Copper-Catalyzed Chemoselective Cyclization Reaction of 2-Isocyanoacetophenone: Synthesis of 4-Hydroxyquinoline Compounds

Article abstract of DOI:10.1021/acs.joc.9b02903

A copper-catalyzed intramolecular cyclization reaction of 2-isocyanoacetophenone derivatives to afford 4-hydroxyquinolines chemoselectively is described. The transformation proceeds through enol tautomerism and a subsequent C-C bond formation. Compared to previous methods, this study provides a new protocol for the construction of 4-hydroxyquinoline compounds from functionalized isocyanides under mild conditions.

Full text of DOI:10.1021/acs.joc.9b02903

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Note
Copper-Catalyzed Chemoselective Cyclization Reaction of 2-
Isocyanoacetophenone: Synthesis of 4-Hydroxyquinoline Compounds
Qing Yuan, Weidong Rao, Shun-Yi Wang, and Shun-Jun Ji
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02903 • Publication Date (Web): 11 Dec 2019
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Copper-Catalyzed Chemoselective Cyclization Reaction of 2-
Isocyanoacetophenone: Synthesis of 4-Hydroxyquinoline Compounds
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Qing Yuan, Weidong Rao, Shun-Yi Wang,* and Shun-Jun Ji*
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical
Engineering and Materials Science & Collaborative Innovation Center of Suzhou Nano Science and
Technology, Soochow University, Suzhou, 215123, P. R. China; E-mail: shunyi@suda.edu.cn;
shunjun@suda.edu.cn
RECEIVED DATE
*CORRESPONDING AUTHOR FAX: 86-512-65880307.
O
OH
N
R1
R1
CuI
R2
R2
DBU, MeCN
RT
NC
20 examples
up to 86% yield
R1 = H, alkyl
R2 = H, CH3, CF3
Mild conditions
Easy handle
Chemoselective
C-C bond formation
Abstract:
A
copper-catalyzed intramolecular cyclization reaction of 2-
isocyanoacetophenone derivatives to afford 4-hydroxyquinolines chemoselectively is
described. The transformation proceeds through enol tautomerism and subsequently C-
C bond formation. Compared to previous methods, this study provides a new protocol
for the construction of 4-hydroxyquinoline compounds from functionalized isocyanides
under mild conditions.
socyanides are versatile building blocks and intermediates in chemical synthesis
I
with wide applications for their unique structures and reactivities.1a Besides the
well-known multicomponent Ugi1b,2 and Passerini3 reactions, isocyanides insertion and
cyclization reaction are of the most powerful strategies for the preparation of nitrogen-
containing heterocycles.4,5 In view of their high reaction activities and variabilities, the
application of isocyanides has drawn considerable attention. Notably, 2-
isocyanoacetophenone derivatives was easily available starting materials for the
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construction of various heterocyclic compounds in recent years.6-13 In 2009, Konishi
and co-workers reported a simple method for the synthesis of 4-alkylidene-4H-3,1-
benzoxazine derivatives via acid-catalyzed cyclization of 2-isocyanophenyl ketones in
the presence of vinyl ether.6 Later, cyclization reaction of 2-isocyanoacetophenone
derivatives with sulfur and Eschenmoser’s salt were well developed for the preparation
of corresponding nitrogen-containing heterocycles.7 In addition, Würthwein8 group
reported the intramolecular cycloaddition of 2-isocyanoacetophenone for the synthesis
of 4‐methylene‐4H‐benzo[d][1,3]oxazine (Scheme 1, eq. 1). Recently, silver-catalyzed
cyclization reaction of 2-isocyanoacetophenone derivatives with isocyanoacetamides
has been developed for the facile and efficient synthesis of quinolones by Xu group.9
As versatile building blocks, 2-isocyanoacetophenone derivatives have recently been
employed in the assembly of indole/furan-fused heterocycles,10 quinazolines11
(Scheme 1, eq. 2) and indolin-3-ol derivatives.12 Among these transformations,
isocyanides attacked by nucleophile is indispensable. However, for the most parts,
nucleophiles are heteroatom nucleophiles and carbon atom nucleophiles are not typical.
