Journal of the American Chemical Society
Communication
synthesis of the appetite suppressant phentermine on a gram
scale.63,64 Starting from 10 mmol of 3 in the presence of only
100 ppm of the rhodium complex 2, the crystalline tertiary
structure) was isolated in 91% yield and a T/B ratio of >25:1
(Scheme 5). The use of 100 ppm of the catalyst on a 50 mmol
amination,58 these results highlight the possibility to uncover a
set of various conditions for the selective amination of different
classes of C(sp3)−H bonds by varying both the rhodium
catalyst and the nitrene precursor. We are currently exploring
this strategy to obtain new site-selectivity and to apply the
C(sp3)−H amination reaction to the late-stage derivatization
of complex natural products.
Scheme 5. Gram-Scale Synthesis of Phentermine
ASSOCIATED CONTENT
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sı
* Supporting Information
The Supporting Information is available free of charge at
Experimental procedures, characterization data, spectra
for all new compounds, and crystallographic data (PDF)
Accession Codes
crystallographic data for this paper. These data can be obtained
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
scale led to 3T in 80% yield. The tert-butylphenyloxysulfonyl
group could then be removed under mild conditions with
pyridine in a 2:1 mixture of acetonitrile and water at 75 °C.
The free amine 29 was obtained in 95% yield after a simple
extractive workup that also allows the full recovery of 4-tert-
butylphenol.
These results demonstrate that the combination of Rh2(S-
tfpttl)4 1 and sulfamate TBPhsNH2 2 allows us to override the
higher reactivity of benzylic C(sp3)−H bonds under C−H
amination reaction conditions. Hypotheses to rationalize this
observation can be proposed from the X-ray structure of
latter confirms that it adopts the aforementioned all-up
conformation with the four phthalimido groups on the same
side. Thus, they shape a pocket that is wider than the other one
delineated by the tBu groups so that the nitrene would bind to
that face of the catalyst. The presence of the fluorine atoms
also induces secondary interactions with the imide carbonyl
groups and the protons α to the carboxylic acid function. This
contributes to the rigidification of the tight pocket that is
maintained in solution.56,65 Such a tightening effect is
supported by the lower T/B ratio of 10:1 obtained with the
nonhalogenated complex Rh2(S-pttl)4. Accordingly, upon
coordination of the nitrene, the pocket would be poorly
accessible to the benzylic motif of the substrate, thereby
disfavoring the benzylic C−H amination reaction for steric
reasons. A test reaction with propylbenzene was performed to
give support to this hypothetical scenario. Gratifyingly, our
catalyst system was found to be sufficiently discriminating to
favor the amination of the nonactivated secondary C(sp3)−H
bond (BDE of 98 kcal·mol−1) in the presence of the secondary
benzylic site (Scheme 6).
AUTHOR INFORMATION
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Corresponding Author
Philippe Dauban − Université Paris-Saclay, CNRS, Institut de
Chimie des Substances Naturelles, 91198 Gif-sur-Yvette,
Authors
Erwan Brunard − Université Paris-Saclay, CNRS, Institut de
Chimie des Substances Naturelles, 91198 Gif-sur-Yvette,
France
Vincent Boquet − Université Paris-Saclay, CNRS, Institut de
Chimie des Substances Naturelles, 91198 Gif-sur-Yvette,
France
Elsa Van Elslande − Université Paris-Saclay, CNRS, Institut
de Chimie des Substances Naturelles, 91198 Gif-sur-Yvette,
France
Tanguy Saget − Université Paris-Saclay, CNRS, Institut de
Chimie des Substances Naturelles, 91198 Gif-sur-Yvette,
France
Complete contact information is available at:
Author Contributions
‡E.B. and V.B. contributed equally.
In conclusion, this study demonstrates that the amination of
nonactivated C(sp3)−H bonds can be efficiently performed in
the presence of an electronically activated benzylic center. Key
to the success of the strategy is the selectivity control by a
discriminating rhodium-bound nitrene species. Together with
our previously reported protocol for enantioselective benzylic
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This article is dedicated to Prof. Barry M. Trost on the
occasion of his 80th birthday. We wish to thank the French
National Research Agency (Program No. ANR-11-IDEX-0003-
02, CHARMMMAT ANR-11-LABX-0039, fellowship to E.B.;
Scheme 6. Selective Amination of Propylbenzene
̀
Program No. ANR-19-CE07-0043-02), the Ministere de
l’Enseignement Supérieur et de la Recherche (fellowships to
E.B. and V.B.), and the ICSN for their support. Dr. Benjamin
Darses and Dr. Pascal Retailleau are gratefully acknowledged
for fruitful discussions.
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J. Am. Chem. Soc. 2021, 143, 6407−6412