Acid-Catalyzed Synthesis of Quinoline Derivatives from 2-Methylquinolines and 2-Aryloxy/Alkoxybenzaldehyde in Aqueous Medium

Article abstract of DOI:10.1002/ejoc.201901331

A HOAc-catalyzed aryloxy/alkoxy-assisted nucleophilic addition of 2-methylquinolines to aldehydes in water has been described. With this highly environmentally benign protocol, a series of hydroxyquinolines were efficiently prepared in moderate to good yields. In addition, a HOAc/1,3-DMBBA (1,3-dimethylbarbituric acid) synergistic organocatalysis system was also developed for the synthesis of alkenylquinolines which involved a sequence of Knoevenagel condensation, Micheal addition, and retro-Micheal addition steps.

Full text of DOI:10.1002/ejoc.201901331

A Journal of
Accepted Article
Title: Acid-Catalyzed Synthesis of Quinoline Derivatives from 2-
Methylquinolines and 2-Aryloxy/Alkoxybenzaldehyde in Aqueous
Medium
Authors: Yinrong Wu, Xianchen Lu, Hang Wang, En Liang, Yingying
Yuan, Qiaorun Zhao, Zhongzhi Zhu, Jiaping Huang, and
Xiaodong Tang
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201901331
Link to VoR: http://dx.doi.org/10.1002/ejoc.201901331
Supported by

European Journal of Organic Chemistry
10.1002/ejoc.201901331
FULL PAPER
Acid-Catalyzed Synthesis of Quinoline Derivatives
from 2-
Methylquinolines and 2-Aryloxy/Alkoxybenzaldehyde in Aqueous
Medium
‡
[a]
‡ [a]
[a]
[a]
[a]
[a]
Yinrong Wu,
Xianchen Lu,
Hang Wang, En Liang, Yingying Yuan, Qiaorun Zhao,
[
b]
[a]
[a]
Zhongzhi Zhu* , Jiaping Huang and Xiaodong Tang*
[
11]
Abstract: A HOAc-catalyzed aryloxy/alkoxy-assisted nucleophilic
addition of 2-methylquinolines to aldehydes in water has been
described. With this highly environmentally benign protocol, a series
of hydroxyquinolines were efficiently prepared in moderate to good
yields. In addition, a HOAc/1,3-DMBBA (1,3-dimethylbarbituric acid)
synergistic organocatalysis system was also developed for the
increasing attention. As a green solvent, water featured easy
available, nontoxic, nonflammable and noncorrosive. However,
organic reactions in aqueous media have not received attention
until the pioneering work by Breslow showing how water
[
12]
enhances the Diels-Alder reactions. Compared with common
organic solvents, water has some unique physical and chemical
properties which could influence the reactivity and selectivity of
chemical reactions, and organic reactions in aqueous media
synthesis of alkenylquinolines which involved
a sequence of
Knoevenagel condensation, Micheal addition and retra-Micheal
addition steps.
[
13]
have been made a great development in the last few decades.
In addition, organocatalysis has rapidly gained tremendous
growth due to easy available and non-toxic catalysts, broad
substrate scope, mild reaction conditions and excellent
Introduction
[14]
functional group tolerance.
efficient transformation of 2-methylquinolines,
Based on our previous works on
[
15]
herein, we
As important motifs, quinolines widely occur in natural products
report a HOAc-catalyzed aryloxy/alkoxy-assisted nucleophilic
addition of 2-methylquinolines to aldehydes (Scheme 1b). The
transformation proceeded smoothly in water, providing various
hydroxyquinolines in moderate to good yields. It is worth
mentioning that alkenylquinolines were obtained as products
instead of hydroxyquinolines when 20 mol % 1,3-DMBBA was
added into the reaction system.
[
1]
and bioactive pharmaceutical drugs. Therefore, a great deal of
efforts have been conducted to introduce quinoline moieties into
organic molecules. 2-Methylquinolines are inexpensive and
easily available raw materials, and the functionalization of 2-
methylquinolines has made great progress which gradually
becomes an important method for introducing quinoline
[
2-6]
moieties.
Among them, the most attention has been paid to
the reaction of 2-methylquinolines with aldehydes which
produces two important kinds of quinoline derivatives:
hydroxyquinolines and alkenylquinolines. The traditional method
for the synthesis of hydroxyquinolines from 2-methylquinolines
and aldehydes required equivalent strong base such as BuLi or
o
[7]
LDA and low temperature (-78 C) (Scheme 1a). And the
reaction of 2-methylquinolines with aldehydes using Ac O as
solvent at high temperature (150 C) could produce the
2
o
[
8]
alkenylquinolines. Recently, some modified methods have
been reported for the synthesis of alkenylquinolines from 2-
[9]
methylquinolines and aldehydes. However, the synthesis of
hydroxyquinolines from 2-methylquinolines with aldehydes under
[
10]
mild conditions were limited reported.
Thus, it is of great
importance to develop efficient and green approaches for the
synthesis of hydroxyquinolines from 2-methylquinolines and
aldehydes.
Nowadays, green and sustainable chemistry has attracted
Scheme 1. Synthesis of hydroxyquinolines from 2-methylquinolines and
aldehydes.
[
a]
Y. Wu, X. Lu, H. Wang, E. Liang, Y. Yuan, Q. Zhao, H. Jiang, Prof.
Dr. X. Tang. Guangdong Provincial Key Laboratory of New Drug
Screening, School of Pharmaceutical Sciences, Southern Medical
University, 1023 South Shatai Road, Baiyun District, Guangzhou
510515, P. R. China.
E-mail: tangxdong@smu.edu.cn
[
b]
Dr. Z. Zhu. School of Biotechnology and Health Sciences, Wuyi
University, Jiangmen 529020, China.
Results and Discussion
E-mail: wyuchemzzz@126.com
‡
These authors contributed equally to this work.
To start our studies, 2-phenoxybenzaldehyde (1a) and 2-
methylquinoline (2a) were chosen as model substrates, and the
Supporting information for this article is given via a link at the end of
the document.
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European Journal of Organic Chemistry
10.1002/ejoc.201901331
FULL PAPER
2
reaction was performed in H O at 100 °C for 24 h. To our delight, were presented (Scheme 2, 3ah, 3ai). It was worth noting that
the nucleophilic addition reaction proceeded smoothly in the
presence of 20 mol % HCl, providing 3aa in 68% yield (Table 1,
entry 1). In the next catalyst screening, HOAc showed to be
better than other Brønsted acids (Table 1, entries 2-7), which
afforded the desired product in 81% yield (Table 1, entry 3).
Several Lewis acids were also examined and they decreased
the yields (Table 1, entries 8-11). Only trace amounts of the
desired product was observed in the absence of catalyst (Table
the halo groups were well compatible in the transformation,
facilitating further functionalization of the products. The structure
of 3aj was confirmed by single-crystal X-ray analysis. Besides
2-methylquinolines, 1-methylisoquinoline and 2-
methylquinoxaline also served as effective coupling partners to
afford the corresponding products in 78% and 37%, respectively
(Scheme 2, 3am, 3an). However, when using 4-methylquinoline,
2-ethylquinoline or 2-benzylquinoline as starting material, the
reactions did not happen.
[16]
1
, entry 12). The yields decreased when the reaction was run at
a lower (80 °C) or higher temperature (120 °C) (Table 1, entries
3-14). In the solvent screening, H O was found to be the
1
2
optimal solvent for this transformation (Table 1, entries 15-20).
The yield did not increase with increasing the amount of HOAc
(
Table 1, entry 21). Thus, the optimal catalytic system for this
HOAc-catalyzed aryloxy/alkoxy-assisted nucleophilic addition
was: 1a (0.3 mmol), 2a (0.45 mmol), HOAc (20 mol %), in H
1.5 mL) at 100 °C for 24 h.
2
O
(
[
a]
Table 1. Optimization of the Reaction Conditions.
o
Entry
Catalyst
Solvent
T ( C)
Yield (%)
1
2
3
4
5
6
7
8
9
HCl
HBr
H
H
H
H
H
H
H
H
H
H
H
H
H
H
2
2
2
2
2
2
2
2
2
2
2
2
2
2
O
O
O
O
O
O
O
O
O
O
O
O
O
O
100
100
100
100
100
100
100
100
100
100
100
100
80
120
100
100
100
100
100
100
100
68
58
81
64
57
69
36
49
32
16
trace
trace
63
53
14
trace
32
trace
14
HOAc
PivOH
TFA
HNO
L-Proline
[
a]
Scheme 2. Synthesis of hydroxyquinolines from various 2-methylquinolines.
2
a] Reaction conditions: 1a (0.3 mmol), 2 (0.45 mmol), HOAc (20 mol %), H O
[
3
o
(1.5 mL), at 100 C for 24 h. Isolated yield.
FeCl
ZnCl
3
2
Next, the scope of 2-aryloxy/alkoxybenzaldehydes was
evaluated (Scheme 3). The reactions were successfully
performed by employing 2-aryloxy benzenecarbaldehydes with
different substituents on the phenoxy group, affording the
desired products in moderate to good yields (Scheme 3, 3ba-
10
11
12
13
14
15
16
17
18
19
20
21
2
Ag CO
3
CuBr
---
2
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
toluene
dioxane
DMSO
DMF
(CH
DCE
3
ja). When 2-(naphthalen-2-yloxy)benzaldehyde was employed
in the transformation, 3ka was obtained in 57% yield.
Furthermore, benzaldehyde with different functionalities (Me, Cl,
OMe) can also be applied to the reaction to provide the desired
products in 53%-73% yields (Scheme 3, 3la-3pa). Finally, 2-
alkoxybenzaldehydes could be transformed into 3qa-3sa with
slightly lower yields than 2-aryloxy benzaldehydes (Scheme 3).
2
OH)
2
Trace
78
[
b]
2
H O
[
a] Reaction conditions: unless otherwise noted, all reactions were
performed with 1a (0.3 mmol), 2a (0.45 mmol), catalyst (20 mol %), solvent
o
(
1.5 mL), at T C for 24 h. Isolated yield. [b] 50 mol % HOAc was used.
With the optimal conditions established, the generality and
limitations of the nucleophilic addition reaction were explored.
The scope of methylazaarenes was firstly studied (Scheme 2).
Various 2-methylquinolines bearing different substituents on the
aromatic ring proceeded smoothly to furnish the desired
products in moderate to good yields (Scheme 2, 3aa-3al). Lower
yields were obtained when methoxyl and ethyoxyl substituents
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European Journal of Organic Chemistry
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FULL PAPER
Scheme 3. Synthesis of hydroxyquinolines from various 2-aryloxy/alkoxy
[
a]
benzaldehydes. [a] Reaction conditions: 1 (0.3 mmol), 2a (0.45 mmol), HOAc
o
(
2
20 mol %), H O (1.5 mL), at 100 C for 24 h. Isolated yield.
[
a]
Scheme 4. Synthesis of alkenylquinolines. [a] 1 (0.3 mmol), 2 (0.3 mmol),
o
HOAc (20 mol %), 1,3-DMBBA (20 mol %), H
Isolated yields.
2
O (1.5 mL), at 100 C for 24 h.
Surprisingly, when 20 mol % DMBBA was added to the
reactions, the alkenylquinolines were obtained as the products.
The reaction scope for the synthesis of alkenylquinolines was
evaluated since the alkenylquinolines widely present in
[
17]
pharmaceutical
agents
(Scheme
4).
