Ligand-free Cu-catalyzed [3 + 2] cyclization for the synthesis of pyrrolo[1,2-a] quinolines with ambient air as a terminal oxidant

Article abstract of DOI:10.1039/c6ob01316c

A ligand-free Cu-catalyzed [3 + 2] cycloaddition of ethyl 2-(quinolin-2-yl)acetates, ethyl 2-(isoquinolin-1-yl)acetates, and ethyl 2-(pyridin-2-yl)acetates with (E)-chalcones for a "one-pot" synthesis of pyrrolo[1,2-a]quinolines, pyrrolo[2,1-a]isoquinolines and indolizines has been developed. The annulation products were isolated in moderate to good yields with air as the sole oxidant under mild conditions.

Full text of DOI:10.1039/c6ob01316c

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DOI: 10.1039/C6OB01316C
Organic & Biomolecular Chemistry
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Ligand-free Cu-Catalyzed [3+2] Cyclization for the Synthesis of
Pyrrolo[1,2-a]quinolines with Ambient Air as Terminal Oxidant
Yang Yu,a Yuan Liu,a Aoxia Liu,a Hexin Xie,a Hao Li,*a and Wei Wang*a,b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A ligand-free Cu-catalyzed [3+2] cycloaddition of ethyl 2- hypervalent iodine reagents, peroxides, MnO2, K2S2O8 etc.. On
(quinolin-2-yl)acetates, ethyl 2-(isoquinolin-1-yl)acetates, and the other hand, chemists lay emphasis on green and
ethyl 2-(pyridin-2-yl)acetates with (E)-chalcones for a “one- sustainable manufacturing in order to solve problems of
pot” synthesis of pyrrolo[1,2-a]quinolines, pyrrolo[2,1- environmental pollution and resource shortage. Therefore, air
a]isoquinolines and indolizines has been developed. The or O2, which has environment-friendly and inexpensive
annulation products were isolated in moderate to good yields characters existing in the nature, has been widely used as an
with air as the sole oxidant under the mild conditions.
oxidant.9
Pyrrolo[1,2-a]quinolines, pyrrolo[2,1-a]isoquinolines and
Transition-metal-catalyzed oxidative C-H amination reaction indolizines and their derivatives are important classes of N-
via C-H activation is one of the most demanding procedures to containing heterocycles occurring in numerous
form C-N bonds.1 Cross dehydrogenative coupling (CDC) pharmaceuticals,10 natural products,11 and functional
reaction using direct C-H bond activation strategy, which is a materials.12 For example, pyrrolo[1,2-a]quinoline compound
A
powerful method for constructing C-N bonds, would eliminate has been investigated extensively to induce apoptosis which
prefunctionalization and make synthetic schemes shorter.2 plays a key role for the maintenance of cell homeostasis.13
Various late transition metal catalysts such as Pd,3 Ru,4 Rh,5 Ir,6 pyrrolo[2,1-a]isoquinoline compound
B
(Lamellarin
as a selective HIV integrase
could inhibit carcinoma
D) is a
Cu7 have been applied in CDC reactions. However, comparing potent inhibitor of topoisomerase
to other late transition metals, copper salt is low-costed and inhibitor.14 Indolizine compound
I
C
low-toxic. Therefore, Cu-catalyzed CDC reactions between C-H cell’s proliferation (Fig. 1).15 The synthesis of these derivatives
and N-H bonds have received significant interest over the has received a lot of progress.16 Recently, some [3+2] reactions
recent decades.7,8 In Cu-catalyzed CDC reactions, oxidant plays were reported by Jia17, and Adimurthy18 groups to synthesize
an important role and has been widely employed, such as
indolizines from ethyl 2-(pyridin-2-yl)acetates and unsaturated
double bonds. However, equivalents of copper salt or
inorganic oxidants were used in these reactions. Moreover,
other heterocycles such as quinoline, isoquinoline and
Fig
1
Pyrrolo[1,2-a]quinoline, pyrrolo[2,1-a]isoquinoline and indolizine
derivatives with biological activities.
a.State Key Laboratory of Bioengineering Reactor, Shanghai Key Laboratory of New
Drug Design, and School of Pharmacy, East China University of Science and
Technology, 130 Mei-long Road, Shanghai 200237, China
Email: hli77@ecust.edu.cn
Fig.
