Tandem Cyclization?Annulation of α-Acidic Isocyanides with 2-Methyleneaminochalcones: Synthesis of Pyrrolo[2,3-c]quinoline Derivatives

Article abstract of DOI:10.1002/adsc.201801103

Tandem cyclization-annulation of tosylmethyl isocyanide and isocyanoacetate with 2-methyleneaminochalcones as aza-1,5-dielectrophiles has been successfully developed. These domino transformations feature simultaneous formation of three bonds and two rings

Full text of DOI:10.1002/adsc.201801103

Title: Tandem Cyclization-Annulation of α-Acidic Isocyanides with 2-
Methyleneaminochalcones: Synthesis of Pyrrolo[2,3-c]quinoline
Derivatives
Authors: Jinhuan Dong, Xin Wang, Hui Shi, Lei Wang, Zhongyan Hu,
Yifei Li, and Xianxiu Xu
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201801103
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10.1002/adsc.201801103
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Tandem Cyclization–Annulation of -Acidic Isocyanides with
2-Methyleneaminochalcones: Synthesis of Pyrrolo[2,3-
c]quinoline Derivatives
Jinhuan Dong,a,b Xin Wang,a Hui Shi,b Lei Wang,a Zhongyan Hu,a,* Yifei Li,b and
Xianxiu Xua,*
a
College of Chemistry, Chemical Engineering and Materials Science, Collaborative Innovation Center of Functionalized
Probes for Chemical Imaging in Universities of Shandong, Key Laboratory of Molecular and Nano Probes, Ministry of
Education, Institute of Molecular and Nano Science, Shandong Normal University, Jinan 250014, China.
xuxx677@sdnu.edu.cn; huzy@sdnu.edu.cn
b
Department of Chemistry, Jilin Province Key Laboratory of Organic Functional Molecular Design & Synthesis,
Northeast Normal University, Changchun 130024, China
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. Tandem cyclization-annulation of tosylmethyl
isocyanide
methyleneaminochalcones as aza-1,5-dielectrophiles has
been successfully developed. These domino
and
isocyanoacetate
with
2-
transformations feature simultaneous formation of three
bonds and two rings in a single operation, and represent
novel protocols for the expedient synthesis of both aromatic
and partially aromatic pyrrolo[2,3-c]quinoline derivatives
from readily available precursors under metal-free
conditions.
Notably,
tetrahydro-3H-pyrrolo[2,3-
c]quinolones that bear three adjacent stereocenters were
obtained in a highly diastereoselective manner.
Keywords: tosylmethyl isocyanide; aza-1,5-
dielectrophiles; pyrrolo[2,3-c]quinolines; tandem reactions;
isocyanoacetate
Figure 1. Natural pyrrolo[2,3-c]quinolone alkaloids.
imine
cyclization,[9]
Bischler-Napieralski-type
cyclization[10] and arene–ynamide cyclization[11]
.
Alternatively, methods involving the synthesis of
pyrrole ring by Bartoli indolization[12a] or reductive
cyclization reaction[12b,c] have also been documented.
However, these syntheses mainly rely on the
formation of one ring with a tricyclic framework
from aryl-substituted pyrrole[6-11] or quinoline
During the past decade, a few marine natural products
containing tricyclic 3H-pyrrolo[2,3-c]quinoline ring
system have been reported (Figure 1), including
marinoquinoline A–F,[1,2] aplidiopsamine A[3] and
trigonoine B.[4] The alkaloids marinoquinoline A–F
derivatives[12]
.
