Nickel-Catalyzed Electrochemical Phosphorylation of Aryl Bromides

Article abstract of DOI:10.1021/acs.orglett.9b02475

A nickel-catalyzed electrochemical cross-coupling reaction of aryl bromides with dialkyl phosphites, ethyl phenylphosphinate, and diphenylphosphine oxide has been developed. This reaction utilizes a simple undivided cell with inexpensive carbon electrodes to synthesize aryl phosphonates, aryl phosphinates, and arylphosphine oxides at room temperature. This protocol provides a mild and efficient route for the construction of C-P bond in moderate to high yields with broad substrate scope.

Full text of DOI:10.1021/acs.orglett.9b02475

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Nickel-Catalyzed Electrochemical Phosphorylation of Aryl Bromides
Ya Bai,†,§ Nian Liu,†,§ Shutao Wang,† Siyu Wang,† Shulin Ning,† Lingling Shi,† Lili Cui,*,‡
Zhuoqi Zhang,† and Jinbao 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
‡School of Chemistry and Environmental Engineering, Changchun University of Science and Technology, 7989 Weixing Road,
Changchun, Jilin 130022, P.R. China
S
* Supporting Information
ABSTRACT: A nickel-catalyzed electrochemical cross-cou-
pling reaction of aryl bromides with dialkyl phosphites, ethyl
phenylphosphinate, and diphenylphosphine oxide has been
developed. This reaction utilizes a simple undivided cell with
inexpensive carbon electrodes to synthesize aryl phosphonates,
aryl phosphinates, and arylphosphine oxides at room temper-
ature. This protocol provides a mild and efficient route for the
construction of C−P bond in moderate to high yields with
broad substrate scope.
ransition metal-catalyzed cross-coupling reactions are
among the most important and attractive methods for
suffered from limited scope of aryl bromides and poor
tolerance of functional groups. For example, 5-bromopyrimi-
dine and cyano/oxo-containing substrates were not successful
under this reaction system. Recently, Baran’s group disclosed
the nickel-catalyzed electrochemical amination where anodic
and cathodic processes are reconciled to synergistically
generate reactive catalyst species in different oxidation states.11
Inspired by the important work and as part of our continuing
interest for the synthesis of organophosphorus compounds, we
envisioned that phosphorus 3 could be readily prepared from
aryl bromide 1 and compound 2 via a nickel-catalyzed
electrochemical C−P bond formation using a nonsacrificial
anode in an undivided cell (Scheme 1). Herein, the details of
these studies are presented.
T
both academia and industry.1 Among them, transition-metal-
catalyzed phosphorylation of aryl halides is an efficient way to
synthesize aryl phosphorus compounds,2 which could be
widely applied to pharmaceuticals, biochemistry, organic
synthesis, and material science.3 At present, for the
construction of C−P bonds, a number of catalytic systems
based on palladium,4 copper,5 and nickel6 have been developed
by several groups. For example, Herzon’s group reported the
palladium-mediated P-arylation of secondary phosphine oxides
at room temperature;4c Fu’s group disclosed the proline/
pipecolinic acid-promoted copper-catalyzed P-arylation of
organophosphorus compounds at 110 °C for 20−36 h;5a and
Han’s group described the formation of C−P bond through
the cross-coupling of aryl halides with H−phosphonates by
using [NiCl2(dppp)] as catalyst at 100−120 °C.6b Very
recently, Che’s group7 and Li’s group8 reported the photo-
induced phosphinylation of aryl halides in the presence of
Scheme 1. Nickel-Catalyzed Electrochemical C−P Bond
Formation
t
strong base (tBuOK or BuONa), respectively. Despite being
interesting, these methods have some drawbacks, such as
limited substrate scope, the requirement of a noble catalyst,
high reaction temperature, long reaction time, and/or strong
base, which likely limit their application in organic synthesis.
Consequently, the development of more concise and universal
methods to solve the aforementioned deficiencies is highly
desirable and presents considerable challenges.
