Synthesis of N -Aryl-4-arylhexahydroquinoline Derivatives by Reaction of Cyclic Enaminones with Arylidenemalononitriles in DMSO

Article abstract of DOI:10.1055/s-0040-1705984

The reaction of cyclic enaminones with arylidenemalono nitriles was carried out in the presence of 13X molecular sieves in dimethyl sulfoxide. Under these mild reaction conditions, various bioactive N -aryl-4-arylhexahydroquinoline derivatives were obtain

Full text of DOI:10.1055/s-0040-1705984

SYNTHESIS
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2020, 52, A–H
paper
A
en
W. Han et al.
Paper
Synthesis
Synthesis of N-Aryl-4-arylhexahydroquinoline Derivatives by
Reaction of Cyclic Enaminones with Arylidenemalononitriles in
DMSO
Ar2
Wei Han
O
O
CN
Chika Inoue
CN
CN
MS 13X
Ar2
+
Ar1
Tsunaki Onizawa
Takeshi Oriyama*
R
DMSO, r.t., 24 h
R
N
N
NH2
R
R
H
0
0
0
0
-
0
0
0
1-9
2
4
2
-3
0
1
6
Ar1
mild reaction conditions
gram-scale synthesis
23 examples
up to 100% yield
Department of Chemistry, Faculty of Science, Ibaraki University,
2-1-1 Bunkyo, Mito Ibaraki 310-8512, Japan
takeshi.oriyama.sci@vc.ibaraki.ac.jp
broad substrate scope
valuable bioactive products
TDeMaekpaeaiCslrhotmairrkOeeernssiptyhoaoi.mnfodrCaiihyneagmAiaus.tsrhcyio@,rFvacc.iublatyraokfi.Sacci.ejpnce, Ibaraki University, 2-1-1 Bunkyo, Mito Ibaraki 310-8512, Japan
Received: 23.09.2020
Accepted after revision: 12.11.2020
Published online: 08.12.2020
Molecular sieves (MS) are not merely known as a dehy-
drating agent, but are also used as the promoter for many
organic reactions due to their weak basicity.7 Moreover,
molecular sieves are all inexpensive, commercially avail-
able, and recyclable.7c,f
DOI: 10.1055/s-0040-1705984; Art ID: ss-2020-f0502-op
Abstract The reaction of cyclic enaminones with arylidenemalono-
nitriles was carried out in the presence of 13X molecular sieves in di-
methyl sulfoxide. Under these mild reaction conditions, various bioac-
tive N-aryl-4-arylhexahydroquinoline derivatives were obtained in high
yields without the necessity of using transition-metal catalyst, organo-
base, or reflux conditions.
We have reported various reactions using the combina-
tion of dimethyl sulfoxide (DMSO) and molecular sieves.8
For example, the double Michael addition of dithiols to
acetylenic carbonyl compounds,8g the aza-Henry reaction
of N-tosylimines with nitroalkanes,8i and the ring-opening
reaction of aziridines with amines8j proceed smoothly in
DMSO with MS 4A at room temperature, without the neces-
sity of a transition-metal catalyst or an organobase.
Encouraged by these results, we here report the cascade
Michael–cyclization reaction of cyclic enaminones with
arylidenemalononitriles, which yields useful N-aryl-4-aryl-
hexahydroquinoline derivatives under mild reaction condi-
tions when using DMSO with MS 13X.
Key words dimethyl sulfoxide, molecular sieves, cyclic enaminones,
arylidenemalononitriles, N-aryl-4-arylhexahydroquinolines
N-Aryl-4-aryl-hexahydroquinoline derivatives exhibit a
range of significant antitumor,1 anticancer, cytotoxic,2 anti-
oxidant,3 antiproliferative,4 and antibacterial bioactivities5
(Figure 1). Because of their great pharmaceutical value, the
synthesis of N-aryl-4-arylhexahydroquinoline derivatives
has attracted much attention.
O
Ar
O
Ar
The reaction of cyclic enaminones with arylidenemalono-
nitriles is an effective and straightforward process for the
preparation of N-aryl-4-arylhexahydroquinoline deriva-
tives. Although some examples of this type of reaction have
been reported,1–6 catalysts such as oxidovanadium(V) metal
complexes,6a ZnO nanoparticles,6b chitosan,6c tetrabutyl-
ammonium fluoride (TBAF),6d or triethylbenzylammonium
chloride (TEBAC)6e are usually needed in these reports. In
some of the other previous studies for the reaction of cyclic
enaminones with arylidenemalononitriles, ultrasonic irra-
diation was used.5,6b Moreover, in most of the above exam-
ples, either a base or reflux conditions are necessary for this
transformation. However, from a green chemical point of
view, a simple and convenient procedure for constructing
CN
CN
O
Ar
N
O
CN
N
NH2
N
N
H
NH2
SO2NH2
SO2NH2
anticancer and cytotoxic
antioxidant
more potent antitumor activity
than standard drug doxorubicin
O
Ar
N
O
Ar
N
CO2Et
NH2
CN
NH2
CN
N
SO2NH2
Ph
Ph
cytotoxic against three tumor cell lines
MCF-7, HeLa, and HepG2
antibacterial against Gram-positive bacteria
and Gram-negative bacterium
N-aryl-4-arylhexahydroquinoline
derivatives
under
transition-metal-catalyst-, organobase-, and refluxing-free
conditions is more desirable.
Figure 1 Selected bioactive N-aryl-4-arylhexahydroquinoline deriva-
tives
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–H
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
W. Han et al.
Paper
Synthesis
Initially, we attempted the reaction of cyclic enaminone
1a (0.1 mmol) with benzylidenemalononitrile 2a (1.2
equiv) using MS 4A (100 mg) in various solvents (Table 1,
entries 1–7). Although the desired product 3aa was ob-
tained in only 35% yield, we found that DMSO was the most
suitable solvent (entry 1). Other aprotic and protic polar
solvents such as MeCN, DMF, dimethylacetamide (DMA), N-
methylpyrrolidone (NMP), THF, and MeOH were less effec-
tive for this reaction (entries 2–7). Therefore, we decided to
screen other reaction conditions in DMSO to improve the
yield of 3aa.
Fortunately, despite decreasing the amount of MS 13X to
300 or 200 mg, almost no loss of yield occurred (entries 5,
7, and 8). Further reducing the amount of MS 13X resulted
in lower yields of 3aa (entries 8, 9, and 10). Thus, the opti-
mal reaction conditions were determined to be enaminone
1 (0.4 mmol), arylidenemalononitrile 2 (0.48 mmol), and
MS 13X (200 mg) in DMSO (1 mL) at room temperature.