It was seldom achieved when heteroatom and carbon atom nucleophile coexist
simultaneously.13 It’s desirable to control the chemoselective cyclization of
isocyanides. As continuation of our interests in isocyanides reactions,14 herein, we
reported a copper-catalyzed cyclization reaction of 2-isocyanoacetophenone for the
synthesis of 4-hydroxyquinoline derivatives chemsoselectively under mild conditions.
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a) Würthwein's wrok
-alanine
O
O
(1)
(2)
N
NC
b) Xu's work
R1
R1
Ag2CO3
NH4OAc
N
O
N
NC
c) This work
R1
OH
N
R1
CuI
O
R2
R2
(3)
NC
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Scheme 1 The cyclization reaction of 2-isocyanoacetophenones
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Initially, we investigated the reaction of 2-isocyanoacetophenone 1a in 2 mL DMF
at room temperature catalyzed by CuI in the presence of KOH. To our delight, the
desired product quinolin-4-ol 2a was formed in 32% yield (Table 1, entry 1).
Encouraged by this promising result, we further tried the reactions by screening
different copper catalysts. Nevertheless, other copper catalysts could not increase the
yield of 2a (Table 1, entries 2-6). Then, diverse bases have been applied to the reaction
(Table 1, entries 7-12). When 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) was served
as the base, the yield of 2a could be increased to 46%. A series of other solvents such
as MeOH, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF) and acetonitrile were
also applied to the reactions and it was found that acetonitrile was the most suitable
solvent for this reaction, affording 2a in 57% yield (Table 1, entries 13-18). Thus, the
optimized conditions is following, 2a and DBU (1.2 equiv) catalyzed by CuI (10 mol%)
in MeCN at room temperature for 6 h.
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Table 1. Optimization of The Reaction Conditionsa
OH
Conditions
O
N
NC
Entry
Cat (mol%).
Base (equiv)
Solvent
Yieldb (%)
1
CuI (10)
CuBr (10)
CuCl (10)
Cu(OTf)2 (10)
CuO (10)
Cu(OAc)2 (10)
CuI (10)
KOH (1.2)
KOH (1.2)
KOH (1.2)
KOH (1.2)
KOH (1.2)
KOH (1.2)
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
DMA
CH3OH
DCM
THF
32
28
30
19
10
25
28
5
2
3
4
5
6
7
CsOH (1.2)
NaOH (1.2)
LDA (1.2)
DIPEA (1.2)
DABCO (1.2)
DBU (1.2)
DBU (1.2)
DBU (1.2)
DBU (1.2)
DBU (1.2)
DBU (1.2)
DBU (1.2)
8
CuI (10)
9
CuI (10)
13
37
35
46
44
39
21
48
52
57
10
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12
13
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18
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
MeCN
aReaction conditions: 1a (0.5 mmol)，base (0.6 mmol)，copper reagent (10 mol%) , solvent (2 mL).
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stirred at room temperature for 6 h under an air atmosphere. bIsolated yield.
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With the optimization conditions in hand, we next explored the scope of the
isocyanide substrates (Table 2). The reaction of 1-(2-isocyanophenyl)pentan-1-one 1b
afforded 3-propylquinolin-4-ol 2b in 63% yield. 1-(2-Isocyanophenyl)-3-
phenylpropan-1-one 1c underwent smoothly to give 3-benzylquinolin-4-ol 2c in 70%
yield. 1-(2-isocyanophenyl)-3-ortho substituted arylpropan-1-ones reacted also well to
furnish the corresponding 3-ortho substituted benzylquinolin-4-ols 2d-f in 72% to 76%
yields. The reactions of 3-(3-chlorophenyl)-1-(2-isocyanophenyl)propan-1-one 1g and
1-(2-isocyanophenyl)-3-(3-methoxyphenyl)propan-1-one 1h led to 2g and 2h in 77%
and 70% yields, respectively. Unfortunately, 1-(2-isocyanophenyl)-3-(3-
nitrophenyl)propan-1-one 2i bearing NO2 functional group failed to give the desired
product. It should be noted that the reactions of 3-(4-chlorophenyl)-1-(2-
isocyanophenyl)propan-1-one 1j and 3-(4-bromophenyl)-1-(2-isocyanophenyl)propan-
1-one 1k frunished 2j and 2k in 82% and 84% yields, respectively. Similarly, no desired
product was observed when di-NO2 functionalized 1l was applied to the reaction. To
our delights, some 1-(2-isocyanophenyl)-3-disubstituted arylpropan-1-ones reacted
well to give 2m and 2n in 72% and 86% yields, respectively. The isocyanides bearing
heterocycle or naphthalenyl functionalized groups such as 3-(furan-2-yl)-1-(2-
isocyanophenyl)propan-1-one 1o, 1-(2-isocyanophenyl)-3-(thiophen-2-yl)propan-1-
one 1p, 3-(naphthalen-2-ylmethyl)quinolin-4-ol 1q and 3-(naphthalen-1-
ylmethyl)quinolin-4-ol 1r could undergo smoothly to give 2o-2r in 66% to 72% yields.
