Diethyl Phosphite Promoted Electrochemical Oxidation of Tetrahydroisoquinolines to 3,4-Dihydroisoquinolin-1(2 H)-ones

Article abstract of DOI:10.1055/s-0039-1690704

A diethyl phosphite mediated electrochemical oxidation strategy for the synthesis of 3,4-dihydroisoquinolin-1(2 H)-ones from tetrahydroisoquinolines under mild conditions has been developed. This protocol provides an environmentally friendly and simple way for the construction of C=O bonds in an undivided cell unit.

Full text of DOI:10.1055/s-0039-1690704

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–D
letter
A
en
W. Xie et al.
Letter
Synlett
Diethyl Phosphite Promoted Electrochemical Oxidation of Tetra-
hydroisoquinolines to 3,4-Dihydroisoquinolin-1(2H)-ones
Wenxia Xie
C
Pt
Bowen Gong
Shulin Ning
Nian Liu
N
N
HPO(OEt)2, Et4NOTs
CH2Cl2 (wet), rt
R
R
O
R = aryl, alkyl
21 examples
32–86% yield
Zhuoqi Zhang
Xin Che
• Simple reaction conditions • High regioselectivity
Lianyou Zheng
Jinbao Xiang*
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0
0
0-0
0
0
2-2
6
2
8-3
0
7
5
The Center for Combinatorial Chemistry and Drug Discovery of Jilin
University, The School of Pharmaceutical Sciences, Jilin University,
1266 Fujin Road, Changchun, Jilin 130021, P. R. of China
jbxiang@jlu.edu.cn
Received: 26.08.2019
Accepted after revision: 19.09.2019
Published online: 09.10.2019
OMe
HO
MeO
Me
N
OMe
N
Me
NH
O
Me
DOI: 10.1055/s-0039-1690704; Art ID: st-2019-k0448-l
HO
O
OH
O
O
CHO
Abstract A diethyl phosphite mediated electrochemical oxidation
strategy for the synthesis of 3,4-dihydroisoquinolin-1(2H)-ones from
tetrahydroisoquinolines under mild conditions has been developed. This
protocol provides an environmentally friendly and simple way for the
construction of C=O bonds in an undivided cell unit.
baluchistanamine
ruprechstyril
OMe
O
O
O
N
O
N
O
Me
Me
Key words electrochemistry, oxidation, diethyl phosphite, tetra-
O
hydroisoquinoline, C=O bond formation
dorianine
thalflavine
Figure 1 Naturally occurring isoquinolin-1(2H)-one derivatives
Isoquinoline alkaloids represent an important group of
natural products and exhibit a broad spectrum of biological
activities.1 Isoquinolin-1(2H)-one derivatives exist exten-
sively in naturally and biologically interesting molecules
such as baluchistanamine, ruprechstyril, dorianine, and
thalflavine depicted in Figure 1.2 Traditional methods for
the synthesis of 3,4-dihydroisoquinolin-1(2H)-ones gener-
ally rely on multi-step processes,3 transition-metal cata-
lysts,4 a photocatalyst,5 and/or stoichiometric oxidants,6
which would produce undesired waste. More recently, Lee
and co-workers developed an efficient oxidation reaction of
N-substituted tetrahydroisoquinolines to dihydroisoquino-
lones using eosin Y as an organo-photocatalyst and oxygen
as a green oxidant.7
Organic electrosynthesis, which achieves redox reac-
tions with traceless electric current, is accepted to be an en-
vironment-friendly and enabling synthetic tool.8 In 2013,
Zeng and Little described the electrochemical oxidative
functionalization of benzylic C–H bonds for the synthesis of
N-alkyl tetrahydroisoquinolones using bromide ion/2,2,6,6-
tetramethylpiperidinyl-N-oxyl dual redox catalysts in a
two-phase electrolytic system.9 Recently, we reported a
metal- and reagent-free electrochemical CDC reaction of
tetrahydroisoquinolines with phosphites and indole using
an undivided cell.10 As shown in Scheme 1, when tetrahy-
droisoquinoline 1a was treated with diethyl phosphite 2a
under mild electrochemical conditions to prepare amino-
phosphonate 3a, 2% yield of the lactam 4a was also isolated.
Intrigued by these findings and in continuation of our re-
search into the development of environmentally benign
synthetic methods, we developed an efficient operationally
simple protocol, with no chemical oxidant needed and mild
reaction conditions, for the synthesis of isoquinolones 4
from tetrahydroisoquinolines 1 by a one-pot direct electro-
chemical oxidative C=O bond formation in an undivided
cell. Herein, the details of these studies are presented.
