An efficient method for the synthesis of 2-pyridones: Via C-H bond functionalization

Article abstract of DOI:10.1039/d0cc06834a

A simple and practical method to access N-substituted 2-pyridones via a formal [3+3] annulation of enaminones with acrylates based on RhIII-catalyzed C-H functionalization was developed. Control and deuterated experiments led to a plausible mechanism involving C-H bond cross-coupling and aminolysis cyclization. This strategy provides a short synthesis of structural motifs of N-substituted 2-pyridones.

Full text of DOI:10.1039/d0cc06834a

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An efficient method for the synthesis of
2-pyridones via C–H bond functionalization†
Cite this:DOI: 10.1039/d0cc06834a
Shuguang Zhou,ab Duan-Yang Liu,c Suo Wang,ab Jie-Sheng Tian*abc and
abcd
Received 14th October 2020,
Accepted 2nd November 2020
Teck-Peng Loh
*
DOI: 10.1039/d0cc06834a
rsc.li/chemcomm
A simple and practical method to access N-substituted 2-pyridones C–H functionalization and cyclization by introducing a reactive
via a formal [3+3] annulation of enaminones with acrylates based on functional group on one coupling molecule. In view of this,
RhIII-catalyzed C–H functionalization was developed. Control and N-substituted enaminones with a reactive site,10 which can be
deuterated experiments led to a plausible mechanism involving C–H readily prepared from commercially available ketone- or amide-
bond cross-coupling and aminolysis cyclization. This strategy provides a containing materials, may be suitable for the control of the
short synthesis of structural motifs of N-substituted 2-pyridones.
configuration of the coupling product through the formation of a
2-pyridone core (Scheme 2b), which was synthesized in a previous
Many functional molecules containing 2-pyridone frameworks exhi- report11 as a class of potential drug molecules in at least six steps.
bit specific and interesting bioactivities.1 Presented in Scheme 1 are Here, we describe a novel strategy for the synthesis of N-substituted
selected examples of natural products and pharmaceutical mole- 2-pyridones through formal [3+3] annulation via RhIII-catalyzed
cules with N-substituted 2-pyridone cores.2 Therefore, there has C–H functionalization. This approach has the advantages of using
been much interest focused on the development of new and readily prepared enaminones and commercially available acrylates,
efficient methods for the synthesis of 2-pyridone core structures.3 one-step operation, and high efficiency. In addition, a plausible
Representative approaches include C(N)–H functionalization of mechanism was also proposed based on control and deuterated
2-pyridones,4 intramolecular cyclization reaction,5 intermolecular experiments.
cycloaddition,6 and multicomponent domino reaction.7 Though
To verify this idea, reaction optimization was carefully studied
great progress has been achieved in the synthesis of 2-pyridone (see the ESI,† for more details). The results showed that
analogs, the development of effective and practical methods for [Cp*RhCl2]2 (2.0 mol%), AgOAc (8.0 mol%), Cu(OAc)2 (2.0 equiv.),
the construction of novel 2-pyridones, especially functionalized and KOAc (2.0 equiv.) in methanol at 90 1C under a N2 atmo-
N-substituted 2-pyridones,8 is of great significance in synthetic and sphere for 12 h were identified as the optimal reaction conditions
medicinal chemistry. Recently, cross-coupling reaction of enamides (Table S1, ESI,† entry 11).
or cyclic enaminones with acrylates for the synthesis of linear
Next, we evaluated the scope of N-substituted enaminones
conjugated dienes (Z, E) has been reported9 (Scheme 2a). However, in their reactions with methyl acrylate 2. In general, a wide
the synthesis of nitrogen-containing heterocyclic compounds or
E, Z-diene structural motifs has not yet been fully explored by
utilizing alkenylation of enaminones with acrylates as the key step.
We envisage that it may be feasible to realize the synthesis of
E, Z-diene structural fragments after undergoing C–C coupling via
a Institute of Advanced Synthesis (IAS), Northwestern Polytechnical University
(NPU), Xi’an 710072, China
b Yangtze River Delta Research Institute of NPU, Taicang, Jiangsu, 215400, China.
