An Approach to Quinoline-Fused Imidazopyridines via CDC of Ethers with Imidazopyridines under Metal-Free Conditions

Article abstract of DOI:10.1021/acs.joc.9b02897

An NH₄I-catalyzed cross-dehydrogenative coupling (CDC) reaction of ethers with imidazopyridine cascade cyclization under transition-metal-free conditions has been developed. Cheap, commercially available ethers were used as both reagents and solvents, and green aqueous H₂O₂ was used as an oxidizing agent. A series of substituents on 2-(2-aminoaryl) imidazo[1,2-a]pyridines were tolerated, and the reaction gave quinoline-fused imidazopyridines in moderate to good yields.

Full text of DOI:10.1021/acs.joc.9b02897

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Note
An Approach to Quinoline-Fused Imidazopyridines via CDC
of Ethers with Imidazopyridines under Metal-Free Conditions
Guifang Lian, Jingyu Li, Ping Liu, and Peipei Sun
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02897 • Publication Date (Web): 27 Nov 2019
Downloaded from pubs.acs.org on November 27, 2019
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An Approach to Quinoline-Fused Imidazopyridines via CDC of
Ethers with Imidazopyridines under Metal-Free Conditions
Guifang Lian, Jingyu Li, Ping Liu,* and Peipei Sun*
1
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School of Chemistry and Materials Science, Jiangsu Provincial Key Laboratory of Material Cycle
Processes and Pollution Control, Jiangsu Collaborative Innovation Center of Biomedical
Functional Materials, Nanjing Normal University, Nanjing 210023, China
sunpeipei@njnu.edu.cn; pingliu@njnu.edu.cn
4
ABSTRACT: A NH I-catalyzed cross-dehydrogenative coupling (CDC) reaction of ethers with
imidazopyridines cascade cyclization under transition-metal-free conditions has been developed.
Cheap, commercially available ethers were used as both reagents and solvents, and green aqueous
H
2
O
2
was used as oxidizing agent. A series of substituents on the 2-(2-aminoaryl)
imidazo[1,2-a]pyridines were tolerated and the reaction gave quinoline-fused imidazopyridines in
moderate to good yields.
Ethers are widely used as solvents or extracting agents in organic synthesis. As the cheap and
1
easily available reagents, the application of ethers as reactants has also aroused much interest.
3
Many reports focused on the cleavage of α-C(sp )–H bond of ethers via cross-dehydrogenative
coupling (CDC) to construct C–C bond, e.g., the C–H functionalization of arenes or heteroarenes.
Liu et al. introduced a copper-catalyzed oxidative Povarov reaction between N, N-dialkylanilines
and ethers in the presence of peroxide to obtain fused nitrogen and oxygen-containing
2
heterocycles. Wang et al. developed a peroxide-promoted C2-alkoxymethylation on the aromatic
3
heterocyclic compounds such as benzothiazoles and benzimidazoles. These CDC reactions of
4
5
6
azoles with ethers can also be catalyzed by Cu, Fe, Pd, or by a visible-light-induced photoredox
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approach using Ir(III) as the catalyst. Meanwhile, some works involved the direct α-C(sp )–H
amination of ethers to build C–N bonds. This strategy has been employed to construct hemiaminal
8
ether skeletons. Li et al. described an efficient Fe-catalyzed oxidation of ethers to access
9
N-substituted azole derivatives. An aminophosphinoylation of ethers via TEMPO-catalyzed
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α-C(sp )–H and C(sp )–O bond cleavage was developed for the synthesis of α-aminophosphine
10
oxides. Thus it can be seen that to further exploit the synthetic use of ethers is of great
importance.
Imidazo[1,2-a]pyridine moiety is known to be “drug prejudice” scaffold due to the extensive
11
biological and pharmacological activities of the compounds based on this heterocycle, such as
12
13
14
15
16
anticancer, antiinflammatory, antiulcer, antiprotozoal, anti-Alzheimer's disease, and etc.
Therefore, the modification and functionalization of imidazo[1,2-a]pyridine have attracted
1
7
attention of many synthetic and pharmaceutical chemists. We have developed a series of
1
8
methods for the C3-functionalization of imidazo[1,2-a]pyridines such as fluorination,
1
9
20
21
cyanomethylation, azolylation, and alkoxycarbonylation in our previous works. Fused
heterocycles combined from several heterocycles are expected to exhibit synergistic activities and
diverse biological activities. As the continuous study of our group on the selective direct inert C–
3
H bond functionalization, we herein report a cleavage of α-C(sp )–H bond of ethers initiated
radical CDC/cyclization cascade reaction with imidazo[1,2-a]pyridines to assemble
quinoline-fused imidazopyridines.
Initially, we employed 2-(imidazo[1,2-a]pyridin-2-yl)aniline (1a) and tetrahydrofuran (2a,
THF) as the model substrates to optimize the reaction conditions (Table 1). To our delight, using
NH
4
I (20 mol %) as the catalyst and TBHP (3 equiv, 70% in water) as the oxidant at 80 °C, the
desired product 3-(pyrido[2',1':2,3]imidazo[4,5-c]quinolin-6-yl)propan-1-ol (3a) was obtained in
4
4
8% yield (entry 1). When the reaction was carried out without NH I, no target product was
n
observed (entry 2). Other catalysts such as Bu
4
NI and KI gave inferior yields, and CuI and I
2
were ineffective to this reaction (entries 3–6). The screening experiments also revealed that 20
mol % of NH I could give the best result (entries 1, 7 and 8). The oxidants were then explored
entries 9–12). We were delighted to find that the yield of 3a could be raised to 78% in the
4
(
presence of H
2
O
2
(30% in water), and the appropriate amount of H
2
O
2
was 3 equiv (entries 12–14).
o
Temperature was also important for this reaction. Rising the reaction temperature to 90 C brought
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o
a higher yield of 83% (entry 15). At 100 C, however, the yield no longer had significant change
(
entry 16).
a
Table 1. Optimization of the Reaction Conditions
1
1
1
1
1
1
1
1
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b
Entry
Catalyst (mol %) Oxidant (equiv)
Temperature
°C)
Yield (%)
(
1
2
3
4
5
6
7
8
9
NH
4
I (20)
NI (20)
TBHP (3)
TBHP (3)
TBHP (3)
TBHP (3)
TBHP (3)
TBHP (3)
TBHP (3)
TBHP (3)
DTBP (3)
BPO (3)
80
80
80
80
80
80
80
80
80
80
80
80
80
80
90
100
48
0
–
n
Bu
4
43
38
0
KI (20)
CuI (20)
I
2
(20)
0
NH
NH
NH
NH
NH
NH
NH
NH
4
4
4
4
4
4
4
4
I (10)
I (30)
I (20)
I (20)
I (20)
I (20)
I (20)
I (20)
37
48
43
<10
0
1
1
0
1
K
H
H
H
2
2
2
2
2 8
S O (3)
12
O
O
O
2
2
2
(3)
(4)
(2)
(3)
(3)
78
78
67
83
82
1
1
3
4
15
NH
NH
4
I (20)
2 2
H O
1
6
4
I (20)
2 2
H O
a
Reaction conditions: 1a (0.2 mmol), 2a (2 mL), oxidant and catalyst were
b
stirred in a sealed tube under air for 12 h upon heating. Based on 1a.
With the optimized reaction conditions in hand, we started to evaluate the scope of
imidazopyridines with THF for this tandem cyclization reaction (Scheme 1). A variety of
substituents on the pyridine ring were well tolerated. It seemed that the electronic effect of the
substituents had no significant influence to the reaction. Either an electron-donating group (alkyl,
alkoxy) or an electron-withdrawing group (halogen, cyano, trifluoromethyl) substituted substrates
gave the desired products (3b–3m) in moderate to good yields, only the presence of carbamyl led
to a decrease of the yield (3k). The reaction was also not sensitive to position of the substituents
(
3b–3d, 3g–3i). The disubstituted substrate 1n could also be applied in the reaction to give the
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product 3n in 55% yield. Moreover, instead of pyridine ring, the substrates (1o–1q) possessing
quinoline, pyrimidine or thiazole rings also successfully underwent this transformation and gave
the desired products in good yields (3o, 79%; 3p, 78%; 3q, 77%). The effect of the substituents on
benzene ring was then studied. The reactants with electron-withdrawing groups such as halogen
0
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0
(
1s–1u) or ester (1v) group gave higher yields than that with the methoxyl group (1r). Finally,
when the reaction of 1a with THF was performed on a gram scale (5 mmol), the product 3a was
still obtained in 75% yield (3.75 mmol, 1.04 g).
a
Scheme 1. Substrate Scope for Reaction of Imidazopyridines with THF
a
4 2 2
Reaction conditions: 1 (0.2 mmol), 2a (2 mL), NH I (0.04 mmol, 20 mol %) and H O (3.0 equiv,
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o
b
3
0% in H
2
O) were stirred in a sealed tube at 90 C under air for 12 h. Using 5 mmol of 1a.
