Electrocatalytic Tandem Synthesis of 1,3-Disubstituted Imidazo[1,5- a]quinolines via Sequential Dual Oxidative C(sp3)-H Amination in Aqueous Medium

Article abstract of DOI:10.1021/acs.joc.8b03014

An NH₄I-mediated tandem electrosynthesis of 1,3-disubstituted imidazo[1,5-a]quinolines was developed from readily available starting materials in aqueous medium, affording a variety of 1,3-disubstituted imidazo[1,5-a]quinolines with good to excellent yields.

Full text of DOI:10.1021/acs.joc.8b03014

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Article
Electrocatalytic Tandem Synthesis of 1,3-Disubstituted
Imidazo[1,5-a]quinolines via Sequential Dual
Oxidative C(sp3)-H Amination in Aqueous Medium
Peng Qian, Zicong Yan, Zhenghong Zhou, Kangfei Hu,
Jiawei Wang, Zhibin Li, Zhenggen Zha, and Zhiyong Wang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b03014 • Publication Date (Web): 16 Jan 2019
Downloaded from http://pubs.acs.org on January 17, 2019
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Electrocatalytic Tandem Synthesis of 1,3-Disubstituted
Imidazo[1,5-a]quinolines via Sequential Dual Oxidative
C(sp3)−H Amination in Aqueous Medium
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Peng Qian,† Zicong Yan,† Zhenghong Zhou, Kangfei Hu, Jiawei Wang, Zhibin Li, Zhenggen
Zha* and Zhiyong Wang*
Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory of Soft
Matter Chemistry & Center for Excellence in Molecular Synthesis of Chinese Academy of
Sciences, Collaborative Innovation Center of Suzhou Nano Science and Technology & School of
Chemistry and Materials Science, University of Science and Technology of China, Hefei, Anhui
230026, P. R . China.
†These authors contributed equally to this work
E-mail:zwang3@ustc.edu.cn
zgzha@ustc.edu.cn
R3
R1
NH2
R3
electricity
undivided cell
CCE
R2
N
COOH
NH2
R2
N
R2 = COOEt, COOMe
R4
N
Aqueous medium
R
COPh
43 examples
up to 99% yield
External oxidant-free
Transition metal-free
Broad substrate scope
Scalable
Readily available starting materials
ABSTRACT:
An
NH4I-mediated
tandem
electrosynthesis
of
1,3-disubstituted
imidazo[1,5-a]quinolines was developed from readily available starting materials in aqueous
medium, affording a variety of 1,3-disubstituted imidazo[1,5-a]quinolines with good to
excellent yields
.
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Introduction
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N-containing compounds are widely existed in pharmaceutical, agrochemical and material
industries.1 Methods development for direct C(sp3)−H/N−H oxidative coupling to construct C−N
bonds in a more efficient and sustainable manner has been pursued by organic chemists.2, 3 The
rapid growth in direct amination of C(sp3)−H bonds catalysed by transition-metals has been
witnessed in recent years.2d-e However, the residue of transition metal catalysts on drugs synthesis
leads to concern about human healthy. Afterwards, some metal-free amination reactions3 were
reported in the presence of stoichiometric chemical oxidants. Nevertheless, the usage of
stoichiometric chemical oxidants inevitably leads to waste, undesired reactions and low atom
economy. Therefore, it remains to be desirable and challenging for organic chemists to construct
C−N bonds under metal catalysts and chemical oxidants free conditions.
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Organic electrochemistry provides the possibility for C−N formation because it employs electrons
as reagents.4, 5 In general, the electrochemical reaction can be performed at room temperature
without the use of chemical oxidants, which makes it safety and low cost for large-scale industrial
application. Recently, organic electrochemistry has undergone a renaissance. Major elegant
contributions have been made by Moeller,6 Xu,7 Yoshida8 Lei,9 Mei,10 and Ackermannm11 for
C(sp2)–H amination reactions. However, the direct intermolecular C(sp3)–H amination
cyclization of reactions have not been explored yet.
1,3-Disubstituted imidazo[1,5-a]quinolines as one of the important scaffolds in N-containing
compounds, are widely present in pharmaceutical agent molecules and optoelectronic materials.12
However, the reported methods13 usually suffered from the metal catalysts, chemical oxidants and
high temperature. To overcome these issues and in continuation of our recent work on
electrochemistry in the presence of iodine,14 we herein report a tandem electrosynthesis of
1,3-disubstituted imidazo[1,5-a]quinolines from readily available amines and amino acids under
mediation of NH4I in aqueous medium at room temperature in the absence of metal and external
chemical oxidants. To the best of our knowledge, this work should represent one of the most
simple, green and efficient approach for the construction of 1,3-disubstituted
imidazo[1,5-a]quinolines under mild conditions.
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Results and Discussion
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Initially, the model reaction of ethyl 2-(quinolin-2-yl)acetate 1a with benzylamine 2a was
electrolyzed in an undivided cell at a constant current density of 15 mA/cm2, while KI was used as
the supporting salt in the co-solvent of CH3CN/H2O (5 : 1). Gratifyingly, the desired product was
obtained with a yield of 66% (Table 1, entry 1). Inspired by this result, the supporting salts were
firstly investigated. All iodide salts could conduct this reaction smoothly while either NH4Br or
LiClO4 hardly afforded the desired products (entries 5 and 6). Among these tested iodide salts,
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Table 1. Optimization of the Reaction Conditionsa
O
electrolysis
rt
O
Ph
NH2
N
OEt
N
OEt
N
Ph
1a
2a
3aa
entry
electrolyte
KI
solvent
anode/cathode
Pt/Pt
j (mA/cm2)
15
yield (%)b
66
1
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
EtOH
2
Me4NI
n-Bu4NI
NH4I
Pt/Pt
15
15
15
15
15
15
20
10
15
15
15
15
65
3
Pt/Pt
82
4
Pt/Pt
95
5
NH4Br
LiClO4
NH4I
Pt/Pt
trace
n. d.
65
6
Pt/Pt
7c
8
Pt/Pt
NH4I
Pt/Pt
83
9
NH4I
Pt/Pt
92
10
11
12
13
NH4I
C/Pt
65
NH4I
Pt/C
71
NH4I
Pt/Pt
88
NH4I
DMF
Pt/Pt
89
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NH4I
NH4I
NH4I
NH4I
CH3CN
Pt/Pt
Pt/Pt
Pt/Pt
Pt/Pt
15
91
93
91
95
15d
16e
17 f
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
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aReaction conditions: 1a (0.3 mmol), 2a (1.2 mmol), electrolyte (0.3 mmol), CH3CN/H2O = 5:1 (3
b
mL); the electrolysis was conducted in an undivided cell at room temperature. Yields of the
c
d
isolated products. The loading of NH4I was 20 mol %. The ration of CH3CN/H2O was 4:1.
eUnder O2. fUnder N2. n. d. = not detected.
NH4I gave the best result (entries 1−4). When we decreased the loading of NH4I to 20 mol %, the
reaction was still carried smoothly to afford the desired product with a moderate yield (entry 7). A
sacrificial yield was observed when the current density was increased or decreased (entries 8 and
9). The experimental results showed that the Pt electrode was the optimal electrode materials both
for anode and cathode (entries 10 and 11). Moreover, changing the solvent to EtOH, DMF,
CH3CN or the ration of CH3CN/H2O to 4 : 1 had little effect on the yield (entries 12−15). When
the reaction was performed under an oxygen atmosphere or nitrogen atmosphere, the desired
product can be obtained with yields of 91% and 95%, respectively (entries 16 and 17). These
results indicated that the reaction atmosphere also had little influence on the yields. After
investigation in detail, the optimal electrolytic conditions were described as entry 4 of table 1.
With the optimized electrolytic conditions established, we investigated the scope of aromatic
benzylamines first under the standard conditions. As shown in Table 2, all of the substrates could
tolerate this reaction well, providing the desired products 3aa−3av with 78−96% yields. The
electronic effect of the substituents on the phenyl ring of the benzylamines had little influence on
the reaction. Both electron-donating and electron-withdrawing substitutions afforded the desired
products with excellent yields (3ab−3ag vs 3ap and 3aq). Halide substituents, such as F, Cl, Br,
were also proceeded smoothly to afford the desired products with 78−93% yields (3ah−3ao).
When the ring-fused and the multi-substituted benzylamines were employed as substrates, the
corresponding products can be obtained with 89% and 82% yields (3ar and 3as), respectively.
When the phenyl ring of the benzylamines was replaced by the heterocyclic rings, these
heterocyclic rings can be compatible with the reaction conditions, giving the corresponding
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product in 84−95% yields (3at−3av). However, for the aliphatic amines with long chain, no
desired product was observed (3aw).
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Table 2. The Scope of Aminesa
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O
NH4I (1 equiv)
CH3CN/H2O (5/1)
Pt/Pt J = 15 mA/cm2
O
R1
NH2
N
OEt
N
OEt
N
R1
3aa-3aw
rt
1a
2a-2w
entry
R1
product
yield (%)b
1
2
Ph (2a)
3aa
95
90
90
89
91
96
91
87
90
86
89
91
88
78
93
96
4-Me-Ph (2b)
3-Me-Ph (2c)
2-Me-Ph (2d)
4-OMe-Ph (2e)
2-OMe-Ph (2f)
3,4-CH2O-Ph (2g)
4-F-Ph (2h)
3ab
3ac
3ad
3ae
3af
3
4
5
6
7
3ag
3ah
3ai
8
9
3-F-Ph (2i)
10
11
12
13
14
15
16
2-F-Ph (2j)
3aj
4-Cl-Ph (2k)
3-Cl-Ph (2l)
3ak
3al
2-Cl-Ph (2m)
4-Br-Ph (2n)
2-Br-Ph (2o)
4-CF3-Ph (2p)
3am
3an
3ao
3ap
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3-CF3-Ph (2q)
1-naphthyl (2r)
2-Cl-4-F-Ph(2s)
2-furyl (2t)
3aq
3ar
3as
3at
90
89
82
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87
2-thienyl (2u)
2-pryidyl (2v)
Bn (2w)
3au
3av
3aw
84
95
n.d.
aReaction conditions: 1a (0.3 mmol), 2a-2w (1.2 mmol), NH4I (0.3 mmol), CH3CN/H2O = 5:1 (3
mL); the electrolysis was conducted in an undivided cell at room temperature. bThe isolated yields
after column chromatography. n. d. = not detected.
