Direct C-OH/P(O)-H dehydration coupling forming phosphine oxides

Article abstract of DOI:10.1039/c8ob01299g

A t-BuONa-mediated C-OH/P(O)-H cross dehydration coupling to produce alkylphosphine oxides is developed. This reaction employed readily available alcohols and P(O)-H compounds as the starting materials, providing an efficient alternative method for constructing sp³ C-P bonds. A reasonable reaction path involving dehydration and subsequent regio-selective hydrophosphorylation of the resulting alkenes was proposed.

Full text of DOI:10.1039/c8ob01299g

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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Direct C-OH/P(O)-H Dehydration Coupling Forming Phosphine
Oxides
Long Chen,a Yueyue Zhu,a Tieqiao Chen,*a,b Long Liu,b Ji-Shu Zhanga and Li-Biao Han*c
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A t-BuONa-mediated C-OH/P(O)-H cross dehydration coupling to that then gave the phosphorus compounds.8 Herein we
produce alkylphosphine oxides is developed. This reaction disclose a direct conversion of alcohols to phosphine oxides by,
employed the readily available alcohols and P(O)-H compounds as formally, dehydration of the alcohol with a H-phosphine oxide
the starting materials, providing an efficient alternative method losing water (Scheme 1).
for constructing sp3C-P bonds.
involving dehydration and
A
reasonable reaction path
The transformation of a halide to a phosphorus compound
R'2P(OR''), R'2P(O)H, R'2POLi etc
subsequent regio-selective
hydrophosphorylation of the resulting alkenes was proposed.
R
X
R
P(O)R'2
Nucleophilic substitution,
Michaelis-Arbusov reaction etc
Organophosphorus compounds play an important role in
medicinal chemistry, agro-chemistry, biological chemistry and
material chemistry.1 The development of efficient methods for
their preparation is of current concern.2-5 The transformation
of a halide RX to a phosphoryl compound RP(O)Z2 (conversion
of C-X bond to C-P(O) bond) is a traditional way for the
preparation of organophosphorus compounds, that is widely
The transformation of an alcohol to a phosphorus compound
Indirectly
OH
R
R
R
X
R
R
OTs (OTf)
OC(O)R
P(O)R'2
.
c
t
e
I2
n
Z
(R'O)3P
,
e
d
R
OP(OR')2
i
l
a
h
used in both laboratory and industry 2,4,5a-5c
.
However, some of
Directly This work: direct conversion of alcohol
base
halides can heavily damage the environment.
OH
H
R
+
R
R'2P(O)
P(O)R'2
- H2O
Formally a cross-dehydration coupling
Compared with the conversion of a halide to a phosphorus
compound, the conversion of an alcohol to a phosphorus
compound is apparently more attractive. Alcohols are
abundant in nature and are readily available chemical raw
materials from the industry.6 They are environmentally benign
because of the low toxicity. In addition, since a lot of halides
are prepared by the transformation of alcohols, the direct
preparation of a phosphorus compound from an alcohol, can
also substantially shorten the synthetic paths. However, to our
knowledge, a direct conversion of simple ROH to RP(O)R’2 has
not been realized (Scheme 1).7 Thus, an alcohol was usually
first transformed to a halide, tosylate, ester, phosphate etc.
Scheme 1 Methods for constructing C-P bonds.
We accidently found this reaction during our study on the
dehydrogenative coupling of alcohols with H-phosphine oxides
catalysed by iron.9 We noted that occasionally a trace amount
of a phosphine oxide such as 3a could be detected. Therefore,
we decided to make a detailed study on this phenomenon. We
initiated the work by investigating the reactivity of phenethyl
alcohol 1a with diphenyl phosphine oxide 2a and the results
were summarised in Table 1. It was found that a trace amount
of 3a was produced by refluxing the mixture of phenethyl
alcohol and diphenylphosphine oxide in toluene overnight in
the presence of 10 mol% t-BuONa (Table 1, entry 1). By
employing more t-BuONa, the yield of 3a could be improved to
43% (Table 1, entries 2 and 3). t-BuOK could also mediate this
dehydration coupling (Table 1, entry 4). However, the reaction
proceeded sluggishly or no reaction took place with other
bases such as t-BuOLi, NaOH, Cs2CO3, Na2CO3 and NaOAc
(Table 1, entries 5-9). This transformation could also take place
in other solvents, and DMAc (N,N-dimethyl acetamide) seems
to be the best choice (Table 1, entries 10-16). The loading of
a State Key Laboratory of Chemo/Biosensing and Chemometrics, College of
Chemistry and Chemical Engineering, Hunan University, Changsha 410082, China.
b Key Laboratory of Ministry of Education for Advanced Materials in Tropical Island
Resources, College of Materials and Chemical Engineering, Hainan University,
Haikou, 570228, China.
