Chemoselective acylation of 2-amino-8-quinolinol in the generation of C2-amides or C8-esters

Article abstract of DOI:10.1039/c7ra05287a

Two different ways to carry out the chemoselective acylation of 2-amino-8-quinolinol with unique features to generate C2-amides or C8-esters were developed. The coupling reaction with a variety of carboxylic acids using EDCI and DMAP provided C8-ester derivatives, whereas N-heteroaromatic acids were not introduced on the C8-hydroxy group, but rather on the C2-amino group under the same conditions. To obtain C2-amides selectively, the anionic nucleophile from 2-amino-8-quinolinol was treated with less reactive acyl imidazolides or esters.

Full text of DOI:10.1039/c7ra05287a

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Chemoselective acylation of 2-amino-8-quinolinol
in the generation of C2-amides or C8-esters†
Cite this: RSC Adv., 2017, 7, 41955
Yongseok Park,‡a Xiang Fei,‡a Yue Yuan,a Sanha Lee,a Joonseong Hur,b
c
a
Sung Jean Park,a Jae-Kyung Jung
and Seung-Yong Seo
*
Two different ways to carry out the chemoselective acylation of 2-amino-8-quinolinol with unique features
to generate C2-amides or C8-esters were developed. The coupling reaction with a variety of carboxylic
acids using EDCI and DMAP provided C8-ester derivatives, whereas N-heteroaromatic acids were not
introduced on the C8-hydroxy group, but rather on the C2-amino group under the same conditions. To
obtain C2-amides selectively, the anionic nucleophile from 2-amino-8-quinolinol was treated with less
reactive acyl imidazolides or esters.
Received 10th May 2017
Accepted 23rd August 2017
DOI: 10.1039/c7ra05287a
rsc.li/rsc-advances
exhibits various biological activities such as anthelmintic,
antiprotozoal, anti-depressant, some effectiveness in the treat-
ment of Alzheimer's disease.4 Toward that end, we paid atten-
tion to unique 2-amino-8-quinolinol (1), which contains
important structural components of 8-HQ and 2-AQ.5 The
synthesis of its derivatives may prove to be useful, owing to the
utility of the parent compounds; however, the previous works
for O- and N-acylation of 1 have hardly been reported to date.6
We sought the synthesis of its derivatives, especially the ester-
ication on C8 and the amidation on C2 (Fig. 1).
Recently, we reported an acyl derivative of 2-amino-8-
quinolinol (1) called SG-HQ2. This compound is an anti-
allergic inammatory agent.7 Unfortunately, NMR spectro-
scopic studies cast doubt on the originally proposed structure,
which was regarded as the amide form. To prove that the
ester form was obtained as the major product of the EDCI-
mediated coupling reaction of 2-amino-8-quinolinol (1) and
3,4,5-tris(benzyloxy)benzoic acid, we reexamined the acylation
and analyzed the structure of SG-HQ1 via NMR spectroscopy
and X-ray crystallography.8 SG-HQ2 from the catalytic hydroge-
nation of SG-HG1 was determined to be the C8-ester instead of
the amide as reported previously (Scheme 1).
Introduction
Ester and amide functionalities are important structural
components that serve as key motifs in a variety of bioactive
natural products and pharmaceuticals. Amide and ester for-
mation are fundamental reactions in chemical synthesis.1
Typically, carbodiimides such as dicyclohexylcarbodiimide
(DCC) and 1-ethyl-3-(30-dimethylaminopropyl)-carbodiimide
(EDCI) are applied as coupling reagents for esterication and
amidation reactions. To increase the overall rate of the cou-
pling reaction, DMAP (4-dimethylaminopyridine), 1-hydroxy-
1H-benzotriazole (HOBt) and 1-hydroxy-7-azabenzotriazole
(HOAt) are commonly used for carbodiimide-mediated reac-
tions in either stoichiometric or catalytic fashions. Mean-
while, 1,10-carbonyl diimidazole (CDI) is used because of the en-
hanced stability relative to that of acid halides and viability in
large-scale syntheses.2 In addition, numerous other methods
have been developed for ester and amide bond formation.1c
Quinolines are valuable synthons and precursors in
synthetic organic chemistry, as they comprise important
heterocyclic pharmacophores with a broad spectrum of bio-
logical and me-dicinal activities. In particular, 8-hydrox-
yquinoline (8-HQ) is a well-known metal ion chelator and
represents an excellent scaffold with a wide spectrum of phar-
macological applica-tions.3 Similarly, 2-aminoquinoline (2-AQ)
Results and discussion
Encouraged by the chemoselective O-acylation of 2-amino-8-
quinolinol, our synthetic investigations regarding C2-amide
derivatives began with initial studies of the 2 step synthesis
aCollege of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon
University, Incheon 21936, South Korea
bCollege of Pharmacy, Seoul National University, Seoul 08826, South Korea
cCollege of Pharmacy, Chungbuk National University, Cheongju, Chungbuk 28644,
South Korea
† Electronic supplementary information (ESI) available: Experimental procedures,
spectral and analytical data (PDF) and X-ray crystallographic analyses of SG-HQ1
(3f), 3b, and 4b (CIF). CCDC 1548392–1548394. For ESI and crystallographic data
in CIF or other electronic format see DOI: 10.1039/c7ra05287a
‡ Both authors contributed equally to this manuscript.