Subsequently, a variety of ethyl 2-(quinolin-2-yl)acetate derivatives were also examined. As
shown in scheme 1, both electron-donating and electron-withdrawing groups on the quinolinyl
ring had influence on the reaction (3ba−3ha). Generally, the withdrawing groups of R3 gave
superior results to the donating groups of R3 (3ha vs 3ea−3ga). When R2 was varied from COOEt
to COOMe or benzoyl group, the reaction also worked well, affording the corresponding products
with 85% and 65% yields, respectively (3ia and 3ja). Furthermore, ethyl
2-(isoquinolin-1-yl)acetate 1k and ethyl 2-(pyridin-2-yl)acetate 1l, in which the quinolinyl ring
was changed, were also good substrates in this reaction, providing the desired products with good
yields (3ka and 3la).
Scheme 1. The Scope of 1
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R3
R3
NH4I (1 equiv)
CH3CN/H2O (5/1)
Pt/Pt J = 15 mA/cm2
R2
N
Ph
NH2
R2
N
N
rt
Ph
3ba-3la
7
1b-1l
2a
8
9
3
3
COOMe
3ba 95%
3fa 85%
,
R = Cl,
,
R = CH3,
N
3
3
t
3ca 99%
3ga 86%
R = Br,
,
R = Bu,
,
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N
R3 = F,
,
R3 = CF3,
,
3da 98%
3ha 98%
Ph
R3 = OMe,
,
R2 = COOEt
3ea 86%
3ia, 85%
COOEt
COPh
Ph
N
N
N
N
N
N
Ph
Ph
3la, 75%
EtOOC
3ka, 64%
3ja, 65%
aReaction conditions: 1b-1l (0.3 mmol), 2a (1.2 mmol), NH4I (0.3 mmol), CH3CN/H2O = 5:1 (3
mL); the electrolysis was conducted in an undivided cell at room temperature; the isolated yields
after column chromatography.
To demonstrate the practicality of this reaction, a gram scale experiment was conducted (scheme
2a). Gratifyingly, the desired product 3aa can be obtained with good yields. It was noted that an
unexpected transfer esterification cyclizaiton product was obtained when the co-solvent was
replaced by the methanol (scheme 2b). What is more, this electrocatalytic reaction can be also
applied to the synthesis of polysubstituted oxazoles 3ma in aqueous medium (scheme 2c), which
further enhanced the practicality of this reaction.
Scheme 2. Gram-Scale and Transfer Esterification Cyclization Reaction.
O
NH4I (1 equiv)
CH3CN/H2O (5/1)
Pt/Pt J = 15 mA/cm2
O
a)
Ph
NH2
N
OEt
N
OEt
N
Ph
rt
19.2 mmol
4.8 mmol (1.03 g )
3aa, 80% yield (1.21 g )
nBu4NI (1 equiv)
O
O
MeOH
b)
Ph
NH2
N
OMe
Pt/Pt J = 15 mA/cm2
rt
N
O
OEt
N
Ph
2a
2a
3ia, 61% yield
1a
Ph
NH4I (1 equiv)
CH3CN/H2O (5/1)
Pt/Pt J = 15 mA/cm2
O
O
c)
O
Ph
NH2
Ph
OEt
N
OEt
Ph
rt
1m
3ma, 65% yield
Recently, utilization of α-amino acids for the synthesis of heterocyclic compounds are increasing
due to its low cost and readily available. Then we further extended the substrate scope by the use
of the amino acids in place of amines with a modified condition (scheme 3). As expected, both
aromatic and alkyl amino acids could proceed the reaction smoothly to afford the corresponding
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products with moderate yields (3aa−3aB). The wide scope of amino acids provided a great
5
6
practicality of this electrocatalytic reaction.
7
8
Scheme 3. Electrosynthesis of 1,3-Disubstituted Imidazo[1,5-a]quinolines from Amino Acids.
9
CH3CN/NaHCO3 (sat)
O
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nBu4NI (1 equiv)
COOH
O
N
R4
NH2
OEt
Pt/Pt J = 10 mA/cm2
50 oC
N
OEt
N
R4
3aa-3aB
1a
3aa 55%
2'
4
4
3ab 45%
R = Ph,
,
R =4-Me-Ph,
,
4
3ah 51%
R =4-F-Ph,
,
4
4
3am 50%
3ax 50%
,
R =2-Cl-Ph,
,
R = H,
4
n
4
i
3ay 41%
3az 38%
R = Pr,
,
R = Pr,
,
4
s
4
i
3aA 39%
3aB 48%
R = Bu,
,
R = Bu,
,
To gain a better understanding of the reaction mechanism, some control experiments were carried
out (scheme 4). First, the reaction was intercepted to investigate the possible reaction intermediate.
Actually, both amine 7 and desired product 3aa could be observed when the model substrates
were electrolyzed for 12 h. The imine 7 could be further transformed into 3aa with a prolonged
electrolysis time (scheme 4a). The imine intermediate could be further confirmed by the forming
of ethyl 2-((4-methoxyphenyl)imino)-2-(quinolin-2-yl)acetate 7' (scheme 4b). These results
indicate that the imine 7 was a key intermediate under our conditions. Furthermore, when the
secondary amine, such as piperidine, was used to replace benzylamine, an aminated product 5'
was obtained with 80% yield (scheme 4c). This result implies that the aminated intermediate may
be also involved under our conditions, which could be further oxidized into the imine intermediate
7. On the other hand, the imine intermediate 7 could be also formed via the condensation reaction
between 6 and 2a. When the compound 6 was employed under the standard conditions, only 42%
yield of the desired product was obtained and the reaction mixture was messy (scheme 4d). This
result indicates that the compound 6 was not the major intermediate in the reaction. When
molecular iodine was employed as oxidant, the desired product and intermediate 7 were obtained
with the yield of 32% and 50%, respectively (scheme 4e). These results suggest that the in situ
electrogenerated molecular iodine should be the active specie in the reaction.
Scheme 4.Control Experiments for the Reaction
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standard conditions
O
O
3aa
a)
2a
N
OEt
N
OEt
NBn
1a
7
electrolysis time
yield of 7
yield of 3aa
8
9
12 h
24 h
21%
75%
95%
trace
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NH2
O
standard conditions
O
O
b)
c)
N
OEt
N
OEt
OEt
N
1a
OMe
7', 92%
OMe
O
standard conditions
HN
N
OEt
N
N
1a
5', 80%
3aa
standard conditions
I2 (2.0 equiv.)
O
d)
2a
2a
N
OEt
42%
O
O
6
O
3aa
e)
NH4BF4 (1.0 equiv.)
CH3CN/H2O
N
OEt
N
OEt
NBn
7, 50%
1a
32%
Based on the above-mentioned results and the previous reports,13 a possible reaction mechanism
was proposed and depicted in scheme 5. First, anodically in situ generated molecular iodine reacts
with substrate 1a to generate the iodinated intermediate 4. The reaction between intermediate 4
and benzylamine 2a gives intermediate 5. Subsequently, the intermediate 5 could be sequentially
oxidized in the presence of molecular iodine to yield intermediate 8, which could be further
converted to the desired product 3aa through the tandem cyclization process. Meanwhile, the
proton is reduced on the cathode surface with the liberation of hydrogen gas. In the case of
phenylglycine as the coupling partner, it reacts with the iodinated intermediate 4 to afford
intermediate 9, followed by the oxidation of molecular iodine to give intermediate 10. The
intermediate 10 can convert to intermediate 11 in the presence of molecular iodine and sodium
bicarbonate.15 The intermediate 11 is unstable and easily undergoes decarboxylative/oxidative
amination/aromatization process to give the final product 3aa.
Scheme 5. Proposed Reaction Mechanism for the Formation of 3aa
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Ph
N
N
OEt
amination
-H+
3aa
7
8
O
H2
8
9
-CO2
-HI
-e
COOI
COOH
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N
Ph
N
Ph
N
OEt
N
OEt
NaHCO3
I2
2H
Cathode
O
O
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10
I2
COOH
-2HI
HN
Ph
I2
N
OEt
O
N
N
OEt
NH2
O
Ph
COOH
1a
4
9
I
NHBn
N
OEt
O
OEt
BnNH2
-HI
I
Anode
O
5
Ph
I2
-2HI
N
NBn
O
N
OEt
N
OEt
I2
amination
-H+
3aa
O
-2HI
8
7
In summary, we developed a facile and efficient approach for the electrosynthesis of
1,3-disubstituted imidazo[1,5-a]quinolines in aqueous medium under the metal and chemical
oxidants free conditions. A wide scope of substrates, readily available starting materials and
gram-scale experiments made this reaction practicality.
Experimental Section
General Information: All products were characterized by H NMR and 13C{1H}NMR, using
1
TMS as an internal reference (1H NMR: 400MHz, 13C{1H}NMR: 100MHz). HRMS (ESI) data
were recorded on a Q-TOF Premier. Commercial reagent and solvents were used without
purification unless otherwise indicated.
Preparation of Substrates: Substrates 1l, 1m and 2 are commercially available. Substrates 1f, 1i
and 1j were prepared according to the previously reported procedures.16-18 Other substrates 1
(1a-1e, 1g, 1h and 1k) were synthesized by using our previous literature procedure.19
General Procedures for the Synthesis of 1: A mixture of 7.08 g diisopropylamine (9.8 mL, 70
mmol) and 10 mL of dried THF was added to a three-necked flask by syringe under N2. After
cooling down to -78 °C, 28.4 mL of n-butyl lithium (2.4 M in hexane, 68 mmol) was slowly added.
