Organoselenium-Catalyzed Aza-Wacker Reactions: Efficient Access to Isoquinolinium Imides and an Isoquinoline N -Oxide

Article abstract of DOI:10.1055/s-0039-1690103

An efficient approach for the organoselenium-catalyzed aza-Wacker reaction of olefinic hydrazones and an oxime to form isoquinolinium imides and an isoquinoline N -oxide is developed. This transformation involves a direct intramolecular C-H amination using hydrazones and an oxime as imine-type nitrogen sources. This work not only provides a new approach for the construction of isoquinoline derivatives, but also expands the scope of nitrogen sources in electrophilic selenium catalysis.

Full text of DOI:10.1055/s-0039-1690103

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© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–E
cluster
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en
H. Li et al.
Cluster
Synlett
Organoselenium-Catalyzed Aza-Wacker Reactions: Efficient
Access to Isoquinolinium Imides and an Isoquinoline N-Oxide
Huimin Li
catalytic
PhSeSePh
XH
N
O
N
N
PG
N
Lihao Liao
R1
or
R1
Oxidant
Xiaodan Zhao*
R2
R2
Ph
X = NPG, O
19 examples
up to 99% yield
Institute of Organic Chemistry and MOE Key Laboratory of Bioinorganic
and Synthetic Chemistry, School of Chemistry, Sun Yat-Sen University,
Guangzhou 510275, P. R. of China
Imine Derivatives (Hydrazones and Oximes) as Nitrogen Sources
in Electrophilic Selenium Catalysis
zhaoxd3@mail.sysu.edu.cn
Published as part of the Cluster Organosulfur and Organoselenium
Compounds in Catalysis
Received: 30.04.2019
Accepted after revision: 07.06.2019
Published online: 28.06.2019
purpose of synthetic diversity, developing efficient meth-
ods to incorporate new nitrogen sources into alkenes by di-
rect C–H functionalization is in high demand.
DOI: 10.1055/s-0039-1690103; Art ID: st-2019-w0243-c
δ-
δ+
Abstract An efficient approach for the organoselenium-catalyzed aza-
Wacker reaction of olefinic hydrazones and an oxime to form isoquino-
linium imides and an isoquinoline N-oxide is developed. This transfor-
mation involves a direct intramolecular C–H amination using hydra-
zones and an oxime as imine-type nitrogen sources. This work not only
provides a new approach for the construction of isoquinoline deriva-
tives, but also expands the scope of nitrogen sources in electrophilic se-
lenium catalysis.
R3
R4
R3
R4
N
R3
R1
R4
R3
R1
R4
N
N
H
N
H
cat.
cat.
LG
R2
R2
R2
R1
[O]
aza-Wacker reaction
LG = OR, N2, etc.
