1.4 Hz, 1H, cyclopentane), 4.18 – 4.07 (m, 1H, CH ), 3.38
2
– 3.24 (m, 1H, CH ), 3.16 – 3.09 (m, 1H, cyclopropane), 2.07 – 2.01 (m, 1H, cyclopropane), 1.78
2
(d, J = 9.8 Hz, 1H, CH ), 1.27 – 1.25 (m, 2H, CH ), 1.24 (s, 1H, CH ), 1.22 – 1.20 (m, 2H, CH ).
3
3
3
3
13C NMR (151 MHz, Chloroform-d) δ 169.74 (O=C-O), 153.03 (CONH), 150.86 (oxadiazine-
CN), 144.11 (phenyl-C), 141.00 (phenyl-C), 137.57 (C=C), 132.68 (phenyl-C), 128.86 (C=C),
126.35 (phenyl-C), 126.30 (phenyl-C), 125.37 (phenyl-C), 125.10 (phenyl-C), 124.37 (CF3),
122.65 (phenyl-C), 121.16 (phenyl-C), 118.76 (phenyl-C), 79.15 (oxadiazine-CN), 69.34
(oxadiazine-CH ), 63.64 (CH O), 39.34 (cyclopentane-CH ), 33.05 (cyclopropane-C), 31.41
2
2
2
(cyclopropane-C), 29.70 (CH ), 28.23 (CH ). J3-L-Rf (Lower Rf value compd) Yield: 29.4%;
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white solid: mp 111–112 °C; H NMR (600 MHz, Chloroform-d) δ 8.55 – 8.36 (m, 1H, NH), 7.67
(dd, J = 8.6, 3.4 Hz, 1H, phenyl), 7.60 – 7.55 (m, 2H, phenyl), 7.55 – 7.49 (m, 3H, phenyl), 7.19
(d, J = 8.8 Hz, 1H, phenyl), 5.53 (dd, J = 9.6, 3.0 Hz, 1H, vinyl), 5.41 (dd, J = 9.5, 3.7 Hz, 1H,
oxadiazine), 4.57 – 4.48 (m, 1H, oxadiazine), 4.14 – 4.09 (m, 1H, cyclopentane), 3.32 (dd, J =
15.8, 3.8 Hz, 1H, cyclopentane), 3.11 (d, J = 15.9 Hz, 1H, CH ), 2.17 (t, J = 9.0 Hz, 1H, CH ),
2
2
1.91 (d, J = 8.3 Hz, 1H, cyclopropane), 1.77 (d, J = 8.5 Hz, 1H, cyclopropane), 1.27 (d, J = 5.9
1
3
Hz, 3H, CH ), 1.26 (d, J = 5.2 Hz, 3H, CH ). C NMR (151 MHz, Chloroform-d) δ 169.43 (O=C-
3
3
O), 153.12 (CONH), 151.14 (oxadiazine-CN), 144.07 (phenyl-C), 136.53 (C=C), 133.12 (phenyl-
C), 131.75 (phenyl-C), 129.60 (C=C), 129.57 (phenyl-C), 129.27 (phenyl-C), 125.77 (phenyl-C),
122.88 (CF ), 121.81 (phenyl-C), 120.46 (phenyl-C), 79.23 (oxadiazine-CN), 69.55 (oxadiazine-
3
CH ), 64.61 (CH O), 39.24 (cyclopentane-CH ), 31.25 (cyclopropane-C), 29.70 (CH ), 28.19
2
2
2
3
+
(CH ). HRMS (ESI-TOF) m/z: calcd for C H F B Cl N O [M + Na] 682.0093; found
3
27 23
3
r
2
3
4
682.0105.
(7-bromo-2-((4-(trifluoromethyl)phenyl)carbamoyl)-2,5-tetrahydroindeno[1,2-
e][1,3,4]oxadiazin-4a-yl)methyl 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate
1
(J4). J4-H-Rf (Higher Rf value compd) Yield: 36.4%; white solid: mp 74–76 °C; H NMR (600
MHz, Chloroform-d) δ 8.54 (s, 1H, NH), 7.68 (d, J = 8.6 Hz, 2H, phenyl), 7.64 – 7.58 (m, 3H,
phenyl), 7.39 (d, J = 8.2 Hz, 1H, phenyl), 7.37 (s, 1H, phenyl), 6.16 (d, J = 9.0 Hz, 1H, vinyl), 5.58
(d, J = 9.5 Hz, 1H, oxadiazine), 5.43 (d, J = 9.5 Hz, 1H, oxadiazine), 4.52 (d, J = 13.2 Hz, 1H,
cyclopentane), 4.10 (d, J = 12.3 Hz, 1H, cyclopentane 3.33 (d, J = 15.8 Hz, 1H, CH ), 3.12 (d, J =
2
15.8 Hz, 1H, CH ), 2.05 (t, J = 8.7 Hz, 1H, cyclopropane), 1.78 (d, J = 8.5 Hz, 1H, cyclopropane),
2
1
3
1.24 (s, 3H, CH ), 1.21 (s, 3H, CH ). C NMR (151 MHz, Chloroform-d) δ 170.40 (O=C-O),
3
3
152.96 (CONH) , 151.08 (oxadiazine-CN) , 144.77 (phenyl-C), 136.60 (C=C), 133.25 (phenyl-C)
, 131.66 (phenyl-C) , 131.62 (phenyl-C) , 129.28 (phenyl-C) , 129.21 (C=C) , 126.55 (CF ), 126.51
3
(phenyl-C) , 125.71 (phenyl-C), 124.52 (phenyl-C), 122.91 (phenyl-C), 122.87 (phenyl-C),
122.78 (phenyl-C) , 122.50 (CF ) , 120.45 (phenyl-C), 79.25 (oxadiazine-CN), 69.30 (oxadiazine-
3
CH ), 64.39 (CH O), 39.25 (cyclopentane-CH ), 34.23 (cyclopropane-C), 34.13 (cyclopropane-
2
2
2
C), 29.48 (cyclopropane-C(Me) ), 27.99 (CH ), 22.39 (CH ). J4-L-Rf (Lower Rf value compd)
2
3
3
1
Yield: 48.8%; white solid: mp 112–113 °C; H NMR (600 MHz, Chloroform-d) δ 8.53 (s, 1H,
NH), 7.68 (d, J = 8.5 Hz, 2H, phenyl), 7.60 (d, J = 8.6 Hz, 2H, phenyl), 7.54 (d, J = 6.0 Hz, 3H,
phenyl), 6.16 (d, J = 9.0 Hz, 1H, vinyl), 5.62 (d, J = 8.4 Hz, 1H, oxadiazine), 5.57 (d, J = 9.5 Hz,
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1H, oxadiazine), 5.43 (d, J = 9.5 Hz, 1H, cyclopentane), 4.52 (d, J = 13.1 Hz, 1H, cyclopentane),
4.10 (d, J = 12.3 Hz, 1H, CH ), 3.33 (d, J = 15.8 Hz, 1H, CH ), 3.13 (d, J = 15.7 Hz, 1H,
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2
cyclopropane), 2.24 (dd, J = 8.4, 5.4 Hz, 1H, cyclopropane), 1.21 (s, 3H, CH ), 1.20 (s, 3H, CH ).
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13C NMR (151 MHz, Chloroform-d) δ 169.74 (O=C-O), 153.06 (CONH), 150.86 (oxadiazine-
CN), 144.30 (phenyl-C), 140.99 (phenyl-C), 140.98 (phenyl-C), 131.71 (phenyl-C), 129.33 (C=C),
127.12 (phenyl-C), 126.30 (phenyl-C) , 125.84 (phenyl-C), 125.02 (phenyl-C) 124.36 (CF3),
122.85 (phenyl-C), 118.78 (phenyl-C), 69.33 (oxadiazine-CH ), 63.62 (CH O), 39.26
2
2
(cyclopentane-CH ), 34.87 (cyclopropane-C), 33.05 (cyclopropane-C), 31.40 (cyclopropane-
2
C(Me) ), 28.23 (CH ) , 28.13 (CH ). HRMS (ESI-TOF) m/z: calcd for C H F B Cl N O [M +
2
3
3
27 23
3
r
2
3
5
+
CH CN] 714.0254; found 714.0224.
3
7-fluoro-2-((4-(trifluoromethyl)phenyl)carbamoyl-2,5-tetrahydroindeno-[1,2-
e][1,3,4]oxadiazin-4a-yl)methyl3-(2,2-dichlorovinyl)2,2-dimethylcyclopropane
Carboxylate
1
(J5). J5-H-Rf (Higher Rf value compd) Yield: 33.5%; white solid: mp 88–89 °C; H NMR (600
MHz, Chloroform-d) δ 8.52 (s, 1H, NH), 7.69–7.64 (m, 3H, phenyl), 7.59 (d, J = 8.6 Hz, 2H,
phenyl), 7.09 (dt, J = 8.6, 2.2 Hz, 1H, phenyl), 7.06 (d, J = 8.3 Hz, 1H, phenyl), 6.15 (d, J = 9.0
Hz, 1H, vinyl), 5.52 (d, J = 9.4 Hz, 1H, oxadiazine), 5.43 (d, J = 9.4 Hz, 1H, oxadiazine), 4.49 (dd,
J = 12.3, 1.4 Hz, 1H, cyclopentane), 4.10 (d, J = 12.3 Hz, 1H, cyclopentane), 3.32 (d, J = 15.8 Hz,
1H, CH ), 3.12 (d, J = 15.8 Hz, 1H, CH ), 2.03 (t, J = 8.7 Hz, 1H, cyclopropane), 1.77 (d, J = 8.5
2
2
1
3
Hz, 1H, cyclopropane), 1.22 (s, 3H, CH ), 1.19 (s, 3H, CH ). C NMR (151 MHz, Chloroform-d)
3
3
δ 169.92 (O=C-O), 165.97 (phenyl-C), 164.30 (phenyl-C), 153.55 (CONH), 151.11 (oxadiazine-
CN), 145.24 (phenyl-C), 141.23 (phenyl-C), 130.33 (C=C), 130.31 (C=C), 126.50 (phenyl-C),
126.47 (phenyl-C), 126.45 (phenyl-C), 126.42 (phenyl-C), 125.27 (phenyl-C), 124.55 (phenyl-C),
123.57 (CF ), 123.51 (phenyl-C), 121.29 (phenyl-C), 118.90 (phenyl-C), 116.31 (phenyl-C), 79.36
3
(oxadiazine-CN), 69.50 (oxadiazine-CH ), 63.87 (CH O), 39.67 (cyclopentane-CH ), 33.18
2
2
2
(cyclopropane-C), 31.57 (cyclopropane-C), 28.37 (CH ), 28.23 (CH ). HRMS(ESI-TOF) m/z:
3
3
+
calcd for C H F N O [M + Na] 622.0894; found 622.0908. J5-L-Rf (Lower Rf value compd)
2
2
20
3
3
7
1
Yield: 54.6%; white solid: mp 100–102 °C; H NMR (600 MHz, Chloroform-d) δ 8.51 (d, J = 7.3
Hz, 1H, NH), 7.68 (d, J = 7.9 Hz, 1H, phenyl), 7.66 (d, J = 2.9 Hz, 1H, phenyl), 7.65 (d, J = 6.7
Hz, 1H, phenyl), 7.58 (d, J = 8.6 Hz, 2H, phenyl), 7.09 (d, J = 4.1 Hz, 1H, phenyl), 7.06 (d, J =
8.2 Hz, 1H, phenyl), 5.53 (dd, J = 15.5, 8.3 Hz, 1H, vinyl), 5.51 – 5.46 (m, 1H, oxadiazine), 5.46
– 5.41 (m, 1H, oxadiazine), 4.49 (dd, J = 18.0, 12.3 Hz, 1H, cyclopentane), 4.15 (d, J = 12.2 Hz,
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1H, cyclopentane), 3.31 (dd, J = 28.0, 15.8 Hz, 1H, CH ), 3.13 (dd, J = 15.8, 5.1 Hz, 1H, CH ),
2
2
2.17 (dt, J = 8.3, 5.4 Hz, 1H, cyclopropane), 1.52 (dd, J = 9.3, 5.3 Hz, 1H) , cyclopropane, 1.24
1
3
(d, J = 3.1 Hz, 3H, CH ), 1.13 (d, J = 3.0 Hz, 3H, CH ). C NMR (151 MHz, Chloroform-d) δ
3
3
170.63 (O=C-O), 165.98 (phenyl-C), 165.94 (phenyl-C), 164.30 (phenyl-C), 164.28 (phenyl-C),
153.90 (phenyl-C), 153.61 (phenyl-C), 151.08 (oxadiazine-CN), 145.25 (phenyl-C), 145.19
(phenyl-C), 145.16 (phenyl-C), 145.10 (phenyl-C), 141.20 (phenyl-C), 130.32 (phenyl-C), 126.65
(CF ), 126.49 (phenyl-C), 126.47 (phenyl-C), 126.44 (phenyl-C), 126.42 (phenyl-C), 125.47
3
(phenyl-C), 125.45 (phenyl-C), 125.26 (phenyl-C), 125.24 (phenyl-C), 123.66 (phenyl-C), 123.60
(phenyl-C), 79.38 (oxadiazine-CN), 69.54 (oxadiazine-CH ), 64.66 (CH O), 39.68 (cyclopentane-
2
2
CH ), 34.31 (cyclopropane-C), 33.53 (cyclopropane-C), 29.67 (cyclopropane-C(Me) ), 22.58
2
2
+
(CH ), 20.11 (CH ). HRMS (ESI-TOF) m/z: calcd for C H F N O [M + Na] 622.0894; found
3
3
22 20
3
3
7
622.0892.
