Wet and dry processes for the selective transformation of phosphonates to phosphonic acids catalyzed by br?nsted acids

Article abstract of DOI:10.1021/acs.joc.0c00550

A "wet"process and two "dry"processes for converting phosphonate esters to phosphonic acids catalyzed by a Bronsted acid have been developed. Thus, in the presence of water, a range of alkyl-, alkenyl-, and aryl-substituted phosphonates can be generally hydrolyzed to the corresponding phosphonic acids in good yields catalyzed by trifluoromethyl sulfonic acid (TfOH) at 140 °C (the wet process). On the other hand, with specific substituents of the phosphonate esters, the conversion to the corresponding phosphonic acids can be achieved under milder conditions in the absence of water (the dry process). Thus, the conversion of dibenzyl phosphonates to the corresponding phosphonic acids took place smoothly at 80 °C in toluene or benzene in high yields. Moreover, selective conversion of benzyl phosphonates RP(O)(OR′)(OBn) to the corresponding mono phosphonic acids RP(O)(OR′)(OH) can also be achieved under the reaction conditions. The dealkylation via the generation of isobutene of ditert- butyl phosphonate, and the related catalysis by TfOH took place even at room temperature to give the corresponding phosphonic acids in good to high yields. Nafion also shows high catalytic activity for these reactions. By using Nafion as the catalyst, phosphonic acids could be easily prepared on a large scale via a simple process.

Full text of DOI:10.1021/acs.joc.0c00550

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Article
Wet and Dry Processes for the Selective Transformation of
Phosphonates to Phosphonic Acids Catalyzed by Brønsted Acids
Chunya Li, Yuta Saga, Shun-ya Onozawa, Shu Kobayashi,
Kazuhiko Sato, Norihisa Fukaya, and Li-Biao Han
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00550 • Publication Date (Web): 21 May 2020
Downloaded from pubs.acs.org on May 22, 2020
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Wet and Dry Processes for the Selective Transformation of Phosphonates to
Phosphonic Acids Catalyzed by Brønsted Acids
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a,b
c
a
a
a
Chunya Li, Yuta Saga, Shun-ya Onozawa, Shu Kobayashi, Kazuhiko Sato,
a
a,b
Norihisa Fukaya, and Li-Biao Han*
aNational Institute of Advanced Industrial Science and Technology (AIST), Tsukuba,
Ibaraki 305-8565, Japan
bDivision of Chemistry, Faculty of Pure and Applied Sciences, University of Tsukuba,
Tsukuba, Ibaraki 305-8571, Japan.
cNew Products Development Laboratory, Maruzen Petrochemical Co., Ltd., Ichihara,
Chiba 290-8503, Japan
E-mail: libiao-han@aist.go.jp
Abstract: A “wet” process and two “dry” processes for converting phosphonate esters
to phosphonic acids catalyzed by a Brønsted acid have been developed. Thus, in the
presence of water, a range of alkyl, alkenyl and aryl substituted phosphonates can be
generally hydrolyzed to the corresponding phosphonic acids in good yields catalyzed
o
by trifluoromethyl sulfonic acid (TfOH) at 140 C (the wet process). On the other hand,
with specific substituents of the phosphonate esters, the conversion to the
corresponding phosphonic acids can be achieved under milder conditions in the absence
of water (the dry process). Thus, the conversion of dibenzyl phosphonates to the
o
corresponding phosphonic acids took place smoothly at 80 C in toluene or benzene in
high yields. Moreover, a selective conversion of benzyl phosphonates
RP(O)(OR’)(OBn) to the corresponding mono phosphonic acids RP(O)(OR’)(OH) can
also be achieved under the reaction conditions. The dealkylation via the generation of
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isobutene of ditert-butyl phosphonate and related catalyzed by TfOH took place even
at room temperature to give the corresponding phosphonic acids in good to high yields.
Nafion also shows high catalytic activity for these reactions. By using Nafion as the
catalyst, phosphonic acids could be easily prepared in a large scale via a simple process.
0
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a "wet" process
o
(a)
H O, 140 C
2
-
R'OH, - R"OH
cat. TfOH
or Nafion
a "dry" process
b) toluene(Ar-H), 80 C
O
OR'
o
(
O
O
OH
OH
OR'
OH
R P
or
OR"
R P
R P
-Bn-Ar
(
a) R', R" = alkyl, Ph
(b) R' = Bn, alkyl, R'' = Bn
c) R', R" = t-Bu, CH(CH3)Ph
a "dry" process
o
(c)
r.t. ~ 40 C
olefine
(
-
INTRODUCTION
Phosphonic acids are an important class of compounds in medical and agricultural
1
chemistry. For examples, fosfomycin is a clinically used antibiotic, FR-900098 is an
antimalarial, and alendronate is a widely employed anti-osteoporosis (Scheme 1).2a-2c
These phosphonic acids are also widely used in the preparation of hybrid functional
materials, as exemplified by compounds 4, DOTP 5 and 6 (Scheme 1).2d-2f Despite the
importance, efficient and general methods for their synthesis are limited (Scheme 2).1a,3-
8
Scheme 1. Selected Examples of Biomedicines and Hybrid Materials of
Phosphonic Acids.
Biomedicines
O
OH
O
P
OH
N
O
P
OH
OH
OH
OH
HO
P
P
OH
OH
H N
2
O
O
OH
O
1
2
3
fosfomycin
antibiotic)
FR-900098
(antimalarial)
alendronate
(anti-osteoporosis)
(
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Hybrid functional materials
O
P
O
P
O
P
O
P
HO
HO
OH
OH
OH
OH
OH
N
N
N
N
OH
organic or
inorganic
support
O
P
O
P
HO
HO
OH
OH
R
COOH
DOTP 5
chelator of metallic salts
6
4
modified on solid phase for
chromatography, or water
treatment
precursor of crystalline
1
1
1
1
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1
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4
5
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7
8
9
0
bone targeting, pH sensitive NMR probe
precursor of materials
hybrid material
Scheme 2. Synthesis of Phosphonic Acids.
