Additive-free coupling of bromoalkynes with secondary phosphine oxides to generate alkynylphosphine oxides in acetic anhydride

Article abstract of DOI:10.1039/c9ob02750e

A coupling of bromoalkynes with secondary phosphine oxides was developed for the synthesis of alkynylphosphine oxides. This transformation was accomplished under additive-free conditions in acetic anhydride (Ac₂O). The reaction could be carried out under mild conditions, and a wide range of secondary phosphine oxides were obtained in good yields.

Full text of DOI:10.1039/c9ob02750e

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DOI: 10.1039/C9OB02750E
COMMUNICATION
Additive-free coupling of bromoalkynes with secondary
phosphine oxides to generate alkynylphosphine oxides in acetic
anhydride
Received 00th January 20xx,
Accepted 00th January 20xx
Hongjie Ruan,a Ling-Guo Meng,*,a Hailong Xu,a Yuqing Liang,a and Lei Wang*,a,b
DOI: 10.1039/x0xx00000x
Previous work:
A coupling of bromoalkynes with secondary phosphine oxides was
developed for the synthesis of alkynylphosphine oxides. This
transformation was accomplished under additive-free conditions
in acetic anhydride (Ac2O). The reaction could be furnished with
mild conditions, and a wide range of secondary phosphine oxides
were obtained in good yields.
Ph
(a)
Pd(OAc)2
ref 3a
dehyd
rogenative
coupl
ing
2 equiv Ag2CO3
(b)
(c)
H
+
H
ref 4a
Ph
O
P
Ph2
CuI
ref 4b
Direct construction of carbon-phosphorus (C−P) bonds is a
shortcut strategy for the formation of organophosphorus
compounds, which play important roles in the pharmaceutical and
agrochemical industries. Among existing various phosphorus
species, alkynyl-phosphorus compounds have been shown to be
important precursors, due to their polar unsaturated bond, for the
construction of functional organophosphorus derivatives.1 Until
now, different procedures have been developed to synthesize
alkynylphosphoryl compounds.2 The general method for their
preparation is the cross-coupling of P(O)−H with terminal alkynes in
the presence of transition metal catalysts (Scheme 1). For example,
Han and Chen reported the Pd-catalyzed dehydrogenative coupling
of terminal alkynes with H-phosphonates to generate
alkynylphosphonates (Scheme 1a);3 Lei and Zhao4 achieved
phosphorylation of terminal alkynes by employing Ag or Cu salts as
a promoter or catalyst, respectively (Scheme 1b and 1c). Although
the above dehydrogenative coupling can be carried out using
terminal alkynes without prefunctionalization, such oxidative cross-
coupling transformations cannot be workable without transition-
metal catalysts and harsh reaction conditions.
As an effective and alternative strategy, heterosubstituted
alkynes or alkyne derivatives have been used as candidate
substrates for coupling with secondary phosphine oxides for the
synthesis of phosphonoalkynes. For example, Yang and Wu used
arylpropiolic acids to couple with H-phosphonates to afford
alkynylphosphine oxides through the oxidative decarboxylative
process (Scheme 1d);5a furthermore, alkynyl sulfones have also
been used as potent alkynyl precursors to accomplish a similar C−P
bond construction (Scheme 1e).6 However, prominent deficiencies
of the above methods still require a transition metal, large amount
Cu(OAc)2
(2 euqiv)
ref 5a
O
P
O
Ph2
+
(d)
Ph
COOH
H
H
P
Ph2
Ph2
Cs2CO3
(1.5 euqiv)
O
P
(e)
(g)
Ph
Ts
Br
+
ref 6a
This work:
OV
P
OV
Ac2O
Ph
Ph2
Ph
+
P
H
Ph2
N2, rt, 24 h
Ac2O
Ph
Br
mild conditions
III
P
AcO Ph2
no metal
no base
Scheme 1 Different Routes to Phosphonoalkynes.