Table 2 Screening of Additivesa
O
Ph
O
NC
Ph
CN
CN
additive
+
Ph
DMSO, r.t., 24 h
N
NH2
N
Table 1 Screening of Solventsa
H
Ph
1a
2a
3aa
O
Ph
O
NC
Ph
CN
CN
Entry
Additive
Yieldb (%)
MS 4A
+
Ph
solvent, r.t., 24 h
N
NH2
1
2
none
trace
4
N
H
Ph
1a
2a
3aa
H2O (100 L)
MS 3A
3
37
35
9
Entry
Solvent
Yieldb (%)
4
MS 4A
1
2
3
4
5
6
7
DMSO
MeCN
DMF
35
7
5
MS 5A
6
MS 13X
69
48
8
16
15
18
trace
5
7
MgSO4
DMA
NMP
8
Na2SO4
9
Drierite®
activated alumina
11
19
THF
10
MeOH
a Reaction conditions: 1a (0.1 mmol), 2a (0.12 mmol), additive (100 mg),
DMSO (1 mL), r.t., 24 h.
a Reaction conditions: 1a (0.1 mmol), 2a (0.12 mmol), MS 4A (100 mg),
solvent (1 mL), r.t., 24 h.
b Isolated yield by TLC.
b Isolated yield by TLC.
Table 3 Optimization of the Reaction Conditionsa
Subsequently, we investigated various additives for the
cascade reaction in DMSO as summarized in Table 2. With-
out an additive, the desired product 3aa was obtained in
trace amounts (entry 1). The use of H2O as an additive was
also unsuccessful (entry 2). In contrast, MS 3A promoted
the reaction to afford 3aa in similar yield to MS 4A (entries
3 and 4). However, MS 5A was less effective for the reaction
(entry 5). MS 13X was more suitable than other molecular
sieves, given that the corresponding yield of 3aa was 69%
(entry 5). Other dehydrating agents (MgSO4, Na2SO4, and
Drierite) and activated alumina were also tested as addi-
tives in DMSO, but the yields decreased (entries 7–10).
Overall, MS 13X was determined to be the most suitable ad-
ditive for this reaction.
Next, the effects of reaction concentration and additive
loading on the cascade reaction were screened (Table 3). We
found that increasing the concentration of the reaction im-
proved the yield of 3aa. By scaling the amount of MS 13X
used with 1a from 0.1–0.5 mmol in 1 mL DMSO, the yield of
the desired product was improved from 69% to 95% (entries
1–6). However, considering both purification9 and yield, we
next conducted all reactions on a 0.4 mmol scale of enami-
none 1a to optimize the amount of MS 13X (entries 7–10).
O
Ph
O
NC
Ph
CN
CN
MS 13X
+
Ph
DMSO (1 mL), r.t., 24 h
N
NH2
N
H
Ph
1a
2a
3aa
Entry
1a (mmol)
MS 13X (mg)
Yield (%)
1b
2b
3b
4c
0.1
0.2
0.3
0.3
0.4
0.5
0.4
0.4
0.4
0.4
100
200
300
300
400
500
300
200
150
100
69
84
89
86
94
95
93
92
88
78
5c
6c
7c
8c
9c
10c
a Reaction conditions: 1a, 2a (1.2 equiv), MS 13X, DMSO (1 mL), r.t., 24 h.
b Isolated yield by TLC.
c Product 3aa was purified by recrystallization and TLC due to its high crys-
tallinity.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–H

C
W. Han et al.
Paper
Synthesis
O
Ph
O
NC
Ph
CN
CN
MS 13X
DMSO, r.t., 24 h
+
Ar
R
R
R
1
N
NH2
N
H
R
Ar
2a
3
O
Ph
O
Ph
N
O
Ph
O
Ph
CN
CN
CN
CN
N
NH2
NH2
N
NH2
N
NH2
OMe
Cl
3aa, 92% (96%)a
3ba, 90%
3ca, 86%
3da, 100%
O
Ph
O
Ph
O
Ph
O
Ph
CN
CN
CN
CN
H
N
NH2
N
NH2
N
NH2
N
NH2
H
Br
NO2
3fa, N.R.b
3ea, 99%
3ga, 90%
3ha, 77%
O
Ph
O
Ph
N
O
Ph
N
CN
CN
CN
N
NH2
NH2
NH2
3ia, N.R.b
3ja, N.R.b
3ka, N.R.b
Scheme 1 Scope of enaminones. Reagents and conditions: 1 (0.4 mmol), 2a (0.48 mmol), DMSO (1 mL), MS 13X (200 mg), r.t., 24 h; products 3
purified by recrystallization and TLC. a Gram-scale reaction: 1a (4.64 mmol, 1.0 g), 2a (5.57 mmol), DMSO (20 mL), MS 13X (2.0 g), 2 d. b N.R. = no
reaction.
With the optimized reaction conditions in hand, we
next examined the cascade Michael–cyclization reaction of
various enaminones 1 with benzylidenemalononitrile (2a)
(Scheme 1). Enaminones 1 bearing electron-donating and
halogen-atom substituents at the para-position of the phe-
nyl ring yielded the corresponding products 3ba–3ea in
good to excellent yields (86–100%). However, when the
strongly electron-withdrawing group NO2 was present at
the para-position of the aromatic ring, the reactivity of the
enaminone decreased significantly, so that no reaction oc-
curred (3fa). Enaminone 1g prepared from 1-naphthyl-
amine and dimedone provided the corresponding product
in 90% yield (3ga).
Furthermore, 1,3-cyclohexanedione-derived enami-
none 1h was also tolerated under the optimal reaction con-
ditions, resulting in a 77% yield of product 3ha. However,
enaminones derived from benzylamine and hexylamine
(aliphatic amines) and an acyclic enaminone gave poor re-
sults (3ia, 3ja, and 3ka, respectively). Moreover, the gram-
scale synthesis of 3aa was also achieved in 96% yield.
