Multistep Synthesis and Nematicidal Activity of 2-(8-azabicyclo[3.2.1]octan-3-yl)-3-imino-2,3-dihydro-1H-isoindol-1-One Derivatives

Article abstract of DOI:10.1007/s10593-021-02864-z

[Figure not available: see fulltext.] Novel 2-(8-azabicyclo[3.2.1]octan-3-yl)-3-imino-2,3-dihydro-1H-isoindol-1-ones derived from 5-HT3 receptor antagonists hexahydroazepinylbenzamides were designed and synthesized through isocyanide insertion reaction. All target compounds were evaluated against pinewood nematodes B. xylophilus and root-knot nematodes M. incognita. Good lethal rate (75%) for 3-(tert-butylimino)-5-chloro-2-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-2,3-dihydro-1H-isoindol-1-one and serious nervous curl effect against pinewood nematodes B. xylophilus for 3-(tert-butylimino)-2-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-2,3-dihydro-1H-isoindol-1-one were observed at 10 mg/l. The inhibition activities of 3-[(4-methoxyphenyl)imino]-2-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-2,3-dihydro-1H-isoindol-1-one against root-knot nematodes M. incognita were 84% at 160 mg/l and 60% at 20 mg/l for in vitro test and test tube test, respectively.

Full text of DOI:10.1007/s10593-021-02864-z

DOI 10.1007/s10593-021-02864-z
Chemistry of Heterocyclic Compounds 2021, 57(1), 31–39
Multistep synthesis and nematicidal activity
of 2-(8-azabicyclo[3.2.1]octan-3-yl)-3-imino-
2,3-dihydro-1H-isoindol-1-one derivatives
Jun Xu1, Tianjiao Yang1, Jiayi Wang1, Gonghua Song1*
1 School of Pharmacy, East China University of Science and Technology,
130 Meilong Road, Shanghai 200237, China; e-mail: ghsong@ecust.edu.cn
Published in Khimiya Geterotsiklicheskikh Soedinenii,
Submitted July 2, 2020
2021, 57(1), 31–39
Accepted after revision November 13, 2020
Novel 2-(8-azabicyclo[3.2.1]octan-3-yl)-3-imino-2,3-dihydro-1H-isoindol-1-ones derived from 5-HT3 receptor antagonists hexahydro-
azepinylbenzamides were designed and synthesized through isocyanide insertion reaction. All target compounds were evaluated against
pinewood nematodes B. xylophilus and root-knot nematodes M. incognita. Good lethal rate (75%) for 3-(tert-butylimino)-5-chloro-
2-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-2,3-dihydro-1H-isoindol-1-one and serious nervous curl effect against pinewood nematodes
B. xylophilus for 3-(tert-butylimino)-2-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-2,3-dihydro-1H-isoindol-1-one were observed at 10 mg/l. The
inhibition activities of 3-[(4-methoxyphenyl)imino]-2-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-2,3-dihydro-1H-isoindol-1-one against
root-knot nematodes M. incognita were 84% at 160 mg/l and 60% at 20 mg/l for in vitro test and test tube test, respectively.
Keywords: azabicyclo, iminoisoindoline, isocyanide insertion, nematicidal activity.
It has been reported that the annual crop loss caused by
plant-parasitic nematodes is approximately $125 billion
globally.1 Phytonematodes can also seriously endanger the
health of pinewood forest.2 While great success has been
achieved for synthetic nematicides in eliminating the
damage of nematodes, a large part of synthetic nematicides
such as halogenated hydrocarbons (methyl bromide),
carbamates (aldicarb), organophosphates (fenamiphos) are
restrictedly used or weeded out recently because of their
toxicity to environment or mammals.3 More recently,
biological source nematicides such as avermectins received
extensive attention. But they still suffer from some
shortages such as complex using method, soil adsorption,
and long effective time.4 Thus, the development of novel
environmentally friendly, efficient, and less toxic
nematicides has become one of the actual research topics in
pesticide discovery and has a huge market prospect.
Serotonin (5-hydroxytryptamine, 5-HT) is a significant
monoamine neurotransmitter which exists widely in both
vertebrates and invertebrates. It is widely distributed in
both central and peripheral nervous system of vertebrates,
and participate in various physiological activities like
intestinal movements, mood, appetite, and sleeping.5 It is
also found in the central nervous, digestive, and repro-
ductive systems of nematodes and influence various
biological behaviors like eating, movement, and repro-
duction.6
Because of the homology between the 5-HT receptors of
nonmammalian and mammals, some classical mammalian
5-HT receptor ligands show certain nematicidal activity. In
2003, Trowell and coworkers found that the selective
mammalian 5-HT3 receptor antagonist MDL 72222 could
bind to the 5-HT3Ce receptor in C. elegans and, in turn,
inhibit the pharyngeal pumping contraction and even kill
the nematode under a certain level of concentration.7
According to the pharmacophoric requirements for 5-HT3
receptor antagonists proposed by Hibert et al., the
pharmacophore consists of three components: an aromatic/
heteroaromatic ring, a carbonyl-containing linking moiety,
and a basic center in a specific spatial arrangement
(Scheme 1).8 Inspecting the structures of classical 5-HT3
receptor antagonists, tropane is often used as an effective
basic center. Besides, tropane exhibits a broad spectrum of
biological activities9 and has been proven to be an effective
functional group in some active nematicidal compounds.10
On the other hand, in 1998, substituted hexahydroazepinyl-
benzamides were reported with high affinity for 5-HT3
receptor.11 In 1991, Zabrowski et al. reported N-azabicyclo-
[3.3.0]octaneisoindolin-1-one derivatives to be mammalian
5-HT3 receptor antagonists and exhibited prokinetic
0009-3122/21/57(1)-0031©2021 Springer Science+Business Media, LLC
31

Chemistry of Heterocyclic Compounds 2021, 57(1), 31–39
nematicidal activity,14 and 3) the introduction of imine is
Scheme 1. Molecular design of the target compounds
aimed to improve the nematicidal activity in view of the
fact that imine is often used as an effective active fragment
in pesticides.15 A series of novel compounds combining
tropane, lactam, and imine moieties were thus synthesized
and screened against the root-knot nematodes M. incognita
and pinewood nematodes B. xylophilus.
An efficient Pd-catalyzed isocyanide insertion pathway was
adopted to synthesize the target compounds (Scheme 2).16
tert-Butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate
(1) was treated with NH2OH·HCl to afford tert-butyl
3-(hydroxyimino)-8-azabicyclo[3.2.1]octane-8-carboxylate
(2). tert-Butyl 3-amino-8-azabicyclo[3.2.1]octane-8-carb-
oxylate (3) was obtained via reduction of compound 2 by
Na and catalytic amount of Raney Ni. Furthermore,
amidation of compound 3 with substituted 2-bromobenzoyl
chlorides 4a–d afforded the respective substituted tert-butyl
3-[(2-bromobenzoyl)amino]-8-azabicyclo[3.2.1]octane-8-carb-
oxylates 5a–d. Boc removal with TFA (compounds 6a–d)
followed by substitution reaction with alkyl halides leads to
intermediate substituted N-(8-azabicyclo[3.2.1]octan-3-yl)-
2-bromobenzamides 7a–k. Finally, target compounds 9a–q
were obtained via isocyanide 8a–g insertion reaction from
compounds 7a–k and the respective isocyanides 8a–g in
the presence of Pd(OAc)2 as catalyst.
All target compounds were evaluated against the
pinewood nematodes B. xylophilus and the root-knot
nematodes M. incognita. In the in vitro test, 96-well plates
were used to investigate the contact toxicity of the
compounds against nematodes. Apart from the in vitro test,
the target compounds were also tested against the infection
of M. incognita in cucumber plants. In the root-knot
nematode test, the inhibitory effect of the nematode
infection of plant roots and the compound's phytotoxic
effects on plants could be observed by a test tube test.
