Umpolung-like Cross-coupling of Tosylhydrazones with 4-Hydroxy-2-pyridones under Palladium Catalysis

Article abstract of DOI:10.1021/acs.orglett.9b03119

Tosylhydrazones under palladium catalysis were found to perform cross-coupling reactions with 4-hydroxy-2-pyridones. The umpolung-like reactivity, between the α-carbon of tosylhydrazone and the 3-position of the heterocycle, which is observed in the obtai

Full text of DOI:10.1021/acs.orglett.9b03119

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Umpolung-like Cross-coupling of Tosylhydrazones with 4‑Hydroxy-
2-pyridones under Palladium Catalysis
Tania Katsina, Kyriaki Eleni Papoulidou, and Alexandros L. Zografos*
Department of Chemistry, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece
S
* Supporting Information
ABSTRACT: Tosylhydrazones under palladium catalysis were
found to perform cross-coupling reactions with 4-hydroxy-2-
pyridones. The umpolung-like reactivity, between the α-carbon of
tosylhydrazone and the 3-position of the heterocycle, which is
observed in the obtained products, indicates the directed sp3-CH-
activation of an alkylated phenol intermediate by the pendant
3-palladated heterocycle. The reaction and its intercepted variants
are surveyed in their scope, allowing the synthesis of inaccessible
3-carbocyclic pyridones in moderate to excellent yields.
their well-established biological importance,5 methods for the
CH-activation of 2-pyridone heteroaromatic ring has attracted
considerable attention in recent years.1 CH-functionalization at
CH-activation of the related 4-hydroxy-2-pyridones are rather
scarce6 due to the nucleophilicity of the attached 4-phenol sub-
the 3-position is mainly relying on radical mediators, such as
nickel, manganese, iron, and iridium complexes,2 whereas the
stituent that leads preferentially to dimerized products when
metals are applied. Recently, our group revealed the ability of
the 4-hydroxy-2-pyridone core to palladate at the 3-position with
the aid of palladium acetate under mild conditions, enabling the
application of Suzuki−Miyaura7a and Heck7b reactions to
produce 3-aryl and 3-alkyl derivatives, respectively (Figure 1).
Despite the undeniable power of the latter method to easily
provide 3-alkylated products, its inability to access more com-
plex derivatives has been witnessed when endocyclic alkenes
were utilized as coupling partners. The latter is especially unfor-
tunate, due to the longstanding interest of our group in the total
synthesis of 4-hydroxy-2-pyridone alkaloids (Figure 1),8 where
the direct C-3 selective alkylation is highly desirable to access
these complex carbocyclic cores.
functionalization of the 5-position is almost exclusively depen-
dent on palladium chemistry (Figure 1).3 However, the electron
Tosylhydrazones have been well recognized the past decade
as powerful cross-coupling partners for several transformations,
including their application as alkylating agents and metal
carbene precursors.9 Based on these literature precedents, we
quested whether tosylhydrazones can act as alkylating reagents
for 4-hydroxy-2-pyridone heteroaromatic core allowing not
only to access more complex members but also to trespass the
regioselectivity issues posed by a typical Heck-type reaction.
To test this hypothesis, N-methyl-2-pyridone (1) and
acetophenone-tosylhydrazone (2) were chosen as readily avail-
able materials to model the reaction. Based on our previous
studies,7 it was known that the addition of a base is advanta-
geous for the formation of dipyridone as a byproduct. How-
ever, in the case of tosylhydrazones the use of a base was
necessary for the formation of the diazo components. The first
attempts, utilizing K2CO3 in different reaction sets (entries 1−5),
Figure 1. Existing methods for the CH-activation of 2-pyridone and
4-hydroxy-2-pyridone cores and the reported herein sequential
alkylation-CH-activation of 4-hydroxy-2-pyridone heteroaromatic.