Organic electrosynthesis, which achieves redox reactions
with traceless electric current, is accepted to be an environ-
mentally friendly and enabling synthetic tool.9 In 2018,
We first identified the optimal reaction conditions for the
electrochemical cross-coupling reaction of 1-bromo-4-
(trifluoromethyl)benzene 1a with diethyl phosphite 2a,
which involved constant-current electrolysis using RVC as
anode and cathode in an undivided cell containing NiBr2·
3H2O (catalyst), di-tBubpy (ligand), phthalimide (additive),
Cs2CO3 (base), Et4NPF6 (electrolyte), and DMA (solvent) at
́
Leonel’s group reported the synthesis of arylphosphonates
via an interesting nickel-catalyzed electrochemical reaction of
aryl bromides with dialkyl phosphites under high current (200
mA) using a sacrificial iron anode.10 However, the substrates
Received: July 16, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02475
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a b
,
room temperature for 3 h (Table 1) (see the Supporting
Information for an extensive sampling). Under these mild
Table 2. Synthesis of Arylphosphonates 3
a
Table 1. Optimization of the Reaction Conditions
b
entry
variation from standard conditions
none
graphite as anode
Ni foam as cathode
no phthalimide or 0.2 equiv of phthalimide
DBU instead of Cs2CO3
CH3CN instead of DMA
under air
yield (%)
c
1
90
62
53
50/64
69
37
69
0
2
3
4
5
6
7
8
9
no NiBr2·3H2O
no di-tBubpy
5
10
no electric current
0
a
Standard conditions: RVC anode, RVC cathode, 1a (0.4 mmol), 2a
(0.8 mmol), NiBr2·3H2O (0.08 mmol), di-tBubpy (0.08 mmol),
phthalimide (0.4 mmol), Cs2CO3 (0.5 mmol), Et4NPF6 (0.4 mmol),
DMA (6.25 mL), undivided cell, constant current = 10 mA, N2
protection, room temperature, 3 h (2.8 F/mol). Isolated yield. 94%
yield of phthalimide was recovered. DMA = N,N′-dimethylacetamide,
RVC = reticulated vitreous carbon, di-tBubpy = 4,4′-di-tert-butyl-2,2′-
bipyridine, DBU = 1,8-diazabicyclo(5.4.0)undec-7-ene.
b
c
a
Standard conditions (except where designated): RVC anode, RVC
cathode, 1 (0.4 mmol), 2a (0.8 mmol), NiBr2·3H2O (0.08 mmol),
di-tBubpy (0.08 mmol), phthalimide (0.4 mmol), Cs2CO3 (0.5
mmol), Et4NPF6 (0.4 mmol), DMA (6.25 mL), undivided cell,
constant current = 10 mA, N2 protection, room temperature, 3 h (2.8
conditions, the desired phosphonate 3a was isolated in 90%
yield (entry 1). In comparison, reduced yields were obtained
when the reaction conditions were modified in one of the
following manners: changing the anode to graphite (entry 2)
or changing the cathode to Ni foam (entry 3), removing or
reducing the amount of phthalimide (entry 4), using other
base such as DBU (entry 5), or changing the solvent to
CH3CN (entry 6). Although optimal results were obtained
when the reaction was set up under a protective atmosphere of
nitrogen, rigorous deoxygenation was unnecessary. The
coupling product was afforded in 69% yield even under air
(entry 7). NiBr2·3H2O, di-tBubpy, and electrical current are
necessary for this reaction on the basis of control experiments
(entries 8−10).
