Facial conversion of secondary phosphine oxides R1R2P(O)H to chlorophosphines R1R2PCl by acetyl chloride

Article abstract of DOI:10.1016/j.tetlet.2019.151556

A practically useful protocol for the reductive transformation of secondary phosphine oxides R¹R²P(O)H to chlorophosphines R¹R²PCl using acetyl chloride was disclosed. Various secondary phosphine oxides could be readily reduced to the corresponding chlorophosphines in high yields under mild conditions.

Full text of DOI:10.1016/j.tetlet.2019.151556

Journal Pre-proofs
1
2
Facial conversion of secondary phosphine oxides R R P(O)H to chlorophos-
1
2
phines R R PCl by acetyl chloride
Jian-Qiu Zhang, Shangdong Yang, Li-Biao Han
PII:
S0040-4039(19)31355-3
DOI:
https://doi.org/10.1016/j.tetlet.2019.151556
TETL 151556
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
14 November 2019
16 December 2019
19 December 2019
Please cite this article as: Zhang, J-Q., Yang, S., Han, L-B., Facial conversion of secondary phosphine oxides
1
2
1
2
R R P(O)H to chlorophosphines R R PCl by acetyl chloride, Tetrahedron Letters (2019), doi: https://doi.org/
0.1016/j.tetlet.2019.151556
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Facial conversion of secondary phosphine
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1
2
oxides R R P(O)H to chlorophosphines
1
2
R R PCl by acetyl chloride
Jian-Qiu Zhang, Shangdong Yang, and Li-Biao Han
AcCl
O
AcOH
1
1
R P H
R P Cl
o
THF, 25- 50 C
R2
R2
1
2
R , R = aryl, alkyl

1
Tetrahedron Letters
journal homepage: www.elsevier.com
1
2
Facial conversion of secondary phosphine oxides R R P(O)H to
1
2
chlorophosphines R R PCl by acetyl chloride
a,b
c
a,b*
Jian-Qiu Zhang, Shangdong Yang, and Li-Biao Han
a
National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki 305-8568, Japan
b
Division of Chemistry, Faculty of Pure and Applied Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8571, Japan
College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China
c
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A practically useful protocol for the reductive transformation of secondary phosphine oxides
1
2
1
2
R R P(O)H to chlorophosphines R R PCl using acetyl chloride was disclosed. Various
secondary phosphine oxides could be readily reduced to the corresponding chlorophosphines in
high yields under mild conditions.
Available online
2
009 Elsevier Ltd. All rights reserved.
Keywords:
Chlorophosphines
Secondary phosphine oxides
Reductive conversion
Acyl chloride
4
e,f
Introduction
afford Ph PCl. However, heating at a very high temperature is
2
required for this transformation. In addition, the preparation of
Chlorophosphines are key starting materials for the synthesis
of trivalent phosphines, that have broad applications in organic
synthesis as reagents and in metal-catalysis as ligands. For
example, alkylation of chlorophosphines with organolithium or
Grignard reagents was a general method for the preparation of a
PhPCl
2
also suffers from the same problems as mentioned for
Ph PCl. Because of the rather severe conditions required for this
2
disproportionation reaction, this method cannot be readily
adopted in the laboratory synthesis.
1
Known method
series of monodentate and bidentate phosphine ligands. On the
O
R1 Cl
other hand, the corresponding phosphinoamine and phosphinites
can also be easily obtained by the nucleophilic substitution
1) R1
P
HOPCl2 PCl3 used as solvent
(
P
R2
H
+ PCl3
+
R2
Moderate yields
2
3
reactions of chlorophosphines with amines and alcohols.
Moreover, chlorophosphines can be also converted to the
59-80 % yield
This work
1
2
corresponding alkali metal phosphides R R PM, and subsequent
substitution reactions with organic halides can generate a wide
R1 Cl
O
2
equivalents MeC(O)Cl
P
1
+
AcOH
(2)
R
P
R2
H
+
AcCl
AcOH the only byproduct
High yield, easy purification
1
c
THF
R2
range of tertiary phosphines.
up to 99% yield
Among the chlorophosphines, perhaps diphenylphosphine
Scheme 1. Preparation of chlorophosphines from secondary
phosphine oxides.
chloride Ph PCl is one of the most frequently employed reagent
for introducing a diphenylphosphino Ph P functionality to a
molecular frame to generate the corresponding phosphine ligands.
Industrially, Ph PCl is produced from benzene and PCl in the
presence of an equivalent of AlCl under heating. However, this
process is inefficient because the generation of Ph PCl is
accompanied by the formation of a lot of wastes such as HCl,
2
2
Unlike tertiary phsophines R
air, secondary phosphine oxides R
3
P that are easily oxidized under
P(O)H can be easily handled
2
3
2
4
3
under air without the need to pay attention to oxygen and
moisture. Moreover, they are relatively easily prepared
2
5
chemicals. In particular, we very recently reported that
4
a-d
AlCl
3
and a reagent used for deliberating Ph
2
PCl from AlCl
3
.
Disproportionation reactions of PhPCl
2
with ZnCl
2
or Ph P also
3

