One-pot synthesis of polyfunctionalized quinolines: Via a copper-catalyzed tandem cyclization

Article abstract of DOI:10.1039/c8ob02078g

An efficient one-pot approach for the synthesis of polyfunctionalized quinolines was developed via a sequence of copper-catalyzed coupling reaction/propargyl-allenyl isomerization/aza-electrocyclization. Easily available starting materials, mild conditions, and a wide substrate scope make this approach potentially useful.

Full text of DOI:10.1039/c8ob02078g

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One-Pot Synthesis of Polyfunctionalized Quinolines via a Copper-
Catalyzed Tandem Cyclization†
Dianpeng Chen,*a Xuejun Sun,a Yingying Shan,*a Jinmao You*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
An efficient one-pot approach for the synthesis of polyfunctionalized quinolines was developed via a sequence of copper-
catalyzed coupling reaction /propargyl-allenyl isomerization/aza-electrocyclization. Easily available starting materials, mild
conditions, and a wide substrate scope make this approach potentially useful.
www.rsc.org/
Tandem cyclizations, in which multistep reactions are
combined into one synthetic operation, have emerged as a
powerful tool for the rapid construction of complex molecular
Introduction
Quinoline derivatives represent an important group of
heterocycles due to their privileged scaffold motifs of
physicochemical properties, biological activities, and
pharmacological value.1-3 Many famous molecules in the
quinoline family, especially for the 4-substituted quinolines,
have attracted much more attention for the widely application
in medicinal chemistry (Figure. 1). As a 4-aminoquinoline
compound, Amodiaquine is used to treat malaria.4 Mefloquine
possesses significant anti-inflammatory and antiasthmatic
skeletons.10 Since Müller pioneered the coupling-isomerization
reactions, continuous efforts have been devoted to this area.11
During our research on the in situ propargyl-allenyl
isomerization,12 we found that alkynyl imides equipped with
electron-withdrawing groups could offer corresponding allenes
in the presence of appropriate base.13 Herein, we wish to
report a sequence of copper-catalyzed coupling reaction
/propargyl-allenyl isomerization/aza-electrocyclization by one-
pot, yielding polyfunctionalized quinolines, which are difficult
to prepare by other methods (Scheme 1).
activities.5 TSPO is
a
recognized biomarker of
neuroinflammation, with high affinity and human genotype
insensitivity.6
OH
NEt2
N
HO
O
N
Ph
N
H
N
O
N
N
CF3
Cl
N
CF3
Amodiaquine
Mefloquine
TSPO
Figure. 1 Bioactive quinoline derivatives quinolines
Classical methods for the synthesis of quinolines have been
frequently employed, such as Combes,7 Doebner-von Miller8
and Skraup reactions9. Although these methods are efficient,
harsh reaction conditions and poor tolerance of functional
groups may limit the synthetic applications in some cases.
Accordingly, developing new and effective approach for the
Scheme 1 Proposal for the construction of polyfunctionalized
quinolines
construction of polyfunctionalized quinolines remains
formidable challenge.
a
Results and discussion
Stimulated by this proposal, we chose (Z)-N-phenylbenzimidoyl
chloride
(1a) and tert-butyl 1-(4-chlorophenyl)prop-2-ynyl
carbonate (2a) as the starting material. Our study was initiated
by testing the reaction of 1a and 2a in the presence of CuI and
triethylamine (TEA) in THF at -78 oC followed by warming to
room temperature. To our delight, this set of conditions
afforded the expected tert-butyl (4-chlorophenyl)(2-
phenylquinolin-4-yl)methyl carbonate (3a) in 62% yield (Table
1, entry 1). Then we began to optimize the reaction with
a
The Key Laboratory of Life-Organic Analysis and Key Laboratory of
Pharmaceutical Intermediates and Analysis of Natural Medicine, School of
Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165,
Shandong, China.
*chendp@zju.edu.cn; shanyying@zju.edu.cn; Jmyou6304@163.com
† Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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respect to different bases, solvents, and temperatures. Table 2 Reaction scope of imidoyl chloridesa,b
OBoc
R1
Cl
OBoc
Replacing TEA by DIPEA (N,N-diisopropylethylamine) or the
stronger organic base DBU (1,8-diazabicyclo[5.4.0]undec-7-ene)
gave similar yields (Table 1, entries 2-3). Inorganic bases, such
as Na2CO3, K2CO3 and t-BuOK, showed poor reactivity and gave
3a in 17-28% yields (Table 1, entries 4-6). Whereas subsequent
screening of other common solvents, such as acetonitrile, 1,4-
dioxane and toluene, did not improve the yield obviously, DCE
(1,2-dichloroethane) was found to be an appropriate solvent
for this reaction that afforded the product in 87% yield (Table
1, entries 7-10). In addition, increasing the reaction
temperature to 60 oC led to a low yield (Table 1, entry 11), and
keeping the reaction temperature at 80 oC offered an
unidentified mixture (Table 1, entry 12). Thus, the optimized
reaction conditions were chosen as follows: 1a (0.5 mmol), 2a
(0.6 mmol), CuI (10 mol %) and TEA (1.5 equiv) in 2 mL of DCE
were stirred at -78 oC followed by warming to room
temperature.
