Metal-free synthesis of chlorinated and brominated phosphinoyl 1,3-butadiene derivatives and its synthetic applications

Article abstract of DOI:10.1016/j.tetlet.2015.10.029

We report here an efficient and transition-metal free strategy for the synthesis of chlorinated and brominated phosphinoyl 1,3-butadienes and derivatives. Pre-prepared HCl/HBr solutions enabled the in situ rearrangement of phosphinoyl-α-allenic alcohols to conjugated vinyl cations, which afforded various novel polysubstituted phosphinoyl 1,3-butadienes in medium to excellent yields. The resulting products could be converted into multi-functionalized allylphosphine oxides; moreover, their couplings with electron-deficient arylboronic acid provided an efficient approach to synthesize electron-deficient phosphinoyl 1,3-butadienes.

Full text of DOI:10.1016/j.tetlet.2015.10.029

Tetrahedron Letters 56 (2015) 6508–6512
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Metal-free synthesis of chlorinated and brominated phosphinoyl
1,3-butadiene derivatives and its synthetic applications
⇑
Teng Liu, Yun-Tao Xia, Jie Zhu, Ai-Min Lu, Lei Wu
Jiangsu Key Laboratory of Pesticide Science and Department of Chemistry, College of Sciences, Nanjing Agricultural University, Nanjing 210095, China
a r t i c l e i n f o
a b s t r a c t
Article history:
We report here an efficient and transition-metal free strategy for the synthesis of chlorinated and bromi-
nated phosphinoyl 1,3-butadienes and derivatives. Pre-prepared HCl/HBr solutions enabled the in situ
rearrangement of phosphinoyl-a-allenic alcohols to conjugated vinyl cations, which afforded various
novel polysubstituted phosphinoyl 1,3-butadienes in medium to excellent yields. The resulting products
could be converted into multi-functionalized allylphosphine oxides; moreover, their couplings with elec-
tron-deficient arylboronic acid provided an efficient approach to synthesize electron-deficient phosphi-
noyl 1,3-butadienes.
Received 6 September 2015
Revised 5 October 2015
Accepted 7 October 2015
Available online 8 October 2015
Keywords:
Chlorinated phosphinoyl 1,3-butadiene
Brominated phosphinoyl 1,3-butadiene
Metal-free
Ó 2015 Elsevier Ltd. All rights reserved.
Allenic alcohols
Allylphosphine oxide
Introduction
a nucleophilic substitution with preformed 1,3-butadienylphos-
phonic dichloride.8 These methods incur obnoxious odor and also
Organophosphorus compounds, particularly those possessing
reactive functionalities, are versatile building blocks for varieties
of transformations in catalysis, biochemistry, materials chemistry
and organic synthesis.1 Primarily, from the synthetic point of view,
suffer from complicated and trivial substrate preparations. More-
over, preparation of multisubstituted phosphinoyl 1,3-dienes is
especially challengeable. Alternatively, transition-metal catalysis
for the synthesis of phosphinoyl 1,3-dienes and their derivatives
were commonly developed during the past decade, among which
addition of R2P(O)H to alkynes through oxidative addition of tran-
sition metals to P-H bonds has been recognized as the most
promising and atom-economical process. In 2005, Han et al.
reported the nickel-catalyzed generation of phosphinoyl 1,3-buta-
dienes, consisting of the metal catalyzed addition of diphenylphos-
phine oxide and related P(O)H compounds to propargyl alcohols
followed by an acid-catalyzed dehydration.9 Takaiki and co-work-
ers prepared dipenylphosphinyl-dienes via a one-pot process con-
taining dimerization, hydrophosphination and oxidative work-up.
Enynes were first generated through Ytterbium-catalyzed dimer-
ization of terminal alkynes, after which hydrophosphination with
Ph2PH was carried out to give phosphinoyl-1,3-dienes as target
compound after oxidative work-up.10 Very recently, our group
revealed the first palladium-catalyzed Suzuki–Miyaura couplings
of aryl ether functionalized allenylphosphine oxides with aryl-
boronic acids to generate phosphinoyl 1,3-butadienes and deriva-
tives.11 More interestingly, changing the substrates into allenic
alcohols enabled the atom-economical preparation smoothly ‘on
water’ without any additives.12 However, those catalytic methods
are associated with one or more limitations such as expensive,
a,b-unsaturated phosphorous compounds is so appealing to syn-
thetic researchers because they can be useful synthons for the
preparation of biologically active compounds. As representative
functionalized organophosphorus compounds, phosphinoyl 1,3-
butadienes are widely used intermediates in organic reactions,
including Michael addition with nucleophiles to afford allylic phos-
phonates,2 Diels–Alder reaction with dienophiles to form
cycloadducts,3 cycloaddition with enamines to give cyclohexadi-
enylphosphonates,4 addition with aldehydes to yield vinyl allenes,5
polymerization to phosphine-functionalized copolymers etc.6
However, the methods to generate phosphinoyl 1,3-butadienes
are still underdeveloped comparing with the blooming of 1,3-
dienes.7
The conventional methods for synthesizing phosphinoyl 1,3-di-
enes involve the reaction of P(OEt)3 with 1,4-dichloro-2-butene, or
⇑
Corresponding author. Tel./fax: +86 25 84396716.
E-mail address: rickywu@njau.edu.cn (L. Wu).
http://dx.doi.org/10.1016/j.tetlet.2015.10.029
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

