Mn(OAc)3-Mediated Synthesis of 3-Phosphonyldihydrofurans from β-Ketophosphonates and Alkenes

Article abstract of DOI:10.1055/s-0036-1588112

A new, general method for the synthesis of 3-phosphonyldihydrofuran derivatives has been achieved through Mn(OAc)₃-mediated radical cyclization between β-ketophosphonates and alkenes. This transformation allows the direct formation of C-C/C-O bonds and the construction of a dihydrofuran ring in one reaction with operational simplicity and excellent functional-group compatibility.

Full text of DOI:10.1055/s-0036-1588112

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–E
letter
A
G. Lu et al.
Letter
Synlett
Mn(OAc)3-Mediated Synthesis of 3-Phosphonyldihydrofurans
from β-Ketophosphonates and Alkenes
R5
R4
Guozhang Lu
Binzhou Lin
Yuzhen Gao
Jianxi Ying
Guo Tang*
Yufen Zhao
O
R1
O
O
P
Mn(OAc)3•2H2O
R2
R3
R5
R4
O
+
R1
R2
AcOH, 80 °C Ar, 6 h
P
R3
R
1 = aryl, alkyl
R4, R5 = aryl, alkyl
29 examples
up to 85% yield
Convenient Gram-Scale Preparation
Department of Chemistry, College of Chemistry
and Chemical Engineering, and the Key Laboratory
for Chemical Biology of Fujian Province,
Xiamen University,
Xiamen, Fujian 361005, P. R. of China
t12g21@xmu.edu.cn
Received: 24.09.2016
Accepted after revision: 13.11.2016
Published online: 01.12.2016
oping an efficient method for the construction of 3-
phosphonyldihydrofuran derivatives is highly desirable.
However, the efficient synthesis of dihydrofuran bearing a
phosphonyl group is quite rare.6,11
DOI: 10.1055/s-0036-1588112; Art ID: st-2016-w0639-l
Abstract A new, general method for the synthesis of 3-phosphonyldi-
hydrofuran derivatives has been achieved through Mn(OAc)3-mediated
radical cyclization between β-ketophosphonates and alkenes. This
transformation allows the direct formation of C–C/C–O bonds and the
construction of a dihydrofuran ring in one reaction with operational
simplicity and excellent functional-group compatibility.
Owing to our continuous interest in the synthesis of
heterocyclic phosphonates based on phosphonyl/phosphi-
noyl radicals,12 we reason that β-ketophosphonate A reacts
with oxidant to generate α-phosphonyl radical B, which
then reacts with alkene C to produce intermediate D. Sub-
sequently, the single-electron oxidation of D delivers cat-
ionic intermediate E, which follows an intramolecular at-
tack way to afford 3-phosphonyldihydrofuran F (Scheme 1,
path a).13a–d Alternatively, the cyclization of D can form G.
Oxidative termination of G followed by loss of a proton can
form the desired product F (path b).13e,f This transformation
allows the direct formation of 3-phosphonyldihydrofuran
derivatives from readily prepared β-ketophosphonates and
commercially available alkenes.