R1
CuI, TEA, DCE
-78 oC to rt
N
+
N
R2
Cl
R2
Cl
1
2a
3
_____________________________________________________________________________________________
3f, R2 = 7-Me, 72%
OBoc
OBoc
R2
3a, R1 = Ph, 87%
3g, R2 = 6-Me, 80%
3h, R2 = 6-Et, 81%
3i, R2 = 6-Pri, 78%
3j, R2 = 6-But, 76%
3k, R2 = 6-Cl, 79%
R1
3b, R1= 4-MePh, 83%
3c, R1 = 4-MeOPh, 81%
3d, R1 = 4-ClPh, 82%
3e, R1= 4-FPh, 80%
N
N
Cl
Cl
MeO
Cl
OBoc
OBoc
OBoc
OBoc
S
N
N
N
N
Cl
Cl
Cl
Cl
OMe
3o, 74%
3l, 78%
3m, 80%
3n, 71%
_____________________________________________________________________________________________
a
Conditions: 1 (0.5 mmol), 2a (0.6 mmol), CuI (10 mol %) and TEA
(1.5 equiv) in 2 mL of DCE were stirred at -78 oC followed by
b
warming to room temperature under a N2 atmosphere. Isolated
Table 1 Optimization of the reaction conditionsa
yield based on 1.
OBoc
OBoc
Cl
CuI, Base, Solvent
It was noteworthy that DBU was used to trigger the reaction
due to the weak acidity of protons adjacent to the nitrogen
+
N
N
Temperature
Cl
Cl
atom (Table 3, 4h
greatly when the R3 was alkyl (Table 3, 4e) or hydrogen (Table
3, 4h 4i). We hypothesized that allene intermediates might be
, 4i). Furthermore, the yield decreased
1a
2a
3a
,
Entry
Base (equiv)
Solvent
THF
Temperature (oC)
Yield (%)b
more stable and the occurrence of aza-electrocyclization could
be more easy-going when the R3 was aryl.
Table 3 Reaction scope of alkynesa,b
1
2
TEA (1.5)
DIPEA (1.5)
DBU (1.5)
Na2CO3 (1.5)
K2CO3 (1.5)
t-BuOK (1.5)
TEA (1.5)
-78 to rt
-78 to rt
-78 to rt
-78 to rt
-78 to rt
-78 to rt
-78 to rt
-78 to rt
-78 to rt
-78 to rt
-78 to 60
-78 to 80
62
60
THF
3
THF
57
4
THF
28
5
THF
25
6
THF
17
7
CH3CN
52
8
TEA (1.5)
dioxane
toluene
DCE
70
9
TEA (1.5)
41
10
11
12
TEA (1.5)
87
TEA (1.5)
DCE
23
TEA (1.5)
DCE
Complex
a Conditions: 1a (0.5 mmol), 2a (0.6 mmol), CuI (10 mol %) and TEA
(1.5 equiv) in 2 mL of DCE were stirred at -78 oC followed by
b
warming to room temperature under a N2 atmosphere. Isolated
yield based on 1a.
a
With the optimized conditions in hand, the scope of this
reaction was investigated further. As shown in Table 2, various
functional groups could be tolerated. The R1 and R2 could be
phenyl groups optionally substituted with an electron-
donating or an electron-withdrawing group, and the yields
were satisfactory. Moreover, the reaction could proceed
smoothly when the R1 was thienyl (Table 2, 3n) or alkyl (Table
2, 3o).
Conditions: 1 (0.5 mmol), 2a (0.6 mmol), CuI (10 mol %) and TEA
(1.5 equiv) in 2 mL of DCE were stirred at -78 oC followed by
b
warming to room temperature under a N2 atmosphere. Isolated
yield based on 1. c DBU was used as the base instead of TEA.
Compounds containing the 4-substituted quinoline moiety
are always present in pharmacology. To demonstrate the
scalability of this carbonylation protocol, a gram-scale reaction
of imidoyl chloride (1a) and alkyne (2a) was carried out under
standard conditions. As shown in Scheme 2, the corresponding
3a was obtained in 85% yield.
Then we turned our attention to explore the scope of the
alkyne partners. As shown in Table 3,
a series of
polyfunctionalized quinolines were synthesized in good yields.