deficient 6-position of the heteroaromatic core has been
accessed by the aid of directing groups attached on the
nitrogen atom,4 or by cooperative catalysis between electro-
philic activation employing Lewis acids and electron-rich metal
complexes (Figure 1).4 These methods render 2-pyridones as a
reliable heteroaromatic template for CH-functionalization by a
wide range of reagents, including electron-rich and -poor
aromatics, alkenes, and alkyl groups. On the contrary, despite
Received: September 2, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03119
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
provided only traces of a cross-coupling product (5−20%),
favoring, as expected, the production of dipyridone 3. To our
surprise, purification and characterization of the cross-coupling
fraction led to the 5-methyl-2-phenylfuro[3,2c]-pyridin-4(5H)-
one (4) as the sole product, identical to the one produced by
the acidic Heck reaction of styrene with N-methyl-4-hydroxy-
2-pyridone (1).7b Besides these unpredicted findings, the
reaction sets reveal the expected enhancement of dipyridone
byproduct under polar solvents at high temperatures (entries 1
and 6; Table 1).7a These effects were minimized by utilization
For this study, a range of linear and carbocyclic hydrazones were
prepared and allowed to react under our optimized conditions
with different N-protected 4-hydroxy-2-pyridones (Scheme 1).
a
Scheme 1. Reaction Scope
a
Table 1. Optimization of Reaction Parameters
temp
(°C)
yield (%)
b
b
c
entry
base
solvent
conv (%)
(3/4)
1
2
3
4
5
6
7
8
9
K2CO3 (2 equiv) dioxane
K2CO3 (2 equiv) dioxane
K2CO3 (2 equiv) dioxane
K2CO3 (2 equiv) AcOEt
130 100
80 89
60 29
80 50
70:10
55:20
20:5
30:10
58:12
80:10
70:10
64:10
decomp
26:64
65:15
63:22
65:20
30:58
97:0
K2CO3 (2 equiv) acetonitrile 80 78
K2CO3 (2 equiv) DMF
K2CO3 (3 equiv) dioxane
LiOtBu (1 equiv) dioxane
80 100
80 85
80 80
80 100
80 94
80 87
80 100
80 100
80 90
80 100
80 100
DBN (1 equiv)
dioxane
dioxane
dioxane
DMF
10 DBU (1 equiv)
11 DBU (2 equiv)
12 DBU (1 equiv)
13 DABCO (1 equiv) DMF
14 DABCO (1 equiv) dioxane
15 DBU (1 equiv)
16 DBU (1 equiv)
17 DBU (1 equiv)
18 DBU (2 equiv)
d
DMF
e
dioxane
dioxane
dioxane
dioxane
decomp
f
80 100 (based on 2) 20:66
80 100
80 93
g
55:35
20:70
h
19 DBU (1 equiv)
a
Reaction conditions unless otherwise noticed: (a) 1 (0.16 mmol), 2
(0.16 mmol), solvent (1 mL), Pd(OAc)2 (10 mmol %), Cu(OAc)2
(0.16 mmol), base (indicated equivalents), 80 °C, 12 h in a 4 mL
b
sealed screw capped vial. Conversion as indicated by crude NMR
c
d
using internal standard. Yields referred to isolated products. In the
e
absence of Cu(OAc)2; oxygen as oxidant. Benzoquinone (1 equiv)
f
was used as oxidant. The ratio of pyridone/hydrazine was 2:1
g
(0.32 mmol: 0.16 mmol). The ratio of pyridone/hydrazone was 1:2
(0.16 mmol: 0.32 mmol). Premixing conditions of tosylhydrazone
h
and the base were applied followed by heating at 40 °C for 10 min
before pyridone 1, Cu(OAc)2, and Pd(OAc)2 were introduced and
heated to 80 °C.
a
Reaction conditions of Table 1 utilizing tosylhydrazones obtained
of dioxane at 80 °C (entry 2; Table 1). The use of hindered
bases in stoichiometric quantities, like DBU, improved the
results, affording 64% yield of 4 (entry 10; Table 1). Premixing
hydrazone 2 with DBU before the addition of the hetero-
aromatic substrate followed by the oxidant and the catalyst was
found to be advantageous delivering 4 in 70% yield (entry 19).
