Copper-Promoted Double Oxidative C-H Amination Cascade for the Synthesis of Imidazo[1,5-a]quinolines

Article abstract of DOI:10.1021/acs.joc.6b00569

A copper-promoted cascade reaction of 2-methylazaarenes and benzylamines has been developed via sequential double oxidative C(sp³)-H aminations. This protocol provides straightforward access to imidazo[1,5-a]quinoline derivatives without employing prefunctionalized substrates.

Full text of DOI:10.1021/acs.joc.6b00569

Subscriber access provided by Brown University Library
Note
Copper-promoted Double Oxidative C-H Amination
Cascade for the Synthesis of Imidazo[1,5-a]quinolines
Zhong Li, Song-Song Wu, Zai-Gang Luo, Wei-Kang Liu, Cheng-Tao Feng, and Shi-Tang Ma
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00569 • Publication Date (Web): 25 Apr 2016
Downloaded from http://pubs.acs.org on April 25, 2016
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 21
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Copperꢀpromoted Double Oxidative CꢀH Amination
Cascade for the Synthesis of Imidazo[1,5ꢀa]quinolines
Zhong Li †, SongꢀSong Wu †, ZaiꢀGang Luo †, WeiꢀKang Liu †, ChengꢀTao Feng †* and ShiꢀTang
Ma ‡ *
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
†School of Chemical Engineering, Anhui University of Science and Technology, Huainan, Anhui, 232001,
P. R. China
Eꢀmail: fengct2010@163.com
‡College of Food and Drug, Anhui Science and Technology University, Fengyang, Anhui, 233100,
P. R. China
Eꢀmail: nothingchina@126.com
ABSTRACT: A copperꢀpromoted cascade reaction of 2ꢀmethylazaarenes and benzylamines has been
developed via sequential double oxidative C(sp3)−H aminations. This protocol provides straightforward
access to imidazo[1,5ꢀa]quinoline derivatives without employing preꢀfunctionalized substrates.
Imidazo[1,5ꢀa]quinolines are an important class of fused Nꢀheterocyclic compounds due to their wide
applications in medicinal chemistry (e.g., NK1 receptor ligands).1 A great deal of attention has been paid
to synthesize imidazo[1,5ꢀa]quinoline derivatives.2 The most popular strategy for the synthesis of
imidazo[1,5ꢀa]quinolines is Vilsmeierꢀtype cyclizations, which involved the use of
Nꢀ2ꢀpyridylmethylamides as substrates.3 Another attractive tool is C−H amination based strategy. Zeng4
(Scheme 1a) and Xu5 (Scheme 1b) have respectively developed interesting copper catalyzed oxidative
tandem cyclization reactions of Nꢀheteroaryl aldehydes or ketones with alkylamines to construct
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 21
1
2
3
4
5
imidazo[1,5ꢀa]quinolines. Recently, Wang has reported
a
novel protocol to synthesize
6
7
8
9
imidazo[1,5ꢀa]pyridines and ꢀquinolines via sequential dual oxidative amination of C(sp3)ꢀH bonds in
the presence of stoichiometric Nꢀiodobutanimide (Scheme 1c).6a Later, the same reaction was performed
employing CuI as catalyst by Adimurthy.6b However, electronꢀwithdrawing substituents on the carbon
are necessary for these reactions. Moreover, the amination of 2ꢀalkylazaarenes with aliphatic primary
amines is difficult because of oxidative olefination reactions.7 The development of efficient methods for
the synthesis of imidazo[1,5ꢀa]quinolines from 2ꢀmethylquinolines without an activating group or
preꢀfunctionalization still remains a significant challenge.8
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 1. C−H amination based strategies for the synthesis of imidazo[1,5ꢀa]quinolines.
2ꢀalkylazaarenes, which are inexpensive and broadly available, have emerged as a useful class of
building blocks mainly in the form of a nucleophilic coupling partner for syntheses of various important
organic compounds.9 The additions of 2ꢀalkylazaarenes to a series of unsaturated bonds, including C=N
double bond,10a C=C double bond,10b C=O double bond,10c N=N double bond,10d have been developed
mostly to form acyclic compounds, while the cascade reactions of 2ꢀalkylazaarenes to synthesize
heterocyclic compounds have not been extensively studied. Metal catalyzed intermolecular direct
ACS Paragon Plus Environment

Page 3 of 21
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
oxidative aminations of the sp2 C−H bond have been well established in recent years.11 As
2ꢀmethyquinoline can be isomerized to a nonaromatic emamine intermediate in the presence of transition
metal,9 we hypothesized that metal catalyzed or promoted dual C(sp3)−H amination of
2ꢀmethylazaarenes with alkylamines might be doable to construct heterocyclic compounds. In
continuation of our interest in the quinolineꢀbased synthesis of heterocycles,12 herein, we describe the
direct synthesis of imidazo[1,5ꢀa]quinoline derivatives from commercially accessible 2ꢀmethylazaarenes
and benzylamines (Scheme 1d).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
We began to study the dual C(sp3)−H amination reaction utilizing 2ꢀmethylquinoline 1a and
benzylamine 2a as model substrates to optimize the reaction conditions (Table 1). When the reaction was
performed in DMF in the presence of 1 equiv. of CuI and 2 equiv. of diꢀtꢀbutyl peroxide (DTBP) for 12 h
at 110℃, the desired 1ꢀphenylimidazo[1,5ꢀa]quinoline 3aa was obtained in a 35% yield (Table 1, entry
1). The effect of solvents for this cascade reaction was examined. DMSO was found to be the optimal
solvent to give 3aa in a 57% yield (Table 1, entry 2). When other solvents (polar protic solvents or
nonpolar solvents) were utilized, inferior results were obtained (Table 1, entries 3ꢀ6). A screening of
oxidants, including DTBP, O2, TBHP, I2, K2S2O8 and DDQ, showed that DTBP was still to be the best
choice (Table 1, entries 7ꢀ11). Subsequently, we turned our attention to the effect of copper salts. Among
