Copper-catalyzed decarboxylative C?P cross coupling of arylpropiolic acids with dialkyl hydrazinylphosphonates leading to alkynylphosphonates

Article abstract of DOI:10.1080/00397911.2016.1192648

A facile and novel copper-catalyzed decarboxylative coupling of various arylpropiolic acids with readily available dialkyl hydrazinylphosphonates has been developed, providing an attractive synthetic tool for the synthesis of valuable alkynylphosphonates

Full text of DOI:10.1080/00397911.2016.1192648

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Copper-Catalyzed Decarboxylative C–P
Cross-Coupling of Arylpropiolic Acids with
Dialkyl Hydrazinylphosphonates Leading to
Alkynylphosphonates
Weizhu Chen, Dumei Ma, Gaobo Hu, Zhuan Hong, Yuxing Gao & Yufen Zhao
To cite this article: Weizhu Chen, Dumei Ma, Gaobo Hu, Zhuan Hong, Yuxing Gao & Yufen
Zhao (2016): Copper-Catalyzed Decarboxylative C–P Cross-Coupling of Arylpropiolic Acids with
Dialkyl Hydrazinylphosphonates Leading to Alkynylphosphonates, Synthetic Communications,
DOI: 10.1080/00397911.2016.1192648
To link to this article: http://dx.doi.org/10.1080/00397911.2016.1192648
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Date: 19 June 2016, At: 21:19

Copper-Catalyzed Decarboxylative C−P Cross-Coupling of Arylpropiolic Acids with
Dialkyl Hydrazinylphosphonates Leading to Alkynylphosphonates
1
,2
1
1
2
1
1
Weizhu Chen , Dumei Ma , Gaobo Hu , Zhuan, Hong , Yuxing Gao , Yufen Zhao
1
Department of Chemistry and Key Laboratory for Chemical Biology of Fujian Province,
College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian,
China, Third Institute of Oceanography, State Oceanic Administration, Xiamen, P. R.
2
China
Corresponding Author: Yuxing Gao, Email: gaoxingchem@xmu.edu.cn
Abstract
A facile and novel copper-catalyzed decarboxylative coupling of various arylpropiolic
acids with readily available dialkyl hydrazinylphosphonates has been developed, providing
an attractive synthetic tool for the synthesis of valuable alkynylphosphonates with
operational simplicity and mild reaction conditions.
Graphical Abstract:
KEYWORDS: Decarboxylative coupling, arylpropiolic acids, dialkyl
hydrazinylphosphonates, alkynylphosphonates
1

INTRODUCTION
The phosphorus-containing compounds are of great importance in organic synthesis,
[
1-5]
pharmaceuticals, and bioactive products.
Among them, alkynylphosphonates have
attracted intense attention over the past decades, since they are an important class of triple
bond-containing, extremely valuable chemicals in modern synthesis chemistry, which are
extensively used as the key precursors for biologically active molecules in medicinal
chemistry and for synthesizing structurally diverse phosphorus-containing products
through hydrations, reductions, metallacycle formation, conjugate-addition reactions and
[
6]
cycloaddition reactions. However, synthetic approaches to such useful frameworks are
so far limited. The traditional methods for the synthesis of alkynylphosphonates mainly
employ readily hydrolyzable Ph P(O)Cl and Li or Mg acetylides as the substrates,
2
[
6a]
suffering from poor tolerance of functional groups. In recent years, the
transition-metal-catalyzed C-P bond forming reactions have emerged as one of the most
reliable and robust tools for the preparation of alkynylphosphonates, including
[
7]
Pd-catalyzed cross-coupling of 1,1-dibromo-1-alkenes with H-phosphites, Cu-catalyzed
[
8]
[9]
oxidative coupling of terminal alkynes with H-phosphonates, and the other approaches
Despite their usefulness, almost all of these methods have common problems such as
relatively strict reaction conditions, excess reagents, poor substrate scope or unsatisfactory
yields. Thus, the development of more simple and efficient methods to prepare
alkynylphosphonates is still desirable.
2

