An expedient access to still-gennari phosphonates

Article abstract of DOI:10.1055/s-0032-1317698

An inexpensive and efficient route to the Still-Gennari phosphonates, methyl and ethyl bis(2,2,2-trifluoroethyl)phosphono acetates, has been developed. This short reaction sequence is operationally simple and makes these versatile reagents for the prepara

Full text of DOI:10.1055/s-0032-1317698

PRACTICAL SYNTHETIC PROCEDURES
▌167
pArancticEal sxynptheetdiciperoncetduAresccess to Still–Gennari Phosphonates
Synthesis of Still–Gennari Phosphonates
Frauke Messik, Markus Oberthür*
Department of Chemistry, Philipps University Marburg, Hans-Meerwein-Strasse, 35032 Marburg,
Germany
Fax +49(6421)2822021; E-mail: oberthuer@chemie.uni-marburg.de
PSP
Received: 03.10.2012; Accepted after revision: 31.10.2012
No241
Abstract: An inexpensive and efficient route to the Still–Gennari phosphonates, methyl and ethyl bis(2,2,2-trifluoroethyl)phosphono-
acetates, has been developed. This short reaction sequence is operationally simple and makes these versatile reagents for the preparation of
Z-alkenes, according to the Still–Gennari modification of the Horner–Wadsworth–Emmons olefination reaction, available in multigram
quantities.
Key words: Z-alkenes, olefination, phosphorus, Horner–Wadsworth–Emmons reaction, Still–Gennari modification
(COCl)2
DMF (cat.)
CH2Cl2
CF3CH2OH
Et3N, CH2Cl2
DMAP (cat.)
O
P
O
O
P
O
O
P
O
O
P
O
TMSCl
(neat)
CF3CH2O
RO
TMSO
Cl
OR
OR
OR
OR
RO
CF3CH2O
TMSO
Cl
1 R = Me
2 R = Et
3 R = Me
4 R = Et
5 R = Me
6 R = Et
7 R = Me (77%, 3 steps)
8 R = Et (71%, 3 steps)
80 °C, 4 d
100 °C, 7 d
Scheme 1 Synthesis of the Still–Gennari phosphonates 7 and 8
Olefination reactions of carbonyl compounds are versatile A drawback of the Still–Gennari modification is the high
C–C bond forming reactions that are widely used in the to- price of the phosphonate reagent 7 and its ethyl ester
tal synthesis of complex products as well as in the indus- analogue 8 (7: 5 g, 164 €; 8: 5 g, 137 €, Sigma-Aldrich,
trial production of important reaction intermediates. In Germany, August 2012). Therefore, a laboratory scale
addition to the Wittig reaction and modifications thereof, synthesis of both reagents is a worthwhile alternative, es-
in which phosphonium ylides are employed, the Horner– pecially if larger quantities of these reagents are required.
Wadsworth–Emmons (HWE) reaction,1–3 that is, the reac- In the original procedure developed by Still and Gennari,
tion of aldehydes or ketones with deprotonated phospho- trimethyl phosphonoacetate (1) is converted to the corre-
nates to afford α,β-unsaturated esters, is an important sponding dichloride 5 with phosphorous pentachloride,
synthetic transformation for the synthesis of complex which is subsequently reacted with trifluoroethanol.4 Un-
products in a convergent fashion. A pivotal question in fortunately, this approach has some limitations because of
this context is the stereoselectivity of the olefination reac- the low overall yields (40% for 7 starting from 1,4 18% for
tion. While the HWE reaction preferentially gives the 8 starting from ethyl bromoacetate7) and practical prob-
more stable E-configured α,β-unsaturated esters, the Still– lems especially for large scale preparations. In this case,
Gennari4 and the Ando5,6 procedures lead predominantly the removal of the excess of PCl5 and the by-product
to the Z-isomers. In their pioneering studies, Still and POCl3, which are both toxic, high boiling, and reactive
Gennari discovered that the use of electrophilic trifluoro- compounds, can be quite tedious.
ethyl phosphonates, for example, methyl bis(2,2,2-tri-
fluoroethyl)phosphonoacetate (7), and a strongly dissociated
base system, for example, potassium hexamethyldisila-
zane (KHMDS)/18-crown-6 in THF, afford good Z-selec-
While searching for alternative protocols, we were sur-
prised that no other procedures for methyl bis(2,2,2-tri-
fluoroethyl)phosphonoacetate (7) have been reported so
far. Furthermore, besides an adaption of Still and Gennari’s
tivities in HWE reactions with various aldehydes. The
original procedure employing ethyl dimethylphosphono-
selectivity is attributed to an increased rate of elimination
acetate instead of the methyl derivative 1,7 only two addi-
tional approaches for the generation of phosphonate 8
were found. Patois et al. reported a three-step synthesis
of the bis(trifluoroalkyl) phosphate from the kinetically
preferred cis-oxaphosphetane adduct to yield the Z-al-
kene, which prevents efficient equilibration of the
that features the reaction of methylphosphonic dichloride
oxaphosphetane stereoisomers towards the thermody-
with trifluoroethanol, deprotonation of the obtained
namically more stable trans-isomer.
