One-Pot Base-Mediated Synthesis of Functionalized Aza-Fused Polycyclic Quinoline Derivatives

Article abstract of DOI:10.1055/s-0034-1380506

A new one-pot protocol has been developed for the facile and efficient synthesis of aza-fused polycyclic quinolines (e.g., pyrrolo[1,2-a]quinolines) by the base-catalyzed reaction of 2-formylpyrroles and 2-halophenylacetonitriles. This reaction proceeded under transition metal-free conditions and showed high functional group tolerance, with the desired products being formed in good yields.

Full text of DOI:10.1055/s-0034-1380506

SYNTHESIS
0
0
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1
1
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0
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© Georg Thieme Verlag Stuttgart · New York
2015, 47, 1913–1921
paper
1913
Z.-q. Jiang et al.
Paper
Synthesis
One-Pot Base-Mediated Synthesis of Functionalized Aza-Fused
Polycyclic Quinoline Derivatives
Zeng-qiang Jianga
Da-zhuang Miaoa
Yao Tonga
Qiang Pana
Xiao-tong Lia
Ren-he Hua
Z
N
H
O
Z
K3PO4 (1.5 equiv)
X
+
Aryl
R
R
DMSO, 130 °C, 24 h
N
H
EWG
Shi-qing Han*a,b
EWG
X = I, Br, Cl
EWG = CN, CO2Et
Z = C, N
(also indoles, imidazole,
benzimidazole, pyrazole)
36 examples
15–99% yields
a College of Biotechnology and Pharmaceutical Engineering,
Nanjing Tech University, Nanjing 211816, P. R. of China
b Key Laboratory of Synthetic Chemistry of Natural Substances,
Shanghai Institute of Organic Chemistry, CAS, 345 Lingling
Road, Shanghai 200032, P. R. of China
hanshiqing@njtech.edu.cn
Received: 15.12.2014
Accepted after revision: 03.03.2015
Published online: 02.04.2015
O
O
i-Pr
N
H
DOI: 10.1055/s-0034-1380506; Art ID: ss-2014-h0759-op
H
Me
N
N
i-Pr
O
CO2Me
N
Abstract A new one-pot protocol has been developed for the facile
and efficient synthesis of aza-fused polycyclic quinolines (e.g., pyrro-
lo[1,2-a]quinolines) by the base-catalyzed reaction of 2-formylpyrroles
and 2-halophenylacetonitriles. This reaction proceeded under transi-
tion metal-free conditions and showed high functional group tolerance,
with the desired products being formed in good yields.
O
O
CO2Me
R
B
A
Ph
O
O
Key words one-pot, base-catalyzed, transition metal free, aza-fused
polycyclic quinolones, pyrrolo[1,2-a]quinolines
CF3
N
N
R1
Ph
EtOOC
N
CF3
C
Aza-fused polycyclic quinoline ring systems can be
found in several natural products and synthetic heterocy-
clic compounds, and compounds belonging to this structur-
al class have been reported to exhibit a wide range of bio-
logical activities.1 For example, pyrrolo[1,2-a]quinoline de-
rivatives possess a broad range of medicinal properties,
including antimicrobial (A),2 antileukemic (B),3 antibacteri-
al (C),4 and human recombinant NK1 receptor ligand (D)5
activities (Figure 1). Furthermore, imidazo[1,2-a]quinoline
derivatives have been shown to play important roles as to-
poisomerase II inhibitors and inducers of strong G2/M cell
cycle arrest (E),6 as well as being used as clinical antiallergic
reagents (F).7
D
CO2H
Me
H
N
N
N
Cl
N
N
H+ Cl–
N
F
E
Figure 1 Some important aza-fused polycyclic quinoline derivatives
tion of aza-polycyclic aromatic compounds. Several other
synthetic protocols have also been developed to provide ac-
cess to aza-fused quinolines using transition-metal cata-
lysts,10 such as palladium, platinum, and gold. Furthermore,
copper-catalyzed Ullmann-type coupling have been ex-
plored extensively in recent years and widely used for the
formation of diversified heterocyclic compounds.11 For ex-
ample, Ding12 reported the synthesis of benzimidazo[1,2-
a]quinolines following this strategy. However, the use of
these methods has been limited by their requirement for
expensive catalysts and ligands, multistep syntheses, or the
generation of waste products.