We then turned our attention to a series of other commercial ethers to expand the scope and
generality of our reaction (Schemes 2). Employing 2-methyltetrahydrofuran (2b), tetrahydropyran
(2c), 1,3-dioxolane (2d) or linear ethers such as benzyl methyl ether (2e) and di-n-butyl ether (2f)
to react with 1a under the standard reaction conditions, the corresponding quinoline-fused
imidazopyridines (4b–4f) were obtained in good yields (42–80%). For diethyl ether (2g), however,
almost no desired product 4g was observed maybe due to the low boiling point of diethyl ether.
1
1
1
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1
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0
a
Scheme 2. Scope of Ethers 2
a
4 2 2
Reaction conditions: 1a (0.2 mmol), 2 (2 mL), NH I (0.04 mmol, 20 mol %) and H O (3.0 equiv,
o
3
0% in H
2
O) were stirred in a sealed tube at 90 C under air for 12 h.
A set of experiments were performed to investigate the mechanism (Scheme 3). When a
radical scavenger 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO, 2 equiv) was added to the
reaction mixture of 1a and 2a, the cyclization reaction was obviously suppressed, and a coupling
product (H) was detected, which indicated that the reaction might proceed via a radical pathway
(
Scheme
3(a)).
Moreover,
Using
2-phenylimidazo[1,2-a]pyridine
(I)
or
2
-(imidazo[1,2-a]pyridin-2-yl)aniline (1a) to react with THF under the standard reaction
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conditions
for
2
h,
the
possible
intermediate
product
or
2
2
-phenyl-3-(tetrahydrofuran-2-yl)imidazo[1,2-a]pyridine
(J)
-(3-(tetrahydrofuran-2-yl)imidazo[1,2-a]pyridin-2-yl)aniline (D) was detected by HRMS analysis
from the mixture(Scheme 3(b) and 3(c)). In addition, when 1,3-dioxolane (2d) was used as a
reaction partner under the standard reaction conditions, 4d was the only product and no another
product 4d’ was found. This result further demonstrated that the intermediate K generated from
the CDC of 2-(imidazo[1,2-a]pyridin-2-yl)aniline with ether was likely to be involved in this
transformation (Scheme 3(d)).
0
1
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Scheme 3. Control Experiments
According to above results and previous reports, a plausible mechanism is depicted in
Scheme 4. Initially, the reaction might begin with the decomposition of H
2 2 4
O catalyzed by NH I
to generate hydroxyl radical, along with the generation of I . Subsequently, the hydroxyl radical
2
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captured α-hydrogen atom from THF to give the tetrahydrofuran radical (A). The radical A
attacked 1a to afford the radical intermediate B. The oxidation of B gave the carbocation C, which
was converted into D through the proton elimination. A further hydrogen abstraction by hydroxyl
2
2
radical and one-electron oxidation with iodine resulted in the oxonium F. Finally, the cation F
underwent an intramolecular nucleophilic cyclization to give the unstable intermediate product G,
which could be easily transformed into 3a via the aromatization owing to the electron-donating
1
1
1
1
1
1
1
1
1
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property of the nitrogen atom.
Scheme 4. Possible Mechanism
In summary, we have developed a NH
imidazopyridines with ethers for the synthesis of quinoline-fused imidazopyridines. A “green”
oxidant H was used in this process. The operational simplicity and metal-free conditions are
4
I-catalyzed CDC cascade cyclization reaction of
2
O
2
the key features of our methodology, which increase its utility in the construction of
pharmaceutically important heterocycles.
■
EXPERIMENTAL SECTION
General Information. All reagents and solvents were obtained from chemical suppliers, and
1
were used without further purification. The NMR spectra were recorded at 400 MHz ( H) and 100
1
3
1
MHz ( C{ H}) in CDCl
3
6
or DMSO-d using TMS as an internal standard. Chemical shifts are
1
13
1
given relative to CDCl
3
(7.26 ppm for H NMR, 77.16 ppm for C{ H} NMR) or DMSO-d
6
(2.50
1
13
1
ppm for H NMR, 39.6 ppm for C{ H} NMR). The following abbreviations were used to explain
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2
2
2
2
2
2
2
2
3
3
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3
4
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4
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4
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4
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5
5
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the multiplicities: s = singlet, d = doublet, dd = doublet of doublet, t = triplet, dt = doublet of
triplet, m = multiplet. High-resolution mass spectra (HRMS) were obtained by ESI on TOF mass
analyzer. Melting points are uncorrected.
General Procedure for the Synthesis of 1. Some starting materials were known compounds
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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2
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5
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9
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2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
3
24
25
and were prepared according to known methods (1a, 1k; 1c; 1j, 1o; ). Compounds 1b, 1d−1i,
1
l−1n and 1p−1v were new compounds and all of them were prepared according to the literature
24
(
10 mmol of substituted 2-amino pyridines were used).
2
-(6-Methylimidazo[1,2-a]pyridin-2-yl)aniline (1b). White solid (1.61 g, 72% yield). mp 150−152
o
1
C. H NMR (400 MHz, DMSO-d
6
) δ (ppm) 8.30 (s, 1H), 8.18 (s, 1H), 7.56–7.49 (m, 2H), 7.11–
13
1
7
.00 (m, 2H), 6.75 (d, J = 8.0 Hz, 1H), 6.61–6.56 (m, 3H), 2.28 (s, 3H). C{ H} NMR (100 MHz,
6
DMSO-d ) δ (ppm) 147.1, 146.1, 143.1, 128.7, 128.0, 127.8, 124.2, 122.1, 116.5, 116.1, 116.0,
+
+
1
14 3
15.8, 108.9, 18.0. HRMS (ESI) m/z calcd for C14H N [M+H] 224.1182, found 224.1180.
2
-(8-Methylimidazo[1,2-a]pyridin-2-yl)aniline (1d). White solid (1.54 g, 69% yield). mp 90−92
o
1
C. H NMR (400 MHz, DMSO-d
6
) δ (ppm) 8.38 (d, J = 6.4 Hz, 1H), 8.27 (s, 1H), 7.57 (d, J = 7.6
Hz, 1H), 7.06–7.01 (m, 2H), 6.82 (t, J = 6.8 Hz, 1H), 6.77 (d, J = 8.4 Hz, 1H), 6.67 (s, 2H), 6.59 (t,
1
3
1
J = 7.4 Hz, 1H), 2.53 (s, 3H). C{ H} NMR (100 MHz, DMSO-d
6
) δ (ppm) 147.1, 145.6, 144.4,
128.8, 128.1, 126.0, 124.5, 123.5, 116.5, 116.0, 115.8, 112.8, 109.6, 17.0. HRMS (ESI) m/z calcd
+
+
14 3
for C14H N [M+H] 224.1182, found 224.1187.
2
-(8-Methylimidazo[1,2-a]pyridin-2-yl)aniline (1e). White solid (1.77 g, 74% yield). mp 147−149
o
1
C. H NMR (400 MHz, DMSO-d
6
) δ (ppm) 8.38 (d, J = 7.2 Hz, 1H), 8.07 (s, 1H), 7.51 (d, J = 7.2
1
3
1
Hz, 1H), 7.00 (s, 2H), 6.73 (d, J = 8.0 Hz, 1H), 6.65–6.55 (m, 4H), 3.85 (s, 3H). C{ H} NMR
(
100 MHz, DMSO-d ) δ (ppm) 157.7, 147.0, 145.8, 145.5, 128.6, 127.9, 127.4, 116.5, 116.1,
6
+
+
1
2
07.8, 107.2, 94.6, 56.0. HRMS (ESI) m/z calcd for C14
40.1131.
