Electrochemical Cross-Dehydrogenative Coupling of N-Aryl-tetrahydroisoquinolines with Phosphites and Indole

Article abstract of DOI:10.1002/ejoc.201801883

A metal- and reagent-free, electrochemical cross-dehydrogenative coupling reaction of N-aryl-tetrahydroisoquinolines with phosphites and indole is developed. This method provides an environmentally benign and simple approach for the construction of C–P an

Full text of DOI:10.1002/ejoc.201801883

A Journal of
Accepted Article
Title: Electrochemical cross-dehydrogenative coupling of N-aryl-
tetrahydroisoquinolines with phosphites and indole
Authors: Wenxia Xie, Nian Liu, Bowen Gong, Shulin Ning, Xin Che, Lili
Cui, and Jinbao Xiang
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801883
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10.1002/ejoc.201801883
European Journal of Organic Chemistry
COMMUNICATION
Electrochemical cross-dehydrogenative coupling of N-aryl-
tetrahydroisoquinolines with phosphites and indole
Wenxia Xie,[a] Nian Liu,[a] Bowen Gong,[a] Shulin Ning,[a] Xin Che,[a] Lili Cui*[b] and Jinbao Xiang*[a]
Abstract:
A
metal- and reagent-free, electrochemical cross-
these reported procedures have the disadvantages of
complicated procedure, harsh reaction condition, and non-
environmental friendliness. Inspired by the seminal example of
electrochemical CDC reaction involving a two-step synthesis
protocol in a divided cell by Li and co-workers,[26] It is envisioned
that aminophosphonates 3 and compounds 5 can be readily
prepared from tetrahydroisoquinoline 1 and nucleophile 2 or 4
via a one-pot direct electrochemical oxidative C–P and C–C
bonds formation in an undivided cell (Scheme 1). Herein, the
details on these studies are exhibited.
dehydrogenative coupling reaction of N-aryl-tetrahydroisoquinolines
with phosphites and indole is developed. This method provides an
environmentally benign and simple approach for the construction of
C−P and C−C bonds from moderate to high yields with wide
tolerance of functional groups.
Introduction
With increased consciousness of the chemical process
impacting on environmental, to develop clean and sustainable
synthetic methodology has been paid much attentions.[1] It is
accepted that electrochemical synthesis is sustainable and eco-
friendly in comparison with the conventional redox processes,
because electrons are employed as reagents without the
existance of transition-metal catalysts or toxic oxidants.[2]
Recently, several important milestones in electrochemical
synthesis have been accomplished,[3] such as the cation-pool
method,[4] N−N bond formation,[5] allylic oxidation,[6]
cross/homo-coupling,[7] and amination.[8]
C
Pt
C
Pt
N
N
O
N
R1
R1
R1
Phosphites
Indole
R2O
R2O
2
1
4
P
NH
3
5
Scheme 1. One-pot Oxidant-free Dehydrogenative C–P and C–C Bonds
Formation.
Results and Discussion
Direct formation of C–P and C–C bonds by oxidative cross-
dehydrogenative coupling (CDC) reaction is an attractive
research area in organic synthesis,[9]since pre-functionalized
precursors is not required in CDC methods, which are atom
economical and environmentally benign.[10] Among all of
substrates which can be used for C–P and C–C coupling
reactions using CDC, tetrahydroisoquinoline is the most
interesting ones attributed to its prevalence and abundance in
natural products.[10c,11] Most of the CDC reactions unavoidably
have to use transition-metal catalysts (Cu,[9,12] Mo,[13] Au,[14] and
The optimized reaction conditions for the CDC reaction of N-
phenyltetrahydroisoquinoline 1a with diethyl phosphite 2a is first
identified, which involved constant-current electrolysis employing
a graphite rod as anode and and Pt plate as cathode in an
undivided cell containing an electrolyte solution of n-Bu4NBr in
CH2Cl2 at room temperature (Table 1). Under these mild
conditions, the desired
Table 1. Optimization of the Reaction Conditions[a]
so on.[15]
TBHP,[17] DEAD,[18] and so on.[19]), which would produce
undesired waste. Moreover, visible-light-mediated
)
or stoichiometric non-metal oxidants (DDQ,[16]
phosphorylation and indolation of N-aryl-tetrahydroisoquinolines,
under the assistance of expensive Ir(III)-[20] and Ru(II)-based
catalysts[21] and Eosin Y[22], are also reported.[23] More recently,
Prabhu’s group synthsized α-aminophosphonate via CDC
reaction employing air as the oxidant in DCE under reflux for 48
hours.[24] Suib’s group reported the CDC reaction of
tetrahydroisoquinolines with indoles using a heterogeneous
mesoporous manganese oxide catalyst at 100 oC.[25] However,
entry
Variation from standard conditions
none
yield (%)[b]
1
2
3
4
5
6
7
8
83
49
41
58
67
66
61
< 1
Et4NOTs instead of n-Bu4NBr
n-Bu4NPF6 instead of n-Bu4NBr
EtOH instead of CH2Cl2
CH3CN instead of CH2Cl2
TsOH (0.1 equiv.) was added
DBU (0.1 equiv.) was added
no electric current
[a]
Dr. W. Xie, Dr. N. Liu, Dr. B. Gong, Dr. S. Ning, Dr. X. Che and Prof.
Dr. J. Xiang
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. China.
E-mail: jbxiang@jlu.edu.cn
http://yxy.jlu.edu.cn/info/1025/1467.htm
[b]
Prof. Dr. L. Cui
[a] Standard conditions: graphite rod anode (d = 5 mm), Pt plate cathode
(0.5 cm × 0.5 cm), constant current = 5 mA, 1a (0.25 mmol), 2a (0.3 mmol),
n-Bu4NBr (0.5 mmol), CH2Cl2 (5 mL), undivided cell, room temperature, 3.0
F/mol. [b] Isolated yield.
Department of Chemistry and Chemical Engineering, Changchun