The reaction of 1-(2-isocyano-5-methylphenyl)ethan-1-one 1a under the standard
conditions gave 2a in 82% yield. In order to test the application of the reaction, we
conducted the reaction of 1a in 5 mmol scale and the desired product 2s could be
isolated in 78% yield. Unfortunately, 1-(2-isocyano-5-(trifluoromethyl)phenyl)ethan-
1-one could not yield the desired 3-propylquinolin-4-ol for the strong electron-
withdrawing effect.
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Table 2. Substrate scope of 2-Isocyanoacetophenonea
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OH
N
O
CuI (10 mol%)
DBU (1.2 equiv)
R1
R1
R2
R2
MeCN (2 mL)
rt, 6h
NC
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1a-1t
2a-2t
OH
N
OH
N
, R1 = H, 57%
, R1 = n-Pr, 63%
2a
2b
OH
OH
N
OH
N
R3
N
R3
R3
, R3 = H, 70%
2c
2d
2e
, R3 = Cl, 77%
2g
2h
, R3 = CH3, 75%
,
R3 = Cl, 82%
2j
, R3 = OMe, 70%
R3 = NO2, trace
3
3
, R = Cl, 72%
2k
, R = Br, 84%
2i
,
2f
,
R3 = Br, 76%
OH
NO2
OH
OH
N
Cl
N O2N
N
OMe
2l
2m
2n
, 86%
, trace
, 72%
OH
OH
OH
O
S
N
N
N
2o
2p
2q
, 74%
, 66%
, 69%
OH
OH
OH
H3C
F3C
N
N
N
2r
2s
2t
, 72%
, 82%
, trace
Gram-Scale synthesis:
O
OH
N
CH3
CH3
CuI (10 mol%)
DBU (1.2 equiv)
MeCN (2 mL)
rt, 6h
NC
(5 mmol)
1s
2s
(78%, 0.62g)
aReaction conditions: 1a (0.5 mmol)，DBU (0.6 mmol)，copper reagent (10 mol%) , MeCN (2 mL).
stirred at room temperature for 6 h under an air atmosphere. bIsolated yield.
To understand the reaction mechanism, control experiments were performed
(Scheme 2). When the reaction was carried out in the absence of CuI, no desired product
was observed (Scheme 2, A). When the radical scavenger TEMPO was added to the
reaction system, 2a could also be obtained in the yield of 54% (Scheme 2, B). This
result indicates that the reaction might not involve radical process.
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O
OH
DBU (1.2 equiv)
A
MeCN, RT
NC
N
8
1a
2a
9
NR
10
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TMEPO (2 equiv)
CuI (10 mol%)
DBU (1.2 equiv)
O
OH
B
MeCN, RT
NC
N
1a
2a
54%
Scheme 2. Control experiments
Based on the above results and related literature precedents,15 we proposed a
reasonable mechanism for the reaction (Scheme 3). The in situ generated Copper(I) A
from CuI reacts with isocyanide B15a to give Complex C. De-protonation of C with the
assistance of DBU leads to copper complex D via keto-enol tautomerism.
Intramolecular cyclization of D affords E. Subsequently, the aromatization of E affords
4-hydroxyquinoline and releases the active copper complex A.
Cu(I)I
OH
O
Ln
Cu(I)Ln
N
N
C
2a
A
B
O
O
N
C
CuLn
N
CuLn
C
E
O
DBU
N
C
CuLn
D
Scheme 3. Proposed Mechanism
In summary, we have developed a copper-catalyzed cyclization reaction of 2-
isocyanoacetophenone derivatives for the construction of 4-hydroxyquinoline
compounds. Moreover, the reaction explored the chemistry of copper-mediated carbon
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atom nucleophile addition to isocyanides, which represents a valuable addition to
isocyanide chemistry.