the tested copper salts, such as CuCl, CuBr, Cu(OAc)2·H2O, CuI and CuI2, CuI afforded 3aa in the
highest yield (Table 1, entries 12ꢀ15). The reaction did not proceed at all in the absence of a copper salt
(Table 1, entry16). When the amount of CuI was increased to two equivalents, a positive result was
observed and the yield of 3aa was improved to 68% (Table 1, entry 17). Recently, Zhang found that the
combination of 1 equiv. of CuCl and 1 equiv. of Cu(OAc)2·H2O could mediate annulation of alkyl
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 21
1
2
3
4
5
6
7
8
9
ketones with α,βꢀunsaturated carboxylic acids to afford furan products.13 Inspired by this results, we
carried out our reaction in the presence of 1 equiv. of CuI and 1 equiv. of Cu(OAc)2·H2O, the yield of
3aa was increased to 83% (Table 1, entry18). When 2.0 equiv. of Cu(OAc)2·H2O was used, the yield of
3aa was decreased to 34% (Table 1, entry19). Based on these results, the optimized reaction conditions
of 100 mol% CuI, 100 mol% Cu(OAc)2·H2O, and 200 mol% DTBP in DMSO at 110℃ were used for
further investigation.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 1. Optimization of reaction conditions.a
Copper salt,
Oxidant,
N
NH2
+
N
Solvent, 110°C
N
1a
2a
3aa
Entry
Cu salt
CuI
Oxidant
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
TBHP
K2S2O8
I2
Solvent
DMF
Yield (%)b
35
1
2
CuI
DMSO
DMA
57
3
CuI
41
4
CuI
EtOH
trace
12
5
CuI
H2O
6
CuI
PhMe
nd
7
CuI
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
36
8
CuI
trace
trace
trace
38
9
CuI
10
11
12
CuI
DDQ
O2
CuI
CuBr
DTBP
26
ACS Paragon Plus Environment

Page 5 of 21
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
13
14
CuCl
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
40
45
17
nd
68
83
34
Cu(OAc)2·H2O
15
CuI2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
16
ꢀ
17c
18d
19e
CuI
CuI/Cu(OAc)2·H2O
Cu(OAc)2·H2O
aReaction conditions: 1a (0.2 mmol), 2a (0.6 mmol), Cu salt (0.2 mmol), DTBP (0.4 mmol), solvent (1.5
ml), 110 °C, 24 h. bIsolated yield. Two equivalents of CuI were used. dCuI (0.2 mmol) and
c
Cu(OAc)2·H2O (0.2 mmol) were used. eTwo equivalents of Cu(OAc)2·H2O were used.
With the optimal conditions in hand, the substrate scope of the double oxidative CꢀH amination
cascade was investigated. As showed in Table 2, a series of aliphatic amines 2 were employed to react
with 2ꢀmethylquinoline 1a under the optimized reaction conditions. Benzylamine derivatives with both
electronꢀdonating (4ꢀMe, 4ꢀOMe) and electronꢀwithdrawing (4ꢀCF3) groups on the aromatic ring
proceeded in this reaction smoothly to afford the desired products 3 in good to excellent yields.
Generally, electronꢀwithdrawing substituents on the aromatic ring have negative effect on the yield.
Halogen substituted benzylamine derivatives, including fluorobenzylamines, chlorobenzylamines, or
bromobenzylamine, were also well tolerated in this cascade reaction (Table 2, 3ahꢀ3am), which provides
the possibility to allow additional coupling reactions. Interestingly, 2ꢀchlorobenzylamines gave the
corresponding product in 85% yield (Table 2, 3aj). Steric effects had a little influence on the reaction
since 2ꢀmethylbenzylamine gave similar yield than 4ꢀmethylbenzylamine (Table 2, 3ab and 3ad).
Notably, the ringꢀfused and heterocyclic derived substrates also amenable to current reaction conditions
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 21
1
2
3
4
5
6
7
8
9
to deliver the corresponding products (3anꢀ3ap) in good yields (41%ꢀ89%). Additionally, the present
system is applicable to simple aliphatic amine, and the corresponding imidazo[1,5ꢀa]quinoline (Table 2,
3aq) was obtained in moderate yield.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 2. Scope of Benzylaminesa
N
N
N
N
N
N
N
N
Me
Me
Me
3aa 83%
3ab 92%
3ac 84%
3ad 88%
N
N
N
N
N
N
N
N
OMe
F3C
MeO
Cl
3ag 51%
3ae 72%
3af 77%
3ah 52%
N
N
N
N
N
N
N
N
F
Cl
Cl
F
3ai
3aj 85%
3ak
3al
68%
71%
73%
N
N
N
N
N
N
N
N
O
O
Br
O
3am
3an
3ao
3ap
60%
41%
89%
58%
N
N
3aq
61%
aReaction conditions: 1a (0.2 mmol), 2 (0.6 mmol), CuI (0.2 mmol), Cu(OAc)2·H2O (0.2 mmol), DTBP
(0.4 mmol), DMSO (1.5 ml), 110 °C, 24 h. Isolated yield.
ACS Paragon Plus Environment

Page 7 of 21
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Next, we turned our attention to the scope of various 2ꢀmethylquinoline derivatives to prove the
general applicability of the reaction and the results were summarized in Table 3. The reaction is sensitive
to the electronic effect of the aromatic ring. 2ꢀMethylquinoline derivatives with electronꢀdonating groups
such as ꢀMe, ꢀOMe and ꢀOEt successfully gave the desired imidazo[1,5ꢀa]quinolines in good yields
(Table 3, 3baꢀ3fa). Electronꢀwithdrawing substituents such as –NO2 (3ka) and –Ph (3ga) also had
deleterious effect on this reaction. Halogenꢀsubstituted 2ꢀmethylquinolines (Table 3, 3haꢀ3ja) were
tolerated. Moreover, 4ꢀmethylꢀ2ꢀphenylquinazoline also was found to be a suitable substrate and afforded
the desired product (3la). However, the present system is not applicable for 2ꢀmethyl pyridine (Table 3,
3ma), most of 2ꢀmethylquinoline remained unconsumed.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 3. Scope of 2ꢀMethylquinnolinesa
Me
Me
O
O
N
Me
N
N
N
N
N
N
N
3ba
65%
3ca 68%
3da 31%
3ea 42%
Ph
Br
Cl
N
N
N
N
N
OMe
N
N
N
3ga
3fa 67%
41%
N
3ha 72%
3ia 53%
F
O2N
N
N
N
N
N
N
N
N
3ja 52%
3ka 57%
3la 36%
3ma trace
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 21
1
2
3
4
5
6
aReaction conditions: 1a (0.2 mmol), 2a (0.6 mmol), CuI (0.2 mmol), Cu(OAc)2·H2O (0.2 mmol),
DTBP (0.4mmol), DMSO (1.5ml), 110 °C, 24h. Isolated yield.