2 | J. Name., 2012, 00, 1-3
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solvents. Splitting pattern was described as follows: s for
singlet, d for doublet, t for triplet, q for quartet, and m for
multiplet. Coupling constants were reported in Hz. The high-
resolution mass spectrum (HRMS) was performed on Waters
Xevo G2-S QTof mass spectrometer.
Scheme 2 Gram-scale reaction of 1a with 2a
General procedure for the reaction
We proposed a plausible pathway as shown in Scheme 3.
Intermediate A was formed through the insertion of copper species
with alkyne 2. Then an imidoyl chloride 1 insertion would be
involved to afford the intermediate B by oxidant addition. After
reductive elimination, intermediate C was generated. Subsequently,
Intermediate D was offered by propargyl-allenyl isomerisation,
which underwent aza-electrocyclization reaction to give product 3
or 4. The copper species was able to fulfill the catalytic cycle in the
presence of base.14
Under nitrogen condition, CuI (0.05 mmol) was successively added
to a 25mL vial equipped with a stir bar at -78 oC. A solution of the
imidoyl chloride 1 (0.5 mmol) in DCE (2 mL) was added using a
syringe. Then, the corresponding alkyne 2 (0.6 mmol) was added to
the mixture. TEA (0.75 mmol) was added at last. The reaction was
stirred for 30 minutes at -78 oC, and stirred for another 12 hours
(monitored by TLC) at room temperature. Solvent was removed in
vacuo to leave a crude mixture, which is purified by silica gel
column chromatography to afford pure product 3 or 4.
EWG
R3
H
EWG
Base
Base
+
R1
Base
tert-butyl
(4-chlorophenyl)(2-phenylquinolin-4-yl)methyl
[Cu]
R3
2
carbonate (3a): Pale white solid, 193mg, 87% yield; Mp: 183-185 oC;
1H NMR (400 MHz, CDCl3) δ 8.23–8.17 (m, 3H), 8.07 (s, 1H), 7.88 (d,
J = 8.0 Hz, 1H), 7.69 (m, 1H), 7.57–7.52 (m, 2H), 7.51–7.45 (m, 2H),
7.37 (m, 3H), 7.32–7.29 (m, 2H), 1.49 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 157.2, 152.7, 148.7, 144.9, 139.5, 136.7, 134.7, 130.7,
129.6, 129.5, 129.2, 129.1, 128.9, 127.7, 126.8, 124.2, 123.2, 116.4,
83.4, 75.5, 27.8; IR (neat) 2927, 1866, 1390cm-1; HRMS (EI-TOF)
calcd for C27H24ClNO3 445.1445, found 445.1446.
N
Propargyl-allenyl
Isomerization
Reductive
Elimination
R2
C
Insertion
EWG
R1
R3
Cl
N
EWG
R3
R2
R1 [Cu]
N
EWG
R3
[Cu]
D
A
R2
EWG
R3
R1
B
Aza-electrocyclization
N
R1 Cl
N
R2
Oxidant
Addition
3 or 4
R2
tert-butyl
(4-chlorophenyl)(2-p-tolylquinolin-4-yl)methyl
1
carbonate (3b): Pale white solid, 190mg, 83% yield; Mp: 164-166 oC;
1H NMR (400 MHz, CDCl3) δ 8.18 (d, J = 8.0 Hz, 1H), 8.09 (d, J = 8.0
Hz, 2H), 8.05 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.71–7.65 (m, 1H),
7.48–7.43 (m, 1H), 7.36 (m, 3H), 7.33 (s, 2H), 7.31 (s, 1H), 7.31–7.28
(m, 1H), 2.45 (s, 3H), 1.49 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
157.2, 152.7, 148.7, 144.7, 139.7, 136.7, 134.7, 130.6, 129.6, 129.5,
129.3, 129.0, 127.5, 126.6, 124.1, 123.2, 116.2, 83.4, 75.6, 27.8,
21.4; IR (neat) 2946, 1857, 1384cm-1; HRMS (EI-TOF) calcd for
C28H26ClNO3 459.1601, found 459.1603.
Scheme 3 Plausible mechanism
Conclusions
In summary, we have developed an approach for the synthesis
of polyfunctionalized quinolines via a sequence of copper-
catalyzed
coupling
reaction/propargyl-allenyl
isomerization/aza-electrocyclization by one-pot. Easily
available starting materials, mild conditions, and a wide
substrate scope make this protocol potentially very useful.