Traditional Methods:
O
O
P
OR'
OR'
concentrated HCl or HBr
OH
OH
(
a)
R
R
P
R
R
reflux - R'X
O
P
O
P
OR'
OR'
1) 3 equiv. TMSX
OH
OH
(b)
2) H O or MeOH
2
(
X = Br, I) - R'X
O
P
1) 1.8 equiv. BBr , toluene/hexane
O
3
OR'
OR'
OH
P
(
c)
R
R
R
2) MeOH - R'Br
OH
O
P
O
2
~4 equiv. Amberlite 200C
OCH(CH )R'
OH
3
(
d)
e)
R
P
toluene
OCH(CH )R'
OH
3
O
P
O
2
equiv. TsOH
OR'
OR'
OH
(
R
R
R
R
P
OH
O
P
O
Pd/C, H2
OBn
OBn
OH
(
f)
R
P
OH
O
P
O
P
excess CF CO H
3
2
Ot-Bu
Ot-Bu
OH
OH
(g)
R
a "wet" process
h) H O, 140 C
This Work:
o
(
2
-
R'OH, - R"OH
a "dry" process
cat. TfOH
or cat. Nafion
O
P
O
P
O
o
OR'
(i) toluene(Ar-H), 80 C
OH
OH
OR'
OH
or
R
R
R
P
OR"
-Bn-Ar
(
h) R', R" = alkyl, Ph
(i) R' = Bn, alkyl, R'' = Bn
j) R', R" = t-Bu, CH(CH3)Ph
a "dry" process
(j)
o
(
r.t. ~ 40 C
olefine
-
Currently, phosphonic acids are generally prepared via the hydrolysis of dialkyl
phosphonates in hot concentrated hydrochloric acid (Scheme 2a)3 or using
4
halotrimethylsilanes (Scheme 2b). However, the former requires a rather harsh
reaction conditions and the later uses expensive halosilanes. Two equivalents of the
toxic R’X were concomitantly generated from the reactions. In addition, the purification
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of the obtained phosphonic acids from the mixture was also a hard work. Dealkylation
5
of dialkyl phosphonates could also be achieved by using BBr (Scheme 2c). Nitta et al
3
reported the reaction of phosphonates with a cation-exchange resin (Amberlite 200C)
6
a
6b
(
Scheme 2d) or TsOH (Scheme 2e) to prepare phosphonic acids. However, all these
0
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reactions require an excess amount of BBr , cation exchange resin (Amberlite 200C) or
3
TsOH. Hydrolysis by the palladium-catalyzed debenzylation with hydrogen was also
7
known (Scheme 2f). However, the contamination of the heavy metal in the resulted
phosphonic acids could be a problem. Ditert-butyl phosphonate was also used to
prepare the corresponding phosphonic acid by treating it with a large excess amount of
trifluoroacetic acid (Scheme 2g).8
Herein, we report two catalytic ways for converting phosphonate esters to
phosphonic acids, i.e. the wet process: a Brønsted acid TfOH can catalyze the
hydrolysis of phosphonate esters to produce the corresponding phosphonic acids in
good to high yields in the presence of water (Scheme 2h), and the dry process: in the
absence of water, benzyl phosphonates can be converted to the corresponding
phosphonic acids under mild conditions in toluene (Scheme 2i). In addition,
monosubstituted phosphonic acids could be selectively obtained by using this dry
process from the corresponding benzyl phosphonates (Scheme 2i). Moreover, tert-butyl
phosphonates and related can readily give the corresponding phosphonic acids even at
room temperature (Scheme 2j). The recyclable solid acid Nafion also shows high
catalytic activity for these reactions. By using Nafion as the catalyst, phosphonic acids
can be easily prepared from the corresponding phosphonate esters in gram-scale
reaction via a simple process.
RESULTS AND DISCUSSION
The “wet” process for converting phosphonate esters to phosphonic acids.
As an extension of our study on the selective cleavage of C–O and P–O bonds of
9
phosphites (RO) P catalyzed by a Brønsted acid, we found that TfOH was able to
3
catalyze the C–O cleavage of dimethyl vinylphosphonate (1a) to generate the
corresponding vinylphosphonic acid in the presence of water. As shown in Table 1,
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2% yield of 2a was obtained by heating a mixture of 1a and water in the presence of
0 mol% H PO (Table 1, entry 1). Only 27% yield of 2a was formed under similar
1
3
3
reaction conditions without the acid (Table 1, entry 2). When 1a was treated with a
perfluorinated sulfonic acid (TfOH) under similar conditions, the yield of 2a increased
to 96% (Table 1, entry 3). The yield of 2a reduced to 52% when the reaction was
conducted at 120 °C (Table 1, entry 4). This reaction also took place smoothly by using
only 2 equivs water (Table 1, entry 5). Under similar reaction conditions, 1a was heated
1
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1
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9
0
o
at 140 C for 8 h and 16 h to produce 2a in 65% and 93% yield, respectively (Table 1,
10
entries 6 and 7). Practically importantly, a solid acid Nafion is equally active as the
catalyst, affording almost a quantitative yield of 2a under similar reaction conditions
(Table 1, entry 8). As described below, the use of Nafion catalyst can dramatically
simplify the preparation process of phosphonic acids since unlike the difficult removal
8
a
of TfOH from the products Nafion can be easily separated from the products by a
simple filtration.10
Table 1. A Brønsted Acid-Catalyzed Hydrolysis of 1a.a
O
P
O
P
cat., H O
2
+
MeOH
OMe
OMe
OH
OH
1a
2a
b
entry
cat.
H O
2
temperature/℃ time yield (2a)
1
2
3
4
5
6
7
8c
H PO 0.2 mL
140
140
140
120
140
140
140
140
24 h
24 h
24 h
24 h
24 h
8 h
92%
27%
96%
52%
88%
65%
93%
95%
3
3
none 0.2 mL
TfOH 0.2 mL
TfOH 0.2 mL
TfOH 2 equiv.
TfOH 0.2 mL
TfOH 0.2 mL
Nafion 0.2 mL
16 h
24 h
a
Reaction conditions: a mixture of 1a (2.53 mmol), catalyst (10 mol%) and H O was
2
b
31
c
heated for 24 h in a 10 mL sealed glass tube. Yields based on P NMR analysis. 10
mg was used.