The mixture was stirred for 30 minutes. Then 3.5 g of 2-methyl quinoline (3.3 mL, 24 mmol) was
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slowly added. The colour turned to orange rapidly then dark-brown. After 30 minutes, 10.6 g of
diethyl carbonate (11 mL, 90 mmol) was added and the mixture was stirred for 2 hours. The
reaction was quenched by 10 mL of water followed by extracted by EtOAc. The combined organic
layers were dried over Na2SO4 and evaporated in vacuo. The residue was purified by silica gel
column chromatography (petroleum ether / ethyl acetate = 20:1) to give 1a as a light yellow oil:
(3.8 g, 74%); 1H NMR (CDCl3, 400 MHz, ppm): δ = 8.14 (d, J = 8.4 Hz, 1H), 8.07 (d, J = 8.7 Hz,
1H), 7.82−7.80 (m, 1H), 7.73−7.68 (m, 1H), 7.55−7.51 (m, 1H), 7.44 (d, J = 8.4 Hz, 1H), 4.20 (q,
J = 7.1 Hz, 2H), 4.04 (s, 2H), 1.27 (t, J = 7.1 Hz, 3H); 13C{1H}NMR (CDCl3, 100 MHz, ppm): δ =
170.5, 154.8, 147.8, 136.7, 129.6, 129.1, 127.5, 127.1, 126.4, 121.8, 61.1, 44.8, 14.2. HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C13H14NO2 216.1025; Found 216.1023.
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Synthesis of 1b: The title compound was prepared according to the general working procedure for
the synthesis of 1 using 6-chloro-2-methylquinoline (10 mmol, 1.77 g) as the starting material in
70% (1.74 g) yield as yellow solid. m.p. 101–103 oC; 1H NMR (CDCl3, 400 MHz, ppm): δ = 8.05
(d, J = 8.5 Hz, 1H), 8.00 (d, J = 9.0 Hz, 1H), 7.79−7.78 (m, 1H), 7.65−7.62 (m, 1H), 7.46 (d, J =
8.5 Hz, 1H), 4.20 (q, J = 7.1 Hz, 2H), 4.03 (s, 2H), 1.27 (t, J = 7.1 Hz, 3H); 13C{1H}NMR (CDCl3,
100 MHz, ppm): δ = 170.3, 155.2, 146.1, 135.8, 132.2, 130.7, 130.6, 127.6, 126.2, 122.7, 61.2,
44.7, 14.2. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C13H13ClNO2 250.0635; Found 250.0634.
Synthesis of 1c: The title compound was prepared according to the general working procedure for
the synthesis of 1 using 6-bromo-2-methylquinoline (10 mmol, 2.21 g) as the starting material in
75% (2.20 g) yield as yellow solid. m.p. 104–106 oC; 1H NMR (CDCl3, 400 MHz, ppm): δ = 8.05
(d, J = 8.5 Hz, 1H), 7.97−7.93 (m, 2H), 7.78−7.75 (m, 1H), 7.46 (d, J = 8.5 Hz, 1H), 4.20 (q, J =
7.1 Hz, 2H), 4.03 (s, 2H), 1.27 (t, J = 7.2 Hz, 3H); 13C{1H}NMR (CDCl3, 100 MHz, ppm): δ =
170.2, 155.3, 146.3, 135.7, 133.1, 130.8, 129.6, 128.2, 122.7, 120.3, 61.2, 44.7, 14.2. HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C13H13BrNO2 294.0130; Found 294.0131.
Synthesis of 1d: The title compound was prepared according to the general working procedure for
the synthesis of 1 using 6-fluoro-2-methylquinoline (10 mmol, 1.61 g) as the starting material in
1
60% (1.40 g) yield as yellow oil. H NMR (CDCl3, 400 MHz, ppm): δ = 8.08−8.03 (m, 2H),
7.48−7.39 (m, 3H), 4.20 (q, J = 7.1 Hz, 2H), 4.01 (s, 2H), 1.26 (t, J = 7.1 Hz, 3H); 13C{1H}NMR
(CDCl3, 100 MHz, ppm): δ = 170.4, 160.4 (d, J = 246.5 Hz), 154.2 (d, J = 2.7 Hz), 144.9, 136.0 (d,
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J = 5.2 Hz), 131.6 (d, J = 9.0 Hz), 127.6 (d, J = 9.8 Hz), 122.6, 119.7 (d, J = 25.5 Hz), 110.5 (d, J
= 21.7 Hz), 61.2, 44.6, 14.2. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C13H13FNO2 234.0930;
Found 234.0929.
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Synthesis of 1e: The title compound was prepared according to the general working procedure for
the synthesis of 1 using 6-methoxy-2-methylquinoline (10 mmol, 1.73 g) as the starting material in
65% (1.59 g) yield as yellow solid. m.p. 45–47 oC; 1H NMR (CDCl3, 400 MHz, ppm): δ = 8.02 (d,
J = 8.5 Hz, 1H), 7.95 (d, J = 9.2 Hz, 1H), 7.39−7.33 (m, 2H), 7.06−7.05 (m, 1H), 4.19 (q, J = 7.1
Hz, 2H), 3.99 (s, 2H), 3.91 (s, 3H), 1.26 (t, J = 7.2 Hz, 3H); 13C{1H}NMR (CDCl3, 100 MHz,
ppm): δ = 170.7, 157.7, 152.2, 143.9, 135.5, 130.4, 128.0, 122.3, 122.0, 105.1, 61.1, 55.5, 44.5,
14.2. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C14H16NO3 246.1130; Found 246.1128.
Synthesis of 1g: The title compound was prepared according to the general working procedure for
the synthesis of 1 using 6-(tert-butyl)-2-methylquinoline (10 mmol, 1.99 g) as the starting material
in 62% (1.68 g)yield as yellow oil. 1H NMR (CDCl3, 400 MHz, ppm): δ = 8.09 (d, J = 8.4 Hz, 1H),
8.00 (d, J = 8.9 Hz, 1H), 7.81−7.78 (m, 1H), 7.71−7.70 (m, 1H), 7.40 (d, J = 8.4 Hz, 1H), 4.18 (q,
J = 7.1 Hz, 2H), 4.02 (s, 2H), 1.41 (s, 9H), 1.25 (t, J = 7.1 Hz, 3H); 13C{1H}NMR (CDCl3, 100
MHz, ppm): δ = 170.6, 154.1, 149.2, 146.4, 136.6, 128.6, 128.6, 126.8, 122.5, 121.7, 61.1, 44.8,
34.9, 31.2, 14.2. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C17H22NO2 272.1651; Found
272.1651.
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Synthesis of 1h: The title compound was prepared according to the general working procedure for
the synthesis of 1 using 2-methyl-6-(trifluoromethyl)quinoline (10 mmol, 2.11 g) as the starting
o
1
material in 70% (1.98 g) yield as yellow solid. m.p. 105–107 C; H NMR (CDCl3, 400 MHz,
ppm): δ = 8.22 (d, J = 8.5 Hz, 1H), 8.18−8.12 (m, 2H), 7.88−7.85 (m, 1H), 7.54 (d, J = 8.5 Hz,
1H), 4.21 (q, J = 7.1 Hz, 2H), 4.07 (s, 2H), 1.27 (t, J = 7.2 Hz, 3H); 13C{1H}NMR (CDCl3, 100
MHz, ppm): δ = 170.1, 157.3, 148.8, 137.3, 130.3, 128.3 (q, J = 32.4 Hz), 126.0, 125.5 (q, J = 4.4
Hz), 125.3 (q, J = 3.1 Hz), 124.0 (q, J = 269.9 Hz), 123.1, 61.3, 44.8, 14.2. HRMS (ESI-TOF) m/z:
[M + H]+ Calcd for C14H13F3NO2 284.0898; Found 284.0899.
Synthesis of 1k: The title compound was prepared according to the general working procedure for
the synthesis of 1 using 1-methylisoquinoline (10 mmol, 1.43 g) as the starting material in 64%
1
(1.38 g) yield as yellow oil. H NMR (CDCl3, 400 MHz, ppm): δ = 8.47 (d, J = 5.7 Hz, 1H),
8.10−8.07 (m, 1H), 7.84 (d, J = 8.1 Hz, 1H), 7.71−7.67 (m, 1H), 7.64−7.59 (m, 2H), 4.35 (s, 2H),
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4.19 (q, J = 7.2 Hz, 2H), 1.23 (t, J = 7.1 Hz, 3H); 13C{1H}NMR (CDCl3, 100 MHz, ppm): δ =
170.4, 154.6, 141.9, 136.4, 130.2, 127.6, 127.4, 127.4, 125.2, 120.5, 61.2, 42.2, 14.2. HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C13H14NO2 216.1025; Found 216.1025.
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Representative Procedures for the Synthesis of 1,3-Disubstituted Imidazo[1,5-a]quinolines
from Amines (method A): An undivided cell was equipped with a magnet stirrer, platinum-plate
(1.0 x 1.0 cm2) electrode as the working electrode and counter electrode. In the electrolytic cell, a
mixture of ethyl 2-(quinolin-2-yl)acetate derivatives 1 (0.3 mmol), amines 2 (1.2 mmol), NH4I
(0.3 mmol, 43.5 mg), CH3CN/H2O= 5:1 (3 mL) was allowed to stir and electrolyze at a constant
current conditions (15 mA/cm2) under room temperature until the reaction intermediate finished
(TLC analysis). Then the solvent was removed with a rotary evaporator and the residue was
purified by column chromatography on silica gel to afford the desired product. The product was
dried under high vacuum for at least 0.5 h before it was weighed and characterized by NMR
spectroscopy.
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Representative Procedures for the Synthesis of 1,3-Disubstituted Imidazo[1,5-a]quinolines
from Amino Acids (method B): An undivided cell was equipped with a magnet stirrer,
platinum-plate (1.0 x 1.0 cm2) electrode as the working electrode and counter electrode. In the
electrolytic cell, a mixture of ethyl 2-(quinolin-2-yl)acetate 1a, amino acids 2' (1.2 mmol),
n-Bu4NI (0.3 mmol, 110.8 mg), CH3CN/NaHCO3 (Sat) = 5:1 (3 mL) was allowed to stir and
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electrolyze at a constant current conditions (10 mA/cm2) under 50 C (water bath) until the ethyl
2-(quinolin-2-yl)acetate 1a finished (TLC analysis). Then the solvent was removed with a rotary
evaporator and the residue was purified by column chromatography on silica gel to afford the
desired product. The product was dried under high vacuum for at least 0.5 h before it was weighed
and characterized by NMR spectroscopy.
