Carbene-catalyzed aerobic oxidation of isoquinolinium salts: Efficient synthesis of isoquinolinones

Article abstract of DOI:10.1039/c8gc01488d

A mild and environmentally friendly carbene-catalyzed aerobic oxidation of isoquinolinium salts was successfully realized. Accordingly, a diverse set of isoquinolinones and phenanthridinones was efficiently prepared in good to excellent yields. The mechanistic study indicates that the formation of an aza-Breslow intermediate is the crucial step in this transformation. This reaction features ambient air as the sole oxidant and oxygen source, a broad substrate scope, and excellent functional-group tolerance and proceeds under mild reaction conditions. Furthermore, a highly efficient synthesis of bioactive molecules and natural products including N-methylcrinasiadine, N-isopentylcrinasiadine, N-phenethylcrinasiadine, isoindolo[2,1-b]isoquinolin-5(7H)-one, PJ-34, rac-Gusanlung D, rosettacin, 8-oxopseudopalmatine and ilicifoline B was accomplished.

Full text of DOI:10.1039/c8gc01488d

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Carbene-Catalyzed Aerobic Oxidation of Isoquinolinium Salts:
Efficient Synthesis of Isoquinolinones
Guanjie Wang,a Wanyao Hu,a Zhouli Hu,a Yuxia Zhang,a Wei Yao,a Lin Li,a Zhenqian Fu,*a,b and Wei
Huang,*a,b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
A mild and environmentally friendly carbene-catalyzed aerobic oxidation of isoquinolinium salts was successfully realized.
Accordingly, a diverse set of isoquinolinones and phenanthridinones was efficiently prepared in good to excellent yields.
The mechanistic study indicates that the formation of aza-Breslow intermediate is the crucial step in this transformation.
This reaction features ambient air as the sole oxidant and oxygen source, a broad substrate scope, excellent functional-
group tolerance and proceeds under mild reaction conditions. Furthermore, the highly efficient synthesis of bioactive
molecules and natural products including N-mehtylcrinasiadine, N-isopentylcrinasiadine, N-phenethylcrinasiadine,
isoindolo [2,1-b]isoquinolin-5(7H)-one, PJ-34, rac-Gusanlung D, rosettacin, 8-oxopseudopalmatine and ilicifoline B, was
accomplished.
www.rsc.org/
and air as the sole oxidant. Owning to the importance of
isoquinolinones, the development of conceptually new
environmentally friendly synthetic strategies is still highly
desirable.
Introduction
As an important family of N-heterocycles, isoquinolinone is
often presented as a core structural scaffold in numerous
biological natural products and pharmaceuticals (Figure 1).1
For example, 8-oxopseudopalmatine which was isolated from
Guatteria hispida by the Costa group,2 exhibits cytotoxic
activity towards MDA-MB-231 cells. Significantly, this type of
isoquinolinones shows stronger biological activities than the
related isoquinoline.3 Accordingly, several methods have been
well addressed for the synthesis of isoquinolinones.4 Among
them, the oxidation of isoquinolinium salts, which were easily
prepared from a variety of widespread isoquinolines with alkyl
halides, is a particularly reliable and straightforward strategy.
However, traditional oxidative methods require the
employment of excess K3Fe(CN)6 as a reagent and cannot
avoid generation of equivalents of toxic byproducts.5 In
contrast, mild, environmentally friendly oxidative methods are
highly desirable and urgent to be developed. A particularly
attractive approach was recently reported by Fu and co-
workers,6 who described
a visible light-mediated radical
Figure 1 Some representative natural products containing isoquinolinones and
process to form isoquinolinones using an organic photocatalyst
phenanthridinones.