Since Roberts and Gates8 reported the first synthesis of
pyrrolo[1,2-a]quinoline derivatives via the thermal and
acid-catalyzed cyclization of 1-(2-quinoly1)propane-2,3-
diol, several other synthetic methods have been developed
for the construction of these interesting compounds. For in-
stance, Zamola et al.6 described the synthesis of benzimid-
azo[1,2-a]quinolines via a photochemical dehydrocycliza-
tion reaction, whereas Klumpp9 reported the development
of a superelectrophilic cyclization method for the construc-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1913–1921

1914
Z.-q. Jiang et al.
Paper
Synthesis
Significant progress has recently been made in the de-
velopment of metal-free transformations for the formation
of C–N bonds.13 For example, the groups of Yus14 and
Ramón 15 have developed new methods for the arylation of
different aromatic heterocycles under strongly basic condi-
tions without the need for a transition metal catalyst. Fur-
thermore, Heo et al.16 recently reported the transition-
metal-free synthesis of a series of dibenzo[b,f]oxepine-10-
carbonitrile derivatives via the formation of an intramolec-
ular C–O bond between 2-halobenzaldehydes and (2-hy-
droxyphenyl)acetonitriles in the presence of Cs2CO3. Here-
in, we report the development of a one-pot, base-mediated
process for the synthesis of pyrrolo[1,2-a]quinolines from
2-formylpyrrole derivatives and various 2-halophenylaceto-
nitriles (Scheme 1).
ment in the yield of the product (entry 16). A further in-
crease in the amount of 1H-pyrrole-2-carbaldehyde to 1
mmol provided the expected product in 84% yield (entry
17). Finally, the reaction failed in the presence of air (entry
18).
Table 1 Optimization of the Reaction Conditionsa
base
(150 mol%)
N
H
Br
+
solvent
CN
N
O
H
CN
3aa
1a
2a
Base
NaOH
Entry
Solvent
Temp (°C) Time (h) Yield (%)b
1
2
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
THF
130
130
130
130
130
130
130
130
130
130
130
130
130
130
110
140
130
130
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
0
0
KOH
X
H
O
K3PO4
Z
3
KOt-Bu
Cs2CO3
K2CO3
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
13
68
64
86
70c
43d
<10e
27
34
36
<5
55
72
85
84f
0g
Z
N
+
Aryl
R
EWG
4
DMSO
130 °C
24 h
R
N
H
5
X = I, Br, Cl
Z = C, N
EWG
EWG = CN, CO2Et
6
7
Scheme 1 Reaction of 2-formylpyrroles with 2-halophenylacetonitriles
to give pyrrolo[1,2-a]quinolines
8
9
The reaction between 2-bromophenylacetonitrile (1a)
and 1H-pyrrole-2-carbaldehyde (2a) was selected as a
model reaction to identify the optimum conditions for the
transformation. All of the optimization reactions were car-
ried out in DMSO at 130 °C using a variety of different bas-
es, and the results are shown in Table 1. The use of strong
bases such as KOH and NaOH failed to provide any of the
desired product (Table 1, entries 1 and 2). Pleasingly, the
use of potassium tert-butoxide afforded the desired prod-
uct 3aa, albeit in a low yield of 13% (entry 3). The yield of
the 3aa was improved dramatically to 68% when Cs2CO3
(150 mol%) was used as the base in DMSO at 130 °C (entry
4). The use of potassium phosphate led to a further increase
in the yield of 3aa to 86% (entry 6). Attempts to increase the
amount of potassium phosphate added to the reaction,
however, were unsuccessful, with the yield of 3aa being re-
duced to 70% (entry 7). A significant reduction in the yield
of 3aa was also observed when the reaction was conducted
in the presence of a stoichiometric amount of potassium
phosphate (entry 8). Moreover, further reducing the charge
of potassium phosphate to 50 mol% resulted in a yield of
<10% after an extended reaction time of one day at 130 °C
(entry 9). Several other solvents were also screened against
this reaction, including THF, DMF, toluene, and 1,4-dioxane,
but they failed to provide better yields than DMSO (entries
10–14). Decreasing the temperature to 110 °C also led to a
decrease in the yield of 3aa to 72% (entry 15). Furthermore,
increasing the temperature failed to provide any improve-
10
11
12
13
14
15
16
17
18
DMF
toluene
1,4-dioxane
MeCN
DMSO
DMSO
DMSO
DMSO
a Reaction conditions: 2-bromophenylacetonitrile (1a; 0.2 mmol), 1H-pyr-
role-2-carbaldehyde (2a; 0.2 mmol), and base (0.3 mmol) in solvent (2.0 mL)
under a N2 atmosphere, for 24 h at the specified reaction temperature.