Fig. 1 2-Amino-8-quinolinol (1) and its acyl derivatives.
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DMAP as an additive increased the chemical yield and ester
selectivity (entry 1 and 7). However, when HOBt was employed,
the formation of diacyl derivative 5a increased with that of
C8-ester (entry 3–5). Though the use of HOAt provided the C2-
ester selectively, the isolated yield of 3a was not satisfactory
(entry 6). Uranium (HATU) and phosphonium (PyBop) salts did
not exhibit signicant effects (entry 8 and 9). The use of
4-methoxybenzoyl chloride with iPr2NEt gave the C8-ester as the
major product (entry 10). The yield decreased slightly when
pyridine was used as a solvent (entry 11). Finally, we chose CDI
for the amidation through the acyl imidazolide, leading to the
formation of C2-amide 4a although the C8-ester formed as the
major product. Higher temperature increased the formation of
C2-amide slightly (entry 12–14). C2-amide 4a could be obtained
in 75% yield with the ratio of 5 : 88 : 7, when the anionic
nucleophile by the treatment of 2-amino-8-quinolinol with NaH
reacted with the acyl imidazolide derived from 4-methox-
ybenzoic acid and CDI (entry 15).
The optimized acylation conditions were further investigated
using a cheap and readily available ester instead of acyl imi-
dazolide 6 with other strong bases (Table 2).10 Methyl 4-
methoxybenzoate 7 was used as an acyl donor. Even though the
use of the methyl ester provided a lower yield than acyl imida-
zolide 6, the acylation resulted in the selective formation of
C2-amide. When NaH and n-BuLi were used to generate the
anionic intermediate of 2-amino-8-quinolinol, the excellent
selectivity was observed (entries 2 and 3). The use of iPrMgCl as
a base resulted in a signicant loss of reactivity and selectivity
(entry 4). The formation of C2-amide 4a was improved as the
amount of t-BuOK was increased (entry 5–8). The anionic
nucleophile of 2-amino-8-quinolinol could mostly be converted
into C2-amide rather than C8-ester.
Scheme
1 Synthesis of SG-HQ1 and SG-HQ2 and their revised
structures.8
comprised of the diacylation with excess of aromatic acid (up to
5 equiv.) and the hydrolysis of the ester moiety (Scheme 2). C2-
amides of various aromatic acids were prepared, and the
structures of 3b and 4b were conrmed by X-ray crystallog-
raphy.8 Interestingly, the acylation with heteroaromatic acids
such as 2-picolinic acid and pyrazinecarboxylic acid afforded
only the C2-amides (4h and 4i), excluding C8-ester and diacyl
compounds, albeit in low yield. Thus, the selective and efficient
introduction of various carboxylic acids on 2-amino-8-
quinolinol remains a challenge,9 although some C2 and
C8-acyl derivatives were prepared successfully. Inspired by the
unique characteristics of 2-amino-8-quinolinol, herein we
present the optimization of the chemoselective O- or
N-acylation.
To investigate possible synthetic routes towards C2-amide
and C8-ester derivatives of 2-amino-8-quinolinol, we rst
examined various acylation conditions with 4-methoxybenzoic
acid (Table 1). THF was selected as the most favorable solvent in
terms of solubility and purication. The use of carbodiimides
provided the C8-ester 3a preferentially as the major product.