Preliminary nematicidal activity of the target compounds
against B. xylophilus is shown in Table 1. Most compounds
activity.12 As a continuous effort of searching for novel
pesticides potentially targeted on the 5-HT receptors of
pests,13 herein, we propose a new structure based on our
previous works and literature reports based on the
following considerations: 1) tropane is employed according
to its excellent performance as a 5-HT3 receptor antagonist
pharmacophore and our previous works, 2) lactam is
introduced to increase the stability of target compounds,
since benzolactam derivatives were reported to have
Scheme 2
32

Chemistry of Heterocyclic Compounds 2021, 57(1), 31–39
Table 1. Nematicidal activity of target compounds 9a–q
against B. xylophilus in 72 h as fatality rate, %
Table 2. Nematicidal activity of target compounds 9a–q
against M. incognita in 72 h as fatality rate, %
Concentration
of compound, mg/l
Concentration
Test
Compound
R1
R2
R3
of compound, mg/l tube
test at
Compound R1
R2
R3
80
66
69
72
53
40
67
71
73
65
20
–
10
–
160 80
40
20 mg/l
H
H
Bn
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
Bn
9a
H
H
Bn
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
Bn
74
60
32
18
22
30
49
70
41
67
60
58
50
73
51
70
54
38
52
20
22
66
57
39
67
32
42
42
43
39
27
36
99
33
29
30
23
23
28
29
19
10
30
16
13
10
11
18
20
23
33
9a
4-MeС6H4CH2
–
–
9b
4-MeС6H4CH2
57
9b
H
4-F3CС6H4CH2
–
–
9c
H
4-F3CС6H4CH2
33
9c
H
3-ClС6H4CH2
–
–
9d
H
3-ClС6H4CH2
30
9d
H
4-ClС6H4CH2
10** <10**
48 51
–
–
9e
H
2-ClС6H4CH2
–
–
9f
H
4-ClС6H4CH2
45
9e
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
86** 82** 61** 60**
9g
H
2-ClС6H4CH2
40
9f
5-F
6-OMe
5-Cl
H
85** 73** 53
67 73
77** 76** 75
70
–
9h
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
28
9g
–
9i
5-F
6-OMe
5-Cl
H
<10
60
9h
75
–
9j
9i
82
73
74
55
–
–
–
–
9k
15
9j
H
Cy
–
9l
28
9k
H
n-Bu
i-Pr
51** 45**
48** 36**
–
9m
H
Cy
43
9l
H
–
9n
H
n-Bu
i-Pr
62
9m
H
Ph
69** 64** 38
38
–
9o
9p
H
4-MeOС6H4 36** 24**
–
H
35
9n
H
t-Bu 74** 54** 59
54
9q
H
Ph
32
9o
Fenamiphos*
Avermectin*
28
H
4-MeOС6H4 84
t-Bu 45
60
9p
9q
100
H
36
* Positive control experiments were performed with fenamiphos and
avermectin at 5 mg/l.
Avermectin*
100
** Nematodes showed neurogenic curvature at this concentration.
* Positive control experiments were performed with avermectin at 1 mg/l.
show certain nematicidal activity. Among these derivatives,
compounds 9g,h,k exhibited good nematicidal activities
with the fatality rate over 80% at 80 mg/l. Compounds
9a–d,i,j,l,m,o,q showed certain activities with the fatality
rate ranging from 51 to 77%. It is worth mentioning that
when an alkyl group was employed as R2 substituent, the
nematicidal activity of the compound could be improved
(compare compounds 9g,q with compounds 9a–f). In terms
of the R1 substituent, employment of a halogen atom
(compounds 9h,j) or electron-donating group (compound
9i) did not cause much influence on nematicidal activity.
Besides, the employ of large sterically demanding tert-butyl
group (compound 9g) or benzyl group (compound 9k) as
R3 could slightly increase the activity (compare with
compounds 9l–p).
Apart from the lethal activity, part of the target
compounds could cause nematodes to display neurogenic
curvature of varying degrees. For example, after contacting
with the solution of compound 9g (80 mg/l), almost all
nematodes curled up within 1 h. After 24 h, parts of
nematodes were dead and the remaining kept curved.
Based on this phenomenon, a further gradient experiment
was carried out to select compounds 9g,h,j,o,q which
exhibited both good nematicidal activity and visible curl
phenomenon. As the result in Table 1 indicates, com-
pounds 9h,j remained over 70% nematicidal activity even
at 10 mg/l. Meanwhile, obvious neurogenic curl phenomenon
was observed for nematodes treated with a solution of
compound 9g at a concentration level of 10 mg/l.
vitro test, some compounds exhibited moderate nematicidal
activities at a concentration of 160 mg/l. Among these
derivatives, compound 9p exhibited the highest nematicidal
activity of 84% fatality rate. Unfortunately, all the target
compounds exhibited poor nematicidal activities at the
concentration of 40 mg/l. In the test tube tests, compounds
9b,i,m,p showed moderate inhibition activities ranging
from 57 to 62%.
In conclusion, 17 novel 2-(8-azabicyclo[3.2.1]octan-
3-yl)-3-imino-2,3-dihydro-1H-isoindol-1-ones derived from
5-HT3 receptor antagonists hexahydroazepinylbenzamides
were synthesized. Part of the target compounds exhibited
certain lethal activities and curl effect against pinewood
nematodes B. xylophilus. Among them, 3-(tert-butylimino)-
5-fluoro-2-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-2,3-di-
hydro-1H-isoindol-1-one and 3-(tert-butylimino)-5-chloro-
2-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-2,3-dihydro-1H-
isoindol-1-one were highlighted due to their good
nematicidal activities (over 70% at 10 mg/l). 3-(tert-Butyl-
imino)-2-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-2,3-di-
hydro-1H-isoindol-1-one was also worth noting because of
its obvious neurogenic curl effect against pinewood
nematodes B. xylophilus at 10 mg/l.
The common inhibitory effects against root-knot
nematodes M. incognita were not as good as B. xylophilus.
3-[(4-Methoxyphenyl)imino]-2-(8-methyl-8-azabicyclo-
[3.2.1]octan-3-yl)-2,3-dihydro-1H-isoindol-1-one was high-
lighted because of its relatively higher activities both in the
in vitro test (84% at 160 mg/l) and in the test tube test
(60% at 20 mg/l). Further studies are still in progress and
will be reported in due course.
Preliminary nematicidal activity of the target com-
pounds against M. incognita is shown in Table 2. In the in
33

Chemistry of Heterocyclic Compounds 2021, 57(1), 31–39
Experimental
dropwise to a solution of compound 3 (2.26 g, 10 mmol)
and Et3N (3.03 g, 30 mmol) in CH2Cl2 (30 ml) at 0°C.
After the mixture was stirred at room temperature for 8 h, it
was washed with brine and extracted with CH2Cl2 (3×50 ml).
The combined organic layers were dried over Na2SO4,
filtered, and the solvent was evaporated under reduced
pressure. The solid residue was washed with solvent
mixture petroleum ether – CH2Cl2, 10:1 (2×100 ml). The
residue was filtered off to give the crude product as a white
solid which was purified by flash chromatography on silica
gel (eluent cyclohexane–EtOAc, 3:1).
1H and 13C NMR spectra were acquired on a Bruker
AM-400 spectrometer (400 and 101 MHz, respectively)
using CDCl3 as the solvent and TMS as internal standard.
High-resolution mass spectra were recorded on a Waters
GCT Premier mass spectrometer with electron impact ion
source or a Thermo Fisher Q Exactive Plus instrument
using electrospray ionization source. Melting points were
determined on an EZ-Melt 120 automated melting point
apparatus and are uncorrected. Flash chromatography was
performed using Merck silica gel 60 (230–400 mesh).
tert-Butyl 3-[(2-bromobenzoyl)amino]-8-azabicyclo-
[3.2.1]octane-8-carboxylate (5a). Yield 2.86 g (75%),
tert-Butyl 3-(hydroxyimino)-8-azabicyclo[3.2.1]octane-
8-carboxylate (2). A 100-ml round-bottomed flask equipped
with a magnetic stirrer was charged with tert-butyl 3-oxo-
8-azabicyclo[3.2.1]octane-8-carboxylate (1) (2.25 g, 10 mmol),
HONH2·HCl (834 mg, 12 mmol), AcONa (984 mg, 12 mmol),
and EtOH (40 ml). After stirring at refluxing temperature
for 4 h, the reaction mixture was distilled to a solid residue
by using a rotary evaporator. The residue was extracted
with EtOAc (2×30 ml). The combined organic extracts
were dried over Na2SO4, filtered, and the solvent was
evaporated under reduced pressure. Yield 2.2 g (92%),
1
white solid, mp 213–215°C (cyclohexane–EtOAc). H NMR
spectrum, δ, ppm (J, Hz): 1.47 (9H, s, C(CH3)3); 1.56–1.61
(2H, m, CHCH2CH2CH); 1.80–1.85 (2H, m, CHCH2CH2CH);
2.00–2.07 (4H, m, CHCH2CHCH2CH); 4.28 (2H, br. s,
CHNCH); 4.51–4.61 (1H, m, CHNH); 5.73 (1H, d, J = 8.0,
NH); 7.24–7.28 (1H, m, H-5 Ph); 7.33–7.37 (1H, m, H-4 Ph);
7.49 (1H, dd, J = 7.6, J = 1.4, H-3 Ph); 7.57 (1H, d, J = 8.0,
H-6 Ph). 13C NMR spectrum, δ, ppm: 28.0; 28.5; 37.6;
42.1; 53.0; 79.4; 119.2; 127.6; 129.4; 131.2; 133.3; 137.9;
153.2; 166.9. Found, m/z: 409.1104 [M+H]+. C19H2679BrN2O3.
Calculated, m/z: 409.1121. Found, m/z: 411.1081 [M+H]+.
C19H2681BrN2O3. Calculated, m/z: 411.1101.
