Aerobic Copper-Catalyzed Halocyclization of Methyl N-Heteroaromatics with Aliphatic Amines: Access to Functionalized Imidazo-Fused N-Heterocycles

Article abstract of DOI:10.1021/acs.joc.6b02117

A new aerobic copper-catalyzed halocyclization reaction of methyl N-heteroaromatics and aliphatic amines has been developed, which enables straightforward access to functionalized imidazo-fused N-heterocycles with the merits of good functional tolerance, use of easily available copper salts as the catalysts, lithium halides as the halogen sources, and O₂ as a sole oxidant. Due to the reaction features' selective introduction of halogen functionalities to the newly formed imidazo ring, further extensions of the developed chemistry toward synthetic diversity, including effective access to functional materials, are easily envisioned.

Full text of DOI:10.1021/acs.joc.6b02117

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Article
Aerobic Copper-catalyzed Halocyclization of Methyl N-Heteroaromatics with
Aliphatic Amines: Access to Functionalized Imidazo-fused N-heterocycles
Zhenda Tan, He Zhao, Changjian Zhou, Huanfeng Jiang, and Min Zhang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02117 • Publication Date (Web): 03 Oct 2016
Downloaded from http://pubs.acs.org on October 8, 2016
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Aerobic
Copper-catalyzed
Halocyclization
of
Methyl
N-Heteroaromatics with Aliphatic Amines: Access to Functionalized
Imidazo-fused N-heterocycles
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Zhenda Tan, He Zhao, Changjian Zhou, Huanfeng Jiang and Min Zhang*
Key Lab of Functional Molecular Engineering of Guangdong Province, School of Chemistry and Chemical Engineering, South
China University of Technology, Guangzhou 510641, China
Eꢀmail: minzhang@scut.edu.cn
Abstract:
A
new aerobic copperꢀcatalyzed halocyclization reaction of
methylꢀNꢀheteroaromatics and aliphatic amines has been developed, which enables
straightforward access to functionalized imidazoꢀfused Nꢀheterocycles with the merits
of good functional tolerance, use of easilyꢀavailable copper salts as the catalysts,
2
lithium halides as the halogen sources and O as a sole oxidant. Owing to the reaction
features selective introduction of halogen functionalities to the newly formed
imidazoꢀring, further extensions of the developed chemistry towards synthetic
diversity, including effective access to functional materials, are easily envisioned.
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INTRODUCTION
Aerobic copperꢀcatalysed CꢀH functionalization constitutes one of the
most powerful tools for carbonꢀcarbon and carbonꢀheteroatom bond
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formations. Among which, the direct aryl CꢀH halogenation is of particular
2
importance in both laboratory chemical preparation and industry applications.
Conventionally, such a goal was realized on the basis of using various halogen
3
sources such as bromine, iodine, hypobromites and etc. To obtain more green
and efficient halogenated aromatics, contributions on aerobic copperꢀcatalysed
halogenation of arenes and heteroarenes have also been elegantly
4
demonstrated. However, direct access to aryl halides from readily available
raw materials, through in-situ introduction of halogens to the newly constructed
aryl ring in one operation, has been rarely studied.
Imidazo[1,5ꢀa]ꢀ and imidazo[1,5ꢀc]ꢀ
N
ꢀheteroaromatics constitute
a
5
significant important class of compounds that exhibit diverse bioꢀactivities and
6
interesting optoelectronic properties . Therefore, the search for alternative
approaches to give these products has long been an attractive topic in synthetic
7
organic chemistry. Pioneered by Vilsmeierꢀtype cyclization, various new
8
protocols have also been developed during the past decade, representative
examples mainly involve the iodineꢀmediated cyclization of Nꢀ2ꢀpyridylmethyl
8a
thioamides, oxidative condensationꢀcyclization of aldehydes with aryl
8
b
2ꢀpyridylmethylamines in the presence of elemental sulfur, dehydrative
8c
aromatization of Nꢀ(2ꢀpyridinylmethyl)benzamide, and the oxidative coupling
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of 2ꢀcarbonyl Nꢀheteroaromatics with amines or amino acids . Interestingly,
direct oxidative cyclization of 2ꢀalkylꢀNꢀheteroaromatics with alkyl amines has
1
1
also been recently explored.
halocyclization of heteroaromatics with aliphatic amines, leading to
imidazoꢀfused ꢀheteroaryl halides, still remains unresolved.
Associating with the catalytic aminohalogenation of alkenes reported by
Despite these important advances, the
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N
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our group, we set out to address the aboveꢀdescribed synthetic issue. Herein,
we wish to report a new aerobic copperꢀcatalysed halocyclization reaction of
methylꢀ
Nꢀheteroaromatics 1 with alkyl amines 2 by employing easilyꢀavailable
lithium halides as the halogen sources, which enables versatile access to
imidazo[1,5ꢀa]ꢀ and imidazo[1,5ꢀc]ꢀ
manner (Scheme 1).
Nꢀheteroaryl halides in a straightforward
Scheme 1 Halocyclization of methylꢀNꢀheteroaromatics with aliphatic amines
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RESULTS AND DISCUSSION
To initiate our study, we chose the coupling of 2ꢀmethylquinoline 1a with
benzylamine 2a as a model reaction to evaluate different parameters. First, in
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presence of 6 equiv LiBr, the reaction in chlorobenzene was performed at 120 C for
2
2
2 h under 1 atm of O . Gratifyingly, all the tested copper salts could afford the
desired halocyclization product 3aa (Table 1, entries 1ꢀ7), and CuBr
2
exhibited the
best activity. However, the absence of copper salt failed to give any product (entry 8).
Next, we examined several polar and lessꢀpolar solvents with catalytic amount of
CuBr , but they showed to be less effective or totally ineffective for the product
2
formation (entries 9ꢀ11). Decrease or increase of reaction temperature led to
diminished yield (entry 12). Further, the absence of LiBr gave only 8% yield (entry
1
3), showing that LiBr served as the halogen source. Finally, decreasing the catalyst
loading (entry 14) and replacing LiBr with NaBr or KBr (entry 15) significantly
decreased the product yields. Hence, the optimal reaction conditions are as described
in entry 4 of table 1.
a
Table 1. Screening of the reaction conditions
b
entry
catalyst (mol %)
Br source
solvent
yields of 3aa
1
2
3
4
CuCl
CuCl2
CuI
LiBr
LiBr
LiBr
LiBr
chlorobenzene
chlorobenzene
chlorobenzene
chlorobenzene
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4
9
CuBr
2
90
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1
CuBr
Cu(OAc)
Cu(OTf)
ꢀ
LiBr
LiBr
LiBr
LiBr
LiBr
LiBr
LiBr
LiBr
ꢀ
chlorobenzene
chlorobenzene
chlorobenzene
chlorobenzene
pꢀxylene
DMSO
DMF
chlorobenzene
chlorobenzene
chlorobenzene
70
85
51
0
44
0
0
(48, 88)
8
(28, 66)
(18, 15)
2
2
CuBr
2
0
CuBr2
CuBr2
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c
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a
CuBr
CuBr
CuBr
CuBr
2
2
2
2
d
LiBr
e
(NaBr or KBr) chlorobenzene
Unless otherwise stated, the reaction was performed with 1a (0.25 mmol), 2a (0.5 mmol), cat. (20 mol %), Br
o
b
c
2
source (1.5 mmol) in solvent (1.5 mL) at 120 C for 22 h using O balloon. GC yield. Yields are with respect to
o
c
d
at 110 and 130 C, respectively. GC Yields (%). yields are with respect to catalyst loadings of 15 mol% and 18
d
mol%, respectively. yields are with respect to using NaBr and KBr as the Bromine sources, respectively.
