The structure modification of seven-membered aza-brigded neonicotinoids in order to investigate their impact on honey bees

Article abstract of DOI:10.1177/17475198211012237

In order to explore the relationship between the structure and the toxicity to honey bees of seven-membered aza-bridged neonicotinoids, 16 novel seven-membered aza-bridged neonicotinoid analogues are synthesized by replacing the pyridine ring, and changing the substituents on the pyridine ring, the electron-withdrawing group NO₂ and the imidazole ring of our previously developed aza-bridged neonicotinoid 1-[(6-chloropyridin-3-yl)methyl)]-10-(2,5-dimethylphenyl)-9-nitro-2,3,5,6,7,8-hexahydro-1H-5,8-epiminoimidazo azepine (C-29). The insecticidal bioactivities against cowpea aphid (Aphis craccivora) and the bee toxicities of these compounds are tested. Some of the title compounds present good insecticidal activities against cowpea aphid. The results also show that some of the title compounds exhibit lower bee toxicity than that of C-29 and imidacloprid. This suggests that changing the substituents on the neonicotinoids can influence the toxicity toward honey bees of these analogues.

Full text of DOI:10.1177/17475198211012237

1012237CHL0010.1177/17475198211012237Journal of Chemical ResearchChen et al.
research-article2021
Research Paper
Journal of Chemical Research
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The structure modification of seven-membered
aza-brigded neonicotinoids in order to
investigate their impact on honey bees
https://doi.org/10.1177/17475198211012237
DOI: 10.1177/17475198211012237
journals.sagepub.com/home/chl
Yuce Chen , Xiaofeng Cao, Xi Chen, Zhong Li
and Xiaoyong Xu
Abstract
In order to explore the relationship between the structure and the toxicity to honey bees of seven-membered aza-
bridged neonicotinoids, 16 novel seven-membered aza-bridged neonicotinoid analogues are synthesized by replacing the
pyridine ring, and changing the substituents on the pyridine ring, the electron-withdrawing group NO2 and the imidazole
ring of our previously developed aza-bridged neonicotinoid 1-[(6-chloropyridin-3-yl)methyl)]-10-(2,5-dimethylphenyl)-9-
nitro-2,3,5,6,7,8-hexahydro-1H-5,8-epiminoimidazo azepine (C-29). The insecticidal bioactivities against cowpea aphid
(Aphis craccivora) and the bee toxicities of these compounds are tested. Some of the title compounds present good
insecticidal activities against cowpea aphid. The results also show that some of the title compounds exhibit lower bee
toxicity than that of C-29 and imidacloprid. This suggests that changing the substituents on the neonicotinoids can
influence the toxicity toward honey bees of these analogues.
Keywords
aza-bridged neonicotinoids, bee toxicity, cowpea aphid, insecticidal bioactivity, modification
Date received: 21 December 2020; accepted: 6 April 2021
be reduced by low doses of neonicotinoids, which would
Introduction
lead to the loss of the weight and even death.5–10 At the
Neonicotinoids have played an important role in the con-
same time, the survival of worker bees significantly
trol of pests, particularly in sucking pests, coleopterans,
decreased on a large scale.11 These severe effects have
and dipterans.1 They are used worldwide, accounting for
resulted in the ban of three kinds of neonicotinoid: imida-
more than one-fourth of the global insecticide market.2,3
cloprid, clothianidin, and thiamethoxam in the European
However, more and more research has found that, after
Union from May 2018,12 and much more attention has
more than 20 years of use, neonicotinoids represent a
been directed toward studying the toxicity of
major threat to bees through increased mortality and
decreased colony establishment, a condition which is
known as colony collapse disorder (CCD).4–8 Bees con-
Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East
China University of Science and Technology, Shanghai, P.R. China
tribute to about 80% of insect pollination,9 so it is imper-
ative to verify the causes of bee colony losses, which may
threaten plant systems based on the key role of bees in
pollination. It has been reported that imidacloprid-treated
bees move more actively at first and then become
Corresponding author:
Xiaoyong Xu, Shanghai Key Laboratory of Chemical Biology, School of
Pharmacy, East China University of Science and Technology, Shanghai
200237, P.R. China.
exhausted. In addition, the foraging ability of bees may Email: xyxu@ecust.edu.cn
Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons
Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use,
reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and
Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).

2
Journal of Chemical Research
Results and discussion
Synthesis of the intermediates
The syntheses of the intermediates are summarized in
Scheme 1 and the details are available in the experimental
section. Intermediate 7 was obtained by stirring (2-nitroe-
thene-1,1-diyl)bis(methylsulfane) with 1,2-ethylenedi-
amine 6 under reflux conditions (equation (1)). The
preparations of intermediates 9–16 were accomplished
through nucleophilic substitution reactions using interme-
diate 7 via nucleophilic attack on the appropriate halogen-
ated reagent 8 (equation (1)). The preparation of
intermediate 20 was similar to the preparations of interme-
diates 9–16, only the starting material 1,2-ethylenediamine
was replaced by 1,3-propylenediamine 17 (equation (2)).
To obtain the intermediate 23, (6-chloropyridin-3-yl)
methanamine 21 was reacted with bis(methylsulfane) to gen-
erate intermediate 22, and amination was conducted with
methanamine to result in intermediate 23 (equation (3)).
Intermediates 25–26 were prepared by displacing the
methylthiol of bis(methylsulfane) with the appropriate
alkyl mercaptan 24 (equation (4)).
Figure 1. Some commercial nAChRs compounds.
Figure 2. An aza-bridged compound.
neonicotinoids to honey bees.13 Thus, it is important to
explore neonicotinoids with low bee toxicity. Novel neo-
nicotinoid insecticides with low bee toxicity have gradu-
ally been developed, for example, sulfoxaflor14,15 and
flupyradifurone16,17 are new members of the neonicoti-
noid family that act via the same mechanism, that is, as
agonists of postsynaptic nicotinic acetylcholine receptors
(nAChRs; Figure 1).
The most recent one is reported to be an antagonist of
nAChRs.18 Even sulfoxaflor was banned by France in
January 2020. Thus, the exploration of the relationship
between structure change and bee toxicity is beneficial for
finding new insecticidal lead compounds.
In our previous work, seven-membered aza-bridged
neonicotinoid analogues were designed and synthesized on
the basis of novel seven-membered oxa-bridged com-
pounds and aza-bridged neonicotinoid analogues.19
Unfortunately, the product with the highest activity of this
series (compound C-29; Figure 2), is much more toxic to
honey bees than imidacloprid (bee contact toxicity of C-29,
LC50 = 0.062 mg L−1; imidacloprid, LC50 = 0.213 mg L−1).