aza-Heck reaction
Scheme 1 Two methods for alkene C–H amination
Electrophilic selenium catalysis (ESC) has emerged as a
powerful tool for alkene oxidative functionalization.8–16 Us-
ing this catalytic approach, diverse oxygen nucleophiles
such as carboxylic acids,9 alcohols,10 and phosphoric ac-
ids,11 as well as halogen anions (Cl–, F–, etc.),12 can be incor-
porated into alkenes efficiently. Nevertheless, the introduc-
tion of different nitrogen sources into alkenes by a similar
strategy has been far less explored, possibly because of the
instability of the aminated products and the incompatibili-
ty between the oxidative system and nucleophilic nitrogen
sources.13–16 Only a few relevant examples have been re-
ported by using sulfonimides,13 sulfonamides,10g,14 and hy-
drazines15 as nitrogen sources to afford allyl or vinyl amina-
tion products (Scheme 2a). Recently, we disclosed that 1,3-
dienes could be aminated selectively at the C-2 position
with pyridines as nitrogen sources by ESC (Scheme 2b).16a
This discovery revealed that imine-type nitrogen sources
might be appropriate in ESC. As a continuation of our inter-
est in ESC,8d especially for C–N bond-forming reac-
tions,10g,13b,14a,16 we were interested in developing efficient
methods with new nitrogen sources. We noticed that easily
prepared imine-type derivatives, e.g., hydrazones and ox-
imes, had not been utilized as potential nitrogen sources for
ESC. Herein, we report our discovery that isoquinolinium
imides could be synthesized by electrophilic-selenium-cat-
Key words organoselenium catalysis, aza-Wacker reaction, C–H ami-
nation, hydrazones, isoquinoline derivatives
Owing to the ubiquity of nitrogen-containing com-
pounds in natural products, pharmaceuticals, agrochemi-
cals, and synthetic intermediates,1 the development of effi-
cient methods for their synthesis has drawn considerable
attention from chemists over recent decades.2–7 Among the
developed methods, direct C–H amination of simple start-
ing materials is a more straightforward pathway3 because
of the atom economy in comparison with classical cross-
coupling reactions such as the Buchwald–Hartwig amina-
tion.4 In this field, many efforts have been devoted toward
direct vinylic C–H aminations due to the prevalence of
alkenes.5–7 Conventionally, two types of reactions have
been developed (Scheme 1). One is the aza-Wacker reaction
in which a nucleophilic nitrogen source is utilized in the
presence of external oxidants.6 The other is the aza-Heck
reaction in which an electron-deficient nitrogen source is
used and acts as an internal oxidant at the same time.7 Us-
ing these two reactions, many valuable molecules such as
enamides and nitrogen-containing heterocycles can be pre-
pared. Despite these significant advances, the nitrogen
sources that are introduced into alkenes are limited. For the
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
H. Li et al.
Cluster
Synlett
alyzed intramolecular aza-Wacker reactions with hydra-
zones as nitrogen sources (Scheme 2c). This method could
also be applied to the construction of an isoquinoline N-ox-
ide from an oxime.
H
N
10 mol%
PhSeSePh
N
N
PG
N
PG
Me
1.2 equiv NFSI, MeCN
r.t., 12 h
Ph
Ph
1
2
PG:
a) Common nitrogen sources in ESC for alkene amination
R3
O
Me
Me
Ph
R3
R3
R3
path a
path b
N
S
N
H
N
H
R2
[O]
NH
O
Me
O
RSe
R2
b
R1
O
O
R2
SeR
R1
R1
R4
R3
RSe
2a, complex 2b, complex
2c, complex
2d, 35%
2e, 98%
a
H
N
R1
R1
R4
N
N
possible
competitive
by-products:
N
N
Nitrogen sources: sulfonimides, sulfonamides, hydrazines
N(SO2Ph)2
N
PG
N
PG
PG
N(SO2Ph)2
OH
Ph
Ph
A
B
C
Ph
Me
CO2Bn
Ph
N(SO2Ph)2
Ph
Scheme 3 Screening of protecting groups and the structures of possi-
ble by-products
O
N
Ts
Ph
N
N
N
Ph
Ph
N
Ph
Ts
Having determined the most suitable protecting group,
other reaction conditions were investigated (Table 1). Vari-
ous oxidants, solvents, types and amounts of catalysts, and
reaction concentrations were screened. It was found that all
other conditions were less effective than our initial condi-
tions. NFSI was found to be the best oxidant for this trans-
formation (Table 1, entry 1). Other solvents such as THF,
PhMe and DCE were less effective than MeCN, probably ow-
ing to the low solubility of the ylide product 2e (Table 1, en-
try 8). No improvements were observed on changing the
catalyst to electron-rich diaryl, electron-deficient diaryl, or
dibenzyl diselenides (Table 1, entries 11–13). Besides, prod-
uct 2e was generated in only 14% yield in the absence of a
diselenide, which indicates the importance of the catalyst in
this process (Table 1, entry 16).
With optimized conditions in hand, the scope of the
olefinic hydrazones was evaluated (Scheme 4).18 Initially,
substrates with different substituents R2 on the vinyl moi-
ety were tested. Substituents such as Me, MeO, F, Cl, and Br
at the para-position of the phenyl group did not have a
large impact on this aza-Wacker reaction (2f–j, 81–97%).
However, a CF3-substituted substrate gave the correspond-
ing product 2k in a somewhat lower 67% yield. Similarly,
substituents such as Me and F at the ortho- or meta-posi-
tion of the phenyl group had a slight impact on this trans-
formation (2l, 83%; 2m, 72%). The conditions were also suit-
able for the aza-Wacker reaction of a substrate bearing a
heterocyclic aryl group, i.e., thiophene vinyl hydrazone 1n.
