Multicomponent Synthesis of Isoindolinones by RhIII Relay Catalysis: Synthesis of Pagoclone and Pazinaclone from Benzaldehyde

Article abstract of DOI:10.1021/acs.orglett.8b04026

A practical one-pot isoindolinone synthesis enabled by Rh^III catalysis was developed. The advantage of this protocol is that it does not require pre-preparation of amide substrates, because Rh^III participates in two reactions independently. This mild, operationally multicomponent process transforms a wide variety of commercially available aldehydes into the corresponding γ-lactams in good yields, thereby demonstrating that N-pyridin-2-yl benzamide is an effective directing group. Notably, the anxiolytic drugs pagoclone and pazinaclone can be directly prepared by this methodology.

Full text of DOI:10.1021/acs.orglett.8b04026

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Multicomponent Synthesis of Isoindolinones by RhIII Relay Catalysis:
Synthesis of Pagoclone and Pazinaclone from Benzaldehyde
Yan Zhang,* Haiqian Zhu, Yuting Huang, Qi Hu, Yu He, Yihang Wen, and Gangguo Zhu*
Key Laboratory of the Ministry of Education for Advanced Catalysis Materials, Zhejiang Normal University, 688 Yingbin Road,
Jinhua 321004, China
S
* Supporting Information
ABSTRACT: A practical one-pot isoindolinone synthesis enabled by RhIII catalysis was developed. The advantage of this
protocol is that it does not require pre-preparation of amide substrates, because RhIII participates in two reactions
independently. This mild, operationally multicomponent process transforms a wide variety of commercially available aldehydes
into the corresponding γ-lactams in good yields, thereby demonstrating that N-pyridin-2-yl benzamide is an effective directing
group. Notably, the anxiolytic drugs pagoclone and pazinaclone can be directly prepared by this methodology.
itrogen-containing organic compounds are ubiquitous in
nature and are essential to life. They are also important
intermediates and products of the chemical and pharmaceutical
industries. Among these, isoindolinones represent a significant
class of heterocycles that are widely found in natural products
and biologically active compounds.1 Some representative
examples of these compounds are depicted in Figure 1.
powerful support to the design and synthesis of various skeletons
such as lactams,5 pyridines,6 and others.7 In particular, rhodium-
catalyzed C−H olefination of benzamide with terminal olefins
followed by annulation to form γ-lactam is one of the most
classic of such syntheses (Scheme 1A). Li8 first reported RhIII-
N
Scheme 1. Rh(III)-Catalyzed C−H Olefination toward
Isoindolinones
Figure 1. Representative biologically active molecules including
isoindolinone.
catalyzed oxidative-coupling reactions between benzamides and
olefins, followed by intramolecular Michael reactions to form γ-
lactam. On the basis of the competitive reaction, it was
concluded that transformation is favored for benzamides with
electron-poor N-phenyl groups. Thus, Sun and Yu9 later
reported an elegant improved synthesis and showed that the
Pagoclone is an anxiolytic drug from the cyclopyrrolone family
that is known to bind to the benzodiazepine receptor site of the
GABA-A receptor.2 In addition, pazinaclone and JM-1232 also
have been reported to be benzodiazepine receptor agonists for
the treatment of anxiety.3 The last two compounds have been
studied as an NHE1 inhibitor and a potential drug for the
treatment of cardiac arrhythmias, respectively.4
In the past decade, explosive progress has been made in the
development of Cp*Rh-catalyzed C−H activation that offers
Received: December 18, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b04026
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Letter
use of an N-pentafluorophenyl benzamide directing group is
crucial for this transformation.
nitrogen atmosphere facilitated this one-pot transformation,
improving the yield to 91% yield (entry 9).
With the optimized reaction conditions in hand (Table 1,
entry 9), we first investigated the scope of the substituted
benzaldehydes (Scheme 2). Various benzaldehydes with
On the other hand, multicomponent reactions (MCRs),
defined as the processes that combine at least three reactants in
the same pot to generate a product containing most of the atoms
of the starting materials,10 have been heavily exploited to prepare
small molecules with atom/step economy, efficiency, and
structural diversity. Therefore, the development of MCRs for
the construction of biologically interesting molecules always
exhibits opportunities and challenges due to the simple
experimental procedures and one-pot ecofriendly synthesis
method. In light of our ongoing interest in heterocycles
synthesis,11 herein we designed the one-pot multicomponent
isoindolinone synthesis enabled by relay catalysis of rhodium-
(III), starting from commercially available aldehydes, 2-
pyridinamine, and olefins (Scheme 1B). However, to achieve
the expected reaction, the following two challenges must be
overcome: (1) amide rather than iminium should be generated
in situ from benzaldehydes and aromatic amine and (2) the
catalytic amount of [Cp*RhCl2]2 must act as the relay catalyst
for both oxidative amidation and olefination.
a
Scheme 2. Scope of Benzaldehyde Substrate
To our delight, we overcame these challenges and obtained
the target product. Unlike the many previously reported studies
where the formed iminium acted as the directing group,12 we
selectively realized amidation in our catalytic system, similar to
that previously reported for copper and other metal catalysts.13
We began our investigation with the coupling among
benzaldehyde 1a, pyridin-2-amine 2a, and ethyl acrylate 3a.
Selected results are shown in Table 1. The use of [Cp*RhCl2]2
a
Table 1. Optimization of the Reaction Conditions
b
entry
additive
solvent
