Rhodium-Catalyzed C4-Selective C-H Alkenylation of 2-Pyridones by Traceless Directing Group Strategy

Article abstract of DOI:10.1021/acs.orglett.1c00050

A rhodium-catalyzed C4-selective C-H alkenylation of 3-carboxy-2-pyridones with styrenes has been developed. The carboxylic group at the C3 position works as the traceless directing group, and the corresponding C4-alkenylated 2-pyridones are obtained exclusively with concomitant decarboxylation. Unlike the reported procedures, the exclusive C4 selectivity is uniformly observed even in the presence of potentially more reactive C-H bonds at the C5 and C6 positions. By using this strategy, the multiply substituted 2-pyridone can be prepared via sequential C-H functionalization reactions.

Full text of DOI:10.1021/acs.orglett.1c00050

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Letter
Rhodium-Catalyzed C4-Selective C−H Alkenylation of 2‑Pyridones
by Traceless Directing Group Strategy
Sunit Hazra, Koji Hirano,* and Masahiro Miura*
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ABSTRACT: A rhodium-catalyzed C4-selective C−H alkenyla-
tion of 3-carboxy-2-pyridones with styrenes has been developed.
The carboxylic group at the C3 position works as the traceless
directing group, and the corresponding C4-alkenylated 2-pyridones
are obtained exclusively with concomitant decarboxylation. Unlike
the reported procedures, the exclusive C4 selectivity is uniformly
observed even in the presence of potentially more reactive C−H
bonds at the C5 and C6 positions. By using this strategy, the
multiply substituted 2-pyridone can be prepared via sequential C−H functionalization reactions.
2-pyridone that has the unique unsaturated system in the
N-containing six-membered ring is one of the most
A
widely occurring heterocyclic cores in natural products,
biologically active molecules, and pharmaceutical agents.1
Such ubiquity has promoted the development of protocols
for the preparation of 2-pyridones, particularly, the multiply
substituted ones in synthetic communities. Strategically, the
substituted 2-pyridone can be obtained either by functionaliza-
tion of the pyridone ring2 or by constructing the ring from
suitable acyclic precursors.1a The former can provide a more
convergent and modular approach to the target structure, but
the reported methodologies largely relied on the stoichiometric
halogenation and metalation.
Figure 1. Reactivity profile of C−H bonds on 2-pyridone in metal-
mediated C−H activation.
Thus, there still remains a large demand for the C4 site
selectivity that is independent of the substituent. Herein, we
report a Cp*Rh(III)-catalyzed, carboxylic acid directed highly
C4-selective C−H alkenylation of 2-pyridones with styrenes
(Scheme 1d): the key to success is the introduction of the
carboxylic acid group at the C3 position, which works as the
traceless directing group,8 and the corresponding C4-
alkenylated 2-pyridones are obtained with the concomitant
decarboxylation. The introduction of the carboxyl group at the
C3 position sometimes requires some synthetic steps (see the
Supporting Information for details), but unlike the afore-
mentioned precedents, the exclusive C4 selectivity is uniformly
observed even in the presence of the potentially more reactive
C−H bond at the C6 position. Additionally, the installation of
the vinyl group is possible, which is difficult to achieve by other
C4-selective C−H functionalization protocols and thus
complementary and useful from the synthetic point of view.
In the past two decades, the metal-mediated C−H activation
has been utilized for a wide range of transformations of C−H
bonds to C−C or C−heteroatom bonds with better atom
efficiency compared to the traditional cross-coupling method-
ologies.3 In this context, synthetic chemists have been greatly
prompted to adopt the 2-pyridone in the C−H activation.4
However, there are four possibly reactive C−H bonds on the
2-pyridone ring, and the control of site selectivity is thus the
most important and challenging issue. While the C3-, C5-, and
C6-selective C−H functionalizations have greatly progressed
to date, the selective access to the C−H bond at the C4
position still remains largely elusive (Figure 1). To the best of
our knowledge, only a few successful examples include the in
situ protection/lithiation strategy using CO2 and BuLi/t-BuLi
(Scheme 1a),5 Ni/Al-cooperative alkylation with alkenes
(Scheme 1b),6 and sterically controlled Ir-catalyzed borylation
with pinB−Bpin (Scheme 1c).7 The former is the stoichio-
metric reaction and suffers from the harsh conditions
associated with the strongly basic organolithium reagents.
