Copper-Catalyzed Dihydroquinolinone Synthesis from Isocyanides and O-Benzoyl Hydroxylamines

Article abstract of DOI:10.1021/acs.joc.9b00262

A copper-catalyzed protocol has been realized for the rapid assembly of dihydroquinolinones from readily accessible isocyanides and O-benzoyl hydroxylamines. The reactions (10 mol % of CuOAc, 10 mol % of dppe, 3 equiv of PhONa, 30 °C) deliver various stru

Full text of DOI:10.1021/acs.joc.9b00262

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Note
Copper-Catalyzed Dihydroquinolinone Synthesis
from Isocyanides and O-Benzoyl Hydroxylamines
Zhen Yang, Kun Jiang, Ying-Chun Chen, and Ye Wei
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00262 • Publication Date (Web): 26 Feb 2019
Downloaded from http://pubs.acs.org on February 26, 2019
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Copper-Catalyzed Dihydroquinolinone Synthesis from Isocyanides and O-Benzoyl
Hydroxylamines
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Zhen Yang, Kun Jiang, Ying-Chun Chen,* and Ye Wei*,†
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College of Pharmacy, Army Medical University, Chongqing, 400038, China
O
O
R
OMe
NR'2
N
C
O
R
Cu
+
Ph
O
NC
O
NR'2
Abstract: A copper-catalyzed protocol has been realized for the rapid assembly of
dihydroquinolinones from readily accessible isocyanides and O-benzoyl hydroxylamines. The
reactions (10 mol % of CuOAc, 10 mol% of dppe, 3 equiv of PhONa, 30 °C) deliver various
structurally interesting dihydroquinolinones in moderate to good yields (up to 76%). The reactions
may proceed in a cascade manner involving isocyanide insertion into N–O bond, Mumm-type
rearrangement, and intramolecular nucleophilic substitution.
Isocyanides represent a valuable class of synthons in organic synthesis,1 and several types of
reactions based on such compounds have been developed, such as multicomponent reactions,2
cycloaddition reactions,3 and insertion reactions.4 In terms of the isocyanide insertions, it has been
known that the isocyanides can take part in various insertion reactions, such as the insertion into
heteroatom–hydrogen, carbon–hydrogen, carbon–heteroatom, and carbon–metal bonds, for the
construction of a range of organic and organometallic compounds (Scheme 1a). Nevertheless, it is
still necessary to expand the type of the iscyanide insertion reactions, because some important and
useful chemical bonds are difficult to participate in the insertion reactions, which might restrict the
structural diversity of molecules. For instance, nitrogen–oxygen (N–O) bonds exist in a number of
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Scheme 1. Reactions Involving Isocyanide Insertion
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(a) Isocyanide insertion into chemical bonds
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heteroatom/C-H
C-heteroatom/M
isocyanide
insertion
N-O
9
well-established
rare
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(b) Our previous work: reactions of isocyanides with cyclic oximes
O
O
O
[Ag]
CN R
insertion
Mumm-type
rearrangement
R
O
N
O
O
R
N
N
H
N
N
H
(c) This work: reactions of isocyanides with O-benzoyl hydroxylamines
R1
E
BzO NR'2
E
N
R
NC
O
NR'2
insertion
cyclization
Mumm-type
rearrangement
E
R
E
R
- PhCO+
N
N
O
O
NR'2
O
NR'2
Ph
A
(E = electrophile)
B
O
cat. Cu
R
OMe
BzO NR'2
N
O
R
_
PhCO2Me
NC
O
NR'2
molecules,5 and many compounds containing the N–O bond (e.g., oximes and hydroxylamines) can
be used to construct nitrogen-containing molecules. However, examples involving the isocyanide
insertion into the N–O bond remain scarce.6
Our group recently disclosed a silver-catalyzed protocol for the difunctionalization of the
isocyano group with cyclic oximes.6c,7 The reactions involve the insertion of the isocyanide into the
N–O bond and a Mumm-type rearrangement8 of an imidate (Scheme 1b). These results and our
continuous research interests9 in the N–O bond transformations (NOT)10 towards N-heterocycles
spurred us to investigate the isocyanide insertion into other N–O bond-containing compounds. We
envisioned that O-benzoyl hydroxylamines, a useful class of electrophilic aminating agents, might
be applicable in the insertion strategy because the N–O bond in such molecules can be cleavaged
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by several transition metals, such as Cu, Fe, Co, Ni, and Pd.11 As depicted in Scheme 1c, a reaction
between an aryl isocyanide bearing an electrophilic moiety and the O-benzoyl hydroxylamine might
generate an imidate A, which would occur the Mumm-type rearrangement to give rise to a nitrogen
anion B. Then, B undergoes a cyclization step to deliver a N-heterocycle. Herein, we describe a
copper-catalyzed method for the assembly of dihydroquinolinone skeletons, which are of great
significance in pharmaceutical, biological and synthetic chemistry,12 using the aryl isocyanides and
the O-benzoyl hydroxylamines as readily available starting materials. The reactions took place
under mild conditions, and delivered a series of structurally interesting dihydroquinolinones.
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Table 1. Optimization of Reaction Conditionsa
O
N
O
conditions
OMe
BzO
N
O
+
O
N
NC
1a
O
2a
3aa
additive
PhONa
(1.5 equiv)
entry
catalyst
ligand
solvent
yield (%)b
1
2
3
4
5
6
7
8
9
10
CuOAc
none
dppe
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
74
0c
dppe
dppe
dppe
dppe
dppe
none
dppm
PhONa
PhONa
PhONa
PhONa
PhONa
PhONa
PhONa
PhONa
CuCl
CuBr
17
19
24
0c
Cu(OAc)2
FeCl2, NiCl2, or CoCl2
CuOAc
60
64
46
0c
CuOAc
CuOAc
1,10-phenanthroline
dppe
CuOAc
t-BuONa, NaOAc,
or Na2CO3
11
12
CuOAc
CuOAc
dppe
dppe
PhONa
PhONa
1,4-dioxane
56
0c
MeCN, DMF,
DMSO, or DCM
THF
13
CuOAc
dppe
PhONa
tracec,d
O
O
O
OPh
NC
NC
1b
1c
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a
Conditions unless otherwise indicated: 1a (0.2 mmol), 2a (1.5 equiv), catalyst (10 mol %), ligand (10 mol %),
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additive (3 equiv), solvent (1 mL), 30 °C, 24 h, under Ar. b Isolated yields. c Most of the isocyanides and O-benzoyl
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d
hydroxylamines were decomposed.
1b or 1c were used instead of 1a. Abbreviation: dppe = 1,2-
9
bis(diphenylphosphino)ethane. dppm = 1,1-bis(diphenylphosphino)methane.
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A reaction between isocyanide (1a) and 4-benzoyloxymorpholine (2a) was chosen as the
model reaction to optimize the reaction conditions (Table 1). After considerable experimentation,
we found that the dihydroquinolinone (3aa) was produced in 74% isolated yield in the presence of
CuOAc (10 mol %) as a catalyst, dppe (1,2-bis(diphenylphosphino)ethane) as a ligand, and PhONa
as a base at 30 °C in THF within 24 h (entry 1, Table 1). The structure of 3aa was unambiguously
confirmed by X-ray crystallographic analysis (Figure 1).13 The copper salt plays a key role in the
reaction because no desired product was obtained without CuOAc (entry 2). Besides CuOAc, other
copper salts such as CuCl, CuBr, and Cu(OAc)2 were also examined, which all led to significantly
lower yields (entries 3–5). The reaction failed in the presence of FeCl2, NiCl2, or CoCl2 as the
catalyst (entry 6). Phosphine ligands such as dppm (1,1-bis(diphenylphosphino)methane), and
nitrogen ligands such as 1,10-phenanthroline were also screened, albeit negative results were
obtained (entries 8 and 9). Note that, the PhONa is also crucial to the reaction. Other commonly
used inorganic bases including t-BuONa, NaOAc, and Na2CO3 did not afford the target product
(entry 10). The reaction occurred sluggishly in 1,4-dioxane (entry 11), and cannot generate 3aa at
all in MeCN, DMF, DMSO, and DCM (entry 12). In addition, the reactions of isocyanides 1b or 1c
with 2a were also surveyed, which only delivered a trace amount of the desired product (entry 13).
