(4 + 2) cyclization of aza-o-quinone methides with azlactones: construction of biologically important dihydroquinolinone frameworks

Article abstract of DOI:10.1039/d0ob02388d

A base-promoted (4 + 2) cyclization of aza-o-quinone methides (aza-o-QMs)in situgenerated fromN-(o-chloromethyl)aryl amides was established. In this approach, azlactones were utilized as competent two-atom reaction partners to undergo (4 + 2) cyclization with aza-o-QMs, which afforded a series of dihydroquinolinone derivatives in overall good yields (up to 98%). This protocol has not only advanced the development of aza-o-QM-involved reactions, but also offered a useful method for constructing biologically important dihydroquinolinone frameworks.

Full text of DOI:10.1039/d0ob02388d

Organic &
Biomolecular Chemistry
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(4 + 2) cyclization of aza-o-quinone methides with
azlactones: construction of biologically important
dihydroquinolinone frameworks†
Cite this: Org. Biomol. Chem., 2021,
19, 1334
Hai-Qing Wang,‡a Wenjing Ma,‡b Ao Sun,‡a Xin-Yue Sun,a Chao Jiang,*b
a
Yu-Chen Zhang*a and Feng Shi
*
A base-promoted (4 + 2) cyclization of aza-o-quinone methides (aza-o-QMs) in situ generated from N-
(o-chloromethyl)aryl amides was established. In this approach, azlactones were utilized as competent
two-atom reaction partners to undergo (4 + 2) cyclization with aza-o-QMs, which afforded a series of
dihydroquinolinone derivatives in overall good yields (up to 98%). This protocol has not only advanced the
development of aza-o-QM-involved reactions, but also offered a useful method for constructing biologi-
cally important dihydroquinolinone frameworks.
Received 1st December 2020,
Accepted 12th January 2021
DOI: 10.1039/d0ob02388d
rsc.li/obc
tions involving aza-o-QM for the construction of biologically
important nitrogenous heterocyclic frameworks.
Introduction
Heterocyclic compounds, especially nitrogenous and oxyge-
In this context, N-(ortho-chloromethyl)aryl amides have
nous heterocycles are widely distributed in biologically impor- been recognized as a class of important precursors of aza-o-
tant natural products and synthetic pharmaceuticals.1 So, QMs because they can easily transform into aza-o-QMs in the
developing efficient methods toward the construction of presence of a base, thus undergoing cyclization reactions to
heterocyclic scaffolds has become an important goal in the construct nitrogenous scaffolds (Scheme 2).8–11 Nevertheless,
community of synthetic chemistry and medicinal chemistry.2 most of the (4 + n) cyclizations involving aza-o-QMs in situ gen-
In recent years, ortho-quinone methides (o-QMs) have been erated from N-(o-chloromethyl)aryl amides are confined to (4 +
proven to be versatile building blocks for the construction of 1) and (4 + 3) cyclizations (eqn (1) and (2)),8,9 which provide
oxygenous heterocyclic frameworks.3,4 As illustrated in robust methods for the construction of five-membered and
Scheme 1a, both 1,4-addition reactions and (4 + n) cyclizations seven-membered nitrogenous heterocyclic frameworks. In con-
of o-QMs have been well established, and lots of phenol deriva- trast, (4 + 2) cyclizations of such aza-o-QMs have been rarely
tives and oxygen-containing heterocycles have been syn- reported (eqn (3)) although this type of cyclization could con-
thesized efficiently.5,6
struct six-membered nitrogenous cyclic skeletons,10 which are
However, in sharp contrast, aza-o-QMs, a class of analogues frequently found in bioactive molecules. This might be
of o-QMs, have received far less attention from the synthetic ascribed to the challenges in finding suitable two-atom reac-
community in spite of the fact that aza-o-QMs should be con- tion partners for (4 + 2) cyclizations with such precursors of
venient building blocks for constructing nitrogenous hetero- aza-o-QMs in the presence of a base.
cyclic skeletons.7 Consequently, both 1,4-addition reactions
and (4 + n) cyclizations of aza-o-QMs are underdeveloped
(Scheme 1b). Therefore, there is great demand to develop reac-
aSchool of Chemistry and Materials Science, Jiangsu Normal University, Xuzhou,
221116, China. E-mail: fshi@jsnu.edu.cn, zhangyc@jsnu.edu.cn
bCore Facility Center of Affiliated Hospital of Nanjing Medical University, Nanjing,
210029, China. E-mail: jc_484@163.com
†Electronic supplementary information (ESI) available: Original NMR spectra of
products 3–5 and compound I. CCDC 2046973 for compound 3aa. For ESI and
crystallographic data in CIF or other electronic format see DOI: 10.1039/
d0ob02388d
‡These authors contributed equally to the work.
Scheme 1 Comparison of reactions involving o-QM and aza-o-QM.
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Scheme 3 Design of the (4 + 2) cyclization of aza-o-QMs with azlac-
tones for constructing biologically important dihydroquinolinone
frameworks.
It should be noted that the dihydroquinolinone scaffold
exists in many bioactive compounds (Scheme 3b).16 For
instance, compound I is a human glycogen phosphorylase
inhibitor;16a compound II is a chitin synthase inhibitor and an
antifungal agent;16b and compound III is a CCK1 receptor
antagonist.16c So, the designed (4 + 2) cyclization of aza-o-QMs
with azlactones could provide a useful protocol for the con-
struction of biologically important dihydroquinolinone
frameworks.
Scheme 2 Profile of (4 + n) cyclizations involving aza-o-QMs in situ
generated from N-(o-chloromethyl)aryl amides.
The survey of the literature only revealed very limited
examples of (4 + 2) cyclizations of aza-o-QMs in situ generated
from N-(o-chloromethyl)aryl amides (eqn (4)–(6)).10 In these
cases, compatible two-atom reaction partners were discovered
for (4 + 2) cyclizations of aza-o-QMs. For example, Wang’s
group utilized [60]fullerene as an electron-rich olefin (eqn
(4));10a Liu’s group employed 1,3,5-triazinanes as equivalents
of two-atom reaction partners (eqn (5));10b Mo, Lu and co-
workers used substituted furans as electron-rich arenes (eqn
Results and discussion
(6)).10c In spite of these elegant works, (4 + 2) cyclizations of Based on this design, the reaction of N-(o-chloromethyl)aryl
aza-o-QMs in situ generated from N-(o-chloromethyl)aryl amide 1a with azlactone 2a was utilized as a model reaction to
amides are still rather underdeveloped. Thus, it is highly valu- testify the feasibility of our design (Table 1). As expected, in
able to find other competent two-atom reaction partners and the presence of caesium carbonate as a base, the two sub-
to develop (4 + 2) cyclizations of such aza-o-QMs.
strates of 1a and 2a smoothly underwent the designed (4 + 2)
To achieve this goal, and with our long-lasting efforts in cyclization to generate the dihydroquinolinone derivative 3aa
constructing heterocyclic frameworks,12 we designed a base- in a good yield of 77% (entry 1). Because caesium carbonate
promoted (4 + 2) cyclization of this class of aza-o-QMs, belongs to an inorganic base, to increase its effect in organic
wherein azlactones were selected as suitable two-atom reaction solvent (acetonitrile), tetra-butylammonium bromide (TBAB)
partners (Scheme 3a). This design was based on the consider- as a phase-transfer catalyst was added to the reaction mixture,
ation that azlactone can utilize its C4,C5-reactivity to serve as which indeed increased the yield to 87% (entry 2). Then, the
two-atom synthons and perform (2 + n) cyclizations.13–15 In evaluation of different solvents such as tetrahydrofuran, di-
addition, azlactones can be promoted by a base via deprotona- chloromethane and toluene revealed that no other solvents
tion to generate the enolates of azlactones. As illustrated in were better than acetonitrile in terms of yield (entries 3–5 vs.