We further evaluated the cascade Michael–cyclization
reaction of various arylidenemalononitriles 2 with enami-
none 1a (Scheme 2). Arylidenemalononitriles 2 containing
a methyl group at the ortho-, meta-, and para-positions of
the aromatic ring were tolerated, giving high yields of the
corresponding products 3ab–3ad. Moreover, arylidene-
malononitriles 2 bearing various halo substituents (F, Cl and
Br) at the para-position and 2,4-dichloro substituents on
the phenyl ring reacted smoothly with 1a to produce the
desired products 3ae–3ah in good to excellent yields (88–
97%). Electron-donating groups such as 4-dimethylamino
(3ai) and 4-hydroxy (3aj) drastically reduced the reactivity
of the arylidenemalononitriles. Fortunately, when the 4-
methoxy group was present on the phenyl ring instead of a
free hydroxy group (3aj), the reaction proceeded smoothly,
resulting in 79% yield of product 3ak. In contrast, the reac-
tivity of the arylidenemalononitriles bearing electron-
withdrawing groups (4-NO2, 4-CN, and 4-CO2Me) was too
high, causing side reactions in these cases. An unidentified
complex mixture was obtained instead of 3al. Reacting 4-
cyanobenzylidenemalononitrile for either 24 or 3 h gave
3am in nearly the same yield (26% or 28%, respectively). A
low yield of 3an was also obtained (20%). Gratifyingly,
arylidenemalononitriles bearing heteroaryl rings (2-furyl
and 2-thienyl) gave products 3ao and 3ap in quantitative
and 91% yield, respectively. Despite the low yields, the
naphthyl-group-containing products 3aq and 3ar were also
isolated. Although cyclohexylmethylenemalononitrile was
explored, product 3as was obtained only in trace amounts.
In addition, isatylidenemalononitrile was examined pro-
ducing a 40% yield of the corresponding product 3at.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–H

D
W. Han et al.
Paper
Synthesis
O
Ar
O
NC
Ar
CN
CN
MS 13X
DMSO, r.t., 24 h
+
Ph
N
NH2
N
H
Ph
1a
2
3
F
Cl
Br
Cl
O
O
O
O
O
O
O
Cl
CN
CN
CN
CN
CN
CN
CN
N
NH2
N
NH2
N
NH2
N
NH2
N
NH2
N
NH2
N
NH2
Ph
Ph
Ph
Ph
Ph
Ph
Ph
3ab, 83%
3ac, 92%
3ad, 91%
3ae, 89%
3af, 88%
3ag, 97%
3ah, 96%
NMe2
OH
OMe
NO2
CN
CO2Me
O
O
O
O
O
O
O
O
NC
NC
NC
CN
CN
CN
CN
H2N
N
H2N
N
H2N
N
N
NH2
N
NH2
N
NH2
N
NH2
Ph
Ph
3aj, 14%
Ph
3ak, 79%
Ph
Ph
Ph
3an, 20%
Ph
3ao, 100%
3ai, N.R.a
3al, N.D.b
3am, 26% (3 h, 28%)
S
Ph
O
O
O
O
N
CN
NH2
CN
NH2
CN
NH2
CN
O
NH2
CN
N
N
N
N
NH2
O
N
H
Ph
3ap, 91%
Ph
3aq, 32%
Ph
3ar, 9%
Ph
3as, trace
3at, 40%
Scheme 2 Scope of arylidenemalononitriles. Reagents and conditions: 1 (0.4 mmol), 2a (0.48 mmol), DMSO (1 mL), MS 13X (200 mg), r.t., 24 h; prod-
ucts 3 purified by recrystallization and TLC. a N.R. = no reaction. b N.D. = not determined.
In conclusion, we have developed an efficient and envi-
ronmentally friendly cascade Michael–cyclization reaction
of cyclic enaminones with arylidenemalononitriles by using
a combination of MS 13X and DMSO. In contrast to the con-
ventional methods, this reaction was carried out success-
fully for the first time without using a transition-metal cat-
alyst, an organobase, or heating conditions. Moreover, this
protocol resulted in high yields (up to 100%) of various bio-
active N-aryl-4-arylhexahydroquinoline derivatives. Fur-
ther studies on the development of other useful and novel
reactions in DMSO are currently being assessed in our labo-
ratory.
otherwise, all reactions were carried out under open air condition.
Enaminones 1 and arylidenemalononitriles 2 were synthesized ac-
cording to literature procedures.10,11
2-Amino-7,7-dimethyl-5-oxo-1,4-diphenyl-1,4,5,6,7,8-hexahydro-
quinoline-3-carbonitrile (3aa);6d Typical Procedure
Enaminone 1a (86.1 mg, 0.4 mmol), benzylidenemalononitrile 2a
(74.0 mg, 0.48 mmol), DMSO (1 mL), and MS 13X (200 mg) were load-
ed into a 30 mL two-necked flask at r.t. The reaction mixture was
stirred for 24 h at r.t., and then quenched with phosphate buffer. After
extraction with EtOAc and washing with brine, the organic phase was
dried over Na2SO4, filtered, and concentrated under reduced pressure.
The residue was recrystallized from hexane/EtOAc and filtered to give
most of product 3aa. The filtrate was concentrated and purified by
TLC (silica gel, hexane–EtOAc, 3:1); this afforded the remaining 3aa.
Yield: 136 mg (92%); white solid; mp 238–239 °C.
1H and 13C NMR spectra were recorded at 500 MHz and 125 MHz, re-
spectively, on a Bruker spectrometer. Chemical shifts  in ppm were
determined relative to TMS as an internal standard. IR spectra were
recorded on an IR spectrometer by using KBr disc plates. Melting
points were measured by using a Mel-Temp® apparatus. DMSO and
other solvents were purchased from Wako Pure Chemical Industries,
Ltd. and used without further purification. Molecular sieves (MS)
were powdered in a mortar and dried by using a heat gun prior to use.
TLC was performed on Wakogel® B-5F. Commercially available mate-
rials and solvents were used without further purification. If not noted
IR (KBr): 3461, 3333, 3220, 2957, 2179, 1655, 1620, 1571, 1490, 1415,
1373, 1258, 1176, 1145, 1041, 738, 697, 575 cm–1
.
1H NMR (500 MHz, CDCl3):  = 0.84 (s, 3 H), 0.96 (s, 3 H), 1.79–1.82 (d,
J = 17.45 Hz, 1 H), 2.03–2.06 (d, J = 17.45 Hz, 1 H), 2.13–2.22 (dd, J =
16.35, 14.22 Hz, 2 H), 4.01 (s, 2 H, NH2), 4.76 (s, 1 H), 7.18–7.59 (m, 10
H).
13C NMR (125 MHz, CDCl3):  = 27.02, 29.46, 32.40, 36.00, 41.71,
49.99, 63.68, 113.26, 120.84, 126.67, 127.13, 128.57, 129.78, 130.33,
130.62, 136.32, 145.56, 149.13, 150.09, 195.57.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–H

E
W. Han et al.
Paper
Synthesis
2-Amino-7,7-dimethyl-5-oxo-4-phenyl-1-(4-tolyl)-1,4,5,6,7,8-
hexahydroquinoline-3-carbonitrile (3ba)
HRMS (ESI): m/z [M + Na]+ calcd for C24H22BrN3NaO: 470.0838; found:
470.0837.