bis(2,2,2-trifluoroethyl)
methylphosphonate
with
LiHMDS, and subsequent acylation of the carbanion with
ethyl chloroformate.8,9 Ciszewski and Jackson10 used a
Michaelis–Becker reaction to synthesize bis(2,2,2-tri-
fluoroethyl)phosphono esters, but obtained phosphonate 8
SYNTHESIS 2013, 45, 0167–0170
Advanced online publication: 20.11.2012
DOI: 10.1055/s-0032-1317698; Art ID: SS-2012-T0771-PSP
© Georg Thieme Verlag Stuttgart · New York
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

168
F. Messik, M. Oberthür
PRACTICAL SYNTHETIC PROCEDURES
by deprotonation of bis(2,2,2-trifluoroethyl) phosphite DMF was added followed by oxalyl chloride.14 Due to the
with sodium hydride and subsequent reaction of the sodi- vigorous evolution of the by-products CO and CO2, the
um salt with ethyl bromoacetate in only 30% yield. Ac- oxalyl chloride has to be added slowly and dropwise to the
cordingly, for this reagent an efficient and operationally reaction mixture for large scale conversions. Again, 31P
simple synthesis is also desirable.
NMR spectroscopy was used to monitor the reaction prog-
ress, which showed that the reaction proceeds quantita-
tively within one hour and without the formation of
significant amounts of any phosphorous containing side
products. Therefore, removal of all volatiles under re-
duced pressure using a rotary evaporator was again found
to be sufficient to obtain the dichloride 5 in good purity
(Figure 1).
Herein, we present a reliable synthesis of both Still–
Gennari reagents using inexpensive starting materials. In
addition, the sequence is operationally simple, amenable
to scale-up, and affords the phosphonates 7 and 8 in good
overall yields.
To circumvent the problem of high boiling side products
as in Still and Gennari’s original procedure, a two-step
procedure was used for the synthesis of dichloride 5 via
the bis(trimethylsilyl) derivative 3 (Scheme 1).
The crude dichloride 5 was then converted into trifluoro-
ethylphosphonoacetate 7 by reaction with 2,2,2-trifluoro-
ethanol in the presence of an amine base. In the original
procedure by Still and Gennari, benzene was used as the
solvent. Not surprisingly, it is possible to replace benzene
by CH2Cl2 and to accelerate the reaction by the addition of
DMAP.12 Because of the very exothermic nature of the
conversion, however, the reaction mixture had to be
cooled carefully. Accordingly, it is most convenient to
add a solution of 2,2,2-trifluoroethanol and Et3N in
CH2Cl2 very slowly via a dropping funnel to a solution of
the dichloride 5 in CH2Cl2 that was cooled with an ice-
water mixture. Following the addition of DMAP, the reaction
mixture was stirred at room temperature for 16 hours to
ensure a complete conversion. After an extractive workup
and purification of the residue by flash chromatography
using a short pad of silica gel, methyl bis(2,2,2-trifluoro-
ethyl)phosphonoacetate (7) was obtained in an overall
yield of 77% on a 10 mmol scale. Following this protocol,
up to 15 grams of phosphonate 7 could be obtained in a
single batch conversion in similar yields (70–75%). It
should be noted that purification by distillation instead of
flash chromatography is also possible, which leads to
phosphonoacetate 7 in similar yields.
The dealkylation of phosphonic esters with trimethylsilyl
halides11–13 is a known transformation for which different
conditions and combination of reagents have been devel-
oped. In our hands, treatment of trimethyl phosphonoace-
tate (1) with TMSCl (2 equiv) and NaI (2 equiv) in
anhydrous acetonitrile13 led to a mixture of products,
whereas heating the phosphonoacetate 1 in neat TMSCl in
a screw-cap pressure tube (80 °C, 4 d) provided the corre-
sponding bis(trimethylsilyl) derivative 3 without signifi-
cant formation of side-products.11,12 The dealkylation
reactions as well as the subsequent transformations were
conveniently monitored using 31P NMR spectroscopy
(Figure 1) by removing small aliquots from the reaction
mixture, evaporation under reduced pressure, and dissolu-
tion in CDCl3.
