An efficient and highly selective synthesis of (Z)-fluoroenol phosphates from hydroxy difluorophosphonates

Article abstract of DOI:10.1055/s-0028-1087803

Substituted 2-aryl-2-hydroxy-1,1-difluorophosphonates undergo a reaction with potassium tert-butoxide to provide selectively (Z)-2-fluoro-1-arylvinyl phosphates in high yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1087803

PAPER
957
An Efficient and Highly Selective Synthesis of (Z)-Fluoroenol Phosphates from
Hydroxy Difluorophosphonates
Synthesis of
(
Z
e
)
-Fluoroen
t
ol Phos
r
phates Beier,* Radek Pohl, Anastasia V. Alexandrova
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo nám. 2, 166 10 Prague 6,
Czech Republic
Fax +420(220)183578; E-mail: beier@uochb.cas.cz
Received 13 November 2008
venient route to fluorinated enol phosphates from easily
Abstract: Substituted 2-aryl-2-hydroxy-1,1-difluorophosphonates
accessible difluorophosphonates. Moreover, conditions
have been developed for selective formation of the Z-iso-
mer of the product.
undergo a reaction with potassium tert-butoxide to provide selec-
tively (Z)-2-fluoro-1-arylvinyl phosphates in high yields.
Key words: phosphonates, phosphates, rearrangements, elimina-
tions, enols
Previously, we have investigated the use of diethyl difluo-
romethylphoshonate (1) for [CF2H]– and [CF2]2– transfer
in nucleophilic reactions with carbonyl compounds.13,14
Common precursors for these transformations are difluo-
rophosphonates 2, which are prepared from 1 and alde-
hydes.15 In the presence of a base, under various
conditions, phosphonates 2 were transformed into a range
of products containing difluoromethyl or difluoromethyl-
ene groups (Scheme 1). Thus, in the presence of an alde-
hyde and potassium tert-butoxide in aprotic solvent
(DMF), hydroxyphosphates 3 were formed. Such com-
pounds could be easily transformed into 2,2-difluoro-1,3-
diols.14 Sodium methoxide, in the presence of a protic sol-
vent (MeOH) gave rise to difluoromethyl-containing al-
cohols 4.14 A mild base (K2CO3) facilitated the efficient
rearrangement of phosphonates into phosphates 5
(Scheme 1).13
Enol phosphates represent an important class of com-
pounds. In living organisms, phosphoenolpyruvate (PEP)
plays a vital role in a number of biological processes.
Some enol phosphates have also been reported to exhibit
interesting biological activity.1,2 In organic synthesis, enol
phosphates are versatile substrates that can be converted
into many functional groups and undergo a variety of
metal-catalyzed cross-coupling reactions.3 Typically,
such compounds are prepared by the reaction of metal
enolates with ClP(O)(OR)2,4 or by the Perkow reaction1,5
of a-halogenated carbonyl compounds with P(OR)3, or by
other methods.6 The Perkow reaction often suffers from a
competing Arbuzov reaction, yielding acyl phosphonates
instead of the desired enol phosphates.
The presence of fluorine substituents often leads to dra-
matic changes in the physicochemical properties and im-
proved biological activity.7 Some fluorinated enol
phosphates have been reported. Fluorinated ketones have
been used for their preparation through reactions with tri-
alkylphosphites (Perkow reaction),8 which led to fluoro-
PEP and its derivatives,9 and with dialkylphosphites.10
Reactions of perfluoroalkanoic acid chlorides with tri-
alkylphosphites resulted in double addition to give fluori-
nated phosphono enol phosphates.11 Recently, Demir and
2
R2 OH
R1
OH
O
R
OP(O)(OEt)2
R1
a
b
R3
R1
R2
CF2P(O)(OEt)2
2
F
F
3
d
c
R2 OH
R1
R2 OP(O)(OEt)2
c
R1
CF2H
CF2H
4
5
co-workers have used trifluoromethyltrimethylsilane Scheme 1 Preparation and reactions of difluorophosphonates 2.
Reagents and conditions: (a) (EtO)2(O)PCF2H (1), LDA, THF, –74 °C,
(TMSCF3) in the reaction with benzoyl phosphonates to
form the alcoholate which underwent phosphonate–phos-
phate rearrangement to form the acyl anion, followed by
0.5–6 h; (b) R3CHO, t-BuOK, DMF, –60 °C, 0.5–2 h; (c) MeONa,
MeOH, THF, 20–40 °C, 1–3 h; (d) K2CO3, DMF, r.t., 24 h.
fluoride elimination to give 1-aryldifluoroethenyl phos-
phates.12
It can be expected that reactions leading to compounds 3–
5 proceed through the putative difluoromethyl carbanion
6 (Figure 1) – an intermediate that further reacts with a
proton source or other electrophile.