Yield: 138 mg (90%); yellow solid; mp 192–194 °C.
2-Amino-7,7-dimethyl-1-(1-naphthyl)-5-oxo-4-phenyl-1,4,5,6,7,8-
hexahydroquinoline-3-carbonitrile (3ga)13
IR (KBr): 3564, 3462, 3336, 2956, 2925, 2179, 1653, 1570, 1509, 1452,
1414, 1373, 1257, 1177, 1144, 1043, 1017, 755, 699, 591, 560, 533
cm–1
.
Yield: 151 mg (90%); white solid; mp 264–266 °C.
1H NMR (500 MHz, CDCl3):  = 0.84 (s, 3 H), 0.96 (s, 3 H), 1.81–1.84 (d,
J = 17.55 Hz, 1 H), 2.04–2.14 (d, J = 17.55 Hz, 1 H), 2.12–2.21 (dd, J =
16.3, 14.5 Hz, 2 H), 2.47 (s, 3 H), 4.01 (s, 2 H, NH2), 4.75 (s, 1 H), 7.16–
7.20 (m, 3 H), 7.29–7.37 (m, 6 H).
13C NMR (125 MHz, CDCl3):  = 21.30, 27.02, 29.46, 32.37, 35.98,
41.66, 49.98, 63.48, 113.14, 120.93, 126.63, 127.12, 128.54, 129.40,
133.49, 140.65, 145.64, 149.39, 150.24, 195.57.
IR (KBr): 3463, 3370, 2951, 2927, 2881, 2184, 1650, 1640, 1604, 1572,
1454, 1402, 1394, 1372, 1345, 1335, 1311, 1259, 1239, 1147, 1040,
809, 778, 756, 707, 699, 573 cm–1
.
1H NMR (500 MHz, CDCl3):  (mixture of rotamers) = 0.74 (0.87) (s,
2.5 H), 0.79 (0.83) (s, 3.5 H), 1.74–1.78 (1.91–1.95) (d, J = 17.30 Hz, 1
H), 2.11–2.16 (2.17–2.24) (m, 2 H), 3.93 (4.06) (s, 2 H, NH2), 4.85
(4.93) (s, 1 H), 7.19–8.07 (m, 12 H).
13C NMR (125 MHz, CDCl3):  (mixture of rotamers) = 27.57 (26.37),
28.46 (29.71), 32.51 (32.04), 36.21 (35.91), 40.25 (41.31), 50.14
(50.01), 63.73 (63.09), 113.26 (113.07), 120.97 (120.88), 121.78
(121.65), 125.35, 126.71 (126.00), 127.25 (127.35), 127.73 (127.76),
128.04 (128.37), 128.58 (128.61), 128.61 (128.65), 129.13, 130.09
(130.97), 131.34 (131.44), 132.65 (132.15), 134.50 (134.67), 145.69
(145.42), 149.87 (149.92), 150.47 (150.27), 195.64 (195.79).
HRMS (ESI): m/z [M + Na]+ calcd for C25H25N3NaO: 406.1890; found:
406.1881.
2-Amino-1-(4-methoxyphenyl)-7,7-dimethyl-5-oxo-4-phenyl-
1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile (3ca)
Yield: 137 mg (86%); orange solid; mp 196–198 °C.
IR (KBr): 3455, 3418, 3322, 3214, 2957, 2934, 2181, 1732, 1648, 1564,
1509, 1454, 1441, 1417, 1374, 1297, 1252, 1170, 1144, 1040, 1026,
2-Amino-5-oxo-1,4-diphenyl-1,4,5,6,7,8-hexahydroquinoline-3-
carbonitrile (3ha)6a
762, 701, 565, 548 cm–1
.
1H NMR (500 MHz, CDCl3):  = 0.84 (s, 3 H), 0.96 (s, 3 H), 1.82–1.85 (d,
J = 17.45 Hz, 1 H), 2.03–2.06 (d, J = 17.45 Hz, 1 H), 2.11–2.21 (dd, J =
16.3, 15.2 Hz, 2 H), 3.89 (s, 3 H), 4.07 (s, 2 H, NH2), 4.74 (s, 1 H), 7.04–
7.05 (m, 2 H), 7.16–7.20 (m, 3 H), 7.28–7.35 (m, 4 H).
13C NMR (125 MHz, CDCl3):  = 14.21, 21.07, 27.03, 29.51, 32.34,
35.98, 41.69, 49.97, 55.70, 60.41, 113.15, 126.62, 127.12, 128.39,
128.54, 130.78, 145.68, 149.73, 150.52, 160.56, 195.61.
Yield: 105 mg (77%); pale yellow solid; mp 149–151 °C.
IR (KBr): 3564, 3472, 3425, 3318, 3216, 2948, 2179, 1735, 1650, 1621,
1589, 1566, 1489, 1453, 1409, 1372, 1337, 1264, 1192, 1074, 1045,
1002, 746, 702, 637, 547 cm–1
.
1H NMR (500 MHz, CDCl3):  = 1.73–2.04 (m, 3 H), 2.14–2.40 (m, 3 H),
4.00 (s, 2 H, NH2), 4.82 (s, 1 H), 7.15–7.22 (m, 1 H), 7.30–7.37 (m, 6 H),
7.54–7.59 (m, 3 H).
13C NMR (125 MHz, CDCl3):  = 14.2, 20.98, 28.28, 35.66, 36.51, 60.41,
63.48, 114.22, 126.68, 127.10, 128.60, 129.77, 130.32, 136.30, 145.63,
150.10, 151.01, 195.73.
HRMS (ESI): m/z [M + Na]+ calcd for C25H25N3NaO2: 422.1839; found:
422.1860.
2-Amino-1-(4-chlorophenyl)-7,7-dimethyl-5-oxo-4-phenyl-
1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile (3da)12
2-Amino-7,7-dimethyl-5-oxo-1-phenyl-4-(2-tolyl)-1,4,5,6,7,8-
hexahydroquinoline-3-carbonitrile (3ab)14
Yield: 162 mg (100%); white solid; mp 249–250 °C.
IR (KBr): 3463, 3335, 2956, 2180, 1655, 1620, 1591, 1572, 1488, 1413,
Yield: 112 mg (83%); white solid; mp 266–267 °C.