14 3
H N O [M+H] 240.1131, found
2
-(6-Fluoroimidazo[1,2-a]pyridin-2-yl)aniline (1f). White solid (1.54 g, 68% yield). mp 129−131
o
1
C. H NMR (400 MHz, DMSO-d
6
) δ (ppm) 8.77 (s, 1H), 8.31 (s, 1H), 7.67 (dd, J = 9.6, 5.2 Hz,
1
1
H), 7.56 (d, J = 7.6 Hz, 1H), 7.35 (t, J = 8.4 Hz, 1H), 7.04 (t, J = 7.4 Hz, 1H), 6.77 (d, J = 8.0 Hz,
13
1
6
H), 6.60 (t, J = 7.2 Hz, 1H). C{ H} NMR (100 MHz, DMSO-d ) δ (ppm) 153.1 (d, J = 231.1
Hz), 147.3, 146.9, 141.9, 129.1, 128.2, 117.2 (d, J = 9.4 Hz), 116.7, 116.6 (d, J = 25.5 Hz), 116.2,
+
+
1
3
15.3, 113.6 (d, J = 41.3 Hz), 110.8. HRMS (ESI) m/z calcd for C13H11FN [M+H)] 228.0932,
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found 228.0931.
2
-(6-Chloroimidazo[1,2-a]pyridin-2-yl)aniline (1g). White solid (1.63 g, 67% yield). mp 159−161
o
1
C. H NMR (400 MHz, DMSO-d
6
) δ (ppm) 8.79 (s, 1H), 8.27 (s, 1H), 7.64 (d, J = 9.6 Hz, 1H),
7
.55 (d, J = 7.6 Hz, 1H), 7.29 (dd, J = 9.6, 1.6 Hz, 1H), 7.05 (t, J = 7.4 Hz, 1H), 6.77 (d, J = 8.4
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
1
Hz, 1H), 6.62–6.55 (m, 3H). C{ H} NMR (100 MHz, DMSO-d
6
) δ (ppm) 147.2, 147.2, 142.5,
1
29.2, 128.2, 125.7, 124.7, 119.6, 117.4, 116.6, 116.2, 115.2, 109.9. HRMS (ESI) m/z calcd for
+
+
C
13 3
H11ClN [M+H] 244.0636, found 244.0636.
2
-(7-Chloroimidazo[1,2-a]pyridin-2-yl)aniline (1h). White solid (1.58 g, 65% yield). mp 168−170
o
1
C. H NMR (400 MHz, DMSO-d
6
) δ (ppm) 8.62 (d, J = 5.6 Hz, 1H), 8.38 (s, 1H), 7.76 (s, 1H),
7
.56 (d, J = 6.8 Hz, 1H), 7.07–7.02 (m, 2H), 6.81 (d, J = 7.2 Hz, 1H), 6.62 (t, J = 6.6 Hz, 1H).
1
3
1
6
C{ H} NMR (100 MHz, DMSO-d ) δ (ppm) 146.3, 146.3, 143.6, 130.4, 129.3, 128.3, 127.9,
+
+
1
2
17.1, 116.8, 115.5, 115.1, 114.2, 110.0. HRMS (ESI) m/z calcd for C13
44.0636, found 244.0633.
H
11ClN
3
[M+H]
2-(8-Chloroimidazo[1,2-a]pyridin-2-yl)aniline (1i). White solid (1.51 g, 62% yield). mp 141−143
o
1
C. H NMR (400 MHz, DMSO-d
6
) δ (ppm) 8.55 (d, J = 6.4 Hz, 1H), 8.45 (s, 1H), 7.59 (d, J = 7.2
Hz, 1H), 7.46 (d, J = 7.2 Hz, 1H), 7.06 (t, J = 7.0 Hz, 1H), 6.94 (t, J = 6.8 Hz, 1H), 6.78 (d, J =
1
3
1
8.0 Hz, 1H), 6.63–6.59 (m, 3H). C{ H} NMR (100 MHz, DMSO-d
6
) δ (ppm) 147.2, 146.5,
141.1, 129.3, 128.2, 126.0, 124.1, 121.0, 116.7, 116.1, 115.0, 112.7, 111.2. HRMS (ESI) m/z
+
+
calcd for C13
H
11ClN
3
[M+H] 244.0636, found 244.0634.
2
-(2-Aminophenyl)imidazo[1,2-a]pyridine-6-carbonitrile (1l). White solid (1.50 g, 64% yield). mp
o
1
1
6
85−187 C. H NMR (400 MHz, DMSO-d ) δ (ppm) 9.37 (s, 1H), 8.44 (s, 1H), 7.76 (d, J = 8.4
Hz, 1H), 7.60 (d, J = 6.8 Hz, 1H), 7.52 (d, J = 8.8 Hz, 1H), 7.06 (t, J = 6.2 Hz, 1H), 6.78 (d, J =
1
3
1
7
.2 Hz, 1H), 6.62–6.55 (m, 3H). C{ H} NMR (100 MHz, DMSO-d
6
) δ (ppm) 148.1, 147.4,
1
43.4, 133.9, 129.6, 128.5, 124.9, 117.7, 117.4, 116.8, 116.2, 114.5, 110.5, 97.5. HRMS (ESI) m/z
+
+
11 4
calcd for C14H N [M+H] 235.0978, found 235.0975.
2
-(6-(Trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)aniline (1m). White solid (1.83 g, 66% yield).
o
1
mp 150−152 C. H NMR (400 MHz, DMSO-d
6
) δ (ppm) 9.23 (s, 1H), 8.44 (s, 1H), 7.79 (d, J =
9
.6 Hz, 1H), 7.57 (d, J = 7.6 Hz, 1H), 7.47 (d, J = 9.2 Hz, 1H), 7.06 (t, J = 7.2 Hz, 1H), 6.79 (d, J
13
1
=
6
8.0 Hz, 1H), 6.62–6.57 (m, 3H). C{ H} NMR (100 MHz, DMSO-d ) δ (ppm) 147.9, 147.3,
1
43.8, 129.4, 128.4, 126.5 (q, J = 5.7 Hz), 124.4 (q, J = 269.1 Hz), 120.3 (q, J = 2.4 Hz), 117.5,
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2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
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5
5
5
5
5
5
5
5
5
5
6
+
1
11 3 3
16.7, 116.2, 115.2 (q, J = 33.1 Hz), 114.9, 110.8. HRMS (ESI) m/z calcd for C14H F N
+
(
M+H) 278.0900, found 278.0899.
2
1
-(8-Bromo-6-methylimidazo[1,2-a]pyridin-2-yl)aniline (1n). White solid (1.57 g, 52% yield). mp
o
1
6
48−150 C. H NMR (400 MHz, DMSO-d ) δ (ppm) 8.34 (s, 2H), 7.56 (d, J = 7.6 Hz, 1H), 7.48
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
s, 1H), 7.04 (t, J = 7.2 Hz, 1H), 6.76 (d, J = 8.0 Hz, 1H), 6.59 (t, J = 7.2 Hz, 1H), 2.27 (s, 3H).
13
1
6
C{ H} NMR (100 MHz, DMSO-d ) δ (ppm) 147.1, 146.3, 140.8, 130.0, 129.1, 128.1, 124.0,
+
+
1
3
22.8, 116.7, 116.1, 115.1, 110.9, 109.3, 17.7. HRMS (ESI) m/z calcd for C14
02.0287, found 302.0288.
H
13BrN
3
[M+H]
o
2
-(Imidazo[1,2-a]pyrimidin-2-yl)aniline (1p). White solid (1.11 g, 53% yield). mp 164−166 C.
