Catalytic Enantioselective Intermolecular Benzylic C(sp3)?H Amination

Article abstract of DOI:10.1002/anie.201902882

A practical general method for asymmetric intermolecular benzylic C(sp³)?H amination has been developed by combining the pentafluorobenzyl sulfamate PfbsNH₂ with the chiral rhodium(II) catalyst Rh₂(S-tfptad)₄. Various substrates can be used as limiting components and converted to benzylic amines with excellent yields and high levels of enantioselectivity. Additional key features for the reaction are the low catalyst loading and the ability to remove the Pfbs group under mild conditions to give NH-free benzylic amines.

Full text of DOI:10.1002/anie.201902882

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Accepted Article
Title: Catalytic Enantioselective Intermolecular Benzylic C(sp3)—H
Amination
Authors: Philippe Dauban, Ali Nasrallah, Vincent Boquet, Alexandra
Hecker, Pascal Retailleau, and Benjamin Darses
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201902882
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10.1002/anie.201902882
Angewandte Chemie International Edition
COMMUNICATION
Catalytic Enantioselective Intermolecular Benzylic C(sp3)—H
Amination
Ali Nasrallah, Vincent Boquet, Alexandra Hecker, Pascal Retailleau, Benjamin Darses, and Philippe
Dauban[*]
Dedicated to Paul Müller on the occasion of his 80th birthday
Rivastigmine
Abstract: A practical general method for asymmetric intermolecular
benzylic C(sp3)—H amination has been developed by combining the
pentafluorobenzyl sulfamate PfbsNH2 with the chiral rhodium(II)
catalyst Rh2(S-tfptad)4. Various substrates can be used as limiting
components and converted to benzylic amines with excellent yields
and high levels of enantioselectivity. Additional key features for the
reaction are the low catalyst loading and the ability to remove the Pfbs
group under mild conditions to give NH-free benzylic amines.
N
F
HN
N
O
Cinacalcet
O
CF3
NH2
NH2
O
Indaziflam
H
N
N
N
N
N
N
N
New small N-contaning
NH2
building blocks
Chiral benzylic amines are useful nitrogen compounds that can
be found in the structure of pharmaceuticals (Rivastigmine,
Cinacalcet), agrochemicals (Indaziflam), chiral auxiliaries and
ligands for asymmetric synthesis (Figure 1).[1] They are also new
motifs that have been incorporated in recent leads to improve their
“drug-likeness”.[2] Such a key role for these nitrogen-containing
molecules has translated to the design of catalytic asymmetric
C—N bond forming reactions.[3]
Catalytic enantioselective C(sp3)—H functionalization reactions
have recently emerged as efficient tools for the synthesis of
optically pure organic compounds. The asymmetric conversion of
a C—H bond is a great challenge, and though this field of
investigation is still in its infancy, significant achievements have
been reported.[4] The prevalence of nitrogen in life sciences, in
this context, has motivated the search for conditions to develop
catalytic C(sp3)—H amination reactions.[5] Notable progress has
been made through the development of catalytic nitrene C(sp3)—
H insertions.[6] The design of chiral transition metal complexes,
then, has led to the discovery of catalytic asymmetric C(sp3)—H
amination reactions that mostly involve nitrenes generated from
azides, or in the presence of iodine(III) oxidants.[7]
Figure 1. Chiral benzylic amines in life sciences.
reported new catalysts for the asymmetric benzylic C(sp3)—H
amination. The latter, however, proceed under substrate-excess
conditions and, in most cases, with limited enantiocontrol.[13]
Inspired by the Rh2(esp)2 complex,[14] Bach has developed a
supramolecular approach to address this issue,[15] but again, the
yields and enantiomeric excesses are moderate while the scope
is limited to 3-benzylquinolones. In this context, the use of azides
in combination with a Ru-salen complex[16] or an engineered iron-
haem enzyme[17] has afforded relevant solutions. However, there
is still room for improvement as these processes have also their
limitations such as the need of an excess of substrate, a high
catalyst loading or low yields in some cases.