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EXPERIMENTAL SECTION
1. General Information.
Unless otherwise noted, all commercially available compounds were used as provided without further
purification. Solvents for chromatography were analytical grade and used without further purification. Analytical
thin-layer chromatography (TLC) was performed on silica gel, visualized by irradiation with UV light. For column
chromatography, 200-300 mesh silica gel was used. 1H and 13C{1H} NMR were recorded on a BRUKER 400 MHz
spectrometer in (CD3)2SO. Chemical shifts (δ) were reported referenced to an internal tetramethylsilane standard or
the C2D6OS residual peak (δ 2.50) for 1H NMR. Chemical shifts of 13C{1H} NMR are reported relative to (CD3)2SO
(δ 39.52). Data are reported in the following order: chemical shift (δ) in ppm; multiplicities are indicated s (singlet),
bs (broad singlet), d (doublet), t (triplet), m (multiplet); coupling constants (J) are in Hertz (Hz). Melting points were
measured on an Electrothermal digital melting point apparatus and were uncorrected. IR spectra were recorded on a
BRUKER MODEL ALPHA spectrophotometer and are reported in terms of frequency of absorption (cm-1). HRMS
spectra were obtained by using BRUKER MICROTOF-Q III instrument with ESI source. The starting materials
were isolated by SepaBean machine Flash Chromatography, which purchased from Santai Technologies Inc.
2.Synthesis of 2-isocyanoacetophenone
Method A: To a 100 mL round-bottom flask were added 2-aminoecetophenone (1.2 mL, 1.0 equiv, 10 mmol),
benzaldehyde (1.1 mL, 1.1 equiv, 11 mmol), 10 % NaOH aqueous solution (40 mL), EtOH (10 mL). The reaction
mixture was stirred for another 12-24h at room temperature. After the reaction was completed, mixture was solid
recrystallized (EtOH) and reduced by H2（balloon） and Pd/C (Palladium 10% on activated carbon, 100mg) in
ethyl acetate to afford 1-(2-aminophenyl)-3-phenylpropan-1-one. Then according to the literature procedures12 by
the typical formylation and dehydration procedure to afford desired 2-isocyanoacetophenone.
Method B: To a 100 mL round-bottom flask were added 2-iodo-4-methylaniline (2.331 g, 1.0 equiv, 10 mmol),
Trimethylsilylacetylene (1.7 mL, 1.2 equiv, 12 mmol), PdCl2(PPh3)2 (0.140 g, 0.02 equiv, 0.2 mmol), CuI(0.076 g,
0.04 equiv, 0.4mmol), Et3N (4 mL, 3 equiv, 30 mmol), THF (10 mL). The reaction mixture was stirred for 12h at
room temperature under argon. After the reaction was completed, mixture was purified by flash chromatography on
silica gel to afford the 2-(trimethylsilyl)ethynyl)aniline. Potassium carbonate (1.659 g, 1.2 equiv, 12 mmol) and 2-
(trimethylsilyl)ethynyl)aniline (2.031 g, 1.0 equiv, 10mmol) were blended to stir for 12h at room temperature in
MeOH (15 mL), then saturated salt solution was added and mixture was extracted by ethyl acetate for three times to
afford 2-ethynylaniline. Concentrated hydrochloric acid (5 mL) and surfactant CTAB(hexadecyl trimethyl
ammonium bromide, 5.5 g, 1.5 equiv, 15 mmol) were mixtured with 2-ethynylaniline to stir at 80℃ for 12h in
distilled water to generate substituted 2-aminoecetophenone.Then according to the literature procedures12 by the
typical formylation and dehydration procedure to afford desired 2-isocyanoacetophenone
3.General procedure for the synthesis of compounds 2
To a stirring solution of 2-isocyanoacetophenone 1 (29 mg, 1.0 equiv, 0.2 mmol), copper iodide (3.8 mg, 0.1
equiv, 0.02 mmol), and DBU (36 μL, 1.2 equiv, 0.24 mmol). The mixture was pour into saturated salt solution and
extracted three times with ethyl acetate. The pure products were obtained after purification by column
chromatography on silica gel with petroleum ether/ethyl acetate (v:v = 1:1 − 3:1) as the eluent.
