An expedient synthesis of diethyl diazomethylphosphonate

Article abstract of DOI:10.1016/j.mencom.2011.04.009

A simple three-step preparation of diethyl diazomethylphosphonate was performed from chloroacetone and triethyl phosphite in total yield 70%.

Full text of DOI:10.1016/j.mencom.2011.04.009

Mendeleev
Communications
Mendeleev Commun., 2011, 21, 142–143
An expedient synthesis of diethyl diazomethylphosphonate
Mikhail D. Kosobokov, Igor D. Titanyuk* and Irina P. Beletskaya
Department of Chemistry, M. V. Lomonosov Moscow State University, 119991 Moscow, Russian Federation.
Fax: +7 495 939 8846; e-mail: i-titan@yandex.ru
DOI: 10.1016/j.mencom.2011.04.009
A simple three-step preparation of diethyl diazomethylphosphonate was performed from chloroacetone and triethyl phosphite in total
yield 70%.
2
–
The phosphonate (PO ) moiety is a common structural frag­
3
O
O
O
P
1,2
KI
ment present in a wide range of biologically active compounds.
+
OEt
OEt
Cl
P(OEt)3
Me
MeCN/acetone
Despite structural and electronic differences between phosphonate
and carboxylic functionalities the phosphonate one is regarded
as a bioisostere of the carboxylic group.
Me
2
3 (85%)
Diethyl diazomethylphosphonate 1 is widely used for pre­
paration of various derivatives of phosphonic acids, such as cyclo­
O
O
O
P
OEt
OEt
OEt
P
TsN3
Et3N
Base
OEt
3
4
5
6
propanes, aziridines, phosphonoketones, imines and a,b­un­
Me
MeOH
7
N2
saturated phosphonates (Scheme 1). In addition, it is often used
N2
for the Regitz reaction, i.e. transformation of carbonyl compounds
4
(88%)
1
into acetylene derivatives.8
Scheme 2
Ar
Ar
literature methodologies10,11 diethyl 2­oxopropylphosphonate 3
and diethyl 2­oxo­1­diazopropylphosphonate 4 were obtained.
Diazo grouping was introduced into keto phosphonate 3 by
reacting with tosyl azide.
OEt
OEt
N
R
N
P
OEt
OEt
N
N
P
O
O
Ar
Ar
RCHO
O
Analysis of literature data revealed that a­acetyl­a­diazo­
methylphosphonates can easily undergo deacetylation under basic
methanolysis, e.g., by treating them with K CO in methanol
(the Ohira’s method). However, this technique was not applied
for obtaining these compounds in pure form. Conversion of 4 into
O
P
S
OEt
OEt
R
R
2
3
OEt
OEt
R
R2
R1
12
P
N2
1
R
O
R3
R4
ArNH2
Diethyl 2-oxopropylphosphonate 3.10 A solution of chloroacetone 2
(5.33 g, 57.6 mmol) and KI (9.4 g, 56.6 mmol) in 16 ml of dry acetone
was stirred at room temperature for 2 h, then triethyl phosphite (9.25 g,
55.6 mmol) in 16 ml of dry diethyl ether was added, and the solution was
refluxed for 2 h. The mixture was cooled to room temperature and the
precipitate was filtered off.After evaporation of the solvent under reduced
pressure the crude product 3 was distilled in vacuo. Yield 9.19 g (85%),
O
R2 R1
OEt
OEt
R
R
Ar
N
P
R3
OEt
OEt
R4
P
O
R
R
O
(
the Regitz reaction)
14
colourless liquid, bp 101–105°C (1.5 Torr) [lit., bp 75°C (0.2 Torr)].
Scheme 1
1
3
H NMR (CDCl ) d: 1.35 (t, 6H, Me, J 7.1 Hz), 2.33 (s, 3H, Me), 3.07 (d,
3
2
31
2
H, CH , J 24 Hz), 4.17 (m, 4H, OCH2). P NMR (CDCl ) d: 19.75.
2
H
P
3
11
Diethyl 1-diazo-2-oxopropylphosphonate 4. A mixture of 3 (7.74 g,
The conventional method for preparation of diazo compound
is based on diazotization of diethyl aminomethylphosphonate,
19
40 mmol), tosyl azide (7.88 g, 40 mmol) and triethylamine (40 ml) was
stirred at room temperature for 18 h. After evaporation of triethylamine
under reduced pressure the residue was dissolved in minimal amount
of MTBE and 100 ml of light petroleum was added. The precipitate was
filtered off, the filtrate was evaporated and the residue was purified by
column chromatography on silica gel [ethyl acetate–hexane (1:2), then
which requires four labourious synthetic stages, the last diazoti­
zation step occurring with moderate yield of ~45%. An essential
drawback of this approach is a vacuum distillation of the final
product which makes this procedure rather dangerous especially
in large scale preparations.
Here we describe an alternative efficient synthesis of diethyl
diazomethylphosphonate from readily available chloroacetone 2
and triethyl phosphite (Scheme 2). With the use of modified
1
pure ethyl acetate]. Yield 7.39 g (88%), yellow liquid. H NMR (CDCl )
3
3
d: 1.35 (t, 6H, Me, J 7.1 Hz), 2.27 (s, 3H, Me), 4.25 (m, 4H, OCH2).
31
P NMR (CDCl3) d: 11.3.
†
Diethyl diazomethylphosphonate 1. A solution of 4 (4.0 g, 18 mmol) in
0 ml of MeOH was stirred with sodium phosphate (1.29 g, 13.3 mmol) at
5
†
NMR spectra were recorded on Bruker AV­300 and AV­400 spectro­
meters [300 and 400 ( H), 75 and 100 ( C), 121.5 and 162 MHz ( P),
H PO as an external reference]. All solvents used in the reactions were
dried with appropriate drying agents. The reaction progress was monitored
by TLC (plates with silica gel Merck 60 F254, UV irradiation or treating
with cerium molibdate in 5% H SO solution). The column chromato­
room temperature for 15 min [during this time the starting compound
completely disappeared (TLC control)]. The precipitate was filtered off.
After evaporation of the solvent under reduced pressure MTBE was added
and the precipitate was filtered off again. Solvent was removed on rotary
evaporator and compound 1 was obtained essentially pure. Yield 3.0 g
1
13
31
3
4
1
3
(93%), yellow liquid. H NMR (CDCl ) d: 1.29 (t, 6H, Me, J 7.0 Hz), 3.7
2
4
3
2
31
graphy was carried out on silica gel Merck 60 (230–400 ASTM).
(d, 1H, CH, J 12 Hz), 4.15 (m, 4H, OCH2). P NMR (CDCl ) d: 19.2.
H
P
3
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2011 Mendeleev Communications. All rights reserved.
– 142 –

