Copper-catalyzed one-pot synthesis of alkynylphophonates

Article abstract of DOI:10.1080/00397911.2019.1566474

Copper is found to be an effective catalyst for the preparation of alkynylphophonates. A novel copper-catalyzed one-pot synthesis of alkynylphophonates from terminal alkynes and dialkyl phosphites is developed which involves the haloalkynes intermediates. This method provides a unique and alternative approach to the well-documented oxidative coupling or arylpropiolic acid strategies.

Full text of DOI:10.1080/00397911.2019.1566474

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Copper-catalyzed one-pot synthesis of
alkynylphophonates
Wang-Ze Song, Jun-Hao Li, Ming Li, Jun-Nan He, Kun Dong, Karim Ullah & Yu-
Bin Zheng
To cite this article: Wang-Ze Song, Jun-Hao Li, Ming Li, Jun-Nan He, Kun Dong, Karim Ullah
& Yu-Bin Zheng (2019): Copper-catalyzed one-pot synthesis of alkynylphophonates, Synthetic
Communications, DOI: 10.1080/00397911.2019.1566474
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https://doi.org/10.1080/00397911.2019.1566474
Copper-catalyzed one-pot synthesis of alkynylphophonates
Wang-Ze Songa,b , Jun-Hao Lia, Ming Lia, Jun-Nan Hec, Kun Donga, Karim Ullaha,
and Yu-Bin Zhengc
aState Key Laboratory of Fine Chemicals, School of Pharmaceutical Science and Technology, Dalian
b
University of Technology, Dalian, P. R. China; Zhongli Science and Technology Group Co., Ltd.
c
Changshu, P. R. China; School of Chemical Engineering, Dalian University of Technology, Dalian,
P. R. China
ABSTRACT
ARTICLE HISTORY
Received 20 August 2018
Copper is found to be an effective catalyst for the preparation of
alkynylphophonates. A novel copper-catalyzed one-pot synthesis of
alkynylphophonates from terminal alkynes and dialkyl phosphites is
developed which involves the haloalkynes intermediates. This
method provides a unique and alternative approach to the well-
documented oxidative coupling or arylpropiolic acid strategies.
KEYWORDS
Alkynylphophonates;
copper; haloalkynes;
one-pot
GRAPHICAL ABSTRACT
Introduction
The phosphorus-containing compounds could be widely applied as ligands and
organocatalysts or could be converted into diverse molecules by Wittig,
Horner–Wadsworth–Emmons (HWE) reactions, cross-couplings, and cyclization in
organic synthesis.[1] Alkynylphosphonates, as one of the most focused phosphorus
reagents, are very useful building blocks for the synthesis of versatile phosphorus-con-
taining compounds by conjugate-additions or cycloaddition reactions.[2] In addition, the
alkynylphosphonates have attracted increasing attention due to their potential biological
activities.[3] The traditional ways to access the alkynylphosphonates, including
Michaelis–Arbuzov reaction, Michaelis–Becker reaction, and palladium-catalyzed reac-
tion, usually suffer from a lack of functionality tolerance.[4]
In recent years, earth-abundant metal-catalyzed Csp–P coupling reaction emerges to
be the most straightforward and sustainable approach to prepare the alkynylphospho-
nates. In 2009, Han and Zhao group reported copper-catalyzed oxidative coupling of
CONTACT Wang-Ze Song
wzsong@dlut.edu.cn, Yu-Bin Zheng zybwl@163.com
State Key Laboratory of Fine
Chemicals, School of Pharmaceutical Science and Technology, Dalian University of Technology, No. 2 Linggong Road,
Dalian 116024, P. R. China.
Supplemental data for this article is available online at on the publisher’s website.
ß 2019 Taylor & Francis Group, LLC

