Manganese(III)-mediated direct phosphonylation of arenes

Article abstract of DOI:10.1016/j.tetlet.2010.03.029

Manganese (III)-promoted direct phosphonylation of mono- and disubstituted arenes with dialkylphosphite afforded regioselective dialkylphosphonates in good yields. The reactions can apply to arenes bearing electron-donating groups and electron-withdrawing

Full text of DOI:10.1016/j.tetlet.2010.03.029

Tetrahedron Letters 51 (2010) 2639–2643
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Tetrahedron Letters
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Manganese(III)-mediated direct phosphonylation of arenes
b,
Wei Xu a, Jian-Ping Zou a, , Wei Zhang
*
*
a Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry and Chemical Engineering, Suzhou University, 199 Renai Street, Suzhou, Jiangsu 215123, China
b Department of Chemistry, University of Massachusetts Boston, 100 Morrissey Boulevard, Boston, MA 02125, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Manganese (III)-promoted direct phosphonylation of mono- and disubstituted arenes with dial-
kylphosphite afforded regioselective dialkylphosphonates in good yields. The reactions can apply to are-
nes bearing electron-donating groups and electron-withdrawing groups such as ester and nitrile.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 12 February 2010
Revised 5 March 2010
Accepted 8 March 2010
Available online 12 March 2010
.
Arylphosphonate compounds have broad applications in organ-
ic, medicinal, and agricultural chemistry.1 The general methods for
the preparation of arylphosphonates relay on the reactions of reac-
tive functional groups such as displacement arylhalides2 or phos-
pho-Fries rearrangement.3 Direct phosphonylations of C–H bonds
promoted by tert-butyl peroxide, CAN, or Na2S2O8/AgNO3 have
been reported.4–6 However, these reactions are mainly for arenes
bearing electron-donating groups and usually have low regioselec-
tivities. The Ishii group recently reported a direct phosphonylation
of arenes using Mn(OAc)2/Co(OAc)2/O2 redox system and gener-
ated a mixture of regioisomers.7 Reported in this Letter is a simple
Mn(OAc)3 H2O-promoted phosphonylation reaction system which
has improved regieoselectivities.8
We recently reported Mn(OAc)3-promoted direct phosphonyla-
tions of heteroarenes,9 alkenes, and alkynes.10 Since these reac-
tions have demonstrated a good regioselectivity, we envisioned
that they may be employed for reactions of arenes. In this project,
the reaction of toluene and diethylphosphite was first carried out
at 80 °C in the presence of Mn(OAc)3ꢀH2O and using acetic acid as
a solvent. A mixture of 2-, 3-, and 4-phosphonated products was
obtained in 92% yield. The major isomer 2a was isolated in 82%
yield (Table 1, entry 1). The reaction was then conducted at a
lower temperature of 60 °C in order to improve the regioselectiv-
ity. Under this condition, we found that 2a was the major product
in 90% isolated yield (entry 2). Decreasing temperature to 40 °C,
no reaction was observed even after 24 h (entry 3). Reactions
were also carried out at different ratios of Mn(III) to 1a (entries
4–6).
Table 1
Phosphonylation of toluenea
O
Phosphonylations of dimethylated benzenes were explored (Ta-
ble 2, entries 2–4).11 Except p-xylene, both m- and o-xylenes gave
two regioisomers. The reaction of tetrahydronaphthalene afforded
2e as a major product (entry 5). The reaction of methoxybenzene
gave 2- and 4-methoxybenzene phosphonates 2f and 2f0 in a ratio
of 82:18 (entry 6). The reaction of both 1,2- and 1,4-dimethoxy-
benzenes produced single products (entries 7 and 9), while that
of 1,3-dimethoxybenzene gave 2h and 2h0 in a ratio of 90:10 (entry
8). Reactions of methylene-1,3-dioxybenzene 1j and ethylene-1,3-
dioxybenzene 1k produced single products 2j and 2k, respectively
(entries 10 and 11). The regioisomer ratio was determined by iso-
lated yields, and their structures were determined by 3JHH and 3JPH
coupling constants of the 1H NMR.
Phosphonylations of arenes bearing electron-withdrawing
groups were also explored. Methylbenzoate mainly afforded
para-phosphonated product 2l (Table 3, entry 1). Dimethyl phthal-
ate and dimethyl isophthalate afforded single phosphonated prod-
ucts 2m and 2n in 73% and 75% yields, respectively (entries 2 and
3). Reactions of both cyanobenzene and 1,3-dicyanobenzene pro-
duced a single product (entries 4 and 6). The reactions of carbonyl
PO(OEt)2
Mn(OAc)3
AcOH
+
HP(OEt)2
1a
2a
Entry
Mn(III):1a
Temp (°C)
Time (h)
Yieldb (%)
1
2
3
4
5
6
3:1
3:1
3:1
4:1
2:1
1:1
80
60
40
60
60
60
7
7
24
7
7
7
92c
90
No reaction
90
75
32
a
Reaction conditions: toluene (3 mmol), diethylphosphite (6 mmol), and
Mn(OAc)3ꢀ2H2O (9 mmol) under air.
b
Overall yield of a mixture of 2-, 3-, and 4-tolylphosphonates.
c
2-Tolylphosphonate isolated in 82% yield.
* Corresponding authors. Tel./fax: +86 512 65880336 (J.-P. Z.); tel.: +1 617 287
6147; fax: +1 617 287 6030 (W.Z.).
E-mail addresses: jpzou@suda.edu.cn (J.-P. Zou), wei2.zhang@umb.ed (W.
Zhang).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.03.029