1
H NMR (400 MHz, DMSO-d
6
) δ (ppm) 8.98 (dd, J = 6.6, 1.8 Hz, 1H), 8.52 (dd, J = 4.0, 2.0 Hz,
1
6
1
H), 8.29 (s, 1H), 7.60 (dd, J = 7.8, 1.4 Hz, 1H), 7.11–7.04 (m, 2H), 6.78 (dd, J = 8.2, 1.0 Hz, 1H),
1
3
1
.63–6.58 (m, 3H). C{ H} NMR (100 MHz, DMSO-d
6
) δ (ppm) 150.0, 147.4, 147.4, 147.2,
+
34.8, 129.5, 128.1, 116.7, 116.1, 115.0, 109.5, 107.5. HRMS (ESI) m/z calcd for C12
H
11
N
4
+
[M+H] 211.0978, found 211.0975.
o
1
2-(Imidazo[2,1-b]thiazol-6-yl)aniline (1q). Brown solid (1.31 g, 61% yield). mp 115−117 C. H
NMR (400 MHz, CDCl
7.13 (t, J = 7.6 Hz, 1H), 6.77–6.73 (m, 2H), 6.63 (d, J = 4.4 Hz, 1H), 5.51 (s, 2H). C{ H} NMR
(100 MHz, CDCl ) δ (ppm) 148.7, 147.8, 145.2, 128.5, 127.6, 118.7, 117.7, 117.5, 116.8, 112.2,
3
) δ (ppm) 7.53 (s, 1H), 7.41 (d, J = 7.6 Hz, 1H), 7.20 (d, J = 4.4 Hz, 1H),
1
3
1
3
+
+
1
2
1
08.6. HRMS (ESI) m/z calcd for C11
10 3
H N S [M+H] 216.0590, found 216.0588.
-(Imidazo[1,2-a]pyridin-2-yl)-4-methoxyaniline (1r). White solid (1.60 g, 67% yield). mp
o
1
45−147 C. H NMR (400 MHz, CDCl3) δ (ppm) 7.97 (d, J = 6.4 Hz, 1H), 7.71 (s, 1H), 7.52 (d,
J = 9.2 Hz, 1H), 7.12–7.04 (m, 2H), 6.77–6.70 (m, 2H), 6.64 (t, J = 6.6 Hz, 1H), 5.41 (s, 2H), 3.76
1
3
1
(
s, 3H). C{ H} NMR (100 MHz, CDCl3) δ (ppm) 151.8, 146.0, 144.5, 139.9, 125.4, 124.3,
+
1
14 3
18.1, 117.8, 116.9, 115.4, 113.2, 112.4, 108.8, 55.9. HRMS (ESI) m/z calcd for C14H N O
+
[
M+H] 240.1131, found 240.1134.
4
1
-Fluoro-2-(imidazo[1,2-a]pyridin-2-yl)aniline (1s). White solid (1.48 g, 65% yield). mp
o
1
6
41−143 C. H NMR (400 MHz, DMSO-d ) δ (ppm) 8.53 (d, J = 6.4 Hz, 1H), 8.39 (s, 1H), 7.61
(
d, J = 9.2 Hz, 1H), 7.44 (dd, J = 10.4, 2.8 Hz, 1H), 7.27 (t, J = 7.8 Hz, 1H), 6.96–6.88 (m, 2H),
13
1
6
6
.76 (dd, J = 8.8, 5.2 Hz, 1H), 6.46 (s, 2H). C{ H} NMR (100 MHz, DMSO-d ) δ (ppm) 154.4
(
d, J = 228.3 Hz), 145.0 (d, J = 2.5 Hz), 144.1, 143.7, 126.9, 125.3, 117.5 (d, J = 7.5 Hz), 116.8,
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1
16.2 (d, J = 7.1 Hz), 115.6 (d, J = 22.1 Hz), 113.5 (d, J = 22.7 Hz), 113.1, 110.0. HRMS (ESI)
+
+
3
m/z calcd for C13H11FN [M+H] 228.0932, found 228.0931.
4
-Chloro-2-(imidazo[1,2-a]pyridin-2-yl)aniline (1t). Yellow solid (1.51 g, 62% yield). mp
o
1
1
3
65−167 C. H NMR (400 MHz, CDCl ) δ (ppm) 8.14 (d, J = 6.4 Hz, 1H), 7.82 (s, 1H), 7.60 (d,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
J = 8.8 Hz, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.20 (t, J = 7.8 Hz, 1H), 7.06 (dd, J = 8.4, 2.4 Hz, 1H),
13
1
6
.82 (t, J = 6.6 Hz, 1H), 6.70 (d, J = 8.4 Hz, 1H), 5.46 (s, 2H). C{ H} NMR (100 MHz, CDCl
3
)
δ (ppm) 144.9, 144.4, 128.6, 127.5, 125.4, 124.8, 121.7, 118.0, 117.7, 117.1, 112. 9, 112.8, 108.7.
+
+
HRMS (ESI) m/z calcd for C13
H
11ClN
3
[M+H] 244.0636, found 244.0635.
5
-Bromo-2-(imidazo[1,2-a]pyridin-2-yl)aniline (1u). White solid (1.75 g, 61% yield). mp
o
1
1
6
44−146 C. H NMR (400 MHz, DMSO-d ) δ (ppm) 8.54 (d, J = 5.2 Hz, 1H), 8.33 (s, 1H), 7.60
(
d, J = 8.4 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.27 (t, J = 6.6 Hz, 1H), 6.96–6.91 (m, 4H), 6.72 (d,
1
3
1
J = 7.2 Hz, 1H). C{ H} NMR (100 MHz, DMSO-d
6
) δ (ppm) 148.7, 145.1, 144.0, 129.8, 126.9,
+
1
25.3, 121.7, 118.4, 118.2, 116.7, 114.8, 113.1, 109.5. HRMS (ESI) m/z calcd for C13H11BrN
3
+
[M+H] 288.0131, found 288.0137.
Methyl 3-amino-4-(imidazo[1,2-a]pyridin-2-yl)benzoate (1v). Yellow solid (1.39 g, 52% yield).
o
1
mp 185−187 C. H NMR (400 MHz, DMSO-d
6
) δ (ppm) 8.57 (d, J = 6.8 Hz, 1H), 8.44 (s, 1H),
7.71 (d, J = 8.0 Hz, 1H), 7.62 (d, J = 9.2 Hz, 1H), 7.43 (s, 1H), 7.29 (t, J = 7.8 Hz, 1H), 7.17 (d, J
1
3
1
= 8.4 Hz, 1H), 6.97–6.90 (m, 3H), 3.83 (s, 3H). C{ H} NMR (100 MHz, DMSO-d
6
) δ (ppm)
1
5
66.9, 147.1, 144.9, 144.1, 129.5, 128.2, 127.0, 125.5, 119.7, 117.2, 116.8, 116.5, 113.2, 110.5,
+
+
14 3 2
2.3. HRMS (ESI) m/z calcd for C15H N O [M+H] 268.1081, found 268.1081.
General Procedure for the Synthesis of 3 and 4. To a sealed tube were added imidazopyridines
1
(0.2 mmol), NH
4
2 2
I (5.8 mg, 0.04 mmol, 20 mol %), ether (2 mL) and H O (61 µL, 3.0 equiv, 30%
o
in H
2
O). The reaction mixture was stirred at 90 C (using oil bath as the heat source) for 12 h.
After cooled to room temperature, the resulting solution was diluted with DCM (15 mL). The
organic layer was washed with brine (15 mL), dried over Na SO , and concentrated under reduced
2
4
pressure. The residue was purified by silica gel column chromatography with ethyl acetate as
eluent to afford the desired products 3 or 4.
3
-(Pyrido[2',1':2,3]imidazo[4,5-c]quinolin-6-yl)propan-1-ol (3a). White solid (46.0 mg, 83%
yield; 1.04 g, 75% yield (1a 1.05 g (5 mmol), NH I 0.145 g (1 mmol), H 1.7 mL (3.0 equiv, 30%
) δ (ppm) 9.13 (d, J = 6.4
4
2 2
O
o
1
in H
2
O), THF 30 mL)). mp 170−172 C. H NMR (400 MHz, DMSO-d
6
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2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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4
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4
4
4
4
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5
5
5
5
6
Hz, 1H), 8.56 (d, J = 7.6 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.96 (d, J = 8.8 Hz, 1H), 7.74–7.64 (m,
3
2
1
C
H), 7.24 (t, J = 6.6 Hz, 1H), 4.85 (s, 1H), 3.68 (t, J = 5.0 Hz, 2H), 3.52 (t, J = 7.6 Hz, 2H), 2.09–
1
3
1
6
.02 (m, 2H). C{ H} NMR (100 MHz, DMSO-d ) δ (ppm) 150.8, 149.1, 146.3, 144.6, 130.7,
29.4, 129.0, 128.7, 126.1, 122.6, 121.3, 117.8, 113.4, 60.7, 33.0, 30.8. HRMS (ESI) m/z calcd for
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
+
17
H
16
N
3
O [M+H] 278.1288, found 278.1290.