2 Tandem Michael additon-oxidative cyclization for the synthesis of
pyrrolo[1,2-a]quinolones.
b.Department of Chemistry and Chemical Biology
University of New Mexico, Albuquerque, NM 87131-0001, USA
Email: wwang@unm.edu
†
Electronic Supplementary Information (ESI) available: 1H and 13C NMR spectra.
See DOI: 10.1039/x0xx00000x
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Table 1 Optimization of reaction conditionsa
Table 2 Copper-catalyzed aerobic oxidative [3+2] cyclization for the synthesis of
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pyrrolo[1,2-a]quinolinesa
DOI: 10.1039/C6OB01316C
Entry
1
Cat.
Base
TBD
Solvent
DMSO
DMSO
DMSO
DMSO
toluene
DCE
Yield (%)b
44
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
CuBr2
2
DBU
DMAP
DABCO
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
81
3
trace
trace
5
4
5
6
trace
17
7
dioxane
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
8
36
9
CuI
59
10
11
12c
13d
14e
Cu(OTf)2
CuCl
54
34
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
61
35
a
Unless otherwise noted, the reaction was carried out by using 1 (0.2 mmol), 2
(0.4 mmol), Cu(OAc)2 (0.06 mmol) and DBU (0.4 mmol) in DMSO (1 mL) at 75 oC
for 18 h. b Isolated yield. c With CuCl and TBD (see SI).
67
a
Unless specifized, a mixture of ethyl 2-(quinolin-2-yl)acetate 1a (2.0 mmol) and
(E)-chalcone 2a (4.0 mmol) in the presence of copper salt (30 mol%) and base (2
equiv) in solvent (1.0 mL) was stirred at 75 oC for 18 h. b Isolated yields. c Reaction
was carried for 12 h. d 0.15 equiv Cu(OAc)2 was used. e 1 equiv of DBU was used.
salts were screened, CuI, Cu(OTf)2, CuBr2, and CuCl were less
effective than Cu(OAc)2 (entries 8-11). What’s more, when the
reaction was carried out for 12 h, the reaction yield was
decreased to 61% (entry 12). Further lowering of the catalyst
loading to 15 mol%, the yield was decreased to 35% (entry 13).
Decreasing the equivalent of DBU also resulted the lower yield
(67%, entry 14).
benzo[f]quinoline have not been tested. Recently, our
research interest is focused on C-N bond formation
methodologies.19 In 2011, our group developed a very efficient
methodology
to
synthesize
pyrrolo[2,1-a]isoquinoline
derivatives.20 Herein, to continue our research, we reported a
simple and practical [3+2] annulation reaction via Michael
addition-oxidative cyclization by using ambient air as terminal
oxidant (Fig. 2).
After optimizing the reaction conditions, we examined the
scope of a variety of 2-(quinolin-2-yl)acetates
1 and (E)-
chalcones . As shown in Table 2, almost all of the tested
2
combinations produced the desired pyrrolo[1,2-a]quinolines
with moderate to good isolated yields. Both electron-
withdrawing and electron-donating substituents on the (E)-
chalcones and 2-(quinolin-2-yl)acetates were tolerated in this
reaction. Generally, electron-withdrawing groups on the
benzene ring of (E)-chalcones have positive effects on the yield
due to their capacity to elevate the activity of (E)-chalcones
We initiated our investigation with the cyclization of ethyl 2-
(quinolin-2-yl)acetate 1a (0.2 mmol) and (E)-chalcone 2a (0.4
mmol) in DMSO as the modal reaction in the presence of
Cu(OAc)2 (0.06 mmol) and 2,3,4,6,7,8-hexahydro-1H-
pyrimido[1,2-a]pyrimidine (TBD) (0.4 mmol), which is a good
catalyst for Michael addition.21 Fortunately, the desired [3+2]
product 3a was obtained in 44% yield after 18h at 75 oC (Table
1, entry 1). When DBU was used as the base, the yield of
product 3a was increased to 81% (entry 2). Then other organic
bases were screened, DMAP and DABCO were found to be
ineffective (entries 3 and 4). The solvent screening revealed
that toluene and DCE afforded the products with poor yields
(entries 5 and 6). Dioxane gave a slightly higher yield than
toluene (17%, entry 7). The results showed that DMSO was the
most suitable solvent for the reaction. When different copper
(Table 2, 3b-
3d). The reaction gave lower yields when R3 was
para-OMe (3e) and ortho-OMe (3f), this implied that electronic
effect and steric effect had an influence on the reaction.