1373, 1257, 1145, 1090, 1042, 1013, 757, 700, 581 cm–1
.
IR (KBr): 3472, 3342, 2957, 2177, 1652, 1620, 1592, 1570, 1488, 1412,
1H NMR (500 MHz, CDCl3):  = 0.85 (s, 3 H), 0.98 (s, 3 H), 1.79–1.82 (d,
J = 17.40 Hz, 1 H), 2.03–2.06 (d, J = 17.40 Hz, 1 H), 2.13–2.22 (dd, J =
16.3, 11.9 Hz, 2 H), 3.97 (s, 2 H, NH2), 4.75 (s, 1 H), 7.18–7.57 (m, 9 H).
13C NMR (125 MHz, CDCl3):  = 27.03, 29.47, 32.44, 35.96, 41.76,
49.92, 64.28, 113.56, 120.54, 126.76, 127.08, 128.61, 130.88, 131.12,
134.79, 136.56, 145.29, 148.64, 149.74, 195.47.
1372, 1258, 1144, 1047, 744, 706, 575 cm–1
.
1H NMR (500 MHz, CDCl3):  = 0.88 (s, 3 H), 0.96 (s, 3 H), 1.83–1.87
(dd, J = 17.40 Hz, 0.8 Hz, 1 H), 2.04–2.19 (m, 3 H), 2.66 (s, 3 H), 3.92 (s,
2 H, NH2), 4.99 (s, 1 H), 7.04–7.22 (m, 4 H), 7.34–7.35 (m, 2 H), 7.58–
7.61 (m, 3 H).
13C NMR (125 MHz, CDCl3):  = 19.70, 27.12, 29.46, 31.87, 32.47,
41.72, 49.87, 64.36, 113.87, 120.91, 126.27, 126.45, 127.29, 129.86,
130.32, 130.50, 135.38, 136.34, 144.81, 149.31, 149.50, 195.62.
2-Amino-1-(4-bromophenyl)-7,7-dimethyl-5-oxo-4-phenyl-
1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile (3ea)
Yield: 178 mg (99%); white solid; mp 240–242 °C.
2-Amino-7,7-dimethyl-5-oxo-1-phenyl-4-(3-tolyl)-1,4,5,6,7,8-
hexahydroquinoline-3-carbonitrile (3ac)14
IR (KBr): 3463, 3333, 3221, 2955, 2180, 1655, 1644, 1621, 1571, 1486,
1413, 1373, 1255, 1145, 1069, 1041, 1011, 755, 700, 576 cm–1
.
Yield: 141 mg (92%); pale yellow solid; mp 233–235 °C.
1H NMR (500 MHz, CDCl3):  = 0.85 (s, 3 H), 0.97 (s, 3 H), 1.79–1.82 (d,
J = 17.50 Hz, 1 H), 2.02–2.05 (d, J = 17.50 Hz, 1 H), 2.13–2.22 (dd, J =
16.5, 10.5 Hz, 2 H), 3.97 (s, 2 H, NH2), 4.74 (s, 1 H), 7.17–7.21 (m, 3 H),
7.29–7.34 (m, 4 H), 7.71–7.73 (d, J = 8.50 Hz, 2 H).
13C NMR (125 MHz, CDCl3):  = 27.03, 29.47, 32.45, 35.96, 41.76,
49.92, 64.31, 113.55, 120.52, 124.62, 126.76, 127.08, 128.61, 131.41,
133.89, 135.33, 145.27, 148.57, 149.66, 195.46.
IR (KBr): 3461, 3328, 3218, 2970, 2957, 2903, 2868, 2177, 1647, 1620,
1594, 1568, 1490, 1449, 1416, 1372, 1315, 1296, 1260, 1235, 1178,
1167, 1144, 1124, 1070, 1024, 805, 765, 752, 697, 583, 572 cm–1
.
1H NMR (500 MHz, CDCl3):  = 0.85 (s, 3 H), 0.96 (s, 3 H), 1.79–1.83 (d,
J = 17.40 Hz, 1 H), 2.03–2.06 (d, J = 17.40 Hz, 1 H), 2.13–2.22 (dd, J =
16.30, 4.9 Hz, 2 H), 2.34 (s, 3 H), 4.02 (s, 2 H, NH2), 4.70 (s, 1 H), 6.99–
7.00 (d, J = 7.40 Hz, 1 H), 7.11–7.21 (m, 3 H), 7.29–7.30 (m, 2 H), 7.57–
7.59 (m, 3 H).
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–H

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W. Han et al.
Paper
Synthesis
13C NMR (125 MHz, CDCl3):  = 21.64, 27.04, 29.44, 32.41, 35.90,
41.69, 49.97, 63.83, 113.25, 120.90, 123.94, 127.47, 128.02, 128.46,
129.76, 130.29, 130.59, 136.35, 137.94, 145.50, 149.16, 150.00,
195.59.
13C NMR (125 MHz, CDCl3):  = 26.94, 29.42, 32.38, 35.70, 41.69,
49.90, 62.86, 112.81, 120.48, 120.66, 128.97, 129.69, 130.45, 130.70,
131.62, 136.05, 144.64, 149.33, 150.26, 195.57.
2-Amino-4-(2,4-dichlorophenyl)-7,7-dimethyl-5-oxo-1-phenyl-
1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile (3ah)15
2-Amino-7,7-dimethyl-5-oxo-1-phenyl-4-(4-tolyl)-1,4,5,6,7,8-
hexahydroquinoline-3-carbonitrile (3ad)6a
Yield: 168 mg (96%); light orange solid; mp 254–256 °C.
Yield: 140 mg (91%); white solid; mp 241–242 °C.
IR (KBr): 3585, 3564, 3459, 3345, 2959, 2182, 1644, 1591, 1562, 1490,
1468, 1417, 1370, 1256, 1153, 1098, 1071, 1047, 1023, 1001, 858,
IR (KBr): 3458, 3333, 2952, 2178, 1653, 1619, 1593, 1571, 1491, 1412,
1384, 1371, 1257, 1179, 1169, 1144, 1124, 1039, 1017, 699, 575 cm–1
.
732, 703, 574 cm–1
.
1H NMR (500 MHz, CDCl3):  = 0.85 (s, 3 H), 0.95 (s, 3 H), 1.78–1.82 (d,
J = 17.40 Hz, 1 H), 2.02–2.05 (d, J = 17.40 Hz, 1 H), 2.12–2.22 (dd, J =
16.30, 7.95 Hz, 2 H), 2.30 (s, 3 H), 3.98 (s, 2 H, NH2), 4.72 (s, 1 H), 7.11–
7.12 (d, J = 7.75 Hz, 2 H), 7.23–7.31 (m, 4 H), 7.57–7.61 (m, 3 H).