This hydrolysis reaction was rather general for the synthesis of phosphonic acids. A
variety of phosphonate esters under the present reaction conditions gave the
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
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3
3
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4
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6
Table 2. Hydrolysis of Phosphonate Esters Catalyzed by TfOH.a
O
10 mol% TfOH, H O
O
2
R P OR`
OR`
R P OH
OH
o
140 C, 24 h
1
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
entry
1
substrate 1
product 2 (isolated yield)
O
O
1a
2a, 91%
P OMe
OMe
P OH
OH
O
O
2b
3
1
b
2a, 76%
P OEt
OEt
P OH
OH
O
O
1c
2a, 96%
P OCH CF
OCH CF
P OH
OH
2
3
2
3
O
O
4
5
1d
1e
2a, 95%
2e, 89%
P OPh
OPh
P OH
OH
O
O
P OMe
OMe
P OH
OH
O
O
6
1f
2f, 93%
2g, 90%
Me P OMe
OMe
Me P OH
OH
O
O
7b
8
1g
Ph P OMe
OMe
Ph P OH
OH
O
O
1h
1i
2h, 54%
2i, 81%
n-C H
P OMe
OMe
n-C H
P OH
OH
6
13
6
13
O
O
9
Ph
P OMe
OMe
Ph
P OH
OH
a
Reaction conditions: a mixture of 1 (2.53 mmol), 10 mol% TfOH and 0.2 mL H O was
2
b
heated under air in a 10 mL sealed glass tube at 140 °C for 24 h. 48 h.
corresponding phosphonic acids 2 in good to excellent yields. As shown in Table 2,
compared to dimethyl vinylphosphonate 1a, the hydrolysis of diethyl vinylphosphonate
1
b (Table 2, entry 2) was slow and 76% yield of vinylphosphonic acid was obtained
after 48 h heating. In contrast, bis(2,2,2-trifluoroethyl) vinylphosphonate 1c readily
produced vinylphosphonic acid 2a in 96% yield (Table 2, entry 3). Therefore, an
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electron-deficient group fastens the hydrolysis. Similarly, diphenyl vinylphosphonate
1
d (Table 2, entry 4) was also readily hydrolyzed to give a high yield of
vinylphosphonic acid 2a under the standard conditions. Under similar conditions,
allylphosphonic acid 2e was obtained in 89% yield by the hydrolysis of the
corresponding dimethyl allylphosphonate 1e (Table 2, entry 5). Methylphosphonic acid
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
f and phenylphosphonic acid 2g were also obtained from the hydrolysis of the
corresponding dimethyl phosphonates 1f and 1g, in high yields (Table 2, entries 6 and
), respectively. Similarly, the hydrolysis of dimethyl 1-octen-2-yl-phosphonate 1h and
7
dimethyl (1-phenylvinyl)phosphonate 1i (Table 2, entries 8 and 9) produced good
yields of the corresponding phosphonic acids 2h and 2i, respectively.
Table 3. A Brønsted Acid-Catalyzed Debenzylation of 1j.a
O
P
O
P
cat.,solvent
Ph
OBn
OBn
Ph
OH
OH
1j
2g
b
entry
cat.
solvent temperature/℃ time yield (2g)
1
2
3
4
5
6
7
8
9
TfOH toluene
TfOH toluene
TfOH toluene
TfOH toluene
TfOH toluene
TfOH benzene
TfOH benzene
TfOH benzene
TfOH CH Cl
80
80
80
60
40
80
80
80
80
80
80
80
80
4 h
6 h
8 h
8 h
8 h
8 h
12 h
16 h
8 h
8 h
8 h
8 h
8 h
25%
54%
>99%
8%
2%
35%
68%
>99%
trace
N.D.
N.D.
N.D.
>99%
2
2
1
0
TfOH
H O
2
11
none toluene
H PO toluene
1
1
2
3
3
3c Nafion toluene
aReaction conditions: a mixture of 1j (0.5 mmol) and a catalyst (10 mol%) in a solvent
b
31
(
1 mL) was heated in a 10 mL sealed glass tube. Yields based on P NMR analysis
c
dissolved in methanol. 10 mg was used.
“Dry” processes for converting phosphonate esters to phosphonic acids.
As described above, the wet process by the hydrolysis of phosphonates with water
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4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
catalyzed by a Brønsted acid could give the corresponding phosphonic acids. However,
o
a long-time heating at a high temperature (140 C) was necessary. In addition, the
removal of water from the products under vacuum also takes a long time. Therefore, a
more efficient process for converting phosphonate esters to phosphonic acids under dry
and mild conditions is desirable. Fortunately, we could solve this problem. Thus, to our
delight, we found that, in the absence of water, by simply heating dibenzyl
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
o
phenylphosphonate 1j in benzene or toluene at 80 C in the presence of a catalytic
amount of TfOH, the debenzylation took place efficiently to produce the corresponding
phosphonic acid 2g in high yields (Table 3). For example, in the presence of 10 mol%
o
TfOH, 1j was heated in toluene at 80 C for 4 h and 6 h to produce 2g in 25% and 54%
11
yield, respectively. (Table 3, entries 1 and 2). When the reaction time was extended to
8
2
h, a quantitative yield of 2g was obtained (Table 3, entry 3). However, only 8% and
o
o
% yields of 2g were obtained when the reactions were performed at 60 C and 40 C,
respectively (Table 3, entries 4 and 5). The debenzylation took place slowly in benzene,
o
and 35% and 68% yields of 2g were obtained at 80 C in 8 h and 12 h, respectively
(Table 3, entries 6 and 7). When the reaction time was extended to 16 h, a quantitative
yield of 2g was also produced (Table 3, entry 8). In CH Cl , only a trace amount of
2
2
product was detected (Table 3, entry 9). For comparison, 2g could not be observed at
all in water (Table 3, entry 10). No reaction took place in the absence of the acid catalyst
(
Table 3, entry 11) or with H PO (Table 3, entry 12), showing the exceptional catalytic
3 3
reactivity of the perfluorinated sulfonic acids for this reaction. Solid Nafion was also
active for this reaction, and gave a quantitative yield of 2g under similar reaction
conditions (Table 3, entry 13).
