Mn(III)-mediated phosphonation-azidation of alkenes: A facile synthesis of β-azidophosphonates

Article abstract of DOI:10.1039/c5cc03995a

A new and general method for the synthesis of β-azidophosphonates has been achieved through Mn(OAc)₃-mediated radical oxidative phosphonation-azidation of alkenes. The starting materials of P(O)-H compounds, alkenes, and azidotrimethylsilane are stable and cheap. This method can be easily adapted for large-scale preparation.

Full text of DOI:10.1039/c5cc03995a

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Journal Name
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Mn(III)ꢀMediated PhosphonationꢀAzidation of Alkenes:
A Facile Synthesis of βꢀAzidophosphonates
Cite this: DOI: 10.1039/x0xx00000x
Jian Xu,a Xueqin Li,a Yuzhen Gao,a Liangliang Zhang,a Weizhu Chen,ab Hua Fang,b
Guo Tang,*a and Yufen Zhaoa
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
www.rsc.org/
Reactions involving organophosphorus radicals have a long
history, and are useful reactive species in organic synthetic
chemistry.9 Owing to our continuous interests in the P−C bond
formation10 and the reaction of organophosphorus radicals,11 we
reasoned that generating directly the radical B by addition of
phosphorous radical A onto an alkene would produce cationic
intermediate C through singleꢀelectron oxidation ultimately leading
to the formation of βꢀazidophosphonate via a nucleophilic attack by
A new and general method for the synthesis of βꢀazido
phosphonates has been achieved through Mn(OAc)3ꢀ
mediated radical oxidative phosphonationꢀazidation of
alkenes. The starting materials of P(O)ꢀH compounds,
alkenes, and azidotrimethylsilane are stable and cheap. This
method can be easily adapted to largeꢀscale preparations.
Orangoazides have been widely applied in medicinal chemistry
because of their versatile bioactivities.1 Furthermore, orangoazides
are powerful precursors for the generation of a variety of amines,
amides, as well as heterocyclic compounds.2 Therefore, the
introduction of an azido group into organic molecules has attracted
much attention.3 Molecules bearing both azido and phosphono
groups have extensively been used in pharmaceuticals and fire
retardants (Scheme 1).4 Treatment of azidoalkylphosphonates with
terminal alkynes results in the formation of the triazole bridgeꢀ
connected phosphonates for biotechnology and materials science via
the wellꢀknown Huisgenꢀclick reaction.5
azidotrimethylsilane(Scheme 2, path a). Alternatively, the radical
B
could be directly trapped by an azido radical to form the
desired product (path b).3b This transformation allows the direct
formation of βꢀazidophosphonates via tandem phosphonationꢀ
azidation of alkenes (Scheme 2).
Scheme 2. Possible reaction pathways.
Scheme 1. Biologically active azidoꢀcontaining phosphonates.
Traditionally, phosphonates with an azido group have been
prepared by the nucleophilic substitution of haloalkylphosphonates
or αꢀhydroxyphosphonates with sodium azide under Mitsunobu
conditions.6 Reaction of sulfonyl azides with bisphosphonate esters
provides a complementary way to azidoalkylphosphonates.7 Snider
group described reaction of 2ꢀoxoalkylphosphonate with 2ꢀiodoethyl
azide in the presence of strong base and phase transfer catalyst.8
However, these methodologies suffer from multiꢀstep synthesis and
limited substrate scope. To develop a simple and efficient approach
to βꢀazidophosphonates from readily available substrates is still
highly desired.
This idea was first examined by using styrene (1a), diethyl Hꢀ
phosphonate (2a), and azidotrimethylsilane (3a) as reaction partners
(Table 1). In the beginning, AgNO3 was tested (entry 1),12 but no
desired product was observed. The combined use of Cu(II) and
TBHP
organophosphorus radical reactions,13 but the reaction did not work
well under these conditions (entries and 3). When
(tertꢀbutylhydroperoxide)
was
often
used
in
2
Mn(OAc)3·2H2O was choosen as the oxidant and HOAc as the
solvent,11,14 the product 4a was obtained in 35% yield at 70 oC under
a nitrogen atmosphere (entry 4). Other manganese salts such as
Mn(acac)3 and Mn(OAc)2/MnO2 were also investigated, but no
desired product was obtained under these conditions (entries 5 and
6). The solvent systems employed also notably affected the related
reaction efficiencies. Conducting the reaction in CH3CN, DCE, 1,4ꢀ
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DOI: 10.1039/C5CC03995A
dioxane, toluene, PhCF3, DMF, DMA, and DMSO gave the product results are summarized in Table 2. In general, most of the functional
4a in low yields (entries 7ꢀ14), while the reaction conducted in NMP groups were tolerated under the present conditions. The methyl
gave 4a in 73% yield (entry 17).14b Further screening indicated that substituted styrenes, such as ortho-methyl, metaꢀmethyl, and paraꢀ
the choice of temperature is also very crucial for the reaction (entries methyl groups on the aryl ring, reacted efficiently and gave the