7
8
9
To establish a possible mechanism of the copperꢀpromoted oxidative CꢀH amination cascade, some
control experiments were carried out. First of all, traces of 2ꢀmethylquinoline 1a were converted into
quinolineꢀ2ꢀcarbaldehyde 4a in the absence of 2a under standard conditions, and most of
2ꢀmethylquinoline 1a remained unconsumed (Scheme 2, eqn. 1). When quinolineꢀ2ꢀcarbaldehyde 4a was
allowed to react with 2a, the target product 3aa was obtained in 57% yield (Scheme 1, eqn. 2). The
reaction course through formation of aldehyde 4a cannot be excluded. In order to confirm whether the
reaction process was performed via a radical pathway, 1a and 2a were subjected to the standard
conditions using TEMPO as radical scavenger (Scheme 2, eqn. 3). As expected, only 12% yield of target
product 3aa was obtained, which suggested that the reaction presumably proceeded through a radical
formation pathway.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 2. Control Experiments for Mechanism
CuI (1 equiv)
Cu(OAc)2 . H2O (1 equiv)
(1)
O
N
N
110°C, DTBP, DMSO
H
4a, trace
1a
CuI (1 equiv)
Cu(OAc)2 . H2O (1 equiv)
N
NH2
(2)
H
+
N
N
110°C, DTBP, DMSO
O
4a
2a
3aa
, 57%
CuI (1 equiv)
Cu(OAc)2 . H2O (1 equiv)
N
(3)
NH2
+
N
110°C, DTBP, DMSO
N
TEMPO (2 equiv)
1a
2a
3aa, 12% yield
Based on results described above and literature reports,9 a plausible mechanism was proposed (Scheme
3). Initially, 2ꢀmethylquinoline 1a is involved a hydrogen abstraction to form a carbonꢀcentered radical A.
ACS Paragon Plus Environment

Page 9 of 21
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
The reaction of A with copper (II) gives a benzylic carbocation B via a singleꢀelectronꢀtransfer (SET)
process. The nucleophilic addition of benzylamine 2a to B provides intermediate C (path I). Furthermore,
another pathway may occur according to previous reports.14ꢀ15 A nitrogen centered radical I is generated
by oxidation of benzylamine 2a. The addition of the nitrogen radical I to the enamine intermediate H
which is formed from 2ꢀmethylquinoline 1a through the copperꢀpromoted isomerization, afford another
intermediate J. Then, the intermediate J could generate intermediate C by the action of copper and
DTBP (path II). The intermediate C can be oxidated to imine intermediate D, which is converted into
carbocation E by oxidative dehydrogenation in the presence of copper and oxidant. And intermediate E
can be cyclized by an intramolecular nucleophilic addition to provide intermediate G, which can undergo
oxidative aromatization to afford imidazo[1,5ꢀa]quinoline 3aa.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 3. Plausible Mechanism
In summary, we have developed a copperꢀpromoted tandem cyclization reaction via sequential
intermolecular oxidative amination, intramolecular oxidative amination and oxidative aromatization to
construct imidazo[1,5ꢀa]quinoline derivatives from 2ꢀmethylquinolines and benzylamines. This protocol
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 21
1
2
3
4
5
6
7
8
9
can tolerate a broad range of functional groups. In particular, substrate preꢀfunctionalization was not
required in the reaction, which avoided the need of extra preparation steps for active precursors.
Experiment Section
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General Remarks. Unless otherwise indicated, all commercial reagents and solvents were used without
additional purification. 1HNMR and 13CNMR spectra were recorded at 400MHz and 100MHz,
respectively, in CDCl3, using tetramethylsilane (TMS) as internal reference. HRMS were recorded using
ESIꢀTOF techniques. Products were purified by flash chromatography on 200−300 mesh silica gels using
petroleum ether/ethyl acetate as eluent.
General Procedure for the Synthesis of 3. CuI (38.1 mg, 0.2 mmol) and Cu(OAc)2·H2O (39.9 mg, 0.2
mmol) was dissolved in a reaction tube using 1.5mL of DMSO, and then benzylamine 2a (65.6 ꢁl, 0.6
mmol), 2ꢀmethylquinoline 1a (27.1 ꢁl, 0.2 mmol) and DTBP (73.3 ꢁl, 0.4 mmol) were added,
sequentially. The mixture was stirred at 110 °C for 24 h, and the reaction process was monitored by TLC.
After the reaction was completed, The reaction system was allowed to attain room temperature and
extracted with ethyl acetate (3×20 ml), and then the organic layer was washed with brine (2×10 ml) and
dried with anhydrous Na2SO4. Subsequently, the solvent was removed under reduced pressure and the
remaining crud product was purified by column chromatography over silica gel (PE/EtOAc=3:1) to
afford 1ꢀphenylimidazo[1,5ꢀa]quinoline (3aa) (40.5 mg, 83%) as a yellow solid.
1ꢀphenylimidazo[1,5ꢀa]quinoline (3aa).2d
Yellow solid (40.5 mg, 83%), melting point 113−115°C; 1HꢀNMR (400MHz, CDCl3) δ 7.67ꢀ7.65 (m, 3H),
7.55ꢀ7.52 (m, 5H), 7.34ꢀ7.28 (m, 2H), 7.19ꢀ7.16 (m, 1H), 7.03ꢀ7.01 (m, 1H); 13CꢀNMR (100MHz, CDCl3)
δ 142.4, 133.8, 132.3, 130.6, 129.6, 129.3, 128.7, 128.6, 127.3, 125.6, 125.1, 122.4, 121.4, 117.4, 117.1.
ACS Paragon Plus Environment

Page 11 of 21
The Journal of Organic Chemistry
1
2
3
4
5
HRMS(ESI) m/z: [M+H]+ calcd for C17H13N2 245.1073, found 245.1076.
6
7
1ꢀ(pꢀtolyl)imidazo[1,5ꢀa]quinoline (3ab).
8
9
1
Yellow solid (47.5 mg, 92%), melting point 121ꢀ125°C; HꢀNMR (400 MHz, CDCl3) δ 7.63ꢀ7.54 (m,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5H), 7.35ꢀ7.28 (m, 4H), 7.22ꢀ7.18 (m, 1H), 7.02 (d, J=9.3Hz, 1H), 2.49 (s, 3H); 13CꢀNMR (100 MHz,
CDCl3) δ 142.6, 139.2, 132.5, 130.9, 130.5, 129.4, 128.5, 127.2, 125.6, 125.0, 122.3, 121.2, 117.4, 117.2,
21.5. HRMS(ESI) m/z: [M+H]+ calcd for C18H15N2 259.1237, found 259.1235.
1ꢀ(mꢀtolyl)imidazo[1,5ꢀa]quinoline (3ac).