Scheme 3a, in the presence of a base, the enolates of azlac- entry 2). Next, different bases including an organic base (NEt3)
tones would undergo 1,4-addition with aza-o-QMs which are and inorganic bases (NaHCO3 and Na2CO3) were evaluated for
generated from N-(o-chloromethyl)aryl amides, thus affording this reaction (entries 6–8), and it was discovered that these
intermediates A. Then, intermediates A would undergo an bases were inferior to caesium carbonate in promoting the
intramolecular aminolysis of the ester group and a ring- reaction (entries 6–8 vs. entry 2). Subsequently, the reagent
opening reaction, thus accomplishing the (4 + 2) cyclization ratio was carefully modulated (entries 9–13), and it was found
and constructing the dihydroquinolinone scaffold.
that suitably increasing the amount of azlactone 2a could
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Table 1 Optimization of reaction conditionsa
Table 2 Substrate scope of N-(o-chloromethyl)aryl amides 1a
Entry
Solvent
Base
1a : 2a
Additive
Yieldb (%) Entry
R (1)
3
Yieldb (%)
1c
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
CH3CN
CH3CN
THF
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
NEt3
NaHCO3
Na2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
1 : 1.5
1 : 1.5
1 : 1.5
1 : 1.5
1 : 1.5
1 : 1.5
1 : 1.5
1 : 1.5
1 : 2
1 : 3
1.5 : 1
2 : 1
3 : 1
1 : 3
—
—
—
—
—
—
—
—
—
—
—
—
77
87
85
85
44
84
44
51
90
91
81
90
87
93
98
91
91
92
1
2
3
4
5
6
7
H (1a)
3aa
3ba
3ca
3da
3ea
3fa
92
86
91
84
98
91
88
6-Me (1b)
5-Cl (1c)
4-Me (1d)
4-Cl (1e)
3-Me (1f)
3-Cl (1g)
CH2Cl2
Toluene
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
3ga
a The reaction was carried out on a 0.1 mmol scale in CH3CN (1 mL)
with MgSO4 (100 mg) as an additive for 3 h, and the molar ratio of
1 : 2a was 1 : 3. b Isolated yield.
—
Na2SO4
MgSO4
3 Å MS
4 Å MS
5 Å MS
Table 3 Substrate scope of azlactones 2a
1 : 3
1 : 3
1 : 3
1 : 3
a Unless indicated otherwise, the reaction was carried out on a
0.1 mmol scale at room temperature (r.t.) in a solvent (1 mL) without
or with an additive (100 mg) for 3 h. b Determined by 1H NMR. c In the
absence of TBAB.
Entry
R1/R2 (2)
3
Yieldb (%)
1
2
3
4
5
6
7
8
Ph/o-ClC6H4 (2b)
Ph/p-ClC6H4 (2c)
o-FC6H4/Ph (2d)
m-ClC6H4/Ph (2e)
p-ClC6H4/Ph (2f)
p-MeOC6H4/Ph (2g)
Ph/CO2Et (2h)
o-FC6H4/CO2Et (2i)
o-MeC6H4/CO2Et (2j)
m-ClC6H4/CO2Et (2k)
p-CF3C6H4/CO2Et (2l)
p-MeC6H4/CO2Et (2m)
Me/CO2Et (2n)
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
3aj
3ak
3al
3am
3an
3hn
79
87
78
75
77
81
85
60
62
81
81
75
78
82
further improve the yield to 91% (entry 10). Finally, some addi-
tives such as anhydrous sulfates and different molecular sieves
(MS) were added to the reaction system (entries 14–18), and it
was revealed that the addition of magnesium sulfate could
greatly enhance the yield to 98% (entry 15). So, the reaction
conditions as illustrated in entry 15 were chosen as the
optimal conditions for this (4 + 2) cyclization.
9
10
11
12
13c
14c,d
After establishing the optimal reaction conditions, we
studied the generality of the (4 + 2) cyclization between N-(o-
chloromethyl)aryl amides 1 and azlactones 2. First, the sub-
strate scope of N-(o-chloromethyl)aryl amides 1 was investi-
gated (Table 2). It was discovered that a range of N-(o-chloro-
methyl)aryl amides 1 bearing a methyl group or a chloro-group
at different positions of the phenyl ring could successfully par-
ticipate in the (4 + 2) cyclization with azlactone 2a, which gen-
Me/CO2Et (2n)
a The reaction was carried out on a 0.1 mmol scale in CH3CN (1 mL)
with MgSO4 (100 mg) as an additive for 3 h, and the molar ratio of 1a:2
was 1 : 3. b Isolated yield. c The molar ratio of 1a : 2n was 1 : 1.2. d Using
N-Boc-protected 1h as a reactant.
erated dihydroquinolinone derivatives 3 in high isolated yields and 8–12). More importantly, an aliphatic methyl group could
(84%–98%), which demonstrated that this reaction was amen- serve as a suitable R1 group for substrate 2n, which success-
able to various N-(o-chloromethyl)aryl amides 1.
fully participated in the (4 + 2) cyclizations with 1a and N-Boc-
Then, the substrate scope of azlactones 2 was investigated protected 1h to give products 3an and 3hn in high yields
by their reaction with N-(o-chloromethyl)aryl amide 1a under (entries 13 and 14). So, this (4 + 2) cyclization could be appli-
standard reaction conditions (Table 3). In general, a variety of cable to a series of azlactones 2.
azlactones
2
bearing different R1/R2 substituents could
To further improve the generality of the substrate scope, we
smoothly take part in the (4 + 2) cyclization, which gave rise to utilized azlactones 2 bearing alkyl (R2) groups as substrates in
dihydroquinolinone derivatives 3 with structural diversity in the (4 + 2) cyclization (Table 4). Initially, the reaction of N-Ts-
moderate to good yields (60%–87%). In detail, R2 groups could protected amide 1a with benzyl-substituted azlactone 2o was
be substituted phenyl (entries 1 and 2), phenyl (entries 3–6) performed under standard conditions, which could undergo
and ester (entries 7–14) groups. Moreover, R1 groups could be the desired (4 + 2) cyclization to give product 3ao albeit with a
a wide range of phenyl groups bearing electronically different low yield of 40% (entry 1). To improve the yield, N-Boc-pro-
substituents at ortho-, meta-, and para-positions (entries 3–6 tected amide 1h was utilized as a reaction partner for azlactone
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Table 4 Application of azlactones 2 bearing alkyl (R2) groups as sub-
strates in the reactiona
Entry
R1 (1)
R2 (2)
3
Yieldb (%)
1c
2
3
4
5
Ts (1a)
Bn (2o)
Bn (2o)
Me (2p)
i-Pr (2q)
Allyl (2r)
3ao
3ho
3hp
3hq
3hr
40
75
82
58
73
Boc (1h)
Boc (1h)
Boc (1h)
Boc (1h)
a The reaction was carried out on a 0.1 mmol scale with 1.1 equiv. DBU
in CH3CN (1 mL) at r.t. for 3 h, and the molar ratio of 1 : 2 was 1 : 1.2.
b Isolated yield. c Catalyzed by 10 mol% TBAB and 1.1 equiv. Cs2CO3 in
CH3CN (1 mL) with MgSO4 (100 mg) as an additive at r.t. for 3 h, and
the molar ratio of 1a : 2o was 1 : 1.2.