(7-fluoro-2-((4-(trifluoromethoxy)phenyl)carbamoyl)-2,5-tetrahydroindeno[1,2-
e][1,3,4]oxadiazin-4a-yl)methyl
3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate
1
(J6). J6-H-Rf (Higher Rf value compd) Yield: 33.2%; white solid: mp 144–146 °C; H NMR
(600 MHz, Chloroform-d) δ 8.43 – 8.36 (m, 1H, NH), 7.66 (ddd, J = 12.2, 8.4, 5.0 Hz, 1H, phenyl),
7.60 – 7.54 (m, 2H, phenyl), 7.22 – 7.17 (m, 2H, phenyl), 7.12 – 7.04 (m, 2H, phenyl), 5.57 – 5.48
(m, 1H, vinyl), 5.47 (d, J = 1.2 Hz, 1H, oxadiazine), 5.46 – 5.42 (m, 1H, oxadiazine), 4.56 – 4.43
(m, 1H, cyclopentane), 4.19 – 4.06 (m, 1H, cyclopentane), 3.34 (d, J=8.4Hz, 1H, CH ), 3.13 (d, J
2
= 5.3 Hz, 1H, CH ), 2.04(dd, J = 11.0, 5.3 Hz, 1H, cyclopropane), 1.78(d, J=6.6Hz, 1H,
2
1
3
cyclopropane) 1.25 (d, J = 3.5 Hz, 3H, CH ), 1.19 (d, J = 2.3 Hz, 3H, CH ). C NMR (151 MHz,
3
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Chloroform-d) δ 169.75 (O=C-O), 165.77 (phenyl-C), 164.10 (phenyl-C), 153.30 (CONH), 151.24
(oxadiazine-CN), 145.04 (phenyl-C), 144.84 (phenyl-C), 136.59 (phenyl-C), 130.24 (C=C),
126.95 (phenyl-C), 124.41 (phenyl-C), 123.28 (CF ), 121.78 (phenyl-C), 121.71 (phenyl-C),
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121.13 (phenyl-C), 120.50 (phenyl-C), 116.10 (phenyl-C), 79.21 (oxadiazine-CN), 69.38
(oxadiazine-CH ), 63.77 (CH O), 39.53 (cyclopentane-CH ), 33.01 (cyclopropane-C), 31.43
2
2
2
(cyclopropane-C), 28.21 (CH ), 22.42 (CH ). J6-L-Rf (Lower Rf value compd) Yield: 38.6%;
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3
1
white solid: mp 120–122 °C; H NMR (600 MHz, Chloroform-d) δ 8.53 (d, J = 7.5 Hz, 1H, NH),
7.71 – 7.66 (m, 3H, phenyl), 7.60 (d, J = 8.6 Hz, 2H, phenyl), 7.14 – 7.06 (m, 2H, phenyl), 5.58 –
5.52 (m, 1H, vinyl), 5.51 – 5.43 (m, 2H, oxadiazine), 4.50 (dd, J = 17.7, 12.3 Hz, 1H,
cyclopentane), 4.16 (d, J = 12.3 Hz, 1H, cyclopentane), 3.32 (dd, J = 28.4, 15.8 Hz, 1H, CH2),
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3.14 (dd, J = 15.8, 5.1 Hz, 1H, CH ), 2.21 – 2.16 (m, 1H, cyclopropane), 1.54 (dd, J = 9.2, 5.3 Hz,
2
1
3
1H, cyclopropane), 1.26 (d, J = 3.2 Hz, 3H, CH ), 1.15 (d, J = 2.9 Hz, 3H, CH ). C NMR (151
3
3
MHz, Chloroform-d) δ 170.454 (O=C-O), 165.84 (phenyl-C), 164.16 (phenyl-C), 153.78 (CONH),
150.94 (oxadiazine-CN), 145.01 (phenyl-C), 130.07 (C=C), 126.44 (phenyl-C), 126.27 (phenyl-
C), 125.11 (phenyl-C), 123.51 (CF ), 122.56 (phenyl-C), 118.73 (phenyl-C), 116.20 (phenyl-C),
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116.05 (phenyl-C), 113.44 (phenyl-C), 113.28 (phenyl-C) ， 79.33 (oxadiazine-CN), 69.41
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(oxadiazine-CH ), 64.54 (CH O), 39.56 (cyclopentane-CH ), 34.26 (cyclopropane-C), 33.37
2
2
2
(cyclopropane-C), 29.48 (cyclopropane-C(Me) ), 22.44 (CH ). HRMS(ESI-TOF) m/z: calcd for
2
3
+
C H Cl F N O [M + Na] 616.1024; found 616.0997.
2
7
23
2
4
3
5
(7-chloro-2-((4-(trifluoromethyl)phenyl)carbamoyl)-2,5-tetrahydroindeno[1,2-
e][1,3,4]oxadiazin-4a-yl)methyl-3-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-2,2-
dimethylcyclopropanecarboxylate(J7). J7-H-Rf (Higher Rf value compd) Yield: 23.5%; white
1
solid: mp 133–134 °C; H NMR (600 MHz, Chloroform-d) δ 8.53 (d, J = 10.6 Hz, 1H, NH), 7.67
(d, J = 8.4 Hz, 2H, phenyl), 7.59 (d, J = 6.1 Hz, 3H, phenyl), 7.36 (d, J = 12.0 Hz, 2H, phenyl),
6.82 (dd, J = 12.0, 9.8 Hz, 1H, vinyl), 5.53 (dd, J = 25.5, 9.4 Hz, 1H, oxadiazine), 5.44 (dd, J =
24.1, 9.8 Hz, 1H, oxadiazine), 4.52 (dd, J = 25.0, 12.3 Hz, 1H, cyclopentane), 4.13 (dd, J = 34.4,
12.3 Hz, 1H, cyclopentane), 3.29 (dd, J = 45.1, 15.8 Hz, 1H, CH ), 3.11 (d, J = 15.8 Hz, 1H, CH ),
2
2
2.17 (q, J = 9.0 Hz, 1H, cyclopropane), 1.92 (dd, J = 8.4, 3.6 Hz, 1H, cyclopropane), 1.27 (s, 3H,
1
3
CH ), 1.25 (s, 3H, CH ). C NMR (151 MHz, Chloroform-d) δ 169.49 (O=C-O), 153.09 (CONH),
3
3
150.86 (oxadiazine-CN), 144.28 (phenyl-C), 140.98 (phenyl-C), 133.07 (C=C), 131.71 (phenyl-
C), 129.55 (phenyl-C), 129.52 (phenyl-C), 129.50 (=C-Cl), 129.47 (=C-Cl), 129.29 (phenyl-C),
126.32 (phenyl-C), 126.30 (phenyl-C), 126.27 (phenyl-C), 126.25 (phenyl-C), 125.85 (phenyl-C),
125.37 (CF ), 125.09 (CF ), 122.85 (phenyl-C), 118.80 (phenyl-C), 79.01 (oxadiazine-CN), 69.29
3
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(oxadiazine-CH ), 63.64 (CH O), 39.24 (cyclopentane-CH ), 32.36 (cyclopropane-C), 31.25
2
2
2
(cyclopropane-C), 28.19 (CH ), 14.75. J7-L-Rf (Lower Rf value compd) Yield: 32.4%; white
3
1
solid: mp 115–117 °C; H NMR (600 MHz, Chloroform-d) δ 8.51 (s, 1H, NH), 7.68 (d, J = 8.5
Hz, 2H, phenyl), 7.61 (d, J = 8.6 Hz, 2H, phenyl 7.55 (d, J = 8.1 Hz, 1H, phenyl), 7.19 (d, J = 8.4
Hz, 2H, phenyl), 5.58 (d, J = 9.6 Hz, 1H, vinyl), 5.32 (d, J = 9.5 Hz, 1H, oxadiazine), 4.54 (d, J =
12.3 Hz, 1H, oxadiazine), 4.02 (d, J = 12.4 Hz, 1H, cyclopentane), 3.21 (d, J = 15.8 Hz, 1H,
cyclopentane), 3.10 (d, J = 10.5 Hz, 1H, CH ), 3.07 (d, J = 15.8 Hz, 1H, CH ), 2.24 (dd, J = 13.1,
2
2
6.6Hz, 1H, cyclopropane), 1.97(q, J=3.9Hz, 1H, cyclopropane), 1.01 (d, J = 6.5 Hz, 3H, CH3),
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0.68 (d, J = 6.7 Hz, 3H, CH ). C NMR (151 MHz, Chloroform-d) δ 172.89 (O=C-O), 152.53
3
(CONH), 150.81 (oxadiazine-CN), 143.95 (phenyl-C), 141.00 (phenyl-C), 137.50 (phenyl-C),
136.06 (phenyl-C), 133.41 (C=C), 132.64 (=C-Cl), 129.66 (=C-Cl), 128.85 (C=C), 128.75
(phenyl-C), 126.32 (CF ), 126.31 (CF ), 122.56 (phenyl-C), 118.77 (phenyl-C), 79.02 (oxadiazine-
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CN), 69.21 (oxadiazine-CH ), 64.26 (CH O), 39.31 (cyclopentane-CH ), 31.81 (cyclopropane-C),
2
2
2
+
29.70 (CH ), 21.29 (CH ), 19.98. HRMS (ESI-TOF) m/z: calcd for C H Cl F N O [M + H]
3
3
28 23
2
6
3
4
672.0862; found 672.0881.
7-chloro-2-((4-(trifluoromethoxy)phenyl)carbamoyl-2,5-tetrahydroindeno
e][1,3,4]oxadiazin-4a-yl)methyl 2,2-dimethyl
[1,2-
-3-(2,3,3,3-tetrafluoroprop-1-en-1-yl)
cyclopropanecarboxylate (J8). J8-H-Rf (Higher Rf value compd) Yield: 38.5%; white solid: mp
1
125–126 °C; H NMR (600 MHz, Chloroform-d) δ 8.37 (s, 1H, NH), 7.57(d, J = 8.1Hz, 1H,
phenyl), 7.56–7.53 (m, 2H, phenyl), 7.36 (d, J = 8.2 Hz, 1H, phenyl), 7.34 (s, 1H, phenyl), 7.19
(d, J = 8.5 Hz, 2H, phenyl), 6.81 (d, J = 9.4 Hz, 1H, vinyl), 5.52 (d, J = 9.5 Hz, 1H, oxadiazine),
5.41 (d, J = 9.5 Hz, 1H, oxadiazine), 4.51 (dd, J = 12.2, 0.1 Hz, 1H, cyclopentane), 4.09 (d, J =
12.3 Hz, 1H, cyclopentane), 3.31(d, J = 15.8 Hz, 1H, CH ), 3.10 (d, J = 16.0 Hz, 1H, CH ), 2.16
2
2
(t, J = 8.8 Hz, 1H, cyclopropane), 1.90 (d, J = 8.3 Hz, 1H, cyclopropane), 1.26 (s, 3H, CH ) , 1.25
3
1
3
(s, 3H, CH ). C NMR (151 MHz, Chloroform-d) δ 169.58 (O=C-O), 153.28 (CONH), 151.31
3
(oxadiazine-CN), 144.99 (phenyl-C), 144.02 (phenyl-C), 137.66 (C=C), 136.68 (phenyl-C),
132.80 (phenyl-C), 129.77 (phenyl-C), 129.74 (phenyl-C), 129.71 (phenyl-C), 129.68 (=C-Cl),
129.05 (=C-Cl), 126.45 (CF ), 122.83 (CF ), 121.95 (phenyl-C), 120.60 (phenyl-C), 79.45
3
3
(oxadiazine-CN), 69.72 (oxadiazine-CH ), 64.80 (CH O), 39.46 (cyclopentane-CH ), 32.55
2
2
2
(cyclopropane-C), 31.39 (cyclopropane-C), 29.25 (CH ), 28.33 (CH ), 14.90. HRMS (ESI-TOF)
3
3
+
m/z: calcd for C H F N O [M + Na] 688.0811; found 688.0822. J8-L-Rf (Lower Rf value
2
2
20
3
3
7
1
compd) Yield: 44.5%; white solid: mp 142–143 °C; H NMR (600 MHz, Chloroform-d) δ 8.35
(s, 1H, NH), 7.57 (d, J = 8.2 Hz, 1H, phenyl), 7.56–7.54 (m, 2H, phenyl), 7.36 (d, J = 8.2 Hz, 1H,
phenyl), 7.33 (s, 1H, phenyl), 7.19 (d, J = 8.3 Hz, 2H, phenyl), 6.79 (dd, J = 9.3, 0.8 Hz, 1H, vinyl),
5.47 (d, J = 9.4 Hz, 1H, oxadiazine), 5.45 (d, J = 9.4 Hz, 1H, oxadiazine), 4.47 (dd, J = 12.4, 1.1
Hz, 1H, cyclopentane), 4.14 (d, J = 12.3 Hz, 1H, cyclopentane 3.23 (d, J = 15.8 Hz, 1H, CH ), 3.10
2
(d, J = 15.0 Hz, 1H, CH ), 2.14 (t, J = 8.6 Hz, 1H, cyclopropane), 1.90 (d, J = 8.4 Hz, 1H,
2
1
3
cyclopropane), 1.24 (s, 3H, CH ), 1.23 (s, 3H, CH ). C NMR (151 MHz, Chloroform-d) δ 169.58
3
3
(O=C-O), 153.25 (CONH), 151.30 (oxadiazine-CN), 144.02 (phenyl-C), 137.65 (phenyl-C),
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136.68 (C=C), 132.79 (C=C), 129.78 (phenyl-C), 129.75 (phenyl-C), 129.72 (phenyl-C), 129.69
(phenyl-C), 129.04 (phenyl-C), 126.44 (CF ), 122.82 (CF ), 121.95 (phenyl-C), 120.59 (phenyl-
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C), 79.44 (oxadiazine-CN), 69.70 (oxadiazine-CH ), 64.77 (CH O), 39.44 (cyclopentane-CH ),
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2
2
32.53 (cyclopropane-C), 31.37 (cyclopropane-C), 28.32 (CH ). HRMS (ESI-TOF) m/z: calcd for
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+
C H F N O [M + Na] 688.0811; found 688.0826.