New approaches to the synthesis of fluorinated enol phos-
phates are valuable both because of the potential biologi-
cal activity of the products, and because such compounds
constitute valuable intermediates for the synthesis of other
fluorine-containing compounds. Here, we present a con-
R2 OP(O)(OEt)2
R1
CF2– M+
6
SYNTHESIS 2009, No. 6, pp 0957–0962
Advanced online publication: 11.02.2009
DOI: 10.1055/s-0028-1087803; Art ID: Z24508SS
x
x
.
x
x
.2
0
0
9
Figure 1 Difluoromethyl carbanion 6 – a crucial intermediate in the
formation of compounds 3–5 from phosphonates 2
© Georg Thieme Verlag Stuttgart · New York

958
P. Beier et al.
PAPER
In order to gain an insight into the stability and reactivity of 7a (Figure 2). The E-isomer was found to be less polar
of anion 6 in N,N-dimethylformamide (DMF), we initially on silica gel than the Z-isomer, due to its lower molecular
focused on the base-induced rearrangement of the phos- dipole. A comparison of the 13C NMR spectra showed a
phorus moiety from carbon to oxygen using 2a clear difference between the coupling constants of (Z)-7a
(R1 = phenyl, R2 = H) as a model starting phosphonate. (3JC–F = 1.8 Hz) and (E)-7a (3JC–F = 5.8 Hz); the differ-
The results are summarized in Table 1. It is known that ence in coupling constants between phosphorus and fluo-
clean formation of 5a is observed using potassium carbon- rine atoms was found to be relatively small [4JP–F = 6.8 Hz
ate (entry 1).13 Other bases (Et3N, LiHMDS, MeONa or for (Z)-7a and 4JP–F = 7.1 Hz for (E)-7a].
0.3 equiv of t-BuOK) gave either no reaction or little con-
O
P
O
P
version into 5a (entries 2–5). However, with one equiva-
lent of potassium tert-butoxide, even after one minute at
–60 °C, almost complete disappearance of the starting
phosphonate was observed. Some phosphate 5a was
formed but the main product was identified as a new com-
pound which, after isolation, was characterized as a mix-
ture of the E- and Z-isomers of the fluorinated enol
phosphates 7a (entry 6).
OCH2CH3
OCH2CH3
OCH2CH3
F
H
O
OCH2CH3
H
O
H
NOE
F
H
H
H
NOE
(E)-7a
(Z)-7a
Figure 2 DPFGSE-NOE identification of E- and Z-isomers of
diethyl 2-fluoro-1-phenylvinyl phosphate (7a)
Table 1 Reactions of Difluorophosphonate 2a with Various Basesa
OH
UV light affects isomerization of the Z-isomer into the E-
isomer of 7a. Thus, when compound 7a (Z/E = 97:3) was
exposed to UV light in a quartz tube, conversion of the Z-
isomer into the E-isomer was observed using GC–MS.
After four hours, the resulting mixture contained 7a in an
Z/E ratio of 58:42; however, during the process, 40% of
7a decomposed into unidentified compounds. Neverthe-
less, the E-isomer of 7a was isolated in 23% yield from
the resulting mixture.
OP(O)(OEt)2
OP(O)(OEt)2
F
base
DMF
+
Ph
CF2P(O)(OEt)2
Ph
CF2H
Ph
2a
5a
7a
Entry Base (equiv) Temp Time Convb Convb Z/E b
(°C)
(min) 5a (%) 7a (%) 7a
113
2
K2CO3 (4)
Et3N (2)
r.t.
24 h
1 h
10
10
10
1
>98c
–
–
–
60d
–
–
In order to probe the general utility of this newly devel-
oped cascade reaction, a variety of phosphonates 2 were
examined; the results are summarized in Table 2.
3
LiHMDS (2) –60
MeONa (2) –60
t-BuOK (0.3) –60
–
–
–
4
7
–
–
5
–
–
–
Table 2 Preparation of (Z)-Fluoroenol Phosphates (Z)-7 and Di-
fluoromethyl Phosphates 5a
6
t-BuOK (1)
t-BuOK (1)
t-BuOK (1)
t-BuOK (2)
t-BuOK (2)
t-BuOK (4)
–60
–60
–60
–60
–60
–60
11
22
3
87
78
97
83
>98
>98
84:16
87:13
86:14
92:8
93:7
97:3
OP(O)(OEt)2
7
10
30
1
F
R1
(Z)-7, R2 = H
8
R2 OH
t-BuOK (4 equiv)
or
9
–
R1
CF2P(O)(OEt)2
DMF, –60 °C
30 min
R2 OP(O)(OEt)2
R1
2
10
11
30
30
–
CF2H
–
5
a Reagents and conditions: 2a (0.3 mmol), base (0.3–4 equiv), anhyd
DMF (3 mL).
Phosphonate
Product
Entry
2
R1
R2
H
H
H
H
H
Yield (%)b Z/Ec
b Determined using GC–MS.
c 5a was isolated in 96% yield.13
1
2
3
4
5
6
2a
2b
2c
2d
2e
2f
Ph
(Z)-7a
(Z)-7b
(Z)-7c
(Z)-7d
5e
88
90
79
83
85
89
97:3
98:2
84:16
95:5
–
d No conversion into 5a or 7a at either r.t. or –60 °C.