In this manuscript, we, thus, wish to report a catalytic asymmetric
intermolecular C(sp3)—H amination that applies to a wide range
of benzylic substrates (Scheme 1). The reaction, which relies on
the design of a new benzylic sulfamate as a nitrene precursor and
chiral rhodium(II) complexes, occurs under stoichiometric
conditions on a mmole scale and with a low catalyst loading.
Efficient intramolecular processes have been reported in the
presence of chiral Rh, Ru, Ir, and Co complexes or mutated P450
enzymes. The internal delivery of a tethered nitrene generally
allows the reaction to proceed with excellent yields and
enantioselectivities either from sulfamates[8] or sulfonyl azides.[9]
By contrast, the corresponding intermolecular reaction has been
less explored. Following the pioneering study of Müller with chiral
rhodium(II) complexes,[10] Hashimoto[11] and Davies[12] have
benzylic sulfamate
0.1 mol% Rh2L*4
easy
NHR1
H H
Ar
H
deprotection H NH2
R
Ar
R
Ar
R
Iodine(III) oxidant
1 equiv.
mmole scale
> 20 examples
Scheme 1. High yielding enantioselective intermolecular C(sp3)—H amination.
[*]
A. Nasrallah, V. Boquet, A. Hecker, Dr. P. Retailleau, Dr. B. Darses,
Dr. P. Dauban
Our studies have started with the commercially available chiral
Institut de Chimie des Substances Naturelles, CNRS UPR 2301,
Univ. Paris-Sud, Université Paris-Saclay, 1, av. de la Terrasse,
91198 Gif-sur-Yvette (France).
E-mail: philippe.dauban@cnrs.fr
Dr. B. Darses
complex
dirhodium(II)
tetrakis[N-tetrafluorophtaloyl-(S)-tert-
leucinate] (Rh2(S-tfpttl)4) 4a. The reaction of ethylbenzene 1a,
used as the limiting reagent, with the benzylic sulfamate 3a
proceeds in 73% yield and with an enantiomeric ratio (e.r.) of 4:1
(entry 1, Table 1). This preliminary result, thus, led us to consider
benzylic sulfamates as highly reactive nitrene sources. These
sulfamates have been rarely considered as nitrene precursors so
Université Grenoble Alpes, Département de Chimie Moléculaire,
CNRS UMR-5250, 38058 Grenoble (France)
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/anie.201902882
Angewandte Chemie International Edition
COMMUNICATION
far,[18] and are easily accessible from the corresponding alcohols
following reaction with sulfamoyl chloride.[19]
Table 2. Screening of the dirhodium(II) complexes.[a]
F
F
F
cat.
O
Rh2L*4
4
H
H
O O
F
NHPfbs
H
Table 1. Screening of sulfamates with Rh2(S-tfpttl)4.[a]
+
S
H
Ph
C6F5
O
NH2
N
O
R
2 equiv.
Ph
F
F
F
O
1 equiv. 1.2 equiv. PfbsNH2 PhI(OPiv)2
2ae
O
O
2 mol%
Rh2(S-tfpttl)4 4a
O
O
1a
3e
C6H5CF3, rt
H
H
O
O
S
4a: R = t-Bu
4b: R = Adamantyl
4c: R = 3,5-dimethyladamantyl
F
Rh Rh
HN
OR
H
+
S
N
O
t-Bu
H
Ph
RO
NH2
2 equiv.
PhI(OPiv)2
Benzene, rt
Ph
O
2a-
O
1 equiv.
1a
1.2 equiv.