Over the past decade, N-heterocylic carbene (NHC) has been
proven to be one of the most powerful organocatalysts in
organic synthesis.7 O2 (or ambient air) is recognized as the
ideal oxidant and oxygen source. Despite considerable
advances heavily relying on transition metal catalysts, the use
of O2 in organocatalysis is still less explored.8 Specifically, in
organocatalysis by carbene, oxygenation of reactive substrates
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(such as aldehydes and enals) as the side reactions cannot be and imidazolium pre-catalyst N-Mes
Journal Name
D
) could also realize this
avoided when O2 (or ambient air) was used as the oxidant, transformation, albeit with comparatively lower efficiency
which significantly limited the use of O2.9 As a part of our (entries 2-4). Several bases were next evaluated and DBU
ongoing interest in carbene catalysis,10 we envisaged that a proved to be the most effective choice (entries 5-9).
conceptually
new
aerobic
oxidative
strategy
for Subsequent solvent screening revealed that THF was the most
isoquinolinones from new substrates isoquinolinium salts effective (entries 10-14). Gratifyingly, lowering the catalyst
promoted by carbene might be achieved. The carbene should loading to 10 mol % decreased the product yield only slightly
be able to attack the isoquinolinium salt to form an aza- (entry 15). Reducing the amount of base decreased the
Breslow intermediate10a,11 via deprotonation. And following product yield considerably (entry 16). Without NHC, only 24%
aerobic oxidation by ambient air might furnish isoquinonlinone yield of 2a was achieved when DBU was used as base (entry
and regenerate carbene. We herein firstly describe a mild, 17).
environmentally friendly carbene-catalyzed aerobic oxidation
Table 1. Optimization of reaction conditionsa
of isoquinolinium salts. Notably, ambient air was used as the
sole oxidant and oxygen source under mild conditions in this
NHC
organocatalyzed reaction. Accordingly,
a diverse set of
N
I
N
base, solvent
25℃,12h
isoquinolinones and phenanthridinones was efficiently
prepared. Furthermore, many related bioactive molecules and
natural products, including N-mehtylcrinasiadine, N-
isopentylcrinasiadine, N-phenethylcrinasiadine, isoindolo [2,1-
b]isoquinolin-5(7H)-one, PJ-34, rosettacin, rac-Gusanlung D, 8-
oxopseudopalmatine and ilicifoline B, could be efficiently
constructed by this flexible strategy.
O
2a
1a
Mes
Ph
N
N
N
N
N
N
N
N
N
N
N
Mes
Mes
I
BF4
BF4
Cl
A
B
C
D
Entrya
NHC
base
solvent
Yield(%)b
1
2
A
B
C
D
A
A
A
A
A
A
A
A
A
A
A
A
-
DBU
DBU
THF
THF
99
56
3
DBU
THF
83
4
DBU
THF
43
5
K2CO3
KOtBu
Cs2CO3
Et3N
THF
98
6
THF
79
7
THF
97
8
THF
N.R.
N.R.
82
9
NaOAc
DBU
THF
10
11
12
13
14
15c
16d
17e
18e,f
19c,f
20e
21g
DMF
CH3CN
MeOH
1,4-dioxane
toluene
THF
DBU
88
DBU
40
DBU
95
DBU
89
DBU
96
DBU
THF
61
DBU
THF
24
-
DBU
THF
N.R.
97
A
-
DBU
THF
K2CO3
DBU
THF
N.R.
N.R.
Figure 2 Some representative oxidative approaches.
A
THF
a Reaction conditions: NHC (15 mol%), 1a (0.2 mmol, 1.0 equiv), base (1.5 equiv),
solvent (0.1 M), under air atmosphere, 25
, 12 h. b Isolated yields after column
e
℃
Results and discussion
c
d
chromatography. 10 mol % of NHC was used. 0.5 equiv of base was used.
Without NHC. f Under dark conditions. g Under nitrogen atmosphere.
We began our investigation by selecting 2-methylisoquinolin-
2-ium iodide 1a as a model isoquinolinium salt. The key results
of our initial studies and optimization of the reaction
conditions are summarized in Table 1. To our delight, the
desired isoquinolinone 2a was obtained in nearly quantitative
Notably, no desired product was found under dark conditions
(entry 18). These results indicate that sun light slightly
influences this transformation when DBU was used as the base
and in the absence of NHC. Comparatively, no desired product
was found by using K2CO3 as the base and in the absence of
NHC (entry 20). Further experiment was performed under the
same conditions with entry 15 except in dark, the desired
yield when the achiral triazolium N-Mes pre-catalyst
A was
used with DBU as a base in THF under an air atmosphere at
room temperature (entry 1). Other NHC pre-catalyst (including
triazolium N-Ph pre-catalyst B, triazolium pre-catalyst N-Me C
2 | J. Name., 2012, 00, 1-3
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product 2a was obtained without any loss yield (entry 19).