Additive effect on reactivity and selectivity was evaluated in
order to reveal the role of acyl imidazolide in C8-acylation. Some
amines (such as pyridine, DMAP, and HOBt) and their HCl salts
were treated in the reaction of 1 with the isolated acyl imida-
zolide 6 (Table 3). Without additives, C2-amide (4a) was ob-
tained even though the reaction yield and ratio was slightly
different with CDI-mediated acylation. However, the use of
pyridine and DMAP at reux provided C8-ester (3a) reversely.
The use of their HCl salt (Pyr$HCl and DMAP$HCl) and HOBt
provided selectively the C8-ester in good yield even at room
temperature.
A variety of carboxylic acids were introduced on 2-amino-8-
quinolinol under the optimized acylation conditions. Either
condition A (EDCI, iPr2NEt and catalytic DMAP) or condition B
(PyBop and iPr2NEt) was used for the synthesis of the C8-esters
(Table 4). Various substituted-benzoic acids and furoic acid
(i.e. 3a–3f, 3j and 3k) were introduced on the C8 position in
good yields, regardless of electron-withdrawing and donating
groups. However, N-heteroaromatic acids were not incorporated
on the phenol group in the C8 position; C2-amides (4h–4i, 4l–
4m) were isolated even in low yields instead. Interestingly, Boc-
leucinyl C8-ester (3n) seems to be unstable during ash column
chromatography like heteroaromatic acid, however Boc-valinyl
C8-ester (3o) was obtained in moderate yield.
Scheme 2 Initial synthesis of C8-ester and C2-amide derivatives of 2-
amino-8-quinolinol. Aromatic acids including 4-methoxybenzoic (a),
4-chlorobenzoic (b), 4-(trifluoromethyl)benzoic (c), 4-tert-butylben-
zoic (d), 3-methoxybenzoic (e), 3,4,5-tris(benzyloxy)benzoic (f), 2-
furoic (g), picolinic (h), and pyrazinecarboxylic (i) acids.
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Table 1 Optimization of acylation conditionsa
% yieldb
Entry
Activator (equiv.)
Base
Time (h)
3a
4a
Ratioc (3a : 4a : 5a)
1
2
DCC (1.3), DMAP (0.5)
EDCI (1.3)
24
24
24
24
24
24
3
24
4
4
24
24
24
24
3
54
21
60
65
58
35
92
65
50
82
65
30
40
36
4
0
0
0
4
1
0
0
0
1
1
0
9
14
19
75
>99 : 0 : <1
>99 : 0 : <1
67 : 1 : 32
73 : 5 : 22
79 : 1 : 20
93 : 0 : 7
iPr2NEt
iPr2NEt
iPr2NEt
Et3N
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
Et3N
3
EDCI (1.3), HOBt (0.5)
EDCI (1.3), HOBt (0.5)
EDCI (1.3), HOBt (0.5)
EDCI (1.3), HOAt (0.5)
EDCI (1.3), DMAP (0.5)
HATU (1.3)
4d
5
6
7
8
9
99 : 0 : 1
83 : 0 : 17
58 : 1 : 41
86 : 1 : 13
81 : 0 : 19
70 : 22 : 8
56 : 19 : 24
44 : 23 : 33
5 : 88 : 7
PyBOP (1.3)
10e
11e
12
13d
14d
15f
Pyridine
CDI (1.3)
CDI (1.3)
CDI (1.0)
CDI (1.3)
NaH
a
b
c
The reactions were carried out three times. Isolated yield of 3a and 4a aer column chromatography. Ratio of 3a, 4a and 5a determined by
d
e
f
HPLC analysis. At reux. 4-Methoxybenzoyl chloride was used. Reaction conditions: a THF solution of CDI and 4-methoxybenzoic acid was
added to 2-amino-8-quinolinol and NaH (2 equiv.) in THF.
Table 2 The amidation of 2-amino-8-quinolinol with acyl imidazole Table 3 The effect on additives in the reaction of 2-amino-8-qui-
and ester under anionic conditions
nolinol with acyl imidazole
%
yieldb
Entry Acyl donor Base (equiv.)