b Isolated yields after column chromatography.
c Reaction with 200 mol% of base.
d Reaction with 100 mol% of base.
e Reaction with 50 mol% of base.
f The reaction was carried out with 1a (1 mmol), 2a (1 mmol), and base (1.5
mmol) in solvent (5 mL).
g Reaction under air.
It should be noted that some metal elements are pres-
ent as impurities in the K3PO4. This minor amount of transi-
tion-metal elements might be the real catalyst, as it was
previously demonstrated for the copper cases.14 So as to re-
move the possibility of the existence of trace transition-
metal elements in the commercially available K3PO4 that
would possibly affect our investigation results, high-purity
K3PO4 (99.99% from Aldrich) was applied in the reaction in-
stead of K3PO4 (99.6% from Shanghai), providing almost the
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1913–1921

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Z.-q. Jiang et al.
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Synthesis
Table 2 Investigation on the Scope of 2-Halophenylacetonitriles or
2-Halophenylacetates for the Formation of Pyrrolo[1,2-a]quinolinesa
With the optimized conditions in hand, the scope of re-
action was investigated using a variety of 2-halophenylace-
tonitriles and ethyl 2-halophenylacetates. As shown in Ta-
ble 2, when the reaction was carried out with 2-halophen-
ylacetonitriles 1a–c, only the pyrrolo[1,2-a]quinoline-5-
carbonitrile (3aa) was obtained (Table 2, entries 1–3). Ethyl
2-(2-bromophenyl)acetate (1d) also reacted smoothly un-
der the optimized conditions to give ethyl pyrrolo[1,2-
a]quinoline-5-carboxylate (3da) (entry 4). However, when
the protocol was applied to ethyl 2-(2-iodophenyl)acetate
(1e) and ethyl 2-(2-chlorophenyl)acetate (1f), longer reac-
tion times were required and the product 3da was formed
in low yields (entries 5, 6).
K3PO4
(1.5 equiv)
N
X
H
O
+
EWG
DMSO
130 °C
24 h
N
H
EWG
1a–f
X = I, Br, Cl
EWG = CN, CO2Et
2a
3
Entry
Substrate
Product
Yield (%)b
The scope of the formylpyrrole compounds was also in-
vestigated, and the results are shown in Table 3. Substitu-
ents were found to be well tolerated at the 3-, 4-, and 5-po-
sitions of the pyrrole ring, with the corresponding products
3ab,ac being formed in good yields (Table 3, entries 1–6).