4-hydroxyquinoline (2a).White solid (89 mg, 57% yield); Mp (°C) 200.1 – 202.4; IR v (cm-1): 2775, 1501,
1472, 1200; 1H NMR (400 MHz, DMSO-d6) δ 11.80 (s, 1H), 8.11 (d, J = 9.2 Hz, 1H), 7.91 (d, J = 6.8 Hz, 1H), 7.64
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– 7.61 (m, 2H), 7.55 – 7.28 (m, 1H), 6.06 (d, J = 7.4 Hz, 1H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 177.4, 140.5,
139.9, 132.1, 126.3, 125.4, 123.5, 118.7, 109.2; HRMS (ESI+) calcd for C9H7NO [M + H]+: 145.0522, found
145.0519.
3-propylquinolin-4-ol (2b). White solid (75 mg, 63% yield); Mp (°C) 205.5 – 208.1; IR v (cm-1): 2906, 1551,
1474, 1206; 1H NMR (400 MHz, DMSO-d6) δ 11.60 (s, 1H), 8.10 (d, J = 6.6 Hz, 1H), 7.80 (d, J = 5.7 Hz, 1H), 7.59
– 7.57 (m, 1H), 7.49 (d, J = 7.3 Hz, 1H), 7.26 (t, J = 7.5 Hz, 1H), 2.43 – 2.37 (m, 2H), 1.57 – 1.49 (m, 2H), 0.89 (t,
J = 7.3 Hz, 3H); 13C{1H} (100 MHz, DMSO-d6) δ176.2, 139.6, 136.6, 131.0, 125.0, 124.5, 122.5, 120.6, 118.0, 29.5,
21.7, 13.8; HRMS (ESI+) calcd for C12H13NO [M + H]+: 187.0992, found 187.0990.
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3-benzylquionlin-4-ol (2c). White solid (80 mg, 75% yield); Mp (°C) 204.2 – 206.2; IR v (cm-1): 2891, 1549,
1477, 1203; 1H NMR (400 MHz, DMSO-d6) δ 11.69 (s, 1H), 8.11 (d, J = 7.8 Hz, 1H), 7.85 (s, 1H), 7.59 (d, J = 7.1
Hz, 1H), 7.52 (d, J = 8.3 Hz, 1H), 7.30 – 7.24 (m, 5H), 7.16 (d, J = 7.1 Hz, 1H), 3.77 (s, 2H); 13C{1H} (100 MHz,
DMSO-d6) δ 176.4, 141.9, 138.0, 131.7, 129.0, 128.6, 126.1, 125.6, 123.2, 118.6, 33.4; HRMS (ESI+) calcd for
C16H13NO [M + H]+: 235.0992, found 235.0995.
3-(2-methylbenzyl)quionlin-4-ol (2d). White solid (85 mg, 75% yield); Mp (°C) 205.5 – 207.1; IR v (cm-1):
2909, 1553, 1501, 1205; 1H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H), 8.15 (d, J = 8.1 Hz, 1H), 7.63 – 7.59 (m,
1H), 7.52 – 7.49 (m, 2H), 7.31 – 7.28 (m, 1H), 7.16 – 7.07 (m, 4H), 3.75 (s, 2H), 2.27 (s, 3H); 13C{1H} (100 MHz,
DMSO-d6) δ 176.0, 139.6, 138.6, 137.1, 135.9, 131.3, 129.8, 129.1, 125.9, 125.7, 125.1, 124.4, 122.8, 119.4, 118.1,
30.2, 19.2; HRMS (ESI+) calcd for C17H15NO [M + H]+: 249.1148, found 249.1150.
3-(2-chlorobenzyl)quionlin-4-ol (2e). White solid (100 mg, 72% yield); Mp (°C) 199.7 – 201.2; IR v (cm-1):
2773, 1554, 1499, 1207; 1H NMR (400 MHz, DMSO-d6) δ11.73 (s, 1H), 8.12 (d, J = 6.6 Hz, 1H), 7.87 – 7.70 (m,
1H), 7.61 (d, J = 8.6, 7.7 Hz, 1H), 7.53 (d, J = 8.5 Hz, 1H), 7.37 – 7.02 (m, 5H), 3.82 (d, J = 38.2 Hz, 2H); 13C{1H}
(100 MHz, DMSO-d6) δ 176.4, 159.8, 140.2, 138.1, 131.8, 131.4, 128.3, 127.9, 125.5, 125.1, 124.5, 123.3, 118.9,
118.6, 115.5, 115.3, 26.6; HRMS (ESI+) calcd for C16H12ClNO [M + H]+: 269.0602, found 269.0600.
