Copper Triflate as a Useful Catalyst for the High-Yielding Preparation of α-Acetyloxyphosphonates under Solvent-Free Conditions

Article abstract of DOI:10.1055/s-2003-815919

A high-yielding and convenient procedure for the efficient conversion of α-hydroxyphosphonates to α-acetyloxyphosphonates using acetic anhydride in the presence of catalytic amounts of copper triflate is described.

Full text of DOI:10.1055/s-2003-815919

PAPER
295
Copper Triflate as a Useful Catalyst for the High-Yielding Preparation of
-Acetyloxyphosphonates under Solvent-Free Conditions
P
reparationof -A
a
cetyloxyph
bosphonates ib Firouzabadi,* Nasser Iranpoor,* Sara Sobhani, Zohreh Amoozgar
Department of Chemistry, College of Sciences, Shiraz University, Shiraz 71454, Iran
Fax +98(711)2280926; E-mail: Firouzabadi@chem.susc.ac.ir; E-mail: Iranpoor@chem.susc.ac.ir
Received 1 October 2003
Reactions of diethyl -hydroxyphosphonates have been
under investigation in our laboratory in recent years.10
Along this line, recently we have introduced [Cu(OTf)2]
as a mild and efficient catalyst for the silylation of -hy-
droxyphosphonates with HMDS.10d A recent report on the
acetylation of traditional hydroxy functional groups with
Ac2O catalyzed by Cu(OTf)211 prompted us to apply this
Lewis acid catalyst for direct acetylation of diethyl -hy-
droxyphosphonates. We have studied the reactions of var-
ious diethyl -hydroxyphosphonates 1a–o in the presence
of Ac2O catalyzed by 0.013–0.08 equivalents of Cu(OTf)2
in the absence of solvent at room temperature (Scheme 1
and Table 1).
Abstract: A high-yielding and convenient procedure for the effi-
cient conversion of -hydroxyphosphonates to -acetyloxyphos-
phonates using acetic anhydride in the presence of catalytic
amounts of copper triflate is described.
Key words: hydroxyphosphonates, solvent-free, copper triflate,
acetic anhydride, acetyloxyphosphonates
-Acetyloxyphosphonates are considered as important
and valuable phosphorus compounds for the synthesis of
optically active -hydroxyphosphonates. Enzymatic sys-
tems have been introduced for the enantioselective hy-
drolysis of racemic -acetyloxyphosphonates.1 Chiral and
nonracemic -hydroxyphosphonates are useful precursors
for a variety of -substituted phosphonates especially for
-aminophosphonic acids which have received consider-
able attention in medical, bioorganic and organic chemis-
try owing to their potential activities as analogues of -
amino acids.1a,2
Scheme 1
Literature survey indicates that a practical and high yield-
ing method for the synthesis of pure -acetyloxyphospho-
nates is rare. The reactions of aldehydes and ketones with
acyl phosphites is reported for the preparation of -acetyl-
oxyphosphonates at 120 °C to produce the desired prod-
ucts in low yields.3 The other reported procedures for this
As shown in Table 1, various types of diethyl -hy-
droxy(arylmethyl)phosphonates 1a–k were cleanly con-
verted
into
their
corresponding
diethyl
-
acetyloxyphosphonates 2a–k in excellent yields (92–
98%). Diethyl -hydroxy-2-naphthyl-, 3-pyridyl-, alkyl-
and aryl- , -unsaturated phosphonates 1l–o were also
acetylated efficiently giving the corresponding diethyl -
acetyloxyphosphonates 2l–o in 90–96% yields.
purpose
include
direct
acetylation
of
-
hydroxyphosphonates4 with ketene catalyzed by
BF3·Et2O5 or H2SO4.6 These protocols suffer from usually
low yields5, requiring rather high temperatures (70–80 °C)
and long reaction times (10–15 h).6 Acetylation of -hy-
droxyphosphonates with Ac2O or AcCl in the presence of
Et3N or pyridine has been conducted at room temperature
in 1–18 hours resulting in low to excellent yields.1b,1c,7 In
the other reported procedure, AcCl has been used for di-
rect acetylation of -trimethylsilyloxyphosphonates at a
rather high temperature (120 °C) to produce -acetyloxy-
phosphonates in moderate yields (55–70%).8
In all the reactions we have reported in this paper cleavage
of C–P bond of the phosphonates were not detected and
the conversion of the substrates to their corresponding
acetyloxy compounds was clean and quantitative. Work-
up of the reaction mixture is very easy and gives highly
pure liquid products, which do not need further purifica-
tion (detected by TLC and their spectral data).