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W. Xu et al. / Tetrahedron Letters 51 (2010) 2639–2643
Table 2
Phosphonylation of arenes bearing electron-donating groupsa
R1
R1
O
Mn(OAc)3
R2
R2
HP(OEt)2
PO(OEt)2
+
AcOH
1a-k
2a-k
Entry
1
Substrate
Product
Yield (%)
90b
PO(OEt)2
1a
2a
PO(OEt)2
2
93c
PO(OEt)2
1b
2b
2b'
63 : 37
PO(OEt)2
(EtO)2OP
3
4
91c
87
1c
2c'
2c
75 : 25
PO(OEt)2
2d
1d
PO(OEt)2
PO(OEt)2
5
6
86c
1e
2e
2e'
70 : 30
OCH3
OCH3
OCH3
PO(OEt)2
90
1f
OCH3
1g
OCH3
2'f
PO(OEt)2
2f
82 : 18
OCH3
CH3O
CH3O
7
8
95
2g
PO(OEt)2
OCH3
OCH3
(EtO)2OP
CH3O
PO(OEt)2
91c
CH3O
OCH3
1h
CH3O
2h
2h'
90 : 10
OCH3
PO(OEt)2
9
85
1i
2i
OCH3
OCH3
O
O
O
O
1j
10
11
2j
90
85
PO(OEt)2
PO(OEt)2
O
O
O
O
1k
2k
a
b
c
Reaction conditions: arene (3 mmol), dialkylphosphite (6 mmol), and Mn(OAc)3ꢀ2H2O (9 mmol) in HOAc at 60 °C under air, 7 h for entries 1–5, 5 h for entries 6–11.
Isolated from a mixture of 2-, 3-, and 4-tolyphosphonates.
The ratio was determined by 1H NMR.
substituted arenes such as benzaldehyde and acetophenone had
low regioselectivities and yielded complex reaction mixtures (en-
tries 7 and 8) presumably due to the competitive reaction of dialkyl
phosphate with the carbonyl groups. The reaction of nitrobenzene
gave no product because the electron-withdrawing effect of the ni-
tro group is too strong which stop electrophilic phosphonyl radical
addition process (entry 9).
Phosphonylations of arenes bearing both electron-donating and
electron-withdrawing substituents were also conducted. The reac-
tion of methyl 4-methoxybenzoate 1r yielded single product 2r in