1
Yellow solid (43.3 mg, 84%), melting point 134ꢀ137°C; HꢀNMR (400 MHz, CDCl3) δ 7.60ꢀ7.54 (m,
3H), 7.50 (s, 1H), 7.44ꢀ7.38 (m, 2H), 7.34ꢀ7.27 (m, 3H), 7.19ꢀ7.15 (m, 1H), 6.99 (d, J=9.3Hz, 1H), 2.43
(s, 3H); 13CꢀNMR (100 MHz, CDCl3) δ 142.6, 138.6, 133.7, 132.4, 130.5, 130.2, 130.0, 128.5, 128.5,
127.2, 126.5, 125.6, 125.0, 122.3, 121.3, 117.4, 117.1, 21.4. HRMS(ESI) m/z: [M+H]+ calcd for
C18H15N2 259.1234, found 259.1235.
1ꢀ(oꢀtolyl)imidazo[1,5ꢀa]quinoline (3ad).
1
Yellow oil (45.4 mg, 88%); HꢀNMR (400 MHz, CDCl3) δ 7.62ꢀ7.58 (m, 2H), 7.49ꢀ7.46 (m, 2H),
7.39ꢀ7.34 (m, 3H), 7.31ꢀ7.27 (m, 1H), 7.22 (d, J=8.4Hz, 1H), 7.16ꢀ7.12 (m, 1H), 7.02 (d, J=9.3Hz, 1H),
2.06 (s, 3H); 13CꢀNMR (100 MHz, CDCl3) δ 141.5, 138.4, 133.9, 132.6, 130.5, 130.4, 129.9, 129.8,
128.5, 127.8, 126.4, 125.3, 125.0, 122.0, 121.2, 117.2, 115.9, 19.57. HRMS(ESI) m/z: [M+H]+ calcd for
C18H15N2 259.1233, found 259.1235.
1ꢀ(4ꢀmethoxyphenyl)imidazo[1,5ꢀa]quinoline (3ae).
Yellow solid (39.5 mg, 72%), melting point 117ꢀ121°C; 1HꢀNMR (400 MHz, CDCl3) δ 7.62ꢀ7.56 (m, 4H),
7.53 (s, 1H), 7.33ꢀ7.28 (m, 2H), 7.21ꢀ7.19 (m, 1H), 7.06 (d, J=8.7Hz, 2H), 7.00 (d, J=9.3Hz, 1H), 3.92 (s,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 21
1
2
3
4
5
6
7
8
9
3H); 13CꢀNMR (100 MHz, CDCl3) δ 160.3, 142.3, 132.5, 130.9, 130.4, 128.5, 127.2, 126.1, 125.6, 125.0,
122.2, 121.2, 117.3, 117.2, 114.2, 55.3. HRMS(ESI) m/z: [M+H]+ calcd for C18H15N2O 275.1182, found
275.1184.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1ꢀ(2ꢀmethoxyphenyl)imidazo[1,5ꢀa]quinoline (3af).
Yellow solid (42.2 mg, 77%), melting point 118ꢀ122°C; 1HꢀNMR (400 MHz, CDCl3) δ 7.62ꢀ7.59 (m, 3H),
7.57ꢀ7.52 (m, 1H), 7.44 (d, J=8.5Hz, 1H), 7.36 (d, J=9.3Hz, 1H), 7.32ꢀ7.28 (m, 1H), 7.20ꢀ7.14 (m, 2H),
7.03 (d, J=8.9Hz, 2H), 3.59 (s, 3H); 13CꢀNMR (100 MHz, CDCl3) δ 158.1, 139.3, 133.0, 131.9, 131.1,
130.3, 128.2, 127.3, 125.2, 124.8, 123.3, 122.1, 121.2, 121.0, 117.2, 116.4, 111.0, 55.3. HRMS(ESI) m/z:
[M+H]+ calcd for C18H15N2O 275.1182, found 275.1184.
1ꢀ(4ꢀ(trifluoromethyl)phenyl)imidazo[1,5ꢀa]quinoline (3ag).
1
Yellow solid (31.8 mg, 51%), melting point 152ꢀ156°C; HꢀNMR (400 MHz, CDCl3) δ 7.84ꢀ7.79 (m,
4H), 7.69 (d, J=7.7Hz, 1H), 7.60 (s, 1H), 7.52 (d, J=8.4Hz, 1H), 7.40ꢀ7.37 (m, 2H), 7.29ꢀ7.25 (m, 1H),
7.11 (d, J=9.4Hz, 1H); 13CꢀNMR (100 MHz, CDCl3) δ 140.7, 137.2, 132.0, 131.2, 131.1, 130.9, 129.8,
128.9, 128.0, 127.5, 125.7, 125.7, 125.6, 125.5, 125.3, 123.0, 122.6, 121.9, 117.3, 117.1. HRMS(ESI)
m/z: [M+H]+ calcd for C18H12N2F3 313.0951, found 313.0953.
1ꢀ(4ꢀchlorophenyl)imidazo[1,5ꢀa]quinoline (3ah).
1
Yellow solid (29.0 mg, 52%), melting point 148ꢀ151°C; HꢀNMR (400 MHz, CDCl3) δ 7.64ꢀ7.61 (m,
3H), 7.56ꢀ7.51 (m, 4H), 7.37ꢀ7.35 (m, 2H), 7.28ꢀ7.23 (m, 1H), 7.06 (d, J=9.3Hz, 1H); 13CꢀNMR (100
MHz, CDCl3) δ 141.1, 135.3, 132.2, 132.2, 130.9, 130.8, 129.0, 128.7, 127.4, 125.6, 125.3, 122.7, 121.6,
117.3, 117.1. HRMS(ESI) m/z: [M+H]+ calcd for C17H12N2Cl 279.0689, found 279.0687.
1ꢀ(3ꢀchlorophenyl)imidazo[1,5ꢀa]quinoline (3ai).
ACS Paragon Plus Environment

Page 13 of 21
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Yellow solid (37.9 mg, 68%), melting point 149ꢀ152°C; 1HꢀNMR (400 MHz, CDCl3) δ 1.03 (s, 1H), 7.63
(d, J=6.9Hz, 1H), 7.55ꢀ7.43 (m, 5H), 7.35ꢀ7.32 (m, 2H), 7.25ꢀ7.21 (m, 1H), 7.04 (d, J=9.3Hz, 1H);
13CꢀNMR (100 MHz, CDCl3) δ 140.7, 135.4, 134.7, 132.1, 130.8, 129.9, 129.7, 129.4, 128.8, 127.7,
127.5, 125.6, 125.3, 122.7, 121.7, 117.3, 117.0. HRMS(ESI) m/z: [M+H]+ calcd for C17H12N2Cl
279.0688, found 279.0689.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1ꢀ(2ꢀchlorophenyl)imidazo[1,5ꢀa]quinoline (3aj).