Furthermore, the results also revealed that quinolines carrying
a substituent group at C-6 or C-7 afforded the corresponding
products in generally acceptable to good yields. It is worth
mentioning that the reactions gave poor yields when Br or CH3
were substitutes at C-6 in Cu(OAc)2/DBU system. However,
when the catalyst system was changed to CuCl as the catalyst
and TBD as the base, the reactions proceeded smoothly with
2 | J. Name., 2012, 00, 1-3
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Table
3 Copper-catalyzed aerobic oxidative [3+2] cyclization for the synthesis of
View Article Online
DOI: 10.1039/C6OB01316C
pyrrolo[2,1-a]isoquinolines and indolizinesa
Fig. 4 The proposed mechanism.
To confirm the proposed mechanism (Fig. 2), the reaction
was carried out in two steps. We found that nearly
quantitative Michael addition product 6d was formed in the
existence of DBU or TBD after 20 min at room temperature.
And C-N coupling procedure happened with 59% yield under
CuCl/TBD system and 69% yield under Cu(OAc)2/DBU system
(See SI). Although the mechanistic details are unclear at the
present time, a probable mechanism is shown in Fig. 4. DBU or
TBD21 activated ethyl 2-(pyridin-2-yl)acetate to give the
Michael addition product 6d, which was also activated by base
a
Unless otherwise noted, the reaction was carried out by using 1 (0.2 mmol), 2
(0.4 mmol), Cu(OAc)2 (0.06 mmol) and DBU (0.4 mmol) in DMSO (1 mL) at 75 oC
for 18 h. b Isolated yield. c With CuCl and TBD (see SI).
the yield of 64% and 78% (3g and 3h). Additionally, the yield
would be as low as 47% when Cl was at C-7 (3i). Product 3j
with double electron donating groups (R1 = Me, R2 = ortho-
OMe) was well tolerated with 52% yield. Besides, thienyl was
also a compatible substrate with the formation of product 3k
in 50% yield. Moreover, the benzo[f]quinoline’s derivative
reacted well to give the desired product 3l in 70% yield.
To further expand the scope of the reaction, ethyl 2-
(isoquinolin-3-yl)acetate and ethyl 2-(pyridin-2-yl-acetate were
investigated (Table 3). The catalytic system of the combination
of CuCl as catalyst and TBD as base afforded higher yields for
to form
intermediate III that is then oxidized to the reactive copper
complex IV 25
Afterwards, IV afforded the product through
I. Then I reacted with Cu(II) to produce the
.
V
reductive elimination along with Cu(I) species which is oxidized
by the aerobic oxygen to enter the catalytic cycle. Finally, 5d
was formed by oxidative aromatization.26
most substrates (5a
neutral or electron-withdrawing substitutions at the para-
position of the benzene ring gave slightly higher yield (5a 5b
5d 5f). While electron-donating groups afforded lower yields
5c 5g). Moreover, when the substituted group was changed
-5d, 5g). Similarly, the (E)-chalcone with
Conclusions
,
,
-
,
We have disclosed an efficient aerobic copper-catalyzed [3+2]
cycloaddition for
a]quinolines, pyrrolo[2,1-a]isoquinolines and indolizines. This
procedure was involved tandem Michael addition, C-N
coupling and annulation. Moreover,
demethylation of the methoxy group and intramolecular ester
exchange to obtain polycyclic coumarin compound in
moderate yield.
(
a “one-pot” synthesis of pyrrolo[1,2-
to ortho-OMe, the yield was decreased to 48% (5h).
Coumarins play crucial roles in natural products and they
exhibit a broad pharmacological profile such as antitumor
activity,22 HIV-1 protease,23 and inhibition of antidiabetic.24 To
test the usefulness of our methodology, demethylation of the
methoxy group of 5h by BBr3 followed by intramolecular ester
exchange reaction afforded the chromeno[3,4-c]pyrrol
derivative 6h in 61% yield (Fig. 3).
a
procedure by
Acknowledgements
Financial support of this research from the program for
Professor of Special Appointment (Eastern Scholar) at
Shanghai Institutions of Higher Learning (No. 201226, H. L.),
the National Science Foundation of China (21372073,
21572054 and 21572055), the Fundamental Research Funds
for the Central Universities and the China 111 Project (Grant
B07023) is gratefully acknowledged.
Fig 3 Synthesis of polycyclic compound 6h
.
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