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3
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(7-bromo-2-((4-(trifluoromethyl)phenyl)carbamoyl)-2,5-tetrahydroindeno[1,2-
e][1,3,4]oxadiazin-4a-yl)methyl-3-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-2,2-
dimethylcyclopropanecarboxylate (J9). J9-H-Rf (Higher Rf value compd) Yield: 27.6%; white
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solid: mp 145–147 °C; H NMR (600 MHz, Chloroform-d) δ 8.52 (d, J = 10.0 Hz, 1H, NH), 7.67
(d, J = 8.3 Hz, 2H, phenyl), 7.60 (d, J = 7.6 Hz, 2H, phenyl), 7.55 – 7.50 (m, 3H, phenyl), 6.81
(dd, J = 11.9, 9.8 Hz, 1H, vinyl), 5.54 (dd, J = 25.4, 9.5 Hz, 1H, oxadiazine), 5.44 (dd, J = 24.8,
9.5 Hz, 1H, oxadiazine), 4.52 (dd, J = 25.0, 12.3 Hz, 1H, cyclopentane), 4.20 – 4.06 (m, 1H,
cyclopentane), 3.29 (dd, J = 46.6, 15.8 Hz, 1H, CH ), 3.13 (d, J = 15.8 Hz, 1H, CH ), 2.17 (q, J =
2
2
9.0 Hz, 1H, cyclopropane), 1.92 (dd, J = 8.4, 3.6 Hz, 1H, cyclopropane), 1.27 (d, J = 3.8 Hz, 3H,
1
3
CH ), 1.25 (d, J = 3.0 Hz, 3H, CH ). C NMR (151 MHz, Chloroform-d) δ 169.69 (O=C-O),
3
3
152.95 (CONH), 151.54 (oxadiazine-CN), 146.23 (phenyl-C), 142.98 (phenyl-C), 133.83 (C=C),
131.99 (phenyl-C), 131.52 (phenyl-C), 129.54 (phenyl-C), 126.29 (phenyl-C), 125.83 (phenyl-C),
124.87 (phenyl-C), 124.14 (phenyl-C), 124.03 (CF ), 123.43 (CF ), 121.66 (phenyl-C), 119.98
3
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(phenyl-C), 79.52 (oxadiazine-CN), 69.79 (oxadiazine-CH ), 64.71 (CH O), 32.78 (cyclopropane-
2
2
C), 30.68 (cyclopropane-C), 29.50 (CH ), 27.47 (CH ). J9-L-Rf (Lower Rf value compd) Yield:
3
3
1
45.3%; white solid: mp 155–157 °C; H NMR (600 MHz, Chloroform-d) δ 8.36 (s, 1H, NH), 7.57
– 7.56 (m, 1H, phenyl), 7.56 (d, J = 2.1 Hz, 1H, phenyl), 7.53 (d, J = 1.7 Hz, 2H, phenyl), 7.52 (s,
1H, phenyl), 7.21 (s, 1H, phenyl), 7.20 (s, 1H, phenyl), 6.80(d, J=1.7Hz, 1H, vinyl), 5.49 (d, J =
9.4 Hz, 1H, oxadiazine), 5.46 (d, J = 9.4 Hz, 1H, oxadiazine), 4.48 (d, J = 12.9 Hz, 1H,
cyclopentane), 4.16 (d, J = 12.3 Hz, 1H, cyclopentane), 3.25(d, J=15.8Hz, 1H, CH ), 3.11(d,
2
J=2.1Hz, 1H, CH ), 2.16 (t, J = 8.9 Hz, 1H, cyclopropane), 1.92 (d, J = 8.4 Hz, 1H, cyclopropane),
2
1
3
1.26 (s, 3H, CH ), 1.25 (s, 3H, CH ). C NMR (151 MHz, Chloroform-d) δ 169.43 (O=C-O),
3
3
153.12 (CONH), 151.14 (oxadiazine-CN), 144.83 (phenyl-C), 144.07 (phenyl-C), 136.53 (phenyl-
C), 133.12 (C=C), 131.75 (C=C), 129.60 (phenyl-C), 129.27 (phenyl-C), 125.77 (phenyl-C),
124.48 (CF ), 123.97 (CF ), 122.88 (phenyl-C), 121.81 (phenyl-C), 120.46 (phenyl-C), 118.80
3
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(phenyl-C), 79.23 (oxadiazine-CN), 69.55 (oxadiazine-CH ), 64.61 (CH O), 39.24 (cyclopentane-
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CH ), 32.40 (cyclopropane-C), 31.43 (cyclopropane-C), 30.19 (cyclopropane-C(Me) ), 29.12
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(CH ), 28.19 (CH ). HRMS (ESI-TOF) m/z: calcd for C H BrClF N O [M + Na] 716.0357;
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4
found 716.0359.
(7-bromo-2-((4-(trifluoromethoxy)phenyl)carbamoyl)-2,5-tetrahydroindeno[1,2-
e][1,3,4]oxadiazin-4a-yl)methyl-3-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-2,2-dimethyl-
cyclopropanecarboxylate (J10). J10-H-Rf (Higher Rf value compd) Yield: 32.4%; white solid:
1
mp 127–128 °C; H NMR (600 MHz, DMSO-d ) δ 9.59 (s, 1H, NH), 7.91 (d, J = 8.6 Hz, 2H,
6
phenyl), 7.75 (d, J = 8.1 Hz, 1H, phenyl), 7.68 (s, 2H, phenyl), 7.66 (s, 1H, phenyl), 7.65 (s, 1H,
phenyl), 6.88(d, J=8.6Hz, 1H, vinyl), 5.36 (d, J = 9.3 Hz, 1H, oxadiazine), 5.26 (d, J = 9.4 Hz, 1H,
oxadiazine), 4.35 (d, J = 12.4 Hz, 1H, cyclopentane), 4.31 (d, J = 12.4 Hz, 1H, cyclopentane), 3.30
(d, J = 16.0 Hz, 1H, CH ), 3.12 (d, J = 15.9 Hz, 1H, CH ), 2.18 (t, J = 8.8 Hz, 1H, cyclopropane),
2
2
1
3
2.08 (d, J = 8.3 Hz, 1H, cyclopropane), 1.17 (s, 3H, CH ), 1.16 (s, 3H, CH ). C NMR (151 MHz,
3
3
DMSO-d ) δ 169.72 (O=C-O), 153.82 (CONH), 151.63 (oxadiazine-CN), 145.37(phenyl-C),
6
133.60 (C=C), 132.03 (phenyl-C), 131.54 (phenyl-C), 129.57 (phenyl-C), 126.29 (phenyl-C),
124.87 (C=C), 124.13 (CF ), 124.03 (CF ), 123.41 (phenyl-C), 123.20 (phenyl-C), 121.82 (phenyl-
3
3
C), 121.66 (phenyl-C), 120.29 (phenyl-C), 119.49 (phenyl-C), 79.62 (oxadiazine-CN), 69.59
(oxadiazine-CH ), 64.24 (CH O), 32.80 (cyclopropane-C), 30.68 (cyclopropane-C), 30.64
2
2
(cyclopropane-C), 29.41 (CH ), 27.50 (CH ). J10-L-Rf (Lower Rf value compd) Yield: 41.6%;
3
3
1
white solid: mp 138–140 °C; H NMR (600 MHz, Chloroform-d) δ 8.37 (d, J = 10.2 Hz, 1H, NH),
7.57 (d, J = 9.1 Hz, 2H, phenyl), 7.55 – 7.51 (m, 3H, phenyl), 7.21 (d, J = 8.6 Hz, 2H, phenyl),
6.83 – 6.78 (m, 1H, vinyl), 5.56 – 5.48 (m, 1H, oxadiazine), 5.47 – 5.40 (m, 1H, oxadiazine), 4.51
(dd, J = 28.5, 12.3 Hz, 1H, cyclopentane), 4.13 (dd, J = 38.5, 12.3 Hz, 1H, cyclopentane), 3.29
(dd, J = 48.0, 15.8 Hz, 1H, CH ), 3.13 (d, J = 15.8 Hz, 1H, CH ), 2.17 (q, J = 9.2 Hz, 1H,
2
2
cyclopropane), 1.92 (dd, J = 8.4, 2.1 Hz, 1H, cyclopropane), 1.26 (s, 3H, CH ), 1.25 (s, 3H, CH ).
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13C NMR (151 MHz, Chloroform-d) δ 169.44 (O=C-O), 153.07 (CONH), 151.12 (oxadiazine-
CN), 144.76 (phenyl-C), 136.58 (C=C), 133.13 (phenyl-C), 131.70 (phenyl-C), 129.69 (phenyl-
C), 129.66 (phenyl-C), 129.24 (C=C), 125.72 (CF ), 122.86 (CF ), 121.76 (phenyl-C), 121.37
3
3
(phenyl-C), 121.31 (phenyl-C), 120.43 (phenyl-C), 119.67 (phenyl-C), 119.51 (phenyl-C), 79.22
(oxadiazine-CN), 69.50 (oxadiazine-CH ), 64.49 (CH O), 39.19 (cyclopentane-CH ), 32.40
2
2
2
(cyclopropane-C), 31.22 (cyclopropane-C), 29.10 (CH ), 28.11 (CH ). HRMS(ESI-TOF) m/z:
3
3
+
calcd for C H BrClF N O [M + Na] 734.0286; found 734.0266.