3
7
8
-(9-Methylpyrido[2',1':2,3]imidazo[4,5-c]quinolin-6-yl)propan-1-ol (3b). White solid (41.3 mg,
o
1
1% yield). mp 198−200 C. H NMR (400 MHz, DMSO-d
.0 Hz, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.84 (d, J = 9.2 Hz, 1H), 7.73 (t, J = 7.4 Hz, 1H), 7.64 (t, J
7.4 Hz, 1H), 7.57 (d, J = 9.2 Hz, 1H), 5.01 (s, 1H), 3.69 (t, J = 5.8 Hz, 2H), 3.51 (t, J = 7.8 Hz,
6
) δ (ppm) 8.93 (s, 1H), 8.53 (d, J =
=
13
1
2
1
1
3
H), 2.43 (s, 3H), 2.07–2.00 (m, 2H). C{ H} NMR (100 MHz, DMSO-d
6
) δ (ppm) 150.8, 148.2,
46.3, 144.3, 133.5, 128.8, 128.6, 126.7, 126.0, 122.8, 122.6, 121.4, 121.1, 117.1, 60.6, 32.9, 30.9,
+
+
8.2. HRMS (ESI) m/z calcd for C18
18 3
H N O [M+H] 292.1444, found 292.1448.
-(10-Methylpyrido[2',1':2,3]imidazo[4,5-c]quinolin-6-yl)propan-1-ol (3c). White solid (44.3 mg,
o
1
76% yield). mp 225−227 C. H NMR (400 MHz, CDCl
3
) δ (ppm) 8.92 (d, J = 5.2 Hz, 1H), 8.71
(d, J = 7.6 Hz, 1H), 8.48 (d, J = 7.2 Hz, 1H), 7.85–7.73 (m, 3H), 7.09 (d, J = 4.8 Hz, 1H), 5.32 (s,
1
3
1
1H), 3.91–3.89 (m, 4H), 2.61 (s, 3H), 2.33–2.27 (m, 2H). C{ H} NMR (100 MHz, DMSO-d
6
) δ
(ppm) 150.4, 149.8, 146.7, 144.3, 144.3, 142.1, 128.8, 128.7, 128.5, 126.1, 122.7, 121.3, 121.2,
+
+
18 3
116.0, 60.7, 32.7, 30.9, 21.6. HRMS (ESI) m/z calcd for C18H N O [M+H] 292.1444, found
2
92.1448.
-(11-Methylpyrido[2',1':2,3]imidazo[4,5-c]quinolin-6-yl)propan-1-ol (3d). White solid (43.1 mg,
3
o
1
7
6
4% yield). mp 179−181 C. H NMR (400 MHz, DMSO-d ) δ (ppm) 8.95 (d, J = 6.8 Hz, 1H),
8
.56 (d, J = 7.6 Hz, 1H), 8.06 (d, J = 8.0 Hz, 1H), 7.73 (t, J = 7.2 Hz, 1H), 7.64 (t, J = 7.4 Hz, 1H),
.52 (d, J = 6.8 Hz, 1H), 7.13 (t, J = 6.8 Hz, 1H), 3.67 (t, J = 6.0 Hz, 2H), 3.48 (t, J = 7.8 Hz, 2H),
7
1
3
1
2
.69 (s, 3H), 2.07–2.00 (m, 2H). C{ H} NMR (100 MHz, DMSO-d
6
) δ (ppm) 150.7, 149.6,
1
45.9, 144.3, 129.0, 128.7, 127.3, 126.9, 126.1, 122.7, 121.8, 121.4, 113.3, 60.7, 32.8, 30.8, 17.7.
+
+
HRMS (ESI) m/z calcd for C18
H
18
N
3
O [M+H] 292.1444, found 292.1448.
3
-(10-Methoxypyrido[2',1':2,3]imidazo[4,5-c]quinolin-6-yl)propan-1-ol (3e). White solid (46.1
o
1
mg, 75% yield). mp 201−203 C. H NMR (400 MHz, DMSO-d
6
) δ (ppm) 8.95 (d, J = 7.2 Hz,
1
1
H), 8.50 (d, J = 7.6 Hz, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.71 (t, J = 6.8 Hz, 1H), 7.62 (t, J = 6.8 Hz,
H), 7.31 (s, 1H), 6.90 (d, J = 6.0 Hz, 1H), 4.85 (s, 1H), 3.97 (s, 3H), 3.66 (t, J = 5.8 Hz, 2H), 3.46
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7
8
9
1
3
1
(
t, J = 7.0 Hz, 2H), 2.07–2.00 (m, 2H). C{ H} NMR (100 MHz, DMSO-d
6
) δ (ppm) 161.2,
1
3
3
7
8
51.7, 149.9, 147.1, 144.7, 129.8, 128.9, 128.4, 125.7, 122.5, 121.2, 121.2, 107.7, 95.3, 60.7, 56.6,
+
+
2.7, 30.9. HRMS (ESI) m/z calcd for C18
18 3 2
H N O [M+H] 308.1394, found 308.1397.
-(9-Fluoropyrido[2',1':2,3]imidazo[4,5-c]quinolin-6-yl)propan-1-ol (3f). White solid (46.0 mg,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
o
1
8% yield). mp 218−220 C. H NMR (400 MHz, DMSO-d
6
) δ (ppm) 9.29 (d, J = 2.8 Hz, 1H),
.54 (d, J = 8.0 Hz, 1H), 8.09–8.02 (m, 2H), 7.90–7.85 (m, 1H), 7.76 (t, J = 7.0 Hz, 1H), 7.67 (t, J
=
7.2 Hz, 1H), 4.94 (s, 1H), 3.68 (t, J = 5.8 Hz, 2H), 3.52 (t, J = 7.8 Hz, 2H), 2.08–1.99 (m, 2H).
13
1
C{ H} NMR (100 MHz, DMSO-d
6
) δ (ppm) 152.8 (d, J = 232.6 Hz), 150.9, 146.8, 144.4, 129.0,
1
4
2
3
7
28.9, 126.3, 122.6, 122.5, 122.3 (d, J = 3.3 Hz), 121.4, 118.5 (d, J = 8.8 Hz), 118.4, 118.5 (d, J =
+
+
1.5 Hz), 60.6, 32.6, 30.7. HRMS (ESI) m/z calcd for C17
96.1198.
3
H15FN O [M+H] 296.1194, found
-(9-Chloropyrido[2',1':2,3]imidazo[4,5-c]quinolin-6-yl)propan-1-ol (3g). White solid (45.4 mg,
o
1
6
3% yield). mp 211−213 C. H NMR (400 MHz, DMSO-d ) δ (ppm) 9.23 (s, 1H), 8.53 (d, J =
7.6 Hz, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.98 (d, J = 9.2 Hz, 1H), 7.79–7.74 (m, 2H), 7.66 (t, J = 7.0
1
3
1
Hz, 1H), 4.96 (s, 1H), 3.67 (t, J = 5.4 Hz, 2H), 3.51 (t, J = 7.2 Hz, 2H), 2.08–2.01 (m, 2H). C{ H}
NMR (100 MHz, DMSO-d
6
) δ (ppm) 151.0, 147.4, 146.5, 144.6, 131.4, 129.1, 129.0, 127.3, 126.4,
+
3
122.6, 121.6, 121.2, 119.9, 118.5, 60.6, 32.7, 30.6. HRMS (ESI) m/z calcd for C17H15ClN O
+
[M+H] 312.0898, found 312.0900.
