Mn(OAc)3-mediated synthesis of β-hydroxyphosphonates from P(O)-H compounds and alkenes

Article abstract of DOI:10.1039/c4ra10593a

A new and general method for the synthesis of β-hydroxy phosphonates has been achieved through Mn(OAc)₃-mediated radical oxidative phosphonation of alkenes with H-phosphonates and H-phosphine oxide. The starting materials of P(O)-H compounds and alkenes are stable and cheap. Mn(OAc)₃ can be readily prepared from Mn(OAc)₂ in the laboratory. This method can be easily adapted to large-scale preparations. This journal is

Full text of DOI:10.1039/c4ra10593a

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Mn(OAc)3-mediated synthesis of
b-hydroxyphosphonates from P(O)–H compounds
and alkenes†
Cite this: RSC Adv., 2014, 4, 51776
a
a
a
a
a
Yuzhen Gao, Ju Wu, Jian Xu, Pengbo Zhang, Guo Tang and Yufen Zhaoab
Received 17th September 2014
Accepted 6th October 2014
*
DOI: 10.1039/c4ra10593a
www.rsc.org/advances
A new and general method for the synthesis of b-hydroxy phospho- phosphorohydrazidates as starting materials, but only gem-
nates has been achieved through Mn(OAc)3-mediated radical oxida- dialkyl/aryl-substituted alkenes could afford satisfactory yields.8
tive phosphonation of alkenes with H-phosphonates and
Reactions involving organophosphorus radicals have a long
H-phosphine oxide. The starting materials of P(O)–H compounds and history, and are useful reactive species in organic synthetic
alkenes are stable and cheap. Mn(OAc)3 can be readily prepared from chemistry.9 Economically and environmentally benign manga-
Mn(OAc)2 in the laboratory. This method can be easily adapted to nese salts are attractive because manganese is one of the most
large-scale preparations.
abundant metals in the world. Manganese salts have been used
for many transformations in the last few years.10 Mn(OAc)3-
promoted phosphonations are important methods for the
formation of P–C bond.11 Our continued interest in the
synthesis of a-hydroxy-,12 a-amino-phosphonates13 and the
formation of C–P bonds2c,d,14 prompted us to explore a general
method for the synthesis of b-hydroxyphosphonates via
P-centered radical difunctionalization of alkenes.
This idea was rst examined by using styrene (1a) and dii-
sopropyl H-phosphonate (2a) as reaction partners (Table 1). In
the beginning, various copper and silver salts were tested
(entries 1–4), most of which behaved poorly. Other oxidants
such as AgNO3/K2S2O8 and TBHP were also investigated, but the
reaction did not work well under these conditions (entries 5 and
6). Pleasingly, when Mn(OAc)3$2H2O was chosen as the oxidant,
and HOAc as the solvent, the product 3a was obtained in 73%
yield at 80 ꢀC under nitrogen atmosphere (entry 7). It should be
b-Hydroxyphosphonates are extremely valuable compounds in
organic chemistry for their potential applications in herbicides,
horticulture agents, antioxidants, and moisture-resistant
compounds.1 Treatment of b-hydroxyphosphonates with
oxidizing agents results in the formation of b-ketophospho-
nates which could be used in the preparation of a, b-unsatu-
rated carbonyl compounds via the well-known HWE (Horner–
Wadsworth–Emmons) reaction.2 Furthermore, the hydroxyl
group in b-hydroxyphosphonates could be converted into a
variety of functional groups, such as esters, amines, phenyl
ethers and so on, which have interesting biological properties.3
Generally, b-hydroxyphosphonates have been prepared by
the hydrogenation of b-ketophosphonates4 or the ring-opening
reaction of epoxy compounds with phosphorus nucleophiles5
(Scheme 1). Alternative procedures have been reported
including reaction of alkylphosphonates with aldehydes via an
aldol-like reaction in the presence of strong bases6 and reaction
of dialkyl(iodomethyl)phosphonate with aldehydes by employ-
ing SmI2.7 In 2011, Taniguchi's group described iron-catalyzed
aerobic oxidative phosphonation of alkenes by using
aDepartment of Chemistry, College of Chemistry and Chemical Engineering, The Key
Laboratory for Chemical Biology of Fujian Province, Xiamen University, Xiamen,
Fujian 361005, China. E-mail: t12g21@xmu.edu.cn; Fax: +86-592-2185780
bKey Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry
of Education), Department of Chemistry, Tsinghua University, Beijing 100084, China
† Electronic supplementary information (ESI) available: Experimental procedures
for the synthesis, spectral data and NMR spectra of compounds 3a, 3b, 4a–4w and
5–7. See DOI: 10.1039/c4ra10593a
Scheme 1 Synthetic routes to b-hydroxyphosphonates.