This efficient debenzylation reaction could be applied to other substrates. As shown
in Table 4, dibenzyl vinylphosphonate 1k and octylphosphonate 1l also gave the
corresponding vinylphosphonic acid 2a and octylphosphonic acid 2l in 93% and 95%
yield, respectively, under similar conditions (Table 4, entries 2 and 3). Similarly, diallyl
phenylphosphonate produced phenylphosphonic acid 2g in 75% yield (Table 4, entry
4
). However, phenylphosphonic acid 2g was not formed at all from dimethyl
phenylphosphonate (Table 4, entry 5) under this water-free condition. This novel
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Table 4. Selective Generation of Phosphonic Acids by Debenzylation of Benzyl
Phosphonates and Related Catalyzed by TfOH.a
O
O
10% TfOH, toluene
R P OR`
OR``
R P OH
OH
o
80 C, 8 h
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
entry
1
substrate 1
product 2 (isolated yield)
O
O
Ph P OBn
OBn
1j
Ph P OH
OH
2g, 90%
2a, 93%
2l, 95%
2g, 75%
O
O
2
P OBn
OBn
1k
P OH
OH
O
O
3b
n-C H
P OBn 1l
OBn
n-C8H17 P OH
8
17
OH
O
O
4c
5
Ph P Oallyl
Oallyl
1m
1g
Ph P OH
OH
O
O
Ph P OMe
OMe
Ph P OH
OH
2g, N.D
2n, 82%
O
O
1
n
6
Ph P OBn
MeO
Ph P OH
MeO
O
O
7
8
1o
1p
2o, 93%
2p, 94%
EtO P OBn
EtO
EtO P OH
EtO
O
O
EtO P OBn
OBn
EtO P OH
OH
aReaction conditions: a mixture of 1 (0.5 mmol), 10 mol% TfOH and 1 mL toluene was
b
c
heated in a 10 mL sealed glass tube at 80 °C for 8 h. 100 °C, 24 h. 120 °C, 24 h.
difference in reactivity between methyl and benzyl groups makes the generation of
monosubstituted phosphonic acids possible via selective dealkylation of phosphonates
and related. For example, the benzyl group was selectively removed from benzylmethyl
phenylphosphonate 1n to produce methyl phenylphosphonic acid 2n in 82% yield
(Table 4, entry 6). Similarly, benzyldiethyl phosphate and dibenzylethyl phosphate
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
were selectively debenzylated to selectively produce the disubstituted phosphoric acid
diethyl phosphoric acid 2o and monosubstituted phosphoric acid monoethyl phosphoric
acid 2p in 93% and 94% yield, respectively (Table 4, entries 7 and 8). Note that a
selective synthesis of these phosphoric acid derivatives is rather difficult and required
complicated manipulations.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Table 5. A Brønsted Acid-Catalyzed Detert-butylation of 1q.a
O
P
O
P
cat., solvent
Ph
Ot-Bu
Ot-Bu
Ph
OH
OH
1q
2g
b
entry
cat.
solvent temperature/℃ time yield (2g)
1
2
3
4
5
6
7
8
9c
TfOH toluene
TfOH toluene
TfOH toluene
TfOH toluene
TfOH benzene
80
60
40
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
30 min
30 min
2 h
5 h
5 h
5 h
5 h
5 h
8 h
>99%
>99%
>99%
>99%
92%
90%
N.D.
N.D.
>99%
TfOH CH Cl
2
2
none toluene
H PO toluene
3
3
Nafion toluene
aReaction conditions: a mixture of 1q (0.5 mmol) and a catalyst (10 mol%) in a solvent
b
31
(
1 mL) was heated in a 10 mL sealed glass tube. Yields based on P NMR analysis
c
dissolved in methanol. 10 mg was used.
Worth noting is that, when the benzyl group was replaced by tert-butyl, the reaction
could take place at room temperature to give almost a quantitative yield of the
corresponding phosphonic acid 2g (Table 5). For example, in the presence of 10 mol%
o
o
TfOH, 1q was heated in toluene at 80 C or 60 C for 30 minutes to produce 2g in
quantitative yield (Table 5, entries 1 and 2). A quantitative yield of 2g was also obtained
o
by carrying out the reaction at 40 C for 2 h or at room temperature for 5 h (Table 5,
entries 3 and 4). Similarly, the dealkylation also took place in benzene or CH Cl to
2
2
give 2g in 92% and 90% yield, respectively (Table 5, entries 5 and 6). It was noted that
no reaction took place in the absence of the acid (Table 5, entry 7) or with H PO (Table
3
3
5
, entry 8), showing the exceptional catalytic reactivity of the perfluorinated sulfonic
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acids for this reaction. Solid Nafion was also active for this reaction, and gave a
quantitative yield of 2g under similar reaction conditions (Table 5, entry 9).
Table 6. Generation of Phosphonic Acids by Dealkylation Catalyzed by TfOH.a
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
O
O
10% TfOH, toluene
R P OR`
OR`
R P OH
OH
o
4
0 C, 2 h
1
2
entry
1
substrate 1
product 2 (isolated yield)
O
O
Ph P Ot-Bu
Ot-Bu
1q
Ph P OH
OH
2g, 95%
O
O
2
Ph P OCH(CH )Ph 1r
3
Ph P OH
OH
2g, 94%
2g, 92%
2a, 92%
2l, 61%
OCH(CH )Ph
3
O
O
3b
4b
5c
Ph P Oi-Pr
Oi-Pr
1s
1t
Ph P OH
OH
O
O
P Oi-Pr
Oi-Pr
P OH
OH
O
O
1u
n-C H
P Oi-Pr
Oi-Pr
n-C H
8 17
P OH
OH
8
17
aReaction conditions: a mixture of 1 (0.5 mmol), 10 mol% TfOH and 1 mL toluene was
b
c
o
heated in a 10 mL sealed glass tube at 40 °C for 2 h. 120 °C, 24 h. 120 C, 50 h.
This efficient dealkylation reaction could also be applied to other sec-alkyl
substituent phosphonates. As shown in Table 6, di(1-phenylethyl) phenylphosphonate
1
r also gave the corresponding phenylphosphonic acid 2g in 94% yield under similar
conditions (Table 6, entry 2). Moreover, diisopropyl phenylphosphonate 1s also
produced phenylphosphonic acid 2g in 92% yield under similar conditions, though a
higher temperature was required (Table 6, entry 3). Similarly, diisopropyl
vinylphosphonate and octylphosphonate were deisopropylated to produce the
corresponding vinylphosphonic acid 2a and octylphosphonic acid 2l in 92% and 61%
yield, respectively (Table 6, entries 4 and 5).
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Scheme 3. 10 mmol-Scale Reactions Using Solid Acid Nafion as the Catalyst.
