Organic Letters
Letter
realized. This protocol can be directly used in the synthesis of
bepotastine besilate with high TON and high ee, exhibiting
great potential in the practical synthesis of pharmaceuticals.
The hydrogenation of other heteroaryl ketones is underway in
our laboratory.
Table 2. [Rh(COD)Binapine]BF4 Catalyzed Asymmetric
Hydrogenation of Other Heteroaromatic Ketone
Derivatives
a
ASSOCIATED CONTENT
* Supporting Information
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S
The Supporting Information is available free of charge on the
Experimental details and characterization data (PDF)
AUTHOR INFORMATION
Corresponding Authors
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Author Contributions
†H.Y. and N.H. contributed equally
Notes
The authors declare no competing financial interest.
a
Unless otherwise noted, all reactions were carried out with a
[Rh(COD)Binapine]BF4/substrate ratio of 1:100 in 2 mL of CH2Cl2
ACKNOWLEDGMENTS
b
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at room temperature under hydrogen (8 bar) for 24 h. Determined
c
1
We are grateful for the financial support by a grant from Wuhan
University (203273463), “111” Project of the Ministry of
Education of China, and the National Natural Science
Foundation of China (Grant No. 21372179, 21432007,
21402145)
by H NMR. Determined by HPLC analysis using a chiral stationary
d
phase. 0.1 mmol of 1u was hydrogenated because the poor solubility
of 2-acetyyl benzothiazole in CH2Cl2. Isolated yield.
e
oxygen and sulfur atoms could not coordinate well with the
catalysts compared to the nitrogen. Then we synthesized the 2-
acetyl benzothiazole and 2-benzoyl benzothiazole, and the
hydrogenation results were in agreement with our initial
hypothesis. 2-Acetyl benzothiazole mostly converted to the
product with 92% ee, and 2-benzyoyl benzothiazole underwent
total conversion with 99% ee (Table 2, entries 3, 4).16
To demonstrate the practical utility of current methodology,
we synthesized the key intermediate of bepotastine besilate 2j
by asymmetric hydrogenation with excellent ee and high TON
(Scheme 3). As shown in Scheme 3, when the hydrogenation of
ketone 1j was conducted under S/C = 5000, we achieved an
89% yield and >99% ee.
REFERENCES
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In summary, we have developed an effective method for the
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Scheme 3. Asymmetric Synthesis of Bepotastine Besilate
with High TON
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