10.1002/anie.202007403
Angewandte Chemie International Edition
RESEARCH ARTICLE
Although there is no definite evidences of a very small electron
donation from the naphthalene to Cu(II) d-orbital, the small
donation may induce the distribution change of the unpaired
electron in the Cu(II) d-orbital. These results may also suggest
the possibility of the ligand exchange between a triflate anion and
the 2-naphthyl moiety of L2 at the apical position of
L2•Cu(OTf)2•1a in a solution state.[34]
The enantioselectivity was not influenced by the presence of
excess NaOTf (Scheme 3). This result suggests that the p–Cu(II)
interaction was stable even in the presence of NaOTf. The bent
conformation of L2 might be stabilized by the p–Cu(II) electronic
interaction and the steric effect of L2. The Lewis acidity of Cu(II)
decreases due to strong p–Cu(II) electronic interaction but
increases due to the release of its counter anion (–OTf). Therefore,
appropriate p–Cu(II) electronic interaction and the steric effect is
important to appear Lewis acidity of Cu(II).
of a-hydrogen atoms, (3) the substrate scope has been widely
broadened, (4) the catalyst loading is reduced to 1.0~10 mol%,
(5) the reaction is fast (1~24 h) and scalable (0.3~6.0 mmol), and
(6) a-fluorinated products are converted to the corresponding
esters, secondary amides, tertiary amides, ketones, and alcohols
with almost no epimerization. In addition, the p–Cu(II) interaction
between 3-aryl-L-alanine amide and CuX2 has been clarified by
X-ray single-crystal analysis, the UV absorption difference
spectral analysis, and ESR analysis.[10–16,30–33] The further
application of these catalysts in other asymmetric reactions is
underway. Acknowledgements
Acknowledgements
Dr. Masahiro Hori, Dr. Yoshihiro Ogura, and Yanzhao Wang are
gratefully acknowledged for their contributions. And also Prof.
Jun Kumagai (Nagoya Univ.) is acknowledged for ESR analysis.
This work was financially supported by JSPS KAKENHI Grant
Numbers JP15H05755 (to K.I.) and JP15H05810 (to K.I.) for
Precisely Designed Catalysts with Customized Scaffolding. K.Y.
thanks the JSPS Research Fellowships for Young Scientists, and
K.N. and K.Y. thank the Program for Leading Graduate Schools:
IGER Program in Green Natural Sciences (MEXT).
Cu(OTf)2 (10 mol%)
L2 (11 mol%)
2,6-lutidine (1.0 equiv)
O
O
NaOTf (0 or 1.0 equiv)
Ph
Ph
N
N
N
+ F1 (1.1 equiv)
N
MS 4Å (100 mg)
F
MeCN (0.2 M), –40 °C, 6 h)
1b
2b
NaOTf (0 equiv)
NaOTf (1.0 equiv)
91% yield, 89% ee
80% yield, 87% ee
Scheme 3. The influence of sodium triflate on the enantioselective a-fluorination
of 1b
Keywords: p–cation • enantioselective • asymmetric catalysis •
a-fluorination • pyrazole
Based on these evidences of the p–Cu(II) interaction, the
proposed (Z)-enol-type transition state assembly is shown in
Figure 5. The 2-naphthalene ring of L2 may effectively shield the
re-face of the (Z)-enol form of 1b through p–Cu(II) interaction.
Thus, F+ reagent can approach the si-face of the (Z)-enol form of
1b to give (R)-2b. In contrast, an (E)-enol-type transition state is
disfavored due to the steric hindrance between the 5-methyl
group and phenyl group. In this a-fluorination, HX was produced
together with (R)-2b, and was neutralized with 2,6-lutidine.
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H
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i-Pr
X–
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(F1 or F2)
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Figure 5. Proposed transition-state assembly.
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Conclusion
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In summary, we have developed a highly enantio-, and site-
selective a-fluorination of N-acyl-3,5-dimethylpyrazoles catalyzed
by chiral p–Cu(II) catalysts. This new catalytic method is highly
useful even compared to those described in previous reports:[10–
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(2008).
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pseudo-Z conformation of N-acylpyrazoles increases the acidity
6
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