Magnesiate-Utilized/Benzyne-Mediated Approach to Indenopyridones from 2-Pyridones: An Attempt to Synthesize the Indenopyridine Core of Haouamine

Article abstract of DOI:10.1021/acs.orglett.9b03806

An efficient, short-staged synthesis of cis-fused indeno[2,1-b]- and indeno[1,2-c]pyridin-2-ones, starting from 2-pyridones, using magnesiates of type R₃MgLi as nucleophilic and deprotonation agents, mediated by benzyne generated in situ, under optimized conditions, is described. Following the developed protocol, rare C4a-arylsubstituted indeno[2,1-b]pyridones, resembling the core of haouamine, were obtained. The protocol offering the one-pot synthesis directly from 2-pyridone is also described.

Full text of DOI:10.1021/acs.orglett.9b03806

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Magnesiate-Utilized/Benzyne-Mediated Approach to
Indenopyridones from 2‑Pyridones: An Attempt To Synthesize the
Indenopyridine Core of Haouamine
́
Tomasz J. Idzik, Aleksandra Borzyszkowska-Ledwig, Łukasz Struk, and Jacek G. Sosnicki*
West Pomeranian University of Technology, Szczecin, Faculty of Chemical Technology and Engineering, Department of Organic
́
and Physical Chemistry, Al. Piastow 42, Szczecin, 71-065, Poland
S
* Supporting Information
ABSTRACT: An efficient, short-staged synthesis of cis-fused
indeno[2,1-b]- and indeno[1,2-c]pyridin-2-ones, starting from
2‑pyridones, using magnesiates of type R3MgLi as nucleophilic and
deprotonation agents, mediated by benzyne generated in situ, under
optimized conditions, is described. Following the developed
protocol, rare C4a-arylsubstituted indeno[2,1-b]pyridones, resem-
bling the core of haouamine, were obtained. The protocol offering
the one-pot synthesis directly from 2-pyridone is also described.
he indenopyridine(piperidine) ring-fused system occurs
Being aware of the high value of indenopyridines and their
derivatives as potential pharmaceuticals, we decided to obtain
this fused system by intramolecular cyclization of benzyl group
of 6-benzyl-3,6-dihydropyridin-2-one derivatives, which were
obtained by us earlier in the nucleophilic addition of
benzylmagnesiate to 2-pyridones.6 In planning the synthesis,
we considered the use of substrates with or without a
substituent at C5, bearing in mind that C5-aryl-functionalized
substrates could lead to C4a-substituted indenopyridones with
quaternary chiral center at C4a, which are closely related to the
haouamine core. As far as the construction of the
indenotetrahydropyridine center of haouamines is concerned,
the strategies based on the intramolecular annulation of benzyl
moiety connected to a piperidine ring at a position adjacent to
the N atom have been successfully applied, using the Friedel−
Crafts,5a,c,j,m Pd-catalyzed α-C-arylation5k and Heck’s5f ring
closure methods. In the hitherto-described attempts, 6-benzyl-
3,6-dihydropyridin-2-ones have not yet been used as
substrates. Moreover, although 4-methoxypyridine,5k 3,5-
dimethoxypyridine,5c and pyridinium salts5h have been used
as primary starting compounds, 2-pyridones have not, although
2-pyridones have been recognized as a universal precursor
applied in the synthesis of alkaloid-inspired compounds.7
In our earlier work, the annulation of 6-benzyl-3,6-
dihydropyridin-2-one with the use of the electrophilic aromatic
substitution, prompted by NBS/P(OR)3, did not bring the
indenopiperidine ring system but benzomorphanone deriva-
tives,8 which, only after the subsequent thionation and
reduction, gave hexahydro-1H-indeno[2,1-c]pyridines
(Scheme 1, top).9 Since the direct synthesis of indenopyr-
idinones was not possible in this way, in the present study, we
decided to reverse the electrons flow between the reacting
T
in many bioactive compounds, including synthetic 11β-
HSD-1 inhibitor,1 anticancer agents,2 compounds exhibited
strong antispermatogenic activity,3 and naturally occurring
sisterly alkaloidshaouamines A and B (Scheme 1) isolated
Scheme 1. Benzyl Moiety of 3 Acting (Top) as a
Nucleophile Results in Benzomorphanone Formation and
(Bottom) as an Electrophile in the Direct Synthesis of the
Indenopyridine Ring System
from the marine ascidian Aplidium haouarianum.4 The unique
structure of the latter, and their strong and selective anticancer
activity against the human colon carcinoma cell line HT-29,
are the reasons why attempts to synthesize these alkaloids have
been continued.5 Some of the difficulties encountered in the
synthesis of their derivatives are linked to obtaining the
indenotetrahydropyridine system, which has a quaternary
chiral center.5a−c,h,j−l
Received: October 28, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03806
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Organic Letters
Letter
fragments by applying benzyne (as an electrophilic site)
formed from the benzyl group and metalated lactam as the
nucleophilic center (Scheme 1, bottom).