T. Liu et al. / Tetrahedron Letters 56 (2015) 6508–6512
6509
toxic or metallic catalysts, air-sensitive reagents, low regioselectiv-
ity, long reaction time, elevated temperatures, and so on. Thus, the
potential development of such chemical synthesis in a metal-free
manner with higher selectivity/efficiency and easier operations is
in a great demand. In continuation of our work on the synthesis
and application of organophosphorus chemistry,13 we report
herein an efficient and transition-metal free strategy for the syn-
thesis of chlorinated and brominated phosphinoyl 1,3-butadienes
and its applications (Scheme 1).14
widely accepted as ideal combinations to generate HCl, and in situ
generation of HCl from NaCl/conc.H2SO4 gave negative results as
well. Encouraged by these initial results, we were curious to investi-
gate the solvent effects on this reaction. To improve the yield, vari-
eties of pre-prepared hydrogen chloride solutions were applied,
and the results are listed in Table 1. Hydrogen chloride in common
aprotic solvents including dichloromethane, ethyl acetate, THF,
ether and acetone facilitated the reactions with medium to good
yields (entries 4–8), among which ethyl ether as solvent gave the
best result of 80% isolated yield within 20 h. Interestingly, hydrogen
chloride from 37% concentrated HCl solution worked as well (entry
12), albeit with a little lower yield, which provided a convenient pro-
cedure for scale-up preparations. In all the cases of protic solvents
(entries9–11), thesubstrates remainedintact, evenwithhighercon-
centration of hydrogen chloride or extended reaction time.
Results and discussion
Thephosphinoyl-a-allenicalcohols(1a–1h)werereadily synthe-
sized according to our reported procedures.12 When 3-cyclohexyli-
dene-2-(diphenylphosphine oxide) prop-2-en-1-ol (1a) was
treated with in situ generated hydrogen chloride in acetyl chlo-
ride/dichloromethane (technical grade) solution for 5 h, (1-chloro-
1-cyclo-hexylideneprop-2-en-2-yl)diphenylphosphine oxide (3a)
was isolated in 37% yield (entry 1). No product was observed in
acetyl chloride/methanol solution, although AcCl/MeOH has been
With optimized reaction conditions in hand (Table 1, entry 7),
several substituted phosphinoyl-a-allenic alcohols were applied
to investigate the substrate scopes, and the results are summarized
in Table 2. To be noted, when we utilized various substituted
phosphinoyl-
a-allenic alcohols, most of the substrates except 1a
exhibited poor solubility in HCl/ethyl ether solution. The reactions
Previous work:
a. Nickel and Ytterbium catalysis (terminal alkynes)
R
Ph2
O
P
Cat. Ni(0)/Ph2P(O)H
HO
+
R
P
O
R
+
Ph2P(O)H
Ph2
-H2O
anti-Markovnikov
Markovnikov
(Org. Lett. 2005, 7, 2909-2911.)
R
i) 5 mol% Y[N(SiMe3)2]3, 5 mol% 4-ClC6H4NH2
PhMe, 100 oC
R
R
Ph2P
O
ii) HPPh2, 15 mol% HMPA;
iii) 30% H2O2
(J. Org. Chem. 2005, 70, 7260-7266.)
b. Palladium-catalysis (phosphinoyl allenes)
R3 R4
R3
R4
OAr
+
Ph2
5 mol% Pd(PPh3)2Cl2
K2CO3, THF, reflux
P
Ar'B(OH)2
Ar'
O
O
Ph2P
(J. Org. Chem. 2015, 80, 673-680.)
R1 R2
Ph2
R1
R2
OH
5 mol% Pd(PPh3)2Cl2
B(OH)2
P
R3
O
R3
+
O
Ph2P
Water, reflux
(RSC Advances 2014, 4, 61722-61726.)
c. This work
R1 R2
R1
OH
Ph2
HX (X=Cl, Br)
P
X
O
R2
O
Ph2P
ethyl acetate, r.t.
Scheme 1. (a) Synthesis of phosphinoyl 1,3-butadienes from terminal alkynes catalyzed by Nickel or Ytterbium; (b) synthesis of phosphinoyl 1,3-butadienes from
phosphinoyl allenes catalyzed by palladium; (c) this work.