Attempts to further diminish dipyridone formation by screen-
ing oxidants (entries 15−16) or by altering the ratio of the
reagents (entries 17−18; Table 1) did not allow any observ-
able improvement.
from the indicated ketones. The reported yields are after isolation;
yields indicated with an (*) correspond to the in situ formation of
tosylhydrazones in the reaction mixture.
In all tested cases, reactions proceeded smoothly to provide
furo[3,2c]-pyridin-4(5H)-one in moderate to excellent yields.
As expected, linear methyl alkyl or methyl phenyl hydrazones
delivered products 4−11 (Scheme 1), which are identical to
those obtained from the cross-coupling of the associated termi-
nal alkenes.7b These results validate our initial assumption over a
Heck-type mechanistic pathway resulting from the dissociation
Having in our hands the optimized conditions, we sought to
test if diverse tosylhydrazone substrates lead to similar results.
B
DOI: 10.1021/acs.orglett.9b03119
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Letter
of tosylhydrazones to provide the most accessible alkenes.
In sharp contrast to our previous observations,7b where internal
alkenes (like compound 27, Scheme 2) were unable to cyclize
was used as the solvent in both cases. Both tosylhydrazone of
acetophenone 2 and 4-methyl cyclohexanone 30 were trans-
formed to diazo derivatives 31 and 32, respectively, within 1 h
of heating with DBU, without the evidence of any produced
alkenes. The same was also apparent even after several hours of
heating under the same conditions. Applying the same set of
reactions in the presence of Pd(OAc)2 afforded 15% of styrene
within 1 h of heating and dimerization products as major
components after extended hours of heating. However, no
formation of alkene product was detected for hydrazone 30 in
the same series of reactions (Scheme 2).
Scheme 2. Studies on Reaction Mechanism
Taking into account this information, we next turned our
attention to potential isolated intermediates from the reac-
tion mixture. To this end, aliquots were taken from the reac-
tion of N-propyl-4-hydroxy-2-pyridone 33 and cyclopentanone
tosylhydrazone 34, at different reaction times (Scheme 2).
In all cases, the only observed coupling product, apart from 14,
was compound 3510 (or its deuterated form 35-d depending
on the quenching conditions). What is more, exclusion of
dioxygen from the reaction mixture led to the isolation of
dihydro component 36 (Scheme 2).
To further exclude reactive intermediates on the reaction path-
way, we synthesized and tested compounds 35 and 37 for their
ability to cyclize to 14 and 5, respectively (Schemes 1 and 2).
Heating, even for prolonged reaction times, compounds 35
and 37 in the presence of DBU and Pd(OAc)2 did not provide
any products. This corroborates our previous observations7 for
the necessity of a free phenol as mediator to deliver Pd(II) in
the heterocycle for the formation of the cyclized products.
These preliminary studies on the reaction mechanism sug-
gest a catalytic cycle that starts with the incorporation of palla-
dium acetate into the pyridone-2 core to form 38 (Scheme 3).
Then, the subsequent formation of diazo-compound 39 under
the basic conditions allows the formation of palladium carbene
40. Intramolecular phenol insertion on the carbene forms inter-
mediate 41, which bears both O-alkylation and palladium(II) in
the 3-position of the heterocycle. We hypothesize that the
latter is responsible for a directed CH-activation of the pendant
sp3 bond to produce intermediate 43 and then form the final
products. As discussed earlier, an additional synergistic mecha-
nism (Heck type reaction) might still be valid for the cases of
methyl-tosylhydrazones where alkenes even in small quantities
have been witnessed (Scheme 3).
In our attempts to make the described protocol more appli-
cable, we tested the in situ preparation of tosylhydrazones in
the reaction mixture. Thus, mixing the desired ketone with
tosylhydrazide followed by stirring and sequential addition of
DBU, N-protected 4-hydroxy-2-pyridone, copper acetate, and
palladium acetate afforded the expected products in equal or
better yields compared to the ordinary procedure (Scheme 1,
yields with an *). Finally, reaction of 3-propyl-4-hydroxy-2-
pyridone 33 with 34 in a 2 mmol scale under our optimized
protocol provided a similar yield of 14 (67%), even by
lowering the catalyst loading to 5 mol %.
under Heck reaction conditions when tosylhydrazone of
3-pentanone 28 was applied in the reaction conditions, the
formation of compound 12 was evidenced (Scheme 2). The
latter inconsistency regarding Heck reaction pathway has also
been demonstrated when several carbocyclic hydrazones have
been utilized to deliver compounds 13−20 (Scheme 1). The
cyclized products were obtained in moderate yields, whereas
endocyclic alkenes under Heck conditions (see compound 29,
Scheme 2) did not provide any coupling products.