4a
Entry
R (L) (mol %)
Yields of 2ae
[%][b]
e.r.[c]
Rh Rh
3
1
Me (S-tfpta) (2)
i-Pr (S-tfptv) (2)
Bn (S-tfptpa) (2)
t-Bu (S-tfpttl) (2)
t-Bu (S-tfpttl) (2)
33
59
-
-
Entry
Sulfamate
Yields of 2a- [%][b]
e.r.[c]
2
78:22
-
O
S
O
1
2
2aa: 73
2ab: 73
80:20
75:25
O
NH2
3
3a: R1 = H
3b: R1 = NO2
R1
4
97
82
92
90
90
82
92
80
82:18
87:13
84:16
89:11
89:11
91:9
82:18
86:14
O
O
5[d]
6
Cl
S
O
NH2
3
2ac: 86
80:20
Adamantyl (S-tfptad) (2)
Adamantyl (S-tfptad) (2)
Adamantyl (S-tfptad) (1)
Adamantyl (S-tfptad) (0.1)
3,5-Dimethyladamantyl (2)
3,5-Dimethyladamantyl (2)
3c
Cl
7[d]
8[d]
9[d]
10
11[d]
F
O
O
R1
4[d]
5[d]
2ad: 95
2ae: 97
80:20
81:19
S
O
NH2
3d: R1 = H
3e: R1 = F
R1
F
R1
R1
6
7
2af: 34
2ag: 39
69:31
77:23
O
O
S
3f: R1 = H
3g: R1 = F
O
NH2
R1
[a] Reaction conditions unless otherwise stated: A mixture of 1a (0.10 mmol),
3e (0.12 mmol), and catalyst 4 (2 mol%) in trifluorotoluene (1 mL) was stirred at
rt for 16 h. [b] Isolated yields after flash chromatography. [c] Determined by
chiral HPLC (Daicel Chiralpak IA-5 or IC-5). [d] Reaction performed at -10 °C.
8[e]
9
2ah: 75
2ai: 80
81:19
78:22
O
O
3h: R1 = CCl3
S
R1
3i: R1 = CF2CF3
NH2
O
[a] Reaction conditions: A mixture of 1a (0.10 mmol), 3 (0.12 mmol), and catalyst
4a (2 mol%) in benzene (1 mL) was stirred at rt for 16 h. [b] Isolated yields after
flash chromatography. [c] Determined by chiral HPLC (Daicel Chiralpak IC-5). [d]
Reaction performed in triplicate. [e] Reaction performed in duplicate.
The screening revealed that the enantioselectivity increases with
ligands having bulkier side chains. Thus, switching from a methyl
to a t-butyl substituent allowed for improving both the yield and
the e.r. (entries 1-4). This observation led us to prepare sterically
more demanding ligands having either an adamantyl or a 3,5-
dimethyladamantyl side chain.[23] In both cases, excellent yields
were obtained, however, the Rh2(S-tfptad)4 4b proved to be
slightly more efficient in terms of enantioselectivity (entries 6 and
10). Further improvement was achieved by running the reaction
at -10 °C (entries 5, 7 and 11) with the Rh2(S-tfptad)4 complex 4b
affording again the highest e.r..[24] Finally, the same levels of
reactivity and selectivity were maintained with catalyst loadings
as low as 1 mol% or 0.1 mol% (entries 8 and 9). The conditions
of entries 8 and 9, therefore, were chosen to investigate the scope
of the asymmetric benzylic C(sp3)—H amination (Scheme 2).[25]
The optimal conditions have been applied to a wide range of
substrates. The use of 1 mol% of complex 4b led to isolate the
corresponding products with yields of up to 99% and e.r. of up to
92:8. On the other hand, the reactions involving 0.1 mol% of 4b
were performed on the mmole scale and generally led to slightly
improve the e.r. of up to 94.5:5.5,[26,27] though the yields, in some
cases, were reduced by roughly 5-15%.
Various sulfamates were evaluated for the amination of
ethylbenzene catalyzed by 4a. The screening confirmed the high
reactivity of benzylic sulfamoyl nitrenes, the highest yields being
obtained in the presence of halogen-substituted derivatives
(entries 3-5). Gratifyingly, the pentafluorobenzyl sulfamate
(PfbsNH2) 3e led us to isolate the expected product 2ae with an
excellent yield of 97% and an e.r. of 81:19 and was chosen as the
nitrene precursor for the subsequent studies.[20] The screening
also included sulfamates 3f-i previously designed by Du Bois for
intermolecular C(sp3)—H amination (entries 6-9).[21] However,
under these conditions, all proved to react less efficiently.