In order to explore the relationship between the structure
and bee toxicity and to decrease the bee toxicity by struc-
ture modification, we selected seven-membered aza-
bridged neonicotinoid C-29 and adopted different strategies
to modify its structure (Figure 3). Sixteen seven-membered
aza-bridged neonicotinoid analogues were synthesized
according to our strategy. We replaced the substituents at
position 2 of the pyridine ring (1a, b)20 and the type of het-
erocycle on the basis of the imidazole ring (2a–c). In addi-
tion, a fluoroalkyl chain was used to replace the pyridine
ring based on the bioactivity of fluorine atoms (2d–f).21 We
also tried to modify imidazole ring by expansion or removal
(3a, b). In addition, we removed the (heteroaryl)methyl
groups (4a–d) and introduced CN and COOEt instead of
NO2 (5a, b) after considering the low bee toxicity of aceta-
miprid and thiacloprid.22 The insecticidal activities and the
bee toxicities of all the compounds were investigated and
compared so that we can elucidate structural characteristics
that decrease toxicity toward bees.
Intermediate 29 was obtained via the classic Pinner reac-
tion, starting with commercially available nitriles 27 (malon-
onitrile and ethyl cyanoacetate) and ethanol, and then
neutralized by Et3N to give intermediates 29. Cyclization
with N1-[(6-chloropyridin-3-yl)methyl]ethane-1,2-diamine
30 gave intermediates 31 and 32 (equation (5)).
General synthesis of the compounds
The target compounds were obtained by the reaction of the
above-mentioned synthetic intermediates (7, 9–16, 18, 20,
23, 25–26, 31–32), 2,5-dimethylaniline and the key reac-
tant succinaldehyde, the latter being obtained by stirring
2,5-dimethoxy-tetrahydrofuran with aqueous acid.23 The
corresponding products were obtained by the following
synthetic routes shown in Scheme 2, the details of which
are available in the experimental section and the NMR
spectra are available in supplement material.
Insecticidal activity and the bee toxicity of
the synthesized compounds
Compounds 1a, b in which the chloro group at the 6-posi-
tion of the pyridine ring were replaced by a bromo and a
fluoro group, and compounds 2a–f with different substitu-
ents on the nitrogen atom of the imidazole ring were synthe-
sized initially. The activity of compounds 1a, b was
dependent on the nature of the substituents on the pyridine
ring. It is apparent that the electron-withdrawing chloro
group contributed to an increase in the bioactivity against
cowpea aphid compared with the compounds bearing a
bromo group (1a) and a fluoro group (1b). The bioassay also
showed that a substituted pyridine ring played an important
role in the activity of compounds 2 (Figure 3). The activity
of the 2-chlorothiazol-5-yl derivative 2a was lower than that
of the bromopyridyl derivative 1a. For compounds 2b and
2c, in which phenyl and tetrahydrofuran-3-yl were attached

Chen et al.
3
Figure 3. The optimization of the C-29.
Scheme 1. Synthetic routes to the intermediates.

4
Journal of Chemical Research
Scheme 2. General synthesis for target compounds.
respectively. However, these compounds showed no activ-
ity against cowpea aphids.
to the N-methyl group, the bioactivity disappeared totally,
which proved the necessity of a pyridine among the four
aromatic heterocycles. When fluoroalkyl chains were intro-
duced as replacements for the aromatic heterocycle, the
activities of resulting compounds 2d–f were lower than that
of C-29 against cowpea aphids; compound 2f (n = 3) had
relatively higher activity among compounds 2d–f at 100 mg
L−1, the mortality reached 90%, which indicated the impor-
These findings again indicated the importance of the
N-[(6-chloro-3-pyridyl)methyl]group.Neonicotinoidsbear-
ing a CN group are regarded as insecticides with low bee
toxicity,23 so a cyano group 5a and ester group 5b were
introduced into C-29 to replace the nitro group. However,
this led to a decrease in the activity against cowpea aphids,
tance of the distance between the fluorine atom and the imi- which further clarified the key role of the nitro group.
dazole ring. Unfortunately, when the concentration is
decreased to 20 mg L−1, the bioactivity of compounds 2d–f
totally disappeared (Table 1).
Although some of the compounds exhibited good insecti-
cidal activities, the activities were much lower compared
with that of C-29.
Compounds possessing the feature structures of com-
mercialized neonicotinoids were next synthesized (3a, b,
4a–d). First, hexahydropyrimidine 3a and compound 3b
were synthesized after the imidazole ring of C-29 was
opened. It was found that these two compounds maintained
good activity against cowpea aphid, but still lower than that
of C-29. Next, the structures with the 6-chloro-3-pyridyl
and 2-chlorothiazol-5-yl substituents of the N terminus of
the nitrogen-containing heterocyclic ring removed and only
preserving imidazole (4a), hexahydropyrimidine (4b), thia-
zolidine (4c), and 1,3-thiazinane (4d) were synthesized,
Next, the bee toxicities of the synthesized compounds
with higher insecticidal activity were determined. The bee
contact toxicities of the compounds are listed in Table 2.
All the tested compounds exhibited lower contact toxic-
ity toward honey bees than C-29, which has an extremely
high level of toxicity. First, the Br at the 2-position of the
pyridine ring in 1a maintained the bee contact toxicity,
which implies that bee toxicity is caused by halogens on the
pyridine ring. Next, compounds 3a and 3b, in which the
imidazole ring was either expanded or removed completely,
showed much lower bee contact toxicity than C-29. This

Chen et al.
5
Table 1. Insecticidal activities of the target compounds against
cowpea aphids.
structure, it is not satisfactory that the toxicity level of com-
pound 3a is still very high.
Based on the data of bee contact and oral toxicity at 24
and 48 h, it was found that the bee toxicity at 24 h was lower
than that at 48 h. This indicates that the compounds were
degraded after they entered the body of the honey bee and the
degradation products exhibited higher bee toxicity than the
parent compounds. It is known that C-29 is easily degraded
into intermediate (E)-2-chloro-5-{[2-(nitromethylene)imida-
zolidin-1-yl]methyl}pyridine (NTN32692), which is a com-
pound with higher bee toxicity (see Scheme 1). This may
indicate that the high bee toxicity of NTN32692 might be the
cause of the bee toxicity of all the derivatives of NTN32692.
The best approach to decrease the bee toxicity is to give up
the structural skeleton of NTN32692 and select a novel
structural skeleton.
Compounds Mortality (%)
100 mg L−1 20 mg L−1 LC50
C-29
1a
1b
2a
2b
2c
100
100
80
100
0
100
66.97
LC50 = 0.426 mg L−1
LC50 = 7.216 mg L−1
0
–
50.36
LC50 = 20.363 mg L−1
0
0
–
–
0
2d
2e
2f
3a
3b
4a
4b
4c
0
0
0
0
–
–
–
80
90
100
100
0
96.11
100
0
LC50 = 3.335 mg L−1
LC50 = 3.650 mg L−1
–
–
–
0
0
0
0
Conclusion
4d
5a
5b
0
0
40
0
0
0
100
–
–
–
Sixteen novel seven-membered aza-bridged neonicoti-
noid analogues are synthesized on the basis of C-29,
which has high insecticidal activity but is more toxic to
honey bees than imidacloprid. Compound 3a bearing a
hexahydropyrimidine moiety retained insecticidal bioac-
tivity comparable to that of C-29 and exhibited toxicity
toward honey bee inferior to that of C-29 (bee contact
toxicity of C-29, LC50 = 0.062 mg L−1; 3a, LC50 = 17.065
mg L−1. Insecticidal bioactivity against cowpea aphid of
C-29, LC50 = 0.426 mg L−1; 3a, LC50 = 3.335 mg L−1). In
summary, compound 3a exhibits good insecticidal bioac-
tivity against cowpea aphid and lower toxicity toward
honey bees, making it a potential lead compound in the
discovery of new insecticide.