More interestingly, the carbocyclic tosylhydrazones bearing
substituents afforded exclusively one of the possible isomeric
products that attributed solely to an initial chemoselective
attack from the phenol group of the heterocycle to the sp2
carbon atom of the hydrazone (16−20, Scheme 1). The latter
clearly indicates the direct involvement of hydrazones, instead
of alkenes, as the active partners of the umpolung-like coupling
between its α-carbon and the 3-position of the heterocycle.
In an attempt to rationalize these results, an array of kinetic
experiments was set up with the aid of NMR to establish the
potential existence of in situ produced alkenes in the reaction
mixture (Scheme 2). Tosylhydrazones 2 and 30 were allowed
to react in NMR tubes under two different sets: (a) in the
presence of 1 equiv of DBU at 80 °C and (b) in the presence
of 1 equiv of DBU and 10 mol % of Pd(OAc)2. Chloroform-d
The ability of furo[3,2c]-pyridin-4(5H)-ones to serve as
excellent entry points for structural modifications5i is evidenced
when these are treated with aqueous acid. Furo[3,2c]-pyridin-
4(5H)-ones, especially those bearing substituents in both
2- and 3-positions of the furan moiety, were found to be prone
to cationic cleavage of the furan ring under acidic conditions.
The free phenol compounds that formed are in equilibrium
with the cyclized form, which allows further transformations.
Indicative examples for their ability to serve as excellent
C
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Scheme 3. Postulated Reaction Mechanism for the Cross-coupling of Tosylhydrazones with 4-Hydroxy-2-pyridones
Scheme 4. Indicative Transformations of Selected
Furo[3,2c]-pyridin-4(5H)-ones under Acidic Conditions
alkylation of the phenol substituent of the heterocycle by
tosylhydrazone, followed by directed CH-bond activation of
the more unshielded sp3-bond to deliver a formal umpolung
coupling between the α-position of a ketone and the C-3
position of the heterocycle. The reaction allows the incorpo-
ration of carbocyclic substituents in the heterocycle permitting
an easy access to natural and synthetic privileged structures.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b03119.
Experimental procedures, kinetic experiments, and full
characterization of all newly prepared compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: alzograf@chem.auth.gr.
ORCID
Alexandros L. Zografos: 0000-0002-1834-2100
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the project “OPENSCREEN-GR”
(MIS 5002691), which is implemented under the Action
“Reinforcement of the Research and Innovation Infra-
structure”, funded by the Operational Program “Competitive-
ness, Entrepreneurship and Innovation” (NSRF 2014-2020)
and cofinanced by Greece and the European Union (European
Regional Development Fund). Funding is also provided by
ΕΠΑνεΚ Action (Τ1ΕΔΚ-01161), which is implemented in
collaboration with Pharmathen S.A. and cofinanced by Greece
and the European Union. Part of the project was inspired by
helpful discussions within CHAOS COST ActionCA15106.
precursors of diverse pyridone compounds are presented in
Scheme 4.
In conclusion, we describe the cross-coupling of the
4-hydroxy-2-pyridones core by tosylhydrazones under palla-
dium catalysis. The reaction is proposed to involve an initial
D
DOI: 10.1021/acs.orglett.9b03119
Org. Lett. XXXX, XXX, XXX−XXX

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Zincation or Magnesiation of the 2-Pyridone and 2,7-Naphthyridone
Scaffold Using TMP Bases. Org. Lett. 2017, 19, 5760−5763. (l) Ni, J.;
Zhao, H.; Zhang, A. Manganese(I)-Catalyzed C-H 3,3-Difluoroally-
lation of Pyridones and Indoles. Org. Lett. 2017, 19, 3159−3162. For
selected C-6 activation of 2-pyridones based on cooperative catalysis,
see: (m) Nakao, Y.; Idei, H.; Kanyiva, K. S.; Hiyama, T. Direct
Alkenylation and Alkylation of Pyridone Derivatives by Ni/
AlMe3Catalysis. J. Am. Chem. Soc. 2009, 131, 15996−15997.