Recently,
a
tandem cyclization-
showed
antibacterial,
antifungal,
and
acetylcholinesterase activities.[1,2] Aplidiopsamine A
annulation protocol has emerged as an efficient and
promising strategy for the construction of this
tricycilic frameworks. For example, Wang, Ji and co-
workers have developed an efficient synthesis of
pyrrolo[2,3-c]quinolines by the sequential formation
of the pyridine and pyrrole rings through a domino
reaction of 3-(2-oxo-2-ethylidene)indolin-2-ones with
alk-1-enyl substituted TosMICs.[13] Last year, we
was found to be a potent antimalarial agent[3] and
trigonoine
B
displayed anti-HIV activity.[4]
Furthermore, some 4-substituted pyrrolo[2,3-
c]quinolones were found to possess antitubercular
activity.[5] The rare and unique structural feature and
interesting bioactive properties of these heterocycles
inspired continuous interest in developing efficient
protocols for their preparation.[6-11] The well-
established strategy is the formation of central
pyridine ring from aryl-substituted pyrroles by
Morgen-Walls reaction,[6] Pictet–Spengler reaction,[7]
tandem reductive cyclization reaction,[8] Pd-catalyzed
reported
a
tandem cyclization-annulation of
azomethine ylides with methyleneaminochalcones for
the facile synthesis of pyrrolo[2,3-c]-quinolines by
the sequential formation of the pyridine and pyrrole
rings.[14] Despite these great achievements, the
1
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10.1002/adsc.201801103
Advanced Synthesis & Catalysis
development of novel domino strategies for the
efficient synthesis of these tricyclic scaffolds is still
highly desirable.
-Acidic isocyanides such as tosylmethyl
isocyanide (TosMIC) and isocyanoacetate are
versatile building blocks for the synthesis of a diverse
class of five-membered heterocycles through formal
[3+2] cycloaddition reactions.[15] In recent years, our
research efforts have been devoted to the domino
transformation of functionalized isocyanides.[16,17]
Initially, the reaction of 2-methyleneaminochalcone
1a (0.2 mmol) with tosylmethyl isocyanide (TosMIC)
2a (0.3 mmol) was studied carefully in the presence
of
different
amount
of
DBU
(1,8-
diazabicyclo[5.4.0]undec-7-ene) in acetonitrile at
room temperature (Table 1, entries 1–3). The
reactions gave 3H-pyrrolo[2,3-c]quinoline 3a in 70%
yields when 2.0 equivalent of DBU was used (Table
1, entry 3), whereas 1.2 and 1.5 equivalent of DBU
led to lower yield of 3a (Table 1, entries 1 and 2). In
comparison to other bases tested, such as TMG
(1,1,3,3-tetramethylguanidine), Et3N, NaOH and
K2CO3 (Table 1, entries 4–7), DBU proved to be the
best choice with respect to the yield (Table 1, entry 3
vs entries 4–7). Different solvents were also screened
(Table 1, entries 8–11). While 3a was only obtained
in 29% yield in THF (Table 1, entry 8) and a trace
amount in EtOH (Table 1, entry 9), in DMF and
Accordingly,
a range of structurally complex
heterocycles, including pyrrolizidines,[17a] C2-tethered
pyrrole/oxazole pairs,[17b] tricyclic indolizidines,[17c]
8-azabicyclo[5.2.1]dec-8-enes[17d] and bi-/tricyclic
oxazolines,[17e] were efficiently constructed from the
domino reaction of -acidic isocyanides with all-
carbon 1,4-, 1,5- or 1,7-dielectrophiles (Scheme 1,
top). In continuation of our studies on isocyanide-
based reactions,[18] as well as inspired by Xu’s work[19] CH2Cl2 it was obtained in good yield (Table 1, entries
wherein 2-methyleneaminochalcones were used as
aza-dielectrophiles, we herein report the tandem
cyclization-annulation of -acidic isocyanides with
2-methyleneaminochalcones for the straightforward
and efficient synthesis of 3H-pyrrolo[2,3-c]quinolines
10 and 11).
Table 1. Screening of Reaction Conditions[a]
and
tetrahydro-3H-pyrrolo[2,3-c]quinolines,
respectively (Scheme 1, bottom). Both the aromatic
and partially aromatic tricyclic pyrroloquinolines
were efficiently assembled by simultaneous
formation of the pyridine and pyrrole rings in a single
operation. Notably, the domino reaction of
isocyanoacetate with 2-methyleneaminochalcones
was found to proceed in a highly diastereoselective
manner, and only one of the four possible
Entry Base
Solvent
Time
(h)
50
46
41
41
41
41
41
41
41
41
41
Yield of
3a (%)[b]
38
49
70
1
DBU (1.2)
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
THF
2
3
4
5
6
7
8
9
DBU (1.5)
DBU (2.0)
TMG (2.0)
Et3N (2.0)
NaOH (2.0)
K2CO3 (2.0)
DBU (2.0)
DBU (2.0)
DBU (2.0)
DBU (2.0)
diastereomers
of
tetrahydro-3H-pyrrolo[2,3-
32
NR
c]quinolines was obtained.