Imidacloprid 100
LC50 = 0.921 mg L−1
The insecticidal activities of the synthesized compounds were tested
at 100 mg L−1. When the mortality of the compound reached 100%,
the concentration was decreased to 20 mg L−1 and the bioactivity was
tested again. When the mortality was greater than 50% at 20 mg L−1,
LC50 value was obtained.
suggested that the change of substituents and imidazole
ring contributed to the decrease in bee contact toxicity. In
addition, compound 2a also exhibited lower contact toxic-
ity than C-29, which means that replacing the 6-chloropyri-
dine with a 2-chlorothiazole also decreases the bee contact
toxicity. In addition, the LD50 values of the bee toxicity of
compounds 2a and 3a were also lower than those of imida-
cloprid at 24 and 48 h, but toxicological grade was still the
same (Table 2).
Experimental
Instrumentation and chemicals
High-resolution mass spectra were recorded under electron
impact (70 eV) conditions using a Micromass GCT CA 055
instrument. Melting points were recorded on a Buchi I-540
The bee oral toxicities of some of the prepared com-
pounds with high insecticidal activity are listed in Table 3.
These compounds all exhibited lower bee oral toxicity than
C-29. Among them, the toxicity level of two compounds 1a
and 3a decreased from extremely toxic A to highly toxic B
according to the data at 48 h. However, only the bee oral
toxicity of compound 3a was lower than that of imidaclo-
prid. In the process of testing of the bee contact toxicity and
oral toxicity, the poisoning symptoms of bee were observed,
it was found that the honey bees moved slowly and errati-
cally and the body color of honey bees gradually became
black.
By comprehensively comparing the bee contact and oral
toxicities of these compounds, there are two, 1a and 3a,
that show bee contact toxicities lower than imidacloprid,
and only compound 3a has a lower bee oral toxicity than
imidacloprid. Moreover, compound 3a maintained rela-
tively good activity against cowpea aphids (Table 1). Thus,
compound 3a with a hexahydropyrimidine and a 6-chloro-
pyridine ring is the best candidate compound following
modification of C-29. Although we realized the design tar-
get to decrease the toxicity of C-29 by modification of the
apparatus and are uncorrected. 1H NMR, 13C NMR and 19
F
NMR spectra were recorded on a Bruker AM-400 (400
MHz) spectrometer with CDCl3 or DMSO-d6 as the solvent
and tetramethylsilane (TMS) as the internal standard.
Chemical shifts are reported in δ (parts per million) values.
Analytical thin-layer chromatography (TLC) was carried
out on precoated plates (silica gel 60 F254), and spots were
visualized with ultraviolet (UV) light.
Unless otherwise noted, reagents and solvents were pur-
chased from Shanghai Tansoole Chemicals Company, Ltd.
(Shanghai, China) and Shanghai Bide Pharmatech Ltd.
(Shanghai, China).
Insecticidal assay
According to statistical requirements, the bioassay was
repeated three times at 25 °C ± 1 °C. All compounds were
dissolved in N, N-dimethylformamide and diluted with
water containing Triton X-100 (0.1 mg L−1) to obtain series

6
Journal of Chemical Research
Table 2. Bee acute contact toxicity of several of the prepared compounds.
Compound
Time
LD50 (μg bee−1)
Toxic regression
equation
R2a
Toxicological
gradeb
3a
24
48
24
48
24
48
24
48
24
48
24
48
24
48
0.328
0.256
0.320
0.191
0.181
0.125
0.081
0.028
0.028
0.023
0.213
0.076
0.062
0.024
y = 1.540x + 0.746
y = 1.639x + 0.971
y = 0.702x + 0.347
y = 1.074x + 0.773
y = 1.559x + 1.157
y = 1.765x + 1.596
y = 2.537x + 2.769
y = 2.357x + 3.662
y = 2.047x + 3.191
y = 2.485x + 4.097
y = 0.637x + 0.428
y = 0.837x + 0.935
y = 1.769x + 3.331
y = 1.858x + 3.689
0.981
0.975
0.965
0.966
0.999
0.990
0.947
0.985
0.881
0.972
0.962
0.988
0.983
0.996
B
B
B
B
B
B
B
2a
3b
1a
NTN32692
Imidacloprid
C-29
aCoefficient of determination of the toxic regression equation, which represents the goodness of fit of the toxic regression equation.
bThe grade of the bee toxicity—Extreme toxicity: A; high toxicity: B; moderate toxicity: C; low toxicity: D.
Table 3. Bee acute oral toxicity of several of the prepared compounds.
Compound
Time
LC50 (mg L−1)
Toxic regression
equation
R2a
Toxicological
gradeb
3a
1a
2a
3b
24
48
24
48
24
48
24
48
48
24
48
154.396
17.065
8.706
2.594
0.483
0.201
0.409
0.328
10.560
0.214
0.087
y = 1.078x − 2.359
y = 3.151x − 3.882
y = 2.357x − 2.215
y = 4.111x − 1.702
y = 1.405x + 0.444
y = 1.952x + 1.360
y = 1.995x + 0.775
y = 2.010x + 0.973
y = 1.142x − 1.169
y = 3.061x + 2.051
y = 2.924x + 3.104
0.911
0.997
0.949
0.981
0.984
0.991
0.977
0.984
0.926
0.987
0.998
B
B
A
A
Imidacloprid
C-29
B
A
aCoefficient of determination of the toxic regression equation, which represents the goodness of fit of the toxic regression equation.
bThe grade of the bee toxicity—Extreme toxicity: A; high toxicity: B; moderate toxicity: C; low toxicity: D.
concentrations of 500.0, 100.0 mg L−1, and others for
bioassays.
Bee toxicity assay
All compounds were dissolved in acetone and diluted with
water to obtain series concentrations for bioassays.
For cowpea aphids: The insecticidal activities of title
compounds against cowpea aphids were tested according
to the previously reported procedure.24 Horsebean seed-
lings with 40−60 healthy apterous adults were dipped in
diluted solutions of the chemicals containing Triton
X-100 (0.1 mg L−1) for 5 s, and then the shoots were
placed in a conditioned room (25 °C ± 1 °C, 50% relative
humidity (RH) Water containing Triton X-100 (0.1 mg
L−1) was used as control. The mortality rates were
assessed after 24 h. Each treatment had three repetitions,
and the data were corrected and subjected to probit
analysis.