c National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba,
Ibaraki 305-8565, Japan
E-mail: chentieqiao@hnu.edu.cn; libiao-han@aist.go.jp
Electronic Supplementary Information (ESI) available: General information,
experimental procedures, copies of 1H, 31P and 13C NMR spectra for products. See
DOI: 10.1039/b000000x/
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Table 2 Direct dehydration coupling between alcohols and P(O)-H compounds forming
C-P bonds.a
phenethyl alcohol was also investigated. With an addition of
0.4 mmol 1a, 3a was produced in 70% yield, whereas 81% yield
of 3a was obtained by using 0.5 mmol 1a under similar
reaction conditions (Table 1, entries 17 and 18). Elevating the
reaction temperature did not enhance the product yield;
base
- H2O
H
R
R
OH
P(O)R'2
P(O)R'2
+
1
2
3
Entry
Alcohols
CH2CH2OH
1a, R = 4-H
P(O)-H
Products
CH2CH2P(O)Ph2
however when the reaction was conducted at
a low
temperature (100 oC), only 56% yield of 3a was generated
Ph2P(O)H
R
R
(Table 1, entries 19 and 20).
2a
1
2
3
4
5
6
3a, R = 4-H, 80%
3b, R = 4-Me, 73%
3c, R = 4-OMe, 70%
3d, R = 4-F, 59%
3e, R = 4-Cl, 89%
3f, R = 3-Br, 88%
1b, R = 4-Me
1c, R = 4-OMe
1d, R = 4-F
1e, R = 4-Cl
1f, R = 3-Br
Table 1 Dehydration coupling between phenethyl alcohol and diphenyl phosphine
oxides.a
CH2CH2P(O)Ph2
CH2CH2OH
7
8
1g
S
3g, 91%
S
CH2CH2OH
CH2CH2OH
CH2CH2P(O)Ph2
1h
3h, 78%
CH2CH2P(O)Ph2
N
N
9
1i
1j
3i, 65%
Me
Me
OH
P(O)Ph2
10
3j, 76%
3k, 57%
Me
OH
Me
P(O)Ph2
11
1k
1l
OH
OH
P(O)Ph2
12
13
3l, 71%
a Reaction conditions: a mixture of 1a (0.3 mmol), Ph2P(O)H (0.2 mmol), and base
P(O)Ph2
Ph
b
(0.2 mmol) in a solvent (1 mL) was heated at 130 oC for 24 h. 31P NMR yield
using triphenylphosphine oxide as an internal standard. c 10 mol% base. d 50 mol%
base. e 0.4 mmol 1a. f 0.5 mmol 1a. g 150 oC. h 100 oC.
Ph
Ph
Ph
1m
3m, 46%
OH
P(O)Ph2
Ph
With the optimal reaction conditions in hand, we then
studied the substrate scope (Table 2). Various alcohols could
successfully couple with H-phosphine oxides under the
reaction conditions to produce the corresponding tertiary
phosphine oxides in moderate to high yields. Thus, phenethyl
alcohols bearing methyl and methoxy groups served well and
dehydratively coupled readily with 2a (Table 2, entries 2 and 3).
Halo groups like F, Cl and Br on the aromatic ring survived
under the reaction conditions, facilitating further derivation of
the products via cross coupling (Table 2, entries 4-6). Polycyclic
and heterocyclic substrates also underwent dehydration
coupling with 2a smoothly to furnish the expected coupling
products in good yields (Table 2, entries 7-9). Under the
reaction conditions, 2-phenylpropan-1-ol was phosphorylated
with 2a via dehydration coupling to produce 3j in 76% yield
(Table 2, entry 10). Secondary alcohols could also be used as
substrates and couple with 2a to generate the corresponding
products in moderate to good yields (Table 2, entries 11-14).
The long chain aliphatic alcohols like ethanol and heptan-1-ol
Ph
Ph
Ph
14
1n
3n, 32%
Me
Me
1o
OH
P(O)Ph2
15b
3o, 35%
n-C6H13
3p, 38%
n-C6H13
OH
P(O)Ph2
16b
17
18b
19
20
21
22
1p
R'2P(O)H
2b, R' = 4-MeC6H4
PhCH2CH2P(O)R2
3q, R' = 4-MeC6H4, 76%
1a
1a
1a
1a
1a
1a
2c, R' = 4-(Me2N)C6H4 3r, R' = 4-(Me2N)C6H4, 84%
2d, R' = mesityl
2e, R' = naphth-2-yl
2f, R' = Cy
3s, R' = mesityl, 71%
3t, R' = naphth-2-yl, 69%
3u, R' = Cy, 60%
2g, R' = n-Bu
3v, R' = n-Bu, 65%
a Reaction conditions: a mixture of 1 (0.5 mmol), H-phosphine oxide 2 (0.2 mmol),
and base (t-BuONa, 0.2 mmol) in DMAc (1 mL) was heated at 130 oC for 24 h.
b
150 oC.
were also applicable to this reaction, despite with relatively
low yields (Table 2, entries 15 and 16).