15ꢀ17). The yield of product 4a decreased when the temperature was desired products 4bꢀ4d in high yields. Various aromatic alkenes with
raised to 80 oC. However, it remained approximately the same when electronꢀdonating (tꢀbutyl and methoxyl) groups or electronꢀ
o
the temperature was decreased from 70 to 55 C. The attempt to
Table 2. Phosphonationꢀazidation of alkenes
decrease the amount of Mn(OAc)3·2H2O was failed. In our reaction,
only 19% yield of product was obtained when the reaction was
performed in the open air with 0.5 equivalent of Mn(OAc)3·2H2O
(entry 18). A yield of 23% was observed when 2 equivalents of
MnO2 were used as oxidant instead of air (entry 19),14e but the
combined use catalytic amount of Mn(II or III) and other oxidants
such as DTBP, TBHP, dioxygen led to lower yield in this reaction
(entries 19ꢀ24).
Table 1. Reaction conditions optimizationa
Entry
Additive (equiv)
Solvent
CH3CN
CH3CN
CH3CN
HOAc
T[oC]
100
100
60
Yield [%]
1
2
3
4
5
6
AgNO3(0.2)+K2S2O8(2)
CuCl2 (0.2)+TBHP (3)
CuSO4 (0.2)+TBHP (3)
Mn(OAc)3·2H2O (3)
Mn(acac)3
0
0
0
70
35
0
HOAc
100
100
Mn(OAc)2·(1)+ MnO2(4) NMP
15
7
8
9
Mn(OAc)3·2H2O (3)
Mn(OAc)3·2H2O (3)
Mn(OAc)3·2H2O (3)
CH3CN
70
70
70
23
0
DCE
Dioxane
32
10
11
12
13
14
15
16
17
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 (3)
Mn(OAc)3·2H2O (2.5)
Mn(OAc)3·2H2O (0.5)
Toluene
PhCF3
DMF
70
70
70
70
70
70
80
55
55
55
43
65
54
67
60
73
65
75
19
23
DMA
DMSO
NMP
NMP
NMP
NMP
18b
19
Mn(OAc)3·2H2O (0.5) + NMP
MnO2(2)
Mn(OAc)3·2H2O (0.1) + NMP
DTBP(2)
Mn(OAc)3·2H2O (0.1) + NMP
TBHP(2)
Mn(OAc)3·2H2O (0.1) + NMP
Air
Mn(OAc)3·2H2O (0.1) + NMP
O2
MnCl2 (0.1) + O2
20
21
22
23c
55
55
55
55
55
0
13
0
0
24c
NMP
0
a
Reaction conditions: 1a (0.4 mmol), 2a (0.6 mmol), 3a (0.8 mmol),
additive in solvent (3 mL) stirring under nitrogen for 12 h. Oil bath
b
c
temperature. Yield of the isolated product. Under air. Under O2
(balloon).
With this preliminary result in hand, the generality of the method
was explored under the optimized conditions [alkene (0.4 mmol),
P(O)ꢀH (0.6 mmol), TMSN3 (0.8 mmol), Mn(OAc)3·2H2O (1.0
o
mmol), in NMP (3 mL) at 55 C under nitrogen for 12 h], and the
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withdrawing (COOEt and NO2) groups on the benzene ring were azidophosphonates in moderate to good yields. Moreover, this
investigated, and the corresponding products were obtained in lower reaction can be effectively scaled up and the product can be
yields (4eꢀ4h). These examples imply that the reaction involves conveniently obtained in a oneꢀpot process.
radical and cationic intermediates. Halogen atoms such as fluoro,
chloro, and bromo on the aromatic ring were unaffected under the
Acknowledgements
present reaction conditions to afford the corresponding products 4iꢀ
4m in good yields, which could allow for further synthetic
transformations. More bulky substrates such as 2ꢀvinylnaphthalene
and etheneꢀ1,1ꢀdiyldibenzene also smoothly converted into product
4n and 4o in 66% and 75% yields. When propꢀ1ꢀenꢀ2ꢀylbenzene and
(1ꢀcyclopropylvinyl)benzene were used, they reacted smoothly to
result in products 4p and 4q in 81% and 60% yield, respectively.
Moreover, cyclic aromatic alkene also reacted smoothly, leading to
the desired product 4r in 56% yield. In addition, 2ꢀvinylthiophene
could also provide the expected product 4s in 63% yield. Aliphatic
alkenes were also examined. Unfortunately, only low yields of the
desired products were obtained (4t and 4u).
We acknowledge financial support from the Chinese National
Natural Science Foundation (21173178, 21232005, 21375113),
2014Y0068, and the National Basic Research Program of China
(2012CB821600).
Notes and references
a Department of Chemistry, College of Chemistry and Chemical Engineering,
and the Key Laboratory for Chemical Biology of Fujian Province, Xiamen
University,
Xiamen,
Fujian
361005,
China
Diisopropyl H–phosphonate (2b) was also used in the βꢀ
azidophosphonation of alkenes process, and led to the formation of
products 4v and 4w in 78 and 73% yields. Dibenzyl H–phosphonate
Fax: (86)592ꢀ2185780; Eꢀmail: t12g21@xmu.edu.cn
b
Third Institute of Oceanography, State Oceanic Administration, Xiamen,
Fujian 361005, China.
(2c) gave
a low yield of product 4x. Treatment of ethyl
phenylphosphinate (2d) with styrene and azidotrimethylsilane
afforded the desired product 4y in 85% yield. Diphenylphosphine
oxide produced the desired product 4z in only 55% yield.
Electronic Supplementary Information (ESI) available: Experimental
procedures for the synthesis, spectral data and NMR spectra of
compounds 4aꢀ4z. See DOI: 10.1039/c000000x/
In order to demonstrate the practical application of this method,
styrene (1a, 20 mmol) was employed in a gramꢀscale reaction and
delivered 4a in 74% yield (Scheme 3).
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subsequent
reductive
alkylation
process
with
4ꢀtertꢀ
butylbenzaldehyde. Biphosphonate 5c was easily obtained via the
reduction of the azide and phosphonationꢀrearrangement process.
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