Catalyst-free phosphorylation of aryl halides with trialkyl phosphites through electrochemical reduction

Article abstract of DOI:10.1039/c9cc07069a

A catalyst-free electrochemical cross-coupling reaction of aryl halides with trialkyl phosphite has been developed. This reaction proceeds in an undivided cell with a low-cost Ni anode and a graphite cathode under mild and neutral conditions. A wide range of functional groups are well-tolerated and the phosphorylated product can be obtained on the gram scale, showing that this transformation has the potential to be a valuable method for the construction of aromatic carbon-phosphorus bonds.

Full text of DOI:10.1039/c9cc07069a

ChemComm
View Article Online
View Journal | View Issue
COMMUNICATION
Catalyst-free phosphorylation of aryl halides with
trialkyl phosphites through electrochemical
reduction†
Cite this: Chem. Commun., 2019,
55, 14035
Received 10th September 2019,
Accepted 28th October 2019
ab
Shuai Wang,a Cheng Yang,a Shuo Suna and Jianbo Wang
*
DOI: 10.1039/c9cc07069a
rsc.li/chemcomm
A catalyst-free electrochemical cross-coupling reaction of aryl
Recently, the application of visible-light-induced photo
halides with trialkyl phosphite has been developed. This reaction redox catalyst systems was proved to be an efficient way to
proceeds in an undivided cell with a low-cost Ni anode and a achieve transition-metal-catalyzed aromatic C–P bond construction
graphite cathode under mild and neutral conditions. A wide range under mild conditions.9 In 2017, Baran and co-workers reported
of functional groups are well-tolerated and the phosphorylated the nickel-catalyzed electrochemical amination of aryl halides
product can be obtained on the gram scale, showing that this under mild conditions through paired electrolysis.10 This catalyst
transformation has the potential to be a valuable method for the system was further developed and applied in other functional
construction of aromatic carbon–phosphorus bonds.
group transformations of aryl halides,11 including the recent work
of nickel-catalyzed electrochemical phosphorylation of aryl
11b
Aryl phosphorus compounds have attracted attention due to their bromides of Leonel’s group
and Xiang’s group.11c Despite
´
broad applications in organic synthesis,1 materials science,2 these significant improvements, the transition-metal catalyst
medicinal chemistry, biological chemistry,3 and other fields. (usually with ligand) and base are still necessary. Very recently,
The widespread use of this type of compound has caused Che’s group12a and Li’s group12b reported the catalyst-free
continuous demand for the development of the synthesis photo-induced phosphorylation of aryl halides, but in these
methods. The traditional methods for the construction of transformations, the presence of a strong base (tBuONa or
aromatic C–P bonds, including the nucleophilic substitution tBuOK) was still needed (Scheme 1b). Therefore, a catalyst-free
reaction of an organometallic nucleophile and a phosphine phosphorylation process under neutral and mild conditions is
electrophilic reagent,4 Friedel–Crafts reaction5 and Michaelis– still highly demanded.
Arbuzov reaction,6 suffer from the limitation of harsh reaction
We have previously reported a metal-free Sandmeyer-type
conditions and poor substrate scopes. The transition-metal- phosphorylation reaction of aryldiazonium salts under weak
catalyzed phosphorylation of aryl(pseudo) halides, which was acidic conditions,13 which indicated the possibility of catalyst-free
first reported by Hirao and co-workers as a palladium-catalyzed
cross-coupling process in the 1980’s,7 has been explored extensively
by several groups,8 and the metal catalyst employed in these
transformations has been expanded to nickel and copper. Despite
significant progress in the efficiency and functional group tolerance,
a relatively high temperature (generally above 100 1C) and long
reaction time are usually needed in these transition-metal
catalyzed processes.
a Beijing National Laboratory of Molecular Sciences (BNLMS), Key Laboratory of
Bioorganic Chemistry and Molecular Engineering of Ministry of Education,
College of Chemistry, Peking University, Beijing 100871, China.