The LC50 values against Cowpea Aphids of low bee tox-
icity compounds were tested by similar method under dif-
ferent concentrations. The mortality rates of the cowpea
aphids were recorded after 72 h. The test data were pro-
cessed by the SPSS12.0 and obtained the LC50 for 72 h and
95% confidence limit.
Contact assay: Honey bees were put into a dryer and
were anesthetized by 5 mL diethyl ether for 3 min before
the test. Then, different concentration solutions were drop-
wise added on the pronotums of the bees by 1.00 μL micro-
dropper. The bees were enclosed in the cage in time before
the bees fully recovered and were fed with 33% honey
water. The cage was put on the laboratory table and covered
by black cloth and acetone was used as control.
Uptake assay: Degrease cotton was dipped in diluted
solutions of the chemicals, which was added to Tween 80
and diluted by 33% honey water until saturation. Then,
degrease cotton was spread on gauze net in the cage and a
50 mL beaker was put on the degrease cotton so that the
honey bees could suck up the liquid. The cage was put on
the laboratory table and covered by the black cloth. The
amount of acetone with Tween 80 was the same as the

Chen et al.
7
maximum concentration of diluted solution. It was used as
control.
To a solution of 2-chloro-5-(chloromethyl)pyridine 19
(2 mmol) and intermediate 18 (2 mmol) in DMSO (10
The mortality rates and poisoning symptoms were mL) was added KOH (1.5 mmol) and the mixture was
recorded 24 and 48 h after treatment. The test data were stirred at room temperature. After the disappearance of
processed by the SPSS12.0 and obtained the LC50 (bee con- the reactant (monitored by TLC), the reaction mixture was
tact toxicity) for 24 and 48 h, LD50 (bee oral toxicity) for 24 poured into water and extracted with dichloromethane (50
and 48 h and 95% confidence limit.
mL × 3). The combined organic layers were washed with
saturated aqueous NaCl and dried over sodium sulfate.
After evaporation of the solvent, the residue was sub-
jected to a flash chromatography on silica gel to afford the
General synthetic procedures
Intermediates 9–13. The synthetic procedures of interme- intermediate 20.26
diates 9–13 are shown in equation (1). To a solution of
(2-nitroethene-1,1-diyl)bis(methylsulfane) (6.5 mmol) in (E)-N-((6-chloropyridin-3-yl)methyl)-N-methyl-2-nitroethene-
ethanol (50 mL) was added hydrazine 6 dropwise, and the 1,1-diamine 23. The synthetic procedures of intermediate
resulting mixture was stirred at reflux for 8 h. After the 23 were shown in equation (3). To a solution of
disappearance of the reactant (monitored by TLC), the bis(methylsulfane) (6.5 mmol) in ethanol (50 mL) was
reaction mixture was evaporated and the residue treated added the prepared intermediate 21 dropwise, and the
with water (10 mL). The mixture was extracted with dichlo- resulting mixture was stirred at reflux for 8 h. After the
romethane (50 mL × 3), and the combined organic layer disappearance of the reactant (monitored by TLC), the
was dried over Na2SO4, filtered, and concentrated under reaction mixture was evaporated and the residue treated
reduced pressure to yield the crude intermediate 7. The with water (10 mL). The mixture was extracted with dichlo-
crude intermediate 7 was used in next step.
romethane (50 mL × 3), and the combined organic layer
To a solution of commercially available halogen rea- was dried over Na2SO4, filtered, and concentrated under
gents 8 (2 mmol), respectively, and intermediates 8 (2 reduced pressure to yield the crude product. The crude
mmol) in dimethyl sulfoxide (DMSO; 10 mL) was added product was purified via flash silica gel chromatography
KOH (1.5 mmol) and the mixture was stirred at room tem- (CH2Cl2/MeOH, 10:1) to give the intermediate 22.
perature. After the disappearance of the reactant (moni-
A solution of methylamine in ethanol was added to the
tored by TLC), the reaction mixture was poured into water prepared intermediate 22 dropwise, and the resulting mix-
and extracted with dichloromethane (50 mL × 3). The ture was stirred at reflux for 8 h. After the disappearance of
combined organic layers were washed with saturated the reactant (monitored by TLC), the reaction mixture
aqueous NaCl and dried over sodium sulfate. After evapo- evaporated the solvent and quenched with water. The mix-
ration of the solvent, the residue was subjected to a flash ture was extracted with dichloromethane (50 mL × 3), and
chromatography on silica gel to afford the target the combined organic layer was dried over Na2SO4, fil-
intermediates.25
tered, and concentrated under reduced pressure to yield the
crude product. The crude product was purified via flash
Intermediates 14–16. The synthetic procedures of intermedi- silica gel chromatography (CH2Cl2/MeOH, 15:1) to give
ates 14–16 are shown in equation (1). To a solution of the the intermediate 23.27
fluorine-substituted brominated hydrocarbons 8 (2 mmol) in
acetonitrile (25 mL) was added tetrabutylammonium bro- Intermediates 25–26. The synthetic procedures of inter-
mide (TBAB; 2 mmol), intermediates 7 (2 mmol) and mediates 25–26 are shown in equation (4). To
Cs2CO3 (2 mmol). The resulting mixture was stirred and bis(methylsulfane) (10 mmol) in ethanol (20 mL) at 78 °C
heated at 82 °C for 8 h. After the disappearance of the reac- was added commercially available reactants 24 (10 mmol)
tant (monitored by TLC), the mixture was cooled to room dropwise, respectively, and the mixture was stirred at
temperature and filtered. The solvent was evaporated and the reflux 78 °C. After the disappearance of the reactant (mon-
residue was subjected to a flash chromatography on silica gel itored by TLC), the reaction mixture was cooled to room
(CH2Cl2/EtOH, 20:1) to give the corresponding temperature during which time the product separated out
intermediates.
as a solid. The product was filtered and dried to obtain
target intermediate.28
(E)-1-(4-chlorobenzyl)-2-(nitromethylene)hexahydropyrimidine
20. The synthetic procedures of intermediates 20 are Intermediates 31–32. The synthetic procedures of inter-
shown in equation (2). To a solution of bis(methylsulfane) mediates 31–32 are shown in equation 5. To a flask with
(6.5 mmol) in ethanol (50 mL) was added methanediamine three necks was added commercially available reactants
17 dropwise, and the resulting mixture was stirred at reflux 27 (100 mmol), respectively, ethanol (100 mmol) and
for 8 h. After the disappearance of the reactant (monitored diethyl ether (30 mL). Then, hydrochloric acid was bub-
by TLC), the reaction mixture was evaporated and the resi- bled into the flask and the formed solid was separated
due treated with water (10 mL). The mixture was extracted out. After 4 h, the intermediate 28 was filtered out. After
with dichloromethane (50 mL × 3), and the combined the reaction was completed, the mixture was filtered and
organic layer was dried over Na2SO4, filtered, and concen- the residue was dissolved in dichloromethane. Triethyl-
trated under reduced pressure to yield the crude product. amine was added dropwise to the mixture until the pH
The crude product was purified via flash silica gel chroma- became alkaline. The obtained solution could be used
tography (CH2Cl2/MeOH, 18:1) to give intermediate 18.
directly in the next step.