Further applications of this tandem cyclization to the synthesis
of diverse nitrogen heterocycles are currently underway.
tert-butyl
(4-chlorophenyl)(2-(4-methoxyphenyl)quinolin-4-
yl)methyl carbonate (3c): Pale yellow solid, 192mg, 81% yield; Mp:
142-144 oC; 1H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 7.0 Hz, 3H), 8.03
(s, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.66 (t, J = 8.0 Hz, 1H), 7.43 (t, J = 8.0
Hz, 1H), 7.37 (d, J = 8.0 Hz, 2H), 7.31 (t, J = 9.0 Hz, 3H), 7.06 (d, J =
9.0 Hz, 2H), 3.89 (s, 3H), 1.49 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
161.0, 156.7, 152.7, 148.8, 144.7, 136.7, 134.7, 132.0, 130.5, 129.5,
129.3, 129.1, 129.0, 126.4, 123.9, 123.2, 115.9, 114.3, 83.4, 75.6,
55.4, 27.8; IR (neat) 1690, 1473, 1366cm-1; HRMS (EI-TOF) calcd for
C28H26ClNO4 475.1550, found 475.1547.
Experimental
General methods and materials
Unless stated otherwise, reactions were conducted in dried
glassware. Commercially available reagents and solvents were
used as received. 300-400 Mesh silica gel was used for flash
column chromatography. Visualization on TLC was achieved by
the use of UV light (254 nm). 400 MHz and 100 MHz were used
for the record of 1H NMR and 13C NMR spectra. Chemical shifts
tert-butyl
(4-chlorophenyl)(2-(4-chlorophenyl)quinolin-4-
yl)methyl carbonate (3d): Pale white solid, 196mg, 82% yield; Mp:
199-201 oC; 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 8.0 Hz, 1H),
7.73–7.67 (m, 1H), 7.51 (d, J = 9.0 Hz, 2H), 7.50–7.45 (m, 1H), 7.35
(t, J = 6.0 Hz, 3H), 7.31 (d, J = 9.0 Hz, 2H), 1.49 (s, 9H); 13C NMR (100
(δ ppm) were reported in parts per million referring to either
the internal standard of TMS or the residue of the deuterated
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MHz, CDCl3) δ 155.8, 152.6, 148.7, 145.2, 137.8, 136.6, 135.8, 134.8, CDCl3) δ 156.4, 152.7, 147.6, 147.1, 144.3, 139.4, 136.9, 136.7,
130.7, 129.8, 129.2, 129.1, 128.9, 127.0, 124.2, 123.3, 115.9, 83.5, 134.6, 130.4, 129.6, 129.4, 129.3, 129.0, 127.4, 124.0, 119.4, 116.0,
75.5, 27.8; IR (neat) 1658, 1510, 1443cm-1; HRMS (EI-TOF) calcd for 83.3, 75.5, 34.3, 27.8, 23.9, 23.7, 21.4; IR (neat) 1706, 1603,
C27H23Cl2NO3 479.1055, found 479.1056.
1369cm-1; HRMS (EI-TOF) calcd for C31H32ClNO3 501.2071, found
501.2075.
tert-butyl
(4-chlorophenyl)(2-(4-fluorophenyl)quinolin-4-
yl)methyl carbonate (3e): Pale white solid, 185mg, 80% yield; Mp:
tert-butyl
(6-tert-butyl-2-p-tolylquinolin-4-yl)(4-
o
1
181-183 C; H NMR (400 MHz, CDCl3) δ 8.23–8.15 (m, 3H), 8.03 (s, chlorophenyl)methyl carbonate (3j): Pale yellow solid, 195mg, 76%
o
1
1H), 7.87 (d, J = 8.0 Hz, 1H), 7.73–7.66 (m, 1H), 7.50–7.44 (m, 1H), yield; Mp: 96-98 C; H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 9.0 Hz,
7.36 (t, J = 7.0 Hz, 3H), 7.32–7.29 (m, 2H), 7.25 (t, J = 3.0 Hz, 1H), 1H), 8.05 (d, J = 8.0 Hz, 2H), 7.98 (s, 1H), 7.79–7.74 (m, 2H), 7.41 (d,
7.20 (d, J = 2.0 Hz, 1H), 1.49 (s, 9H); 13C NMR (100 MHz, CDCl3) δ J = 9.0 Hz, 2H), 7.35–7.32 (m, 4H), 7.31 (d, J = 2.0 Hz, 1H), 2.44 (s,
164.0 (JC-F = 248 Hz), 156.0, 152.6, 148.7, 145.1, 136.6, 135.6 (JC-F = 3 3H), 1.49 (s, 9H), 1.34 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 156.5,
Hz), 134.8, 130.6, 129.7, 129.5 (JC-F = 16 Hz), 129.2, 129.1, 126.8, 152.7, 149.3, 147.2, 144.5, 139.4, 136.9, 136.7, 134.7, 130.1, 129.6,
124.1, 123.3, 115.9 (JC-F = 2 Hz), 115.7, 83.5, 75.5, 27.8; IR (neat) 129.4, 129.0, 128.3, 127.4, 123.6, 118.3, 115.9, 83.3, 75.7, 35.2,
1256, 1011, 790cm-1; HRMS (EI-TOF) calcd for C27H23ClFNO3 31.2, 27.8, 21.4; IR (neat) 1690, 1478, 1368cm-1; HRMS (EI-TOF)
463.1350, found 463.1349.