E-mail: wangjb@pku.edu.cn
b The State Key Laboratory of Organometallic Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
† Electronic supplementary information (ESI) available: Experimental details,
Scheme 1 Methods for the construction of aromatic C–P bonds.
Chem. Commun., 2019, 55, 14035--14038 | 14035
and characterization data. See DOI: 10.1039/c9cc07069a
This journal is ©The Royal Society of Chemistry 2019

View Article Online
Communication
ChemComm
radical-type aromatic C–P bond formation under neutral conditions.
The catalyst-free electrochemical reduction of aryl halides to afford
aryl radicals has been reported in the past few decades, but can only
be applied in limited transformations.14 In light of the importance
of aromatic phosphorus compounds and our continuous interest
in radical chemistry, we report herein an efficient approach for
catalyst-free electrochemical C–P bond formation under neutral
conditions (Scheme 1c).
We started the investigation with methyl 4-iodobenzoate (1a)
as the standard material and triethyl phosphite (2a) as the
phosphorylation reagent (Table 1). To our delight, 94% isolated
yield of the desired product (3a) was obtained under constant-
current electrolysis using a Ni plate anode and graphite cathode
in an undivided cell at 15 mA for 5 h in a mixed solvent of
1,1,1,3,3,3-hexafluoro-2-propanol (HFIP): N,N-dimethylform-
amide (DMF) = 20 : 1 with 0.1 M tetrabutyl ammonium chloride
(TBAC) as electrolyte (entry 1). In comparison, the anode material
showed a crucial influence on the transformation (entry 2).
Changing the solvent to DMF or MeCN resulted in the dramatical
decrease of the yield of 3a (entry 3). Removal of DMF leads to a
diminished yield because of the relatively poor solubility of the
starting material in HFIP (entry 4). In addition, replacing the
electrolyte with Bu4NClO4 (entry 5), lower loading of 2a (entries 6
and 7), and lower concentration (entry 8) all lead to decreased
yields. The deoxygenation (entry 9) and electrical current (entry
10) are both necessary for this reaction.
Scheme 2 Substrate scope of aryl and heteroaryl Iodides. Standard con-
ditions: Ni plate anode, graphite cathode, 1a–z (0.4 mmol), 2a (1.2 mmol),
TBAC (0.2 mmol), HFIP (2 mL), DMF (0.1 mL), undivided cell, rt, 15 mA, 5 h.
Isolated yields. a The reaction time was 8 h. b The reaction time was 4 h.
With the optimized reaction conditions in hand, we then
examined the substrate scope of this transformation of a series
of functionalized aryl iodides (Scheme 2). The electrochemical
phosphorylation process has shown good functional group
tolerance. Both electron-withdrawing and electron-donating
groups were tolerated on the aromatic ring, including acyl
(3b), trifluoromethyl (3c and 3u), methyl (3d), methoxyl (3e),
trifluoromethoxyl (3f), phenyl (3g), halogen (3h, 3i, 3s and 3t),
acetamido (3k), and cyano (3l). It is noteworthy that aryl iodide
showed good selectivity over aryl bromide and aryl chloride (3h,
3i). The meta-substituted materials afforded similar yields com-
pared with the corresponding para-substituted ones (3m, 3n, 3o),
and the ortho-methyl-substituted aryl iodide gave an even higher
yield (3p). Naphthyl and thienyl iodide also underwent this reac-
tion and gave the corresponding product in moderate yields. Aryl
iodide with a nitro group could not give the phosphorylation
product 3x because over-reduction occurred and gave the hydro-
genation byproduct. Similar results were observed with pyridyl
iodides as the starting materials (3y, 3z).
Table 1 Optimization of the reaction conditionsa
We then explored the substrate scope of different phos-
phites, and the results are shown in Scheme 3. When trimethyl
phosphite (2b) was used as a phosphorylation reagent instead
of 2a, only a trace of the corresponding products was observed.
