NaOH-Promoted Chemoselective Cascade Cyclization of Cyclopropyl Esters with Unsaturated Imines: Access to Bioactive Cyclopenta[c]pyridine Derivatives

Article abstract of DOI:10.1021/acs.orglett.9b02088

A chemoselective cascade cycloaddition reaction is developed for green and efficient access to cyclopenta[c]pyridine derivatives. Simple and inexpensive NaOH is used as the sole catalyst for this process. The δ-carbon of cyclopropyl ester is activated as a nucleophilic carbon to initiate highly chemoselective cascade reactions. Cyclopenta[c]pyridines bearing various substituents are afforded in excellent yields. Preliminary studies on the bioactivities of the afforded products show promising antibacterial activities for potential applications in plant protections.

Full text of DOI:10.1021/acs.orglett.9b02088

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
NaOH-Promoted Chemoselective Cascade Cyclization of
Cyclopropyl Esters with Unsaturated Imines: Access to Bioactive
Cyclopenta[c]pyridine Derivatives
Dingwu Pan,†,⊥ Chengli Mou,‡,⊥ Ningning Zan,† Ya Lv,† Bao-An Song,† Yonggui Robin Chi,†,§
and Zhichao Jin*,†
†Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering, Key Laboratory of Green Pesticide and Agricultural
Bioengineering, Ministry of Education, Guizhou University, Huaxi District, Guiyang 550025, China
‡Guizhou University of Traditional Chinese Medicine, Huaxi District, Guiyang 550025, China
§Division of Chemistry & Biological Chemistry, School of Physical & Mathematical Sciences, Nanyang Technological University,
Singapore 637371, Singapore
S
* Supporting Information
ABSTRACT: A chemoselective cascade cycloaddition reac-
tion is developed for green and efficient access to cyclopenta-
[c]pyridine derivatives. Simple and inexpensive NaOH is used
as the sole catalyst for this process. The δ-carbon of
cyclopropyl ester is activated as a nucleophilic carbon to
initiate highly chemoselective cascade reactions. Cyclopenta-
[c]pyridines bearing various substituents are afforded in
excellent yields. Preliminary studies on the bioactivities of
the afforded products show promising antibacterial activities for potential applications in plant protections.
a
Table 1. Condition Optimization
yclopenta[c]pyridines are frequently found as core
Cstructures in natural products and bioactive synthetic
molecules (Figure 1a).1 For instance, pyracyclumines B and C
are key alkali fragments isolated from the roots of Anacyclus
pyrethrum, a traditional medicine for treatment of epilepsy.1c
Tishaviolamine A is one of the important components in the
extract of Viola tianshanica, a plant that has long been used as a
b
c
entry
base
solvent
yield (%)
dr
1
2
3
4
5
6
7
8
NaOH
NaOCH3
KOtBu
Cs2CO3
DBU
NaOH
NaOH
NaOH
NaOH
THF
THF
THF
THF
THF
EtOAc
H2O
84
83
52
37
<5
54
<5
<5
98
4:1
3:1
4:1
4:1
-
3:1
-
-
toluene
THF
d
9
4:1
a
Reaction conditions: 1a (0.10 mmol), 2a (0.05 mmol), base (0.01
b
c
mmol), solvent (1.0 mL), 30 °C, 24 h. Isolated yields of 3a. dr
1
values were determined by H NMR on the crude product mixture.
d
1a (0.075 mmol), 2a (0.05 mmol), NaOH (0.01 mmol), THF (1.0
mL), 40 °C, 24 h.
traditional Uygur medicine to treat pharyngalgia, headache,
fever, and acute pyogenic infection.1b These functional
molecules contain substituted cyclopenta[c]pyridine cores in
Figure 1. Cyclopenta[c]pyridines and our method for their quick and
green access.
Received: June 17, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02088
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a b
,
a
Scheme 1. Scope of α,β-Unsaturated Imines 2
Scheme 3. Reactions of 1a with Imine 4 and Enone 6
a
Reactions were carried out under conditions as in Table 1, entry 9.
Yields were isolated yields. dr values were determined by 1H NMR on
the crude product mixture.
a
Scheme 4. Reaction of 2-Cyclopropyl Ketone 1h with 2a
a
Reactions were carried out under conditions as in Table 1, entry 9.
Yields were isolated yields. dr values were determined by 1H NMR on
the crude product mixture.
Scheme 5. Synthetic Transformation of 3a
a
Reactions were carried out under condition as in Table 1, entry 9.