Consequently, in this paper, we have described a simple
procedure for the high yielding synthesis of a variety of
diethyl -acetyloxyphosphonates by direct acetylation of
diethyl -hydroxyphosphonates with Ac2O catalyzed by
Cu(OTf)2 as a mild Lewis acid. This method is superior
with respect to the other reported methods, which use cor-
rosive BF3·Et2O, H2SO4 and AcCl and also purification of
the acetyloxy products from pyridine and Et3N is a tedious
and a time consuming process. Solvent-free and mild re-
action conditions, short reaction times and easy workup
In this article we present a new procedure in which a mild
Lewis acid, copper triflate [Cu(OTf)2]9 has been used for
the first time for direct acetylation of -hydroxyphospho-
nates with Ac2O at room temperature in the absence of
solvent in excellent yields with short reaction times.
SYNTHESIS 2004, No. 2, pp 0295–0297
x
x
.
x
x
.2
0
0
4
Advanced online publication: 13.01.2004
DOI: 10.1055/s-2003-815919; Art ID: P08603SS
© Georg Thieme Verlag Stuttgart · New York

296
H. Firouzabadi et al.
PAPER
1JPH = 13.6 Hz, CH), 7.35 (d, JHH = 7.1 Hz, 3 H, C6H5), 7.50 (d,
Table 1 Acetylation of Diethyl -Hydroxyphosphonates 1a–o to
Diethyl -Acetyloxyphosphonates 2a–o with Ac2O in the Presence of
Cu(OTf)2 under Solvent-Free Conditions at Room Temperature
JHH = 7.3 Hz, 2 H, C6H5).
13C NMR (CDCl3/TMS): = 16.68 (d, 3JCP = 5.85 Hz, OCH2CH3),
3
16.80 (d, JCP = 5.7 Hz, OCH2CH3), 21.26 [OC(O)CH3], 63.74 (d,
Prod-
R
1/Ac2O/Cu(OTf)2 Time
Yielda
(%)
1
2JCP = 6.5 Hz, 2-OCH2CH3), 70.84 (d, JCP = 170.1 Hz, CH),
uct 2
Ratio
(min)
3
128.25–129.15, 133.8 (C6H5), 169.66 (d, JCP = 8.9 Hz,
OC(O)CH3).
MS (70 eV): m/z = 286 (M+).
a
b
c
d
e
f
Ph
1:5:0.013
1:5:0.027
1:5:0.013
1:5:0.027
1:5:0.08
1:5:0.08
1:5:0.08
1:5:0.013
1:5:0.053
1:5:0.027
1:5:0.027
1:5:0.013
1:3:0.013
1:5:0.013
1:5:0.027
30
98
97
92
97
96
94
94
92
92
92
96
94
96
92
90
4-MeC6H4
4-MeOC6H4
2,4,6-Me3C6H2
2-ClC6H4
30
Anal. Calcd for C13H19O5P: C, 54.54; H, 6.64. Found: C, 54.50; H,
6.60.
30
30
2c
IR (neat): 1750 cm–1 (C=O).
240
60
1H NMR (CDCl3/TMS): = 1.22–1.40 (m, 6 H, OCH2CH3), 2.19 [s,
3 H, OC(O)CH3], 3.84 (s, 3 H, 4-OCH3), 3.96–4.28 (m, 4 H,
OCH2CH3), 6.13 (d, 1 H, JPH = 13.08 Hz, CH), 6.94 (d, 2 H,
JHH = 8.0 Hz, C6H4), 7.48 (d, JHH = 8.0 Hz, 2 H, C6H4).