O
P
O
P
Nafion (20 mg), H O (1.5 mL)
2
(a)
OMe
OMe
OH
OH
o
1
40 C, 24 h
1a
2a, 1.03 g
10 mmol
95% isolated yield
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
O
O
Nafion (33 mg), toluene (7 mL)
Ph
P
OR
OR
0 mmol
Ph
P
OH
OH
1
2
g, 1.48 g
o
(
b) 1j, R = Bn, 80 C, 50 h
94% isolated yield
2g, 1.53 g
97% isolated yield
o
(
c) 1q, R = t-Bu, 40 C, 12 h
The advantages of the present methods compared to the old ones are apparent (See
1
0
ESI for details) as demonstrated in Scheme 2. As shown in Scheme 3a, a trace amount
of Nafion catalyst effectively catalyzed the conversion of 1a to 2a in a 10 mmol scale
reaction of dimethyl vinylphosphonate 1a with water. After the reaction, a simple
filtration removing the solid catalyst Nafion followed by evaporation of the solution
under vacuum could give highly pure vinylphosphonic acid in a high yield. Similarly,
as shown in Scheme 3b and 3c, all the reactions are very efficient for the conversion of
1
j and 1q, to give the corresponding phosphonic acid 2g in 94% and 97% isolated yields,
respectively, by simply removing the solid catalyst via filtration.
Scheme 4. A Proposed Mechanism of the Hydrolysis of Dialkyl Phosphonates
Catalyzed by a Brønsted Acid in Water.
O
OR`
R P
R`OH
OH
6
H O
2
H
TfO
H
TfO
H
TfO
TfO H
O
O
TfOH
3
O
O
OR`
OR`
OR`
OR`
OH
O R`
R P
R P
R P
R P
O R`
OH
4
H O
2
5
7
8
O
OR`
R`OH
O
R P
OH
OH
OR`
R P
2
1
On the bases of the literatures reported,12,13 a plausible mechanism of the hydrolysis
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of dialkyl phosphonates catalyzed by Brønsted acid in water was proposed (Scheme 4).
Firstly, TfOH may protonize dialkyl phosphonate 1 to give the intermediate 4 which
was transformed to phosphonium salt 5. Phosphonium salt 5 may undergo C–O
cleavage via a S 2-type attack of H O at the R’ group of 5 to give intermediate 6, R’OH,
N
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
-
14
and regenerate TfOH, as TfO is a weak nucleophile. On the one hand, the regenerated
TfOH may then protonize 6 to give the 7 and 8. Subsequently, phosphonium salt 8
reacts with water to produce 2, R’OH, and regenerate TfOH.
It should be noted that the above S 2-type C–O bond cleavage mechanism might not
N
be applicable to diphenyl phosphonates RP(O)(OPh) . Alternatively, a P–O bond
2
cleavage, rather than an O–Ph bond cleavage, might take place in cases of
RP(O)(OPh)2.1a
On the other hand, to probe the debenzylation reaction mechanism in toluene or
benzene, control reactions were conducted (Scheme 5) (See ESI for details). When
dibenzyl phenylphosphonate 1j was allowed to debenzylate in benzene-d catalyzed by
6
TfOH under the standard reaction conditions, 3 having a C D unit was produced in
6
5
1
almost a quantitative yield as determined by H NMR spectroscopy using 1,4-dioxane
as an internal standard, indicating that the reaction took place as shown in Scheme 5.15
Scheme 5. The Reaction of Dibenzyl Phenylphosphonate (1j) with Benzene-d6
Catalyzed by TfOH.
O
P
O
P
10 mol% TfOH
+
C6D6
2
+
C6D5
Ph
OCH Ph
Ph
Ph
OD
OD
2
o
8
0 C
OCH Ph
2
3
(0.288 mmol,
96% yield)
1
j (0.15 mmol)
0.5 mL
2g’
The mechanism is not fully understood at present. A plausible mechanism of the
debenzylation of dibenzyl phosphonates catalyzed by a Brønsted acid in benzene was
shown in Scheme 6.6,11 TfOH may firstly protonize dibenzyl phosphonate 1 to give the
intermediate 4 which could be transformed to phosphonium salt 5. Phosphonium salt 5
may directly decompose undergo C–O cleavage via a S 1-type mechanism to give 9
N
and intermediate 6. Then 9 reacts with benzene to give diphenylmethane that could be
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9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
6
detected by GC-MS and regenerates TfOH. The regenerated TfOH then should further
react with 6 to produce 2.
Scheme 6. A Proposed Mechanism of the Debenzylation of Dibenzyl Phosphonate
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
1j) Catalyzed by Brønsted Acid in Benzene.
O
OCH Ph
2
R
P
6
OH
PhCH2 OTf
9
C H
6
6
H
TfO
H
TfO
PhCH Ph
2
H
TfO
TfO
H
O
P
O
P
O
P
O
P
OCH Ph
OCH Ph
TfOH
3
2
2
OCH Ph
O
CH Ph
2
R
R
2
R
R
O
CH Ph
OCH Ph
4
2
2
OH
7
OH
PhCH2Ph
5
8
C H
6
6
PhCH2 OTf
O
9
O
OH
P
OCH Ph
R
2
R
P
OH
2
OCH Ph
2
1
The detert-butylation reaction was considered as a similar reaction with the well-
employed regeneration of an alcohol ROH from t-BuOR by the deprotection of the tert-
1
7
butyl group. Indeed, when ditert-butyl phenylphosphonate 1q was allowed to react in
benzene-d in the presence of TfOH under the standard reaction conditions, isobutene
6
1
4
was generated as confirmed by H NMR spectroscopy (Scheme 7).
Scheme 7. The Detert-butylation of Ditert-butyl Phenylphosphonate (1q) in
Benzene-d Catalyzed by TfOH.
6
O
P
O
P
1
0 mol% TfOH
+
Ph
Ot-Bu
Ot-Bu
Ph
OH
OH
C D (0.5 mL), r.t.
6
6
1
q (0.15 mmol)
4
2g
In summary, we have developed a wet and two dry methods to prepare phosphonic
acids from phosphonate esters catalyzed by Brønsted acids. A variety of phosphonates
could be efficiently protonated in water or, in the absence of water, in toluene and
benzene. Furthermore, selective monodealkylation of dialkyl phosphonates could be
achieved by employing this Brønsted acid-catalyzed method in toluene under mild
conditions. The reusable solid acid Nafion could be used as the catalyst for these
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reactions, that made the preparation of phosphonic acids simple and easy.