Scheme 4 One-mmol-scale reactions and deprotection of N-Ts.
2o under modified reaction conditions, which smoothly
underwent (4 + 2) cyclization to afford product 3ho in a good
yield of 75% (entry 2). Furthermore, it was revealed that the (4
+
2) cyclization could tolerate azlactones 2p–2r bearing
different alkyl (R2) groups such as methyl, iso-propyl and allyl
groups, which generated products 3hp–3hr in moderate to
good yields (entries 3–5).
The structures of dihydroquinolinone derivatives 3 were
determined based on their H NMR, 13C NMR, IR and HR MS
spectra. In addition, the structure of product 3aa was con-
firmed by X-ray analysis of its single crystal (Fig. 1).17
1
Scheme 5 Synthesis of bioactive molecules.
To examine whether the reaction could be scaled up or not,
two one-mmol-scale reactions of N-Ts-protected amide 1a with
azlactone 2a and N-Boc-protected amide 1h with azlactone 2n
were carried out under standard conditions (Scheme 4, eqn (7)
and (8)). These (4 + 2) cyclization reactions smoothly occurred
to give products 3aa and 3hn in good yields, which were com-
parable to those of the small-scale reactions (Table 2, entry 1;
Table 3, entry 14). These results demonstrated that this (4 + 2)
cyclization reaction could be scaled up without sacrifice of the
yield. In addition, the deprotection of the N-Ts group in
product 3aa could be successfully performed with the action of
samarium(II) iodide, generating NH-unprotected product 4 in a
good yield of 70% (Scheme 4, eqn (9)).
pound 5 underwent decarboxylation reaction to give an inter-
mediate product 6, which directly reacted with 5-chloroindole-
2-carboxylic acid without isolation to afford compound I as an
inhibitor of human glycogen phosphorylase in a total yield of
72% over three steps.
Conclusions
In summary, we have established a base-promoted (4 + 2) cycli-
zation of aza-o-QMs in situ generated from N-(o-chloromethyl)
aryl amides, which utilized azlactones as competent two-atom
reaction partners. By this approach, a series of dihydroquinoli-
none derivatives were synthesized in overall good yields. This
reaction has not only enriched the research contents of aza-o-
QM-involved reactions, but also provided a useful protocol for
constructing biologically important dihydroquinolinone
frameworks.
Finally, to demonstrate the utility of this methodology, the
synthesis of the bioactive molecule (compound I, in
Scheme 3b) was performed by using 3hn as a starting material
(Scheme 5). In brief, the deprotection of the N-Boc group in
3hn generated compound 5 in a high yield of 85%. Then, com-
Experimental
General information
1H and 13C NMR spectra were measured at 400 and 100 MHz,
respectively. The solvents used for NMR spectroscopy were
CDCl3 and DMSO-d6, using tetramethylsilane as the internal
Fig. 1 X-ray single-crystal structure of 3aa.
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reference. HRMS (ESI) was determined using a HRMS/MS (C29H23ClN2O4S + Na)+ requires m/z 553.0959, found m/z
instrument. The X-ray source used for the single crystal X-ray 553.0967.
diffraction analysis of compound 3aa was MoKα (λ = 0.71073),
N-(6-Methyl-2-oxo-3-phenyl-1-tosyl-1,2,3,4-tetrahydroquinolin-
and the thermal ellipsoid was drawn at the 30% probability 3-yl)benzamide (3da). Yield: 84% (42.8 mg); white solid;
1
level. Analytical grade solvents for column chromatography m.p. 222–224 °C; H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 8.4
were distilled before use. All commercially available starting Hz, 2H), 7.64 (d, J = 7.6 Hz, 2H), 7.57 (s, 1H), 7.48–7.41 (m,
materials were used directly. Substrates 1 and 2 were syn- 2H), 7.39–7.32 (m, 4H), 7.28–7.27 (m, 1H), 7.17–7.08 (m, 4H),
thesized according to the literature methods.8,13
6.98 (d, J = 8.4 Hz, 1H), 4.44 (d, J = 15.6 Hz, 1H), 3.43 (d, J =
15.6 Hz, 1H), 2.47 (s, 3H), 2.31 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 171.0, 165.7, 145.3, 137.0, 136.3, 135.2, 134.3, 131.7,
129.6, 129.1, 128.7, 128.5, 128.3, 128.0, 127.7, 127.1, 127.0,
123.2, 63.2, 33.7, 21.8, 21.0; IR (KBr): 3567, 1701, 1664, 1498,
1275, 764, 750, 668, 559 cm−1; ESI FTMS exact mass calcd for
Typical procedure for the synthesis of products 3
N-(o-Chloromethyl)aryl amides 1 (0.1 mmol), azlactones 2
(0.3 mmol), Cs2CO3 (0.11 mmol), TBAB (0.01 mmol) and
MgSO4 (100 mg) were added to a reaction tube. Then, CH3CN
(1 mL) was added to the reaction mixture, which was stirred at
r.t. for 3 h. After the completion of the reaction which was
indicated by TLC, the reaction mixture was directly purified
through preparative thin layer chromatography on silica gel to
afford pure products 3.
(C30H26N2O4S
533.1510.
+
Na)+ requires m/z 533.1505, found m/z
N-(6-Chloro-2-oxo-3-phenyl-1-tosyl-1,2,3,4-tetrahydroquinolin-
3-yl)benzamide (3ea). Yield: 98% (51.9 mg); white solid;
1
m.p. 149–151 °C; H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 8.0
Hz, 2H), 7.61 (d, J = 8.0 Hz, 2H), 7.51 (d, J = 8.8 Hz, 1H),
7.47–7.42 (m, 1H), 7.42–7.33 (m, 5H), 7.27–7.29 (m, 2H),
7.19–7.12 (m, 4H), 4.33 (d, J = 15.6 Hz, 1H), 3.59 (d, J = 15.6
Characterization of products 3
N-(2-Oxo-3-phenyl-1-tosyl-1,2,3,4-tetrahydroquinolin-3-yl)benz- Hz, 1H), 2.47 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.4,
amide (3aa). Yield: 92% (45.6 mg); white solid; 166.0, 145.7, 135.9, 134.9, 134.1, 132.8, 132.2, 131.8, 129.8,
1
m.p. 190–192 °C; H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 8.0 129.7, 128.9, 128.7, 128.6, 128.3, 127.5, 127.0, 126.9, 124.6,
Hz, 2H), 7.64 (d, J = 7.2 Hz, 2H), 7.57–7.52 (m, 2H), 7.48–7.43 63.3, 33.8, 21.8; IR (KBr): 3446, 1730, 1665, 1481, 1174, 749,
(m, 1H), 7.40–7.34 (m, 4H), 7.33–7.30 (m, 1H), 7.27–7.23 (m, 666, 566 cm−1; ESI FTMS exact mass calcd for (C29H23ClN2O4S
2H), 7.20–7.15 (m, 2H), 7.14–7.07 (m, 3H), 4.50 (d, J = 15.6 Hz, + Na)+ requires m/z 553.0959, found m/z 553.0973.