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Scheme 2. Scope of O-Benzoyl Hydroxylaminesa
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O
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CuOAc (10 mol %)
dppe (10 mol %)
N
O
OMe
+
BzO N
PhONa (3 equiv)
THF, 30 °C, 24 h
O
N
O
NC
1a
2
3
N
O
N
O
N
O
N
O
N
O
N
O
N
O
N
O
S
NBoc
3aa
5 mmol scale
3ab
3ac
3ad
, 66% (
)
, 61%
O
, 60%
, 69%
N
O
N
O
N
O
O
N
N
O
N
O
N
O
N
CO2Et
, 68% (dr = 1.5 : 1)
Ph
OMe
, 60% (dr = 1.6 : 1)
3ae
3af
3ag
3ah
, 62% (dr = 1.2 : 1)
, 72%
N
O
N
O
N
O
O
N
O
N
O
O
N
O
3ai
3aj
3ak
, 45%
, 65%
, 63%
F
unreactive substrates
O
O
N
N
N
NH
N
N
O
O
O
OBz
OBz
OBz
2m
OBz
2n
2o
2p
3al
, 70% (dr = 1.8 : 1.5 : 1 )
a Reactions conditions: 1a (0.2 mmol), 2 (0.3 mmol, 1.5 equiv), CuOAc (10 mol %), dppe (10 mol %), PhONa (0.6
mmol, 3 equiv), THF (2 mL), 30 °C, 24 h, under Ar. Isolated yields are indicated.
After establishing the optimal reaction conditions, we explored the substrate scope with regard
to the O-benzoyl hydroxylamines (Scheme 2). Besides morpholine-derived O-benzoyl
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hydroxylamine, the method was also amenable to the O-benzoyl hydroxylamines derived from
piperidine (3ab), thiomorpholine (3ac), and piperazine (3ad). The piperidine-derived O-benzoyl
hydroxylamine with phenyl (3ae), methoxy (3af), ester (3ag), and methyl groups (3ah) could also
react with 1a to produce the corresponding products in moderate yields. In addition, the O-benzoyl
hydroxylamines derived from spiropiperidines (3ai and 3aj) and azepane (3ak) showed moderate
reactivity in the transformation. Interestingly, the newly developed method was suitable for the
hydroxylamine derived from paroxetine (3al), a drug used to treat major depressive disorder and
obsessive-compulsive disorder. Unfortunately, the hydroxylamines derive drom five- and eight-
membered amines (2m and 2n) as well as acyclic amines (2o and 2p) display no reactivity in the
reactions. Note that, this method is suitable for gram-scale synthesis, which was demonstrated by a
5 mmol scale reaction between 1a and 2a.
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Scheme 3. Scope of Isocyanidesa
O
R
CuOAc (10 mol %)
N
O
OMe
dppe (10 mol %)
R
+
BzO N
PhONa (3 equiv)
THF, 30 °C, 24 h
O
N
NC
O
1
2
3
MeO
Me
Me
Me
N
O
N
O
R
N
O
N
O
O
N
O
N
O
N
O
N
O
O
O
O
3fa
, R = Me, 68%
3ga
b
3ea
, 60%
3da
3ha
, 40%
, 76%
, R = Cl, 67%
Me
Me
Cl
F3C
MeO2C
N
O
N
O
N
N
O
N
O
O
N
O
N
O
O
N
O
O
O
3hj
3ia
3ja
3ka
, 33%
, 40%
, 54%
, 25%
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a Reactions conditions: 1 (0.2 mmol), 2a (0.3 mmol, 1.5 equiv), CuOAc (10 mol %), dppe (10 mol %), PhONa (0.6
5
6
7
8
mmol, 3 equiv), THF (2 mL), 30 °C, 24 h, under Ar. Isolated yields are indicated. b Reaction was performed at 50
°C.
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Subsequently, we evaluated the scope of the aryl isocyanides. As shown in Scheme 3, a series
of groups, including methoxy (3da), methyl (3ea, 3fa, 3ha, and 3hj), chloro (3ga and 3ia), ester
(3ja), and trifluoromethyl groups (3ka) can be tolerated under the reactions, and the reactions
afforded the corresponding products in synthetically useful yields.
Scheme 4. Proposed Reaction Mechanism
(a)
CO2Me
R
N
O
CuX
O
O
NR'2
NR'2
Ph
O
E
Ph
2
CO2Me
NR'2
O
R
Ph
N
O
O
X
O
Cu
catalytic cycle
CO2Me
Cu
Ph
O
NR'2
X
R
Ph
C
D'
N
or
O
NR'2
F
CO2Me
R
O
CO2Me
N
R
O
NC
Cu NR'2
R
1
+
Ph
X
PhCO2Me
N
O
D
observed by
GC-MS
O
NR'2
3
CO2Me
CuOAc (10 mol %)
dppe (10 mol %)
CO2Me
NH
(b)
+
BzO
N
O
PhONa (3 equiv)
THF, 30 °C, 24 h
NC
O
N
O
1l
2a
4
, 59%
CO2Me
PhONa (3 equiv)
THF, 30 °C, 24 h
N
O
(c)
NH
O
N
O
N
O
O
5
3aa
, 55%
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Based on our observed results and the previous work on Cu-catalyzed amination reactions
using the O-benzoyl hydroxylamines as the aminating agent,11 we proposed the following possible
reaction mechanism (Scheme 4a). Initially, the oxidative addition of Cu(I) salt with the O-benzoyl
hydroxylamine 2 forms an aminocopper species C,14 which then reacts with isocyanide 1 to generate
copper complexes D or D’ through the isocyanide insertion. After C–O or C–N bond reductive
elimination steps, an imidate E could be furnished. Such a compound would undergo Mumm-type
rearrangement8 to produce a nitrogen anion F and an acyl cation. Finally, an intramolecular
nucleophilic substitution produces the target product 3. According to this proposed reaction
pathway, the overall transformation generates methyl benzoate as the only byproduct. Indeed, such
a byproduct was observed by GC-MS analysis. Regarding the transformation of F into 3, if the ester
group is linked with a rigid C=C bond, the nucleophilic substitution of the nitrogen anion might be
inhibited. To verify such an assumption, we prepared an isocyanide 1l, and found that the reaction
between 1l and 2a led to a urea derivative 4 in 59% yield (Scheme 4b). Moreover, compound 5 can
be converted into 3aa in 55% yield with PhONa as the base (Scheme 4c). These results may
indirectly support the process that involves the formation of F and the intramolecular nucleophilic
substitution.
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In conclusion, we developed a new synthetic approach to construct dihydroquinolinones
through copper-catalyzed reactions of isocyanides with O-benzoyl hydroxylamines under mild
reaction conditions. The reaction pathway may involve the isocyanide insertion into the N–O bond,
Mumm-type rearrangement, and intramolecular nucleophilic substitution. The development of more
synthetic strategies involving the isocyanide insertion into N–O bonds is ongoing in our group.
Experimental Section
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General Information
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All reactions dealing with air- and moisture-sensitive compounds were carried out in dry reaction
vessels under a nitrogen atmosphere. 1H and 13C nuclear magnetic resonance (NMR) spectra were
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1
recorded on Agilent 600 MHz NMR spectrometer. H and 13C NMR spectra are reported in parts
per million (ppm) downfield from an internal standard, tetramethylsilane (0 ppm) and CHCl3 (77.0
ppm), respectively. HRMS (m/z) was recorded using ESI (Q-TOF) mode. Single crystal X-ray data
were recorded in a diffractometer with Mo Kα radiation. Melting points were determined using a
capillary melting point apparatus and are uncorrected.
Preparation of Substrates
All O-benzoyl hydroxylamines15,16 and isocyanides17-20 were synthesized according to the literatures.
(1) Preparation of isocyanides
Mizoroki-Heck reaction: Methyl acrylate (20 mmol) was added to a solution of 2-iodoaniline
derivatives (10 mmol), palladium acetate (5 mol %), triphenylphosphine (10 mol %), potassium
carbonate (10 mmol) and tetrabutylammonium bromide (2.5 mmol) in N,N’-dimethylformamide
(90 mL). The reaction mixture was stirred at 80 °C for 2 h. The mixture was cooled to room
temperature, diluted with water (50 mL) and extracted with diethyl ether (3 × 50 mL). The organic
layer was washed with water (10 mL) and brine (10 mL), dried over MgSO4, and concentrated by
rotary evaporation. The residue was purified by column chromatography (petroleum ether/ethyl
acetate = 10:1) to give ortho-olefinic anilines.