EXPERIMENTAL SECTION
General Information
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Unless otherwise noted, reactions with water were carried out in Schlenk tubes under
air atmosphere, and reactions with toluene were carried out in oven-dried Schlenk tubes
under Ar atmosphere. All reagents were purchased and used as received. Phosphonate
esters were either purchased or prepared from the corresponding alcohols and
6
a
phosphorochloridate according to literature procedures. Mass spectra were recorded
at Shimadzu GCMS-QP 2010 plus spectrometer. Flash column chromatography was
1
13
31
performed using 200-300 mesh silica gel. H, C, and P NMR were recorded on a
JEOL JNM-ECS400 (400 MHz for 1H, 100 MHz for 13C, and 162 MHz for 31
P
1
spectroscopy). Chemical shifts for H NMR are referred to internal Me Si (0 ppm) and
4
reported as follows: chemical shift (δ ppm), multiplicity, coupling constant (Hz) and
31
integration. Chemical shifts for P NMR were relative to H PO (85% solution in D O,
3
4
2
0
ppm).
(a) A typical procedure for TfOH-catalyzed hydrolysis of phosphonate esters in
H O: To a 10 mL Schlenk tube in air was added dimethyl vinylphosphonate 1a (0.59
2
mL, 5 mmol), H O (0.4 mL) and trifluoromethanesulfonic acid (44.2 µL, 10 mol%).
2
o
The tube was heated at 140 C using a heating aluminum block for 24 h and 1a was
3
1
consumed as confirmed by P NMR spectroscopy. After removal of the volatiles, the
residues (light brown oil) were purified by passing through a short silica gel column
(200-300 mesh, dichloromethane/methanol = 4:1 as eluent) to obtain pure product 2a
(colorless oil) in 91% isolated yield (491.5 mg) after removing the volatiles under
o
vacuum (ca 20 Pa) at 130 C overnight.
(
b) 10 mmol-Scale hydrolysis of dimethyl vinylphosphonate with H O using Nafion
2
as catalyst: To a 10 mL Schlenk tube was added dimethyl vinylphosphonate 1a (1.19
o
mL, 10 mmol), H O (1.5 mL) and Nafion (20 mg). The tube was then heated at 140 C
2
for 24 h. Pure 2a was obtained after filtration removing Nafion and evaporation under
vaccum removing volatiles in 95% isolated yield (1.03 g).
(c) A typical procedure for TfOH-catalyzed debenzylation of phosphonates in
toluene: To a 10 mL Schlenk tube was added dibenzyl phenylphosphonate 1j (676.8
mg, 2 mmol), trifluoromethanesulfonic acid (17.7 µL, 10 mol%) and toluene (2 mL)
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o
under Ar. The tube was then heated at 80 C for 24 h. The product precipitated as a light
brown solid. After removal of the liquids, the residues (light brown solid) were purified
by passing through a short silica gel column (200-300 mesh, dichloromethane/methanol
=
3:1) to obtain 2g (white solid) in 91% isolated yield after drying under vacuum (287.8
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mg).
(d) 10 mmol-Scale debenzylation of phosphonates in toluene using Nafion as
catalyst: To a 25 mL Schlenk tube was added dibenzyl phenylphosphonate 1j (3.4 g,
1
8
0 mmol), Nafion (33 mg) and toluene (7 mL) under Ar. The tube was then heated at
o
0 C for 50 h. Water was added to dissolve the product precipitated out and then Nafion
was removed by filtration. The aqua solution was collected and volatiles were pumped
off under vacuum to give pure 2g as a white solid in 94% isolated yield (1.48 g).
(
e) A typical procedure for TfOH-catalyzed detert-butylation of phosphonates in
toluene: To a 10 mL Schlenk tube was added ditert-butyl phenylphosphonate 1q (540.6
mg, 2 mmol), trifluoromethanesulfonic acid (17.7 µL, 10 mol%) and toluene (2 mL)
o
under Ar. The tube was then heated at 40 C for 2 h and 1q was completely consumed.
The product precipitated out as a light brown solid. After removal of the liquid mixture,
the residues (light brown solid) were purified by passing through a short silica gel
column (200-300 mesh, dichloromethane/methanol = 3:1 as eluent) to obtain pure
product 2g in 92% isolated yield (white solid, 290.9 mg).
(
f) 10 mmol-Scale de-tert butylation of phosphonates in toluene catalyzed by
Nafion: To a 25 mL Schlenk tube was added ditert-butyl phenylphosphonate 1q (2.7
g, 10 mmol), Nafion (33 mg) and toluene (7 mL) under Ar. The tube was then heated
o
at 40 C for 12 h. The product precipitated as a white solid. 7 mL MeOH was added to
dissolve the white solid. Pure 2g was obtained after filtration removing Nafion and
pumping off the volatiles under vacuum in 97% isolated yield (white solid, 1.53 g).
(
g) The reaction of dibenzyl phenylphosphonate (1j) in benzene-d catalyzed by
6
TfOH: To an NMR tube was added dibenzyl phenylphosphonate 1j (50.8 mg, 0.15
1
mmol) and C D (0.5 mL), and its H NMR was taken. Trifluoromethanesulfonic acid
6
6
(
1.3 µL, 10 mol%) was then added to the NMR tube. The tube was gently shaken at
1
room temperature for ca. 0.5 h, and was subjected to H NMR measurement again. The
o
1
tube was then heated at 80 C, and its H NMR were taken after 1 h and 13 h,
1
o
respectively. H NMR revealed that the reaction completed after 13 h at 80 C. 1,4-
Dioxane (25.7 µL, 0.3 mmol) was added to the NMR tube as an internal standard, and
1
H NMR showed that diphenylmethane-d was obtained in 96% yield (0.288 mmol).
5
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(
h) The detert-butylation of ditert-butyl phenylphosphonate (1q) in benzene-d6
catalyzed by TfOH: To an NMR tube was added ditert-butyl phenylphosphonate 1q
1
(40.6 mg, 0.15 mmol) and C D (0.5 mL) and subjected to H NMR measurement.
6
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Trifluoromethanesulfonic acid (1.3 µL, 10 mol%) was then added to the NMR tube.
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The tube was slightly shaken at room temperature and was subjected to H NMR
1
measurement after 0.5 h, 1.5 h, 3.5 h and 5 h, respectively. H NMR showed that the
reaction completed after 5 h and isobutene 4 was generated.
