Ruthenium-catalyzed chemoselective N?H bond insertion reactions of 2-pyridones/7-azaindoles with sulfoxonium ylides

Article abstract of DOI:10.1021/acs.orglett.0c04229

A ruthenium-catalyzed highly chemoselective N-alkylation of 2-pyridones has been developed, affording N-alkylated 2-pyridone derivatives in good yields and excellent N-selectivity. The key to achieve this unprecedented N?H rather than O?H insertion reaction is the use of CpRu(PPh₃)₂Cl as the catalyst and sulfoxonium ylides as the alkylation reagents. Moreover, this protocol is also amenable to 7-azaindoles by slightly varying the reaction conditions. Furthermore, sulfonium ylides are also suitable alkylation reagents, providing the N-alkylated 2-pyridones in good selectivity.

Full text of DOI:10.1021/acs.orglett.0c04229

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Letter
Ruthenium-Catalyzed Chemoselective N−H Bond Insertion
Reactions of 2‑Pyridones/7-Azaindoles with Sulfoxonium Ylides
Xiaofeng Liu, Ying Shao, and Jiangtao Sun*
Cite This: Org. Lett. 2021, 23, 1038−1043
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ABSTRACT: A ruthenium-catalyzed highly chemoselective N-alkylation of 2-pyridones has been developed, affording N-alkylated
2-pyridone derivatives in good yields and excellent N-selectivity. The key to achieve this unprecedented N−H rather than O−H
insertion reaction is the use of CpRu(PPh3)2Cl as the catalyst and sulfoxonium ylides as the alkylation reagents. Moreover, this
protocol is also amenable to 7-azaindoles by slightly varying the reaction conditions. Furthermore, sulfonium ylides are also suitable
alkylation reagents, providing the N-alkylated 2-pyridones in good selectivity.
Scheme 1. Previous Reports and Our Protocol
ulfoxonium ylide derived metal−carbenes have been
Sextensively used in constructing various carbon−carbon
and carbon−heteroatom bonds.1 Typically, compared with
traditional carbene precursors, diazo compounds, sulfoxonium
ylides are stable, safe, and can be stored for longer time.
Therefore, these compounds have been utilized as diazo
alternatives in diverse carbene transfer reactions,2,3 including
the formal X−H (X = N, O, S, B) bond insertion reactions.4−7
Since the pioneering work by Baldwin and co-workers on the
rhodium-catalyzed intramolecular N−H bond insertions,4a4b to
date, a range of X-H insertion reactions have been developed
(Scheme 1a). Just recently, Mattson, Burtoloso, and co-
workers described an elegant enantioselective S−H bond
insertion reaction by using chiral thiourea as the catalyst,6b
which expanded the applications of sulfoxonium ylides. In
continuation of our interest in metal carbene chemistry, we try
to use sulfoxonium ylides instead of diazo compounds to
develop novel X−H insertion reactions.
N-Alkylated 2-pyridones are important motifs in natural
products and biologically active pharmaceuticals.8 Since the 2-
pyridone molecule exists in equilibrium (tautomerism) with 2-
hydroxypyridine, the direct alkylation of 2-pyridones remains
elusive and often suffers poor chemoselectivity, leading to a
mixture of N- and O-alkylated products. Thus, the highly
chemoselective N-alkylation of 2-pyridones remains a great
challenge.9 Given that diazo compounds can readily undergo
X−H insertion reactions, the alkylation of 2-pyridones with
diazo compounds has been previously investigated (Scheme
1b). However, the O-alkylation proved to be the dominant
insertion reaction under either rhodium10 or gold catalysis.11
Recently, using 2-oxypyridines as the substrates, we have
Received: December 22, 2020
Published: January 21, 2021
https://dx.doi.org/10.1021/acs.orglett.0c04229
Org. Lett. 2021, 23, 1038−1043
© 2021 American Chemical Society
1038

Organic Letters
pubs.acs.org/OrgLett
Letter
developed a rhodium-catalyzed synthesis of N-alkylated
pyridones via a novel O-to-N acyl rearrangement.12 Inspired
by the pioneering reports and our own interest in metal−
carbene chemistry, we envisaged that the reaction of 2-
pyridones with stabilized sulfoxonium ylides might occur in the
presence of a metal catalyst. In this paper, we wish to report
the highly chemoselective N-alkylation of 2-pyridones with
sulfoxonium ylides under ruthenium catalysis.
furnished 3aa in moderate yields (entries 12−15). Reducing
the catalyst loading to 2.5 mol % delivered 74% yield of 3aa
(entry 16), and 1 mol % of CpRu(PPh3)2Cl provided 3a in
52% yield (entry 17).