4-ClC6H4
4-MeOC6H4
2-naphthyl
Ph(CH2)2
Ph
Increasing the amount of base to two and four equivalents
lead to clean conversion of 2a into 7a, without formation
of the side product 5a (entries 9–11). Furthermore, the
presence of an excess of base dramatically increased the
product Z/E ratio. The best result, in terms of efficiency
and selectivity of the formation of 7a, was achieved using
four equivalents of potassium tert-butoxide (entry 11).
The E- and Z-isomers of 7a were distinguished either
chromatographically (TLC, GC–MS) or spectroscopically
(NMR). Each isomer was isolated and characterized;
DPFGSE-NOE was used to identify the E- and Z-isomers
Me 5f
–
a Reagents and conditions: phosphonate 2 (1 mmol), t-BuOK (4
mmol), anhyd DMF (7 mL), 30 min, –60 °C.
b Isolated yields.
c Z/E ratios were determined using GC–MS of the crude reaction mix-
ture.
Synthesis 2009, No. 6, 957–962 © Thieme Stuttgart · New York

PAPER
Synthesis of (Z)-Fluoroenol Phosphates
959
R2 OH
R1
OP(O)(OEt)2
OP(O)(OEt)2
F
R1
R1
CF2P(O)(OEt)2
(Z)-7
(E)-7
2
F
– F–
F
t-BuO– t-BuOH
R2 O–
– F–
t-BuOH
or H3O+
R2 OP(O)(OEt)2
R1
R2 OP(O)(OEt)2
t-BuO–
H
F
H
t-BuO–
R1
CF2P(O)(OEt)2
R1
CF2
–
R1
OP(O)(OEt)2
R1
OP(O)(OEt)2
t-BuOH
CF2H
R
2 = H
F
8 A
F
5
6
8 B
Scheme 2 Proposed mechanism for formation of phosphates 5 and 7
NMR spectra were recorded at r.t. in CDCl3 on a Bruker Avance
400 MHz or 500 MHz instrument. Chemical shifts (d) are reported
in ppm and coupling constants (J values) are given in Hz. GC–MS
spectra were recorded on an Agilent 7890A gas chromatograph cou-
pled with a 5975C quadrupole mass-selective electron impact (EI)
detector (70 eV). High-resolution mass spectra (HRMS) were re-
corded on a LTQ Orbitrap XL instrument using electrospray ioniza-
tion (ESI). Elemental analyses were obtained using a Perkin–Elmer
PE 2400 Series II CHNS analyzer. Reactions were conducted under
Ar. Solvents were dried either by using activated 3 Å molecular
sieves (DMF, MeOH) or by distillation over Na/benzophenone
(THF). All other chemicals were used as received. Purification of
the products was performed by flash chromatography using silica
gel 60.
Phosphonates 2a–d, which were prepared from the corre-
sponding aromatic aldehydes, reacted cleanly to form enol
phosphates 7a–d in high yields and selectivities for the Z-
isomers (entries 1–4). An electron-withdrawing group on
the aromatic ring (4-chloro) had a beneficial effect on
both the yield and the selectivity (entry 2). The presence
of an electron-donating group (4-methoxy) presented no
problem, however the yield and Z/E selectivity were
slightly reduced (entry 3). In the case of phosphonate 2e,
which was prepared from the corresponding alkyl alde-
hyde, the sole product was the difluoromethyl-containing
phosphate 5e (entry 5). The same type of product was also
obtained through reaction of phosphonate 2f, which was
derived from acetophenone (entry 6).
(Z)-Fluoroenol Phosphates (Z)-7; General Procedure
A solution of t-BuOK (4 mmol) in DMF (4 mL) was added to a
stirred solution of substituted diethyl difluoro hydroxyphosphonate
2 (1 mmol) in DMF (3 mL) cooled to –60 °C. After stirring for 30
min, the reaction mixture was quenched with sat. aq NH4Cl (20
mL), and extracted with tert-butyl methyl ether (3 × 15 mL). The
combined organic phase was washed with distilled H2O (20 mL)
and brine (15 mL), dried (anhyd MgSO4), filtered through glass
wool, and the solvent was removed to give the crude product. Flash
column chromatography afforded the pure (Z)-fluoroenol phos-
phates.
From these observations a plausible mechanism can be
envisaged (Scheme 2). After base-induced deprotonation
of phosphonate 2, rearrangement to the phosphate car-
boanion 6 occurs. Proton capture gives the difluorometh-
yl-containing phosphate 5, which is the final product in
cases when R2 π H. When R2 = H and R1 = aryl, another
route is opened: deprotonation with excess base to give
the anion 8 (this does not occur when R1 = alkyl). Anion
8 can exist in two relatively stable conformations (A and
B), both with a fluorine atom antiperiplanar to the lone
Diethyl (Z)-2-Fluoro-1-phenylvinyl Phosphate [(Z)-7a]
electron pair. Conformation A is expected to have lower Purified by chromatography (EtOAc–hexanes, 25:75).
energy than conformation B, both because of the two fa-
vorable gauche interactions between the phosphate oxy-
gen and fluorine atoms and because of the lower vicinal
steric interactions between the R1 group and hydrogen.
Therefore, fluoride elimination gives preferentially (Z)-7.