Corresponding author. Tel.: +81-29-861-4855; fax: +81-29-861-6344; e-mail: libiao-han@aist.go.jp

2
aReaction conditions: under argon atmosphere, Ph
P(O)H 1a (0.05 mmol)
2
Ph
2
P(O)H could be easily prepared from the so far deposited
5
d
was dissolved in 0.5 mL solvent in an NMR tube. RC(O)Cl was added and
the mixture was heated overnight at the temperature indicated. Yield refers to
P NMR yield based on 1a used (Mes: 1,3,5-trimethylphenyl). The yields in
chemical waste Ph
3
P(O) at room temperature.
3
1
b
In this sense, using R
preparation should be a convenient alternative laboratory method.
Quin et al. reported that secondary phosphine oxides R P(O)H
could be converted into R PCl using PCl as the chlorination
reagent, which has been widely used in the preparation of
phosphine ligands. However, this method has drawbacks such as
2
P(O)H as the substrate for R PCl
2
o
parenthesis were obtained at 50 C.
2
reactivity of other acyl chlorides (Table1, runs 8–10), and found
that the simplest acetyl chloride showed highest reactivity for this
reductive chlorination reaction (Table1, run 10). The effect of
solvent was also investigated (Table1, runs 11–13). Solvents like
2
3
6
7
the requirement of a large excess amount of PCl
to P(O)H) and the difficult purification of the products (Scheme 1
1)).
3
(10 equivalents
1
,4-dioxane and toluene could also be used in this transformation.
Dichloromethane gave 77% yield of the product under similar
conditions (Table1, run 13). To avoid potential safety problems at
high temperatures, we then tried to conduct the above reaction
again under mild conditions. To our surprise, such a reductive
transformation smoothly proceeded even at room temperature by
using acetyl chloride AcCl (Table1, runs 14–15). The reaction
could also take place smoothly with less loadings of acetyl
chloride (Table1, runs 16-18) under room temperature. However,
in order to obtain a high yield (over 90%) of the desired product
(
During our studies on the reactivity of secondary phosphine
oxides, we accidently found that Ph PCl could be quantitatively
generated by simply treating Ph P(O)H with MesC(O)Cl (Mes:
,4,6-trimethylphenyl). Eventually, we realized that, instead of
2
2
2
the expensive MesC(O)Cl, the cheap and readily accessible
acetyl chloride AcCl was an efficient reagent for this
transformation. Herein, we disclose a facial transformation of
1
2
2
Ph PCl, the use of a slightly higher temperature 50 °C was
secondary phosphine oxides R R P(O)H to chlorophoshpines
1
2
preferred. Therefore, after the above comprehensive evaluation
on the reaction conditions, the reaction conditions by using THF
as solvent and 2.0 equivalents of acetyl chloride were chosen as
the optimized parameters for this reaction.
R R PCl by using acetyl chloride as the reductive chlorination
reagent (Scheme 1 (2)). Compared to the literature method using
3
PCl , this method using acetyl chloride AcCl possesses
advantages such as low toxicity, corrosiveness and less amounts
of the chlorination reagents as well as easy purification and high
yield of the products.
As shown in Table 2, to explore its generality, a variety of
representative secondary phosphine oxides (SPOs) were used as
Results and discussion
Table 2. Ready conversion of secondary phosphine oxides by acetyl
chloride to chlorophosphines.
a
Initially, a mixture of diphenylphosphine oxide 1a (0.05
mmol) and mesityl chloride (0.06 mmol) in THF (0.5 mL) in a
sealed NMR tube was heated at 100 °C overnight. As indicated
O
AcCl
R1
P
R2
Cl
R1
P
R2
H
o
THF, 25 C, overnight
3
1
by P NMR spectroscopy, a new signal at 82.8 ppm assignable
to Ph PCl was observed and 85% yield of Ph PCl was generated
Table1, run 1). Under similar conditions, when we increased the
amount of mesityl chloride to 0.1 mmol (2.0 equivalents to 1a)
Table1, runs 2 and 3), Ph PCl was obtained in 94% yield. At low
1
2
2
2
1
2
1 2
(
Run
1
R R P(O)H (1)
R R PCl (2)
Yield
93%
O
P
H
P
Cl
(
2
temperatures, however, only low yields of the product were
obtained (Table1, runs 4–7). Then we decided to investigate the
1
a
2a
Table 1. Reaction condition optimizationa
O
P
2
MeO
H MeO
P
Cl
87%
O
RC(O)Cl
Ph
P
H
Ph
P
Cl
overnight
Ph
Ph
OMe
OMe
2b
1a
2a
1
b
O
P
RC(O)Cl
Run
R
Solvent
Tempt./°C
Yield/%
3b
CF3
H
CF3
P
Cl
96%
(equiv.)
1
2
3
4
5
6
7
8
9
Mes
Mes
Mes
Mes
Mes
Mes
Mes
Ph
1.2
THF
THF
100
100
100
80
85
87
1.6
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
1.5
1.2
1.0
CF3
CF3
2c
THF
94
1
c
THF
73
O
P
THF
70
48
H
P
Cl
94%
98%
4
THF
60
30
THF
50
8
1
d
2d
THF
100
100
100
100
100
100
25
25
iPr
THF
90
O
P
5c
1
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
8
Me
Me
Me
Me
Me
Me
Me
Me
Me
THF
97
H
H
P Cl
Ph
Ph
Dioxane
Toluene
99
1
e
2e
92
O
P
n
n
2 2
CH Cl
77
0%d
6
Oct
Oct
P
Cl
7
n
n
Oct
Oct
Dioxane
THF
THF
95
2
f 1) nBuMgCl
25
95
1f
2
) H2O2
82(95)b
81(94)b
66(92)b
O
25
n
Oct
P
Bun
6%e
6
n
THF
25
Oct
3f
THF
25

