A Chiral Phenanthroline Ligand with a Hydrogen-Bonding Site: Application to the Enantioselective Amination of Methylene Groups

Article abstract of DOI:10.1021/jacs.0c02803

A silver-catalyzed amination is reported that occurs at the aliphatic C3-substituent of various quinolones and pyridones. The C-H amination reaction proceeded with high site-and enantioselectivity (14 examples, 83-97% ee). The key to its success is the use of a chiral phenanthroline ligand that is attached via an ethynyl linker to the 8-position of octahydro-1H-4,7-methanoisoindol-1-one. AgPF6 (10 mol %) served as the silver source, PhI.NNs as the nitrene precursor, and 1,10-phenanthroline as the coligand. The reaction outcome can be understood by assuming a nitrene C-H insertion within a hydrogen-bonded silver complex in which a single C-H bond is exposed to the catalytic reaction center.

Full text of DOI:10.1021/jacs.0c02803

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Communication
A Chiral Phenanthroline Ligand with a Hydrogen Bonding Site:
Application to the Enantioselective Amination of Methylene Groups
Rajasekar Reddy Annapureddy, Christian Jandl, and Thorsten Bach
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c02803 • Publication Date (Web): 07 Apr 2020
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A Chiral Phenanthroline Ligand with a Hydrogen Bonding
Site: Application to the Enantioselective Amination of Meth-
ylene Groups
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Rajasekar Reddy Annapureddy, Christian Jandl, and Thorsten Bach*
Department Chemie and Catalysis Research Center (CRC), Technische Universität München, Lichtenbergstrasse 4,
85747 Garching, Germany
Supporting Information Placeholder
Scheme 1. First Report on an Ag-Catalyzed Intermo-
lecular Amination Reaction by He and co-workers12
ABSTRACT: A silver-catalyzed amination is reported which
occurs at the aliphatic C3-substituent of various quinolones
and pyridones. The C-H amination reaction proceeded with
high site- and enantioselectivity (14 examples, 83-97% ee). Key
to its success is the use of a chiral phenanthroline ligand that
is attached via an ethynyl linker to the 8-position of octahy-
dro-1H-4,7-methanoisoindol-1-one. AgPF6 (10 mol%) served as
the silver source, PhINNs as the nitrene precursor and 1,10-
phenanthroline as the coligand. The reaction outcome can be
understood by assuming a nitrene C-H insertion within a hy-
drogen-bonded silver complex in which a single C-H bond is
exposed to the catalytic reaction center.
When searching for new classes of catalysts and chiral lig-
ands to be used in enantioselective amination reactions, we
came across the silver-catalyzed amination reaction originally
reported by He and co-workers (Scheme 1).12 Although the fact
that the nitrene precursor N-(p-nitrophenylsulfonyl)imino]-
phenyl iodinane (PhI=NNs) was used as the limiting reagent
was not optimal, the low catalyst loading and the conceptually
novel approach were appealing to us. In more recent years, the
chemistry of silver-catalyzed nitrene transfer has been more
extensively studied,13 most notably by the groups of Scho-
maker14 and Pérez.15 Although an enantioselective intramolec-
ular aziridination has been achieved with a chiral silver com-
plex,16 intermolecular amination reactions have to the best of
our knowledge remained elusive.
