Advanced Synthesis & Catalysis
10.1002/adsc.201900029
Next, we explored the possibility of the formation
enolates, which underwent conjugate addition to
another molecule of the 2-aminochalcones affording
dimers of the 2-aminochalcones connected through
of biquinolines 3 through sequential production of
quinolines 2 followed by the second quinoline ring
formation at the C-3 position. Under this scenario, 2-
aminochalcone 1 initially undergoes dehydrative
cyclization to generate quinoline 2. Deprotonation of
the initially formed quinoline 2 with tert-butoxide at
the C-3 position would generate 3-quinolinyl anion 9,
which would act as the nucleophilic catalyst for the
second quinoline formation with 2-aminochalcone 1
C -Cβ’ bond. Condensation of each pair of the amino
α
and carbonyl groups in the adjacent position followed
by aromatization provided the desired 3,4’-
biquinoline products. Various 2-aminochalcones
could be applicable to this protocol and the desired
biquinolines were obtained in good to high yields.
Further application of the resulting 3,4’-biquinolines
leading to biquinoline 3. To test this reaction pathway, and the development of a novel protocol using a
we subjected a mixture of 1a and 2b to the standard
reaction conditions. Under these conditions, only 3a
was observed without any formation of mixed
biquinoline 10. Based on this result, we could rule out
this reaction pathway (Scheme 3b).
Furthermore, we attempted to analyze the reaction
mixture by high resolution mass spectrometry
nucleophile are currently underway in our laboratory
and will be reported in due course.
Experimental Section
General procedure for the synthesis of 3,4’-biquinolines
3
from 2-aminochalcones 1 (Table 2): To a solution of
(
(
HRMS) before the reaction went to the completion
(
(
E)-2-aminochalcone 1 (0.20 mmol) in dimethyl sulfoxide
2.0 mL) was added sodium tert-butoxide (19.2 mg, 0.20
Scheme 3c). When 1f was subjected to the standard
conditions at room temperature, we did observe
several compounds A, B, and C from HRMS analysis,
which could be generated from their tert-butoxide
adducts 11, 12, and 13 via elimination of tert-butanol
during the ionization.[
mmol) at room temperature. The reaction mixture was
o
allowed to stir at 40 C in an open flask and monitored by
TLC. After complete consumption of compound 1, the
reaction mixture was cooled to room temperature and
concentrated under reduced pressure. Then the crude
reaction mixture was extracted with a mixture of water and
ethyl acetate. The organic layers were combined, dried
over MgSO , and concentrated. The crude mixture was
4
purified by short flash column chromatography on silica to
provide the desired biquinoline product 3.
15,16]
Based on these experimental results, we proposed a
plausible reaction mechanism for this transformation
(
Scheme 4). As expected, tert-butoxide would
undergo conjugate addition to 2-aminochalcones 1 to
afford enolates 4. Conjugate addition of 4 to another
molecule of
intermediates 11. Subsequent dehydrative cyclization
1
would afford 1,5-dicarbonyl
between the amino and carbonyl groups would lead Acknowledgements
to intermediates 12, which would undergo oxidation
to form 2-aminochalcone derivatives 13, bearing a
This work was supported by National Research Foundation of
Korea (NRF) grants funded by the Korean Government (NRF-
018R1D1A1A02086110 and NRF-2014-011165, Center for New
Directions in Organic Synthesis). J.J. acknowledges the financial
support from an NRF-2018-Fostering Core Leaders of the Future
Basic Science Program/Global Ph.D. Fellowship Program
funded by the Korean Government.
quinoline ring and tert-butoxide at the α and β-
2
17]
positions,
respectively.[
Final
dehydrative
cyclization of intermediates 13 would provide the
desired 3,4’-biquinolines 3.
References
[
1] For a review of biquinolines, see: P. J. Still, Aromatic
Biheterocycles: Syntheses, Structures, and Properties.
In Advances in Heterocyclic Chemistry; A. R. Katritzky,
Ed.; Elsevier; 1996, Vol. 67, 1-117.
[
2] 2,2’-Biquinolines have been used as chelating ligands
and analytical reagents for copper. For recent selected
examples, see: a) A. Gaál, G. Orgován, V. C. Mihucz, I.
Pape, D. Ingerle, C. Streli, N. Szoboszlai, J. Trace
Elem. Med. Biol. 2018, 47, 79; b) A. Kyziot, A.
Cierniak, J. Gubernator, A. Markkowski, M. Jeżowska-
Bojczuk, U. K. Komarnicka, Dalton Trans. 2018, 47,
Scheme 4. Plausible Reaction Mechanism for the
Synthesis of 3,4’-Biquinolines 3 from 2-Aminochalcones 1
1
981; c) L. Wang, H. Yin, P. Cui, M. Hetu, C. Wang, S.
Monro, R. D. Schaller, C. G. Cameron, B. Liu, S.
Kilina, S. A. McFarland, W. Sun, Dalton Trans. 2017,
In conclusion, we developed a novel protocol for
the synthesis of 3,4’-biquinoline derivatives from 2-
aminochalcones using tert-butoxide as a nucleophilic
promotor. The conjugate addition of tert-butoxide to
4
6, 8091, and references therein.
2-aminochalcones generated the corresponding
4
This article is protected by copyright. All rights reserved.