The latter two cases are more attractive catalytic reactions, but
the high C4-selectivity is obtained only when the competitively
reactive C−H at the C6 position is blocked by substituents.
Received: January 7, 2021
Published: February 8, 2021
https://dx.doi.org/10.1021/acs.orglett.1c00050
© 2021 American Chemical Society
Org. Lett. 2021, 23, 1388−1393
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Letter
Scheme 1. C4-Selective C−H Functionalizations on 2-
Pyridones
Table 1. Optimization Studies for Decarboxylative C4-
Selective C−H Alkenylation of 1a with 2a
a
b
entry
catalyst
oxidant
additives yield (%)
1
2
3
4
5
6
7
[Cp*RhCl2]2
[Cp*IrCl2]2
Cp*Co(CO)I2
[RuCl2(p-cymene)]2
Pd(OAc)2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
AgOAc
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
MS 4A
Na2CO3
MS 4A
K2CO3
MS 4A
Cs2CO3
MS 4A
43
0
0
0
0
11
17
60
Ag2CO3
Cu(OAc)2·H2O
c
8
c
9
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
26
c
10
11
c
11
0
c
12
NaHCO3
MS 4A
KHCO3
MS 4A
K4P2O7
MS 4A
23
The blue print for the catalytic C4-selective C−H
functionalization of 2-pyridones is based on the recent progress
of carboxylic acid directed formal meta-selective C−H
functionalization of benzenes, which was developed by our
group,9 Larrosa,10 and others.11 Our working hypothesis is
shown in Scheme 2. The initial ligand exchange between the
c
13
25
c
14
82 (78)
a
Conditions: 1a (0.20 mmol), 2a (0.40 mmol), catalyst (0.010 mmol
on metal), oxidant (0.20 mmol), additives (0.40 mmol), toluene (1.0
b
1
Scheme 2. Working Hypothesis of Carboxylic Acid-Directed
C4-Selective C−H Alkenylation of 2-Pyridone 1a with
Styrene 2a with Concomitant Decarboxylation
mL), 160 °C, 16−24 h, N2. Estimated by H NMR with CH2Br2 as
the internal standard. Isolated yield in parentheses. With 0.60 mmol
of 2a and 100 mg of MS 4A.
c
additive, and solvent, we were pleased to find that the reaction
proceeded in the presence of [Cp*RhCl2]2 catalyst, Cu-
(OAc)2·H2O oxidant, and K2HPO4 base in heated toluene
1
(160 °C) to deliver the targeted 3aa in 43% H NMR yield
(entry 1). Notably, the C−C bond formation occurred
exclusively at the C4 position, and the COOH-remaining
byproduct 3aa-COOH was not detected at all. Additionally,
the structure of 3aa was unambiguously confirmed by X-ray
analysis (CCDC 2032339). No alkenylated product 3aa was
observed with other catalysts including [Cp*IrCl2]2, Cp*Co-
(CO)I2, [RuCl2(p-cymene)]2, and Pd(OAc)2 (entries 2−5),
some of which are known to promote the related
decarboxylative C−H functionalization of benzene deriva-
tives.8−11 The Cu(OAc)2·H2O was found to be better than the
1
catalyst A and 3-carboxy-2-pyridone 1a is followed by the
directed C−H cleavage to form the corresponding metallacycle
C. Subsequent insertion of styrene 2a into the pyridone C(4)−
M bond and β-H elimination afford the intermediate E. The
C4-alkenylated product 3aa then follows from decarboxylation
and reductive elimination. The catalytic cycle is closed by the
reoxidation of reduced G with the external oxidant.
On the basis of the above assumption, we started the
optimization studies with 1a (0.20 mmol) and 2a (0.40 mmol;
Table 1). After the initial screening of catalyst, oxidant,
Ag-based oxidants (entries 6 and 7). The H NMR yield
further increased to 60% by using 3.0 equiv of 2a and addition
of MS 4A (entry 8). Final investigation of base (entries 9−14)
revealed that K4P2O7 showed the best performance,12 and 3aa
was finally isolated in 78% yield (82% 1H MR yield; entry 14).
