An alternative route for the preparation of α,α-difluoropropargylphosphonates

Article abstract of DOI:10.1016/S0040-4039(00)01354-X

The organometallic reagent, (EtO)₂P(O)CF₂ZnBr, reacts with 1-bromoalkynes in the presence of CuBr to give good yields (50-61%) of α,α-difluoropropargylphosphonates. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01354-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 7791–7794
An alternative route for the preparation of
a,a-difluoropropargylphosphonates
Xin Zhang and Donald J. Burton*
Department of Chemistry, The University of Iowa, Iowa City, IA 52242, USA
Received 29 June 2000; revised 19 July 2000; accepted 20 July 2000
Abstract
The organometallic reagent, (EtO) P(O)CF ZnBr, reacts with 1-bromoalkynes in the presence of CuBr
2
2
to give good yields (50–61%) of a,a-difluoropropargylphosphonates. © 2000 Elsevier Science Ltd. All
rights reserved.
Keywords: phosphonates; phosphorylation; fluorine compounds.
Interest in the preparation and utility of a,a-difluorophosphonates has increased steadily in
1
recent years. Numerous biological and chemical studies have demonstrated that a,a-
2
difluorophosphonates exhibit excellent electronic and structural similarity to phosphate. How-
ever, unlike phosphate, the phosphonate linkage is not readily hydrolyzed in a biological
environment and this unique property has made a,a-difluorophosphonates attractive for poten-
tial utilization in medicinal and pharmaceutical applications. Thus, the development of new
methodology for the preparation of functionalized a,a-difluorophosphonate derivatives con-
tinues to be an active area of research.
Recently, Hammond reported a successful approach to the preparation of a,a-difluoropropar-
3
gylphosphonates via fluorination (DAST, Et NSF ) of a-ketophosphonates. Although this
2
3
approach provides the propargyl phosphonates, it requires a three-step procedure utilizing an
a-ketophosphonate of limited stability and a large excess of the fluorinating agent DAST (20
equivalents).
*
Corresponding author.
0
040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01354-X

7792
Since our initial report on the generation of the stable zinc reagent, (EtO) P(O)CF ZnBr, 1,
2
2
in 1986, this reagent has been utilized by ourselves and others with various electrophiles, such
as allylic halides, vinyl halides, aryl halides and propargyl chloride to provide functionalized
4
a,a-difluorophosphonate derivatives. Herein we report an alternative route for the preparation
5
of a,a-difluoropropargylphosphonates via the CuBr catalyzed reaction of 1 with 1-haloalkynes.
Preliminary results indicated that the reaction of 1 in THF with 1-haloalkynes in the presence
of CuBr gave two major side reactions; namely, metal exchange and dimerization of the
1
-haloalkyne. For example, treatment of a THF solution of 1 with 1-iodophenylacetylene in the
presence of CuBr gave not only the propargylphosphonate but also significant amounts of
EtO) P(O)CF I and C H CꢀCꢁCꢀCꢁC H (30%). Although DMF and DMAC
CH C(O)N(CH ) ] are good solvents for stabilization of the intermediate (EtO) P(O)CF Cu
(
2
2
6
5
6
5
[
3
3 2
2
2
reagent, 2, these solvents produced not only the cross-coupled product but also phosphoryl
fluoride from the decomposition of 2. Thus, the best conditions for preparation of the
propargylphosphonates were THF solvent at −5°C and the use of 1-bromoalkynes to minimize
exchange and dimerization reactions. CuBr catalysis is necessary for useful reaction times, since
the reaction of 1 with 1-bromophenylacetylene in the absence of CuBr took 10 days for
completion.
Our results are summarized in Table 1.
Table 1
Preparation of a,a-difluoropropargylphosphonates
CuBr
RCꢀCX
(
EtO) P(O)CF ZnBr ꢁꢁꢁꢁꢁꢂ ꢁꢁꢁꢁꢁꢁꢁꢂ RCꢀCCF P(O)(OEt)
B5°C
B5°C to rt
2
2
2
2
THF
a,b
Entry
R
X
Reaction time (h)
Isolated yield (%)
1
2
3
4
5
6
7
8
9
C H9
Br
Br
I
Br
I
Br
I
Br
I
72
72
48
72
48
72
48
36
24
51
50
30
51
31
56
32
61
50
4
C H
5
11
C H
5
11
13
13
15
15
C H
6
C H
6
C H
7
C H
7
C H5
6
C H5
6
a
Isolated yield based on alkynyl halide.
All products gave satisfactory F, H, C, P NMR and GC-MS data.
b
19
1
13
31

7793
In a typical experimental procedure, a 25 mL round bottom flask with a magnetic stir bar, a
N tee and ice cooled water bath was charged with 5 mL of pre-generated (EtO) P(O)CF ZnBr
2
2
2
4
a
(
1.0 M, 5 mmol) in THF. This solution was cooled at <5°C for about 15 minutes, and the
copper(I) bromide (0.64 g, 5 mmol) was added into the reaction mixture all at once. The
resulting mixture was stirred at <5°C for an additional 15 minutes, then 0.72 g (4 mmol) of
1
-bromophenylacetylene was introduced into the solution, and the reaction mixture was slowly
allowed to warm to room temperature with stirring over 36 hours. The mixture was then diluted
with 150 mL of ether. The resulting solid was removed by filtration and the solid was washed
with 3×25 mL of ether. The combined organic solutions were then mixed with a NaOH (5%)
solution (50 mL) and stirred vigorously at room temperature for at least 15 minutes to remove
any PꢁF derivatives. The organic layer was separated and washed with water (3×40 mL), brine
solution (40 mL) and dried over anhydrous MgSO . After removal of ether, the residue was
4
purified further on a silica gel column using a mixture of ethyl acetate and hexanes (1:4) to give
1
9
0
(
1
1
6
.70 g (61%) of diethyl 1,1-difluoro-3-phenyl-2-propynephosphonate, GLPC >99%. F NMR
1
CDCl ): −96.8 (d, J=108 Hz) ppm. H NMR (CDCl ): 7.24–7.53 (m, 5H), 4.30–4.40 (m, 4H),
.40 (td, J=7.1 Hz, J=0.7 Hz, 6H) ppm. C NMR (CDCl ): 132.2 (m), 130.4, 128.5, 119.4 (m),
09.44 (td, J=253.2 Hz, J=229.6 Hz), 91.48 (q, J=7.3 Hz), 78.30 (td, J=33.4 Hz, J=17.1 Hz),
5.38 (d, J=6.9 Hz), 16.32 (d, J=5.4 Hz) ppm. P NMR (CDCl ): 3.89 (t, J=108 Hz) ppm.
3
3
1
3
3
31
3
GC-MS: 288 (M+, 3.9), 259 (6.2), 232 (22.5), 216 (4.9), 180 (7.0), 151 (100), 132 (33.8), 1.09
61.3), 81 (33.1). IR (neat, NaCl plate): 3063 (s), 2986 (w), 2236 (m), 1163 (w), 810 (s). The
(
3
spectroscopic data is in agreement with the data reported by Hammond. TLC: R =0.30
f
(
hexanes: ethyl acetate=1:1).
In conclusion, a short useful preparation of a,a-difluoropropargylphosphonates is easily
achieved from readily available reagents via the CuBr catalyzed reaction of (EtO) P(O)CF ZnBr
2
2
with 1-haloalkynes.
Acknowledgements
We thank the National Science Foundation for support of this work.
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. 1-Alkynyl halide was prepared by the reaction of 1-alkynyl lithium with I or Br at −20°C.
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.