With the optimal conditions established, we then examined the generality and
limitations of the synthetic protocol. By using 2ꢀmethylquinoline 1 as the benchmark
substrate and LiBr as the halogen source, we evaluated a number of readily available
aliphatic amines 2 (2aꢀ2j: for structures see supporting information Scheme S1).
Gratifyingly, all the reactions proceeded smoothly and furnished the desired products
in good to excellent yields upon isolation (3aaꢀ3aj). Substituents such as ꢀMe, ꢀOMe
and other functional ones (ꢀCN, ꢀCl, ꢀBr) on the aryl ring of 2 were well tolerated, and
the electronic property of which affected the product yields to some extent.
Specifically, electronꢀrich ones enabled to afford better results (3abꢀ3ad) than those
of electronꢀdeficient ones (3aeꢀ3ah). Notably, heteroaryl methylamine 2j also served
as effective coupling partner to afford the desired product 3aj, a potential hemilabile
bidentate ligand that could be applied in the fields of catalysis and organometallic
chemistry. And aliphatic amine 2k also could be transformed into 2ꢀalkyl product,
albeit the yield was somewhat low (3ak).
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CuBr / LiBr
2
+
R2
N
Br
NH2
o
N
chlorobenzene, O , 120 C
2
3a
N
N
1
a
2
R2
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N
N
N
Br
Br
Br
N
N
3
aa, 90%, 22 h
3ab, 85%, 22 h
3ac, 76%, 22 h
N
N
N
Br
N
Br
Br
Br
N
N
N
N
Cl
Cl
NC
O
3
ad, 66%, 22 h
3ae, 65%, 32 h
3af, 65%, 22 h
3ag, 61%, 22 h
N
N
N
N
Br
N
N
N
N
Br
Br
Br
S
Br
ah, 58%, 22 h
3
3ai, 91%, 24 h
3aj, 81%, 24 h
3ak, 15%, 28 h
a
The reaction was performed with 1a (0.25 mmol), 2 (0.5 mmol), CuBr (20 mol %), LiBr (1.5
2
o
mmol) in chlorobenzene (1.5 mL) at 120 C for 22ꢀ32 h using O
2
balloon.
Scheme 2 Variation of aliphatic amines
Next, we turned our attention to apply different types of
oꢀmethylꢀheteroaromatics 1. The combinations of various 2ꢀmethylquinolines 1 with
different benzylic amines 2 (for structures see supporting information) were firstly
examined. Analogous to the results described in scheme 2, all the reactions afforded
the imidazoꢀfused Nꢀheterocycles by selective introducing bromo functionality to Cꢀ3
(scheme 3). It was found that substrates 1 possessing electroꢀdonating groups (3ba,
3
bj, 3ca) gave much higher yields than those of relatively electronꢀpoor ones (3da,
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db, 3ea). Then, dinitrogen heteroaromatics such as 4ꢀmethylquinazoline (1f),
2
ꢀmethylquinoxaline (1g), and 2ꢀmethylꢀ1,8ꢀnaphthyridine (1h) also underwent
smooth bromoꢀcyclization reactions to give the desired products in moderate to high
yields (3fa, 3ga, 3ha). Finally, the reaction of 1ꢀmethylisoquinoline 1i with
benzylamine 2a could produce a 1ꢀbromoꢀ3ꢀphenyl product 3ia in 72% yield.
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Z
Y
R1
Z
Z
Y
Cu/O2
LiBr
R1
N
Z
Ar
NH2
or
or
N
N
X
Ar
2
(
Y, Z = CH or N)
N
N
N
3a
Ar
X
1
Cl
N
N
N
Br
Br
Br
N
O
Br
N
N
N
N
S
3
ba, 75%, 24 h
3bj, 68%, 24 h
Br
3ca, 78%, 28 h
3da, 50%, 26 h
Br
N
N
Cl
N
N
N
Br
N
N
N
N
Br
Br
N
3
db, 58%, 28 h
3ea, 55%, 24 h
3fa, 45%, 30 h
3ga, 71%, 32 h
N
N
N
Br
N
N
Br
3ha, 75%, 24 h
3ia, 72%, 28 h
a
The reaction was performed with 1 (0.25 mmol), 2 (0.5 mmol), CuBr (20 mol %), LiBr (1.5
2
o
mmol) in chlorobenzene (1.5 mL) at 120 C for 24ꢀ32 h using O
2
balloon.
Scheme 3 Variation of methyl Nꢀheteroaromatics
In addition to the above bromocyclization reaction, we further wished to
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incorporate other halogen functionalities into the product skeletons in the presence of
suitable copper catalysts and lithium halides. As shown in Scheme 4, replacing
2
CuBr /LiBr of the optimal conditions with different copper catalysts and LiF failed to
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give the fluorinated product, whereas the combination of CuCl /LiCl enabled the
2
chlorocyclization reactions, affording the chlorinated products in good yields (4aa,
4
2
ab, 4ia). Pleasingly, by employing Cu(OAc) as an effective catalyst and LiI as the
iodine source, the catalytic cyclization reactions also proceeded smoothly to afford the
iodinated products within shorter time (5aa and 5ab).
a
The reaction was performed with 1 (0.25 mmol), 2a (0.5 mmol), CuCl
2
(20 mol %), LiCl (1.5
o
b
mmol) in chlorobenzene (1.5 mL) at 120 C for 36 h using O
2
balloon. The reaction was
performed with 1a (0.25 mmol), 2a (0.5 mmol), Cu(OAc)
2
(20 mol %), LiI (1.5 mmol) in
o
chlorobenzene (1.5 mL) at 120 C for 16ꢀ18 h using O balloon.
2
Scheme 4 Variation of halogen sources
To gain insight into the reaction information, several control experiments were
performed. First, the reaction of 1a and 2a under standard conditions was interrupted
after 1.5 h to analyse the intermediates (Scheme 5, eq 1). Except for the generation of
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nonꢀbrominated product 3aa-1 (33.7% yield), compounds 1a-1 and 1a-2 arising from
methyl bromination and oxidation were observed in 15.5% and 7% yields,
respectively. Further, both 1a-1 and 1a-2 were able to couple with 2a to afford 3aa in
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1% and 65% yields (eq 2), respectively. Similarly, 3aa-1 underwent direct
bromocyclization reaction to give 3aa in almost quantitative yield (eq 3). These
results suggest that 1a-1, 1a-2 and 3aa-1 are the reaction intermediates. However,
upon addition of radical scavengers (TEMPO), the bromination of 3aa-1 only led to a
1
3% product yield (eq 4), indicating that the transformation of 3aa-1 into the final
product 3aa mainly undergoes a radical pathway. Under the same conditions，the
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bromocyclization of 1a and 2a was totally suppressed (eq 5), showing that radical
intermediates are also involved to generate 3aa-1, which is agreement with the early
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reported references.