1
13
31
H, C and P NMR Spectral Data of the Products
Vinylphosphonic acid (2a).18a Colorless oil (248.7 mg, 91%). H NMR (400 MHz,
1
13
D O): δ 5.70‒5.66 (m, 2H), 5.64‒5.63 (m, 1H). C{1H} NMR (100 MHz, D O): δ
2
2
31
1
33.8, 126.7 (d, JC-P = 176.6 Hz). P NMR (162 MHz, D O): δ 16.7.
2
Allylphosphonic acid (2e).18b White solid (274.8 mg, 89%). H NMR (400 MHz,
1
1
3
(CD ) CO): δ 8.89 (s, 2H), 5.90 (s, 1H), 5.34‒5.27 (m, 2H), 2.74‒2.71 (m, 2H). C{1H}
3 2
NMR (100 MHz, (CD ) CO): δ 128.5 (d, J = 20.0 Hz), 119.6 (d, JC-P = 10.9 Hz),
3
2
C-P
3
1
3
2.6 (d, JC-P = 140.1 Hz). P NMR (162 MHz, (CD ) CO): δ 28.4.
3 2
Methylphosphonic acid (2f).18c Colorless oil (225.9 mg, 93%). H NMR (400 MHz,
1
13
D O): δ 1.28 (dt, J = 17.2 Hz, 5.2 Hz, 3H). C{1H} NMR (100 MHz, D O): δ 11.7 (d,
2
2
3
1
JC-P = 135.7 Hz). P NMR (162 MHz, D O): δ 31.1.
2
6
a
1
Phenylphosphonic acid (2g). White solid (71.1 mg, 90%). H NMR (400 MHz,
1
3
D O): δ 7.63‒7.57 (m, 2H), 7.45‒7.41 (m, 1H), 7.37‒7.32 (m, 2H). C{1H} NMR (100
2
MHz, D O): δ 132.3 (d, J = 2.7 Hz), 130.5 (d, JC-P = 182.2 Hz), 130.4 (d, JC-P = 10.4
2
C-P
3
1
Hz), 128.7 (d, JC-P = 14.8 Hz). P NMR (162 MHz, D O): δ 17.2.
2
Oct-1-en-2-ylphosphonic acid (2h).18d White solid (262.6 mg, 54%). H NMR (400
1
MHz, CDCl ): δ 9.59 (s, 2H), 5.96 (d, J = 23.6 Hz, 1H), 5.63 (d, J = 49.6 Hz, 1H),
3
1
3
2.28‒2.21 (m, 2H), 1.50‒1.48 (m, 2H), 1.27‒1.25 (m, 6H), 0.88‒0.85 (m, 3H). C{1H}
NMR (100 MHz, CDCl ): δ 139.9 (d, J = 176.6 Hz), 127.4 (d, JC-P = 9.4 Hz), 31.8,
3
C-P
3
1
31.7, 28.9, 27.9 (d, JC-P = 5.7 Hz), 22.7, 14.1. P NMR (162 MHz, CDCl ): δ 21.9.
3
1
1
-Phenylvinylphosphonic acid (2i).18e White solid (377.3 mg, 81%). H NMR (400
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MHz, (CD ) CO): δ 9.94 (s, 2H), 7.65‒7.64 (m, 2H), 7.47‒7.43 (m, 3H), 6.32 (d, J =
3 2
1
3
2
2.0 Hz, 1H), 6.17 (d, J = 46.0 Hz, 1H). C{1H} NMR (100 MHz, (CD ) CO): δ 141.5
3 2
3
1
(
d, JC-P = 174.5 Hz), 137.1 (d, JC-P = 10.4 Hz), 130.2, 128.7, 128.5, 127.7. P NMR
(
162 MHz, (CD ) CO): δ 17.6.
3
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
n-Octylphosphonic acid (2l).18f White solid (92.2 mg, 95%). H NMR (400 MHz,
1
CDCl ): δ 9.04 (s, 2H), 1.78‒1.69 (m, 2H), 1.65‒1.55 (m, 2H), 1.36‒1.26 (m, 10H),
3
1
3
0.89‒0.86 (m, 3H). C{1H} NMR (100 MHz, CDCl ): δ 31.9, 30.5 (d, J = 17.1 Hz),
3
C-P
3
1
29.1, 26.2, 24.7, 22.7, 22.1 (d, JC-P = 4.6 Hz), 14.1. P NMR (162 MHz, CDCl ): δ
3
37.8.
6
a
1
Methyl phenylphosphonic acid (2n). White solid (70.6 mg, 82%). H NMR (400
MHz, D O): δ 7.59‒7.53 (m, 2H), 7.43‒7.41 (m, 1H), 7.37‒7.32 (m, 2H), 3.42 (dd, J =
2
1
3
4
.0 Hz, 11.6 Hz, 3H). C{1H} NMR (100 MHz, D O): δ 132.6 (d, J = 2.4 Hz), 131.0
2 C-P
(d, JC-P = 10.0 Hz), 128.8 (d, JC-P = 14.8 Hz), 128.4 (d, JC-P = 182.7 Hz), 52.5 (d, JC-P =
31
5
.0 Hz). P NMR (162 MHz, D O): δ 20.4.
2
6
a
1
Diethyl phosphoric acid (2o). White solid (71.7 mg, 93%). H NMR (400 MHz,
1
3
D O): δ 3.88‒3.84 (m, 4H), 1.12 (t, J = 7.0 Hz, 6H). C{1H} NMR (100 MHz, D O):
2
2
3
1
δ 63.5 (d, JC-P = 5.4 Hz), 15.5 (d, JC-P = 6.6 Hz). P NMR (162 MHz, D O): δ 0.6.
2
6
a
1
Ethyl phosphoric acid (2p). Colorless oil (59.2 mg, 94%). H NMR (400 MHz,
1
3
D O): δ 3.78‒3.70 (m, 2H), 0.98 (dt, J = 2.4 Hz, 7.2 Hz, 3H). C{1H} NMR (100 MHz,
2
31
D O): δ 63.5 (d, J = 5.1 Hz), 15.3 (d, JC-P = 6.4 Hz). P NMR (162 MHz, D O): δ
2
C-P
2
0
.2.
ASSOCIATED CONTENT
Supporting Information.
The Supporting Information is available free of charge on the ACS Publications website
at http://pubs.acs.org. Details of the typical produces, the control experiments of the
1
31
13
mechanistic studies and copies of H, P and C NMR spectra.
AUTHOR INFORMATION
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ORCID
Li-Biao Han: 0000-0001-5566-9017
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was primarily supported by a joint research between AIST and Maruzen
Petrochemical Co., Ltd. This paper is also partially based on results obtained from a
project commissioned by the New Energy and Industrial Technology Development
Organization (NEDO).