2-Phenoxy
benzaldehydes containing methyl, tertiary butyl, phenyl, bromide,
choride, and methoxyl substituents on the phenoxy group
generally were compatible with the reaction and provided the
corresponding products in moderate to good yields (Scheme 4,
4
a-4g). Similarly, 2-methylquinolines and 1-methylisoquinoline
could be successfully converted to the alkenylquinolines with 2-
phenoxybenzaldehyde (Scheme 4, 4h-4l). In addition, 2-
ethoxybenzaldehyde and 2-(benzyloxy)benzaldehyde were also
evaluated, affording 4m and 4n in 65% and 59% yields,
respectively.
Scheme 5. Synthetic utilities of the products.
To illustrate the synthetic utilities of these hydroxyquinolines, we
performed some transformations (Scheme 5). Oxidative
conversion of the hydroxyl group into a carbonyl group with PCC
was carried out, surprisingly, we found the dicarbonyl product 5
was obtained in 73% yield. The dehydration reaction of 3qa was
carried out with ln(OTf) and the product 6 was produced in 92 %
3
yield. Methylation of the hydroxyl group with MeI and NaH was
carried out to give 7 in 78 % yield. Moreover, benzylation of the
hydroxymethyl
group
proceeded
smoothly,
and
the
corresponding product 8 was formed in 91% yield.
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European Journal of Organic Chemistry
10.1002/ejoc.201901331
FULL PAPER
a Michael addition with intermediate A to form intermediate 11.
Finally, intermediate 11 dissociates into the product 4a and 1,3-
[
15b]
DMBBA (path b).
Conclusions
In conclusion, we have established
aryloxy/alkoxy-assisted nucleophilic
a
HOAc-catalyzed
addition of 2-
methylquinolines to aldehydes in water, providing an efficient
access to hydroxyquinolines. Moreover, the combination of two
organocatalyssts (HOAc and 1,3-DMBBA) affords rapid access
to the alkenylquinolines with moderate to good yields. The
significant advantages of those methods include non-toxic
catalysts, mild conditions and simple operation. Further study
about effective transformation of 2-methylquinolines are ongoing
in our laboratory.
Scheme 6. Mechanistic studies.
To gain mechanistic insights into this reaction, control
experiments were performed (Scheme 6). When benzaldehyde
was directly used to react with 2-methylquinoline in presence of
Experimental Section
General Information.
20 mol % HOAc, 2-styrylquinolinethe 9 was obtained in 22%
yield [Eq. (1)]. This experiment suggests the phenoxyl in 2-
phenoxybenzaldehyde may not only promote nucleophilic
addition but also stabilize the newly formed hydroxyl though the
Melting points were measured with a melting point instrument and
were uncorrected. H and C NMR spectra were recorded using a 400
MHz NMR spectrometer. The chemical shifts are referenced to signals at
1
13
7
.26 and 77.0 ppm, respectively, and chloroform was used as the solvent
intramolecular hydrogen bond.
The reaction of
2-
with TMS as the internal standard. HRMS was obtained with a LCMS-IT-
TOF mass spectrometer. TLC was performed by using commercially
prepared 100-400 mesh silica gel plates, and visualization was effected
at 254 nm. IR spectra were obtained either as potassium bromide pellets
or as liquid films between two potassium bromide pellets with an infrared
Fourier spectrometer. 2-Methylquinolines were obtained from commercial
suppliers and aldehydes were synthesized according to the methods of
phenoxybenzaldehyde 1a and 1,3-DMBBA under the standard
conditions resulted in a high yield of 10 [Eq. (2)]. The compound
10 could react with 2a to form the compound 11 and 4a [Eq. (3)].
Compound 11 continued to transform to product 4a under same
conditions [Eq. (4)]. These three experiments indicated that the
compounds 10 and 11 were the intermediates in the reaction for
the synthesis of alkenylquinolines 4a.
[
20]
previous lectures without modifications.
General Procedure for Products 3.
Aldehydes 1 (0.3 mmol), 2-methylquinolines 2 (0.45 mmol), HOAc (20
mol %), H O (1.5 mL) were added to a 25 mL tube with magnetic stirrer
bar. The reaction mixture was stirred at 100 C (oil bath temperature) for
4 h. After the reaction was finished (monitored by TLC), the mixture was
cooled to room temperature, quenched with solution of NaHCO (10 mL)
and extracted with EtOAc (3 × 10 mL). The combined organic layers
were dried over anhydrous MgSO and the solvent was removed under
vacuum. The crude product was purified by column chromatography
EtOAc/hexanes) on silica gel.
2
o
2
3
4
(
General Procedure for Products 4.
Aldehyde 1 (0.3 mmol), 2-methylquinoline 2 (0.3 mmol), HOAc (20
mol %), 1,3-DMBBA (20 mol %), H
tube with magnetic stirrer bar. The reaction mixture was stirred at 100 C
oil bath temperature) for 24 h. After the reaction was finished (monitored
by TLC), the mixture was cooled to room temperature, quenched with
solution of NaHCO (10 mL) and extracted with EtOAc (3 × 10 mL). The
combined organic layers were dried over anhydrous MgSO and the
2
O (1.5 mL) were added to a 25 mL
o
Scheme 7. Proposed Mechanism.
(
Based on the above findings, a possible mechanism was
proposed in Scheme 7. Enamine intermediate
generated from 2a via isomerization in the presence of HOAc.
Assisted by the phenoxyl group, the intermediate
3
A is first
[18]
4
solvent was removed under vacuum. The crude product was purified by
column chromatography (EtOAc/hexanes) on silica gel.
A
nucleophilically add to the proton-preactivated carbonyl group,
[
19]
which affords product 3aa via transition state B (path a). In
the presence of 1,3-DMBBA, 1a and 1,3-DMBBA firstly undrego
Knoevenagel condensation to form intermediate 10, followed by
1-(2-Phenoxyphenyl)-2-(quinolin-2-yl)ethan-1-ol (3aa): Yellow solid
o
1
(83 mg, 81 %); m.p.= 89-91 C. H NMR (400 MHz, CDCl
3
) δ 8.06 (dd, J
= 8.3, 4.2 Hz, 2H), 7.80 – 7.68 (m, 3H), 7.55 – 7.49 (m, 1H), 7.37 – 7.29
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European Journal of Organic Chemistry
10.1002/ejoc.201901331
FULL PAPER
(
7
m, 2H), 7.25 – 7.20 (m, 1H), 7.19 – 7.13 (m, 2H), 7.08 (t, J = 7.4 Hz, 1H),
.02 – 6.98 (m, 2H), 6.89 (dd, J = 8.0, 1.2 Hz, 1H), 5.65 (dd, J = 8.9, 2.7
Hz, 1H), 3.46 (dd, J = 15.4, 2.8 Hz, 1H), 3.30 (dd, J = 15.4, 8.9 Hz, 1H).
C NMR (100 MHz, CDCl ) δ 160.7, 157.5, 153.0, 146.8, 136.8, 135.2,
3
29.8, 129.7, 128.6, 128.2, 127.5, 127.4, 126.8, 126.2, 124.0, 122.9,
Hz, 1H), 5.65 (dd, J = 8.9, 2.5 Hz, 1H), 3.45 (dd, J = 15.5, 2.8 Hz, 1H),
3.30 (dd, J = 15.5, 8.9 Hz, 1H). C NMR (100 MHz, CDCl ) δ 161.0,
3
13
157.3, 153.0, 145.2, 135.8, 134.9, 131.8, 130.6, 130.2, 129.7, 128.2,
127.3, 127.3, 126.2, 123.9, 123.0, 123.0, 118.7, 118.1, 67.7, 44.6. IR
1
3
-
1
1
1
7
(KBr): 3045 , 2921, 1641, 1475, 1066, 751, 681 cm . HRMS (ESI) m/z:
+
22.1, 118.8, 118.1, 67.8, 44.5. IR (KBr): 3059, 2920, 1737, 1546, 1224,
2
calcd for C23H19ClNO [M+H] , 376.1098; found, 376.1091.
-
1
+
2
53, 682 cm . HRMS (ESI) m/z: calcd for C23H20NO [M+H] , 342.1488;
found, 342.1481.
2-(6-Bromoquinolin-2-yl)-1-(2-phenoxyphenyl)ethan-1-ol
Yellow solid (82 mg, 65 %); m.p.=113-115 C. H NMR (400 MHz, CDCl
(3ag):
o
1
3
)
2
-(4-Methylquinolin-2-yl)-1-(2-phenoxyphenyl)ethan-1-ol
(3ab):
Yellow solid (63 mg, 59 %); m.p.=115-116 C. H NMR (400 MHz, CDCl
δ 8.06 (d, J = 8.4 Hz, 1H), 7.95 (d, J = 8.3 Hz, 1H), 7.77 (d, J = 6.6 Hz,
δ 8.00 – 7.93 (m, 3H), 7.78 (dd, J = 9.0, 2.1 Hz, 1H), 7.69 (dd, J = 7.6,
1.5 Hz, 1H), 7.35 – 7.28 (m, 2H), 7.25 – 7.12 (m, 3H), 7.08 (t, J = 7.4 Hz,
1H), 7.01 – 6.96 (m, 2H), 6.88 (dd, J = 8.0, 1.0 Hz, 1H), 5.62 (dd, J = 8.8,
2.7 Hz, 1H), 3.45 (dd, J = 15.4, 2.7 Hz, 1H), 3.30 (dd, J = 15.4, 8.8 Hz,
o
1
3
)
1H), 7.74 – 7.67 (m, 1H), 7.54 (dd, J = 11.2, 4.0 Hz, 1H), 7.37 – 7.30 (m,
2H), 7.25 – 7.14 (m, 2H), 7.08 (t, J = 7.4 Hz, 1H), 7.00 (d, J = 9.0 Hz, 3H),
6.90 – 6.87 (m, 1H), 5.63 (dd, J = 8.9, 2.1 Hz, 1H), 3.40 (dd, J = 15.4, 2.7
13
3
1H). C NMR (100 MHz, CDCl ) δ 161.1, 157.4, 153.0, 145.3, 135.8,
134.9, 133.2, 130.2, 129.8, 129.6, 128.3, 127.9, 127.3, 124.0, 123.0,
123.0, 120.0, 118.7, 118.2, 67.7, 44.6. IR (KBr): 3059, 2923, 1570, 1486,
13
Hz, 1H), 3.24 (dd, J = 15.4, 9.0 Hz, 1H), 2.64 (s, 3H). C NMR (100 MHz,
CDCl ) δ 160.3, 157.5, 153.0, 146.5, 145.2, 135.3, 129.7, 129.5, 129.1,
28.1, 127.5, 126.9, 125.9, 124.0, 123.6, 122.9, 122.7, 118.7, 118.2,
-
1
+
3
1231, 1049, 754 cm . HRMS (ESI) m/z: calcd for C23
H19BrNO
2
[M+H] ,
1
6
420.0594; found, 420.0583.
-1
7.8, 44.3, 18.6. IR (KBr): 3112, 2924, 1722, 1545, 1264, 755, 677 cm .
+
HRMS (ESI) m/z: calcd for
C
24
H
22NO
2
[M+H] , 356.1645; found,
2-(6-Methoxyquinolin-2-yl)-1-(2-phenoxyphenyl)ethan-1-ol
Gray solid (59 mg, 53 %); m.p.=90-91 C. H NMR (400 MHz, CDCl
(3ah):
3
) δ
o
1
356.1635.