Scheme 5 Control experiments
Based on the above findings, a tentative reaction pathway is depicted in Scheme
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. Initially, aldehyde 1a-2 is generated from 1a through an aerobic Cuꢀcatalyzed
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single electron transfer (SET) process. In which, the carbocupration intermediate B
ꢀ
+
2
is oxidized to hyperꢀvalent species D in the presence of X , H and O , and the
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reductive elimination (RE) of D leads to form a benzyl halogenated intermediate 1a-1.
Then, the oxidative coupling of 1a-1 with amine 2a or the condensation of 1a-2 with
2
a gives imine E, which undergoes intramolecular oxidative cyclization to afford
9
a
n
heterocycle 3aa-1. Further, the acidic CꢀH bond of 3aa-1 reacts with [Cu ] followed
n+1
2
by SET from Cu to O , affording the [Cu ]ꢀsuperoxo radical F. SET from
electronꢀrich imidazo ring to the oxygen radical forms a radical cation G. Finally, the
+
n
H abstraction by the oxygen anion of G, elimination of [Cu OOH] and nucleophilic
ꢀ
addition of X to the cationic heterocyclic ring would yield product 3. Alternatively,
successive oxidation of carbocupration species H and RE of I also rationalize the
product formation. Moreover, other Cu oxidized forms, serving as oxidants to
14
regenerate the catalytic species, can also be possible in the transformation.
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Scheme 6 Proposed reaction pathway
To explore the utility of the developed synthetic method, the synthesis of
compound 3aa was scaled up by using 5 mmol of 1a, which still afforded a good
product yield (62%). Then, 3aa was applied to synthesize products 6a (78% yield)
and 7a (65% yield) via Suzuki and Sonogashira coupling reactions, respectively
(Figure 1). Through determination of their photophysical and thermal properties (see
supporting information), it showed that the absorption and emission spectra of 6a and
7a exhibited a typical bathochromic shift compared to 3aa. Moreover, the coupling
products (6a, 7a) showed intense fluorescence in both solution (quantum efficiencies
Φ
F,s : 52.6%, 52.5%) and crystalline solid (ΦF,c : 12%, 10.2%) states, typical
crystalliztionꢀinduced emission enhancement (CIEE) characteristics and excellent
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thermal stability (T
d
: 381°C, 328 °C). These results indicate that the developed
halocyclization reaction, enabling versatile access to imidazoꢀfused Nꢀheterocycles,
offers the potential to effectively obtain optoelectronic materials with excellent
performance.
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Figure 1 The synthetic utility of the halocyclization reaction.
CONCLUSION
In summary, we have demonstrated a new aerobic copperꢀcatalyzed halocyclization
reaction of methyl Nꢀheteroaromatics with aliphatic amines, which enables
straightforward access to functionalized imidazoꢀfused Nꢀheterocycles with the merits
of good functional group tolerance, use of easily available copper salts as the catalysts,
2
lithium halides as the halogen sources and O as a sole oxidant. One of the obtained
products was utilized for classical crossꢀcoupling reactions, and the resulting products
exhibited unique photophysical properties and excellent thermal stability. Owing to
the reaction features selective and versatile introduction of halogen functionalities to
the newly formed imidazoꢀring, further extensions of the developed chemistry
towards synthetic diversity, including facile access to functional materials, are easily
envisioned.
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EXPERIMENTAL SECTION
General methods. Melting points were measured by a melting point instrument and
1
13
were uncorrected. H and C NMR spectra were recorded by using a 400 MHz NMR
spectrometer. The chemical shifts are referenced to signals at 7.24 and 77.0 ppm,
respectively, and chloroform is used as a solvent with TMS as the internal standard.
IR spectra were obtained either as potassium bromide pellets or as liquid films
between two potassium bromide pellets with an infrared spectrometer. GCꢀMS was
obtained using electron ionization. The data of HRMS was carried out on a
highꢀresolution mass spectrometer (LCMSꢀITꢀTOF). TLC was performed by using
commercially available 100ꢀ400 mesh silica gel plates. Unless otherwise noted, all
purchased chemicals were used without further purification. The absorption and
fluorescence spectra were recorded. The solution fluorescence quantum yield was
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F
estimated by using 9,10ꢀdiphenylanthracen as standard (Φ = 90% in cyclohexane).
Solidꢀstate efficiencies were determined with the excitation wavelength of 365 nm.
Glass transition temperature was determined by DSC measurements carried out.
Thermal stability was determined by thermogravimetric analyzer over a temperature
o
o
ꢀ1
range of 28ꢀ600 C at a heating rate of 10 C min under a nitrogen atmosphere.
General Procedure for synthesis of 3 : The mixture of 2ꢀmethylquinoline
(0.25mmol), benzylamine (0.5mmol), lithium bromide (1.5mmol) and CuBr2
(0.05mmol) in chlorobenzene (1.5ml) was stirred at 120°C for 22 hours under 1 atm
of O atmosphere(using O balloon). After cooling down to room temperature, the
2
2
2 3
resulting mixture was extracting with chloroform, washed with 5% Na CO solution,
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dried with anhydrous sodium sulfate, and then concentrated by removing the solvent
under vacuum. Finally, the residue was purified by preparative TLC on silica
(petroleum ether / ethyl acetate) to give 3ꢀbromoꢀ1ꢀphenylimidazo[1,5ꢀa]quinoline 3.
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3-bromo-1-phenylimidazo[1,5-a]quinoline (3aa): Pale yellow solid, (72.4 mg, 90% yield), m.p:
1
1
63ꢀ164°C; H NMR (400 MHz, CDCl ) δ 7.67ꢀ7.59 (m, 3H), 7.56ꢀ7.46 (m, 4H), 7.33 (t, J = 7.5
3
13
Hz, 1H), 7.29 (d, J = 9.4 Hz, 1H), 7.19 (t, J = 7.8 Hz, 1H), 7.08 (d, J = 9.4 Hz, 1H). C NMR (101
MHz, CDCl ) δ 141.6, 132.7, 132.2, 129.7, 129.7, 128.9, 128.9, 127.9, 127.7, 125.7, 125.6, 122.4,
17.3, 116.1, 109.3. IR (KBr): 3061, 2954, 2924, 2852, 1622, 1604, 1452, 1393, 1360, 793, 754,
3
1
7
3
ꢀ1
+
+
00, 559 cm . MS (EI, m/z): 322 [M] . HRMS (ESI): Calcd. for C17
2
H11BrN Na [M+ Na] :
44.9998; found: 344.9996.