calcd for C32H34ClNO3 515.2227, found 515.2230.
tert-butyl (4-chlorophenyl)(7-methyl-2-p-tolylquinolin-4-
tert-butyl (6-chloro-2-p-tolylquinolin-4-yl)(4-
yl)methyl carbonate (3f): Pale white solid, 170mg, 72% yield; Mp: chlorophenyl)methyl carbonate (3k): Pale white solid, 194mg, 79%
173-175 oC; 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 8.0 Hz, 2H), 7.97 yield; Mp: 172-174 oC; 1H NMR (400 MHz, CDCl3) δ 8.12–8.02 (m,
(d, J = 4.0 Hz, 2H), 7.75 (d, J = 9.0 Hz, 1H), 7.35 (dd, J = 8.0, 7.0 Hz, 4H), 7.84 (s, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.34 (d, J = 5.0 Hz, 6H), 7.24
4H), 7.31–7.27 (m, 4H), 2.52 (s, 3H), 2.44 (s, 3H), 1.48 (s, 9H); 13C (s, 1H), 2.43 (s, 3H), 1.49 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 157.3,
NMR (100 MHz, CDCl3) δ 157.1, 152.7, 149.0, 144.5, 139.8, 139.6, 152.6, 147.2, 144.1, 140.0, 136.2, 136.1, 134.9, 132.4, 132.1, 130.5,
136.8, 134.6, 129.7, 129.6, 129.2, 129.0, 128.8, 127.5, 122.9, 122.1, 129.7, 129.2, 129.1, 127.5, 124.8, 122.4, 117.0, 83.6, 75.3, 27.8,
115.4, 83.3, 75.6, 27.8, 21.7, 21.4; IR (neat) 1715, 1602, 1369cm-1; 21.4; IR (neat) 1689, 1487, 1356cm-1; HRMS (EI-TOF) calcd for
HRMS (EI-TOF) calcd for C29H28ClNO3 473.1758, found 473.1761.
C
28H25Cl2NO3 493.1211, found 493.1210.
tert-butyl (4-chlorophenyl)(6-methyl-2-p-tolylquinolin-4-
tert-butyl (4-chlorophenyl)(2-(4-methoxyphenyl)-6-
yl)methyl carbonate (3g): Pale yellow solid, 189mg, 80% yield; 164- methylquinolin-4-yl)methyl carbonate (3l): Pale yellow solid,
166 oC; 1H NMR (400 MHz, CDCl3) δ 8.07 (dd, J = 8.0, 2.0 Hz, 3H), 190mg, 78% yield; Mp: 135-137 oC; 1H NMR (400 MHz, CDCl3) δ 8.08
7.99 (s, 1H), 7.62 (s, 1H), 7.50 (dd, J = 9.0, 1.0 Hz, 1H), 7.37 (d, J = (d, J = 9.0 Hz, 1H), 8.04 (d, J = 8.0 Hz, 2H), 7.97 (s, 1H), 7.38 (d, J =
9.0 Hz, 2H), 7.32 (t, J = 8.0 Hz, 5H), 2.47 (s, 3H), 2.42 (s, 3H), 1.48 (s, 9.0 Hz, 2H), 7.35–7.31 (m, 5H), 7.26 (s, 1H), 7.08 (d, J = 3.0 Hz, 1H),
9H); 13C NMR (100 MHz, CDCl3) δ 156.3, 152.7, 147.3, 144.0, 139.5, 3.82 (s, 3H), 2.43 (s, 3H), 1.49 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
136.8, 136.7, 136.5, 134.7, 131.8, 130.3, 129.6, 129.3, 129.0, 127.4, 157.7, 154.8, 152.7, 144.8, 143.2, 139.2, 136.8, 136.6, 134.7, 132.0,
124.1, 122.1, 116.1, 83.4, 75.4, 27.8, 22.1, 21.4; IR (neat) 1688, 129.6, 129.2, 129.0, 127.2, 125.0, 121.8, 116.6, 101.7, 83.4, 75.7,
1497, 1320cm-1; HRMS (EI-TOF) calcd for C29H28ClNO3 473.1758, 55.4, 27.8, 21.3; IR (neat) 1689, 1490, 1368cm-1; HRMS (EI-TOF)
found 473.1757.
calcd for C29H28ClNO4S 489.1707, found 489.1705.