In the past few years, the decarboxylative coupling reaction as a new synthetic strategy has
[
10-19]
wide applications in the construction of C-C and C-heteroatom bonds.
Among these
couplings, as a practical alternative, using arylpropiolic acids instead of terminal alkynes
as the coupling partner is safer and more promising since arylpropiolic acids are usually
[20]
solid-state without unpleasant smell and easy to prepare, store, and transport. Following
this viewpoint, in 2011, Yang’s group first reported the Pd/Cu cocatalyzed decarboxylative
coupling of arylpropiolic acid with H-phosphonate for the synthesis alkynylphosphonates.
[
21]
However, this reaction did not work well for the dialkyl H-phosphonate. In 2014, Wu’s
group improved the above method and developed an efficient Cu-catalyzed
decarboxylative coupling of arylpropiolic acids with dialkyl H-phosphonates leading to
[
22]
alkynylphosphonates. Although the reaction could proceed smoothly under air, this
method required 2.0 equivalent of copper catalyst, 2.5 equivalent of ligand, 2.0 equivalent
of K PO and 3.0 equivalent of additive, thus increasing the cost and limiting their
3
4
applications. As we know, the dialkyl H-phosphonate is not stable, tend to decompose to
phosphorous acid and alcohol. In contrast, dialkyl hydrazinylphosphonates is more stable
and easily available, which can be conveniently prepared according to the known
[
23]
literature. Therefore, using dialkyl hydrazinylphosphonates instead of H-phosphonates
might make the coupling reaction easier to operate. In this context, we attempt to develop a
mild, simple, and green protocol for the copper-mediated oxidative decarboxylative
coupling of arylpropiolic acids with dialkyl hydrazinyl phosphonates. Herein, we
described a convenient and practical Cu-catalyzed oxidative decarboxylative coupling of
3

various arylpropiolic acids with dialkyl hydrazinylphosphonates for the preparation of
alkynylphosphonates through using a simple catalysis system. To the best of our
knowledge, this transformation has not been reported to date.
RESULTS AND DISCUSSION
As the outset of our studies, we chose phenylpropiolic acid (1a) as the model substrate to
optimize the reaction conditions (Table 1). Initially, the coupling reaction was performed
with diethyl hydrazinylphosphonate (2a) in the presence of CuSO (30 mol%) in
4
N,N'-dimethyl formamide (DMF) at 70 °C for 12 h. Gratifyingly, the desired product was
obtained in 50% yield (entry 1). Encouraged by this result, we further optimized the
reaction conditions. A screening of various bases illustrated that pyridine was the best base
for this reaction (entries 2-6) and the use of pyridine (10 mol%) could significantly
enhance the product yield to 90% (entry 4), demonstrating the base plays a crucial role in
this catalytic system. Subsequently, using pyridine as base, we evaluated different copper
catalysts but no better results were obtained (entries 7-9). The transformation could not
proceed without the participation of CuSO , revealing that CuSO catalyst was essential to
4
4
achieve a high yield of product 2a. To advance the process further, the effect of solvents
was also investigated, such as CH CN, 1, 4-dioxane and toluene, however, no desired
3
product was observed (entries 10-12). Subsequent survey on the role of oxidants disclosed
H O or tert-butyl hydroperoxide (TBHP) could not promote this reaction (entries 13-14).
2
2
Decreasing the loading of CuSO or 2a led to the yield reduction (entries 15-16). When
4
4