Having optimized the reaction conditions, we next examined
the scope of the cross-coupling reaction by testing a series of
aryl bromides (Table 2). To our satisfaction, a variety of
functional groups, including alkoxy (OMe), alkyl (Me and
CF3), halogen (F and Cl), cyano, carbonyl (COMe), and ester
substituents in the phenyl ring, were well tolerated in the
reaction system (3a−j). Bromobenzene substituted with a mild
electron-donating group (Me) gave the best yield of coupling
product 3d. When R = COMe, a lower yield (39%) of product
3g was obtained, and the corresponding hydrolysis product 3g′
was also isolated in 27% yield. It is noteworthy that inert
chlorobenzene derivative is also compatible in our electro-
chemical conditions, albeit in moderate yield (3a). Moreover,
other aryl bromides, such as 1- or 2-bromonaphthalene, 9-
bromophenanthrene, and even oxidation-prone 2-bromo-9H-
fluorene, underwent a smooth reaction with diethyl phosphite
2a, furnishing the coupled products 3k−n in moderate to good
yields (Table 2). Finally, heterocyclic products 3o−r were also
easily prepared from corresponding 2-bromoquinoline, 5-
b
c
F/mol). Isolated yield. 1-Chloro-4-(trifluoromethyl)benzene was
d
e
used. 6 h (5.6 F/mol). 27% yield of 1-(4-hydroxyphenyl)ethan-1-
f
one 3g′ was isolated. 24% yield of 2-methylbenzo[d]thiazol-5-ol 3r′
was isolated.
bromopyrimidine, 2-bromothiophene, and 5-bromo-2-
methylbenzo[d]thiazole by this method (Table 2).
The successful synthesis of aryl phosphonates 3 from aryl
bromide and diethyl phosphite under the above mild
electrochemical conditions encouraged us to investigate other
phosphorus-based nucleophiles. As shown in Table 3, ethyl
phenylphosphinate and diphenylphosphine oxide participated
in the current reaction effectively to produce the desired
products aryl phosphinates 4a−e and arylphosphine oxides
5a−e in moderate to high yields. In most cases, ethyl
phenylphosphinate and diphenylphosphine oxide showed
higher coupling reactivity than diethyl phosphite.6b
Control experiments indicated that the desired product 3a
was completely suppressed when radical scavenger TEMPO
was added in the standard reaction conditions, suggesting that
a radical process should be involved in the cross-coupling
reaction (Scheme 2).
On the basis of the observations above and a literature
report,12 a possible mechanism for the electrochemical cross-
coupling reaction was proposed (Scheme 3). As a start, diethyl
phosphite loses a proton and an electron on the anode to
generate the radical intermediate 6. Meanwhile, the [Ni0]
species is formed from [NiII] by cathodic reduction. Oxidative
addition of [Ni0] to an aryl bromide generates [ArNiIIBr] 7,
which traps the radical 6 to furnish a Ni(III) complex 8.
B
DOI: 10.1021/acs.orglett.9b02475
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
method offers an alternative to conventional methods and
provides an efficient tool for oxidative C−P bonds formation.
Table 3. Synthesis of Arylphosphinates 4 and Arylphosphine
Oxides 5
a b
,
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02475.
Experimental procedures, full characterization data,
copies of NMR spectra for all products (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: jbxiang@jlu.edu.cn.
*E-mail: cuilili1127@gmail.com.
ORCID
Shutao Wang: 0000-0003-4895-2687
Lingling Shi: 0000-0002-8641-1657
Jinbao Xiang: 0000-0002-2628-3075
Author Contributions
§Y.B. and N.L. contributed equally to this work.
a
Standard conditions: RVC anode, RVC cathode, 1 (0.4 mmol), 2b/
2c (0.8 mmol), NiBr2·3H2O (0.08 mmol), di-tBubpy (0.08 mmol),
phthalimide (0.4 mmol), Cs2CO3 (0.5 mmol), Et4NPF6 (0.4 mmol),
DMA (6.25 mL), undivided cell, constant current = 10 mA, N2
Notes
The authors declare no competing financial interest.
b
protection, room temperature, 3 h (2.8 F/mol). Isolated yield.
ACKNOWLEDGMENTS
■
This work was supported by the Natural Science Foundation
of China (No. 21273024), the Sci-Tech Development Project
of Jilin Province in China (No. 20170101095JC), the
Foundation of Jilin Educational Committee (Nos.
JJKH20180244KJ and JJKH20181091KJ), the China Post-
doctoral Science Foundation (NO. 2016M601355), and the
Norman Bethune Program of Jilin University (No. 2015330).
Additional support was provided by Changchun Discovery
Sciences, Ltd.
Scheme 2. Control Experiment
Scheme 3. Proposed Reaction Mechanism
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DOI: 10.1021/acs.orglett.9b02475
Org. Lett. XXXX, XXX, XXX−XXX