Nucleophilic difluoromethylenation of aldehydes and ketones using diethyl difluoro(trimethylsilyl)methylphosphonate

Article abstract of DOI:10.1016/j.jfluchem.2009.02.015

A new nucleophilic difluoromethylenation of aldehydes and ketones using diethyl difluoro(trimethylsilyl)methylphosphonate (1) has been achieved. The reactive carbanion species were generated under mild reaction conditions with a catalytic amount of initiator. This methodology was compatible with non-enolizable and in some cases with enolizable aldehydes and ketones and provided a straightforward access to phosphates of syn and anti 2,2-difluoro-1,3-diols.

Full text of DOI:10.1016/j.jfluchem.2009.02.015

Journal of Fluorine Chemistry 130 (2009) 493–500
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Nucleophilic difluoromethylenation of aldehydes and ketones using diethyl
difluoro(trimethylsilyl)methylphosphonate
*
Anastasia V. Alexandrova, Petr Beier
´
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo nam. 2, 166 10 Prague 6, Czech Republic
A R T I C L E I N F O
A B S T R A C T
Article history:
A new nucleophilic difluoromethylenation of aldehydes and ketones using diethyl difluoro(trimethyl-
silyl)methylphosphonate (1) has been achieved. The reactive carbanion species were generated under
mild reaction conditions with a catalytic amount of initiator. This methodology was compatible with
non-enolizable and in some cases with enolizable aldehydes and ketones and provided a straightforward
access to phosphates of syn and anti 2,2-difluoro-1,3-diols.
Received 12 January 2009
Received in revised form 20 February 2009
Accepted 21 February 2009
Available online 9 March 2009
ß 2009 Elsevier B.V. All rights reserved.
Keywords:
Phosphonates
Phosphates
Difluoromethylenation
Nucleophilic addition
1. Introduction
for the difluoromethylenation of aldehydes and ketones. We were
particularly intrigued by the possibility of base-free generation of
Nucleophilic difluoromethylation is an important synthetic
strategy for the introduction of the CF2 group into organic
compounds and thereby expansion of the diversity of available
selectively fluorinated compounds useful in drug design and
material research.
Previously, nucleophilic difluoromethylation has been achieved
using sulfur [1] and selenium [2] containing reagents. For the
nucleophilic installation of difluoromethylene group PhSO2CF2H
was used as a [CF2]2À equivalent [3] and PhSCF2TMS as a [CF2]À
equivalent [4].
(diethylphosphinyl)difluoromethyl carbanion under mild condi-
tions (with only catalytic amount of initiator) and consecutive
multistep conversions to difluoromethylene containing products
in ‘‘one-pot’’.
A number of initiators are known for the generation of
fluorinated carbanions from the trimethylsilyl precursors such
as CF3TMS [7], PhSO2CF2TMS [8], PhSCF2TMS [1b] [4]. They include
fluoride source (CsF, TBAF, TBAT [9]), oxygen anions (metal
alkoxides, carboxylic acid salts, potassium carbonate, phosphate
salts [10], triethylamine N-oxide [11]), Lewis bases (Et3N, pyridine,
PPh3, AsPh3, SbPh3) [12] and N-heterocyclic carbenes [13].
Phosphonates containing the trimethylsilyl group are known
and their chemistry has been investigated [14]. Fluorinated
phosphonates [15] with a TMS group have also received some
attention. Phosphonate 1 was used for the synthesis of 1,1-
difluoro-2-hydroxyalkylphosphonates by the reaction of carbonyl
compounds using catalytic amount of CsF [16] or TBAF [17]. Toru
and co-workers have used excess of 1 and TMAF to transform an
aromatic aldehyde into a difluoromethyl containing phosphate
[18]. Phosphonate 1 was also used for the preparation of 14C
labeled difluoroethene starting from 14C formaldehyde followed by
a modification of Wadsworth–Emmons reaction [19].
Recently, we have reported the use of diethyl difluoromethyl-
phosphonate (2) for the nucleophilic difluoromethylation and
difluoromethylenation of aldehydes and ketones. Utilization of
phosphonate
2 gave access to a variety of CF2 containing
compounds such as 2,2-difluoroethan-1-ols and their phosphates,
2,2-difluoro-1,3-diols and their phosphates [5], and also to
substituted flurovinyl phosphates [6]. However, there were some
drawbacks: the employment of strong bases such as t-BuOK in
nucleophilic difluoromethylenation reactions prohibited the use of
enolizable carbonyl compounds and required isolation of inter-
mediate phosphonates.