Gram-Scale Synthesis of 3aa
An undivided cell was equipped with a magnet stirrer, platinum-plate (1.5 x 1.5 cm2) electrode as
the working electrode and counter electrode. In the electrolytic cell, a mixture of ethyl
2-(quinolin-2-yl)acetate 1a (4.8 mmol), benzylamine 2a (19.2 mmol) NH4I (4.8 mmol, 696 mg),
CH3CN/H2O= 5:1 (48 mL) was allowed to stir and electrolyze at a constant current conditions (15
mA/cm2) under room temperature until the reaction intermediate finished (about 3 d). Then the
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solvent was removed with a rotary evaporator and the residue was recrystallized by EtOAc to
afford the desired product (1.21 g, 80% yield).
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Transfer Esterification Cyclizaiton Reaction
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An undivided cell was equipped with a magnet stirrer, platinum-plate (1.0 x 1.0 cm2) electrode as
the working electrode and counter electrode. In the electrolytic cell, a mixture of ethyl
2-(quinolin-2-yl)acetate 1a (0.3 mmol), benzylamine 2a (1.2 mmol), n-Bu4NI (0.3 mmol, 110.8
mg), MeOH (3 mL) was allowed to stir and electrolyze at a constant current conditions (15
mA/cm2) under room temperature until the reaction intermediate finished (TLC analysis). Then
the solvent was removed with a rotary evaporator and the residue was purified by column
chromatography on silica gel to afford the desired product. The product was dried under high
vacuum for at least 0.5 h before it was weighed and characterized by NMR spectroscopy.
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Ethyl 1-phenylimidazo[1,5-a]quinoline-3-carboxylate (3aa)13a
The title compound was prepared according to the general working procedure A (24 h, 44.8 F
mol-1) and purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give the
product as a light yellow solid: 95% yield, (90 mg), m.p. 167–168 oC; 1H NMR (CDCl3, 400 MHz,
ppm): δ = 8.20 (d, J = 9.5 Hz, 1H), 7.75−7.73 (m, 1H), 7.66−7.63 (m, 2H), 7.57−7.48 (m, 4H),
7.42−7.38 (m, 2H), 7.28−7.23 (m, 1H), 4.51 (q, J = 7.1 Hz, 2H), 1.47 (t, J = 7.1 Hz, 3H);
13C{1H}NMR (CDCl3, 100 MHz, ppm): δ = 163.7, 142.5, 134.6, 133.0, 132.1, 130.0, 129.9, 129.0,
128.9, 128.4, 126.3, 125.9, 125.4, 123.4, 117.7, 117.6, 60.6, 14.7.
Ethyl 1-(p-tolyl)imidazo[1,5-a]quinoline-3-carboxylate (3ab)
The title compound was prepared according to the general working procedure A (24 h, 44.8 F
mol-1) and purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give the
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product as a light yellow solid: 90% yield, (89 mg) , m.p. 160–163 C; H NMR (CDCl3, 400
MHz, ppm): δ = 8.19 (d, J = 9.4 Hz, 1H), 7.74−7.72 (m, 1H), 7.55−7.51 (m, 3H), 7.42−7.38 (m,
2H), 7.34−7.32 (m, 2H), 7.29−7.24 (m, 1H), 4.50 (q, J = 7.1 Hz, 2H), 2.48 (s, 3H),1.47 (t, J = 7.1
Hz, 3H); 13C{1H}NMR (CDCl3, 100 MHz, ppm): δ = 163.7, 142.7, 140.0, 134.5, 132.2, 130.0,
129.8, 129.6, 128.9, 128.3, 126.2, 125.8, 125.4, 123.2, 117.7, 117.6, 60.6, 21.6, 14.7. HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C21H19N2O2 331.1447; Found 331.1445.
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Ethyl 1-(m-tolyl)imidazo[1,5-a]quinoline-3-carboxylate (3ac)
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The title compound was prepared according to the general working procedure A (28 h, 52.2 F
mol-1) and purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give the
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product as a light yellow solid: 90% yield, (89 mg) , m.p. 139–141 C; H NMR (CDCl3, 400
MHz, ppm): δ = 8.20 (d, J = 9.5 Hz, 1H), 7.74−7.72 (m, 1H), 7.55 (d, J = 8.6 Hz, 1H), 7.50 (s, 1H),
7.44−7.36 (m, 5H), 7.29−7.25 (m, 1H) 4.52 (q, J = 7.1 Hz, 2H), 2.44 (s, 3H),1.48 (t, J = 7.1 Hz,
3H); 13C{1H}NMR (CDCl3, 100 MHz, ppm): δ = 163.6, 142.6, 138.7, 134.4, 132.7, 132.0, 130.5,
130.5, 128.8, 128.6, 128.2, 126.8, 126.2, 125.7, 125.3, 123.2, 117.5, 60.5, 21.3, 14.6. HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C21H19N2O2 331.1447; Found 331.1447.
Ethyl 1-(o-tolyl)imidazo[1,5-a]quinoline-3-carboxylate (3ad)
The title compound was prepared according to the general working procedure A (24 h, 44.8 F
mol-1) and purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give the
product as a light yellow solid: 89% yield, (88 mg), m.p. 142–145 oC; 1H NMR (CDCl3, 400 MHz,
ppm): δ = 8.22 (d, J = 9.5 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.51−7.47 (m, 2H), 7.42−7.35 (m,
4H), 7.28−7.21 (m, 2H), 4.51 (q, J = 7.1 Hz, 2H), 2.02 (s, 3H),1.47 (t, J = 7.1 Hz, 3H);
13C{1H}NMR (CDCl3, 100 MHz, ppm): δ = 163.7, 141.8, 138.5, 134.1, 133.0, 132.3, 130.6, 130.4,
130.3, 128.9, 126.5, 126.2, 125.8, 125.2, 123.1, 117.7, 116.1, 60.6, 19.6, 14.7. HRMS (ESI-TOF)
m/z: [M + H]+ Calcd for C21H19N2O2 331.1447; Found 331.1446.
Ethyl 1-(4-methoxyphenyl)imidazo[1,5-a]quinoline-3-carboxylate (3ae)
The title compound was prepared according to the general working procedure A (36 h, 67.2 F
mol-1) and purified by column chromatography (petroleum ether / ethyl acetate = 4:1) to give the
product as a light yellow solid: 91% yield, (94 mg), m.p. 171–173 oC; 1H NMR (CDCl3, 400 MHz,
ppm): δ = 8.18 (d, J = 9.4 Hz, 1H), 7.72 (d, J = 7.7 Hz, 1H),, 7.57−7.55 (m, 3H), 7.41−7.37 (m,
2H), 7.29−7.25 (m, 1H), 7.06−7.04 (m, 2H), 4.50 (q, J = 7.1 Hz, 2H), 3.92 (s, 3H),1.47 (t, J = 7.1
Hz, 3H); 13C{1H}NMR (CDCl3, 100 MHz, ppm): δ = 163.7, 160.8, 142.5, 134.5, 132.3, 131.3,
128.9, 128.3, 126.2, 125.7, 125.4, 125.2, 123.2, 117.7, 117.5, 114.3, 60.6, 55.4, 14.7. HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C21H19N2O3 347.1396; Found 347.1396.
Ethyl 1-(2-methoxyphenyl)imidazo[1,5-a]quinoline-3-carboxylate (3af)
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The title compound was prepared according to the general working procedure A (36 h, 67.2 F
mol-1) and purified by column chromatography (petroleum ether / ethyl acetate = 4:1) to give the
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product as a light yellow solid: 96% yield, (100 mg), m.p. 173–175 C; H NMR (CDCl3, 400
MHz, ppm): δ = 8.21 (d, J = 9.4 Hz, 1H), 7.72−7.70 (m, 1H),, 7.63−7.61 (m, 1H), 7.57−7.52 (m,
1H), 7.49 (d, J = 8.6 Hz, 1H), 7.40−7.36 (m, 2H), 7.27−7.23 (m, 1H), 7.16−7.12 (m, 1H),
7.00−6.98 (m, 1H), 4.54 −4.45 (m, 2H), 3.55 (s, 3H), 1.46 (t, J = 7.1 Hz, 3H); 13C{1H}NMR
(CDCl3, 100 MHz, ppm): δ = 163.8, 158.3, 139.8, 134.5, 132.7, 132.1, 131.7, 128.6, 128.4, 126.2,
125.6, 125.0, 123.1, 122.5, 121.1, 117.7, 116.5, 110.8, 60.5, 55.3, 14.7. HRMS (ESI-TOF) m/z:
[M + H]+ Calcd for C21H19N2O3 347.1396; Found 347.1397.
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Ethyl 1-(benzo[d][1,3]dioxol-5-yl)imidazo[1,5-a]quinoline-3-carboxylate (3ag)
The title compound was prepared according to the general working procedure A (27 h, 50.4 F
mol-1) and purified by column chromatography (petroleum ether / ethyl acetate = 3:1) to give the
product as a light yellow solid: 91% yield, (98 mg), m.p. 209–212 oC; 1H NMR (CDCl3, 400 MHz,
ppm): δ = 8.19 (d, J = 9.4 Hz, 1H), 7.75−7.73 (m, 1H), 7.62 (d, J = 8.5 Hz, 1H), 7.44−7.39 (m,
2H), 7.35−7.31 (m, 1H), 7.14−7.12 (m, 1H), 7.07−7.06 (m, 1H), 6.96 (d, J = 8.0 Hz, 1H), 6.10 (s,
2H), 4.50 (d, J = 7.1 Hz, 2H), 1.46 (t, J = 7.1 Hz, 3H); 13C{1H}NMR (CDCl3, 100 MHz, ppm): δ =
163.6, 149.0, 148.0, 142.0, 134.5, 132.1, 129.0, 128.5, 126.3, 126.3, 125.8, 125.4, 124.2, 123.1,
117.7, 117.6, 110.3, 108.8, 101.6, 60.6, 14.7. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C21H17N2O4 361.1188; Found 361.1185.
Ethyl 1-(4-fluorophenyl)imidazo[1,5-a]quinoline-3-carboxylate (3ah)
The title compound was prepared according to the general working procedure A (24 h, 44.8 F
mol-1) and purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give the
product as a light yellow solid: 87% yield, (87 mg), m.p. 173–176 oC; 1H NMR (CDCl3, 400 MHz,
ppm): δ = 8.19 (d, J = 9.5 Hz, 1H), 7.76−7.74 (m, 1H), 7.66−7.61 (m, 2H), 7.48−7.40 (m, 3H),
7.32−7.21 (m, 3H), 4.51 (q, J = 7.1 Hz, 2H), 1.47 (t, J = 7.1 Hz, 3H); 13C{1H}NMR (CDCl3, 100
MHz, ppm): δ = 163.7, 163.6 (d, J = 249.1 Hz), 141.4, 134.6, 132.0 (d, J = 8.5 Hz), 129.1, 129.1
(d, J = 3.5 Hz), 128.5, 126.4, 126.0, 125.4, 123.4, 117.7, 117.3, 116.2, 116.0, 60.7, 14.7. HRMS
(ESI-TOF) m/z: [M + Na]+ Calcd for C20H15FN2O2Na 357.1015; Found 357.1010.