The ubiquitous presence of amino-substituted alkyl moieties
in biologically active compounds has stimulated extensive
synthetic work on the stereoselective introduction of an
amino group.1 Traditional approaches rely on nucleophilic
substitution reactions which require a pre-functionalization
at the respective sp3-carbon atom. A more straightforward ap-
proach aims at the direct insertion of a nitrene or nitrene pre-
cursor into a C-H bond.2 Major challenges to be met for this
strategy to be successful include the control of several selec-
tivity parameters, such as chemoselectivity, site-selectivity
and most notably enantioselectivity. Particularly, the intermo-
lecular enantioselective amination at prostereogenic meth-
ylene groups poses a formidable challenge and requires new
concepts for the construction of suitable catalysts.3 Previous
studies on chiral metal complexes that enable an enantiose-
lective intermolecular sp3-C-H amination reaction can be
grouped by the choice of ligands. A chiral modification of rho-
dium complexes has been frequently attempted with chiral
carboxylates4 and has led to remarkably efficient catalysts, as
shown by the groups of Davies5 and Dauban.6 Matsunaga and
co-workers have successfully employed chiral carboxylates in
combination with rhodium and cobalt complexes.7 The Che
group demonstrated that chiral porphyrins8 are suitable tetra-
dentate ligands if the catalytically active center is manganese
or ruthenium.9 Studies by Katsuki and co-workers have estab-
lished that chiral salens represent another class of tetraden-
tate ligands which can be combined with the same metals to
achieve an enantioselective intermolecular amination.10 Clark
and Roche have exploited with considerable success chiral bi-
soxazolines for copper-catalyzed amination reactions.11
We envisioned that chiral phenanthroline ligands could be
created by covalently attaching the phenanthroline core to a
chiral octahydro-1H-4,7-methanoisoindol-1-onyl skeleton17,18
which exhibits a hydrogen bonding site for substrate coordi-
nation. Starting from 3-, 4-, and 5-bromophenanthroline, the
respective Sonogashira cross-coupling reactions led to the de-
sired ligands (see the SI for further details). Based on the anal-
ysis of molecular models, preliminary experiments were per-
formed with ligand 2 (Table 1) in combination with silver tri-
flate (10 mol%) as the silver source and PhI=NNs as the nitrene
precursor (2 equiv.). The chosen substrate was 7,8,9,10-tetra-
hydro-6(5H)-phenanthridinone (3) which displays a lactam
binding site and four non-identical methylene groups within
the cyclohexene ring. At ambient temperature a slow but no-
table conversion was observed from which a single regioiso-
meric product 4 was isolated with a significant enantiomeric
excess (ee) of 65% (entry 1).
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Table 1. Optimization of the Catalytic Enantioselec-
tive Amination of Substrate 3 by Variation of the Silver
Salt and the Coligand (30 mol scale)
Table 2. Enantioselective Ag-Catalyzed Amination of
Various 2-Quinolone Substrates Employing Ligand 2
as the Source of Chirality (60 mol scale)
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entrya Ag source
coligand
yield (%)b ee (%)c
1
2
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
Ag(BF4)
Ag(SbF6)
Ag(PF6)
Ag(PF6)
Ag(PF6)
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60
71
65
78
80
82
73
38
81

4,7-(Ph2)-phen
4,7-(Me2)-phen
4,7-(MeO2)-phen
3,4,7,8-(Me4)-phen
2,9-(Me2)-phen
phen
3
4
50
48
27
69
70
77
74
70
<10
5
6
7
8
phen
85
88
94
84

9
phen
10
11d
12e
phen
phen
phen
a 88% conversion. b 78% conversion. c 86% conversion.
a The reaction mixture was stirred for 26 hours (c = 10 mM)
in the presence of 4Å molecular sieves (4Å MS); low yields in-
dicate low conversion (see SI). b Yields were determined by 1H-
NMR spectroscopy using dimethyl fumarate as the internal
When performing the reaction on preparative scale under
optimized conditions (Table 2), we could isolate product 4
with the same enantioselectivity (94% ee) and a similar yield
as in the preliminary experiments. The absolute configuration
at the stereogenic center (S) was determined by single crystal
X-ray crystallography (see the SI). The functional group toler-
ance of the reaction was established for methyl (product 5),
fluoro (product 6), and methoxy (product 7). A modification
of the annulated ring at the quinolone core was tolerated by
the chiral silver catalyst and conversion to aminated products
8, 9, 10, and 11 was achieved with high enantioselectivity. The
reaction with 6-bromo substituted quinolone was sluggish
and did not go to completion. Even an acyclic ethyl group at
position C3 of the quinolone was processed with a high pref-
erence for amination at one of the two enantiotopic meth-
ylene C-H bonds (product 12).
c
standard. The enantiomeric excess was calculated from the
ratio of enantiomers (4/ent-4) as determined by chiral HPLC
analysis. d The 5-substituted isomer of 2 was employed. e The
3-substituted isomer of 2 was employed.