In this article we wish to report the use of diethyl difluoro
(trimethylsilyl)methylphosphonate (1) as a new [CF2]2À synthon
2. Results and discussion
At the outset of our study we have optimized reaction
conditions the type and amount of initiator for the formation of
* Corresponding author. Tel.: +420 220 183 533; fax: +420 233 331 733.
E-mail address: beier@uochb.cas.cz (P. Beier).
0022-1139/$ – see front matter ß 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2009.02.015

494
A.V. Alexandrova, P. Beier / Journal of Fluorine Chemistry 130 (2009) 493–500
phosphonate 3a (R1 = Ph, R2 = H) using diethyl difluoro(trimethyl-
silyl)methylphosphonate (1) [20] and benzaldehyde. The results of
optimization are summarized in Table 1.
Table 1
Formation of 3a from 1 and benzaldehydea.
Potassium fluoride (entry 1) was found to be very slow
initiator. The reaction with 1 equiv of potassium carbonate was
fast and clean, however because of the basic character of this
activator the reaction mixture could not be used for further
conversions without isolation of 3a as intended. With catalytic
potassium carbonate the reaction was very slow. Contrary to the
literature [16], the employment of CsF (5 mol%) in THF gave only
traces of 3a after 20 h. It is interesting to mention that switching
to DMF as a solvent gave a mixture of 3a, 4a and 5a. TBAT was
identified as an initiator of choice, because of its low basicity,
good solubility in organic solvents and non-hydroscopic nature.
With only 1 mol% of TBAT the reaction was finished in 4 h giving
the product 3a in 94% isolated yield without the need of
chromatographic separation. Similarly 3e was prepared starting
.
Entry
Initiator (mol%)
Time
Solvent
1
2
3
4
5
KF (5)
15 h
1 h
DMF
DMF
DMF
DMF
THF
K2CO3 (100)
K2CO3 (1)
TBAT (1)
TBAT (1)
24 h
4 h
4 h
aAll reactions were performed with PhCHO (1 equiv) at rt and lead to the product 3a
in quantitative GC yield.
Table 2
Optimization of reaction conditions for the formation of 5ab from 1 or 3aa.
.
Entry
Initiator (mol%)
Method
Solvent
Temperature
Time
Yield 5ab (%)b
Yield 7a (%)b
1
2
3
4
5
6
7
8
CsF (100)
CsF (50)
A
B
B
C
B
B
B
B
DMF
DMF
DMF
DMF
DMF
DMF
THF
À30 8C to 0 8C
À50 8C to 0 8C
0 8C to rt
0 8C to rt
rt
2 h
85
94
90
78
98
98
89
94
15
6
4 h
TBAT (100)
TBAT (50)
TBAT (30)
TBAT (30)
TBAT (30)
TBAT (10)
4 h
10
22
2
15 h
3 h
40 8C
rt
1 h
2
15 h
4 d
11
4
DMF
40 8C
a
Reaction conditions (solvent, temp. and reaction time) shown in table refer to the formation of 4ab and 5ab from 3a.
b
Determined by GC–MS analysis.
Method A: To the solution of 3a prepared in situ 4-ClC6H4CHO (2 equiv) and initiator were added.
Method B: Solution of 3a prepared in situ was added to the mixture of 4-ClC6H4CHO (2 equiv) and initiator.
Method C: Initiator was added to the mixture of 3a and 4-ClC6H4CHO (2 equiv).
Table 3
Difluoromethylenation of aldehydes leading to phosphates 5a.
.
Entry
R1
R2
R3
Method
Initiator (mol%)
Time
Yield 5 (%)b
1
2
3
4
5
6
7
Ph
H
4-ClC6H4
4-MeC6H4
4-MeOC6H4
n-C6H13
Ph
B
B
B
C
C
C
C
TBAT (30)
CsF (50)
CsF (50)
TBAT (50)
CsF (50)
CsF (50)
CsF (50)
3 h
1 h
1.5 h
1 h
3 h
3 h
4 h
5ab 84
5ac 73
5bd 68
5ae 70c
5ea 64
5eb 62
5fb 56
Ph
H
4-ClC6H4
Ph
H
H
n-C6H13
n-C6H13
Me
H
H
4-ClC6H4
4-ClC6H4
Me
a
Reaction conditions (solvent, temp. and reaction time) shown in table refer to the formation of 5 from 3.