As for the hydrogen phosphoryl compounds, both aromatic
and aliphatic H-phosphine oxides were applicable to this
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dehydration coupling. Thus, di(p-methylphenyl)phosphine phenylacetaldehyde was detected from the reaction mixture
oxides and di(p-dimethylaminophenyl)phosphine oxides by GC-MS. In addition, when 2-phenylacetaldehyde was
dehydratively coupled with phenethyl alcohol to yield the allowed to react with equivalent 2a under the reaction
coupling products 3q and 3r in 76% and 84% yields, conditions, a polycyclic compound 1,3,5-triphenylbenzene was
respectively (Table 2, entries 17 and 18). The highly steric produced in 35% yield, while the expected alkenylphosphoryl
dimesitylphosphine oxide and dinaphth-2ylphosphine oxide compound was not detectable at all (eqn 2). Therefore, we
also underwent dehydration coupling with 1a smoothly under thought that the Xu’s reaction should not take place in our
the reaction conditions (Table 2, entries 19 and 20). The current reaction. This conclusion was further supported by the
aliphatic Cy2P(O)H and n-Bu2P(O)H could also be used as the following additional experimental results: only a trace amount
substrates and converted to the expected products in good of product via dehydration coupling was generated from the
yields (Table 2, entries 21 and 22). It should be noted that the reaction of phenylmethanol with 2a under the reaction
H-phosphinates and H-phosphonates were not applicable to conditions (eqn 3). Then, we deduced that the hydroxyl group
this dehydration coupling due to the severe hydrolysis and might act as a leaving group and an alkene could be formed as
interesterification under the current reaction conditions.
an active intermediate in this reaction. Indeed, a trace amount
of styrene was detected by GC and GC-MS analysis of the
reaction mixture of 1a and 2a. Especially, ca. 37% yield of 1-
vinylnaphthalene was generated after reaction of 2-
(naphthalen-1-yl)ethanol with 2a. Meanwhile, when styrene
was allowed to react with equivalent 2a under the reaction
conditions, 90% yield of 3a was given (eqn 4).11
Scheme 2 10 mmol scale experiments.
Thus, on the basis of those experimental results described
above, a plausible reaction path was proposed. At first,
alcohols underwent dehydration to produce an alkene by the
aid of a base, which then was hydrophosphorylation under
similar reaction conditions (Michael Addition)11 to give the
This reaction could be conducted at 10 mmol scale without
decrease of the reaction efficiency (Scheme 2). Thus, heating a
minxture of Ph2P(O)H (10 mmol), phenethyl alcohol (25 mmol)
and t-BuONa (10 mmol) in DMAc (40 mL) at 130 oC for 24 h
produced 3a in 85% isolated yield. Worth noting is that when
the dehydration coupling reaction was performed in the
absence of solvent under similar reaction conditions, 3a was
also generated in 76% yield.
corresponding alkyl phosphine oxides 3.
Conclusions
In summary, we have disclosed
a novel dehydration
coupling reaction between alcohols and H-phosphine oxides in
the presence of a simple base. This transformation provided a
new alternative strategy that is more environmental benign for
the preparation of alkyl phosphine oxides. Mechanistic studies
showed that this reaction might proceed via two steps
involving dehydration and subsequent regio-selective
hydrophosphorylation of the resulting alkenes.
Partial financial supports from NFSC (21573064, 21403062,
21373080), HNNSF 2015JJ3039 and the Fundamental Research
Funds for the Central Universities (Hunan University) are
gratefully acknowledged.
Notes and references
1
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Scheme 3 Control experiments.
To get some mechanistic information to this reaction, we
carried out several control experiments. As shown in Scheme 3,
in the presence of TEMPO, this dehydration coupling also took
place to give 3a in 55% yield, indicating that this reaction
probably is not a radical reaction (eqn 1). Since Xu reported
that a base could mediate the dehydration coupling between
alcohols and carbonyl compounds via a borrowing-hydrogen
reduction,10 we initially thought that the current coupling may
Quin,
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a similar process. However, no 2-
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7
In 2017, Xie and Loh described a cross dehydrative coupling
between Morita–Baylis–Hillman (MBH) alcohols and
secondary phosphine oxides forming allylic phosphorus
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a cross dehydrative
4
5
coupling between special triarylmethanols and P(O)-H
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2465; Biaryl alkyl alcohols react with P(O)-H compounds
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