Ethyl 1-(3-fluorophenyl)imidazo[1,5-a]quinoline-3-carboxylate (3ai)
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The title compound was prepared according to the general working procedure A (15 h, 28.0 F
mol-1) and purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give the
product as a light yellow solid: 90% yield, (90 mg), m.p. 139–142 oC; 1H NMR (CDCl3, 400 MHz,
ppm): δ = 8.19 (d, J = 9.4 Hz, 1H), 7.76−7.74 (m, 1H), 7.54−7.49 (m, 2H), 7.45−7.38 (m, 4H),
7.33−7.25 (m, 2H), 4.51 (q, J = 7.1 Hz, 2H), 1.47 (t, J = 7.1 Hz, 3H); 13C{1H}NMR (CDCl3, 100
MHz, ppm): δ = 163.5, 162.7 (d, J = 246.9 Hz), 140.9 (d, J = 2.7 Hz), 134.8 (d, J = 8.1 Hz), 134.6,
131.8, 130.6 (d, J = 8.3 Hz), 129.1, 128.6, 126.6, 126.1, 125.8 (d, J = 3.2 Hz), 125.4, 123.5, 117.5
(d, J = 15.2 Hz), 117.3, 117.1, 116.9, 60.7, 14.7. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C20H16FN2O2 335.1196; Found 335.1194.
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Ethyl 1-(2-fluorophenyl)imidazo[1,5-a]quinoline-3-carboxylate (3aj)
The title compound was prepared according to the general working procedure A (15 h, 28.0 F
mol-1) and purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give the
product as a light yellow solid: 86% yield, (86 mg), m.p. 183–185 oC; 1H NMR (CDCl3, 400 MHz,
ppm): δ = 8.21 (d, J = 9.5 Hz, 1H), 7.76−7.71 (m, 2H), 7.61−7.56 (m, 1H), 7.51 (d, J = 8.6 Hz,
1H), 7.44−7.40 (m, 2H), 7.39−7.35 (m, 1H), 7.33−7.29 (m, 1H), 7.25−7.20 (m, 1H), 4.54− 7.48
(m, 2H), 1.47 (t, J = 7.1 Hz, 3H); 13C{1H}NMR (CDCl3, 100 MHz, ppm): δ = 163.5, 160.9 (d, J =
246.8 Hz), 136.7, 134.7, 132.4 (d, J = 1.6 Hz), 132.3, 132.2, 129.0, 128.9, 126.6, 126.0, 125.2,
124.9 (d, J = 3.6 Hz), 123.7, 121.6 (d, J = 15.4 Hz), 117.5, 116.2, 115.9, 60.7, 14.7. HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C20H16FN2O2 335.1196; Found 335.1193.
Ethyl 1-(4-chlorophenyl)imidazo[1,5-a]quinoline-3-carboxylate (3ak)
The title compound was prepared according to the general working procedure A (15 h, 28.0 F
mol-1) and purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give the
product as a light yellow solid: 89% yield, (93 mg), m.p. 199–202 oC; 1H NMR (CDCl3, 400 MHz,
ppm): δ = 8.20 (d, J = 9.4 Hz, 1H), 7.77−7.75 (m, 1H), 7.62−7.59 (m, 2H), 7.54−7.50 (m, 3H),
7.46−7.41 (m, 2H), 7.34−7.30 (m, 1H), 4.51 (q, J = 7.2 Hz, 2H), 1.47 (t, J = 7.1 Hz, 1H);
13C{1H}NMR (CDCl3, 100 MHz, ppm): δ = 163.5, 141.2, 136.0, 134.7, 131.9, 131.4, 131.3, 129.2,
129.1, 128.5, 126.5, 126.0, 125.4, 123.5, 117.6, 117.4, 60.7, 14.6. HRMS (ESI-TOF) m/z: [M +
Na]+ Calcd for C20H15ClN2O2Na 373.0720; Found 373.0723.
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Ethyl 1-(3-chlorophenyl)imidazo[1,5-a]quinoline-3-carboxylate (3al)
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product as a light yellow solid: 91% yield, (95 mg) , m.p. 167–169 C; H NMR (CDCl3, 400
MHz, ppm): δ = 8.20 (d, J = 9.5 Hz, 1H), 7.77−7.75 (m, 1H), 7.70−7.69 (m, 1H), 7.56−7.51 (m,
3H), 7.49−7.41 (m, 3H), 7.34−7.30 (m, 1H) 4.51 (q, J = 7.1 Hz, 2H), 1.47 (t, J = 7.1 Hz, 3H);
13C{1H}NMR (CDCl3, 100 MHz, ppm): δ = 163.5, 140.8, 134.9, 134.7, 134.6, 131.8, 130.1, 130.1,
130.1, 129.2, 128.6, 128.1, 126.6, 126.1, 125.4, 123.6, 117.6, 117.5, 60.7, 14.7. HRMS (ESI-TOF)
m/z: [M + H]+ Calcd for C20H16ClN2O2 351.0900; Found 351.0896.
Ethyl 1-(2-chlorophenyl)imidazo[1,5-a]quinoline-3-carboxylate (3am)
The title compound was prepared according to the general working procedure A (22 h, 41.0 F
mol-1) and purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give the
product as a light yellow solid: 88% yield, (92 mg), m.p. 189–192 oC; 1H NMR (CDCl3, 400 MHz,
ppm): δ = 8.23 (d, J = 9.5 Hz, 1H), 7.76−7.74 (m, 1H), 7.70−7.67 (m, 1H), 7.56−7.54 (m, 2H),
7.50−7.40 (m, 3H), 7.32−7.29 (m, 2H) 4.51 (q, J = 7.1 Hz, 2H), 1.47 (t, J = 7.1 Hz, 3H);
13C{1H}NMR (CDCl3, 100 MHz, ppm): δ = 163.6, 139.2, 135.4, 134.3, 132.7, 132.6, 132.1, 131.6,
129.8, 129.0, 129.0, 127.5, 126.6, 126.0, 125.1, 123.3, 117.6, 116.0, 60.7, 14.7. HRMS (ESI-TOF)
m/z: [M + H]+ Calcd for C20H16ClN2O2 351.0900; Found 351.0904.
Ethyl 1-(4-bromophenyl)imidazo[1,5-a]quinoline-3-carboxylate (3an)
The title compound was prepared according to the general working procedure A (8 h, 14.9 F mol-1)
and purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give the product
as a light yellow solid: 78% yield, (92 mg), m.p. 215–218 oC; 1H NMR (CDCl3, 400 MHz, ppm):
δ = 8.18 (d, J = 9.4 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.68 (d, J = 8.3 Hz, 2H), 7.55−7.50 (m, 3H),
7.45−7.40 (m, 2H), 7.33−7.29 (m, 1H), 4.50 (q, J = 7.1 Hz, 2H), 1.47 (t, J = 7.1 Hz, 3H);
13C{1H}NMR (CDCl3, 100 MHz, ppm): δ = 163.5, 141.2, 134.7, 132.1, 131.9, 131.5, 129.2, 128.5,
126.5, 126.1, 125.4, 124.3, 123.7, 117.7, 117.4, 60.7, 14.6. HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C20H16BrN2O2 395.0395; Found 395.0397.
Ethyl 1-(2-bromophenyl)imidazo[1,5-a]quinoline-3-carboxylate (3ao)
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The title compound was prepared according to the general working procedure A (12 h, 22.4 F
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product as a light yellow solid: 93% yield, (110 mg), m.p. 184–186 C; H NMR (CDCl3, 400
MHz, ppm): δ = 8.23 (d, J = 9.5 Hz, 1H), 7.76−7.73 (m, 2H), 7.67−7.65 (m, 1H), 7.55−7.51 (m,
1H), 7.49−7.40 (m, 3H), 7.30−7.28 (m, 2H), 4.51 (q, J = 7.1 Hz, 2H), 1.47 (t, J = 7.1 Hz, 3H);
13C{1H}NMR (CDCl3, 100 MHz, ppm): δ = 163.6, 140.4, 134.8, 134.2, 133.0, 132.7, 132.1, 131.7,
129.0, 129.0, 128.0, 126.6, 126.0, 125.3, 125.1, 123.2, 117.6, 116.2, 60.7, 14.7. HRMS (ESI-TOF)
m/z: [M + H]+ Calcd for C20H16BrN2O2 395.0395; Found 395.0392.
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Ethyl 1-(4-(trifluoromethyl)phenyl)imidazo[1,5-a]quinoline-3-carboxylate (3ap)
The title compound was prepared according to the general working procedure A (10 h, 18.7 F
mol-1) and purified by column chromatography (petroleum ether / ethyl acetate = 4:1) to give the
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product as a light yellow solid: 97% yield, (112 mg), m.p. 215–217 C; H NMR (CDCl3, 400
MHz, ppm): δ = 8.22 (d, J = 9.4 Hz, 1H), 7.84−7.78 (m, 5H), 7.49−7.45 (m, 3H), 7.35−7.31 (m,
1H), 4.52 (q, J = 7.1 Hz, 2H), 1.48 (t, J = 7.1 Hz, 3H); 13C{1H}NMR (CDCl3, 100 MHz, ppm): δ =
163.4, 140.8, 136.5, 134.9, 131.8 (q, J = 32.7 Hz), 131.7, 130.4, 129.3, 128.6, 126.7, 126.2, 125.8
(q, J = 3.7 Hz), 125.5, 123.9, 123.9 (q, J = 270.9 Hz), 117.7, 117.4, 60.7, 14.6. HRMS (ESI-TOF)
m/z: [M + H]+ Calcd for C21H16F3N2O2 385.1164; Found 385.1160.