7.97 – 7.92 (m, 2H), 7.72 (dd, J = 7.6, 1.7 Hz, 1H), 7.33 (ddt, J = 7.6, 4.3,
2
-(4-Chloroquinolin-2-yl)-1-(2-phenoxyphenyl)ethan-1-ol
(3ac):
2.6 Hz, 3H), 7.22 (tt, J = 5.9, 2.9 Hz, 1H), 7.15 (td, J = 7.5, 1.1 Hz, 1H),
7.12 – 6.98 (m, 5H), 6.88 (dd, J = 8.0, 1.2 Hz, 1H), 5.61 (dd, J = 8.9, 2.6
Hz, 1H), 3.91 (s, 3H), 3.41 (dd, J = 15.3, 2.7 Hz, 1H), 3.25 (dd, J = 15.3,
o
1
Yellow solid (70 mg, 62 %); m.p.=117-118 C. H NMR (400 MHz, CDCl
δ 8.18 (d, J = 8.3 Hz, 1H), 8.08 (d, J = 8.4 Hz, 1H), 7.80 – 7.71 (m, 2H),
3
)
13
7
1
2
1
.61 (t, J = 7.6 Hz, 1H), 7.33 (t, J = 7.9 Hz, 2H), 7.22 (dd, J = 7.8, 1.5 Hz,
H), 7.16 (t, J = 7.1 Hz, 1H), 7.09 (t, J = 7.4 Hz, 1H), 6.99 (d, J = 7.9 Hz,
H), 6.88 (d, J = 8.0 Hz, 1H), 5.63 (dd, J = 8.8, 2.5 Hz, 1H), 3.42 (dd, J =
5.4, 2.7 Hz, 1H), 3.29 (dd, J = 15.4, 8.9 Hz, 1H). C NMR (100 MHz,
) δ 160.5, 157.4, 153.1, 147.7, 143.2, 134.8, 130.7, 129.8, 128.9,
28.4, 127.4, 127.2, 125.1, 124.0, 124.0, 123.1, 122.1, 118.7, 118.2,
3
8.9 Hz, 1H). C NMR (100 MHz, CDCl ) δ 158.0, 157.5, 153.0, 142.8,
135.7, 135.3, 129.9, 129.7, 128.1, 127.8, 127.4, 124.0, 122.9, 122.4,
122.3, 118.7, 118.1, 105.1, 67.8, 55.5, 44.2. IR (KBr): 3360, 2923, 1711,
13
-1
+
1506, 1233, 755, 677 cm . HRMS (ESI) m/z: calcd for C24
H
22NO
3
[M+H] ,
CDCl
3
372.1594; found, 372.1588.
1
6
-
1
7.7, 44.5. IR (KBr): 3035, 2925, 1580, 1482, 1227, 1047, 754 cm .
2-(6-Ethoxyquinolin-2-yl)-1-(2-phenoxyphenyl)ethan-1-ol (3ai): Gray
+
o
1
HRMS (ESI) m/z: calcd for C23
H
19ClNO
2
[M+H] , 376.1099; found,
3
solid (54 mg, 47 %); m.p.=126-127 C. H NMR (400 MHz, CDCl ) δ 7.93
3
76.1090.
(t, J = 8.9 Hz, 2H), 7.72 (d, J = 7.6 Hz, 1H), 7.39 – 7.29 (m, 3H), 7.22 (td,
J = 7.7, 1.5 Hz, 1H), 7.15 (t, J = 7.4 Hz, 1H), 7.09 (d, J = 8.4 Hz, 2H),
7.03 – 6.97 (m, 3H), 6.88 (d, J = 8.0 Hz, 1H), 5.66 – 5.56 (m, 1H), 4.14 (q,
J = 7.0 Hz, 2H), 3.40 (dd, J = 15.3, 2.7 Hz, 1H), 3.24 (dd, J = 15.3, 8.9 Hz,
2
-(6-Methylquinolin-2-yl)-1-(2-phenoxyphenyl)ethan-1-ol
(3ad):
) δ
.95 (d, J = 8.1 Hz, 2H), 7.75 (d, J = 7.6 Hz, 1H), 7.57 – 7.51 (m, 2H),
o
1
Yellow solid (78 mg, 73%); m.p.=89-91 C. H NMR (400 MHz, CDCl
3
13
7
7
7
3
1H), 1.49 (t, J = 7.0 Hz, 3H). C NMR (100 MHz, CDCl ) δ 157.9, 157.5,
.33 (dd, J = 11.2, 4.6 Hz, 2H), 7.26 – 7.13 (m, 2H), 7.12 – 7.06 (m, 2H),
.03 – 6.99 (m, 2H), 6.90 (d, J = 8.0 Hz, 1H), 5.68 – 5.61 (m, 1H), 3.43
156.8, 153.0, 142.8, 135.6, 135.3, 129.9, 129.7, 128.1, 127.8, 127.4,
124.0, 122.9, 122.7, 122.2, 118.8, 118.1, 105.8, 67.9, 63.8, 44.2, 14.7. IR
-
1
(
dd, J = 15.4, 2.2 Hz, 1H), 3.27 (dd, J = 15.4, 8.9 Hz, 1H), 2.53 (s, 3H).
(KBr): 3356, 2917, 1581, 1480, 1226, 1041, 752 cm . HRMS (ESI) m/z:
1
3
+
C NMR (100 MHz, CDCl
3
) δ 159.7, 157.5, 152.9, 145.4, 136.1, 135.9,
calcd for C25
3
H24NO [M+H] , 386.1750; found, 386.1745.
1
1
1
3
35.3, 132.0, 129.7, 128.2, 128.1, 127.4, 126.8, 126.4, 123.9, 122.9,
22.0, 118.7, 118.1, 67.7, 44.3, 21.5. IR (KBr): 3113, 2922, 1783, 1564,
2-(7-Fluoroquinolin-2-yl)-1-(2-phenoxyphenyl)ethan-1-ol (3aj): Yellow
-
1
+
o
1
226, 752, 675 cm . HRMS (ESI) m/z: calcd for C24
H
22NO
2
[M+H] ,
solid (66 mg, 61 %); m.p.=107-108 C. H NMR (400 MHz, CDCl
(d, J = 8.4 Hz, 1H), 7.83 – 7.74 (m, 2H), 7.70 (dd, J = 10.1, 2.4 Hz, 1H),
.41 – 7.08 (m, 7H), 7.02 (d, J = 7.8 Hz, 2H), 6.91 (d, J = 8.0 Hz, 1H),
6.06 (br, 1H), 5.66 (dd, J = 8.7, 1.8 Hz, 1H), 3.47 (dd, J = 15.4, 2.8 Hz,
3
) δ 8.05
56.1645; found, 356.1636.
7
2-(6-Fluoroquinolin-2-yl)-1-(2-phenoxyphenyl)ethan-1-ol
(3ae):
o
1
13
Yellow solid (68 mg, 63%); m.p.=107-108 C. H NMR (400 MHz, CDCl
3
)
3
1H), 3.32 (dd, J = 15.4, 8.9 Hz, 1H). C NMR (100 MHz, CDCl ) δ 163.2
δ 8.09 – 8.00 (m, 2H), 7.75 (d, J = 7.5 Hz, 1H), 7.50 (t, J = 8.7 Hz, 1H),
(d, J = 248.7 Hz), 161.8, 157.4, 153.0, 147.9 (d, J = 12.6 Hz), 136.6,
135.0, 129.7, 129.6 (d, J = 9.9 Hz), 128.2, 127.3, 123.9, 123.8, 123.0,
121.4 (d, J = 2.5 Hz), 118.7, 118.1, 116.6 (d, J = 25.3 Hz), 112.4 (d, J =
20.5 Hz), 67.7, 44.6. IR (KBr): 3109, 2917, 1717, 1534, 1225, 755, 682
7
7
5
.41 (d, J = 8.7 Hz, 1H), 7.34 (t, J = 7.7 Hz, 2H), 7.30 – 7.15 (m, 3H),
.11 (t, J = 7.3 Hz, 1H), 7.02 (d, J = 8.1 Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H),
.66 (d, J = 8.7 Hz, 1H), 3.47 (d, J = 15.3 Hz, 1H), 3.32 (dd, J = 15.4, 8.9
13
-1
+
Hz, 1H). C NMR (100 MHz, CDCl
3 Hz), 157.4, 153.0, 144.0, 136.1 (d, J = 5 Hz), 135.0, 131.0 (d, J = 9
Hz), 129.7, 128.2, 127.4, 127.3 (d, J = 10 Hz), 123.9, 123.0, 122.8, 119.9
3
) δ 160.1 (d, J = 246 Hz), 160.0 (d, J
cm . HRMS (ESI) m/z: calcd for C23
H19FNO
2
[M+H] , 360.1394; found,
=
360.1387.
(
3
d, J = 25 Hz), 118.72, 118.1, 110.6 (d, J = 22 Hz), 67.8, 44.6. IR (KBr):
2-(7-Chloroquinolin-2-yl)-1-(2-phenoxyphenyl)ethan-1-ol
Yellow solid (70 mg, 62 %); m.p.=82-84 C. H NMR (400 MHz, CDCl ) δ
(3ak):
-
1
o
1
054, 2923, 1719, 1574, 1487, 1227, 753 cm . HRMS (ESI) m/z: calcd
3
+
for C23
H19FNO
2
[M+H] , 360.1394 ; found, 360.1391.
8.03 (dd, J = 13.1, 5.2 Hz, 2H), 7.74 – 7.67 (m, 2H), 7.46 (dd, J = 8.7, 2.0
Hz, 1H), 7.35 – 7.29 (m, 2H), 7.23 (td, J = 7.7, 1.8 Hz, 1H), 7.18 – 7.12
(m, 2H), 7.08 (t, J = 7.4 Hz, 1H), 6.99 (dd, J = 8.6, 0.9 Hz, 2H), 6.88 (dd,
J = 8.0, 1.1 Hz, 1H), 5.93 (br, 1H), 5.63 (dd, J = 8.8, 2.7 Hz, 1H), 3.45 (dd,
2
-(6-Chloroquinolin-2-yl)-1-(2-phenoxyphenyl)ethan-1-ol (3af): Yellow
o
1
solid (83 mg, 74 %); m.p.=104-105 C. H NMR (400 MHz, CDCl
3
) δ 7.96
13
(dd, J = 11.9, 8.8 Hz, 2H), 7.73 (dd, J = 9.3, 1.6 Hz, 2H), 7.63 (dd, J = 8.9,
J = 15.5, 2.8 Hz, 1H), 3.30 (dd, J = 15.5, 8.8 Hz, 1H). C NMR (100 MHz,
CDCl ) δ 161.8, 157.4, 153.0, 147.2, 136.5, 135.6, 134.9, 129.7, 128.7,
128.2, 127.6, 127.3, 127.2, 125.1, 123.9, 123.0, 122.3, 118.7, 118.1,
2
2
.3 Hz, 1H), 7.36 – 7.29 (m, 2H), 7.25 – 7.21 (m, 1H), 7.18 – 7.13 (m,
H), 7.09 (t, J = 7.4 Hz, 1H), 7.01 – 6.98 (m, 2H), 6.89 (dd, J = 8.0, 1.0
3
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201901331
FULL PAPER
-
1
6
7.7, 44.6. IR (KBr): 3024, 2928, 1478, 1224, 1053, 752, 683 cm .
CDCl
3
) δ 8.09 (t, J = 8.4 Hz, 2H), 7.81 (d, J = 7.3 Hz, 2H), 7.74 (t, J = 7.4
+
HRMS (ESI) m/z: calcd for C23
H
19ClNO
2
[M+H] , 376.1099; found,
Hz, 1H), 7.59-7.53 (m, 5H), 7.46 (t, J = 6.8 Hz, 2H), 7.37 (d, J = 6.7 Hz,
1H), 7.29 (d, J = 6.7 Hz, 1H), 7.22 (dd, J = 15.4, 7.7 Hz, 2H), 7.10 (d, J =
376.1091.