o
decreasing the reaction temperature to 60 C, however, it also gave a decreased yield of 56%
o
(
entry 17). Moreover, when rasing the temperature to 80 C, it only afforded a trace amount
of desired compounds (entry 18). After a series of detailed investigations, the reaction
conditions were eventually optimized as shown in Table 1, entry 4.
With the optimized conditions in hand, we next explored the scope of the substrates and
generality of the method by varying the structures of the arylpropiolic acids. The results are
summarized in Table 2. Various valuable alkynylphosphonates could be conveniently
obtained by this novel copper-catalyzed decarboxylative C-P cross-coupling of
arylpropiolic acids with dialkyl hydrazinylphosphonates, and the corresponding oxidative
coupling products were produced in 20% to 90% yields. Some electron-rich and
electron-deficient arylpropiolic acids were suitable for this method. Thus, a variety of
functionalities, such as methyl, nitro, trifluoromethyl, fluoro and cyano groups, were all
tolerated under the present reaction conditions. Generally, arylpropiolic acids with both
electron-rich and electron-neutral functional groups have a relatively high reactivity,
affording the corresponding products in higher yield (Table 2, 5-11). In contrast,
electron-poor arylpropiolic acids afforded the products in relatively low yields, along with
the generation of diynes as the byproducts. The results indicated that electronic effect had
an obvious influence on this decarboxylative coupling. For example, 3-(4-tolyl)propiolic
acid 1b could well be coupled with diethyl hydrazinylphosphonate 2a to afford the desired
product in a good yield of 70%, but 3-(4-nitrophenyl)propiolic acid 1m having a strong
5

electron-withdrawing nitro group could only generate the desired product in a low yield of
0% (Table 2, entry 13). Nevertheless, the substrates 1e and 1i bearing the
2
electron-withdrawing cyano and trifluoromethyl groups, respectively, were also good
coupling partners for this oxidative coupling reaction, giving the corresponding products in
moderate yields (3e, 3i, 61%, 45%, respectively, entries 5 and 9). Notably, the
3
7
-(p-tolyl)propiolic acid 1b and meta-substituted counterpart 1c afforded similar yields of
0% and 61%, respectively, but sterically demanding 3-(o-tolyl)propiolic acid only gave a
very low yield of 9%, illustrating that this coupling reaction is sensitive to steric hindrance
entries 2 and 3). Interestingly, fluoro group substituted substrates such as 1f, 1g and 1h
(
could well be coupled with diethyl hydrazinylphosphonate 2a, affording the desired
products in moderate yields (Table 2, entries 6-8). However, 3-(3-cyanophenyl)propiolic
acid(1j), 3-(3-bromophenyl)propiolic acid (1k) and 3-(m-tolyl)propiolic acid (1l) only
afforded the corresponding products in lower yields of 37%, 30% and 31%, respectively
(Table 2, entries 10-12). To gain more insight into the substrate scope of the reaction, in
addition to 1a, the alkynylation of diisopropyl hydrazinylphosphonate (1b) and
P,P-diphenylphosphinic hydrazide were also detected. Unfortunately, diisopropyl
hydrazinylphosphonate (2b) and dibutyl hydrazinylphosphonate (2c) only afforded the
desired products in a lower yield of 35% and 43%, respectively, probably owing to the
steric hindrance of bulky isopropyl and butyl substituents (Table 2, entries 14-15). In
addition, P,P-diphenylphosphinic hydrazide was not suitable for this protocol and gave no
product.
6

[
8a,24]
On the basis of the above experimental results and previous reports,
a possible
mechanism is proposed (Scheme 2). First, dialkyl hydrazinylphosphonate 2 released one
molecule N and H O to form copper phosphate B in the presence of Cu(II) and O .
2
2
2
Meanwhile, the decarboxylative reaction of 1 occurred with the assistance of Cu(I) to
produce alkynyl copper intermediate A, which was observed as a yellow precipitate at the
very beginning of the reaction and completely disappeared at the end of the reaction.
Indeed, (phenylethynyl)copper (0.2 mmol) did react with 2a (0.8 mmol) in DMF (1 mL) at
7
0 °C for 12 h under dry air to give 3a in 47% yield. The subsequent coordination of B to
A led to the formation of intermediate C. Finally, C reacted with 1 and O leading to the
2
generation of the desired product 3 and catalytically active Cu species to fulfill the catalytic
cycle. However, the details of the mechanism are not clear at present.
EXPERIMENTAL
Diaryl hydrazinylphosphonate (1.2 mmol), arylpropiolic acids (0.3 mmol) and CuSO (30
4
mol%) were dissolved in DMF (1 mL) and stirred at 70 °C for 12 h under dry air. The
resulting mixture was concentrated under vacuum and the crude product was purified by
silica gel chromatography using a mixture of petroleum ether and ethyl acetate as eluent.
7