Isolated yields unless noted otherwise.
b
c
Determined by GC–MS analysis. Side-product 7a (30%) was also formed.
Method B: Solution of 3 prepared in situ was added to the mixture of R3CHO (2 equiv) and initiator.
Method C: Initiator was added to the mixture of 3 and R3CHO (2 equiv).

A.V. Alexandrova, P. Beier / Journal of Fluorine Chemistry 130 (2009) 493–500
495
from n-heptanal in 93% isolated yield1 and 3f from acetone in
85% yield.
Table 4
Difluoromethylenation of aldehydes leading to phosphates 5 of symmetrical diolsa.
Having identified optimal reaction conditions for the formation
of 3, we turned our attention to difluoromethylenation. Again some
optimization of reaction conditions was needed. We have used
benzaldehyde in the first step (formation of 3a) and 4-chlor-
obenzaldehyde in the second step leading to difluoromethylene
containing phosphates 4ab and 5ab. We have started either from
isolated 3a or prepared in situ from 1 and benzaldehyde using
conditions described in Table 1, entries 4 and 5. Results are shown
in Table 2.
As shown in Table 2, CsF or TBAT were identified as efficient
initiators. This time the required amount of initiator was 0.3–1
equiv. With lower amount of initiator the reactions was found to be
very slow (entry 8). The product was formed as a mixture of TMS
protected alcohol 4ab and free alcohol 5ab. Compound 4ab can be
smoothly converted into 5ab by the addition of small amounts of
water. We avoided the use of more common TBAF reagent for the
removal of TMS moiety, because the fluoride ion also attacked
phosphorus atom giving rise to neurotoxin diethyl phosphoro-
fluoridate (detected by GC–MS). The starting phosphonate 3a was
prepared in situ, the second aldehyde together with initiator were
added subsequently (method A). Alternatively, reversed addition
was used (method B). In method C isolated 3a was used as a
starting phosphonate. The by-product phosphate 7a was observed
in all cases; however its formation can be minimized using method
B. The most efficient formation of 5ab was observed using
conditions shown in entries 2, 5 and 6.
.
Entry
R
Initiator (50 mol%)
Temperature
Time
Yield 5 (%)b
1
2
3
4
5
Ph
TBAT
TBAT
CsF
0 8C to rt
0 8C to rt
À5 8C to rt
À5 8C to rt
À50 8C to rt
5 h
2 h
2 h
4 h
15 h
5aa 89
5bb 77
5cc 83
5dd 79
5ee 23c
4-ClC6H4
4-MeC6H4
4-MeOC6H4
n-C6H13
CsF
TBAT
a
All reactions were performed with 1, RCHO (4 equiv) and initiator in DMF.
Isolated yields unless noted otherwise.
b
c
Determined by GC–MS analysis. Side-products 2, 3e, 7e, and products of
enolization and aldol reaction of n-heptanal were also formed.
3. Conclusion
In conclusion we have developed a new method for nucleophilic
difluoromethylenation of aldehydes and ketones using diethyl
difluoro(trimethylsilyl)methylphosphonate (1). In contrast to
previously described diethyl difluoromethylphosphonate (2),
where low temperatures and excess of strong bases were needed,
the application of TMS containing phosphonate 1 allowed the
generation of (diethylphosphinyl)difluoromethyl carbanion under
mild conditions with catalytic amount of fluoride initiator, giving
rise to 1,1-difluoro-2-alkyl-2-(trimethylsilyloxy)ethylphospho-
nates (3) and phosphates of 2,2-difluoro-1,3-diols 5 in respectable
yields. Starting from aryl aldehydes phosphates 5 of symmetrical
diols were prepared in a single step, phosphates 5 of unsymme-
trical diols in a reaction sequence from in situ preformed
phosphonates 3 and in case of enolizable aldehydes and ketones
from isolated 3.
Results of preparative synthesis of phosphates 5 are presented
in Table 3.
In reactions where R3CHO is an activated aldehyde, such as 4-
chlorobenzaldehyde, TBAF works as efficient activator (entry 1).