This mechanism is supported by results from a control ex-
periment in which 5a was reacted with potassium tert-
Yield: 241 mg (88%); colorless liquid; Rf = 0.30 (EtOAc–hexanes,
40:60).
3
4
1H NMR (500 MHz): d = 1.29 (dt, JH–H = 7.1 Hz, JH–P = 1.2 Hz,
6 H, 2 × CH3), 4.06–4.24 (m, 4 H, 2 × CH2), 6.98 (dd, 2JH–F = 75.2
Hz, 4JH–P = 2.9 Hz, 1 H, CHF), 7.34–7.39 (m, 3 H, ArH), 7.44–7.48
(m, 2 H, ArH).
3
13C NMR (125 MHz): d = 15.9 (d, JC–P = 7.1 Hz, CH3), 64.6 (d,
butoxide under the optimized reaction conditions, to give 2JC–P = 5.9 Hz, CH2), 125.3 (d, JC–F = 3.5 Hz, Ar), 128.5, 129.1 (d,
JC–F = 1.3 Hz, Ar), 131.0 (t, 3JC–F = 3JC–P = 1.8 Hz, CArCO), 135.9 (t,
7a quantitatively in an Z/E ratio of 97:3.
2JC–F = 2JC–P = 9.0 Hz, CO), 138.9 (dd, 1JC–F = 262.4 Hz, 3JC–P = 6.9
Hz, CHF).
In summary, a facile and efficient synthesis of (Z)-2-fluo-
ro-1-arylvinyl phosphates, starting from 2-aryl-2-hy-
2
4
19F NMR (470 MHz): d = –148.2 (dd, JF–H = 75.2 Hz, JF–P = 6.8
droxy-1,1-difluorophosphonates, is described. The
reaction involves phosphonate–phosphate rearrangement
to give the intermediate difluoromethyl phosphates fol-
lowed by HF elimination. With both 2-alkyl-2-hydroxy-
1,1-difluorophosphonates and 2-aryl-2-alkyl-2-hydroxy-
1,1-difluorophosphonates, the reaction terminates at the
difluoromethyl phosphate stage. The simple execution,
readily available substrates, high yields and high Z/E se-
lectivities make this protocol very attractive.
Hz).
31P NMR (202 MHz): d = –5.38 (d, 4JP–F = 6.8 Hz).
GC–MS (tR = 11.1 min): m/z (%) = 274 (30) [M]+, 226 (30), 217
(15), 198 (100), 137 (20), 109 (25), 105 (20), 101 (15), 81 (20), 78
(20), 77 (15) [C6H5]+.
HRMS: m/z [M + Na]+ calcd for C12H16O4FNaP: 297.0662; found:
297.0663.
Anal. Calcd for C12H16FO4P: C, 52.56; H, 5.88. Found: C, 52.54; H,
5.92.
Synthesis 2009, No. 6, 957–962 © Thieme Stuttgart · New York

960
P. Beier et al.
PAPER
2
4
Diethyl (Z)-2-Fluoro-1-(4-clorophenyl)vinyl Phosphate [(Z)-7b]
Purified by chromatography (EtOAc–hexanes, 30:70).
19F NMR (376 MHz): d = –147.4 (dd, JF–H = 75.2 Hz, JF–P = 6.9
Hz).
Yield: 277 mg (90%); colorless liquid; Rf = 0.41 (EtOAc–hexanes,
40:60).
31P NMR (162 MHz): d = –5.55 (d, 4JP–F = 6.9 Hz).
GC–MS (tR = 13.8 min): m/z (%) = 324 (70) [M]+, 295 (20), 276
(20), 267 (30), 248 (100), 187 (30), 170 (35), 159 (40), 155 (30),
128 (35), 127 (30), 81 (25).
HRMS: m/z [M + Na]+ calcd for C16H18O4FNaP: 347.0819; found:
347.0814.
3
4
1H NMR (400 MHz): d = 1.31 (dt, JH–H = 7.1 Hz, JH–P = 1.2 Hz,
6 H, 2 × CH3), 4.10–4.25 (m, 4 H, 2 × CH2), 6.98 (dd, 2JH–F = 74.8
Hz, 4JH–P = 2.9 Hz, 1 H, CHF), 7.32–7.33 (m, 2 H, ArH), 7.38–7.42
(m, 2 H, ArH).
13C NMR (100 MHz): d = 15.9 (d, 3JC–P = 7.0 Hz, CH3), 64.7 (d,
2JC–P = 6.0 Hz, CH2), 126.6 (d, JC–F = 3.6 Hz, Ar), 128.8, 129.7,
135.0, 135.2, 139.0 (dd, 1JC–F = 263.5 Hz, 3JC–P = 6.8 Hz, CHF).
Anal. Calcd for C16H18FO4P: C, 59.26; H, 5.59. Found: C, 59.60; H,
5.52.