7
.6 Hz, 2H), 7.00 (d, J = 7.6 Hz, 1H), 5.72 (s, 1H), 3.51 (d, J = 15.3 Hz,
13
2
-(8-Chloroquinolin-2-yl)-1-(2-phenoxyphenyl)ethan-1-ol (3al): Yellow
3
1H), 3.39-3.33 (m, 1H). C NMR (100MHz, CDCl ) δ 160.7, 157.1, 152.9,
1
oil (64 mg, 57 %). H NMR (400 MHz, CDCl
3
) δ 8.09 (d, J = 8.4 Hz, 1H),
.85 (d, J = 7.5 Hz, 2H), 7.72 (d, J = 8.1 Hz, 1H), 7.45 (t, J = 7.8 Hz, 1H),
.34 (t, J = 7.6 Hz, 2H), 7.27 – 7.16 (m, 3H), 7.10 (t, J = 7.4 Hz, 1H), 7.02
146.9, 140.4, 136.8, 136.0, 135.3, 129.7, 128.7, 128.6, 128.4, 128.2,
127.5, 127.0, 126.8, 126.1, 124.1, 122.0, 119.0, 118.3, 67.8, 44.6. IR
7
7
-
1
(KBr): 3048, 2926, 1718, 1505, 1229, 755, 685 cm . HRMS (ESI) m/z:
+
(
d, J = 8.0 Hz, 2H), 6.90 (d, J = 7.9 Hz, 1H), 5.71 (d, J = 8.5 Hz, 1H), 3.52
2
calcd for C29H24NO [M+H] , 418.1801; found, 418.1791.
13
(
d, J = 16.0 Hz, 1H), 3.36 (dd, J = 16.0, 8.7 Hz, 1H). C NMR (100 MHz,
) δ 161.7, 157.5, 152.9, 142.9, 137.1, 135.2, 132.8, 129.7, 129.7,
28.1, 128.0, 127.5, 126.5, 126.1, 123.9, 122.9, 122.8, 118.7, 118.1,
CDCl
1
6
3
1-(2-(4-Fluorophenoxy)phenyl)-2-(quinolin-2-yl)ethan-1-ol
Yellow solid (76 mg, 72 %); m.p.=112-113 C. H NMR (400 MHz, CDCl )
δ 8.08 (d, J = 8.3 Hz, 2H), 7.83 – 7.71 (m, 3H), 7.54 (t, J = 7.3 Hz, 1H),
7.31 – 7.15 (m, 5H), 6.91 (dd, J = 14.5, 7.8 Hz, 3H), 5.63 (d, J = 8.7 Hz,
1H), 3.43 (d, J = 15.4 Hz, 1H), 3.31 (dd, J = 15.3, 8.9 Hz, 1H). C NMR
100 MHz, CDCl ) δ 160.5, 156.2, 152.6, 146.8, 136.9, 135.3, 129.8,
(3ea):
o
1
3
-1
7.6, 43.9. IR (KBr): 3058, 2924, 1590, 1484, 1228, 753, 680 cm .
+
2
HRMS (ESI) m/z: calcd for C23H19ClNO [M+H] , 376.1099; found,
3
13
76.1086.
(
3
2
-(Isoquinolin-1-yl)-1-(2-phenoxyphenyl)ethan-1-ol (3am): Yellow
129.7, 128.6, 128.3, 127.9, 127.6, 127.5, 126.8, 126.2, 124.4, 122.0,
119.2, 118.9, 67.6, 44.5. IR (KBr): 3106, 2922, 1734, 1583, 1234, 755,
o
1
solid (80 mg, 78 %); m.p.=115-116 C. H NMR (400 MHz, CDCl
3
) δ 8.44
-
1
+
(d, J = 5.8 Hz, 1H), 8.03 – 7.98 (m, 1H), 7.88 (dd, J = 7.3, 1.8 Hz, 1H),
2
683 cm . HRMS (ESI) m/z: calcd for C23H19FNO [M+H] , 360.1394;
7
7
1
.82 (d, J = 8.2 Hz, 1H), 7.72 – 7.67 (m, 1H), 7.61 – 7.51 (m, 2H), 7.38 –
.23 (m, 4H), 7.13 – 7.08 (m, 1H), 7.07 – 7.02 (m, 2H), 6.96 (dd, J = 7.7,
.4 Hz, 1H), 5.78 – 5.72 (m, 1H), 3.94 (dd, J = 16.0, 2.2 Hz, 1H), 3.42 (dd,
found, 360.1386.
1-(2-(4-Chlorophenoxy)phenyl)-2-(quinolin-2-yl)ethan-1-ol
White solid (87 mg, 77 %); m.p.=115-116 C. H NMR (400 MHz, CDCl
δ 8.08 (d, J = 8.3 Hz, 2H), 7.83 – 7.71 (m, 3H), 7.54 (t, J = 7.3 Hz, 1H),
7.43 – 7.40 (m, 2H), 7.30 – 7.20 (m, 2H), 7.17 (d, J = 8.4 Hz, 1H), 6.93 –
6.86 (m, 3H), 5.62 (dd, J = 8.8, 2.7 Hz, 1H), 3.43 (dd, J = 15.5, 2.8 Hz,
(3fa):
13
o
1
J = 16.0, 9.6 Hz, 1H). C NMR (100 MHz, CDCl
3
) δ 160.1, 157.5, 152.8,
40.6, 136.1, 135.5, 130.2, 129.7, 128.2, 127.4, 127.3, 127.3, 127.2,
24.9, 124.2, 122.9, 119.8, 118.9, 117.9, 67.2, 40.5. IR (KBr): 3053,
3
)
1
1
2
-
1
922, 1734, 1573, 1483, 1061, 751 cm . HRMS (ESI) m/z: calcd for
+
13
C
23
H
20NO
2
[M+H] , 342.1489; found, 342.1481.
3
1H), 3.31 (dd, J = 15.5, 8.8 Hz, 1H). C NMR (100 MHz, CDCl ) δ 160.5,
156.8, 152.5, 146.8, 136.9, 135.4, 132.6, 129.8, 128.6, 128.3, 127.7,
1
-(2-Phenoxyphenyl)-2-(quinoxalin-2-yl)ethan-1-ol (3an): Red oil (38
127.5, 126.8, 126.2, 124.5, 122.0, 119.6, 119.0, 115.3, 67.6, 44.5. IR
1
-1
mg, 37 %). H NMR (400 MHz, CDCl
3
) δ 8.63 (s, 1H), 8.09 (dd, J = 9.7,
.8 Hz, 2H), 7.83 – 7.68 (m, 3H), 7.37 – 7.31 (m, 2H), 7.26 (dd, J = 7.8,
.6 Hz, 1H), 7.18 (td, J = 7.5, 1.0 Hz, 1H), 7.11 (t, J = 7.1 Hz, 1H), 7.00
(KBr): 3253, 2922, 1569, 1476, 1228, 823, 754 cm . HRMS (ESI) m/z:
+
7
1
calcd for C23H19ClNO
2
[M+H] , 376.1099; found, 376.1091.
(
d, J = 7.3 Hz, 2H), 6.91 (dd, J = 8.1, 1.0 Hz, 1H), 5.67 (dd, J = 8.7, 3.1
1-(2-(4-Bromophenoxy)phenyl)-2-(quinolin-2-yl)ethan-1-ol
White solid (81 mg, 64 %); m.p.=112-114 C. H NMR (400 MHz, CDCl
δ 8.07 (d, J = 8.4 Hz, 2H), 7.83 – 7.76 (m, 2H), 7.73 (t, J = 7.7 Hz, 1H),
7.54 (t, J = 7.5 Hz, 1H), 7.30 – 7.15 (m, 5H), 6.96 – 6.88 (m, 3H), 5.64
(3ga):
o
1
Hz, 1H), 3.55 (dd, J = 15.4, 3.1 Hz, 1H), 3.41 (dd, J = 15.4, 8.7 Hz, 1H).
3
)
1
3
C NMR (100 MHz, CDCl
3
) δ 157.1, 155.0, 153.1, 146.1, 141.4, 134.3,
1
1
30.3, 129.8, 129.4, 129.2, 128.7, 128.6, 127.2, 124.0, 123.2, 118.8,
-
1
18.2, 67.9, 42.6. IR (KBr): 3047, 2922, 1559, 1486, 1229, 755, 684 cm .
(dd, J = 8.8, 2.7 Hz, 1H), 3.44 (dd, J = 15.4, 2.8 Hz, 1H), 3.32 (dd, J =
+
13
HRMS (ESI) m/z: calcd for
C
H N O
22 19 2 2
[M+H] , 343.1441; found,
3
15.4, 8.8 Hz, 1H). C NMR (100 MHz, CDCl ) δ 160.5, 156.2, 152.6,
3
43.1433.
146.8, 136.8, 135.3, 129.8, 129.6, 128.6, 128.3, 127.8, 127.6, 127.5,
26.8, 126.2, 124.4, 122.0, 119.2, 118.8, 67.6, 44.5. IR (KBr): 3050,
1
-
1
2-(Quinolin-2-yl)-1-(2-(p-tolyloxy)phenyl)ethan-1-ol (3ba): Yellow solid
2923, 1569, 1483, 1232, 753, 675 cm . HRMS (ESI) m/z: calcd for
o
1
+
(
8
7
62 mg, 58 %); m.p.=93-94 C. H NMR (400 MHz, CDCl
3
) δ 8.05 (d, J =
.2 Hz, 2H), 7.78 (d, J = 8.0 Hz, 1H), 7.71 (t, J = 7.6 Hz, 2H), 7.51 (t, J =
.3 Hz, 1H), 7.22 – 7.10 (m, 5H), 6.87 (dd, J = 21.9, 7.6 Hz, 3H), 5.66 (d,
23 2
C H19BrNO [M+H] , 420.0594; found, 420.0585.
1-(2-(4-Methoxyphenoxy)phenyl)-2-(quinolin-2-yl)ethan-1-ol
White solid (97 mg, 87 %); m.p.=128-129 C. H NMR (400 MHz, CDCl
(3ha):
o
1
J = 8.8 Hz, 1H), 3.47 (d, J = 14.2 Hz, 1H), 3.30 (dd, J = 15.2, 9.0 Hz, 1H),
3
)
13
2
1
1
1
.32 (s, 3H). C NMR (100 MHz, CDCl
36.7, 134.8, 132.5, 130.2, 129.7, 128.6, 128.1, 127.5, 127.3, 126.8,
26.1, 123.5, 122.1, 118.3, 118.1, 67.8, 44.5, 20.6. IR (KBr): 3044, 2924,
3
) δ 160.8, 155.0, 153.5, 146.9,
δ 8.06 (d, J = 8.1 Hz, 2H), 7.78 (d, J = 8.0 Hz, 1H), 7.70 (d, J = 7.1 Hz,
2H), 7.51 (t, J = 7.3 Hz, 1H), 7.18 (t, J = 7.8 Hz, 2H), 7.10 (t, J = 7.3 Hz,
1H), 6.96 (d, J = 8.3 Hz, 2H), 6.87 (d, J = 8.0 Hz, 2H), 6.78 (d, J = 8.1 Hz,
-
1
592, 1496, 1228, 1047, 754 cm . HRMS (ESI) m/z: calcd for C24
H22NO
2
1H), 5.70 (d, J = 8.7 Hz, 1H), 3.79 (s, 3H), 3.49 (d, J = 15.4 Hz, 1H), 3.31
+
13
[M+H] , 356.1645; found, 356.1637.
