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RSC Advances
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DOI: 10.1039/C5RA26931H
ARTICLE
Journal Name
40 °C. Water (50 mL) was added and the reaction mixture was
extracted with EtOAc (2 × 50 mL). The combined organic layers
were dried over MgSO4 and concentrated to 5 mL under
reduced pressure. Petroleum ether was added to the organic
layers and kept at room temperature to give the pure product
3a as crystal in the yield of 90%.
enaminonitrile moiety attacking C=O to give intermediates B,
which eliminate a molecule of H2O to provide products 4.
Synthesis of DHPs 4. KTAs
mmol), β-enaminonitriles
were placed into a flask and the mixture was stirred for 5 min
at 90 °C in oil bath until were completely consumed. After
1
(0.5 mmol), aldehydes
2 (0.75
3
(0.5 mmol), and AcOH (0.5 mmol)
3
completion of the reaction as indicated by TLC (petroleum
ether/EtOAc, 4:1 v/v), the mixture was cooled to room
temperature, and the solid mixture was washed with DCM to
give the pure products
by MPLC.
4. Specially, compound 4k was obtained
Scheme 4 Plausible mechanism for the formation of 4.
Acknowledgements
This work was financially supported by the National Natural
Science Foundation of China (21372137 and 21572110) and
the Natural Science Foundation of Shandong Province
(ZR2014BM006).
Conclusions
In summary, we have successfully developed
a novel,
operationally simple one-pot three-component reaction
promoted by AcOH to synthesize novel multisubstituted DHPs.
The high efficiency and chemoselectivity, short reaction time
(within 5 min), free solvents, good functional compatibility,
and broad substrate scope render this reaction particularly
valuable for organic synthesis. This novel method not only
extends the application of KTAs in organic synthesis but also
provides an access to structurally diverse DHPs.
Notes and references
1
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Willems, K. Okolotowicz, P. Bushway, C. Wahlquist, C. Gilley,
Experimental section
M. Mercola and J. R. Cashman, J. Med. Chem., 2012, 55,
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General information
Unless otherwise specified, all reagents and solvents were
obtained from commercial suppliers and used without further
purification. All reagents were weighed and handled in air at
room temperature. Melting points were recorded on a RY-1
2
1
microscopic melting apparatus and were uncorrected. H NMR
spectra were recorded at 500 MHz and 13C NMR spectra were
3
4
recorded at 125 MHz by using
a Bruker Avance 500
spectrometer. Chemical shifts were reported in parts per
million (δ) relative to tetramethylsilane (TMS). HRMS was
performed on an Ultima Global spectrometer with an ESI
source. The X-ray single-crystal diffraction was performed on
Saturn 724+ instrument. The medium pressure liquid
chromatography (MPLC) purification was performed by the
Swiss company Büchi with reversed-phase column prepacked
with C-18 silica gel, mobile phase: MeOH-H2O 1:1 (v/v), flow
rate 2.5 mL/min. The substrate KTAs were prepared according
to a reported procedure.24
5
6
7
8
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Leelavathi, Eur. J. Med. Chem., 1994, 29, 975.
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K. Chu, V. S. Bhadti, K. J. Doshi, J. T. Etse, J. M. Gallo, F. D.
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9
General procedure
Synthesis of β-enaminonitriles (3a for example). Benzylcyanide (5
mmol), acetonitrile (5 mmol) in toluene (30 mL) was stirred in
a flask in oil bath, then powdered tBuOK (14 mmol) was added
to the stirring solution. The mixture was stirred for 10 min at
10 S. M. Alvarez, A. S. Miner, B. M. Browne and P. H. Ratz, Brit.
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4 | J. Name., 2012, 00, 1-3
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