magnesiates17 because these species, applied by us mainly in
the addition reactions,18 were recognized also as powerful
metalating agents.19
The results of optimization of the model transformation of
3c into 5c showed that the best conditions included
application of 2 equiv of iPrsBu2MgLi in the first deprotonation
step (at 0 °C, 1 h) and 5-fold excess of n-BuLi to cause ortho-
lithiation at the fluorobenzene ring (−80 °C, 3 h) and
temperature 0 °C for 3 min in order to achieve benzyne
formation and effective cyclization (see Scheme 2).
The last two decades have witnessed great progress in the
field of aryne-mediated synthetic organic chemistry. Among
many synthetic applications,10 an approach based on benzyne
methodology has played a particularly important role in the
synthesis of heterocyclic compounds11 and natural products,12
including alkaloids13 and other polycyclic azaheterocycles.14
Nevertheless, the aryne chemistry has not been often applied
for the functionalization of 2-pyridones and their derivatives.15
Exploring the aryne strategy, herein, we report the result of
our study, that is a new method for the synthesis of the
indenopyridine system mediated by benzyne, generated from
benzyl-functionalized moiety of unsaturated δ-lactams, and the
results of our efforts on the extension of developed procedure
for the synthesis of indenopyridine core of haouamine.
Our investigation started by choosing the functionalization
type of benzyl group of 3 capable for benzyne formation.
Among many methods allowing the generation of benzyne
from a functionalized benzene ring,10 we have chosen that
involving spontaneous elimination of LiF from the appropriate
fluorosubstituted benzene derivatives initiated by ortho-
lithiation using organolithium reagents.16 For these reasons,
o-fluorobenzyl group was introduced into 3,6-dihydropyridin-
2-one 3 by the addition of nucleophilic magnesiates 2a and 2b,
to diversely substituted 2-pyridones 1, according to the
method described earlier (Scheme 2).6 The detailed results
are collected in Table S1 in the Supporting Information.
On the basis of the results presented above, we can conclude
that successful synthesis of indenopyridines through benzyne
annulation to a lactam moiety is dependent on the proper
n
selection of deprotonating reagents (iPrsBu2MgLi and BuLi),
which are able to deprotonate the substrate at different sites at
different temperatures. It means that there is no conflict
between magnesiate and n-BuLi, which permits the reaction
control. Furthermore, an important factor observed in the
reaction of obtaining indenopyridone is a short cyclization
time at 0 °C, which is 3 min. A short reaction time as a factor
enabling efficient reaction with benzyne has also been
described earlier.20
Having optimized the reaction conditions, we next tested the
use of the following compounds: 6-(o-fluorobenzyl), N-
substituted (3a−3f) and N-Bn, C3-Ph disubstituted (3g), as
well as 6-(o-fluoro-p-methoxybenzyl), N-substituted (3s−3u)
derivatives. According to the result depicted in Scheme 3, 6-(o-
Scheme 3. Synthesis of indeno[2,1-b]pyridin-2-ones 5 under
Optimized Conditions
Scheme 2. Synthesis of 6-(o-fluorobenzyl)-3,6-dihydro-
pyridin-2-ones 3 and 4-(o-fluorobenzyl)-3,4-dihydropyri-
din-2-ones 4 and Optimized Conditions for 5c Formation
We next searched for the best conditions to obtain
indenopyridone 5 from 3 adjusting the time and temperature
of the following steps: deprotonation of lactam ring, lithation
at benzene moiety, benzyne formation and cyclization
(Scheme 2, detailed results are collected in Table S2 in the
Supporting Information). In the first two steps, the appropriate
metalation agents were searched considering their different
quantities, relative to 3. Because in the primary attempts,
organolithium bases (n-BuLi, sec-BuLi and t-BuLi, LiTMP)
used in 2-fold to 4-fold excess as sole deprotonation agents
definitively gave no positive results, we turned our attention to
fluorobenzyl)-substituted compounds gave the corresponding
indenopyridone products 5a−5g in satisfactory isolated yields,
while, surprisingly, 6-(o-fluoro-p-methoxybenzyl)-substituted
3s−3u did not lead to products 5h−5j, because of their
instability during the reaction or decomposition after
extraction.