Time (h) % yielda Ratiob
Entry Additive (equiv.) Temp (ꢀC) 3a 4a Ratioc (3a : 4a : 5a)
1
2
3
4
5
6
7
8
6
7
7
7
7
7
7
7
NaH (2.0)
NaH (2.0)
n-BuLi (2.0)
4
24
4
75
25
56
8
11
63
72
85
5 : 88 : 7
2 : 98 : 0
0 : 99 : 1
0 : 86 : 14
4 : 93 : 3
3 : 96 : 0
1 : 93 : 7
1 : 96 : 3
1d,e
2d
3d
4
—
65
65
65
rt
9
15 15 : 25 : 60
Pyridine (1.5)
DMAP (1.5)
HOBt (1.5)
Pyr$HCl (1.5)
67
63
56
78
75
0
0
0
0
0
80 : 0 : 20
73 : 0 : 27
80 : 0 : 20
87 : 0 : 13
87 : 0 : 13
iPrMgCl (2.0) 24
t-BuOK (1.0)
t-BuOK (2.0)
t-BuOK (2.5)
t-BuOK (3.0)
24
2
1
5
rt
6
DMAP$HCl (1.5) rt
0.5
a
a
b
Reaction conditions: 2-amino-8-quinolinol (1 equiv.), acyl imidazolide
(1.2 equiv.), an additive (1.5 equiv.), THF (4 mL), at room temperature.
Isolated yield. Ratio determined by HPLC analysis. At reux.
Isolated yield of amide 3a. Ratio (3a : 4a : 5a) determined by HPLC
analysis.
b
e
c
d
Added iPr2NEt (3 equiv.).
Next, we turned our attention to the amidation of 2-amino-8-
quinolinol on the C2 position. The CDI-mediated amidation of separate. With the optimized reaction conditions in hand, the
some aromatic acids with electron-withdrawing substituents substrate scope was examined (condition D, Table 5). 4-
provided C2-amides as the major product in contrast to Methoxybenzoyl derivatives (2a) was obtained in 75% yield,
carbodiimide-mediated acylation (condition C, Table 5). whereas the isolated yields of other substituted benzoic acids
Nevertheless, this general amidation was accompanied by the and heteroaromatic acids were improved up to 99% (4a vs. 4b–
formation of the C8-ester species, which was difficult to 4m). Interestingly amides with N-protected amino acids (4n and
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Table 4 Scope of C8-ester formationa,b
Table 5 Scope of C2-amide formationa,b
a
Reaction conditions: 1 (0.2 mmol), carboxylic acid (0.4 mmol), EDCI
a
Reaction conditions: a mixture of the carboxylic acid (1.2 equiv.) and
CDI (1.3 equiv.) was added to a THF (4 mL) solution of 1 (0.20 mmol)
(2.5 equiv.), DMAP (10 mol%), iPr2NEt (3 equiv.), THF (1 mL).
Isolated yield by ash column chromatography. Not obtained C8-
ester; isolated yield of C2-amide in parenthesis.
b
c
b
and NaH (2 equiv.) at room temperature. Isolated yield from ash
c
column chromatography. Isolated yield based on recovered starting
material in parenthesis.
4o) were easily prepared from the corresponding acyl
imidazolides.
and 4k) in 40% and 82% yields, respectively. The observed
conversion from the C8-ester to the C2-amide revealed that the
C2-amide was the thermodynamically stable product. The
conversion of 3k to 4k was superior to that of 3a, because of the
electronic effect on substituents of benzene ring. This result is
relevant to the lack of formation of C8-esters with N-hetero-
aromatic carbonyls (3h–3n) under most of conditions, as shown
in Scheme 3. In order to determine the origin of the unique
reactivity of 2-amino-8-quinolinol, 8-hydroxyquinoline (8) and
2-aminoquinoline (9) reacted with 4-methoxybenzoic acid
under various coupling conditions. The yields with EDCI,
PyBop, HBTU, and CDI were not satisfactory, but the acylation
was successful with using the reactive acid chloride in good
yields (up to 92%). As the weak reactivity of 8 and 9, it is
considered to have a benecial effect between the 2-amino and
8-hydroxy moieties for the introduction of an acyl group to 1.