Key words manganese, phosphonyldihydrofurans, β-ketophospho-
nates, alkenes, radicals
Among various organophosphorus compounds, β-keto-
phosphonate derivatives are an extremely useful class of
carbonyl- and phosphorus-containing organic compounds,
which have been widely utilized as prominent precursors
for the synthesis of various compounds.1 In recent years,
many strategies have been developed for the synthesis of β-
ketophosphonates2 which could be used for the synthesis of
α,β-unsaturated carbonyl compounds via the well-known
Horner–Wadsworth–Emmons (HWE) reaction,3 and for the
preparation of chiral β-amino4 and β-hydroxy5 phosphonic
acids. However, the reactions involving α-phosphonyl radi-
cals generated by β-ketophosphonates are rare.6
O
O
P
O
O
P
R2
R3
R2
R3
R1
R4
O
O
P
R1
R2
R3
oxidation
B
R1
R5
A
R4
R5
D
C
Dihydrofuran derivatives constitute the basic skeleton
in many naturally compounds, mostly being found in ma-
rine organisms and plants.7 They possess a variety of bio-
logical activities, such as fish antifeedant agents, antifungal,
flavor, and insecticidal,8 and are important as building
blocks in total synthesis.9 Moreover, organophosphorus
compounds have broad applications in the fields of organic
synthesis, materials science, medicinal chemistry, and li-
gand chemistry.10 Therefore, we assume that 3-phospho-
nyldihydrofuran derivatives might have potential in biolog-
ical activities and pharmaceutical applications, and devel-
O
O
OH
O
P
R2
P
R2
R3
R1
R3
R1
R4
R4
R5
O
R4 R5
– H
R5
R1
R2
R3
E
P
R4
O
R4
R5
O
R1
R2
R3
R1
R2
R3
F
oxidation
O
R5
P
P
G
H
O
O
Scheme 1 Synthetic routes to 3-phosphonyldihydrofurans
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

B
G. Lu et al.
Letter
Synlett
This idea was first examined by using diethyl (2-oxo-2-
phenylethyl)phosphonate (1a) and ethene-1,1-diyldiben-
zene (2a) as reaction partners (Table 1). In the beginning,
some additives such as silver salt, copper salt, and peroxide
were tested (entries 1–6),14a–c but the reaction did not work
under these conditions. Cerium salt gave low yield.14d Pleas-
ingly, when Mn(OAc)3·2H2O was chosen as the oxidant,15
using acetic acid (AcOH) as the solvent, the product 3a was
obtained in 55% yield at 60 °C under an argon atmosphere
(entry 8). For this process, examination of various solvents
suggested that AcOH is optimal (entries 8–12). Moreover,
conducting the reaction in AcOH at 80 °C gave 3a in 75%
yield (entry 13). Increasing the amount of alkene to two
equivalents gave 3a in 40% yield (entry 15). Decreasing the
amount of Mn(OAc)3·2H2O or 1a gave 3a in lower yield (en-
tries 14 and 15). Only 60% yield of the product was obtained
when the reaction was performed in the open air (entry
16). After optimization of the reaction conditions, we es-
tablished an efficient route to formation of 3-phosphonyl-
dihydrofurans. The optimal reaction conditions are 1.0
equivalent of alkenes, 2.0 equivalents of β-ketophospho-
nates, 3.0 equivalents of Mn(OAc)3·2H2O as the oxidant, and
AcOH as the solvent at 80 °C for six hours under an argon
atmosphere (entry 13).
Having the optimal conditions in hand, we next exam-
ined the reaction of various β-ketophosphonates with dif-
ferent alkenes to understand the scope of the reaction
(Scheme 2). Firstly, various functional groups of β-keto-
phosphonates were examined and most of which were tol-
erated under the present conditions. 2-Oxo-2-arylethyl-
phosphonate with 4-methyl substituted on the aromatic
ring, reacted efficiently and gave the desired product 3b in
71% yield. Halogen atoms such as fluorine, chlorine, and
bromine on the aromatic ring were unaffected under the
present reaction conditions to afford the corresponding
products 3c–e in good yields, which could allow for further
synthetic transformations. Treatment of 2a with 2-(4-me-
thoxyphenyl)-2-oxoethylphosphonate led to the formation
of product 3f in 58% yield.