E-mail: ias_jstian@njtech.edu.cn, teckpeng@ntu.edu.sg
c Institute of Advanced Synthesis (IAS), Nanjing Tech University (NanjingTech),
Nanjing 211816, P. R. China
d Division of Chemistry and Biological Chemistry, School of Physical and
Mathematical Sciences, Nanyang Technological University, 637371, Singapore
Scheme 1 Examples of natural products and pharmaceutical molecules
with N-substituted 2-pyridone cores.
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
d0cc06834a
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Table 1 Scope of N-substituted enaminonesab
Scheme 2 Strategy for the synthesis of N-substituted 2-pyridones
through RhIII-catalyzed C–H activation.
range of structurally diverse 2-pyridone derivatives can be
obtained in moderate to excellent yields, as illustrated in
Table 1. N-Methyl enaminones tethered with a variety of aryl
substituents were found to be suitable substrates for this transfor-
mation, providing the corresponding benzoyl-substituted 2-pyridone
products 3a–3o (Table 1). Upon comparison of the same group at
the ortho-, meta-, and para-positions of the aryl ring, most of the
para-substituted substrates showed the best reactivity, which is
perhaps due to the influence of steric hindrance. Also, electronic
effects played an important role in this process (3d, 3g vs. 3l).
Additionally, the reaction displayed good compatibility to other poly-
and heteroaromatic substituents, such as naphthyl 3p, furyl 3q,
thienyl 3r, and ferrocenyl 3s, under the standard reaction condi-
tions. It is noteworthy that N-methyl enaminones bearing conju-
gated polyenyl and alkyl structures worked well, generating the
desired products 3t and 3u in 56% and 66% yields, respectively.
To our delight, this protocol can be applied to the structural
modification of the natural product 16-dehydropregnenolone. The
a
Reaction conditions: enaminone 1a (0.2 mmol, 1.0 equiv.), methyl
acrylate 2 (0.3 mmol, 1.5 equiv.), Cu(OAc)2 (0.4 mmol, 2.0 equiv.), KOAc
(0.4 mmol, 2.0 equiv.), MeOH (1.0 mL), [Cp*RhCl2]2 (2.0 mol%), AgOAc
b
c
(8.0 mol%), 90 1C, and 12 h. Isolated yields. [Cp*RhCl2]2 (0.2 mol%)
and AgOAc (0.8 mol%) on a 2.0 mmol scale. [Cp*RhCl2]2 (5.0 mol%)
and AgOAc (20 mol%). 36 h.
d
e
broad scope of R group prompted us to further examine the other ESI,† for more details) were conducted, which helped to clarify
substituents of N-substituted enaminones to obtain the more useful the intermediates and their transformation processes. As
2-pyridone derivatives 3t–3af. When the N-functional group (R2) was
shown in Scheme 3, two thirds of (Z)-1a can be converted to
changed to Bn, trifluoroethyl, allyl, Ph, and tert-butylphenyl, the
corresponding N-substituted 2-pyridones 3w–3aa were successfully
obtained in 37–61% yields. What’s more, enaminone 1ab equipped
with a chiral amino group displayed reactivity to give the target
(E)-1a in CD3OD at 90 1C in 3 h in the absence of the rhodium
catalyst. Whereas, in the [Cp*RhCl2]2 and AgOAc catalytic
system, the hydrogen of (Z)-1a at the a-position can be almost
completely deuterated according to 1H NMR detection. This C–H/
product 3ab. Then, alteration of the R3 substituent to a methyl group C–D exchange supports a reversible activation by the rhodium
proceeded smoothly. Intrigued by the scope of R2 and R3 groups catalyst. On the other hand, alkenylation of the N-methyl enam-
investigated, bicyclic N-substituted 2-pyridone frameworks were inone 1a can provide diene 3a0 in good yield by using modified
further pursued. Luckily, azabicyclic compounds 3ad–3af with a
2-pyridone core and a 5, 6, or 7-membered ring can also be
efficiently constructed. Additionally, the potential utility of this
method was demonstrated on the basis of modification of natural
products and low catalytic loading (0.2 mol%) on a 2.0 mmol scale.