Some additional observations are to be noted: the carboxylic
acid group was indispensable for the alkenylation, and no
conversion of the corresponding ester and simple 2-pyridone
substrate was observed. Other ethereal, halogenated, and polar
solvents were also tested, but toluene proved to be best.13
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With the optimal conditions in hand (Table 1, entry 14), we
examined the scope and limitation of this strategy (Scheme 3).
Scheme 4. Derivatizations of 3da
Scheme 3. Rhodium-Catalyzed C4-Selective C−H
Alkenylation of 3-Carboxy-2-pyridones 1 with Styrenes 2 by
a
Traceless Directing Group Strategy
AcOH solvent to furnish the C4-alkylated 2-pyridone 4 in 81%
yield. On the other hand, the saturated piperidin-2-one
structure 5 was selectively obtained under the hydrogenation
in EtOH. Additionally, the 2-pyridone has an electron-rich
vinylogous enamide character, and 3da thus underwent the
Diels−Alder reaction with the triazoledione. After additional
treatment with PPTS,15 the corresponding tricyclic system 6
was isolated in 61% overall yield.
We next implemented some control experiments to gain
mechanistic insight (Scheme 5). First, to check the role of
Scheme 5. Control Experiments
a
Reaction conditions: 1 (0.20 mmol), 2 (0.60 mmol), [Cp*RhCl2]2
(0.0050 mmol), Cu(OAc)2·H2O (0.20 mmol), K4P2O7 (0.40 mmol),
MS 4A (100 mg), toluene (1.0 mL), 160 °C, 24 h, N2. Isolated yields
b
c
are shown. On a 1.0 mmol scale. NMR yield.
The larger alkyl groups on the pyridone nitrogen were
compatible to form the corresponding C4-alkenylated 2-
pyridones 3ba−da in good yields. The substituents at the C6
position were also accommodated (3ea−ha). Particularly
notable is the successful reaction of 2-pyridones that bear
the amino (3ia) and alkoxyl (3ja) functionalities. On the other
hand, the C5-substituted pyridone was the reluctant substrate
probably due to the steric factors (3ka). The reaction was
scalable, and 3aa was obtained in 69% yield on a 1.0 mmol
scale.
Several para-substituted styrenes were smoothly coupled
with 1a: electron-donating and -withdrawing as well as
halogenated substituents all were tolerated under the reaction
conditions (3ab−3ah).14 The meta-substituted substrates were
also viable substrates (3ai and 3aj), but the sterically
demanding ortho-substitution was somewhat detrimental to
the reaction (3ak). Unfortunately, the acrylate showed lower
reactivity than the styrene derivatives (3al), but the reactivity
trend was highly dependent on the position of carboxy group
(vide infra).
Cu(OAc)2, the stoichiometric reaction to Rh was performed in
the absence of Cu(OAc)2: the targeted 3aa was formed in 70%
yield without any difficulties. Thus, Cu(OAc)2 can work as just
an oxidant in the catalyst regeneration step (G to A in Scheme
2). Additionally, the reaction with styrene-d8 (2a-d8)
successfully incorporated a partial but significant amount of
deuterium selectively at the C3 position.16 These outcomes
suggest that as shown in Scheme 2 the decarboxylative C−C
bond forming process is operated by the Rh alone rather than
the stepwise C−C bond formation and Cu-promoted
protodecarboxylation, which is consistent with no observation
of COOH-remaining 3aa-COOH (Table 1) and the lower
yield of 3aa in the presence of Ag-based oxidants (entries 6
and 7 in Table 1) that more strongly accelerate the
nonproductive simple protodecarboxylation.17 A similar
reaction mechanism was proposed in the related Ru-catalyzed
decarboxylative C−H alkenylation with alkynes.11a−c
We also investigated the applicability and site selectivity of
this strategy in the reaction of regioisomeric carboxy-2-
pyridones (Scheme 6). As a general trend, K2HPO4 instead
of K4P2O7 showed better performance in these cases. The 4-
The obtained product 3da underwent some derivatizations
(Scheme 4). The vinylene selective reduction was possible
under the hydrogenation conditions using Pd(OH)2/H2 in
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Scheme 6. Attempts To Apply Regioisomeric Carboxy-2-
pyridones
Scheme 7. Synthesis of Multiply Substituted 2-Pyridone 17
by Sequential Site-Selective C−H Functionalization
Reactions
pyridones with styrenes. Taking advantage of the carboxy
group as the traceless directing group, we can access the
otherwise challenging C−H bond at the C4 position,
irrespective of the substituents at the competitively reactive
C6 position. Additionally, by using the newly developed
strategy, the multiply substituted 2-pyridone can be prepared
via sequential C−H functionalization reactions.