3
7
8
-(10-Chloropyrido[2',1':2,3]imidazo[4,5-c]quinolin-6-yl)propan-1-ol (3h). White solid (48.5 mg,
o
1
8% yield). mp 177−179 C. H NMR (400 MHz, DMSO-d
6
) δ (ppm) 9.09 (d, J = 7.6 Hz, 1H),
.51 (d, J = 7.6 Hz, 1H), 8.10–8.06 (m, 2H), 7.75 (t, J = 7.2 Hz, 1H), 7.66 (t, J = 7.4 Hz, 1H), 7.27
(
(
dd, J = 7.2, 2.0 Hz, 1H), 4.86 (s, 1H), 3.67 (t, J = 6.0 Hz, 2H), 3.48 (t, J = 7.8 Hz, 2H), 2.08–2.01
1
3
1
m, 2H). C{ H} NMR (100 MHz, DMSO-d
6
) δ (ppm) 150.7, 148.9, 146.7, 144.7, 135.8, 130.3,
1
29.1, 129.0, 126.3, 122.6, 121.3, 121.1, 116.4, 114.2, 60.7, 32.8, 30.6. HRMS (ESI) m/z calcd for
+
+
C
17 3
H15ClN O [M+H] 312.0898, found 312.0901.
3
7
8
4
-(11-Chloropyrido[2',1':2,3]imidazo[4,5-c]quinolin-6-yl)propan-1-ol (3i). White solid (48.5 mg,
o
1
8% yield). mp 152−154 C. H NMR (400 MHz, DMSO-d
6
) δ (ppm) 8.96 (d, J = 6.8 Hz, 1H),
.48 (d, J = 7.6 Hz, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.81–7.58 (m, 3H), 7.11 (t, J = 7.0 Hz, 1H),
13
1
.88 (s, 1H), 3.67 (t, J = 5.6 Hz, 2H), 3.39 (t, J = 7.4 Hz, 2H), 2.06–1.98 (m, 2H). C{ H} NMR
(
100 MHz, DMSO-d
6
) δ (ppm) 150.6, 146.0, 145.7, 144.5, 129.2, 128.9, 128.8, 128.2, 126.2,
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2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
4
4
4
4
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4
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5
5
5
5
5
5
5
6
+
1
3
22.5, 122.2, 122.1, 121.0, 112.8, 60.7, 32.8, 30.5. HRMS (ESI) m/z calcd for C17H15ClN O
+
[
M+H] 312.0898, found 312.0902.
3
7
7
3
1
3
6
-(9-Bromopyrido[2',1':2,3]imidazo[4,5-c]quinolin-6-yl)propan-1-ol (3j). White solid (54.7 mg,
o
1
7% yield). mp 203−205 C. H NMR (400 MHz, DMSO-d
6
) δ (ppm) 9.26 (s, 1H), 8.52 (d, J =
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
.6 Hz, 1H), 8.06 (d, J = 8.0 Hz, 1H), 7.93–7.65 (m, 4H), 4.94 (s, 1H), 3.67 (t, J = 7.4 Hz, 2H),
13
1
.49 (t, J = 7.0 Hz, 2H), 2.07–2.01 (m, 2H). C{ H} NMR (100 MHz, DMSO-d
6
) δ (ppm) 151.1,
47.5, 146.3, 144.6, 133.5, 129.4, 129.1, 129.0, 126.4, 122.6, 121.5, 121.2, 118.8, 106.9, 60.6,
+
+
2.7, 30.6. HRMS (ESI) m/z calcd for C17
3
H15BrN O [M+H] 356.0393, found 356.0398.
-(3-Hydroxypropyl)pyrido[2',1':2,3]imidazo[4,5-c]quinoline-11-carboxamide (3k). White solid
o
1
(
(
33.9 mg, 53% yield). mp 245−247 C. H NMR (400 MHz, DMSO-d
6
) δ (ppm) 9.80 (s, 1H), 9.28
d, J = 6.8 Hz, 1H), 8.58 (d, J = 8.0 Hz, 1H), 8.46 (d, J = 7.2 Hz, 1H), 8.24 (s, 1H), 8.05 (d, J =
8
4
.4 Hz, 1H), 7.74 (t, J = 7.6 Hz, 1H), 7.64 (t, J = 7.4 Hz, 1H), 7.39 (t, J = 7.0 Hz, 1H), 4.79 (t, J =
1
3
1
.8 Hz, 1H), 3.68 (q, J = 5.2 Hz, 2H), 3.50 (t, J = 7.8 Hz, 2H), 2.09–2.03 (m, 2H). C{ H} NMR
(100 MHz, DMSO-d
6
) δ (ppm) 164.0, 150.7, 147.2, 145.0, 144.7, 133.2, 132.5, 129.1, 129.0,
+
17 4 2
126.3, 122.8, 121.2, 121.0, 120.6, 113.1, 60.7, 32.9, 30.6. HRMS (ESI) m/z calcd for C18H N O
+
[M+H] 321.1346, found 321.1347.
6-(3-Hydroxypropyl)pyrido[2',1':2,3]imidazo[4,5-c]quinoline-9-carbonitrile (3l). White solid
o
1
(46.5 mg, 77% yield). mp 239−241 C. H NMR (400 MHz, DMSO-d
6
) δ (ppm) 9.70 (s, 1H), 8.49
(
d, J = 7.6 Hz, 1H), 8.07–7.99 (m, 2H), 7.91 (d, J = 9.2 Hz, 1H), 7.77 (t, J = 7.2 Hz, 1H), 7.67 (t, J
=
7.0 Hz, 1H), 4.93 (s, 1H), 3.69 (t, J = 5.2 Hz, 2H), 3.50 (t, J = 7.0 Hz, 2H), 2.11–2.04 (m, 2H).
1
3
1
C{ H} NMR (100 MHz, DMSO-d
6
) δ (ppm) 150.9, 148.1, 146.9, 144.8, 136.7, 130.1, 129.4,
1
29.1, 126.6, 122.6, 121.4, 120.8, 118.4, 117.3, 98.0, 60.6, 32.5, 30.3. HRMS (ESI) m/z calcd for
+
+
C
18 15 4
H N O [M+H] 303.1240, found 303.1246.
3
-(9-(Trifluoromethyl)pyrido[2',1':2,3]imidazo[4,5-c]quinolin-6-yl)propan-1-ol (3m). White solid
o
1
(
(
53.1 mg, 77% yield). mp 202−204 C. H NMR (400 MHz, DMSO-d
d, J = 8.0 Hz, 1H), 8.14–8.08 (m, 2H), 7.97 (d, J = 9.6 Hz, 1H), 7.78 (t, J = 7.0 Hz, 1H), 7.69 (t, J
7.4 Hz, 1H), 4.94 (t, J = 3.8 Hz, 1H), 3.66 (q, J = 4.7 Hz, 2H), 3.53 (t, J = 7.8 Hz, 2H), 2.07–
6
) δ (ppm) 9.45 (s, 1H), 8.54
=
13
1
2
1
1
6
.00 (m, 2H). C{ H} NMR (100 MHz, DMSO-d ) δ (ppm) 151.2, 148.8, 147.2, 144.8, 129.3,
29.2 (q, J = 5.4 Hz), 129.1, 126.6, 126.0 (q, J = 2.4 Hz), 124.2 (q, J = 269.5 Hz), 122.7, 121.9,
+
15 3 3
21.1, 118.8, 115.3 (q, J = 33.7 Hz), 60.4, 32.7, 30.8. HRMS (ESI) m/z calcd for C18H F N O
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+
[
M+H] 346.1162, found 346.1162.
3
-(11-Bromo-9-methylpyrido[2',1':2,3]imidazo[4,5-c]quinolin-6-yl)propan-1-ol (3n). White solid
o
1
(
40.6 mg, 55% yield). mp 221−223 C. H NMR (400 MHz, DMSO-d
6
) δ (ppm) 8.94 (s, 1H), 8.55
(
d, J = 5.6 Hz, 1H), 8.06–7.95 (m, 2H), 7.76–7.65 (m, 2H), 5.03 (s, 1H), 3.68 (t, J = 10.6 Hz, 2H),
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
1
3
6
.48 (t, J = 7.6 Hz, 2H), 2.43 (s, 3H), 2.06–1.98 (m, 2H). C{ H} NMR (100 MHz, DMSO-d ) δ
(
ppm) 151.1, 145.8, 145.7, 144.5, 135.5, 129.0, 128.9, 126.4, 126.3, 123.1, 122.6, 122.4, 121.3,
+
+
1
3
3
1
8
10.4, 60.6, 32.9, 30.8, 17.9. HRMS (ESI) m/z calcd for C18
70.0549.
