Rh(I)-Catalyzed Direct C6?H Arylation of 2-Pyridones with Aryl Carboxylic Acids

Article abstract of DOI:10.1002/adsc.202100596

A Rh(I)-catalyzed C6-selective C?H arylation of 2-pyridones with inexpensive, readily available, safe and structurally diverse aryl carboxylic acids with the aid of a pyridine directing group is developed. This decarbonylative arylation protocol features an easy-to-handle catalytic system, and is amenable to diversely substituted 2-pyridones and aryl carboxylic acids. It allows access to a wide range of C6-arylated 2-pyridones, including those that are difficult to prepare using conventional C?H arylation processes. The method tolerates various electron-neutral, electron-rich and electron-deficient functional groups, and affords the products in 41–91% yields. (Figure presented.).

Full text of DOI:10.1002/adsc.202100596

RESEARCH ARTICLE
doi.org/10.1002/adsc.202100596
Rh(I)-Catalyzed Direct C6À H Arylation of 2-Pyridones with Aryl
Carboxylic Acids
a, c
a
a
a, b
a
a,
Haoqiang Zhao, Jianbin Xu, Xin Xu, Yixiao Pan, Zexin Yu, Lijin Xu, *
b,
c,
Qinghua Fan, * and Patrick J. Walsh *
a
Department of Chemistry, Renmin University of China, Beijing 100872, People’s Republic of China
E-mail: 20050062@ruc.edu.cn
b
Beijing National Laboratory for Molecular Sciences and Institute of Chemistry, Chinese Academy of Sciences, Beijing, 100190,
People’s Republic of China
E-mail: fanqh@iccas.ac.cn
c
Roy and Diana Vagelos Laboratories, Penn/Merck Laboratory for High-Throughput Experimentation, Department of Chemistry,
University of Pennsylvania, 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, United States
E-mail: pwalsh@sas.upenn.edu
Manuscript received: May 17, 2021; Revised manuscript received: June 19, 2021;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202100596
Abstract: A Rh(I)-catalyzed C6-selective CÀ H arylation of 2-pyridones with inexpensive, readily available,
safe and structurally diverse aryl carboxylic acids with the aid of a pyridine directing group is developed. This
decarbonylative arylation protocol features an easy-to-handle catalytic system, and is amenable to diversely
substituted 2-pyridones and aryl carboxylic acids. It allows access to a wide range of C6-arylated 2-pyridones,
including those that are difficult to prepare using conventional CÀ H arylation processes. The method tolerates
various electron-neutral, electron-rich and electron-deficient functional groups, and affords the products in 41–
9
1% yields.
Keywords: 2-Pyridone; Rhodium; Arylation; Aryl carboxylic acid; CÀ H activation; Decarbonylation.
bonds directly onto the pyridone skeleton with more
Introduction
[4]
atom- and step-economical methods. Consequently,
The 2-pyridone structural motif is widely found in recent years have witnessed progress in site-selective
biologically active natural products and is commonly CÀ H functionalization at the C3À C6 positions of 2-
[1]
,[5–8]
incorporated into synthetic targets (Figure 1). As a pyridones.
Notably, in order to achieve efficient
result, tremendous effort has been devoted to the CÀ H activation, Hirano, Miura and coworkers intro-
[2]
synthesis of these useful N-heterocycles. Further- duced the easily attachable and detachable 2-pyridyl
more, the development of more efficient protocols to directing group at the nitrogen of 2-pyridones. Based
prepare these ubiquitous heterocycles remains in great on this strategy, they successfully accomplished the
[3]
demand. Recent advances in transition metal-cata- copper-mediated C6-selective dehydrogenative hetero-
lyzed regioselective CÀ H bond functionalizations have arylation of 2-pyridones with 1,3-azoles (Scheme 1a,
[
8a]
inspired methods to introduce new CÀ C and CÀ X path A).
Following this seminal work, several
transition-metal catalyzed systems were developed for
the arylation of 2-pyridones at the C6 position with the
assistance of 2-pyridyl directing groups.
[8b–e]
The
[8b]
[8d]
groups of Liu and Das achieved the direct C6-
arylation of 1-(2-pyridyl)-2-pyridones with aryl tri-
fluoroborates and aryl boronic acids under Rh(III) or
Ru(II) catalysis (Scheme 1a, paths B). Samanta and
coworkers described the application of quinone dia-
zides as arylation reagents for C6-selective CÀ H
Figure 1. Biologically active 2(1H)-pyridone molecules.