carboxy-2-pyridone 7a afforded the C3-alkenylated product
8aa exclusively, the site selectivity of which can be controlled
by the additional coordination of the pyridone carbonyl.18
Additionally notable is the successful coupling of acrylate in
this case (8al). The 5-carboxy-2-pyridone 9a specifically
reacted only with the acrylate 2l to form the C4- and C6-
doubly alkenylated 10al as the major product. A mixture of the
corresponding five-membered lactones19 11al and 12al was
also isolated, thus suggesting the competitive reaction order at
the C3 and C6 positions. In the reaction of the 6-carboxy-2-
pyridone 13a, as in the case of the 3-carboxy-2-pyridone 1a,
only the styrene 2a was reactive, and the expected C5-
alkenylated product 14aa was obtained in 60% yield.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00050.
1H, 13C{1H}, and 19F{1H} NMR spectra, ORTEP
drawing, detailed optimization studies, detailed D-
labeling experiments, and protodecarboxylation test
(PDF)
Accession Codes
CCDC 2032339 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Finally, we attempted to synthesize the multiply substituted
2-pyridone by the sequential site-selective C−H functionaliza-
tion reactions (Scheme 7). The starting platform is the N-(2-
pyridyl)-3-methoxycarbonyl-2-pyridone (15), and the rhodi-
um-catalyzed, pyridine-directed C6-selective C−H arylation
with the aryltrifluoroborate20 was first conducted to afford 16
in 78% yield. The subsequent ester hydrolysis and N-
substituent switch from Py to Me formed 1h in 54% (4
steps). The styryl group was introduced at the C4 position by
the present traceless directing group strategy (3ha). The C−H
at the C3 position was then selectively arylated with the
hydrazine derivative under radical conditions21 to form the
trisubstituted 2-pyridone 17 with two different aryl groups and
one alkenyl group at the C3, C6, and C4 positions. As
demonstrated in Scheme 7, the combination of the presently
developed protocol and literature procedures can provide a
modular C−H functionalization approach to the multiply
substituted 2-pyridones, which will find wide applications in
the development of more complex, pyridone-based bioactive
molecules.1
AUTHOR INFORMATION
Corresponding Authors
■
Koji Hirano − Department of Applied Chemistry, Graduate
School of Engineering, Osaka University, Suita, Osaka 565-
0871, Japan; orcid.org/0000-0001-9752-1985;
Email: k_hirano@chem.eng.osaka-u.ac.jp
Masahiro Miura − Department of Applied Chemistry,
Graduate School of Engineering, Osaka University, Suita,
Osaka 565-0871, Japan; orcid.org/0000-0001-8288-
6439; Email: miura@chem.eng.osaka-u.ac.jp
Author
Sunit Hazra − Department of Applied Chemistry, Graduate
School of Engineering, Osaka University, Suita, Osaka 565-
0871, Japan
In conclusion, we have developed a rhodium-catalyzed
decarboxylative C4-selective C−H alkenylation of 3-carboxy-2-
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Letter
J.-Q. A Simple and Versatile Amide Directing Group for C-H
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00050
through Activation and Cleavage of C-H Bonds. Angew. Chem., Int.
Ed. 2016, 55, 11000−11019. (l) Ping, L.; Chung, D. S.; Bouffard, J.;
Lee, S. Transition Metal-Catalyzed Site- and Regio-divergent C−H
Bond Functionalization. Chem. Soc. Rev. 2017, 46, 4299−4328.
(m) Mihai, M. T.; Genov, G. R.; Phipps, R. J. Access to the meta
Position of Arenes Through Transition Metal Catalysed C−H Bond
Functionalisation: A Focus on Metals Other than Palladium. Chem.
Soc. Rev. 2018, 47, 149−171. (n) Chu, J. C. K.; Rovis, T.
