Streamlining the Synthesis of Pyridones through Oxidative Amination of Cyclopentenones

Abstract

Herein we report the development of an oxidative amination process for the streamlined synthesis of pyridones from cyclopentenones. Cyclopentenone building blocks can undergo in situ silyl enol ether formation, followed by the introduction of a nitrogen atom into the carbon skeleton with successive aromatisation to yield pyridones. The reaction sequence is operationally simple, rapid, and carried out in one pot. The reaction proceeds under mild conditions, exhibits broad functional group tolerance, complete regioselectivity, and is well scalable. The developed method provides facile access to the synthesis of ¹⁵N‐labelled targets, industrially relevant pyridone products and their derivatives in a fast and efficient way.

Full text

Ring Expansion
Streamlining the Synthesis of Pyridones through Oxidative Amination
of Cyclopentenones
Bence B. Botlik, Micha Weber, Florian Ruepp, Kazuki Kawanaka, Patrick Finkelstein, and
Bill Morandi*
Abstract: Herein we report the development of an
oxidative amination process for the streamlined syn-
thesis of pyridones from cyclopentenones. Cyclopente-
none building blocks can undergo in situ silyl enol ether
formation, followed by the introduction of a nitrogen
atom into the carbon skeleton with successive aromati-
sation to yield pyridones. The reaction sequence is
operationally simple, rapid, and carried out in one pot.
The reaction proceeds under mild conditions, exhibits
broad functional group tolerance, complete regioselec-
tivity, and is well scalable. The developed method
provides facile access to the synthesis of 15N-labelled
targets, industrially relevant pyridone products and their
derivatives in a fast and efficient way.
N-Heterocyclic compounds are ubiquitous motifs in organ-
ic chemistry, both in industrial and academic research. Their
prevalence is well reflected by the fact that more than half
of FDA-approved drugs feature an N-heterocycle.[1] Pyr-
idones are commonly found among drug molecules (Sche-
me 1A), with five examples present among the top 200 drug
molecules by retail sales as of 2024.[2] Pyridones are also
widely used in organometallic chemistry,[3] often employed
as ligands in CH functionalisation reactions.[4,5] Further-
more, pyridones are useful intermediates en route to densely
functionalised pyridines, which are challenging to access
otherwise.[6,7]
The traditional methods for the synthesis of 2-pyridones
include classical condensation processes of acyclic building
blocks such as the Guareschi synthesis and Knoevenagel-
type condensations,[8,9] the reaction of 2H-pyran-2-one
derivatives with ammonia,[9] the rearrangements of pyridine-
N-oxides or pyridinium salts,[10,11] and transformations of the
corresponding pyridine derivatives,[9] among other
methods.[9,12,13] However, these pathways are often lengthy,
require pre-functionalised building blocks, employ harsh
conditions, or lack generality.
An alternative, more facile access to pyridones would be
the direct ring expansion of readily available carbocycles.
Cyclopentenones, which are abundant and versatile building
blocks in synthetic organic chemistry,[14] could be ideal
precursors for the synthesis of a wide range of pyridones
through oxidatively introducing a nitrogen atom in the
carbon skeleton.[15–27] An analogous process is the Beckmann
rearrangement, which has found broad applications in the
synthesis of saturated lactams from cyclic ketones through
oxime intermediates under acid catalysis, as illustrated by
the industrial synthesis of Nylon (Scheme 1B).[28–34]
Inspired by the Beckmann rearrangement and the
experience of our group in electrophilic amination,[35–38] we
hypothesised that instead of NO reagents, the highly
electrophilic species formed upon mixing an iodine(III)
reagent and a nitrogen source could serve as an efficient
reactant in achieving a direct cyclopentenone to pyridone
conversion.[23–25,39–44] Such bis-electrophilic species would not
only serve as a nitrogen source, but also provide a synthon
in which the nitrogen atom has the correct oxidation state to
directly enable the desired oxidative process. We further
reasoned that forming silyl enol ethers[45] from the cyclo-
[*] B. B. Botlik, M. Weber, F. Ruepp, K. Kawanaka, Dr. P. Finkelstein,
Prof. Dr. B. Morandi
Laboratorium für Organische Chemie, ETH Zürich
Vladimir Prelog Weg 3, HCI, 8093 Zürich (Switzerland)
E-mail: bill.morandi@org.chem.ethz.ch
© 2024 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
NoDerivs License, which permits use and distribution in any med-
ium, provided the original work is properly cited, the use is non-
commercial and no modifications or adaptations are made.
