Synthesis of β-hydroxyphosphonates by iron-catalyzed oxidative addition of phosphonyl radicals to alkenes

Article abstract of DOI:10.1016/j.tetlet.2011.07.026

Phosphorohydrazidates have been shown to work as radical precursors by iron-catalyzed aerobic oxidation to generate corresponding phosphonyl radicals. Generated radicals cause intermolecular addition to various alkenes in the presence of molecular oxygen

Full text of DOI:10.1016/j.tetlet.2011.07.026

Tetrahedron Letters 52 (2011) 4768–4770
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of b-hydroxyphosphonates by iron-catalyzed oxidative addition
of phosphonyl radicals to alkenes
⇑
Tsuyoshi Taniguchi , Atsushi Idota, Shin’ichi Yokoyama, Hiroyuki Ishibashi
School of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Phosphorohydrazidates have been shown to work as radical precursors by iron-catalyzed aerobic oxida-
tion to generate corresponding phosphonyl radicals. Generated radicals cause intermolecular addition to
various alkenes in the presence of molecular oxygen to give b-hydroxyphosphonate compounds in good
yield.
Received 3 June 2011
Revised 1 July 2011
Accepted 6 July 2011
Available online 19 July 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Iron catalysis
Radical reactions
Oxygenation
Phosphonates
Phosphorus-centered radicals are useful reactive species in
organic synthetic chemistry.1 Phosphites or thiophosphites can
be substituted for toxic organotin reagents as radical mediators.1
Furthermore, these compounds cause hydrophosphonation with
alkenes or alkynes under suitable radical conditions to give corre-
sponding organophosphorus compounds.1,2 Ingeniously designed
radical reactions using various phosphorus compounds bearing a
P–X bond (X = halides, selenide, metals, etc.) are also known.1,3
Recently, we reported new methods for generation of aryl, alkoxy-
carbonyl, or sulfonyl radicals from corresponding hydrazine com-
pounds in the presence of an iron catalyst and molecular
oxygen.4 In these reactions, addition of generated radicals to
alkenes and subsequent aerobic oxidation takes place to give cor-
responding b-hydroxyesters,4a b-hydroxysulfones,4b or 2-arylper-
oxides.4c In radical reactions using hydrazides as radical
precursors, reactions are initiated by iron-catalyzed aerobic oxida-
tion of hydrazides 2 to give diazenes C via supposed intermediates
A and B. Generated radicals E from diazenes C with release of
molecular nitrogen cause addition reaction to alkenes, and sequent
trapping of radical intermediates F by oxygen gives b-hydroxy
compounds via intermediates G, H, and I (Scheme 1). Herein, we
wish to report iron-catalyzed generation of phosphonyl radicals
from phosphorohydrazidates and oxidative addition to alkenes
under aerobic conditions to give b-hydroxyphosphonate com-
pounds.5 b-Hydroxyphosphonate compounds are valuable com-
pounds because they are known as bioisosteres of carboxylic acid
derivatives and their potential biological properties have attracted
broad interest.6,7
Treatment of
a-methylstyrene (1a) with 2.5 equiv of diethyl
phosphorohydrazidate (2b) in the presence of a catalytic amount
of iron (III) chloride (FeCl3) (10 mol %) and air in heating THF gave
b-hydroxyphosphonate compound 3b in 18% yield (Table 1, Entry
1). Iron (III) oxide (Fe2O3) was an ineffective catalyst (Entry 2),
whereas the use of iron (II) phthalocyanine [Fe(Pc)] significantly
improved in the yield of the product (Entry 3).8 The reaction under
oxygen atmosphere gave a similar yield (Entry 4). When the
amount of the iron catalyst was reduced to half, a large decrease
in yield of the product was observed (Entry 5). The reaction hardly
proceeded in the absence of an iron catalyst (Entry 6).