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7-fluoro-2-((4-(trifluoromethyl)phenyl)carbamoyl-2,5-tetrahydroindeno[1,2-
e][1,3,4]oxadiazin-4a-yl)methyl-3-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-2,2-dimethyl-
cyclopropanecarboxylate (J11). J11-H-Rf (Higher Rf value compd) Yield: 46.5%; white solid:
1
mp 110–111 °C; H NMR (600 MHz, Chloroform-d) δ 8.51 (s, 1H, NH), 7.67–7.63 (m, 3H,
phenyl), 7.59 (d, J = 8.6 Hz, 2H, phenyl), 7.09 (td, J = 8.7, 2.3 Hz, 1H, phenyl), 7.06 (d, J = 8.2
Hz, 1H, phenyl), 6.81 (dd, J = 9.4, 0.7 Hz, 1H, vinyl), 5.50 (d, J = 9.4 Hz, 1H, oxadiazine), 5.43
(d, J = 9.4 Hz, 1H, oxadiazine), 4.50 (dd, J = 12.2, 1.3 Hz, 1H, cyclopentane), 4.11 (d, J = 12.3 Hz,
1H, cyclopentane), 3.33 (d, J = 15.8 Hz, 1H, CH ), 3.12 (d, J = 15.8 Hz, 1H, CH ), 2.15 (t, J = 8.6
2
2
Hz, 1H, cyclopropane), 1.90 (d, J = 8.3 Hz, 1H, cyclopropane), 1.26 (s, 3H, CH ), 1.25 (s, 3H,
3
1
3
CH ). C NMR (151 MHz, Chloroform-d) δ 169.69 (O=C-O), 165.98 (phenyl-C), 164.31 (phenyl-
3
C), 153.55 (CONH), 151.10 (oxadiazine-CN), 145.22 (phenyl-C), 145.16 (phenyl-C), 141.19
(C=C), 130.26 (C=C), 129.70 (phenyl-C), 129.67 (phenyl-C), 129.64 (phenyl-C), 126.48 (phenyl-
C), 126.45 (phenyl-C), 125.50 (phenyl-C), 125.28 (phenyl-C), 125.26 (phenyl-C), 123.57 (CF3),
123.51 (CF ), 122.38 (phenyl-C), 122.13 (phenyl-C), 121.41 (phenyl-C), 119.61 (phenyl-C),
3
118.90 (phenyl-C), 116.34 (phenyl-C), 79.30 (oxadiazine-C), 69.46 (oxadiazine-CH ), 63.88
2
(CH O), 39.64 (cyclopentane-CH ), 32.53 (cyclopropane-C), 31.40 (cyclopropane-C), 29.30
2
2
(cyclopropane-C(Me) ), 28.35 (CH ), 14.91. J11-L-Rf (Lower Rf value compd) Yield: 42.7%;
2
3
1
white solid: mp 145–146 °C; H NMR (600 MHz, Chloroform-d) δ 8.50 (s, 1H, NH), 7.66–7.63
(m, 3H, phenyl), 7.58 (d, J = 8.6 Hz, 2H, phenyl), 7.10 (td, J = 8.7, 2.2 Hz, 1H, phenyl), 7.05 (d, J
= 8.3 Hz, 1H, phenyl), 6.79 (dd, J = 9.4, 0.8 Hz, 1H, vinyl), 5.47 (d, J = 9.3 Hz, 1H, oxadiazine),
5.45 (d, J = 9.4 Hz, 1H, oxadiazine), 4.48 (dd, J = 12.3, 1.1 Hz, 1H, cyclopentane), 4.15 (d, J =
12.2 Hz, 1H, cyclopentane), 3.24 (d, J = 15.9 Hz, 1H, CH ), 3.12 (d, J = 15.8 Hz, 1H, CH ), 2.13
2
2
(t, J = 8.6 Hz, 1H, cyclopropane), 1.90 (d, J = 8.4 Hz, 1H, cyclopropane), 1.24 (s, 3H, CH ), 1.24
3
1
3
(s, 3H, CH ). C NMR (151 MHz, Chloroform-d) δ 169.60 (O=C-O), 165.98 (phenyl-C), 164.31
3
(phenyl-C), 153.78 (CONH), 151.13 (oxadiazine-CN), 145.00 (phenyl-C), 144.94 (phenyl-C),
141.21 (C=C), 130.22 (C=C), 129.78 (phenyl-C), 129.75 (phenyl-C), 129.72 (phenyl-C), 129.69
(phenyl-C), 126.48 (phenyl-C), 126.46 (CF ), 125.47 (phenyl-C), 125.26 (phenyl-C), 123.65
3
(CF ), 123.59 (CF ), 122.40 (phenyl-C), 122.15 (phenyl-C), 121.43 (phenyl-C), 119.63 (phenyl-
3
3
C), 116.40 (phenyl-C), 79.55 (oxadiazine-C), 69.71 (oxadiazine-CH ), 64.88 (CH O), 39.64
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(cyclopentane-CH ), 32.56 (cyclopropane-C), 31.38 (cyclopropane-C), 29.25 (cyclopropane-
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C(Me) ), 28.34 (CH ). HRMS (ESI-TOF) m/z: calcd for C H F N O [M + Na] 656.1158;
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22 20
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found 656.1156.
(7-fluoro-2-((4-(trifluoromethoxy)phenyl)carbamoyl)-2,5-tetrahydroindeno[1,2-
e][1,3,4]oxadiazin-4a-yl)methyl-3-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-2,2-dimethyl-
cyclopropanecarboxylate (J12). J12-H-Rf (Higher Rf value compd) Yield: 28.4%; white solid:
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mp 160–161 °C; H NMR (600 MHz, Chloroform-d) δ 8.39 (d, J = 11.0 Hz, 1H, NH), 7.65 (dd, J
= 8.5, 4.9 Hz, 1H, phenyl), 7.56 (d, J = 9.0 Hz, 2H, phenyl), 7.20 (d, J = 8.6 Hz, 2H, phenyl), 7.10
(td, J = 8.6, 2.2 Hz, 1H, phenyl), 7.05 (d, J = 8.2 Hz, 1H, phenyl), 6.81 (dd, J = 9.5, 1.2 Hz, 1H,
vinyl), 5.48 (d, J = 9.3 Hz, 1H, oxadiazine), 5.43 (d, J = 9.3 Hz, 1H, oxadiazine), 4.48 (d, J = 12.3
Hz, 1H, cyclopentane), 4.16 (d, J = 12.3 Hz, 1H, cyclopentane), 3.29 (dd, J = 47.7, 15.9 Hz, 1H,
CH ), 3.13 (d, J = 15.9 Hz, 1H, CH ), 2.15 (t, J = 9.0 Hz, 1H, cyclopropane), 1.92 (d, J = 8.4 Hz,
2
2
1
3
1H, cyclopropane), 1.27 (s, 1H, CH ), 1.26 (s, 1H, CH ), 1.25 (s, 2H, CH ), 1.25 (s, 2H, CH ). C
3
3
3
3
NMR (151 MHz, Chloroform-d) δ 169.54 (O=C-O), 153.24 (CONH), 151.22 (oxadiazine-CN),
144.82 (phenyl-C), 136.57 (C=C), 130.19 (phenyl-C), 129.58 (C=C), 123.36 (CF ), 121.82 (CF ),
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121.74 (phenyl-C), 121.37 (phenyl-C), 121.27 (phenyl-C), 120.47 (phenyl-C), 119.67 (phenyl-C),
115.98 (phenyl-C), 79.15 (oxadiazine-CN), 69.33 (oxadiazine-CH ), 63.77 (CH O), 39.49
2
2
(cyclopentane-CH ), 32.39 (cyclopropane-C), 31.42 (cyclopropane-C), 30.19 (cyclopropane-
2
C(Me) ), 29.15 (CH ), 28.19 (CH ), 14.77. J12-L-Rf (Lower Rf value compd) Yield: 36.6%;
2
3
3
1
white solid: mp 146–148 °C; H NMR (600 MHz, Chloroform-d) δ 8.39 (d, J = 11.0 Hz, 1H, NH),
7.65 (dd, J = 8.5, 4.9 Hz, 1H, phenyl), 7.56 (d, J = 9.0 Hz, 2H, phenyl), 7.20 (d, J = 8.6 Hz, 2H,
phenyl), 7.08 (dd, J = 32.4, 9.4 Hz, 2H, phenyl), 6.82 (t, J = 9.8 Hz, 1H, vinyl), 5.48 (d, J = 9.3
Hz, 1H, oxadiazine), 5.43 (d, J = 9.3 Hz, 1H, oxadiazine), 4.49 (dd, J = 18.5, 12.3 Hz, 1H,
cyclopentane), 4.14 (dd, J = 27.8, 12.2 Hz, 1H, cyclopentane), 3.29 (dd, J = 47.7, 15.9 Hz, 1H,
CH ), 3.13 (d, J = 15.9 Hz, 1H, CH ), 2.15 (t, J = 9.0 Hz, 1H, cyclopropane), 1.92 (d, J = 8.4 Hz,
2
2
1
3
1H, cyclopropane), 1.28 – 1.25 (m, 3H, CH ), 1.25 (s, 3H, CH ). C NMR (151 MHz, Chloroform-
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d) δ 169.43 (O=C-O), 153.63 (CONH), 150.97 (oxadiazine-CN), 144.79 (phenyl-C), 141.063
(phenyl-C), 130.05 (C=C), 129.57 (phenyl-C), 126.30 (C=C), 125.10 (phenyl-C), 123.49 (CF3),
122.26 (CF ), 122.01 (phenyl-C), 121.28 (phenyl-C), 118.72 (phenyl-C), 116.24 (phenyl-C), 79.40
3
(oxadiazine-CN), 69.56 (oxadiazine-CH ), 64.73 (CH O), 39.52 (cyclopentane-CH ), 32.41
2
2
2
(cyclopropane-C), 31.23 (cyclopropane-C), 29.09 (CH ), 28.19 (CH ). HRMS (ESI-TOF) m/z:
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calcd for C H ClF N O [M + Na] 672.1107; found 672.1083.
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(7-chloro-2-((4-(trifluoromethyl)phenyl)carbamoyl)-2,5-tetrahydroindeno[1,2-
e][1,3,4]oxadiazin-4a-yl)methyl-2,2,3,3-tetramethylcyclopropanecarboxylate (J13). Yield:
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76.8%; white solid: mp 98–99 °C; H NMR (600 MHz, Chloroform-d) δ 8.40 (s, 1H, NH), 7.60
(d, J = 8.1 Hz, 1H, phenyl), 7.59 – 7.54 (m, 2H, phenyl), 7.38 – 7.33 (m, 2H, phenyl), 7.22 – 7.17
(m, 2H, phenyl), 5.55(d, J=6.5Hz, 1H, oxadiazine), 5.44(d, J=12.3Hz, 1H, oxadiazine), 4.45 (d, J
= 13.0 Hz, 1H, cyclopentane), 4.10 (d, J = 12.3 Hz, 1H, cyclopentane), 3.31 (d, J = 15.8 Hz, 1H,
CH ), 3.10 (d, J = 15.7 Hz, 1H, CH ), 1.20 (d, J = 6.5 Hz, 6H, CH ), 1.14 (d, J = 3.7 Hz, 6H, CH )
2
2
3
3
1
3
, 1.11(s, 1H, cyclopropane). C NMR (151 MHz, Chloroform-d) δ 171.17 (O=C-O), 153.14
(phenyl-C-cyclopentane), 151.16 (CONH), 144.77 (phenyl-C), 144.26 (phenyl-C), 137.29
(phenyl-C), 132.92 (phenyl-C), 128.70 (phenyl-C), 126.25 (CF ), 122.59 (phenyl-C), 121.79
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(phenyl-C), 121.37 (phenyl-C), 120.47 (phenyl-C), 119.67 (phenyl-C), 79.28 (oxadiazine-CN),
69.41 (oxadiazine-CH ), 63.22 (CH O), 39.41 (cyclopentane-CH ), 35.34 (cyclopropane-C), 31.08
2
2
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(cyclopropane-C), 30.99 (cyclopropane-C(Me) ), 29.70 (CH ), 23.41 (CH ), 23.37 (CH ), 16.48
2
3
3
3
+
(CH ), 16.46 (CH ). HRMS(ESI-TOF) m/z: calcd for C H ClF N O [M + Na] 572.1534; found
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3
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4
572.1537.
7-chloro-2-((4-(trifluoromethoxy)phenyl)carbamoyl-2,5-tetrahydroindeno[1,2-
e][1,3,4]oxadiazin-4a-yl)methyl 2,2,3,3-tetramethylcyclopropanecarboxylate (J14). Yield:
1
64.6%; white solid: mp 134–135 °C; H NMR (600 MHz, Chloroform-d) δ 8.38 (s, 1H, NH), 7.58
(d, J = 8.1 Hz, 1H, phenyl), 7.56–7.54 (m, 2H, phenyl), 7.34 (d, J = 8.2 Hz, 1H, phenyl), 7.33 (s,
1H, phenyl), 7.18 (d, J = 8.4 Hz, 2H, phenyl), 5.53 (d, J = 9.4 Hz, 1H, oxadiazine), 5.43 (d, J = 9.4
Hz, 1H, oxadiazine), 4.44 (dd, J = 12.3, 1.1 Hz, 1H, cyclopentane), 4.09 (d, J = 12.3 Hz, 1H,
cyclopentane), 3.29 (d, J = 15.6 Hz, 1H, CH ), 3.08 (d, J = 15.7 Hz, 1H, CH ), 1.19 (s, 3H, CH ),
2
2
3
1
3
1.18 (s, 3H, CH ), 1.13 (s, 3H, CH ), 1.12 (s, 3H, CH ) , 1.09(s, 1H, cyclopropane). C NMR (151
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3
3
MHz, Chloroform-d) δ 171.30 (O=C-O), 153.27 (phenyl-C-cyclopentane), 151.28 (CONH),
144.91 (phenyl-C), 144.39 (phenyl-C), 137.43 (phenyl-C), 136.76 (phenyl-C), 133.06 (phenyl-C),
128.83 (phenyl-C), 126.38 (phenyl-C), 122.72 (CF ), 121.91 (phenyl-C), 120.59 (phenyl-C), 79.41
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(oxadiazine-CN), 69.55 (oxadiazine-CH ), 63.36 (CH O), 39.54 (cyclopentane-CH ), 35.47
2
2
2
(cyclopropane-C), 31.20 (cyclopropane-C), 31.12 (cyclopropane-C(Me) ), 23.53 (CH ), 23.49
2
3
+
(CH ). HRMS (ESI-TOF) m/z: calcd for C H F N O [M + Na] 588.1484; found 588.1499.