3
-bromo-1-(p-tolyl)imidazo[1,5-a]quinoline (3ab): Pale yellow solid, (71.4 mg, 85%
1
yield), m.p: 167ꢀ168°C; H NMR (400 MHz, CDCl
3
) δ 7.61 (dd, J = 7.8, 1.1 Hz, 1H), 7.56ꢀ7.48
(
m, 3H), 7.35ꢀ7.29 (m, 3H), 7.27 (d, J = 9.4 Hz, 1H), 7.22ꢀ7.16 (m, 1H), 7.06 (d, J = 9.4 Hz, 1H),
13
2.46 (s, 3H). C NMR (101 MHz, CDCl
3
) δ 141.8, 139.8, 132.3, 129.7, 129.6, 129.5, 128.9, 127.8,
127.7, 125.7, 122.2, 117.3, 116.0, 109.1, 21.6. IR (KBr): 3024, 2953, 2921, 2856, 1606, 1552,
ꢀ1
+
1526, 1475, 1451, 1359, 793, 754, 722, 558 cm . MS (EI, m/z): 336 [M] . HRMS (ESI): Calcd.
+
for C18
H13BrN
2
Na [M+ Na] : 359.0154; found: 359.0149.
3-bromo-1-(o-tolyl)imidazo[1,5-a]quinoline (3ac): Pale yellow solid, (63.8 mg, 76%
1
yield) m.p: 155ꢀ156°C; H NMR (400 MHz, CDCl
3
) δ 7.64 (d, J = 7.8 Hz, 1H), 7.47 (dd, J = 13.8,
1
3
7.2 Hz, 2H), 7.40ꢀ7.29 (m, 4H), 7.22ꢀ7.13 (m, 2H), 7.09 (d, J = 9.4 Hz, 1H), 2.06 (s, 3H). C
3
NMR (101 MHz, CDCl ) δ 140.8, 138.5, 132.7, 132.4, 130.6, 130.5, 130.2, 128.8, 128.3, 127.3,
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26.5, 125.7, 125.4, 122.2, 116.1, 115.9, 108.7, 19.6. IR (KBr): 3059, 2952, 2922, 2855, 1619,
ꢀ1
+
1605, 1552, 1508, 1475, 1448, 1359, 795, 757, 728, 596 cm . MS (EI, m/z): 336 [M] . HRMS
+
(
ESI): Calcd. for C18
H
13BrN
2
Na [M+ Na] : 359.0154; found: 359.0151.
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3
-bromo-1-(3-methoxyphenyl)imidazo[1,5-a]quinoline (3ad): Pale yellow oil liquid,
1
(58.0 mg, 66% yield); H NMR (400 MHz, CDCl
3
) δ 7.67ꢀ7.59 (m, 1H), 7.56ꢀ7.48 (m, 1H),
13
7
1
5
7
3
.46ꢀ7.13 (m, 6H), 7.09 (s, 2H), 3.83 (s, 3H). C NMR (101 MHz, CDCl ) δ 159.9, 141.4, 133.8,
3
32.1, 129.9, 128.9, 127.9, 127.8, 125.8, 125.6, 122.4, 122.0, 117.4, 116.2, 115.99, 114.6, 109.1,
5.5. IR (KBr): 3066, 3001, 2958, 2927, 2852, 2834, 1603, 1580, 1469, 1434, 1359, 1249, 1228,
ꢀ1
+
+
92, 754, 703, 556 cm . MS (EI, m/z): 352 [M] . HRMS (ESI): Calcd. for C18
2
H14BrN O [M+H] :
53.0284; found: 353.0276.
4-(3-bromoimidazo[1,5-a]quinolin-1-yl)benzonitrile (3ae): Pale yellow solid, (56.4 mg,
1
65% yield), m.p: 186ꢀ187°C; H NMR (400 MHz, CDCl
3
) δ 7.84ꢀ7.75 (m, 4H), 7.71 (d, J = 7.8 Hz,
13
1H), 7.50ꢀ7.38 (m, 2H), 7.31 (dd, J = 19.5, 9.1 Hz, 2H), 7.18 (d, J = 9.4 Hz, 1H). C NMR (101
MHz, CDCl ) δ 139.4, 136.8, 132.5, 131.6, 130.1, 129.4, 128.9, 128.0, 126.3, 125.8, 123.2, 118.3,
117.2, 116.0, 113.2, 110.3. IR (KBr): 3062, 2925, 2853, 2228, 1752, 1684, 1606, 1452, 1426, 1363,
3
ꢀ1
+
843, 796, 754, 594, 543 cm . MS (EI, m/z): 347 [M] . HRMS (ESI): Calcd. for C H BrN
18 11 3
+
[M+H] : 348.0131; found: 348.0127.
3
-bromo-1-(4-chlorophenyl)imidazo[1,5-a]quinoline (3af): Pale yellow solid, (57.8 mg,
1
65% yield), m.p: 213ꢀ214°C; H NMR (400 MHz, CDCl
3
) δ 7.66 (d, J = 7.7 Hz, 1H), 7.59 (d, J =
7
.3 Hz, 2H), 7.50 (d, J = 8.2 Hz, 3H), 7.37 (t, J = 7.5 Hz, 1H), 7.33ꢀ7.22 (m, 2H), 7.11 (d, J = 9.4
13
Hz, 1H). C NMR (101 MHz, CDCl ) δ 140.3, 135.8, 132.0, 131.1, 131.0, 129.2, 129.1, 128.2,
3
127.9, 126.0, 125.7, 122.6, 117.2, 116.0, 109.5. IR (KBr): 3062, 2954, 2923, 2852, 1625, 1476,
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ꢀ
1
+
1
447, 1359, 831, 789, 754, 588 cm . MS (EI, m/z): 356 [M] . HRMS (ESI): Calcd. for
+
C
17
H10BrClN
2
Na [M+ Na] : 378.9608; found: 378.9607.
3
-bromo-1-(2-chlorophenyl)imidazo[1,5-a]quinoline (3ag): White solid, (54.3 mg,
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1% yield) , m.p: 181ꢀ182°C; H NMR (400 MHz, CDCl
3
) δ 7.68ꢀ7.59 (m, 2H), 7.58ꢀ7.49 (m, 2H),
13
7
.46 (t, J = 7.1 Hz, 1H), 7.38ꢀ7.29 (m, 2H), 7.25ꢀ7.17 (m, 2H), 7.13 (d, J = 9.4 Hz, 1H). C NMR
(
101 MHz, CDCl ) δ 138.1, 135.3, 132.5, 132.4, 132.3, 131.5, 129.9, 128.9, 128.4, 127.8, 127.5,
3
1
25.9, 125.3, 122.7, 115.9, 115.9, 108.9. IR (KBr): 3059, 2955, 2924, 2853, 1622, 1475, 1438,
ꢀ1
+
1
365, 862, 794, 757, 666, 593 cm . MS (EI, m/z): 356 [M] . HRMS (ESI): Calcd. for
+
C
17
H10BrClN
2
Na [M+ Na] : 378.9608; found: 378.9609.
