Catalytic Intermolecular C(sp3)-H Amination: Selective Functionalization of Tertiary C-H Bonds vs Activated Benzylic C-H Bonds

Article abstract of DOI:10.1021/jacs.1c03872

A catalytic intermolecular amination of nonactivated tertiary C(sp3)-H bonds (BDE of 96 kcal·mol-1) is reported for substrates displaying an activated benzylic site (BDE of 85 kcal·mol-1). The tertiary C(sp3)-H bond is selectively functionalized to afford α,α,α-Trisubstituted amides in high yields. This unusual site-selectivity results from the synergistic combination of Rh2(S-Tfpttl)4, a rhodium(II) complex with a well-defined catalytic pocket, with tert-butylphenol sulfamate (TBPhsNH2), which leads to a discriminating rhodium-bound nitrene species under mild oxidative conditions. This catalytic system is very robust, and the reaction was performed on a 50 mmol scale with only 0.01 mol % of catalyst. The TBPhs group can be removed under mild conditions to afford the corresponding NH-free amines.

Full text of DOI:10.1021/jacs.1c03872

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Catalytic Intermolecular C(sp3)−H Amination: Selective
Functionalization of Tertiary C−H Bonds vs Activated Benzylic C−H
Bonds
Erwan Brunard,‡ Vincent Boquet,‡ Elsa Van Elslande, Tanguy Saget, and Philippe Dauban*
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ABSTRACT: A catalytic intermolecular amination of nonactivated tertiary C(sp3)−H bonds (BDE of 96 kcal·mol−1) is reported for
substrates displaying an activated benzylic site (BDE of 85 kcal·mol−1). The tertiary C(sp3)−H bond is selectively functionalized to
afford α,α,α-trisubstituted amides in high yields. This unusual site-selectivity results from the synergistic combination of Rh2(S-
tfpttl)4, a rhodium(II) complex with a well-defined catalytic pocket, with tert-butylphenol sulfamate (TBPhsNH2), which leads to a
discriminating rhodium-bound nitrene species under mild oxidative conditions. This catalytic system is very robust, and the reaction
was performed on a 50 mmol scale with only 0.01 mol % of catalyst. The TBPhs group can be removed under mild conditions to
afford the corresponding NH-free amines.
he design of site-selective C(sp3)−H functionalization
designed for the amination of benzylic40−42 (BDE of 85 kcal
Treactions is a great challenge with important applications mol−1) or tertiary43,44 (BDE of 96 kcal mol−1) C(sp3)−H
in organic synthesis and medicinal chemistry.1−3 A first general
approach to meet this goal is based on directed functionaliza-
bonds. However, in the case of substrates displaying both
C(sp3)−H bonds, the more activated benzylic site is always
preferentially functionalized irrespective of the sulfamate41 or
tion reactions that include the use of coordinating groups or
the metal catalyst42 (Scheme 1a). The same trend determined
by the relative BDE is also observed in intermolecular C(sp3)−
H amination with azides45−50 or involving iodine catalysis51
(Scheme 1b).
intramolecular reactions.4−9 These processes convert proximal
C−H bonds with high levels of selectivity, but substrates
devoid of such a directing effect remain out of their scope.
Thus, undirected C−H functionalization has emerged as a
conceptually different strategy.10 The site-selectivity for such
reactions is mostly driven by inherent parameters of the
substrates, i.e., the bond dissociation energy (BDE) of C−H
bonds or polar effects.11 However, unactivated C−H bonds
remain inaccessible, so that other undirected processes under
catalyst and/or reagent control must be developed to
overcome these limitations.12−14 This challenging approach
should enhance the scope of C−H functionalization reactions
as shown by the reports on alkane borylation,15 carbene
insertion,16−18 C−H oxidation,19−21 or in biocatalysis.22
Catalytic C(sp3)−H amination reactions have emerged as
valuable synthetic tools in the 2000s.23−26 Significant progress
has been achieved through the design of catalytic nitrene C−H
insertions using azides,27 N-oxy reagents,28 or iminoiodi-
nanes.29−34 The latter, particularly, have received much
attention with applications in total synthesis and medicinal
chemistry. With respect to the site-selectivity issue, nitrene
C(sp3)−H insertion reactions preferentially proceed at
benzylic or tertiary positions.30 However, what happens
when these two reacting sites are in competition within the
same substrate?