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e][1,3,4]oxadiazin-4a-yl)methyl 2,2,3,3-tetramethylcyclopropanecarboxylate (J15). Yield:
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67.7%; white solid: mp 80–81 °C; H NMR (600 MHz, DMSO-d ) δ 9.44 (s, 1H, NH), 7.77 (d, J
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= 9.0 Hz, 2H, phenyl), 7.73 (d, J = 8.1 Hz, 1H, phenyl), 7.68 – 7.62 (m, 2H, phenyl), 7.32 (d, J =
8.7 Hz, 2H, phenyl), 5.38 (d, J = 9.2 Hz, 1H, oxadiazine), 5.29 (d, J = 9.3 Hz, 1H, oxadiazine),
4.34 (d, J = 12.3 Hz, 1H, cyclopentane), 4.21 (d, J = 12.3 Hz, 1H, cyclopentane), 3.26 (d, J = 16.0
Hz, 1H, CH ), 3.09 (d, J = 15.9 Hz, 1H, CH ), 1.10 (d, J = 13.7 Hz, 6H, CH ), 1.04 (d, J = 8.8 Hz,
2
2
3
1
3
6H, CH ) , 1.01(s, 1H, cyclopropane). C NMR (151 MHz, DMSO-d ) δ 171.17 (O=C-O), 153.14
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(phenyl-C-cyclopentane), 151.16 (CONH), 144.77 (phenyl-C), 144.26 (phenyl-C), 137.29
(phenyl-C), 136.62 (phenyl-C), 132.92 (phenyl-C), 128.70 (phenyl-C) 126.25(CF ), 122.59
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(phenyl-C), 121.79 (phenyl-C), 121.37 (phenyl-C), 120.47 (phenyl-C), 119.67 (phenyl-C), 79.28
(oxadiazine-CN), 69.41 (oxadiazine-CH ), 63.22 (CH O), 39.41 (cyclopentane-CH ), 35.34
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(cyclopropane-C), 30.99 (cyclopropane-C), 23.37 (CH ). HRMS(ESI-TOF) m/z: calcd for
3
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C H BrF N O [M + Na] 616.1029; found 616.1023.
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(7-bromo-2-((4-(trifluoromethoxy)phenyl)carbamoyl)-2,5-tetrahydroindeno[1,2-
e][1,3,4]oxadiazin-4a-yl)methyl 2,2,3,3-tetramethylcyclopropanecarboxylate (J16). Yield:
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64.4%; white solid: mp 103–104 °C; H NMR (600 MHz, Chloroform-d) δ 8.40 (s, 1H, NH), 7.65
(dd, J = 8.4, 5.1 Hz, 1H, phenyl), 7.57 (d, J = 9.0 Hz, 2H, phenyl), 7.20 (d, J = 8.6 Hz, 2H, phenyl),
7.12 – 7.04 (m, 2H, phenyl), 5.51 (d, J = 9.4 Hz, 1H, oxadiazine), 5.45 (d, J = 9.4 Hz, 1H,
oxadiazine), 4.45 (d, J = 13.0 Hz, 1H, cyclopentane), 4.11 (d, J = 12.3 Hz, 1H, cyclopentane), 3.32
(d, J = 15.8 Hz, 1H, CH ), 3.11 (d, J = 15.8 Hz, 1H, CH ), 1.19 (s, 6H, CH ), 1.14 (d, J = 4.7 Hz,
2
2
3
1
3
6H, CH ), 1.02 (s, 1H, cyclopropane). C NMR (151 MHz, Chloroform-d) δ 171.18 (O=C-O),
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165.74 (phenyl-C), 153.65 (phenyl-C-cyclopentane), 150.96 (CONH), 145.23 (phenyl-C), 144.45
(phenyl-C), 141.14 (phenyl-C), 130.32 (phenyl-C), 126.28 (phenyl-C), 125.13 (phenyl-C), 125.01
(phenyl-C), 123.37 (CF ), 118.71 (phenyl-C), 116.02 (phenyl-C), 79.38 (oxadiazine-CN), 69.41
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(oxadiazine-CH ), 63.27 (CH O), 39.59 (cyclopentane-CH ), 35.36 (cyclopropane-C), 31.06
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2
+
(cyclopropane-C), 23.41 (CH ). HRMS(ESI-TOF) m/z: calcd for C H BrF N O [M + Na]
3
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632.0978; found 632.0965.
7-fluoro-2-((4-(trifluoromethyl)phenyl)carbamoyl-2,5-tetrahydroindeno[1,2-
e][1,3,4]oxadiazin-4a-yl)methyl 2,2,3,3-tetramethylcyclopropanecarboxylate (J17). Yield:
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68.3%; white solid: mp 131–133 °C; H NMR (600 MHz, Chloroform-d) δ 8.53 (s, 1H, NH), 7.67–
7.64 (m, 3H, phenyl), 7.58 (d, J = 8.6 Hz, 2H, phenyl), 7.08 (td, J = 8.6, 2.1 Hz, 1H, phenyl), 7.05
(d, J = 8.3 Hz, 1H, phenyl), 5.51 (d, J = 9.4 Hz, 1H, oxadiazine), 5.45 (d, J = 9.4 Hz, 1H,
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oxadiazine), 4.44 (dd, J = 12.3, 1.2 Hz, 1H, cyclopentane), 4.10 (d, J = 12.3 Hz, 1H, cyclopentane),
3.31 (d, J = 15.8 Hz, 1H, CH ), 3.10 (d, J = 15.7 Hz, 1H, CH ), 1.19 (s, 3H, CH ), 1.18 (s, 3H,
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3
1
3
CH ), 1.13 (s, 3H, CH ), 1.12 (s, 3H, CH ), 1.10 (s, 1H, cyclopropane). C NMR (151 MHz,
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Chloroform-d) δ 171.35 (O=C-O), 165.89 (phenyl-C-cyclopentane), 153.79 (phenyl-C), 151.11
(CONH), 145.38 (phenyl-C), 141.29 (phenyl-C), 130.46 (phenyl-C), 130.44 (phenyl-C), 126.46
(phenyl-C), 126.43 (phenyl-C), 126.41 (phenyl-C), 126.38 (CF ), 125.37 (phenyl-C), 125.28
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(phenyl-C), 125.15 (phenyl-C), 123.53 (phenyl-C), 123.4 (phenyl-C), 118.86 (phenyl-C), 116.17
(phenyl-C), 79.52 (oxadiazine-CN), 69.54 (oxadiazine-CH ), 63.40 (CH O), 39.72 (cyclopentane-
2
2
CH ), 35.48 (cyclopropane-C), 31.22 (cyclopropane-C), 31.14 (cyclopropane-C(Me) ), 23.55
2
2
+
(CH ), 23.51 (CH ). HRMS (ESI-TOF) m/z: calcd for C H 0F N O [M + Na] 556.1830; found
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22
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3
3
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556.1836.
(7-fluoro-2-((4-(trifluoromethoxy)phenyl)carbamoyl)-2,5-tetrahydroindeno[1,2-
e][1,3,4]oxadiazin-4a-yl)methyl-2,2,3,3-tetramethylcyclopropanecarboxylate (J18). Yield:
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58.0%; white solid: mp 108–109 °C; H NMR (600 MHz, Chloroform-d) δ 8.55 (s, 1H, NH), 7.67
(t, J = 7.4 Hz, 3H, phenyl), 7.59 (d, J = 8.6 Hz, 2H, phenyl), 7.10 (td, J = 8.7, 2.0 Hz, 1H, phenyl),
7.06 (d, J = 8.3 Hz, 1H, phenyl), 5.53 (d, J = 9.4 Hz, 1H, oxadiazine), 5.46 (d, J = 9.4 Hz, 1H,
oxadiazine), 4.46 (d, J = 12.3 Hz, 1H, cyclopentane), 4.12 (d, J = 12.3 Hz, 1H, cyclopentane), 3.32
(d, J = 15.8 Hz, 1H, CH ), 3.12 (d, J = 15.8 Hz, 1H, CH ), 1.20 (d, J = 5.2 Hz, 6H, CH ), 1.14 (d,
2
2
3
1
3
J = 6.8 Hz, 6H, CH ) , 1.12 (s, 1H, cyclopropane). C NMR (151 MHz, Chloroform-d) δ 171.18
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(O=C-O), 165.74 (phenyl-C-cyclopentane), 164.07 (phenyl-C), 153.65 (phenyl-C), 150.96
(CONH), 145.23 (phenyl-C), 144.45 (phenyl-C), 141.14 (phenyl-C), 130.32 (phenyl-C), 126.28
(CF ), 125.22 (phenyl-C), 125.13 (phenyl-C), 125.01 (phenyl-C), 123.37 (CF ), 123.31 (phenyl-
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3
C), 118.71 (phenyl-C), 116.02 (phenyl-C), 79.38 (oxadiazine-CN), 69.41 (oxadiazine-CH ), 63.27
2
(CH O), 39.59 (cyclopentane-CH ), 35.36 (cyclopropane-C), 31.06 (cyclopropane-C), 23.41
2
2
+
(CH ). HRMS (ESI-TOF) m/z: calcd for C H F N O [M + Na] 572.1779; found 572.1762.
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5
(7-chloro-2-((4-(trifluoromethyl)phenyl)carbamoyl)-2,5-tetrahydroindeno[1,2-
e][1,3,4]oxadiazin-4a-yl)methyl 3-chloropropanoate (J19). Yield: 60.8%; white solid: mp 75–77
1
°C; H NMR (600 MHz, DMSO-d ) δ 9.43 (s, 1H, NH), 7.76 (d, J = 2.0 Hz, 1H, phenyl), 7.76 –
6
7.73 (m, 2H, phenyl), 7.68 (s, 1H, phenyl), 7.65 (d, J = 8.2 Hz, 1H, phenyl), 7.32 (d, J = 8.7 Hz,
2H, phenyl), 6.20 (d, J = 16.0 Hz, 1H, oxadiazine), 6.09 (dd, J = 17.3, 10.4 Hz, 1H, oxadiazine),
5.92 (d, J = 10.3 Hz, 1H, cyclopentane), 5.39 (d, J = 9.3 Hz, 1H, cyclopentane), 5.30 (d, J = 9.3
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Hz, 1H, CH ), 4.51 (d, J = 12.3 Hz, 1H, CH ), 4.24 (d, J = 12.3 Hz, 1H, CH ), 3.13 (d, J = 16.0
2
2
2
1
3
Hz, 1H, CH ). C NMR (151 MHz, DMSO-d ) δ 172.52 (O=C-O), 153.27 (CONH), 151.54
2
6
(oxadiazine-CN), 145.03 (phenyl-C), 136.93 (phenyl-C), 133.29 (phenyl-C), 130.46 (phenyl-C),
128.89 (phenyl-C), 126.62 (phenyl-C), 123.87 (CF ), 120.03 (phenyl-C), 119.99 (phenyl-C),
3
79.42 (oxadiazine-CN), 69.65 (oxadiazine-CH ), 65.37 (CH O), 56.62 (C-Cl), 39.42
2
2
+
(cyclopentane-CH ). HRMS (ESI-TOF) m/z: calcd for C H Cl F N O [M + H] 502.0543;
2
21 18
2
3
3
4
found 502.0539.