Scheme 1. Context of this work.
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pentenones in situ would be highly beneficial, firstly for
leveraging their high nucleophilicity, and secondly for
enabling full control over the regioselectivity of the sub-
sequent nitrogen atom insertion step (Scheme 1C). Herein,
the successful development, optimisation, and applications
of this reaction are presented.
In preliminary experiments, the effect of the reaction
parameters was investigated for the nitrogen atom insertion
step using isolated silyl enol ether starting material 1 a’ for
the formation of unsubstituted 2-pyridone 2 a (Scheme 2,
Tables S1–S9, see Supporting Information). The reaction
was found to proceed only in the presence of protic solvents,
among which methanol proved to be the most efficient for
the formation of the desired product. However, binary
solvent mixtures, such as methanol:tetrahydrofuran (THF)
or methanol:pentane in a 1: 1 ratio were also suitable for the
reaction. This is especially opportune, as the silylation of
cyclopentenones typically proceeds in THF or pentane.
We thus envisaged that the silyl enol ether formation
step and the nitrogen atom insertion step could be carried
out in one pot, directly converting cyclopentenones into
pyridones, thereby significantly increasing the synthetic
utility of the transformation. Therefore, the reaction con-
ditions were next optimised for the one-pot reaction using 2-
methylcyclopentenone (1 b) as the model substrate (Ta-
ble 1). Different silyl groups were tested, with tert-butyl-
dimethylsilyl (TBS) significantly outperforming both more
and less bulky silylating agents, such as triisopropylsilyl
(TIPS) and trimethylsilyl (TMS) groups, respectively (Ta-
ble 1, entries 1–3). For the subsequent nitrogen atom
insertion step (diacetoxyiodo)benzene (PIDA) and bis(tert-
butoxylcarbonyloxy)iodobenzene (PhI(OPiv)2) were demon-
strated to be the most efficient oxidants, with other iodine-
(III) reagents such as (bis(trifluoroacetoxy)iodo)benzene
(PIFA) providing significantly lower yields of the desired
product 2 b (Table 1, entries 4–5). The two most effective
nitrogen sources were ammonium carbamate, and the
combination of ammonium chloride and potassium
carbonate (Table 1, entry 6). It was observed that 3 equiv-
alents of PIDA and 4 equivalents of ammonium carbamate
are needed to achieve high yields, however, further increas-
ing their equivalencies did not lead to significant improve-
ments (Table 1, entries 7–10). The reaction exhibited low
dependence on temperature and concentration, compatibil-
ity with different solvent mixtures (Table 1, entries 11–12),
and fast reaction kinetics, leading to full conversion of the
model substrate within 30 minutes. As a compromise
between efficiency and operational simplicity (Tables S10–
S11, see Supporting Information), the optimal conditions
were determined to be 3 equivalents of PIDA and 4
equivalents of ammonium carbamate in a 1: 1 mixture of
THF and methanol, carrying out both steps at room temper-
ature (Table 1, entry 8).
With the optimal reaction conditions in hand, we
proceeded to explore the scope of the transformation
(Scheme 3). Unsubstituted pyridone 2 a and its 3-alkylated
derivatives 2 b–2 d were isolated in good yields, alongside 3-
arylated 2 e. The benzo-fused system of isoquinolinone 2 f
was also obtained in excellent yield. As an interesting result
of the reaction design, in the case of 1-indanone derived
starting materials, the reaction resulted in the regioselective
formation of isoquinolinones, which is the opposite of the
nitrogen insertion regioselectivity observed in traditional
Beckmann rearrangements (2 f”),[29,31] which further in-
creases the synthetic appeal of our reaction for this class of
substrates. First, different substitution patterns were exam-
ined, with the successful formation of 3-substituted (2 g) and
4-substituted (2 h and 2 i) isoquinolinones, as well as 3,4-
disubstituted pyridone (2 j). Remarkably, tetrasubstituted
pyridone 2 k was also obtained in high yield. Different
methoxy-substitution patterns on the benzene ring of 1-
indanone substrates were well tolerated (2 l–2 o). Since a
variety of substituted 1-indanone derivatives are commer-
cially available, the functional group tolerance of the
reaction was examined using this class of starting materials.