The next group of compounds tested were 5-substituted and
3,5-disubstituted derivatives 3 (Scheme 4). Fortunately, in
most reactions, the desired indenopyridone products 6
containing quaternary C4a-carbon atoms and α,β-positioned
double bonds in lactam moieties were obtained. However, note
that the yields were dependent on the structure of the substrate
and, in a few reactions, the formation of additional byproducts
7a, 7b, and 8a was observed. Most importantly, products 6e
magnesiates of the type R1R2 MgLi, obtained prior to use by
2
simple mixing of 1 equiv of a Grignard reagent (R1 MgCl) and
2 equiv of organolithium (R2Li). We decided to use lithium
B
DOI: 10.1021/acs.orglett.9b03806
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Organic Letters
Letter
Scheme 4. Yields of Desired Product 6 and Byproducts 7
and 8 Obtained As the Result of Cyclization of 3 under
Optimized Conditions
Scheme 6. Possible Mechanism of 6 and 7 Formation
at the first deprotonation step under the optimized conditions.
In addition, in the final product 7d-D, the deuterium atom is
present at a vinyl position adjacent to carbonyl, and this
position cannot be easily deprotonated; therefore, we conclude
that, at the first step, dimagnesiated product M1 is formed by
CH-α deprotonation, double bonds are shifted, and a second
deprotonation of benzyl/allyl position C5 of the lactam ring
occurs. Second, deuteration of the CH2 of N-PMB group in
7d-D clearly proved that byproduct 6a-D is formed through a
less-preferred nucleophilic attack of N-CHLiPMB toward the
benzyne site (see Scheme 6, route b). Finally, note that, in
almost all of the reactions, cyclization involving the connection
of C5-magnesiate to benzyne sites is preferred (see Scheme 6,
route a).
and 6f, structurally similar to houamine, were isolated in 61%
and 23% yields, respectively. The low yield of the latter is the
effect of incomplete conversion and isomerization of the
substrate to α,β-unsaturated isomer 3n-2 during the reaction
(see Table S1, entry 14, in the Supporting Information).
In continued studies, an attempt to cyclize 4-methyl-
substituted compounds (3o) led to a complex mixture while
4-aryl substituted derivatives 3p, 3r yielded polyaromatic
compounds 9a and 9b in low yields; this indicates a
competitive sequential [4 + 2] cycloaddition reaction, followed
by an aromatization process (Scheme 5). Only the 4-(furan-2-
yl)-substituted derivative 3r gave an indenopyridone product
(5k) in 53% yield.