Complementary Strategies for Directed C(sp3)-H Functionalization:
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by JSPS KAKENHI Grant Nos. JP
18K19078 (Grant-in-Aid for Challenging Research (Explor-
atory)) to K.H. and JP 17H06092 (Grant-in-Aid for Specially
Promoted Research) to M.M. We thank Dr. Yuji Nishii (Osaka
University) for his assistance with the X-ray analysis.
̈
2018, 57, 62−101. (o) Sambiagio, C.; Schonbauer, D.; Blieck, R.;
Dao-Huy, T.; Pototschnig, G.; Schaaf, P.; Wiesinger, T.; Zia, M. F.;
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Organic Letters
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Hydroarylation of Internal Alkynes with Arenecarboxylates: Carbox-
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55, 6933−6937. (d) Biafora, A.; Krause, T.; Hackenberger, D.; Belitz,
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W. ortho-C−H Arylation of Benzoic Acids with Aryl Bromides and
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(12) The reason for the unique effect of K4P2O7 additive is unclear
at this stage, but its suitable basicity (the pKa value of the conjugate
3−
acid HP2O7 is 9.25) can play an important role in the ligand
exchange step on Rh (Scheme 2, A to B). In addition, it may suppress
the nonproductive protodecarboxylation. For an example of the
unique effect of K4P2O7 base, see: He, Z.; Song, F.; Sun, H.; Huang,
Y. Transition-Metal-Free Suzuki-Type Cross-Coupling Reaction of
Benzyl Halides and Boronic Acids via 1,2-Metalate Shift. J. Am. Chem.
Soc. 2018, 140, 2693−2699.
(13) See the Supporting Information for more detailed optimization
studies.
(14) We have no explanation for the reason why the yields of 3ab,
3ad, and 3af were lower at this stage. We repeated these reactions two
times, but almost the same yields were observed.
(15) The initially formed Diels−Alder adduct was somewhat
unstable and gradually underwent the olefin isomerization into 6,
which was accelerated by addition of acid such as PPTS.
(16) We confirmed that the deuterium content at the C3 position
did not increase in the reaction even with anhydrous Cu(OAc)2 and
toluene-d8. Additionally, the isolated 3aa underwent just a partial H/
D exchange (9%) at the C3 position with AcOH-d4 under otherwise
identical conditions (see the Supporting Information for details).
Thus, we believe that the lower deuterium content is mainly
attributed to the H/D exchange on Rh−H species (E and/or F in
Scheme 2) with the carboxylic acid H of the starting pyridone.
(17) Ag: (a) Lu, P.; Sanchez, C.; Cornella, J.; Larrosa, I. Silver-
Catalyzed Protodecarboxylation of Heteroaromatic Carboxylic Acids.
Org. Lett. 2009, 11, 5710−5713. Cu: (b) Gooßen, L. J.; Thiel, W. R.;
Rodríguez, N.; Linder, C.; Melzer, B. Copper-Catalyzed Proto-
decarboxylation of Aromatic Carboxylic Acids. Adv. Synth. Catal.
2007, 349, 2241−2246. We also compared the activity of Cu(OAc)2·
H2O, AgOAc, and Ag2CO3 in the protodecarboxylation of 1d and
confirmed no protodecarboxylation only with Cu(OAc)2·H2O. See
the Supporting Information for details.
(18) Chen, Y.; Wang, F.; Jia, A.; Li, X. Palladium-catalyzed selective
oxidative olefination and arylation of 2-pyridones. Chem. Sci. 2012, 3,
3231−3236.
(19) The formation of similar lactones is trivial in the literature. For
example, see: Ueura, K.; Satoh, T.; Miura, M. An Efficient Waste-Free
Oxidative Coupling via Regioselective C−H Bond Cleavage: Rh/Cu-
Catalyzed Reaction of Benzoic Acids with Alkynes and Acrylates
under Air. Org. Lett. 2007, 9, 1407−1409.
(20) Peng, P.; Wang, J.; Jiang, H.; Liu, H. Rhodium(III)-Catalyzed
Site-Selective C−H Alkylation and Arylation of Pyridones Using
Organoboron Reagents. Org. Lett. 2016, 18, 5376−5379.
(21) 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.
1393
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Org. Lett. 2021, 23, 1388−1393