3
-bromo-1-(4-bromophenyl)imidazo[1,5-a]quinoline (3ah): Pale yellow solid, (58.0 mg, 58%
1
yield), m.p: 173ꢀ174°C; H NMR (400 MHz, CDCl ) δ 7.66 (d, J = 8.2 Hz, 3H), 7.57ꢀ7.48 (m, 3H),
3
13
7
.38 (t, J = 7.5 Hz, 1H), 7.33ꢀ7.22 (m, 2H), 7.12 (d, J = 9.4 Hz, 1H). C NMR (101 MHz, CDCl
3
)
δ 140.4, 132.1, 132.0, 131.5, 131.2, 129.1, 128.3, 127.9, 126.0, 125.7, 124.1, 122.6, 117.2, 116.0,
09.6. IR (KBr): 3061, 2954, 2923, 2852, 1676, 1592, 1473, 1448, 1398, 1361, 1010, 828, 793,
1
ꢀ1
+
+
754, 588 cm . MS (EI, m/z): 400 [M] . HRMS (ESI): Calcd. for C17
2 2
H11Br N [M+H] : 400.9283;
found: 400.9285.
3-bromo-1-(naphthalen-1-yl)imidazo[1,5-a]quinoline (3ai): White solid, (84.6 mg,
1
9
1% yield) , m.p: 185ꢀ186°C; H NMR (400 MHz, CDCl
3
) δ 8.06 (d, J = 8.2 Hz, 1H), 7.95 (d, J =
8.2 Hz, 1H), 7.71 (d, J = 6.9 Hz, 1H), 7.61 (t, J = 8.5 Hz, 2H), 7.49 (t, J = 7.2 Hz, 1H), 7.42ꢀ7.28
13
(
m, 3H), 7.22 (t, J = 7.2 Hz, 1H), 7.13 (d, J = 9.5 Hz, 1H), 6.99ꢀ6.84 (m, 2H). C NMR (101 MHz,
CDCl ) δ 139.7, 133.7, 132.4, 132.1, 130.5, 130.4, 129.1, 128.8, 128.5, 128.1, 127.8, 127.4, 126.6,
3
1
25.6, 125.6, 125.5, 125.4, 122.5, 116.9, 116.0, 109.2. IR (KBr): 3053, 2954, 2924, 2853, 1607,
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ꢀ
1
+
1
473, 1448, 1360, 1247, 798, 777, 752, 741, 561, 527 cm . MS (EI, m/z): 372 [M] . HRMS (ESI):
+
Calcd. for C21
H13BrN
2
Na [M+ Na] : 395.0154; found: 395.0158.
3
-bromo-1-(thiophen-2-yl)imidazo[1,5-a]quinoline (3aj): Pale yellow solid, (66.4 mg,
10
11
12
13
14
15
16
17
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58
59
60
1
8
6
9
1
1
3
1% yield) , m.p: 156ꢀ157°C; H NMR (400 MHz, CDCl ) δ 7.65 (d, J = 7.7 Hz, 1H), 7.59 (d, J =
.8 Hz, 2H), 7.40ꢀ7.33 (m, 2H), 7.28 (dd, J = 12.7, 6.2 Hz, 2H), 7.23ꢀ7.18 (m, 1H), 7.11 (d, J =
13
.4 Hz, 1H). C NMR (101 MHz, CDCl ) δ 134.3, 132.9, 132.2, 130.1, 129.0, 128.8, 128.6, 128.1,
3
27.5, 126.0, 125.6, 122.9, 116.9, 115.8, 109.4. IR (KBr): 3068, 2954, 2924, 2852, 1620, 1473,
ꢀ1
+
447, 1361, 1251, 794, 751, 741, 706, 672, 555 cm . MS (EI, m/z): 328 [M] . HRMS (ESI):
+
Calcd. for C15
H
9
BrN
2
NaS [M+ Na] : 350.9562; found: 350.9568.
1
-benzyl-3-bromoimidazo[1,5-a]quinoline (3ak): Pale yellow solid, (12.6 mg, 15%
1
yield) , m.p: 109ꢀ110°C; H NMR (400 MHz, CDCl ) δ 7.97ꢀ7.87 (m, 1H), 7.63ꢀ7.53 (m, 1H),
3
13
7
.39ꢀ7.10 (m, 8H), 7.00 (d, J = 9.3 Hz, 1H), 4.78 (s, 2H). C NMR (101 MHz, CDCl
3
) δ 140.7,
136.3, 132.3, 129.0, 128.8, 128.2, 128.0, 126.9, 125.6, 125.6, 122.0, 116.8, 116.1, 107.9, 37.6. IR
ꢀ1
(
KBr): 3060, 3029, 2923, 2852, 1604, 1494, 1377, 1076, 792, 751, 721, 694, 512 cm . MS (EI,
+
+
2
m/z): 336 [M] . HRMS (ESI): Calcd. for C18H14BrN [M+H] : 337.0335; found: 337.0336.
3
-bromo-7-methyl-1-phenylimidazo[1,5-a]quinoline (3ba): Grey solid, (63.0 mg, 75%
1
yield) , m.p: 189ꢀ190°C; H NMR (400 MHz, CDCl
3
) δ 7.62 (d, J = 6.8 Hz, 2H), 7.51 (d, J = 5.1
Hz, 3H), 7.42 (s, 1H), 7.36 (d, J = 8.6 Hz, 1H), 7.27 (d, J = 8.8 Hz, 1H), 7.02 (t, J = 9.7 Hz, 2H),
13
2.39 (s, 3H). C NMR (101 MHz, CDCl
3
) δ 141.3, 135.6, 132.7, 130.1, 129.7, 129.7, 128.8, 128.8,
1
27.9, 125.7, 122.3, 117.1, 115.9, 109.1, 20.8. IR (KBr): 3055, 2953, 2920, 2854, 1603, 1562,
ꢀ1
+
1482, 1448, 1366, 803, 767, 697, 592 cm . MS (EI, m/z): 336 [M] . HRMS (ESI): Calcd. for
+
C
18
H13BrN
2
Na [M+ Na] : 359.0154; found: 359.0158.
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-bromo-7-methyl-1-(thiophen-2-yl)imidazo[1,5-a]quinoline (3bj): Grey solid, (58.1
1
mg, 68% yield) , m.p: 182ꢀ183°C; H NMR (400 MHz, CDCl
3
) δ 7.58 (d, J = 5.1 Hz, 1H),
7
.51ꢀ7.42 (m, 2H), 7.36 (d, J = 2.9 Hz, 1H), 7.27 (d, J = 9.6 Hz, 1H), 7.20 (t, J = 4.3 Hz, 1H), 7.08
0
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2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
(
t, J = 8.8 Hz, 2H), 2.41 (s, 3H). C NMR (101 MHz, CDCl
3
) δ 135.8, 134.0, 132.9, 130.2, 130.1,
1
2
29.2, 128.8, 128.7, 128.5, 127.4, 125.6, 122.8, 116.7, 115.7, 109.2, 20.9. IR (KBr): 3062, 2956,
ꢀ1
+
922, 2854, 1615, 1591, 1563, 1479, 1365, 1258, 806, 704, 553 cm . MS (EI, m/z): 342 [M] .