1
white solid, mp 113–115°C (cyclohexane–EtOAc). H NMR
spectrum, δ, ppm: 1.48 (9H, s, C(CH3)3); 1.54–1.69 (2H,
m, CHCH2CH2CH); 1.93–2.03 (2H, m, CHCH2CH2CH); 2.16
–2.27 (2H, m, CHCH2CCH2CH); 2.52–2.61 (1H, m,
CHCH2CCH2CH); 3.11–3.15 (1H, m, CHCH2CCH2CH); 4.32–
4.38 (2H, m, CHNCH). 13C NMR spectrum, δ, ppm: 27.6;
28.5; 29.2; 31.6; 37.7; 52.5; 53.2; 79.9; 153.4; 155.6. Found, m/z:
241.1536 [M+H]+. C12H21N2O3. Calculated, m/z: 241.1547.
tert-Butyl 3-amino-8-azabicyclo[3.2.1]octane-8-carb-
oxylate (3). A 100-ml three-necked round-bottomed flask
was equipped with a magnetic stirrer and a condenser pipe
sealed with an empty balloon. Metallic Na (2.30 g, 100 mmol)
was added to a mixture of compound 2 (2.41 g, 10 mmol)
and Raney Ni (30 mg, 0.5 mmol) in PrOH (30 ml) over 10 min
under reflux. The mixture was then maintained refluxing
for 1 h. After cooling down to room temperature, H2O
(20 ml) was added and the solvent was evaporated using a
rotary evaporator. The residue was extracted with CH2Cl2
(3×50 ml). The resulting organic phase was concentrated
and purified by flash chromatography on silica gel (CH2Cl2–
MeOH, 20:1). Yield 1.56 g (69%), white solid, mp 97–99°C
tert-Butyl 3-[(2-bromo-4-chlorobenzoyl)amino]-8-aza-
bicyclo[3.2.1]octane-8-carboxylate (5b). Yield 3.37 g (76%),
white solid, mp 196–198°C (cyclohexane–EtOAc).
1H NMR spectrum, δ, ppm (J, Hz): 1.46 (9H, s, C(CH3)3);
1.55–1.61 (2H, m, CHCH2CH2CH); 1.79–1.84 (2H, m,
CHCH2CH2CH); 2.00–2.05 (4H, m, CHCH2CHCH2CH);
4.27 (2H, br. s, CHNCH); 4.48–4.59 (1H, m, CHNH); 5.78
(1H, d, J = 8.2, NH); 7.33 (1H, dd, J = 8.2, J = 1.9, H-5 Ph);
7.44 (1H, d, J = 8.3, H-6 Ph); 7.59 (1H, d, J = 1.9, H-3 Ph).
13C NMR spectrum, δ, ppm: 28.0; 28.5; 37.5; 42.2; 53.0;
79.5; 119.8; 127.9; 130.4; 132.9; 136.2; 136.5; 153.2;
166.0. Found, m/z: 443.0727 [M+H]+. C19H2579Br35ClN2O3.
Calculated, m/z: 443.0732. Found, m/z: 445.0704 [M+H]+.
C19H2581Br35ClN2O3. Calculated, m/z: 445.0711.
tert-Butyl 3-[(2-bromo-4-fluorobenzoyl)amino]-8-aza-
bicyclo[3.2.1]octane-8-carboxylate (5c). Yield 2.89 g (68%),
1
white solid, mp 199–201°C (cyclohexane–EtOAc). H NMR
spectrum, δ, ppm (J, Hz): 1.46 (9H, s, C(CH3)3); 1.58–1.62
(2H, m, CHCH2CH2CH); 1.79–1.85 (2H, m, CHCH2CH2CH);
2.00–2.02 (4H, m, CHCH2CHCH2CH); 4.27 (2H, br. s,
CHNCH); 4.48–4.59 (1H, m, CHNH); 5.85 (1H, d, J = 8.2,
NH); 7.06 (1H, td, J = 8.3, J = 2.5, H-5 Ph); 7.31 (1H, dd,
J = 8.2, J = 2.4, H-6 Ph); 7.50 (1H, dd, J = 8.6, J = 5.9, H-3 Ph).
13C NMR spectrum, δ, ppm (J, Hz): 28.0; 28.5; 37.6; 42.2;
52.9; 79.5; 114.9 (d, 2JCF = 21.3, C-5 Ph); 119.9 (d, 3JCF = 9.7,
1
(cyclohexane–EtOAc). H NMR spectrum, δ, ppm: 1.42–
1.46 (11H, m, C(CH3)3, CHCH2CH2CH); 1.61 (2H, br. s,
CHCH2CH2CH); 1.95–1.96 (2H, m, CHCH2CHCH2CH);
2.09–2.17 (4H, m, CHCH2CHCH2CH, NH2); 3.31–3.33
(1H, m, CHNH2); 4.12–4.21 (2H, m, CHNCH). 13C NMR
spectrum, δ, ppm: 28.3; 28.5; 28.9; 37.5; 38.1; 43.5; 52.2;
53.0; 79.0; 153.4. Found, m/z: 227.1745 [M+H]+. C12H23N2O2.
Calculated, m/z: 227.1754.
Synthesis of tert-butyl 3-[(2-bromobenzoyl)amino]-
8-azabicyclo[3.2.1]octane-8-carboxylates 5a–d (General
method). Substituted 2-bromobenzoic acid (10 mmol) was
added to SOCl2 (15 ml). The mixture was stirred at reflux
for 4 h. After cooling down to room temperature, the
solvent was evaporated using a rotary evaporator. 2-Bromo-
benzoyl chloride 4a–d was obtained as colorless oily residue.
Solution of compound 4a–d in CH2Cl2 (10 ml) was added
2
3
C-2 Ph); 120.6 (d, JCF = 24.7, C-3 Ph); 131.1 (d, JCF = 8.9,
1
C-6 Ph); 134.1; 153.2; 162.8 (d, JCF = 254.5, C-4 Ph);
166.0. Found, m/z: 427.1023 [M+H]+. C19H2579BrFN2O3.
Calculated, m/z: 427.1027. Found, m/z: 429.1002 [M+H]+.
C19H2581BrFN2O3. Calculated, m/z: 429.1007.
tert-Butyl 3-[(2-bromo-5-methoxybenzoyl)amino]-8-aza-
bicyclo[3.2.1]octane-8-carboxylate (5d). Yield 3.15 g
(72%), white solid, mp 172–174°C (cyclohexane–EtOAc).
1H NMR spectrum, δ, ppm (J, Hz): 1.48 (9H, s, C(CH3)3);
1.79–1.83 (2H, m, CHCH2CH2CH); 1.89–1.91 (2H, m,
34

Chemistry of Heterocyclic Compounds 2021, 57(1), 31–39
CHCH2CH2CH); 2.07–2.09 (2H, m, CHCH2CHCH2CH);
413.1223. Found, m/z: 415.1183 [M+H]+. C22H2681BrN2O.
2.29–2.32 (2H, m, CHCH2CHCH2CH); 3.82 (3H, s,
OCH3); 4.26 (2H, br. s, CHNCH); 4.38–4.40 (1H, m,
CHNH); 6.57 (1H, d, J = 6.8, NH); 6.85 (1H, dd, J = 8.8,
J = 2.4, H-4 Ph); 7.15–7.16 (1H, m, H-3 Ph); 7.45 (1H, d,
J = 8.9, H-6 Ph). 13C NMR spectrum, δ, ppm: 27.9; 28.5;
35.3; 42.7; 52.5; 55.7; 79.5; 109.2; 115.1; 118.1; 134.3;
138.0; 153.3; 159.1; 166.3. Found, m/z: 439.1223 [M+H]+.
C20H2879BrN2O4. Calculated, m/z: 439.1227. Found, m/z:
441.1201 [M+H]+. C20H2881BrN2O4. Calculated, m/z: 441.1206.
Synthesis of N-(8-azabicyclo[3.2.1]octan-3-yl)-2-bromo-
benzamides 6a–d (General method). Compound 5a–d
(10 mmol) was dissolved in CH2Cl2 (30 ml), and TFA
(5.07 g, 50 mmol) was added. The mixture was stirred
overnight at room temperature. The solvent and excess
TFA were distilled off using a rotary evaporator. The
residue was dissolved in CH2Cl2 (20 ml) and washed with
brine (3× 0 ml). The organic phase was dried over anhydrous
MgSO4 and concentrated to afford crude product which
was used directly without further purification.
Synthesis of substituted N-(8-azabicyclo[3.2.1]octan-
3-yl)-2-bromobenzamides 7a–k (General method). Com-
pound 6a–d (2.0 mmol), K2CO3 (331 mg, 2.4 mmol), and
alkyl halide (2.4 mmol) were added to EtOH (30 ml). The
mixture was stirred under reflux for 12 h, and the solvent
was distilled using a rotary evaporator. The residue was
extracted with CH2Cl2 (3×20 ml). The resulting organic
phase was concentrated and purified by flash chromato-
graphy on silica gel (CH2Cl2–MeOH, 20:1).
Calculated, m/z: 415.1203.
2-Bromo-N-(8-{[4-(trifluoromethyl)phenyl]methyl}-
8-azabicyclo[3.2.1]octan-3-yl)benzamide (7c). Yield 494 mg
(53%), white solid, mp 140–141°C (cyclohexane–EtOAc).