3
(dd, J = 15.2, 9.0 Hz, 1H). C NMR (100 MHz, CDCl ) δ 160.8, 155.6,
154.3, 150.5, 146.9, 136.7, 134.2, 129.7, 128.6, 128.0, 127.5, 127.2,
1
-(2-(4-(tert-Butyl)phenoxy)phenyl)-2-(quinolin-2-yl)ethan-1-ol (3ca):
126.8, 126.1, 123.1, 122.1, 120.0, 117.1, 114.8, 67.8, 55.6, 44.5. IR
o
1
-1
Yellow solid (60 mg, 50 %); m.p.=98-99 C. H NMR (400 MHz, CDCl
3
) δ
.06 (t, J = 6.3 Hz, 2H), 7.78 (d, J = 8.0 Hz, 1H), 7.71 (t, J = 8.4 Hz, 2H),
.52 (t, J = 7.3 Hz, 1H), 7.33 (d, J = 7.5 Hz, 2H), 7.21 (t, J = 7.4 Hz, 1H),
.15 (dd, J = 10.5, 8.4 Hz, 2H), 6.93 (d, J = 7.5 Hz, 2H), 6.89 (d, J = 7.9
(KBr): 3056, 2924, 1719, 1562, 1501, 1214, 754 cm . HRMS (ESI) m/z:
+
8
7
7
calcd for C24
H
22NO
3
[M+H] , 372.1594; found, 372.1585.
4-(2-(1-Hydroxy-2-(quinolin-2-yl)ethyl)phenoxy)benzonitrile
Yellow solid (67 mg, 61 %); m.p.=99-100 C. H NMR (400 MHz, CDCl )
(3ia):
o
1
Hz, 1H), 5.66 (d, J = 8.7 Hz, 1H), 3.47 (d, J = 15.3 Hz, 1H), 3.30 (dd, J =
3
13
1
1
1
3
5.1, 9.0 Hz, 1H), 1.32 (s, 9H). C NMR (100 MHz, CDCl
55.0, 153.4, 146.9, 145.9, 136.8, 135.0, 129.7, 128.7, 128.1, 127.5,
27.3, 126.8, 126.5, 126.1, 123.6, 122.1, 118.4, 117.8, 67.8, 44.6, 34.3,
3
) δ 160.8,
δ 8.06 (dd, J = 17.3, 8.4 Hz, 2H), 7.81 (dd, J = 7.3, 2.4 Hz, 2H), 7.77 –
7.70 (m, 1H), 7.61 – 7.51 (m, 3H), 7.36 – 7.28 (m, 2H), 7.14 (d, J = 8.4
Hz, 1H), 7.02 – 6.96 (m, 3H), 5.51 (dd, J = 8.2, 3.4 Hz, 1H), 3.43 – 3.26
-
1
13
1.5. IR (KBr): 3111, 2917, 1712, 1521, 1235, 754, 681 cm . HRMS
3
(m, 2H). C NMR (100 MHz, CDCl ) δ 161.5, 160.2, 150.8, 146.8, 137.0,
+
(ESI) m/z: calcd for C27
H28NO
2
[M+H] , 398.2115; found, 398.2108.
136.1, 134.1, 129.9, 128.7, 128.5, 128.1, 127.6, 126.8, 126.3, 125.8,
21.9, 120.4, 118.7, 117.4, 105.8, 67.5, 44.5. IR (KBr): 3124, 2919, 1734,
1
-
1
1-(2-([1,1'-Biphenyl]-4-yloxy)phenyl)-2-(quinolin-2-yl)ethan-1-ol
1515, 1238, 756, 670 cm . HRMS (ESI) m/z: calcd for C24
[M+H] , 367.1441; found, 367.1443.
H N O
19 2 2
o
1
+
(3da): Yellow solid (68 mg, 54 %); m.p.=146-147 C. H NMR (400 MHz,
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201901331
FULL PAPER
4.1 Hz, 1H), 7.49 (t, J = 7.5 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.07 – 7.04
1
-(2-(3,4-Dimethylphenoxy)phenyl)-2-(quinolin-2-yl)ethan-1-ol (3ja):
(m, 2H), 6.96 – 6.91 (m, 2H), 6.88 – 6.85 (m, 2H), 6.65 – 6.61 (m, 1H),
5.94 (dd, J = 9.1, 4.2 Hz, 1H), 3.86 (dd, J = 14.3, 9.2 Hz, 1H), 3.79 (s,
3H), 3.46 (dd, J = 14.3, 4.3 Hz, 1H). C NMR (100 MHz, CDCl ) δ 159.7,
3
o
1
Yellow solid (66 mg, 59 %); m.p.=74-75 C. H NMR (400 MHz, CDCl
.06 (t, J = 7.7 Hz, 2H), 7.78 (d, J = 8.1 Hz, 1H), 7.71 (dd, J = 11.3, 4.2
Hz, 2H), 7.52 (t, J = 7.2 Hz, 1H), 7.23 – 7.10 (m, 3H), 7.07 (d, J = 8.2 Hz,
3
) δ
13
8
158.1, 156.4, 149.2, 147.5, 136.4, 133.9, 130.1, 129.4, 128.9, 128.7,
127.5, 126.9, 126.0, 124.2, 121.9, 121.1, 116.0, 115.0, 70.7, 55.6, 44.6.
1H), 6.88 – 6.84 (m, 1H), 6.81 (d, J = 2.2 Hz, 1H), 6.76-6.73 (m, 1H),
13
-1
5
.68-5.65 (m, 1H), 3.52-3.47 (m, 1H), 3.34-3.28 (m, 1H), 2.23 (s, 6H).
) δ 160.8, 155.2, 153.6, 146.9, 138.2, 136.8,
34.8, 131.3, 130.6, 129.7, 128.6, 128.0, 127.5, 127.2, 126.8, 126.1,
23.4, 122.1, 119.7, 118.1, 115.7, 67.9, 44.5, 19.9, 18.9. IR (KBr): 3055,
C
IR (KBr): 3463, 2920, 1638, 1503, 1280, 755, 680 cm . HRMS (ESI) m/z:
+
NMR (100 MHz, CDCl
3
calcd for C24H21ClNO
3
[M+H] , 406.1204; found, 406.1195.
1
1
2
1-(4-Methoxy-2-(4-methoxyphenoxy)phenyl)-2-(quinolin-2-yl)ethan-1-
-
1
o
1
930, 1734, 1511, 1262, 754, 687 cm . HRMS (ESI) m/z: calcd for
ol (3pa): Yellow solid (64 mg, 53 %); m.p.= 99-100 C. H NMR (400
MHz, CDCl ) δ 8.06 (d, J = 8.3 Hz, 2H), 7.79 (t, J = 7.9 Hz, 1H), 7.74 –
.67 (m, 1H), 7.58 (d, J = 8.5 Hz, 1H), 7.51 (t, J = 7.1 Hz, 1H), 7.20 (d, J
+
C
23
H
19ClNO
2
[M+H] , 376.1099; found, 376.1092.
3
7
1
-(2-(Naphthalen-2-yloxy)phenyl)-2-(quinolin-2-yl)ethan-1-ol
(3ka):
= 8.4 Hz, 1H), 6.98 – 6.94 (m, 2H), 6.88 – 6.84 (m, 2H), 6.64 (dd, J = 8.6,
2.4 Hz, 1H), 6.32 (d, J = 2.4 Hz, 1H), 5.62 (dd, J = 8.8, 2.6 Hz, 1H), 3.79
(s, 3H), 3.70 (s, 3H), 3.45 (dd, J = 15.3, 2.8 Hz, 1H), 3.32 (dd, J = 15.3,
1
Yellow oil (67 mg, 57 %). H NMR (400 MHz, CDCl
3
) δ 8.14 – 8.06 (m,
2
7
H), 7.87 – 7.79 (m, 4H), 7.78 – 7.69 (m, 2H), 7.54 (t, J = 7.5 Hz, 1H),
.49 – 7.38 (m, 2H), 7.32 – 7.20 (m, 4H), 7.15 (d, J = 8.4 Hz, 1H), 6.98 (d,
13
3
8.8 Hz, 1H). C NMR (100 MHz, CDCl ) δ 160.8, 159.6, 155.8, 155.3,
J = 7.9 Hz, 1H), 5.74 – 5.67 (m, 1H), 3.53 (d, J = 15.2 Hz, 1H), 3.39 (dd,
150.2, 146.8, 136.8, 129.8, 128.5, 127.9, 127.5, 126.8, 126.4, 126.1,
122.2, 120.2, 114.9, 108.0, 103.6, 67.6, 55.6, 55.3, 44.8. IR (KBr): 3105,
13
J = 15.1, 8.8 Hz, 1H). C NMR (100 MHz, CDCl
3
) δ 160.6, 155.3, 152.9,
-
1
1
1
46.8, 136.9, 135.4, 134.3, 130.0, 129.9, 129.8, 128.5, 128.3, 127.7,
2921, 1730, 1516, 1271, 755, 655 cm . HRMS (ESI) m/z: calcd for
+
27.5, 127.0, 126.8, 126.5, 126.2, 124.6, 124.2, 122.1, 119.4, 119.2,
C
25
H
24NO
4
[M+H] , 402.1700; found, 402.1689.
-
1
13.0, 67.8, 44.6. IR (KBr): 3052, 2922, 1718, 1582, 1501, 1234, 753 cm
1
+
.
HRMS (ESI) m/z: calcd for C27
H
22NO
2
[M+H] , 392.1645; found,
1-(2-Methoxyphenyl)-2-(quinolin-2-yl)ethan-1-ol (3qa): Yellow solid
o
1
392.1635.
3
(36 mg, 43 %); m.p.=113-114 C. H NMR (400 MHz, CDCl ) δ 8.11 (dd,
J = 8.2, 6.0 Hz, 2H), 7.82 (d, J = 8.1 Hz, 1H), 7.75 (dt, J = 7.4, 3.7 Hz,
1H), 7.60 (dd, J = 7.5, 1.3 Hz, 1H), 7.58 – 7.52 (m, 1H), 7.30-7.24 (m,
2H), 7.00 (t, J = 7.5 Hz, 1H), 6.92 (d, J = 8.1 Hz, 1H), 5.64 (dd, J = 8.9,
2.7 Hz, 1H), 3.88 (s, 3H), 3.46 (dd, J = 15.3, 2.8 Hz, 1H), 3.29 (dd, J =
1
-(2-(4-Methoxyphenoxy)-5-methylphenyl)-2-(quinolin-2-yl)ethan-1-ol
o
1
(
3la): Yellow solid (62 mg, 54 %); m.p.=96-97 C. H NMR (400 MHz,
CDCl ) δ 8.07 (d, J = 8.3 Hz, 2H), 7.78 (d, J = 8.1 Hz, 1H), 7.71 (t, J = 7.7
Hz, 1H), 7.56 – 7.47 (m, 2H), 7.19 (d, J = 8.4 Hz, 1H), 7.00 (dd, J = 8.2,
3
13
3
15.3, 8.9 Hz, 1H). C NMR (100 MHz, CDCl ) δ 161.0, 155.9, 146.8,
1
1
.7 Hz, 1H), 6.95 – 6.90 (m, 2H), 6.87 – 6.81 (m, 2H), 6.71 (d, J = 8.2 Hz,
H), 5.63 (dd, J = 9.2, 2.4 Hz, 1H), 3.78 (s, 3H), 3.45 (dd, J = 15.4, 2.5
136.8, 132.0, 129.8, 128.5, 128.0, 127.5, 126.8, 126.7, 126.1, 122.2,
120.7, 110.1, 68.0, 55.3, 44.3. IR (KBr): 3457, 2924, 1634, 1490, 1235,
13
-1
+
Hz, 1H), 3.29 (dd, J = 15.4, 9.2 Hz, 1H), 2.33 (s, 3H). C NMR (100 MHz,
CDCl ) δ 160.8, 155.4, 151.8, 151.1, 146.8, 136.8, 134.2, 132.9, 129.8,
28.6, 127.7, 127.5, 126.8, 126.2, 122.1, 119.4, 117.7, 114.8, 67.8, 55.6,
1041, 753 cm . HRMS (ESI) m/z: calcd for C18
H18NO
2
[M+H] , 280.1332;
3
found, 280.1325.