(n) Tamura, R.; Yamada, Y.; Nakao, Y.; Hiyama, T. Alkylation of
Pyridone Derivatives By Nickel/Lewis Acid Catalysis. Angew. Chem.,
Int. Ed. 2012, 51, 5679−5682. (o) Donets, P. A.; Cramer, N. Ligand-
controlled regiodivergent nickel-catalyzed annulation of pyridines.
Angew. Chem. 2015, 127, 643−647.
REFERENCES
■
(1) For excellent reviews on the topic, see: (a) Hirano, K.; Miura, M.
A lesson for site-selective C-H functionalization on 2-pyridones:
radical, organometallic, directing group and steric controls. Chem. Sci.
2018, 9, 22−32. (b) Prendergast, A. M.; McGlacken, G. P. Transition
Metal Mediated C-H Activation of 2-Pyrones, 2-Pyridones, 2-
Coumarins and 2-Quinolones. Eur. J. Org. Chem. 2018, 44, 6068−
6082.
(2) For selected examples on C-3 activation of 2-pyridones, see:
(a) Kino, T.; Nagase, Y.; Ohtsuka, Y.; Yamamoto, K.; Uraguchi, D.;
Tokuhisa, K.; Yamakawa, T. Trifluoromethylation of various aromatic
compounds by CF3I in the presence of Fe(II) compound, H2O2 and
dimethylsulfoxide. J. Fluorine Chem. 2010, 131, 98−105. (b) Nakatani,
A.; Hirano, K.; Satoh, T.; Miura, M. Nickel-Catalyzed Direct
Alkylation of Heterocycles with α-Bromo Carbonyl Compounds:
C3-Selective Functionalization of 2-Pyridones. Chem. - Eur. J. 2013,
19, 7691−7695. (c) Nakatani, A.; Hirano, K.; Satoh, T.; Miura, M.
Manganese-Mediated C3-Selective Direct Alkylation and Arylation of
2-Pyridones with Diethyl Malonates and Arylboronic Acids. J. Org.
Chem. 2014, 79, 1377−1385. (d) Najib, A.; Tabuchi, S.; Hirano, K.;
Miura, M. Highly C3-Selective Direct Alkylation and Arylation of 2-
Pyridones under Visible-Light-Promoted Photoredox Catalysis.
Heterocycles 2016, 92, 1187−1203. (e) Modak, A.; Rana, S.; Maiti,
D. Iron-Catalyzed Regioselective Direct Arylation at the C-3 Position
of N-Alkyl-2-pyridone. J. Org. Chem. 2015, 80, 296−303. (f) Chauhan,
P.; Ravi, M.; Singh, S.; Prajapati, P.; Yadav, P. P. Regioselective α-
arylation of coumarins and 2-pyridones with phenylhydrazines under
transition-metal-free conditions. RSC Adv. 2016, 6, 109−118.
(3) (a) Maity, S.; Das, D.; Sarkar, S.; Samanta, R. Direct Pd(II)-
Catalyzed Site-Selective C5-Arylation of 2-Pyridone Using Aryl
Iodides. Org. Lett. 2018, 20, 5167−5171. (b) Chen, Y.; Wang, F.;
Jia, A.; Li, X. Palladium-catalyzed selective oxidative olefination and
arylation of 2-pyridones. Chem. Sci. 2012, 3, 3231−3236. (c) Li, Y.;
Xie, F.; Li, X. Formal Gold- and Rhodium-Catalyzed Regiodivergent
C-H Alkynylation of 2-Pyridones. J. Org. Chem. 2016, 81, 715−722.
(d) Itahara, T.; Ouseto, F. Synthesis 1984, 1984, 488.