2
4
19F NMR (376 MHz): d = –147.1 (dd, JF–H = 74.8 Hz, JF–P = 6.9
Diethyl (E)-2-Fluoro-1-phenylvinyl Phosphate [(E)-7a]
A solution of t-BuOK (448.9 mg, 4 mmol) in DMF (4 mL) was add-
ed to a stirred solution of diethyl 1,1-difluoro-2-hydroxy-2-phenyl-
ethylphosphonate (2a; 294.2 mg, 1 mmol) in DMF (3 mL) cooled to
–60 °C. After 30 min of stirring, the reaction mixture was quenched
with sat. aq NH4Cl (20 mL) and extracted with tert-butyl methyl
ether (3 × 15 mL). The combined organic phase was washed with
distilled H2O (20 mL) and brine (15 mL), dried (anhyd MgSO4), fil-
tered through glass wool, and the solvent was removed to give the
crude mixture of isomers (Z/E = 97:3). This mixture was dissolved
in THF (4 mL) and transferred into a quartz tube equipped with a
stirring bar and a septum. Isomerization under UV light (50 W Hg
lamp) was followed by GC–MS. After 4 h, the temperature of the
mixture was raised to 50 °C and the solvent was removed. The pure
product was isolated by flash column chromatography (EtOAc–
hexanes, 25:75).
Hz).
31P NMR (162 MHz): d = –5.66 (d, 4JP–F = 6.9 Hz).
GC–MS (tR = 12.0 min): m/z (%) = 310 (10) [M]+, 308 (30) [M]+,
279 (10), 262 (12), 260 (36), 251 (15), 234 (30), 232 (100), 171
(15), 143 (15), 139 (15), 120 (15), 109 (10), 81 (20).
HRMS: m/z [M + Na]+ calcd for C12H15O4ClFNaP: 331.0274;
found: 331.0273.
Anal. Calcd for C12H15ClFO4P: C, 46.69; H, 4.90. Found: C, 46.71;
H, 4.98.
Diethyl (Z)-2-Fluoro-1-(4-methoxyphenyl)vinyl Phosphate [(Z)-
7c]
Purified by chromatography (EtOAc–hexanes, 25:75).
Yield: 240 mg (79%); colorless liquid; Rf = 0.28 (EtOAc–hexanes,
40:60).
Yield: 63 mg (23%); colorless liquid; Rf = 0.38 (EtOAc–hexanes,
40:60).
3
4
1H NMR (400 MHz): d = 1.30 (dt, JH–H = 7.1 Hz, JH–P = 1.2 Hz,
6 H, 2 × CH3), 3.81 (s, 3 H, OCH3), 4.07–4.24 (m, 4 H, 2 × CH2),
6.88 (dd, 2JH–F = 75.8 Hz, 4JH–P = 2.9 Hz, 1 H, CHF), 6.87–6.91 (m,
2 H, ArH), 7.37–7.41 (m, 2 H, ArH).
3
4
1H NMR (500 MHz): d = 1.30 (dt, JH–H = 7.1 Hz, JH–P = 1.1 Hz,
6 H, 2 × CH3), 4.08–4.22 (m, 4 H, 2 × CH2), 7.35 (m, 1 H, ArH),
7.36 (dd, 2JH–F = 76.9 Hz, 4JH–P = 3.2 Hz, 1 H, CHF), 7.41 (m, 2 H,
ArH), 7.66 (m, 2 H, ArH).
3
13C NMR (100 MHz): d = 16.0 (d, JC–P = 7.1 Hz, CH3), 55.3
3
13C NMR (125 MHz): d = 16.0 (d, JC–P = 6.7 Hz, CH3), 64.8 (d,
2
(OCH3), 64.5 (d, JC–P = 6.1 Hz, CH2), 114.0, 123.4, 127.1 (d,
2JC–P = 6.1 Hz, CH2), 126.5 (d, JC–F = 7.9 Hz, Ar), 128.3, 129.0 (d,
JC–F = 3.4 Hz, Ar), 135.8 (t, 2JC–F = 2JC–P = 9.1 Hz, CO), 137.9 (dd,
1JC–F = 260.7 Hz, 3JC–P = 7.0 Hz, CHF), 160.3.
3
3
JC–F = 1.8 Hz, Ar), 130.7 (dd, JC–F = 5.8 Hz, JC–P = 3.8 Hz,
CArCO), 137.9 (dd, 2JC–F = 26.8 Hz, 2JC–P = 9.0 Hz, CO), 144.2 (dd,
1JC–F = 259.9 Hz, 3JC–P = 5.3 Hz, CHF).
2
4
19F NMR (376 MHz): d = –150.1 (dd, JF–H = 75.8 Hz, JF–P = 6.8
Hz).
2
4
19F NMR (470 MHz): d = –156.1 (dd, JF–H = 76.9 Hz, JF–P = 7.1
31P NMR (162 MHz): d = –5.66 (d, 4JP–F = 6.8 Hz).
Hz).
GC–MS (tR = 12.4 min): m/z (%) = 304 (80) [M]+, 275 (30), 247
(60), 228 (100), 167 (30), 135 (50), 108 (25), 81 (25).
HRMS: m/z [M + Na]+ calcd for C13H18O5FNaP: 327.0768; found:
327.0767.
31P NMR (202 MHz): d = –3.79 (d, 4JP–F = 7.1 Hz).