+
HRMS (ESI): Calcd. for C16
H
11BrN
2
NaS [M+ Na] : 364.9719; found: 364.9721.
3
-bromo-9-methoxy-1-phenylimidazo[1,5-a]quinoline (3ca): Pale yellow oil liquid,
1
(68.6 mg, 78% yield); H NMR (400 MHz, CDCl
3
) δ 7.48 (d, J = 7.3 Hz, 2H), 7.40ꢀ7.26 (m, 4H),
13
7
.21 (t, J = 8.5 Hz, 2H), 6.97 (d, J = 9.3 Hz, 1H), 6.77 (d, J = 8.0 Hz, 1H), 2.99 (s, 3H). C NMR
(101 MHz, CDCl ) δ 149.1, 146.1, 135.5, 129.0, 128.7, 128.1, 128.0, 126.6, 125.2, 122.2, 121.8,
3
119.7, 116.7, 110.4, 110.3, 53.7. IR (KBr): 3061, 3005, 2963, 2932, 2838, 1600, 1558, 1463, 1442,
ꢀ1
+
1358, 1319, 1278, 1253, 1133, 1077, 960, 803, 737, 697, 593 cm . MS (EI, m/z): 352 [M] .
+
HRMS (ESI): Calcd. for C18
H
14BrN
2
O [M+H] : 353.0284; found: 353.0289.
3-bromo-8-chloro-1-phenylimidazo[1,5-a]quinoline (3da): Pale yellow solid, (44.5 mg,
1
50% yield) , m.p: 180ꢀ181°C; H NMR (400 MHz, CDCl ) δ 7.64ꢀ7.51 (m, 6H), 7.44 (s, 1H),
3
1
3
7.33ꢀ7.22 (m, 2H), 7.03 (d, J = 9.4 Hz, 1H). C NMR (101 MHz, CDCl
3
) δ 141.8, 133.3, 132.6,
132.0, 130.2, 129.8, 129.5, 129.1, 127.8, 126.1, 124.1, 121.5, 117.5, 116.3, 109.7. IR (KBr): 3062,
ꢀ1
+
2955, 2923, 2853, 1608, 1474, 1447, 1385, 1091, 840, 692, 582 cm . MS (EI, m/z): 356 [M] .
+
HRMS (ESI): Calcd. for C17
H
10BrClN
2
Na [M+ Na] : 378.9608; found: 378.9615.
3-bromo-8-chloro-1-(p-tolyl)imidazo[1,5-a]quinoline (3db): Red solid, (53.6 mg, 58%
1
yield), m.p: 213ꢀ214°C; H NMR (400 MHz, CDCl
3
) δ 7.59ꢀ7.47 (m, 4H), 7.35 (d, J = 7.7 Hz, 2H),
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.32ꢀ7.22 (m, 2H), 7.02 (d, J = 9.4 Hz, 1H), 2.48 (s, 3H). C NMR (101 MHz, CDCl ) δ 142.0,
3
40.3, 133.2, 132.7, 129.7, 129.4, 129.0, 127.7, 126.1, 124.2, 121.4, 117.5, 116.4, 109.5, 21.6. IR
ꢀ1
(
KBr): 3072, 3041, 2922, 2853, 1602, 1455, 1415, 1355, 1247, 1091, 828, 739, 577 cm . MS (EI,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
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35
36
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42
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44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
+
+
2
m/z): 370 [M] . HRMS (ESI): Calcd. for C18H12BrClN Na [M+ Na] : 392.9765; found: 392.9775.
3
,7-dibromo-1-phenylimidazo[1,5-a]quinoline (3ea): Red solid, (55.0 mg, 55% yield),
1
m.p: 203ꢀ204°C; H NMR (400 MHz, CDCl ) δ 7.75 (s, 1H), 7.60 (d, J = 7.3 Hz, 2H), 7.56ꢀ7.47
3
1
3
(
m, 3H), 7.38ꢀ7.24 (m, 3H), 6.98 (d, J = 9.5 Hz, 1H). C NMR (101 MHz, CDCl
3
) δ 141.8, 132.2,
1
3
4
31.1, 131.0, 130.5, 130.0, 129.6, 129.1, 127.7, 127.5, 121.1, 119.0, 118.8, 117.4, 110.0. IR (KBr):
ꢀ1
056, 2954, 2922, 2852, 1600, 1546, 1469, 1448, 1362, 962, 798, 699, 590 cm . MS (EI, m/z):
+
+
2 2
00 [M] . HRMS (ESI): Calcd. for C17H10Br N Na [M+ Na] : 422.9103; found: 422.9107.
1-bromo-3,5-diphenylimidazo[1,5-c]quinazoline (3fa): Yellow solid, (44.9 mg, 45%
1
yield), m.p: 229ꢀ230°C; H NMR (400 MHz, CDCl
3
) δ 8.86 (d, J = 7.4 Hz, 1H), 7.89 (d, J = 7.4
13
Hz, 1H), 7.67ꢀ7.52 (m, 2H), 7.30 (d, J = 7.7 Hz, 2H), 7.22ꢀ6.97 (m, 8H). C NMR (101 MHz,
CDCl ) δ 145.6, 141.8, 138.5, 133.4, 130.5, 130.1, 129.2, 128.8, 128.7, 128.5, 128.4, 128.2, 127.8,
127.5, 125.6, 121.7, 118.9, 109.0. IR (KBr): 3052, 2954, 2922, 2852, 1605, 1566, 1532, 1462,
3
ꢀ1
+
1
329, 1234, 949, 753, 695, 541 cm . MS (EI, m/z): 399 [M] . HRMS (ESI): Calcd. for
+
22
C H15BrN
3
[M+H] : 400.0444; found: 400.0449.
3
-bromo-1-phenylimidazo[1,5-a]quinoxaline (3ga): Pale yellow solid, (57.3 mg, 71%
1
yield) , m.p: 206ꢀ207°C; H NMR (400 MHz, CDCl
3
) δ 8.83 (s, 1H), 7.97 (d, J = 7.0 Hz, 1H), 7.67
13
(
d, J = 6.7 Hz, 2H), 7.64ꢀ7.53 (m, 3H), 7.52ꢀ7.42 (m, 2H), 7.30ꢀ7.20 (m, 1H). C NMR (101 MHz,
CDCl ) δ 144.4, 143.1, 137.3, 131.1, 130.5, 130.5, 129.7, 129.0, 128.0, 127.3, 126.2, 123.3, 116.4,
3
ꢀ1
1
14.1. IR (KBr): 3067, 2954, 2922, 2851, 1612, 1585, 1465, 1440, 1387, 1257, 762, 695, 587 cm .
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3
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3
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3
3
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3
4
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4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
+
MS (EI, m/z): 323 [M] . HRMS (ESI): Calcd. for C H BrN [M+H] : 324.0131; found:
16
11
3
324.0134.