Pleasingly, almost all of the 2-formylindole compounds
evaluated bearing electron-withdrawing or electron-donat-
ing groups reacted smoothly with the 2-halophenylacetoni-
triles to provide the desired products in excellent or moder-
ate yields (entries 7–18). 1H-Indole-2-carbaldehyde (2d) af-
forded the desired product 3ad in 84% yield (entry 8), and
5-chloro-1H-indole-2-carbaldehyde (2e) and 5-bromo-1H-
indole-2-carbaldehyde (2f) gave 3ae and 3af in yields of 90
and 93%, respectively (entries 11 and 14). It is noteworthy
that the 2-formyldiazole components 2h,i reacted with sev-
eral 2-halophenylacetonitriles 1a–c to give the correspond-
ing imidazo[1,2-a]quinoline derivatives 3ah,ai in modest
yields (30–48%), albeit under drastic conditions (24 h,
150 °C) (entries 19–24). Furthermore, 5-methyl-1H-ben-
zo[d]imidazole-2-carbaldehyde (2j) participated in the cy-
clization reaction to give a mixture of the two isomers 9-
methylbenzo[4,5]imidazo[1,2-a]quinoline-5-carbonitrile
(3aj) and 10-methylbenzo[4,5]imidazo[1,2-a]quinoline-5-
carbonitrile (3aj′) in a combined yield of 32% (1.1:1 ratio by
1H NMR analysis) (entry 26). Unfortunately, 5-nitro-1H-
benzo[d]imidazole-2-carbaldehyde (2k) and 5-nitro-1H-in-
dole-2-carbaldehyde (2l) failed to provide any of the de-
sired products under the optimized reaction conditions
(entries 28–33). Notably, the annulation of formylimidazole
(2m) with 1a also worked well to provide the desired prod-
uct 3am in 67% yield (entry 35).
N
Br
1
1a
3aa
86
CN
CN
N
I
2
3
4
1b
1c
1d
3aa
3aa
3da
65
70
34
CN
CN
N
Cl
CN
CN
N
Br
CO2Et
CO2Et
N
I
5
6
1e
1f
3da
3da
25c
CO2Et
CO2Et
N
Cl
19c
CO2Et
CO2Et
a Reaction conditions: 1H-pyrrole-2-carbaldehyde (2a; 0.2 mmol), 2-halo-
phenylacetonitrile or 2-halophenylacetate 1a–f (0.2 mmol), and K3PO4 (0.3
mmol) in DMSO (2.0 mL) under a N2 atmosphere, for 24 h at 130 °C.
b Isolated yield.
Lastly, we wondered about the most likely mechanism
for this reaction and it was initially suspected that an aryne
intermediate was involved in this transformation.13b 2-(3-
Bromophenyl)acetonitrile (1g) and 1H-pyrrole-2-carbalde-
hyde (2a) were selected as substrates to evaluate the likeli-
hood of this reaction pathway, with the expectation that
pyrrolo[1,2-a]quinoline-5-carbonitrile (3aa) would be iso-
lated as the product13c,17 (Scheme 2). However, as shown in
Scheme 2, none of the desired product was formed in this
experiment.
c Reaction time 48 h and at 150 °C.
same results. Therefore, we are confident that the possible
impurities are not responsible for the reaction depicted in
this process.
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Paper
Synthesis
Table 3 Investigation on the Scope of the Heterocyclic Substratesa
K3PO4
(1.5 equiv)
Z
N
H
O
Z
X
+
Aryl
DMSO
130 °C
24 h
CN
N
H
1a–c
2b–m
CN
X = I, Br, Cl
Z = C, N
3ab–am
Entry
Heterocyclic substrate
X
Product
Yield (%)b
Me
H
1
2
3
I
Br
Cl
72
93
81
N
2b
3ab
3ac
N
O
Me
H
CN
N
Me
Me
4
5
6
I
Br
Cl
79
98
82
H
Me
2c
N
O
Me
H
CN
H
7
8
9
I
Br
Cl
73
84
69
N
2d
3ad
N
O
H
CN
Cl
Cl
H
O
10
11
12
I
Br
Cl
57
90
61
2e
3ae
N
N
H
CN
Br
Br
H
O
13
14
15
I
Br
Cl
70
93
76
2f
3af
N
N
H
CN
Me
Me
H
O
16
17
18
I
Br
Cl
62
99
70
2g
3ag
N
N
H
CN
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Synthesis
Table 3 (continued)
Entry
Heterocyclic substrate
X
Product
Yield (%)b
N
H
O
N
N
19
20
21
I
Br
Cl
30c
48c
35c
2h
3ah
N
H
CN
H
O
N
22
23
24
I
Br
Cl
33c
41c
34c
N
N
2i
3ai
N
H
CN
Me
N
Me
Me
H
O
21c
32c
15c
N
25
26
27
I
Br
Cl
N
N
N
2j
3aj + 3aj′
N
H
CN
CN
1.1:1
NO2
O2N
H
0d
0d
0d
N
28
29
30
I
Br
Cl
2k
3ak
N
N
N
H
O
CN
NO2
O2N
H
O
31
32
33
I
Br
Cl
0d
0d
0d
2l
3al
N
N
H
CN
N
N
H
H
O
N
Me
34
35
36
I
Br
Cl
57
67
61
2m
3am
N
Me
CN
a Reaction conditions: Compounds 1a–c (0.2 mmol), 2b–m (0.2 mmol), and K3PO4 (0.3 mmol) in DMSO (2.0 mL) under a N2 atmosphere for 24 h at 130 °C.