1
4
-1
4.7, 20.8. IR (KBr): 3116, 2922, 1714, 1515, 1036, 754, 684 cm .
1-(2-Ethoxyphenyl)-2-(quinolin-2-yl)ethan-1-ol (3ra): Gray solid (36
+
o
1
HRMS (ESI) m/z: calcd for
C
25
H
24NO
3
[M+H] , 386.1751; found,
mg, 41 %); m.p.=90-91 C. H NMR (400 MHz, CDCl
6.4 Hz, 2H), 7.80 (dd, J = 8.1, 1.4 Hz, 1H), 7.72 (ddd, J = 8.5, 6.9, 1.5 Hz,
H), 7.59 – 7.49 (m, 2H), 7.25 – 7.17 (m, 2H), 6.96 (td, J = 7.5, 1.1 Hz,
3
) δ 8.09 (dd, J = 8.4,
386.1742.
1
1
-(5-Chloro-2-(4-methoxyphenoxy)phenyl)-2-(quinolin-2-yl)ethan-1-ol
1H), 6.87 (dd, J = 8.2, 1.1 Hz, 1H), 5.60 (dd, J = 8.9, 2.9 Hz, 1H), 4.17 –
4.00 (m, 2H), 3.47 (dd, J = 15.1, 2.9 Hz, 1H), 3.26 (dd, J = 15.1, 8.8 Hz,
1H), 1.42 (t, J = 7.0 Hz, 3H). C NMR (100 MHz, CDCl ) δ 161.1, 155.2,
3
o
1
(
3ma): Yellow solid (75 mg, 62%); m.p.=134-136 C. H NMR (400 MHz,
CDCl ) δ 8.07 (t, J = 5.5 Hz, 2H), 7.80 – 7.68 (m, 3H), 7.52 (t, J = 7.1 Hz,
H), 7.19 (d, J = 8.2 Hz, 1H), 7.13 (d, J = 8.6 Hz, 1H), 6.94 (d, J = 7.5 Hz,
H), 6.87 (d, J = 7.5 Hz, 2H), 6.70 (d, J = 8.6 Hz, 1H), 5.66 (d, J = 9.0 Hz,
H), 3.79 (s, 3H), 3.47 (d, J = 15.5 Hz, 1H), 3.25 (dd, J = 15.2, 9.3 Hz,
H). C NMR (100 MHz, CDCl
36.9, 136.0, 129.8, 128.6, 128.3, 127.9, 127.6, 127.4, 126.9, 126.2,
22.0, 120.1, 118.2, 114.9, 67.4, 55.6, 44.1. IR (KBr): 3358, 2922, 1735,
13
3
1
2
1
1
1
1
1
147.0, 136.8, 132.2, 129.8, 128.7, 127.9, 127.6, 126.9, 126.7, 126.1,
122.2, 120.6, 111.0, 68.3, 63.5, 44.5, 15.0. IR (KBr): 3051, 2922, 1578,
-
1
1502, 1227, 1040, 749 cm . HRMS (ESI) m/z: calcd for C19
H
20NO
2
13
+
3
) δ 160.5, 155.9, 152.9, 150.1, 146.9,
[M+H] , 294.1488; found, 294.1284.
1-(2-(benzyloxy)phenyl)-2-(quinolin-2-yl)ethan-1-ol (3sa): Yellow solid
-
1
o
1
492, 1223, 826, 752 cm . HRMS (ESI) m/z: calcd for C24
H
21ClNO
3
(41 mg, 38 %); m.p.=91-92 C. H NMR (400 MHz, CDCl
8.5 Hz, 1H), 8.06 (d, J = 8.3 Hz, 1H), 7.81 (d, J = 8.1 Hz, 1H), 7.78 – 7.72
m, 1H), 7.67 (dd, J = 7.6, 1.7 Hz, 1H), 7.55 (t, J = 7.5 Hz, 1H), 7.47 (d, J
3
) δ 8.11 (d, J =
+
[M+H] , 406.1204; found, 406.1199.
(
1
-(2-(4-Methoxyphenoxy)-4-methylphenyl)-2-(quinolin-2-yl)ethan-1-ol
= 6.6 Hz, 2H), 7.43 – 7.34 (m, 3H), 7.30 – 7.24 (m, 1H), 7.13 (d, J = 8.4
Hz, 1H), 7.07 – 6.96 (m, 2H), 5.70 (dd, J = 8.9, 2.6 Hz, 1H), 5.21 – 5.10
(m, 2H), 3.51 (dd, J = 15.1, 2.7 Hz, 1H), 3.27 (dd, J = 15.0, 8.9 Hz, 1H).
o
1
(
3na): Yellow solid (70 mg, 61 %); m.p.=118-119 C. H NMR (400 MHz,
CDCl ) δ 8.09 (d, J = 8.1 Hz, 2H), 7.84 – 7.68 (m, 2H), 7.54 (d, J = 7.4 Hz,
H), 7.23 – 7.18 (m, 1H), 6.99 (d, J = 7.8 Hz, 1H), 6.92 (d, J = 9.1 Hz,
H), 6.84 (d, J = 9.1 Hz, 2H), 6.71 (d, J = 8.2 Hz, 1H), 5.61 (d, J = 9.0 Hz,
H), 3.78 (s, 3H), 3.48-3.33 (m, 2H), 2.32 (s, 3H). C NMR (100 MHz,
) δ 160.9, 155.3, 151.8, 151.1, 146.9, 136.7, 134.2, 132.8, 129.7,
28.6, 128.6, 127.7, 127.5, 126.8, 126.1, 122.1, 119.4, 117.7, 114.8,
7.8, 55.6, 44.7, 20.8. IR (KBr): 3052, 2924, 1597, 1490, 1214, 1034,
3
13
2
2
1
3
C NMR (100 MHz, CDCl ) δ 161.0, 154.9, 147.0, 137.1, 136.7, 132.5,
129.7, 128.7, 128.5, 127.9, 127.8, 127.5, 127.1, 126.8, 126.7, 126.1,
122.1, 121.1, 111.4, 69.9, 68.2, 44.5. IR (KBr): 3358, 2920, 1588, 1496,
13
-
1
+
CDCl
3
1234, 1045, 753 cm . HRMS (ESI) m/z: calcd for C24
H
22NO
2
[M+H] ,
1
6
7
3
356.1645; found, 356.1650 .
-
1
+
1
52 cm . HRMS (ESI) m/z: calcd for C25
H24NO
3
[M+H] , 386.1751; found,
(E)-2-(2-phenoxystyryl)quinoline (4a): Yellow oil (85 mg, 88 %).
NMR (400 MHz, CDCl
H), 7.89 (dd, J = 7.8, 1.7 Hz, 1H), 7.79 (dd, J = 8.1, 1.4 Hz, 1H), 7.72
H
86.1741.
3
) δ 8.11 (d, J = 8.6 Hz, 2H), 8.01 (d, J = 16.5 Hz,
1
1
-(2-Chloro-6-(4-methoxyphenoxy)phenyl)-2-(quinolin-2-yl)ethan-1-ol
(dd, J = 8.5, 6.9 Hz, 2H), 7.58 – 7.47 (m, 2H), 7.38 (dd, J = 8.6, 7.3 Hz,
2H), 7.31 – 7.27 (m, 1H), 7.20 (td, J = 7.5, 1.2 Hz, 1H), 7.14 (td, J = 7.4,
1.2 Hz, 1H), 7.10 – 7.05 (m, 2H), 6.95 (dd, J = 8.1, 1.2 Hz, 1H). C NMR
o
1
(3oa): Yellow solid (75 mg, 62 %); m.p.=119-120 C. H NMR (400 MHz,
13
CDCl ) δ 8.09 – 8.01 (m, 2H), 7.77 (d, J = 8.1 Hz, 1H), 7.67 (dd, J = 11.3,
3
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201901331
FULL PAPER
(
100 MHz, CDCl
3
) δ 157.5, 156.3, 154.9, 148.1, 136.2, 130.4, 129.8,
1H), 7.12 (td, J = 7.5, 1.2 Hz, 1H), 7.02 (d, J = 9.0 Hz, 2H), 6.91 (d, J =
13
1
1
6
3
29.7, 129.7, 129.1, 128.5, 128.2, 127.4, 127.3, 127.2, 126.2, 123.9,
9.0 Hz, 2H), 6.81 (dd, J = 8.2, 1.2 Hz, 1H), 3.80 (s, 3H). C NMR (100
MHz, CDCl ) δ 156.3, 156.2, 155.9, 150.4, 148.0, 136.3, 130.0, 129.7,
23.2, 119.3, 118.9, 118.7. IR (KBr): 3046, 2923, 1580, 1484, 1228, 749,
3
-
1
+
89 cm . HRMS (ESI) m/z: calcd for C23
H
18NO [M+H] , 324.1383; found,
129.0, 128.9, 127.4, 127.3, 127.3, 127.1, 126.1, 123.0, 120.6, 118.9,
117.8, 114.9, 55.6. IR (KBr): 3050, 2922, 1721, 1569, 1503, 1220, 754
24.1376 .
-
1
+
cm . HRMS (ESI) m/z: calcd for C24
2
H20NO [M+H] , 354.1489 ; found,
1
(
E)-2-(2-(p-tolyloxy)styryl)quinoline (4b): Yeiiow oil (77 mg, 76 %).
NMR (400 MHz, CDCl
Hz, 1H), 7.88 (dd, J = 7.8, 1.8 Hz, 1H), 7.80 (dd, J = 8.1, 1.6 Hz, 1H),
H
354.1480.
3
) δ 8.12 (dd, J = 8.6, 2.0 Hz, 2H), 8.04 (d, J = 16.6
(E)-6-methyl-2-(2-phenoxystyryl)quinoline (4h): Yellow oil (61 mg,
1
7
=
3
1
1
1
.76 – 7.69 (m, 2H), 7.60 – 7.48 (m, 2H), 7.31 – 7.24 (m, 2H), 7.18 (d, J
3
60 %). H NMR (400 MHz, CDCl ) δ 8.02 – 7.94 (m, 3H), 7.89 (dd, J =
8.4 Hz, 2H), 7.01 – 6.95 (m, 2H), 6.90 (dd, J = 8.2, 1.4 Hz, 1H), 2.36 (s,
7.8, 1.7 Hz, 1H), 7.65 (d, J = 8.6 Hz, 1H), 7.56 – 7.50 (m, 3H), 7.38 (dd, J
= 8.6, 7.3 Hz, 2H), 7.29 (td, J = 7.5, 1.7 Hz, 1H), 7.20 (td, J = 7.5, 1.2 Hz,
1H), 7.17 – 7.12 (m, 1H), 7.10 – 7.06 (m, 2H), 6.96 (d, J = 1.2 Hz, 1H),
13
3
H). C NMR (100 MHz, CDCl ) δ 156.3, 155.5, 155.0, 148.1, 136.2,
32.9, 130.3, 130.3, 129.7, 129.6, 129.1, 128.7, 127.9, 127.4, 127.3,
27.1, 126.1, 123.5, 118.9, 118.9, 118.7, 20.7. IR (KBr): 3045, 2922,
13
3
2.53 (s, 3H). C NMR (100 MHz, CDCl ) δ 157.5, 155.4, 154.8, 146.6,
-
1
579, 1502, 1229, 822, 752 cm . HRMS (ESI) m/z: calcd for C24
H20NO
136.1, 135.6, 131.9, 130.4, 129.8, 129.6, 128.7, 128.3, 128.0, 127.3,
127.1, 126.4, 123.9, 123.2, 119.3, 118.8, 118.6, 21.5. IR (KBr): 3034,
+
[M+H] , 338.1539; found, 338.1530.