tert-butyl (4-chlorophenyl)(6-ethyl-2-p-tolylquinolin-4-yl)methyl
tert-butyl (4-chlorophenyl)(2-(4-chlorophenyl)-6-
carbonate (3h): Pale yellow solid, 197mg, 81% yield; Mp: 129-131 methylquinolin-4-yl)methyl carbonate (3m): Pale white solid,
1
oC; H NMR (400 MHz, CDCl3) δ 8.08 (dd, J = 14.0, 8.0 Hz, 3H), 7.98 197mg, 80% yield; Mp: 156-158 oC; 1H NMR (400 MHz, CDCl3) δ 8.12
(s, 1H), 7.63 (s, 1H), 7.55 (d, J = 9.0 Hz, 1H), 7.38 (d, J = 8.0 Hz, 2H), (d, J = 8.0 Hz, 2H), 8.07 (d, J = 9.0 Hz, 1H), 7.97 (s, 1H), 7.63 (s, 1H),
7.32 (t, J = 8.0 Hz, 5H), 2.77 (q, J = 7.0 Hz, 2H), 2.43 (s, 3H), 1.49 (s, 7.53 (dd, J = 9.0, 2.0 Hz, 1H), 7.51–7.48 (m, 2H), 7.38–7.35 (m, 2H),
9H), 1.27 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 156.3, 7.32 (t, J = 7.0 Hz, 3H), 2.48 (s, 3H), 1.49 (s, 9H); 13C NMR (100 MHz,
152.7, 147.5, 144.2, 142.6, 139.4, 136.9, 136.7, 134.7, 130.7, 130.4, CDCl3) δ 154.9, 152.7, 147.2, 144.5, 137.9, 137.1, 136.6, 135.6,
129.6, 129.3, 129.0, 127.4, 124.1, 120.7, 116.1, 83.3, 75.5, 29.2, 134.8, 132.1, 130.3, 129.2, 129.1, 129.0, 128.8, 124.2, 122.1, 115.8,
27.8, 21.4, 15.3; IR (neat) 1687, 1472, 1323cm-1; HRMS (EI-TOF) 83.5, 75.3, 27.8, 22.1; IR (neat) 1693, 1482, 1354cm-1; HRMS (EI-
calcd for C30H30ClNO3 487.1914, found 487.1917.
TOF) calcd for C28H25Cl2NO3 493.1211, found 493.1214.
tert-butyl (4-chlorophenyl)(6-isopropyl-2-p-tolylquinolin-4-
tert-butyl (4-chlorophenyl)(2-(thiophen-2-yl)quinolin-4-
yl)methyl carbonate (3i): Pale yellow solid, 195mg, 78% yield; Mp: yl)methyl carbonate (3n): Pale yellow solid, 160mg, 71% yield; Mp:
112-114 oC; 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 9.0 Hz, 1H), 8.05 132-135 oC; 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 8.0 Hz, 1H), 7.99
(d, J = 8.0 Hz, 2H), 7.97 (s, 1H), 7.65 (s, 1H), 7.59 (dd, J = 9.0, 2.0 Hz, (s, 1H), 7.79 (t, J = 5.0 Hz, 2H), 7.65 (t, J = 8.0 Hz, 1H), 7.49 (d, J = 5.0
1H), 7.39 (d, J = 9.0 Hz, 2H), 7.36–7.29 (m, 5H), 3.09–2.97 (m, 1H), Hz, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.35 (d, J = 9.0 Hz, 2H), 7.30 (d, J =
2.43 (s, 3H), 1.49 (s, 9H), 1.28 (t, J = 7.0 Hz, 6H); 13C NMR (100 MHz, 7.0 Hz, 3H), 7.17 (dd, J = 5.0, 4.0 Hz, 1H), 1.49 (s, 9H); 13C NMR (100
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MHz, CDCl3) δ 152.6, 152.2, 148.5, 145.3, 144.8, 136.5, 134.8, 130.2, 75.6, 27.8; IR (neat) 1664, 1538, 1421cm-1; HRMS (EI-TOF) calcd for
129.7, 129.3, 129.1, 128.9, 128.1, 126.5, 126.2, 124.2, 123.3, 114.9, C27H24FNO3 429.1740, found 429.1742.
83.5, 75.4, 27.8; IR (neat) 1689, 1485, 1302cm-1; HRMS (EI-TOF)
tert-butyl cyclohexyl(2-phenylquinolin-4-yl)methyl carbonate
(4e): Light yellow oil, 108mg, 52% yield; 1H NMR (400 MHz, CDCl3) δ
calcd for C25H22ClNO3S 451.1009, found 451.1006.
