Tandem Reaction Approaches to Isoquinolones from 2-Vinylbenzaldehydes and Anilines via Imine Formation-6π-Electrocyclization-Aerobic Oxidation Sequence

Article abstract of DOI:10.1021/acs.orglett.9b04233

Two distinctive transition-metal-promoted aerobic oxidation protocols have been developed for the synthesis of isoquinolones from 2-vinylbenzaldehydes and aniline derivatives. Thus, the one-pot tandem reaction sequence of imine formation, thermal 6π-electrocyclization, followed by either Cu(OAc)₂-mediated or Pd(OAc)₂-catalyzed aerobic oxidation protocol allowed the ready access to isoquinolone derivatives. The control experiments revealed that the 1,2-dihydroisoquinoline intermediates from the 6π-electrocyclization of 1-azatrienes were aerobically oxidized to isoquinolones in the presence of either Cu(OAc)₂ or Pd(OAc)₂ catalyst.

Full text of DOI:10.1021/acs.orglett.9b04233

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Tandem Reaction Approaches to Isoquinolones from
2‑Vinylbenzaldehydes and Anilines via Imine Formation−6π-
Electrocyclization−Aerobic Oxidation Sequence
Jiyeon Lee, Hun Young Kim, and Kyungsoo Oh*
Center for Metareceptome Research, Graduate School of Pharmaceutical Sciences, Chung-Ang University, 84 Heukseok-ro,
Dongjak, Seoul 06974, Republic of Korea
S
* Supporting Information
ABSTRACT: Two distinctive transition-metal-promoted aerobic
oxidation protocols have been developed for the synthesis of
isoquinolones from 2-vinylbenzaldehydes and aniline derivatives.
Thus, the one-pot tandem reaction sequence of imine formation,
thermal 6π-electrocyclization, followed by either Cu(OAc)2-medi-
ated or Pd(OAc)2-catalyzed aerobic oxidation protocol allowed the
ready access to isoquinolone derivatives. The control experiments revealed that the 1,2-dihydroisoquinoline intermediates from
the 6π-electrocyclization of 1-azatrienes were aerobically oxidized to isoquinolones in the presence of either Cu(OAc)2 or
Pd(OAc)2 catalyst.
Scheme 1. 6π-Electrocyclization of 1-Azatrienes and
he 6π-electrocyclization reactions are characterized by the
Proposed Synthetic Pathway to Isoquinolones
T
formation of cyclohexadienes from 1,3,5-hexatrienes under
thermal and photochemical processes.1 Although the use of
azatrienes with suitable electronic and steric characteristics in
6π-electrocyclization reactions has enabled the synthesis of
azaheterocycle natural products,2 the thermodynamic prefer-
ences between dihydropyridines and azatrienes are generally
controlled by the azatriene substrates under thermal conditions
(Scheme 1a). Thus, the 1-azatrienes with a leaving group at the
nitrogen atom allow facile aromatization to pyridine deriva-
tives,3 and 1-azatrienes with 4,6-disubstitution are known to
facilitate the formation of 1,2-dihydropyridines through
conformational and electronic controls.4 Given the wide
synthetic utility of 6π-electrocyclization of 1-azatrienes, it is
rather puzzling to find that there are no examples of 6π-
electrocyclization of isolated 1-azatrienes derived from N-aryl
derivatives.5 In contrast, the N-aryl-1,2-dihydropyridines are
accessible from the transition-metal-catalyzed olefinic C−H
alkenylation of α,β-unsaturated imines with alkynes6 where the
transient N-aryl-1-azatriene intermediates were proposed to
undergo the 6π-electrocyclization. To fill the gap in knowledge
in the 6π-electrocyclization of 1-azatrienes, we investigated the
cyclization of N-aryl-1-azatrienes derived from anilines (Scheme
1b). Herein, we report the discovery of a tandem reaction
sequence of 6π-electrocyclization of N-aryl-1-azatrienes fol-
lowed by transition-metal-promoted aerobic oxidations to
isoquinolone derivatives. The key finding of the current work
includes the identification of complementary Cu(II)-mediated
and Pd(0)-catalyzed aerobic oxidation protocols, allowing the
direct access to isoquinolones from 2-vinylbenzaldehydes and
anilines in a one-pot fashion.