-
1
2
C
925, 1419, 1231, 969, 754, 678 cm . HRMS (ESI) m/z: calcd for
+
(
E)-2-(2-(4-(tert-butyl)phenoxy)styryl)quinoline (4c): Yellow solid (57
24
H
20NO [M+H] , 338.1539; found, 338.1532.
o
1
mg, 50 %); m.p.=118-119 C. H NMR (400 MHz, CDCl
3
) δ 8.12 (dd, J =
8
7
7
7
.6, 2.5 Hz, 2H), 8.04 (d, J = 16.6 Hz, 1H), 7.88 (dd, J = 7.9, 1.6 Hz, 1H),
(E)-6-fluoro-2-(2-phenoxystyryl)quinoline (4i): Yellow solid (71 mg,
69 %); m.p.=94-95 C. H NMR (400 MHz, CDCl ) δ 8.11 – 7.97 (m, 3H),
3
o
1
.79 (d, J = 8.2 Hz, 1H), 7.73 (d, J = 8.3 Hz, 2H), 7.60 – 7.49 (m, 2H),
.42 – 7.38 (m, 2H), 7.31 – 7.25 (m, 1H), 7.18 (t, J = 7.5 Hz, 1H), 7.04 –
7.87 (dd, J = 7.8, 1.6 Hz, 1H), 7.70 (d, J = 8.7 Hz, 1H), 7.53 – 7.44 (m,
2H), 7.42 – 7.36 (m, 3H), 7.32 – 7.27 (m, 1H), 7.17 (dt, J = 24.6, 7.5 Hz,
13
.00 (m, 2H), 6.94 (dd, J = 8.2, 1.3 Hz, 1H), 1.35 (s, 9H). C NMR (100
) δ 156.3, 155.4, 154.9, 146.2, 136.4, 129.9, 129.8, 129.0,
28.9, 127.9, 127.5, 127.3, 127.1, 126.6, 126.2, 123.5, 118.9, 118.8,
13
MHz, CDCl
3
2H), 7.08 (d, J = 8.0 Hz, 2H), 6.95 (d, J = 8.2 Hz, 1H). C NMR (100
MHz, CDCl ) δ 160.3 (d, J = 246.6 Hz), 157.4, 155.7, 154.9, 145.1, 135.6
1
1
3
-
1
18.4, 34.3, 31.5. IR (KBr): 3056, 2929, 1714, 1584, 1498, 829, 753 cm .
(d, J = 246.6 Hz) , 131.5 (d, J = 9.0 Hz), 129.9, 129.8, 128.60, 128.10,
127.8 (d, J = 9.8 Hz), 127.2, 123.9, 123.3, 119.9, 119.7, 119.6, 119.3,
+
HRMS (ESI) m/z: calcd for C27
H26NO [M+H] , 380.2009; found, 380.2000.
1
18.7, 110.6 (d, J = 21.6 Hz). IR (KBr): 3046, 2924, 1561, 1480, 1221,
-
1
+
(
E)-2-(2-([1,1'-biphenyl]-4-yloxy)styryl)quinoline (4d): Yellow solid (79
746, 646 cm . HRMS (ESI) m/z: calcd for C23
H17FNO [M+H] , 342.1289 ;
o
1
mg, 66 %); m.p.=137-138 C. H NMR (400 MHz, CDCl
m, 2H), 8.03 (d, J = 16.6 Hz, 1H), 7.92 (dd, J = 7.8, 1.7 Hz, 1H), 7.79 (dd,
J = 8.2, 1.4 Hz, 1H), 7.75 – 7.70 (m, 2H), 7.64 – 7.51 (m, 6H), 7.46 (t, J =
3
) δ 8.14 – 8.10
found, 342.1281.
(
(E)-6-chloro-2-(2-phenoxystyryl)quinoline (4j): Yellow solid (74 mg,
o
1
7
.7 Hz, 2H), 7.39 – 7.31 (m, 2H), 7.24 (dd, J = 7.6, 1.2 Hz, 1H), 7.16 –
3
69 %); m.p.=109-110 C. H NMR (400 MHz, CDCl ) δ 8.05 – 7.99 (m,
13
7.13 (m, 2H), 7.02 (dd, J = 8.1, 1.2 Hz, 1H). C NMR (100 MHz, CDCl
3
)
3H), 7.87 (dd, J = 7.8, 1.6 Hz, 1H), 7.76 (d, J = 2.3 Hz, 1H), 7.70 (d, J =
8.7 Hz, 1H), 7.64 (dd, J = 9.0, 2.3 Hz, 1H), 7.50 (d, J = 16.5 Hz, 1H), 7.41
– 7.36 (m, 2H), 7.33 – 7.27 (m, 1H), 7.23 – 7.12 (m, 2H), 7.09 – 7.06 (m,
2H), 6.94 (dd, J = 8.2, 1.2 Hz, 1H). C NMR (100 MHz, CDCl ) δ 157.4,
3
156.5, 155.0, 146.4, 135.3, 131.7, 130.6, 130.5, 129.9, 129.8, 129.0,
128.0, 127.8, 127.2, 126.1, 123.8, 123.3, 119.8, 119.3, 118.7. IR (KBr):
δ 157.1, 156.2, 154.8, 140.4, 136.4, 136.3, 130.3, 129.8, 129.7, 129.0,
1
1
1
4
28.7, 128.7, 128.6, 128.5, 128.3, 127.4, 127.3, 127.0, 126.8, 126.2,
24.0, 119.5, 118.8, 118.8, 118.2. IR (KBr): 3127, 2919, 1586, 1486,
231, 754, 689 cm . HRMS (ESI) m/z: calcd for C29
00.1696; found, 400.1709.
13
-
1
+
H
22NO [M+H] ,
-
1
3
C
477, 2923, 1479, 1228, 1072, 751, 680 cm . HRMS (ESI) m/z: calcd for
+
(
E)-2-(2-(4-chlorophenoxy)styryl)quinoline (4e): Yellow oil (78 mg,
23
H
17ClNO [M+H] , 358.0993; found, 358.0986.
1
7
(
1
5 %). H NMR (400 MHz, CDCl
d, J = 16.6 Hz, 1H), 7.89 (dd, J = 7.7, 1.6 Hz, 1H), 7.80 (d, J = 8.1 Hz,
H), 7.75 – 7.68 (m, 2H), 7.57 – 7.50 (m, 2H), 7.35 – 7.28 (m, 3H), 7.23
3
) δ 8.12 (dd, J = 8.5, 5.5 Hz, 2H), 7.95
(E)-6-bromo-2-(2-phenoxystyryl)quinoline (4k): Yellow oil (91 mg,
76 %). H NMR (400 MHz, CDCl ) δ 8.05 – 7.91 (m, 4H), 7.86 (dd, J =
3
7.8, 1.7 Hz, 1H), 7.78 – 7.74 (m, 1H), 7.68 (d, J = 8.6 Hz, 1H), 7.49 (d, J
= 16.5 Hz, 1H), 7.38 (t, J = 8.0 Hz, 2H), 7.31 – 7.27 (m, 1H), 7.21 – 7.12
(m, 2H), 7.08 (d, J = 8.0 Hz, 2H), 6.94 (d, J = 8.1 Hz, 1H). C NMR (100
MHz, CDCl ) δ 157.4, 156.6, 155.0, 146.6, 135.2, 133.1, 130.8, 129.9,
129.8, 129.5, 129.2, 128.3, 128.0, 127.2, 123.8, 123.3, 119.9, 119.8,
119.3, 118.7, 118.1. IR (KBr): 3129, 2922, 1740, 1544, 1232, 754, 684
cm . HRMS (ESI) m/z: calcd for C23H17BrNO [M+H] , 402.0488; found,
402.0480.
1
13
(t, J = 7.5 Hz, 1H), 7.00 (d, J = 8.7 Hz, 2H), 6.93 (d, J = 8.1 Hz, 1H).
C
3
NMR (100 MHz, CDCl ) δ 156.1, 156.0, 154.4, 148.0, 136.3, 130.5,
13
1
1
7
29.8, 129.7, 129.7, 129.0, 128.3, 128.1, 127.4, 127.2, 127.2, 126.2,
24.3, 119.6, 119.3, 118.8. IR (KBr): 3047, 2921, 1578, 1480, 1231, 825,
51 cm . HRMS (ESI) m/z: calcd for C23
3
-
1
+
H
17ClNO [M+H] , 358.0993 ;
found, 358.1000.
-
1
+
(
E)-2-(2-(4-bromophenoxy)styryl)quinoline (4f): Yellow oil (97 mg,
1
8
1
7
6
3
1 %). H NMR (400 MHz, CDCl ) δ 8.13 – 8.05 (m, 2H), 7.96 (d, J =
6.6 Hz, 1H), 7.88 (dd, J = 7.8, 1.7 Hz, 1H), 7.78 – 7.75 (m, 1H), 7.73 –
.64 (m, 2H), 7.55 – 7.46 (m, 2H), 7.34 – 7.28 (m, 3H), 7.21 (dd, J = 8.2,
.8 Hz, 1H), 6.99 (d, J = 6.9 Hz, 2H), 6.93 (dd, J = 8.2, 1.3 Hz, 1H).
) δ 156.1, 156.0, 154.4, 148.1, 136.2, 130.6,
29.7, 129.7, 129.6, 129.1, 128.3, 128.1, 128.0, 127.4, 127.2, 127.2,
26.1, 124.2, 119.7, 119.3, 118.9. IR (KBr): 3053, 2921, 1591, 1483,
(E)-1-(2-phenoxystyryl)isoquinoline (4l): Yellow solid (82 mg, 84 %);
m.p.=107-108 C. H NMR (400 MHz, CDCl ) δ 8.56 (d, J = 5.6 Hz, 1H),
3
o
1
13
C
8.31 – 8.11 (m, 3H), 7.88 (dd, J = 7.7, 1.7 Hz, 2H), 7.82 (d, J = 8.2 Hz,
1H), 7.67 (ddd, J = 8.2, 6.8, 1.2 Hz, 2H), 7.61 – 7.54 (m, 2H), 7.38 (dd, J
= 8.6, 7.3 Hz, 2H), 7.34 – 7.28 (m, 1H), 7.22 (td, J = 7.5, 1.3 Hz, 1H),
7.16 – 7.08 (m, 3H), 6.98 (dd, J = 8.2, 1.3 Hz, 1H). C NMR (100 MHz,
CDCl ) δ 157.4, 155.2, 154.9, 142.4, 136.6, 130.7, 129.8, 129.8, 129.6,
128.7, 128.5, 127.2, 127.1, 126.8, 124.9, 124.6, 123.7, 123.1, 119.9,
NMR (100 MHz, CDCl
3
1
1
1
4
13
-
1
+
233, 824, 751 cm . HRMS (ESI) m/z: calcd for C23
02.0488 ; found, 402.0479.
H
17BrNO [M+H] ,
3
-
1
1
19.4, 118.6. IR (KBr): 3052, 2923, 1562, 1479, 1228, 746, 682 cm .
HRMS (ESI) m/z: calcd for C23H18NO [M+H] , 324.1383; found, 324.1375.