Mendeleev Commun., 2011, 21, 142–143
Table 1 Methanolysis of compound 4.
In conclusion, we elaborated an efficient and convenient three­
step protocol for the preparation of diethyl diazomethylphos­
phonate. An essential advantage of Na PO over other bases during
Entry no. Base
T/°C
Time
Yield of 1 (%)a
3
4
1
2
3
4
5
6
7
8
9
Et N
20
50
24 h
8 h
10 h
15 min
10 min
30 min
30 min
1 h
traces
traces
40b
deacetylation of diazo compound 4 was discovered, leading to
the desired product quantitatively, which gives advantage of large
scale preparations without dangerous distillation.
3
Et N
3
Et N
64 (reflux)
3
NaOH
NaOEt
K CO
20
20
20
20
20
20
—c
—c
85
75
83
References
2
3
1
F. Heaney, in Comprehensive Organic Functional Group Transforma-
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Na CO
2
3
DBU
Na PO
15 min
100 (93d)
2 R. Filler, Y. Kobayashi and L. M. Yagupolski, in Organofluorine Com-
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Amsterdam, 1999.
3
4
a
Yield based on 31P NMR. bLarge quantity of by­products. cNo product.
Isolated yield.
d
3
4
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1
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however, the product was not purified and its formation was con­
firmed by NMR and IR spectra only. Following the mentioned
procedure we have revealed that treatment of compound 4 with
7
S. Lesniak, G. Mloston, K. Urbaniak, P. Wasiak, A. Linden and
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Et N/MeOH at 20 or 50°C led to trace amount of 1 after 24 h.
3
8
E. W. Colvin and B. J. Hamill, J. Chem. Soc., Perkin Trans. 1, 1977,
Under reflux conditions, diazophosphonate 1 was formed in 40%
yield along with large quantity of by­products. Therefore, addi­
tional study for optimization was performed. It was found that
strong bases like sodium hydroxide and sodium ethoxide induced
fast decomposition of starting material without formation of
desired product. In case of sodium hydrogen carbonate starting
compound remained without change, whereas sodium or potas­
sium carbonates as well as DBU appeared to be effective bases
affording the desired diazophosphonate 1 in 75–85% yield.
Finally, sodium phosphate (Na PO ) has proved to be the most
8
69.
9 (a) D. Zeyferth, R. Marmor and P. Hilbert, J. Org. Chem., 1971, 36,
1379; (b) R. T. Lewis and W. B. Motherwell, Tetrahedron, 1992, 1465.
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1
1
1
1
17, 2931.
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4
13 H. Tomioka, N. Toriyama and Y. Izawa, J. Org. Chem., 1977, 42, 552.
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3
4
perspective base leading to almost quantitative formation of 1
without any impurities.After simple filtration and removal of solvent
1
13
diethyl diazomethylphosphonate 1 was obtained pure ( H, C and
3
1
P NMR data) and did not require distillation.
Received: 1st December 2010; Com. 10/3635
–
143 –