Several variations of the alkoxy moiety of phosphorohydrazi-
dates were examined (Scheme 2). First, the reaction of dimethyl
phosphorohydrazidate (2a) did not gave a product due to its insol-
ubility in THF, but addition of MeOH as a co-solvent to the reaction
mixture caused a desired reaction to give b-hydroxyphosphonate
compound 3a in good yield. On the other hand, when phospho-
rohydrazidates 2c and d having secondary or aromatic alkoxy
groups were employed in this reaction, sluggish reactions were
observed and yields of products 3c and d were low. In the case
of diphenyl phosphorohydrazidate (2d), the presence of electron-
withdrawing phenoxy groups might interfere in the generation of
the corresponding phosphonyl radical, but the reasonable reason
of lower reactivity of 2c and d is unclear at present.
Results of radical reactions of various alkenes are summarized
in Table 2. Since our preliminary experiments indicated that the
use of O2 gave better results than air in many cases, suitable atmo-
sphere for the reaction was different depending on each substrate.
⇑
Corresponding author. Tel./fax: +81 76 234 4439.
E-mail address: tsuyoshi@p.kanazawa-u.ac.jp (T. Taniguchi).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.07.026

T. Taniguchi et al. / Tetrahedron Letters 52 (2011) 4768–4770
4769
Table 2
Reactions of various alkenes
O
R2
(EtO)2PNHNH2 (2.5 equiv)
Fe(Pc) (10 mol%)
R2
O
P
HO
R1
OEt
OEt
R1
THF, Air or O2, 65 ºC
24 h
−
1a m
3b,4b-m
Entry Substrate
Atmosphere Producta
O
P
HO
OEt
OEt
X
X = H
X = Br
X = MeO
X = NO2
X
1
2
3
4
a
b
c
Air
O2
O2
Air
84%
81%
82%
39%
d
OH
O
P
Ph
OEt
OEt
5
e
f
O2
Ph
34%
HO
O
P
OEt
OEt
Scheme 1. Iron-catalyzed radical generation and oxidative addition to alkenes.
6
O2
74%
Table 1
O
P
Optimizations of reaction conditions
OEt
OEt
7
g
O2
OH
O
61%
(EtO)2PNHNH2
2b (2.5 equiv)
O
P
O
P
[Fe] catalyst
HO
Ph
OEt
OEt
HO
Ph
OEt
OEt
8
9
h
i
O2
Ph
Ph
THF, 65 ºC
24 h
3b
1a
60%
Entry
Fe catalyst
Atmosphere
Yield%a
O
P
HO
OEt
OEt
Air
1
2
3
4
5
6
FeCl3 (10 mol %)
Fe2O3 (10 mol %)
Fe(Pc) (10 mol %)
Fe(Pc) (10 mol %)
Fe(Pc) (5 mol %)
None
Air
Air
Air
O2
Air
Air
18
5
84
85
25
3
Ph
Ph
Ph
67%
O
P
HO
OEt
OEt
10
j
O2
O2
O2
Ph
52%
a
Yield of isolated product.
O
P
HO
OEt
OEt
TBDPSO
TBDPSO
11
k
l
18%
O
O
P
BuO
OEt
OEt
O
12b
BuO
(RO)2PNHNH2
2a d (2.5 equiv)
45%
−
a
3a
R = Me ( ): 83%
O
P
O
P
Fe(Pc) (10 mol%)
HO
O
OEt
OEt
HO
Ph
OR
OR
3b
R = Et ( ): 84%
O
Ph
THF, Air, 65 ºC
24 h
3c
R = iPr ( ): 31%
13
m
Air
1a
3d
R = Ph ( ): trace
OEt
OEt
53%
Scheme 2. Reactions using several phosphorohydrazidates (aTHF-MeOH (2:1) was
a
used as solvent).
Yield of isolated product.
