Modular Approach to Substituted Pyridoazepinones

Article abstract of DOI:10.1021/acs.orglett.1c00321

Pyridoazepinones are potentially interesting structures, yet they are still underexploited in the medicinal chemistry field and hard to obtain synthetically. We present a general and flexible synthetic route to substituted pyridoazepinones, enabled by the xanthate addition-transfer process, which furnishes the target molecules from readily available starting materials in generally good yields. The method shows good functional group tolerance and allows the preparation of pyridoazepinone scaffolds on gram scale.

Full text of DOI:10.1021/acs.orglett.1c00321

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Modular Approach to Substituted Pyridoazepinones
Valentin S. Dorokhov and Samir Z. Zard*
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ABSTRACT: Pyridoazepinones are potentially interesting structures, yet
they are still underexploited in the medicinal chemistry field and hard to
obtain synthetically. We present a general and flexible synthetic route to
substituted pyridoazepinones, enabled by the xanthate addition−transfer
process, which furnishes the target molecules from readily available starting
materials in generally good yields. The method shows good functional group
tolerance and allows the preparation of pyridoazepinone scaffolds on gram
scale.
he pyridine ring is one of the most common subunits in
pharmaceuticals and agrochemicals. It also appears in a
variety of fused scaffolds possessing a myriad of medicinal
properties. Thus, the search for efficient and reliable strategies
toward pyridine-containing structures represents an important
challenge in organic chemistry.
Pyridoazepinones constitute such scaffolds. They are
present in nature as fragments of biologically active
substances, for example in adina alkaloids, isolated from
Adina rubescens (Figure 1).1 Synthetic derivatives of this class
compounds dates from 1969.5 The most common method to
access pyridoazepinones is based on ring expansion reactions,
such as the Beckmann and Schmidt rearrangements (Scheme
1A).6
T
However, in most cases, this strategy requires the
preparation of highly functionalized substrates and incudes
de novo pyridine ring formation. Furthermore, the variety of
structures that can be attained by this route is limited due to
low functional group tolerance. The same problems arise
when the seven-membered ring is constructed via a
Dieckmann condensation (Scheme 1A).3,7 Even though
these methods have furnished target materials for biological
evaluations, they lack flexibility and do not allow the
preparation of the large libraries of compounds needed for
drug discovery. A completely different method, based on
palladium-catalyzed C−H arylation, was described by Cramer
and co-workers.8 Being tailored mostly for the preparation of
benzazepinones containing quaternary stereocenters in the
seven-membered ring, this method also allowed the synthesis
of pyridoazepinone. However, only one example was reported
and the reaction required harsh conditions and a high catalyst
loading. Summing up the above, a new, practical, and
convergent approach to pyridoazepinones would be highly
valuable.
Figure 1. Some biologically active pyridoazepinones
include Nevirapine, a non-nucleoside inhibitor of HIV reverse
transcriptase.2 Nevirapine was approved in 1996 by the FDA
and is currently in the WHO List of Essential Medicines.
Another medicinally active pyridoazepinone is 1-azakenpaul-
lone, which inhibits glycogen synthase kinase 3, a therapeutic
target in the development of antidiabetic drugs.3
Finally, pyridoazepinones are classical isosteres of benzaze-
pinones, which are an important family of biologically active
compounds (they act, for example, as sodium channel
blockers).4 Thus, it would be desirable to make nitrogen-
containing analogues of various biologically active benzaze-
pinones. This sort of modification may result in better
binding with protein active sites and in improved
pharmacokinetic properties.
Following a longstanding interest in the synthesis of
heterocyclic scaffolds in our group,9 we developed a few
pathways to benzazepinones10 and N-alkyl-substituted pyr-
idoazepinones11 (Scheme 1B). In this paper, we present a
general and modular synthesis of N-unsubstituted pyridoaze-
pinones. Our method features the construction of the seven-
Received: January 27, 2021
Published: March 2, 2021
This being said, however, it was surprising to find that no
general method for the synthesis of these structures has been
established, even though the first record of obtaining such
https://dx.doi.org/10.1021/acs.orglett.1c00321
© 2021 American Chemical Society
Org. Lett. 2021, 23, 2164−2168
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Scheme 1. Methods for the Synthesis of Pyridoazepinones
Scheme 2. Proposed Strategy toward Pyridoazepinones
formation of delocalized dihydropyridinyl radical E, in
which the fragmentation of the N−S bond occurs to give
intermediate F with extrusion of a methanesulfonyl radical.
This latter species can extrude sulfur dioxide to furnish a
methyl radical that can participate in the chain propagation.