Actually, examples of undirected C(sp3)−H functionaliza-
tion reactions favoring nonactivated alkyl C−H bonds in the
presence of an activated secondary benzylic center remain
extremely rare.52,53 In this context, we wish to report a novel
catalyst- and reagent-controlled intermolecular C−H amina-
tion of tertiary centers in the presence of benzylic positions
with T/B ratio of >25:1 (Scheme 1c). The reaction gives
access to a variety of α,α,α-trisubstituted primary amines that
are important motifs in medicinal chemistry.54
With the aim of favoring the amination of a tertiary C−H
bond in the presence of a secondary benzylic center, we turned
our attention to dirhodium(II) tetracarboxylates derived from
α-N-(phthaloyl)amino acids. Such complexes are known to
adopt an α,α,α,α-conformation with all the amino acid side
chains oriented on one face and the imido groups on the
other,55−57 as shown by the X-ray structure of the Rh2(S-
tfptad)4 (Figure 1).58 Thus, the phthalimido groups induce the
formation of a tunable C4-symmetrical hydrophobic pocket.
Such a pocket cannot be found in the Rh2(esp)2 complex
Received: April 13, 2021
Published: April 26, 2021
Whereas solutions relying on catalyst modification were
developed to address this chemoselectivity issue in intra-
molecular C(sp3)−H amination reactions,35−39 the selectivity
in intermolecular reactions with competitive substrates has not
yet been addressed. Indeed, several catalytic systems have been
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Scheme 1. Site-Selectivity in Catalytic Intermolecular
Scheme 2. Screening of Sulfamate/Rhodium(II) Complex
Combinations
a
C(sp3)−H Amination Reactions
Figure 1. Structures of the Rh2(S-tfptad)4 and Rh2(esp)2 complexes.
a
Reaction conditions: isoamylbenzene (0.20 mmol), sulfamate (0.24
mmol), PhI(OPiv)2 (0.40 mmol), and rhodium catalyst (1 mol %) in
pivalonitrile (0.5 mL) at rt. Isolated yields.
designed for intermolecular C−H amination.30,40 Importantly,
its size and shape can be fine-tuned by changing either the
phthaloyl substitution or the side chain. In combination with a
sterically demanding nitrene precursor, we thus expected that
the pocket could host a discriminating rhodium-bound nitrene
species able to induce novel site-selective reactions.
sulfamates derived from phenols having a bulky group in the
para position, with an optimal ratio >25:1 being obtained with
the 4-tert-butylphenol-derived sulfamate TBPhsNH2 2.
The TBPhSNH2 reagent 2, thus, was selected for a parallel
evaluation of the rhodium catalysts to determine the key
parameters necessary to achieve high yield and site-selectivity.
Modification of the nitrogen protecting group of the amino
acid ligand first revealed that a perfluorinated phthaloyl motif
was required to maintain a T/B ratio of >25:1. On the other
hand, the steric bulk of the amino acid side chain also proved
to have an influence. The best results both in terms of yields
and T/B ratio were obtained with the tert-butyl and the
adamantyl derivatives. Importantly, Rh2(S-tfpttl)4 1 is
commercially available and easily synthesized in two high-
yielding steps from tert-leucine so that it was chosen for the
rest of the study.
With this hypothesis in mind, we started our investigations
by screening several combinations of nitrene precursors and
rhodium(II) complexes for the catalytic C−H amination of
isoamylbenzene in pivalonitrile as this solvent led to the
highest conversions (Scheme 2). We first focused on
sulfamates, which were easily prepared by reacting the
corresponding alcohols with sulfamoyl chloride,59 in the
presence of the readily available dirhodium(II) tetrakis[N-
tetrafluorophthaloyl-(S)-tert-leucinate] complex (Rh2(S-
40
tfpttl)4) 1. The use of aliphatic sulfamates such as TcesNH2
or the pentafluorobenzyl sulfamate (PfbsNH2),58 both
previously developed for catalytic benzylic C(sp3)−H amina-
tion, was not satisfactory as the T/B ratio did not exceed 3:1.