1H), 3.47 (d, J = 16.0 Hz, 1H), 2.48 (s, 3H); 13C NMR (100 MHz,
N-(5-Methyl-2-oxo-3-phenyl-1-tosyl-1,2,3,4-tetrahydroquinolin-
CDCl3) δ 171.0, 165.8, 145.5, 136.3, 135.0, 134.3, 134.2, 131.8, 3-yl)benzamide (3fa). Yield: 91% (46.4 mg); white solid;
1
129.7, 128.8, 128.7, 128.6, 128.4, 128.0, 127.6, 127.2, 127.1, m.p. 207–209 °C; H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 8.0
127.0, 123.4, 63.2, 33.8, 21.9; IR (KBr): 3406, 3027, 1698, 1508, Hz, 2H), 7.65 (d, J = 8.0 Hz, 2H), 7.56 (s, 1H), 7.50–7.42 (m,
1476, 1375, 741, 698, 616 cm−1; ESI FTMS exact mass calcd for 1H), 7.40–7.33 (m, 5H), 7.23–7.17 (m, 2H), 7.15–7.09 (m, 3H),
(C29H24N2O4S
519.1340.
+
Na)+ requires m/z 519.1349, found m/z 7.09–6.99 (m, 2H), 4.64 (d, J = 15.6 Hz, 1H), 3.25 (d, J = 16.0
Hz, 1H), 2.48 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 171.0,
N-(8-Methyl-2-oxo-3-phenyl-1-tosyl-1,2,3,4-tetrahydroquinolin-3- 165.8, 145.4, 136.3, 135.6, 135.5, 134.3, 134.1, 131.8, 129.6,
yl)benzamide (3ba). Yield: 86% (43.9 mg); white solid; 128.8, 128.7, 128.5, 128.4, 128.3, 127.0, 126.9, 126.7, 121.4,
1
m.p. 147–149 °C; H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 8.0 63.5, 29.9, 21.8, 19.8; IR (KBr): 3650, 1701, 1670, 1473, 1265,
Hz, 2H), 7.56 (d, J = 7.6 Hz, 2H), 7.48–7.43 (m, 2H), 7.38–7.33 748, 668, 570 cm−1
;
ESI FTMS exact mass calcd for
(m, 4H), 7.27–7.25 (m, 2H), 7.16–7.06 (m, 5H), 7.02–7.00 (d, (C30H26N2O4S
1H), 4.46 (d, J = 15.6 Hz, 1H), 3.10 (d, J = 15.6 Hz, 1H), 2.44 (s, 533.1498.
+
Na)+ requires m/z 533.1505, found m/z
3H), 2.35 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 172.8, 165.5,
N-(5-Chloro-2-oxo-3-phenyl-1-tosyl-1,2,3,4-tetrahydroquinolin-
145.7, 136.0, 135.7, 135.0, 134.4, 133.7, 131.7, 130.5, 130.4, 3-yl)benzamide (3ga). Yield: 88% (46.6 mg); white solid;
1
129.5, 128.5, 128.2, 128.1, 127.7, 127.0, 126.9, 126.2, 64.2, 33.9, m.p. 123–125 °C; H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 8.4
21.8, 20.0; IR (KBr): 3404, 1670, 1508, 1475, 1363, 764, 699, Hz, 2H), 7.63 (d, J = 8.0 Hz, 2H), 7.48–7.42 (m, 2H), 7.41–7.33
668 cm−1; ESI FTMS exact mass calcd for (C30H26N2O4S + Na)+ (m, 4H), 7.32–7.27 (m, 3H), 7.23 (d, J = 8.0 Hz, 1H), 7.20–7.14
requires m/z 533.1505, found m/z 533.1508.
(m, 3H), 7.13–7.08 (m, 1H), 4.82 (d, J = 16.4 Hz, 1H), 3.45 (d, J
N-(7-Chloro-2-oxo-3-phenyl-1-tosyl-1,2,3,4-tetrahydroquinolin-3- = 16.0 Hz, 1H), 2.49 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
yl)benzamide (3ca). Yield: 91% (48.2 mg); white solid; 170.3, 165.9, 145.7, 135.9, 135.3, 134.7, 134.1, 133.0, 131.8,
1
m.p. 141–143 °C; H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 8.0 129.7, 128.9, 128.8, 128.7, 128.6, 127.7, 127.0, 126.9, 126.8,
Hz, 2H), 7.63–7.61 (m, 3H), 7.49–7.41 (m, 2H), 7.41–7.33 (m, 122.1, 63.5, 30.5, 21.9; IR (KBr): 3588, 1734, 1655, 1475, 1274,
4H), 7.25–7.19 (m, 3H), 7.16–7.13 (m, 4H), 4.42 (d, J = 15.6 Hz, 764, 668, 568 cm−1
; ESI FTMS exact mass calcd for
1H), 3.52 (d, J = 15.6 Hz, 1H), 2.49 (s, 3H); 13C NMR (100 MHz, (C29H23ClN2O4S + Na)+ requires m/z 553.0959, found m/z
CDCl3) δ 170.5, 165.9, 145.7, 135.9, 135.0, 134.8, 134.1, 132.8, 553.0967.
131.8, 129.7, 129.5, 128.8, 128.6, 128.5, 127.0, 126.9, 126.3,
N-(3-(2-Chlorophenyl)-2-oxo-1-tosyl-1,2,3,4-tetrahydroquinolin-
123.4, 63.1, 33.4, 21.8; IR (KBr): 3588, 1730, 1508, 1476, 1173, 3-yl)benzamide (3ab). Yield: 79% (41.9 mg); white solid;
1
747, 668, 564 cm−1
; ESI FTMS exact mass calcd for m.p. 228–230 °C; H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.4
1338 | Org. Biomol. Chem., 2021, 19, 1334–1343
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Hz, 2H), 7.71–7.59 (m, 4H), 7.49–7.42 (m, 1H), 7.39–7.31 (m, 136.2, 134.9, 134.1, 132.6, 129.6, 128.8, 128.7, 128.5, 128.4,
4H), 7.25–7.12 (m, 5H), 7.08–7.02 (m, 1H), 6.97–6.91 (m, 1H), 127.8, 127.4, 127.1, 127.0, 123.3, 63.3, 33.7, 21.8; IR (KBr):
4.46 (d, J = 15.6 Hz, 1H), 3.53 (d, J = 16.0 Hz, 1H), 2.45 (s, 3H); 3502, 1731, 1655, 1474, 1362, 1173, 750, 562 cm−1; ESI FTMS
13C NMR (100 MHz, CDCl3) δ 170.2, 166.0, 145.3, 135.8, 134.7, exact mass calcd for (C29H23ClN2O4S + H)+ requires m/z
134.3, 132.8, 132.1, 131.8, 131.5, 131.2, 129.7, 129.5, 128.9, 531.1140, found m/z 531.1148.
128.6, 128.4, 128.2, 127.6, 127.1, 127.0, 126.0, 123.6, 63.9, 34.2,
4-Methoxy-N-(2-oxo-3-phenyl-1-tosyl-1,2,3,4-tetrahydroquino-
21.8; IR (KBr): 3537, 1731, 1655, 1476, 1173, 751, 656, lin-3-yl)benzamide (3ag). Yield: 81% (42.6 mg); white solid;
1
562 cm−1; ESI FTMS exact mass calcd for (C29H23ClN2O4S + m.p. 118–120 °C; H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 8.4
H)+ requires m/z 531.1140, found m/z 531.1143.