3
H17BrN O [M+H] 370.0550, found
-(Imidazo[1,2-a:5,4-c']diquinolin-6-yl)propan-1-ol (3o). White solid (51.7 mg, 79% yield). mp
o
1
80−182 C. H NMR (400 MHz, DMSO-d
6
) δ (ppm) 8.58 (dd, J = 8.0, 0.8 Hz, 1H), 8.35 (d, J =
.4 Hz, 1H), 8.13–8.08 (m, 3H), 7.86–7.82 (m, 2H), 7.78–7.74 (m, 1H), 7.68–7.61 (m, 2H), 4.52
1
3
1
(
s, 1H), 3.48 (t, J = 7.6 Hz, 2H), 3.38 (t, J = 5.8 Hz, 2H), 2.08–2.02 (m, 2H). C{ H} NMR (100
MHz, DMSO-d ) δ (ppm) 150.6, 149.6, 147.2, 144.6, 134.6, 132.9, 129.5, 129.5, 128.8, 128.5,
126.2, 125.7, 124.5, 124.0, 122.5, 120.7, 120.5, 117.4, 60.7, 35.4, 31.9. HRMS (ESI) m/z calcd for
6
+
+
C
21
H
18
N
3
O [M+H] 328.1444, found 328.1450.
3-(Pyrimido[2',1':2,3]imidazo[4,5-c]quinolin-6-yl)propan-1-ol (3p). White solid (43.4 mg, 78%
o
1
yield). mp 210−212 C. H NMR (400 MHz, DMSO-d
6
) δ (ppm) 9.53 (d, J = 6.4 Hz, 1H), 8.95 (s,
1H), 8.55 (d, J = 8.0 Hz, 1H), 8.06 (d, J = 8.0 Hz, 1H), 7.76 (t, J = 7.4 Hz, 1H), 7.67 (t, J = 7.4 Hz,
1
H), 7.38 (t, J = 5.0 Hz, 1H), 3.66 (t, J = 5.4 Hz, 2H), 3.47 (t, J = 7.4 Hz, 2H), 2.08–2.01 (m, 2H).
1
3
1
C{ H} NMR (100 MHz, DMSO-d
6
) δ (ppm) 155.9, 151.2, 151.1, 146.3, 144.6, 138.2, 129.2,
+
1
15 4
26.3, 122.8, 120.9, 119.6, 109.7, 60.6, 32.7, 30.5. HRMS (ESI) m/z calcd for C16H N O
+
[
M+H] 279.1240, found 279.1246.
3
-(Thiazolo[2',3':2,3]imidazo[4,5-c]quinolin-6-yl)propan-1-ol (3q). White solid (43.6 mg, 77%
o
1
yield). mp 185−187 C. H NMR (400 MHz, DMSO-d
6
) δ (ppm) 8.53 (d, J = 4.4 Hz, 1H), 8.42 (d,
J = 7.2 Hz, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.70–7.59 (m, 3H), 4.87 (s, 1H), 3.62 (t, J = 5.8 Hz, 2H),
13
1
3
.38 (t, J = 7.8 Hz, 2H), 2.04–1.97 (m, 2H). C{ H} NMR (100 MHz, DMSO-d
6
) δ (ppm) 158.0,
1
49.4, 148.9, 144.2, 129.1, 128.0, 126.1, 122.8, 122.0, 121.4, 121.2, 114.7, 60.6, 31.9, 31.4.
+
+
14 3
HRMS (ESI) m/z calcd for C15H N OS [M+H] 284.0852, found 284.0854.
3
-(2-Methoxypyrido[2',1':2,3]imidazo[4,5-c]quinolin-6-yl)propan-1-ol (3r). Brown solid (43.6
o
1
6
mg, 71%). mp 173−175 C. H NMR (400 MHz, DMSO-d ) δ (ppm) 9.10 (d, J = 6.8 Hz, 1H),
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2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
4
4
4
4
5
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5
5
5
5
5
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6
7
3
.99–7.87 (m, 3H), 7.72 (t, J = 7.8 Hz, 1H), 7.35 (dd, J = 9.0, 2.6 Hz, 1H), 7.23 (t, J = 6.6 Hz, 1H),
1
3
1
.97 (s, 3H), 3.67 (t, J = 6.0 Hz, 2H), 3.47 (t, J = 7.8 Hz, 2H), 2.06–2.00 (m, 2H). C{ H} NMR
(
100 MHz, DMSO-d
6
) δ (ppm) 157.5, 148.9, 148.0, 145.8, 139.7, 130.6, 130.4, 129.4, 122.1,
+
1
18 3 2
21.4, 119.9, 117.7, 113.3, 101.7, 60.7, 55.9, 32.7, 30.9. HRMS (ESI) m/z calcd for C18H N O
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
[
M+H] 308.1394, found 308.1397.
3
8
8
7
-(2-Fluoropyrido[2',1':2,3]imidazo[4,5-c]quinolin-6-yl)propan-1-ol (3s). White solid (48.4 mg,
o
1
6
2% yield). mp 214−216 C. H NMR (400 MHz, DMSO-d ) δ (ppm) 9.09 (d, J = 7.2 Hz, 1H),
.12–8.07 (m, 2H), 7.92 (d, J = 9.2 Hz, 1H), 7.73 (t, J = 7.8 Hz, 1H), 7.58 (td, J = 8.9, 2.9 Hz, 1H),
.24 (t, J = 6.8 Hz, 1H), 4.81 (s, 1H), 3.67 (t, J = 6.0 Hz, 2H), 3.47 (t, J = 7.8 Hz, 2H), 2.06–1.99
13
1
(
m, 2H). C{ H} NMR (100 MHz, DMSO-d
6
) δ (ppm) 160.0 (d, J = 245.1 Hz), 150.2, 149.1,
1
45.8, 141.6, 131.8 (d, J = 9.2 Hz), 130.8, 129.4, 122.1 (d, J = 12.0 Hz), 121.5, 117.8, 117.8 (d, J
=
C
24.0 Hz), 113.6, 106.5 (d, J = 22.7 Hz), 60.7, 32.9, 30.7. HRMS (ESI) m/z calcd for
+
+
17 3
H15FN O [M+H] 296.1194, found 296.1199.
3-(2-Chloropyrido[2',1':2,3]imidazo[4,5-c]quinolin-6-yl)propan-1-ol (3t). White solid (49.8 mg,
o
1
6
80% yield). mp 208−210 C. H NMR (400 MHz, DMSO-d ) δ (ppm) 9.07 (d, J = 6.8 Hz, 1H),
8.38 (d, J = 2.0 Hz, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.75–7.66 (m, 2H),
7.25 (t, J = 6.6 Hz, 1H), 4.81 (s, 1H), 3.67 (q, J = 5.3 Hz, 2H), 3.45 (t, J = 7.8 Hz, 2H), 2.06–1.99
1
3
1
(m, 2H). C{ H} NMR (100 MHz, DMSO-d
6
) δ (ppm) 151.3, 149.2, 145.2, 142.9, 131.1, 131.0,
1
30.4, 129.4, 128.9, 122.1, 121.7, 121.4, 117.8, 113.6, 60.7, 32.9, 30.6. HRMS (ESI) m/z calcd for
+
+
C
17 3
H15ClN O [M+H] 312.0898, found 312.0902.