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Table 1 Reaction conditions optimizationa
investigated, and the corresponding products were obtained in
high yields (4b–4e). When 2-naphthalenylethene was examined,
70% yield was obtained (4f). Halogen atoms such as bromo and
chloro on the aromatic ring were unaffected under the present
reaction conditions, giving products 4g and 4h in 83% and 84%
yields, respectively. However, 4-cyano and 3-nitrostyrene were
examined for their reactivity with 2a under similar reaction
conditions, gave the expected products 4i and 4j in 25% and
33% yield, respectively. These examples imply that the reaction
involves cationic intermediates. 2-Vinylthiophene also reacted
smoothly with H-phosphonate to afford products 4k in 58%
Entry Additive
Solvent
T [ꢀC] Yield [%]
1
2
3
4
AgNO3 (0.5)
CuCl (0.5)
CuCl2 (0.5)
AgOAc (3)
CH3CN
CH3CN
CH3CN
DMF
100
100
100
100
100
100
80
80
80
100
60
50
16 (4a)
Trace
Trace
Trace
Trace
Trace
73 (3a)
35 (3a)
62 (3a)
43 (3a)
87 (3a)
66 (3a)
n.d.
5
Bu4NI (0.2) + TBHP (3)
CH3CN
6
AgNO3 (0.2) + K2S2O8 (2) CH3CN
Table 2 Reaction of P(O)–H compounds with alkenesa
7
Mn(OAc)3$2H2O (3)
Mn(OAc)3$2H2O (3)
Mn(OAc)3$2H2O (3)
Mn(OAc)3$2H2O (3)
Mn(OAc)3$2H2O (3)
Mn(OAc)3$2H2O (3)
Mn(acac)3 (3)
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
8b
9c
10
11
12
13
14
15
16
17
60
—
60
0
Mn(OAc)3$2H2O (3)
Mn(OAc)3$2H2O (3)
Mn(OAc)3$2H2O (3)
CH3CN
Propionic acid
Pivalic acid
60
60
60
70 (3a + 4a)
73 (3b)
n.d.
a
Reaction conditions: 1a (0.5 mmol), 2a (1.0 mmol), additive in solvent
(3 mL) stirring under nitrogen for 8 h. Oil bath temperature. Yield of the
isolated product; n.d.: not detected. b Under O2. c Under air.
noted that 3a could transform into b-hydroxyphosphonate 4a
quantitatively through a simple alcoholysis process. The reac-
tion gave much lower yields when carried out under O2 and air
conditions (entries 8 and 9).
Further screening indicated that the choice of temperature is
also very crucial for the reaction (entries 10–12). The reaction
ꢀ
performed well at 60 C and gave 3a in 87% yield. However, the
yield of product 3a decreased greatly when the temperature was
ꢀ
ꢀ
raised to 100 C or decreased to 50 C. No desired product was
obtained when Mn(acac)3 was chosen as the oxidant (entry 13).
The reaction did not occur at all in the absence of Mn(OAc)3$2H2O
(entry 14). A mixture of 3a and 4a was obtained when CH3CN
was chosen as the solvent (entry 15). When propionic acid was
chosen as the solvent, the only product 3b was obtained in 73%
yield (entry 16). Unfortunately, when the bulky pivalic acid
was selected as solvent, no product was detected (entry 17).
Aer optimization of the reaction conditions, we established a
highly efficient route to formation of b-hydroxyphosphonate. The
optimal reaction conditions are: (1) 3.0 equiv. of Mn(OAc)3$2H2O
ꢀ
as the oxidant, and HOAc as the solvent at 60 C for 8 h under
nitrogen atmosphere (entry 11 and (2) alcoholysis using 1 M
NaOH in CH3OH at room temperature for 1 hour.
Having the optimal conditions in hand, we next examined
the reaction by using various alkenes including aromatic
a
Conditions: (1) alkene
1 (0.5 mmol), P–H 2 (1.0 mmol),
Mn(OAc)3$2H2O (1.5 mmol), CH3COOH (3 mL), 8 h, 60 ꢀC (oil bath
alkenes and aliphatic alkenes with different H-phosphonates temperature), under N2; (2) alcoholysis: 1 M NaOH in CH3OH, 1 hour,
r.t. isolated yield.