Since it had been shown in mechanistic studies by Berry and
Schomaker that bis(phenathroline) complexes are involved in
nitrene transfer reactions14d an achiral phenanthroline colig-
and was added (entries 2-7) to favor formation of a heterolep-
tic vs. a homoleptic silver complex. Indeed, several coligands
facilitated an accelerated and more selective reactions with
the unsubstituted 1,10-phenanthroline (phen) displaying to-
gether with 4,7-(Me2)-phen the best results. Optimization was
continued by varying the counterion of the silver complex and
an increase of enantioselectivity was recorded for OTf < BF4 <
SbF6 < PF6 (entries 7-10). The best conditions led to product 4
in a yield of 74% and with 94% ee. The superior performance
of ligand 2 as compared to its constitutional isomers (3- and
5-phenanthroline substitution) was confirmed by performing
the reaction under optimized conditions but with the latter
ligands (entries 11, 12). The 5-substituted isomer was catalyti-
cally active but resulted in a lower enantioselectivity (entry 11)
while the 3-substituted isomer turned out to be not competent
to promote the reaction (entry 12). The site-selectivity of the
amination showed a clear preference for an attack at position
C7 of the phenanthridinone substrate. The electronically sim-
ilar position C10 remained untouched nor was any other of the
methylene groups involved in the amination reaction.
Table 3. Enantioselective Ag-Catalyzed Amination of
Various 2-Pyridone Substrates (60 mol scale)
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An extension of possible substrates was attempted by em-
was higher. The relative ratio of 12 and 12-d1 was determined
by H NMR spectroscopy after ca. 30% conversion and a pri-
1
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3
4
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6
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ploying annulated pyridones as substrates (Table 3). To our
delight, it was found that products 13-17 were consistently
generated in high yield and with excellent enantiomeric ex-
cess. The enormous impact of the hydrogen bonding event
was not only corroborated by the high site- and enantioselec-
tivity of the amination protocol but also by the significantly
increased activity of the catalyst as compared to any achiral
silver complex. In several cases, racemic material which was
required for HPLC comparison was not accessible by a silver-
catalyzed amination reaction with achiral phenanthroline lig-
ands. Instead, we had to use racemic ligand rac-2 to get our
hands on racemic products (see the SI for further details).
mary KIE of 5.5 was calculated. Albeit preliminary, the results
suggest the C-H insertion to be not rate-determining. In the
selectivity-determining step, a significant differentiation by
the catalyst seems to occur, however. Based on the known co-
ordination behavior of silver bis(phenanthroline) com-
plexes14d it is suggested that the silver salt and the two ligands
form heteroleptic complex 20 with a tetrahedral coordination
sphere around the metal and a free site for hydrogen bonding
by the substrate (Figure 2). Upon rate-determining delivery of
the nitrene fragment from PhI=NNs to the silver atom the co-
ordination sphere is expanded to a distorted trigonal bipyra-
mid14c and the amination occurs site- and enantioselectively
because only one of the hydrogen atom is properly displayed
to the active center as indicated by structure 21. The observed
primary KIE of 5.5 is congruent with values obtained for some
intermolecular rhodium- and ruthenium-catalyzed amination
reactions (KIE = 4.5-4.8)22 and suggests a transition state in
which the C-H bond is significantly elongated. It has been pro-
posed for a related intramolecular silver-catalyzed amination
(KIE = 3.4) that the reaction proceeds by attack of a triplet
nitrene species which undergoes intersystem crossing prior to
the formation of any intermediates.14c,15b A similar scenario is
conceivable also for the reaction within complex 21.