Substrates bearing halogens, including fluoro-, chloro-,
and bromo- derivatives (2 p–2 r) were obtained in moderate
yields. The reaction is compatible with free hydroxy groups,
which are silylated in the first step, as showcased by entry 2 s
and 2 t. Among others, nitro (2 u), amide (2 v), primary
amine (2 w), pyridine (2 x), ester (2 y), alkyne (2 aa and 2 ab),
Scheme 2. Proof of concept.
Table 1: Selected optimisation data for the transformation of cyclo-
pentenones to pyridones.[a]
Entry Deviations from above Yield[b] of 2b [%]
1 None 66
2 TIPSOTf instead of TBSOTf 31
3 TMSOTf instead of TBSOTf 57
4 PhI(OPiv)2instead of PIDA 67
5 PIFA instead of PIDA 36
6 NH4Cl (4 equiv.)+K2CO3(4 equiv.)
instead of NH2CO2NH4
65
7 2 equiv. PIDA instead of 4 equiv. 14
8 3equiv. PIDA instead of 4equiv. 67
9 6 equiv. PIDA instead of 4 equiv. 67
10 6 equiv. NH2CO2NH4instead of 4 equiv.,
3 equiv. PIDA instead of 4 equiv.
63
11 THF:MeOH =4 : 1 instead of 1 : 1 60
12 Pentane instead of THF 55
[a] Reaction conditions: 2-methylcyclopentenone (0.30 mmol), Et3N
(0.45 mmol), TBSOTf (0.36 mmol), THF (0.14 M), r.t., 30 min.; then
ammonium carbamate (1.20 mmol), PIDA (1.20 mmol), THF:MeOH
(1 : 1, 0.07 M), r.t., 30 min. [b] Determined by 1H NMR using
mesitylene as internal standard.
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Scheme 3. Substrate scope of the reaction. Yields are isolated yields, unless stated otherwise. [a] Determined by 1H NMR using mesitylene as
internal standard. [b] Pentane used as solvent in the first step instead of THF, and pentane:methanol =1 : 1 mixture as solvent in the second step.
[c] 2.5 equiv. of Et3N and 2.2 equiv. TBSOTf used in the first step. [d] Traditional Beckmann conditions. 1) NH2OH 2) PPA[46] [e] Modified Beckmann
conditions. NH2OH, thiamine hydrochloride.[47] For details, see Supporting Information.
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carboxylic acid (2 ac), and trifluoromethoxy (2 ad) function-
alities were found to be tolerated in the reaction. Moreover,
cyclotene propionate derived 2 z and cis-jasmone derived
2 ae could also be accessed.
The developed strategy also offers an attractive oppor-
tunity to rapidly and cost-effectively synthesise 15N-labelled
pyridone products (Scheme 4A). Due to the favourable
magnetic properties of the 15N-nucleus (I =1
=
2), 15N NMR is
a widely used tool in biological and medical contexts, and
has significant importance in investigating reaction mecha-
nisms and structure–reactivity relationships.[19,48–52] However,
its low natural abundance of 0.4 % often necessitates the use
of isotope-enriched probes for sufficient detection in NMR
experiments.[49] The use of 15NH4Cl as an inexpensive
isotopic source was possible in our methodology in the
presence of an equivalent amount of K2CO3. Using slightly
modified conditions allowed the formation of pyridones 15N-
2 f,15N-2 o and 15N-2 s in yields comparable to those obtained
with the use of ammonium carbamate as the nitrogen
source. 15N-insertion into cyclopentenone 1 a, followed by
arylation has provided a short synthesis of a 15N-pirfenidone
analogue (15N-3). Furthermore, we synthesised the 15N-
labelled variant of the anesthetic drug quinisocaine (15N-4)
in three steps from commercially available starting materi-
als. Moreover, palladium-catalysed CH activation reactions
often employ pyridone ligands, such as 2 f.[3,5] We believe
that the facile access to 15N-labelled ligands of this class that
our methodology provides could offer a convenient way for
mechanistic elucidations of such reactions.[53,54]
The reaction proved to scale well, and the gram-scale
synthesis of 2 c allowed us to explore different product
valorisation pathways (Scheme 4B). Pyridone derivatives
can be quickly accessed, including the N-arylated product 6
and deoxychlorination product 7. Through 7, both 2-arylated
product 8and pyridine-derivative 9could be rapidly
synthesised.