N-Formylation: Acetyl formyl anhydride (prepared by stirring 2.5 equiv of acetic anhydride and
2.5 equiv of formic acid at 55 °C for 2 h) was added dropwise at 0 °C to a stirred solution of the
ortho-olefinic anilines (9 mmol) in THF (15 mL), and the mixture was stirred for 2 h at room
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temperature. Then the saturated solution of NaHCO3 was added and the aqueous phase was
extracted with ethyl acetate. The organic layer was dried over MgSO4, and concentrated by rotary
evaporation. The residue was purified by column chromatography (petroleum ether/ ethyl acetate =
3:1) to give N-formylated products.
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Reduction: A solution of the N-formylated products (5 mmol) and Pd/C (10 wt. %. 106 mg) in
EtOAc (10 ml) was stirred vigorously under 1 atm of H2 overnight. The suspension was filtered to
remove solids, and the filtrate was concentrated in vacuo to give reduction products.
Dehydration: To a solution of the reduction products (5 mmol) and Et3N (2.1 ml, 15 mmol) in
CH2Cl2 (10 ml) at 0 °C was added triphosgene (0.74 g, 2.5 mmol) in CH2Cl2 (10 ml). The solution
was stirred at 0 °C for 3 h. Then methanol was added to the suspension solution, and the solution
was concentrated by rotary evaporation. The residue was purified by column chromatography
(petroleum ether) to give the isocyanides.
(2) Preparation of O-benzoyl hydroxylamines: To a 100 mL flask charged with benzoyl peroxide
(2 mmol), dipotassium hydrogen phosphate (3 mmol), and N,N’-dimethylformamide. Amine
starting material (3 mmol) was added dropwise at room temperature. The suspension was stirred at
ambient temperature for the indicated reaction time. The reaction was quenched with water (10 mL)
and the contents were stirred vigorously for several minutes until all solids dissolved. The reaction
mixture was extracted with ethyl acetate (3 × 30 mL). The organic phase was collected and washed
with two 25 mL portions of saturated aq. NaHCO3 solution, 25 mL of brine, dried over anhydrous
Na2SO4, filtered and concentrated under vacuum. The residue was purified by column
chromatography on silica gel to give desired product O-benzoyl hydroxylamines.
Methyl 3-(2-isocyanophenyl)propanoate (1a). Yellow oil, 775.2 mg, 82% yield. Eluent
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composition petroleum ether. 1H NMR (600 MHz, CDCl3): δ 7.38–7.23 (m, 4H), 3.68 (s, 3H), 3.10
(t, J = 7.6 Hz, 2H), 2.69 (t, J = 7.6 Hz, 2H). 13C{1H} NMR (150 MHz, CDCl3): δ 172.6, 166.5,
137.0, 129.8, 129.5, 127.4, 127.0, 51.8, 33.5, 27.4. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C11H11NO2Na 212.0682; Found 212.0683.
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Methyl 3-(2-isocyano-5-methoxyphenyl)propanoate (1d). White solid, 821.6 mg, 75% yield.
Mp = 53–54 oC. Eluent composition petroleum ether. 1H NMR (600 MHz, CDCl3): δ 7.29 (d, J =
8.7 Hz, 1H), 6.79 (d, J = 2.4 Hz, 1H), 6.74 (dd, J = 8.7, 2.5 Hz, 1H), 3.80 (s, 3H), 3.68 (s, 3H), 3.06
(t, J = 7.6 Hz, 2H), 2.68 (t, J = 7.6 Hz, 2H). 13C{1H} NMR (150 MHz, CDCl3): δ 172.6, 165.1,
159.9, 138.7, 128.3, 115.0, 112.6, 55.5, 51.8, 33.5, 27.7. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd
for C12H13NO3Na 242.0788; Found 242.0789.
Methyl 3-(2-isocyano-5-methylphenyl)propanoate (1e). Yellow oil, 792.6 mg, 78% yield.
Eluent composition petroleum ether. 1H NMR (600 MHz, CDCl3): δ 7.23 (d, J = 8.0 Hz, 1H), 7.09
(s, 1H), 7.03 (d, J = 8.0 Hz, 1H), 3.68 (s, 3H), 3.04 (t, J = 7.7 Hz, 2H), 2.66 (t, J = 7.7 Hz, 2H), 2.34
(s, 3H). 13C{1H} NMR (150 MHz, CDCl3): δ 172.7, 165.7, 139.9, 136.7, 130.4, 128.1, 126.8, 51.8,
33.6, 27.4, 21.3. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C12H13NO2Na 226.0838; Found
226.0840.
Methyl 3-(2-isocyano-4-methylphenyl)propanoate (1f). Yellow oil, 731.3 mg, 72% yield.
Eluent composition petroleum ether. 1H NMR (600 MHz, CDCl3): δ 7.17 (d, J = 7.3 Hz, 2H), 7.13
(d, J = 8.0 Hz, 1H), 3.67 (s, 3H), 3.04 (t, J = 7.6 Hz, 2H), 2.66 (t, J = 7.6 Hz, 2H), 2.32 (s, 3H).
13C{1H} NMR (150 MHz, CDCl3): δ 172.7, 166.0, 137.6, 133.9, 130.4, 129.6, 127.4, 51.7, 33.6,
27.0, 20.6. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C12H13NO2Na 226.0838; Found 226.0839.
Methyl 3-(4-chloro-2-isocyanophenyl)propanoate (1g). Yellow oil, 758.2 mg, 68% yield.
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Eluent composition petroleum ether. 1H NMR (600 MHz, CDCl3): δ 7.37 (s, 1H), 7.32 (d, J = 8.2
Hz, 1H), 7.27 (s, 1H), 3.68 (s, 3H), 3.07 (t, J = 7.4 Hz, 2H), 2.68 (t, J = 7.5 Hz, 2H). 13C{1H} NMR
(150 MHz, CDCl3): δ 172.4, 168.2, 135.6, 132.9, 131.1, 129.9, 126.9, 51.8, 33.3, 26.9. HRMS (ESI-
TOF) m/z: [M + Na]+ Calcd for C11H10ClNO2Na 246.0292; Found 246.0295.
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Methyl 3-(2-isocyano-4,5-dimethylphenyl)propanoate (1h). White solid, 705.7 mg, 65% yield.
Mp = 54–55 oC. Eluent composition petroleum ether. 1H NMR (600 MHz, CDCl3): δ 7.12 (s, 1H),
7.03 (s, 1H), 3.67 (s, 3H), 3.01 (t, J = 7.7 Hz, 2H), 2.65 (t, J = 7.7 Hz, 2H), 2.24 (s, 3H), 2.21 (s,
3H). 13C{1H} NMR (150 MHz, CDCl3): δ 172.78, 165.3, 138.6, 136.1, 134.1, 130.8, 127.7, 51.7,
33.8, 27.0, 19.6, 19.1. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C13H15NO2Na 240.0995; Found
240.0996.
Methyl 3-(5-chloro-2-isocyanophenyl)propanoate (1i). Yellow oil, 781.1 mg, 70% yield.
Eluent composition petroleum ether. 1H NMR (600 MHz, CDCl3): δ 7.30 (d, J = 8.5 Hz, 2H), 7.23
(dd, J = 8.5, 1.9 Hz, 1H), 3.69 (s, 3H), 3.06 (t, J = 7.5 Hz, 2H), 2.68 (t, J = 7.5 Hz, 2H). 13C{1H}
NMR (150 MHz, CDCl3): δ 172.2, 168.0, 138.9, 135.4, 130.0, 128.1, 127.7, 51.9, 33.1, 27.3. HRMS
(ESI-TOF) m/z: [M + Na]+ Calcd for C11H10ClNO2Na 246.0292; Found 246.0295.
Methyl 4-isocyano-3-(3-methoxy-3-oxopropyl)benzoate (1j). White solid, 766.4 mg, 62% yield.