As for intermediate F, it rapidly undergoes a tautomerization
to yield the desired pyridoazepinone G. This last
fragmentation thus serves to rearomatize the pyridine ring
and furnish at the same time the N-unsubstituted seven-
membered ring lactam.
For the starting point for our studies, we chose 2-chloro-5-
aminopyridine because our previous experience showed the
utility of a substituent on position 2 in curtailing the
nucleophilicity of the pyridine nitrogen and preventing an
ionic destruction of the xanthate group.10 Following this
consideration, we converted 2-chloro-5-aminopyridine into
the corresponding xanthate 3a via a simple three-step
sequence, with each step proceeding in good to excellent
yield (Scheme 3). It is also worth noting that the reactions
membered ring by C−C bond formation via a xanthate
addition−transfer process, radical cyclization, and rearomati-
zation of the pyridine ring enabled by homolytic cleavage of
the sulfonamide bond (Scheme 1C).
The synthesis of pyridoazepinones from simple precursors
must address several challenges. First, the formation of seven-
membered rings is a rather unfavorable process, due to low
reaction rates12 that may result in lower yields and the
formation of side products. Additionally, the pyridine moiety
is more electron-deficient but is less aromatic than the
benzene ring, making the final oxidative aromatization step
more difficult. Finally, the most interesting examples of this
family possess a secondary amide group, which can partake in
constructive hydrogen bonding within the receptor or be
used as an additional functionalization site. However, an N-
monosubstituted amide can also be a drawback because it
adopts an E conformation that prevents the cyclization, as
shown by our previous reports;10 thus, a protecting group is
required that can be easily removed, preferably during the last
step of synthesis.
Scheme 3. First Example of Pyridoazepinone Synthesis
According to our method, substituted aminopyridines A
can be converted into xanthates B by a simple sequence that
includes sulfonylation, introduction of α-chloroacetyl group,
and xanthate formation (Scheme 2). Due to the high
commercial availability of substituted aminopyridines and
the ease of preparation of xanthates, a vast array of starting
materials can be synthesized in principle. The next step is the
peroxide-promoted intermolecular radical addition of xanthate
C to an unactivated olefin, which can bear various functional
groups. The xanthate addition−transfer process leads to
another, more complex xanthate C, which in turn gives a
radical D when treated with peroxide at high temperature.
The following intramolecular addition results in the
were carried out on multigram scale. All the materials are
crystalline and can be easily purified by recrystallization,
which makes this procedure highly suitable for further scaling
up.
The resulting xanthate 3a was then introduced into a test
reaction with allyl acetate, under thermal conditions with
substoichiometric amounts of dilauroyl peroxide (DLP) as
the initiator (10 mol %; DLP is also sold under lauroyl
peroxide, Laurox, or Luperox). This reaction proceeded with
very good yield (85%), and the isolated adduct 4aa was
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purified by column chromatography. We next examined the
ability of this xanthate to undergo the desired key cyclization
reaction. Based on our previous experience, a higher
temperature is usually required to induce the cleavage of
the sulfonamide moiety, and DLP was therefore replaced with
the more thermally robust di-tert-butyl peroxide (DTBP).
After screening three high-boiling solvents (chlorobenzene,
tert-butylbenzene, and octane), we found that the best results
were obtained with chlorobenzene. To our delight, the target
pyridoazepinone 5aa was produced in good yield (64%).
We next expanded the study to other olefins (Scheme 4).
Model xanthate 3a, derived from 2-chloro-5-aminopyridine,
does not therefore cause any significant complications in the
present context.
We also explored the scope of the pyridines that can be
involved in this sequence (Scheme 5). Thus, we prepared
Scheme 5. Scope of Pyridines
Scheme 4. Olefin Scope
four xanthates, bearing bromo (3b), methyl (3c), and
trifluoromethyl substituents (3d) in the 2-position of the
pyridine ring and, finally, a methyl group in the α-position to
the carbonyl group (3e) (see Supporting Information for
details). In the case of xanthates 3b, 3d, and 3e we were glad
to find that both the radical addition and cyclization steps
proceeded with moderate to good yields; for xanthate 3c,
however, we quite surprisingly isolated only the sulfonylated
product 6ca. In this case, the oxidation of the intermediate
radical (radical E in Scheme 2) seems to be more favorable
than the extrusion of methanesulfonyl radical, for as yet
unknown reasons.
