Synthesis of 3 H -Pyrrolo[2,3- c ]quinoline by Sequential i 2 -Promoted Cyclization/Staudinger/Aza-Wittig/Dehydroaromatization Reaction

Article abstract of DOI:10.1055/s-0037-1610688

A facile synthetic approach to access of 3 H -pyrrolo[2,3- c ]quinoline derivatives has been achieved by a sequential I ₂ -promoted cyclization/Staudinger/aza-Wittig/dehydroaromatization reaction. The targeted products were received in moderate

Full text of DOI:10.1055/s-0037-1610688

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© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–D
letter
A
en
F. Zou et al.
Letter
Synlett
Synthesis of 3H-Pyrrolo[2,3-c]quinoline by Sequential I2-Promoted
Cyclization/Staudinger/Aza-Wittig/Dehydroaromatization Reaction
Fakai Zoua,1
Fei Peia,1
Liping Wanga
Zhilin Ren*a
Xiaohong Chengb
Yang Suna
O
O
R2
R1
O
1) I2, K2CO3,
DCE, 80 °C
N3
+
N
N
R3
2) PPh3,
toluene,reflux
R1
R3
N
H
Jing Wua
Ping He*a,b
17 examples
62–81% overall yield
R2
O
O
0
0
0
0-0
0
0
1-8
6
2
4-6
8
0
X
R1, R3 = Ar
2 = Me, Et
a College of Chemical Engineering, Hubei University of Arts and Science,
Xiangyang, 441053, Hubei Province, P. R. of China
renzhilin@hbuas.edu.cn
R
pinghe129@hbuas.edu.cn
b Hubei Key Laboratory of Low Dimensional Optoelectronic Materials
and Devices, Hubei University of Arts and Science, Xiangyang,
441053, Hubei Province, P. R. of China
Received: 14.11.2018
Accepted after revision: 07.01.2019
Published online: 18.02.2019
NH
NH
R
DOI: 10.1055/s-0037-1610688; Art ID: st-2018-w0746-l
N
N
N
Abstract A facile synthetic approach to access of 3H-pyrrolo[2,3-
c]quinoline derivatives has been achieved by a sequential I2-promoted
cyclization/Staudinger/aza-Wittig/dehydroaromatization reaction. The
targeted products were received in moderate to good yields (62–81%).
The broad substrate scope and easy availability of the starting materials
make this method a valuable tool for generating 3H-pyrrolo[2,3-c]quin-
oline products.
N
marinoquinolines A–F
N
N
A: R = methyl D: R = p-OH benzyl
B: R = isobutyl E: R = 3-indolyl
C: R = benzyl F: R = indole-3-carbonyl
NH2
aplidiopsamine A
NH
N
Key words 3H-pyrrolo[2,3-c]quinolines, I2-promoted cyclization, aza-
Wittig reaction, azides, dehydroaromatization
O
N
O
trigonoine B
Figure 1 Representative bioactive compounds containing 3H-pyrro-
lo[2,3-c]quinoline skeletons
The rapid construction of N-heterocyclic scaffolds is an
attractive and lively research area in organic synthesis be-
cause of their promising biochemical and materials proper-
ties.2 Among them, the pyrrolo[2,3-c]quinoline system is
one of the privileged structural motifs, and its derivatives
can be found in numerous natural products and biologically
active molecules such as marinoquinolines A–F,3 aplid-
iopsamine A,4 and trigonoine B5 (Figure 1). These com-
pounds and their various analogues exhibit important bio-
logical activities, such as antimicrobial,6 antimalarial,7 ace-
tylcholinesterase-inhibiting activity,8 antitubercular,9 and
antitumor10 along with metal- and anion-sensing capabili-
ties.11 Hence, the study on pyrrolo[2,3-c]quinolines contin-
ues to be an active research area.
constructed the 3H-pyrrolo[2,3-c]quinoline frameworks fa-
vorably through a brønsted acid-promoted arene-ynamide
cyclization.4b In 2017, Xu et al. described a straightforward
and facile access to highly functionalized 3H-pyrrolo[2,3-
c]quinolines through bicyclization of azomethine ylide.12a
Very recently, Bhattacharya et al. utilized a microwave-as-
sisted approach for the synthesis of 4-substituted pyrro-
lo[2,3-c]quinolines starting from easily available quino-
line.12b However, some of the synthetic methods suffer from
multistep processes, difficult-to-synthesize starting mate-
rials, and poor precursor scopes with low substituent diver-
sities. Thus, the development of new and straightforward
So far, tremendous efforts have been devoted to the ex-
ploration of efficient methodologies for the synthesis of the
pyrrolo[2,3-c]quinoline molecules.12 In 2015, Takasu et al.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D