12
trace[c]
29
EtOH
DMF
CH2Cl2
trace[d]
65
10
11
60
[a]Reaction conditions: 1a (0.2 mmol), 2 (0.3 mmol), base
and solvent (2 mL).
[b]Yields of isolated products.
[c]1a was recovered in 22% yield.
[d]1a was recovered in 10% yield.
With the optimal conditions in hand (Table 1, entry
3), various 2-methyleneaminochalcones 1 were
explored to investigate the generality of this domino
bicyclization reaction (Scheme 2). In general, a wide
range of substrates 1a–y bearing various functional
groups reacted smoothly with TosMIC 2a at room
temperature, giving rise to the desired pyrrolo[2,3-
c]quinolines 3a–y in good to high yields. The R2
group in 1 may be electron-deficient aryl (1a–c, 1h,
1i and 1k), electron-neutral aryl (1d), electron-rich
aryl (1e–g and 1j), hetereoaryl (1l and 1m) and alkyl
(1n) groups, and the corresponding pyrrolo[2,3-
c]quinolines 3a–n were obtained in good to high
yields. Various aryl and heteroaryl substituents as R3
Scheme 1. Tandem reactions of -acidic isocyanides
2
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10.1002/adsc.201801103
Advanced Synthesis & Catalysis
substrates 1 were also tolerated and 4-substituted
pyrroloquinolines 3o–w were thus obtained in good
yields. Substrates 1x and 1y with both electron-
donating and -withdrawing R1 groups on the benzene
ring afforded the desired pyrrolo[2,3-c]quinolines 3x
and 3y in good yields.
Scheme
3.
Tandem
cyclization-annulation
of
isocyanoacetate 2b with 2-methyleneaminochalcones 1.
Reactions were carried out with 1 (0.2 mmol), 2b (0.3
mmol) and DBU (0.4 mmol) in CH3CN (2 mL); yields of
isolated product.
To gain mechanistic insight of this tandem
cyclization-annulation,
a
series
of
control
experiments were conducted (Scheme 4). Under the
optimal conditions (Table 1, entry 3), the reaction of
1e with TosMIC 2a for 5 h gave the pyrrolo[2,3-
c]quinoline product 3e and the corresponding
dihydropyrrolo[2,3-c]quinoline 5 in 20% and 44%
yields, respectively (Scheme 4, eq 1). Exposure of 5
under identical conditions or without DBU for 20 h
produced 3e in quantitative yield (Scheme 4, eq 2).
These results illustrate that 5 is likely the reaction
intermediate and DBU is not required for the aerobic
oxidation of 5. When the reaction of 1e with
isocyanoacetate 2b was quenched at
2
h,
tetrahydroquinolines 6a and 6b were obtained in a
combined yield of 60% (4 : 1 d.r.), along with
tetrahydro-3H-pyrrolo[2,3-c]quinolone 4c in 23%
yield (Scheme 4, eq 3). The relative configuration of
major diastereomer 6a was unambiguously confirmed
by single-crystal X-ray analysis.[20] The substituents
on C2 and C4 of the minor product 6b were assigned
as trans by NOSEY analysis (see Supporting
Information). Treatment of 6a under the standard
conditions as Scheme 3 for 9.5 h led to the formation
of tetrahydro-3H-pyrrolo[2,3-c]quinoline 4c in 86%
yield (Scheme 4, eq 4). This result indicates that
tetrahydroquinoline 6a is most likely the intermediate
en route to tetrahydropyrroloquinoline 4c. In contrast,
when 6b was treated with the identical conditions, the
expected product 4c’ was not detected (Scheme 4, eq
5). Instead, after quenching the reaction within 9.5 h,
the same product 4c was obtained in 27% yield, along
with recovery of a mixture of 6a and 6b (in a ratio of
1 : 4) in 35% combined yield (Scheme 4, eq 6). These
results demonstrate that intermediate 6b could
convert to 6a and then gave the same product 4c
under the standard conditions. Furthermore, the
Scheme 2. Synthesis of 3H-pyrrolo[2,3-c]quinoline 3.
Reactions were carried out with 1 (0.2 mmol), 2a (0.3
mmol) and DBU (0.4 mmol) in CH3CN (2 mL); yields of
isolated product. [a] 1 mmol scale synthesis.