1H NMR (500 MHz, CDCl3):  = 0.89 (s, 3 H), 0.95 (s, 3 H), 1.77–1.81 (d,
J = 17.65 Hz, 1 H), 2.02–2.05 (d, J = 17.65 Hz, 1 H), 2.08–2.19 (dd, J =
16.35, 18.25 Hz, 2 H), 4.01 (s, 2 H, NH2), 5.13 (s, 1 H), 7.20–7.22 (dd, J =
8.30, 2.15 Hz, 1 H), 7.30–7.36 (m, 4 H), 7.59–7.60 (m, 3 H).
13C NMR (125 MHz, CDCl3):  = 21.11, 27.11, 29.43, 32.42, 35.61,
41.70, 50.01, 63.97, 113.35, 120.86, 126.98, 129.30, 129.79, 130.29,
130.60, 136.12, 136.39, 142.69, 149.00, 149.91, 195.59.
13C NMR (125 MHz, CDCl3):  = 27.16, 29.36, 32.32, 35.49, 41.76,
49.75, 61.71, 110.97, 120.41, 127.24, 130.03, 130.49, 130.63, 131.69,
132.92, 133.79, 135.93, 140.73, 150.41, 195.48.
2-Amino-4-(4-fluorophenyl)-7,7-dimethyl-5-oxo-1-phenyl-
1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile (3ae)6d
2-Amino-4-(4-hydroxyphenyl)-7,7-dimethyl-5-oxo-1-phenyl-
1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile (3aj)6d
Yield: 138 mg (89%); yellow solid; mp 254–255 °C.
Yield: 22.0 mg (14%); yellow solid; mp 262–263 °C.
IR (KBr): 3453, 3336, 2957, 2178, 1652, 1640, 1593, 1557, 1504, 1490,
1416, 1372, 1257, 1216, 1203, 1173, 1153, 1042, 850, 702, 574, 528
IR (KBr): 3626, 3585, 3564, 3543, 3470, 3332, 2961, 2178, 1651, 1633,
1613, 1591, 1565, 1557, 1510, 1489, 1454, 1415, 1376, 1257, 1228,
cm–1
.
1168, 1147, 1041, 852, 703, 576 cm–1
.
1H NMR (500 MHz, CDCl3):  = 0.82 (s, 3 H), 0.95 (s, 3 H), 1.78–1.81 (d,
J = 17.30 Hz, 1 H), 2.02–2.05 (d, J = 17.30 Hz, 1 H), 2.12–2.22 (dd, J =
16.35, 8.90 Hz, 2 H), 4.02 (s, 2 H, NH2), 4.75 (s, 1 H), 6.98–7.01 (m, 2
H), 7.28–7.34 (m, 4 H), 7.59–7.60 (m, 3 H).
13C NMR (125 MHz, CDCl3):  = 26.92, 29.43, 32.38, 35.44, 41.69,
49.94, 63.45, 113.19, 115.22, 115.39, 120.70, 128.66, 128.72, 129.72,
130.41, 136.16, 141.45, 149.07, 150.09, 195.58.
1H NMR (500 MHz, DMSO-d6):  = 0.74 (s, 3 H), 0.88 (s, 3 H), 1.67–
1.70 (d, J = 17.45 Hz, 1 H), 1.99–2.02 (d, J = 17.45 Hz, 1 H), 2.17–2.21
(dd, J = 19.50, 3.70 Hz, 2 H), 4.37 (s, 1 H), 5.24 (s, 2 H, NH2), 6.70–6.72
(d, J = 8.40 Hz, 2 H), 7.07–7.08 (d, J = 6.85 Hz, 2 H), 7.38–7.39 (d, J =
6.85 Hz, 2 H), 7.57–7.61 (m, 3 H).
13C NMR (125 MHz, DMSO-d6):  = 26.71, 29.57, 32.32, 35.84, 41.42,
49.86, 61.44, 112.74, 115.52, 122.12, 128.23, 130.16, 130.41, 130.65,
136.84, 137.54, 150.13, 151.42, 156.25, 195.33.
2-Amino-4-(4-chlorophenyl)-7,7-dimethyl-5-oxo-1-phenyl-
1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile (3af)6d
2-Amino-4-(4-methoxyphenyl)-7,7-dimethyl-5-oxo-1-phenyl-
1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile (3ak)6d
Yield: 142 mg (88%); white solid; mp 261–262 °C.
Yield: 126 mg (79%); pale yellow solid; mp 243–244 °C.
IR (KBr): 3731, 3708, 3646, 3605, 3593, 3584, 3542, 3465, 3330, 2952,
2352, 2178, 1694, 1681, 1651, 1620, 1594, 1567, 1557, 1488, 1454,
1415, 1385, 1258, 1171, 1144, 1125, 1087, 1041, 1011, 858, 842, 698,
IR (KBr): 3457, 3331, 2955, 2937, 2176, 1646, 1592, 1564, 1508, 1490,
1452, 1412, 1373, 1301, 1256, 1239, 1177, 1143, 1030, 850, 841, 705,
574, 517 cm–1
.
573 cm–1
.
1H NMR (500 MHz, CDCl3):  = 0.82 (s, 3 H), 0.95 (s, 3 H), 1.77–1.81 (d,
J = 17.50 Hz, 1 H), 2.02–2.05 (d, J = 17.50 Hz, 1 H), 2.12–2.22 (dd, J =
16.35, 8.90 Hz, 2 H), 4.06 (s, 2 H, NH2), 4.74 (s, 1 H), 7.27–7.31 (m, 6
H), 7.58–7.62 (m, 3 H).
1H NMR (500 MHz, CDCl3):  = 0.83 (s, 3 H), 0.95 (s, 3 H), 1.78–1.81 (d,
J = 17.45 Hz, 1 H), 2.01–2.05 (d, J = 17.45 Hz, 1 H), 2.12–2.22 (dd, J =
16.35, 13.70 Hz, 2 H), 3.78 (s, 3 H), 3.98 (s, 2 H, NH2), 4.71 (s, 1 H),
6.84–6.86 (d, J = 8.55 Hz, 2 H), 7.27–7.31 (m, 4 H), 7.58–7.59 (m, 3 H).
13C NMR (125 MHz, CDCl3):  = 26.95, 29.44, 32.40, 35.64, 41.70,
49.93, 63.08, 112.93, 120.64, 128.60, 128.70, 129.72, 130.45, 130.71,
132.33, 136.11, 144.13, 149.26, 150.21, 195.55.