THF-MeOH (2:1) was used as solvent.
b
Since additions of phosphorus-centered radicals to alkenes are sug-
gested to be reversible,1a high concentration of oxygen might be
required for the efficient trapping of the resultant carbon-centered
radical by oxygen depending on the radical instability. Various sty-
rene-type alkenes 1b–h underwent oxidative additions of the
phosphonyl radical to give corresponding b-hydroxyphosphonate
compounds 4b–h (Entries 2–8).9 Of these entries, p-nitro deriva-
tive 4d showed a moderate reactivity (Entry 4). The difference in
stability of benzyl-position radical intermediates generated by
addition of the phosphonyl radical might affect the reactivity. In
b-ketophosphonate derivative [PhCOCH2P(O)(OEt)2] was detected
along with b-hydroxyphosphonate 4e by 1H NMR analysis of the
crude material. Enyne 1i could be used as substrates and corre-
sponding b-hydroxyphosphonate compounds 4i were obtained in
reasonable yields (Entry 9).10 As shown in reactions of aliphatic
alkenes 1j and k, the generality of reactions using nonconjugated
alkenes is unlikely to be high (Entries 10 and 11).
When vinyl ether 1l was subjected to the present radical reac-
tion, a reaction involving over oxidation occurred to give diethyl-
the case of styrene (4e) (Entry 5),
a small amount of a

4770
T. Taniguchi et al. / Tetrahedron Letters 52 (2011) 4768–4770
phosphonoacetate 4l in moderate yield (Entry 12).11 Radical addi-
tion to ,b-unsaturated ester bearing an electron-deficient alkene
1m also proceeded to give corresponding b-hydroxyphosphonate
Bruch, A.; Ambrosius, A.; Fröhlich, R.; Studer, A.; Guthrie, D. B.; Zhang, H.;
Curran, D. P. J. Am. Chem. Soc. 2010, 132, 11452; (e) Lamas, M.-C.; Studer, A. Org.
Lett. 2011, 13, 2236.
a
4. (a) Taniguchi, T.; Sugiura, Y.; Zaimoku, H.; Ishibashi, H. Angew. Chem., Int. Ed.
2010, 49, 10154; (b) Taniguchi, T.; Idota, A.; Ishibashi, H. Org. Biomol. Chem.
2011, 9, 3151; (c) Taniguchi, T.; Zaimoku, H.; Ishibashi, H. Chem. Eur. J. 2011, 17,
4307.
5. Recent examples of phosphorus centered radical reactions under oxidative
conditions: (a) Kagayama, T.; Nakano, A.; Sakaguchi, S.; Ishii, Y. Org. Lett. 2006,
8, 407; (b) Mu, X.-J.; Zou, J.-P.; Qian, Q.-F.; Zhang, W. Org. Lett. 2006, 8, 5291; (c)
Elamparuthi, E.; Linker, T. Angew. Chem., Int. Ed. 2009, 48, 1853; (d) Xu, W.; Zou,
J.-P.; Zhang, W. Tetrahedron Lett. 2010, 51, 2639; (e) Zhou, J.; Zhang, G.-L.; Zou,
J.-P.; Zhang, W. Eur. J. Org. Chem. 2011, 3412; (f) Pan, Z.-Q.; Wang, L.; Zou, J.-P.;
Zhang, W. Chem. Commun. 2011, 47, 7875.
6. Recent reports on biological properties of b-hydroxyphosphonate compounds:
(a) Cui, P.; Tomsig, J. L.; McCalmont, W. F.; Lee, S.; Becker, C. J.; Lynch, K. R.;
Macdonald, T. L. Bioorg. Med. Chem. Lett. 2007, 17, 1634; (b) Macchiarulo, A.;
Pellicciari, R. J. Mol. Graphics Modell. 2007, 26, 728; (c) Woodyer, R. D.; Li, G.;
Zhao, H.; van der Donk, W. A. Chem. Commun. 2007, 359.
compounds 4m (Entry 13).
In conclusion, we have developed a new method for synthesis of
b-hydroxyphosphonate derivatives using a radical methodology.