B
F. Zou et al.
Letter
Synlett
synthetic pathways for the construction of diversified pyr-
rolo[2,3-c]quinolines is still highly desirable.
Table 1 Optimization of the Reaction Conditionsa
O
Over the past decades, great efforts have been made by
chemists to construct C–N bonds, and lots of methods have
constantly been reported.13 Among them, the traditional
aza-Wittig reaction has received considerable attention for
the synthesis of heterocyclic compounds and natural prod-
ucts because of its mild reaction conditions.14 In previous
work, Gao and co-workers had reported the iodine-promot-
ed construction of multisubstituted 2,3-dihydropyrrole de-
rivatives.15 Inspired by this, we embarked on a project to ex-
plore the synthesis of pyrrolo[2,3-c]quinoline derivatives
(Scheme 1) initiated from 2-azidobenzaldehyde 1 and ace-
tophenones 2 (2-azido chalcones 316 were prepared), with
acetoacetates 4 and aromatic amines 5 (β-enamine esters
O
O
(i) I2, solvent,
base, 80 °C
N3
3a
N
+
N
(ii) PPh3, toluene,
reflux
N
H
O
O
6a
8a
Entry
Ratio (3a/6a)
Base
Solvent
Yield (%)b
1
2
1:1
–
DCE
53
1.5:1
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
–
DCE
47
3
–
DCE
62
6
17 were presynthesized). As part of our ongoing investiga-
4
NEt3
DCE
52
tion into the synthesis of nitrogen-containing heterocycles,
herein, we wish to disclose a new and concise synthesis of
polysubstituted pyrrolo[2,3-c]quinoline derivatives by
means of sequential I2-promoted cyclization/Stauding-
er/aza-Wittig/dehydroaromatization procedures.
Our initial investigations were focused on optimizing
the reaction conditions of chalcone 3a and β-enamine ester
6a in different ratios, in the presence of bases and solvents.
A model reaction (3a/6a = 1:1) was performed in the pres-
ence of 1.0 equivalent of iodine in 1,2-dichloroethane (DCE)
as the solvent without any base at 80 °C for 10 h. Gratifying-
ly, without the isolation of 2,3-dihydropyrrole 7a, product
8a could obtained by Staudinger/aza-Wittig reaction in a
yield of 53% (Table 1, entry 1).
5
DABCO
NaHCO3
Na2CO3
K2CO3
DMAP
DBU
DCE
55
6
DCE
64
7
DCE
69
8
DCE
75
9
DCE
60
10
11
12
13
14
DCE
51
K2CO3
K2CO3
K2CO3
K2CO3
EtOH
CH3CN
toluene
DMF
22
trace
65
trace
a Reaction conditions: (i) chalcone 3a (1.0 equiv), β-enamine ester 6a, base
(1.0 equiv), and I2 (1.0 equiv) in solvent (5 mL) at 80 °C for 10 h; (ii) PPh3
(1.0 equiv), toluene, reflux, 12 h.
b Isolated yields based on substrate 3a.
O
O
N3
R1
a
+
R1
N3
CHO
NaHCO3, Na2CO3, K2CO3, DMAP, DBU was studied (Table 1,
entries 4–10), and K2CO3 was the most effective base for
this reaction to give the desired product 8a in 75% yield.
Moreover, further investigation on switching the solvents
from DCE to EtOH, CH3CN, toluene, or DMF did not give a
better result (Table 1, entries 11–14).
The structure of 3H-pyrrolo[2,3-c]quinoline 8c was con-
firmed by its spectral data. Furthermore, a single crystal of
8c was grown from the ethyl acetate/petroleum ether solu-
tion, and its structure was verified by single-crystal X-ray
analysis (Figure 2).18
1
2
3
O
R3
O
b
N
+
R3 NH2
H
R2
R2
O
O
O
4
5
6
O
O
R2
R2
O
O
c
d
R3
R1
N
R3
N
N
R1
N3 O
7
8
Having the optimized conditions in hands, we employed
a variety of chalcones 3 and β-enamine esters 6 in the reac-
tion. As shown in Table 2, chalcones 3 bearing various elec-
tron-withdrawing and electron-donating substituents (R1 =
Ph, 2,4-Cl2Ph, 4-ClPh, 2-ClPh, 4-BrPh, 4-CH3Ph, 4-OCH3Ph)
on the aryl rings were smoothly converted to the corre-
sponding products in moderate to good yields (Table 2, 8a–
e, 8i–l, 8m–q). As a whole, the reactions gave slightly better
yields in the presence of electron-withdrawing substitu-
ents. For some substituted β-enamine esters (R3 = Ph, 3-
Scheme 1 Proposed pathway for the synthesis of compounds 8.
Reagents and conditions: (a) NaOH, EtOH,0 °C, 2 h; (b) CF3SO3Zn (20%),
15 min, rt; (c) I2, K2CO3, dry DCE, 80 °C; (d) PPh3, toluene, reflux
Subsequently, a substrates ratio screening showed that
3a/6a (1:1.5) was optimal and the yield was promoted to
62% (Table 1, entries 2–3). Encouraged by this result, the
conversion with a series of bases such as NEt3, DABCO,
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D