8
Journal of Chemical Research
To a solution of intermediates 29 in dichloromethane (50 (dd, J = 17.6, 10.8 Hz, 1H). 13C NMR (100 MHz,
1
mL) was added intermediates 30 (100 mmol, 2.0 mmol DMSO-d6): δ 162.4 (d, JCF = 233 Hz), 155.8, 146.8 (d,
mL−1 in dichloromethane) dropwise and the mixture was 2JCF = 15 Hz), 142.6, 141.6 (d, 3JCF = 8 Hz), 135.3, 131.4,
3
stirred at reflux for 5–6 h. After the disappearance of the 130.6 (d, JCF = 4 Hz), 126.5, 123.2, 119.9, 109.4, 108.4,
reactant (monitored by TLC), the mixture was cooled to 72.3, 58.1, 50.4, 48.8, 46.2, 31.2, 31.0, 21.0, 18.6. 19F NMR
room temperature, and filtered to give the intermediate 31 (376 MHz, DMSO-d6): δ −70.59 (d, J = 7.5 Hz). HRMS
and 32.29
(EI): m/z [M+] calcd for C22H24N5O2F: 409.1914; found:
409.1912.
2-Chloro-5-{[10-(2,5-dimethylphenyl)-9-nitro-
2,3,5,6,7,8-hexahydro-1H-5,8-epiminoimidazo[1,2-a]
Target compounds, general procedure
The synthetic procedures of the target compounds are azepin-1-yl]methyl}thiazole (2a): Yellow solid; 69 mg,
shown in Scheme 2. To a solution of intermediates 7, 9–16, 38%; m.p. 163 °C–164 °C; 1H NMR (400 MHz, DMSO-d6):
18, 20, 23, 25–26, 31–32 (2 mmol), respectively, and δ 7.59 (s, 1H), 7.02 (d, J = 7.6 Hz, 1H), 6.74 (d, J = 7.6
2,5-dimethylaniline (5 mmol) in acetonitrile acidified to pH Hz, 1H), 6.57 (s, 1H), 5.11 (d, J = 3.6 Hz, 1H), 5.01 (d, J
2 by adding HCl (1 M) was added succinaldehyde (3 mmol) = 4.6 Hz, 1H), 4.90 (q, J = 15.4 Hz, 2H), 3.74–3.59 (m,
dropwise and the mixture was stirred in an ice bath for 1.5 2H), 3.58–3.40 (m, 2H), 2.23 (s, 3H), 2.19–2.18 (m, 1H),
h. After the disappearance of the reactant (monitored by 2.17 (s, 3H), 2.13–1.84 (m, 3H). 13C NMR (100 MHz,
TLC), the mixture was adjusted to pH 7−8 with saturated DMSO-d6): δ 155.6, 151.9, 143.0, 141.5, 136.6, 135.7,
aqueous NaHCO3 and evaporated under reduced pressure. 131.8, 127.0, 123.8, 120.3, 109.2, 72.8, 58.5, 49.3, 46.9,
The solution was extracted with dichloromethane (50 mL 46.4, 31.8, 31.6, 21.5, 19.1. HRMS (EI): m/z [M-HNO2]+
× 3). The combined organic layer was washed with brine calcd for C20H2135ClN4S: 384.1175; found: 384.1169; calcd
and dried over anhydrous sodium sulfate. After evaporation for C20H2137ClN4S: 386.1146; found: 386.1148.
of the solvent, the residue was purified by silica gel column
chromatography to afford the target product.
1-Benzyl-10-(2,5-dimethylphenyl)-9-nitro-2,3,5,6,7,8-
hexahydro-1H-5,8-epiminoimidazo[1,2-a]azepine
(2b):
Yellow solid; 69 mg, 42%; m.p. 132 °C–133 °C; 1H NMR
(400 MHz, DMSO-d6): δ 7.29–7.22 (m, 3H), 7.14 (dd, J =
6.0, 2.4 Hz, 2H), 7.05 (d, J = 7.6 Hz, 1H), 6.78 (d, J = 7.6
Succinaldehyde
A mixture of 2,5-dimethoxytetrahydrofuran (0.290 g, 2.2 Hz, 1H), 6.69 (s, 1H), 5.17 (d, J = 4.0 Hz, 1H), 5.01 (d, J
mmol) and 0.4 mL of 10% aqueous HCl was stirred at room = 4.8 Hz, 1H), 4.85–4.74 (m, 2H), 3.75–3.61 (m, 1H),
temperature. After 12 h, the pH value of the mixture was 3.61–3.49 (m, 1H), 3.43–3.27 (m, 2H), 2.24 (s, 3H), 2.20
adjusted to 2−3 with saturated aqueous NaHCO3. The (m, 1H), 2.19 (s, 3H), 2.17–1.94 (m, 2H), 1.90 (dd, J =
obtained solution could be used directly in the next step.22
18.0, 10.8 Hz, 1H). 13C NMR (100 MHz, DMSO-d6): δ
1-[(6-Bromopyridin-3-yl)methyl]-10-(2, 5- 156.0, 142.6, 136.6, 135.4, 131.5, 128.5 (2C), 127.4, 127.3
dimethylphenyl)-9-nitro-2,3,5,6,7,8-hexahydro-1H-5,8- (2C), 126.3, 123.2, 120.0, 108.3, 72.2, 58.2, 53.2, 48.3,
epiminoimidazo[1,2-a]azepine (1a): White solid; 68 mg, 46.3, 31.2, 30.7, 21.1, 18.7. HRMS (EI): m/z [M-HNO2]+
43%; m.p. 151 °C–152 °C; 1H NMR (400 MHz, CDCl3): δ calcd for C23H25N3: 343.2048; found: 343.2049.