University of Science and Technology, 7989 Weixing Road,
Changchun, Jilin 130022, P. R. China.
E-mail: cuilili1127@gmail.com
http://hxhj1.cust.edu.cn/dep_info.asp?id=118
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201801883
European Journal of Organic Chemistry
COMMUNICATION
aminophosphonate 3a was isolated in 83% yield (entry 1). In
comparison, reduced yields were isolated when one of the
following factors of the reaction conditions was modified:
changing the electrolyte to Et4NOTs (entry 2) or n-Bu4NPF6
(entry 3), using other organic solvents such as EtOH (entry 4) or
MeCN (entry 5), or adding the catalytic p-toluenesulfonic acid
(TsOH) (entry 6) or 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU)
(entry 7). A control experiment revealed that only trace of 3a
was obtained in the absence of electric current, suggesting the
key role of electric energy for the reaction (entry 8).
and particularly diphenyl phosphite, underwent a smooth CDC
reaction with N-phenyl-tetrahydroisoquinoline 1a, furnishing the
desired products 3n and 3o in good yields (85% and 61% yields,
respectively, Table 2).
The success of C–P bond formation of tetrahydroisoquinoline
under the above mild electrochemical conditions encouraged us
to study C–C bond formation reactions. Indole, as a privileged
scaffold, plays an important role in the field of drug discovery.[27]
In this work, free indole could react with various
tetrahydroisoquinolines to afford the desired products 5 from
moderate to good yields with an exclusive regioselectivity (Table
3).
Having optimized the reaction conditions, we next examined
the scope of the CDC reaction by testing
a series of
tetrahydroisoquinoline substrates (Table 2). To our delight,
various functional groups, including alkoxy (OMe), alkyl (Me and
CF3), halogen (F and Cl), carbonyl (COMe), and cyano
substituents in the N-phenyl ring, were tolerated in the reaction
conditions (3a−l). It shows that mild electron-withdrawing
substituents generally offer a higher yield than strong electron-
donating group (3f−i versus 3b-d) or strong electron-
Table 3. CDC Reaction of Tetrahydroisoquinolines with Indole[a][b]
Table 2. Synthesis of α-Aminophosphonates 3[a][b]
[a] Standard conditions: graphite rod anode (d = 5 mm), Pt plate cathode (0.5 cm ×
0.5 cm), constant current = 5 mA, 1 (0.25 mmol), 4 (0.3 mmol), n-Bu4NBr (0.5 mmol),
CH2Cl2 (5 mL), undivided cell, room temperature, 3.0–4.5 F/mol. [b] Isolated yield.
Based upon careful observations and existing literature
reports,[24-26] a possible mechanism for the electrochemical
cross-dehydrogenative coupling reaction was proposed
(Scheme 2). As a start, compound 1a loses an electron on the
anode to generate the radical cation I, which then loses a proton
and an electron to generate the iminium-ion intermediate II.
Finally, intermediate II is captured by the reactive nucleophile to
afford the CDC product 3 or 5.
[a] Standard conditions: graphite rod anode (d = 5 mm), Pt plate cathode (0.5
cm × 0.5 cm), constant current = 5 mA, 1 (0.25 mmol), 2 (0.3 mmol), n-Bu4NBr
(0.5 mmol), CH2Cl2 (5 mL), undivided cell, room temperature, 3.0–6.7 F/mol.
[b] Isolated yield. [c] The reaction was conducted under N2 protection.
withdrawing one (3f−i versus 3l). Tetrahydroisoquinolines
bearing other N-aryl ring including naphthalene could be
accessed (3m). Other phosphites, such as dibenzyl phosphite
Scheme 2. Proposed Reaction Mechanism.
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10.1002/ejoc.201801883
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COMMUNICATION
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electrochemical CDC reaction of N-aryl-tetrahydroisoquinolines
with phosphites and indole using an undivided cell. This reaction
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or additives at room temperature. This protocol offers an
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A 10 mL distillation flask equipped with a magnetic stir bar was charged
with phosphite 2 or indole 4 (0.3 mmol), CH2Cl2 (5.0 mL), compound 1
(0.25 mmol) and n-Bu4NBr (0.5 mmol). The resulting suspension was
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This work was supported by the Sci-Tech Development Project
of Jilin Province in China (Nos. 20160520039JH and
20170101095JC), the Foundation of Jilin Educational Committee
(No. JJKH20180244KJ), and the Norman Bethune Program of
Jilin University (No. 2015330). Additional support was provided
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Keywords: Electrochemistry • Cross-dehydrogenative coupling
reaction • Tetrahydroisoquinoline • Phosphite • Indole
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Entry for the Table of Contents (Please choose one layout)
Layout 2:
COMMUNICATION
Electrochemical CDC reaction*
Wenxia Xie,[a] Nian Liu,[a] Bowen Gong,[a]
Shulin Ning,[a] Xin Che,[a] Lili Cui*[b] and
Jinbao Xiang*[a]
Page No. – Page No.
A metal- and reagent-free, electrochemical cross-dehydrogenative coupling
Electrochemical cross-
reaction of N-aryl-tetrahydroisoquinolines with phosphites and indole was reported.
dehydrogenative coupling of N-aryl-
tetrahydroisoquinolines with
phosphites and indole
*one or two words that highlight the emphasis of the paper or the field of the study
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