of base or complicated reaction conditions. Accordingly, the
development of a simpler and more practical approach for the
synthesis of phosphonoalkynes remains meaningful and interesting
for chemists. Bromoalkynes are easily obtained from commercial
terminal alkynes and N-bromosuccinimide (NBS) with a catalytic
amount of AgNO3, emerging as prominent synthetic precursors due
to their good chemical reactivity in the reported organic
transformations.7,8 Therefore, we attempted the coupling reaction
between bromoalkynes with secondary phosphine oxides under
catalyst-free conditions, but no reaction was observed when the
reaction was stirred in the classic solvents. To our delight, Ac2O
propelled the coupling of bromoalkynes with diarylphosphine oxide,
and phosphonoalkynes were obtained with good chemoselectivity.
Notably, in most reported works, the phosphorus valence remained
unchanged during the formation of C−P bonds.3-6 Conversely, this
new protocol accomplished such transformations through an
interesting procedure in acetic anhydride and had the advantages
of simple reaction conditions to afford the desired coupling
products in satisfactory yields with improving functional group
tolerance (Scheme 1g). Herein, we report this facile platform for the
synthesis of alkynylphosphine oxides from bromoalkynes with
a. Department of Chemistry, Huaibei Normal University, Huaibei, Anhui 235000, P.R.
China.
E-mail: milig@126.com, leiwang@chnu.edu.cn
b. State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, Shanghai 200032, P. R. China.
†
Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: See DOI: 10.1039/x0xx00000x
1
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Scheme 2 The scope of bromoalkynesa,b
DOI: 10.1039/C9OB02750E
Table 1 Optimization of reaction conditionsa
O
O
Ac2O
Ar
Br
+
P
Ar
Ph2
P
H
Ph2
N2, rt, 24 h
3
2a
1
O
O
Ac2O
P
Ph
Ph2
Ph
Br
+
P
H
Ph2
N2, rt, 24 h
O
O
O
1a
2a
3aa
P
Ph2
, 92%
, 70%
MeO
P
Ph2
P
Me
Ph2
3aa
3aa
3ba
3ca
, 90%
, 88%
4 mmol,
Entry
Solvent
Yield (%)b
Ac2O
c
1
2
3
4
Me
67
O
O
O
Ac2O
Ac2O
d
Ph2
tBu
Ph2
78
P
P
P
Pr
Ph2
92
81e
3da
3fa,77%
, 89%
3ea
3ha
, 86%
Ac2O
F
O
O
O
Ac2O
f
5
6
76
P
P
Ph2
F
Ph2
P
Ph2
Cl
CH3CN
toluene
THF
NR
NR
NR
NR
NR
NR
, 86%
3ia
, 81%
3ga
3ja
, 85%
7
Br
Cl
O
O
O
8
P
Ph2
P
Br
P
Ph2
Ph2
DMSO
DMF
9
, 75%
3la
, 80%
3ka
3na
, 70%
10
11
H2O
O
O
O
P
Ph2
P
CF3
NC
Ph2
P
Ph2
NO2
aReaction conditions: 1a (0.20 mmol), 2a (0.60 mmol), solvent (1.0
mL) at room temperature under a N2 atmosphere for 24 h. bIsolated
yield. Compound 2a (0.2 mmol) was added. Compound 2a (0.4
mmol) was added. The reaction was stirred under air. The
reaction was stirred under O2. NR = no reaction.
3ma
, 81%
, 84%
3oa
, 64%
Br
Cl
c
d
O
O
O
e
f
P
Ph2
P
Ph2
P
Ph2
S
3sa
, 67%
3qa
, 80%
3ra
, 73%
O
secondary phosphine oxides under metal- and base-free
conditions at room temperature in Ac2O.