Yield was isolated yield. dr value was determined by 1H NMR on the
crude product mixture. Data in parentheses indicate the results from
b
the reaction carried out at 1.0 mmol scale based on 2a.
a
Scheme 2. Scope of Ester Substrates 1
and long synthetic steps have been required.2 Cascade
cyclization reactions promoted by simple and inexpensive
small molecules are promising strategies for the synthesis of
these complex structures.3
Here, we report a one-step method for highly efficient access
to bicyclic cyclopenta[c]pyridine derivatives bearing multiple
substituents (Figure 1b). Our reactions use NaOH as the only
catalyst, and most of the reactions give desired products with
over 90% yields. The key reaction processes include a NaOH-
promoted activation of a 2-cyclopropyl ester (e.g., 1a) to form
intermediate I bearing multiple reactive carbons. Although
multiple different reactions from intermediate I are possible (see
SI), we are delighted to see that with α,β-unsaturated imines as
the other substrate the reaction cascades are highly chemo-
selective. Briefly, formal [3 + 2] reaction initiated from addition
of the δ-carbon of intermediate I to unsaturated imine 2a forms
intermediate II.4 Related [3 + 2] process was observed before by
Jørgensen and co-workers in which 2-cyclopropyl ketones were
activated by amine/thiourea catalysts to react with nitro-
alkenes.5 Proton transfer of II gives intermediate III, which
subsequently undergoes lactam formation to afford cyclopenta-
[c]pyridine product 3a with excellent yield. Several of the
cyclopenta[c]pyridine products from our approach exhibit
a
Reactions were carried out under conditions as in Table 1, entry 9.
Yields were isolated yields. dr values were determined by 1H NMR on
the crude product mixture. Data in parentheses indicate the results
from the reaction carried out at 1.0 mmol scale based on 2a.
b
either racemic or enantiomerically pure forms. Therefore, the
rapid construction and bioactivity evaluation of substituted
cyclopenta[c]pyridine derivatives are of considerable interests.
However, despite of their importance, the preparation of this
class of cyclopenta[c]pyridine derivatives remains challenging,
B
DOI: 10.1021/acs.orglett.9b02088
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Letter
a
Table 2. Inhibition Rate of Compounds 3 against Bacteria
a
b
c
d
All data were average data of three replicates. Commercial bactericide, used as the positive control. Not tested. DMSO was used as the negative
control.
encouraging antibacterial activities against X. oryzae pv oryzae,6
X. axonopodis pv citri,7 and P. syringae pv actinidiae.8
group (1c) resulted in only trace formation of the final product.
It is worth noting that the cyclopropyl aldehyde 1d cannot be
used as a reaction partner for this NaOH-promoted cyclo-
addition reaction with the imine 2a. Both substrates
decomposed without any cycloaddition products formed. Both
aliphatic and aromatic substituents were well tolerated as the R′
groups on the ester substrates 1, with the corresponding
products afforded in moderate yields (1e to 1g). Notably,
excellent diastereoselectivity (>20:1) could be observed when
using ester substrate 1g bearing phenyls as the R′ groups.
Electron deficient cyclic imine 4 and enone 6 can also be used
as suitable electrophiles in the NaOH-promoted reactions with
the 2-cyclopropyl ester 1a (Scheme 3). However, in these cases,
pyrrole 5 and cyclopentane 7 from formal [3 + 2] cycloaddition
reactions were afforded as the final products in moderate to good
yields.
2-Cyclopropyl ketone substrate 1h could also serve as an
effective substrate in the cycloaddition reaction with α,β-
unsaturated imine 2a (Scheme 4). The [3 + 2] cyclization
product 8 could be isolated in 82% yield as a single diastereomer
under the current optimized reaction conditions.
The multifunctionalized cyclopenta[c]pyridine product (3a)
is amenable for further transformations (Scheme 5). For
example, addition of methanol to the lactam moiety of 3a
under a basic condition could produce ester 9 in 88% yield. The
lactam group in 3a could be selectively reduced by BH3 (without
affecting the ester groups) to afford N,O-hemiaminal adduct 10
with 58% yield.
We chose 2-cyclopropyl ester 1a and α,β-unsaturated imine
2a as the model substrates to search for suitable reaction
conditions (Table 1). We initially intended to use N-
heterocyclic carbene (NHC) organic catalysts to activate the
ester substrates9 for cascade reactions. We found that NHC did
not participate in the reaction, and the reaction proceeded
smoothly with the presence of a simple base alone. For example,
a variety of common inorganic bases could efficiently promote
the cascade process and give the desired cyclopenta[c]pyridine
products in moderate to good yields with moderate diaster-
eoselectivities (Table 1, entries 1−4). Organic bases tested for
this transformation were generally ineffective (e.g., entry 5).
Organic solvents with high polarities could serve as suitable
medium for this NaOH-catalyzed process (e.g., entry 6), while
the reactions could not proceed well in either aqueous system or
nonpolar organic solvents (entries 7−8). The product yield
could be dramatically improved by slightly increasing the
reaction temperature to 40 °C. Under this temperature, the
loading of 1a could be decreased and the desired product 3a
could be obtained in almost quantitative yield without erosion of
the diastereoselectivity (entry 9). Further decreasing the
amount of either NaOH or ester 1a led to some drops on the
product yields (see SI for details).
Having established optimized reaction conditions (Table 1,
entry 9), we next examined the scope of α,β-unsaturated imines
(2) bearing various substituents (Scheme 1). Both substituents
R1 and R2 of the imine substrate 2 could be phenyl rings with
different substitution patterns. The fused cyclopenta[c]pyridine
products 3 were afforded in generally excellent yields with
moderate to excellent diastereoselectivities (3a to 3q).
Heteroaromatic groups were also well tolerated on both sides
of the imine substrates 2, with the corresponding products
afforded in excellent yields (3r to 3u). It is worth noting that the
aromatic R2 group could be replaced with an ester substituent,
although the corresponding product 3v was only afforded in a
low yield with a poor diastereoselectivity under current reaction
conditions.
The cyclopenta[c]pyridine products (3) obtained from our
reactions were evaluated for their bioactivities with potential
uses in plant protections (Table 2). X. oryzae pv oryzae is a
harmful bacterium that causes leaf blast in rice and seriously
damages rice production.6 Bismerthiazol is widely used an
agrochemical in controlling the rice leaf blast via inhibition of X.
oryzae pv oryzae.10 To our delight, several of our cyclopenta-
[c]pyridine products showed excellent inhibition rate against X.
oryzae pv oryzae. For example, products 3a and 3r showed
similar antibacterial activities as the bismerthiazol, and product
3e provided a better effect in the inhibition of X. oryzae pv
oryzae.
We then examined the scope of the 2-cyclopropyl ester
substrates (1) (Scheme 2). The electron deficient 4-nitrophenol
group on 1a could be switched to an electron-rich aromatic
group (1b), although the product yield decreased to 61%.
Replacing the R group on ester substrate 1 with a simple methyl
X. axonopodis pv citri7 and P. syringae pv actinidiae8 are
widespread bacteria that cause decay in various kinds of fruits.
Our cyclopenta[c]pyridine products showed encouraging
antibacterial activities against both X. axonopodis pv citri and
C
DOI: 10.1021/acs.orglett.9b02088
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
P. syringae pv actinidiae (Table 2). For example, compounds 3a,
3c, 3m, and 3r exhibited superior antibacterial activities against
X. axonopodis pv citri, compared to the commercially used
thiodiazole-copper.11 Our products 3c, 3f, 3g, 3m, 3q, and 3s all
showed better results than thiodiazole-copper in the inhibition
of P. syringae pv actinidiae.
In summary, we have developed a chemoselective cascade
cycloaddition reaction promoted by simple and inexpensive
NaOH. Cyclopenta[c]pyridine derivatives are afforded as the
final products in up to quantitative yields. The δ-carbon of the in
situ generated α,β-unsaturated carboxylic ester is activated as the
nucleophile to react with α,β-unsaturated imines in highly
chemoselective manners. The multifunctional cyclopenta[c]-
pyridine products obtained from our method exhibit encourag-
ing antibacterial activities with potential applications in the
development of new green pesticides.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b02088.
Experimental procedures and spectral data for all new
compounds (PDF)
Accession Codes
CCDC 1911186−1911188 contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by email-
ing data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road, Cam-
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: zcjin@gzu.edu.cn.
ORCID
Yonggui Robin Chi: 0000-0003-0573-257X
Zhichao Jin: 0000-0003-3003-6437
Author Contributions
⊥These authors contributed equally to this work.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge financial support from the National Natural
Science Foundation of China (No. 21772029, 21801051),
National Key Technologies R Program (No. 2014BAD23B01),
The 10 Talent Plan (Shicengci) of Guizhou Province [2016]
5649, Guizhou Province Returned Oversea Student Science and
Technology Activity Program (2014)-2, Science and Technol-
ogy Department of Guizhou Province [2018]2802, [2019]1020,
Guizhou University, the Guizhou Province First-Class Dis-
ciplines Project (Yiliu Xueke Jianshe Xiangmu)-GNYL(2017)
008, Guizhou University of Traditional Chinese Medicine
QMYY [2017]101 (China). Singapore National Research
Foundation (NRF-NRFI2016-06), the Ministry of Education
of Singapore (MOE2013-T2-2-003; MOE2016-T2-1-032;
RG108/16), A*STAR Individual Research Grant
(A1783c0008), Nanyang Research Award Grant, and Nanyang
Technological University.
D
DOI: 10.1021/acs.orglett.9b02088
Org. Lett. XXXX, XXX, XXX−XXX