(4) For selected directed C-6 activation of 2-pyridones, see:
(a) Odani, R.; Hirano, K.; Satoh, T.; Miura, M. Copper-mediated
C6-selective dehydrogenative heteroarylation of 2-pyridones with 1,3-
azoles. Angew. Chem., Int. Ed. 2014, 53, 10784−10788. (b) Miura, W.;
Hirano, K.; Miura, M. Rhodium-Catalyzed C6-Selective C-H
Borylation of 2-Pyridones. Org. Lett. 2016, 18, 3742−3745.
(c) Miura, W.; Hirano, K.; Miura, M. Nickel-Catalyzed Directed
C6-Selective C-H Alkylation of 2-Pyridones with Dienes and
Activated Alkenes. J. Org. Chem. 2017, 82, 5337−5344. (d) Anil
Kumar, K.; Kannaboina, P.; Das, P. Ruthenium-catalyzed site-selective
C-H arylation of 2-pyridones and 1-isoquinolinones. Org. Biomol.
Chem. 2017, 15, 5457−5461. (e) Das, D.; Biswas, A.; Karmakar, U.;
Chand, S.; Samanta, R. C6-Selective Direct Alkylation of Pyridones
with Diazo Compounds under Rh(III)-Catalyzed Mild Conditions. J.
Org. Chem. 2016, 81, 842−848. (f) Das, D.; Poddar, P.; Maity, S.;
Samanta, R. Rhodium(III)-Catalyzed C6-Selective Arylation of 2-
Pyridones and Related Heterocycles Using Quinone Diazides:
Syntheses of Heteroarylated Phenols. J. Org. Chem. 2017, 82,
3612−3621. (g) Das, D.; Samanta, R. Iridium(III)-Catalyzed
Regiocontrolled Direct Amidation of isoquinolones and pyridines.
Adv. Synth. Catal. 2018, 360, 379−384. (h) Li, T.; Wang, Z.; Xu, K.;
Liu, W.; Zhang, X.; Mao, W.; Guo, Y.; Ge, X.; Pan, F. Rhodium-
Catalyzed/Copper-Mediated Tandem C(sp2)-H Alkynylation and
Annulation: Synthesis of 11-Acylated Imidazo[1,2-a:3,4-a’]dipyridin-
5-ium-4-olates from 2H-[1,2’-Bipyridin]-2-ones and Propargyl Alco-
hols. Org. Lett. 2016, 18, 1064−1067. (i) Li, T.; Fu, C.; Ma, Q.; Ma,
Z.; Yang, Y.; Yang, H.; Lv, R.; Li, B. Cobalt/Copper-Cocatalyzed
Synthesis of Imidazo[1,2-a:3,4-a’]dipyridiniums from 2H-[1,2’-Bipyr-
idin]-2-ones and 2-Bromoacetophenones. J. Org. Chem. 2017, 82,
10263−10270. (j) Peng, P.; Wang, J.; Li, C.; Zhu, W.; Jiang, H.; Liu,
H. Cu(II)-catalyzed C6-selective C-H thiolation of 2-pyridones using
air as the oxidant. RSC Adv. 2016, 6, 57441−57445. (k) Ziegler, D. S.;
Greiner, R.; Laura, H.; Karaghiosoff, K.; Knochel, P. Directed
(5) For selected recent isolations and biological studies of 4-
hydroxy-2-pyridones, see: (a) Li, L.-N.; Wang, L.; Cheng, Y.-N.; Cao,
Z.-Q.; Zhang, X.-K.; Guo, X.-L. Discovery and Characterization of 4-
Hydroxy-2-pyridone Derivative Sambutoxin as a Potent and
Promising Anticancer Drug Candidate: Activity and Molecular
Mechanism. Mol. Pharmaceutics 2018, 15, 4898−4911. (b) Bao, J.;
Zhai, H.; Zhu, K.; Yu, J.-H.; Zhang, Y.; Wang, Y.; Jiang, C.-S.; Zhang,
X.; Zhang, Y.; Zhang, H. Bioactive Pyridone Alkaloids from a Deep-
Sea-Derived Fungus Arthrinium sp. UJNMF0008. Mar. Drugs 2018,
16, 174. (c) Isaka, M.; Haritakun, R.; Mongkolsamrit, S.; Supothina,
S.; Feng, T.; Liu, J.-K. Pyridone alkaloids from the scale-insect
pathogenic fungus Hypocrella discoidea BCC 71382. Tetrahedron
Lett. 2018, 59, 620−623. (d) Chicca, A.; Berg, R.; Jessen, H. J.;
Marck, N.; Schmid, F.; Burch, P.; Gertsch, J.; Gademann, K.