C
F. Zou et al.
Letter
Synlett
I2
R3
R3
O
2–
CO3
N
O
NH
R1
+
O
Michael addition
–
HCO3
N3
O
protonation
R2
O
R2
6
6'
3
O
O
R3
I2
R3
I
R1
2–
R1
HN
O
CO3
HN
HI
–
N
3 O
N
3 O
HCO3
Figure 2 X-Ray crystal structure of compound 8c
Table 2 Synthesis of 3H-Pyrrolo[2,3-c]quinolines 8a
O
R2
9
10
R2
R2
R2
PPh3,Staudinger
/aza-Wittig
O
O
N3
O
O
[– 2 H]
R2
O
O
N
O
8
(i) I2, K2CO3,
DCE, 80 °C
O
R3
R1
N2
N
N
R3
R1
N
R1
R3
N
H
R3
+
(ii) PPh3,
toluene,reflux
N3
O
R2
O
11
N
R1
7
3
6
8
Scheme 2 A possible mechanism for the synthesis of 8
Comp.
R1
Ph
R2
Me
R3
Yield (%)
On the basis of the previous reports19,12a and abovemen-
tioned results, a plausible reaction mechanism for the for-
mation of 8 is depicted in Scheme 2. It presumably involves
in the following steps: (i) transformation of β-enamine es-
ters 6 into the carbanions 6' in the presence of solid K2CO3;
(ii) a Michael addition reaction between chalcones 3 and
carbanions 6' gives intermediates 9 followed by an electro-
philic substitution with iodine to generate intermediates
10; (iii) intramolecular nucleophilic substitution to give the
key dihydropyrrole intermediates 7 in the presence of base
K2CO3; (iv) tandem Staudinger/aza-Wittig reaction of 7 to
produce 11, which undergoes a dehydroaromatization reac-
tion to afford the target 3H-pyrrolo[2,3-c]quinoline deriva-
tives 8.
In summary, we have illustrated a convenient synthesis
of highly substituted 3H-pyrrolo[2,3-c]quinoline deriva-
tives by a sequential I2-promoted cyclization/Stauding-
er/aza-Wittig/ dehydroaromatization reaction in moderate
to good yields.20 Additionally, the easily accessible starting
materials and broad substrate scope make this method a
valuable tool for generating diverse 3H-pyrrolo[2,3-c]quin-
oline derivatives, which are of considerable interest in syn-
thetic and medicinal chemistry.
8a
8b
8c
8d
8e
8f
Ph
Ph
Ph
Ph
Ph
75
70
79
67
81
72
77
73
68
70
62
72
79
77
74
71
75
4- CH3Ph
4-ClPh
4-OCH3Ph
2,4-Cl2Ph
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
3-ClPh
8g
8h
8i
Ph
4-OCH3Ph
4-CH3Ph
2-CH3Ph
2-CH3Ph
2-CH3Ph
2-CH3Ph
2-CH3Ph
2-CH3Ph
2-CH3Ph
3-ClPh
Ph
Ph
8j
2-ClPh
4-OCH3Ph
4-CH3Ph
4-BrPh
Ph
8k
8l
8m
8n
8o
8p
8q
Et
4-CH3Ph
Ph
Et
Et
4-ClPh
Et
3-ClPh
a Isolated yields based on substrates 3
ClPh, 2-CH3Ph, 4-CH3Ph, 4-OCH3Ph), the reactions proceed-
ed well and provided the desired products (Table 2, 8f–i, 8n,
8p). Further reactions successfully afforded the expected
products when R2 groups were replaced by methyl or ethyl.
In addition, the steric effects of the substituents on the ben-
zene ring (R1 or R3) were examined, and the results indicate
that steric hindrance does not significantly affect the reac-
tions (Table 2, 8c, 8e, 8j, 8q).
Funding Information
This work was supported by the National Natural Science Foundation
of China (No. 21302047 and No. 21502047) and the Doctoral Starting
up Foundation of Hubei University of Arts and Science.
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D