Ethyl 1-(3-(trifluoromethyl)phenyl)imidazo[1,5-a]quinoline-3-carboxylate (3aq)
The title compound was prepared according to the general working procedure A (14 h, 26.1 F
mol-1) and purified by column chromatography (petroleum ether / ethyl acetate = 3:1) to give the
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product as a light yellow solid: 90% yield, (104 mg), m.p. 163–166 C; H NMR (CDCl3, 400
MHz, ppm): δ = 8.20 (d, J = 9.6 Hz, 1H), 7.98 (s, 1H) 7.86−7.81 (m, 2H), 7.78−7.75 (m, 1H),
7.69−7.65 (m, 1H), 7.46−7.42 (m, 3H), 7.31−7.27 (m, 1H), 4.51 (q, J = 7.2 Hz, 2H), 1.47 (t, J =
7.1 Hz, 3H); 13C{1H}NMR (CDCl3, 100 MHz, ppm): δ = 163.4, 140.7, 134.8, 133.8, 133.2, 131.7,
131.4 (q, J = 32.6 Hz), 129.4, 129.3, 128.5, 127.0 (q, J = 3.7 Hz), 126.6, 126.6 (q, J = 3.7 Hz),
126.2, 125.5, 123.8, 123.7 (q, J = 270.1 Hz), 117.6, 117.3, 60.7, 14.6. HRMS (ESI-TOF) m/z: [M
+ H]+ Calcd for C21H16F3N2O2 385.1164; Found 385.1162.
Ethyl 1-(naphthalen-1-yl)imidazo[1,5-a]quinoline-3-carboxylate (3ar)
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The title compound was prepared according to the general working procedure A (24 h, 44.8 F
mol-1) and purified by column chromatography (petroleum ether / ethyl acetate = 4:1) to give the
product as a light yellow solid: 89% yield, (98 mg), m.p. 196–198 oC; 1H NMR (CDCl3, 400 MHz,
ppm): δ = 8.30 (d, J = 9.5 Hz, 1H), 8.10 (d, J = 8.3 Hz, 1H), 7.97 (d, J = 8.2 Hz, 1H), 7.78−7.76
(m, 1H), 7.72−7.71 (m, 1H), 7.67−7.63 (m, 1H), 7.52−7.48 (m, 1H), 7.46 (d, J = 9.5 Hz, 1H),
7.35−7.26 (m, 3H), 7.03−6.97 (m, 2H), 4.53 (q, J = 7.1 Hz, 2H), 1.48 (t, J = 7.1 Hz, 3H);
13C{1H}NMR (CDCl3, 100 MHz, ppm): δ = 163.8, 140.7, 134.4, 133.6, 132.5, 132.0, 130.6, 130.6,
129.2, 128.8, 128.7, 128.5, 127.3, 126.6, 126.5, 125.7, 125.6, 125.3, 125.2, 123.5, 117.7, 117.1,
60.6, 14.7. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C24H18N2O2Na 389.1266; Found
389.1267.
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Ethyl 1-(2-chloro-4-fluorophenyl)imidazo[1,5-a]quinoline-3-carboxylate (3as)
The title compound was prepared according to the general working procedure A (16 h, 29.9 F
mol-1) and purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give the
product as a light yellow solid: 82% yield, (90 mg), m.p. 218–220 oC; 1H NMR (CDCl3, 400 MHz,
ppm): δ = 8.24 (d, J = 9.5 Hz, 1H), 7.79−7.77 (m, 1H), 7.71−7.67 (m, 1H), 7.48−7.44 (m, 2H),
7.37−7.30 (m, 3H), 7.25−7.20 (m, 1H), 4.52 (q, J = 7.1 Hz, 2H), 1.48 (t, J = 7.1 Hz, 3H);
13C{1H}NMR (CDCl3, 100 MHz, ppm): δ = 163.6 (d, J = 253.0 Hz), 163.4, 138.2, 136.7 (d, J =
10.3 Hz), 134.4, 133.9 (d, J = 9.1 Hz), 132.0, 129.1, 129.1, 129.0 (d, J = 3.7 Hz), 126.6, 126.1,
125.1, 123.4, 117.6, 117.5 (d, J = 25.0 Hz), 115.8, 114.9 (d, J = 21.4 Hz), 60.7, 14.6. HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C20H15FClN2O2 369.0806; Found 369.0803.
Ethyl 1-(furan-2-yl)imidazo[1,5-a]quinoline-3-carboxylate (3at)
The title compound was prepared according to the general working procedure A (24 h, 44.8 F
mol-1) and purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give the
product as a light yellow solid: 87% yield, (80 mg), m.p. 144–146 oC; 1H NMR (CDCl3, 400 MHz,
ppm): δ = 8.20 (d, J = 9.4 Hz, 1H), 7.78−7.75 (m, 1H), 7.68−7.67 (m, 1H), 7.49−7.41 (m, 3H),
7.15−7.13 (m, 1H), 6.97−6.96 (m, 1H), 6.69−6.67 (m, 1H), 4.51 (q, J = 7.1 Hz, 2H), 1.48 (t, J =
7.1 Hz, 3H); 13C{1H}NMR (CDCl3, 100 MHz, ppm): δ = 163.4, 143.9, 143.6, 134.8, 132.5, 131.8,
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129.2, 129.0, 127.0, 126.2, 125.3, 123.7, 117.3, 116.9, 114.0, 112.0, 60.7, 14.6. HRMS (ESI-TOF)
m/z: [M + H]+ Calcd for C18H15N2O3 307.1083; Found 307.1082.
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Ethyl 1-(thiophen-2-yl)imidazo[1,5-a]quinoline-3-carboxylate (3au)
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The title compound was prepared according to the general working procedure A (14 h, 26.1 F
mol-1) and purified by column chromatography (petroleum ether / ethyl acetate = 4:1) to give the
product as a light yellow solid: 84% yield, (81 mg), m.p. 165–168 oC; 1H NMR (CDCl3, 400 MHz,
ppm): δ = 8.20 (d, J = 9.4 Hz, 1H), 7.76−7.74 (m, 1H), 7.62−7.60 (m, 1H), 7.56 (d, J = 8.6 Hz,
1H), 7.45−7.40 (m, 3H), 7.36−7.32 (m, 1H), 7.24−7.22 (m, 1H), 4.50 (q, J = 7.1 Hz, 2H), 1.47 (t, J
= 7.1 Hz, 3H); 13C{1H}NMR (CDCl3, 100 MHz, ppm): δ = 163.5, 135.2, 134.9, 132.8, 132.1,
130.7, 129.0, 128.9, 128.7, 127.5, 126.7, 126.0, 125.4, 123.6, 117.4, 117.2, 60.7, 14.6. HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C18H15N2SO2 323.0854; Found 323.0850.
Ethyl 1-(pyridin-2-yl)imidazo[1,5-a]quinoline-3-carboxylate (3av)
The title compound was prepared according to the general working procedure A (24 h, 44.8 F
mol-1) and purified by column chromatography (petroleum ether / ethyl acetate = 2:1) to give the
product as a light yellow solid: 95% yield, (90 mg), m.p. 156–158 oC; 1H NMR (CDCl3, 400 MHz,
ppm): δ = 8.72−8.70 (m, 1H), 8.17 (d, J = 9.4 Hz, 1H), 7.99−7.97 (m, 1H), 7.94−7.90 (m, 1H),
7.72−7.70 (m, 1H), 7.47−7.38 (m, 4H), 7.32−7.27 (m, 1H), 4.49 (q, J = 7.1 Hz, 2H), 1.46 (t, J =
7.1 Hz, 3H); 13C{1H}NMR (CDCl3, 100 MHz, ppm): δ = 163.4, 151.5, 149.2, 141.2, 137.3, 135.0,
131.7, 128.7, 128.2, 126.9, 126.0, 125.7, 125.3, 124.3, 123.5, 118.3, 117.3, 60.6, 14.5. HRMS
(ESI-TOF) m/z: [M + Na]+ Calcd for C19H15N3O2Na 340.1062; Found 340.1059.
Ethyl 7-chloro-1-phenylimidazo[1,5-a]quinoline-3-carboxylate (3ba)
The title compound was prepared according to the general working procedure A (24 h, 44.8 F
mol-1) and purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give the
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product as a light yellow solid: 95% yield, (100 mg), m.p. 177–180 C; H NMR (CDCl3, 400
MHz, ppm): δ = 8.22 (d, J = 9.5 Hz, 1H), 7.69−7.68 (m, 1H), 7.62−7.51 (m, 5H), 7.41 (d, J = 9.2
Hz, 1H), 7.29 (d, J = 9.5 Hz, 1H), 7.21−7.18 (m, 1H), 4.50 (q, J = 7.1 Hz, 2H), 1.46 (t, J = 7.1 Hz,
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3H); 13C{1H}NMR (CDCl3, 100 MHz, ppm): δ = 163.4, 142.5, 134.0, 132.5, 131.4, 130.4, 130.1,
129.8, 129.0, 128.3, 127.9, 126.7, 125.0, 123.8, 118.9, 118.8, 60.7, 14.6. HRMS (ESI-TOF) m/z:
[M + H]+ Calcd for C20H16ClN2O2 351.0900; Found 351.0900.
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Ethyl 7-bromo-1-phenylimidazo[1,5-a]quinoline-3-carboxylate (3ca)
The title compound was prepared according to the general working procedure A (16 h, 29.9 F
mol-1) and purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give the
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product as a light yellow solid: 99% yield, (117 mg), m.p. 197–199 C; H NMR (CDCl3, 400
MHz, ppm): δ = 8.21 (d, J = 9.5 Hz, 1H), 7.86 (s, 1H), 7.62−7.59 (m, 2H), 7.57−7.51 (m, 3H),
7.34−7.29 (m, 3H), 4.50 (q, J = 7.1 Hz, 2H), 1.46 (t, J = 7.1 Hz, 3H); 13C{1H}NMR (CDCl3, 100
MHz, ppm): δ = 163.4, 142.6, 134.1, 132.5, 131.2, 131.1, 130.9, 130.2, 129.8, 129.1, 127.1, 125.0,
123.8, 119.2, 119.1, 119.0, 60.8, 14.6. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C20H16BrN2O2
395.0395; Found 395.0391.