CONCLUSION
In conclusion, we have developed the first copper-catalyzed decarboxylative coupling of
various arylpropiolic acids with dialkyl hydrazinylphosphonates to access
alkynylphosphonates. Importantly, the reaction is performed without excess catalysts,
ligands, bases and additives, and various products can be conveniently obtained in a
one-pot process. In addition, in view of the following desirable features, such as cheap
catalysts, readily available materials, operation simplicity and mild reaction conditions,
this method provides an attractive synthetic tool for simple synthesis of valuable
P-alkynylated motifs. Further mechanistic investigations and synthetic applications are
currently underway.
ACKNOWLEDGMENTS
This work was supported by the Chinese National Natural Science Foundation (21202135),
the Natural Science Foundation of Fujian Province of China (No. 2013J05031, No.
2
015N0009) and the National Basic Research Program of China (2012CB821600).
SUPPLEMENTAL MATERIAL
Supplemental data for this article can be accessed on publisher’s website.
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11

a
Table 1. Optimization of the Reaction Conditions
b
entry catalyst
base
-
solvent
yield (%)
1
2
3
4
5
6
7
8
9
1
CuSO4
CuSO4
CuSO4
CuSO4
CuSO4
CuSO4
CuI
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
50
66
44
90
37
trace
15
13
31
0
DPPE
Et N
3
pyridine
TMEDA
K CO
2
3
pyridine
pyridine
pyridine
pyridine
pyridine
pyridine
pyridine
pyridine
pyridine
pyridine
pyridine
pyridine
CuO
Cu(OAc)2
CuSO4
CuSO4
CuSO4
CuSO4
CuSO4
CuSO4
CuSO4
CuSO4
CuSO4
0
CH CN
3
11
Dioxane
Toluene
DMF
0
1
1
1
1
1
1
2
3
4
5
6
7
8
1
0
c
d
e
f
0
DMF
0
DMF
83
43
56
trace
DMF
g
h
DMF
1
DMF
a
a (0.3 mmol), 2a (1.2 mmol), CuSO (0.09 mmol), pyridine (0.03 mmol), DMF (1 mL),
4
b
c
d
7
7
8
0 °C, 12 h, under dry air. Isolated yield. using 30% H O (0.6 mmol) in water. using
2 2
e
f
g
h
0% TBHP (0.6 mmol) in water. 2a (0.9 mmol). CuSO (0.05 mmol). At 60 °C. At
4
0 °C.
12

Table 2. Copper-catalyzed decarboxylative coupling of arylpropiolic acids with dialkyl
a
hydrazinylphosphonate
c
entry
1
arylpropiolic acids
product
yield (%)
90
1a
1b
1c
3a
3b
3c
2
3
70
61
4
5
6
7
1d
1e
1f
3d
3e
3f
41
61
64
55
1g
3g
13

8
9
1
1h
1i
3h
3i
48
4
5
0
1j
3j
37
30
31
20
11
1k
1l
3k
3l
1
1
2
3
1m
3m
b
1
1
4
1n
1o
3n
3o
35
43
5
a
Reaction conditions: diethyl hydrazinylphosphonate (1.2 mmol), arylpropiolic acids (0.3
mmol), CuSO (30 mol%), pyridine (10 mol%), DMF (1 mL), 70 °C, 12 h, under dry air.
4
b
c
diisopropyl hydrazinylphosphonate (1.2 mmol). Isolated yield.
14

Scheme 1. A plausible mechanism
15