Moreover, when the aliphatic β-ketophosphonate was
used as the substrate, the corresponding product 3g was
obtained in moderate yield. With respect to the phosphonyl
groups of β-ketophosphonates, dimethyl-, dibenzyl-, and
diisopropyl-β-ketophosphonate all could be used as sub-
strates, generating the corresponding products 3h–j in 65–
33% isolated yields. Ethyl phenylphosphinoyl group was
also suitable for producing the product 3k in 70% yield. We
Table 1 Optimization of Reaction Conditionsa
Ph
Ph
O
O
O
Ph
+
P(OEt)2
Ph
Ph
Ph
P(O)(OEt)2
3a
1a
2a
Entry
Initiator (equiv)
AIBN (0.1)
Solvent
Temp (°C)
Yield (%)
1
2
toluene
DCE
80
60
0
0
DTBP (2) + CuBr (0.2)
TBHP (4)
3
MeCN
MeCN
MeCN
DMSO
AcOH
AcOH
MeCN
NMP
60
0
4
K2S2O8 (3) + AgNO3 (0.1)
Ce(NH4)2(NO3)6 (2.0)
Mn(OAc)2 (0.05)
100
100
100
60
0
5
36
0
6
7
MnO2 (2) + Mn(OAc)2·2H2O (0.2)
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(OAc)3·2H2O (2)
Mn(OAc)3·2H2O (3)
Mn(OAc)3·2H2O (3)
0
8
60
55
33
24
32
16
75
44
40b,c
60d
9
60
10
11
12
13
14
15
16
60
DMSO
DMF
60
60
AcOH
AcOH
AcOH
AcOH
80
80
80
80
a Reaction conditions: 1a (0.2 mmol), 2a (0.1 mmol), additive in solvent (1 mL) stirring under argon for 6 h. Oil-bath temperature.
b 1a (0.1 mmol), 2a (0.2 mmol).
c 1a (0.15 mmol), 2a (0.1 mmol).
d Under air.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

C
G. Lu et al.
Letter
Synlett
R5
R4
O
R1
O
O
P
Mn(OAc)3•2H2O
AcOH, Ar, 6 h
R2
R3
R5
R4
O
R1
+
R2
P
R3
1
2
3
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
O
O
O
O
O
Ph
Me
F
Cl
Br
P(O)(OEt)2
P(O)(OEt)2
P(O)(OEt)2
P(O)(OEt)2
3d 61%
P(O)(OEt)2
3e 68%
3a 75% (72%, 5 mmol scale)
3b 71%
3c 85%
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
O
O
O
O
Ph
Ph
O
OMe
n-Bu
Ph
Ph
Ph
P(O)(OEt)2
P(O)(OEt)2
P(O)(OMe)2
P(O)(OBn)2
P(O)(Oi-Pr)2
3j 65%
3f 58%
3g 56%
3h 45%
3i 33%
Ph
Ph
Ph
Ph
Ph
Ph
Ph
O
O
O
O
O
Ph
Ph
Ph
P(O)(OEt)2
Ph
P(O)(OEt)2
Ph
P(O)(OEt)Ph
3k 70%
P(O)Ph2
3l trace
P(O)(OEt)2
F
Cl
3m 66%
3n 48%
3o 68%
Ph
Ph
Ph
Ph
O
O
O
O
Ph
Ph
Ph
Ph
P(O)(OEt)2
P(O)(OEt)2
P(O)(OEt)2
P(O)(OEt)2
Br
F3C
MeO
Ph
MeS
3p 45%
3q 56%
3r 36%
3s 41%
Ph
Ph
O
O
Ph
Ph
Et
Ph
O
O
Ph
O
Ph
Ph
P(O)(OEt)2
3x 40%
Ph
P(O)(OEt)2
P(O)(OEt)2
P(O)(OEt)2
MeO2C
P(O)(OEt)2
NC
3t 58%
3u 53%
3v 60%
3w 44%
Ph
Ph
Ph
Ph
O
O
MeO
Ph
Me
Ph
H
O
O
Ph
O
O
Ph
O
Ph
P(O)(OEt)2
3y 63%
Ph
P(O)(OEt)2
3aa trace
Ph
Me
P
P
OH
P(O)(OEt)2
Ph
OH
HO
3ac trace
3z 45%
3ab trace
Scheme 2 Synthesis of 3-phosphonyldihydrofurans
did not obtain the desired product 3l when diphenylphos-
phinoyl group was introduced into this reaction, along with
unidentified byproducts, and no β-ketophosphonate and
alkene were recovered.
products 3s–u in 58–41% yields. More bulky substrates
such as naphthyl also smoothly reacted with 1a and gave
product 3v in 60% yield. 1-Alkyl-1-arylethene derivatives
(cyclopropyl, ethyl, and methyl) were also examined, and
the desired products 3w–z were obtained in 63–40% yields.