P
Ph2
3ta
, 0%
We commenced our work to optimize the cross-coupling reaction
of phenylethynyl bromide 1a and diphenylphosphine oxide 2a, and
the results are listed in Table 1. The model substrates 1a and 2a
were stirred in Ac2O at room temperature under a N2 atmosphere
for 24 h to afford the cross-coupling product 3aa in 67% yield (entry
1, Table 1). The yield of 3aa was improved with increasing amounts
of 2a, and 92% yield of 3aa was obtained when 3.0 equiv. of 2a was
added in the reaction (entries 2 and 3, Table 1). The yield of 3aa
was slightly decreased when the reaction environment was
changed from N2 to air or O2 (entries 4 and 5, Table 1). Further
investigation of different solvents demonstrated that Ac2O was an
irreplaceable choice for the coupling reaction of 1a and 2a, and the
efficiency of the reaction disappeared when the reaction was
performed in CH3CN, toluene, THF, DMSO, DMF and H2O (entries 6–
11, Table 1).
aReaction conditions: 1 (0.20 mmol), 2a (0.60 mmol), Ac2O (1.0 mL)
at room temperature under a N2 atmosphere for 24 h. bIsolated
yield.
benzene ring in the bromoalkynes 1, the desired phosphonoalkyne
products could be obtained with 81%, 84% and 64% yields,
respectively, and no obvious electronic effects of the substituent
were observed. Furthermore, ortho-substituted aromatic
bromoalkynes, such as 1-(bromoethynyl)-2-chlorobenzene (1q) and
1-(bromoethynyl)-2-bromobenzene (1r) proceeded well in the
reaction with 2a, providing the corresponding products 3qa and 3ra
in satisfactory yields, and no steric hindrance effect was found (3qa
vs 3ia and 3ja; 3ra vs 3ka and 3la). It should be noted that the
heterosubstituted bromoalkyne 2-(bromoethynyl)thiophene (1s)
reacted with 2a to produce the anticipated product 3sa in 67% yield.
When the scope of substrate 1 was switched to an aliphatic
substrate, e.g., 3-bromoprop-2-yn-1-yl benzene, no desired product
was detected. When the model reaction was carried out on a gram-
scale (4 mmol), a 70% yield of 3aa was obtained.
With the optimized conditions in our hands, the scope of the
coupling of bromoalkynes with diphenylphosphine oxide (2a) was
investigated. As shown in Scheme 2, all bromoalkynes (1a−1s) with
different substituents on the phenyl ring reacted smoothly with 2a
to give the corresponding products (3aa−3sa) in 64−92% yield. The
1-bromo-2-arylacetylenes (1) with an electron-rich group, such as
Subsequently, the range of substrates was expanded to a variety
of secondary phosphine oxides, and the detailed results are listed in
Scheme 3. For the diaryl substituted phosphine substrates 2,
whether symmetrical electron-donating or electron-withdrawing
groups were located on the aromatic rings, the couplings were
comparable to give the desired alkynyl(diaryl)phosphine oxides
(3ab−3ah) in 60%−80% yields. Using 2i, which contained a dimethyl
phenyl group, product 3ai was afforded in 76% yield. Substrates 2
n
t
CH3O, CH3, Pr, or Bu on the para- or meta-position of the phenyl
ring reacted with 2a to afford the desired products (3ba−3fa) in
77−90% yields. The reactions of 1 with a weaker electron-poor
group, including F, Cl or Br on the para- or meta-position of the