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W.-Z. SONG ET AL.
Scheme 1. Copper-catalyzed one-pot synthesis of alkynylphosphonates from terminal alkynes and
dialkyl phosphite.
terminal alkynes and dialkyl phosphites under dry air (Scheme 1a).[5] Later, Zhao,
Yang, and Wu group achieved the preparation of alkynylphosphonates from the aryl-
propiolic acids (Scheme 1b).[6] The advantages of those methodologies are using air
(oxygen) as the oxidant to release water as the by-product. Beyond the well-documented
copper-catalyzed reactions, new strategies are still highly desired. Haloalkynes, usually
as the alternative substrates to the propiolic acids, could be easily converted to various
internal alkynes by the transition metal-catalyzed reactions,[7] which would make the
alkynylphosphonates formation safer and more approachable. It is also very convenient
to generate haloalkynes in situ from the terminal alkynes. Herein, we report a copper-
catalyzed one-pot synthesis of alkynylphophonates from terminal alkynes and dialkyl
phosphite involving haloalkyne intermediate and Csp–P bond formation (Scheme 1c).
Results and discussion
Initially, phenylethyne 1a and diethyl phosphite 2a were selected as model substrates for
the optimal reaction conditions. Treating 1a with NBS and silver nitrate in acetone
afforded crude bromoalkyne intermediate, which was used directly in the next step
without further purification. In the presence of Cu(I) or Cu(II), the coupling reaction
could occur smoothly for the preparation of diethyl (phenylethynyl)phosphonate 3a
(Table 1, entries 1–3). Among the copper sources, CuSO4Á5H2O gave the best yield
when using 1,10-phenanthroline and potassium carbonate as ligand and base. Without
ligand, the yield decreased dramatically (Table 1, entry 4). Compared to other commer-
cially available ligands (e.g. triethylamine and TMEDA), 1,10-phenanthroline was dem-
onstrated to be the best ligand in this reaction (Table 1, entries 5 and 6). Besides
potassium carbonate, other potassium salts were also screened (Table 1, entries 7
and 8). To our delight, tripotassium phosphate also worked in this transformation. But
for the potassium tert-butoxide, no desired product was acquired. The reaction could be
conducted in DMSO or DMF with lower yields (Table 1, entries 9 and 10). It failed to
proceed in MeCN or CHCl3 (Table 1, entries 11 and 12). We also briefly investigated

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Table 1. Optimization of the reaction conditionsa.
Entry
Cu salt
Ligand
Base
Solvent
Yield(%)b
1
2
3
4
5
6
7
8
CuSO4Á5H2O
1,10-Phen
1,10-Phen
1,10-Phen
–
NEt3
TMEDA
1,10-Phen
1,10-Phen
1,10-Phen
1,10-Phen
1,10-Phen
1,10-Phen
1,10-Phen
1,10-Phen
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K3PO4
KOt-Bu
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DMSO
DMF
MeCN
CHCl3
toluene
86
81
78
46
57
48
77
trace
66
67
trace
trace
trace
82
CuI
CuCl
CuSO4Á5H2O
CuSO4Á5H2O
CuSO4Á5H2O
CuSO4Á5H2O
CuSO4Á5H2O
CuSO4Á5H2O
CuSO4Á5H2O
CuSO4Á5H2O
CuSO4Á5H2O
CuSO4Á5H2O
CuSO4Á5H2O
9
10
11
12
13c
14d
toluene
aThe reaction conditions: under N2 atmosphere, 1-phenylethyne (1 equiv.), NBS (1.2 equiv.), silver nitrate (0.1 equiv.) in
acetone (1 M) at RT for 1 h, then removal of precipitation and solvent to afford crude bromoalkyne intermediate.
Diethyl phosphite (1 equiv.), copper salt (0.1 equiv.), ligand (0.2 equiv.), base (2 equiv.) and solvent (0.5 M) were
added to the crude bromoalkyne intermediate at 65 ꢀC overnight.
bIsolated yield based on 1a.
cThe reaction was set at room temperature.
dThe reaction was set at 110 ꢀC.
Note: 1,10-phen: 1,10-phenanthroline; TMEDA: tetramethylethylenediamine.
the temperature for this reaction. No reaction occurred at room temperature.
Surprisingly, the yield slightly dropped to 82% in reflux condition (Table 1, entries 13
and 14).
With the optimized conditions in hand, we explored the scope of this one-pot synthe-
sis of alkynylphophonates from terminal alkynes and dialkyl phosphite. Various dialkyl
phosphites were used as substrates at 65 ꢀC in inert gas protection to afford alkynyl-
phophonates in good yields (up to 86%) (Table 2, entries 1–4). Besides diethyl
phosphite, other dialkyl phosphites, such as methyl, isopropyl, and n-butyl phosphites,
could also participate in this “one-pot” reaction smoothly (3a–3d). However, the yield
for n-butyl phosphite was lower than other substrates. Subsequently, the electronic effect
for the terminal alkynes was examined (Table 2, entries 5–10). No obvious electronic
effect was observed in this transformation. The introduction of electron-donating
groups could slightly decrease the yields comparing to electron-withdrawing groups.
The methoxyl, methyl, tert-butyl, halogen, and nitro groups could be well tolerated in
this process with good yields obtained (3e–3j). When the aliphatic alkyne 1k was used
instead of the aryl alkyne, the yield of 3k was dramatically decreased to 61% (Table 2,
entry 11).
Finally, the derivation of the alkynylphophonates was explored (Scheme 2). A tandem
cycloaddition and deprotection process were employed to afford related fully
substituted 1,2,3-triazolyl-4-phosphonic acid in 72% yield. The cycloaddition
between the alkynylphophonate 3e and benzyl azide 4 occurred firstly, followed