7
-bromo-9-phenylimidazo[1,5-a][1,8]naphthyridine (3ha): Pale yellow solid, (60.5 mg,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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5
6
7
8
9
0
1
2
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4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
7
7
1
1
7
3
5% yield), m.p: 183ꢀ184°C; H NMR (400 MHz, CDCl
3
) δ 8.24 (d, J = 4.5 Hz, 1H), 7.91 (d, J =
.8 Hz, 1H), 7.80ꢀ7.70 (m, 2H), 7.48ꢀ7.38 (m, 3H), 7.35ꢀ7.26 (m, 2H), 6.98 (d, J = 9.3 Hz,
13
H). C NMR (101 MHz, CDCl ) δ 146.6, 143.9, 143.1, 136.3, 132.5, 130.4, 128.8, 128.7, 127.27,
3
22.0, 120.3, 120.2, 117.4, 110.6. IR (KBr): 3055, 2954, 2922, 2853, 1617, 1593, 1422, 1366, 814,
ꢀ1
+
+
61, 699, 675, 590 cm . MS (EI, m/z): 323 [M] . HRMS (ESI): Calcd. for C16
3
H11BrN [M+H] :
24.0131; found: 324.0132.
1
-bromo-3-phenylimidazo[5,1-a]isoquinoline (3ia): White green solid, (57.9 mg, 72%
1
yield) , m.p: 155ꢀ156°C; H NMR (400 MHz, CDCl ) δ 8.88 (d, J = 8.0 Hz, 1H), 7.92 (d, J = 7.5
3
13
Hz, 1H), 7.74 (d, J = 7.2 Hz, 2H), 7.60ꢀ7.41 (m, 6H), 6.77 (d, J = 7.5 Hz, 1H). C NMR (101
MHz, CDCl
3
) δ 140.1, 129.5, 129.0, 129.0, 128.6, 128.4, 127.5, 127.3, 127.0, 124.7, 124.3, 122.5,
1
20.3, 115.0, 108.3. IR (KBr): 3060, 2955, 2923, 2852, 1602, 1476, 1457, 1364, 1237, 787, 695,
ꢀ1
+
+
567 cm . MS (EI, m/z): 322 [M] . HRMS (ESI): Calcd. for C17
2
H11BrN Na [M+ Na] : 344.9998;
found: 344.9999.
General Procedure for synthesis of 4 : The mixture of 2ꢀmethylquinoline
0.25mmol), benzylamine (0.5mmol), lithium chloride (1.5mmol) and CuCl
(0.05mmol) in chlorobenzene (1.5ml) was stirred at 120°C for 36 hours under 1 atm
of O atmosphere(using O balloon). After cooling down to room temperature, the
resulting mixture was extracting with chloroform, washed with 5% Na CO solution,
(
2
2
2
2
3
dried with anhydrous sodium sulfate, and then concentrated by removing the solvent
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under vacuum. Finally, the residue was purified by preparative TLC on silica
(petroleum ether / ethyl acetate) to give 3ꢀ chloroꢀ1ꢀphenylimidazo[1,5ꢀa]quinoline 4.
3
-chloro-1-phenylimidazo[1,5-a]quinoline (4aa): Brownish red solid, (50.0 mg, 72%
10
11
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13
14
15
16
17
18
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40
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43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
yield) , m.p: 145ꢀ146°C; H NMR (400 MHz, CDCl
3
) δ 7.63 (d, J = 6.8 Hz, 3H), 7.55ꢀ7.47 (m,
1
3
4
H), 7.33 (t, J = 8.6 Hz, 2H), 7.19 (t, J = 7.8 Hz, 1H), 7.06 (d, J = 9.4 Hz, 1H). C NMR (101
MHz, CDCl ) δ 140.1, 132.7, 132.1, 129.7, 129.7, 128.9, 128.9, 127.7, 125.8, 125.7, 125.4, 122.2,
3
1
22.0, 117.3, 115.5. IR (KBr): 3061, 2924, 2853, 1605, 1553, 1477, 1448, 1364, 799, 755, 700,
ꢀ1
+
+
5
2
95 cm . MS (EI, m/z): 278 [M] . HRMS (ESI): Calcd. for C17H11ClN Na [M+ Na] : 301.0503;
found: 301.0504.
3
-chloro-1-(p-tolyl)imidazo[1,5-a]quinoline (4ab): Brownish red solid, (44.5 mg, 61%
1
yield) , m.p: 153ꢀ154°C; H NMR (400 MHz, CDCl ) δ 7.61 (d, J = 7.8 Hz, 1H), 7.52 (t, J = 8.6
3
13
Hz, 3H), 7.36ꢀ7.27 (m, 4H), 7.19 (t, J = 7.9 Hz, 1H), 7.03 (d, J = 9.4 Hz, 1H), 2.46 (s, 3H). C
NMR (101 MHz, CDCl
3
) δ 140.3, 139.8, 132.2, 129.7, 129.6, 129.5, 128.8, 127.7, 125.7, 125.3,
1
22.1, 121.8, 117.3, 115.5, 21.5. IR (KBr): 3062, 2922, 2855, 1620, 1553, 1452, 1405, 1362, 822,
ꢀ1
+
+
793, 593 cm . MS (EI, m/z): 292 [M] . HRMS (ESI): Calcd. for C18
2
H13ClN Na [M+ Na] :
3
15.0659; found: 315.0664.
1-chloro-3-phenylimidazo[5,1-a]isoquinoline (4ia): White green solid, (48.6 mg, 70%
1
yield) , m.p: 161ꢀ162°C; H NMR (400 MHz, CDCl
3
) δ 8.62 (d, J = 8.0 Hz, 1H), 7.86 (d, J = 7.6
13
Hz, 1H), 7.72 (d, J = 7.6 Hz, 2H), 7.56ꢀ7.34 (m, 6H), 6.71 (d, J = 7.6 Hz, 1H). C NMR (101
MHz, CDCl ) δ 138.4, 129.4, 129.0, 129.0, 128.5, 128.5, 127.3, 127.1, 126.9, 124.6, 122.7, 122.3,
122.2, 120.2, 114.9. IR (KBr): 3066, 3027, 2919, 2849, 1602, 1553, 1477, 1453, 1364, 977, 790,
3
ꢀ1
+
+
7
2
37, 691, 596 cm . MS (EI, m/z): 278 [M] . HRMS (ESI): Calcd. for C17H11ClN Na [M+ Na] :
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5
5
5
5
5
5
5
5
6
3
01.0503; found: 301.0511.
General Procedure for synthesis of 5 : The mixture of 2ꢀmethylquinoline
(
0.25mmol), benzylamine (0.5mmol), lithium iodide (1.5mmol) and Cu(OAc)
0.05mmol) in chlorobenzene (1.5ml) was stirred at 120°C for 16 hours under 1 atm
atmosphere(using O balloon). After cooling down to room temperature, the
resulting mixture was extracting with chloroform, washed with 5% Na CO solution,
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
of O
2
2
2
3
dried with anhydrous sodium sulfate, and then concentrated by removing the solvent
under vacuum. Finally, the residue was purified by preparative TLC on silica
(petroleum ether / ethyl acetate) to give 3ꢀ iodoꢀ1ꢀphenylimidazo[1,5ꢀa]quinoline 5.