Hz, 2H), 7.61 (d, J = 8.8 Hz, 2H), 7.57–7.52 (m, 1H), 7.46 (s,
N-(3-(4-Chlorophenyl)-2-oxo-1-tosyl-1,2,3,4-tetrahydroquinolin- 1H), 7.37 (d, J = 8.0 Hz, 2H), 7.33–7.28 (m, 1H), 7.25–7.23 (m,
3-yl)benzamide (3ac). Yield: 87% (46.1 mg); white solid; 1H), 7.20–7.15 (m, 2H), 7.13–7.07 (m, 3H), 6.85 (d, J = 8.8 Hz,
1
m.p. 156–158 °C; H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 8.4 2H), 4.48 (d, J = 16.0 Hz, 1H), 3.80 (s, 3H), 3.49 (d, J = 15.6 Hz,
Hz, 2H), 7.69–7.62 (m, 3H), 7.61–7.54 (m, 1H), 7.50–7.43 (m, 1H), 2.47 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 171.1, 165.3,
1H), 7.42–7.31 (m, 5H), 7.25–7.14 (m, 4H), 7.07 (d, J = 8.8 Hz, 162.4, 145.4, 136.2, 135.2, 134.2, 129.6, 128.8, 128.7, 128.3,
2H), 4.56 (d, J = 15.6 Hz, 1H), 3.35 (d, J = 15.6 Hz, 1H), 2.47 (s, 128.0, 127.3, 127.2, 127.0, 126.5, 123.3, 113.7, 63.1, 55.5, 33.9,
3H); 13C NMR (100 MHz, CDCl3) δ 170.7, 165.7, 136.0, 134.3, 21.8; IR (KBr): 3565, 1729, 1660, 1474, 1174, 750, 560 cm−1
;
134.0, 133.4, 131.9, 129.7, 128.7, 128.6, 128.5, 127.6, 127.3, ESI FTMS exact mass calcd for (C30H26N2O5S + H)+ requires
127.0, 123.5, 62.4, 33.5, 21.9; IR (KBr): 3447, 1727, 1663, 1478, m/z 527.1635, found m/z 527.1633.
1173, 750, 652, 556 cm−1; ESI FTMS exact mass calcd for
Ethyl 3-benzamido-2-oxo-1-tosyl-1,2,3,4-tetrahydroquinoline-
(C29H23ClN2O4S + H)+ requires m/z 531.1140, found m/z 3-carboxylate (3ah). Yield: 85% (41.8 mg); white solid;
1
531.1154.
m.p. 158–160 °C; H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 8.4
2-Fluoro-N-(2-oxo-3-phenyl-1-tosyl-1,2,3,4-tetrahydroquinolin- Hz, 2H), 7.71–7.69 (m, 3H), 7.54–7.48 (m, 1H), 7.44–7.32 (m,
3-yl)benzamide (3ad). Yield: 78% (40.1 mg); white solid; 5H), 7.28–7.20 (m, 3H), 4.01–3.85 (m, 2H), 3.60 (q, J = 15.2 Hz,
m.p. 154–156 °C; 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 13.2 2H), 2.46 (s, 3H), 0.83 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
Hz, 1H), 7.94 (d, J = 8.4 Hz, 2H), 7.88–7.79 (m, 1H), 7.58–7.53 CDCl3) δ 166.6, 166.5, 166.4, 145.4, 136.0, 134.8, 133.2, 132.1,
(m, 1H), 7.44–7.39 (m, 1H), 7.36 (d, J = 8.4 Hz, 2H), 7.31–7.27 129.6, 128.9, 128.8, 128.6, 127.7, 127.2, 126.8, 126.3, 122.9,
(m, 2H), 7.22–7.15 (m, 3H), 7.15–7.11 (m, 3H), 7.08–7.01 (m, 65.2, 62.7, 34.3, 21.8, 13.4; IR (KBr): 3447, 1734, 1654, 1489,
1H), 4.34 (d, J = 15.6 Hz, 1H), 3.60 (d, J = 15.6 Hz, 1H), 2.46 (s, 1260, 749, 575 cm−1
;
ESI FTMS exact mass calcd for
3H); 13C NMR (100 MHz, CDCl3) δ 170.4, 161.8, 160.6 (J = (C26H24N2O6S
247.0 Hz), 145.4, 135.1, 134.2, 133.6 (J = 9.2 Hz), 131.7, 131.6, 493.1432.
+
H)+ requires m/z 493.1428, found m/z
129.7, 129.6, 128.9, 128.6, 128.4, 127.8, 127.4, 127.2, 127.0,
Ethyl 3-(2-fluorobenzamido)-2-oxo-1-tosyl-1,2,3,4-tetrahydro-
124.6 (J = 3.2 Hz), 123.4, 121.1 (J = 11.4 Hz), 116.1 (J = 24.7 quinoline-3-carboxylate (3ai). Yield: 60% (30.6 mg); white
1
Hz), 63.7, 34.0, 21.8; 19F NMR (376 MHz, CDCl3) δ −112.3; IR solid; m.p. 153–155 °C; H NMR (400 MHz, CDCl3) δ 8.00 (d,
(KBr): 3403, 1705, 1670, 1478, 1173, 751, 698, 563 cm−1; ESI J = 8.0 Hz, 2H), 7.93–7.86 (m, 1H), 7.80–7.67 (m, 2H), 7.52–7.43
FTMS exact mass calcd for (C29H23FN2O4S + H)+ requires m/z (m, 1H), 7.36–7.34 (m, 3H), 7.25–7.17 (m, 3H), 7.15–7.06 (m,
515.1436, found m/z 515.1441.
1H), 4.04–3.85 (m, 2H), 3.68 (d, J = 15.2 Hz, 1H), 3.46 (d, J =
3-Chloro-N-(2-oxo-3-phenyl-1-tosyl-1,2,3,4-tetrahydroquinolin- 15.2 Hz, 1H), 2.45 (s, 3H), 0.82 (t, J = 7.2 Hz, 3H); 13C NMR
3-yl)benzamide (3ae). Yield: 75% (39.8 mg); white solid; (100 MHz, CDCl3) δ 166.6, 166.2, 162.4, 160.8 (J = 248.7 Hz),
1
m.p. 165–167 °C; H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 8.4 145.2, 136.0, 135.1, 134.0 (J = 9.3 Hz), 132.0, 129.5, 129.0,
Hz, 2H), 7.62–7.58 (m, 1H), 7.58–7.53 (m, 1H), 7.50–7.48 (m, 128.6, 127.8, 126.6, 125.9, 124.8, 124.7, 122.9, 120.0 (J = 11.3
2H), 7.44–7.36 (m, 3H), 7.33–7.27 (m, 2H), 7.25–7.22 (m, 2H), Hz), 116.1 (J = 24.7 Hz), 65.5, 62.7, 34.7, 21.8, 13.4; 19F NMR
7.21–7.15 (m, 2H), 7.14–7.08 (m, 3H), 4.41 (d, J = 15.6 Hz, 1H), (376 MHz, CDCl3) δ −112.1; IR (KBr): 3567, 1734, 1613, 1480,
3.53 (d, J = 15.6 Hz, 1H), 2.49 (s, 3H); 13C NMR (100 MHz, 1363, 1175, 751, 576 cm−1; ESI FTMS exact mass calcd for
CDCl3) δ 170.8, 164.5, 145.5, 136.1, 136.0, 134.8, 134.7, 134.1, (C26H23FN2O6S
+
H)+ requires m/z 511.1334, found m/z
131.8, 129.8, 129.6, 128.8, 128.7, 128.5, 128.4, 127.7, 127.4, 511.1352.
127.1, 127.0, 125.0, 123.3, 63.4, 33.7, 21.9; IR (KBr): 3397,
Ethyl
3-(2-methylbenzamido)-2-oxo-1-tosyl-1,2,3,4-tetrahy-
1725, 1664, 1490, 1173, 749, 562 cm−1; ESI FTMS exact mass droquinoline-3-carboxylate (3aj). Yield: 62% (31.4 mg); white
calcd for (C29H23ClN2O4S + Na)+ requires m/z 553.0959, found solid; m.p. 156–158 °C; H NMR (400 MHz, CDCl3) δ 7.97 (d,
1
m/z 553.0957.