However the application of TBAT in the case of non-activated aryl
aldehydes (such as 4-methyl or 4-methoxy benzaldehyde) gave
very slow conversion to the product 5 and formation of significant
amount of by-product 7. The use of CsF on the other hand was
found to be successful (entries 2 and 3). The application of
enolizable aldehydes was met with limited success. Phosphonate
3a with n-heptanal in the presence of TBAT gave the desired
phosphate, however large amount of by-product 7a was formed
(entry 4). Starting from phosphonate 3e and various aryl aldehydes
(entries 5 and 6) the desired phosphates could be isolated in good
yields in the presence of CsF. With TBAT only TMS group
deprotection of 3e was observed. Moderate yield of phosphate
5fb was obtained starting from phosphonate 3f derived from
acetone and activated aldehyde (entry 7).
4. Experimental
1H, 13C, 19F and 31P NMR spectra were recorded in CDCl3 on a
Bruker 400 MHz instrument at 400, 100.6, 470 and 202 MHz.
Chemical shifts (d) are reported in ppm relative to Me4Si (0 ppm,
for 1H NMR), residual CHCl3 (7.26 ppm for 1H NMR and 77.0 ppm
for 13C NMR), internal CFCl3 (0 ppm for 19F NMR), internal
(MeO)3PO (3.0 ppm for 31P NMR) and external H3PO4 in water
(0 ppm for 31P NMR). GC–MS spectra were recorded on an Agilent
7890A gas chromatograph coupled with 5975C quadrupole mass
selective electron impact (EI) detector (70 eV). High resolution
mass spectra (HRMS) were recorded on a LTQ Orbitrap XL
instrument using electrospray (ESI) ionization. Infrared spectra
were measured on a FTIR instrument. Reactions were conducted
under Ar. DMF was dried by refluxing with calcium hydride
Products 5 were formed as a mixture of syn and anti isomers in
1:1 ratio. These isomers were conveniently separated on silica gel
column chromatography and characterized individually. During
the formation of phosphates 5 migration of phosphorus group from
one oxygen atom to the other took place and the products are
mixtures of isomeric phosphates in different ratios as mentioned in
our previous study [5a]. Phosphate moiety of 5 can be conveniently
removed affording 2,2-difluoro-1,3-diols [5a].
˚
followed by distillation and kept over molecular sieves (3 A). THF
Application of an excess of aromatic aldehyde in the reaction
with 1 and initiator (TBAT for activated aldehydes and CsF for less
reactive ones) gave rise to phosphates 5 of symmetrical diols in one
step and very good yields (Table 4, entries 1–4). The use of
enolizable aldehyde (n-heptanal) gave only low GC yield of the
desired product 5ee together with significant amounts of by-
products 2, 3e and 7e (entry 5). With ketones such as acetone or
acetophenone no difluromethylene containing products were
observed.
was dried by distillation over Na/benzophenone. Aldehydes were
distilled before use. Cesium fluoride was dried (0.1 torr, 250 8C,
1 h). All other chemicals were used as received.
4.1. Preparation of diethyl
difluoro(trimethylsilyl)methylphosphonate (1) [20]
A solution of n-BuLi (23.4 mL, 2.5 M, 58.5 mmol) in petrol ether
was added dropwise to a stirred solution of i-Pr2NH (5.92 g,
58.5 mmol) in THF (100 mL) cooled to À78 8C. The reaction
mixture was warmed up to 0 8C, stirred for 5 min, and again cooled
down to À78 8C. A solution of diethyl difluoromethylphosphonate
1
Cis and trans TMS enols of n-heptanal and 2 were detected as side products in ca.
5% yield.

496
A.V. Alexandrova, P. Beier / Journal of Fluorine Chemistry 130 (2009) 493–500
(2) (10.0 g, 53.2 mmol) in THF (50 mL) was added dropwise,
followed by stirring at this temperature for 30 min. A solution of
TMSCl (8.69 g, 79.8 mmol) in THF (50 mL) was added, the mixture
was stirred for 40 min at À78 8C and then warmed up to rt. The
reaction mixture was poured into a solution of phosphoric acid
(4.2 g, 85% aqueous) in water/ice (350 mL). The organic layer was
separated and the aqueous layer was extracted with petrol ether
(2 Â 200 mL). Organic phases were combined, washed with brine
(50 mL), dried (MgSO4), filtered, concentrated under reduced
pressure and purified by distillation (85–86 8C, 0.2 torr) affording
(40), 103 (15), 165 (20), 187 (75), 233 (50), 260 (100), 303 (25), 359
(35), 374 [M]+ (1); HRMS (ESI+) calculated for C15H34F2O4PSi:
375.1927, found: 375.1926.