Under the optimized reaction conditions, the scope of this
reaction was examined (Scheme 2). Initially, the scope with
a,b
Scheme 2. Scope for N-Alkylation of 2-Pyridones
We commenced our studies by using 2-pyridone 1a and
sulfoxonium ylide 2a as model reaction substrates by screening
a series of metal catalysts in dichloromethane (DCM) at room
temperature (Table 1). Since rhodium catalysts4a,b and
a
Table 1. Optimization of the Reaction Conditions
b
temp
(°C)
3aa/
3aa′
yield
(%)
entry
catalyst
Rh2(OAc)4
Rh2(TFA)4
solvent
1
2
3
DCM
DCM
DCM
rt
rt
rt
[Ir(COD)Cl]2
4
5
6
7
8
9
10
11
12
13
14
15
[Ru(p-cymene)Cl2]2 DCM
rt
rt
rt
rt
rt
rt
40
60
60
60
60
60
60
60
>19:1
>19:1
>19:1
17
34
65
<5
<5
[Ru(p-cymene)I2]2
CpRu(PPh3)2Cl
Cp*Ru(cod)Cl2
Ru(PPh3)3Cl2
DCM
DCM
DCM
DCM
DCM
DCM
DCM
MeCN
CHCl3
DCE
CpRu(PPh3)2Cl
CpRu(PPh3)2Cl
CpRu(PPh3)2Cl
CpRu(PPh3)2Cl
CpRu(PPh3)2Cl
CpRu(PPh3)2Cl
CpRu(PPh3)2Cl
CpRu(PPh3)2Cl
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
74
95
58
79
74
60
74
52
toluene
DCM
DCM
c
16
17
d
a
Reaction conditions: To a solution of 1a (0.2 mmol) and 2a (0.4
mmol) in 2.0 mL of solvent was added 5 mol % of catalyst. Then the
mixture was stirred at the corresponding reaction temperature for 4 h
in a sealed tube. The ratio of 3aa/3aa′ was determined by crude
b
c
d
NMR analysis. Yield of isolated products. 2.5 mol % catalyst. 1 mol
% of catalyst.
4c−e
[Ir(COD)Cl]2
have been successfully used to accomplish
several X−H insertion reactions, we first tested these catalysts.
Unfortunately, no reaction occurred under either rhodium or
iridium catalysis (entries 1−3). We then attempted to explore
13
a
other catalysts. When [Ru(p-cymene)Cl2]2 (5 mol %) was
Reaction conditions: To a solution of 1 (0.2 mmol) and 2 (0.4
used, the N-alkylated product 3aa was isolated in 17% yield
with no detection of the O-alkylated product 3aa′ (entry 4).
The use of [Ru(p-cymene)I2]2 slightly improved the yield of
3aa to 34% (entry 5). To our delight, the yield of 3aa was
increased to 65% when CpRu(PPh3)2Cl was used (entry 6). In
contrast, Cp*Ru(cod)Cl2 and Ru(PPh3)3Cl2 were almost
inactive in promoting the alkylation reaction (entries 7 and
8). Moreover, no reaction occurred in the absence of a catalyst
(entry 9). It should be noted that a higher reaction
temperature was beneficial to the formation of 3aa. Performing
the reaction at 40 °C provided 3aa in 74% yield (entry 10),
which was further increased to 95% at 60 °C (entry 11).