Yellow solid (47.4 mg, 85%), melting point 121ꢀ124°C; 1HꢀNMR (400MHz, CDCl3) δ 7.66ꢀ7.46 (m, 6H),
7.40ꢀ7.32 (m, 2H), 7.28ꢀ7.19 (m, 2H), 7.08 (d, J=9.3Hz, 1H); 13CꢀNMR (100MHz, CDCl3) δ 139.0,
135.3, 133.6, 132.4, 132.4, 131.0, 130.3, 129.8, 128.6, 127.9, 127.3, 125.3, 125.2, 122.3, 121.6, 117.0,
115.9. HRMS(ESI) m/z: [M+H]+ calcd for C17H12N2Cl 279.0687, found 279.0689.
1ꢀ(3ꢀfluorophenyl)imidazo[1,5ꢀa]quinoline (3ak).
1
Yellow solid (37.2 mg, 71%), melting point 102ꢀ105°C; HꢀNMR (400 MHz, CDCl3) δ 7.66ꢀ7.65 (m,
1H), 7.57ꢀ7.45 (m, 4H), 7.41ꢀ7.35 (m, 3H), 7.28ꢀ7.22 (m, 2H), 7.08ꢀ7.04 (m, 1H); 13CꢀNMR (100 MHz,
1
3
CDCl3) δ164.0ꢀ161.5 (d, JC-F=246.2 Hz), 140.9, 135.8ꢀ135.7 (d, JC-F=8.3 Hz), 132.1, 130.8,
3
4
130.4ꢀ130.3 (d, JC-F=8.3 Hz), 128.7, 127.5, 125.6, 125.4 (d, JC-F=3.0 Hz), 125.3, 122.6, 121.7, 117.3,
2
2
117.1, 116.8ꢀ116.6 (d, JC-F=22.3 Hz), 116.4ꢀ116.2 (d, JC-F=21.0 Hz). HRMS(ESI) m/z: [M+H]+ calcd
for C17H12N2F 263.0982, found 263.0985.
1ꢀ(2ꢀfluorophenyl)imidazo[1,5ꢀa]quinoline (3al).
1
Yellow solid (38.3 mg, 73%), melting point 102ꢀ104°C; HꢀNMR (400 MHz, CDCl3) δ 7.72ꢀ7.68 (m,
1H), 7.64ꢀ7.61 (m, 2H), 7.56ꢀ7.55 (m, 1H), 7.49 (d, J=8.2Hz, 1H), 7.38ꢀ7.31 (m, 3H), 7.28ꢀ7.24 (m, 2H),
1
7.05 (d, J=9.2Hz, 1H); 13CꢀNMR (100 MHz, CDCl3) δ161.9ꢀ159.4 (d, JCꢀF=248.2 Hz), 136.3, 132.4,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 21
1
2
3
4
5
6
7
8
9
4
3
132.1 (d, JCꢀF=1.6 Hz), 131.5ꢀ131.4 (d, JCꢀF=8.0 Hz), 130.7, 128.5, 127.7, 125.3, 125.2, 124.7 (d,
3JCꢀF=3.5 Hz), 122.6, 122.4ꢀ122.2 (d, 2JCꢀF=15.2 Hz), 121.7, 116.9, 116.1ꢀ115.9 (d, 2JCꢀF=20.9 Hz), 116.0.
HRMS(ESI) m/z: [M+H]+ calcd for C17H12N2F 263.0984, found 263.0985.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1ꢀ(4ꢀbromophenyl)imidazo[1,5ꢀa]quinoline (3am).
1
Yellow solid (38.8 mg, 60%), melting point 138ꢀ140°C; HꢀNMR (400 MHz, CDCl3) δ 7.69ꢀ7.63 (m,
3H), 7.57ꢀ7.53 (m, 4H), 7.38ꢀ7.33 (m, 2H), 7.28ꢀ7.25 (m, 1H), 7.08ꢀ7.03 (m, 1H); 13CꢀNMR (100 MHz,
CDCl3) δ 141.1, 137.9, 132.7, 132.0, 131.1, 129.6, 128.7, 127.4, 125.6, 125.3, 123.5, 122.7, 121.6, 117.3,
117.2. HRMS(ESI) m/z: [M+H]+ calcd for C17H12N2Br 323.0183, found 323.0184.
1ꢀ(benzo[d][1,3]dioxolꢀ5ꢀyl)imidazo[1,5ꢀa]quinoline (3an).
Yellow solid (23.6 mg, 41%), melting point 115ꢀ119°C; 1HꢀNMR (400 MHz, CDCl3) δ 7.63ꢀ7.61 (m, 2H),
7.52 (s, 1H), 7.35ꢀ7.32 (m, 2H), 7.28ꢀ7.23 (m, 1H), 7.14 (dd, J1=7.9Hz, J2=1.4Hz, 1H), 7.09ꢀ7.08 (m,
1H), 7.02 (d, J=9.3Hz, 1H), 6.97 (d, J=7.9Hz, 1H), 6.09 (s, 2H); 13CꢀNMR (100 MHz, CDCl3) δ 148.5,
147.9, 141.9, 132.4, 130.4, 128.6, 127.3, 125.6, 125.1, 123.7, 122.2, 121.3, 117.4, 117.1, 110.0, 108.7,
101.4. HRMS(ESI) m/z: [M+H]+ calcd for C18H13N2O2 289.0975, found 289.0977.
1ꢀ(naphthalenꢀ1ꢀyl)imidazo[1,5ꢀa]quinoline (3ao).
Yellow solid (52.3 mg, 89%), melting point 199ꢀ201°C; 1HꢀNMR (400 MHz, CDCl3) δ 8.09 (d, J=8.1Hz,
1H), 7.98 (d, J=8.2Hz, 1H), 7.75 (d, J=6.9Hz, 1H), 7.71 (s, 1H), 7.68ꢀ7.60 (m, 2H), 7.53ꢀ7.50 (m, 1H),
7.44 (d, J=9.4Hz, 1H ), 7.41ꢀ7.33(m, 2H), 7.24ꢀ7.21 (m, 1H), 7.09 (d, J=9.3Hz, 1H), 7.01 (d, J=8.0Hz,
1H), 6.95ꢀ6.91 (m, 1H); 13CꢀNMR (100 MHz, CDCl3) δ 140.4, 133.7, 132.6, 132.3, 131.6, 130.3, 130.0,
128.8, 128.4, 128.4, 127.6, 127.1, 126.4, 125.6, 125.5, 125.4, 124.9, 122.5, 121.5, 117.2, 117.0.