conditions to reduce aminolysis cyclization (Scheme 4, eqn (1)),
while no coupling product 3a00 was obtained with N,N-dimethyl
enaminone 1a0 (Scheme 4, eqn (2)). These results imply that the
amino functionality with the N–H bond was deprotonated and
then coordinated to the rhodium catalyst as a directing group for
To better understand the mechanism of the synthesis of C–H bond activation to form the reactive four-membered rhoda-
2-pyridone derivatives through the RhIII-catalyzed formal [3+3] cycle intermediate, which further reacted with acrylate to realize
annulation of N-substituted enaminones with methyl acrylate, the cross-coupling reaction. Next, the reaction pattern of forming
several deuterium-labeling and control experiments (see the
C–C and C–N bonds in a one-step manner was evaluated to
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Scheme 3 Deuterium-labeling experiments detected by 1H NMR. (a) (Z)-1a
(0.1 mmol), CD3OD, 90 1C, and 3 h; (b) (Z)-1a (0.1 mmol), [Cp*RhCl2]2
(2.0 mol%), AgOAc (8 mol%), CD3OD, 90 1C, and 3 h.
Scheme 5 Mechanistic hypothesis.
A plausible mechanism of our formal [3+3] annulation
reaction by RhIII-catalyzed C–H activation is presented in
Scheme 5 on the basis of the mechanistic study (See ESI,† for
more details) and the relevant literature.12 Briefly, the reaction
starts by anion exchange forming the reactive rhodium acetate
species A, which activates (Z)-N-substituted enaminone 1 by
successive N–H deprotonation and C–H bond activation lead-
ing to the E configuration species B and rhodacycle complex C.
After that, coordination and migratory insertion of methyl
acrylate form a new six-membered rhodacycle intermediate E,
which undergoes b-hydride elimination to afford a RhIII
hydride species F. Subsequent intramolecular aminolysis reac-
tion of the ester and reductive elimination provide the target
product 3 and Rh(I)Cp*. Here, we also do not rule out that
the intermediate G is generated by aminolysis cyclization
before b-hydride elimination. Finally, the resulting RhI complex
is further oxidized by Cu(OAc)2 to regenerate RhIII acetate
species A to complete the catalytic cycle.
In summary, we have accomplished the synthesis of
N-substituted 2-pyridones through the RhIII-catalyzed formal
[3+3] annulation of enaminones with acrylates. A plausible
mechanism involving C–C coupling via C–H bond functionali-
zation and subsequent aminolysis cyclization was proposed
through control and deuterated experiments. Further investiga-
tions on the practical applications of this method, especially in
the synthesis of drug candidates, are underway.
Scheme 4 Control experiments.
We gratefully acknowledge Northwestern Polytechnical Univer-
sity, the Fundamental Research Funds for the Central Universities
(31020200QD046), the Natural Science Foundation of Jiangsu
Province (BK20171463), the grant of MOE-Tier 1 (M4012045.110
RG12/18-(S)), Nanjing Tech University, and Nanyang Technological
University for the generous financial support.
determine the possible process by designing control experiments.
When diene intermediate 3a0 was subjected to standard conditions,
the reaction proceeded smoothly, affording the cyclization product
3a in 91% yield (Scheme 4, eqn (3)). However, without the rhodium
catalyst, the desired product 3a was obtained in 48% yield. Maybe
the rhodium species after N–H deprotonation helps to promote the
aminolysis cyclization (Scheme 4, eqn (4)). In contrast, no product
3a was detected in the cyclization experiment of 3a00 0 by Michael
addition (Scheme 4, eqn (5)). These observations also suggested
that this [3+3] annulation involves b-hydride elimination after
coordination and migratory insertion of a four-membered rhoda-
cycle species with acrylate.
Conflicts of interest
There are no conflicts to declare.
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