Because methyl chloride is the only additional product of
the dealkylation reaction, it is possible to purify the reac-
tion mixture by a simple evaporation using a rotary evap-
orator (40 °C). For the subsequent formation of dichloride
5, the crude bis(trimethylsilyl)phosphonoacetate 3 was
dissolved in anhydrous CH2Cl2, and a catalytic amount of
Figure 1 Monitoring of the reaction progress by 31P NMR spectroscopy for the transformation from 1 to 7
Synthesis 2013, 45, 167–170
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Synthesis of Still–Gennari Phosphonates
169
moved under reduced pressure using a rotary evaporator. The crude
dichloride 5 was obtained as a light orange oil (1.95 g, quant.) and
was used directly in the next reaction step.
1H NMR (300 MHz, CDCl3): δ = 3.83 (d, J = 0.7 Hz, 3 H), 3.76 (d,
J = 19.1 Hz, 2 H).
The corresponding ethyl derivative 8 was synthesized
starting from the inexpensive triethyl phosphonoactate (2;
25 g, 25.60 €) instead of the corresponding dimethyl phos-
phonoacetate (10 g, 55 €). In comparison to trimethyl
phosphonoacetate (1), a longer reaction time and higher
temperature was necessary for the complete dealkylation
of 2 with TMSCl (100 °C, 7 d). A further increase of the
reaction temperature to 120 °C did not result in an accel-
31P NMR (121 MHz, CDCl3): δ = 32.2.
Methyl Bis(2,2,2-trifluoroethyl)phosphonoacetate (7)
To a solution of crude 5 (10.0 mmol) in CH2Cl2 (10 mL) cooled with
eration of the reaction rate. Nevertheless, the bis(trimeth- an ice-water mixture was added dropwise a solution of Et3N (8.40
mL, 60.0 mmol) and 2,2,2-trifluoroethanol (2.90 mL, 40.0 mmol) in
CH2Cl2 (10 mL). After the addition of a catalytic amount of DMAP
(24 mg, 0.20 mmol), the yellow reaction mixture was stirred for 16
ylsilyl) derivative 4 was obtained in good purity, which
makes the prolonged reaction time acceptable.
Conversion of 4 to the dichloride 6 and the subsequent
reaction with trifluoroethanol was conducted in analogy
to the preparation of 7 and led to ethyl phosphonoacetate
8 in good overall yield (71%) for conversions on a 10
mmol scale and higher.
h at r.t. The mixture was then diluted with CH2Cl2 (200 mL), washed
with brine (100 mL), dried (MgSO4), filtered, and evaporated. The
residue was purified by flash chromatography (silica gel, PE–
EtOAc, 2:1 → 1:1) to afford 7 (2.44 g, 77% over 3 steps) as a col-
orless oil; Rf = 0.27 (PE–EtOAc, 2:1).
1H NMR (300 MHz, CDCl3): δ = 4.51–4.40 (m, 4 H), 3.76 (s, 3 H),
3.16 (d, J = 21.1 Hz, 2 H).
In conclusion, we have developed a facile and cheap ac-
cess to the Still–Gennari phosphonates, methyl bis(2,2,2-
trifluoroethyl)phosphonoacetate (7) and ethyl bis(2,2,2-
trifluoroethyl)phosphonoacetate (8). The three-step pro-
cedure is operationally simple and requires only a single
extractive workup and a final purification to afford pure
products in good overall yields. Both reaction sequences
have been used to prepare phosphonates 7 and 8 in quan-
tities of ca. 15 grams per batch with similar yields com-
pared to experiments on a 10 mmol scale. Therefore, these
procedures can provide both phosphonates with a minimal
operational effort in sufficient quantities for the multi-
gram synthesis of Z-configured α,β-unsaturated esters.
13C NMR (75 MHz, CDCl3): δ = 165.2 (d, 2JC,P = 4.2 Hz), 122.6 (dq,
2
1JC,F = 277.4 Hz, 3JC,P = 8.3 Hz), 62.8 (dq, JC,F = 38.2 Hz, 2JC,P
=
5.6 Hz), 53.1 (s), 33.9 (d, 1JC,P = 144.6 Hz).
19F NMR (282 MHz, CDCl3): δ = –76.1.
31P NMR (121 MHz, CDCl3): δ = 22.5.
MS (ESI+): m/z [M + Na]+ calcd for C7H9F6O5P + Na: 340.9984;
found: 340.9982.
Ethyl Bis(trimethylsilyl)phosphonoacetate (4)
Triethyl phosphonoacetate (2; 2.00 mL, 10.0 mmol) and Me3SiCl
(6.40 mL, 50.0 mmol) were stirred for 7 d at 100 °C in a screw-cap
pressure tube. After cooling the solution to r.t., the mixture was
transferred to a round-bottomed flask and the volatiles were re-
moved under reduced pressure. The crude bis-trimethylsilyl ester 4
was obtained as a colorless oil (3.15 g, quant.) and was used without
further purification.