Initially, simple prolonging the reaction time from 4
hours to 11 hours led to the desired lactam 4a in 43% yield
(Scheme 1 and Table 1, entry 1). The choice of electrolyte
has a substantial impact on the reaction outcome.
We identified the optimal reaction conditions for the
oxidation reaction with Et4NOTs instead of nBu4NBr, which
involved constant-current electrolysis using a graphite rod
anode and a Pt plate cathode in CH2Cl2 at room tempera-
ture, and the desired isoquinolone 4a was obtained in 86%
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–D
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
W. Xie et al.
Letter
Synlett
O
P
OEt
C
Pt
+
+
OEt
N
O
N
N
H
nBu4NBr (0.1 M)
CH2Cl2 (wet), rt
Ph
Ph
Ph
EtO
EtO
P
O
1a
2a
constant current = 5 mA, 4 h
3a (83% yield)
4a (2% yield)
Scheme 1 Electrochemical oxidative C–P and C=O bond formation of tetrahydroisoquinolines
yield (entry 2).11 In comparison, reduced yields were ob-
tained when the reaction conditions were modified in one
of the following manners: changing the electrolyte to
nBu4NPF6 (entry 3), removing (entry 4) or reducing (entry 5)
the amount of diethyl phosphite, switching to other nucleo-
philes including H2O (entry 6), MeOH (entry 7), and mor-
pholine (entry 8), using other solvents such as EtOH (entry
9) or MeCN (entry 10), or adjusting the current to 10 mA
(entry 11). A control experiment revealed that no desired
product 4a was observed in the absence of supplying elec-
tricity (entry 12).
system (4a–k). Tetrahydroisoquinolines bearing other N-
aryl rings including naphthalene could be accessed (4m).
Moreover, it is noteworthy that various alkyl substituents,
including (un)substituted benzyl (4n–r), n-butyl (4s), allyl
(4t), 2-ethoxy-2-oxoethyl (4u), and hydroxyethyl (4v), un-
derwent a smooth oxidation reaction, furnishing the de-
sired products 4n–v in moderate to good yields (Table 2).
Table 2 Synthesis of Dihydroisoquinolones 4a
C
Pt
Having optimized the reaction conditions, we next ex-
amined the generality of the oxidation reaction by testing a
series of tetrahydroisoquinoline substrates (Table 2). To our
satisfaction, a variety of functional groups, including strong
electron-donating (ortho-, meta- and para-MeO), a mild
electron-donating (para-Me), moderate electron-with-
drawing (ortho-, meta- and para-F, para-Cl), and strong
electron-withdrawing (para-CF3, para-COMe) substituents
at the N-phenyl ring, were well tolerated in the reaction
N
N
Et4NOTs (0.1 M)
HPO(OEt)2 (1.2 equiv)
CH2Cl2 (wet), rt
R
R
O
1
4
constant current = 5 mA
Entry
R
Time (h)
Product
Yield (%)b
1
2
Ph
9
7
9
8
5
7
6
8
7
9
9
9
4a
4b
4c
4d
4e
4f
86
76
59
59
79
62
68
55
70
65
40
trace
72
58
43
54
52
73
72
32
47
38
p-MeOC6H4
m-MeOC6H4
o-MeOC6H4
p-MeC6H4
p-FC6H4
3
4
5
Table 1 Optimization of the Reaction Conditionsa
6
7
m-FC6H4
4g
4h
4i
C
Pt
N
N
8
o-FC6H4
Et4NOTs (0.1 M)
HPO(OEt)2 (1.2 equiv)
CH2Cl2 (wet), rt
Ph
Ph
O
9
p-ClC6H4
1a
4a, 86%
constant current = 5 mA, 9 h
10
11
12
13
14
15
16
17
18
19
20
21
22
p-CF3C6H4
p-AcC6H4
p-O2NC6H4
4j
Yield (%)b
4k
4l
Entry
Variation from reaction conditions above
1
2
nBu4NBr instead of Et4NOTs, 11 h
none
43
86
46
36
57
18
46
27
5
naphthalen-1-yl
Bn
6
5
4
4
4
5
4
6
6
6
4m
4n
4o
4p
4q
4r
3
nBu4NPF6 instead of Et4NOTs, 8 h
no HPO(OEt)2, 7 h
m-MeOC6H4CH2
o-MeC6H4CH2
o-ClC6H4CH2
p-NCC6H4CH2
nBu
4
5
0.2 equiv HPO(OEt)2 was used
H2O instead of HPO(OEt)2, 6 h
MeOH instead of HPO(OEt)2, 7 h
morpholine instead of HPO(OEt)2, 5 h
EtOH instead of CH2Cl2, 8 h
CH3CN instead of CH2Cl2, 10 h
10 mA instead of 5 mA, 5 h
no electric current, 11 h
6
7
4s
4t
8
allyl
9
EtO2CCH2
HOCH2CH2
4u
4v
10
11
12
25
77
0
a Reaction conditions: graphite rod anode (d = 5 mm), Pt plate cathode
(0.5×0.5 cm), constant current = 5 mA, 1 (0.25 mmol), diethyl phosphite
(0.3 mmol), Et4NOTs (0.5 mmol), CH2Cl2 (5 mL), undivided cell, rt.