8.20 (d, J = 1.6 Hz, 1H), 7.54 (dd, J = 8.2, 2.0 Hz, 1H), 7.37
10-(2,5-Dimethylphenyl)-9-nitro-1-[(tetrahydrofuran-
(d, J = 8.2 Hz, 1H), 7.06 (d, J = 7.6 Hz, 1H), 6.83 (d, J = 7.6 3-yl)methyl]-2, 3, 5, 6, 7, 8-hexahydro-1H-5, 8-
Hz, 1H), 6.78 (s, 1H), 5.12 (t, J = 6.6 Hz, 1H), 5.08 (d, J = epiminoimidazo[1,2-a]azepine (2c): Brown solid; 69 mg,
14.8 Hz, 1H), 4.98 (d, J = 5.6 Hz, 1H), 4.49 (d, J = 15.2 Hz, 39%; m.p. 196 °C–197 °C; 1H NMR (400 MHz, CDCl3): δ
1H), 3.69–3.53 (m, 2H), 3.30–3.16 (m, 2H), 2.36 (ddd, J = 8.04 (s, 1H), 7.27 (s, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.78 (d,
15.2, 11.4, 6.0 Hz, 1H), 2.29 (s, 3H), 2.28–2.24 (m, 2H), 2.23 J = 7.6 Hz, 1H), 6.63 (s, 1H), 5.11 (d, J = 5.6 Hz, 1H),
(s, 3H), 2.10–2.00 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 4.95 (d, J = 4.6 Hz, 1H), 3.84–3.54 (m, 4H), 2.46–2.21 (m,
156.4, 149.5, 142.4, 141.9, 138.7, 136.3, 131.9, 131.1, 128.5, 8H), 2.27 (s, 3H), 2.23 (d, J = 9.2 Hz, 3H), 2.16–2.03 (m,
126.6, 124.1, 120.4, 109.6, 73.2, 58.7, 51.6, 48.6, 47.3, 2H). 13C NMR (100 MHz, CDCl3): δ 156.7, 142.6, 136.3,
31.9, 31.1, 21.5, 19.1. HRMS (EI): m/z [M-HNO2]+calcd 131.6, 126.9, 123.9, 120.3, 108.5, 72.0, 70.8, 56.3, 53.5,
for C22H2379BrN4: 422.1106; found: 422.1108; calcd for 52.8, 46.8, 45.9, 42.7, 32.2, 29.7, 21.5, 19.0, 7.9. HRMS
C22H2381BrN4: 424.1086; found: 424.1090.
(EI): m/z [M-HNO2]+ calcd for C21H27N3O: 337.2154;
10-(2,5-Dimethylphenyl)-1-[(6-fluoropyridin-3-yl) found: 337.2159.
methyl]-9-nitro-2,3,5,6,7,8-hexahydro-1H-5,8-
10-(2,5-Dimethylphenyl)-1-(2-fluoroethyl)-9-nitro-
epiminoimidazo[1,2-a]azepine (1b): Russet solid; 120 mg, 2,3,5,6,7,8-hexahydro-1H-5,8-epiminoimidazo[1,2-a]aze-
40%; m.p. 162 °C–163 °C; 1H NMR (400 MHz, DMSO-d6): pine (2d): Orange solid; 78 mg, 42%; m.p. 143 °C–144 °C;
δ 8.12 (s, 1H), 7.81 (td, J = 8.2, 2.2 Hz, 1H), 7.09 (dd, J = 1H NMR (400 MHz, CDCl3): δ 7.03 (d, J = 7.4 Hz, 1H),
8.4, 2.4 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.76 (d, J = 7.2 6.78 (d, J = 8.0 Hz, 2H), 5.06 (d, J = 4.2 Hz, 1H), 4.94 (d,
Hz, 1H), 6.64 (s, 1H), 5.14 (d, J = 3.6 Hz, 1H), 4.99 (d, J J = 6.0 Hz, 1H), 4.81–4.79 (m, 1H), 4.70–4.52 (m, 1H),
= 4.0 Hz, 1H), 4.86 (d, J = 15.2 Hz, 1H), 4.67 (d, J = 15.2 4.03–3.74 (m, 3H), 3.66–3.44 (m, 2H), 3.18 (dd, J = 19.6,
Hz, 1H), 3.71 (dd, J = 16.6, 8.2 Hz, 1H), 3.61 (dt, J = 16.0, 10.0 Hz, 1H), 2.44–2.16 (m, 3H), 2.28 (s, 3H), 2.23 (s, 3H),
8.0 Hz, 1H), 3.42 (tt, J = 21.0, 6.4 Hz, 2H), 2.23 (s, 3H), 2.08–1.96 (m, 1H). 13C NMR (100 MHz, CDCl3): δ 156.2,
2.22–2.20 (m, 1H), 2.19 (s, 3H), 2.19–2.01 (m, 2H), 1.90 142.5, 136.3, 131.6, 126.6, 124.0, 120.6, 109.4, 83.8 (d,

Chen et al.
9
1JCF = 161 Hz), 73.3, 58.7, 51.8 (d, 2JCF = 19 Hz), 51.6 (d, 6.76 (d, J = 7.6 Hz, 1H), 6.52 (s, 1H), 5.12 (d, J = 4.2 Hz,
3JCF = 2 Hz), 47.9, 31.9, 31.0, 21.2, 18.8. 19F NMR (376 1H), 4.98 (d, J = 3.2 Hz, 1H), 4.61 (d, J = 6.0 Hz, 2H),
MHz, CDCl3): δ −217.20 (s). HRMS (EI): m/z [M+] calcd 3.09 (s, 3H), 2.21 (s, 3H), 2.17 (m, 1H), 2.14 (s, 3H), 2.12–
for C18H23N4O2F: 346.1805; found: 346.1810.
1.95 (m, 3H), 1.89 (t, J = 8.6 Hz, 1H). 13C NMR (100
10-(2,5-Dimethylphenyl)-1-(3-fluoropropyl)-9-nitro- MHz, DMSO-d6): δ 157.5, 149.4, 148.6, 142.3, 138.4,
2,3,5,6,7,8-hexahydro-1H-5,8-epiminoimidazo[1,2-a]aze- 135.4, 133.3, 131.4, 126.4, 124.2, 123.3, 119.6, 112.7, 77.4,
pine (2e): Orange solid; 86 mg, 39%; m.p. 156 °C–157 °C; 57.1, 45.4, 37.8, 31.5, 30.4, 20.9, 18.6. HRMS (EI): m/z
1H NMR (400 MHz, DMSO-d6): δ 7.02 (d, J = 7.6 Hz, [M+] calcd for C21H24N5O235Cl: 413.1619; found:
1H), 6.74 (d, J = 7.6 Hz, 1H), 6.65 (s, 1H), 5.13 (d, J = 4.8 413.1617; calcd for C21H24N5O237Cl: 415.1589; found:
Hz, 1H), 4.92 (d, J = 5.2 Hz, 1H), 4.53–4.37 (m, 1H), 415.1598.