6510
T. Liu et al. / Tetrahedron Letters 56 (2015) 6508–6512
Table 1
Reaction condition optimizations: hydrogen chloride sourcesa
OH
Ph2
P
Solvent, r.t.
[HCl]
+
Cl
O
O
Ph2P
1a
2a
3a
Entry
HCl Source
Solvent
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
AcCl
AcCl
CH2Cl2
MeOH
CH2Cl2
CH2Cl2
Ethyl acetate
THF
Ethyl ether
Acetone
MeOH
5
20
20
20
20
20
20
20
20
20
20
20
37
0
0
49
75
73
80
50
0
NaCl/conc.H2SO4
HClc
HClc
HClc
HClc
HClc
9
HClc
10
11
12
HClc
EtOH
i-PrOH
Ethyl acetate
0
0
71
HClc
HCld
a
b
c
1.5 mmol phosphinoyl-a-allenic alcohol, 3 mmol hydrogen chloride source, 20 h.
Isolated yield based on allenes.
Pre-prepared solution.
37% HCl solution.
d
Table 2
Substrate scopes of substituted phosphinoyl-a
-allenic alcoholsa
Ph2
P
R1
OH
O
R1
X
R2
X
R1
R2
O
Ph2
P
O
R2
+
HX (in Ethyl Acetate)
R2
1a-1h
R1
Ph2P
+
+
Ph2P
O
X
R1
O
3
4
5
Entry
R2
HX
Yield of 3, 4, 5b
1
2
3
4
5
6
7
8
–C5H10– (1a)
–C5H10– (1a)
CH3
HCl
HBr
HCl
HBr
HCl
HBr
HCl
HBr
HCl
HBr
HCl
HCl
HBr
HCl
HBr
75(3a,80c):0:0
92(3b):0:0
23(3c):0:0
39(3d):0:0
84(3e):0:0
34(3f):0:0
83(3g):0:0
55(3h):0:0
70(3i):0:0
48(3j):0:0
55(3k):0:0
0:75(4a):0
0:42(4b):0
0:0:58(5a)
0:0:51(5b)
CH3 (1b)
CH3 (1b)
CH3 (1c)
CH3 (1c)
H (1d)
CH3
p-CF3C6H4
p-CF3C6H4
CH3CH2
CH3CH2
CH3CH2
CH3CH2
H
p-MeOC6H4
p-MeOC6H4
Ph
H (1d)
9
p-ClC6H4 (1e)
p-ClC6H4 (1e)
H (1f)
H (1g)
H (1g)
10
11
12
13
14
15
Ph (1h)
Ph (1h)
Ph
a
b
c
1.5 mmol phosphinoyl-a-allenic alcohol, 3 mmol pre-prepared HCl or HBr solution, 20 h.
Isolated yield based on allenes.
Isolated yield in ether based on allenes.
ceased under such heterogeneous manner, thus, ethyl acetate was
used as solvent for substrates 1b–1h instead of ethyl ether. The
addition of ClÀ or BrÀ smoothly proceeded with good to excellent
yields to produce a variety of chlorinated and brominated phosphi-
noyl 1,3-butadienes.15 Both alkyl substitutions and electron-defi-
cient groups in the allenic alcohols have efficiently worked in
this synthesis. In particular, even sterically hindered substrates
afforded good to excellent yields (entries 5, 6, 9 and 10). To the best
of our knowledge, this is the first synthesis of multi-substituted
chlorinated and brominated phosphinoyl 1,3-butadienes. Notably,
for substrates with strong electron-donation or high conjugation
groups (entries 12–15), the products changed via different inter-
mediates to give compounds 4 or 5, respectively.16
To confirm the significance of this methodology, the application
of resulting product phosphinoyl 1,3-butadiene derivatives was
further studied. Take (1-bromo-1-cyclohexylideneprop-2-en-2-yl)