b Isolated yield.
a Reaction conditions: graphite rod anode (d = 5 mm), Pt plate cathode
(0.5×0.5 cm), constant current = 5 mA, 1a (0.25 mmol), diethyl phosphite
(0.3 mmol), Et4NOTs (0.5 mmol), CH2Cl2 (5 mL), undivided cell, rt, 9 h.
b Isolated yield.
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–D

C
W. Xie et al.
Letter
Synlett
Control experiments showed that 84% yield of product
4a was obtained when intermediate 3a was treated under
the standard conditions (Scheme 2). Moreover, 82% yield of
product 4a was isolated under N2 protection, and no de-
sired product was observed without electricity. These re-
sults further exclude that oxygen is the oxidation source in
this reaction. Additionally, when the above reaction was
conducted in the presence of 3Å molecular sieves, the de-
sired product 4a was suppressed and only 25% yield was
obtained.
tion could be carried out at room temperature without the
use of any oxidants. This process offers an alternative to
conventional methods that require metal catalysts or chem-
ical oxidants and represents an environmentally benign
tool for oxidative C=O bond formation.
Funding Information
This work was supported by the Education Department of Jilin Prov-
ince (No. JJKH20180244KJ), the Jilin Scientific and Technological De-
velopment Program (No. 20160520039JH), and Jilin University (No.
2015330). Additional support was provided by Changchun Discovery
C
Pt
Sciences, Ltd.Ji
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(2
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6
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3
9
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H)
N
O
N
Ph
Ph
Et4NOTs (0.1 M)
CH2Cl2 (wet), rt
constant current = 5 mA, 4 h
EtO
EtO
P
O
4a
Acknowledgment
3a (0.25 mmol)
no deviation: 84% yield
N2 protection: 82% yield
no electricity: 0% yield
3Å MS (250 mg) was added: 25% yield
We thank Mr. Xuyang Luo for NMR measurements.
Scheme 2 Control experiments
Supporting Information
Supporting information for this article is available online at
On the basis of the observations above and literature re-
ports,9 a possible mechanism for the electrochemical oxida-
tive reaction was proposed (Scheme 3). As a start, com-
pound 1a loses two electrons and a proton on the surface of
the anode to generate the iminium-ion intermediate I. In-
termediate I is captured by diethyl phosphite to afford com-
pound 3a. Meanwhile, concomitant cathodic reduction of
H2O releases H2 and HO–. Compound 3a undergoes subse-
quent nucleophilic substitution with HO– to generate inter-
mediate II. Intermediate II is further oxidized to give the
desired product 4a. The mechanism is consistent with the
result of entry 1 (Table 1); prolonging the reaction time will
increase the concentration of HO– and favor the formation
of the desired product 4a.
https://doi.org/10.1055/s-0039-1690704.
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References and Notes
(1) Chrzanowska, M.; Rozwadowska, M. D. Chem. Rev. 2004, 104,
3341.
(2) (a) Krane, B. D.; Shamma, M. J. Nat. Prod. 1982, 45, 377.
(b) Pettit, G. R.; Meng, Y.; Herald, D. L.; Graham, K. A. N.; Pettit,
R. K.; Doubek, D. L. J. Nat. Prod. 2003, 66, 1065. (c) Fatima, N.;
Reddy, B. V. S. Sabitha G.; Yadav, J. S.; Sudhakar, K.; Putta, C. S.
Bioorg. Med. Chem. Lett. 2018, 28, 196.
(3) Chen, Z.-Y.; Wu, L.-Y.; Fang, H.-S.; Zhang, T.; Mao, Z.-F.; Zou, Y.;
Zhang, X.-J.; Yang, M. Adv. Synth. Catal. 2017, 359, 3894.
