Interrupted Pyridine Hydrogenation: Asymmetric Synthesis of δ-Lactams

Article abstract of DOI:10.1002/anie.202016771

Metal-catalyzed hydrogenation is an effective method to transform readily available arenes into saturated motifs, however, current hydrogenation strategies are limited to the formation of C?H and N?H bonds. The stepwise addition of hydrogen yields reactive unsaturated intermediates that are rapidly reduced. In contrast, the interruption of complete hydrogenation by further functionalization of unsaturated intermediates offers great potential for increasing chemical complexity in a single reaction step. Overcoming the tenet of full reduction in arene hydrogenation has been seldom demonstrated. In this work we report the synthesis of sought-after, enantioenriched δ-lactams from oxazolidinone-substituted pyridines and water by an interrupted hydrogenation mechanism.

Full text of DOI:10.1002/anie.202016771

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How to cite: Angew. Chem. Int. Ed. 2021, 60, 6425–6429
International Edition: doi.org/10.1002/anie.202016771
German Edition: doi.org/10.1002/ange.202016771
Asymmetric Catalysis
Hot Paper
Interrupted Pyridine Hydrogenation: Asymmetric Synthesis of
d-Lactams
Tobias Wagener+, Lukas Lꢀckemeier+, Constantin G. Daniliuc, and Frank Glorius*
Dedicated to Professor David A. Evans on the occasion of his 80th birthday
Abstract: Metal-catalyzed hydrogenation is an effective
method to transform readily available arenes into saturated
motifs, however, current hydrogenation strategies are limited to
À
À
the formation of C H and N H bonds. The stepwise addition
of hydrogen yields reactive unsaturated intermediates that are
rapidly reduced. In contrast, the interruption of complete
hydrogenation by further functionalization of unsaturated
intermediates offers great potential for increasing chemical
complexity in a single reaction step. Overcoming the tenet of
full reduction in arene hydrogenation has been seldom
demonstrated. In this work we report the synthesis of sought-
after, enantioenriched d-lactams from oxazolidinone-substi-
tuted pyridines and water by an interrupted hydrogenation
mechanism.
M
etal-catalyzed hydrogenation is known to be a simple and
powerful method to increase molecular complexity.[1] In
particular, the hydrogenation of easily accessible N-hetero-
arenes such as pyridines offers access to important saturated
azacycles.[2] This established reaction is limited solely to the
À
À
formation of new C H and N H bonds; additional synthetic
manipulations are required to introduce further chemical
functionality.[3] The stepwise transfer of molecular hydrogen
in arene hydrogenation yields intermediates with double
bonds remaining, which in principle offer the possibility of
further functionalization (Figure 1).[4] Nevertheless, harness-
ing unsaturated intermediates in arene hydrogenation for
Figure 1. Mechanistic pathways of unsaturated intermediates in arene
hydrogenation and this work. Aux=chiral auxiliary.
synthesized using iridium-catalyzed hydride transfer followed
by hydroxymethylation. This precedent underlines the huge
potential of an interrupted hydrogenation strategy to rapidly
build up chemical complexity, yet, further method develop-
ment is necessary to elevate this approach to a general
synthetic strategy. We now report a pyridine hydrogenation
interrupted by nucleophilic substitution of an unsaturated
intermediate. Our procedure enables the synthesis of valuable
d-lactams by Pd-catalyzed hydrogenation of oxazolidinone-
substituted pyridines in the presence of water.[7]
À
other C X bond forming events is unknown in the literature,
although the partial hydrogenation of certain substrates like
benzene or phenol has been achieved.[5] Recently, Donohoe
À
and co-workers reported a pioneering combination of C H
À
and C C bond formation in a transfer hydrogenation of
pyridinium salts.[6] Protected tetrahydropyridines were thus
Lactams, such as 2-piperidones, are important building
blocks and represent core motifs in many pharmaceuticals
and natural products.[8] Despite interest in this moiety,
synthetic access to enantioenriched d-lactams remains chal-
lenging.[9] In this regard, we envision metal-catalyzed hydro-
genation as a powerful strategy to address this problem.