4.37–4.25 (m, 1H), 3.79–3.61 (m, 3H), 3.60–3.42 (m, 2H),
3.31–3.18 (m, 1H), 2.23 (s, 3H), 2.19 (m, 1H), 2.18 (s, 3H), hexahydro-1H-5,8-epiminoimidazo[1,2-a]azepine
10-(2,5-Dimethylphenyl)-9-nitro-2,3,5,6,7,8-
(4a):
2.17–2.07 (m, 1H), 2.08–1.96 (m, 1H), 1.95–1.73 (m, 3H). Yellow solid; 93 mg, 41%; m.p. 200 °C–202 °C; 1H NMR
13C NMR (100 MHz, DMSO-d6): δ 155.4, 142.7, 135.2, (400 MHz, DMSO-d6): δ 8.55 (s, 1H), 7.01 (d, J = 7.6 Hz,
131.3, 126.4, 123.1, 120.0, 108.1, 81.6 (d, 1JCF = 161 Hz), 1H), 6.72 (d, J = 7.2 Hz, 1H), 6.56 (s, 1H), 5.11 (d, J = 4.4
72.2, 58.2, 49.4, 46.6 (3C), 31.2 (d, 2JCF = 37 Hz), 28.2 (d, Hz, 1H), 4.97 (d, J = 6.0 Hz, 1H), 3.74–3.57 (m, 3H),
3JCF = 19 Hz), 20.9, 18.6. 19F NMR (376 MHz, DMSO-d6): 3.57–3.44 (m, 1H), 2.28 (ddd, J = 20.4, 14.8, 9.4 Hz, 1H),
δ −218.10 (s). HRMS (EI): m/z [M+] calcd for C19H25N4O2F: 2.22 (s, 3H), 2.19 (s, 3H), 2.18–2.04 (m, 2H), 1.94–1.81
360.1962; found: 360.1960.
(m, 1H). 13C NMR (100 MHz, CDCl3): δ 156.7, 142.6,
10-(2,5-Dimethylphenyl)-1-(4-fluorobutyl)-9-nitro- 136.3, 131.6, 126.9, 123.9, 120.3, 108.5, 72.0, 56.3, 46.8,
2,3,5,6,7,8-hexahydro-1H-5,8-epiminoimidazo[1,2-a]aze- 42.7, 32.2 (2C), 21.5, 19.0. HRMS (EI): m/z [M+] calcd for
pine (2f): Orange solid; 86 mg, 43%; m.p. 128 °C–130 °C; C16H20N4O2: 300.1586; found: 300.0629.
1H NMR (400 MHz, DMSO-d6): δ 7.02 (d, J = 7.6 Hz,
11-(2,5-Dimethylphenyl)-10-nitro-1,2,3,4,6,7,8,9-
1H), 6.73 (d, J = 7.6 Hz, 1H), 6.66 (s, 1H), 5.12 (d, J = 5.2 octahydro-6,9-epiminopyrimido[1,2-a]azepine (4b): Light
Hz, 1H), 4.91 (d, J = 5.2 Hz, 1H), 4.45 (t, J = 5.6 Hz, 1H), yellow solid; 99 mg, 40%; m.p. 212 °C–213 °C; 1H NMR
4.34 (t, 1H), 3.75–3.38 (m, 5H), 3.32–3.16 (m, 1H), 2.23 (s, (400 MHz, CDCl3): δ 10.94 (s, 1H), 7.03 (d, J = 7.4 Hz,
3H), 2.20 (m, 1H), 2.18 (s, 3H), 2.13 (td, J = 11.0, 5.6 Hz, 1H), 6.78 (d, J = 6.8 Hz, 1H), 6.56 (s, 1H), 5.28 (s, 1H),
1H), 2.07–1.95 (m, 1H), 1.94–1.81 (m, 1H), 1.65–1.43 (m, 4.72 (s, 1H), 3.48–3.26 (m, 4H), 2.35 (s, 3H), 2.27 (s, 3H),
4H). 13C NMR (100 MHz, DMSO-d6): δ 155.3, 142.7, 2.14 (dd, J = 19.2, 10.8 Hz, 2H), 2.02 (dd, J = 26.8, 6.0
Hz, 4H). 13C NMR (100 MHz, CDCl3): δ 151.8, 142.4,
136.2, 131.7, 127.1, 123.9, 120.2, 109.5, 57.6, 44.0, 38.0,
1
135.2, 131.3, 126.4, 123.1, 120.0, 108.1, 83.5 (d, JCF
=
=
161 Hz), 72.2, 58.3, 54.9, 49.6, 49.1, 46.6, 31.0 (d, 2JCF
34 Hz), 27.0 (d, 3JCF = 19 Hz), 23.2 (d, 4JCF = 4 Hz), 20.9, 32.9, 30.9, 21.5, 20.0, 18.9. HRMS (EI) m/z [M+] calcd for
18.6. 19F NMR (376 MHz, DMSO-d6): δ −218.61 (s). C17H22N4O2: 314.1743; found: 314.1739.
HRMS (EI): m/z [M+] calcd for C20H27N4O2F: 374.2118;
10-(2,5-Dimethylphenyl)-9-nitro-2,3,5,6,7,8-
found: 374.2116.
hexahydro-5,8-epiminothiazolo[3,2-a]azepine (4c): Light
1-[(6-Chloropyridin-3-yl)methyl]-11-(2, 5- yellow solid; 81 mg, 39%; m.p. 205 °C–206 °C; 1H NMR
dimethylphenyl)-10-nitro-1,2,3,4,6,7,8,9-octahydro-6,9- (400 MHz, DMSO-d6): δ 7.05 (d, J = 7.6 Hz, 1H), 6.76 (d,
epiminopyrimido[1,2-a]azepine (3a): Black oil; 130 mg, J = 7.6 Hz, 1H), 6.47 (s, 1H), 5.30 (d, J = 4.0 Hz, 1H),
37%; m.p. 133 °C–134 °C; 1H NMR (400 MHz, DMSO-d6): 5.01 (d, J = 5.6 Hz, 1H), 4.06–3.91 (m, 2H), 3.25 (ddd, J
δ 8.17 (d, J = 2.2 Hz, 1H), 7.46 (dd, J = 8.2, 2.4 Hz, 1H), = 11.3, 8.4, 5.8 Hz, 1H), 3.20–3.08 (m, 1H), 2.31 (ddd, J =
7.37 (d, J = 8.2 Hz, 1H), 7.08 (d, J = 7.6 Hz, 1H), 6.81 (d, 16.0, 10.6, 5.8 Hz, 1H), 2.25 (s, 3H), 2.24–2.20 (m, 2H),
J = 7.6 Hz, 1H), 6.76 (s, 1H), 5.11 (d, J = 5.8 Hz, 1H), 2.19 (s, 3H), 2.03–1.93 (m, 1H). 13C NMR (100 MHz,
4.89 (d, J = 2.8 Hz, 1H), 4.49 (d, J = 15.6 Hz, 1H), 4.31 DMSO-d6): δ 160.9, 142.4, 135.3, 131.5, 126.6, 123.5,
(d, J = 15.4 Hz, 1H), 3.56–3.44 (m, 1H), 3.15–3.06 (m, 119.6 (2C), 73.5, 56.1, 52.8, 32.9, 32.7, 27.6, 21.1, 18.7.
1H), 2.92–2.73 (m, 2H), 2.36–2.28 (m, 1H), 2.26 (s, 3H), HRMS (EI): m/z [M+] calcd for C16H20N3O2S: 317.1198;
2.15 (s, 3H), 2.10 (d, J = 7.6 Hz, 1H), 2.01 (dt, J = 14.0, found: 317.1196.