b Isolated yield after flash chromatography.
c Reaction time 24 h and at 150 °C.
d Reaction time 48 h and at 150 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1913–1921

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Synthesis
N
CN
N
H
O
K3PO4 (1.5 equiv)
H
O
K3PO4 (1.5 equiv)
CN
+
+
DMSO, 130 °C, 24 h
N
DMSO, 130 °C, 24 h
Br
N
H
H
Br
CN
CN
1a
(0.2 mmol)
2a
(0.2 mmol)
3aa
1g
(0.2 mmol)
2a
(0.2 mmol)
3aa
not obtained
no radical scavenger
TEMPO (0.5 equiv)
TEMPO (2.0 equiv)
hydroquinone (2.0 equi)
86%
Scheme 2 Synthesis of pyrrolo[1,2-a]quinoline-5-carbonitrile (3aa)
86%
86%
86%
This result indicated that aryne intermediates do not
play a central role in the current annulation reaction, and it
was therefore assumed that this reaction pathway involved
the formation of short-lived radical intermediates.13c With
this in mind, several experiments were designed to evaluate
the potential role of radical species in the reaction. As
shown in Scheme 3, the presence of radical scavenger,18
such as TEMPO or hydroquinone (HQ), had no impact on
the reaction, with the desired product 3aa being formed in
good yields. This observation therefore indicated that radi-
cal intermediates were not involved in this cascade reac-
tion.
Scheme 3 Radical trapping experiments
Based on these results, we have proposed a base-medi-
ated reaction mechanism19 for the one-pot formation of
3aa, which is shown in Scheme 4. The reaction of 1 with 2a
would yield compound 5 via a base-catalyzed 1,2-addition
between the nitrile and the aldehyde. Then, an intramolec-
ular dehydration reaction of compound 6 would give com-
pound 7. Finally, compound 7 would then undergo an intra-
molecular SNAr reaction to afford the product pyrrolo[1,2-
a]quinoline-5-carbonitrile (3aa).
3–
2–
X
H
PO4
HPO4
O–
X
1,2-addition
X
H
N
CN
CN
H
N
–
CN
4
1
CHO
5
2–
HPO4
2a
3–
PO4
HN
OH
H
CN
X
6
H2O
base
X–
HN
N
X –
CN
N
SNAr
2–
3–
HPO4
PO4
CN
3aa
X
CN
7
8
Scheme 4 A proposed base-promoted mechanism
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1913–1921

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Synthesis
In summary, we have developed a simple and effective
method for the synthesis of aza-fused polycyclic quinolines
under mild reaction conditions. A variety of pyrrolo[1,2-
a]quinoline derivatives were synthesized from 2-
formylpyrroles and 2-halophenylacetonitriles (or 2-halo-
phenylacetates) in moderate to excellent yields. The meth-
od worked well for all of the 2-bromo-, 2-iodo-, and 2-chlo-
roarylacetonitriles tested and showed great functional
group compatibility. This study therefore provides a base-
catalyzed process for the synthesis of pyrrolo[1,2-a]quino-
lines and other quinoline derivatives from readily accessible
starting materials and should find numerous applications
in the synthesis of biologically and medicinally relevant
compounds.