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2
[7u,v,12]
C(sp )À H bonds with carboxylic acids,
we envis-
aged that aryl carboxylic acids could also act as
suitable arylation reagents for the directed C6-arylation
of 2-pyridones. Herein, we describe an efficient Rh(I)-
catalyzed decarbonylative C6-H arylation of 1-(2-
pyridyl)-2-pyridones with a wide range of substituted
(hetero)aryl carboxylic acids to give C6-arylated 2-
pyridone products in good to excellent yields with high
tolerance of functional groups (Scheme 1c).
Results and Discussion
Reaction optimization. We commenced our studies by
investigating the reaction of 1-(2-pyridyl)-2-pyridone
(1a) and benzoic acid (2a). After examination of
various reaction parameters, we were pleased to find
that when performed in 1,4-dioxane in the presence of
[
0
Rh(CO) Cl] (2 mol% Rh), 1.2 equiv. of Boc O and
2
2
2
.5 equiv. of PivOH at 130°C for 8 h, the desired
product, 6-phenyl-2H-[1,2’-bipyridin]-2-one (3aa),
was obtained in 93% AY (Table 1, entry 1, AY=assay
yield, determined by H NMR integration of the crude
Scheme 1. Catalytic direct CÀ H arylation of heteroarenes.
1
arylation of 1-(2-pyridyl)-2-pyridones (Scheme 1a,
[8c]
path C).
The same group recently reported a
[a,b]
Table 1. Optimization of Reaction Conditions.
directing group free Pd(II)-catalysed desulfitative C6-
arylation[ of 2-pyridone using an arylsulfonyl
8e]
chloride.
Despite this progress, the direct C6-
arylation of 2-pyridones remains suboptimal with
regard to reaction efficiency, substrate scope, avail-
ability of the arylation reagents and functional group
tolerance.
Entry Deviation
Yield of
Recent advances have demonstrated that inexpen-
sive, readily available, safe and structurally diverse
aryl carboxylic acids can act as arylation reagents in
3
aa (%)
[c]
1
2
no
[Rh(COD) ]BF , [Rh(CO) (acac)], [RhCl
93 (91)
0
[9]
transition-metal catalyzed arylation reactions.
In
2
4
2
(1,5-HD)] , or [Rh(PPh ) Cl] instead of
2
3 3
particular, transition-metal-catalyzed decarboxylative
CÀ H arylation has been recognized as a powerful tool
for biaryl synthesis that combines both the high
efficiency of CÀ H activation and the commercial
[
Rh(CO) Cl]2
2
3
4
5
6
7
8
9
[Rh(COD)Cl] instead of [Rh(CO) Cl]
[RhCl(NBD)] instead of [Rh(CO) Cl]
THF as solvent
toluene as solvent
DCE as solvent
PhCl as solvent
43
21
0
27
12
13
0
31
11
94
48
0
2
2
2
2
2
2
[10]
availability of diverse aryl carboxylic acids. How-
ever, these reported catalytic systems were only
efficient with ortho-substituted benzoic acids, and
failed to catalyze the CÀ H arylation reactions with
Tf O or (CF CO) O instead of Boc O
2
3
2
2
meta- and para-substituted benzoic acids. Recently, the 10
synthesis of dibenzofurans via Rh(I)-catalyzed decar- 11
bonylative intramolecular CÀ H arylation of 2-arylox- 12
(MeOCO) O instead of Boc O
PivCl instead of Boc
Piv O as the activator without PivOH
2
2
2
O
2
1
1
3
4
in the absence of PivOH
without [Rh(CO) Cl] or Boc O
ybenzoic acids with Ac O as the acid activator has
2
been successfully developed by the group of Ryu
2
2
2
[
11a]
[11b,c]
[11d]
(
Scheme 1b).
The groups of J. Shi
Xu,
[a]
General reaction conditions: 1a (0.2 mmol), 2a (0.22 mmol),
Rh(CO) Cl]2 (1.0 mol%), Boc O (1.2 equiv.), PivOH
[
11e]
[11f]
Hong
and Z. Shi
have accomplished chelation-
[
2
2
assisted decarbonylative CÀ H arylation of heteroarenes
with various ortho-, meta- and para-substituted aryl
carboxylic acids or anhydrides employing similar Rh(I)
catalytic systems (Scheme 1b). Inspired by these
decarbonylative CÀ H arylation studies, and our recent
work on Rh(I)-catalyzed selective decarboxylation of
(0.5 equiv.), 1,4-dioxane (2.0 mL), 130°C, 8 h, in air.