T. Liu et al. / Tetrahedron Letters 56 (2015) 6508–6512
6511
O
O
Ph2P
Ph2P
O
m-CPBA
a)
b)
CH2Cl2, r.t.
Br
Br
3b
6, 46 %
O
Ph2P
B(OH)2
5 mol% Pd(PPh3)2Cl2
K2CO3, THF, reflux
+
Ph2P
NO2
F
Cl
O
NO2
1f
7, 39%
8, 45%
9, 60%
O
Ph2P
B(OH)2
B(OH)2
5 mol% Pd(PPh3)2Cl2
K2CO3, THF, reflux
+
Ph2P
O
F
Cl
1f
O
Ph2P
Br
5 mol% Pd(PPh3)2Cl2
K2CO3, THF, reflux
+
Ph2P
O
Br
Cl
1f
Scheme 2. Transformation of products.
diphenylphosphine oxide (3b) as an example, multi-functionalized
allylphosphine oxides (6) could be easily obtained in 46% yield
(Scheme 2a) through the oxidation of 3b. With m-CPBA as oxidant,
the epoxidation process proceeded exclusively on internal double
bond and the region-selectivity remained even with excess oxida-
tion reagent or higher reaction temperature. In addition, the cou-
plings of chlorinated phosphinoyl 1,3-butadienes with
nucleophiles were also investigated. In the presence of 5 mol %
Pd(PPh3)2Cl2, arylboronic acids bearing electron-deficient groups
attacked 1f to give corresponding arylated phosphinoyl 1,3-butadi-
enes (7, 8, 9) with 39%, 45%, and 60% yields, respectively
(Scheme 2b). It is worthy to mention that our previous couplings
of arylboronic acids bearing electron-deficient groups with phos-
Acknowledgements
The authors thank the Foundation Research Project of Jiangsu
Province (The Natural Science Foundation No. BK20141359), ‘333
High Level Talent Project’ and ‘QinLan Project’ of JiangSu Province
for financial support.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.10.
029.
phinoyl-a
-allenic alcohols didn’t work well,12 where the yields as
References and notes
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1,3-butadienes reacted smoothly with higher yields to afford ary-
lated phosphinoyl 1,3-butadienes, which provide a more efficient
approach to synthesis of electron-deficient phosphinoyl 1,3-
butadienes.
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Conclusion
We have revealed an efficient and transition-metal free strategy
for the synthesis of chlorinated and brominated phosphinoyl 1,3-
butadienes and their derivatives. The pre-prepared HCl/HBr solu-
tions in ether or ethyl acetate enabled the in situ formation of vinyl
cation, which afforded various novel polysubstituted phosphinoyl
1,3-butadienes in medium to excellent yields. The resulting prod-
ucts could be easily transformed into multi-functionalized
allylphosphine oxides; moreover, their smooth couplings with
electron-deficient arylboronic acids provided an alternative
approach to synthesize electron-deficient phosphinoyl 1,3-butadi-
enes. Designing and exploring the new applications of chlorinated
and brominated phosphinoyl 1,3-butadienes are underway in our
laboratory.
9. Han, L.-B.; Ono, Y.; Yazawa, H. Org. Lett. 2005, 7, 2909–2911.
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Takaki, K. Tetrahedron 2006, 62, 2511–2519.
11. Chen, Y.-Z.; Zhang, L.; Lu, A.-M.; Yang, F.; Wu, L. J. Org. Chem. 2015, 80,
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6512
T. Liu et al. / Tetrahedron Letters 56 (2015) 6508–6512
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15. Fluorination of substrates with pyridine-HF or KF was found to be sluggish.
16. From the point of reaction mechanism, substrates 1d and 1g might undergo the
following pathways to afford different products (compounds 4 or 5):
Ph2
P
O
R1, R2 = p-MeOC6H4, H
O
X
H
R1
R2
HX
HO
Ph2P
R1
R2
OMe
4
O
Ph2P
X
Cyclization Product
O
3
HX
X
H2O
Ph2P
R1
R2
R1
-H2O
Ph2P
R1
Ph2P
R2
2
O
R
O
O
R1, R2 =Ph, Ph
X
X
Ph2P
O
5