1H NMR spectrum, δ, ppm (J, Hz): 1.64–1.72 (2H, m,
CHCH2CH2CH); 1.82–1.84 (2H, m, CHCH2CH2CH); 1.96–
2.01 (2H, m, CHCH2CHCH2CH); 2.07–2.10 (2H, m,
CHCH2CHCH2CH); 3.26 (2H, br. s, CHNCH); 3.62 (2H, s,
NCH2Ph); 4.33–4.44 (1H, m, CHNH); 5.77 (1H, d, J = 7.0,
NH); 7.24–7.28 (1H, m, CF3Ph); 7.33–7.37 (1H, m,
CF3Ph); 7.47–7.53 (3H, m, CF3Ph, COPh); 7.57–7.58 (3H,
m, COPh). 13C NMR spectrum, δ, ppm (J, Hz): 26.5; 38.3;
42.3; 56.0; 59.0; 119.2; 124.3 (q, 1JCF = 272.9, CF3); 125.1
3
(q, JCF = 3.8, C-3,5 CH2Ph); 127.5; 128.6; 129.1 (q,
2JCF = 32.3, C-4 Ph); 129.4; 131.1; 133.3; 138.0; 166.9.
Found, m/z: 467.0938 [M+H]+. C22H2379BrF3N2O. Calcu-
lated, m/z: 467.0940. Found, m/z: 469.0916 [M+H]+.
C22H2381BrF3N2O. Calculated, m/z: 469.0920.
2-Bromo-N-{8-[(3-chlorophenyl)methyl]-8-azabicyclo-
[3.2.1]octan-3-yl}benzamide (7d). Yield 689 mg (80%),
white solid, mp 145–147°C (cyclohexane–EtOAc). H NMR
1
spectrum, δ, ppm (J, Hz): 1.68–1.78 (4H, m,
CHCH2CH2CH); 1.89–1.94 (2H, m, CHCH2CHCH2CH);
2.01–2.03 (2H, m, CHCH2CHCH2CH); 3.23 (2H, br. s,
CHNCH); 3.51 (2H, s, NCH2Ph); 4.27–4.38 (1H, m,
CHNH); 5.79 (1H, d, J = 7.6, NH); 7.16–7.20 (3H, m,
CH2Ph); 7.24–7.29 (2H, m, CH2Ph, COPh); 7.36 (1H, br. s,
COPh); 7.40 (1H, dd, J = 7.6, J = 1.7, H-3 COPh); 7.49
(1H, dd, J = 8.0, J = 0.7, H-6 COPh). 13C NMR spectrum,
δ, ppm: 26.5; 38.3; 42.3; 55.9; 59.0; 119.2; 126.6; 127.0;
127.5; 128.5; 129.4; 129.5; 131.1; 133.3; 134.2; 138.0; 142.2;
166.9. Found, m/z: 433.0658 [M+H]+. C21H2379Br35ClN2O.
Calculated, m/z: 433.0677. Found, m/z: 435.0633 [M+H]+.
C21H2381Br35ClN2O. Calculated, m/z: 435.0656.
N-(8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl)-2-bromobenz-
amide (7a). Yield 517 mg (65%), white solid, mp 144–
1
146°C (cyclohexane–EtOAc). H NMR spectrum, δ, ppm
(J, Hz): 1.67–1.73 (2H, m, CHCH2CH2CH); 1.78–1.83 (2H, m,
CHCH2CH2CH); 1.94–1.97 (2H, m, CHCH2CHCH2CH);
2.08–2.11 (2H, m, CHCH2CHCH2CH); 3.29 (2H, br. s,
CHNCH); 3.58 (2H, s, NCH2Ph); 4.33–4.44 (1H, m,
CHNH); 5.79 (1H, d, J = 8.0, NH); 7.25–7.27 (2H, m,
CH2Ph); 7.30–7.36 (3H, m, CH2Ph); 7.38–7.40 (2H, m,
H-3,4 COPh); 7.48 (1H, dd, J = 7.6, J = 1.7, H-3 COPh);
7.56 (1H, dd, J = 8.0, J = 1.0, H-6 COPh). 13C NMR
spectrum, δ, ppm: 26.4; 38.2; 42.3; 56.3; 58.9; 119.2;
127.0; 127.5; 128.3; 128.7; 129.5; 131.1; 133.3; 138.1;
139.5; 166.9. Found, m/z: 399.1048 [M+H]+. C21H2479BrN2O.
Calculated, m/z: 399.1067. Found, m/z: 401.1026 [M+H]+.
C21H2481BrN2O. Calculated, m/z: 401.1046.
2-Bromo-N-{8-[(4-chlorophenyl)methyl]-8-azabicyclo-
[3.2.1]octan-3-yl}benzamide (7e). Yield 536 mg (62%),
white solid, mp 153–155°C (cyclohexane–EtOAc). H NMR
1
spectrum, δ, ppm (J, Hz): 1.83–1.93 (6H, m, CHCH2CH2CH,
CHCH2CHCH2CH); 2.05–2.07 (2H, m, CHCH2CHCH2CH);
3.23 (2H, br. s, CHNCH); 3.59 (2H, s, NCH2Ph); 4.30–4.41
(1H, m, CHNH); 5.88 (1H, d, J = 6.1, NH); 7.17–7.21 (1H,
m, CH2Ph); 7.24–7.29 (3H, m, CH2Ph); 7.36–7.41 (3H, m,
COPh); 7.50 (1H, dd, J = 7.9, J = 0.7, H-6 COPh). 13C NMR
spectrum, δ, ppm: 26.4; 38.3; 42.3; 55.7; 58.9; 119.2; 127.6;
128.4; 129.5; 129.8; 131.1; 132.5; 133.3; 138.0; 138.4;
166.9. Found, m/z: 433.0661 [M+H]+. C21H2379Br35ClN2O.
Calculated, m/z: 433.0677. Found, m/z: 435.0637 [M+H]+.
C21H2381Br35ClN2O. Calculated, m/z: 435.0656.
2-Bromo-N-{8-[(4-methylphenyl)methyl]-8-azabicyclo-
[3.2.1]octan-3-yl}benzamide (7b). Yield 593 mg (72%),
1
white solid, mp 156–158°C (cyclohexane–EtOAc). H NMR
spectrum, δ, ppm (J, Hz): 1.65–1.71 (2H, m, CHCH2CH2CH);
1.77–1.82 (2H, m, CHCH2CH2CH); 1.93–1.98 (2H, m,
CHCH2CHCH2CH); 2.07–2.10 (2H, m, CHCH2CHCH2CH);
2.34 (3H, s, PhCH3); 3.28 (2H, br. s, CHNCH); 3.53 (2H, s,
NCH2Ph); 4.32–4.43 (1H, m, CHNH); 5.75 (1H, d, J = 7.8,
NH); 7.12–7.14 (2H, m, CH2Ph); 7.25–7.28 (3H, m,
CH2Ph, COPh); 7.34 (1H, td, J = 7.5, J = 1.0, COPh); 7.49
(1H, dd, J = 7.6, J = 1.7, H-3 COPh); 7.57 (1H, dd, J = 8.0,
J = 0.8, H-6 COPh). 13C NMR spectrum, δ, ppm: 21.1;
26.4; 38.3; 42.4; 56.0; 58.7; 119.2; 127.5; 128.6; 128.9;
131.1; 133.3; 136.4; 136.7; 138.1; 166.9. Found, m/z:
413.1205 [M+H]+. C22H2679BrN2O. Calculated, m/z:
2-Bromo-N-{8-[(2-chlorophenyl)methyl]-8-azabicyclo-
[3.2.1]octan-3-yl}benzamide (7f). Yield 657 mg (76%),
white solid, mp 161–162°C (cyclohexane–EtOAc). H NMR
1
spectrum, δ, ppm (J, Hz): 1.67–1.72 (2H, m, CHCH2CH2CH);
1.80–1.85 (2H, m, CHCH2CH2CH); 1.97–2.02 (2H, m,
CHCH2CHCH2CH); 2.11–2.14 (2H, m, CHCH2CHCH2CH);
3.29 (2H, br. s, CHNCH); 3.65 (2H, s, NCH2Ph); 4.31–4.45
(1H, m, CHNH); 5.76 (1H, d, J = 7.9, NH); 7.15–7.19 (1H,
m, CH2Ph); 7.24–7.28 (2H, m, CH2Ph,); 7.32–7.36 (2H, m,
COPh); 7.49 (1H, dd, J = 7.6, J = 1.7, H-3 CH2Ph); 7.57
(1H, dd, J = 8.0, J = 0.9, H-3 COPh); 7.65 (1H, d, J = 7.4,
35

Chemistry of Heterocyclic Compounds 2021, 57(1), 31–39
H-6 COPh). 13C NMR spectrum, δ, ppm: 26.7; 38.4; 42.3;
J = 8.3, H-6 Ph); 7.58 (1H, d, J = 2.0, H-3 Ph). 13C NMR
spectrum, δ, ppm: 25.9; 37.8; 40.0; 41.7; 61.1; 119.8;
127.9; 130.5; 132.9; 136.2; 136.4; 166.0. Found, m/z: 357.0356
[M+H]+. C15H1979Br35ClN2O. Calculated, m/z: 357.0364.
Found, m/z: 359.0343 [M+H]+. C15H1981Br35ClN2O. Calcu-
lated, m/z: 359.0343.
53.3; 59.5; 119.2; 126.7; 127.6; 127.8; 129.2; 129.5; 129.9;
131.1; 133.3; 133.7; 137.6; 138.1; 166.9. Found, m/z:
433.0659 [M+H]+. C21H2379Br35ClN2O. Calculated, m/z:
433.0677. Found, m/z: 435.0635 [M+H]+. C21H2381Br35ClN2O.
Calculated, m/z: 435.0656.