(7-bromo-2-((4-(trifluoromethyl)phenyl)carbamoyl)-2,5-tetrahydroindeno[1,2-
e][1,3,4]oxadiazin-4a-yl)methyl 3-chloropropanoate (J20). Yield: 62.5%; white solid: mp 71–73
1
°C; H NMR (600 MHz, Chloroform-d) δ 8.51 (s, 1H, NH), 7.67 (d, J = 8.5 Hz, 2H, phenyl), 7.60
(d, J = 8.5 Hz, 2H, phenyl), 7.57 (d, J = 8.7 Hz, 1H, phenyl), 7.53 (dd, J = 6.4, 1.8 Hz, 2H, phenyl),
6.34 (dd, J = 17.3, 1.2 Hz, 1H, oxadiazine), 6.09 (d, J = 10.5 Hz, 1H, oxadiazine), 5.86 (dd, J =
10.5, 1.2 Hz, 1H, cyclopentane), 5.54 (d, J = 9.5 Hz, 1H, cyclopentane), 5.44 (d, J = 9.5 Hz, 1H,
CH ), 4.59 (dd, J = 12.3, 1.3 Hz, 1H, CH ), 4.18 (d, J = 12.3 Hz, 1H, CH ), 1H), 3.17 – 3.12 (m,
2
2
2
13
1H, CH ). C NMR (151 MHz, Chloroform-d ) δ 172.52 (O=C-O), 153.27 (CONH), 151.54
2
(oxadiazine-CN), 145.03 (phenyl-C), 136.93 (phenyl-C), 136.18 (phenyl-C), 133.29 (phenyl-C),
130.46 (phenyl-C), 128.89 (phenyl-C), 128.82 (phenyl-C), 128.70 (phenyl-C), 126.62 (phenyl-C),
126.25 (phenyl-C), 123.87 (CF ), 120.03 (phenyl-C), 119.99 (phenyl-C), 79.42 (oxadiazine-CN),
3
69.65 (oxadiazine-CH ), 65.37 (CH O), 58.56 (C-Cl), 39.42 (cyclopentane-CH ). HRMS (ESI-
2
2
2
+
TOF) m/z: calcd for C H BrClF N O [M + H] 546.0038; found 546.0035.
2
1
18
3
3
4
(7-bromo-2-((4-(trifluoromethoxy)phenyl)carbamoyl)-2,5-tetrahydroindeno[1,2-
e][1,3,4]oxadiazin-4a-yl)methyl 3-chloropropanoate (J21). Yield: 63.3%; white solid: mp 69–70
1
°C; H NMR (600 MHz, DMSO-d ) δ 9.45 (s, 1H, NH), 7.75 (dd, J = 8.5, 5.5 Hz, 3H, phenyl),
6
7.69 (s, 1H, phenyl), 7.66 (s, 1H, phenyl), 7.33 (d, J = 8.7 Hz, 2H, phenyl), 6.21 (dd, J = 17.3, 1.4
Hz, 1H, oxadiazine), 6.14 – 6.06 (m, 1H, oxadiazine), 5.93 (dd, J = 10.4, 1.4 Hz, 1H,
cyclopentane), 5.39 (d, J = 9.3 Hz, 1H, cyclopentane), 5.30 (d, J = 9.3 Hz, 1H, CH ), 4.52 (d, J =
2
1
3
12.3 Hz, 1H, CH ), 4.24 (d, J = 12.3 Hz, 1H, CH ), 3.13 (d, J = 15.9 Hz, 1H, CH ). C NMR (151
2
2
2
MHz, DMSO-d ) δ 172.52 (O=C-O), 152.98 (CONH), 151.69 (phenyl-C), 151.71 (oxadiazine-
6
CN), 145.23 (phenyl-C), 138.42 (phenyl-C), 133.77 (phenyl-C), 132.44 (phenyl-C), 131.51
(phenyl-C), 130.49 (phenyl-C), 129.54 (phenyl-C), 128.91 (phenyl-C), 128.84 (phenyl-C), 124.83
(phenyl-C), 124.00 (CF ), 121.86 (phenyl-C), 121.77 (phenyl-C), 121.70 (phenyl-C), 79.63
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(oxadiazine-CN), 69.86 (oxadiazine-CH ), 64.32 (CH O), 56.32 (C-Cl),39.42 (cyclopentane-
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+
CH ),. HRMS (ESI-TOF) m/z: calcd for C H BrClF N O [M + H] 561.9987; found 562.0013.
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(7-bromo-2-((4-(trifluoromethoxy)phenyl)carbamoyl)-2,5-tetrahydroindeno[1,2-
e][1,3,4]oxadiazin-4a-yl)methyl 3-chloropropanoate (J22). Yield: 58.8%; white solid: mp 101–
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102 °C; H NMR (600 MHz, Chloroform-d) δ 8.38 (s, 1H, NH), 7.67 (dd, J = 8.4, 5.1 Hz, 1H,
phenyl), 7.59 – 7.54 (m, 2H, phenyl), 7.22 – 7.18 (m, 2H, phenyl), 7.12 – 7.05 (m, 2H, phenyl),
6.33 (dd, J = 17.4, 1.2 Hz, 1H, oxadiazine), 6.07 (dd, J = 17.3, 10.5 Hz, 1H, oxadiazine), 5.85 (dd,
J = 10.5, 1.2 Hz, 1H, cyclopentane), 5.46 (s, 1H, cyclopentane), 5.46 (s, 1H, CH ), 4.56 (dd, J =
2
1
3
12.3, 1.3 Hz, 1H, CH ), 4.20 (d, J = 12.2 Hz, 1H, CH ), 3.16 (s, 1H, CH ). C NMR (151 MHz,
2
2
2
Chloroform-d) δ 165.29 (O=C-O), 153.32 (CONH), 151.21 (oxadiazine-CN), 145.03 (phenyl-C),
144.79 (phenyl-C), 132.01 (phenyl-C), 127.41 (CF ), 123.43 (phenyl-C), 123.36 (CF ), 121.78
3
3
(phenyl-C), 121.37 (phenyl-C), 120.51 (phenyl-C), 119.67 (phenyl-C), 116.10 (phenyl-C), 115.95
(phenyl-C), 113.37 (phenyl-C), 113.21 (phenyl-C), 79.22 (oxadiazine-CN), 69.45 (oxadiazine-
CH ), 64.29 (CH O), 39.58 (cyclopentane-CH ). HRMS (ESI-TOF) m/z: calcd for
2
2
2
+
C H ClF N O [M + H] 502.0787; found 502.0811.
2
1
18
4
3
5
(7-chloro-2-((4-(trifluoromethoxy)phenyl)carbamoyl)-2,5-tetrahydroindeno[1,2-
1
e][1,3,4]oxadiazin-4a-yl)methyl cinnamate (J23). Yield: 56.5%; white solid: mp 133–135 °C; H
NMR (600 MHz, DMSO-d ) δ 9.60 (s, 1H, NH), 7.87 (dd, J = 10.9, 8.5 Hz, 3H, phenyl), 7.64 (d,
6
J = 8.7 Hz, 2H, phenyl), 7.54 (t, J = 6.3 Hz, 4H, phenyl), 7.43 (d, J = 16.1 Hz, 1H, phenyl), 7.37
(t, J = 7.4 Hz, 1H, vinyl), 7.29 (t, J = 7.6 Hz, 2H, phenyl), 6.53 (d, J = 16.1 Hz, 1H, vinyl), 5.50
(d, J = 9.2 Hz, 1H, oxadiazine), 5.27 (d, J = 9.2 Hz, 1H, oxadiazine), 4.47 (d, J = 12.2 Hz, 1H,
cyclopentane), 4.37 (d, J = 12.2 Hz, 1H, cyclopentane), 3.38 (d, J = 16.0 Hz, 1H, CH ), 3.18 (d, J
2
1
3
= 16.0 Hz, 1H, CH ). C NMR (151 MHz, DMSO-d ) δ 165.77 (O=C-O), 154.59 (CONH), 145.63
2
6
(oxadiazine-CN), 145.36 (=C-phenyl), 136.29 (phenyl-C), 134.07 (phenyl-C), 133.25 (phenyl-C),
131.04 (phenyl-C), 129.23 (phenyl-C), 128.76 (phenyl-C), 126.71 (phenyl-C), 126.21 (phenyl-C),
125.84 (phenyl-C), 124.01 (phenyl-C), 123.33 (CF ), 119.86 (=CH), 117.65 (phenyl-C), 79.75
3
(oxadiazine-CN), 70.05 (oxadiazine-CH ), 65.09 (CH O), 39.80 (cyclopentane-CH ). HRMS
2
2
2
+
(ESI-TOF) m/z: calcd for C H ClF N O [M + Na] 578.1165; found 578.1163.
2
8
21
3
3
4
(7-bromo-2-((4-(trifluoromethyl)phenyl)carbamoyl)-2,5-tetrahydroindeno[1,2-
1
e][1,3,4]oxadiazin-4a-yl)methyl cinnamate (J24). Yield: 57.6%; white solid: mp 154–155 °C; H
NMR (600 MHz, Chloroform-d) δ 8.51 (s, 1H, NH), 7.63 (d, J = 8.5 Hz, 2H, phenyl), 7.58 (d, J =
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7.9 Hz, 1H, phenyl), 7.53 (dq, J = 5.9, 3.7, 2.9 Hz, 5H, phenyl), 7.44 – 7.39 (m, 2H, phenyl), 7.36
(s, 1H, vinyl), 7.34 – 7.28 (m, 2H, phenyl), 6.35 (d, J = 16.1 Hz, 1H, vinyl), 5.53 (s, 1H,
oxadiazine), 5.47 (s, 1H, oxadiazine), 4.58 (d, J = 12.2 Hz, 1H, cyclopentane), 4.26 (d, J = 12.1
1
3
Hz, 1H, cyclopentane), 3.32 (d, J = 15.7 Hz, 1H, CH ), 3.18 (s, 1H, CH ). C NMR (151 MHz,
2
2
Chloroform-d) δ 166.00 (O=C-O), 154.09 (CONH), 150.84 (oxadiazine-CN), 146.22 (=C-phenyl),
144.38 (phenyl-C), 140.98 (phenyl-C), 133.82 (phenyl-C), 131.74 (phenyl-C), 130.69 (phenyl-C),
129.34 (phenyl-C), 128.88 (phenyl-C), 128.20 (phenyl-C), 126.28 (phenyl-C), 126.25 (phenyl-C),
126.22 (phenyl-C), 126.20 (phenyl-C), 125.96 (phenyl-C), 125.31 (phenyl-C), 125.10 (phenyl-C),
123.00 (CF ), 118.76 (=CH), 116.60 (phenyl-C), 79.31 (oxadiazine-CN), 69.69 (oxadiazine-CH ),
3
2
64.66 (CH O), 39.43 (cyclopentane-CH ). HRMS (ESI-TOF) m/z: calcd for C H BrF N O [M
2
2
28 21
3
3
4
+
+ Na] 622.0560; found 622.0549.
(7-bromo-2-((4-(trifluoromethoxy)phenyl)carbamoyl)-2,5-tetrahydroindeno[1,2-
e][1,3,4]oxadiazin-4a-yl)methyl cinnamate (J25). Yield: 54.5.8%; white solid: mp 196–197 °C;
1H NMR (600 MHz, Chloroform-d) δ 8.37 (s, 1H, NH), 7.54 (d, J = 8.0 Hz, 1H, phenyl), 7.52 –
7.44 (m, 3H, phenyl), 7.40(s, 1H, phenyl), 7.38(s, 1H, vinyl), 7.34 (t, J = 7.4 Hz, 2H, phenyl),
7.32(d, J=7.2 Hz, 1H, phenyl), 7.30(m, 2H, phenyl), 7.17 (d, J = 8.7 Hz, 2H, phenyl), 6.37 (d, J =
16.0 Hz, 1H, vinyl), 5.54 (d, J = 9.3 Hz, 1H, oxadiazine), 5.47 (d, J = 9.3 Hz, 1H, oxadiazine),
4.59 (dd, J = 12.2, 1.1 Hz, 1H, cyclopentane), 4.28 (d, J = 12.2 Hz, 1H, cyclopentane), 3.33 (d, J
1
3
= 15.8 Hz, 1H, CH ), 3.22 – 3.15 (m, 1H, CH ). C NMR (151 MHz, Chloroform-d) δ 166.04
2
2
(O=C-O), 153.78 (CONH), 151.13 (oxadiazine-CN), 146.19 (=C-phenyl), 144.79 (phenyl-C),
144.35 (phenyl-C), 136.50 (phenyl-C), 133.84 (phenyl-C), 133.10 (phenyl-C), 131.71 (phenyl-C),
130.68 (phenyl-C), 129.32 (phenyl-C), 128.88 (phenyl-C), 128.23 (phenyl-C), 127.99 (phenyl-C),
125.83 (phenyl-C), 122.96 (CF ), 121.77 (phenyl-C), 120.52 (=CH), 116.63 (phenyl-C), 79.27
3
(oxadiazine-CN), 69.72 (oxadiazine-CH ), 64.68 (CH O), 39.41 (cyclopentane-CH ). HRMS
2
2
2
+
(ESI-TOF) m/z: calcd for C H BrF N O [M + Na] 638.0299; found 638.0303.
