Organic Letters
Letter
Boc-hydrazine as cheap starting materials. In comparison to
conventional methods, this approach represents great progress
from the perspective of step- and atom-economy. This reaction
is highly compatible with alcohols bearing alkanes, alkenes,
aromatics with varieties of substituents, and even heterocycles.
Meanwhile, this reaction is scalable and very operationally
simple without any elaborate procedures. The corresponding β-
hydrazino alcohols could be obtained by sequential reduction in
excellent enantioselectivity (up to 98% ee). We hope that this
mild and efficient method will facilitate the late-stage
asymmetric hydrazination of complicated molecules as well as
pharmaceuticals. To clarify the mechanism, further inves-
tigations are underway.
Scheme 3. (a) Gram-Scale Preparation; (b) Facile Synthesis
of N-Boc-L-Phenylalaninol; (c) Control Experiment
ASSOCIATED CONTENT
* Supporting Information
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S
The Supporting Information is available free of charge on the
Experimental procedures, characterization data, and
copies of 1H and 13C NMR spectra and HPLC
alcohol component were tolerated, even those with sterically
demanding substituents (3b, 3f). Additionally, alcohols 1
attached with internal and terminal olefins smoothly underwent
enantioselective hydrazination without further oxidation or
degradation (3h, 3i). This protocol also accommodated a wide
range of alcohols 1 containing aromatics. The absolute
configuration of 3j was assigned as S by analogy.3k In spite of
the steric hindrance, 3-phenylbutan-1-ol still gave the
hydrazination product 3k with moderate yield and excellent
enantioselectivity. Aromatic halides, such as fluorine, chlorine,
and bromine on the alcohol component, were amenable to this
hydrazination process and so were aromatics with tosyloxy,
amide, and methoxy (3l, 3r). Surprisingly, aniline, which readily
undergoes aerobic oxidative dehydrogenative coupling with
nucleophiles under copper-catalyzed conditions, as many
reports have demonstrated,12 also underwent the hydrazination
reaction (3q). Moreover, alcohol 1v bearing the readily
oxidizable thioether also furnished the enantioenriched adduct
3v. This reaction proceeded well with alcohols possessing
heterocycles (1w, 1x), to provide a new entry to complicated
building blocks.
AUTHOR INFORMATION
Corresponding Author
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful for financial support from National Natural
Science Foundation of China (Grant No. 21272024).
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REFERENCES
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To demonstrate the practical utility of this protocol, n-butyl
alcohol was hydrazinated on a multigram scale and the product
3b was obtained with moderate yield (58%) and high
enantioselectivity (96% ee) (Scheme 3a). Of particular note
is that this reaction procedure was operationally simple and no
precautions were needed with regards to moisture exclusion.
Furthermore, the simple transformation method of product 3j
to L-phenylalaninol was established. Deprotection of the Boc
group of 3j, followed by reduction cleavage of the N−N bond
with the aid of Raney Ni and H2, and finally protection by Boc
group furnished the N-Boc-L-phenylalaninol in 57% yield with
the unchanged enantiopurity over three steps (Scheme 3b).
The absolute configuration of N-Boc-L-phenylalaninol was
assigned as (S).13 Control experiments showed that the absence
of TEMPO did not make the reaction run successfully and only
trace product 3a was achieved when the reaction was
performed under a N2 atmosphere, substantiating that air was
the actual oxidant (Scheme 3c). A plausible synergistic catalytic
mechanism merging of aerobic dual oxidation with asymmetric
In summary, we have developed a new approach to prepare
enantioenriched β-hydrazino alcohols using alcohols and N-
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