Entry
Variation from the standard conditions
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
None
PPh3
Trace
o10
80
85
84
65
72
32
0
Fe, Mg or Zn as anode
MeCN (2 mL) or DMF (2 mL) as solvent
No DMF was added
Bu4NClO4 instead of TBAC
0.8 mmol 2a
0.4 mmol 2a
0.2 mmol 1a and 0.6 mmol 2a
Under air
No electric current
a
Scheme 3 Substrate scope of phosphites. Standard conditions: Ni plate
anode, graphite cathode, 1a (0.4 mmol), 2b–f (1.2 mmol), TBAC (0.2 mmol),
HFIP (2 mL), DMF (0.1 mL), undivided cell, rt, 15 mA, 5 h. Isolated yields.
Standard conditions: Ni plate anode, graphite cathode, 1a (0.4 mmol),
2a (1.2 mmol), TBAC (0.2 mmol), HFIP (2 mL), DMF (0.1 mL), undivided
b
cell, rt, 15 mA, 5 h. Isolated yield.
14036 | Chem. Commun., 2019, 55, 14035--14038
This journal is ©The Royal Society of Chemistry 2019

View Article Online
ChemComm
Communication
The propyl- and butyl-phosphonate products could be obtained
in high yields. The triphenyl phosphite gave no products.
For further demonstration of the practical application of this
method, gram-scale synthesis of 3a was carried out with a low-
cost Ni rod (99.99% purity) as the sacrificial anode (Scheme 4).
However, the Ni rod anode gave a lower yield of 70% compared
to the Ni plate anode under the standard conditions (Scheme 4A)
in 0.4 mmol scale. By carrying out the reaction at a current of 25
mA, the yield of 3a could be improved to 86% (Scheme 4B).
When the reaction was carried out in 4 mmol scale under the
optimized conditions, 3a was obtained in 94% isolated yield
(Scheme 4C). However, the reaction time for the gram scale
reaction needed to be extended to 50 h from 5 h for small scale
reaction, which may be the potential limit for the practical
usefulness of this method. Gratifyingly, carrying out the reaction
at a higher current could afford similar yield but with much
shorter reaction time, as shown in Scheme 4D.
Scheme 5 Reaction with aryl bromides. Standard conditions: Ni plate
anode, graphite cathode, 4 (0.4 mmol), 2a (1.2 mmol), TBAC (0.1 mmol),
HFIP (1 mL), MeCN (1 mL), undivided cell, rt, 25 mA, 5 h. All the yields refer
to the isolated products.
obtained in moderate yields with untransformed starting materials
recovered.
We then attempted to carry out this transformation with aryl
bromide. To our disappointment, with 4-bromobenzoate (4a) as
the starting material, the product 3a can only be obtained in a
yield of 40%. One possible reason for the low yield may be that
the cleavage of the C–Br bond is more difficult than the C–I
bond, which may lead to lower current efficiency and lower
selectivity of cathodic reduction for the substrates over the
solvent. Therefore, a higher current density and electric quantity
may be needed. Further optimization of the reaction conditions
for the phosphorylation of aryl bromide was then carried out,
and the results are shown in Scheme 5. The products can be
To gain insights into the mechanistic details of this trans-
formation, several experiments were carried out (Scheme 6).
When the reaction of 1a was carried out with the addition of
radical scavenger 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO),
the generation of 3a was completely suppressed (Scheme 6A).
This result suggests that a radical process is likely to be involved.
To better understand the effect of Ni on this transformation,
control experiments were then carried out (Scheme 6B–D). To
rule out the possibility that a Ni(II)/Ni(0) or Ni(III)/Ni(I) cycle is the
key process as has been reported in the nickel-catalyzed electro-
chemical reactions,10,11 the reaction of 1a was carried out with
Scheme 4 Experiments for gram-scale synthesis.
Scheme 6 Control experiments.
This journal is ©The Royal Society of Chemistry 2019
Chem. Commun., 2019, 55, 14035--14038 | 14037

View Article Online
Communication
ChemComm
method for the synthesis of these compounds. A detailed
mechanistic study and further expansion of the substrate scope
are currently under investigation in our laboratory.