2-Bromo-N-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-
benzamide (7g). Yield 380 mg (59%), white solid, mp 160–
162°C (cyclohexane–EtOAc). H NMR spectrum, δ, ppm
2-Bromo-N-(8-ethyl-8-azabicyclo[3.2.1]octan-3-yl)benz-
amide (7k). Yield 477 mg (71%), white solid, mp 134–
136°C (cyclohexane–EtOAc). H NMR spectrum, δ, ppm
1
1
(J, Hz): 1.66–1.72 (2H, m, CHCH2CH2CH); 1.75–1.80 (2H, m,
CHCH2CH2CH); 1.97–2.01 (2H, m, CHCH2CHCH2CH);
2.07–2.10 (2H, m, CHCH2CHCH2CH); 2.32 (3H, s,
NCH3); 3.24 (2H, br. s, CHNCH); 4.29–4.40 (1H, m,
CHNH); 5.77 (1H, d, J = 6.5, NH); 7.23–7.27 (1H, m, H-5 Ph);
7.32–7.36 (1H, t, J = 7.5, H-4 Ph); 7.50 (1H, dd, J = 7.6,
J = 1.4, H-3 Ph); 7.56 (1H, d, J = 8.0, H-6 Ph). 13C NMR
spectrum, δ, ppm: 25.9; 37.6; 39.8; 41.5; 61.1; 119.2;
127.5; 129.4; 131.1; 133.3; 137.9; 167.0. Found, m/z:
323.0746 [M+H]+. C15H2079BrN2O. Calculated, m/z:
323.0754. Found, m/z: 325.0725 [M+H]+. C15H2081BrN2O.
Calculated, m/z: 325.0733.
(J, Hz): 1.12 (3H, t, J = 7.1, CH2CH3); 1.67–1.79 (4H, m,
CHCH2CH2CH); 1.97–2.00 (4H, m, CHCH2CHCH2CH);
2.47 (2H, q, J = 7.1, CH2CH3); 3.38 (2H, br. s, CHNCH);
4.33–4.44 (1H, m, CHNH); 5.78 (1H, d, J = 6.8, NH); 7.24–
7.26 (1H, m, H-5 Ph); 7.34 (1H, t, J = 7.4, H-4 Ph); 7.49
(1H, dd, J = 7.5, J = 1.1, H-3 Ph); 7.56 (1H, d, J = 7.9, H-6
Ph). 13C NMR spectrum, δ, ppm: 13.6; 26.3; 37.5; 42.2;
45.4; 58.4; 119.2; 127.5; 129.5; 131.1; 133.3; 137.9; 166.9.
Found, m/z: 337.0900 [M+H]+. C16H2279BrN2O. Calculated, m/z:
337.0910. Found, m/z: 339.0880 [M+H]+. C16H2281BrN2O.
Calculated, m/z: 339.0890.
Synthesis of 2-(8-azabicyclo[3.2.1]octan-3-yl)-3-imino-
2,3-dihydro-1H-isoindol-1-ones 9a–q (General method).
Compound 7a–k (1 mmol), Pd(OAc)2 (11.2mg, 0.05 mmol),
Xantphos (29.0 mg, 0.05 mmol), Cs2CO3 (489 mg, 1.5 mmol),
isocyanide 8a–g (1.5 mmol), and MeCN (2 ml) were added
to an oven-dried 10-ml screw cap vial equipped with a stir
bar. The mixture was stirred under N2 atmosphere at 110°C
for 8 h. The resulting reaction mixture was cooled to
ambient temperature, diluted with EtOAc (5 ml), and passed
through a small bed of Celite. The filtrate was extracted
with EtOAc (3×10 ml), and the combined organic layers
were dried over Na2SO4, filtered, and concentrated under
vacuum to provide crude imine which was further purified
by flash chromatography on silica gel (cyclohexane–
EtOAc, 3:1).
2-(8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl)-3-(tert-butyl-
imino)-2,3-dihydro-1H-isoindol-1-one (9a). Yield 268 mg
(67%), white solid, mp 127–130°C (cyclohexane–EtOAc).
1H NMR spectrum, δ, ppm (J, Hz): 1.30–1.34 (2H, m,
CHCH2CH2CH); 1.58 (9H, s, C(CH3)3); 1.72–1.78 (2H, m,
CHCH2CH2CH); 2.04–2.08 (2H, m, CHCH2CHCH2CH);
2.82–2.85 (2H, m, CHCH2CHCH2CH); 3.32 (2H, br. s,
CHNCH); 3.95 (2H, s, NCH2Ph); 4.89 (1H, tt, J = 12.2,
J = 6.0, CONCH); 7.23 (1H, t, J = 7.3, H-4 Ph); 7.32 (2H,
t, J = 7.4, H-3,5 Ph); 7.50 (2H, d, J = 7.3, H-2,6 Ph); 7.56–
7.64 (2H, m, H-5,6 isoindoline); 7.87 (1H, d, J = 6.8, H-4
isoindoline); 7.98 (1H, d, J = 7.2, H-7 isoindoline).
13C NMR spectrum, δ, ppm: 27.5; 30.2; 30.9; 42.6; 53.2;
53.8; 57.7; 123.0; 126.6; 127.1; 128.2; 128.6; 128.7; 130.9;
131.7; 134.4; 146.1; 167.5. Found, m/z: 401.2464 [M]+.
C26H31N3O. Calculated, m/z: 401.2462.
2-Bromo-4-fluoro-N-(8-methyl-8-azabicyclo[3.2.1]octan-
3-yl)benzamide (7h). Yield 374 mg (55%), white solid,
1
mp 163–165°C (cyclohexane–EtOAc). H NMR spectrum,
δ, ppm (J, Hz): 1.92–1.98 (2H, m, CHCH2CH2CH); 2.01–
2.07 (2H, m, CHCH2CH2CH); 2.09–2.20 (4H, m,
CHCH2CHCH2CH); 2.49 (3H, s, NCH3); 3.48 (2H, br. s,
CHNCH); 4.35–4.48 (1H, m, CHNH); 6.28 (1H, d, J = 6.5,
NH); 7.06 (1H, td, J = 8.3, J = 2.5, H-5 Ph); 7.32 (1H, dd,
J = 8.2, J = 2.4, H-6 Ph); 7.50 (1H, dd, J = 8.6, J = 5.9,
H-3 Ph). 13C NMR spectrum, δ, ppm (J, Hz): 25.4; 36.5;
2
39.4; 40.6; 62.1; 114.8 (d, JCF = 21.3, C-5 Ph); 120.0 (d,
2
3JCF = 9.7, C-2 Ph); 120.6 (d, JCF = 24.6, C-3 Ph); 130.9
(d, 3JCF = 8.9, C-6 Ph); 133.9 (d, 4JCF = 3.6, C-1 Ph); 162.8
1
(d, JCF = 254.3, C-4 Ph); 166.4. Found, m/z: 341.0657
[M+H]+. C15H1979BrFN2O. Calculated, m/z: 341.0659.
Found, m/z: 343.0635 [M+H]+. C15H1981BrFN2O. Calcu-
lated, m/z: 343.0639.
2-Bromo-5-methoxy-N-(8-methyl-8-azabicyclo[3.2.1]-
octan-3-yl)benzamide (7i). Yield 436 mg (62%), white solid,
1
mp 136–139°C (cyclohexane–EtOAc). H NMR spectrum,
δ, ppm (J, Hz): 1.74–1.82 (4H, m, CHCH2CH2CH); 1.96–
2.00 (2H, m, CHCH2CHCH2CH); 2.07–2.10 (2H, m,
CHCH2CHCH2CH); 2.33 (3H, s, NCH3); 3.27 (2H, br. s,
CHNCH); 3.78 (3H, s, OCH3); 4.28–4.39 (1H, m, CHNH);
5.96 (1H, d, J = 8.1, NH); 6.79 (1H, dd, J = 8.8, J = 3.1,
H-4 Ph); 7.03 (1H, d, J = 3.1, H-6 Ph); 7.41 (1H, d, J = 8.8,
H-3 Ph). 13C NMR spectrum, δ, ppm: 26.0; 37.9; 40.0;
41.8; 55.6; 61.0; 109.3; 114.7; 117.7; 134.1; 138.4; 158.9;
166.6. Found, m/z: 353.0850 [M+H]+. C16H2279BrN2O2.
Calculated, m/z: 353.0859. Found, m/z: 355.0829 [M+H]+.
C16H2281BrN2O2. Calculated, m/z: 355.0839.