Several solvents were then screened. The use of acetonitrile
(MeCN), chloroform, 1,2-dichloroethane (DCE), and toluene
mmol) in 2.0 mL of DCM was added 5 mol % of CpRu(PPh3)2Cl.
b
The reaction was stirred at 60 °C for 4 h. Yield of isolated products.
respect to sulfoxonium ylides was investigated. Various
functional groups at the phenyl ring of ylides such as methoxy
(3ab), trifluoromethyl (3ac), methyl (3ad, 3af), chloro (3ae),
and naphthyl (3ag) were all tolerated, providing the
corresponding products in good yields. The sulfoxonium
ylides containing a heteroaryl groups were also suitable
substrates, and the desired products (3ah and 3ai) were
obtained in good yields too. For alkyl-substituted sulfoxonium
ylides, the corresponding products (3aj−3am) were obtained
in excellent yields. The ylide bearing a cyclopropane group
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pubs.acs.org/OrgLett
Letter
a,b
afforded the alkylated product (3an) in 61% yield. Moreover,
this reaction was also amenable to an alkenyl ylide, which gave
3ao in 75% yield. The molecular structure of 3ae was
elucidated by X-ray diffraction studies.
Scheme 3. Scope for N7-Alkylation of 7-Azaindoles
Next, the scope of 2-pyridones was evaluated. Generally,
both electron-donating and electron-withdrawing substituents
at the C3, C4, and C5 positions of the pyridone ring were all
tolerated, delivering the corresponding N-alkylated pyridones
in moderate to good yields. 2-Pyridones bearing chloro (3ba),
methyl (3ca), and strong electron-withdrawing cyano (3da)
groups at the C3 position led to moderate yields of the desired
products. Likewise, the C4-substituted with methyl (3ea),
benzyloxy (3fa), bromo (3ga), and ester (3ha) were all
tolerated. Comparatively, 2-pyridones bearing either electron-
donating or electron-withdrawing groups at the C5 position
gave the corresponding products (3ia−3la) in excellent yields.
Typically, this protocol was also applicable to sterically
hindered 5-fluoro-2-pyridone, which gave the desired product
(3ma) in 73% yield. However, 5-methyl substrate failed to give
the corresponding product (3na), indicating the increased
steric hindrance at that position would stop the reaction. It
should be noted that the ylides bearing a substituent at the
ylide carbon atom, and the ester substituted sulfoxonium ylide
did not work.
Similar with indoles, it was reported that the reaction of 7-
azaindoles with diazo compounds resulted in diverse reaction
modes upon different metal catalysts.14 However, the selective
N-7 alkylation of azaindoles with sulfoxonium ylides has not
been reported. Upon the successful N-alkylation of 2-
pyridones, we then focused on using this protocol to achieve
the selective alkylation of 7-azaindoles with sulfoxonium ylides.
Using CpRu(PPh3)2Cl (5 mol %) as the catalyst, the reaction
of unsubstituted 7-azaindole with 2a at 35 °C furnished 5aa in
93% yield. Then the scope of this reaction was investigated
(Scheme 3). With respect to sulfoxonium ylides, similar to
Scheme 2, the substrates containing either electron-donating
or electron-withdrawing substituents at different positions of
the phenyl ring were all tolerated, providing the corresponding
N7-alkylated products (5ab−5ae) in yields of 57−91%. The
heteroaryl- (5af−5ag) and alkyl-substituted (5ah−5ak)
sulfoxonium ylides were also tolerated. With respect to the
scope of 7-azaindoles, the substituents at the C2, C3, C4, and
C5 positions, including electron-donating and electron-with-
drawing groups, were all applicable, leading to the correspond-
ing products (5ba−5la) in excellent yields (85%−97%) except
5ia, which was obtained in 65% yield. However, 6-chloro-7-
azaindole was totally unreactive in this reaction.
a
Reaction conditions: To a solution of 4 (0.2 mmol) and 2 (0.2
mmol) in 2 mL of DCM was added 5 mol % of CpRu(PPh3)2Cl. The
reaction was stirred at 35 °C for 4 h. Yield of isolated products.