The project is supported by NSFC (Grant 21871010).
Conflicts of interest
There are no conflicts to declare.
Notes and references
Scheme 7 The proposed reaction mechanism.
´
1 C. Queffelec, M. Petit, P. Janvier, D. A. Knight and B. Bujoli, Chem.
Rev., 2012, 112, 3777.
2 (a) A. Naik, L. Meina, M. Zabel and O. Reiser, Chem. – Eur. J., 2010,
16, 1624; (b) A. Inoue, H. Shinokubo and K. Oshima, J. Am. Chem.
Soc., 2003, 125, 1484.
3 (a) K. Moonen, I. Laureyn and C. V. Stevens, Chem. Rev., 2004,
104, 6177; (b) Q. Dang, Y. Liu, D. K. Cashion, S. R. Kasibhatla,
T. Jiang, F. Taplin, J. D. Jacintho, H. Li, Z. Sun, Y. Fan, J. DaRe,
F. Tian, W. Li, T. Gibson, R. Lemus, P. D. van Poelje, S. C. Potter and
M. D. Erion, J. Med. Chem., 2011, 54, 153.
4 F. Langer and P. Knochel, Tetrahedron Lett., 1995, 36, 4591.
5 B. Buchner and L. B. Lockhart Jr., J. Am. Chem. Soc., 1951, 73, 755.
6 A. K. Bhattacharya and G. Thyagarajan, Chem. Rev., 1981, 81, 415.
7 (a) T. Hirao, T. Masunaga, Y. Ohshiro and T. Agawa, Synthesis, 1981,
56; (b) T. Hirao, T. Masunaga, T. Yamada, Y. Ohshiro and T. Agawa,
Bull. Chem. Soc. Jpn., 1982, 55, 909.
8 For a review, see: (a) A. L. Schwan, Chem. Soc. Rev., 2004, 33, 218. For
recent selected examples, see: (b) K. Xu, F. Yang, G. Zhang and
Y. Wu, Green Chem., 2013, 15, 1055; (c) W. Xu, G. Hu, P. Xu, Y. Gao,
Y. Yin and Y. Zhao, Adv. Synth. Catal., 2014, 356, 2948; (d) J. Yang,
J. Xiao, T. Chen and L.-B. Han, J. Org. Chem., 2016, 81, 3911;
different anode materials in the presence of a catalytic and
stoichiometric amount of NiCl2 (Schemes 6B and 5). Only a trace
amount of 3a was observed on GC-MS in these experiments,
indicating that the cathode-generated low-valence nickel species
should not be the catalyst in this reaction, which is in agreement
with the fact that Ni(0) and Ni(I) species are not stable in the
solution without ligands. We then carried out cyclic voltammetry
(CV) experiments to further exclude the possibility that Ni(II) was
the reactive species that was discharged from the cathode, and
the result showed that no reductive wave of Ni(II) was observed
(see Fig. S1 in the ESI†). However, when fluoride salts were added
to coordinate with the Ni(II) species generated from the anode,
the reaction was also blocked (Scheme 6D), which indicated that
the Ni(II) species also played an important part. Based on the fact
that some ferromagnetic black powder was observed after the
reaction, which was likely to be metallic nickel, we reasoned that
the Ni(II) species generated from the anode might react with the
radical species generated on the cathode as oxidant.
ˇ
(e) E. Łastawiecka, A. Flis, M. Stankevic, M. Greluk, G. Słowik and
W. Gac, Org. Chem. Front., 2018, 5, 2079; ( f ) D. Gelman, L. Jiang and
S. L. Buchwald, Org. Lett., 2003, 5, 2315.
9 (a) J. Xuan, T.-T. Zeng, J.-R. Chen, L.-Q. Lu and W.-J. Xiao, Chem. –
Eur. J., 2015, 21, 4962; (b) Y. He, H. Wu and F. D. Toste, Chem. Sci.,
2015, 6, 1194.