3-(tert-Butylimino)-2-{8-[(4-methylphenyl)methyl]-
8-azabicyclo[3.2.1]octan-3-yl}-2,3-dihydro-1H-isoindol-
1-one (9b). Yield 299 mg (72%), white solid, mp 179–182°C
2-Bromo-4-chloro-N-(8-methyl-8-azabicyclo[3.2.1]octan-
3-yl)benzamide (7j). Yield 434 mg (61%), white solid,
1
1
mp 167–168°C (cyclohexane–EtOAc). H NMR spectrum,
(cyclohexane–EtOAc). H NMR spectrum, δ, ppm (J, Hz):
δ, ppm (J, Hz): 1.69–1.81 (4H, m, CHCH2CH2CH); 1.95–
2.01 (2H, m, CHCH2CHCH2CH); 2.08–2.11 (2H, m,
CHCH2CHCH2CH); 2.33 (3H, s, NCH3); 3.26 (2H, br. s,
CHNCH); 4.28–4.38 (1H, m, CHNH); 5.87 (1H, d, J = 7.6,
NH); 6.33 (1H, dd, J = 8.3, J = 2.0, H-5 Ph); 7.45 (1H, d,
1.29–1.34 (2H, m, CHCH2CH2CH); 1.57 (9H, s, C(CH3)3);
1.73–1.78 (2H, m, CHCH2CH2CH); 2.08–2.18 (2H, m,
CHCH2CHCH2CH); 2.34 (3H, s, PhCH3); 2.83–2.89 (2H,
m, CHCH2CHCH2CH); 3.39 (2H, br. s, CHNCH); 4.02
(2H, s, NCH2Ph); 4.91 (1H, tt, J = 12.1, J = 5.9, CONCH);
36

Chemistry of Heterocyclic Compounds 2021, 57(1), 31–39
1
7.15 (2H, d, J = 7.7, H-3,5 Ph); 7.44 (2H, d, J = 7.4, H-2,6 Ph);
7.57–7.65 (2H, m, H-5,6 isoindoline); 7.88 (1H, d, J = 6.9,
H-4 isoindoline); 7.99 (1H, d, J = 7.6, H-7 isoindoline).
13C NMR spectrum, δ, ppm: 21.2; 27.1; 27.4; 30.5; 37.7;
49.9; 55.2; 58.5; 122.7; 123.0; 128.7; 129.0; 131.9; 132.0;
132.9; 134.8; 136.4; 148.3; 152.0. Found, m/z: 415.2630
[M]+. C27H33N3O. Calculated, m/z: 415.2618.
(cyclohexane–EtOAc). H NMR spectrum, δ, ppm (J, Hz):
1.47 (9H, s, C(CH3)3); 1.74–1.80 (4H, m, CHCH2CH2CH);
1.98–2.03 (2H, m, CHCH2CHCH2CH); 2.14–2.16 (2H, m,
CHCH2CHCH2CH); 3.31 (2H, br. s, CHNCH); 3.71 (2H, s,
NCH2Ph); 4.27 (1H, tt, J = 12.1, J = 6.0, CONCH); 7.14–
7.28 (2H, m, H-4,5 Ph); 7.32 (1H, d, J = 7.9, H-6 Ph); 7.53–
7.58 (2H, m, H-5,6 isoindoline); 7.76 (1H, d, J = 7.5, H-3 Ph);
7.81–7.87 (2H, m, H-4,7 isoindoline). 13C NMR spectrum,
δ, ppm: 27.4; 30.4; 38.5; 49.7; 53.0; 55.1; 59.5; 122.6;
122.9; 126.7; 127.5; 129.0; 129.9; 131.8; 131.9; 132.7;
133.5; 134.7; 138.2; 148.1; 151.9. Found, m/z: 435.2082
[M]+. C26H3035ClN3O. Calculated, m/z: 435.2072. Found, m/z:
437.2052 [M]+. C26H3037ClN3O. Calculated, m/z: 437.2042.
3-(tert-Butylimino)-2-(8-methyl-8-azabicyclo[3.2.1]octan-
3-yl)-2,3-dihydro-1H-isoindol-1-one (9g). Yield 181 mg
(56%), white solid, mp 107–111°C (cyclohexane–EtOAc).
1H NMR spectrum, δ, ppm (J, Hz): 1.26–1.31 (2H, m,
CHCH2CH2CH); 1.56 (9H, s, C(CH3)3); 1.72–1.79 (2H, m,
CHCH2CH2CH); 2.05–2.10 (2H, m, CHCH2CHCH2CH);
2.60 (3H, s, NCH3); 2.74–2.80 (2H, m, CHCH2CHCH2CH);
3.30 (2H, br. s, CHNCH); 4.87 (1H, tt, J = 12.0, J = 5.9,
CONCH); 7.56–7.64 (2H, m, H-5,6 isoindoline); 7.86 (1H,
d, J = 6.8, H-4 isoindoline); 7.98 (1H, d, J = 7.5, H-7
isoindoline). 13C NMR spectrum, δ, ppm: 27.6; 29.1; 30.9;
36.1; 42.1; 53.7; 59.4; 123.0; 127.1; 128.5; 131.0; 131.8;
134.4; 146.1; 167.4. Found, m/z: 325.2155 [M]+.
C20H27N3O. Calculated, m/z: 325.2149.
3-(tert-Butylimino)-2-(8-{[4-(trifluoromethyl)phenyl]-
methyl}-8-azabicyclo[3.2.1]octan-3-yl)-2,3-dihydro-1H-iso-
indol-1-one (9c). Yield 351 mg (75%), white solid, mp 122–
1
124°C (cyclohexane–EtOAc). H NMR spectrum, δ, ppm
(J, Hz): 1.28–1.33 (2H, m, CHCH2CH2CH); 1.58 (9H, s,
C(CH3)3); 1.74–1.79 (2H, m, CHCH2CH2CH); 2.04–2.07 (2H,
m, CHCH2CHCH2CH); 2.79–2.86 (2H, m, CHCH2CHCH2CH);
3.29 (2H, br. s, CHNCH); 3.99 (2H, s, NCH2Ph); 4.89 (1H,
tt, J = 12.2, J = 6.1, CONCH); 7.56–7.63 (6H, m, H Ph,
H-5,6 isoindoline); 7.88 (1H, d, J = 6.8, H-4 isoindoline);
7.98 (1H, d, J = 7.4, H-7 isoindoline). 13C NMR spectrum,
δ, ppm (J, Hz): 27.5; 30.3; 30.9; 42.5; 53.0; 53.8; 57.8;
1
3
123.0; 124.4 (q, JCF = 271.7, CF3); 125.1 (q, JCF = 3.7,
C-3,5 Ph); 127.2; 128.5; 128.7; 128.8 (q, 2JCF = 32.1, C-4 Ph);
131.0; 131.8; 134.4; 144.8; 146.1; 167.6. Found, m/z:
469.2343 [M]+. C27H30F3N3O. Calculated, m/z: 469.2335.
3-(tert-Butylimino)-2-{8-[(3-chlorophenyl)methyl]-
8-azabicyclo[3.2.1]octan-3-yl}-2,3-dihydro-1H-isoindol-
1-one (9d). Yield 328 mg (75%), white solid, mp 138–141°C
1
(cyclohexane–EtOAc). H NMR spectrum, δ, ppm (J, Hz):
1.30–1.32 (2H, m, CHCH2CH2CH); 1.58 (9H, s, C(CH3)3);
1.75–1.77 (2H, m, CHCH2CH2CH); 2.04–2.06 (2H, m,
CHCH2CHCH2CH); 2.79–2.85 (2H, m, CHCH2CHCH2CH);
3.29 (2H, br. s, CHNCH); 3.91 (2H, s, NCH2Ph); 4.89 (1H,
tt, J = 12.0, J = 5.9, CONCH); 7.17–7.25 (2H, m, H-5,6 Ph);
7.37 (1H, d, J = 7.2, H-4 Ph); 7.49 (1H, s, H-2 Ph); 7.56–
7.64 (2H, m, H-5,6 isoindoline); 7.87 (1H, d, J = 6.7, H-4
isoindoline); 7.98 (1H, d, J = 7.5, H-7 isoindoline). 13C NMR
spectrum, δ, ppm: 27.5; 30.3; 30.9; 42.6; 52.9; 53.8; 57.8;
123.0; 126.7; 126.8; 127.1; 128.6; 129.4; 131.0; 131.8;
134.1; 134.4; 142.7; 146.1; 167.5. Found, m/z: 435.2087
[M]+. C26H3035ClN3O. Calculated, m/z: 435.2072. Found, m/z:
437.2042 [M]+. C26H3037ClN3O. Calculated, m/z: 437.2042.
3-(tert-Butylimino)-2-{8-[(4-chlorophenyl)methyl]-
8-azabicyclo[3.2.1]octan-3-yl}-2,3-dihydro-1H-isoindol-
1-one (9e). Yield 302 mg (69%), white solid, mp 136–138°C
3-(tert-Butylimino)-5-fluoro-2-(8-methyl-8-azabicyclo-
[3.2.1]octan-3-yl)-2,3-dihydro-1H-isoindol-1-one (9h). Yield
202 mg (59%), white solid, mp 152–154°C (cyclohexane–
1
EtOAc). H NMR spectrum, δ, ppm (J, Hz): 1.23–1.26
(2H, m, CHCH2CH2CH); 1.52 (9H, s, C(CH3)3); 1.68–1.73
(2H, m, CHCH2CH2CH); 2.04–2.06 (2H, m,
CHCH2CHCH2CH); 2.56 (3H, s, NCH3); 2.69–2.76 (2H,
m, CHCH2CHCH2CH); 3.26 (2H, br. s, CHNCH); 4.81
(1H, tt, J = 12.1, J = 5.9, CONCH); 7.25 (1H, td, J = 8.3,
J = 5.2, H-6 isoindoline); 7.63 (1H, dd, J = 9.3, J = 2.1, H-7
isoindoline); 7.82 (1H, dd, J = 8.3, J = 5.2, H-4
isoindoline). 13C NMR spectrum, δ, ppm (J, Hz): 27.7;
29.1; 30.9; 36.2; 42.6; 53.8; 59.4; 114.8 (d, 2JCF = 26.3, C-4
2
isoindoline); 118.1 (d, JCF = 23.3, C-6 isoindoline); 124.9
3
4
(d, JCF = 9.5, COCCH); 130.3 (d, JCF = 2.2, NCOC);
130.5 (d, 3JCF = 8.9, FCCHCCN); 144.9; 164.7 (d, 1JCF = 251.1,
CF); 166.41. Found, m/z: 343.2061 [M]+. C20H26FN3O.