However, the synthesis of 2-piperidones via direct asymmet-
ric hydrogenation[10] of pyridone precursors is hampered by
amide resonance and, to the best of our knowledge, has never
been achieved.[11] In contrast, our procedure starts with
oxazolidinone-substituted pyridines, which are readily avail-
able from cheap and abundant 2-halogenated pyridines in
a single step.[12] The oxazolidinone is cleaved within the
reaction, thus acting as a traceless chiral auxiliary which can
be fully recycled.
[*] T. Wagener,[+] L. Lꢀckemeier,[+] Dr. C. G. Daniliuc, Prof. Dr. F. Glorius
Organisch-Chemisches Institut
Westfꢁlische Wilhelms-Universitꢁt Mꢀnster
Corrensstraße 40, 48149 Mꢀnster (Germany)
E-mail: glorius@uni-muenster.de
[+] These authors contributed equally to this work.
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202016771.
ꢂ 2021 The Authors. Angewandte Chemie International Edition
published by Wiley-VCH GmbH. This is an open access article under
the terms of the Creative Commons Attribution Non-Commercial
License, which permits use, distribution and reproduction in any
medium, provided the original work is properly cited and is not used
for commercial purposes.
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After our initial discovery, we studied the influence of the
reaction parameters in more detail (see Supporting Informa-
tion for details). The presence of strong Brønsted acids like
hydrochloric acid is essential.[13] Using weak Brønsted acids
like formic acid resulted in the exclusive formation of
piperidine product (Table S1, Entry 7). Furthermore, differ-
ent solvents were tested, with a combination of THF and H2O
giving the best result (Table S1, Entries 1–6). The nature of
the catalyst is also decisive for the reaction outcome.While
various Pd catalysts generally gave the desired d-lactam in
high yields and enantioselectivities, other catalysts such as
PtO2, Ru/C or Rh/C resulted in little or no yield (Table S2,
Entries 2–9). Various oxazolidinones from the chiral pool
provided the product in a high enantiomeric ratio while
with a 98:2 enantiomeric ratio and only one diastereomer
observed. Additional functional groups such as basic aza-
cycles (7) or alkyl ethers (8) were tolerated without significant
decrease in yield or enantiomeric ratio. Although hydro-
genation of fluorinated arenes is challenging,[16] several
fluorinated d-lactams (9–13) were prepared containing CF,
CF3, and CF2H groups in moderate to good yields. Interest-
ingly, a chemoselective hydrogenation of the pyridine core
over a phenyl substituent was observed for our catalytic
system to give various substituted phenyl-piperidones (14–
17). Moreover, d-lactams carrying important carbonyl func-
tionalities such as esters and amides (18–23) were prepared in
moderate to high yields and high enantiomeric ratios.
Disubstituted d-lactams 24 and 25 were synthesized highly
selectively with only one diastereomer observed in 97:3 and
89:11 enantiomeric ratios, respectively. Substitution in the
pyridine 3-position however decreased product formation and
resulted in an almost racemic mixture (6, see Supporting
Information for details).
a
benzyl substituent gave the best result (Table S2,
Entries 10–12).[14] Lowering the hydrogen pressure to 25 bar
results in a decrease of the enantiomeric ratio (Table S2,
Entry 13). To investigate the reproducibility of our new
method, we performed a reaction-condition-based sensitivity
screen (Table 1; see Supporting Information for details).[15]
With optimized conditions in hand, we investigated the
reaction scope of this new transformation. A series of
alkylated d-lactams (1–4) was synthesized in high yields and
excellent enantiomeric ratios. Furthermore, our method was
capable of forming multiple stereocenters in a highly selective
fashion. Dimethylated lactam 5 was isolated in 66% yield
The absolute configurations of d-lactams 1 and 10 were
unambiguously determined by X-ray analysis and are in
accordance with our previous observations (Figure 2, see
Supporting Information for details).[17,7a,b]Based on the Hori-
uti–Polanyi mechanism[18] for heterogeneous hydrogenation,
the absolute configuration of the products with substituents in
4- and 5- position are assigned analogously (see Scheme S1).
Table 1: Reaction scope for the palladium-catalyzed synthesis of 2-piperidones. See Supporting Information for full experimental details.