3-(2-bromobenzyl)quionlin-4-ol (2f). White solid (82 mg, 75% yield); Mp (°C) 180.0 – 181.4; IR v (cm-1):
2816, 1549, 1472, 1208; 1H NMR (400 MHz, DMSO-d6) δ 11.71 (s, 1H), 8.10 (d, J = 9.6 Hz, 1H), 7.55 – 7.50 (m,
2H), 7.30 – 7.18 (m, 5H), 7.15 (d, J = 7.4 Hz, 1H), 3.81 (d, J = 34.8 Hz, 2H); 13C{1H} (100 MHz, DMSO-d6) δ
141.8, 140.1, 137.9, 131.7, 129.0, 128.5, 126.1, 125.5, 125.2, 123.2, 120.8, 118.6, 40.5, 33.4; HRMS (ESI+) calcd
for C16H12BrNO [M + H]+: 313.0097, found 313.0100.
3-(3-chlorobenzyl)quionlin-4-ol (2g). White solid (85 mg, 77% yield); Mp (°C) 185.0 – 186.9; IR v (cm-1):
2918, 1555, 1503, 1204; 1H NMR (400 MHz, DMSO-d6) δ 11.78 (s, 1H), 8.12 (d, J = 8.1 Hz, 1H), 7.99 (s, 1H), 7.63
– 7.54 (m, 1H), 7.51 (d, J = 8.2 Hz, 1H), 7.36 (s, 1H), 7.31 – 7.23(m, 4H), 3.78 (s, 2H); 13C{1H} (100 MHz, DMSO-
d6) δ 176.4, 144.6, 140.2, 138.3, 133.1, 131.8, 130.3, 128.7, 127.7, 126.1, 125.5, 125.2, 123.3, 120.1, 118.6, 33.3;
HRMS (ESI+) calcd for C16H12ClNO [M + H]+: 269.0602, found 269.0605.
3-(3-methoxybenzyl)quionlin-4-ol (2h). White solid (69 mg, 70% yield); Mp (°C) 210.0 – 211.8; IR v (cm-1):
2926, 1556, 1496, 1248; 1H NMR (400 MHz, DMSO-d6) δ 11.71 (s, 1H), 8.14 (d, J = 7.9 Hz, 1H), 7.85 (s, 1H), 7.6
(t, J = 7.2 Hz, 1H), 7.53 (d, J = 8.2 Hz, 1H), 7.3 (t, J = 7.4 Hz, 1H), 7.17 (t, J = 7.8 Hz, 1H), 6.87 (d, J = 8.3 Hz,
2H), 6.72 (d, J = 6.9 Hz, 1H), 3.75 (s, 2H), 3.42 (s, 3H);13C{1H} (100 MHz, DMSO-d6) δ 176.4, 159.6, 143.4, 140.1,
138.0, 131.7, 129.55, 125.6, 125.1, 123.2, 121.3, 120.8, 118.6, 114.9, 111.3, 55.3, 33.4; HRMS (ESI+) calcd for
C17H15NO2 [M + H]+: 265.1097, found 265.1097.
3-(4-chlorobenzyl)quionlin-4-ol (2j). White solid (110 mg, 82% yield); Mp (°C) 202.4 – 203.8; IR v (cm-1):
2786, 1548, 1474, 1204; 1H NMR (400 MHz, DMSO-d6) δ 11.71 (s, 1H), 8.13 (d, J = 8.1 Hz, 1H), 7.85 (s, 1H), 7.63
– 7.50 (m, 2H), 7.30 – 7.11 (m, 5H), 3.72 (s, 2H); 13C{1H} (100 MHz, DMSO-d6) δ176.4, 159.6, 143.4, 140.11,
138.0, 131.7, 129.6, 125.6, 125.2, 123.2, 121.3, 120.8, 118.6, 115.0, 111.3, 55.3, 33.4; HRMS (ESI+) calcd for
C16H12ClNO [M + H]+: 269.0602, found 269.0599.