W. Xu et al. / Tetrahedron Letters 51 (2010) 2639–2643
2641
Table 3
Phosphonylation of arenes bearing electron-withdrawing groupsa
Entry
Substrate
Product
CO2CH3
Yield (%)
CO2CH3
CO2CH3
PO(OEt)2
1
85
1l
2l
2l'
70 : 30
PO(OEt)2
CO2CH3
CO2CH3
CH3O2C
CH3O2C
2
3
73
75
1m
2m
PO(OEt)2
CO2CH3
CO2CH3
PO(OEt)2
1n
2n
CH3O2C
CN
CH3O2C
CN
4
53b
1o
2o
PO(OEt)2
NC
CN
CN
CN
NC
NC
5
6
58
60
1p
1q
(EtO)2P
CN
PO(OEt)2
2p
2p'
78 : 22
CN
PO(OEt)2
2q
NC
NC
CHO
7
8
9
Complex mixture
Complex mixture
No reaction
COCH3
NO2
a
Reaction conditions: arene (3 mmol), dialkylphosphite (6 mmol), Mn(OAc)3ꢀ2H2O (9 mmol) in HOAc at 60 °C for 6 h under air.
b
Isolated from a mixture of 2-, 3-, and 4-phosphonated cyanobenzenes.
92% yield (Table 4, entry 1), while 1-methoxy-4-acetylbenzene 1s
afforded a mixture of 2s and 2s0 in a ratio of 85:15 (entry 2). Both
Methyl 4-methylbenzoate 1t and 1-methyl-4-acetylbenzene 1u
gave two regioisomers (entries 3 and 4).
toluene, and methyl benzoate were found not reactive under the
general reaction conditions (Table 5, entries 1–3). They each gave
a complicated mixture containing regioisomers at reflux condition.
Reactions of alkoxy benzene such as 1,2-dimethoxy-, 1,4-dime-
thoxy-, and methylene-1,3-dioxybenzenes gave phosphonylation
products 2v, 2w, and 2x in 40%, 45%, and 75% yields, respectively
(entries 4–6). The yields are lower than that of diethyl phosphite.
The method for direct phophonylation of arenes has been ap-
plied to the synthesis of ligands bearing phosphorus moiety, such
as 3,30-bis(OMe)-MeO-BIPHEP 11 (Scheme 2). The new method is
straightforward and it can be carried out under milder conditions
than those reported in literature.13 The structure of compound
13 has been confirmed by X-ray crystal analysis (Fig. 1).
In summary, we have demonstrated that manganese (III) ace-
tate can be used to promote the direct phosphonylation of substi-
tuted arenes with diethylphosphite or diphenylphosphine oxide.
The reaction scope and regioselectivity for mono- and disubsti-
tuted arenes have been explored. The mono-substituted arenes
afforded para- or ortho-phosphonylated compounds as the major
products, whereas 1,2-dimethoxybenzene, dimethyl phthalate,
1,3-dicyanobenzene, and methyl 4-methoxybenzoate produced
The results presented in Tables 2–4 indicate that Mn(OAc)3-pro-
moted direct phosphonylations have ortho and para regioselectivi-
ties for both electron-rich and electron-deficient arenes. A reaction
mechanism is proposed in Scheme 1. For the reaction of a mono-
substituted arene, phosphonyl radical 3 may attack ortho, meta,
and para positions to form radicals 4, 6, and 9. Since a aryl radical
can be stabilized by an electron-donating group or a withdrawing
group through the captodative effect,12 so the formations of radi-
cals 4 and 9 are favorable. The R group can be hyperconjugation
groups such as –CH3, electron-donating groups such as –OCH3
and –OCH2O–, or electron-withdrawing groups such as –CN and
–CO2CH3. After the phosphonyl radical addition, radicals 4 and 9
are then oxidized to cations followed by deprotonation to give 5
and 10 as the major products.
In order to evaluate the reactivity of different phosphorus re-
agents, reactions using diphenylphosphine oxide for phosphonyla-
tion of representative arenes were attempted (Table 5). Benzene,

2642
W. Xu et al. / Tetrahedron Letters 51 (2010) 2639–2643
Table 4
Phosphonylation of arenes bearing electron-donating and electron-withdrawing groupsa
Entry
Substrate
Product
Yield (%)
92
OCH3
OCH3
PO(OEt)2
2r
1r
1
CO2CH3
OCH3
CO2CH3
OCH3
OCH3
PO(OEt)2
1s
2
3
4
2s
2s'
PO(OEt)2
COCH3
CH3
90
80
86
COCH3
CH3
COCH3
CH3
85 : 15
76 : 27
65 : 35
PO(OEt)2
2t'
2t
1t
PO(OEt)2
CO2CH3
CO2CH3
CH3
CO2CH3
CH3
CH3
PO(OEt)2
2u'
1u
2u
PO(OEt)2
COCH3
COCH3
COCH3
a
Reaction conditions: arene (3 mmol), dialkylphosphite (6 mmol), and Mn(OAc)3ꢀ2H2O (9 mmol) in HOAc at 60 °C for 6 h under air.
R
a
Table 5
O
(EtO)2P
3
O
Phosphonylation with diphenylphosphine oxidea
Mn(III)
(EtO)2PH
b
Entry
Substrate
Product
Yield (%)
c
1
2
3
C6H6
CH3C6H5
C6H5CO2Me
No reaction
No reaction
No reaction
R
R
H
a
+
Mn(III)
(EtO)2OP
-H
OCH3
OCH3
(EtO)2OP
POPh2
5 major
4
45
4
2v
R
R
OCH3
H3CO
OCH3
H3CO
+
b
c
Mn(III)
-H
POPh2
2W
H
5
6
40
75
(EtO)2OP
(EtO)2OP
H3CO
O
H3CO
O
7 minor
6
POPh2
2X
R
R
R
O
O
+
Mn(III)
-H
a
Reaction conditions: arene (3 mmol), diphenylphosphine oxide (6 mmol), and
Mn(OAc)3ꢀ2H2O (9 mmol) in HOAc at 60 °C for 1 h under air.
H
H
PO(OEt)2
PO(OEt)2
PO(OEt)2
8
9
major
10
Scheme 1. Mechanism for regioselective phosphonylation.
OCH3
+
OCH3
I2
O
Mn(III)
Ph2PH
LDA/THF
75%
AcOH
45%
H3CO
H3CO
POPh2
2v
OCH3
OCH3
OCH3
Cu
[H]
H3CO
H3CO
POPh2
POPh2
H3CO
H3CO
PPh2
PPh2
DMF
80%
H3CO
POPh2
90%
I
OCH3
OCH3
13
12
11
Scheme 2. Synthesis of arylphosphonate ligand 11.
Figure. 1. X-ray crystal structure of compound 13.