At this stage, the potentially useful sequential one-pot
synthesis of indenopyridones obtained directly from 2-
pyridones was also tested (Scheme 7). Thus, after addition
Scheme 7. Sequential One-Pot Synthesis of
Indenopyridones Obtained Directly from 2-Pyridones
Scheme 5. Magnesiate/Benzyne Cyclization of 3o−3r
To shed more light on indenopyridones 5 and 6 and
byproduct formation, a deuteration experiment was performed,
which consisted of quenching the reaction of 3l conducted
under optimized conditions by treatment with D2O (Scheme
6). The analysis of deuterated products 6d-D and 7a-D
revealed that they were obtained in yields comparable to
nondeuterated products 6d and 7a and that they contained 3
and 2 deuterium atoms, respectively, hence indicating the
metalation sites in the final products before quenching. On the
basis of the above results, a formation mechanism of
indenopyridones 6 and 7 is proposed, in which two issues
should be highlighted. First, since our earlier investigation, we
have observed that 3,5-dialkylated products were formed in
alkyl-allylation of β,γ-unsaturated δ-lactams, deprotonated by
magnesiates;19 furthermore, 2 equiv of magnesiate are required
of o-fluoro-benzylmagnesiate 2a to an appropriate 2-pyridone,
the optimized conditions were applied for cyclization, except
i
the quantity of Pr(sBu)2MgLi, because only 1 equiv of this
reagent was added, because another one was already
introduced in the addition reaction. The results, which are
not fully satisfactory, because of moderate yields, indicate,
however, a high prospect of this reaction, which probably
requires additional optimization adjustment. Note the fact that
byproduct 8b formed in this reaction has the same skeleton as
product 8a described above (Scheme 4, entry 2). An in-depth
structural analysis showed that, in the formation of 8, the δ-
lactam ring is expanded to azepan-3-one ring. A plausible
C
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Organic Letters
Letter
mechanism consisting of the main stages of this reaction,
starting from 3k, is presented in Scheme 7. It includes single
magnesiation of the lactam ring, lithiation at N-CH2 and
benzene groups (M5), subsequent aziridination by intra-
molecular nucleophilic addition to carbonyl group, its
restoration with simultaneous opening of aziridine ring, and
addition of nitrogen nucleophile to benzyne, formed
independently from o-fluorobenzene moiety (M6). Since,
here, the cyclization of the lactam site with benzyne is not
preferred (in contrast to the reaction of indenopyridine
formation), we can conclude a lower degree of magnesiation
of the lactam ring and infer that, under these circumstances,
the reactivity of the N-CHLi site comes to the forefront.
Finally, we apply our magnesiate-utilized benzyne-mediated
protocol for the construction of cis-fused indeno[1,2-c]pyridin-
1-ones 10 from 4 (see Scheme 8). Generally, the products
rare C4a-aryl-functionalized indeno[2,1-b]pyridones with
quaternary C4a-atom, resembling the core of haouamine, is a
promising premise to receive this alkaloid or its derivatives.
Besides, the deuteration experiment pointed toward a broader
range of possible functionalizations of indenopyridine core
through treatment with electrophiles other than D2O. A study
to extend indenopyridine functionalization via trapping of
various electrophiles by metalated indenopyridones intermedi-
ates is currently underway.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03806.
1
Experimental procedures, spectroscopic data and H,
13C, 19F NMR spectra for all new compounds (PDF)
Scheme 8. Syntheses of Indeno[1,2-c]pyridinones 10
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: sosnicki@zut.edu.pl.
ORCID
́
Jacek G. Sosnicki: 0000-0002-3962-9311
Author Contributions
All authors have given approval to the final version of the
manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support by the National Science Center, Poland
(Grant No. 2016/23/N/ST5/00101), is gratefully acknowl-
edged.
were obtained in good yields and formation of byproducts was
not observed. Substrates 4d, 4h, 4t, and 4u, obtained as second
regioisomeric products from the additions of benzyl
magnesiates 2a and 2b to N-functionalized 2-pyridones in
sufficient quantity (see Scheme 2, as well as Table S1 in the
Supporting Information), were submitted directly for cycliza-
tion, while substrates 4a, 4c, 4i, 4k, and 4l were synthesized via
a different route by applying the regioselective C4 addition of
an appropriate magnesiate to N-Li 2-pyridone, followed by N-
alkylation (see Table S3 in the Supporting Information).6,18a−e
The structures of all compounds were elucidated with the
aid of one-dimensional (1D) and two-dimensional (2D)
nuclear magnetic resonance (NMR) spectroscopy, gas
chromatography-mass spectroscopy (GC-MS) and high-
resolution mass spectroscopy (HRMS) analyses (for details,
see the Supporting Information).
In summary, we have demonstrated a novel approach to
indeno[2,1-b]- and indeno[1,2-c]pyridones, achieved from 2-
pyridones as primary substrates. A synthetic, concise method-
ology relies on the addition of o-fluorobenzyl magnesiate to 2-
pyridones, providing o-fluorobenzylated dihydropirydyn-2-
ones, followed by cis-stereoselective cyclization of pendant
benzyne intermediate that was generated in situ from o-
fluorobenzyl moiety under optimized conditions. The method-
ology is based on the application of magnesiates enabled
metalation of δ-lactam ring and facilitated nucleophilic
cyclization at the electrophilic benzyne site. The synthesis of
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