Ethyl 7-fluoro-1-phenylimidazo[1,5-a]quinoline-3-carboxylate (3da)
The title compound was prepared according to the general working procedure A (24 h, 44.8 F
mol-1) and purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give the
product as a white solid: 98% yield, (98 mg), m.p. 184–186 oC; 1H NMR (CDCl3, 400 MHz, ppm):
δ = 8.24 (d, J = 9.5 Hz, 1H), 7.65−7.62 (m, 2H), 7.58−7.52 (m, 3H), 7.49−7.46 (m, 1H), 7.42−7.39
(m, 1H), 7.34 (d, J = 9.5 Hz, 1H), 7.01−6.96 (m, 1H), 4.51 (q, J = 7.1 Hz, 2H), 1.47 (t, J = 7.1 Hz,
3H); 13C{1H}NMR (CDCl3, 100 MHz, ppm): δ = 163.5, 159.7 (d, J = 245.8 Hz), 142.4, 134.0,
132.6, 130.1, 129.9, 129.0, 128.5(d, J = 2.2 Hz), 127.1 (d, J = 8.6 Hz), 125.4 (d, J = 2.7 Hz), 123.7,
119.4 (d, J = 8.2 Hz), 118.9, 116.1 (d, J = 23.8 Hz), 113.9 (d, J = 22.5 Hz), 60.7, 14.6. HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C20H16FN2O2 335.1196; Found 335.1198.
Ethyl 7-methoxy-1-phenylimidazo[1,5-a]quinoline-3-carboxylate (3ea)
The title compound was prepared according to the general working procedure A (28 h, 52.2 F
mol-1) and purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give the
product as a white solid: 85% yield, (88 mg), m.p. 168–170 oC; 1H NMR (CDCl3, 400 MHz, ppm):
δ = 8.18 (d, J = 9.4 Hz, 1H), 7.65−7.62 (m, 2H), 7.55−7.52 (m, 3H), 7.40 (d, J = 9.4 Hz, 1H), 7.34
(d, J = 9.5 Hz, 1H), 7.14−7.13 (m, 1H), 6.85−6.82 (m, 1H), 4.50 (q, J = 7.1 Hz, 2H), 3.86 (s, 3H),
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1.46 (t, J = 7.1 Hz, 3H); 13C{1H}NMR (CDCl3, 100 MHz, ppm): δ = 163.7, 157.0, 142.0, 134.2,
133.0, 130.0, 129.9, 128.9, 126.8, 126.4, 126.1, 123.3, 118.9, 118.1, 116.5, 110.6, 60.6, 55.6, 14.7.
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C21H19N2O3 347.1396; Found 347.1399.
Ethyl 7-methyl-1-phenylimidazo[1,5-a]quinoline-3-carboxylate (3fa)
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The title compound was prepared according to the general working procedure A (28 h, 52.2 F
mol-1) and purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give the
product as a white solid: 85% yield, (84 mg), m.p. 188–191 oC; 1H NMR (CDCl3, 400 MHz, ppm):
δ = 8.16 (d, J = 9.4 Hz, 1H), 7.64−7.62 (m, 2H), 7.55−7.50 (m, 4H), 7.36−7.34 (m, 2H), 7.08−7.06
(m, 1H), 4.50 (q, J = 7.1 Hz, 2H), 2.42 (s, 3H), 1.46 (t, J = 7.1 Hz, 3H); 13C{1H}NMR (CDCl3,
100 MHz, ppm): δ = 163.7, 142.3, 135.7, 134.5, 132.9, 130.1, 130.0, 129.9, 129.6, 128.9, 128.8,
126.4, 125.4, 123.2, 117.5, 117.4, 60.6, 20.9, 14.7. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C21H19N2O2 331.1447; Found 331.1445.
Ethyl 7-(tert-butyl)-1-phenylimidazo[1,5-a]quinoline-3-carboxylate (3ga)
The title compound was prepared according to the general working procedure A (28 h, 52.2 F
mol-1) and purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give the
product as a light yellow solid: 86% yield, (96 mg), m.p. 134–136 oC; 1H NMR (CDCl3, 400 MHz,
ppm): δ = 8.18 (d, J = 9.4 Hz, 1H), 7.69 (d, J = 2.4 Hz, 1H), 7.66−7.63 (m, 2H), 7.57−7.51 (m,
3H), 7.42−7.40 (m, 2H), 7.33−7.30 (m, 1H), 4.50 (q, J = 7.1 Hz, 2H), 1.47 (t, J = 7.1 Hz, 3H),
1.35 (s, 9H); 13C{1H}NMR (CDCl3, 100 MHz, ppm): δ = 163.8, 148.9, 142.2, 134.6, 130.1, 130.0,
129.8, 129.0, 128.8, 126.8, 126.3, 125.1, 125.1, 123.1, 117.4, 117.2, 60.6, 34.6, 31.2, 14.7. HRMS
(ESI-TOF) m/z: [M + Na]+ Calcd for C24H24N2O2Na 395.1735; Found 395.1731.
Ethyl 1-phenyl-7-(trifluoromethyl)imidazo[1,5-a]quinoline-3-carboxylate (3ha)
The title compound was prepared according to the general working procedure A (12 h, 22.4 F
mol-1) and purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give the
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product as a yellow solid: 98% yield, (113 mg), m.p. 170–172 C; H NMR (CDCl3, 400 MHz,
ppm): δ = 8.28 (d, J = 9.5 Hz, 1H), 8.01 (s, 1H), 7.64−7.53 (m, 6H), 7.50−7.47 (m, 1H), 7.43 (d, J
= 9.5 Hz, 1H), 4.51 (q, J = 7.1 Hz, 2H), 1.47 (t, J = 7.1 Hz, 3H); 13C{1H}NMR (CDCl3, 100 MHz,
ppm): δ = 163.3, 142.9, 134.2, 133.8, 132.3, 130.3, 129.8, 129.1, 127.9 (q, J = 33.3 Hz), 126.1 (q,
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J = 4.0 Hz), 125.5, 125.3, 124.7 (q, J = 3.5 Hz), 124.0, 123.5 (q, J = 270.6 Hz), 119.2, 118.1, 60.8,
14.6. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C21H15F3N2O2 Na 407.0983; Found 407.0980.
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Methyl 1-phenylimidazo[1,5-a]quinoline-3-carboxylate (3ia)
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The title compound was prepared according to the general working procedure A (24 h, 44.8 F
mol-1) and purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give the
product as a light yellow solid: 85% yield, (77 mg), m.p. 160–162 oC; 1H NMR (CDCl3, 400 MHz,
ppm): δ = 8.21 (d, J = 9.4 Hz, 1H), 7.76−7.74 (m, 1H), 7.66−7.64 (m, 2H), 7.57−7.51 (m, 4H),
7.43−7.40 (m, 2H), 7.29−7.25 (m, 1H), 4.01 (s, 3H); 13C{1H}NMR (CDCl3, 100 MHz, ppm): δ =
164.0, 142.6, 134.7, 132.9, 132.1, 129.9, 129.9, 129.0, 128.9, 128.5, 126.5, 125.9, 125.4, 123.0,
117.6, 117.5, 51.7. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C19H15N2O2 303.1134; Found
303.1130.
Phenyl(1-phenylimidazo[1,5-a]quinolin-3-yl)methanone (3ja)
The title compound was prepared according to the general working procedure A (24 h, 44.8 F
mol-1) and purified by column chromatography (petroleum ether / ethyl acetate = 20:1) to give the
product as a light yellow solid: 65% yield, (68 mg), m.p. 168–170 oC; 1H NMR (CD3SOCD3, 400
MHz, ppm): δ = 8.37 (d, J = 9.4 Hz, 1H), 8.33−8.31 (m, 2H), 7.99 (d, J = 7.8 Hz, 1H), 7.80 (d, J =
9.5 Hz, 1H), 7.74−7.71 (m, 2H), 7.67−7.58 (m, 4H), 7.54−7.50 (m, 3H), 7.44−7.39 (m, 2H);
13C{1H}NMR (CD3SOCD3, 100 MHz, ppm): δ = 187.6, 141.9, 138.8, 135.6, 133.4, 132.4, 131.8,
130.6, 130.6, 130.3, 129.8, 129.6, 129.4, 128.8, 128.5, 126.7, 125.8, 118.0, 117.4. HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C24H17N2O 349.1341; Found 349.1340.
Ethyl 3-phenylimidazo[5,1-a]isoquinoline-1-carboxylate (3ka)
The title compound was prepared according to the general working procedure A (24 h, 44.8 F
mol-1) and purified by column chromatography (petroleum ether / ethyl acetate = 6:1) to give the
product as a light yellow solid: 94% yield, (61 mg), m.p. 152–154 oC; 1H NMR (CDCl3, 400 MHz,
ppm): δ = 9.85 (d, J = 8.1 Hz, 1H), 7.98 (d, J = 7.4 Hz, 1H), 7.78−7.75 (m, 2H), 7.69−7.65 (m,
2H), 7.60−7.51 (m, 4H), 6.97 (d, J = 7.4 Hz, 1H), 4.57 (q, J = 7.1 Hz, 2H), 1.51 (t, J = 7.1 Hz,
3H); 13C{1H}NMR (CDCl3, 100 MHz, ppm): δ = 164.3, 140.9, 132.8, 129.8, 129.4, 129.1, 128.9,
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128.9, 128.6, 127.8, 126.8, 125.3, 124.3, 120.3, 115.8, 61.0, 14.6. HRMS (ESI-TOF) m/z: [M +
Na]+ Calcd for C20H16N2O2 Na 339.1110; Found 339.1107.
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Ethyl 3-phenylimidazo[1,5-a]pyridine-1-carboxylate (3la)13a
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The title compound was prepared according to the general working procedure A (24 h, 44.8 F
mol-1) and purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give the
product as a light yellow solid: 75% yield, (60 mg), m.p. 129–130 oC; 1H NMR (CDCl3, 400 MHz,
ppm): δ = 8.30−8.23 (m, 2H), 7.80−7.77 (m, 2H), 7.54−7.45 (m, 3H), 7.14−7.10 (m, 1H),
6.79−6.75 (m, 1H) 4.49 (q, J = 7.1 Hz, 2H), 1.46 (t, J = 7.1 Hz, 3H); 13C{1H}NMR (CDCl3, 100
MHz, ppm): δ = 163.6, 139.2, 135.4, 129.6, 129.1, 129.0, 128.8, 124.2, 122.5, 121.8, 120.1, 114.4,
60.4, 14.7.