The corresponding product 2n was obtained in 99% yield. In
comparison with the aryl-substituted substrates, less reac-
tive hydrazone 1o bearing a butyl group generated the de-
sired product 2o in moderate yield. To further explore the
generality of this aza-Wacker reaction, we continued the
investigation by varying the R1 substituent on the aromatic
ring attached to the C–N double bond. It was found that
substrates bearing electron-donating and electron-with-
drawing groups on the aromatic ring underwent C–H ami-
b) Our previous work: pyridines as nitrogen sources
ESC
N
X
R
N
[O]
R
c) This work: imine derivatives as nitrogen sources
XH
X
N
N
ESC
R1
R1
[O], X = NPG, O
R2
R2
Scheme 2 Electrophilic-selenium-catalyzed alkene amina
We initiated our study of the aza-Wacker reaction with
olefinic hydrazone 1 as the model substrate, using N-fluo-
rodibenzenesulfonimide (NFSI) as the oxidant in the pres-
ence of a catalytic amount of diphenyl diselenide in aceto-
nitrile (Scheme 3). Isoquinolinium imide 2, a useful syn-
thetic intermediate for dipolar cycloadditions,17 was
expected as the desired product via nucleophilic attack of
the nitrogen of the imine motif of hydrazine 1. Various pro-
tecting groups were evaluated (Scheme 3, top). When sub-
strates 1a–c bearing free NH, phenyl- and Boc-protecting
groups, respectively, were utilized under the same condi-
tions, complex mixtures were formed owing to their de-
composition. To our delight, the desired product 2d was
produced in 35% NMR yield at room temperature when us-
ing a benzyl protecting group. When a tosyl protecting
group was used, the reaction proceeded with to generate
the desired product 2e in nearly quantitative yield. This ef-
ficient conversion might be attributed to the electron-with-
drawing sulfonyl group resulting in acceleration of the
deprotonation of the NHTs group. It is worth noting that
possible competitive by-products A–C were not observed,
which indicates the high selectivity of this catalytic system
(Scheme 3, bottom).
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E

C
H. Li et al.
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Table 1 Evaluation of the Reaction Conditionsa
This method was compatible with other imine-type nu-
cleophiles as well. For example, olefinic oxime 3 underwent
a similar intramolecular aza-Wacker amination to produce
isoquinoline N-oxide 4 in 63% yield (Scheme 5).
H
N
N
10 mol% Catalyst
N
Ts
N
Ts
1.2 equiv Oxidant, Solvent
r.t., 12 h
Ph
Ph
1e
2e
Me
H
10 mol%
PhSeSePh
N
N
N
PG
N
PG
Oxidants:
R1
R1
1.2 equiv NFSI, MeCN
r.t., 12 h
R2
R2
PhO2S
SO2Ph
1d–u
2d–u
BF4
OTf
N
N
F
N
F
Me
N
F
Me
OTf
F
N
N
N
NFSI
[PyF][OTf]
[PyF][BF4]
N
Ts
N
Ts
N
Ts
[TMPyF][OTf]
Cl
N
F3C
O
O
CF3
I
N
Cl
N
Cl
Me
OMe
2e, 97%
2f, 97%
2g, 81%
O
Ph
O
F
F
OTf
2 BF4
Selectfluor
[DCPyF][OTf]
PhI(TFA)2
N
N
N
N
Ts
Ts
N
Ts
N
Ts
Entry Catalyst
Oxidant
Solvent
Yield (%)b
F
Br
Cl
1
2
(PhSe)2
(PhSe)2
(PhSe)2
(PhSe)2
(PhSe)2
(PhSe)2
(PhSe)2
(PhSe)2
(PhSe)2
(PhSe)2
(p-MeOC6H4Se)2
(p-F3CC6H4Se)2
(BnSe)2
(PhSe)2
(PhSe)2
–
NFSI
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
othersc
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
98 (97)
86
2h, 95%
2i, 87%
2j, 84%
[PyF][OTf]
[PyF][BF4]
[TMPyF][OTf]
[DCPyF][OTf]
Selectfluor
PhI(TFA)2
NFSI
N
N
N
N
N
Ts
N
Ts
3
52
F
4
82
5
81
CF3
Me
2l, 83%
2k, 67%
2m, 72%
6
58
7
9
N
S
N
N
O
O
N
Ts
N
Ts
N
N
Ts
Ts
Ph
8
<37
97
Ph
9d
10e
11
12
13
14f
15g
16
NFSI
Me
Ts
NFSI
72
2n, 99%
2o, 46%
2p, 99%
NFSI
57
F
N
Cl
N
N
NFSI
78
N
N
Ts
Ph
NFSI
59
Ph
Ph
NFSI
89
2q, 99%
2r, 97%
2s, 42%
NFSI
91
N
N
NFSI
14
S
N
N
N
N
Ts
S
a Reaction conditions: 1e (0.025 mmol), catalyst (10 mol%), oxidant (1.2
equiv), solvent (1 mL), r.t., 12 h.