aniline 2a, was chosen as a model substrate (Table 1). Although
our initial experiments were focused on effecting the 6π-
electrocyclization of 3a to 1,2-dihydropyridine derivatives, the
thermal reaction at increased reaction temperature primarily led
to the decomposition of the imine 3a.7 The subjection of 3a in
polar aprotic solvents under aerobic conditions only led to the
To investigate the 6π-electrocyclization reaction of N-aryl-1-
azatrienes, an (E)-N-(2-vinylbenzylidene)aniline 3a, derived
from the in situ condensation between the aldehyde 1a and
Received: November 25, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b04233
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
The requirement of more than stoichiometric amounts of
Cu(OAc)2 salt prompted us to investigate other transition metal
catalysts to effect the catalytic transformation of the imine 3a to
4a. Given that the vinyl arenes and anilines could undergo the
aerobic oxidative hydroamination in the presence of Pd
catalysts,9 aniline 2a was fully transformed into imine 3a before
being exposed to the Pd catalysts (Table 2). Such stepwise
Table 1. Optimization of One-Pot Cu-Mediated Oxidative
Cyclization of 1-Azatriene to Isoquinolone
a
Table 2. Optimization of Stepwise Pd-Catalyzed Oxidative
Cyclization of 1-Azatriene to Isoquinolone
a
4a yield
b
entry
Cu metal
additive
solvent
(%)
comment
1
2
3
4
5
6
7
8
9
DMA
NMP
DMF
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
10
16
12
25
0
CuO
CuOTf
CuCl
CuOAc
Cu(OAc)2
Cu(OAc)2
MgSO4
MgSO4
MgSO4
MgSO4
MgSO4
MgSO4
0
24
56
74
71
4a yield
b
entry
Pd metal
base
ligand
(%)
comment
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
32
38
33
42
46
42
41
0
52
35
43
55
47
59
28
16
55
40
51
22
10
3 equiv of
Cu(OAc)2
i-Pr2NEt
pyridine
Li2CO3
Na2CO3
K2CO3
11
12
Cu(OAc)2
Cu(OAc)2
MgSO4
MgSO4
DMSO
DMSO
65
43
1 equiv of
Cu(OAc)2
0.5 equiv of
Cu(OAc)2
K3PO4
13
14
15
16
17
18
19
20
21
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
MgSO4
MgSO4
DMSO
DMSO
DMSO
DMA
NMP
DMF
DMSO
DMSO
DMSO
60
65
63
41
39
54
56
19
16
0.4 g of MgSO4
0.1 g of MgSO4
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
9
10
11
12
13
14
15
16
17
18
19
proline
PBu3
PCy3
dppe
PPh3
PPh3
PPh3
PPh3
Ph3PO
PPh3
PPh3
MgSO4
MgSO4
MgSO4
MgSO4
MgSO4
MgSO4
130 °C
2 equiv of AcOH
under Ar
under air
Cu(OAc)2
a
under Ar
5 mol % of cat.
Unless stated otherwise, reactions used 1a (0.2 mmol), 2a (0.22
mmol), metal (2 equiv), and MgSO4 (0.2 g) in solvent (0.13 M) at
150 °C for 6 h under air. Isolated yields after column
chromatography.
b
3 equiv of H2O
c
20
1 equiv of
Cu(OAc)2
a
Unless stated otherwise, reactions used 1a (0.3 mmol), 2a (0.33
mmol), and MgSO4 (0.3 g) in CH2Cl2 (0.1 M) at 23 °C for 24 h.
After the reaction mixture was filtered and the CH2Cl2 solvent
was removed, the crude 3a, metal (10 mol %), ligand (20 mol %), and
base (20 mol %) were added in DMSO (0.1 M) at 150 °C for 1 h
formation of isoquinolone 4a in low yields (entries 1−4). After
the necessity of air for the conversion of the imine 3a to the
isoquinolone 4a was confirmed, formation of 4a was interpreted
as the 6π-electrocyclization of 3a followed by aerobic oxidation
of the 1,2-dihydropyridine intermediate (vide infra). Whereas
the 6π-electrocyclization strategy has not been reported for the
direct access to isoquinolones from 1-azatrienes, the novel
oxidative amination pathway of 1-azatrienes encouraged us to
investigate the transition metal catalysis. Thus, a quick survey of
transition metal catalysts swiftly identified the use of Cu(OAc)2
as a suitable aerobic oxidation promoter,8 leading to the
formation of the isoquinolone 4a in 74% yield (entries 5−9).