yield (%)
1
2
3
4
5
6
7
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
AgOAc
Mn(OAc)3
CuSO4
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
MeCN
THF
MeOH
TFIP
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
70
10
trace
trace
trace
trace
trace
40
a
Isolated yields are given. Reaction conditions: 1 (0.2 mmol), 2a (0.3
mmol), 3a (0.4 mmol), [RhCp*Cl2]2 (2.5 mol %), Cu(OAc)2 (0.4
mmol), MeCN (2 mL), under N2 atmosphere, 80 °C, 8 h. PMP =
para-methoxyphenyl.
c
8
d
9
91
76
e
10
a
Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), 3a (0.4 mmol),
valuable functional groups such as methoxy, methylthio,
bromo, cyano, ester, and acyl reacted smoothly with 2a and 3a
to afford the corresponding isoindolinones (4b−4i) in moderate
to excellent yields (45−95%), thus offering a broad range of
opportunities for further derivation. In addition, the structure of
4h was further confirmed by single-crystal X-ray analysis. These
results show that the reactions of the benzaldehydes bearing
electron-donating and -withdrawing groups at the para position
had no obvious effect on this transformation. Additionally, when
meta-substituted benzaldehydes were applied, good regioselec-
tivity favoring the activation of the less hindered C−H bond was
observed, and the sole product was obtained in good yields (4j
and 4k). However, for the ortho- and polysubstituted
benzaldehydes, the yields of the desired products were lower
(4l−4o). Heteroaryl and naphthyl substituents were also
compatible, and the expected products were found in moderate
[RhCp*Cl2]2 (2.5 mol %), additive (0.4 mmol), solvent (2 mL), 80
b
c
d
°C, 8 h. Yields of isolated products. Reaction at 60 °C. Under N2
e
atmosphere. Cu(OAc)2 2.0 equiv. TFIP = hexafluoroisopropanol.
as the single catalyst and Cu(OAc)2 as the oxidant in MeCN
yielded lactam 4a in 70% yield (Table 1, entry 1). Encouraged by
this preliminary observation, we attempted to improve the
reaction efficiency by screening various solvents and oxidant
(entries 2−7). It was found that Cu(OAc)2 was the best oxidant.
Among the screened solvents, MeCN afforded the best yield.
Lowering of the temperature to 60 °C resulted in a lower yield
(entry 8). An attempt to lower the loading of Cu(OAc)2 also
failed, because a smaller yield was obtained (entry 10). On the
other hand, it was found that conducting the reaction under
B
DOI: 10.1021/acs.orglett.8b04026
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Letter
yields (4p and 4q). Interestingly, using 1,4-benzenedicarbox-
aldehyde as the substrate, the expected symmetrical product 4r
was isolated.
Scheme 4. Synthetic Application and Diversification
We then investigated the scope of the olefin-coupling partner
in this transformation. As shown in Scheme 3, electron-deficient
a
Scheme 3. Scope of Olefin- and Aniline-Coupling Partners
good yields by reduction and hydrolysis from 4, respectively
(Scheme 4d).
To obtain insight into the reaction mechanism proposed in
Scheme 5B, several control experiments were performed. First,
Scheme 5. Proposed Mechanism
a
Isolated yields are given. Reaction conditions: 1a (0.2 mmol), 2 (0.3
mmol), 3 (0.4 mmol), [RhCp*Cl2]2 (2.5 mol %), Cu(OAc)2 (0.4
mmol), MeCN (2 mL), under N2 atmosphere, 80 °C, 8 h.
olefins including acrylate, ethyl vinyl ketone, acrylonitrile, and
acrylamide can be coupled in good yield to provide lactam
products (5a−5g). Meanwhile, different types of substituents at
different positions on the aniline had distinct impacts on the
reaction (5h−5k). It should be noted that analogues of the
anxiolytic drugs pagoclone and pazinaclone can be directly
prepared by this method (5l and 5m). We also tested the
reaction using an electron-deficient aniline (2f, see SI) instead of
a pyridine-2-amine, but it is not effective. Clearly, this strategy
opens a new avenue to the synthesis of these biologically
interesting scaffolds with readily available starting materials.
We were particularly interested in applying this strategy to
drug synthesis and accessing other compounds with natural-
product-like cores. 6 (Pagoclone) and 8 (pazinaclone) can be
directly prepared in a single step from benzaldehyde 1a, albeit
with low yields (Scheme 4a,b). We were able to obtain 8
(pazinaclone) with good yield under the standard reactions
using amide 7 as the starting material (Scheme 4c), suggesting
that formation of amide 7 may not proceed well in this catalytic
system. Furthermore, compounds 9 and 10 were obtained in
reaction among benzaldehyde 1b, pyridin-2-amine 2a, and ethyl
acrylate 3a with 2 equiv of Cu(OAc)2 gave no amide 11 and
product 4b (Scheme 5A, eq (1)). Second, the reaction of amide
11 with olefin 3a at the standard conditions was evaluated,
showing that the expected product 4b could be isolated in 90%
yield (Scheme 5A, eq (2)). We can also get evidence suggesting
that the pyridine moiety plays an important role in the direction
group (see SI). Next, considering that this Rh(III)-catalyzed
C
DOI: 10.1021/acs.orglett.8b04026
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b04026.
Detailed experimental procedures and characterization
data for new compounds 4 and 5 (PDF)
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CCDC 1835723 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 Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
Casanova, N.; Quinones, N.; Mascarenas, J. L.; Gulías, M. J. Am. Chem.
̃ ̃
AUTHOR INFORMATION
Corresponding Authors
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■
*E-mail: zhangyan001@zjnu.edu.cn (Y.Z.)
*E-mail: gangguo@zjnu.cn (G.Z.)
ORCID
Yan Zhang: 0000-0002-0694-5131
Gangguo Zhu: 0000-0003-4384-824X
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the NSFC (21702188,
21672191) and the Natural Science Foundation of Zhejiang
Province (LQ17B020001).
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