2a–2g to understand the scope of the reaction. As shown in
Table 2, most of the functional groups were tolerated under the
present oxidative conditions. Various aromatic alkenes with
electron-donating substituents on the benzene ring were
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yield. When 1-methyl-1-phenyl ethene was used, it reacted
smoothly with 2a resulting in product 4l in 60% yield. Moreover,
cyclic aromatic alkene also reacted smoothly with 2a, leading to
the desired product 4m in 68% yield. The present reaction was
also successfully applied to aliphatic alkenes, giving high
conversions of alkenes, albeit in lower yields. The reaction of
aliphatic alkenes gave a mixture containing b-alkenylphospho-
nates and b-hydroxyphosphonate. Thus, allylbenzene, 1-octene
and 1-hexene reacted with diisopropyl H-phosphonate (2a)to
afford the corresponding b-hydroxyphosphonate 4n, 4o and 4p
in 41%, 31% and 26% yield, respectively. 2-Vinylpyridine was
also examined. Unfortunately, only trace amounts of desired
product was detected.
Scheme 4 Experiment for mechanistic study.
With regards to the H-phosphonates, it was also successfully
applied to diethyl, dipropyl and dibutyl. All could be used as the
substrates, generating the corresponding b-hydroxy-
phosphonates (4q–4s) in 73–82% yields. Dibenzyl H-phospho-
nate gave high conversion to b-acetoxyphosphonate. But only
46% yield of b-hydroxyphosphonate 4t was obtained aer
metholysis because benzyl group was easily substituted by OH
in the presence of NaOH. Difunctionalization of alkenes
through treatment of diphenylphosphine oxide with alkenes led
to the formation of product 4u–4w in 67–78% yield which
indicated that the reactivities of these P–H compounds are
almost independent of the alkoxyl and alkyl moieties.
Scheme 5 Possible reaction mechanism.
pathway. Furthermore, 2-vinylpyridine and styrene with
electron-withdrawing group on the benzene ring afford the
corresponding product (4i, 4j) in very low yields which indicates
that the reaction might go through a cationic intermediate
process. On the basis of this result, a mechanistic pathway for
the manganese(III)-mediated radical oxidative phosphonation of
alkenes with H-phosphonate is proposed in Scheme 5. The
reaction of H-phosphonate B with Mn(III) salt generated phos-
phorous radicals C which then reacted with styrene A to
produce D. Subsequently, cationic intermediate E was formed
through single electron oxidation by Mn(III) from D which ulti-
mately was attacked by AcOH (F) to afford G.
In conclusion, we have successfully developed a highly effi-
cient and general method for the preparation of b-hydroxy-
phosphonates through Mn(OAc)3-mediated radical oxidative
phosphination of alkenes under relatively mild reaction
conditions. This method is highly efficient and provides rapid
access to a broad spectrum of b-hydroxyphosphonates in good
to excellent yields. This reaction can be effectively scaled up and
the product can be conveniently obtained in a one-pot process.
Moreover, Mn(OAc)3 can be easily prepared from Mn(OAc)2 in
laboratory. Further application of this method toward the
synthesis of biologically active molecules is in progress.
In order to demonstrate the practical application of this
method, styrene (1a, 10 mmol) was employed in a gram-scale
reaction with (i-PrO)2P(O)H (2a, 20 mmol) and delivered 4a in
84% yield (Scheme 2).
With the synthetic b-hydroxyphosphonates in hand, we next
prepared b-ketophosphonate 5, an important HWE precursor,
in high yield using Dess–Martin reagent. b-Benzoxy-
phosphonate 6 could be easily obtained in good yield from
b-hydroxyphosphonate via Mitsonobu reaction (Scheme 3).
No desired product was obtained when 2.0 equiv. of TEMPO
was added in the reaction under the optimal conditions
(Scheme 4). This result suggests that the radical was intercepted
by TEMPO. N,N-diallyl-4-methylbenzenesulfonamide was
examined, and substituted pyrrolidine was obtained. These
results suggested that the reaction go through a radical
Scheme 2 Gram-scale preparation of 4a.
Acknowledgements
We acknowledge nancial support from the Chinese National
Natural Science Foundation (21173178, 21232005, 21375113),
the National Basic Research Program of China (2012CB821600),
and the Program for Changjiang Scholars and Innovative
Research Team in University. We are grateful to Prof. Dr D. M. J.
Lilley for valuable discussions on this paper.
Scheme 3 Application of b-hydroxyphosphonates.
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