Mp = 73–74 oC. Eluent composition petroleum ether. 1H NMR (600 MHz, CDCl3): δ 8.00 (s, 1H),
7.93 (d, J = 8.2 Hz, 1H), 7.43 (d, J = 8.2 Hz, 1H), 3.93 (s, 3H), 3.69 (s, 3H), 3.14 (t, J = 7.6 Hz,
2H), 2.72 (t, J = 7.6 Hz, 2H). 13C{1H} NMR (150 MHz, CDCl3): δ 172.3, 169.4, 165.5, 137.3, 131.1,
131.0, 128.7, 127.1, 52.5, 51.9, 33.2, 27.3. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C13H13NO4Na 270.0737; Found 270.0739.
Methyl 3-(2-isocyano-5-(trifluoromethyl)phenyl)propanoate (1k). Yellow oil, 771.4 mg, 60%
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yield. Eluent composition petroleum ether. 1H NMR (600 MHz, CDCl3): δ 7.59 (s, 1H), 7.54 (d, J
= 8.3 Hz, 1H), 7.49 (d, J = 8.3 Hz, 1H), 3.68 (s, 3H), 3.16 (t, J = 7.5 Hz, 2H), 2.72 (t, J = 7.5 Hz,
2H). 13C{1H} NMR (150 MHz, CDCl3): δ 172.1, 169.56, 138.1, 131.5 (q, 2JC-F = 33.2 Hz), 127.5,
127.1 (q, 3JC-F = 3.6 Hz), 124.6 (q, 3JC-F = 3.8 Hz), 123.2 (q, 1JC-F = 272.7 Hz), 51.89, 33.1, 27.4.
19F NMR (564 MHz, CDCl3) δ –62.98. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C12H10F3NO2Na 280.0556; Found 280.0558.
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3-Azaspiro[5.5]undecan-3-yl benzoate (2j). White solid, 420.8 mg, 77% yield. Mp = 65–67
oC. Eluent composition petroleum ether/ethyl acetate = 10:1. 1H NMR (600 MHz, CDCl3): δ 8.00
(d, J = 7.3 Hz, 2H), 7.54 (t, J = 7.4 Hz, 1H), 7.42 (t, J = 7.7 Hz, 2H), 3.32 (s, 2H), 2.98 (s, 2H), 1.69
(d, J = 38.2 Hz, 4H), 1.46 (d, J = 38.6 Hz, 8H), 1.30 (s, 2H). 13C{1H} NMR (150 MHz, CDCl3): δ
164.8, 132.9, 129.7, 129.4, 128.3, 52.2, 34.7, 30.3, 26.7, 21.8, 21.4. HRMS (ESI-TOF) m/z: [M +
H]+ Calcd for C17H24NO2 274.1802; Found 274.1803.
General Procedure for the Synthesis of Dihydroquinolinones
A 10 mL of Schlenk tube equipped with a stirrer bar was charged with isocyanides (0.2 mmol), O-
benzoyl hydroxylamines (0.3 mmol), CuOAc (10 mol %), dppe (10 mol %), and PhONa (0.6 mmol).
Then, the Schlenk tube was quickly evacuated and refilled with Ar for three times, followed by the
addition of THF (2 mL). The Schlenk tube was sealed with a Teflon screwcap under Ar flow and
the reaction mixture was stirred at 30 °C for 24 h. Upon cooling to room temperature, the reaction
mixture was diluted with 10 mL of ethyl acetate, filtered through a pad of silica gel, followed by
washing the pad of the silica gel with ethyl acetate (20 mL). Subsequently, the filtrate was
concentrated under reduced pressure. The residue was purified by flash chromatography on silica
gel to afford the desired products.
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5 mmol Scale Reaction Between 1a and 2a
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A 100 mL of Schlenk tube equipped with a stirrer bar was charged with 1a (5 mmol, 0.945 g), 2a
(7.5 mmol, 1.553 g), CuOAc (10 mol %, 61.3 mg), dppe (10 mol %, 199.2 mg), and PhONa (15
mmol, 1.74 g). Then, the Schlenk tube was quickly evacuated and refilled with Ar for three times,
followed by the addition of THF (50 mL). The Schlenk tube was sealed with a Teflon screwcap
under Ar flow and the reaction mixture was stirred at 30 °C for 24 h. Upon cooling to room
temperature, the reaction mixture was diluted with 50 mL of ethyl acetate, filtered through a pad of
silica gel, followed by washing the pad of the silica gel with ethyl acetate (100 mL). Subsequently,
the filtrate was concentrated under reduced pressure. The residue was purified by flash
chromatography on silica gel to afford 3aa in 66% yield (0.858 g).
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1-(Morpholine-4-carbonyl)-3,4-dihydroquinolin-2(1H)-one (3aa). White solid, 38.5 mg, 74%
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yield. Mp = 189–190 C. Eluent composition petroleum ether/ethyl acetate = 2:1. H NMR (600
MHz, CDCl3): δ 7.22 (dd, J = 12.2, 7.3 Hz, 2H), 7.07 (t, J = 7.4 Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H),
3.91–3.82 (m, 3H), 3.75 (td, J = 10.6, 4.2 Hz, 2H), 3.57–3.52 (m, 1H), 3.40 (ddd, J = 13.0, 7.0, 2.9
Hz, 1H), 3.28 (ddd, J = 13.3, 5.9, 2.9 Hz, 1H), 3.06 (dt, J = 15.1, 7.4 Hz, 1H), 2.99–2.92 (m, 1H),
2.71 (t, J = 7.4 Hz, 2H). 13C{1H} NMR (150 MHz, CDCl3): δ 168.7, 152.4, 136.7, 128.4, 127.9,
124.7, 124.1, 115.3, 66.6, 66.4, 46.7, 44.2, 31.4, 25.3. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C14H16N2O3Na 283.1053; Found 283.1054.
1-(Piperidine-1-carbonyl)-3,4-dihydroquinolin-2(1H)-one (3ab). White solid, 31.5 mg, 61%
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yield. Mp = 147–149 C. Eluent composition petroleum ether/ethyl acetate = 3:1. H NMR (600
MHz, CDCl3): δ 7.21 (t, J = 8.3 Hz, 2H), 7.04 (t, J = 7.4 Hz, 1H), 6.83 (d, J = 7.9 Hz, 1H), 3.89 (dd,
J = 11.8, 8.4 Hz, 1H), 3.64 (dd, J = 12.2, 8.7 Hz, 1H), 3.29 (t, J = 5.3 Hz, 2H), 3.04 (dt, J = 15.0,
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7.3 Hz, 1H), 2.99–2.93 (m, 1H), 2.70 (t, J = 7.4 Hz, 2H), 1.78 (s, 1H), 1.70–1.57 (m, 4H), 1.41 (dd,
J = 11.7, 6.4 Hz, 1H). 13C{1H} NMR (150 MHz, CDCl3): δ 168.5, 152.0, 137.0, 128.2, 127.7, 124.7,
123.8, 115.4, 47.5, 44.9, 31.4, 26.2, 25.4, 25.3, 24.1. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C15H19N2O2 259.1441; Found 259.1444.