13C NMR (125 MHz, CDCl3):  = 27.01, 29.45, 32.40, 35.23, 41.69,
50.01, 63.91, 113.48, 113.94, 120.93, 128.17, 129.78, 130.30, 130.60,
136.36, 138.06, 148.85, 149.94, 158.28, 195.68.
2-Amino-4-(4-bromophenyl)-7,7-dimethyl-5-oxo-1-phenyl-
1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile (3ag)6a
2-Amino-4-(4-cyanophenyl)-7,7-dimethyl-5-oxo-1-phenyl-
1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile (3am)
Yield: 174 mg (97%); yellow solid; mp 263–264 °C.
Yield: 41.0 mg (26%); brown solid; mp 263–264 °C.
IR (KBr): 3646, 3626, 3606, 3593, 3584, 3564, 3542, 3463, 3330, 3217,
2953, 2352, 2177, 1681, 1651, 1621, 1593, 1567, 1557, 1487, 1415,
IR (KBr): 3626, 3606, 3593, 3584, 3564, 3469, 3340, 2958, 2224, 2196,
2177, 1650, 1615, 1594, 1565, 1492, 1463, 1416, 1373, 1258, 1143,
1385, 1371, 1258, 1144, 1068, 1039, 1007, 839, 696, 574, 515 cm–1
.
1042, 866, 845, 704, 576 cm–1
.
1H NMR (500 MHz, CDCl3):  = 0.82 (s, 3 H), 0.95 (s, 3 H), 1.77–1.81 (d,
J = 17.35 Hz, 1 H), 2.02–2.05 (d, J = 17.35 Hz, 1 H), 2.12–2.22 (dd, J =
16.35, 8.90 Hz, 2 H), 4.05 (s, 2 H, NH2), 4.73 (s, 1 H), 7.23–7.29 (m, 4
H), 7.43–7.44 (m, 2 H), 7.59–7.60 (m, 3 H).
1H NMR (500 MHz, CDCl3):  = 0.82 (s, 3 H), 0.96 (s, 3 H), 1.80–1.83 (d,
J = 17.45 Hz, 1 H), 2.04–2.07 (d, J = 17.45 Hz, 1 H), 2.12–2.23 (dd, J =
16.35, 8.90 Hz, 2 H), 4.09 (s, 2 H, NH2), 4.82 (s, 1 H), 7.29–7.31 (m, 2
H), 7.46–7.48 (d, J = 8.25 Hz, 2 H), 7.61–7.63 (m, 5 H).
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–H

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W. Han et al.
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Synthesis
13C NMR (125 MHz, CDCl3):  = 26.96, 29.38, 32.42, 36.60, 41.74,
49.84, 62.26, 110.50, 112.20, 119.06, 120.32, 128.08, 129.66, 130.64,
132.55, 135.83, 149.78, 150.42, 150.75, 195.45.
HRMS (ESI): m/z [M + Na]+ calcd for C25H22N4NaO: 417.1686; found:
417.1696.
2-Amino-7,7-dimethyl-4-(1-naphthyl)-5-oxo-1-phenyl-1,4,5,6,7,8-
hexahydroquinoline-3-carbonitrile (3aq)
Yield: 53.7 mg (32%); yellow solid; mp 247–249 °C.
IR (KBr): 3626, 3606, 3593, 3573, 3564, 3460, 3342, 2959, 2922, 2175,
1651, 1594, 1565, 1492, 1415, 1374, 1259, 1240, 1140, 1040, 794,
781, 708, 575, 550 cm–1
.
2-Amino-4-[4-(methoxycarbonyl)phenyl]-7,7-dimethyl-5-oxo-1-
phenyl-1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile (3an)
1H NMR (500 MHz, CDCl3):  = 0.89 (s, 3 H), 0.98 (s, 3 H), 1.90–1.94 (d,
J = 17.45 Hz, 1 H), 2.09–2.14 (dd, J = 12.05, 5.75 Hz, 2 H), 2.18–2.21 (d,
J = 17.45 Hz, 1 H), 3.95 (s, 2 H, NH2), 5.61 (s, 1 H), 7.38–7.49 (m, 5 H),
7.58–7.64 (m, 4 H), 7.71–7.73 (m, 1 H), 7.81–7.83 (d, J = 8.40 Hz, 1 H),
8.60–8.62 (d, J = 8.95 Hz, 1 H).
13C NMR (125 MHz, CDCl3):  = 26.25, 28.43, 31.38, 40.75, 48.82,
63.59, 112.57, 119.79, 122.87, 123.99, 124.30, 124.62, 125.10, 126.47,
127.47, 128.86, 129.34, 129.61, 130.06, 132.99, 135.30, 141.78,
148.45, 148.81, 194.51.
Yield: 34.2 mg (20%); white solid; mp 254–255 °C.
IR (KBr): 3469, 3329, 2956, 2182, 1721, 1656, 1621, 1609, 1592, 1570,
1488, 1434, 1415, 1373, 1307, 1284, 1258, 1147, 1109, 1044, 1019,
753, 702, 575 cm–1
.
1H NMR (500 MHz, CDCl3):  = 0.81 (s, 3 H), 0.96 (s, 3 H), 1.79–1.82 (d,
J = 17.60 Hz, 1 H), 2.04–2.07 (d, J = 17.60 Hz, 1 H), 2.12–2.22 (dd, J =
16.30, 18.45 Hz, 2 H), 3.89 (s, 3 H), 4.06 (s, 2 H, NH2), 4.82 (s, 1 H),
7.30–7.31 (m, 2 H), 7.43–7.44 (d, J = 8.20 Hz, 2 H), 7.60–7.61 (m, 3 H),
7.99–8.01 (d, J = 8.15 Hz, 2 H).
HRMS (ESI): m/z [M + Na]+ calcd for C28H25N3NaO: 442.1890; found:
442.1879.
13C NMR (125 MHz, CDCl3):  = 26.85, 29.47, 32.38, 36.18, 41.71,
49.89, 52.00, 112.70, 120.53, 127.20, 128.53, 129.71, 130.06, 130.48,
130.70, 136.05, 149.51, 150.33, 150.58, 167.07, 195.48.
2-Amino-7,7-dimethyl-4-(2-naphthyl)-5-oxo-1-phenyl-1,4,5,6,7,8-
hexahydroquinoline-3-carbonitrile (3ar)
HRMS (ESI): m/z [M + Na]+ calcd for C26H25N3NaO3: 450.1788; found:
Yield: 15.1 mg (9%); orange solid; mp 172–173 °C.