HRMS (ESI): m/z [M + H]+ calcd for C14H11N2: 207.0863; found:
207.0870.
1,3-Dimethylpyrrolo[1,2-a]quinoline-5-carbonitrile (3ac)
Yield: 43.0 mg (98%); fluorescent yellow solid; mp 168.1–168.6 °C.
1H NMR (300 MHz, CDCl3): δ = 8.13 (d, J = 9.0 Hz, 1 H), 7.85 (d, J = 9.0
Hz, 1 H), 7.58 (s, 1 H), 7.45–7.40 (m, 1 H), 7.36–7.26 (m, 1 H), 6.42 (s, 1
H), 2.84 (s, 3 H), 2.31 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 134.7, 129.6, 127.6, 127.5, 125.9, 125.5,
121.8, 121.7, 118.4, 117.9, 117.7, 115.9, 96.5, 18.2, 10.4.
HRMS (ESI): m/z [M + H]+ calcd for C15H13N2: 221.1014; found:
221.1019.
Indolo[1,2-a]quinoline-5-carbonitrile (3ad)
Yield: 40.5 mg (84%); fluorescent yellow solid; mp 193.7–194.6 °C.
1H NMR (300 MHz, CDCl3): δ = 8.61 (d, J = 8.5 Hz, 1 H), 8.47 (d, J = 8.6
Hz, 1 H), 8.06 (d, J = 7.4 Hz, 1 H), 7.93 (d, J = 8.3 Hz, 2 H), 7.75–7.71 (m,
1 H), 7.57–7.52 (m, 1 H), 7.49–7.42 (m, 2 H), 7.10 (s, 1 H).
13C NMR (75 MHz, CDCl3): δ = 134.5, 133.2, 131.9, 131.7, 130.2, 128.6,
126.9, 124.3, 123.8, 122.8, 122.3, 119.1, 116.9, 115.6, 114.3, 104.5,
102.4.
All starting materials and solvents were either purchased from com-
mercial sources and used as received (compounds 1a–c, 1g, 2b, 2c, 2h,
and 2m) and were purified according to standard procedures or pre-
pared according to literature procedures (compounds 1d–f, 2d–g,i–l;
see the Supporting Information). 1H NMR spectra were recorded at
300 MHz on a Bruker Avance 300 spectrometer with TMS as the inter-
nal standard and CDCl3 or DMSO-d6 as the solvent. 13C NMR spectra
were recorded at 75 MHz on a Bruker Avance 300 spectrometer with
TMS as the internal standard and CDCl3 or DMSO-d6 as the solvent.
HRMS was obtained with a Finnigan MAT 95 spectrometer (ESI).
HRMS (ESI): m/z [M + H]+ calcd for C17H11N2: 243.0826; found:
243.0834.
9-Chloroindolo[1,2-a]quinoline-5-carbonitrile (3ae)
Yield: 49.5 mg (90%); fluorescent yellow solid; mp 208.5–209.6 °C.
1H NMR (300 MHz, CDCl3): δ = 8.53 (d, J = 8.6 Hz, 1 H), 8.39 (d, J = 9.2
Hz, 1 H), 8.08 (d, J = 7.5 Hz, 1 H), 7.90 (d, J = 5.3 Hz, 2 H), 7.75 (s, 1 H),
7.52–7.47 (m, 2 H), 7.04 (s, 1 H).
13C NMR (75 MHz, CDCl3): δ = 136.2, 135.7, 135.6, 134.9, 131.9, 130.6,
128.3, 127.2, 124.5, 124.1, 119.6, 116.9, 116.6, 114.3, 114.0, 105.6,
101.6.