phenyl ring, generated the corresponding coupling products
(3ga−3la) in 70−86% yields. When a stronger electron-poor group,
e.g., CF3, CN or NO2, was located at the para-position of the
2
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Scheme 3 The scope of the secondary phosphine oxidesa,b
Scheme 5 Reaction of bromoalkynes, Ph2DPOCIl:a10n.d10A39c/OCN9OaBa,0b2750E
O
O
R2
R1
O
R1
R2
Ac2O
N2, rt, 24 h
Ph
Br
+
P
H
P
Ph
AcONa
+
Ph2PCl
+
Me
Cl
Ar
Br
P
Ar
(Ph)2
N2, rt, 24 h
Et2O
3
1
1a
3
2
Me
O
O
O
O
O
O
P
Ph2
P
Ph2
P
Ph2
P
P(
P
Ph
(4-MeC6H4)2
, 79%
Ph
4-FC6H4)2
Ph
Ph
Ph
(4-MeOC6H4)2
3ac
3ad
3ab
, 72%
, 70%
3ca
3ia
3da, 82%
3aa
, 75%
, 89%
O
Cl
O
O
O
O
O
tBu
PPh2
P
P
Ph
(3-MeOC6H4)2
(4-ClC6H4)2
P
Ph
(3-MeC6H4)2
PPh2
P
Ph2
3ag
, 69%
3ae
, 80%
3af
, 61%
3ja
, 84%
, 78%
3fa
,85%
O
O
O
O
O
P
Br
Ph2
P
O2N
Ph2
P
P
Ph
3aj
Ph
[3,5-(Me)2C6H3]2
P
(3-FC6H4)2
3oa
, 69%
3ai
3ka
, 76%
, 71%
3ah
, 64%
, 60%
Br
Cl
O
O
O
O
P
Ph2
P
P
Ph2
Ph
P
Ph
3qa
, 86%
3ra
, 77%
3al
, 0%
3ak
, 77%
aReaction conditions: 1 (0.20 mmol), Ph2PCl (0.6 mmol), AcONa (0.6
mmol), Et2O (2 mL) at room temperature under a N2 atmosphere
for 24 h. bIsolated yield.
aReaction conditions: 1a (0.20 mmol), 2 (0.60 mmol), Ac2O (1.0 mL)
at room temperature under a N2 atmosphere for 24 h. bIsolated
yield.
the phenyl ring could also be reacted with Ph2PCl to be converted
to the desired product in the presence of AcONa.
with unsymmetrical groups (one phenyl group and one aliphatic
group) were also investigated and found to be suitable for the
reaction, affording products 3aj and 3ak with 64% and 77% yields,
respectively. However, when both the R1 and R2 groups in substrate
were changed to an aliphatic group, for example, when
diethylphosphine oxide was involved in the reaction, the coupling
reaction was unworkable.
Based on the above mechanistic studies and previous reports, a
possible mechanism is proposed in Scheme 6. A secondary phos-
phine oxide reacts with Ac2O to generate intermediate A,9 which
can be converted to B via an equilibrium isomerization process.
Next, intermediate B was added to bromoalkyne 1a to give dipole
intermediate C, which was followed by an elimination reaction to
give intermediate D. Finally, D might lose an acetyl group in the
presence of Br– to afford the desired product 3aa and
concomitantly might generate acetyl bromide (MeCOBr). It should
be noted that the key important intermediate A would be formed
from the reaction of MeCOBr and 2a.11 To test this possibility,
randomly selected bromoalkyne were examined, and the results are
listed in Scheme 7. Bromoalkynes 1 containing different groups
could react with diphenylphosphine oxide 2a to afford the
corresponding products 3aa, 3da, 3ja−3la in good yield in the
presence of MeCOBr, while heptyl(phenyl)phosphine oxide 2k gave
the desired product 3ak in modest yield. Accordingly, the above
results in Scheme 7 provide a direct evidence to support this
possible pathway. On the other hand, intermediate D might also be
transformed into 3aa with the assistance of 2a and concomitantly
release intermediate B to further drive this coupling reaction.
However, we cannot be sure which is the main pathway that forms
the product.