3-(4-bromobenzyl)quionlin-4-ol (2k). White solid (78 mg, 84% yield); Mp (°C) 192.4 – 194.1; IR v (cm-1):
2893, 1553, 1504, 1206; 1H NMR (400 MHz, DMSO-d6) δ 11.71 (s, 1H), 8.13 (d, J = 8.1 Hz, 1H), 7.85 (s, 1H), 7.62
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– 7.58 (m, 1H), 7.50 (d, J = 8.1 Hz, 1H), 7.30 – 7.21 (m, 5H), 3.78 (s, 2H); 13C{1H} (100 MHz, DMSO-d6) δ176.4,
141.8, 140.1, 138.0, 131.7, 129.0, 128.6, 126.1, 125.6, 125.2, 123.2, 120.9, 118.6, 33.5; HRMS (ESI+) calcd for
C16H12BrNO [M + H]+: 313.0097, found 313.0095.
3-(2,6-dimethylbenzyl)quinolin-4-ol (2m).White solid (80 mg, 72% yield); Mp (°C) 210.3 – 212.5; IR v (cm-1):
2909, 1551, 1503, 1366; 1H NMR (400 MHz, DMSO-d6) δ 11.45 (s, 1H), 8.20 (d, J = 8.1 Hz, 1H), 7.64 (t, J = 7.6
Hz, 1H), 7.50 (d, J = 8.1 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.07 (s, 3H), 6.78 (s, 1H), 3.77 (s, 2H), 2.17 (s, 6H);
13C{1H} (100MHz, DMSO-d6) δ 176.7, 139.9, 137.1, 136.5, 135.0, 131.8, 128.5, 126.6, 125.5, 124.5, 123.3, 118.6,
27.2, 20.0; HRMS (ESI+) calcd for C18H17NO [M + H]+: 263.1305, found 263.1309.
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3-(2-chloro-5-methoxybenzyl)quionlin-4-ol (2n). White solid (105 mg, 86% yield); Mp (°C) 220.1 – 222.4; IR
v (cm-1): 2786, 1549, 1471, 1210; 1H NMR (400 MHz, DMSO-d6) δ 11.69 (s, 1H), 8.12 (d, J = 8.1 Hz, 1H), 7.85 (s,
1H), 7.60 (t, J = 6.9 Hz, 1H), 7.51 (d, J = 8.3 Hz, 1H), 7.32 – 7.25 (m, 1H), 7.15 (t, J = 7.7 Hz, 1H), 6.85 (s, 2H),
3.72 (d, J = 21.3 Hz, 5H); 13C{1H} (100 MHz, DMSO-d6) δ 175.9, 159.1, 143.0, 139.6, 137.5, 131.2, 125.1, 124.7,
122.7, 120.8, 120.3, 118.1, 114.5, 110.8, 54.9, 33.0; HRMS (ESI+) calcd for C17H14ClNO2 [M + H]+: 299.0708,
found 299.0710.
3-(furan-2-ylmethyl)quionlin-4-ol (2o). Flaxen solid (78 mg, 74% yield); Mp (°C) 175.3 – 176.9; IR v (cm-1):
2897, 1498, 1250; 1H NMR (400 MHz, DMSO-d6) δ 11.72 (s, 1H), 8.10 (d, J = 6.6 Hz, 1H), 7.79 (d, J = 6.0 Hz,
1H), 7.62 (t, J = 7.6 Hz, 1H), 7.52 (d, J = 8.2 Hz, 1H), 7.27 (m, 2H), 7.15 – 7.04 (m, 2H), 3.79 (s, 2H); 13C{1H} (100
MHz, DMSO) δ176.4, 162.2, 159.8, 140.2, 138.0, 131.8, 130.7, 130.6, 125.5, 125.2, 123.2, 120.8, 118.6, 115.2,
115.0, 32.7.; HRMS (ESI+) calcd for C14H11NO2 [M + H]+; 225.0784, found 225.0782.