Pyrrolo[1,2-a]quinoline-5-carbonitrile (3aa); Typical Procedure
A flask was equipped with a magnetic stir bar and charged with 1H-
pyrrole-2-carbaldehyde (2a; 19.0 mg, 0.2 mmol, 1.0 equiv), 2-bro-
mophenylacetonitrile (1a; 39.2 mg, 0.2 mmol, 1.0 equiv), and K3PO4
(63.6 mg, 0.3 mmol, 1.5 equiv). The flask was evacuated and filled
with N2, and then anhydrous DMSO (2.0 mL) was introduced via a sy-
ringe. The flask was heated in a 130 °C oil bath for 24 h, at which time
TLC analysis [petroleum ether (bp 60–90 °C)–EtOAc, 10:1] indicated
complete consumption of 2a and 1a. The reaction mixture was cooled
to r.t. and added to a sat. solution of NaCl (20 mL) and extracted with
EtOAc (3 × 10 mL). The combined organic layers were dried (Na2SO4)
and filtered. The filtrate was concentrated, and the residue was puri-
fied by column chromatography on SiO2 [petroleum ether (bp 60–90
°C)–EtOAc, 10:1 to 30:1] to give 3aa; yield: 32.9 mg (86%); tan yellow
solid; mp 155.6–156.3 °C.
HRMS (ESI): m/z [M + H]+ calcd for C17H10ClN2: 277.0542; found:
277.0553.
9-Bromoindolo[1,2-a]quinoline-5-carbonitrile (3af)
Yield: 59.2 mg (93%); fluorescent yellow solid; mp 205.6–207.1 °C.
1H NMR (300 MHz, DMSO-d6): δ = 8.66 (d, J = 24.4 Hz, 2 H), 8.43 (s, 1
H), 8.18 (s, 1 H), 7.92 (s, 1 H), 7.81 (s, 1 H), 7.58 (s, 2 H), 7.24 (s, 1 H).
13C NMR (75 MHz, DMSO-d6): δ = 134.9, 133.9, 131.6, 131.1, 131.0,
129.2, 126.5, 126.1, 124.5, 124.1, 119.4, 116.7, 116.6, 116.2, 115.3,
105.3, 102.1.
1H NMR (300 MHz, DMSO-d6): δ = 8.51 (s, 1 H), 7.95 (d, J = 8.1 Hz, 1
H), 8.25 (s, 1 H), 7.86 (d, J = 6.3 Hz, 1 H), 7.72–7.67 (m, 1 H), 7.56–7.51
(m, 1 H), 6.94 (d, J = 10.0 Hz, 2 H).
HRMS (ESI): m/z [M + H]+ calcd for C17H10BrN2: 320.9941; found:
13C NMR (75 MHz, DMSO-d6): δ = 131.9, 131.4, 129.6, 128.6, 128.0,
320.9949.
125.4, 125.1, 119.4, 117.4, 117.3, 115.5, 114.7, 109.0.
9-Methylindolo[1,2-a]quinoline-5-carbonitrile (3ag)
HRMS (ESI): m/z [M + H]+ calcd for C13H9N2: 193.0766; found:
Yield: 50.8 mg (99%); fluorescent yellow solid; mp 199.4–201.1 °C.
193.0773.
1H NMR (300 MHz, DMSO-d6): δ = 8.73 (d, J = 8.46 Hz, 1 H), 8.55 (d, J =
8.82 Hz, 1 H), 8.39 (s, 1 H), 7.91 (d, J = 7.65 Hz, 1 H), 7.83–7.77 (m, 1
H), 7.74 (s, 1 H), 7.57–7.52 (m, 1 H), 7.37 (d, J = 8.64 Hz, 1 H), 7.18 (s, 1
H), 2.51 (s, 3 H).
13C NMR (75 MHz, DMSO-d6): δ = 135.2, 133.0, 131.9, 131.6, 130.8,
129.8, 129.5, 126.2, 125.9, 124.0, 121.4, 119.4, 116.9, 116.1, 114.6,
103.9, 102.5, 21.0.