W. Xu et al. / Tetrahedron Letters 51 (2010) 2639–2643
2643
NewYork, 1976; (c) Corbridge, D. E. C. Phosphorus: An Outline of Its Chemistry,
Biochemistry and Uses, 5th ed.; Elsevier: Amsterdam, 1995.
2. For a recent review, see: Gorrell, I. B.; Kee, T. P. Sci. Synth. 2007, 31b, 1393.
3. For a recent review, see: Taylor, C. M.; Watson, A. J. Curr. Org. Chem. 2004, 8,
623.
4. Jason, E. F.; Fields, E. K. J. Org. Chem. 1962, 27, 1402.
5. Kottmann, H.; Skarzewski, J.; Effenberger, F. Synthesis 1987, 797.
6. Effenberger, F.; Kottmann, H. Tetrahedron 1985, 41, 4171.
7. Kagayama, T.; Nakano, A.; Sakaguchi, S.; Ishii, Y. Org. Lett. 2006, 3, 407.
8. Selective reviews on Mn(III)-promoted reactions, see: (a) Jeught, S. V.; Stevens,
C. V. Chem. Rev. 2009, 109, 2672; (b) Pan, X.-Q.; Zou, J.-P.; Zhang, W. Mol. Divers.
2009, 13, 421; (c) Demir, A. S.; Emrullahoglu, M. Curr. Org. Chem. 2007, 4, 321;
(d) Snider, B. B. Chem. Rev. 1996, 96, 339.
single phosphonated products. In addition to arenes bearing elec-
tron-donating groups, this reaction also works for some arenes
bearing electron-withdrawing groups such as ester and nitrile,
but it has a low regioselectivity for arenes bearing carbonyl groups,
and is not reactive for nitrobenzene. The phosphonylation reaction
has been successfully used to synthesize phosphorus ligand 3,3’-bi-
s(OMe)-MeO-BIPH.
Acknowledgment
9. Mu, X.-J.; Zou, J.-P.; Zhang, W. Org. Lett. 2006, 8, 5291.
10. Pan, X.-Q.; Zou, J.-P.; Zhang, G.-L.; Zhang, W. Chem. Commun. 2010, 46, 1721–
1723.
J.P.Z. thanks the financial support from National Natural Science
Foundation of China (No. 20772088).
11. General procedures for phosphonylation. To a solution of toluene 1a (0.28 g,
3 mmol) and diethyl phosphite (0.83 g, 6 mmol) in glacial acetic acid (10 mL)
was added Mn(OAc)3ꢀ2H2O (2.41 g, 9 mmol). The mixture was heated at 60 °C
for 7 h until the solution color changed from brown to pale yellow. The mixture
was cooled, and 20 mL water was added, extracted with ethyl acetate for three
times (3 ꢁ 20 mL). The organic layer was dried over anhydrous Na2SO4,
filtered, and concentrated. The crude product was purified by flash column
chromatography on silica gel and eluted with 2:1 petroleum ether/acetone to
give diethyl o-tolylphosphonate 2a in 90% yield. The general procedures can be
used to prepare aryl phophonates shown in Tables 2–5.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.03.029.
References and notes
12. Stella, L.; Harvey, J. N.. In Radicals in Organic Synthesis; Renaud, P., Sibi, M. P.,
Eds.; Wiley-VCH: Weinheim, 2001; Vol. 1, pp 360–380.
13. Keay, B. A.; Gorobets, E. Tetrahedron Lett. 2004, 45, 3597.
1. (a) Swaminathan, S.; Narayanan, K. V. Chem. Rev. 1971, 71, 429; (b)Organic
Phosphorus Compounds; Kosolapoff, G. M., Maier, L., Eds.; Wiley-Interscience: