Asymmetric Dearomative Cascade Multiple Functionalizations of Activated N-Alkylpyridinium and N-Alkylquinolinium Salts

Article abstract of DOI:10.1021/acs.orglett.0c02828

An enantioselective cascade reaction of N-alkylpyridinium and -quinolinium salts with o-hydroxybenzylideneacetones to access fused polyheterocycles through cross dienamine-mediated addition followed by trapping of the dearomatized enamine-type intermediates and aminal formation has been developed. A cascade assembly of N-benzyl-4-methylpyridinium salt and cyclic 2,4-dienones is further disclosed to give bridged frameworks via repetitive dearomatization and aromatization activation.

Full text of DOI:10.1021/acs.orglett.0c02828

pubs.acs.org/OrgLett
Letter
Asymmetric Dearomative Cascade Multiple Functionalizations of
Activated N‑Alkylpyridinium and N‑Alkylquinolinium Salts
Xue Song, Ru-Jie Yan, Wei Du,* and Ying-Chun Chen*
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ABSTRACT: An enantioselective cascade reaction of N-alkylpyridinium and -quinolinium salts with o-hydroxybenzylideneacetones
to access fused polyheterocycles through cross dienamine-mediated addition followed by trapping of the dearomatized enamine-type
intermediates and aminal formation has been developed. A cascade assembly of N-benzyl-4-methylpyridinium salt and cyclic 2,4-
dienones is further disclosed to give bridged frameworks via repetitive dearomatization and aromatization activation.
generally have been constructed in the products with high
itrogen-containing fused and even polycyclic frameworks
Nwith three-dimensional architectures are ubiquitous in molecular complexity. To address such a deficiency, here we
natural products and pharmaceutically important substances,1
disclose previously unreported asymmetric dearomative cascade
functionalizations of N-alkylpyridinium and -quinolinium salts
with simple benzylideneacetones bearing an o-hydroxy group
via aminocatalysis,9 efficiently affording fused heterocyclic
architectures with high levels of stereocontrol (Scheme 1d).
In our initial study, we explored the reaction between
N-benzyl-3-cyanopyridinium salt 1a (Table 1, R1 = Bn) and
o-hydroxybenzylideneacetone (2a) (Table 1, R2 = R3 = H,
X = CH) under aminocatalytic conditions.5k It was pleasing
that the cascade functionalization process took place as expected
via tandem enamine/iminium ion activation, giving the fused
tetracyclic framework 3a as a single diastereomer. It should be
noted that the final aminal formation is crucial for the cascade
process, since only the dearomative addition step was observed
for simple benzylideneacetone.10 After investigation of a variety
of catalytic parameters, product 3a was obtained in 78% isolated
yield with excellent enantioselectivity (98% ee) by employing
quinine-derived primary amine C1 (20 mol %)11 and salicylic
acid (A1) (20 mol %) in the presence of potassium salicylate
(B1) (1.1 equiv), even on a larger scale. Subsequently, we
examined the scope and limitations of this dearomative cascade
reaction. o-Hydroxybenzylideneacetones 2 with a substituent at
and thus, the development of asymmetric reactions to effec-
tively access these drug-like hetero libraries triggers continuing
interest in organic and medicinal chemistry.2 Among them, the
asymmetric dearomative reaction of azaarenes provides a versatile
strategy to construct enantioenriched alkaloid compounds, and a
diversity of elegant processes have been uncovered.3 Nevertheless,
examples of cascade multiple functionalizations4 on the pyridine
and quinoline skeletons still have been rarely reported, though
some potentially reactive species would be usually generated
during the dearomative process. In fact, N-alkylated pyridinium or
quinolinium salts have been demonstrated to be highly active in a
number of dearomative reactions, including asymmetric versions,
through suitable nucleophilic additions. In contrast, most cases
are still limited to furnishing relatively simple monofunctionaliza-
tion of the azaarene ring at C2 or C4,5 though the electron-rich
enamine functionality, showing apparent nucleophilicity,6 is
formed in the dearomative products (Scheme 1a).
Recently, the Yoo group designed a type of pyridinium zwit-
terions that could be regioselectively assembled with palladium−
trimethylenemethane (Pd-TMM) species, followed by intra-
molecular capture of the iminium ions (Scheme 1b).7 Additionally,
Bu and co-workers uncovered base-promoted multiple func-
tionalizations of diverse N-alkyl azaarene salts that usually proceed
by cascade C4- and C2-regioselective attack by bisnucleophilic
enaminones, and sometimes the enamine intermediates could be
captured by suitable electrophiles inter- or even intramolecularly
(Scheme 1c).8 Nevertheless, none of them have achieved the
potential asymmetric control, though multiple stereogenic centers
Received: August 23, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02828
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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Letter
Table 1. Substrate Scope of Multiple Functionalizations of
Scheme 1. Diverse Dearomative Modes of Pyridinium and
Quinolinium Salts
Pyridinium Salts 1 with o-Hydroxybenzylideneacetones
a b c
, ,
2
C3 showed lower reactivity with salt 1a (products 3b and 3c),
probably for steric reasons, whereas excellent enantioselectivity
was still obtained. In addition, moderate to high yields along
with outstanding levels of enantioselectivity were generally
attained for enones 2 with different substituents at C4, C5, or
even C6 (products 3d−o). Naphthalene- and pyridine-based
substrates also afforded similar good results (products 3p and
3q). Nevertheless, low diastereoselectivity was observed for
enones 2 having a substituent at the α′-position, but the
enantiocontrol was still excellent for both isomers (products 3r
and 3s). On the other hand, pyridinium salts 1 with diverse
N-benzyl or other N-alkyl substituents were well-tolerated in
the reactions with enone 2a (products 3t−x). Moreover, when
amine C2 from quinidine was employed, the corresponding
products with the opposite configuration were produced with
similar good data (Table 1, data in parentheses). It should be
noted that the use of pyridinium salts with a 3-cyano group was
important for the cascade reaction, and messy or inert reac-
tions were observed for the salts with other types of func-
tionalities.10
Encouraged by the above results, we further attempted to
extend this strategy to multiple functionalizations of quinolinium
salts. Although trace product (<5%) was observed when a
simple N-benzylquinolinium salt was used, substrate 4a with a
6-nitro group showed promising reactivity with enone 2a under
the previous catalytic conditions, delivering the fused product 5a
(Table 2) effectively but with poor enantiocontrol (>19:1 dr,
3% ee). To enhance the enantioselectivity, a number of amine
catalysts and additives were investigated.10 Gratifyingly, under
the catalysis of a newly designed amine C3 condensed from
quinine and L-tert-leucine in combination with racemic mandelic
acid (A2) and Na2HPO4, the model reaction proceeded smoothly
a
Unless noted otherwise, reactions were performed with 1a
(0.11 mmol, 1.1 equiv), 2 (0.1 mmol, 1.0 equiv), C1 (20 mol %),
A1 (20 mol %), and B1 (1.1 equiv) in DCM (1.0 mL) at rt for 24−
b
c
96 h. Yields of the isolated products are shown. The ee values were
determined by HPLC analysis on a chiral stationary phase. Data in
parentheses were obtained on a 1.0 mmol scale. Data in parentheses
d
e
f
g
were obtained with C2. In DCM (2.0 mL). At 4 °C for 60−192 h.
h
The absolute configuration of enantiopure 3t was determined by
X-ray analysis. The configurations of the other products were assigned
by analogy.
B
https://dx.doi.org/10.1021/acs.orglett.0c02828
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Table 2. Substrate Scope of Multiple Functionalizations of
Quinolinium Salts 4
Scheme 2. Cascade Assembly of Pyridinium Salt 6 with
Cyclic Dienones 7
a b c
, ,
(products 5n and 5o). Moreover, it was pleasing that an o-amino
enone was applicable, although the product 5p was attained in
modest yield and enantioselectivity. We also tested the reactions
with amine C4 condensed from quinidine and D-tert-leucine, and
the desired products with the opposite enantiopurity were provided
with similar good ee values (Table 2, data in parentheses).
We recently reported that N-benzyl-4-methylpyridinium salt
6 could form a dearomative dienamine-type intermediate after
deprotonation, which was combined with benzylideneacetones
to give spirocycles via iminium ion catalysis.12 We further
envisaged that salt 6 would potentially perform as a multi-
reactive agent, as proposed in Scheme 2a, through a repetitive
dearomatization/aromatization process. To our gratification,
cyclic dienone13 7a (R = CO2Me) could be utilized as a suitable
partner under the catalysis of amine C1 and acid (R)-A2,10
efficiently furnishing the fused and bridged architecture 8a in
moderate yield with good enantioselectivity via a domino regio-
selective Michael/Michael/Mannich sequence. Other cyclic
dienones 7 bearing a δ-aryl or -methyl group generally showed
lower reactivity, and the desired frameworks 8b−f were produced
in fair yields with moderate to good levels of enantiocontrol
(Scheme 2b).10
a
Unless noted otherwise, reactions were performed using 4 (0.12 mmol,
1.2 equiv), 2 (0.1 mmol, 1.0 equiv), C3 (20 mol %), A2 (20 mol %), and
Na2HPO4 (0.1 mmol, 1.2 equiv) in DCE (2.0 mL) at rt for 48−60 h.
̈
As illustrated in Scheme 3, a one-pot Friedlander quinoline
synthesis was readily realized to afford the complex archi-
tecture 10 from product 3a and 2-aminobenzaldehyde (9).
Interestingly, an N-debenzylative aromatization process along
with the reduction of nitro group was observed to give product
11 from the bridged skeleton 8a under simple Pd/C-catalyzed
hydrogenation conditions, albeit in a fair yield.14
b
c
Yields of the isolated products are shown. The ee values were
d
determined by HPLC analysis on a chiral stationary phase. Data in
e
f
parentheses were obtained with C4. In DCE (1.0 mL). The absolute
configuration of enantiopure 5k was determined by X-ray analysis.
The configurations of the other products were assigned by analogy.
In conclusion, we have demonstrated that activated pyri-
dinium and quinolinium salts can be utilized in the asymmetric
dearomative multiple functionalization reaction with o-hydro-
xybenzylideneacetones under the catalysis of cinchona-derived
primary amines through dearomative addition and consecutive
trapping of the reactive enamine intermediates and aminal
formation. An array of fused heterocyclic architectures showing
high molecular and stereogenic complexity were effectively
constructed with good to excellent levels of enantioselectivity.
in 1,2-dichloroethane (DCE) at room temperature, and product
5a was obtained in 70% yield with good enantiocontrol (89% ee)
(Table 2). Consequently, an array of enones 2 were explored in
the reactions with quinolinium salt 4a. As summarized in Table 2,
in general, the series of trifunctionalized products 5b−m were
furnished in moderate yields with good enantioselectivities.
In addition, quinolinium salts 4 with a 6-cyano or 7-nitro group
also exhibited good reactivity under the same catalytic conditions
C
https://dx.doi.org/10.1021/acs.orglett.0c02828
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Letter
Research Center for Drug Precision Industrial Technology, West
China School of Pharmacy, Sichuan University, Chengdu
610041, China
Scheme 3. Synthetic Transformations of the Products
Ru-Jie Yan − Key Laboratory of Drug-Targeting and Drug
Delivery System of the Ministry of Education and Sichuan
Research Center for Drug Precision Industrial Technology, West
China School of Pharmacy, Sichuan University, Chengdu
610041, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02828
Funding
We are grateful for the financial support from the National
Natural Science Foundation of China (21772126, 21961132004,
and 21931006).
Notes
The authors declare no competing financial interest.
Moreover, we also realized multiple functionalizations of
4-methylpyridinium salts with cyclic 2,4-dienone substrates
through an unusual and repetitive dearomatization and aroma-
tization activation process, finally affording bridged and fused
frameworks with moderate to good enantiocontrol. We believe
that the current dearomative multiple functionalization strategy
may arouse interest in developing more asymmetric reactions
to produce chiral heterocycles with high value in organic and
medicinal chemistry.
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02828.
Complete experimental procedures and characterization
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mentary crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif,
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AUTHOR INFORMATION
Corresponding Authors
■
Wei Du − Key Laboratory of Drug-Targeting and Drug Delivery
System of the Ministry of Education and Sichuan Research
Center for Drug Precision Industrial Technology, West China
School of Pharmacy, Sichuan University, Chengdu 610041,
China; Email: duweiyb@scu.edu.cn
Ying-Chun Chen − Key Laboratory of Drug-Targeting and
Drug Delivery System of the Ministry of Education and Sichuan
Research Center for Drug Precision Industrial Technology, West
China School of Pharmacy, Sichuan University, Chengdu
610041, China; College of Pharmacy, Third Military Medical
University, Shapingba, Chongqing 400038, China;
orcid.org/0000-0003-1902-0979; Email: ycchen@
scu.edu.cn
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