GC–MS (tR = 10.8 min): m/z (%) = 274 (30) [M]+, 226 (30), 217
(15), 198 (100), 137 (20), 109 (25), 105 (20), 101 (15), 81 (20), 78
(20), 77 (15) [C6H5]+.
HRMS: m/z [M + H]+ calcd for C12H17O4FP: 275.0843; found:
275.0843.
Anal. Calcd for C13H18FO5P: C, 51.32; H, 5.96. Found: C, 51.46; H,
6.08.
Anal. Calcd for C12H16FO4P: C, 52.56; H, 5.88. Found: C, 52.55; H,
6.18.
Diethyl (Z)-2-Fluoro-1-(naphthalene-2-yl)vinyl Phosphate [(Z)-
7d]
Purified by chromatography (EtOAc–hexanes, 25:75).
2,2-Difluoro-1-phenylethyl Diethyl Phosphate (5a)13
Yield: 269 mg (83%); colorless liquid; Rf = 0.25 (EtOAc–hexanes,
30:70).
K2CO3 (165.8 mg, 1.2 mol) was added to a solution of 1,1-difluoro-
2-hydroxy-2-phenylethylphosphonate (2a; 88.2 mg, 0.3 mmol) in
DMF (3 mL). After stirring at r.t. for 24 h, H2O (15 mL) was added
and the product was extracted with tert-butyl methyl ether (4 × 10
mL). The combined organic phase was washed with H2O (10 mL),
brine (10 mL), dried (anhyd MgSO4), filtered through glass wool,
and the solvent was removed to give the crude product. The pure
product was isolated by flash column chromatography (EtOAc–
hexanes, 30:70).
3
4
1H NMR (400 MHz): d = 1.30 (dt, JH–H = 7.1 Hz, JH–P = 1.2 Hz,
6 H, 2 × CH3), 4.11–4.25 (m, 4 H, 2 × CH2), 7.12 (dd, 2JH–F = 75.2
Hz, 4JH–P = 2.9 Hz, 1 H, CHF), 7.46–7.51 (m, 3 H, ArH), 7.79–7.87
(m, 3 H, ArH), 7.95–7.98 (m, 1 H, ArH).
13C NMR (100 MHz): d = 15.9 (d, 3JC–P = 7.0 Hz, CH3), 64.6 (d,
2JC–P = 5.9 Hz, CH2), 122.4 (d, JC–F = 2.3 Hz, Ar), 124.9 (d, JC–F
=
5.0 Hz, Ar), 126.6, 126.7, 127.6, 128.2, 128.4, 130.0, 133.0, 133.4,
Yield: 85 mg (96%); colorless liquid; Rf = 0.48 (EtOAc–hexanes,
50:50).
2
1
136.1 (t, JC–F = 2JC–P = 9.1 Hz, CO), 139.3 (dd, JC–F = 262.9 Hz,
3JC–P = 6.8 Hz, CHF).
Synthesis 2009, No. 6, 957–962 © Thieme Stuttgart · New York

PAPER
Synthesis of (Z)-Fluoroenol Phosphates
961
3
4
1H NMR (400 MHz): d = 1.17 (dt, JH–H = 7.1 Hz, JH–P = 1.1 Hz,
3 H, CH3), 1.28 (dt, 3JH–H = 7.1 Hz, 4JH–P = 1.1 Hz, 3 H, CH3), 3.88–
4.18 (m, 4 H, 2 × CH2), 5.39 (ddt, 3JH–F = 10.2, 9.7 Hz, 3JH–H = 4.2
2JC–P = 5.8 Hz, CCH3), 114.9 (dt, 1JC–F = 249.8 Hz, 3JC–P = 9.0 Hz,
CF2H), 126.5, 128.3, 128.8, 137.4.
19F NMR (376 MHz): d = –130.7 (dd, 2JF–F = 278.9 Hz, 2JF–H = 56.0
2
3
Hz, 1 H, CHO), 5.91 (dt, JH–F = 55.2 Hz, JH–H = 4.2 Hz, 1 H,
2
2
Hz, 1 F, CFaFbH), –129.8 (ddd, JF–F = 278.9 Hz, JF–H = 56.2 Hz,
CF2H), 7.39–7.47 (m, 5 H, ArH).
4JF–P = 1.1 Hz, 1 F, CFaFbH).
13C NMR (100 MHz): d = 15.7 (d, 3JC–P = 7.2 Hz, CH3), 15.8 (d,
31P NMR (162 MHz): d = –5.50 (s).
3JC–P = 7.2 Hz, CH3), 64.0 (d, 2JC–P = 5.8 Hz, CH2), 64.2 (d, 2JC–P
=
GC–MS (tR = 10.9 min): m/z (%) = 257 (30) [M – CF2H]+, 155
2
2
5.8 Hz, CH2), 77.4 (ddd, JC–F = 25.2, 20.2 Hz, JC–P = 5.0 Hz,
CHO), 113.8 (ddd, 1JC–F = 254.4, 245.6 Hz, 3JC–P = 8.8 Hz, CF2H),
127.6, 128.6, 129.5, 132.8–132.9 (m).
(100), 154 (30), 127 (35), 103 (30), 99 (25), 77 (15) [C6H5]+.