3-ClC6H4
1
g
h
i
4-ClC6H4
60
2,6-Cl2C6H3
2-O2NC6H4
3-O2NC6H4
4-O2NC6H4
2-naphthyl
3-pyridyl
70
13C NMR (CDCl3/TMS): = 16.39 (d, 3JCP = 5.85 Hz, OCH2CH3),
16.41 (d, 3JCP = 5.7 Hz, OCH2CH3), 20.91 [OC(O)CH3], 55.26 (4-
2
1
70
OCH3), 63.38 (d, JCP = 6.5 Hz, OCH2CH3), 70.09 (d, JCP = 173
Hz, CH), 113.96–113.99, 128.86–130.96 (C6H4), 169.41 [d,
3JCP = 8.99 Hz, OC(O)CH3].
MS (70 eV): m/z = 316 (M+).
j
60
k
l
30
Anal. Calcd for C14H21O6P: C, 53.16; H, 6.64. Found: C, 53.15; H,
6.62.
30
m
n
o
30
2e
IR (neat): 1743 cm–1 (C=O).
PhCH=CH
MeCH=CH
60
1H NMR (CDCl3/TMS): = 1.16–1.35 (m, 6 H, OCH2CH3), 2.19 [s,
3 H, OC(O)CH3], 4.02–4.16 (m, 4 H, OCH2CH3), 6.12 (d, 1 H,
1JPH = 13.9 Hz, CH), 7.29–7.69 (m, 4 H, C6H4).
90
a Yields refer to isolated products.
13C NMR (CDCl3/TMS): = 16.28 (d, 3JCP = 5.85 Hz, OCH2CH3),
3
16.37 (d, JCP = 5.7 Hz, OCH2CH3), 20.72 [OC(O)CH3], 63.74 (d,
2JCP = 6.4 Hz, OCH2CH3), 69.78 (d, 1JCP = 170.5 Hz, CH), 126.12–
131.09, 134.38–135.72 (C6H4), 169.17 [d, JCP = 8.9 Hz,
OC(O)CH3].
make this protocol a useful addition to the available meth-
ods for this purpose.
3
MS (70 eV): m/z = 320 (M+), 322 (M + 2).
Chemicals were purchased from Merck and Fluka Chemical Com-
panies. The products were characterized by comparison of their
physical data with those of known samples or by their spectral data.
IR spectra were run on a Shimadzu model 8300 FT-IR spectropho-
tometer. NMR spectra were recorded on a Bruker Avance DPX-
250. Mass spectra were recorded on a Shimadzu GCMS-QP 1000
EX. The test for the purity of the products and the progress of the
reactions were accomplished by TLC on silica gel polygram SILG/
UV254 plates.
Anal. Calcd for C13H18ClO5P: C, 48.67; H, 5.62. Found: C, 48.70;
H, 5.65.
2h
IR (neat): 1749 cm–1 (C=O).
1H NMR (CDCl3/TMS): = 1.22–1.35 (m, 6 H, OCH2CH3), 2.17 [s,
3 H, OC(O)CH3], 4.01–4.26 (m, 4 H, OCH2CH3), 6.85 (d, 1 H,
1JPH = 17.9 Hz, CH), 7.17–7.23 (m, 1 H, C6H3), 7.32–7.35 (m, 2 H,
C6H3).
Diethyl -Acetyloxyphosphonates 2; General Procedure
3
13C NMR (CDCl3/TMS): = 16.43 (d, JCP = 5.8 Hz, OCH2CH3),
Cu(OTf)2 (0.005–0.029 g, 0.013–0.08 mmol) was added to a mix-
ture of 1 (0.218–0.342 g, 1 mmol) and Ac2O (0.342–0.57 g, 3–5
mmol) at r.t. The progress of the reaction was monitored by TLC.
After complete conversion of the starting material, Et2O (10 mL)
was added to the reaction mixture and the Et2O phase was washed
with aq sat. NaHCO3 (3 × 10 mL) and then H2O (3 × 10 mL). The
organic layer was separated, dried (Na2SO4), and filtered. Evapora-
tion of the filtrate resulted in highly pure 2 in 90–98% yields
(Table 1). Spectral data for selected compounds are given below.
3
16.57 (d, JCP = 5.8 Hz, OCH2CH3), 22.24 [OC(O)CH3], 63.66 (d,
2JCP = 6.8 Hz, OCH2CH3), 69.45 (d, 1JCP = 174.1 Hz, CH), 128.96,
129.67, 129.69, 130.32, 130.36, 135.94 (C6H3), 169.51 [d,
3JCP = 10.4 Hz, OC(O)CH3].