[a] 4-Isopropyloxazolidinone as chiral auxiliary. [b] 4-tert-Butyloxazolidinone as chiral auxiliary. [c] Epimeric (R)-isopropyloxazolidinone as chiral
auxiliary.
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Figure 2. Absolute configuration of d-lactams 1 and 10.
In agreement with this model, a deuteration experiment
confirms the addition of deuterium to one diastereotopic face
of the pyridine exclusively (see Supporting Information for
details).
Subsequently, we investigated the scalability of our
procedure and the possibility of recycling the auxiliary. The
hydrogenation was performed on a 2 g scale without signifi-
cant loss in yield or enantiomeric ratio (Scheme 1, a). Lactam
ent-4 was obtained in 78% yield and 97:3 enantiomeric ratio
and oxazolidinone 26 was recovered in 92% yield and > 99:1
e.r. thus outlining its good recyclability.
Scheme 1. Gram-scale reaction and ring opening.
As further product application, d-lactam ent-4 was hydro-
lyzed to give the d-amino acid methyl ester 27 in 99% yield
and 97:3 e.r. after heating in hydrochloric acid for 24 h and
treatment with methanol (Scheme 1, b).
Scheme 2. Mechanistic investigation and proposal.
Intrigued by these observations, we investigated the
reaction mechanism. To identify potential intermediates, the
reaction was stopped after 2 h and the mass of an intermedi-
ate with one remaining double bond was detected by GC-MS
(Scheme 2, a). Although unsaturated intermediates are very
short-lived in arene hydrogenation and are rapidly further
hydrogenated, imine 28 was isolated in 5% yield (Scheme 2,
b). Conversion of imine 28 in water/ THF with hydrochloric
acid in the absence of Pd catalyst and H2 provided the d-
lactam product in almost quantitative yield (Scheme 2, c).
Thus, imine 28 is an intermediate species in our procedure and
can undergo nucleophilic substitution with water. It is worth
mentioning that only imine 28 as one of six potential
intermediates in this reaction is suitable to hydrolyze to
yield the desired 2-piperidone (Scheme 2, a). Based on these
experiments we postulate the following reaction mechanism
(Scheme 2, d): By addition of a Brønsted acid, the basic
nitrogen of the oxazilidinone-substituted pyridine is proton-
ated and forms a stable conformer through hydrogen bonding
to the oxazolidinone. Owing to the steric repulsion of the
oxazolidinone substituent of this rigid conformation, a diaste-
reoselective hydrogenation of the unhindered face of the
pyridine proceeds to set the new stereocenter. After the
addition of two equivalents of H2, oxazolidinone-substituted
imine I is formed (see Scheme S1). In contrast to a classic
arene hydrogenation, this intermediate, following our new
protocol, does not undergo another catalytic reduction (see
product III) but reacts with water in a nucleophilic substitu-
tion. In this substitution, the oxazolidinone is released and
therefore serves as a recyclable, traceless auxiliary. The
resulting iminium II tautomerizes rapidly to yield the final
d-lactam product.
In summary, we have disclosed a heteroarene hydro-
genation interrupted by nucleophilic substitution. Hydro-
genation of oxazolidinone-substituted pyridines gives access
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À
À
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Acknowledgements
Generous financial support by the European Research
Council (ERC Advanced Grant Agreement No. 788558),
the Deutsche Forschungsgemeinschaft (Leibniz Award), and
the Alfried Krupp von Bohlen und Halbach Foundation are
gratefully acknowledged. The authors thank Cornelia Weit-
kamp and Lisa Grabinski for experimental support as well as
Toryn Dalton, Arne Heusler, Daniel Moock, Dr. J. Luca
Schwarz, and Marco Wollenburg for many helpful discussions.
Open access funding enabled and organized by Projekt
DEAL.
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Conflict of interest
The authors declare no conflict of interest.
Keywords: asymmetric catalysis · heterogeneous catalysis ·
hydrogenation · lactams · nitrogen heterocycles
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Manuscript received: December 17, 2020
Accepted manuscript online: January 18, 2021
Version of record online: February 12, 2021
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