2
8
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3
5
(7-fluoro-2-((4-(trifluoromethoxy)phenyl)carbamoyl)-2,5-tetrahydroindeno[1,2-
1
e][1,3,4]oxadiazin-4a-yl)methyl cinnamate (J26). Yield: 56.8%; white solid: mp 191–192 °C; H
NMR (600 MHz, DMSO-d ) δ 9.43 (s, 1H, NH), 7.88 (dd, J = 8.5, 5.4 Hz, 1H, phenyl), 7.75 (m,
6
2H, phenyl), 7.56 (s, 1H, phenyl), 7.55 (s, 1H, phenyl), 7.46 (d, J = 16.1 Hz, 1H, phenyl), 7.39 (t,
J = 7.4 Hz, 1H, phenyl), 7.36 – 7.33 (m, 1H, vinyl), 7.31 (s, 1H, phenyl), 7.30(s, 1H, phenyl), 7.29
(dd, J = 8.4, 2.7 Hz, 3H, phenyl), 6.53 (d, J = 16.1 Hz, 1H, vinyl), 5.49 (d, J = 9.1 Hz, 1H,
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oxadiazine), 5.21 (d, J = 9.1 Hz, 1H, oxadiazine), 4.44 (d, J = 12.4 Hz, 1H, cyclopentane), 4.36
(d, J = 12.2 Hz, 1H, cyclopentane), 3.37 (d, J = 16.0 Hz, 1H, CH ), 3.18 (d, J = 16.1 Hz, 1H, CH ).
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C NMR (151 MHz, DMSO-d ) δ 165.80 (O=C-O), 154.70 (CONH), 151.87 (oxadiazine-CN),
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146.06 (=C-phenyl), 145.62 (phenyl-C), 143.80 (phenyl-C), 138.52 (phenyl-C), 134.09 (phenyl-
C), 131.04 (phenyl-C), 130.72 (phenyl-C), 129.23 (phenyl-C), 128.76 (phenyl-C), 124.43 (CF3),
121.81 (phenyl-C), 121.54 (phenyl-C), 117.69 (=CH), 116.14 (phenyl-C), 115.98 (phenyl-C),
79.88 (oxadiazine-CN), 70.04 (oxadiazine-CH ), 65.22 (CH O), 39.86 (cyclopentane-CH ).
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2
+
HRMS (ESI-TOF) m/z: calcd for C H F N O [M + Na] 578.1100; found 578.1111.
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21
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3
4
(7-chloro-2-((4-(trifluoromethyl)phenyl)carbamoyl)-2,5-tetrahydroindeno[1,2-
e][1,3,4]oxadiazin-4a-yl)methyl 2-(thiophen-2-yl)acetate (J27). Yield: 65.8%; white solid: mp
1
109–111 °C; H NMR (600 MHz, DMSO-d ) δ 9.58 (s, 1H, NH), 7.92 (d, J = 8.6 Hz, 2H, phenyl),
6
7.82 (d, J = 8.9 Hz, 1H, phenyl), 7.69 (s, 1H, phenyl), 7.67 (s, 1H, phenyl), 7.52 (s, 1H, phenyl),
7.38 (d, J = 5.1 Hz, 2H, CH ), 6.95(s, 1H, phenyl), 6.94– 6.92 (m, 2H, thiophene), 6.89(s, 1H,
2
thiophene), 5.37 (d, J = 9.4 Hz, 1H, oxadiazine), 5.33 (s, 1H, oxadiazine), 4.51 (d, J = 12.4 Hz,
1H, cyclopentane), 4.17 (d, J = 12.4 Hz, 1H, cyclopentane), 3.35 (s, 1H, CH ), 3.09 (d, J = 16.0
2
1
3
Hz, 1H, CH ). C NMR (151 MHz, DMSO-d ) δ 172.14 (O=C-O), 152.92 (CONH), 151.53
2
6
(oxadiazine-CN), 145.10 (phenyl-C), 143.00 (thiophene-C-S), 136.61 (phenyl-C), 136.13 (phenyl-
C), 135.18 (phenyl-C), 128.73 (phenyl-C), 127.58 (phenyl-C), 127.17 (phenyl-C), 127.16 (phenyl-
C), 127.05 (phenyl-C), 126.68 (phenyl-C), 126.29 (thiophene-C), 126.27 (thiophene-C), 125.97
(phenyl-C), 125.84 (phenyl-C), 125.57 (phenyl-C), 124.04 (CF ), 69.46 (oxadiazine-CH ), 79.24
3
2
(oxadiazine-CN), 64.72 (CH O), 35.35 (cyclopentane-CH ), 31.42 (CH ). HRMS (ESI-TOF) m/z:
2
2
2
+
calcd for C H ClF N O S [M + H] 550.0810; found 550.0788.
25
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3
4
(7-bromo-2-((4-(trifluoromethyl)phenyl)carbamoyl)-2,5-tetrahydroindeno[1,2-
e][1,3,4]oxadiazin-4a-yl)methyl 2-(thiophen-2-yl)acetate (J28). Yield: 77.6%; white solid: mp
1
119–120 °C; H NMR (600 MHz, DMSO-d ) δ 9.57 (s, 1H, NH), 7.91 (d, J = 8.6 Hz, 2H, phenyl),
6
7.76 (d, J = 8.0 Hz, 1H, phenyl), 7.65 (dd, J = 21.3, 9.6 Hz, 4H, phenyl), 7.37 (dd, J = 4.9, 1.4 Hz,
2H, CH ), 6.97 – 6.91 (m, 2H, thiophene), 6.88 (d, J = 3.2 Hz, 1H, thiophene), 5.38 – 5.32 (m, 2H,
2
oxadiazine), 4.49 (d, J = 12.4 Hz, 1H, cyclopentane), 4.16 (d, J = 12.4 Hz, 1H, cyclopentane), 3.35
1
3
(s, 1H, CH ), 3.08 (d, J = 16.0 Hz, 1H, CH ). C NMR (151 MHz, DMSO-d ) δ 170.80 (O=C-O),
2
2
6
153.08 (CONH), 151.53 (oxadiazine-CN), 145.29 (phenyl-C), 136.58 (phenyl-C), 135.13 (phenyl-
C), 133.73 (phenyl-C), 131.52 (phenyl-C), 129.55 (phenyl-C), 127.56 (phenyl-C), 127.15 (phenyl-
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C), 127.05 (phenyl-C), 126.27 (phenyl-C), 126.25 (phenyl-C), 126.22 (thiophene-C), 126.20
(thiophene-C), 125.91 (phenyl-C), 125.81 (phenyl-C), 125.52 (CF ), 124.91 (phenyl-C), 124.17
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(phenyl-C), 124.02 (thiophene-C), 79.41 (oxadiazine-CN), 69.47 (oxadiazine-CH ), 64.84
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+
(CH O), 35.35 (CH ). HRMS (ESI-TOF) m/z: calcd for C H BrF N O S [M + H] 596.0258;
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4
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(7-bromo-2-((4-(trifluoromethoxy)phenyl)carbamoyl)-2,5-tetrahydroindeno[1,2-
e][1,3,4]oxadiazin-4a-yl)methyl 2-(thiophen-2-yl)acetate (J29). Yield: 63.6%; white solid: mp
1
98–100 °C; H NMR (600 MHz, DMSO-d ) δ 9.43 (s, 1H, NH), 7.75 (dd, J = 19.8, 8.6 Hz, 3H,
6
phenyl), 7.67 – 7.63 (m, 2H, phenyl), 7.39 (d, J = 5.0 Hz, 2H, phenyl), 7.34 (d, J = 8.5 Hz, 2H,
CH ), 7.32(m, 1H, thiophene), 6.99 – 6.93 (m, 2H, thiophene), 5.34 (d, J = 9.4 Hz, 1H, oxadiazine),
2
5.32 (d, J = 9.4 Hz, 1H, oxadiazine), 4.49 (dd, J = 12.4, 1.3 Hz, 1H, cyclopentane), 4.16 (d, J =
12.4 Hz, 1H, cyclopentane), 3.88 (s, 2H), 3.30 (d, J = 15.1 Hz, 1H, CH ), 3.09 (d, J = 15.7 Hz, 1H,
2
1
3
CH ). C NMR (151 MHz, DMSO-d ) δ 169.78 (O=C-O), 156.29 (CONH), 152.61 (oxadiazine-
2
6
CN), 144.91 (phenyl-C), 144.15 (thiophene-C-S), 136.48 (phenyl-C), 134.22 (phenyl-C), 131.70
(phenyl-C), 129.32 (phenyl-C), 127.21 (phenyl-C), 127.13 (phenyl-C), 126.93 (phenyl-C), 126.91
(thiophene-C), 125.30 (thiophene-C), 125.28 (CF ), 121.83 (phenyl-C), 121.80 (phenyl-C), 120.69
3
(phenyl-C), 120.58 (phenyl-C), 78.99 (oxadiazine-CN), 69.30 (oxadiazine-CH ), 64.32 (CH O),
2
2
39.29 (cyclopentane-CH ), 34.99 (CH ). HRMS (ESI-TOF) m/z: calcd for C H BrF N O S [M
2
2
25 19
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3
4
+
+ CH CN] 648.0284; found 648.0302.
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(7-fluoro-2-((4-(trifluoromethoxy)phenyl)carbamoyl)-2,5-tetrahydroindeno[1,2-
e][1,3,4]oxadiazin-4a-yl)methyl 2-(thiophen-2-yl)acetate (J30). Yield: 72.5%; white solid: mp
1
89–91 °C; H NMR (600 MHz, DMSO-d ) δ 9.57 (s, 1H, NH), 7.91 (d, J = 8.5 Hz, 2H, phenyl),
6
7.76 (d, J = 8.0 Hz, 1H, phenyl), 7.71(d, J = 8.6 Hz, 2H, phenyl), 7.67 (d, J = 8.6 Hz, 2H, phenyl),
7.65 – 7.62 (m, 2H, CH ), 7.37 (dq, J = 3.9, 1.4 Hz, 2H, thiophene), 6.89 – 6.87 (m, 1H, thiophene),
2
5.36 (d, J = 9.4 Hz, 1H, oxadiazine), 5.34 (d, J = 9.4 Hz, 1H, oxadiazine), 4.49 (dd, J = 12.4, 1.3
Hz, 1H, cyclopentane), 4.16 (d, J = 12.4 Hz, 1H, cyclopentane), 3.35 (s, 1H, CH ), 3.08 (d, J =
2
1
3
15.9 Hz, 1H, CH ). C NMR (151 MHz, DMSO-d ) δ 170.21 (O=C-O), 165.31 (phenyl-C), 163.67
2
6
(phenyl-C), 153.23 (CONH), 151.79 (oxadiazine-CN), 145.77 (phenyl-C), 143.87 (thiophene-C-
S), 138.50 (phenyl-C), 136.61 (phenyl-C), 135.19 (phenyl-C), 127.58 (phenyl-C), 127.17 (phenyl-
C), 127.06 (phenyl-C), 125.98 (thiophene-C), 125.58 (thiophene-C), 124.43 (CF ), 121.85
3
(phenyl-C), 121.68 (phenyl-C), 116.09 (phenyl-C), 115.93 (phenyl-C), 79.60 (oxadiazine-CN),
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69.44 (oxadiazine-CH ), 64.86 (CH O), 34.75 (cyclopentane-CH ), 26.80 (CH ). HRMS (ESI-
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TOF) m/z: calcd for C H 9F N O S [M + H] 550.1050; found 550.1054.
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5
1
4
3
4
(7-chloro-2-((4-(trifluoromethyl)phenyl)carbamoyl)-2,5-tetrahydroindeno[1,2-
e][1,3,4]oxadiazin-4a-yl)methyl 3-(3-(trifluoromethyl)phenyl)acrylate (J31). Yield: 78.6%;
1
white solid: mp 187–189 °C; H NMR (600 MHz, Chloroform-d) δ 8.36 (s, 1H, NH), 7.71 (d, J =
9.6 Hz, 2H, phenyl), 7.62 (d, J = 8.3 Hz, 1H, phenyl), 7.59 (s, 1H, phenyl), 7.57 (s, 1H, phenyl),
7.52 (d, J = 8.9 Hz, 2H, phenyl), 7.44 (t, J = 7.8 Hz, 1H, vinyl), 7.14 (d, J = 8.7 Hz, 2H, phenyl),
7.12 – 7.08 (m, 2H, phenyl), 6.44 (d, J = 16.1 Hz, 1H, vinyl), 5.57 (d, J = 9.2 Hz, 1H, oxadiazine),
5.40 (d, J = 9.2 Hz, 1H, oxadiazine), 4.61 (d, J = 12.1 Hz, 1H, cyclopentane), 4.29 (d, J = 12.1 Hz,
1
3
1H, cyclopentane), 3.34 (d, J = 15.9 Hz, 1H, CH ), 3.23 – 3.17 (m, 1H, CH ). C NMR (151 MHz,
2
2
Chloroform-d) δ 165.45 (O=C-O), 154.15 (CONH), 150.83 (oxadiazine-CN), 144.24 (=C-phenyl),
144.15 (phenyl-C), 140.91 (phenyl-C), 137.75 (phenyl-C), 134.61 (phenyl-C), 132.48 (phenyl-C),
131.58 (phenyl-C), 131.37 (phenyl-C), 131.08 (phenyl-C), 129.45 (phenyl-C), 128.92 (phenyl-C),
127.04 (phenyl-C), 127.02 (phenyl-C), 126.39 (phenyl-C), 126.24 (phenyl-C), 126.22 (phenyl-C),
126.19 (phenyl-C), 124.75 (phenyl-C), 124.72 (phenyl-C), 123.27 (CF ), 122.84 (CF ), 118.38
3
3
(C=C), 79.39 (oxadiazine-CN), 69.70 (oxadiazine-CH ), 64.78 (CH O), 39.46 (cyclopentane-
2
2
+
CH ). HRMS (ESI-TOF) m/z: calcd for C H ClF N O [M + Na] 646.0939; found 646.0949.