Modification of the reaction parameters, then, led us to evaluate
the influence of the solvent on the yield and enantioselectivity. We,
thus, found that the best result was provided by the use of
trifluorotoluene, which afforded 2ae with a yield of 92% and an e.r.
of 82:18 (See Table S1, supporting information). In parallel,
various dirhodium(II) complexes were screened thereby revealing
the critical influence of the perfluorinated phthaloyl protecting
group on the enantioselectivity (See Scheme S1, supporting
information).[22] We, then, decided to study the influence of the
amino acid side chain on the course of the reaction (Table 2).
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10.1002/anie.201902882
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COMMUNICATION
F
F
F
1.2 equiv. PfbsNH2
0.1 or 1 mol%
Rh2(S-tfptad)4 4b
excellent chemoselectivity was observed with the derivatives of
sulbactam 2ve, and cinnamic acid 2we as the reaction only
proceeds at the benzylic ethyl moiety.
H
H
O
NHPfbs
F
R2
H
R1
R2
N
O
2 equiv. PhI(OPiv)2
C6H5CF3, -10 °C
R1
O
1 equiv.
2
O
Rh2(S-tfptad)4
1
4b
Rh Rh
O
S
H
O
OMe
Ph
N
0.1 mol% 4b
1 mol% 4b
O
O
2ae: R1 = H
82% - e.r. 91:9
83% - e.r. 91:9
65% - e.r. 90:10
62% - e.r. 88:12
76% - e.r. 89:11
85% - e.r. 92:8
85% - e.r. 91:9
80% - e.r. 92:8
40% - e.r. 90:10
57% - e.r. 88:12
84% - e.r. 90.5:9.5
83% - e.r. 92:8
90% - e.r. 94.5:5.5
82% - e.r. 92.5:7.5
90% - e.r. 89:11
93% - e.r. 89:11
80% - e.r. 88:12
76% - e.r. 87:13
90% - e.r. 89:11
92% - e.r. 91:9
72% - e.r. 90:10
2be: R1 = OMe
2ce: R1 = Cl
2de: R1 = Br
2ee: R1 = N3
2fe: R1 = t-Bu
2ge: R1 = i-Pr
2he: R1 = Me
2ie: R1 = CF3
O
O
O
NHPfbs
NHPfbs
H
MeO2C
NHPfbs
2ue
2ve
57% - d.r. 90:10
2we
78% - e.r. 85:15
R1
65% - d.r. >98:2
Figure 2. Chemo- and stereoselective late-stage C(sp3)—H amination.
NHPfbs
2je: R1
2ke: R1 = Ph
=
57% - e.r. 88:12
90% - e.r. 90:10
97% - e.r. 92:8
99% - e.r. 90:10
88% - e.r. 91:9
TMS
CH2
Finally, the C(sp3)—H amination reaction can be performed on a
gram-scale with equal efficiency. Starting from 5 mmoles of 1m,
the corresponding product 2me was isolated in 90% yield and with
an e.r. of 94.5:5.5 (Scheme 3). Fundamentally, an X-ray structure
of compound 2me led us to conclude that the use of the Rh2(S-
tfptad)4 complex induces the formation of the (S)-enantiomer (see
supporting information). We, then, demonstrated the ability to
cleave the sulfamoyl group under mild conditions. Treatment of
2me with pyridine in a 2:1 mixture of acetonitrile and water at
75 °C affords the free amine 5 in quantitative yield.
2le: R1 = p-MeOC6H4
2me: R1 = p-MeC6H4
2ne: R1 = p-t-BuC6H4
NHPfbs
2oe: R1 = OMe
81% - e.r. 81.5:18.5 80% - e.r. 81:19
74% - e.r. 81:19
2pe: R1 = p-MeOC6H4
2qe: R1 = p-t-BuC6H4
R1
76% - e.r. 85:15
OMe
NHPfbs
2re
40% - e.r. 81:19
MeO
MeO
NHPfbs
NHPfbs
NH2
2se
2te
56% - e.r. 83:17
62% - e.r. 87:13
1.2 equiv. PfbsNH2
1 mol% Rh2(S-tfptad)4
20 equiv. Pyridine
NHPfbs
2 equiv. PhI(OPiv)2
C6H5CF3, -10 °C
MeCN:H2O 2:1
75 °C, 4 h
5
1m
2me
quantitative
yield
5 mmoles
0.98 g
2.12 g
90% yield
e.r. 94.5:5.5
O
Scheme 3. Gram-scale reaction and removal of the Pfbs protecting group.