tert-butyl
(2-tert-butyl-6-methoxyquinolin-4-yl)(4- 8.14 (m, 4H), 7.90 (s, 1H), 7.73 (s, 1H), 7.51 (m, 4H), 6.10 (d, J = 5.0
chlorophenyl)methyl carbonate (3o): Gum, 168mg, 74% yield; 1H Hz, 1H), 1.93 (m, 2H), 1.70 (m, 3H), 1.42 (s, 9H), 1.21 (m, 6H); 13C
NMR (400 MHz, CDCl3) δ 7.97 (d, J = 9.0 Hz, 1H), 7.60 (s, 1H), 7.31 (s, NMR (100 MHz, CDCl3) δ 156.9, 153.3, 148.6, 146.3, 139.7, 130.7,
4H), 7.28 (dd, J = 9.0, 3.0 Hz, 1H), 7.18 (s, 1H), 7.01 (s, 1H), 3.78 (s, 129.4, 128.8, 127.6, 126.4, 125.1, 123.2, 116.4, 82.6, 78.9, 43.2,
3H), 1.48 (s, 9H), 1.45 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 166.5, 29.6, 28.5, 27.8, 26.1, 26.0, 25.8; IR (neat) 1660, 1546, 1427cm-1;
157.3, 152.7, 143.9, 142.4, 136.5, 134.6, 131.7, 129.3, 129.0, 124.3, HRMS (EI-TOF) calcd for C27H31NO3 417.2304, found 417.2302.
121.1, 115.6, 101.5, 83.2, 76.0, 55.4, 38.0, 30.2, 27.8; IR (neat)
1677, 1490, 1321cm-1; HRMS (EI-TOF) calcd for C26H30ClNO4
phenyl(2-phenylquinolin-4-yl)methyl acetate (4f): Light yellow
oil, 138mg, 78% yield; 1H NMR (400 MHz, CDCl3) δ 8.22–8.14 (m,
455.1863, found 455.1866.
3H), 8.03 (s, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.68 (m, 1H), 7.62 (s, 1H),
tert-butyl phenyl(2-phenylquinolin-4-yl)methyl carbonate (4a): 7.57–7.51 (m, 2H), 7.51–7.43 (m, 2H), 7.41 (dd, J = 8.0, 2.0 Hz, 2H),
1
Pale white solid, 166mg, 81% yield; Mp: 152-154 oC; H NMR (400 7.37–7.28 (m, 3H), 2.23 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 169.9,
MHz, CDCl3) δ 8.22–8.16 (m, 3H), 8.09 (s, 1H), 7.94 (d, J = 8.0 Hz, 157.1, 148.8, 145.3, 139.7, 138.4, 130.6, 129.5, 129.4, 128.9, 128.8,
1H), 7.69 (dd, J = 11.0, 4.0 Hz, 1H), 7.54 (t, J = 7.0 Hz, 2H), 7.46 (m, 128.7, 127.8, 127.6, 126.7, 124.5, 123.6, 116.8, 73.5, 21.3; IR (neat)
4H), 7.39 (s, 1H), 7.34 (m, 3H), 1.49 (s, 9H); 13C NMR (100 MHz, 1672, 1488, 1370cm-1; HRMS (EI-TOF) calcd for C24H19NO2 353.1416,
CDCl3) δ 157.2, 152.8, 148.7, 145.5, 139.6, 138.0, 130.6, 129.5, found 353.1418.
128.9, 128.8, 128.7, 127.9, 127.7, 126.6, 124.4, 123.4, 116.4, 83.2,
76.3, 27.8; IR (neat) 1608, 1511, 1386cm-1; HRMS (EI-TOF) calcd for
(4-chlorophenyl)(2-phenylquinolin-4-yl)methyl acetate (4g):
Light yellow oil, 149mg, 77% yield; 1H NMR (400 MHz, CDCl3) δ
C27H25NO3 411.1843, found 411.1848.
8.23–8.15 (m, 3H), 8.02 (s, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.69 (m, 1H),
tert-butyl (2-phenylquinolin-4-yl)(p-tolyl)methyl carbonate (4b): 7.59–7.52 (m, 3H), 7.51–7.43 (m, 2H), 7.36–7.29 (m, 4H), 2.23 (s,
1
Pale white solid, 161mg, 76% yield; Mp: 166-168 oC; H NMR (400 3H); 13C NMR (100 MHz, CDCl3) δ 169.8, 157.2, 148.8, 144.8, 139.5,
MHz, CDCl3) δ 8.22–8.15 (m, 3H), 8.10 (s, 1H), 7.93 (d, J = 8.0 Hz, 136.9, 134.7, 130.7, 129.6, 129.6, 129.2, 129.1, 128.9, 127.6, 126.8,
1H), 7.71–7.64 (m, 1H), 7.54 (t, J = 7.0 Hz, 2H), 7.46 (m, 2H), 7.36 (s, 124.3, 123.4, 116.8, 72.9, 21.2; IR (neat) 1672, 1490, 1375cm-1;
1H), 7.32 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 8.0 Hz, 2H), 2.31 (s, 3H), 1.48 HRMS (EI-TOF) calcd for C24H18ClNO2 387.1026, found 387.1027.