We carried out a number of control experiments to
better understand the mechanism of the transformation
(Scheme 5A). Cyclopentenone starting material 1 b sub-
jected to the nitrogen insertion reaction conditions without
the silylation step did not yield the corresponding pyridone
product 2 b, and mainly unreacted starting material was
observed by NMR analysis, ruling out an aza-Bayer-
Villiger[55] type reactivity (I).
A different type of reactivity was observed when 3,3-
dimethylindan-1-one 1 ba was subjected to the reaction
conditions, which produced 25 % of N-acyl hemiaminal
ether product 2 ba alongside remaining starting material (II),
indicating that no β-hydrogens are required for the nitrogen
atom insertion, which proceeds even without the strong
driving force of subsequent aromatisation. Furthermore, 2-
indanone 1 ca produced hydroxyisoquinoline product 2 ca
upon being subjected to the reaction conditions (III).
We also carried out a Hammett-analysis to understand
the reaction profile better, which revealed the build-up of
positive charge in the rate determining step, which is
consistent with the oxidative nature of the process.
Based on these preliminary results, a mechanism con-
sistent with all observations could first involve the reaction
of the electron-rich silyl enol ethers (1 b’) to form N-
iodonium aziridine intermediates (12), facilitated by the
hypervalent iodine reagent and the nitrogen source. These
aziridinium intermediates can then undergo ring opening
upon the release of iodobenzene and the cleavage of the
silyl group which acts as an electrofuge. This results in the
formation of intermediate 13 which subsequently tautomer-
ises to the pyridone product 2 b (Scheme 5B).
In conclusion, we have developed an oxidative ring
expansion protocol capable of directly transforming cyclo-
pentenone derivatives into pyridones, through a strategy of
Scheme 4. Applications of the developed methodology for 15N-labelling,
and product derivatisation. Conditions for the derivatisation of
pyridone 2c: (i) 2-iodopyridine (2 equiv.), CuI (10 mol %), K2CO3
(1.2 equiv.), DMF, 150°C, 24 h (ii) POCl3(neat), 100 °C, 16 h (iii) (4-
fluorophenyl)boronic acid (1.2 equiv.), Pd(OAc)2(2.5 mol%), PPh3
(10 mol %), K2CO3(2.7 equiv.), DME/H2O, 90 °C, 18 h (iv) Pd/C,
HCOONH4(2 equiv.), MeOH, 55 °C, 16 h.
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silyl enol ether formation, followed by the introduction of a
nitrogen atom mediated by a hypervalent iodine reagent,
and subsequent aromatisation. The reaction is operationally
simple, rapid, exhibits good functional group tolerance and
complete regioselectivity. The scalability of the transforma-
tion was demonstrated, as well as pathways for further
diversification of the pyridone products. This strategy has
allowed us to install 15N-labels in various synthetic targets,
including the drug molecules quinisocaine and a pirfenidone
analogue, and in pyridones commonly used as ligands in
transition metal catalysis. Control experiments have pro-
vided insight into the mechanism of the reaction, and
showcased other reactivity pathways, such as the formation
of N-acyl hemiaminal ethers and 3-hydroxyisoquinolines.
We believe that the transformation will find interest in
further academic research as well as in industrial settings,
both for its synthetic utility of streamlining pyridone syn-
thesis and for the wide range of applications it provides.
Acknowledgements
We thank Yannick Brägger for valuable discussions. We
thank Jan Hübscher and Benaja Kohli for their experimen-
tal contributions. This work was supported by ETH Zürich
and the Swiss National Science Foundation (SNSF 184658).
B. B. B. acknowledges a fellowship from the Scholarship
Fund of the Swiss Chemical Industry (SSCI). K. K. acknowl-
edges the Program for Leading Graduate Schools: “Inter-
active Materials Science Cadet Program”. We thank the
NMR, MS (MoBiAS), and XRD (SMoCC) service depart-
ments at ETH Zürich for technical assistance and the
Morandi group for critical proofreading of the manuscript.
Open Access funding provided by Eidgenössische Techni-
sche Hochschule Zürich.
Conflict of Interest
The authors declare no conflict of interest.
Data Availability Statement
The data that support the findings of this study are available
from the corresponding author upon reasonable request.
Keywords: amination ·cyclopentenones ·hypervalent iodine ·
pyridones ·ring expansion
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Manuscript received: April 30, 2024
Accepted manuscript online: June 27, 2024
Version of record online: August 16, 2024
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