MS (70 eV): m/z = 355 (M+ ), 357 (M + 2,), 359 (M + 4).
Anal. Calcd for C13H17Cl2O5P: C, 43.9; H, 4.8. Found: C, 43.92; H,
4.83.
2i
IR (neat): 1748 cm–1 (C=O).
2a
IR (neat): 1745 cm–1 (C=O).
1H NMR (CDCl3/TMS): = 1.19–1.38 (m, 6 H, OCH2CH3), 2.24 [s,
3 H, OC(O)CH3], 4.05–4.25 (m, 4 H, OCH2CH3), 6.25 (d, 1 H,
1JPH = 14.2 Hz, CH), 7.59 (t, 1 H, JHH = 7.9 Hz, C6H4), 7.85 (d,
1H NMR (CDCl3/TMS): = 1.17–1.29 (m, 6 H, OCH2CH3), 2.16 [s,
3 H, OC(O)CH3], 3.86–4.13 (m, 4 H, OCH2CH3), 6.14 (d, 1 H,
Synthesis 2004, No. 2, 295–297 © Thieme Stuttgart · New York

PAPER
Preparation of -Acetyloxyphosphonates
297
JHH = 7.5 Hz, 1 H, C6H4), 8.20 (d, JHH = 8.1 Hz, 1 H, C6H4), 8.34 (s,
1 H, C6H4).
References
(1) (a) Li, Y.-F.; Hammerschmidt, F. Tetrahedron 1995, 51,
4933. (b) Li, Y.-F.; Hammerschmidt, F. Tetrahedron:
Asymmetry 1993, 4, 109. (c) Drescher, M.;
13C NMR (CDCl3/TMS): = 16.18 (d, 3JCP = 5.85 Hz, OCH2CH3),
3
16.24 (d, JCP = 5.7 Hz, OCH2CH3), 20.55 [OC(O)CH3], 63.67 (d,
2JCP = 6.5 Hz, OCH2CH3), 69.30 (d, 1JCP = 169.8 Hz, CH), 122.34–
Hammerschmidt, F.; Kahlig, H. Synthesis 1995, 1267.
(d) Eidenhammer, G.; Hammerschmidt, F. Synthesis 1996,
748. (e) Heisler, A.; Rabiller, C.; Douillard, R.; Goalou, N.;
Hagele, G.; Levayer, F. Tetrahedron: Asymmetry 1993, 4,
959. (f) Khushi, T.; O’Toole, K. J.; Sime, J. T. Tetrahedron
Lett. 1993, 34, 2375. (g) Zhang, Y.; Li, J.-F.; Yuan, C.-Y.
Tetrahedron 2003, 59, 473.
3
123.42, 128.67, 135.79 (C6H4), 168.99 [d, JCP = 8.68 Hz,
OC(O)CH3].
MS (70 eV): m/z = 331 (M+).
Anal. Calcd for C13H18NO7P: C, 47.13; H, 5.44. Found: C, 47.11; H,
5.43.
(2) (a) Hammerschmidt, F.; Hanbauer, M. J. Org. Chem. 2000,
65, 6121. (b) Kafarski, P.; Lejczak, B. Phosphorus, Sulfur
Silicon Relat. Elem. 1991, 63, 193. (c) Groth, U.; Richter,
L.; Schöllkopf, U. Tetrahedron 1992, 48, 117. (d) Laschat,
S.; Kunz, H. Synthesis 1992, 90.
(3) Nesterov, L. V.; Sabirova, R. A.; Krepysheva, N. E. J. Gen.
Chem. USSR (Engl. Transl.) 1969, 39, 1906.
(4) (a) Texier-Bullet, F.; Foucaud, A. Synthesis 1982, 916.
(b) Baraldi, P. G.; Guarneri, M.; Moroder, F.; Polloni, G. P.;
Simoni, D. Synthesis 1982, 653.
2l
IR (neat): 1749 cm–1 (C=O).
1H NMR (CDCl3/TMS): = 1.16–1.34 (m, 6 H, OCH2CH3), 2.19
[s, 3 H, OC(O)CH3], 3.89–4.14 (m, 4 H, OCH2CH3), 6.32 (d, 1 H,
1JPH = 13.7 Hz, CH), 7.44–7.48 (m, 2 H, C10H7), 7.61 (d, 1 H,
JHH = 8.5 Hz, C10H7), 7.78–7.86 (m, 3 H, C10H7), 7.96 (s, 1 H,
C10H7).