+
(
E)-2-(2-(4-methoxyphenoxy)styryl)quinoline (4g): Yellow oil (56 mg,
1
53 %). H NMR (400 MHz, CDCl
3
) δ 8.12 – 8.02 (m, 3H), 7.84 (dd, J =
7.9, 1.7 Hz, 1H), 7.78 – 7.67 (m, 3H), 7.57 – 7.46 (m, 2H), 7.27 – 7.20 (m,
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201901331
FULL PAPER
1
(
E)-1-(2-ethoxystyryl)isoquinoline (4m): Yellow oil (54 mg, 65 %). H
NMR (400 MHz, CDCl
3
) δ 8.60 (d, J = 5.6 Hz, 1H), 8.39 (d, J = 8.4 Hz,
2-(2-Methoxy-2-(2-methoxyphenyl)ethyl)quinoline (7): To
a
solution of 3qa (0.3 mmol) in anhydrous THF (1.6 mL) and DMF (0.4 mL)
was added NaH (0.45 mmol) at 0 °C. After being stirred for 30 min, MeI
stirred
1
7
6
H), 8.24 (d, J = 2.0 Hz, 2H), 7.86 – 7.82 (m, 1H), 7.75 – 7.60 (m, 3H),
.56 (d, J = 5.6 Hz, 1H), 7.34 – 7.28 (m, 1H), 7.03 (t, J = 7.5 Hz, 1H),
.97 (d, J = 8.3 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 1.58 (t, J = 7.1 Hz, 3H).
(0.9 mmol) was added at 0°C under N
at room temperature for 12 h under N
O (10 mL) and extracted with EtOAc (3 × 10 mL). The combined
organic layers were dried over anhydrous MgSO and the solvent was
2
. The reaction mixture was stirred
1
3
C NMR (100 MHz, CDCl
3
) δ 157.4, 155.4, 142.4, 136.7, 132.0, 129.7,
2
and quenched with solution of
129.5, 129.0, 127.2, 127.0, 126.8, 125.9, 124.6, 124.1, 120.5, 119.5,
H
2
-
1
.
11.9, 63.8, 15.0. IR (KBr): 3048, 2928, 1563, 1475, 1236, 1009, 748 cm
HRMS (ESI) m/z: calcd for C19
4
1
+
H
18NO [M+H] , 276.1383; found,
removed under vacuum. The crude product was purified by column
276.1378.
chromatography (EtOAc/hexanes) on silica gel to give product 10 as a
1
yellow oil (69 mg, 78 %). H NMR (400 MHz, CDCl
3
) δ 8.15 (d, J = 8.5 Hz,
(
5
E)-1-(2-(benzyloxy)styryl)isoquinoline (4n): Yellow solid (60 mg,
9 %); m.p.=119-120 C. H NMR (400 MHz, CDCl ) δ 8.57 (d, J = 5.6
3
1H), 8.03 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 8.8 Hz, 1H), 7.71 – 7.67 (m,
1H), 7.54 – 7.46 (m, 2H), 7.35 – 7.24 (m, 2H), 7.03 (t, J = 7.4 Hz, 1H),
6.86 (d, J = 8.2 Hz, 1H), 5.23 (dd, J = 7.9, 5.3 Hz, 1H), 3.72 (s, 3H), 3.39
o
1
Hz, 1H), 8.33 – 8.18 (m, 2H), 7.96 (d, J = 8.5 Hz, 1H), 7.80 (d, J = 8.2 Hz,
13
1
7
5
1
1
2
H), 7.72 – 7.63 (m, 2H), 7.62 – 7.58 (m, 2H), 7.54 (d, J = 5.7 Hz, 1H),
3
(dd, J = 6.7, 3.8 Hz, 2H), 3.23 (s, 3H). C NMR (100 MHz, CDCl ) δ
.45 (t, J = 7.5 Hz, 4H), 7.35 – 7.30 (m, 1H), 7.07 (d, J = 7.6 Hz, 2H),
159.7, 156.7, 147.5, 135.3, 129.5, 128.8, 128.7, 128.1, 127.1, 126.6,
126.4, 125.4, 122.0, 120.4, 110.0, 76.5, 56.7, 54.9, 46.2. IR (KBr): 3059,
13
3
.24 (s, 2H). C NMR (100 MHz, CDCl ) δ 157.5, 155.3, 142.2, 136.8,
-
1
36.7, 132.3, 130.6, 129.7, 129.4, 128.7, 128.1, 128.0, 127.0, 126.9,
26.8, 126.0, 124.8, 124.7, 121.0, 119.5, 112.2, 70.5. IR (KBr): 3052,
2928, 1605, 1432, 1101, 749, 623 cm . HRMS (ESI) m/z: calcd for
+
19 2
C H20NO [M+H] , 294.1489; found, 294.1479.
-
1
921, 1552, 1471, 1238, 819, 744 cm . HRMS (ESI) m/z: calcd for
+
C
24
H
20NO [M+H] , 338.1539; found, 338.1530.
2-(2-(Benzyloxy)-2-(2-methoxyphenyl)ethyl)quinoline (8): To a stirred
solution of 3qa (0.3 mmol) in anhydrous THF (1.6 mL) and DMF (0.4 mL)
was added NaH (0.45 mmol) at 0 °C. After being stirred for 30 min, BnBr
1
-(2-Methoxyphenyl)-2-(quinolin-2-yl)ethane-1,2-dione (5): 3qa (0.3
mmol), PCC (0.9 mmol), CH Cl (2.0 mL) were added to a 25 mL tube
2
2
(0.9 mmol) was added at 0°C under N
at room temperature for 12 h under N
O (10 mL) and extracted with EtOAc (3 × 10 mL). The combined
organic layers were dried over anhydrous MgSO and the solvent was
2
. The reaction mixture was stirred
with magnetic stirrer bar. The reaction mixture was stirred at room
temperature for 4 h. After the reaction was finished (monitored by TLC),
the mixture was cooled to room temperature, quenched with solution of
2
and quenched with solution of
H
2
4
NaHCO
3
(10 mL) and extracted with EtOAc (3 × 10 mL). The combined
and the solvent was
removed under vacuum. The crude product was purified by column
organic layers were dried over anhydrous MgSO
removed under vacuum. The crude product was purified by column
chromatography (EtOAc/hexanes) on silica gel to give product 8 as a
4
chromatography (EtOAc/hexanes) on silica gel to give product 10 as a
1
yellow oil (101 mg, 91 %). H NMR (400 MHz, CDCl
3
) δ 8.17 (d, J = 8.4
Hz, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.80 (d, J = 8.1 Hz, 1H), 7.75 – 7.64 (m,
2H), 7.52 (t, J = 7.5 Hz, 1H), 7.33 (t, J = 8.7 Hz, 2H), 7.20 – 7.06 (m, 6H),
6.89 (d, J = 8.2 Hz, 1H), 5.47 – 5.44 (m, 1H), 4.54 (d, J = 12.1 Hz, 1H),
o
1
white solid (64 mg, 73%); m.p.=124-125 C. H NMR (400 MHz, CDCl
.35 (d, J = 8.4 Hz, 1H), 8.23 (d, J = 8.5 Hz, 1H), 8.19 (dd, J = 7.8, 1.8
Hz, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.90 – 7.85 (m, 1H), 7.72 –7.68 (m, 1H),
3
) δ
8
13
4.30 (d, J = 12.0 Hz, 1H), 3.75 (s, 3H), 3.49 – 3.42 (m, 2H). C NMR
(100 MHz, CDCl ) δ 159.8, 156.8, 147.7, 138.4, 135.4, 129.9, 128.9,
7
3
1
1
1
.65 – 7.56 (m, 2H), 7.19 – 7.14 (m, 1H), 6.88 (d, J = 8.3 Hz, 1H), 3.44 (s,
H). C NMR (100 MHz, CDCl
37.2, 136.3, 130.9, 130.0, 130.0, 129.5, 128.9, 127.6, 123.9, 121.5,
18.2, 112.4, 55.7. IR (KBr): 3062, 2923,1703, 1661, 1594, 1475, 1247,
3
015, 752 cm . HRMS (ESI) m/z: calcd for C18H14NO [M+H] , 292.0968;
3
13
3
) δ 195.3, 193.4, 160.5, 151.4, 147.3,
128.9, 128.3, 127.8, 127.3, 127.2, 127.0, 126.7, 126.7, 125.5, 122.4,
120.7, 110.1, 75.1, 70.6, 55.1, 46.5. IR (KBr): 3053, 2926, 1597, 1495,
-
1
+
1240, 749, 694 cm . HRMS (ESI) m/z: calcd for C25
2
H24NO [M+H] ,
-
1
+
370.1802; found, 370.1792.
found, 292.0956.
E)-2-(2-Methoxystyryl)quinoline (6): 3qa (0.3 mmol), ln(OTf)
(
3
(30
Acknowledgments
mol %l), toluene (1.5 mL) were added to a 25 mL tube with magnetic
o
stirrer bar. The reaction mixture was stirred at 100 C for 10 h. After the
reaction was finished (monitored by TLC), the mixture was cooled to
We are grateful to the National Natural Science Foundation of
China (21702096), Natural Science Foundation of Guangdong
Province (2017A030310546), and the High-level Talent
Introduction Foundation of Southern Medical University
room temperature, quenched with solution of NaHCO
extracted with EtOAc (3 × 10 mL). The combined organic layers were
dried over anhydrous MgSO and the solvent was removed under
vacuum. The crude product was purified by column chromatography
EtOAc/hexanes) on silica gel to give product 9 as a yellow oil (72 mg,
3
(10 mL) and
4
(
C1033520) for financial support.
(
1
9
4
6
1
1
1
2 %) . H NMR (400 MHz, CDCl
3
) δ 8.12 – 8.00 (m, 3H), 7.77 – 7.66 (m,
H), 7.51 – 7.44 (m, 2H), 7.32– 7.28 (m, 1H), 7.01 (t, J = 7.5 Hz, 1H),
.92 (d, J = 8.3 Hz, 1H), 3.91 (s, 3H). C NMR (100 MHz, CDCl ) δ
3
57.4, 156.6, 148.0, 136.2, 129.7, 129.6, 129.4, 129.3, 129.0, 127.4,
27.2, 126.0, 125.4, 120.8, 118.9, 110.9, 55.5. IR (KBr): 3055, 2921,
595, 1495, 1244, 1027, 750 cm . HRMS (ESI) m/z: calcd for C18H16NO
Keywords: Acid-catalyzed • Quinoline derivatives •2-
Methylquinolines • Synergistic organocatalysis • Aqueous
medium
13
-
1
+
[M+H] , 262.1226; found, 262.1219.
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European Journal of Organic Chemistry
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Entry for the Table of Contents (Please choose one layout)
FULL PAPER
Organocatalysis
‡
‡
Yinrong Wu, Xianchen Lu, Hang
Wang, En Liang, Yingying Yuan,
Qiaorun Zhao, Zhongzhi Zhu,* Jiaping
Huang and Xiaodong Tang*
Page No. – Page No.
A HOAc-catalyzed aryloxy/alkoxy-assisted nucleophilic addition of 2-
Acid-Catalyzed Synthesis of
Quinoline Derivatives from 2-
Methylquinolines and 2-
Aryloxy/Alkoxybenzaldehyde in
Aqueous Medium
methylquinolines to aldehydes in water has been described. The reaction provides
an efficient and direct access to hydroxyquinolines in moderate to good yields. In
addition, a HOAc/1,3-DMBBA (1,3-dimethylbarbituric acid) synergistic
organocatalysis system were also developed for the synthesis of alkenylquinolines.
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