J = 8.0 Hz, 2H), 7.72 (d, J = 8.4 Hz, 1H), 7.40–7.34 (m, 2H),
4-Chloro-N-(2-oxo-3-phenyl-1-tosyl-1,2,3,4-tetrahydroquinolin- 7.33–7.27 (m, 3H), 7.26–7.20 (m, 2H), 7.20–7.12 (m, 2H), 6.78
3-yl)benzamide (3af). Yield: 77% (40.8 mg); white solid; (s, 1H), 4.02–3.84 (m, 2H), 3.70 (d, J = 14.8 Hz, 1H), 3.49 (d, J =
1
m.p. 174–176 °C; H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 8.4 14.8 Hz, 1H), 2.43 (s, 3H), 2.25 (s, 3H), 0.86 (t, J = 7.2 Hz, 3H);
Hz, 2H), 7.70–7.62 (m, 3H), 7.59–7.55 (m, 1H), 7.50–7.44 (m, 13C NMR (100 MHz,) δ 169.3, 166.7, 166.3, 145.5, 145.4, 136.8,
1H), 7.40–7.32 (m, 5H), 7.24–7.17 (m, 4H), 7.07 (d, J = 8.8 Hz, 136.0, 135.0, 134.9, 131.1, 130.5, 129.6, 129.2, 128.8, 127.8,
2H), 4.56 (d, J = 15.6 Hz, 1H), 3.35 (d, J = 15.6 Hz, 1H), 2.47 (s, 127.0, 126.8, 126.2, 125.8, 123.1, 65.4, 62.6, 34.5, 21.8, 19.7,
3H); 13C NMR (100 MHz, CDCl3) δ 170.9, 164.8, 145.5, 138.0, 13.5; IR (KBr): 3367, 1732, 1664, 1488, 1363, 1189, 743,
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576 cm−1; ESI FTMS exact mass calcd for (C27H26N2O6S + Na)+ = 16.0 Hz, 1H), 2.07 (s, 3H), 1.61 (s, 9H), 1.00 (t, J = 8.0 Hz,
requires m/z 529.1404, found m/z 529.1396.
3H); 13C NMR (100 MHz, CDCl3) δ 170.0, 166.3, 163.9, 150.8,
Ethyl 3-(3-chlorobenzamido)-2-oxo-1-tosyl-1,2,3,4-tetrahydro- 135.0, 128.8, 127.5, 125.1, 123.6, 116.3, 86.1, 62.4, 62.1, 34.3,
quinoline-3-carboxylate (3ak). Yield: 81% (42.6 mg); white 27.6, 23.4, 13.7; IR (KBr): 3177, 1747, 1668, 1504, 1146, 753,
1
solid; m.p. 198–200 °C; H NMR (400 MHz, CDCl3) δ 7.98 (d, J 454 cm−1; ESI FTMS exact mass calcd for (C19H24N2O6 + Na)+
= 8.4 Hz, 2H), 7.69 (d, J = 8.4 Hz, 1H), 7.63–7.61 (m, 1H), 7.54 requires m/z 399.1526, found m/z 399.1530.
(d, J = 7.6 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.37–7.32 (m, 3H),
N-(3-Benzyl-2-oxo-1-tosyl-1,2,3,4-tetrahydroquinolin-3-yl)benz-
7.30–7.28 (m, 1H), 7.25–7.18 (m, 2H), 4.00–3.81 (m, 2H), 3.62 amide (3ao). Yield: 40% (20.4 mg); white solid;
(d, J = 15.2 Hz, 1H), 3.48 (d, J = 14.8 Hz, 1H), 2.44 (s, 3H), 0.81 m.p. 164–166 °C; 1H NMR (400 MHz, CDCl3) δ 7.97–7.89 (m,
(t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.6, 166.5, 3H), 7.57 (d, J = 8.0 Hz, 2H), 7.51–7.44 (m, 2H), 7.42–7.32 (m,
165.4, 145.5, 136.0, 135.0, 134.9, 134.8, 132.2, 130.0, 129.7, 6H), 7.15–7.09 (m, 1H), 7.07–6.98 (m, 3H), 6.74 (d, J = 8.0 Hz,
129.0, 128.8, 127.9, 127.7, 126.8, 126.0, 125.9, 125.3, 122.9, 2H), 4.14 (d, J = 16.0 Hz, 1H), 3.43 (d, J = 16.0 Hz, 1H), 3.15 (d,
65.4, 62.8, 34.5, 21.8, 13.5; IR (KBr): 3567, 1731, 1655, 1527, J = 12.0 Hz, 1H), 2.49 (d, J = 16.0 Hz, 1H), 2.46 (s, 3H); 13C
1489, 1363, 1175, 749, 575 cm−1; ESI FTMS exact mass calcd NMR (100 MHz, CDCl3) δ 170.8, 166.8, 145.4, 136.2, 134.9,
for (C26H23ClN2O6S + Na)+ requires m/z 549.0857, found m/z 134.7, 134.5, 131.7, 129.8, 129.6, 129.3, 128.8, 128.6, 128.2,
549.0861.
127.9, 127.6, 127.3, 127.1, 126.9, 123.2, 62.0, 36.1, 35.4, 21.8;
Ethyl 2-oxo-1-tosyl-3-(4-(trifluoromethyl)benzamido)-1,2,3,4- IR (KBr): 3403, 1707, 1663, 1507, 1147, 743, 572 cm−1; ESI
tetrahydroquinoline-3-carboxylate (3al). Yield: 81% (45.4 mg); FTMS exact mass calcd for (C30H26N2O4S + Na)+ requires m/z
white solid; m.p. 182–184 °C; 1H NMR (400 MHz, CDCl3) δ 533.1505 found m/z 533.1497.
7.99 (d, J = 8.4 Hz, 2H), 7.81 (d, J = 8.0 Hz, 2H), 7.76–7.63 (m,
tert-Butyl 3-benzamido-3-benzyl-2-oxo-3,4-dihydroquinoline-
3H), 7.41–7.33 (m, 3H), 7.31–7.27 (m, 1H), 7.24–7.20 (m, 1H), 1(2H)-carboxylate (3ho). Yield: 75% (34.2 mg); white solid;
4.00–3.86 (m, 2H), 3.60 (s, 2H), 2.46 (s, 3H), 0.83 (t, J = 7.2 Hz, m.p. 123–125 °C; 1H NMR (400 MHz, CDCl3) δ 7.74–7.66 (m,
3H); 13C NMR (100 MHz, CDCl3) δ 166.4, 165.2, 145.4, 135.3 (J 2H), 7.53–7.46 (m, 1H), 7.44–7.38 (m, 3H), 7.37–7.30 (m, 2H),
= 116.5 Hz), 129.6, 128.3 (J = 97.2 Hz), 126.8, 126.0, 125.7 (J = 7.21–7.13 (m, 4H), 7.11–7.05 (m, 2H), 6.98 (d, J = 8.0 Hz, 1H),
3.8 Hz), 122.9, 65.3, 62.9, 34.3, 21.8, 13.4; IR (KBr): 3566, 1724, 4.40 (d, J = 16.0 Hz, 1H), 3.70 (d, J = 16.0 Hz, 1H), 3.32 (d, J =
1656, 1534, 1489, 1326, 1173, 749, 654 cm−1; ESI FTMS exact 16.0 Hz, 1H), 2.90 (d, J = 16.0 Hz, 1H), 1.68 (s, 9H); 13C NMR
mass calcd for (C27H23F3N2O6S + Na)+ requires m/z 583.1121, (100 MHz, CDCl3) δ 169.1, 167.1, 151.6, 135.4, 135.3, 134.9,
found m/z 583.1119.