(4) (a) Han, W.; Mayer, P.; Ofial, A. R. Adv. Synth. Catal. 2010, 352,
1667. (b) Kohls, P.; Jadhav, D.; Pandey, G.; Reiser, O. Org. Lett.
2012, 14, 672. (c) Liu, Y.; Wang, C.; Xue, D.; Xiao, M.; Liu, J.; Li,
C.; Xiao, J. Chem. Eur. J. 2017, 23, 3062. (d) Patil, M. R.; Dedhia, N.
P.; Kapdi, A. R.; Kumar, A. V. J. Org. Chem. 2018, 83, 4477.
(5) (a) Zhang, Y.; Riemer, D.; Schilling, W.; Kollmann, J.; Das, S. ACS
Catal. 2018, 8, 6659. (b) Clark, J. L.; Hill, J. E.; Rettig, I. D.; Beres, J.
J.; Ziniuk, R.; Ohulchanskyy, T. Y.; McCormick, T. M.; Detty, M. R.
Organometallics 2019, 38, 2431. (c) Guryev, A. A.; Hahn, F.;
Marschall, M.; Tsogoeva, S. B. Chem. Eur. J. 2019, 25, 4062.
(6) (a) Song, A.-R.; Yu, J.; Zhang, C. Synthesis 2012, 44, 2903.
(b) Griffiths, R. J.; Burley, G. A.; Talbot, E. P. A. Org. Lett. 2017, 19,
870.
anode
cathode
e–
e–
N
N
Ph
Ph
– 2H+
– 2e–
4a
II
O
–
+ HO
HO–
1/2 H2
–
– PO(OEt)2
OH
N
O
+ HPO(OEt)2
– H+
Ph
H2O
EtO
EtO
3a
P
N
– H+
– 2e–
Ph
Ph
(7) Aganda, K. C. C.; Hong, B.; Lee, A. Adv. Synth. Catal. 2019, 361,
1124.
I
(8) (a) Yan, M.; Kawamata, Y.; Baran, P. S. Chem. Rev. 2017, 117,
13230. (b) Tang, S.; Zeng, L.; Lei, A. J. Am. Chem. Soc. 2018, 140,
13128. (c) Tang, S.; Liu, Y.; Lei, A. Chem 2018, 4, 27.
(9) Li, C.; Zeng, C.-C.; Hu, L.-M.; Yang, F.-L.; Yoo, S. J.; Little, R. D.
Electrochim. Acta 2013, 114, 560.
N
H
1a
Scheme 3 Proposed mechanism
(10) Xie, W.; Liu, N.; Gong, B.; Ning, S.; Che, X.; Cui, L.; Xiang, J. Eur. J.
Org. Chem. 2019, 2498.
(11) 2-Phenyl-3,4-dihydroisoquinolin-1(2H)-one (4a); Typical
Procedure
In summary, we have successfully developed a diethyl
phosphite mediated electrochemical oxidation strategy for
the synthesis of 3,4-dihydroisoquinolin-1(2H)-ones from
tetrahydroisoquinolines using an undivided cell. This reac-
A 10 mL distillation flask equipped with a magnetic stirring bar
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–D

D
W. Xie et al.
Letter
Synlett
was charged with diethyl phosphite (42 mg, 0.3 mmol), wet
CH2Cl2 (5.0 mL), 2-phenyl-1,2,3,4-tetrahydroisoquinoline 1a (52
mg, 0.25 mmol), and Et4NOTs (151 mg, 0.5 mmol). The resulting
suspension was stirred until complete dissolution was achieved.
The flask equipped with graphite rod anode (d = 5 mm) and Pt
plate cathode (0.5×0.5 cm). The reaction mixture was stirred
and electrolyzed at a constant current of 5 mA at rt for 9 h. The
reaction mixture was diluted with CH2Cl2 (15 mL), washed suc-
cessively with water (10 mL) and brine (10 mL), dried with
Na2SO4, and concentrated in vacuo. Purification by flash column
chromatography (silica gel, petroleum ether–ethyl acetate 20:1)
afforded the desired product 4a 48 mg (86%) as a white solid;
mp 119–120 °C. 1H NMR (300 MHz, CDCl3):  = 8.19–8.14 (m, 1
H), 7.51–7.34 (m, 6 H), 7.29–7.21 (m, 2 H), 4.04–3.97 (m, 2 H),
3.15 (t, J = 6.6 Hz, 2 H). 13C NMR (75 MHz, CDCl3):  = 162.8,
143.1, 138.3, 132.0, 129.7, 128.9, 128.7, 127.1, 126.9, 126.2,
125.3, 49.4, 28.6.
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–D