When the reaction was performed under nitrogen
atmosphere, rather than air, none of the desired
substituents at the 4
，
5, 6 and 7 positions on the isoquinoline
a
ring, the reactions proceeded smoothly and led to the
formation of the corresponding diverse isoquinolinone
products (2a-h) in good to excellent yields. Phthalazine and
isoquinolinone 2a was formed (entry 21).
benzo[d]thiazole
afforded the corresponding products (2k
yields. Pyridinium and quinolinium salts also are suitable
substrates for this transformation (2i 2j). Isoquinolinium
salts with a series of N-alkyl groups also worked efficiently as
well (2m 2aa). Pleasingly, ether, NO2, ester, halide, acetal
–
derived iminium salts were also tested and
Table 2. Reaction Scopea
&
2l) in acceptable
&
-
group, three-membered rings, and double and triple bonds
were well-tolerated. Two isoquinolinium moieties in one
molecule also worked well (2ab & 2ac).
Table 3. Reaction Scopea
NHC(10 mol %)
DBU(1.5 equiv)
N
X
R
N
R
℃ air
THF, 25
,
O
N
N
OMe
2
N
Ph
O
O
4c (X = Br, 82%)
O
4b (X = Br, 89%)b
4a (X = I, 89%)
O
O
N
Ph
N
O
N
O
O
N-benzyl
crinasiadine
4d (X = Br, 92%)b
4e (X = I, 98%)
4f (X = Br, 68%)b,d
O
O
O
O
O
N
Ph
2
N
N
O
O
O
O
N-isopentyl
crinasiadine
4i (X = Br, 78%)d
N-methyl
N-phenethyl
crinasiadine
4h (X = Br, 79%)d
crinasiadine
4g (X = I, 83%)
N
O
N
N
Ph
O
O
N-methyl
phenaglydon
N-allyl
phenaglydon
4l (X = Br, 83%)b
N-benzyl
phenaglydon
4k (X = Br, 62%)b,d
4j (X = I, 90%)
Note: 4g-i are natural products.
a
Reaction conditions as in Table 1, entry15; yields (after SiO2
b
chromatography purification) were based on imnium salts 3.
Reaction
temperature -10 ℃. c Reaction temperature -40 ℃. 20 mol % NHC A was
d
used.
a
Reaction conditions as in Table 1, entry15; yields (after SiO2
b
We then extended our strategy to the synthesis of
chromatography purification) were based on imnium salts 1.
Reaction
c
temperature -10
used.
.
Reaction temperature -40 ℃. d 20 mol % NHC A was
phenanthridinones
4, which are widely found in natural
products and bioactive molecules,12 from the corresponding
phenanthridinium salts. Not surprisingly, all reactions
proceeded smoothly and led to formation of the desired
With acceptable optimized conditions in hand (Table 1,
entry 15), we next evaluated the scope of the reaction for
isoquinolinium salts 1 as substrates (Table 2). For a range of
phenanthridinones 4 in good to excellent yields under optimal
conditions (Table 3). In particular, the natural products N-
methyl crinasiadine 4g, N-phenethyl crinasiadine 4h and N-
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2-methylisoquinolin-2-ium iodide 1a produces the NHC-bound
intermediate , which undergoes deprotonation to give the
isopentyl crinasiadine 4i could be easily constructed by our
strategy under mild conditions.
I
aza-Breslow intermediate II (Rovis group.).12b Single electron
To show the practicality of our method, a gram-scale
reaction was carried out (Scheme 1). In the presence of only 1
transfer of the aza-Breslow intermediate II with dioxygen,
followed by radical recombination generates intermediate III 13
.
mol % of NHC pre-catalyst
A, a 5-gram scale reaction of 2-
Further another aza Breslow intermediate II, which might act
as the reducing reagent, reacts with intermediate III to lead to
methylisoquinolin-2-ium iodide 1a worked very well and
afforded 2-methylisoquinolin-1(2H)-one 2a in up to 99% yield.
In contrast, without NHC, 2a was obtained in less than 10%
yield.
the formation of intermediate IV 14
.
Finally, intermediate IV
forms two molecules 2a and regenerates of the free carbene.
Scheme 1 Gram-scale reaction.