Ethyl
131.6, 130.2, 129.6, 128.6, 128.0, 127.0, 126.9, 125.1, 123.6,
3-(4-methylbenzamido)-2-oxo-1-tosyl-1,2,3,4-tetrahy- 116.1, 86.0, 60.2, 37.1, 36.4, 27.7; IR (KBr): 3399, 1761, 1696,
droquinoline-3-carboxylate (3am). Yield: 75% (38.0 mg); white 1663, 1510, 1176, 756, 700, 453 cm−1; ESI FTMS exact mass
solid; m.p. 210–212 °C; H NMR (400 MHz, CDCl3) δ 7.98 (d, calcd for (C28H28N2O4 + Na)+ requires m/z 479.1941, found m/z
1
J = 8.4 Hz, 2H), 7.69 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 8.0 Hz, 2H), 479.1938.
7.39–7.31 (m, 3H), 7.26–7.15 (m, 5H), 3.99–3.80 (m, 2H), 3.58
tert-Butyl
3-benzamido-3-methyl-2-oxo-3,4-dihydroquino-
(q, J = 15.2 Hz, 2H), 2.45 (s, 3H), 2.38 (s, 3H), 0.82 (t, J = 7.2 Hz, line-1(2H)-carboxylate (3hp). Yield: 82% (31.2 mg); white solid;
3H); 13C NMR (100 MHz, CDCl3) δ 166.7, 166.6, 166.5, 145.4, m.p. 142–144 °C; 1H NMR (400 MHz, CDCl3) δ 7.89–7.82 (m,
142.7, 136.0, 134.8, 130.4, 129.6, 129.3, 129.0, 128.9, 127.7, 2H), 7.79 (s, 1H), 7.55–7.48 (m, 1H), 7.47–7.41 (m, 2H),
127.3, 126.8, 126.4, 123.0, 65.2, 62.7, 34.4, 21.8, 21.6, 13.5; IR 7.32–7.25 (m, 2H), 7.16–7.11 (m, 1H), 6.91 (d, J = 8.0 Hz, 1H),
(KBr): 3566, 1724, 1656, 1534, 1489, 1326, 1173, 749, 654 cm−1
;
4.17 (d, J = 16.0 Hz, 1H), 3.21 (d, J = 16.0 Hz, 1H), 1.64 (s, 9H),
ESI FTMS exact mass calcd for (C27H26N2O6S + Na)+ requires 1.56 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.8, 166.4, 151.2,
m/z 529.1404, found m/z 529.1391. 135.4, 134.7, 131.7, 129.5, 128.6, 127.6, 127.0, 125.0, 123.9,
Ethyl 3-acetamido-2-oxo-1-tosyl-1,2,3,4-tetrahydroquinoline- 116.2, 86.0, 55.9, 36.2, 27.7, 19.8; IR (KBr): 3334, 1763, 1663,
3-carboxylate (3an). Yield: 78% (33.5 mg); white solid; 1499, 1147, 750, 453 cm−1; ESI FTMS exact mass calcd for
1
m.p. 126–128 °C; H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 8.0 (C22H24N2O4 + Na)+ requires m/z 403.1628, found m/z 403.1621.
Hz, 2H), 7.64 (d, J = 12.0 Hz, 1H), 7.37–7.30 (m, 3H), 7.22–7.16
tert-Butyl 3-benzamido-3-isopropyl-2-oxo-3,4-dihydroquino-
(m, 2H), 6.63 (s, 1H), 3.91–3.80 (m, 2H), 3.49–3.33 (m, 2H), line-1(2H)-carboxylate (3hq). Yield: 58% (23.7 mg); white solid;
2.43 (s, 3H), 1.94 (s, 3H), 0.79 (t, J = 8.0 Hz, 3H); 13C NMR m.p. 39–41 °C; 1H NMR (400 MHz, CDCl3) δ 7.88–7.84 (m, 2H),
(100 MHz, CDCl3) δ 169.9, 166.7, 145.3, 136.2, 135.0, 129.7, 7.63 (s, 1H), 7.55–7.49 (m, 1H), 7.48–7.42 (m, 2H), 7.31 (d, J =
128.7, 128.6, 127.8, 126.7, 125.9, 122.7, 65.1, 62.5, 34.6, 23.1, 8.0 Hz, 1H), 7.28–7.24 (m, 1H), 7.15–7.09 (m, 1H), 6.86 (d, J =
21.8, 13.4; IR (KBr): 3367, 1731, 1665, 1535, 1148, 754, 8.0 Hz, 1H), 4.54 (d, J = 16.0 Hz, 1H), 3.36 (d, J = 16.0 Hz, 1H),
574 cm−1; ESI FTMS exact mass calcd for (C21H22N2O6S–H)− 2.10–1.99 (m, 1H), 1.63 (s, 9H), 1.06 (d, J = 8.0 Hz, 3H), 0.91 (d,
requires m/z 429.1126, found m/z 429.1128.
J = 8.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 170.1, 166.8,
1-(tert-Butyl) 3-ethyl 3-acetamido-2-oxo-3,4-dihydroquino- 151.3, 135.6, 135.2, 131.6, 129.3, 128.6, 127.7, 127.0, 124.9,
line-1,3(2H)-dicarboxylate (3hn). Yield: 82% (30.8 mg); white 123.5, 115.7, 85.9, 62.0, 33.5, 31.9, 27.6, 17.6, 17.4; IR (KBr):
solid; m.p. 55–57 °C; 1H NMR (400 MHz, CDCl3) δ 7.25–7.18 3393, 1763, 1669, 1515, 1370, 1244, 1147, 752, 629 cm−1; ESI
(m, 2H), 7.14–7.08 (m, 1H), 7.03 (s, 1H), 6.85 (d, J = 8.0 Hz, FTMS exact mass calcd for (C24H28N2O4 + Na)+ requires m/z
1H), 4.06 (q, J = 8.0 Hz, 2H), 3.99 (d, J = 16.0 Hz, 1H), 3.30 (d, J 431.1941, found m/z 431.1925.
1340 | Org. Biomol. Chem., 2021, 19, 1334–1343
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tert-Butyl 3-allyl-3-benzamido-2-oxo-3,4-dihydroquinoline-1 Procedure for the synthesis of bioactive compound I and
(2H)-carboxylate (3hr). Yield: 73% (29.6 mg); white solid; characterization data of compounds 5 and I
m.p. 96–98 °C; 1H NMR (400 MHz, CDCl3) δ 7.86–7.81 (m, 2H),
7.64 (s, 1H), 7.54–7.49 (m, 1H), 7.47–7.42 (m, 2H), 7.30–7.25
(m, 2H), 7.16–7.10 (m, 1H), 6.90 (d, J = 8.0 Hz, 1H), 5.75–5.59
(m, 1H), 5.09–5.00 (m, 2H), 4.20 (d, J = 16.0 Hz, 1H), 3.29 (d,
The solution of 3hn (0.1 mmol) in anhydrous DCM (1 mL) was
added into a flame-dried Schlenk tube under an argon atmo-
sphere. Then, TFA (0.2 mmol) was added to the reaction
mixture, which was stirred at 30 °C for 3 h. After the com-
pletion of the reaction which was indicated by TLC, the reac-
tion mixture was directly purified through preparative thin
layer chromatography on silica gel (PE : EA = 2 : 1) to afford the
pure product 5.