All reactions were carried out under an argon atmosphere. All
chemicals were of reagent grade and were used as purchased.
CH2Cl2 (Rotidry, VWR) was used as purchased. Petroleum ether
(PE) used refers to the fraction boiling in the 40–60 °C range. TLC
was performed on silica gel 60 F254 plates (Merck KGaA). Detec-
tion was carried out by staining with KMnO4 solution. Flash chro-
matography was performed on silica gel 60 (0.040–0.063 mm) from
Merck KGaA. NMR spectra were measured on a Bruker AV 300
spectrometer at the NMR facilities, Department of Chemistry,
Philipps-Universität Marburg. All chemical shifts are given in ppm
referring to the solvent residual signal (CDCl3: δ = 7.26, 1H NMR).
HR-ESI mass spectra were acquired with a LTQ-FT mass spectrom-
eter (Thermo Fischer Scientific). The resolution was set to 100 000.
1H NMR (300 MHz, CDCl3): δ = 4.13 (q, J = 7.2 Hz, 2 H), 2.84 (d,
J = 22.6 Hz, 2 H), 1.24 (t, J = 7.2 Hz, 3 H), 0.27 (s, 18 H).
31P NMR (121 MHz, CDCl3): δ = –1.10.
Ethyl Dichlorophosphonoacetate (6)
Dichloride 6 was prepared from crude 4 (3.15 g, 10.0 mmol) accord-
ing to the procedure described for 5. Crude yield: 2.10 g (quant.);
light orange oil.
1H NMR (300 MHz, CDCl3): δ = 4.27 (dq, J = 7.2, 0.6 Hz, 2 H),
3.73 (d, J = 19.1 Hz, 2 H), 1.30 (t, J = 7.1 Hz, 3 H).
31P NMR (121 MHz, CDCl3): δ = 32.6.
Methyl Bis(trimethylsilyl)phosphonoacetate (3)
Trimethyl phosphonoacetate (1; 1.60 mL, 10.0 mmol) and Me3SiCl
(6.40 mL, 50.0 mmol) were stirred for 4 d at 80 °C in a screw-cap
pressure tube. After cooling the solution to r.t., the mixture was
transferred to a round-bottomed flask and the volatiles were re-
moved under reduced pressure using a rotary evaporator. The crude
bis-trimethylsilyl ester 3 was obtained as a colorless oil (3.05 g,
quant.) and was used without further purification in the next step.
1H NMR (300 MHz, CDCl3): δ = 3.63 (s, 3 H), 2.82 (d, J = 22.5 Hz,
2 H), 0.23 (s, 18 H).
31P NMR (121 MHz, CDCl3): δ = –1.50.
Ethyl Bis(2,2,2-trifluoroethyl)phosphonoacetate (8)
Phosphonate 8 was prepared from crude 6 (2.10 g, 10.0 mmol) ac-
cording to the procedure described for 7. Yield: 2.35 g (71% over 3
steps); colorless oil; Rf = 0.57 (PE–EtOAc, 2:1).
1H NMR (300 MHz, CDCl3): δ = 4.51–4.40 (m, 4 H), 4.22 (q, J =
7.1 Hz, 2 H), 3.15 (d, J = 21.1 Hz, 2 H), 1.29 (t, J = 7.1 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 164.7 (d, 2JC,P = 4.3 Hz), 122.6 (dq,
2
1JC,F = 277.3 Hz, 3JC,P = 8.3 Hz), 62.7 (dq, JC,F = 38.3 Hz, 2JC,P
=
5.6 Hz), 62.4 (s), 34.2 (d, 1JC,P = 144.3 Hz), 14.0 (s).
19F NMR (282 MHz, CDCl3): δ = –76.1.
31P NMR (121 MHz, CDCl3): δ = 22.7.
Methyl Dichlorophosphonoacetate (5)
Crude 3 (10.0 mmol) was dissolved in CH2Cl2 (20 mL) and one
drop of DMF was added. Then oxalyl chloride (2.20 mL, 25.0
mmol) was carefully added dropwise under vigorous evolution of
gas. After stirring the solution for 1 h at r.t., the volatiles were re-
MS (ESI+): m/z [M + Na]+ calcd for C8H11F6O5P + Na: 355.0141;
found: 355.0141.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 167–170

170
F. Messik, M. Oberthür
PRACTICAL SYNTHETIC PROCEDURES
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Acknowledgment
We thank the Deutsche Forschungsgemeinschaft for financial sup-
port. We also thank Dipl. Chem. Sebastian N. Fischer and Ms.
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© Georg Thieme Verlag Stuttgart · New York