2
From the obtained results in Table 1, Ac2O plays an indispensable
role during the formation of the coupling product. In addition, the
yield of 3aa improved with increasing amounts of Ac2O (see SI for
details), which confirmed the important role of Ac2O and promoted
us to speculate that the coupling reaction begins with the reaction
of the diarylphosphine oxide and Ac2O.9 Consequently, the control
experiments were conducted to elaborate the reaction clearly, as
depicted in Scheme 4. First, the above speculation was verified by a
previously reported work,10 and the reaction with equiv. amounts
of diarylphosphine oxide and Ac2O to give the trivalent phosphine
compound (Ph2PIIIOAc), which could be further reacted with 1a to
give the desired product 3aa (Scheme 4a). Moreover, the coupling
reaction could also be achieved via the reaction of equiv. amounts
of 1a, Ph2PCl and AcONa (Scheme 4b). Subsequently, Ph2PCl
aroused our interest, and we attempted to converted different bro-
moalkynes 1 to their corresponding coupling products in the pres-
ence of Ph2PCl and AcONa after quickly searching for the optimal
conditions, as shown in Scheme 5. The results of Scheme 5 showed
that a variety of bromoalkynes containing diverse substituents on
O
Ph2PV
O
2PV
A
III
Ac2O
P
Ph
Ph2 OAc
H
Ac
B
Ph
Br
2a
Ph
Br
O
1a
Br
P
Ph2 Cl
+
Et2O
1a
(a)
2a
P
Ph2 OAc
P
Ph
(Ph)2
O
reflux, 12 h
2a
Ph
N2, rt, 24 h
AcONa
V
Ph2
V
P
3aa
3aa
, 34%
V
P
P
Ph
(Ph)2OAc
Ph
(Ph)2OAc
3aa
Et2O
D
C
MeCOBr
(b)
Ph
Br
, 58%
P
AcONa
Ph2 Cl
+
+
N2, rt, 24 h
1a
Br
Scheme 4 Control experiments
Scheme 6 Proposed mechanism.
3
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7
8
W. Wu, H. Jiang, Acc. Chem. Res., 2014, 47, 2483.View Article Online
Recently, we used bromoalkynes to inDvOesI:ti1g0a.1t0e39th/Ce9OreBa0c2t7io50nEs
with arylamines and alcohols under visible-light irradiation: (
K. Ni, L.-G. Meng, K. Wang, L. Wang, Org. Lett., 2018, 20, 2245.
) K. Ni, L.-G. Meng, H. Ruan, L. Wang, Chem. Commun., 2019,
Scheme 7. Reaction of bromoalkynes, secondary phosphine oxides
and MeCOBra,b
a)
O
O
PV
2
PV
R R
MeCN
1
2
H
R1R2
Ar
Ar
Br
+
+
MeCOBr
(
b
N2, rt, 24 h
3
1
55, 8438.
R1 = R2 = C6H5
R1 = R2 = C6H5
R1 = R2 = C6H5
R1 = R2 = C6H5
R1 = R2 = C6H5
3aa
Ar = C6H5
, 82%
9
J. A. Miller, D. Stewart, J. Chem. Soc. Perkin 1, 1977, 1898.
3da
, 53%
3ja
, 75%
Ar = 3-MeC6H4
Ar = 3-ClC6H4
Ar = 4-BrC6H4
Ar = 3-BrC6H4
Ar = C6H5
10 E. Lindner, J. C. Wuhrmann, Chem. Ber., 1981, 114, 2272.
11 A. N. Pudovik, T. M. Sudakova, Dokl. Chem., 1970, 190, 144.
3ka
, 78%
3la
3ak
, 70%
, 40%
R1 = C6H5, R2
=
nC7H13
aReaction conditions: 1 (0.20 mmol), secondary phosphine oxide
(0.6 mmol), MeCOBr (0.60 mmol), MeCN (2.0 mL) at room
temperature under a N2 atmosphere for 24 h. bIsolated yield.
Conclusions
In conclusion, we have developed
a convenient synthetic
platform for the synthesis of alkynylphosphine oxides through the
direct cross-coupling of bromoalkynes with secondary phosphine
oxides without additive and harsh conditions. This facile and mild
reaction was carried out under mild conditions in Ac2O and
generated
a variety of alkynylphosphine oxides with good
functional group tolerance.
Conflicts of interest
The authors declare no competing financial interest.
Acknowledgements
We gratefully acknowledge the National Natural Science
Foundation of China (21772062, 21402061), the Scientific Research
Project of Anhui Provincial Education Department (KJ2015TD002)
and the Natural Science Foundation of Anhui (1708085MB45) for
financial support of this work.
Notes and references
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4
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