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1-(Thiomorpholine-4-carbonyl)-3,4-dihydroquinolin-2(1H)-one (3ac). White solid, 33.1 mg,
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60% yield. Mp = 179–180 C. Eluent composition petroleum ether/ethyl acetate = 3:1. H NMR
(600 MHz, CDCl3): δ 7.22 (t, J = 7.9 Hz, 2H), 7.06 (t, J = 7.4 Hz, 1H), 6.79 (d, J = 8.0 Hz, 1H),
4.20–4.11 (m, 1H), 4.05–3.97 (m, 1H), 3.66 (ddd, J = 13.7, 7.2, 2.4 Hz, 1H), 3.55 (ddd, J = 13.7,
7.7, 2.4 Hz, 1H), 3.08–3.01 (m, 1H), 3.00–2.93 (m, 1H), 2.90–2.84 (m, 1H), 2.72 (dt, J = 15.1, 10.6
Hz, 4H), 2.45 (dd, J = 12.7, 6.4 Hz, 1H). 13C{1H} NMR (150 MHz, CDCl3): δ 168.7, 152.3, 136.7,
128.4, 127.9, 124.7, 124.1, 115.3, 49.2, 46.6, 31.4, 27.7, 27.3, 25.3. HRMS (ESI-TOF) m/z: [M +
Na]+ Calcd for C14H16N2O2SNa 299.0825; Found 299.0826.
tert-Butyl 4-(2-oxo-1,2,3,4-tetrahydroquinoline-1-carbonyl)piperazine-1-carboxylate (3ad).
o
White solid, 49.5 mg, 69% yield. Mp = 133–135 C. Eluent composition petroleum ether/ethyl
acetate = 3:1. 1H NMR (600 MHz, CDCl3): δ 7.21 (t, J = 6.0 Hz, 2H), 7.06 (t, J = 7.4 Hz, 1H), 6.81
(d, J = 8.3 Hz, 1H), 3.79 (s, 2H), 3.67–3.61 (m, 1H), 3.52 (s, 2H), 3.40–3.33 (m, 1H), 3.32–3.23 (m,
2H), 3.08–3.02 (m, 1H), 3.00–2.93 (m, 1H), 2.71 (t, J = 7.4 Hz, 2H), 1.46 (s, 9H). 13C{1H} NMR
(150 MHz, CDCl3): δ 168.7, 154.4, 152.4, 136.7, 128.4, 127.8, 124.7, 124.1, 115.3, 80.5, 46.3, 43.7,
31.4, 28.3, 25.3. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C19H25N3O4Na 382.1737; Found
382.1738.
1-(4-Phenylpiperidine-1-carbonyl)-3,4-dihydroquinolin-2(1H)-one (3ae). White solid, 41.4
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mg, 62% yield, 1.2:1 dr. Eluent composition petroleum ether/ethyl acetate = 3:1. H NMR (600
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MHz, CDCl3): the major diastereoisomer: δ 7.31 (dd, J = 12.6, 7.1 Hz, 2H), 7.28–7.24 (m, 1H), 7.22
(dd, J = 11.0, 7.4 Hz, 3H), 7.18 (d, J = 7.6 Hz, 1H), 7.06 (dd, J = 17.6, 7.6 Hz, 1H), 6.94 (d, J = 8.0
Hz, 1H), 4.79 (t, J = 11.3 Hz, 1H), 3.79–3.70 (m, 1H), 3.28–3.21 (m, 1H), 3.09–2.94 (m, 3H), 2.74
(dt, J = 14.6, 9.8 Hz, 3H), 2.06 (d, J = 13.8 Hz, 1H), 1.97–1.90 (m, 1H), 1.82 (d, J = 13.4 Hz, 1H),
1.79–1.72 (m, 1H); the minor diastereoisomer: δ 7.31 (dd, J = 12.6, 7.1 Hz, 2H), 7.28–7.24 (m, 1H),
7.22 (dd, J = 11.0, 7.4 Hz, 3H), 7.18 (d, J = 7.6 Hz, 1H), 7.06 (dd, J = 17.6, 7.6 Hz, 1H), 6.81 (d, J
= 8.2 Hz, 1H), 4.79 (t, J = 11.3 Hz, 1H), 3.79–3.70 (m, 1H), 3.14–3.09 (m, 1H), 3.09–2.94 (m, 3H),
2.74 (dt, J = 14.6, 9.8 Hz, 3H), 1.98 (d, J = 12.0 Hz, 1H), 1.97–1.90 (m, 1H), 1.82 (d, J = 13.4 Hz,
1H), 1.48 (qd, J = 12.9, 4.4 Hz, 1H). 13C{1H} NMR (150 MHz, CDCl3): δ 168.8, 168.5, 152.3,
152.0, 144.8, 144.6, 137.0, 136.8, 128.60, 128.55, 128.31, 128.27, 127.80, 127.78, 126.8, 126.64,
126.59, 126.55, 124.8, 124.6, 124.0, 123.9, 115.5, 115.2, 47.6, 46.7, 44.8, 44.5, 42.7, 42.0, 33.6,
33.1, 32.81, 32.79, 31.39, 31.38, 25.4, 25.3. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C21H22N2O2Na 357.1573; Found 357.1573.
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1-(4-Methoxypiperidine-1-carbonyl)-3,4-dihydroquinolin-2(1H)-one (3af).White solid, 34.6
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mg, 60% yield, 1.6:1 dr. Eluent composition petroleum ether/ethyl acetate = 3:1. H NMR (600
MHz, CDCl3): the major diastereoisomer: δ 7.19 (d, J = 7.2 Hz, 2H), 7.04 (t, J = 7.4 Hz, 1H), 6.81
(t, J = 7.6 Hz, 1H), 4.02–3.96 (m, 1H), 3.70–3.64 (m, 1H), 3.56–3.43 (m, 2H), 3.34 (d, J = 6.9 Hz,
3H), 3.26–3.20 (m, 1H), 3.04 (dq, J = 13.8, 6.9 Hz, 1H), 2.99–2.92 (m, 1H), 2.70 (t, J = 7.4 Hz,
2H), 2.08–2.01 (m, 1H), 1.88 (dt, J = 11.0, 4.7 Hz, 1H), 1.76–1.68 (m, 1H), 1.49 (dt, J = 11.8, 5.4
Hz, 1H); the minor diastereoisomer: δ 7.19 (d, J = 7.2 Hz, 2H), 7.04 (t, J = 7.4 Hz, 1H), 6.81 (t, J =
7.6 Hz, 1H), 3.88 (dt, J = 12.8, 6.3 Hz, 1H), 3.82–3.76 (m, 1H), 3.56–3.43 (m, 2H), 3.34 (d, J = 6.9
Hz, 3H), 3.19–3.14 (m, 1H), 3.04 (dq, J = 13.8, 6.9 Hz, 1H), 2.99–2.92 (m, 1H), 2.70 (t, J = 7.4 Hz,
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2H), 1.92 (dd, J = 8.9, 3.6 Hz, 1H), 1.88 (dt, J = 11.0, 4.7 Hz, 1H), 1.76–1.68 (m, 1H), 1.61 (dd, J
= 9.1, 4.2 Hz, 1H). 13C{1H} NMR (150 MHz, CDCl3): δ 168.7, 168.5, 152.10, 152.07, 137.0, 136.8,
128.3, 128.2, 127.8, 127.7, 124.7, 12.6, 123.93, 123.85, 115.4, 115.2, 74.7, 74.0, 55.8, 55.7, 43.6,
43.2, 40.9, 40.5, 31.38, 31.35, 30.8, 30.5, 29.9, 29.7, 25.4, 25.3. HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C16H21N2O3 289.1547; Found 289.1548.
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Ethyl 1-(2-oxo-1,2,3,4-tetrahydroquinoline-1-carbonyl)piperidine-4-carboxylate (3ag). White
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solid, 44.9 mg, 68% yield, 1.5:1 dr. Eluent composition petroleum ether/ethyl acetate = 3:1. H
NMR (600 MHz, CDCl3): the major diastereoisomer: δ 7.24–7.17 (m, 2H), 7.05 (dd, J = 13.5, 6.9
Hz, 1H), 6.82 (d, J = 8.0 Hz, 1H), 4.45 (d, J = 13.5 Hz, 1H), 4.14 (dt, J = 9.8, 5.8 Hz, 2H), 3.59 (t,
J = 14.4 Hz, 1H), 3.24 (ddd, J = 14.0, 7.9, 4.2 Hz, 1H), 3.20–3.14 (m, 1H), 3.05–3.01 (m, 1H), 2.99–
2.92 (m, 1H), 2.70 (t, J = 7.4 Hz, 2H), 2.57–2.49 (m, 1H), 2.11 (d, J = 10.8 Hz, 1H), 1.98–1.89 (m,
1H), 1.85–1.74 (m, 1H), 1.59–1.50 (m, 1H), 1.25 (t, J = 7.1 Hz, 3H); the minor diastereoisomer: δ
7.24–7.17 (m, 2H), 7.05 (dd, J = 13.5, 6.9 Hz, 1H), 6.77 (d, J = 8.1 Hz, 1H), 4.39 (d, J = 13.3 Hz,
1H), 4.14 (dt, J = 9.8, 5.8 Hz, 2H), 3.59 (t, J = 14.4 Hz, 1H), 3.24 (ddd, J = 14.0, 7.9, 4.2 Hz, 1H),
3.07 (d, J = 7.6 Hz, 1H), 3.05–3.01 (m, 1H), 2.99–2.92 (m, 1H), 2.70 (t, J = 7.4 Hz, 2H), 2.57–2.49
(m, 1H), 2.03 (dd, J = 13.6, 3.7 Hz, 1H), 1.98–1.89 (m, 1H), 1.85–1.74 (m, 1H), 1.59–1.50 (m, 1H),
1.25 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (150 MHz, CDCl3): δ 173.9, 173.5, 168.61, 168.58, 152.3,
152.0, 136.9, 136.8, 128.29, 128.27, 127.9, 127.8, 124.68, 124.66, 124.0, 123.9, 115.4, 115.2, 60.73,
60.72, 45.9, 45.5, 43.2, 43.1, 40.5, 40.4, 31.38, 31.36, 28.3, 28.0, 27.7, 27.4, 25.34, 25.30, 14.18,
14.16. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C18H22N2O4Na 353.1472; Found 353.1473.