O
O
O
NO2
Ph
Ph
Ph
b Refers to the NMR yield with BzOBn as the internal standard. The isolated
yield in parentheses is that of the reaction on 0.1 mmol scale.
c Other solvents: THF, 1,4-dioxane, PhMe, CH2Cl2, EtOAc, acetone, EtOH,
DMF, DMSO.
2t, 82%
2u, 99%
2d, 53%a
Scheme 4 Substrate scope of the intramolecular aza-Wacker reaction
with olefinic hydrazones. Reaction conditions: 1 (0.10 mmol), NFSI (1.2
equiv), PhSeSePh (10 mol%), MeCN (4 mL), r.t., 12 h. a MeNO2 was used
as the solvent
d MeCN (0.5 mL)
e MeCN (2 mL).
f (PhSe)2 (5 mol%).
g (PhSe)2 (15 mol%).
10 mol%
PhSeSePh
nation to give the corresponding products in excellent
yields (2p–r, 97–99%). When hydrazone 1s with fused rings
was utilized, the corresponding product 2s was formed in
only 42% yield, possibly due to steric hindrance. Important-
ly, heterocyclic thiophene substrate 1t provided the desired
product 2t in high yield. Furthermore, substrates with dif-
ferent protecting groups on the NH group, for example, 2-
nitrosulfonyl- and benzoyl-protected hydrazones 1u and
1d, were tested. The corresponding products were formed
in moderate to excellent yields.
O
OH
Ph
N
N
1.2 equiv NFSI, MeCN
r.t., 12 h
Ph
4, 63%
3
Scheme 5 Aza-Wacker reaction of olefinic oxime 3
The obtained isoquinolinium imides could be converted
into various valuable compounds. For example, the reaction
of 2e with 4-ethynylanisole afforded fused pyrazoloisoquin-
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E

D
H. Li et al.
Cluster
Synlett
oline 5 in a good 81% yield via Ag-catalyzed 1,3-dipolar cyc-
loaddition and subsequent deprotonation (Scheme 6,
left).17a When 2e was treated with NaBH4, tetrahydroiso-
quinoline 6, a potential microtubule-destabilizing agent in
human triple negative breast cancer cells,19 was formed in
60% yield.
Funding Information
We thank the National Natural Science Foundation of China (Grant
Nos. 21772239 and 91856109), and the Natural Science Foundation of
Guangdong Province (Grant No. 2014A030312018) for financial sup-
port.
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o
n
a
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c
i
e
n
c
e
F
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n
d
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n
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i
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a
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(2
0
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4
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PMB
Supporting Information
H
N
N
N
Supporting information for this article is available online at
https://doi.org/ 10.1055/s-0039-1690103.
N
Ts
N
Ts
a
b
N
S
u
p
p
orti
n
gInformati
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n
S
u
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p
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n
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Ph
Ph
Ph
5, 81%
2e
6, 60%
References and Notes
Scheme 6 Further transformations of 2e. Reaction conditions: (a) 4-
ethynylanisole, cat. AgOTf, DBU, CCl4, r.t. (b) NaBH4, EtOH, 0 °C, 7 h.
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On the basis of previous work,10g,13b,14a,16,20 a possible
mechanism for this aza-Wacker amination is depicted in
Scheme 7. First, PhSeSePh is oxidized by NFSI to form PhSeX
and PhSeY [X = N(SO2Ph)2, if Y = F, or vice versa]. Next,
PhSeX interacts with 1e to generate seleniranium interme-
diate I. This is followed by nucleophilic attack by the imine-
type nitrogen and deprotonation by counterion X– leads to
formation of aminated selenium species II. After oxidation
and subsequent elimination, isoquinolinium imide 2e is
formed and the electrophilic catalyst PhSeX is regenerated.
(PhSe)2
H
N
NFSI
PhSeY
N
Ts
N
N
Ts
+
PhSeX
HY
Ph
1e
Ph
2e
X = N(SO2Ph)2,
if Y = F, or vice versa
H
N
(6) For selected examples, see: (a) Liu, G.; Yin, G.; Wu, L. Angew.