b
Scheme 4. Application and Elaboration
A gram-scale synthesis was conducted with 5 mmol of 1a
and 10 mmol of 2a, affording 3aa in 94% yield (1.0 g)
(Scheme 4a). Considering the similar reactivity of sulfonium
ylides to sulfoxonium ylides,15 we next investigated the use of
sulfonium ylides in this reaction. Subjected 1a to 2 equiv of 6a
afforded 78% yield of 3aa together with 15% yield of O-
alkylated product 3aa′ (Scheme 4b). Using dimethyl ylide 6b
instead, 3aa and 3aa′ were isolated in 53% and 31% yield,
respectively (Scheme 4c). Next, the sulfonium ylides bearing a
substitution at the ylide carbon were tested. The reaction of 1a
with 6c and 6d delivered N-substituted products 7c and 7d in
77% and 83% yield, respectively (Scheme 4d). Moreover,
reaction of pyridazine 8 with 2a led to 70% yield of N-alkylated
product 9 (Scheme 4e). To gain insight into the alkylation
process, compound 3aa′ was prepared according to our
previous gold-catalyzed O-alkylation reaction (Scheme 4f).11
No O-to-N migration reaction occurred in the presence of a
ruthenium catalyst, which excluded the possibility that the
previous formation of O-alkylation product followed by O-to-N
rearrangement to give the N-alkylated 2-pyridones.
The exact reaction mechanism for the selective N-alkylation
reaction is not clear at this moment. Based on the literature
reports1 and our own observations, we proposed the possible
reaction pathways in Scheme 5. The left catalytic cycle
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China; orcid.org/0000-0003-2516-3466;
Email: jtsun08@gmail.com, jtsun@cczu.edu.cn
Scheme 5. Proposed Reaction Mechanism
Authors
Xiaofeng Liu − Jiangsu Key Laboratory of Advanced Catalytic
Materials & Technology, School of Petrochemical
Engineering, Changzhou University, Changzhou 213164,
China
Ying Shao − Jiangsu Key Laboratory of Advanced Catalytic
Materials & Technology, School of Petrochemical
Engineering, Changzhou University, Changzhou 213164,
China; orcid.org/0000-0002-7379-8266
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c04229
Notes
represents carbene mechanism. The reaction of sulfoxonium
ylide 2a with ruthenium catalyst leads to ruthenium carbene
species I. Nucleophilic attack of nitrogen atom in 1a to carbene
carbon atom generates zwitteronic intermediate II. Sub-
sequently intramolecular proton transfer affords 3aa and
regenerates the ruthenium catalyst. The other possibility is
the Lewis acid mechanism. The deprotonation of 1a by 2a
happens at first place to generate anion III. The ruthenium
catalyst may work as a Lewis acid to activate the carbonyl
group or coordinate with the two oxygen atoms of sulfoxonium
ylide (right cycle of Scheme 5). Subsequent substitution of IV
with III via transition state TS1produces 3aa and DMSO
molecule while releasing the ruthenium catalyst.
In summary, we have developed a ruthenium-catalyzed
selective N−H rather than O−H insertion reaction of 2-
pyridones by using safe and stable sulfoxonium ylides as the
alkylating reagents, which is different from the use of diazo
compounds. The use of ruthenium catalyst is the key to
achieve the unique N-selectivity. Likewise, this alkylation
protocol is also amenable to 7-azaindoles, affording the
dearomative N7-alkylated chemoisomer as the single product.
Moreover, using sulfonium ylides bearing a substitution at the
ylide carbon atom as the substrates, the ruthenium-catalyzed
selective N-alkylation also works well to give the N-alkylated 2-
pyridones in good yields.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(No. 21971026) and the Jiangsu Key Laboratory of Advanced
Catalytic Materials & Technology (BM2012110) for financial
support.
REFERENCES
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ASSOCIATED CONTENT
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c04229.
Experimental procedures along with characterization
data and copies of NMR spectra (PDF)
Accession Codes
CCDC 2051495 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
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AUTHOR INFORMATION
Corresponding Author
■
Jiangtao Sun − Jiangsu Key Laboratory of Advanced Catalytic
Materials & Technology, School of Petrochemical
Engineering, Changzhou University, Changzhou 213164,
1041
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