To investigate the acylation pattern of 1, we monitored the
progress of C2-amide and C8-ester formation via CDI-mediated
acylation by HPLC. Ester 3a formed faster than amide 4a (0–6 h).
Aer 24 h, 4a was the major component, while starting material
1, 3a, and 5a were formed in similar amounts (almost 20%,
Table 6).8
By using EDCI-mediated acylation, the bulky aliphatic acyl
moieties such as piperidinylcarboxy, isovaleroyl, pivaloyl and 1-
adamantylcarbonyl were introduced on the C8-hydroxy group
successfully (3p–3s) as shown in Scheme 3. Similarly, sulfonyl
chloride, benzyl chloroformate and Boc2O were used to prepare
the sulfonate and carbonate derivatives (3t–3v) on the C8-
position in good yield, respectively. Meanwhile, the C2-amides
with bulky aliphatic amides bearing piperidinylcarboxy, iso-
valeroyl, pivaloyl and 1-adamantylcarbonyl (4p–4s), were easily
prepared from the corresponding acyl imidazolides. Finally,
a similar method was used to prepare two carbamates with Cbz
and Boc on C2 position, in spite of the unsatisfactory result
obtained with p-toluenesulfonamide (4t vs. 4u and 4v).
Additive effects besides imidazole are shown in Table 3 to
shed light on the mechanism of the chemoselective synthesis of
C8-ester and C2-amide derivatives. Thus, representative amines
(such as pyridine, DMAP, and HOBt) and their HCl salts were
treated with the imidazolide 6 to afford the C8-ester (Scheme 4).
With reactive acyl donors, C8-ester was regarded as the kinetic
product. On the contrary, two C8-esters (3a and 3k) were
reuxed with imidazole to afford the corresponding amides (4a
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Table 6 The representative time-course data (HPLC) for the forma-
tion of C8-ester and C2-amide under CDI-mediated conditiona
Scheme
3 The introduction of aliphaticacyl, sulfonyl and alkox-
ycarbonyl groups. aReaction conditions: 1 (0.2 mmol), carboxylic acid
(0.4 mmol), EDCI (2.5 equiv.), DMAP (10 mol%), iPr2NEt (3 equiv.), THF
(1 mL). bReaction conditions: a mixture of the carboxylic acid (1.2
equiv.) and CDI (1.3 equiv.) was added to a THF (4 mL) solution of 1
(0.20 mmol) and NaH (2 equiv.). cIsolated yield by flash column
chromatography. dp-toluenesulfonyl chloride, benzyl chloroformate
and Boc2O were used for 3t, 3u, and 3v respectively. eIsolated yield
based on recovered starting material in parenthesis. fp-Toluene-
sulfonyl chloride, benzyl chloroformate and Boc2O were used with
imidazole for 4t, 4u, and 4v respectively, but 4t was not isolated.
Time (h)
1 (mmol)
3a (mmol)
4a (mmol)
5a (mmol)
0
1
3
6
12
24
0.3000
0.2780
0.2096
0.1666
0.0753
0.0681
0
0
0
0.0201
0.0593
0.0697
0.0628
0.0656
0.0014
0.0252
0.0512
0.1201
0.1087
0.0005
0.0060
0.0125
0.0418
0.0576
a
Reaction conditions: a THF (4 mL) solution of 2-amino-8-quinolinol (1
equiv.), p-methoxybenzoic acid (1 equiv.), and CDI (1.3 equiv.) was
stirred at reux.
Scheme 5 Proposed reaction pathways.
Scheme 4 Mechanistic investigation.
second anion at C2 might attack acyl donors such as acyl imi-
dazolides and esters. As with the unstable C8-ester (i.e. 3k)
could be converted into the C2-amide by imidazole, the reac-
tivity of the amino at C2 with acyl imidazolides under neutral
conditions remains to be elucidated.