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A major benefit of the nosyl (Ns) compared to other sul-
fonyl-based protecting groups is their facile cleavage from a
given nitrogen atom.19 We demonstrated for product 4 that
the cleavage can be readily performed with thiophenol and
that an in situ protection of the free amine with the most com-
mon amine protecting group tert-butoxycarbonyl (Boc) was
possible (product 18, Scheme 2). The method is thus suited to
introduce amino groups enantioselectively in heterocyclic
skeletons of biological relevance.20
Scheme 2. Facile Cleavage of the Nosyl Protecting
Group and in situ Boc Protection
Some preliminary mechanistic experiments were performed
to elucidate the origin of the selectivity. When racemic prod-
uct rac-4 was submitted to the optimized amination condi-
tions (Table 2), there was a 60% conversion, presumably due
to consecutive oxidation or decomposition. Unreacted sub-
strate was isolated in 40% yield in a low enantiopurity of 33%
ee. An s factor of 2.1 was calculated from this data (Figure 1)
which in turn confirms that the high enantioselectivity of the
amination reaction was not due to a kinetic resolution.
Figure 2. Proposed structure 20 of the 1:1:1 complex of
Ag(PF6), ligand 2 and 1,10-phenanthroline (phen): Upon
transfer of the nitrene fragment from PhI=NNs to the cat-
alyst the reaction occurs with high enantioselectivity
within the hydrogen bonded complex 21.
In summary, the site- and enantioselective amination of al-
iphatic methylene groups in pyridones and quinolones has
been achieved by silver catalysis. The chiral ligand 2 employed
for asymmetric induction bears a hydrogen bonding site
which displays in a highly predictable fashion a single C(sp3)-
H bond to the reactive center. Only methylene groups at-
tached to the C3 carbon atom of the heterocycles are attacked.
Studies are underway to explore the reaction course in more
detail and to find other transition metal-catalyzed reactions in
which the chiral phenanthroline ligand 2 exerts a similar di-
recting effect.
Figure 1. Under the standard reaction conditions, sub-
strate 4 shows almost no kinetic resolution indicated by a
small s = kS/kR; kinetic isotope effect (kH/kD) determined
from parallel and competition reactions on non- and dou-
bly deuterated 3-ethylquinolin-2-one 19 and 19-d2.
Supporting Information
Experimental procedures, analytical data for all new com-
pounds, proof of constitution and configuration (crystal data
of product 4), kinetic resolution and KIE experiments, NMR
spectra. This material is available free of charge via the Inter-
net at http://pubs.acs.org.
The nature of the C-N bond forming step was interrogated
by kinetic isotope effect (KIE) measurements.21 To this end, 3-
ethylquinolin-2-one (19) and its double deuterated analogue
19-d2 were subjected to the amination reaction. The reaction
led to product 12 in the former case and to product 12-d1 in the
latter case. In parallel experiments in which the ratio of the
individual rates kH/kD was determined after ca. 10% conver-
sion a low KIE of only 1.2 was observed. In a competition ex-
periment, in which equimolar amounts of 19 and 19-d2 were
subjected to the reaction condition in a single flask, the KIE
Corresponding Author
thorsten.bach@ch.tum.de
Notes
The authors declare no competing financial interests.
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(12) Li, Z.; Capretto, D. A.; Rahaman, R.; He, C. Silver-Catalyzed In-
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ACKNOWLEDGMENT
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Financial support by the Deutsche Forschungsgemeinschaft
(grant Ba 1372/17-2) is gratefully acknowledged. ARR thanks
the Alexander von Humboldt foundation for a research fellow-
ship. Dr. S. Breitenlechner is acknowledged for his help with
the KIE measurements.
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