The optimal amount of Cu(OAc)2 turned out to be 2 equiv
(entry 9), and the reduced amounts of Cu(OAc)2 provided
lower yields of 4a in 43−65% yields (entries 11−12). Although
the dehydrating agent, MgSO4, did not display the crucial role in
the overall reaction conversion (entries 13−15), the use of 1 g/
mmol of MgSO4 helped improve the yield of 4a to 74% yield
(entry 9). Other polar aprotic solvents were inferior to DMSO
(entries 16−18). The reaction at 130 °C reduced the yield of 4a
to 56% yield (entry 19). The control experiments also confirmed
the critical role of copper salt (entry 20) and the aerobic oxygen
atmosphere (entry 21).
b
using an O2 balloon. Isolated yields after column chromatography.
c
N-Phenylphthalimide was also obtained in 27% yield.
approaches proved to be crucial to obtain isoquinolone 4a from
3a in the presence of 10 mol % of Pd(OAc)2 catalyst (entry 1),
whereas the direct conversion of 1a and 2a to 4a was not
successful at all. The screening of bases revealed that the
carbonates further promoted the conversion of the imine 3a to
4a up to 46% yield (entries 2−7). Whereas the use of PdCl2
failed to give the desired product 4a (entry 8), employment of
Pd(PPh3)4 led to a 52% yield of 4a (entry 9). A survey of ligands
showed that the addition of 20 mol % of PPh3 further improved
the observed yield of 4a to 59% (entries 10−14). The control
experiments suggested that the current Pd-catalyzed oxidative
cyclization reaction required an oxygen atmosphere (entries 15
and 16) and the optimal 10 mol % of Pd(OAc)2 catalyst loading
(entry 17). Also, although the oxidized form of the PPh3 ligand
decreased the observed yield of 4a to 40% (entry 18), the Ph3PO
and residual water did not have a deleterious effect on the
B
DOI: 10.1021/acs.orglett.9b04233
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
reaction (entry 19). The Wacker-type reaction conditions
provided the desired product 4a in 22% yield in the presence of
Cu(OAc)2 (entry 20).
With the optimized conditions in hand, the substrate scope of
respective Cu-mediated and Pd-catalyzed oxidative cyclization
reactions of N-aryl-1-azatrienes was investigated (Scheme 2).
isoquinolones 4 in Scheme 2 represent the overall reaction
efficiency of three consecutive reactions: imine formation, 6π-
electrocyclization, and aerobic oxidation.
To confirm the reaction pathway of 1-azatrienes 3 to
isoquinolones 4, an authentic sample of 2-phenyl-1,2-
dihydroisoquinoline 5a, the 6π-electrocyclization product of
3a, was prepared from the nitroalkane reduction protocol
developed by Asao.10 The subjection of 5a under the optimized
reaction conditions provided the desired oxidation product 4a in
chemical yields almost identical to those of our optimized
conditions, suggesting the quantitative conversion from 1 and 2
to 1,2-dihydroisoquinoline 5a via the condensation−6π-electro-
cyclization process (Scheme 3a). Next, the possible involvement
Scheme 2. Scope of Tandem Reactions to Isoquinolones
Scheme 3. Control Experiments and Synthetic
Transformation
The electronic and steric features of aniline derivatives 2 were
first examined; whereas the Cu-mediated reactions did not
display a significant steric effect, the use of anilines with electron-
donating groups negatively affected the formation of isoquino-
lones (4j and 4k). In contrast, the Pd-catalyzed reactions were
not compatible with an aryl bromide moiety (4g) and generally
provided lower yields of isoquinolones compared to those of the
Cu-mediated reactions. The investigation into the electronic
feature of 2-vinylbenzaldehydes 1 indicated that both Cu-
mediated and Pd-catalyzed reactions tolerated an electron-
donating group at the C-6 and C-7 positions of 2-vinyl-
benzaldehydes (4o−4q). Also, the electronic effect of the C-7
position was minimal (4r and 4s). The current Cu-mediated
oxidative cyclization reaction allows the direct conversion of a