Chem. Int. Ed. 2008, 47, 4733. (b) Ji, X.; Huang, H.; Wu, W.; Li, X.;
Jiang, H. J. Org. Chem. 2013, 78, 11155. (c) Li, X.; He, L.; Chen, H.;
Wu, W.; Jiang, H. J. Org. Chem. 2013, 78, 3636. (d) Liwosz, T. W.;
Chemler, S. R. Chem. Eur. J. 2013, 19, 12771. (e) Jiang, B.; Meng,
F.; Liang, Q.; Xu, Y.; Loh, T. P. Org. Lett. 2017, 19, 914.
X
N
N
Ts
N
Ts
Ph
Ph
III
I
Se
Ph
N(SO2Ph)2
Se
Ph
F
(7) For selected examples, see: (a) Ryu, J.; Kwak, J.; Shin, K.; Lee, D.;
Chang, S. J. Am. Chem. Soc. 2013, 135, 12861. (b) Yang, K.; Zhou,
F.; Kuang, Z.; Gao, G.; Tom, G. D.; Song, Q. Org. Lett. 2016, 18,
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2017, 8, 5248. (e) Das, S. K.; Roy, S.; Khatua, H.; Chattopadhyay,
B. J. Am. Chem. Soc. 2018, 140, 8429.
N
HX
N
Ts
NFSI
Ph
II
SePh
Scheme 7 Proposed mechanism
(8) For selected reviews, see: (a) Freudendahl, D. M.; Shahzad, S. A.;
Wirth, T. Eur. J. Org. Chem. 2009, 1649. (b) Freudendahl, D. M.;
Santoro, S.; Shahzad, S. A.; Santi, C.; Wirth, T. Angew. Chem. Int.
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cules 2017, 22, 835. (e) Ortgies, S.; Breder, A. ACS Catal. 2017, 7,
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(d) Kraetzschmar, F.; Kassel, M.; Delony, D.; Breder, A. Chem.
In summary, we have developed an efficient method for
the intramolecular aza-Wacker amination of olefinic hydra-
zones and an oxime to form isoquinolinium imides and an
isoquinoline N-oxide in good yields. This work enables C–H
amination of alkenes with imine-type nitrogen sources. The
development of novel, selenium-catalyzed reactions is on-
going in our laboratory.
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E

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Eur. J. 2015, 21, 7030. (e) Ortgies, S.; Depken, C.; Breder, A. Org.
Lett. 2016, 18, 2856. (f) Kawamata, Y.; Hashimoto, T.; Maruoka,
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(18) Aza-Wacker Reaction; General Procedure
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To an oven-dried 20 mL vial were added substrate 1 (0.10
mmol), PhSeSePh (3.1 mg, 10 mol%), NFSI (0.12 mmol, 1.2
equiv), and MeCN (4 mL). The mixture was stirred at room tem-
perature for 12 h. After the reaction was complete, the resulting
mixture was concentrated under reduced pressure. The residue
was directly purified by column chromatography on silica gel to
give the corresponding product 2.
(3-Phenylisoquinolin-2-ium-2-yl)(tosyl)amide (2e)
The crude residue was purified by flash column chromatogra-
phy on silica gel (eluent: CH2Cl2/MeOH, 80:1, v/v) to give 2e as a
white solid (35.7 mg, 97% yield). This product is known and its
spectra are in accordance with those reported in the literature,
see: Wu C., Wang Q., Zhao J., Li P., Shi F.; Synthesis 2012, 44,
3033. 1H NMR (400 MHz, CDCl3):  = 9.70 (s, 1 H), 8.16 (d, J = 8.3
Hz, 1 H), 7.93 (d, J = 3.7 Hz, 2 H), 7.85–7.77 (m, 2 H), 7.37–7.28
(m, 3 H), 7.25–7.19 (m, 2 H), 7.03 (d, J = 8.1 Hz, 2 H), 6.78 (d,
J = 8.1 Hz, 2 H), 2.27 (s, 3 H); 13C NMR (101 MHz, CDCl3):
 = 150.83, 148.67, 140.43, 139.99, 135.48, 134.67, 132.35,
130.33, 130.10, 129.19, 128.90, 128.75, 127.65, 127.35, 126.77,
126.52, 125.84, 21.42.
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© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E