[
b]
c]
1
Yields were determined by H NMR analysis of unpurified
reaction mixtures with internal standard CH Br .
2 2
[
Isolated yield. COD: 1,5-cyclooctadiene; NBD: norborna-
diene; HD: 1,4-hexadiene; Cp*: pentameth-
ylcyclopentadienyl.
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[a,b]
reaction mixture against an internal standard). Switch- Table 2. Scope of 2-Pyridones.
ing to [Rh(COD) ]BF , [Rh(CO) (acac)], [RhCl(1,5-
2
4
2
HD)] , or [Rh(PPh ) Cl] as the rhodium source did not
2
3 3
promote the reaction (Table 1, entry 2). Furthermore,
lower yields were obtained when [Rh(COD)Cl] or
2
[
RhCl(NBD)] were employed (43% and 21% AY,
2
Table 1, entries 3 and 4). Subsequently, a brief screen
of solvents revealed that reactions in 1,4-dioxane
outperformed THF, toluene, DCE and PhCl (Table 1,
entries 5–8). Using Tf O, (CF CO) O, (MeOCO) O, or
2
3
2
2
PivCl instead of Boc O resulted in no reaction or lower
2
yields (Table 1, entries 9–11). Although Piv O worked
2
effectively to deliver the product in 94% AY (Table 1,
entry 12), Boc O was chosen for subsequent studies
2
because of its lower cost and greater availability. The
reaction proceeded more slowly in the absence of
PivOH (Table 1, entry 13). Finally, control experiments
[
a]
General reaction conditions: 1a (0.2 mmol), 2a
0.22 mmol), [Rh(CO) Cl] (1.0 mol%), Boc O (1.2 equiv.),
(
2
2
2
indicated that both the rhodium catalyst and Boc O
2
PivOH (0.5 equiv.), 1,4-dioxane (2.0 mL), 130°C, 8 h, air
were indispensable for this transformation (entry 14).
Unfortunately, using free 2-pyridone or 2-pyridone
substrates bearing other N-substituents, such as Me,
Bn, Ph, Ac, Piv or Ts, shut down the desired arylation.
What’s more, replacing 1a with 1-(pyrimidin-2-yl)
pyridin-2(1H)-one (1a’) led to the formation of the
corresponding product 3aa’ in 71% isolated yield (See
SI, Table S3, entry 7). These results highlight the
atmosphere.
[b]
[c]
Isolated yield.
Confirmed by single-crystal X-ray diffraction (CCDC:
1
589804).
[d]
2a (0.44 mmol, 2.2 equiv.), Boc O (2.4 equiv.) and PivOH
2
(1.0 equiv.) were employed.
importance of the 2-pyridyl directing group in this more, the protocol was applicable to substrates beyond
transformation (See SI, Table S3). It should be noted 2-pyridones. Using the standard conditions for 2-
that in all cases, no dried solvents were required and pyridones, 2-(pyridin-2-yl)isoquinolin-1(2H)-one (1t),
the reactions were conducted under air rather than an 2-(pyrimidin-2-yl)isoquinolin-1(2H)-one (1u), 3-(pyr-
inert atmosphere. In general, the reactions in Table 1 idin-2-yl)quinazolin-4(3H)-one (1v), 4H-[1,2’-bipyri-
were very clean without byproduct formation. Reac- din]-4-one (1w) and 1-(pyridin-2-yl)quinolin-4(1H)-
tions with low conversion returned starting materials.
one (1x) were examined and found to give rise to the
Scope of 2-pyridones. With the optimized reaction phenylated products 3ta–3xa in 44–88% yields.
conditions in hand, we next explored the reaction of a Interestingly, in the case of 1w, doubling the amounts
range of 1-(2-pyridyl)-2-pyridones with benzoic acid of 2a and Boc O/PivOH resulted in the generation of
2
(
2a). As shown in Table 2, various 3- and 4-substituted the diarylated product 2,6-diphenyl-4H-[1,2’-bipyri-
-pyridones (1b–l) reacted smoothly, furnishing the din]-4-one 3wa’ in 53% yield.