3-(thiophen-2-ylmethyl)quionlin-4-ol (2p). White solid (99 mg, 66% yield); Mp (°C) 168.4 – 171.1; IR v (cm-
1): 2891, 1477, 1203; 1H NMR (400 MHz, DMSO-d6) δ 11.74 (s, 1H), 8.143 – 8.11 (m, 1H), 7.92 (s, 1H), 7.65 –
7.60 (m, 1H), 7.52 (d, J = 7.3 Hz, 1H), 7.31 – 7.23 (m, 2H), 6.90 (d, J = 3.7 Hz, 2H), 3.96 (s, 2H); 13C{1H} (100
MHz, DMSO) δ 175.6, 144.2, 139.7, 137.5, 131.4, 126.6, 125.1, 124.8, 123.7, 122.9, 119.9, 118.2, 27.2; HRMS
(ESI+) calcd for C14H1NOS [M + H]+: 242.0634, found 242.0631
3-(naphthalene-2-ylmethyl)quinolin-4-ol (2q). White solid (89 mg, 69% yield); Mp (°C) 190.3 – 195.1; IR v
(cm-1): 2898, 1553, 1494, 1202; 1H NMR (400 MHz, DMSO-d6) δ 11.83 (s, 1H), 8.21 (d, J = 7.8 Hz, 1H), 7.94 (s,
1H), 7.78 (d, J = 5.9 Hz, 4H), 7.60 – 7.27 (m, 6H), 3.99 (s, 2H); 13C{1H} (100 MHz, DMSO-d6) δ 176.6, 140.2,
139.5, 138.3, 133.6, 131.9, 128.0, 126.8, 126.3, 125.6, 125.3, 123.3, 120.8, 118.7, 33.7; HRMS (ESI+) calcd for
C20H15NO [M + H]+: 285.1148, found 285.1149.
3-(naphthalene-1-ylmethyl)quinolin-4-ol (2r). Flaxen solid (75 mg, 72% yield); Mp (°C) 195.6 – 197.0; IR v
(cm-1): 2912, 1520, 1471, 1196; 1H NMR (400 MHz, DMSO-d6) δ 11.62 (s, 1H), 8.21 (d, J = 7.4 Hz, 1H), 8.12 –
7.91 (m, 1H), 7.90 – 7.78 (m, 1H), 7.62 (d, J = 6.1 Hz, 1H), 7.53 (t, J = 7.0 Hz, 1H), 7.49 – 7.32 (m, 8H), 4.27 (s,
2H); 13C{1H} (100 MHz, DMSO-d6) δ 176.2, 140.0, 138.0, 137.3, 133.9, 132.0, 131.8, 128.9, 127.1, 126.5, 126.1,
125.7, 125.0, 124.6, 123.4, 120.1, 118.6, 30.0; HRMS (ESI+) calcd for C20H15NO [M + H]+: 285.1148, found
285.1140.
6-methylquinolin-4-ol (2s). Flaxen solid (110 mg, 83% yield); Mp (°C) 189.4 – 191.2; IR v (cm-1): 2768, 1511,
1499, 1216; 1H NMR (400 MHz, DMSO-d6) δ11.71 (s, 1H), 7.90 – 7.83 (m, 2H), 7.45 (s, 2H), 6.00 (d, J = 7.3 Hz,
1H), 2.39 (s, 3H); 13C{1H} (100 MHz, DMSO-d6) δ 177.2, 139.4, 138.6, 133.4, 132.8, 126.2, 124.6, 118.6, 108.8,
21.2; HRMS (ESI+) calcd for C10H9NO [M + H]+: 159.0679, found 159.0676.
ASSOCIATED CONTENT
Supporting Information Available.
This material is available free of charge via the Internet at http://pubs.acs.org.
The synthetic route of substrates and the copies of 1H and 13C spectra of products
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The syntheses and characterization of compounds 2h, 2k, 2m, and 2q were repeated
and checked by Jing-Hao Li in our group.
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Notes
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The authors declare no competing financial interest.
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ACKNOWLEDGMENT
We gratefully acknowledge the National Natural Science Foundation of China
(21971174, 21772137, 21542015 and 21672157), PAPD, the project of scientific and
technologic infrastructure of Suzhou (SZS201708), the Major Basic Research Project
of the Natural Science Foundation of the Jiangsu Higher Education Institutions
(No.16KJA150002), and Soochow University for financial support.
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