Next, the tandem cyclization-annulation of 2-
methyleneaminochalcones 1 with isocyanoacetate 2b
was also investigated. As depicted in Scheme 3, the
reaction of several 1 with isocyanide 2b afforded the
tetrahydro-3H-pyrrolo[2,3-c]quinolines 4a–h in good
to high yields. Notably, only one of the four possible
diastereomers of 4 was obtained in this reaction,
indicating that this domino process proceeds in a
highly diastereoselective manner. The relative
configuration of 4c was confirmed by single-crystal
X-ray diffraction analysis.[20]
reaction of 2-methyleneaminocinnamate
7
and
TosMIC 2a was also performed, but the desired
pyrrolo[2,3-c]quinoline 8 could not be detected
(Scheme 3, eq 7). The result suggests that this
domino reaction is initiated by the attacking at the
carbon-carbon
double
bond
of
2-
3
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10.1002/adsc.201801103
Advanced Synthesis & Catalysis
methyleneaminochalcone 1 rather than the imine
group of 1.
efficient strategy for the construction of these
tricyclic frameworks. A tandem intermolecular
Scheme 5. Proposed mechanism.
Michael
addition/intramolecular
Mannich
reaction/annulation cascade is proposed on the basis
of control experiments. This reaction features high
efficiency, mild reaction conditions, highly regio- and
diasteroselectivity in some cases, convenient
manipulation, and readily availability of starting
materials.
Scheme 4. Mechanistic studies.
On the basis of above observations and the related
work,[16-19,21] a possible pathway for this domino
reaction is proposed in Scheme 5. The tandem
cyclization-annulation may involve the following
domino sequence: Michael addition of isocyanides 2
Experimental Section
General Procedure for Synthesis of pyrrolo[2,3-
c]quinolones 3
to 2-methyleneaminochalcone
1
under basic
DBU (61 L, 0.4 mmol) was added to a solution of 2-
metheneaminochalcones 1 (0.2 mmol) and tosylmethyl
isocyanide 2a (0.059 g, 0.3 mmol) in acetonitrile (2 mL) at
conditions provides the anion I;[21] proton shift takes
place to generate anion II, followed by
intramolecular Mannich reaction to form the bicyclic
nitrogen anion III (this step may be reversible based
on the results of eq 6 in Scheme 4); sequential proton
shift and cyclization give the tricyclic intermediate V,
which undergoes 1,3-proton shift to produce
tetrahydropyrroloquinolines 4 (EWG = CO2Et) or
intermediate VI (EWG = Ts). Then, elimination of p-
o
25 C, the mixture was then stirred until substrate 1a was
consumed and the intermediate was also converted to the
target product 3 as indicated by TLC. The resulting
mixture was concentrated in vacuo, purification of the
crude product with flash column chromatography (silica
gel; petroleum ether : ethyl acetate = 10 : 1-10 : 3) gave
products 3.
Acknowledgements
toluenesulfinic
dihydropyrrolo[2,3-c]quinoline 5.[17e,21,22] Finally,
aerobic oxidative aromatization furnishes
pyrrolo[2,3-c]quinolones 3.[23]
acid
from
VI
affords
Financial support of this research provided by the NSFC
(21672034), the Natural Sciences Foundation of Jilin Province
(20160101330JC) and the open project of Jilin Province Key
Laboratory of Organic Functional Molecular Design & Synthesis
(No.130028834) is gratefully acknowledged.
In summary, a tandem cyclization-annulation of 2-
metheneaminochalcones with activated methylene
isocyanides was successfully developed for the
efficient synthesis of diverse pyrrolo[2,3-c]quinoline
derivatives. The sequential formation of the pyridine
and pyrrole rings in a domino process represents an
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10.1002/adsc.201801103
Advanced Synthesis & Catalysis
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5
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10.1002/adsc.201801103
Advanced Synthesis & Catalysis
UPDATE
Tandem Cyclization-Annulation of -Acidic
Isocyanides with 2-Methyleneaminochalcones:
Expedient Synthesis of Pyrrolo[2,3-c]quinoline
Derivatives
Adv. Synth. Catal. Year, Volume, Page – Page
Jinhuan Dong,a Xin Wang,a Hui Shi,b Lei Wang,a
Zhongyan Hu,a,* Yifei Li,b and Xianxiu Xua,*
6
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