Calculated, m/z: 343.2054.
1
(cyclohexane–EtOAc). H NMR spectrum, δ, ppm (J, Hz):
1.28–1.33 (2H, m, CHCH2CH2CH); 1.57 (9H, s, C(CH3)3);
1.74–1.79 (2H, m, CHCH2CH2CH); 2.03–2.06 (2H, m,
CHCH2CHCH2CH); 2.77–2.82 (2H, m, CHCH2CHCH2CH);
3.28 (2H, br. s, CHNCH); 3.89 (2H, s, NCH2Ph); 4.88 (1H,
tt, J = 12.1, J = 6.0, CONCH); 7.28 (2H, d, J = 8.4, H-3,5 Ph);
7.43 (2H, d, J = 8.3, H-2,6 Ph); 7.56–7.64 (2H, m, H-5,6
isoindoline); 7.87 (1H, d, J = 6.8, H-4 isoindoline); 7.98
(1H, d, J = 7.3, H-7 isoindoline). 13C NMR spectrum, δ,
ppm: 27.4; 30.4; 30.9; 42.5; 52.8; 53.8; 57.7; 123.0; 127.1;
128.3; 128.5; 130.0; 131.0; 131.8; 132.2; 134.4; 138.9;
146.1; 167.5. Found, m/z: 435.2069 [M]+. C26H3035ClN3O.
Calculated, m/z: 435.2072. Found, m/z: 437.2047 [M]+.
C26H3037ClN3O. Calculated, m/z: 437.2042.
3-(tert-Butylimino)-6-methoxy-2-(8-methyl-8-aza-
bicyclo[3.2.1]octan-3-yl)-2,3-dihydro-1H-isoindol-1-one (9i).
Yield 234 mg (66%), white solid, mp 166–169°C
1
(cyclohexane–EtOAc). H NMR spectrum, δ, ppm (J, Hz):
1.23–1.28 (2H, m, CHCH2CH2CH); 1.53 (9H, s, C(CH3)3);
1.70–1.76 (2H, m, CHCH2CH2CH); 2.05–2.10 (2H, m,
CHCH2CHCH2CH); 2.60 (3H, s, NCH3); 2.73–2.79 (2H,
m, CHCH2CHCH2CH); 3.28 (2H, br. s, CHNCH); 3.90
(3H, s, OCH3); 4.84 (1H, tt, J = 12.1, J = 5.9, CONCH);
7.10 (1H, dd, J = 8.6, J = 2.5, H-5 isoindoline); 7.33 (1H,
d, J = 2.3, H-4 isoindoline); 7.86 (1H, d, J = 8.6, H-7
isoindoline). 13C NMR spectrum, δ, ppm: 27.7; 29.0; 30.8;
36.1; 42.2; 53.5; 55.8; 59.4; 106.4; 118.7; 121.0; 128.5;
136.9; 146.0; 161.9; 167.2 Found, m/z: 355.2263 [M]+.
C21H29N3O2. Calculated, m/z: 355.2254.
3-(tert-Butylimino)-2-{8-[(2-chlorophenyl)methyl]-
8-azabicyclo[3.2.1]octan-3-yl}-2,3-dihydro-1H-isoindol-
1-one (9f). Yield 251 mg (58%), white solid, mp 139–144°C
37

Chemistry of Heterocyclic Compounds 2021, 57(1), 31–39
3-(tert-Butylimino)-5-chloro-2-(8-methyl-8-azabicyclo-
[3.2.1]octan-3-yl)-2,3-dihydro-1H-isoindol-1-one (9j). Yield
27.7; 28.9; 34.0; 35.8; 42.5; 50.0; 59.1; 123.2; 125.6;
129.6; 131.2; 132.5; 133.0; 149.8; 167.5. Found, m/z:
325.2153 [M]+. C20H27N3O. Calculated, m/z: 325.2149.
3-(Isopropylimino)-2-(8-methyl-8-azabicyclo[3.2.1]octan-
3-yl)-2,3-dihydro-1H-isoindol-1-one (9n). Yield 176 mg
(57%), white solid, mp 109–111°C (cyclohexane–EtOAc).
1H NMR spectrum, δ, ppm (J, Hz): 1.37 (6H, d, J = 6.2,
CH(CH3)2); 1.66–1.71 (2H, m, CHCH2CH2CH); 2.07–2.13
(2H, m, CHCH2CH2CH); 2.69–2.71 (2H, m,
CHCH2CHCH2CH); 3.01–3.07 (2H, m, CHCH2CHCH2CH);
3.19 (3H, s, NCH3); 3.92 (2H, br. s, CHNCH); 4.59–4.69
(1H, m, NCH(CH3)2); 4.94 (1H, tt, J = 12.0, J = 6.1,
CONCH); 7.64–7.72 (2H, m, H-5,6 isoindoline); 7.80 (1H,
d, J = 6.5, H-4 isoindoline); 7.95 (1H, d, J = 7.4, H-7
isoindoline). 13C NMR spectrum, δ, ppm: 24.5; 25.9; 26.4;
29.7; 39.7; 49.8; 60.0; 123.7; 125.9; 129.2; 131.9; 132.3;
133.5; 148.0; 167.2. Found, m/z: 311.1996 [M]+.
C19H25N3O. Calculated, m/z: 311.1992.
2-(8-Methyl-8-azabicyclo[3.2.1]octan-3-yl)-3-(phenyl-
imino)-2,3-dihydro-1H-isoindol-1-one (9o). Yield 164 mg
(48%), yellow solid, mp 131–133°C (cyclohexane–EtOAc).
1H NMR spectrum, δ, ppm (J, Hz): 1.44–1.49 (2H, m,
CHCH2CH2CH); 1.78–1.83 (2H, m, CHCH2CH2CH); 2.11–
2.13 (2H, m, CHCH2CHCH2CH); 2.58 (3H, s, NCH3); 2.85–
2.92 (2H, m, CHCH2CHCH2CH); 3.34 (2H, br. s,
CHNCH); 4.85 (1H, tt, J = 12.1, J = 6.1, CONCH); 6.57
(1H, d, J = 7.8, H isoindoline); 6.94–6.97 (2H, m, H Ph);
7.20 (1H, t, J = 7.4, H-4 Ph); 7.25–7.29 (1H, m,
H isoindoline); 7.37–7.41 (2H, m, H Ph); 7.50 (1H, t, J = 7.5,
H-4 isoindoline); 7.81 (1H, d, J = 7.5, H-7 isoindoline).
13C NMR spectrum, δ, ppm: 27.3; 29.7; 36.5; 43.2; 59.5; 119.7;
123.1; 124.0; 125.4; 129.4; 129.5; 131.7; 132.4; 132.7; 148.9;
150.4; 167.8. Found, m/z: 345.1843 [M]+. C22H23N3O.
Calculated, m/z: 345.1836.
275 mg (77%), white solid, mp 173–176°C (cyclohexane–
1
EtOAc). H NMR spectrum, δ, ppm (J, Hz): 1.34–1.39
(2H, m, CHCH2CH2CH); 1.55 (9H, s, C(CH3)3); 1.79–1.84
(2H, m, CHCH2CH2CH); 2.22–2.25 (2H, m,
CHCH2CHCH2CH); 2.73 (3H, s, NCH3); 2.76–2.83 (2H,
m, CHCH2CHCH2CH); 3.45 (2H, br. s, CHNCH); 4.87
(1H, tt, J = 12.1, J = 6.0, CONCH); 7.58 (1H, d, J = 8.0,
H-6 isoindoline); 7.80 (1H, d, J = 8.0, H-7 isoindoline);
7.94 (1H, s, H-4 isoindoline). 13C NMR spectrum, δ, ppm:
27.2; 28.3; 31.0; 35.3; 41.7; 54.1; 59.6; 124.2; 127.5; 129.9;
131.3; 132.4; 138.3; 144.6; 166.4. Found, m/z: 359.1763 [M]+.
C20H2635ClN3O. Calculated, m/z: 359.1759. Found, m/z:
361.1727 [M]+. C20H2637ClN3O. Calculated, m/z: 361.1729.
3-(Benzylimino)-2-(8-methyl-8-azabicyclo[3.2.1]octan-
3-yl)-2,3-dihydro-1H-isoindol-1-one (9k). Yield 226 mg
(63%), white solid, mp 124–127°C (cyclohexane–EtOAc).