HRMS(ESI) m/z: [M+H]+ calcd for C21H15N2 295.1234, found 295.1235.
ACS Paragon Plus Environment

Page 15 of 21
The Journal of Organic Chemistry
1
2
3
4
5
1ꢀ(furanꢀ2ꢀyl)imidazo[1,5ꢀa]quinoline (3ap).
6
7
1
Yellow solid (27.1 mg, 58%), melting point 90ꢀ94°C; HꢀNMR (400 MHz, CDCl3) δ 7.67ꢀ7.64 (m, 2H),
8
9
7.57 (s, 1H), 7.40ꢀ7.33 (m, 3H), 7.22ꢀ7.20 (m, 1H), 7.09 (d, J=9.3Hz, 1H), 6.88 (d, J=3.2Hz, 1H),
6.68ꢀ6.67 (m, 1H); 13CꢀNMR (100 MHz, CDCl3) δ 145.2, 143.2, 132.4, 132.1, 131.0, 128.6, 128.1, 125.4,
122.7, 122.2, 116.8, 112.8, 111.8. HRMS(ESI) m/z: [M+H]+ calcd for C15H11N2O 235.0870, found
235.0871.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1ꢀethylimidazo[1,5ꢀa]quinoline (3aq).
1
Yellow oil (24.1mg, 61%), HꢀNMR (400 MHz, CDCl3) δ 8.07 (d, J=8.4Hz, 1H), 7.54ꢀ7.52 (m, 1H),
7.43ꢀ7.39 (m, 1H), 7.30ꢀ7.27 (m, 2H), 7.18ꢀ7.15 (m, 1H), 3.31 (q, J=7.3Hz, 2H), 1.49 (t, J=7.3Hz, 3H);
13CꢀNMR (100 MHz, CDCl3) δ 144.1, 132.1, 129.3, 127.5, 126.6, 124.7, 123.7, 119.6, 119.5, 116.3,
115.5, 24.8, 10.7. HRMS(ESI) m/z: [M+H]+ calcd for C13H13N2 197.1079, found 197.1083.
7ꢀmethylꢀ1ꢀphenylimidazo[1,5ꢀa]quinoline (3ba).
1
Yellow solid (33.5 mg, 65%), melting point 117−120 °C; HꢀNMR (400 MHz, CDCl3) δ 7.66 (s, 2H),
7.53 (s, 4H), 7.42 (s, 2H), 7.34ꢀ7.31 (m, 1H), 7.02ꢀ6.97 (m, 2H), 2.40 (s, 3H); 13CꢀNMR (100 MHz,
CDCl3) δ 142.1, 134.8, 133.9, 130.5, 130.3, 129.6, 129.2, 128.7, 128.5, 128.4, 125.6, 122.3, 121.3, 117.2,
117.1, 20.8. HRMS(ESI) m/z: [M+H]+ calcd for C18H15N2 259.1236, found 259.1235.
6,8ꢀdimethylꢀ1ꢀphenylimidazo[1,5ꢀa]quinoline (3ca).
1
Yellow solid (35.4 mg, 65%), melting point 104−107 °C; HꢀNMR (400 MHz, CDCl3) δ 7.55ꢀ7.53 (m,
2H), 7.43ꢀ7.39 (m, 4H), 7.22ꢀ7.17 (m, 1H), 7.11ꢀ7.08 (m, 2H), 6.90 (s, 1H), 2.47 (s, 3H), 2.04 (s, 3H);
13CꢀNMR (100 MHz, CDCl3) δ 142.2, 136.8, 135.3, 134.0, 132.5, 130.6, 129.5, 129.1, 128.6, 127.8,
121.9, 121.7, 117.6, 116.2, 115.7, 21.6, 19.9. HRMS(ESI) m/z: [M+H]+ calcd for C19H17N2 273.1393,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 21
1
2
3
4
5
found 273.1392.
6
7
7ꢀmethoxyꢀ1ꢀphenylimidazo[1,5ꢀa]quinoline (3da).
8
9
Yellow oil (17.0mg, 31%); 1HꢀNMR (400 MHz, CDCl3) δ 7.66 (d, J=3.5Hz, 2H), 7.55ꢀ7.53 (m, 4H), 7.46
(d, J=9.2Hz, 1H), 7.35 (d, J=9.3Hz, 1H), 7.07 (s, 1H), 6.98 (d, J=9.3Hz, 1H), 6.78 (dd, J1=9.1Hz,
J2=2.2Hz, 1H), 3.86 (s, 3H); 13CꢀNMR (100 MHz, CDCl3) δ 156.5, 141.9, 133.8, 130.3, 129.6, 129.2,
128.7, 126.9, 126.6, 122.5, 121.1, 118.6, 117.6, 114.8, 110.8, 55.5. HRMS(ESI) m/z: [M + H]+ calcd for
C18H15N2O 275.1183, found 275.1184.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
7ꢀethoxyꢀ1ꢀphenylimidazo[1,5ꢀa]quinoline (3ea).
1
Yellow solid (24.2 mg, 42%), melting point 113ꢀ116 °C; HꢀNMR (400 MHz, CDCl3) δ 7.65 (s, 2H),
7.55ꢀ7.52 (m, 4H), 7.44 (d, J=9.1Hz, 1H), 7.33 (d, J=9.2Hz, 1H), 7.06 (s, 1H), 6.96 (d, J=9.2Hz, 1H),
6.77 (d, J=8.3Hz, 1H ), 4.07 (q, J=6.3Hz, 2H), 1.43 (t, J=6.6Hz, 3H); 13CꢀNMR (100 MHz, CDCl3) δ
155.9, 141.9, 133.8, 130.3, 129.6, 129.2, 128.7, 126.9, 126.5, 122.5, 121.2, 118.6, 117.5, 115.3, 111.6,
63.8, 14.8. HRMS(ESI) m/z: [M+H]+ calcd for C19H17N2O 289.1342, found 289.1341.