13C NMR (CDCl3/TMS): = 16.29 (d, 3JCP = 5.85 Hz, OCH2CH3),
3
16.42 (d, JCP = 5.7 Hz, OCH2CH3), 20.88 [OC(O)CH3], 63.42 (d,
2JCP = 6.5 Hz, OCH2CH3), 70.63 (d, 1JCP = 170.3 Hz, CH), 125.33–
(5) McConnell, R. L.; Coover, H. W. Jr. J. Am. Chem. Soc.
1957, 79, 1961.
(6) Pudovik, A. N.; Gozman, I. P.; Nikitina, V. I. J. Gen. Chem.
USSR (Eng. Transl) 1963, 33, 3128.
3
128.27, 130.88, 130.92–133.31 (C10H7), 169.31 [d, JCP = 9.2 Hz,
OC(O)CH3].
MS (70 eV): m/z = 336 (M+).
(7) (a) Alimov, P. I.; Cheplanova, I. V. Izvest. Akad. Nauk.
S.S.S.R., Otdel. Khim. Nauk. 1956, 939; Chem. Abstr. 1957,
51, 5035. (b) Strepikheev, Yu. A.; Kovalenko, L. V.;
Batalina, A. V.; Shvetsova, L. A. Deposited Doc. 1976,
VINITI, 2264; Chem. Abstr. 1978, 89, 129601.
(8) Lebedev, E. P.; Mizhiritskii, M. D.; Baburina, V. A.;
Mironov, V. F.; Ofitserov, E. N. Zh. Obshch. Khim. 1979,
49, 1731; J. Org. Chem. USSR (Engl. Transl.) 1979, 49,
1517.
(9) Jenkins, C. L.; Kochi, J. K. J. Am. Chem. Soc. 1972, 94, 843.
(10) (a) Firouzabadi, H.; Iranpoor, N.; Sobhani, S.; Sardarian, A.
R. Tetrahedron Lett. 2001, 42, 4369. (b) Firouzabadi, H.;
Iranpoor, N.; Sobhani, S. Tetrahedron Lett. 2002, 43, 477.
(c) Firouzabadi, H.; Iranpoor, N.; Sobhani, S. Tetrahedron
Lett. 2002, 43, 3653. (d) Firouzabadi, H.; Iranpoor, N.;
Sobhani, S.; Ghassamipour, S.; Amoozgar, Z. Tetrahedron
Lett. 2003, 44, 891.
Anal. Calcd for C13H19O5P: C, 60.71; H, 6.25. Found: C, 60.70; H,
6.25.
2m
IR (neat): 1759 cm–1 (C=O).
1H NMR (CDCl3/TMS): = 1.03–1.32 (m, 6 H, OCH2CH3), 2.20 [s,
3 H, OC(O)CH3], 3.99–4.20 (m, 4 H, OCH2CH3), 6.19 (d, 1 H,
1JPH = 14.1 Hz, CH), 7.36–7.41 (m, 1 H, C5H4N), 7.91 (d, 1 H,
JHH = 7.7 Hz, C5H4N), 8.61–8.71 (m, 2 H, C5H4N).
13C NMR (CDCl3/TMS): = 16.54 (d, JCP = 5.5 Hz, OCH2CH3),
3
3
16.63 (d, JCP = 5.5 Hz, OCH2CH3), 20.94 [OC(O)CH3], 63.99–
64.16 (OCH2CH3), 68.46 (d, 1JCP = 171.4 Hz, CH), 124.05, 136.67,
148.32–149.28 (C5H4N), 169.36 [d, 3JCP = 8.9 Hz, OC(O)CH3].
MS (70 eV): m/z = 287 (M+).
Anal. Calcd for C12H18NO5P: requires C, 50.2; H, 6.3. Found: C,
50.0; H, 6.0.
(11) Saravanan, P.; Singh, V. K. Tetrahedron Lett. 1999, 40,
2611.
Acknowledgment
We are thankful to the Shiraz University Research Council for par-
tial support of this work.
Synthesis 2004, No. 2, 295–297 © Thieme Stuttgart · New York