The regioisomeric products 5fa, 5fc, 5ga, and 5gc, derived
from 4-amino-2-chloropyridine and 6-amino-2-chloropyridine,
were also prepared in the same manner. Even though
xanthates 4fa and 4fc readily cyclized to the 3-position of the
pyridine ring, the reaction proved to be more problematic in
the case of the products 5ga and 5gc, giving a mixture of
unidentifiable side products. In order to improve the yield,
we tried to perform the cyclization of xanthate 4gc under
microwave heating. However, no increase of the yield was
found. We also conducted the reaction in the presence of
camphorsulfonic acid (CSA), bearing in mind the assumption
that the protonated pyridine nucleus should react faster
(“Minisci-type” reaction conditions). Unfortunately, no
improvement in the yield was observed either, and the
reaction merely resulted in hydrolysis of the amide bond of
most of the starting xanthate 4gc. The reasons for the
delinquent behavior of the 2-chloro-6-amino- series are not
clear at the moment, and further work is needed to probe
this question.
reacted readily with various alkenes, and the cyclization
provided pyridoazepinones bearing different substituents,
including esters, protected amines, boronate esters, silanes,
and more complex structures like purines. 1,1-Disubstituted
alkenes can also be used, leading to the creation of a
quaternary center, as indicated by example 5an. The fact that
the intermolecular addition step to electronically unbiased
alkenes proceeds in higher yield than the cyclization step
underscores the general difficulty of producing a seven-
membered ring by direct radical ring closure, and even more
so when the cyclization is onto an aromatic or heteroaromatic
nucleus. It is also worth noting that, in the absence of alkene,
treatment of xanthates such as B (Scheme 2) leads to
azaoxindoles,11 but even this ring-closure mode appears to be
slower than the intermolecular addition to the alkene and
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To highlight further the practicality of our approach, we
performed the sequence leading to benzazepinone 5aa in a
one-pot process, which furnished the desired product in a
somewhat better overall yield (Scheme 6). We also prepared
hitherto hampered their more extensive exploitation by
medicinal chemists. It is hoped that the present work will
contribute to eliminating this barrier and encourage the
incorporation of such structures in the design of biologically
active substances.
Scheme 6. One-Pot and Gram-Scale Synthesis
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00321.
Experimental procedures, full spectroscopic data, and
1
copies of H and 13C NMR for all new compounds
(PDF)
AUTHOR INFORMATION
Corresponding Author
■
̀
Samir Z. Zard − Laboratoire de Synthese Organique, CNRS,
UMR 7652, Ecole Polytechnique, Palaiseau, Cedex 91128,
France; orcid.org/0000-0002-5456-910X;
Email: samir.zard@polytechnique.edu
pyridoazepinone 5aa from xanthate 3a on gram scale,
affording 1.26 g of the target product (Scheme 6). In this
case, the purification of the product consisted of a single
precipitation from the concentrated reaction mixture instead
of column chromatography.
Finally, to demonstrate the utility of the pyridoazepinone
scaffold for medicinal chemistry, we tried to prepare several
derivatives of compound 5aa, exploiting the presence of the
secondary amide function (Scheme 7). Tetrazoles belong to
Author
̀
Valentin S. Dorokhov − Laboratoire de Synthese Organique,
CNRS, UMR 7652, Ecole Polytechnique, Palaiseau, Cedex
91128, France
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00321
Scheme 7. Derivatization of Pyridoazepinones
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This paper is affectionately dedicated to Professor Ilhyong
Ryu on the occasion of his 70th birthday. We also
respectfully dedicate it to the memory of our friends:
Professors Robert M. Williams (Colorado State University),
Franco
̧
is Diederich (ETH, Switzerland), Chris Abell (Uni-
is Mathey (NTU, Singapore
versity of Cambridge), Franco
̧
and Zhengzhou University, China), and Victor Snieckus
(Queens University, Kingston, Canada). We gratefully
acknowledge financial support by the ANR (project
SULFA) and thank Dr Sophie Bourcier (Laboratoire de
Chimie Moléculaire, Ecole Polytechnique) for recording the
high-resolution mass spectra.
an interesting class of pharmacophore groups and are present
in various medicaments.13 Thus, we prepared tetrazole 7
using the method reported recently by Matsugi and co-
workers.14 Another possible modification of pyridoazepinones
relies on the functionalization of the α-position of the amide
via the corresponding Vilsmeier salt. Thus, treatment with
phosphorus pentachloride furnished dichlorolactam 8 in good
yield. Interestingly, under milder conditions, the monochlori-
nated product 9 is fortuitously produced in the same yield.
In conclusion, we have developed a modular and scalable
synthesis of pyridoazepinones, exploiting cheap and readily
available starting materials and reagents. Most of the
structures described in the preceding schemes would be
quite difficult to obtain by more traditional routes. Indeed, it
is the relative inaccessibility of pyridoazepinones that has
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