3
7
7
1
-(3-Bromopyrido[2',1':2,3]imidazo[4,5-c]quinolin-6-yl)propan-1-ol (3u). White solid (56.1 mg,
o
1
9% yield). mp 219−221 C. H NMR (400 MHz, DMSO-d
6
) δ (ppm) 9.11 (s, 1H), 8.42 (d, J =
.6 Hz, 1H), 8.19 (s, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.76 (t, J = 7.6 Hz, 2H), 7.26 (t, J = 6.0 Hz,
1
3
1
H), 4.83 (s, 1H), 3.67 (t, J = 4.8 Hz, 2H), 3.48 (t, J = 6.2 Hz, 2H), 2.06–1.99 (m, 2H). C{ H}
NMR (100 MHz, DMSO-d
6
) δ (ppm) 151.8, 149.2, 145.8, 145.1, 130.8, 130.7, 129.2, 128.6, 124.4,
+
1
3
21.5, 121.3, 119.9, 117.7, 113.5, 60.7, 32.8, 30.5. HRMS (ESI) m/z calcd for C17H15BrN O
+
[
M+H] 356.0393, found 356.0398.
Methyl 6-(3-hydroxypropyl)pyrido[2',1':2,3]imidazo[4,5-c]quinoline-3-carboxylate (3v). White
o
1
solid (58.3 mg, 87% yield). mp 247−249 C. H NMR (400 MHz, DMSO-d
6
) δ (ppm) 9.15 (d, J =
5
.2 Hz, 1H), 8.62 (s, 2H), 8.12 (d, J = 8.0 Hz, 1H), 7.96 (d, J = 7.6 Hz, 1H), 7.76 (d, J = 6.0 Hz,
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H), 7.27 (t, J = 6.4 Hz, 1H), 3.96 (s, 3H), 3.70 (t, J = 5.6 Hz, 2H), 3.55 (t, J = 5.8 Hz, 2H), 2.15–
1
3
1
2
.09 (m, 2H). C{ H} NMR (100 MHz, DMSO-d
6
) δ (ppm) 166.1, 151.6, 148.9, 145.1, 143.2,
1
30.5, 130.2, 129.0, 124.7, 123.8, 122.7, 121.8, 117.4, 113.2, 60.2, 52.3, 32.4, 29.9. HRMS (ESI)
+
+
18 3 3
m/z calcd for C19H N O [M+H] 336.1343, found 336.1347.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
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5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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4
5
6
7
8
9
0
1
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4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4
-(Pyrido[2',1':2,3]imidazo[4,5-c]quinolin-6-yl)butan-2-ol (4b). Yellow solid (46.0 mg, 79%
o
1
yield). mp 102−104 C. H NMR (400 MHz, DMSO-d
6
) δ (ppm) 9.17 (s, 1H), 8.57 (s, 1H), 8.09–
7
.96 (m, 2H), 7.75–7.66 (m, 3H), 7.26 (s, 1H), 4.94 (s, 1H), 3.91 (s, 1H), 3.62 (t, J = 10.4 Hz, 2H),
13
1
1
.97–1.88 (m, 2H), 1.20 (s, 3H). C{ H} NMR (100 MHz, DMSO-d
6
) δ (ppm) 151.0, 149.1,
1
46.3, 144.6, 130.7, 129.4, 129.0, 128.7, 126.1, 122.6, 121.3, 117.8, 113.4, 66.0, 37.0, 32.8, 24.2.
+
+
18 3
HRMS (ESI) m/z calcd for C18H N O [M+H] 292.1444, found 292.1446.
4
-(Pyrido[2',1':2,3]imidazo[4,5-c]quinolin-6-yl)butan-1-ol (4c). White solid (41.3 mg, 71% yield).
o
1
6
mp 182−184 C. H NMR (400 MHz, DMSO-d ) δ (ppm) 9.08 (d, J = 6.8 Hz, 1H), 8.57 (d, J = 7.6
Hz, 1H), 8.09 (d, J = 8.0 Hz, 1H), 7.96 (d, J = 8.8 Hz, 1H), 7.75 (t, J = 7.0 Hz, 2H), 7.66 (t, J =
7.2 Hz, 1H), 7.26 (t, J = 6.6 Hz, 1H), 4.52 (s, 1H), 3.54–3.46 (m, 4H), 1.97–1.89 (m, 2H), 1.73–
1
3
1
1.66 (m, 2H). C{ H} NMR (100 MHz, DMSO-d
6
) δ (ppm) 150.9, 149.1, 146.3, 144.7, 130.7,
129.4, 129.1, 128.7, 126.1, 122.6, 121.4, 121.3, 117.8, 113.5, 60.9, 36.0, 32.4, 24.1. HRMS (ESI)
+
+
m/z calcd for C18
18 3
H N O [M+H] 292.1444, found 292.1447.
2
6
Pyrido[2',1':2,3]imidazo[4,5-c]quinoline (4d). White solid (38.6 mg, 88% yield). mp 253−255
o
1
C. H NMR (400 MHz, DMSO-d
6
) δ (ppm) 9.82 (s, 1H), 9.39 (d, J = 6.8 Hz, 1H), 8.60 (d, J = 8.0
Hz, 1H), 8.19 (d, J = 8.4 Hz, 1H), 7.93 (d, J = 9.2 Hz, 1H), 7.81–7.71 (m, 3H), 7.25 (t, J = 6.8 Hz,
1
3
1
1
1
H). C{ H} NMR (100 MHz, DMSO-d
6
) δ (ppm) 149.0, 145.7, 145.6, 138.3, 131.7, 130.0,
+
10 3
28.7, 128.0, 126.9, 122.8, 122.7, 122.1, 117.6, 113.1. HRMS (ESI) m/z calcd for C14H N
+
[
M+H] 220.0869, found 220.0869.
2
7
6
2
1
-Phenylpyrido[2',1':2,3]imidazo[4,5-c]quinoline (4e). White solid (47.2 mg, 80% yield). mp
o
1
21−223 C. H NMR (400 MHz, DMSO-d
6
) δ (ppm) 8.65 (d, J = 7.6 Hz, 1H), 8.16 (d, J = 8.4 Hz,
H), 8.03 (d, J = 6.8 Hz, 1H), 7.96 (d, J = 9.2 Hz, 1H), 7.83–7.68 (m, 8H), 7.03 (t, J = 7.0 Hz, 1H).
13
1
C{ H} NMR (100 MHz, DMSO-d
6
) δ (ppm) 149.7, 148.6, 147.0, 144.8, 138.5, 131.3, 130.0,
1
29.6, 129.5, 129.2, 127.5, 126.9, 122.8, 121.5, 120.5, 118.1, 113.0. HRMS (ESI) m/z calcd for
+
+
C
20 14 3
H N [M+H] 296.1182, found 296.1187.
28
6
-Propylpyrido[2',1':2,3]imidazo[4,5-c]quinoline (4f). White solid (21.9 mg, 42% yield). mp
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6
o
1
1
7
7
3
24−126 C. H NMR (400 MHz, CDCl ) δ (ppm) 8.73–8.71 (m, 2H), 8.25 (d, J = 8.0 Hz, 1H),
.95 (d, J = 8.8 Hz, 1H), 7.78 (t, J = 7.4 Hz, 1H), 7.69 (t, J = 7.2 Hz, 1H), 7.60 (t, J = 7.6 Hz, 1H),
.11 (t, J = 6.6 Hz, 1H), 3.47 (t, J = 7.8 Hz, 2H), 2.04–1.95 (m, 2H), 1.21 (t, J = 7.2 Hz, 3H).
1
3
1
C{ H} NMR (100 MHz, CDCl
3
) δ (ppm) 149.7, 149.4, 147.2, 144.3, 129.5, 128.8, 128.4, 127.4,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
1
16 3
26.1, 122.6, 121.2, 121.1, 118.4, 112.9, 38.7, 21.5, 14.2. HRMS (ESI) m/z calcd for C17H N
+
[
M+H] 262.1339, found 262.1337.
■ ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI:
1
13
1
Control experiments, copies of H NMR and C{ H} NMR spectra for all products.
AUTHOR INFORMATION
Corresponding Author
■
*
*
E-mail: sunpeipei@njnu.edu.cn
E-mail: pingliu@njnu.edu.cn
ORCID
Peipei Sun: 0000-0002-1716-2343
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS
This work was supported by the National Natural Science Foundation of China (Project 21672104,
21502097), the Natural Science Foundation of the Education Department of Jiangsu province
(15KJB150015), and the Priority Academic Program Development of Jiangsu Higher Education
Institutions. The authors also thank Mr. Hailong Liu for the determination of HRMS.
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