To probe the reaction pathway, the control experiments
were performed as shown in Scheme 2. Gratifyingly, when the
isoquinolinium salts 1a was treated with 1 equivalent of NHC
A
in presence of K2CO3 in CDCl3 under nitrogen atmosphere at
room temperature, expected aza-Breslow intermediate 5' via
deprotonation of intermediate
5 was successfully captured in
1
89% NMR yield. And the structure of
5
was confirmed by H
NMR, 13C NMR, HRMS and 2D NMR (for details, please see
supporting information). Furthermore, in the presence of
ambient air at room temperature, the aza-Breslow
intermediate 5' was converted to 2a in 83% yield and
Scheme 3 Proposed mechanism.
regenerated NHC
A in 91% yield. These results indicate that
our transformation proceeded through an aza-Breslow
intermediate.
With this efficient route to isoquinolinones in hand, we next
turned our attention to the synthetic utility of these
compounds (Scheme 4). Involving the carbene-catalyzed
umpolung of iminium salts followed by ambient air oxidation
as the key steps, several bioactive molecules and natural
products were efficiently synthesized via 1-4 steps. Specifically,
an obtained isoquinolinone 2y was easily converted to the
topoisomerase
one
in up to 82% yield (the highest yield so far)15 via a Pd-
catalzyed intramolecular cyclization. N-benzyl
phenanthridinone 4b was easily transformed to the PARP
inhibitor PJ-34 was
via a known process.16 Rac-Gusanlung D
I inhibitor isoindolo [2,1-b]isoquinolin-5(7H)-
6
7
8
also obtained from isoquinolinium salts 1ad via our aerobic
oxidative strategy and then acid-mediated intramolecular
cyclization.17 The natural product rosettacin
9 was synthesized
from the isoquinolin-2-ium salt 1ae via a two-step process in
72 total yields using our NHC-catalyzed aerobic oxidative
reaction followed by a Pd-catalyzed intramolecular cyclization.
8-oxopseudopalmatine 10, a natural product with promising
biological activities, also could be formed in 50% overall yield
via our NHC-catalyzed umpolung method followed a known
Pd-catalyzed cyclization process.18 Furthermore, oxidation of
Scheme 2 Mechanistic study. 1, 3, 5-trimethoxybenzene was used as
internal standard.
Based on previous work and the current results, a proposed
reaction pathway for the formation of isoquinolinones from
isoquinoline-derived iminium salts under aerobic oxidative
NHC catalysis is illustrated in Scheme 3. The addition of NHC to
4 | J. Name., 2012, 00, 1-3
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8-oxopseudopalmatine 10 provided ilicifoline B 11 via a known
process.19
Acknowledgements
We acknowledge financial support by the National Key R&D
Program of China (2017YFA0204704), National Key Basic
Research Program of China (973) (2015CB932200), National
Natural Science Foundation of China (21602105, 81672508 and
61605074), Natural Science Foundation of Jiangsu Province
(BK20171460 and BK20140951), and Jilin Province Key
Laboratory of Organic Functional Molecular Design & Synthesis
(130028746). G. Wang is grateful to Postgraduate Research &
Practice Innovation Program of Jiangsu Province (KYCX17_0959)
for financial support. We thank D. Liu in this group for
reproducing the reactions of 2a, 2k, and 4a.
Notes and references
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and witnessed by mechanistic study. Significantly, ambient air
as the sole oxidant and oxygen source was efficiently used in
carbene-catalyzed reactions. This reaction features a broad
substrate scope, excellent functional-group tolerance, and
proceeds under mild conditions. And this transformation can
be easily scaled-up. Furthermore, this strategy enabled the
highly efficient synthesis of many bioactive molecules and
natural products including N-mehtylcrinasiadine, N-
isopentylcrinasiadine, N-phenethylcrinasiadine, isoindolo [2,1-
b]isoquinolin-5(7H)-one, PJ-34, rosettacin, rac-Gusanlung D, 8-
oxopseudopalmatine and ilicifoline B. This economical and
environment-friendly approach may be applied to other types
of NHC-activated iminium salt reactions and further
investigations are ongoing in our laboratory.
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6 | J. Name., 2012, 00, 1-3
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Green Chemistry
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DOI: 10.1039/C8GC01488D
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ARTICLE
Graphic Abstract
A mild and environmentally friendly carbene-catalyzed aerobic
oxidation of isoquinolinium salts was successfully realized.
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