By contrast, we could observe the preferential amination of
tertiary centers by running the reaction with aromatic
sulfamates. In particular, high T/B ratios were obtained with
It is worth pointing out that the reaction performed with
TBPhsNH2 in the presence of the Rh2(esp)2 complex led to a
T/B ratio of 1:1, as did the previous combination of TcesNH2
with Rh2(S-tfpttl)4. Together, these results clearly demonstrate
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the critical role of both the sulfamate and the rhodium complex
on the course of the reaction. Finally, a screening of additional
reaction parameters showed that similar levels of reactivity
could be achieved with only 1.4 equiv of the cheaper iodine
oxidant PhI(OAc)2 at a substrate concentration of 1 M, a
relevant observation with the aim of performing reactions on a
larger scale (see Table S1).
Scheme 4. Selective Amination of Challenging Substrates
The optimized conditions were applied to a wide range of
isobutyl and isoamyl derivatives used as the limiting reagents.
The combination of 1.2 equiv of sulfamate 2 and 1 mol % of
the rhodium(II) complex 1 led to the isolation of the
corresponding tertiary amides 3−20 with yields of up to
96% and high T/B ratio generally greater than 25:1 as
1
indicated by H NMR of the crude mixture (Scheme 3). The
Scheme 3. Scope of the Selective Amination of Tertiary
a
C(sp3)−H Bonds
was always selectively functionalized in catalytic intermolecular
C(sp3)−H amination.60−62 Pleasingly, the isobutyl derivative
24T was obtained in 77% yield with very high levels of
selectivity together with only traces of the diaminated product
24B′. In contrast, when the isoamyl homologue 25 was
reacted, the amination of the tertiary site was slightly favored.
The reactivity of ester 26 demonstrated that the selectivity is
maintained between competitive remote positions. This was
applied to the amination of the isomenthol derivative 27 that
displays three tertiary centers and one secondary benzylic site.
In this case, the amination proceeds preferentially at the
equatorial tertiary C(sp3)−H bond of the cyclohexyl ring.
However, depending on the catalyst configuration, a match/
mismatch effect was observed and a better T/B ratio of 7.3:1
was obtained with the (R)-catalyst. Importantly, a switch in the
sulfamate reagent favors the amination of the benzylic position,
a fundamental result with the aim of producing molecular
diversity.
a
Reaction conditions: substrate (0.5 mmol), sulfamate (0.6 mmol),
PhI(OAc)2 (0.7 mmol), and rhodium catalyst (1 mol %) in
pivalonitrile (0.5 mL) at rt. Isolated yields.
reaction tolerates both electron-withdrawing (5, 7, 10, 15, 17,
18) and electron-donating (4, 14, 16) substituents at the para,
meta, or ortho positions. For substrates 4 and 14 in which the
benzylic position is even more activated by a p-MeO
substituent, the amination of the tertiary C(sp3)−H bond
was still favored, respectively, with a T/B ratio of >25:1 and
6.6:1. In addition, regioselective amination of the unactivated
tertiary site proceeds efficiently in the presence of a
competitive tertiary benzylic C(sp3)−H bond as shown by
products 12 and 20. The reaction was successfully extended to
the substituted higher homologue 21 of isoamylbenzene or
cyclic products such as benzylcycloheptane 22. Finally,
compound 23 highlights that a tertiary center preferentially
reacts in the presence of propargylic C−H bonds.
Ultimately, the result obtained with ibuprofen methyl ester
28 perfectly illustrates the unusual chemoselectivity of our
catalyst- and reagent-controlled reaction. While previously
reported conditions led to mixtures of products or the
exclusive formation of the benzylic amine with yields lower
than 72%, we isolated the tertiary amide 28T with an excellent
yield of 90% and a T/B ratio >25:1.
We then studied the case of more challenging substrates in
terms of site-selectivity (Scheme 4). Attention was first paid to
substrates having a p-ethyl substituent, since this alkyl group
Finally, the efficiency and practicality of the catalytic
C(sp3)−H amination reaction are showcased by the two-step
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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
amide 3T (see the Supporting Information for the X-ray
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
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c03872.
Experimental procedures, characterization data, spectra
for all new compounds, and crystallographic data (PDF)
Accession Codes
CCDC 2059571 and 2074077 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
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
complex 1 (see the Supporting Information for details). The
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
■
Corresponding Author
Philippe Dauban − Université Paris-Saclay, CNRS, Institut de
Chimie des Substances Naturelles, 91198 Gif-sur-Yvette,
France; orcid.org/0000-0002-1048-5529;
Email: philippe.dauban@cnrs.fr
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:
https://pubs.acs.org/10.1021/jacs.1c03872
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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