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W.-Z. SONG ET AL.
Table 2. One-pot synthesis of alkynylphosphonates from terminal alkynes and dialkyl phosphitea.
aThe reaction conditions: under N2 atmosphere, alkyne (1 equiv.), NBS (1.2 equiv.), silver nitrate (0.1 equiv.) in acetone
(1 M) at RT for 1 h, then removal of precipitation and solvent to afford crude bromoalkyne intermediate. Dialkyl phos-
phite (1 equiv.), CuSO4Á5H2O (0.1 equiv.), 1,10-phenanthroline (0.2 equiv.), K2CO3 (2 equiv.) and toluene (0.5 M) were
added to the crude bromoalkyne intermediate at 65 ꢀC overnight.
bIsolated yield based on 1.

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5
Scheme 2. The tandem cycloadditon and deprotection from the alkynylphosphonates.
by adding trimethylsilyl bromide (TMSBr) to deprotect the phophonates in “one-
pot” way.
Conclusion
In summary, we have developed a novel copper-catalyzed one-pot synthesis of alkynyl-
phophonates from terminal alkynes and dialkyl phosphite. Haloalkynes, as the alternative
substrates to the well-defined propiolic acids, could be easily generated in situ from the ter-
minal alkynes, which further reacted with dialkyl phosphites to form Csp–P bond efficiently.
Experimental section
General procedure for the preparation of alkynylphosphonates 3
To the solution of alkyne (1 equiv.) and NBS (1.2 equiv.) in acetone (1 M) silver nitrate
(0.1 equiv.) was added under N2 atmosphere. The mixture was stirred at RT for 1 h,
then removal of precipitation and solvent to afford crude bromoalkyne intermediate.
Dialkyl phosphite (1 equiv.), CuSO4Á5H2O (0.1 equiv.), 1,10-phenanthroline (0.2 equiv.),
K2CO3 (2 equiv.) and toluene (0.5 M) were added to the crude bromoalkyne intermedi-
ate. The mixture was stirred at 65 ꢀC overnight. The mixture was filtered through a
short pad of silica gel using CH2Cl2 as the eluent, and the filtrate was concentrated in
vacuo. Purification of the residue by column chromatography (50% EtOAc/hexane) gave
the alkynylphosphonates 3.
Funding
This work was supported by grants from the National Natural Science Foundation of China [No.
21702025], Fundamental Research Funds for the Central Universities [No. DUT18LK25] and
Natural Science Foundation of Liaoning Province [No. 20180550576].
ORCID
Wang-Ze Song
http://orcid.org/0000-0003-1003-3861
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