Biological evaluation of pyridone alkaloids on the endocannabinoid
system. Bioorg. Med. Chem. 2017, 25, 6102−6114. (e) Han, J.; Liu, C.;
Li, L.; Zhou, H.; Liu, L.; Bao, L.; Chen, Q.; Song, F.; Zhang, L.; Li, E.;
Liu, L.; Pei, Y.; Jin, C.; Xue, Y.; Yin, W.; Ma, Y.; Liu, H. Decalin-
Containing Tetramic Acids and 4-Hydroxy-2-pyridones with Anti-
microbial and Cytotoxic Activity from the Fungus Coniochaeta
cephalothecoides Collected in Tibetan Plateau (Medog). J. Org.
Chem. 2017, 82, 11474−11486. (f) Schroder, P.; Forster, T.; Kleine,
S.; Becker, C.; Richters, A.; Ziegler, S.; Rauh, D.; Kumar, K.;
Waldmann, H. Neuritogenic militarinone-inspired 4-hydroxypyri-
dones target the stress pathway kinase MAP4K4. Angew. Chem., Int.
Ed. 2015, 54, 12398−12403. (g) Fukuda, T.; Shimoyama, K.;
Nagamitsu, T.; Tomoda, H. Synthesis and biological activity of
Citridone A and its derivatives. J. Antibiot. 2014, 67, 445−450. For an
exhaustive review on 4-hydroxy-2-pyridones until 2010 refer to:
(h) Jessen, H. J.; Gademann, K. 4-Hydroxy-2-pyridone alkaloids:
Structures and synthetic approaches. Nat. Prod. Rep. 2010, 27, 1168−
1185. (i) Christoforow, A.; Wilke, J.; Binici, A.; Pahl, A.; Ostermann,
C.; Sievers, S.; Waldmann, H. Designing, Synthesis and Phenotypic
Profiling of Pyrano-Furo-Pyridone Pseudo Natural Products. Angew.
Chem., Int. Ed. 2019, DOI: 10.1002/anie.201907853.
(6) For direct CH-activations of 4-hydroxy-2-pyridones, see:
(a) Furstner, A.; Feyen, F.; Prinz, H.; Waldmann, H. Total Synthesis
and Reassessment of the Phosphatase-Inhibitory Activity of the
Antitumor Agent TMC-69−6H. Angew. Chem., Int. Ed. 2003, 42,
5361−5364. (b) Furstner, A.; Feyen, F.; Prinz, H.; Waldmann, H.
Synthesis and evaluation of the antitumor agent TMC-69−6H and a
focused library of analogs. Tetrahedron 2004, 60, 9543−9558. (c) Lah,
H. U.; Rasool, F.; Yousuf, S. K. Palladium catalyzed C(sp2)-C(sp2)
bond formation. A highly regio- and chemoselective oxidative Heck
C-3 alkenylation of pyrones and pyridines. RSC Adv. 2015, 5, 78958−
78961. For CH-activations of 4-O-alkylated-2-pyridones, see:
(d) Buck, J.; Madelay, J. P.; Pattenden, G. Lithiation of 4-methoxy-
2-pyridones. Synthetic entry to tenellin and funiculosin, and related
natural 3,5-disubstituted 4-oxy-2-pyridones. J. Chem. Soc., Perkin
Trans. 1 1992, 1, 67−73. (e) Majumdar, K. C.; Debnath, P.; Taher,
A.; Pal, A. K. Intramolecular cyclization reaction- Palladium(0)-
catalyzed cyclization is more effective than tin hydride mediated
reaction. Can. J. Chem. 2008, 86, 325−332. (f) Nolan, M.-T.; Bray, J.