Our present work includes several unique points compared with
known synthetic methods using phosphorus-centered radicals,
such as the use of phosphorohydrazidates as radical precursors
and the sequence of the process involving addition of phosphonyl
radicals and oxygenation of alkenes to produce of b-hydroxyphos-
phonate derivatives. We would also like to emphasize the simplic-
ity and safety of the experimental procedure using an inexpensive
and nontoxic iron catalyst and molecular oxygen.12
7. Recent examples of synthesis of b-hydroxyphosphonate compounds: (a) Orsini,
F.; Caselli, A. Tetrahedron Lett. 2002, 43, 7255; (b) Yamagishi, T.; Fujii, K.;
Shibuya, S.; Yokomatsu, T. Tetrahedron 2006, 62, 54; (c) Vargas, S.; Suárez, A.;
Álvarez, E.; Pizzano, A. Chem. Eur. J. 2008, 14, 9856; (d) Sobhani, S.; Vafaee, A.
Tetrahedron 2009, 65, 7691.
Acknowledgments
This research was supported by a Grant-in-Aid for Young Scien-
tists (B) (23790008) from the Ministry of Education, Culture,
Sports, Science and Technology (MEXT) of Japan.
8. Typical procedure: A mixture of
a-methylstyrene (1a) (50.0 mg, 0.423 mmol),
diethyl phosphorohydrazidate (2b) (178 mg, 1.06 mmol) and Fe(Pc) (24.0 mg,
0.0423 mmol) in THF (2.1 ml) was heated at 65 °C (reflux). After cooling to
room temperature, the resulting suspension was diluted with Et2O and
filtered. After removal of solvent under reduced pressure, the residue was
purified by silica gel column chromatography (hexane/EtOAc, 1:1) to give 3b
(97 mg, 84%) as a colorless oil.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.07.026.
9. In the reaction of vinylcyclopropane 1h, opening of the cyclopropane ring was
not observed due to the stability of the resultant benzyl radical. The similar
discussion has been described in our previous manuscript, see Ref. 4c.
10. Two resonance contributions of
a propargyl radical and a allenyl radical
References and notes
could be considered about the radical generated from enyne 1i, but no
allene product was observed. Formation of alkyne-type products has been
experimentally shown to be favored in the case of substituted propargyl
radicals, see: Fantazier, R. M.; Poutsma, M. L. J. Am. Chem. Soc. 1968, 90,
5490.
1. Review: (a) Studer, A.; Amrein, S. Synthesis 2002, 835; (b) Leca, D.; Fensterbank,
L.; Lacôte, E.; Malacria, M. Chem. Soc. Rev. 2005, 34, 858.
2. Recent examples: (a) Jessop, C. M.; Parsons, A. F.; Routledge, A.; Irvine, D. J.
Tetrahedron Lett. 2004, 45, 5095; (b) Antczak, M. I.; Montchamp, J.-L. Synthesis
2006, 3, 3080; (c) Hirai, T.; Han, L.-B. Org. Lett. 2007, 9, 53.
3. Recent examples: (a) Sato, A.; Yorimitsu, H.; Oshima, K. J. Am. Chem. Soc. 2006,
128, 4240; (b) Carta, P.; Puljic, N.; Robert, C.; Dhimane, A.-L.; Fensterbank, L.;
Lacôte, E.; Malacria, M. Org. Lett. 2007, 9, 1061; (c) Vaillard, S. E.; Mück-
Lichtenfeld, C.; Grimme, S.; Studer, A. Angew. Chem., Int. Ed. 2007, 46, 6533; (d)
11.
A
example of oxidative addition of phosphonyl radicals to enol ethers:
Mochizuki, T.; Hayakawa, S.; Narasaka, K. Bull. Chem. Soc. Jpn. 1996, 69, 2317.
12. Iron Catalysis in Organic Chemistry; Plietker, B., Ed.; Wiley-VCH: Weinheim,
2008.