Scheme 2. Scope of the asymmetric benzylic C(sp3)—H amination reaction.
The C(sp3)—H amination was found to tolerate both electron-
withdrawing (2ce, 2de, 2ie) and electron-donating (2be, 2he, 2k-
ne) substituents. However, higher conversions are observed with
electron-rich substrates that better react with the electrophilic
rhodium-bound nitrene. Increasing the bulkiness of the
substituents proved beneficial as the highest e.r. were obtained in
the presence of a t-butyl or an aryl group (compounds 2fe, 2k-ne).
Also worth of mention is the complete regioselectivity in favor of
the ethyl substituent observed in the case of compounds 2ge and
2je for which two benzylic positions are available. Substrates with
longer side chains were also investigated and the corresponding
compounds 2o-re could be isolated again with good yields in the
40-81% range though the e.r. were found to erode. A similar
observation was made with the meta-substituted product 2se and
the dibenzosuberone derivative 2te.[28]
In conclusion, the combination of the pentafluorobenzyl sulfamate
PfbsNH2 3e with the chiral rhodium complex Rh2(S-tfptad)4 4b has
led to the development of a catalytic asymmetric intermolecular
C(sp3)—H amination reaction with a wide scope. Excellent yields
of up to 99% and ees of up to 89% have been obtained from
substrates used in stoichiometric amounts,
a result that
underscores the high reactivity of benzylic sulfamates as nitrene
sources. The reaction can be performed on a mmole scale with
equal efficiency and the corresponding products can be easily
deprotected under mild conditions without epimerization.
Worth of mention is the low loading (0.1 to 1 mol%) of the chiral
rhodium catalyst 4b. The excellent yields obtained for the
products 2 demonstrate the very high catalytic activity of Rh2(S-
tfptad)4 that proves stable under the oxidizing conditions.[30] While
the catalyst loading remains higher than that reported by Arnold
with mutated enzymes, both enantiomers of the rhodium complex
4b are accessible thereby offering the opportunity to prepare both
enantiomers of benzylic amines. Work is in progress to further
investigate the new catalytic system in order to depict a
The reaction conditions involving 1 mol% of Rh2(S-tfptad)4 4b
were then applied to more complex substrates (Figure 2). Thus,
starting from a protected analog of methyl dehydroabietate, a
single isomer 2ue was isolated in 65% yield.[29] On the other hand,
This article is protected by copyright. All rights reserved.

10.1002/anie.201902882
Angewandte Chemie International Edition
COMMUNICATION
[10] I. Nägeli, C. Baud, G. Bernardinelli, Y. Jacquier, M. Moran, P. Müller,
Helv. Chim. Acta 1997, 80, 1087.
stereochemical model and develop a general method for catalytic
asymmetric intermolecular C(sp3)—H amination.
[11] M. Yamawaki, H. Tsutsui, S. Kitagaki, M. Anada, S. Hashimoto,
Tetrahedron Lett. 2002, 43, 9561.
[12] R. P. Reddy, H. M. L. Davies, Org. Lett. 2006, 8, 5013.
[13] The same results were by Katsuki with a tetrabromosalen complex. See:
Y. Kohmura, T. Katsuki Tetrahedron Lett. 2001, 42, 3339.
Acknowledgements
[14] C. G. Espino, K. W. Fiori, M. Kim, J. Du Bois, J. Am. Chem. Soc. 2004,
126, 15378.
We wish to thank the French National Research Agency (program
n° ANR-11-IDEX-0003-02, CHARMMMAT ANR-11-LABX-0039,
and ANR-15-CE29-0014-01; fellowship to A. N.), the Ministère de
l’Enseignement Supérieur et de la Recherche (fellowship to V. B.),
and the ECOS-Sud Committee (Action A15E04), for their support.