On the basis of the mechanism experiments, the literature
reports of electrochemical reduction of aryl halides,14 and our
previous mechanistic understanding of the reaction of aryl
radicals with P(III) reagents,13,15 we have proposed a mecha-
nism as shown in Scheme 7. Firstly, the aryl halide is reduced
by the cathode to generate the radical anion 5, which then
undergoes fragmentation to give aryl radical 6. The aryl radical
is then trapped by 2 to form the phosphoranyl radical 7, which
is then oxidized by Ni2+ generated from the anode to phos-
phoniumyl 8, followed by further reaction with nucleophiles in
the reaction mixture to afford the product 3.
10 C. Li, Y. Kawamata, H. Nakamura, J. C. Vantourout, Z. Liu, Q. Hou,
D. Bao, J. T. Starr, J. Chen, M. Yan and P. S. Baran, Angew. Chem., Int.
Ed., 2017, 56, 13088.
11 (a) D. Liu, H.-X. Ma, P. Fang and T.-S. Mei, Angew. Chem., Int. Ed.,
´
2019, 58, 5033; (b) S. Sengmany, A. Ollivier, E. Le Gall and E. Leonel,
Org. Biomol. Chem., 2018, 16, 4495; (c) During the manuscript
preparation, a related work was published: Y. Bai, N. Liu, S. Wang,
S. Wang, S. Ning, L. Shi, L. Cui, Z. Zhang and J. Xiang, Org. Lett.,
2019, 21, 6835; (d) Y. Kawamata, J. C. Vantourout, D. P. Hickey,
P. Bai, L. Chen, Q. Hou, W. Qiao, K. Barman, M. A. Edwards,
A. F. Garrido-Castro, J. N. deGruyter, H. Nakamura, K. Knouse,
C. Qin, K. J. Clay, D. Bao, C. Li, J. T. Starr, C. Garcia-Irizarry,
N. Sach, H. S. White, M. Neurock, S. D. Minteer and P. S. Baran,
J. Am. Chem. Soc., 2019, 141, 6392.
In summary, we have developed an electrochemical cross- 12 (a) J. Yuan, W.-P. To, Z.-Y. Zhang, C.-D. Yue, S. Meng, J. Chen, Y. Liu,
G.-A. Yu and C.-M. Che, Org. Lett., 2018, 20, 7816; (b) H. Zeng,
Q. Dou and C.-J. Li, Org. Lett., 2019, 21, 1301.
13 S. Wang, D. Qiu, F. Mo, Y. Zhang and J. Wang, J. Org. Chem., 2016,
coupling reaction of aryl halides with trialkyl phosphite for the
construction of aromatic C–P bonds under mild conditions in
an undivided cell. This transformation can be conducted under
neutral conditions without the addition of any catalyst and
ligand. For the phosphorylation of aryl iodides, a wide range of
functional groups were well-tolerated, and the corresponding
products can be obtained in moderate to good yields. The
phosphorylation products of aryl bromides can be obtained
81, 11603.
14 For selected reviews, see: (a) S. R. Waldvogel, S. Lips, M. Selt,
B. Riehl and C. J. Kampf, Chem. Rev., 2018, 118, 6706; (b) M. Yan,
Y. Kawamata and P. S. Baran, Chem. Rev., 2017, 117, 13230. For selected
reports, see: (c) W. S. Nascimento, J. L. Oliveira, J. C. R. Freitas,
M. Navarro and P. H. Menezes, Synthesis, 2014, 2579; (d) K. Mitsudo,
T. Okada, S. Shimohara, H. Mandai and S. Suga, Electrochemistry, 2013,
81, 362.
in moderate yields. This reaction may become a supplementary 15 S. Yasui, K. Shioji and A. Ohno, Heteroat. Chem., 1995, 6, 223.
14038 | Chem. Commun., 2019, 55, 14035--14038
This journal is ©The Royal Society of Chemistry 2019