Based on the above mechanistic investigation, a proposed
reaction pathway is outlined in Scheme 5. Notably, Joussef et al.
reported the chemoselectivity O-sulfonylation at C8.11 For the
C8-ester formation, the nitrogen nucleophile at N1 induced
from the lone pair of the amino at C2 attacks acyl donors such
as acid chlorides preferentially; this step is followed by an intra-
or intermolecular acyl transfer to the neighboring hydroxy at
C8.12 Meanwhile, the formation of C2-amides involves the
anions of 1, generated by strong bases such as NaH. We spec-
ulated that a sodium ion which interacts with the anion at C8
might coordinate to the nitrogen atom at N1, whereas the
Conclusions
In conclusion, we developed chemoselective acylation of 2-
amino-8-quinolinol on amino group at C2 and hydroxy group at
C8. The coupling reaction with a variety of carboxylic acids
using EDCI and DMAP provided C8-ester derivatives in excellent
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yield. When the dianion of 2-amino-8-quinolinol reacts with Aer stirring for 1 h under N2 atmosphere, 2-amino-8-
less reactive acylimidazoles and esters, the corresponding C2- quinolinol (30 mg, 0.19 mmol) was added to the reaction
amides and carbamate derivatives could be prepared as the mixture. Aer stirring for 24 h at reux, the mixture was diluted
major product. Biological evaluations of the C2-amide and C8- with tetrahydrofuran, washed by NH4Cl, saturated NaHCO3,
ester derivatives of 2-amino-8-quinolinol are underway in our and brine, dried by MgSO4, ltered, and concentrated. The
laboratory and will be reported in due course.
residue was puried by ash column chromatography to the
desired product.
Experimental
General procedure of condition D (Table 5) for N-acylation at
All the starting materials, solvents and reagents were obtained
from commercial suppliers and were used without further
purication. Flash column chromatography was performed
using silica gel 60 (230–400 mesh, Merck) with the indicated
solvents. Thin-layer chromatography was performed using
0.25 mm silica gel plates (Merck). 1H and 13C NMR spectra were
recorded on a Bruker 600 MHz spectrometer as solutions in
deuterated CDCl3, methanol-d4 or DMSO-d6. 1H NMR data were
reported in the order of chemical shi, multiplicity (s, singlet; d,
doublet; t, triplet; m, multiplet and/or multiple resonances),
number of protons, and coupling constant (J) in hertz (Hz).
High-resolution mass spectra (HRMS) were recorded on a JEOL
JMS-700 (FAB and EI) and an Agilent 6530 Q-TOF LC/MS/MS
system (ESI). For conversion measurements, the samples
prepared for the HPLC were analyzed at 256 nm using an Agi-
lent 1260 HPLC system equipped with a 6 mm ꢁ 50 mm Sunre
5m C18 column, in which the mobile phase was a gradient from
water to acetonitrile for 30 min.
C2
To a solution of carboxylic acid (1.2 equiv.) in anhydrous
tetrahydrofuran (4 mL), 1,10-carbonyldiimidazole (1.3 equiv.)
was added under N2 atmosphere at ambient temperature. Aer
stirred for 1 h. The mixture was diluted with dichloromethane,
extracted by brine and dichloromethane, dried by MgSO4,
ltered, and concentrated to obtain the acyl imidazolide inter-
mediate. To a solution of 2-amino-8-quinolinol (30 mg,
0.19 mmol) and NaH (2.0 equiv.) in anhydrous tetrahydrofuran
(4 mL) was added the acyl imidazolide intermediate under N2
atmosphere with an ice bath. Aer stirring for 2 h at ambient
temperature, the reaction was quenched with sat. NH4Cl,
washed by dichloromethane and dried by MgSO4, ltered, and
concentrated. The residue was puried by silica gel column
chromatography to afford the desired product.
2-Aminoquinolin-8-yl 4-methoxybenzoate (3a). General
procedure A, white solid, yield: 92%, and purication by column
chromatography (ethyl acetate/n-hexane ¼ 1 : 3, Rf ¼ 0.1). H-
1
NMR (600 MHz, CDCl3) d 8.28 (dd, 2H, J ¼ 9.0 Hz), 7.86 (d,
1H, J ¼ 9.0 Hz), 7.53 (dd, 1H, J ¼ 8.4 and 1.2 Hz), 7.39 (dd, 1H, J
¼ 7.8 and 1.2 Hz), 7.26 (t, 1H, J ¼ 7.8 Hz), 6.99 (dd, 2H, J ¼ 9.0
and 1.8 Hz), 6.66 (d, 1H, J ¼ 9.0 Hz), 4.85 (bs, 2H), 3.89 (s, 3H);
13C-NMR (150 MHz, CDCl3) d 165.3, 163.7, 157.0, 145.3, 140.7,
137.9, 132.5, 125.4, 125.0, 122.2, 122.1, 121.9, 113.7, 112.3, 55.5;
HRMS (EI): m/z calcd for C17H14N2O3: 294.1004; found:
294.1006.