mixture of 1 and 2 to isoquinolones without having to preform
the N-aryl-1-azatriene intermediates. Whereas the Pd-catalyzed
reaction requires the preformed imines due to the interaction
between anilines and Pd catalyst, the ready access to N-aryl-1-
azatrienes under mild reaction conditions clearly demonstrates
the synthetic potential of the current oxidative cyclization
methods to isoquinolones. Thus, the isolated yields of
of N-phenyl-2-vinylbenzamide 5b was investigated;11 however,
the formation of 4a was not observed in both Cu-mediated and
Pd-catalyzed aerobic oxidations. Instead, the formation of N-
phenylphthalimide 5c was observed in 29−30% yields by the
aerobic alkene cleavage.12 Thus, the metal promoters appear to
facilitate the aerobic benzylic oxidations of 1,2-dihydroisoquino-
lines 5,13 where the Cu(OAc)2 is converted to an inactive form
of promoter, CuO, whereas the catalytic cycle of Pd(0) is
established (Scheme 3b). The fact that the use of a radical
C
DOI: 10.1021/acs.orglett.9b04233
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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stability of 1,2-dihydroisoquinoline intermediates from the 6π-
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one-pot condensation−6π-electrocyclization−aerobic oxidation
protocol. Thus, in the absence of metal promoters the 1,2-
dihydroisoquinolines from 6π-electrocyclization are believed to
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oxidation. Accordingly, the preparation of N-alkyl-substituted
isoquinolones 4t−4v was met with limited success in 23−33%
yields, possibly due to the rapid decomposition pathways of 1,2-
dihydroisoquinoline intermediates (see the Supporting In-
formation for details). Although the substitution on the vinyl
group (C3-Ph or C4-Me) strictly hindered the desired reaction
sequence, the NBS treatment with 4a led to the formation of
alkenyl bromide 6a in 95% yield, and the subsequent Suzuki
cross-coupling provided 4-phenyl isoquinolone 7a in 97%
(Scheme 3c).
In summary, we have developed the direct access to
isoquinolone derivatives from readily available 2-vinylbenzalde-
hydes and aniline derivatives. The identification of two
transition metal promoters for the aerobic oxidation of 1,2-
dihydroisoquinoline intermediates to isoquinolones swiftly
allowed the tandem reaction sequence of imine formation−
6π-electrocyclization−aerobic oxidation. Given the synthetic
versatility of 6π-electrocyclization of azatriene derivatives, the
newly discovered aerobic oxidation protocol should find
widespread synthetic applications to various heterocyclic
compounds. Further application of the current tandem reactions
is currently underway in our laboratory, and our results will be
reported in due course.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04233.
Experimental procedures and characterization data for all
new compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: kyungsoooh@cau.ac.kr.
ORCID
Hun Young Kim: 0000-0002-8461-8910
Kyungsoo Oh: 0000-0002-4566-6573
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the National Research
Foundation of Korea (NRF) grants funded by the Korean
government (MSICT) (NRF-2015R1A5A1008958 and NRF-
2019R1A2C2089953).
(5) For a 6π-electrocyclization example of N-alkyl-1-azatriene, see:
(a) Umetsu, K.; Asao, N. An Efficient Method for Construction of
Tetrahydroisoquinoline Skeleton via Double Cyclization Process using
ortho-Vinylbenzaldehydes and Amino Alcohols: Application to the
Synthesis of (S)-Cryptostyline II. Tetrahedron Lett. 2008, 49, 2722−
2725. For N-carbamyl-1-azatriene intermediates, see: (b) Trost, B. M.;
Biannic, B. Redox Cycloisomerization Approach to 1,2-Dihydropyr-
idines. Org. Lett. 2015, 17, 1433−1436.
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DOI: 10.1021/acs.orglett.9b04233
Org. Lett. XXXX, XXX, XXX−XXX