We are grateful to Marie Sircoglou (ICMMO, Université Paris-Sud)
for helpful discussions.
[15] T. Höke, E. Herdtweck, T. Bach, Chem. Commun. 2013, 49, 8009.
[16] Y. Nishioka, T. Uchida, T. Katsuki, Angew. Chem. Int. Ed. 2013, 52,
1739; Angew. Chem. 2013, 125, 1783.
[17] C. K. Prier, R. K. Zhang, A. R. Buller, S. Brinkmann-Chen, F. H. Arnold,
Nat. Chem. 2017, 9, 629.
[18] K. Guthikonda, J. Du Bois, J. Am. Chem. Soc. 2002, 124, 13672.
[19] M. Okada, S. Iwashita, N. Koizumi, Tetrahedron Lett. 2000, 41, 7047.
[20] 2,6-difluorobenzyl sulfamate 3d gives lower yields at -10 °C.
[21] a) K. W. Fiori, J. Du Bois, J. Am. Chem. Soc. 2007, 129, 562; b) E. N.
Bess, R. J. DeLuca, D. J. Tindall, M. S. Oderinde, J. L. Roizen, J. Du
Bois, M. S. Sigman, J. Am. Chem. Soc. 2014, 136, 5783; c) N. D.
Chiappini, J. B. C. Mack, J. Du Bois, Angew. Chem. Int. Ed. 2018, 57,
4956; Angew. Chem. 2018, 130, 5050.
Keywords: amination • enantioselective • rhodium • C—H
functionalization • nitrene
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steps from the corresponding 1-adamantanemethanol, respectively in
47% and 6% yield. See the supporting information for the preparation of
the (S)-tfptad ligand and the X-ray structure of the Rh2(S-tfptad)4 complex.
[24] Lower yields were observed for reactions performed at -20 °C.
[25] Various additives have been screened to improve the yield and
enantioselectivity, however, unsuccessfully (see table S2 in the
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[26] The increased in enantioselectivity with a lower catalyst loading has
already been observed with bifunctional organocatalysts. See: a) G. Rulli,
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[27] The e.r. can be enriched by recrystallization as, for example, in the case
of 2ne that could be obtained with an e.r. of 96:4.
[7]
[28] Similar lower yields with alkylarenes or meta-substituted arenes were
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steric effects. See: a) F. Collet, C. Lescot, C. Liang, P. Dauban, Dalton
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substituted product in 70% yield and with a d.r. of 5:1.
[8]
[9]
[30] A previous study revealed that chiral dirhodium tetracarboxylates derived
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This article is protected by copyright. All rights reserved.

10.1002/anie.201902882
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
COMMUNICATION
Ali Nasrallah, Vincent Boquet, Alexandra
Hecker, Pascal Retailleau, Benjamin
Darses, and Philippe Dauban*
F
F
F
PfbsNH2
Rh2(S-tfptad)4 R1
NHPfbs
R1
• Substrate as the limiting component
• Low catalyst loading: 0.1 to 1 mol%
• Large scope (> 20 examples)
• Excellent yields of up to 99%
• High e.r. of up to 94.5:5.5
O
F
R2
R2
H
N
O
PhI(OPiv)2
C6H5CF3
O
O
Rh2(S-tfptad)4
Rh Rh
Page No. – Page No.
• Easy access to free amines
PfbsNH2: pentafluorobenzyl sulfamate
Catalytic Enantioselective
Intermolecular Benzylic C(sp3)—H
Amination
Benz to benz. A practical method for asymmetric intermolecular benzylic C(sp3)—
H amination is reported. The latter is based on the combination of the
pentafluorobenzyl sulfamate PfbsNH2 with the chiral rhodium(II) catalyst Rh2(S-
tfptad)4. Various substrates, used as limiting components, are converted to benzylic
amines with excellent yields and high levels of enantioselectivity. The Pfbs group
can be removed under mild conditions to afford the NH-free benzylic amines.
This article is protected by copyright. All rights reserved.