1-(4,4-Dimethylpiperidine-1-carbonyl)-3,4-dihydroquinolin-2(1H)-one (3ah). White solid,
41.2 mg,72% yield. Mp = 159–160 oC. Eluent composition petroleum ether/ethyl acetate = 3:1. 1H
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NMR (600 MHz, CDCl3): δ 7.20 (dd, J = 12.8, 7.3 Hz, 2H), 7.04 (t, J = 7.5 Hz, 1H), 6.82 (d, J =
8.0 Hz, 1H), 3.90–3.84 (m, 1H), 3.72–3.66 (m, 1H), 3.32 (ddd, J = 12.7, 8.7, 3.6 Hz, 1H), 3.28–3.22
(m, 1H), 3.06–3.00 (m, 1H), 2.98–2.91 (m, 1H), 2.69 (t, J = 7.4 Hz, 2H), 1.55 (dd, J = 13.8, 7.2 Hz,
1H), 1.48–1.38 (m, 2H), 1.22 (ddd, J = 13.0, 8.7, 4.0 Hz, 1H), 0.99 (s, 3H), 0.96 (s, 3H). 13C{1H}
NMR (150 MHz, CDCl3): δ 168.5, 152.1, 137.0, 128.2, 127.8, 124.7, 123.8, 115.4, 43.2, 40.6, 38.8,
37.9, 31.4, 29.0, 28.4, 26.6, 25.4. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C17H23N2O2 287.1754;
Found 287.1755.
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1-(1,4-Dioxa-8-azaspiro[4.5]decane-8-carbonyl)-3,4-dihydroquinolin-2(1H)-one
(3ai).
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White solid, 41.1 mg, 65% yield. Mp = 138–140 C. Eluent composition petroleum ether/ethyl
acetate = 3:1. 1H NMR (600 MHz, CDCl3): δ 7.20 (t, J = 7.2 Hz, 2H), 7.05 (t, J = 7.5 Hz, 1H), 6.81
(d, J = 8.3 Hz, 1H), 4.01–3.92 (m, 5H), 3.91–3.85 (m, 1H), 3.46 (ddd, J = 12.4, 8.1, 3.9 Hz, 1H),
3.42–3.36 (m, 1H), 3.04 (dt, J = 15.0, 7.3 Hz, 1H), 2.99–2.92 (m, 1H), 2.70 (t, J = 7.6 Hz, 2H),
1.93–1.87 (m, 1H), 1.83–1.74 (m, 2H), 1.59–1.53 (m, 1H). 13C{1H} NMR (150 MHz, CDCl3): δ
168.6, 152.1, 136.9, 128.3, 127.8, 124.7, 123.9, 115.3, 106.5, 64.5, 64.51, 64.47, 44.67, 42.0, 35.3,
34.5, 31.4, 25.3. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C17H20N2O4Na 339.1315; Found
339.1316.
1-(3-Azaspiro[5.5]undecane-3-carbonyl)-3,4-dihydroquinolin-2(1H)-one (3aj). White solid,
41.1 mg, 63% yield. Mp = 155–156 oC. Eluent composition petroleum ether/ethyl acetate = 3:1. 1H
NMR (600 MHz, CDCl3): δ 7.22–7.17 (m, 2H), 7.03 (t, J = 7.4 Hz, 1H), 6.81 (d, J = 8.0 Hz, 1H),
3.88–3.82 (m, 1H), 3.70–3.64 (m, 1H), 3.31 (ddd, J = 12.9, 9.0, 3.7 Hz, 1H), 3.26–3.20 (m, 1H),
3.06–2.99 (m, 1H), 2.97–2.91 (m, 1H), 2.68 (t, J = 7.4 Hz, 2H), 1.69–1.63 (m, 1H), 1.54–1.36 (m,
10H), 1.35–1.23 (m, 3H). 13C{1H} NMR (150 MHz, CDCl3): δ 168.5, 152.1, 137.0, 128.2, 127.7,
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124.7, 123.8, 115.4, 42.4, 39.8, 36.9, 34.9, 31.4, 31.2, 26.6, 25.4, 21.4, 21.3. HRMS (ESI-TOF) m/z:
[M + Na]+ Calcd for C20H26N2O2Na 349.1886; Found 349.1885.
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yield . Mp = 129–130 C. Eluent composition petroleum ether/ethyl acetate = 3:1. H NMR (600
MHz, CDCl3): δ 7.24–7.16 (m, 2H), 7.04 (t, J = 7.4 Hz, 1H), 6.85 (d, J = 8.0 Hz, 1H), 3.81–3.74
(m, 1H), 3.67–3.60 (m, 1H), 3.43–3.36 (m, 1H), 3.29–3.22 (m, 1H), 3.05–2.92 (m, 2H), 2.75–2.63
(m, 2H), 1.93 (d, J = 7.9 Hz, 1H), 1.84–1.74 (m, 1H), 1.73–1.63 (m, 4H), 1.60–1.54 (m, 1H), 1.48–
1.39 (m, 1H). 13C{1H} NMR (150 MHz, CDCl3): δ 168.5, 153.3 136.9, 128.2, 127.7, 124.6, 123.8,
115.2, 48.6, 46.9, 31.3, 28.1, 27.9, 27.7, 26.4, 25.3. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C16H21N2O2 273.1598; Found 273.1599.