J = 16.0 Hz, 1H), 3.20–3.10 (m, 1H), 2.36–2.27 (m, 1H), 1.64 (s,
9H); 13C NMR (100 MHz, CDCl3) δ 169.3, 166.6, 151.3, 135.3,
134.7, 131.7, 131.5, 129.5, 128.6, 127.9, 126.9, 124.9, 123.4,
119.9, 115.9, 85.9, 59.1, 36.0, 35.8, 27.6; IR (KBr): 3399, 1763,
1664, 1511, 1368, 1244, 1147, 754, 574 cm−1; ESI FTMS exact
Compound 5 (0.1 mmol) and HCl (1 mL, 6 M) were added
into a sealed tube and heated to reflux for 6 h. After the com-
pletion of the reaction which was indicated by TLC, the reaction
mass calcd for (C24H26N2O4 + Na)+ requires m/z 429.1785,
found m/z 429.1779.
mixture was quenched with NEt3 and extracted with ethyl acetate
three times. The combined organic layers were dried and concen-
trated under reduced pressure to give a crude product.
Procedure for one-mmol-scale reactions
N-(o-Chloromethyl)aryl amide 1a (295.0 mg, 1 mmol), azlac-
tone 2a (711.0 mg, 3.0 mmol), Cs2CO3 (358.4 mg, 1.1 mol),
TBAB (32.2 mg, 0.1 mmol) and MgSO4 (1.0 g) were added into
The crude product was dissolved in DMF (1 mL) containing
5-chloroindole-2-carboxylic
acid
(0.12
mmol),
EDCI
a reaction bottle. Then, CH3CN (10 mL) was added to the reac-
tion mixture, which was stirred at r.t. for 3 h. After the com-
pletion of the reaction which was indicated by TLC, the reac-
tion mixture was concentrated under reduced pressure and the
residue was purified by flash column chromatography on silica
gel (PE : DCM = 1 : 1) to afford the pure product 3aa (456.0 mg,
92% yield).
(0.12 mmol), HOBt (0.12 mmol). The reaction mixture was
stirred at 30 °C for 5 h before being partitioned between water
and EA. The organic layers were washed with water, saturated
aqueous NaHCO3 and dried over Na2SO4. The solution was
concentrated under reduced pressure and the residue was puri-
fied by flash column chromatography on silica gel (EA) to
afford the pure product I.
N-(o-Chloromethyl)aryl amide 1h (241.0 mg, 1 mmol), azlac-
tone 2n (205.2 mg, 1.2 mmol), Cs2CO3 (358.4 mg, 1.1 mol),
TBAB (32.2 mg, 0.1 mmol) and MgSO4 (1.0 g) were added into a
reaction bottle. Then, CH3CN (10 mL) was added to the reaction
mixture, which was stirred at r.t. for 3 h. After the completion of
the reaction which was indicated by TLC, the reaction mixture
was concentrated under reduced pressure and the residue was
purified by flash column chromatography on silica gel (PE : EA
= 2 : 1) to afford the pure product 3hn (293.3 mg, 78% yield).
Ethyl 3-acetamido-2-oxo-1,2,3,4-tetrahydroquinoline-3-car-
boxylate (5). Yield: 85% (23.5 mg); white solid;
m.p. 141–143 °C; 1H NMR (400 MHz, DMSO-d6) δ 10.54 (s, 1H),
8.34 (s, 1H), 7.18–7.10 (m, 2H), 6.96–6.81 (m, 2H), 4.02–3.88
(m, 2H), 3.44–3.35 (m, 2H), 1.86 (s, 3H), 0.94 (t, J = 8.0 Hz, 3H);
13C NMR (100 MHz, DMSO-d6) δ 170.1, 168.3, 165.5, 137.5,
128.4, 127.9, 122.9, 121.8, 115.3, 62.0, 61.4, 34.8, 22.9, 14.1; IR
(KBr): 3431, 1737, 1698, 1597, 1545, 1434, 1281, 1027, 822,
761 cm−1; ESI FTMS exact mass calcd for (C14H16N2O4 + Na)+
requires m/z 299.1002, found m/z 299.1003.
Procedure for the synthesis of product 4 and characterization
data
5-Chloro-N-(2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)-1H-indole-
2-carboxamide (I). Yield: 72% (24.4 mg); yellow solid; m.p.
Under an argon atmosphere, 3aa (0.1 mmol) and the solution
of SmI2 (1.5 mL) in anhydrous THF (1 mol L−1) were added
into a flame-dried Schlenk tube. The reaction mixture was
stirred at 30 °C for 3 h. After the completion of the reaction
which was indicated by TLC, the mixture was directly purified
through preparative thin layer chromatography on silica gel
(PE : EA = 2 : 1) to afford the pure product 4.
1
168–170 °C; H NMR (400 MHz, DMSO-d6) δ 11.89 (s, 1H), 10.42
(s, 1H), 8.94–8.78 (m, 1H), 7.74 (s, 1H), 7.46 (d, J = 8.0 Hz, 1H),
7.25–7.16 (m, 4H), 6.98–6.88 (m, 2H), 4.83–4.71 (m, 1H),
3.23–3.02 (m, 2H); 13C NMR (100 MHz, DMSO-d6) δ 169.2, 161.3,
138.1, 135.5, 133.4, 128.7, 128.1, 124.8, 124.1, 122.9, 122.8, 121.3,
115.7, 114.5, 103.1, 48.5, 31.9; IR (KBr): 3219, 1690, 1653, 1558,
1321, 1259, 1026, 758 cm−1; ESI FTMS exact mass calcd for
(C18H14ClN3O2–H)− requires m/z 338.0702, found m/z 338.0701.
N-(2-Oxo-3-phenyl-1,2,3,4-tetrahydroquinolin-3-yl)benzamide
(4). Yield: 70% (23.9 mg); white solid; m.p. 251–253 °C; 1H
NMR (400 MHz, CDCl3) δ 8.72 (s, 1H), 8.19 (s, 1H), 7.87–7.79
(m, 2H), 7.56–7.48 (m, 3H), 7.46–7.40 (m, 2H), 7.36 (d, J = 8.0
Hz, 1H), 7.22–7.15 (m, 3H), 7.14–7.09 (m, 1H), 7.08–7.02 (m,
1H), 6.67 (d, J = 8.0 Hz, 1H), 4.77 (d, J = 16.0 Hz, 1H), 3.60 (d, J
= 16.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 170.3, 166.1,
137.3, 135.3, 134.6, 131.8, 128.7, 128.5, 128.4, 128.3, 127.8,
127.2, 127.1, 124.3, 123.4, 115.5, 59.9, 34.8; IR (KBr): 3234,
1686, 1658, 1596, 1479, 1372, 1296, 695, 564 cm−1; ESI FTMS
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
exact mass calcd for (C22H18N2O2 + Na)+ requires m/z 365.1260, We are grateful for financial support from the National Natural
found m/z 365.1249.
Science Foundation of China (21772069 and 21831007),
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Organic & Biomolecular Chemistry
Natural Science Foundation of Jiangsu Province (BK20201018),
Postgraduate Research & Practice Innovation Program of
Jiangsu Province (KYCX20_2238), and Natural Science
Foundation of JSNU (19XSRX010).
Y.-Z. Zhang, X.-H. Zhao, R. Fang and C.-A. Fan, Chem. –
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details.
This journal is © The Royal Society of Chemistry 2021
Org. Biomol. Chem., 2021, 19, 1334–1343 | 1343