(s, 9H); 13C NMR (100 MHz, CDCl3) δ 157.2, 152.8, 148.7, 145.7,
tert-butyl phenyl((2-phenylquinolin-4-yl)methyl)carbamate (4h):
139.7, 138.7, 135.1, 130.6, 129.5, 129.4, 128.9, 127.9, 127.7, 126.6,
Gum, 129mg, 63% yield; 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 8.0
124.4, 123.4, 116.1, 83.1, 76.2, 27.8, 21.2; IR (neat) 1658, 1523,
1437cm-1; HRMS (EI-TOF) calcd for C28H27NO3 425.1991, found
Hz, 1H), 8.08 (d, J = 7.0 Hz, 2H), 8.00 (d, J = 8.0 Hz, 1H), 7.78–7.69 (m,
2H), 7.56–7.42 (m, 4H), 7.27 (d, J = 8.0 Hz, 1H), 7.25–7.11 (m, 4H),
5.38 (s, 2H), 1.43 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 157.0, 154.6,
425.1990.
tert-butyl
(4-methoxyphenyl)(2-phenylquinolin-4-yl)methyl 148.4, 144.2, 142.4, 139.7, 130.6, 129.5, 129.4, 128.9, 127.5, 126.4,
carbonate (4c): Pale yellow solid, 170mg, 77% yield; Mp: 133-135 oC; 126.1, 126.0, 125.3, 122.7, 81.2, 51.3, 28.3; IR (neat) 1689, 1494,
1H NMR (400 MHz, CDCl3) δ 8.18–8.13 (m, 3H), 8.05 (s, 1H), 7.91 (d, 1366cm-1; HRMS (EI-TOF) calcd for C27H26N2O2 410.1994, found
J = 8.0 Hz, 1H), 7.68–7.62 (m, 1H), 7.45–7.40 (m, 3H), 7.38 (s, 1H), 410.1987.
7.36–7.28 (m, 3H), 7.05 (d, J = 9.0 Hz, 2H), 3.88 (s, 3H), 1.48 (s, 9H);
13C NMR (100 MHz, CDCl3) δ 161.0, 156.7, 152.8, 148.7, 145.2,
138.1, 132.2, 130.4, 129.4, 129.0, 128.8, 128.7, 127.9, 126.3, 124.1,
123.4, 115.9, 114.3, 83.1, 76.3, 55.4, 27.8; IR (neat) 1660, 1532,
1438cm-1; HRMS (EI-TOF) calcd for C28H27NO4 441.1940, found
441.1937.
tert-butyl
4-chlorophenyl((2-phenylquinolin-4-
yl)methyl)carbamate (4i): Gum, 133mg, 60% yield; 1H NMR (400
MHz, CDCl3) δ 8.21 (d, J = 8.0 Hz, 1H), 8.10–8.05 (m, 2H), 7.98 (d, J =
8.0 Hz, 1H), 7.73 (m, 2H), 7.56–7.44 (m, 4H), 7.21 (d, J = 9.0 Hz, 2H),
7.12 (d, J = 7.0 Hz, 2H), 5.35 (s, 2H), 1.43 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 157.0, 154.3, 148.5, 143.8, 140.9, 139.5, 131.6, 130.6,
tert-butyl
(4-fluorophenyl)(2-phenylquinolin-4-yl)methyl 129.6, 129.5, 129.0, 128.9, 127.5, 127.2, 126.6, 125.2, 122.7, 81.6,
carbonate (4d): Pale white solid, 180mg, 84% yield; Mp: 176-178 oC; 51.1, 28.2; IR (neat) 1688, 1490, 1368cm-1; HRMS (EI-TOF) calcd for
1H NMR (400 MHz, CDCl3) δ 8.24–8.16 (m, 3H), 8.09 (s, 1H), 7.87 (d, C27H25ClN2O2 444.1605, found 444.1608.
J = 8.0 Hz, 1H), 7.72–7.66 (m, 1H), 7.55 (t, J = 7.0 Hz, 2H), 7.51–7.44
(m, 2H), 7.44–7.38 (m, 2H), 7.36 (s, 1H), 7.02 (t, J = 9.0 Hz, 2H), 1.49
(s, 9H); 13C NMR (100 MHz, CDCl3) δ 162.8 (JC-F = 247 Hz), 157.2,
152.7, 148.7, 145.2, 139.5, 134.0, 130.7, 129.9 (JC-F = 8 Hz), 129.6,
128.9, 127.7, 126.7, 124.2, 123.3, 116.0 (JC-F = 23 Hz), 115.7, 83.3,
Conflicts of interest
We declare no conflicts of interest.
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Acknowledgements
This work was supported by the Natural Science Foundation of
Shandong Province (No. ZR2018BB029).
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