Ethyl 2,5-diphenyloxazole-4-carboxylate (3ma)20
The title compound was prepared according to the general working procedure A (24 h, 44.8 F
mol-1) and purified by column chromatography (petroleum ether / ethyl acetate = 30:1) to give the
product as a yellow solid: 65% yield, (57 mg), m.p. 85–86 oC; 1H NMR (CDCl3, 400 MHz, ppm):
δ = 8.20−8.10 (m, 4H), 7.54−7.46 (m, 6H), 4.47 (q, J = 7.1 Hz, 2H), 1.44 (t, J = 7.1 Hz, 3H);
13C{1H}NMR (CDCl3, 100 MHz, ppm): δ = 162.3, 159.8, 155.1, 131.1, 130.3, 128.8, 128.6, 128.4,
128.3, 127.1, 126.9, 126.4, 61.5, 14.3.
Ethyl imidazo[1,5-a]quinoline-3-carboxylate (3ax)
The title compound was prepared according to the general working procedure B (6 h, 7.5 F mol-1)
and purified by column chromatography (petroleum ether / ethyl acetate = 2:1) to give the product
as a pink solid: 50% yield, (36 mg), m.p. 157–159 oC; 1H NMR (CDCl3, 400 MHz, ppm): δ = 8.65
(s, 1H), 8.09−8.04 (m, 2H), 7.80−7.78 (m, 1H), 7.69−7.65 (m, 1H), 7.55−7.51 (m, 1H), 7.41 (d, J
= 9.5 Hz, 1H), 4.49 (q, J = 7.1 Hz, 2H), 1.48 (t, J = 7.1 Hz, 3H); 13C{1H}NMR (CDCl3, 100 MHz,
ppm): δ = 163.4, 132.8, 130.6, 129.6, 129.2, 128.0, 126.4, 126.0, 124.4, 124.2, 117.5, 114.9, 60.6,
14.6. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C14H12N2O2 Na 263.0797; Found 263.0794.
Ethyl 1-propylimidazo[1,5-a]quinoline-3-carboxylate (3ay)
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The title compound was prepared according to the general working procedure B (7 h, 8.7 F mol-1)
and purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give the product
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as a yellow solid: 41% yield, (35 mg), m.p. 127–129 C; H NMR (CDCl3, 400 MHz, ppm): δ =
8.18 (d, J = 8.6 Hz, 1H), 8.11 (d, J = 9.5 Hz, 1H), 7.76−7.74 (m, 1H), 7.65−7.61 (m, 1H),
7.51−7.47 (m, 1H), 7.31 (d, J = 9.4 Hz, 1H), 4.48 (q, J = 7.1 Hz, 2H), 3.43−3.39 (m, 2H),
2.04−1.94 (m, 2H), 1.46 (t, J = 7.1 Hz, 3H), 1.13 (t, J = 7.4 Hz, 3H); 13C{1H}NMR (CDCl3, 100
MHz, ppm): δ = 163.6, 144.6, 134.6, 132.7, 129.1, 128.8, 125.6, 125.6, 121.9, 117.9, 116.7, 60.5,
34.3, 20.7, 14.7, 13.9. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C17H19N2O2 283.1447; Found
283.1447.
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Ethyl 1-isopropylimidazo[1,5-a]quinoline-3-carboxylate (3az)19b
The title compound was prepared according to the general working procedure B (7 h, 8.7 F mol-1)
and purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give the product
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as a yellow solid: 38% yield, (32 mg), m.p. 118–119 C; H NMR (CDCl3, 400 MHz, ppm): δ =
8.29 (d, J = 8.7 Hz, 1H), 8.13 (d, J = 9.4 Hz, 1H), 7.77−7.75 (m, 1H), 7.65−7.61 (m, 1H),
7.51−7.47 (m, 1H), 7.31 (d, J = 9.5 Hz, 1H), 4.49 (q, J = 7.1 Hz, 2H), 3.92−3.82 (m, 1H), 1.62 (d,
J = 6.7 Hz, 6H), 1.47 (t, J = 7.4 Hz, 3H); 13C{1H}NMR (CDCl3, 100 MHz, ppm): δ = 163.8, 150.0,
134.6, 132.8, 129.2, 128.8, 125.8, 125.6, 125.5, 122.0, 118.1, 117.3, 60.5, 30.3, 21.5, 14.6.
Ethyl 1-(sec-butyl)imidazo[1,5-a]quinoline-3-carboxylate (3aA)
The title compound was prepared according to the general working procedure B (7 h, 8.7 F mol-1)
and purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give the product
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as a yellow solid: 39% yield, (35 mg), m.p. 116–118 C; H NMR (CDCl3, 400 MHz, ppm): δ =
8.23 (d, J = 8.6 Hz, 1H), 8.12 (d, J = 9.5 Hz, 1H), 7.76−7.73 (m, 1H), 7.64−7.60 (m, 1H),
7.50−7.46 (m, 1H), 7.29 (d, J = 9.4 Hz, 1H), 4.48 (q, J = 7.0 Hz, 2H), 3.64−3.56 (m, 1H),
2.28−2.18 (m, 1H), 1.92−1.81 (m, 1H), 1.59 (d, J = 6.7 Hz, 3H), 1.46 (t, J = 7.1 Hz, 3H);
13C{1H}NMR (CDCl3, 100 MHz, ppm): δ = 163.8, 149.4, 134.4, 132.8, 129.2, 128.7, 125.8, 125.5,
125.5, 122.1, 118.1, 117.2, 60.4, 37.0, 28.4, 18.6, 14.6, 12.0. HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C18H21N2O2 297.1603; Found 297.1602.
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Ethyl 1-isobutylimidazo[1,5-a]quinoline-3-carboxylate (3aB)
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The title compound was prepared according to the general working procedure B (7 h, 8.7 F mol-1)
and purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give the product
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as a yellow solid: 48% yield, (43 mg), m.p. 140–142 C; H NMR (CDCl3, 400 MHz, ppm): δ =
8.19 (d, J = 8.6 Hz, 1H), 8.13 (d, J = 9.4 Hz, 1H), 7.77−7.75 (m, 1H), 7.66−7.61 (m, 1H),
7.51−7.47 (m, 1H), 7.32 (d, J = 9.4 Hz, 1H), 4.50 (q, J = 7.1 Hz, 2H), 3.35 (d, J = 7.2 Hz, 2H),
2.42−2.32 (m, 1H), 1.46 (t, J = 7.1 Hz, 3H), 1.06 (d, J = 6.6 Hz, 6H); 13C{1H}NMR (CDCl3, 100
MHz, ppm): δ = 163.6, 143.8, 134.6, 132.5, 129.1, 128.7, 125.5, 125.5, 121.9, 117.8, 116.7, 60.4,
40.7, 26.4, 22.3, 14.6. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C18H21N2O2 297.1603; Found
297.1602.
Ethyl 2-((4-methoxyphenyl)imino)-2-(quinolin-2-yl)acetate (7')
The title compound was prepared according to the general working procedure A (7 h, 13.1 F mol-1)
and purified by column chromatography (petroleum ether / ethyl acetate = 20:1) to give the
product as a light yellow oil: 92% yield, (92 mg); 1H NMR (CDCl3, 400 MHz, ppm): δ = 8.33 (d,
J = 8.6 Hz, 1H), 8.25 (d, J = 8.5 Hz, 1H), 8.12 (d, J = 8.5 Hz, 1H), 7.87−7.84 (m, 1H), 7.75−7.71
(m, 1H), 7.62−7.58 (m, 1H), 7.17−7.13 (m, 2H), 6.95−6.91 (m, 2H), 4.38 (q, J = 7.1 Hz, 2H), 3.84
(s, 3H), 1.25 (t, J = 7.1 Hz, 3H); 13C{1H}NMR (CDCl3, 100 MHz, ppm): δ = 165.7, 159.8, 157.9,
153.3, 147.4, 142.2, 136.6, 130.3, 129.6, 128.7, 127.9, 127.5, 121.9, 118.4, 114.1, 61.4, 55.4, 14.1.
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C20H19N2O3 335.1396; Found 335.1393.
Ethyl 2-(piperidin-1-yl)-2-(quinolin-2-yl)acetate (5')
The title compound was prepared according to the general working procedure A (2 h, 3.7 F mol-1)
and purified by column chromatography (petroleum ether / ethyl acetate = 15:1) to give the
product as a light yellow oil: 82% yield, (73 mg); 1H NMR (CDCl3, 400 MHz, ppm): δ = 8.16 (d,
J = 8.5 Hz, 1H), 8.10 (d, J = 8.3 Hz, 1H), 7.82−7.76 (m, 2H), 7.72−7.68 (m, 1H), 7.55−7.51 (m,
1H), 4.46 (s, 1H), 4.26−4.15 (m, 2H), 2.57−2.47 (m, 4H), 1.64−1.59 (m, 4H), 1.50−1.43 (m, 2H),
1.23 (t, J = 7.2 Hz, 3H); 13C{1H}NMR (CDCl3, 100 MHz, ppm): δ = 171.0, 157.4, 147.5, 136.5,
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129.5, 129.4, 127.6, 127.4, 126.6, 120.6, 76.9, 60.9, 52.2, 25.9, 24.2, 14.2. HRMS (ESI-TOF) m/z:
[M + H]+ Calcd for C18H23N2O2 299.1760; Found 299.1757.
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ASSOCIATED CONTENT
Supporting Information
1H NMR and 13C {1H}NMR spectra for the substrates 1 (1a-1e, 1g, 1h and 1k) and all the
products as well as the photographic depiction of the electrolysis setup. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
Fax: 86-551-3631760. E-mail: zwang3@ustc.edu.cn
zgzha@ustc.edu.cn
ORCID
Zhiyong Wang: 0000-0002-3400-2851
Zhenggen Zha: 0000-0002-5388-0115
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS：
We are grateful for the financial support from the National Natural Science Foundation of China
(21672200, 21472177, 21432009, 21772185) and the assistance of the product characterization
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from the Chemistry Experiment Teaching Center of University of Science and Technology of
China. This work was supported by the Strategic Priority Research Program of the Chinese
Academy of Sciences, Grant No. XDB20000000.
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