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phosphonobenzoic acid and copper (II) as precursors of helical chain and lamellar
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Cu(PO ‐C H )·H O: A Layered Antiferromagnetic Hybrid. Eur. J. Inorg. Chem. 2016,
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2
66–271. (b) Will, G.; Boschloo, G.; Rao, S. N.; Fitzmaurice, D. Potentiostatic
modulation of the lifetime of light-induced charge separation in a heterosupermolecule.
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Procházková, E.; Dračínský, M.; Janeba, Z. Microwave-assisted hydrolysis of
phosphonate diesters: an efficient protocol for the preparation of phosphonic acids.
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Caesar, J. C.; Swetnam, S. P.; Cumming, S. A.; Kelly, J. D. The synthesis of 1-amino-
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-hydroxy-and 2-amino-1-hydroxy-substituted ethylene-1, 1-bisphosphonic acids and
their N-methylated derivatives. Tetrahedron 1997, 53, 17815–17822.
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(
McKenna, M. C. The facile dealkylation of phosphonic acid dialkyl esters by
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Schmidhauser, J. Functional selectivity in phosphonate ester dealkylation with
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9, 408–412. (d) Salomon, C. J., Breuer, E. Efficient and selective dealkylation of
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phosphonate dilsopropyl esters using Me SiBr. Tetrahedron lett. 1995, 36, 6759-6760.
3
(
5) Gauvry, N., Mortier, J. Dealkylation of dialkyl phosphonates with boron
tribromide. Synthesis 2001, 553-554.
6) (a) Nitta, Y.; Arakawa, Y. The selective dealkylation of mixed esters of
(
1
1
1
1
1
1
1
1
1
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phosphoric acid and phenylphosphonic acid using cation exchange resin. Chem. Pharm.
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phosphorus oxyacid esters with p-toluenesulfonic acid. Chem. Pharm. Bull. 1986, 34,
2
710-2718.
7) For selected examples: (a) Biasone, A., Tortorella, P., Campestre, C.,
(
Agamennone, M., Preziuso, S., Chiappini, M., Nuti, E., Carelli, P., Rossello, A., Mazza,
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5, 791–799. (b) Plénat, F., Ibrahim, S., Cristau, H.-J. An improved access to
phosphonic acids and their mono-and diesters. Synthesis 1988, 912–913. (c) Song, Y.,
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(8) (a) Broeren, M. A. C.; de Waal, B. F. M.; van Genderen, M. H. P.; Sanders, H.
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Carboxylic Acid and Phosphonic Acid Based Guests with Dendritic Hosts: An NMR
Study. J. Am. Chem. Soc. 2005, 127, 10334-10343. (b) Choi, W. J.; Kang, S. U.; Burke
Jr, T. R. Preparation of Orthogonally-Protected 3-Methoxy-4-Phosphonomethyl-
LPhenylalanine, a New Reagent for the Synthesis of Phosphotyrosyl Mimetic-
Containing Peptides. Lett. Org. Chem. 2007, 4, 433-439.
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Determines the Products: an Unexpected Brønsted Acid-Catalyzed PO-R Cleavage of
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(10) Powder purchased from Sigma-Aldrich (495786) and used without further
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treatment. The complete removal of TfOH from the products requires a long-time
heating under vaccum. We thank one of our referees pointed out the possibility of the
remaidance of TfOH in the products.
(11) The reaction of diethyl benzylic phosphate with 1.2 equiv arenes can give
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polyarylated alkanes and diethyl phosphoric acid in the presense of a Brønsted acid:
Pallikonda, G.; Chakravarty, M. Benzylic phosphates in Friedel–Crafts reactions with
activated and unactivated arenes: access to polyarylated alkanes. J. Org. Chem. 2016,
8
1, 2135-2142.
12) Trialkyl phosphates are hydrolyzed in neutral and acidic conditions with C-
(
O cleavage via a S 2-type mechanism, see: (a) Blackburn, G. M.; Gait, M. J.; Loakes,
N
D.; Williams, D. M.; Egli, M.; Flavell, A.; Grasby, J. A. Nucleic acids in chemistry and
biology. 3nd ed.,Oxford Press, Oxford, UK, 2006. (b) Lyznicki, E. P.; Oyama, K.;
Tidwell, T. T. Reactivity of organophosphates. IV. acid-catalyzed hydrolysis of triethyl
phosphate: a comparison with ethyl acetate. Can. J. Chem. 1974, 52, 1066−1071. (c)
Thatcher, G.R.J.; Kluger, R. Mechanism and catalysis of nucleophilic substitution in
phosphate esters. Adv. Phys. Org. Chem., 1989, 25, 99–265.
(13) Harsági, N.; Rádai, Z.; Kiss, N. Z.; Szigetvári, A.; Keglevich, G. Two step
acidic hydrolysis of dialkyl arylphosphonates. Mendeleev Commun. 2020, 30, 38-39.
(14) (a) Colle, K. S.; Lewis, E. S. Methoxyphosphonium ions: intermediates in the
Arbuzov reaction. J. Org. Chem. 1978, 43, 571-574. (b) Lewis, E. S.; Colle, K. S.
Alkoxyphosphonium salts. 3. Kinetics and thermodynamics in alkylation by
alkoxyphosphonium salts. J. Org. Chem. 1981, 46, 4369-4372.
(
15) Diphenylmethane-d : White, E. H.; Ribi, M.; Cho, L. K.; Egger, N.; Dzadzic,
5
P. M.; Todd, M. J. Nitrosation of the N-alkyl-O-acylhydroxylamines. a new
deamination method. J. Org. Chem. 1984, 49, 4866-4871.
(16) Diphenylmethane was detected by GC-MS, GC−MS (EI, 70 eV) m/z = 169
+
+
(
[M + H] , 13), 168 (M , 100), 167 (97), 153 (31), 152 (30), 139 (5), 115 (9), 104 (35),
9
1 (28), 89 (12), 65 (19), 51 (14). This is similar with the solvolysis of TsOR to give
alkylated benzene as documented in the literature: Booth, B. L.; Haszeldine, R. N.;
Laali, K. Alkyltrifluoromethanesulphonates as alkylating reagents for aromatic
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Synthesis, molecular structure, and spectroscopical properties of alkenylphosphonic
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