HRMS: m/z [M + Na]+ calcd for C13H19O4F2NaP: 331.0881; found:
331.0879.
19F NMR (470 MHz): d = –129.0 (ddd, JF–F = 286.4 Hz, JF–H
=
2
2
3
2
55.2 Hz, JF–H = 9.7 Hz, 1 F, CFaFbH), –127.2 (ddd, JF–F = 286.4
Anal. Calcd for C13H19F2O4P: C, 50.65; H, 6.21. Found: C, 50.96;
H, 6.51.
Hz, 2JF–H = 55.2 Hz, 3JF–H = 10.2 Hz, 1 F, CFaFbH).
31P NMR (162 MHz): d = –1.63 (s).
GC–MS (tR = 10.5 min): m/z (%) = 274 (70) [M – HF]+, 243 (45),
Acknowledgment
226 (50), 198 (90), 141 (50), 109 (60), 91 (100), 77 (40) [C6H5]+.
We thank the Grant Agency of the Czech Republic (203/08/P310)
and the Academy of Sciences of the Czech Republic (Research Plan
AVZ40550506) for financial support.
HRMS: m/z [M + H]+ calcd for C12H18O4F2P: 295.0905; found:
295.0905.
1,1-Difluoro-4-phenylbutan-2-yl Diethyl Phosphate (5e)
Prepared from diethyl 1,1-difluoro-2-hydroxy-4-phenylbutylphos-
phonate (2e) according to the general procedure for the preparation
of (Z)-7 and purified by chromatography (EtOAc–hexanes, 25:75),
to give 5e.
References
(1) Lichtenthaler, R. W. Chem. Rev. 1961, 61, 607.
(2) Pomeisl, K.; Kvíčala, J.; Paleta, O.; Klásek, A.; Kafka, S.;
Kubelka, V.; Havlíček, J.; Čejka, J. Tetrahedron 2007, 63,
10549.
(3) Protti, S.; Fagoni, M. Chem. Commun. 2008, 3611.
(4) (a) Sasaki, M.; Honda, S.; Tetsuji, N.; Takakura, H.;
Tachibana, K. Synlett 2000, 838. (b) Schroth, W.; Spitzner,
R.; Jörg, F. Synthesis 1983, 827. (c) An, J.; Wilson, J. M.;
An, Y.-Z.; Wiemer, D. F. J. Org. Chem. 1996, 61, 4040.
(d) Whitehead, A.; Moore, J. D.; Hanson, P. R. Tetrahedron
Lett. 2003, 44, 4275. (e) Miller, J. A. Tetrahedron Lett.
2002, 43, 7111. (f) Ding, Y.; Huang, X. Synth. Commun.
2001, 31, 449.
(5) (a) Machleidt, H.; Strehlke, G. U. Angew. Chem. 1964, 76,
494. (b) Sekine, M.; Okimoto, K.; Yamada, K.; Hata, T.
J. Org. Chem. 1981, 46, 2097. (c) Moorhoff, C. M. Synth.
Commun. 2003, 33, 2069. (d) Onishi, J. Y.; Takuwa, T.;
Mukaiyama, T. Chem. Lett. 2003, 32, 994.
(6) (a) Boyce, C. B. C.; Webb, S. B.; Phillips, L.; Ager, I. R.
J. Chem. Soc., Perkin Trans. 1 1974, 1644. (b) Stowell, J.
K.; Widlanski, T. S. J. Am. Chem. Soc. 1994, 116, 789.
(c) Ding, Y.; Wang, W.; Liu, Z. Phosphorus, Sulfur Silicon
Relat. Elem. 1996, 118, 113.
Yield: 274 mg (85%); colorless liquid; Rf = 0.32 (EtOAc–hexanes,
30:70).
3
4
1H NMR (400 MHz): d = 1.35 (dt, JH–H = 7.1 Hz, JH–P = 1.1 Hz,
3 H, CH3), 1.36 (dt, 3JH–H = 7.1 Hz, 4JH–P = 1.1 Hz, 3 H, CH3), 2.02–
2.09 (m, 2 H, CH2), 2.71–2.79 (m, 1 H, CH2CHaHb), 2.84–2.91 (m,
1 H, CH2CHaHb), 4.12–4.20 (m, 4 H, 2 × CH2CH3), 4.43–4.55 (m,
2
3
1 H, CHO), 5.86 (ddd, JH–F = 55.7, 54.7 Hz, JH–H = 3.3 Hz, 1 H,
CF2H), 7.19–7.23 (m, 3 H, ArH), 7.28–7.33 (m, 2 H, ArH).
13C NMR (100 MHz): d = 16.0 (d, 3JC–P = 7.2 Hz, CH3), 16.1 (d,
3JC–P = 7.2 Hz, CH3), 30.3–30.4 (m, CH2), 30.6 (CH2), 64.2–64.3
2
2
(m, CH2CH3), 75.5 (dt, JC–F = 25.7 Hz, JC–P = 5.8 Hz, CHO),
1
3
114.0 (dt, JC–F = 245.2 Hz, JC–P = 4.5 Hz, CF2H), 126.2, 128.3,
128.5, 140.5.