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3
4
(7-bromo-2-((4-(trifluoromethyl)phenyl)carbamoyl)-2,5-tetrahydroindeno[1,2-
e][1,3,4]oxadiazin-4a-yl)methyl 2-(3-(trifluoromethyl)phenyl)acetate (J32). Yield: 68.5%; white
1
solid: mp 159–160 °C; H NMR (600 MHz, Chloroform-d) δ 8.48 (s, 1H, NH), 7.70 (s, 1H,
phenyl), 7.63 (s, 1H, phenyl), 7.61 (d, J = 5.2 Hz, 2H, phenyl), 7.59 (dd, J = 8.6, 5.3 Hz, 2H,
phenyl), 7.56(m, 1H, phenyl), 7.55 – 7.53 (m, 3H, phenyl), 7.52 – 7.44 (m, 1H, vinyl), 7.42 (s, 1H,
phenyl), 6.43 (d, J = 16.0 Hz, 1H, vinyl), 5.55 (d, J = 9.3 Hz, 1H, oxadiazine), 5.46 (d, J = 9.3 Hz,
1H, oxadiazine), 4.62 (d, J = 12.2 Hz, 1H, cyclopentane), 4.28 (d, J = 12.2 Hz, 1H, cyclopentane),
1
3
3.34 (d, J = 15.8 Hz, 1H, CH ), 3.19 (d, J = 15.8 Hz, 1H, CH ). C NMR (151 MHz, Chloroform-d)
2
2
δ 165.44 (O=C-O), 154.19 (CONH), 150.82 (oxadiazine-CN), 144.34 (=C-phenyl), 144.24
(phenyl-C), 140.91 (phenyl-C), 134.62 (phenyl-C), 132.94 (phenyl-C), 131.76 (phenyl-C), 131.59
(phenyl-C), 131.38 (phenyl-C), 131.10 (phenyl-C), 129.45 (phenyl-C), 129.36 (phenyl-C), 127.01
(phenyl-C), 126.24 (phenyl-C), 126.21 (phenyl-C), 126.19 (phenyl-C), 126.02 (phenyl-C), 125.12
(phenyl-C), 125.07 (phenyl-C), 124.74 (phenyl-C), 124.56 (CF ), 123.02 (CF ), 118.70 (C=C),
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79.32 (oxadiazine-CN), 69.70 (oxadiazine-CH ), 64.77 (CH O), 39.40 (cyclopentane-CH ).
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2
+
HRMS (ESI-TOF) m/z: calcd for C H BrF N O [M + H] 668.3812; found 668.3805.
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3
4
(7-bromo-2-((4-(trifluoromethoxy)phenyl)carbamoyl)-2,5-tetrahydroindeno[1,2-
e][1,3,4]oxadiazin-4a-yl)methyl 3-(3-(trifluoromethyl)phenyl)acrylate (J33). Yield: 74.6%;
1
white solid: mp 151–153 °C; H NMR (600 MHz, Chloroform-d) δ 8.36 (s, 1H, NH), 7.70 (s, 1H,
phenyl), 7.61 (t, J = 9.2 Hz, 2H, phenyl), 7.57 (d, J = 3.0 Hz, 1H, phenyl), 7.54 (s, 2H, phenyl),
7.52 (d, J = 9.0 Hz, 2H, phenyl), 7.46 (s, 1H, phenyl), 7.44 (t, J = 7.8 Hz, 1H, vinyl), 7.14 (d, J =
8.5 Hz, 2H, phenyl), 6.43 (d, J = 16.1 Hz, 1H, vinyl), 5.54 (d, J = 9.3 Hz, 1H, oxadiazine), 5.45
(d, J = 9.3 Hz, 1H, oxadiazine), 4.61 (d, J = 12.2 Hz, 1H, cyclopentane), 4.27 (d, J = 12.2 Hz, 1H,
1
3
cyclopentane), 3.34 (d, J = 15.9 Hz, 1H, CH ), 3.18 (d, J = 15.8 Hz, 1H, CH ). C NMR (151
2
2
MHz, Chloroform-d) δ 165.45 (O=C-O), 153.83 (CONH), 151.10 (oxadiazine-CN), 144.80 (=C-
phenyl), 144.30 (phenyl-C), 144.22 (phenyl-C), 136.44 (phenyl-C), 134.64 (phenyl-C), 133.05
(phenyl-C), 131.73 (phenyl-C), 131.38 (phenyl-C), 131.15 (phenyl-C), 129.44 (phenyl-C), 129.34
(phenyl-C), 127.02 (phenyl-C), 126.99 (phenyl-C), 126.38 (phenyl-C), 125.89 (phenyl-C), 124.74
(phenyl-C), 124.71 (phenyl-C), 124.57 (CF ), 122.97 (CF ), 122.76 (phenyl-C), 121.75 (phenyl-
3
3
C), 118.69 (C=C), 79.27 (oxadiazine-CN), 69.73 (oxadiazine-CH ), 64.79 (CH O), 39.40
2
2
+
(cyclopentane-CH ). HRMS (ESI-TOF) m/z: calcd for C H BrF N O [M + H] 684.3806; found
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3
5
684.3792.
(7-fluoro-2-((4-(trifluoromethoxy)phenyl)carbamoyl)-2,5-tetrahydroindeno[1,2-
e][1,3,4]oxadiazin-4a-yl)methyl 3-(3-(trifluoromethyl)phenyl)acrylate (J34). Yield: 73.4%;
1
white solid: mp 178–180 °C; H NMR (600 MHz, Chloroform-d) δ 8.36 (s, 1H, NH), 7.73 – 7.70
(m, 2H, phenyl), 7.64 – 7.61 (m, 1H, phenyl), 7.61 – 7.57 (m, 2H, phenyl), 7.53 – 7.50 (m, 2H,
phenyl), 7.45 (d, J = 7.8 Hz, 1H, vinyl), 7.16 – 7.14 (m, 2H, phenyl), 7.13 – 7.08 (m, 2H, phenyl),
6.44 (d, J = 16.1 Hz, 1H, vinyl), 5.57 (d, J = 9.2 Hz, 1H, oxadiazine), 5.40 (d, J = 9.3 Hz, 1H,
oxadiazine), 4.61 (dd, J = 12.1, 1.2 Hz, 1H, cyclopentane), 4.29 (d, J = 12.1 Hz, 1H, cyclopentane),
1
3
3.34 (d, J = 15.9 Hz, 1H, CH ), 3.20 (d, J = 15.9 Hz, 1H, CH ). C NMR (151 MHz, Chloroform-d)
2
2
δ 165.49 (O=C-O), 154.35 (CONH), 144.20 (=C-phenyl), 136.51 (phenyl-C), 134.65 (phenyl-C),
131.59 (phenyl-C), 131.37 (phenyl-C), 131.10 (phenyl-C), 130.07 (phenyl-C), 129.44 (phenyl-C),
129.29 (phenyl-C), 127.00 (phenyl-C), 126.98 (phenyl-C), 124.77 (phenyl-C), 124.74 (phenyl-C),
124.72 (phenyl-C), 124.69 (phenyl-C), 124.47 (phenyl-C), 123.97 (CF ), 123.56 (CF ), 123.50
3
3
(phenyl-C), 121.75 (phenyl-C), 116.21 (C=C), 79.45 (oxadiazine-CN), 69.76 (oxadiazine-CH2),
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64.94 (CH O). 39.68 (cyclopentane-CH ). HRMS (ESI-TOF) m/z: calcd for C H F N O [M +
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+
H] 623.4750; found 623.4735.
Assessment of Bioactivity on Spodoptera litura F. Larvae of S. litura F. were obtained from
Guangzhou zhongda biological engineering co. LTD. and raised with artificial diet at 26 ± 1 °C
and 75 ± 5% relative humidity under a photoperiod of 16:8 h (light/dark).
The toxicities of indoxacarb and its derivatives against the third-instar larvae of S. litura F. were
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determined by the artificial diet method. The compounds were dissolved in acetone and then
mixed with an artificial diet. The treated artificial diet was placed into Petri dishes (9 cm diameter)
and allowed acetone to volatilize for 2–3 h. Then, 10 larvae were introduced into each dish.
Acetone without test compound was used as the control. The treated larvae in Petri dishes were
kept at 26 ± 1 °C, photoperiod in a climatic chamber with 75 ± 5% relative humidity with a 16:8
h (light/dark). All treatments were replicated five times. Mortalities were determined 48 h after
treatment. The LC values were calculated by the SPSS software.
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Molecular Modeling. We used our most recent model of the bumble bee sodium channel to build
a model of the cockroach channel BgNav1-1 and dock ligands with pyrethric acid (J7) and
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cinnamic acid (J24) moieties. The model is based on the X-ray structure of an open sodium
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channel NavMs. The chiral atom in the five-membered ring had the same configuration as in our
model with an indoxacarb derivative, DCJW.13 Configuration of the chiral atoms in the
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5
dimethylcyclopropane ring was the same as in pyrethric acid. Atom charges at compound J7 and
J24 were calculated by Austin Model 1(AM1) method realized in Motif Finding by Preprocessing
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and Agglomerative Clustering (MOPAC). We designate residues in the model by using a labeling
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scheme, which is universal for P-loop channels. A label includes the domain number (1– 4),
segment type (i, an inner helix S6; p, a P-loop, and o, an outer helix S5), and relative number of
the residue in the segment (Figure 2). Computations were performed using the facilities of the
Shared
www.sharcnet.ca/my/front/).
The ligand docking was performed with the Zimbabwe-Malawi- Mozambique (ZMM) program
Hierarchical
Academic
Research
Computing
Network
(SHARCNET,
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and Monte Carlo energy minimizations method (MCM) as described elsewhere. The ligand was
initially placed in the central cavity and its tricyclic moiety was oriented as in our model of DCJW-
1
3
bound sodium channel. Position, orientation and conformation of the ligand and the channel
sidechain conformations were randomly sampled in the MCM protocol, but all degrees of freedom,
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including translation of the sodium ion, backbone torsions and bond angles of the ligands and
proline residues were energy minimized after each sampling.
RESULTS AND DISCUSSION
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Chemistry. Indoxacarb analogs G1–G6 were synthesized as described in our previous work. The
ester group in G1–G6 was reduced with LiAlH to yield alcohol intermediates H1–H6. These
4
intermediates were synthesized by stirring indoxacarb analogs G1–G6 with dropwise a suspension
of LiAlH in anhydrous THF under argon. H1–H6 were treated with acyl chloride in DMAP and
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dry DIPEA in anhydrous THF under an argon atmosphere to give compounds J1–J34 (Scheme 1).
The TLC assay was supplemented with LiAlH until the reactant consumption was complete. The
4
NMR spectra of the key intermediates were obtained. We followed the same route employed in
the synthesis of H1–H6. The latter were reacted with pyrethric acid chloride, cinnamoyl chloride
and chloroacetyl chloride to give the title compounds J1–J34 (Table 1). These compounds were
esterified with DMAP and dry DIPEA in anhydrous THF under an argon atmosphere and 0 ℃.
After 2 hours, the reaction was quenched by anhydrous EtOH.
Due to compounds J1–J12 containing three chiral centers in alcohol and acid moieties, the two
diastereomeric isomers, less polar isomers (J1-H-Rf to J12-H-Rf) and more polar isomers (J1-L-
Rf to J12-L-Rf) showed different retention factor (Rf) values, were separated from each other by
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1
13
silica gel column chromatography (petroleum ether/ethyl acetate = 8:1, v/v). The H NMR, C
NMR and HRMS for all target compounds may be found in the supporting information.
R1
R1
R1
COOMe
2
R1
OH
COOMe
OH
1
3
COOMe
O
O
O
3
N
NH2
A -A
1
B -B
1
C -C
1
D -D
1 3
3
3
8
8
87
88
O
O
R1
OH
COOMe
R1
O
5
4
N
NH
N
N
O
R2
O
HN
NH
OCN
E1-E2
R2
R2
F1-F6
G -G
1
6
8
89
2
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