1-Methylpyrrolo[1,2-a]quinoline-5-carbonitrile (3ab)
Yield: 38.2 mg (93%); fluorescent yellow solid; mp 154.2–155.7 °C.
1H NMR (300 MHz, CDCl3): δ = 8.27 (d, J = 8.6 Hz, 1 H), 7.96 (d, J = 7.8
Hz, 1 H), 7.69 (s, 1 H), 7.53–7.48 (m, 1 H), 7.43–7.38 (m, 1 H), 6.72 (d,
J = 3.9 Hz, 1 H), 6.62 (d, J = 3.8 Hz, 1 H), 2.95 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 134.7, 130.5, 129.7, 127.9, 126.1, 124.2,
121.7, 117.9, 116.5, 115.0, 107.9, 102.7, 98.6, 18.5.
HRMS (ESI): m/z [M + H]+ calcd for C18H13N2: 257.1053; found:
257.1062.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1913–1921

1920
Z.-q. Jiang et al.
Paper
Synthesis
Imidazo[1,2-a]quinoline-5-carbonitrile (3ah)
Acknowledgment
Yield: 18.7 mg (48%); tan solid; mp 182.3–183.6 °C.
1H NMR (300 MHz, CDCl3): δ = 8.22–8.19 (m, 2 H), 8.10 (s, 1 H), 8.01
(d, J = 4.9 Hz, 1 H), 7.86 (s, 1 H), 7.81–7.78 (m, 1 H), 7.66–7.63 (m, 1
H).
We thank the National Natural Science Foundation of China (Grant
No. 21072095), National High Technology Research and Development
Program of China (863 Program 2014AA022100), and Graduate Stu-
dent Innovation Project in Jiangsu Province (Grant No. CXLX13_433)
for supporting this research.
13C NMR (100 MHz, CDCl3): δ = 147.4, 135.2, 130.5, 127.3, 127.2,
126.2, 125.0, 121.7, 120.0, 115.6, 113.1, 108.3.
HRMS (ESI): m/z [M + H]+ calcd for C12H8N3: 194.0618; found:
194.0625.
Supporting Information
Supporting information for this article is available online at
Benzo[4,5]imidazo[1,2-a]quinoline-5-carbonitrile (3ai)
http://dx.doi.org/10.1055/s-0034-1380506.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
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nrtogI
f
rmoaitn
Yield: 19.9 mg (41%); tan solid; mp 251.7–252.8 °C.
1H NMR (300 MHz, CDCl3): δ = 8.68 (d, J = 8.6 Hz, 1 H), 8.47–8.43 (m, 1
H), 8.28 (d, J = 7.8 Hz, 1 H), 8.16 (s, 1 H), 8.14–8.11 (m, 1 H), 7.95–7.89
(m, 1 H), 7.69–7.63 (m, 3 H).
13C NMR (75 MHz, CDCl3): δ = 145.3, 145.2, 135.4, 131.4, 130.9, 127.6,
127.6, 126.0, 125.5, 125.3, 124.7, 121.7, 120.0, 115.7, 114.3, 113.2.
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9-Methylbenzo[4,5]imidazo[1,2-a]quinoline-5-carbonitrile (3aj)
and 10-Methylbenzo[4,5]imidazo[1,2-a]quinoline-5-carbonitrile
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1H NMR (300 MHz, CDCl3): δ = 8.65 (m, 1 H), 8.32–8.23 (m, 2 H), 8.14
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3-Methylimidazo[1,5-a]quinoline-5-carbonitrile (3am)
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Yield: 27.9 mg (67%); tan solid; mp 191.3–192.0 °C.
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J = 8.3 Hz, 1 H), 7.85 (d, J = 7.9 Hz, 1 H), 7.76–7.71 (m, 1 H), 7.63–7.58
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Ethyl Pyrrolo[1,2-a]quinoline-5-carboxylate (3da)
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7.97–7.91 (m, 2 H), 7.57–7.52 (m, 1 H), 7.44–7.39 (m, 1 H), 6.84 (d, J =
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240.0982.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1913–1921

1921
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Synthesis
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1913–1921