3
a
1
2
Reaction conditions: under argon atmosphere, R R P(O)H 1 (1.0 mmol) was
O
P
AcCl (10 mmol)
vacuum ( 100 Pa)
dissolved in 2.0 mL THF, and then MeC(O)Cl (2.0 mmol) was added to the
solution. The mixture was stirred at room temperature overnight, and volatiles
Ph
H
Ph PCl
2
THF (10 mL)
Ph
b
o
c
were removed under vacuum. Yields were based on 1 used. 50 C.
diastereomeric pure (-)menthylphenylphosphine oxide R( )-1e was used. 1
hour. 2e obtained as a 74/26 mixture of diastereomers (SI). 0°C, 1 h.
A
o
2
5 C, overnight
5 mmol
1.01 g
1
.05 g (4.77 mmol)
P
d
95 % yield
e
n
2 2
Treating 2f with BuMgCl and then H O .
2 2
Scheme 3. Gram-scale preparation of Ph PCl from Ph P(O)H and
AcCl.
the reagents for this transformation. Both aromatic and aliphatic
SPOs were all readily reduced to the corresponding phosphine
chlorides with excellent yields under similar reactions. For
example, in addition to Ph
SPOs bearing an electron-denoting group (p-MeO-C
6 4 2
b and an electron-withdrawing group (p-CF -C H )
all were reduced to the corresponding phosphine chlorides in
high yields (Table 2, runs 2–3). The conversion of an
alkylarylphosphine oxide like Pht-BuP(O)H 1d also could
proceed smoothly to produce the corresponding P-Cl products in
a nearly quantitative yield (Table 2, run 4). Similarly, a chiral
2
P(O)H 1a (Table 2, run 1), aromatic
P(O)H
P(O)H 1c,
Conclusions
6
4 2
H )
1
3
In summary, we have developed a convenient method for the
synthesis of chlorophosphines from secondary phosphine oxides
and acetyl chloride under mild conditions. After the reaction, a
simple removal of the volatiles under vacuum affords the target
3
1
1
2
R PCl in spectroscopically pure form as confirmed by P and H
NMR spectroscopies. Various secondary phosphine oxides,
diarylphosphine oxides, alkyl(aryl)phosphine oxides and
dialkylphosphine oxides, all could be used as the substrates, and
were reduced readily to the corresponding phosphine chlorides in
high yields.
P
(R )-(-)menthylphenylphosphine oxide 1e could also efficiently
produce the corresponding chlorophosphine 2e as a mixture of
diastereomers (run 5) (SI ref. 10). Moreover, dioctyl phosphine
oxide n-Oct
2
P(O)H also reacted with MeC(O)Cl quickly to give
PCl,
n-Oct PCl (Table1, run 6). Since the high reactivity of n-Oct
2
2
the confirmation of its formation was carried out by quenching
the reaction mixture using n-BuMgCl, following oxidation with
hydrogen peroxide to produce the corresponding stable
butyldioctylphosphine oxide 2f (66% isolated yield). However,
Acknowledgments
L.-B.H. thanks a visiting professorship from Lanzhou
University.
2
diethyl phosphite (EtO) P(O)H and ethyl phenylphosphinate
Ph(EtO)P(O)H sluggishly reacted with AcCl even at a high
temperature (120 C).
o
Supplementary Material
Although treating Ph
AcCl in THF all can lead to the formation of Ph
the reaction with AcCl is cleaner than that of PCl
2
P(O)H with 2 equivalents of PCl
PCl (Scheme 2),
which is
3
and
Supplementary data was associated with this article.
2
3
References and notes
accompanied by the formation of a few phosphorus by-products.
In addition, AcOH generated using AcCl, if necessary, can be
easily pumped off from the chlorophosphines under vacuum to
give highly pure chlorophosphines (Scheme 1 (2)).
1
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4
Ph
2
P(O)H with PCl
3
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371.
8
.
A bulb to bulb distillation of the resulted pale yellow oil (160
o
C, 160 Pa) gave pure Ph
0.77 g, 3.50 mmol).
2
PCl as a colorless oil in 70% yield
(