1-(3-((Benzo[d][1,3]dioxol-5-yloxy)methyl)-4-(4-fluorophenyl)piperidine-1-carbonyl)-3,4-
dihydroquinolin-2(1H)-one (3al). White solid, 70.3 mg, 70% yield, 1.8:1.5:1 dr. Eluent composition
petroleum ether/ethyl acetate = 3:1. 1H NMR (600 MHz, CDCl3): the first major diastereoisomer: δ
7.29–7.15 (m, 3H), 7.14–7.04 (m, 2H), 6.97 (q, J = 9.1 Hz, 2H), 6.84 (dd, J = 16.5, 8.3 Hz, 1H),
6.64 (d, J = 8.4 Hz, 1H), 6.39 (s, 1H), 6.17 (d, J = 8.4 Hz, 1H), 5.88 (d, J = 17.1 Hz, 2H), 4.85 (dt,
J = 33.6, 16.3 Hz, 1H), 3.93 (d, J = 13.3 Hz, 1H), 3.79–3.66 (m, 1H), 3.56–3.47 (m, 1H), 3.32 (ddd,
J = 59.3, 20.0, 8.8 Hz, 1H), 3.18–3.10 (m, 1H), 3.05–2.98 (m, 2H), 2.89–2.68 (m, 3H), 2.42 (d, J =
7.6 Hz, 1H), 2.09–1.94 (m, 1H), 1.79 (d, J = 12.6 Hz, 1H); the second major diastereoisomer: δ
7.29–7.15 (m, 3H), 7.14–7.04 (m, 2H), 6.97 (q, J = 9.1 Hz, 2H), 6.84 (dd, J = 16.5, 8.3 Hz, 1H),
6.59 (d, J = 8.4 Hz, 1H), 6.24 (s, 1H), 6.03 (d, J = 8.3 Hz, 1H), 5.88 (d, J = 17.1 Hz, 2H), 4.85 (dt,
J = 33.6, 16.3 Hz, 1H), 3.93 (d, J = 13.3 Hz, 1H), 3.79–3.66 (m, 1H), 3.56–3.47 (m, 1H), 3.32 (ddd,
J = 59.3, 20.0, 8.8 Hz, 1H), 3.18–3.10 (m, 1H), 3.05–2.98 (m, 2H), 2.89–2.68 (m, 3H), 2.28 (s, 1H),
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2.09–1.94 (m, 1H), 1.79 (d, J = 12.6 Hz, 1H); the minor diastereoisomer: δ 7.29–7.15 (m, 3H), 7.14–
7.04 (m, 2H), 6.97 (q, J = 9.1 Hz, 2H), 6.84 (dd, J = 16.5, 8.3 Hz, 1H), 6.55 (d, J = 8.5 Hz, 1H),
6.13 (s, 1H), 5.93 (d, J = 8.2 Hz, 1H), 5.88 (d, J = 17.1 Hz, 2H), 4.85 (dt, J = 33.6, 16.3 Hz, 1H),
3.93 (d, J = 13.3 Hz, 1H), 3.79–3.66 (m, 1H), 3.56–3.47 (m, 1H), 3.32 (ddd, J = 59.3, 20.0, 8.8 Hz,
1H), 3.18–3.10 (m, 1H), 3.05–2.98 (m, 2H), 2.89–2.68 (m, 3H), 2.14 (s, 1H), 2.09–1.94 (m, 1H),
1.79 (d, J = 12.6 Hz, 1H). 13C{1H} NMR (150 MHz, CDCl3): δ 169.0, 168.9, 168.6, 168.5, 161.71
(d, 1JC-F = 245.1), 161.68 (d, 1JC-F = 245.0), 161.66 (d, 1JC-F = 245.1), 154.2, 153.8, 153.5, 152.5,
152.3, 152.1, 148.2, 148.14, 148.12, 141.80, 141.76, 141.7, 138.3, 138.20, 138.18, 136.9, 136.8,
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136.7, 129.0 (d, JC-F = 7.9), 128.8 (d, JC-F = 7.9), 128.7 (d, JC-F = 7.9), 128.6, 128.5, 128.31,
128.28, 127.85, 127.84, 127.74, 127.66, 125.0, 124.9, 124.6, 124.5, 124.2, 124.1, 123.99, 123.95,
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115.7 (d, JC-F = 21.0), 115.64 (d, JC-F = 21.0), 115.62 (d, JC-F = 21.0), 115.51, 115.45, 115.3,
115.2, 107.86, 107.85, 107.8, 105.6, 105.2, 105.1, 101.1, 98.0, 98.0, 97.63, 97.59, 68.4, 68.3, 68.1,
47.5, 47.3, 47.0, 44.9, 44.3, 44.1, 43.8, 43.5, 43.3, 42.3, 42.1, 41.9, 34.2, 33.6, 33.4, 31.42, 31.37,
31.3, 25.4, 25.3. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C29H27FN2O5Na 525.1796; Found
525.1810.
6-Methoxy-1-(morpholine-4-carbonyl)-3,4-dihydroquinolin-2(1H)-one (3da). Yellow solid,
23.2 mg, 40% yield. Mp = 110–111 oC. Eluent composition petroleum ether/ethyl acetate = 3:1. 1H
NMR (600 MHz, CDCl3): δ 6.79–6.71 (m, 3H), 3.89–3.80 (m, 3H), 3.78 (s, 3H), 3.77–3.71 (m, 2H),
3.56–3.51 (m, 1H), 3.39 (ddd, J = 13.1, 7.0, 2.8 Hz, 1H), 3.27 (ddd, J = 13.3, 5.8, 2.8 Hz, 1H), 3.04–
2.98 (m, 1H), 2.94–2.87 (m, 1H), 2.67 (t, J = 7.3 Hz, 2H). 13C{1H} NMR (150 MHz, CDCl3): δ
168.3, 156.2, 152.5, 130.3, 126.3, 116.5, 114.2, 112.6, 66.6, 66.4, 55.6, 46.7, 44.2, 31.4, 25.6.
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C15H19N2O4 291.1339; Found 291.1341.
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6-Methyl-1-(morpholine-4-carbonyl)-3,4-dihydroquinolin-2(1H)-one (3ea). White solid, 32.3
mg, 60% yield. Mp = 142–143 oC. Eluent composition petroleum ether/ethyl acetate = 3:1. 1H NMR
(600 MHz, CDCl3): δ 7.02 (s, 2H), 6.72 (d, J = 8.5 Hz, 1H), 3.90–3.80 (m, 3H), 3.75 (dd, J = 10.7,
6.0 Hz, 2H), 3.56–3.50 (m, 1H), 3.39 (dd, J = 13.1, 4.3 Hz, 1H), 3.29–3.24 (m, 1H), 3.04–2.97 (m,
1H), 2.94–2.87 (m, 1H), 2.68 (t, J = 7.2 Hz, 2H), 2.30 (s, 3H). 13C{1H} NMR (150 MHz, CDCl3):
δ 168.6, 152.5, 134.3, 133.8, 129.0, 128.2, 124.6, 115.2, 66.6, 66.4, 46.7, 44.2, 31.5, 25.3, 20.7.
HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C15H18N2O3Na 297.1210; Found 297.1211.
7-Methyl-1-(morpholine-4-carbonyl)-3,4-dihydroquinolin-2(1H)-one (3fa). White solid, 37.3
mg, 68% yield. Mp = 138–139 oC. Eluent composition petroleum ether/ethyl acetate = 3:1. 1H NMR
(600 MHz, CDCl3): δ 7.08 (d, J = 7.6 Hz, 1H), 6.87 (d, J = 7.6 Hz, 1H), 6.64 (s, 1H), 3.91–3.82 (m,
3H), 3.79–3.72 (m, 2H), 3.55 (dd, J = 13.2, 5.0 Hz, 1H), 3.43–3.37 (m, 1H), 3.31–3.25 (m, 1H),
3.03–2.96 (m, 1H), 2.94–2.86 (m, 1H), 2.68 (t, J = 7.4 Hz, 2H), 2.31 (s, 3H). 13C{1H} NMR (150
MHz, CDCl3): δ 168.9, 152.4, 137.8, 136.6, 128.1, 124.8, 121.7, 115.9, 66.6, 66.4, 46.7, 44.2, 31.6,
24.9, 21.3. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C15H19N2O3 275.1390; Found 275.1392.
7-Chloro-1-(morpholine-4-carbonyl)-3,4-dihydroquinolin-2(1H)-one (3ga). White solid, 39.4
mg, 67% yield. Mp = 116–117 oC. Eluent composition petroleum ether/ethyl acetate = 3:1. 1H NMR
(600 MHz, CDCl3): δ 7.14 (d, J = 8.0 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 6.86 (s, 1H), 3.90–3.81 (m,
3H), 3.81–3.73 (m, 2H), 3.61–3.55 (m, 1H), 3.42–3.37 (m, 1H), 3.32–3.26 (m, 1H), 3.05–2.99 (m,
1H), 2.96–2.89 (m, 1H), 2.70 (t, J = 7.3 Hz, 2H). 13C{1H} NMR (150 MHz, CDCl3): δ 168.4, 151.8,
137.8, 133.5, 129.3, 124.0, 123.1, 115.7, 66.6, 66.4, 46.8, 44.3, 31.2, 24.8. HRMS (ESI-TOF) m/z:
[M + H]+ Calcd for C14H16ClN2O3 295.0844; Found 295.0842.