T. W.; Eccles, K.; Cheung, M. S.; Lin, Z.; Lawrence, S. E.; Whitwood,
A. C.; Fairlamb, I. J. S.; McGlacken, G. P. Pd-catalysed intramolecular
regioselective arylation of 2-pyrones, pyridones, coumarins and
E
DOI: 10.1021/acs.orglett.9b03119
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Organic Letters
Letter
quinolones by C-H bond functionalization. Tetrahedron 2014, 70,
7120−7127. (g) Pardo, L. M.; Prendergast, A. M.; Nolan, M.-T.;
Muimhneachain, E. O.; McGlacken, G. P. Pd/Pivalic Acid Mediated
Direct Arylation of 2-Pyrones and Related Heterocycles. Eur. J. Org.
Chem. 2015, 2015, 3540−3550. (h) Prendergast, A. M.; Pardo, L. M.;
Fairlamb, I. J. S.; McGlacken, G. P. Access to some C5-Cyclised 2-
Pyrones and 2-Pyridones via Direct Arylation; Retention of Chloride
as a Synthetic Handle. Eur. J. Org. Chem. 2017, 2017, 5119−5124.
(7) For CH-activations of 4-hydroxy-2-pyridones developed by our
group, see: (a) Anagnostaki, E. E.; Fotiadou, A. D.; Demertzidou, V.;
Zografos, A. L. Palladium catalyzed C3-arylation of 4-hydroxy-2-
pyridones. Chem. Commun. 2014, 50, 6879−6882. (b) Katsina, T.;
Anagnostaki, E. E.; Mitsa, F.; Sarli, V.; L, A. Zografos, Palladium-
catalyzed direct alkenylation of 4-hydroxy-2-pyridones. RSC Adv.
2016, 6, 6978−6982.
(8) (a) Fotiadou, A. D.; Zografos, A. L. Accessing the Structural
Diversity of Pyridone Alkaloids: Concise Total Synthesis of Rac-
Citridone A. Org. Lett. 2011, 13, 4592−4595. (b) Fotiadou, A. D.;
Zografos, A. L. Electrocyclization of Oxatrienes in the Construction of
Structurally Complex Pyranopyridones. Org. Lett. 2012, 14, 5664−
5667. (c) Anagnostaki, E. E.; Zografos, A. L. Common synthetic
scaffolds” in the synthesis of structurally diverse natural products.
Chem. Soc. Rev. 2012, 41, 5613−5625.
(9) For selected reviews on the chemistry of hydrazones, see:
́
(a) Barluenga, J.; Valdes, C. Tosylhydrazones: new uses for classic
reagents in palladium-catalyzed cross-coupling and metal-free
reactions. Angew. Chem., Int. Ed. 2011, 50, 7486. (b) Shao, Z.;
Zhang, H. N-Tosylhydrazones: versatile reagents for metal-catalyzed
and metal-free cross-coupling reactions. Chem. Soc. Rev. 2012, 41,
560−572. (c) Xiao, Q.; Zhang, Y.; Wang, J. Diazo Compounds and
N-Tosylhydrazones: Novel Cross-Coupling Partners in Transition-
Metal-Catalyzed Reactions. Acc. Chem. Res. 2013, 46, 236−247.
(d) Liu, Z.; Wang, J. Cross-Coupling Reactions Involving Metal
Carbene: From C-C/C-C Bond Formation to C-H Bond Function-
alization. J. Org. Chem. 2013, 78, 10024−10030. (e) Jia, M.; Ma, S.
New Approaches to the Synthesis of Metal Carbenes. Angew. Chem.,
Int. Ed. 2016, 55, 9134−9166.
(10) The O-alkylated products can be easily obtained by heating
tosylhydrazones with N-alkylated pyridones in the presence of
K2CO3. For more information, please consult the Supporting
Information.
F
DOI: 10.1021/acs.orglett.9b03119
Org. Lett. XXXX, XXX, XXX−XXX