9ꢀmethoxyꢀ1ꢀphenylimidazo[1,5ꢀa]quinoline (3fa).2d
1
Yellow solid (36.7 mg, 67%), melting point 115−117 °C; HꢀNMR (400 MHz, CDCl3) δ 7.47 (s, 1H),
7.43ꢀ7.41 (m, 2H), 7.28ꢀ7.15 (m, 5H), 7.09 (d, J=8.0Hz, 1H), 6.82 (d, J=9.2Hz, 1H), 6.67 (d, J=8.0Hz,
1H), 2.90 (s, 3H); 13CꢀNMR (100 MHz, CDCl3) δ 149.1, 146.7, 136.4, 131.7, 128.5, 128.0, 127.5, 125.9,
125.0, 122.9, 122.4, 120.8, 119.5, 117.7, 109.8, 53.6. HRMS(ESI) m/z: [M+H]+ calcd for C18H15N2O
275.1179, found 275.1177.
1,5ꢀdiphenylimidazo[1,5ꢀa]quinoline (3ga).
1
Yellow solid (26.2 mg, 41%), melting point 159ꢀ161 °C; HꢀNMR (400 MHz, CDCl3) δ 7.72ꢀ7.71 (m,
ACS Paragon Plus Environment

Page 17 of 21
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
2H), 7.67 (d, J=8.1Hz, 2H), 7.60 (s, 1H), 7.55ꢀ7.47 (m, 8H), 7.32ꢀ7.20 (m, 3H); 13CꢀNMR (100 MHz,
CDCl3) δ 142.3, 138.8, 133.8, 133.4, 132.5, 130.2, 129.6, 129.5, 129.2, 128.8, 128.6, 127.8, 127.4, 127.3,
125.3, 124.9, 122.9, 117.8, 117.0. HRMS(ESI) m/z: [M+H]+ calcd for C23H17N2 321.1393, found
321.1392.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
7ꢀchloroꢀ1ꢀphenylimidazo[1,5ꢀa]quinoline (3ha).
1
Yellow solid (40.1 mg, 72%), melting point 151ꢀ155 °C; HꢀNMR (400 MHz, CDCl3) δ 7.65ꢀ7.55 (m,
7H), 7.46 (d, J=9.0Hz, 1H), 7.39 (d, J=9.3Hz, 1H), 7.14 (dd, J1=9.0Hz, J2=2.0Hz, 1H), 6.96 (d, J=9.4Hz,
1H); 13CꢀNMR (100 MHz, CDCl3) δ 142.6, 133.4, 130.8, 130.5, 130.3, 129.5, 129.5, 128.9, 127.7, 127.2,
127.1, 123.0, 120.3, 118.7, 118.5. HRMS(ESI) m/z: [M+H]+ calcd for C17H12N2Cl 279.0688, found
279.0689.
7ꢀbromoꢀ1ꢀphenylimidazo[1,5ꢀa]quinoline (3ia).2d
Yellow solid (34.2 mg, 53%), melting point 128ꢀ130 °C; 1HꢀNMR (400 MHz, CDCl3) δ 7.76 (d, J=1.6Hz,
1H), 7.65ꢀ7.63 (m, 2H), 7.59ꢀ7.55 (m, 4H), 7.41ꢀ7.35 (m, 2H), 7.29ꢀ7.25 (m, 1H), 6.96ꢀ6.91 (m, 1H).
13CꢀNMR (100 MHz, CDCl3) δ 142.7, 133.4, 131.2, 130.8, 130.3, 130.1, 129.6, 129.5, 129.0, 127.5,
123.1, 120.2, 119.0, 118.5, 118.3. HRMS(ESI) m/z: [M+H]+ calcd for C17H12N2Br 323.0178, found
323.0175.
7ꢀfluoroꢀ1ꢀphenylimidazo[1,5ꢀa]quinoline (3ja).
1
Yellow solid (27.2 mg, 52%), melting point 113−116 °C; HꢀNMR (400 MHz, CDCl3) δ 7.56ꢀ7.53 (m,
2H), 7.50ꢀ7.39 (m, 5H), 7.30 (d, J=9.3Hz, 1H), 7.22ꢀ7.18 (m, 1H), 6.87 (d, J=9.4Hz, 1H), 6.83ꢀ6.78 (m,
1
1H); 13CꢀNMR (100 MHz, CDCl3) δ160.7ꢀ158.2 (d, JC-F=244.1 Hz), 142.4, 133.5, 130.3, 129.6, 129.5,
129.0, 128.8 (d, 4JC-F=2.1 Hz), 127.4 (d, 3JC-F=8.4 Hz), 123.0, 120.6 (d, 4JC-F=2.5 Hz), 119.1 (d, 3JC-F=8.1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 21
1
2
3
4
5
2
2
Hz), 118.5, 114.9ꢀ114.7 (d, JC-F=23.5 Hz), 113.8ꢀ113.5 (d, JC-F=22.3 Hz). HRMS(ESI) m/z: [M+H]+
6
7
calcd for C17H12N2F 263.0986, found 263.0985.
8
9
7ꢀnitroꢀ1ꢀphenylimidazo[1,5ꢀa]quinoline (3ka).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Yellow solid (32.9 mg, 57%), melting point 200ꢀ203 °C; 1HꢀNMR (400 MHz, CDCl3) δ 8.53 (d, J=2.4Hz,
1H), 8.0 (dd, J1=9.3Hz, J2=2.5Hz, 1H), 7.66ꢀ7.49 (m, 7H), 7.5 (d, J=9.4Hz, 1H), 7.12 (d, J=9.4Hz, 1H);
13CꢀNMR (100 MHz, CDCl3) δ 144.2, 143.5, 136.0, 132.9, 130.4, 130.0, 129.4, 129.2, 126.0, 123.8,
123.6, 121.9, 120.5, 119.6, 118.0. HRMS(ESI) m/z: [M+H]+ calcd for C17H12N3O2 290.0931, found
290.0930.
3,5ꢀdiphenylimidazo[1,5ꢀc]quinazoline (3la).8
1
Yellow solid (23.1 mg, 36%), melting point 142ꢀ145 °C; HꢀNMR (400 MHz, CDCl3) δ 8.14ꢀ8.04 (m,
2H), 7.94ꢀ7.92 (m, 1H), 7.60ꢀ7.57 (m, 2H), 7.35 (d, J=7.4Hz, 2H), 7.28ꢀ7.02 (m, 8H); 13CꢀNMR (100
MHz, CDCl3) δ 146.2, 142.7, 138.1, 133.8, 131.5, 130.3, 129.9, 129.2, 128.6, 128.4, 128.2, 128.0, 127.7,
127.4, 121.7, 120.6, 119.3. HRMS (ESI) m/z: [M+H]+ calcd for C22H16N3 322.1339, found 322.1338.