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6,7-Dimethyl-1-(morpholine-4-carbonyl)-3,4-dihydroquinolin-2(1H)-one (3ha). White solid,
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43.8 mg, 76% yield. Mp = 130–131 oC. Eluent composition petroleum ether/ethyl acetate = 3:1. 1H
NMR (600 MHz, CDCl3): δ 6.96 (s, 1H), 6.60 (s, 1H), 3.91–3.82 (m, 3H), 3.78–3.71 (m, 2H), 3.57–
3.52 (m, 1H), 3.39 (ddd, J = 13.2, 6.8, 2.9 Hz, 1H), 3.27 (ddd, J = 13.4, 6.2, 3.0 Hz, 1H), 3.00–2.94
(m, 1H), 2.90–2.84 (m, 1H), 2.66 (t, J = 7.4 Hz, 2H), 2.21 (d, J = 6.5 Hz, 6H). 13C{1H} NMR (150
MHz, CDCl3): δ 168.7, 152.6, 136.1, 134.5, 132.4, 129.4, 121.9, 116.5, 66.7, 66.4, 46.7, 44.2, 31.7,
24.9, 19.7, 19.0. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C16H21N2O3 289.1547; Found 289.1548.
6,7-Dimethyl-1-(3-azaspiro[5.5]undecane-3-carbonyl)-3,4-dihydroquinolin-2(1H)-one (3hj).
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White solid, 28.3 mg, 40% yield. Mp = 140–141 C. Eluent composition petroleum ether/ethyl
acetate = 3:1. 1H NMR (600 MHz, CDCl3): δ 6.95 (s, 1H), 6.59 (s, 1H), 3.87–3.82 (m, 1H), 3.71–
3.66 (m, 1H), 3.30 (ddd, J = 12.7, 8.8, 3.5 Hz, 1H), 3.25–3.19 (m, 1H), 2.95 (dt, J = 15.0, 7.3 Hz,
1H), 2.90–2.84 (m, 1H), 2.65 (t, J = 7.3 Hz, 2H), 2.20 (s, 6H), 1.65 (dd, J = 14.6, 7.5 Hz, 2H), 1.54–
1.41 (m, 6H), 1.40–1.23 (m, 6H). 13C{1H} NMR (150 MHz, CDCl3): δ 168.6, 152.3, 135.9, 134.7,
132.0, 129.3, 121.8, 116.5, 42.4, 39.8, 36.8, 35.0, 31.7, 31.2, 26.6, 24.9, 21.4, 21.3, 19.7, 19.0.
HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C22H30N2O2Na 377.2199; Found 377.2197.
6-Chloro-1-(morpholine-4-carbonyl)-3,4-dihydroquinolin-2(1H)-one (3ia). White solid, 31.8
mg, 54% yield. Mp = 124–125 oC. Eluent composition petroleum ether/ethyl acetate = 3:1. 1H NMR
(600 MHz, CDCl3): δ 7.19 (d, J = 10.3 Hz, 2H), 6.78 (d, J = 8.4 Hz, 1H), 3.90–3.80 (m, 3H), 3.77–
3.72 (m, 2H), 3.57–3.52 (m, 1H), 3.39 (ddd, J = 13.2, 6.9, 2.8 Hz, 1H), 3.26 (ddd, J = 13.3, 6.0, 2.9
Hz, 1H), 3.06–3.00 (m, 1H), 2.97–2.90 (m, 1H), 2.70 (t, J = 7.4 Hz, 2H). 13C{1H} NMR (150 MHz,
CDCl3): δ 168.2, 152.0, 135.4, 129.3, 128.4, 127.8, 126.5, 116.6, 66.6, 66.4, 46.8, 44.3, 31.0, 25.1.
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C14H16ClN2O3 295.0844; Found 295.0845.
Methyl 1-(morpholine-4-carbonyl)-2-oxo-1,2,3,4-tetrahydroquinoline-6-carboxylate (3ja).
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(s, 3H), 3.89–3.81 (m, 3H), 3.75 (ddd, J = 14.4, 7.4, 3.2 Hz, 2H), 3.57–3.51 (m, 1H), 3.41–3.35 (m,
1H), 3.29–3.24 (m, 1H), 3.13–3.06 (m, 1H), 3.04–2.97 (m, 1H), 2.73 (t, J = 7.4 Hz, 2H). 13C{1H}
NMR (150 MHz, CDCl3): δ 168.5, 166.2, 151.8, 140.5, 129.8, 129.6, 125.8, 124.5, 115.1, 66.6,
66.4, 52.2, 46.8, 44.3, 31.0, 25.1. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C16H18N2O5Na
341.1108; Found 341.1109.
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oil, 21.6 mg, 33% yield. Eluent composition petroleum ether/ethyl acetate = 3:1. H NMR (600
MHz, CDCl3): δ 7.49 (d, J = 8.6 Hz, 2H), 6.94 (d, J = 8.2 Hz, 1H), 3.92–3.80 (m, 3H), 3.79–3.73
(m, 2H), 3.59–3.53 (m, 1H), 3.40 (ddd, J = 13.2, 6.8, 2.8 Hz, 1H), 3.27 (ddd, J = 13.3, 6.0, 2.9 Hz,
1H), 3.16–3.08 (m, 1H), 3.05–2.98 (m, 1H), 2.74 (t, J = 7.4 Hz, 2H). 13C{1H} NMR (150 MHz,
CDCl3): δ 168.3, 151.7, 139.6, 126.2 (q, 2JC-F = 32.8 Hz), 125.5 (q, 3JC-F = 3.7 Hz), 125.1 (q, 3JC-F
= 3.8 Hz), 123.8 (q, 1JC-F = 272.3 Hz), 115.5, 66.6, 66.4, 46.8, 44.3, 30.9, 25.2. 19F NMR (564 MHz,
CDCl3) δ –62.22. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C15H15F3N2O3Na 351.0927; Found
351.0927.
(E)-Methyl 3-(2-(morpholine-4-carboxamido)phenyl)acrylate (4). White solid, 30.4 mg, 59%
o
1
yield. Mp = 182–184 C. Eluent composition petroleum ether/ethyl acetate = 3:1. H NMR (600
MHz, CDCl3): δ 7.81 (d, J = 15.9 Hz, 1H), 7.53 (t, J = 6.8 Hz, 2H), 7.37 (t, J = 7.7 Hz, 1H), 7.17 (t,
J = 7.6 Hz, 1H), 6.40 (d, J = 15.9 Hz, 1H), 6.34 (s, 1H), 3.80 (s, 3H), 3.77–3.74 (m, 4H), 3.51–3.48
(m, 4H). 13C{1H} NMR (150 MHz, CDCl3): δ 167.2, 155.4, 139.9, 137.2, 130.8, 127.7, 127.2, 125.1,
125.04, 119.8, 66.5, 51.8, 44.5. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C15H19N2O4 291.1339;
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Found 291.1341.
5
6
7
8
9
Methyl 3-(2-(morpholine-4-carboxamido)phenyl)propanoate (5): A solution of 4 (0.5 mmol)
and Pd/C (10 wt. %. 10.6 mg) in EtOAc (2 ml) was stirred vigorously under 1 atm of H2 overnight.
The suspension was filtered to remove solids, and the filtrate was concentrated in vacuo to give rise
to compound 5. White solid, 146 mg, 99% yield. Mp = 113–114 oC. Eluent composition petroleum
ether/ethyl acetate = 3:1. 1H NMR (600 MHz, CDCl3): δ 8.07 (s, 1H), 7.59 (d, J = 8.1 Hz, 1H), 7.20
(t, J = 7.6 Hz, 1H), 7.12 (d, J = 7.5 Hz, 1H), 7.06 (t, J = 7.4 Hz, 1H), 3.79–3.76 (m, 4H), 3.63 (s,
3H), 3.61–3.58 (m, 4H), 2.88–2.84 (m, 2H), 2.77–2.73 (m, 2H). 13C{1H} NMR (150 MHz, CDCl3):
δ 175.5, 156.0, 136.7, 132.5, 129.7, 127.0, 125.5, 124.5, 66.7, 52.1, 44.2, 35.5, 25.0. HRMS (ESI-
TOF) m/z: [M + Na]+ Calcd for C15H20N2O4Na 315.1315; Found 315.1316.
ASSOCIATED CONTENT
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Supporting Information
1H NMR and 13C NMR spectra of new compounds, crystallographic data and CIF file of 3aa.
AUTHOR INFORMATION
Corresponding Author
*E-mail: ycchen@scu.edu.cn; weiye712@swu.edu.cn.
Present Addresses
† School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715,
China.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
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Financial support from the NSFC (No. 21772231), the Natural Science Foundation of Chongqing
(No. cstc2016jcyjA0008), and the Army Medical University (No. 2016PY04) is greatly appreciated.
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