corresponding arylated products (3ba–3la) in 68–91% Scope of the aryl acids. We next turned our
2
yields. It is noteworthy that both electron-rich and attention to the scope of aryl carboxylic acids
electron-withdrawing substituents, including À Me, (Table 3). A wide variety of para-substituted benzoic
À OBn, À Ph, À F, À Cl, À Br and À CF , were compatible acid derivatives (1b–1s) were effective, regardless of
3
with the reaction conditions. Initially we were con- the nature of the substituents on the aryl ring, and
cerned that 2-pyridones with substituents at C5 would provided the desired C6-arylated products (3ab–3as)
perform poorly due to increased steric hinderance at in 41–90% yields. Valuable functional groups, includ-
this position. Fortunately, C5-substitsuted 2-pyridones ing hydroxyl (3ad), boronic acid (3ae), amine (3af),
(1m–o) proved to be viable reaction partners, provid- halides (3ag–3ai), nitro (3aj), acetyl (3ak), cyano
ing the desired products (3ma–3oa) in 73–83% yields. (3am), trifluoromethyl (3an), aldehyde (3al), ester
This observation indicates that the method is not overly (3ao), sulfonamide (3ap), and even reactive vinyl
sensitive to increased steric hindrance. The structure of (3ar) and ethynyl (3as) were well tolerated. The
3
na was confirmed by single-crystal X-ray diffraction reaction was successfully extended to meta- and ortho-
[13]
(CCDC: 1589804).
Likewise, the 3,4-disubstituted substituted aryl carboxylic acids (2t–2w), delivering
2
-pyridone 1p afforded the corresponding product 3pa the corresponding products (3at–3aw) in 64–81%
in 85% yield. The 2-pyridone substrates (1q–1s), with yields with good functional group compatibility. Multi-
electron donating or electron withdrawing substituents substituted aryl carboxylic acids (4a–4d) also readily
on the pyridyl rings, also performed well, giving the engaged in the transformation to afford the correspond-
target products 3qa–3sa in 83–88% yields. Further- ing products 5aa–5ad in moderate to high yields (49–
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[a,b]
Table 3. Scope of Aryl Carboxylic Acids.
Scheme 2. Synthetic Applications.
,[11],[15][16]
Based on previous reports,
we envisaged that
the current arylation may proceed via the initial
conversion of aryl acids into the corresponding
anhydrides. We, therefore, investigated the reaction of
compound 1a and benzoic anhydride with catalytic
[Rh(CO) Cl] . The product 3aa was formed in 92%
[
a]
General reaction conditions: 1a (0.2 mmol), 2a
0.22 mmol), [Rh(CO) Cl] (1.0 mol%), Boc O (1.2 equiv.),
(
2
2
2
PivOH (0.5 equiv.), 1,4-dioxane (2.0 mL), 130°C, 8 h, air
2
2
atmosphere.
yield. This result is consistent with in situ generation
of an anhydride (Scheme 3a). Furthermore, we exam-
[
b]
c]
Isolated yield.
[
Piv O (1.2 equiv.) was used instead of Boc O/PivOH.
2
2
ined the reaction of 2a with Boc O (1.2 equiv.) and
2
PivOH (0.5 equiv.) in 1,4-dioxane at 130°C for 8 h in
the absence of the Rh catalyst. This reaction led to the
0%). Notably, 2-naphthoic acid (4e) and the estrone- formation of benzoic anhydride in 77% yield (Sche-
9
[7u,v]
derived acid (4f) participated in the coupling, affording me 3a). Based on our previous studies,
the gen-
the desired products 5ae and 5af in 84% and 83% eration of CO gas during the reaction was detected by
yields, respectively. analysis of the head gas of the reaction mixture with
In light of the importance of heteroaryl compounds GC-TDC, confirming that the involvement of a
[14]
in medicinal chemistry, the generality of the current decarbonylation step in the current transformation,
catalytic system was explored with heteroaryl carbox- which was not from the [Rh(CO) Cl] catalyst (see the
2
2
ylic acids. We were pleased to discover that carboxylic Supporting Information). We next probed the reversi-
acids bearing quinoline, thiophene, furan, benzofuran, bility of the CÀ H activation step at the C6 position.
and indole groups (4g–4j) were viable coupling
partners, generating the desired products 5ag–5aj in
5
4–82% yields. In the case of 1H-indole-2-carboxylic
acid (4k), only trace product was formed under the
current conditions. Fortunately, replacing Boc O/Piv-
2
OH with Piv O as the acid activator furnished the N-
2
protected product 5ak in 47% yield.
Synthetic applications. To showcase the synthetic
utility of the current catalytic method, we carried out
the gram-scale reaction of 1a with 2a and 4d under
the optimized reaction conditions. The desired product
3
aa and 5ad was obtained in 83% and 77% yields,
respectively (Scheme 2a). Next, selective hydrogena-
tion of 3aa was performed with Pd/C in ethanol to
afford the reduction product 6 in 89% yield (Sche-
me 2b). Finally, the N-pyridyl directing group of 3aa
could be smoothly removed by the “quaternization and
alcoholysis” strategy to deliver the free NH- 2-
[8b–d]
pyridone 7 in 61% yield (Scheme 2b).