General procedure of condition A (Table 4) for O-acylation at
C8
To a solution of 2-amino-8-quinolinol (30 mg, 0.19 mmol) and
a carboxylic acid (1.2 equiv.) in anhydrous tetrahydrofuran (4
mL) were added EDCI (1.3 equiv.), DMAP (0.5 equiv.) and N,N-
diisopropylethylamine (3.0 equiv.) under N2 atmosphere with
an ice bath. Aer stirring for 3 h at ambient temperature, the
mixture was diluted with dichloromethane, washed by sat.
NH4Cl, sat. NaHCO3, and brine, dried by MgSO4, ltered, and
concentrated. The residue was puried by silica gel column
chromatography to afford the desired product.
N-(8-Hydroxyquinolin-2-yl)-4-methoxybenzamide
(4a).
General procedure D, white solid, yield: 75%, and purication
by column chromatography (dichloromethane/methanol ¼
20 : 1, Rf ¼ 0.25). 1H-NMR (600 MHz, DMSO-d6) d 10.68 (s, 1H),
9.29 (bs, 1H), 8.34 (d, 1H, J ¼ 9.0 Hz), 8.28 (d, 1H, J ¼ 9.0 Hz),
8.10 (d, 2H, J ¼ 8.4 Hz), 7.38 (d, 1H, J ¼ 7.8 Hz), 7.35 (t, 1H, J ¼
7.8 Hz), 7.10 (t 3H, J ¼ 7.5 Hz), 3.86 (s, 3H); 13C-NMR (150 MHz,
DMSO-d6) d 165.9, 162.8, 152.4, 150.7, 138.4, 137.2, 130.5, 127.0,
126.3, 126.2, 118.2, 116.4, 114.1, 111.9, 55.9; HRMS (EI): m/z
calcd for C17H14N2O3: 294.1004; found: 294.1003.
General procedure of condition B (Table 4) for O-acylation at
C8
To a solution of 2-amino-8-quinolinol (30 mg, 0.19 mmol) and
a carboxylic acid (1.2 equiv.) in anhydrous tetrahydrofuran were
added PyBop (1.3 equiv.) and N,N-diisopropylethylamine
(3.0 equiv.) under N2 atmosphere with an ice bath and stirring
for 4 h at ambient temperature. The reaction mixture was
diluted with dichloromethane, washed by NH4Cl, saturated
NaHCO3, and brine, dried by MgSO4, ltered, and concentrated.
The residue was puried by ash column chromatography to
the desired product.
Conflicts of interest
There are no conicts to declare.
Acknowledgements
General procedure of condition C (Table 5) for N-acylation at
C2
This work was supported by grants from the Basic Science
Research Program through the National Research Foundation
To a solution of a carboxylic acid (1.2 equiv.) in anhydrous of Korea (NRF) funded by the Ministry of Education
tetrahydrofuran was added 1,10-carbodiimidazole (1.3 equiv.). (2016R1D1A1A09917300), the Pioneer Research Center Program
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through the NRF funded by the Ministry of Science, ICT &
Future Planning (2014M3C1A3001556), and the Korea Health
Technology R&D Project through the Korea Health Industry
Development Institute (KHIDI), funded by the Ministry of
Health & Welfare (Grant number HI14C1135).
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561–567. 32% yield in 8-hydroxyquinoline-2-carbonyl
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8 See ESI†, for details.
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12 The pKa values of 2-amino-8-quinolinol (1) and its conjugate
acid are 10.5 and 6.7, respectively, calculated using the ACD/
Percepta 14 (ACD/Labs, Toronto, Canada). The chemical
shi perturbation of the ring proton of N1 positon of 1
depending on pHs was monitored by NMR. The result also
showed three plateaus exist around the calculated pKa
values, which supported that the pKa values should be
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†
correct. For details, see ESI.
This journal is © The Royal Society of Chemistry 2017
RSC Adv., 2017, 7, 41955–41961 | 41961