ASSOCIATED CONTENT
Supporting Information
1H NMR and 13C NMR spectra for all the products. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
Eꢀmail: fengct2010@163.com
Eꢀmail: nothingchina@126.com
ACS Paragon Plus Environment

Page 19 of 21
The Journal of Organic Chemistry
1
2
3
4
5
Notes
6
7
The authors declare no competing financial interest.
8
9
ACKNOWLEDGMENTS：
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
We gratefully thank the financial supports of the Natural Science Foundation of China (81403268,
21102003), Scientific Research Foundation of Anhui University of Science & Technology (QN201508)
and Scientific Research Foundation for the Introduction of Young Teachers.
REFERENCES
(1) For selected examples, see: (a) Kim, D. Bioorg. Med. Chem. Lett. 2005, 15, 2129. (b) Kakehi, S. H.;
Okumura, Y.; Itoh, K.; Kobayashi, K.; Aikawa, Y.; Misawa, K. Chem. Pharm. Bull. 2010, 58, 1502.
(c) Malamas, M. S.; Ni, Y.; Erdei, J.; Stange, H.; Schindler, R.; Lankau, H. J.; Grunwald, C.; Fan, K.
Y.; Parris, K.; Langen, B.; Egerland, U.; Hage, T.; Marquis, K. L.; Grauer, S.; Brennan, J.; Navarra,
R.; Graf, R.; Harrison, B. L.; Robichaud, A.; Kronbach, T.; Pangalos, M. N.; Hoefgen, N.; Brandon,
N. J. J. Med. Chem. 2011, 54, 7621.
(2) (a) Kolar, P.; Tišler, M. Z. Naturforsch. 1991, 46b, 1110. (b) Benincori, T.; Brenna, E.; Sannicolo, F. J.
Chem. Soc., Perkin Trans. 1, 1993, 675. (c) Crawforth, J. M., Paoletti, M. Tetrahedron Lett. 2009,
50, 4916. (d) Wang, Q.; Zhang, S.; Guo, F. F.; Zhang, B. Q.; Hu, P.; Wang, Z. Y. J. Org. Chem. 2012,
77, 11161. (e) Huang, J. R.; Zhang, Q. R.; Qu, C. H.; Sun, X. H.; Dong, L.; Chen, Y. C. Org. Lett.
2013, 15, 1878. (f) Li,Y. J.; Chao, A.; Fleming, F. F. Chem. Commun. 2016, 52, 2111. (g) Joshi, A.;
Mohan, D. C.; Adimurthy, S. Org. Lett. 2016, 18, 464.
(3) Bower, J. D.; Ramage, G. R. J. Chem. Soc. 1955, 2823.
(4) Li, M. Y.; Xie, Y.; Ye, Y.; Zou, Y.; Jiang, H. F.; Zeng, W. Org. Lett. 2014, 16, 6232.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 21
1
2
3
4
5
6
7
8
9
(5) Wang, H. Q.; Xu, W. T.; Wang, Z. Q.; Yu, L. T.; Xu, K. J. Org. Chem. 2015, 80, 2431.
(6) (a) Yan, Y. Z.; Zhang, Y. H.; Zha, Z. G.; Wang, Z. Y. Org. Lett. 2013, 15, 2274. (b) Mohan, D. C.; Rao,
S. N.; Ravi, C.; Adimurthy, S. Org. Biomol. Chem. 2015, 13, 5602.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(7) Gong, L.; Xing, L. J.; Xu, T.; Zhu, X. P.; Zhou, W.; Kang, N.; Wang, B. Org. Biomol. Chem. 2014, 12,
6557.
(8) Very recently, a nice work described the synthesis of imidazo[1,5ꢀc]quinazolines from
4ꢀmethylquinazolines and benzylamines by Li’group; see: Zhao, D.; Wang, T.; Shen, Q.; Li, J. X.
Chem. Commun. 2014, 50, 4302. However, when Li’s approach was applied to our model substrates
(2ꢀmethylquinoline 1a and benzylamine 2a), the desired product 3aa was obtained in 16% yield.
(9) Vanjari, R.; Singh, K. N. Chem. Soc. Rev. 2015, 44, 8062.
(10) For selected reviews, see: (a) Yan, Y. Z.; Xu, K.; Fang, Y.; Wang, Z. Y. J. Org. Chem. 2011, 76, 6849.
(b) Komai, H.; Yoshino, T.; Matsunaga, S.; Kanai, M. Org. Lett. 2011, 13, 1706. (c) Niu, R.; Xiao, J.;
Liang, T.; Li, X. Org. Lett. 2012, 14, 676. (d) Liu, J. Y.; Niu, H. Y.; Wu, S.; Qu, G. R.; Guo, H. M.
Chem. Commun. 2012, 48, 9723.
(11) For recent reviews on sp2 CꢀH amination, see: (a) Muller, P.; Fruit, C. Chem. Rev. 2003, 103, 2905.
(b) Davies, H. M. L.; Long, M. S. Angew. Chem., Int. Ed. 2005, 44, 3518. (c) Davies, H. M. L.;
Manning, J. R. Nature 2008, 451, 417. (d) Collet, F.; Lescot, C.; Dauban, P. Chem. Soc. Rev. 2011,
40, 1926. (e) Cho, S. H.; Kim, J. Y.; Kwak, J.; Chang, S. Chem. Soc. Rev. 2011, 40, 5068. (f)
Louillat, M. L.; Patureau, F. W. Chem. Soc. Rev. 2014, 43, 901.
(12) (a) Feng, C. T.; Su, J. H.; Yan, Y. Z.; Guo, F. F.; Wang, Z. Y. Org. Biomol. Chem. 2013, 11, 6691. (b)
Feng, C. T.; Yan, Y. Z.; Zhang, Z. L.; Xu, K.; Wang, Z. Y. Org. Biomol. Chem. 2014, 12, 4837. (c)
ACS Paragon Plus Environment

Page 21 of 21
The Journal of Organic Chemistry
1
2
3
4
5
6
7
Feng, C. T.; Zhu, H. Z.; Li, Z.; Luo, Z. G.; Wu, S. S.; Ma, S. T. Tetrahedron Lett. 2016, 57, 800.
(13) Yang, Y. Z.; Yao, J. Z.; Zhang, Y. H. Org. Lett. 2013, 15, 3206.
8
9
(14) Liu, F.; Liu, K.; Yuan, X. T.; Li, C. Z. J. Org. Chem. 2007, 72, 10231.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(15) Xiao, F. H.; Chen, S. Q.; Chen, Y.; Huang, H. W.; Deng, G. J. Chem. Commun. 2015, 51, 652.
ACS Paragon Plus Environment