Styrene and β-ketophosphonic acids were also examined.
Unfortunately, only trace amounts of desired product 3aa–
ac were detected.
In order to demonstrate the practical application of this
method, ethene-1,1-diyldibenzene (2a, 5.0 mmol) was em-
ployed in a gram-scale reaction and delivered 3a in 72%
yield (1.56 g, Scheme 2).
In conclusion, we have successfully developed a highly
efficient and general method for the preparation of 3-phos-
phonyldihydrofurans from β-ketophosphonates and
alkenes under relatively mild reaction conditions. More-
over, Mn(OAc)3·2H2O can be easily prepared from Mn(OAc)2
in laboratory. Furthermore, β-ketophosphonates are readily
The substrate scope was further investigated by reacting
1a with different alkenes. Firstly, various diarylethene were
examined and most of which were tolerated under the
present conditions. With methyl-substituted on the ben-
zene ring, 2m reacted efficiently with 1a to give the desire
product 3m in 66% yield. Diarylethene derivatives bearing
halogen atoms such as fluoro, chloro, and bromo reacted
smoothly to give the corresponding products 3n–p in 68–
45% yields. The electron-donating group (OMe) was investi-
gated and gave the corresponding product 3q in 56% isolat-
ed yield. The oxidizable methylthio group could be tolerat-
ed, and the corresponding product 3r was obtained in 36%
yield. Various electron-withdrawing groups, such as CF3,
CO2Me, and CN, reacted smoothly to give the corresponding
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

D
G. Lu et al.
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Synlett
prepared from commercial available alkenes and R2P(O)H
compounds. And this simple protocol may provide a gener-
al approach to 3-phosphonyldihydrofurans of importance
in medicinal and synthetic chemistry.
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Acknowledgment
We acknowledge financial support from the National Natural Science
Foundation of China (21232005, 21375113), the National Basic Re-
search Program of China (2013CB910700), and the Fundamental Re-
search Funds for the Central Universities (20720160030).
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Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588112.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
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(16) Experimental Procedure for the Synthesis of 1a
Styrene (2.08 g, 20 mmol) was added to a mixture of H-diethyl
phosphonate (5.52 g, 40 mmol), CuBr2 (111.5 mg, 0.5 mmol, 2.5
mol%), FeBr3 (162 mg, 1 mmol, 5.0 mol%), and Et3N (2.02g, 20
mmol) in DMSO (40 mL) at r.t. under O2 (balloon). The reaction
mixture was stirred at 55 °C for 48 h. After completion of the
reaction, water (20 mL) was added to the reaction mixture, and
the resulting mixture was extracted with CH2Cl2. The organic
layer was washed with 0.1 mol/L HCl (1 × 20 mL), water (3 × 20
mL), brine (1 × 20 mL), and the separated aqueous phase was
extracted with CH2Cl2 (2 × 20 mL). The combined organic layers
were dried over Na2SO4, filtered, and concentrated in vacuo. The
residue was purified by flash chromatography on silica gel
using a PE–EtOAc mixture (3:1, v/v) as the eluent to afford 1a as
a light yellow oil (3.07 g, 60%). 1H NMR (400 MHz, CDCl3): δ =
8.01 (d, J = 8.0 Hz, 2 H), 7.59 (t, J = 7.5 Hz, 1 H), 7.47 (t, J = 8.5 Hz,
2 H), 4.17–4.09 (m, 4 H), 3.65 (d, J = 22.6 Hz, 2 H), 1.27 (t, J = 6.9
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

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G. Lu et al.