3
-iodo-1-phenylimidazo[1,5-a]quinoline (5aa): White solid, (62.9 mg, 68% yield) m.p:
1
149ꢀ150°C; H NMR (400 MHz, CDCl ) δ 7.65ꢀ7.58 (m, 3H), 7.56ꢀ7.48 (m, 3H), 7.47 (d, J = 8.6
3
Hz, 1H), 7.31 (t, J = 7.5 Hz, 1H), 7.21 (d, J = 9.4 Hz, 1H), 7.16 (t, J = 7.9 Hz, 1H), 7.07 (d, J =
1
3
9.4 Hz, 1H). C NMR (101 MHz, CDCl
3
) δ 144.2, 132.8, 132.4, 132.3, 129.7, 129.7, 128.9, 128.9,
127.7, 125.7, 122.9, 117.2, 117.1, 77.9. IR (KBr): 3061, 2923, 2853, 1605, 1473, 1450, 1359, 795,
ꢀ
1
+
2
754, 699, 587, 512, 463 cm . MS (EI, m/z): 370 [M] . HRMS (ESI): Calcd. for C17H11IN Na [M+
+
Na] : 392.9859; found: 392.9854.
3-iodo-1-(p-tolyl)imidazo[1,5-a]quinoline (5ab): White solid, (43.2 mg, 45% yield), m.p:
1
180ꢀ181°C; H NMR (400 MHz, CDCl
3
) δ 7.63 (d, J = 7.7 Hz, 1H), 7.51 (t, J = 8.9 Hz, 3H),
1
3
7.38ꢀ7.28 (m, 3H), 7.27ꢀ7.15 (m, 2H), 7.08 (d, J = 9.4 Hz, 1H), 2.47 (s, 3H). C NMR (101 MHz,
CDCl ) δ 144.4, 139.8, 132.4, 132.3, 129.8, 129.6, 129.5, 128.8, 127.6, 125.7, 125.6, 122.8, 117.2,
117.2, 77.7, 21.6. IR (KBr): 3056, 3023, 2921, 2853, 1606, 1471, 1449, 1356, 793, 752, 585, 471
3
ꢀ1
+
+
2
cm . MS (EI, m/z): 384 [M] . HRMS (ESI): Calcd. for C18H13IN Na [M+ Na] : 407.0016; found:
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07.0021.
General Procedure for the Synthesis of 6a. Under N
2
atmosphere, 3aa (1 mmol),
(4ꢀ(diphenylamino)phenyl)boronic acid (1.2 mmol), Pd
2
(dba) (5 mol%), P(tꢀBu) (10
3
3
10
11
12
13
14
15
16
17
18
19
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47
48
49
50
51
52
53
54
55
56
57
58
59
60
mol%), KOH (2 mmol) and DMF (1.5 ml) were introduced in a Schlenk tube,
successively. Then the Schlenk tube was closed and the resulting mixture was stirred
o
at 100 C for 10 h. After cooling down to room temperature, the resulting mixture was
2 3
extracting with chloroform, washed with 5% Na CO solution, dried with anhydrous
sodium sulfate, and then concentrated by removing the solvent under vacuum. Finally,
the residue was purified by preparative TLC on silica (petroleum ether / ethyl acetate /
dichloromethane) to 6a.
N,N-diphenyl-4-(1-phenylimidazo[1,5-a]quinolin-3-yl)aniline (6a): Yellow solid, (379.8mg,
1
7
8% yield), m.p: 231ꢀ232°C; H NMR (400 MHz, CDCl
3
) δ 7.82 (d, J = 8.6 Hz, 2H), 7.77ꢀ7.71 (m,
2H), 7.69 (d, J = 9.5 Hz, 1H), 7.64 (d, J = 7.7 Hz, 1H), 7.61ꢀ7.53 (m, 3H), 7.50 (d, J = 8.5 Hz, 1H),
13
7
.37ꢀ 7.26 (m, 5H), 7.25ꢀ7.14 (m, 7H), 7.06 (dd, J = 17.0, 8.5 Hz, 3H). C NMR (101 MHz,
3
CDCl ) δ 147.8, 146.9, 142.0, 133.6, 132.5, 129.8, 129.5, 129.3, 129.0, 128.9, 128.5, 128.4, 127.5,
126.1, 125.9, 125.3, 124.3, 124.3, 122.8, 122.6, 121.8, 117.6, 117.6. IR (KBr): 3057, 3027, 2923,
ꢀ1
+
2853, 1589, 1489, 1315, 1276, 751, 696 cm . HRMS (ESI): Calcd. for C35
26 3
H N [M+H] :
488.2121; found: 488.2137.
General Procedure for the Synthesis of
ethynylbenzene (1.25 mmol), PdCl (5 mol%), CuI (20 mol%), PPh
N(C (3 mmol) and DMF (1.5 ml) were introduced in a Schlenk tube,
7a. Under N atmosphere, 3aa (1 mmol),
2
2
3
(10 mol%),
2
5 3
H )
successively. Then the Schlenk tube was closed and the resulting mixture was stirred
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5
5
6
o
at 90 C for 12 h. After cooling down to room temperature, the resulting mixture was
extracting with chloroform, washed with 5% Na CO solution, dried with anhydrous
2
3
sodium sulfate, and then concentrated by removing the solvent under vacuum. Finally,
the residue was purified by preparative TLC on silica (petroleum ether / ethyl acetate /
dichloromethane) to 7a.
0
1
2
3
4
5
6
7
8
9
0
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0
1
-phenyl-3-(phenylethynyl)imidazo[1,5-a]quinoline (7a): Brown solid, (223.6mg, 65% yield) ,
1
m.p: 186ꢀ187°C; H NMR (400 MHz, CDCl
3
) δ 7.71ꢀ7.57 (m, 5H), 7.57ꢀ7.44 (m, 5H), 7.40ꢀ7.25
13
(
m, 4H), 7.22ꢀ7.10 (m, 2H). C NMR (101 MHz, CDCl
3
) δ 142.4, 133.3, 133.1, 132.4, 131.4,
1
8
29.7, 129.7, 128.8, 128.4, 128.1, 127.9, 125.8, 125.6, 123.5, 123.2, 117.4, 116.9, 116.7, 93.1,
ꢀ1
2.5. IR (KBr): 3056, 2924, 2209, 1599, 1556, 1445, 1359, 1111, 798, 753, 705, 690, 611 cm .
+
HRMS (ESI): Calcd. for C H N [M+H] : 345.1386; found: 345.1395.
25 17
2
Acknowledgments
We thank the National Key Research and Development Program of China
2016YFA0602900), “1000 Youth Talents Plan (206999)”, Science Foundation for
(
Distinguished Young Scholars of Guangdong Province (2014A030306018), and the
Fundamental Research Funds for the Central Universities (2015PT018) for financial
support.
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Supporting Information
1
13
Copies of H and C NMR spectra data for all compounds, and the Xꢀray
crystallographic data (CIF file). This material is available free of charge via the
Internet at http://pubs.acs.org.
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