7.2 Hz, 2H), 1.82 (ddd, J = 14.8, 10.0, 5.6 Hz, 1H), 1.70–
11-(2,5-Dimethylphenyl)-10-nitro-3,4,6,7,8,9-
1.60 (m, 1H). 13C NMR (100 MHz, DMSO-d6): δ 154.6, hexahydro-2H-6,9-epimino[1,3]thiazino[3,2-a]azepine
149.5, 149.3, 142.6, 139.2, 135.5, 131.8, 131.6, 126.4, (4d): Light yellow solid; 55 mg, 44%; m.p. 192 °C–193 °C;
123.9, 123.3, 120.2, 108.1, 77.1, 59.8, 51.98, 46.1, 44.6, 1H NMR (400 MHz, CDCl3): δ 7.04 (d, J = 7.6 Hz, 1H),
31.3, 29.8, 21.3, 18.7, 7.1. HRMS (EI): m/z [M-HNO2]+ 6.79 (d, J = 7.6 Hz, 1H), 6.54 (s, 1H), 5.22 (d, J = 4.0 Hz,
calcd for C23H2535ClN4: 392.1768; found: 392.1766; calcd 1H), 4.72 (d, J = 4.0 Hz, 1H), 3.61–3.44 (m, 1H), 3.31 (dt,
for C23H2537ClN4: 394.1738; found: 394.1731.
J = 13.2, 6.6 Hz, 1H), 2.80 (dtd, J = 17.8, 12.6, 5.4 Hz,
N-[(6-Chloropyridin-3-yl)methyl]-8-(2, 5- 2H), 2.33 (dd, J = 14.4, 4.4 Hz, 2H), 2.29 (s, 3H), 2.25 (s,
dimethylphenyl)-2-methyl-4-nitro-2,8-diazabicyclo[3.2.1] 3H), 2.23–2.07 (m, 4H). 13C NMR (100 MHz, CDCl3): δ
oct-3-en-3-amine (3b): Brown solid; 93 mg, 40%; m.p. 133 157.4, 142.2, 136.3, 131.6, 127.3, 124.3, 121.6, 120.3,
°C–134 °C; 1H NMR (400 MHz, DMSO-d6): δ 10.90 (t, J 80.3, 58.7, 47.8, 33.4, 32.7, 26.7, 22.1, 21.5, 18.7. HRMS
= 5.8 Hz, 1H), 8.26 (d, J = 2.2 Hz, 1H), 7.57 (d, J = 8.2 (EI): m/z [M+] calcd for C17H21N3O2S: 331.1354; found:
Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 331.1351.

10
Journal of Chemical Research
1-[(6-Chloropyridin-3-yl)methyl]-10-(2,5- ORCID iD
dimethylphenyl)-2,3,5,6,7,8-hexahydro-1H-5,8-epi
minoimidazo[1,2-a]azepine-9-carbonitrile (5a): Brown
oil; 55 mg, 44%; m.p. 192 °C–193 °C; 1H NMR (400 MHz,
CDCl3): δ 8.22 (d, J = 2.0 Hz, 1H), 7.54 (dd, J = 8.2, 2.4
Hz, 1H), 7.20 (d, J = 8.2 Hz, 1H), 7.05 (d, J = 7.6 Hz, 1H),
6.91 (s, 1H), 6.81 (d, J = 7.6 Hz, 1H), 4.90 (d, J = 16.0 Hz,
1H), 4.79 (d, J = 4.4 Hz, 1H), 4.43 (d, J = 16.0 Hz, 1H),
4.14 (t, J = 5.2 Hz, 1H), 3.35–3.18 (m, 3H), 3.12–3.02 (m,
1H), 2.27 (s, 3H), 2.26 (s, 3H), 2.25–2.00 (m, 4H). 13C
NMR (100 MHz, CDCl3): δ 155.5, 151.1, 149.1, 143.5,
138.5, 135.9, 131.4, 130.9, 127.0, 124.6, 123.5, 123.0,
120.7, 71.6, 58.5, 52.5, 46.9 (2C), 44.6, 36.4, 32.3, 21.5,
18.9. HRMS (ESI): m/z [M + H]+ calcd for C23H2435ClN5:
406.1720; found: 406.1798; calcd for C23H2437ClN5:
408.1769; found: 408.1749.
Yuce Chen
https://orcid.org/0000-0003-3550-5220
Supplemental material
Supplemental material for this article is available online.
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1-[(6-Chloropyridin-3-yl)methyl]-10-(2,5-dimethyl
p h e n y l ) - 2 , 3 , 5 , 6 , 7 , 8 - h e x a h y d ro - 1 H - 5 , 8 - e p i
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1
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55 mg, 44%; m.p. 114 °C–116 °C; H NMR (400 MHz,
DMSO-d6): δ 8.25 (d, J = 2.3 Hz, 1H), 7.64 (dd, J = 8.2,
2.4 Hz, 1H), 7.33 (d, J = 8.2 Hz, 1H), 6.98 (d, J = 7.6 Hz,
1H), 6.76 (s, 1H), 6.69 (d, J = 7.2 Hz, 1H), 4.94 (d, J = 3.6
Hz, 1H), 4.70 (s, 2H), 4.62 (d, J = 4.8 Hz, 1H), 3.94 (q, J =
7.0 Hz, 2H), 3.39–3.34 (m, 1H), 3.32 (dd, J = 8.2, 3.8 Hz,
1H), 3.27 (dd, J = 6.2, 2.4 Hz, 1H), 3.13–3.02 (m, 1H), 2.22
(s, 3H), 2.16 (s, 3H), 2.10 (dd, J = 21.2, 8.8 Hz, 3H), 1.81
(dd, J = 12.8, 5.4 Hz, 1H), 1.08 (t, J = 7.0 Hz, 3H). 13C
NMR (100 MHz, DMSO-d6): δ 164.3, 157.6, 149.1, 148.8,
144.1, 139.0, 134.8, 133.5, 131.0, 126.0, 123.8, 122.2,
120.2, 77.8, 70.9, 57.2, 57.0, 50.4, 48.3, 44.7, 35.3, 32.1,
21.1, 18.9, 14.8. HRMS (ESI): m/z [M + H]+ calcd for
C25H3035ClN4O2: 453.2057; found: 453.2053; calcd for
C25H3037ClN4O2: 455.2028; found: 455.2033.
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Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with
respect to the research, authorship, and/or publication of this
article.
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The author(s) disclosed receipt of the following financial support
for the research, authorship, and/or publication of this article: This
work was financially supported by the National Natural Science
Foundation of China (21672061) and the work was also supported
by the Innovation Program of Shanghai Municipal Education
Commission (201701070002E00037) and the Fundamental
Research Funds for Central Universities. National Key Research
Program of China (2018YFD0200105, 2017YFD0200505).