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Hz, 6 H). 13C{1H} NMR (100 MHz, CDCl3): δ = 191.9 (d, J = 6.6
Hz), 136.5, 133.7, 129.0, 128.6, 62.7 (d, J = 6.5 Hz), 38.4 (d,
J = 130.1 Hz), 16.2 (d, J = 6.1 Hz). 31P{1H} NMR (162 MHz,
CDCl3): δ = 20.0. Other β-ketophosphonates were prepared sim-
ilarly.
Ketophosphonates (1, 0.40 mmol, 2.0 equiv), alkenes (2, 0.20
mmol, 1.0 equiv), and AcOH (2.0 mL) were sequentially added to
the system at r.t. The reaction mixture was heated with stirring
at 80 °C for 6 h. Upon completion, the reaction solution was
concentrated in vacuo, then added 15 mL sat. NaHCO3 solution,
and extracted with EtOAc (3 × 10 mL). The organic layer was
dried over Na2SO4, and concentrated under vacuum. The residue
was purified by silica gel column chromatography using a PE–
EtOAc mixture (from 3:1 to 1:1, v/v) as the eluent to afford the
corresponding products.
Experimental Procedure for the Synthesis of 2q
A 15 mL Schlenk tube charged with α-bromostyrene (0.377 g,
268 μL, 2.0 mmol), (4-methoxyphenyl) boronic acid (2.6 mmol,
1.3 equiv), K3PO4 (1.27 g, 6.0 mmol, 3.0 equiv), Pd(PPh3)4 (0.116
g, 5 mol%), and THF (10 mL) was heated at 80 °C for 12 h. After
completion, the reaction mixture was evaporated, and the
product was purified by flash silica gel column chromatography
using PE as the eluent to afford 2q as a white solid (307 mg,
73%). 1H NMR (400 MHz, CDCl3): δ = 7.32–7.26 (m, 7 H), 6.85 (d,
J = 8.8 Hz, 2 H), 5.37 (d, J = 17.0 Hz, 2 H), 3.81 (s, 3 H). 13C{1H}
NMR (100 MHz, CDCl3): δ = 159.6, 149.7, 142.0, 134.2, 129.6,
128.5, 128.3, 127.8, 113.7, 113.1, 55.5. Other alkenes were pre-
pared similarly.
Diethyl (2,5,5-Triphenyl-4,5-dihydrofuran-3-yl)phosphonate
(3a; New Compound)
Yield 75% (65 mg); light yellow liquid. 1H NMR (400 MHz,
CDCl3): δ = 7.95–7.93 (m, 2 H), 7.46 (d, J = 8.0 Hz, 4 H), 7.42–
7.39 (m, 2 H), 7.33 (t, J = 7.6 Hz, 4 H), 7.28–7.24 (m, 2 H), 3.97–
3.84 (m, 4 H), 3.78 (d, J = 3.2 Hz, 2 H), 1.12 (t, J = 7.0 Hz, 6 H).
13C{1H} NMR (100 MHz, CDCl3): δ = 163.8 (d, J = 25.8 Hz), 145.0,
130.4, 129.7, 129.0, 128.4, 127.7, 127.6, 125.7, 94.6 (d, J = 213.6
Hz), 91.5 (d, J = 11.6 Hz), 61.77 (d, J = 5.2 Hz), 47.8 (d, J = 9.4Hz),
16.26 (d, J = 6.7 Hz). 31P{1H} (162 MHz, CDCl3): δ = 16.5. HRMS:
m/z calcd for C26H28O4P [M + H]+: 435.1720; found: 435.1719.
Experimental Procedure for the Synthesis of 3-Phosphodihy-
drofuran Derivatives
A 15 mL Schlenk tube containing Mn(OAc)3·H2O (0.60 mmol, 3.0
equiv) was evacuated and purged with argon three times. β-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E