450.1802.
IR (KBr): 3458, 3331, 3220, 2955, 2925, 2176, 1653, 1593, 1569, 1491,
1416, 1376, 1367, 1257, 1152, 1142, 1122, 1041, 704, 574 cm–1
.
2-Amino-4-(2-furyl)-7,7-dimethyl-5-oxo-1-phenyl-1,4,5,6,7,8-
hexahydroquinoline-3-carbonitrile (3ao)
1H NMR (500 MHz, CDCl3):  = 0.83 (s, 3 H), 0.96 (s, 3 H), 1.81–1.85 (d,
J = 17.95 Hz, 1 H), 2.06–2.09 (d, J = 17.95 Hz, 1 H), 2.13–2.23 (dd, J =
16.35, 21.70 Hz, 2 H), 4.05 (s, 2 H, NH2), 4.95 (s, 1 H), 7.33–7.62 (m, 8
H), 7.78–7.84 (m, 4 H).
13C NMR (125 MHz, CDCl3):  = 26.93, 29.51, 32.38, 36.13, 41.75,
49.97, 63.43, 113.18, 120.83, 125.41, 125.65, 125.83, 127.53, 128.14,
128.44, 129.77, 130.37, 130.65, 132.56, 133.55, 136.30, 142.73,
149.25, 150.27, 195.62.
Yield: 144 mg (100%); gray solid; mp 222–223 °C.
IR (KBr): 3408, 3327, 3211, 2956, 2176, 1650, 1617, 1593, 1571, 1492,
1409, 1382, 1370, 1276, 1259, 1145, 1036, 1013, 782, 725, 712, 693,
571 cm–1
.
1H NMR (500 MHz, CDCl3):  = 0.86 (s, 3 H), 0.96 (s, 3 H), 1.76–1.80 (d,
J = 17.55 Hz, 1 H), 2.03–2.07 (d, J = 17.55 Hz, 1 H), 2.18–2.25 (dd, J =
16.35, 2.40 Hz, 2 H), 4.08 (s, 2 H, NH2), 4.89 (s, 1 H), 6.16 (d, J = 3.10
Hz, 1 H), 6.28–6.29 (dd, J = 3.10, 1.90 Hz, 1 H), 7.30–7.31 (m, 3 H),
7.56–7.58 (m, 3 H).
HRMS (ESI): m/z [M + Na]+ calcd for C28H25N3NaO: 442.1890; found:
442.1881.
13C NMR (125 MHz, CDCl3):  = 26.63, 29.52, 29.60, 32.39, 41.62,
49.95, 60.56, 104.96, 110.44, 110.69, 120.68, 129.80, 130.30, 130.59,
136.40, 141.41, 150.15, 151.18, 156.66, 195.41.
HRMS (ESI): m/z [M + Na]+ calcd for C22H21N3NaO2: 382.1526; found:
382.1548.
2′-Amino-1,2,5′,6′,7′,8′-hexahydro-7′,7′-dimethyl-2,5′-dioxo-1′-
phenylspiro[3H-indole-3,4′(1′H)-quinoline]-3′-carbonitrile (3at)16
Yield: 65.7 mg (40%); yellow solid; mp 314–315 °C.
IR (KBr): 3467, 3333, 2957, 2196, 2187, 1712, 1689, 1641, 1620, 1592,
1555, 1489, 1470, 1416, 1362, 1336, 1315, 1260, 1222, 1195, 1176,
1152, 1052, 1017, 740, 723, 688, 647, 573 cm–1
.
2-Amino-7,7-dimethyl-5-oxo-1-phenyl-4-(2-thienyl)-1,4,5,6,7,8-
hexahydroquinoline-3-carbonitrile (3ap)
1H NMR (500 MHz, DMSO-d6):  = 0.82 (s, 3 H), 0.89 (s, 3 H), 1.81–
1.84 (d, J = 17.30 Hz, 1 H), 1.92–1.96 (d, J = 17.30 Hz, 1 H), 2.09–2.15
(dd, J = 14.40, 2.65 Hz, 2 H), 5.36 (s, 2 H, NH2), 6.77–6.78 (d, J = 7.60
Hz, 1 H), 6.91–6.94 (t, J = 7.40 Hz, 1 H), 7.12–7.15 (t, J = 7.40 Hz, 1 H),
7.17–7.19 (d, J = 7.60 Hz, 1 H), 7.49–7.64 (m, 5 H), 10.23 (s, NH, 1 H).
13C NMR (125 MHz, DMSO-d6):  = 27.09, 28.69, 32.58, 41.84, 48.98,
49.78, 61.40, 109.31, 110.86, 119.39, 121.87, 123.63, 128.15, 130.42,
130.78, 136.45, 137.13, 141.92, 151.57, 152.35, 179.94, 194.36.
Yield: 137 mg (91%); brown solid; mp 213–214 °C.
IR (KBr): 3457, 3361, 2947, 2867, 2182, 1648, 1628, 1607, 1593, 1564,
1492, 1402, 1378, 1359, 1315, 1287, 1258, 1240, 1142, 1038, 1023,
698, 666, 575 cm–1
.
1H NMR (500 MHz, CDCl3):  = 0.86 (s, 3 H), 0.96 (s, 3 H), 1.74–1.78 (d,
J = 17.40 Hz, 1 H), 2.04–2.07 (d, J = 17.40 Hz, 1 H), 2.18–2.26 (dd, J =
16.50, 4.40 Hz, 2 H), 4.07 (s, 2 H, NH2), 5.11 (s, 1 H), 6.91–6.93 (dd, J =
3.50, 1.50 Hz, 1 H), 7.01–7.02 (d, J = 3.25 Hz, 1 H), 7.11–7.12 (dd, J =
3.50, 1.50 Hz, 1 H), 7.30–7.32 (m, 2 H), 7.57–7.58 (m, 3 H).
Supporting Information
13C NMR (125 MHz, CDCl3):  = 26.80, 29.61, 30.93, 32.36, 41.53,
49.93, 63.25, 113.37, 120.64, 123.52, 123.61, 127.15, 129.82, 130.37,
136.18, 149.12, 150.51, 150.61, 195.45.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1705984. Su
p
p
ortingInformatio
n
Su
p
p
ortingInformatio
n
HRMS (ESI): m/z [M + Na]+ calcd for C22H21N3NaOS: 398.1298; found:
398.1321.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–H

H
W. Han et al.
Paper
Synthesis
References
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© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–H