D
F. Zou et al.
Letter
Synlett
Supporting Information
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Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610688.
S
u
p
p
orit
n
gInformati
o
n
S
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been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication number CCDC 1870525.
Copies of the data can be obtained, free of charge, on applica-
tion to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK
[deposit@ccdc.cam.ac.uk].
References and Notes
(1) These authors contributed equally.
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(20) General Experimental Procedure for the Synthesis of 3H-
Pyrrolo[2,3-c]quinolines
To a solution of chalcone 3 (1 mmol), β-enamine ester (6, 1.5
mmol), K2CO3 (0.138 g, 1 mmol) in anhydrous DCE (5 mL) was
added iodine (0.254 g, 1 mmol). The reaction was stirred at 80
°C for 10 h, and the reaction progress was monitored by TLC.
Then, the mixture was washed with aqueous Na2S2O3, dried
with dry sodium sulfate, and the solvent was evaporated under
reduced pressure to give the crude product dihydropyrrole
intermediate 7. Afterwards, toluene (5 mL) and PPh3 (0.262 g, 1
mmol) were added to the reaction system, and the mixture was
heated to 110 °C for 12 h. After removal of the solvent under
reduced pressure, the residue was purified by silica gel chroma-
tography (ethyl acetate/petroleum ether = 1:8) to afford 3H-
pyrrolo[2,3-c]quinolines 8a–q in 62–81% yield.
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Analytical Data for Compound 8a:
White solid (yield 0.294 g, 75%), mp 212–214 °C. 1H NMR
(CDCl3, 400 MHz): δ = 9.08 (d, J = 8.0 Hz, 1 H), 8.21 (d, J = 8.0 Hz,
1 H), 7.67–6.88 (m, 12 H), 4.07 (s, 3 H), 2.43 (s, 3 H). 13C NMR
(100 MHz, CDCl3): δ = 166.8, 147.8, 145.3, 143.5, 138.6, 137.1,
129.8, 128.7, 128.4, 127.8, 127.4, 127.3, 126.9, 125.8, 125.3,
122.1, 108.6, 51.7, 13.8. LC-MS: m/z = 392. Anal. Calcd for
(13) (a) Castillo, P. R.; Buchwald, S. L. Chem. Rev. 2016, 116, 12564.
(b) Mailyan, A. K.; Eickhoff, J. A.; Minakova, A. S.; Gu, Z.; Lu, P.;
Zakarian, A. Chem. Rev. 2016, 116, 4441. (c) Beccalli, E. M.;
C
26H20N2O2 (392.46): C, 79.57; H, 5.14; N, 7.14. Found: C, 79.54;
H, 5.23; N, 7.09.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D