1H NMR spectrum, δ, ppm (J, Hz): 1.34–1.39 (2H, m,
CHCH2CH2CH); 1.75–1.81 (2H, m, CHCH2CH2CH); 2.07–
2.12 (2H, m, CHCH2CHCH2CH); 2.51 (3H, s, NCH3); 2.80–
2.87 (2H, m, CHCH2CHCH2CH); 3.29 (2H, br. s,
CHNCH); 4.91 (1H, tt, J = 12.0, J = 6.1, CONCH); 5.25
(2H, s, NCH2Ph); 7.29 (1H, t, J = 7.3, H-4 Ph); 7.39 (2H, t,
J = 7.6, H-3,5 Ph); 7.46 (2H, d, J = 7.4, H-2,6 Ph); 7.61–
7.65 (2H, m, H-5,6 isoindoline); 7.88–7.90 (1H, m, H-4
isoindoline); 7.95–7.97 (1H, m, H-7 isoindoline). 13C NMR
spectrum, δ, ppm: 27.6; 29.4; 36.2; 42.8; 53.7; 59.4; 123.4;
125.6; 126.9; 127.2; 128.5; 129.6; 131.6; 132.8; 133.1; 140.2;
151.1; 167.6. Found, m/z: 359.1997 [M]+. C23H25N3O.
Calculated, m/z: 359.1992.
3-(Cyclohexylimino)-2-(8-methyl-8-azabicyclo[3.2.1]-
octan-3-yl)-2,3-dihydro-1H-isoindol-1-one (9l). Yield 234 mg
(67%), white solid, mp 140–142°C (cyclohexane–EtOAc).
1H NMR spectrum, δ, ppm (J, Hz): 1.25–1.28 (2H, m,
CHCH2CH2CH); 1.37–1.47 (3H, m, H cyclohexane); 1.60–
3-[(4-Methoxyphenyl)imino]-2-(8-methyl-8-azabicyclo-
[3.2.1]octan-3-yl)-2,3-dihydro-1H-isoindol-1-one (9p). Yield
251 mg (67%), white solid, mp 142–147°C (cyclohexane–
1.62 (2H, m,
H cyclohexane); 1.75–1.77 (2H, m, CHCH2CH2CH); 1.86–
1.92 (4H, m, cyclohexane); 2.06–2.10 (2H, m,
H cyclohexane); 1.69–1.73 (1H, m,
1
EtOAc). H NMR spectrum, δ, ppm (J, Hz): 1.41–1.45
H
(2H, m, CHCH2CH2CH); 1.77–1.82 (2H, m, CHCH2CH2CH);
2.06–2.12 (2H, m, CHCH2CHCH2CH); 2.58 (3H, s,
NCH3); 2.84–2.91 (2H, m, CHCH2CHCH2CH); 3.32 (2H,
br. s, CHNCH); 3.86 (3H, s, OCH3); 4.84 (1H, tt, J = 12.1,
J = 6.0, CONCH); 6.69 (1H, d, J = 7.8, H isoindoline); 6.87–
6.95 (4H, m, H Ph); 7.27–7.31 (1H, m, H isoindoline); 7.50
(1H, t, J = 7.5, H-4 isoindoline); 7.81 (1H, d, J = 7.5, H-7
isoindoline). 13C NMR spectrum, δ, ppm: 27.5; 29.6; 36.5;
43.3; 55.6; 59.4; 114.6; 120.8; 123.1; 125.4; 129.3; 131.6;
132.4; 132.7; 142.1; 150.9; 156.5; 167.8. Found, m/z:
375.1951 [M]+. C23H25N3O2. Calculated, m/z: 375.1941.
3-(tert-Butylimino)-2-(8-ethyl-8-azabicyclo[3.2.1]octan-
3-yl)-2,3-dihydro-1H-isoindol-1-one (9q). Yield 254 mg
(75%), white solid, mp 85–86°C (cyclohexane–EtOAc).
1H NMR spectrum, δ, ppm (J, Hz): 1.08 (3H, t, J = 7.2,
CH2CH3); 1.11–1.16 (2H, m, CHCH2CH2CH); 1.47 (9H, s,
C(CH3)3); 1.63–1.66 (2H, m, CHCH2CH2CH); 1.94–1.96
(2H, m, CHCH2CHCH2CH); 2.63–2.69 (2H, m,
CHCH2CHCH2CH); 2.85 (2H, q, J = 6.8, CH2CH3); 3.32
(2H, br. s, CHNCH); 4.80 (1H, tt, J = 12.1, J = 6.0,
CONCH); 7.46–7.55 (2H, m, H-5,6 isoindoline); 7.75 (1H,
d, J = 7.2, H-4 isoindoline); 7.89 (1H, d, J = 7.7, H-7
CHCH2CHCH2CH); 2.64 (3H, s, NCH3); 2.79–2.85 (2H,
m, CHCH2CHCH2CH); 3.28 (2H, br. s, CHNCH); 4.21–
4.26 (1H, m, 1-CH cyclohexane); 4.81 (1H, tt, J = 12.1,
J = 6.0, CONCH); 7.55–7.63 (2H, m, H isoindoline); 7.82–
7.87 (2H, m, H isoindoline). 13C NMR spectrum, δ, ppm:
24.6; 25.7; 27.9; 28.4; 34.5; 35.5; 42.7; 57.5; 59.0; 123.2;
125.3; 129.5; 131.1; 132.6; 133.2; 148.0; 167.4. Found, m/z:
351.2314 [M]+. C22H29N3O. Calculated, m/z: 351.2305.
3-(Butylimino)-2-(8-methyl-8-azabicyclo[3.2.1]octan-
3-yl)-2,3-dihydro-1H-isoindol-1-one (9m). Yield 168 mg
(52%), white solid, mp 123–126°C (cyclohexane–EtOAc).
1H NMR spectrum, δ, ppm (J, Hz): 1.00 (3H, t, J = 7.4,
NCH2CH2CH2CH3); 1.25–1.31 (2H, m, CHCH2CH2CH);
1.48–1.57 (2H, m, NCH2CH2CH2CH3); 1.75–1.83 (4H, m,
NCH2CH2CH2CH3, CHCH2CH2CH); 2.07–2.10 (2H, m,
CHCH2CHCH2CH); 2.62 (3H, s, NCH3); 2.78–2.85 (2H,
m, CHCH2CHCH2CH); 3.29 (2H, br. s, CHNCH); 3.97
(2H, t, J = 6.8, NCH2CH2CH2CH3); 4.81 (1H, tt, J = 12.1,
J = 6.0, CONCH); 7.57–7.64 (2H, m, H-5,6 isoindoline);
7.86 (1H, d, J = 6.6, H-4 isoindoline); 7.92 (1H, d, J = 6.8,
H-7 isoindoline). 13C NMR spectrum, δ, ppm: 14.0; 20.7;
38

Chemistry of Heterocyclic Compounds 2021, 57(1), 31–39
isoindoline). 13C NMR spectrum, δ, ppm: 13.5; 27.7; 28.2;
30.8; 41.5; 42.2; 53.7; 56.5; 122.9; 127.1; 128.4; 130.9;
131.7; 134.3; 146.2; 167.3. Found, m/z: 339.2313 [M]+.
C21H29N3O. Calculated, m/z: 339.2305.
3. (a) de Souza, A.; Narvencar, K. P. S.; Sindhoora, K. V. J.
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In vitro test against nematodes B. xylophilus and
M. incognita. All target compounds were dissolved in DMSO
and diluted to required concentration with 0.1% aqueous
solution of Triton X-100. The sample solution was added
to 96-well plates (50 μl each well), and then nematodes
(about 60 pieces) were added. The plates were capped and
placed in the observation room at 22 ± 1°C. Distilled H2O
containing Triton X-100 and DMSO was used as blank
control. The positive control was run with a solution of
fenamiphos or avermectin.17 For each sample, the bioassay
was repeated twice, and the nematicidal activity is indicated
by the average inhibition ratio on nematode of two trials.
Test against the infestation of M. incognita in
cucumber plants. The germinant cucumber seedlings were
planted in a test tube containing a substrate soil. Sample
solution (3 ml) and around 2000 root-knot nematodes
M. incognita second-instar larvae were added to each tube.
Distilled H2O containing Triton X-100 (0.1 mg/l) and
DMSO was used as blank control. The positive control was
run with a solution of avermectin. All test tubes were
placed in the observation room at 22 ± 1°C. After 2 weeks,
the plant roots were washed out with H2O and the number
of root knots was counted, graded, and scored. For each
sample, the bioassay was repeated three times with four
replicates in each trial. The nematicidal activity is indicated
by the average inhibition ratio on root knots of three trials.
Inhibition ratio (%) = (1 – Treat score/Blank control
score) × 100%.
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Mazmanian, S. K.; Hsiao, E. Y. Cell 2015, 161, 264.
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Faergeman, N. J.; Ashrafi, K. Cell Metab. 2008, 7, 533.
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This work was financially supported by the National Key
Research and Development Plan (grant No. 2018YFD0200105)
and the National Natural Science Foundation of China
(No. 21572060).
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