2
2
19F NMR (376 MHz): d = –128.0 (ddd, JF–F = 289.9 Hz, JF–H
=
=
3
2
54.7 Hz, JF–H = 9.0 Hz, 1 F, CFaFbH), –132.3 (ddd, JF–F
289.9 Hz, 2JF–H = 55.7 Hz, 3JF–H = 13.0 Hz, 1 F, CFaFbH).
31P NMR (162 MHz): d = –1.35 (s).
GC–MS (tR = 10.9 min): m/z (%) = 322 (5) [M]+, 168 (30), 155
(30), 127 (20), 117 (100), 99 (25), 91 (30).
(7) (a) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V.
Chem. Soc. Rev. 2008, 37, 320. (b) Boehm, H. J.; Banner,
D.; Bendels, S.; Kansy, M.; Kuhn, B.; Mueller, K.; Obst-
Sander, U.; Stahl, M. ChemBioChem 2004, 5, 637.
(c) Smart, B. E. J. Fluorine Chem. 2001, 109, 3.
(8) (a) Tarasenko, K. V.; Gerus, I. I.; Kukhar, V. P. J. Fluorine
Chem. 2007, 128, 1264. (b) Wiley, D. W.; Simmons, H. E.
J. Org. Chem. 1964, 29, 1876. (c) Seifert, F. U.;
Röschenthaler, G.-V. J. Fluorine Chem. 1994, 68, 169.
(9) (a) Bergmann, E. D.; Shahak, I. J. Chem. Soc. 1960, 462.
(b) Stubbe, J. A.; Kenyon, G. L. Biochemistry 1972, 11,
338. (c) Sundaram, A. K.; Woodard, R. W. J. Org. Chem.
2000, 65, 5891.
(10) (a) Ishihara, T.; Yamana, M.; Ando, T. Tetrahedron Lett.
1983, 24, 5657. (b) Ishihara, T.; Okada, Y.; Kuroboshi, M.;
Shinozaki, T.; Ando, T. Chem. Lett. 1988, 819.
(11) (a) Ishihara, T.; Maekawa, T.; Ando, T. Tetrahedron Lett.
1983, 24, 4229. (b) Ishihara, T.; Maekawa, T.; Yamasaki,
Y.; Ando, T. J. Fluorine Chem. 1986, 34, 271. (c) Ishihara,
T.; Maekawa, T.; Yamasaki, Y.; Ando, T. J. Fluorine Chem.
1987, 34, 323.
HRMS: m/z [M + H]+ calcd for C14H22O4F2P: 323.1218; found:
323.1219.
Anal. Calcd for C14H21F2O4P: C, 52.17; H, 6.57. Found: C, 52.49;
H, 6.25.
1,1-Difluoro-2-phenylpropan-2-yl Diethyl Phosphate (5f)
Prepared from diethyl 1,1-difluoro-2-hydroxy-2-phenylpropyl-
phosphonate (2f) according to the general procedure for the prepa-
ration of (Z)-7 and purified by chromatography (EtOAc–hexanes,
30:70) to give 5f.
Yield: 274 mg (89%); colorless liquid; Rf = 0.33 (EtOAc–hexanes,
40:60).
1H NMR (400 MHz): d = 1.24–1.30 (m, 6 H, 2 × CH3), 2.02 (s, 3 H,
CH3C), 3.98–4.15 (m, 4 H, 2 × CH2), 6.04 (t, 2JH–F = 56.1 Hz, 1 H,
CF2H), 7.35–7.43 (m, 3 H, ArH), 7.50–7.53 (m, 2 H, ArH).
13C NMR (100 MHz): d = 15.9 (d, 3JC–P = 7.0 Hz, CH3CH2), 16.0 (d,
3JC–P = 7.1 Hz, CH3CH2), 18.9–19.0 (m, CH3C), 63.8 (d, 2JC–P = 5.9
2
2
Hz, CH2), 63.9 (d, JC–P = 6.0 Hz, CH2), 82.8 (dt, JC–F = 24.0 Hz,
Synthesis 2009, No. 6, 957–962 © Thieme Stuttgart · New York

962
P. Beier et al.
PAPER
(12) Demir, A. S.; Eymur, S. J. Org. Chem. 2007, 72, 8527.
(13) Zibinsky, M.; Beier, P.; Prakash, G. K. S. Khim. Interesakh
Ustoich. Razvit. 2008, 16, 71.
(15) (a) Romanenko, V. D.; Kukhar, V. P. Chem. Rev. 2006, 106,
3868. (b) Obayashi, M.; Ito, E.; Matsui, K.; Kondo, K.
Tetrahedron Lett. 1982, 23, 2323. (c) Piettre, S. R.;
Cabanas, L. Tetrahedron Lett. 1996, 37, 5881. (d) Piettre,
S. R.; Girol, C.; Schelcher, C. G. Tetrahedron Lett. 1996, 37,
4711.
(14) Beier, P.; Alexandrova, A. V.; Zibinsky, M.; Prakash, G. K.
S. Tetrahedron 2008, 64, 10977.
Synthesis 2009, No. 6, 957–962 © Thieme Stuttgart · New York