Mechanistic studies. To shed light on the reaction
mechanism, we conducted a series of experiments.
Scheme 3. Mechanistic Studies.
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Conducting the reaction in the presence of D O PivOH to re-enter the cycle as the anhydride. E is
2
(
5 equiv.) with catalytic [Rh(CO) Cl] in the presence envisioned to undergo deinsertion of CO to produce
2 2
and in the absence of (Boc) O/PivOH both led to the RhÀ aryl intermediate F. Reductive elimination of F
2
observation of H/D exchange at the C6-position of the regenerates the Rh(I) species G, which undergoes
2
-pyridone substrate 1a. These experiments indicate a exchange with the solvent or substrate to liberate the
reversible deprotonative CÀ H bond activation step in product 3 and close the catalytic cycle with formation
this transformation, presumably through a concerted of A. At this point, the exact ordering of the steps
metallation deprotonation pathway followed by proto- remains to be determined.
nation of the RhÀ C bond (Scheme 3b). A kinetic
isotope effect (KIE) measurements performed by two
Conclusion
side-by-side reactions employing 1a and [D1]-1a
(
Scheme 3c) was determined to be 2.1�0.1, indicating In summary, we have disclosed the regioselective
that cleavage of the CÀ H bond is likely involved in the C6À H bond arylation of 2-pyridones with readily
turnover-limiting step. available and inexpensive aryl carboxylic acids under
Working mechanism. Based on the aforementioned Rh catalysis. This protocol combines decarbonylation
,[11],[15][16]
results and previous reports,
a plausible mech- of aryl anhydrides, generated in situ from aryl carbox-
anism is proposed (Scheme 4). First, coordination of ylic acids and activators, with CÀ H bond activation.
solvent (S) or the substrate pyridine with the dimer The method furnishes a large variety of C6-arylated 2-
[
Rh(CO) Cl] delivers the monomeric Rh(I) species A pyridones in high yields and with good functional
2 2
that enters the catalytic cycle. At the same time, the group tolerance. This operationally simple protocol is
anhydride, generated in situ from the aryl acid and anticipated to have promising applications in the
Boc O/PivOH, is formed and undergoes oxidative production of biologically active molecules and natural
2
addition to A to form the Rh(III) intermediate B. When products.
S is solvent, ligand exchange with the 2-pyridone
substrate 1 leads to the formation of intermediate C,
which possesses an open coordination site to bind the
Experimental Section
pyridone CÀ H bond. Subsequently, a concerted metal- To an oven-dried pressure tube with a stir bar under air were
ation deprotonation (CMD) by the carboxylate ligand sequentially added 2-pyridones 1a (0.2 mmol), [Rh(CO)
Cl]
2 2
(
0.8 mg, 1.0 mol%), aryl carboxylic acid 2 (0.22 mmol), Boc O
2
via transition state D results in the generation of the
acid and the cyclometallated species E with the key
(
52.4 mg, 0.24 mmol), PivOH (10.2 mg, 0.1 mmol) and 1,4-
dioxane (2.0 mL). The tube was sealed, and the light yellow
RhÀ C bond. The liberated acid can react with Boc O/
2
reaction mixture was heated at 130°C in Wattecs Parallel
Reactor for 8 h with stirring. Then the tube was removed from
the bath and cooled to room temperature. The color of the
reaction mixture changed to brown over the course of the
reaction period. The mixture was washed with saturated sodium
bicarbonate solution (5 mL) and extracted with CH Cl (5 mL×
2
2
3
). The combined yellow organic layers was dried over Na SO
2 4,
filtered and evaporated under vacuum. The residue was purified
by column chromatography on silica gel using a mixture of
ethyl acetate and hexanes to give the purified product.
Acknowledgements
We acknowledge the Program for China Scholarship Council
(No. 201806360122), National Natural Science Foundation of
China (No. 21372258) and Beijing National Laboratory for
Molecular Sciences (BNLMS201845) for financial support.
P.J.W. thanks the U.S. National Science Foundation (CHE-
1
902509).
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RESEARCH ARTICLE
Rh(I)-Catalyzed Direct C6À H Arylation of 2-Pyridones with
Aryl Carboxylic Acids
Adv. Synth. Catal. 2021, 363, 1–8
H. Zhao, J. Xu, X. Xu, Y. Pan, Z. Yu, L. Xu*, Q. Fan*, P. J.
Walsh*