4.2.3. Diethyl 1,1-difluoro-2-methyl-2-
(trimethylsilyloxy)propylphosphonate (3f)
Solution of TBAT (25 mg, 47
mmol) in DMF (1 mL) was added
dropwise to a solution of 1 (1.227 g, 4.70 mmol) and acetone
(330 mg, 5.70 mmol) in DMF (2 mL) at À50 8C. The mixture was
warmed up to rt, after 3 h of stirring brine (3 mL) was added and
the product was extracted into petrol ether (3 Â 30 mL). The
combined organic extract was dried (MgSO4), filtered and
concentrated under reduced pressure. After removal of impurities
under vacuum (50 8C, 0.1 torr, 3 h) pure product was obtained as a
the pure product as a colorless liquid (12.14 g, 88%): 1H NMR:
d
0.27 (s, 9H, SiMe3), 1.37 (t, 6H, 3JHH = 7.1 Hz, 2 Â CH3), 4.25 (dq, 4H,
3JHP = 7.4 Hz, 3JHH = 7.1 Hz, 2 Â CH2); 13C NMR:
À4.6 (br s, SiMe3),
d
3
2
16.4 (d, JCP = 5.6 Hz, CH3), 63.7 (d, JCP = 6.9 Hz, CH2), 126.7 (dt,
1J = 271.7, 165.0 Hz, CF2); 19F NMR:
NMR:
d
À131.2 (d, 2JFP = 92.2 Hz); 31
P
colorless liquid (1.265 g, 85%): 1H NMR:
d 0.17 (s, 9H, SiMe3), 1.37
d
9.65 (t, 2JPF = 92.2 Hz); GC–MS (EI) m/z 29 (12%), 45 (15), 65
(dt, 6H, 3JHH = 7.1 Hz, 4JHP = 0.5 Hz, 2 Â CH3CH2), 1.45–1.46 (m, 6H,
(35), 73 (80), 81 (33), 93 (20), 121 (70), 141 (100), 153 (20), 165
(75), 205 (50), 233 (50), 259 [M]+ (1).
2 Â CH3), 4.20–4.33 (m, 4H, 2 Â CH2); 13C NMR:
d 2.2 (SiMe3), 16.3
(d, 3JCP = 5.8 Hz, CH3CH2), 24.3–24.4 (m, CH3), 63.6–64.3 (m, CH2),
76.2 (dt, 2JCF = 23.3 Hz, 2JCP = 14.3 Hz, CCF2), 107.7–136.1 (m, CF2);
2
4.2. Preparation of phosphonates 3
19F NMR:
d
À118.5 (d, JFP = 105.7 Hz); 31P NMR:
d 6.77 (t,
2JPF = 105.7 Hz); FTIR (film, nmax cmÀ1) 2987 (m), 1389 (w), 1252
(m), 1199 (m), 1125 (m), 1064 (s), 1017 (s), 975 (m), 890 (m), 839
(s), 753 (m), 562 (m); GC–MS (EI) m/z 73 (75%), 131 (100), 155 (30),
260 (30); HRMS (ESI+) calculated for C11H26F2O4PSi: 319.1301,
found: 319.1306.
4.2.1. Diethyl 1,1-difluoro-2-phenyl-2-
(trimethylsilyloxy)ethylphosphonate (3a) [16]
TBAT (22 mg, 0.04 mmol) was added to a solution of 1 (1.04 g,
4 mmol) and benzaldehyde (425 g, 4 mmol) in THF (4 mL). After
5 h of stirring, brine (3 mL) was added and the product was
extracted into petrol ether (3 Â 30 mL). The combined organic
extract was dried (MgSO4), filtered, concentrated under reduced
pressure. After removal of impurities under vacuum (50 8C,
0.1 torr, 3 h) pure product was obtained as a colorless liquid
4.3. Preparation of ‘‘unsymmetrical’’ phosphates (5)
4.3.1. 1-Phenyl-2,2-difluoro-3-hydroxy-3-(4-chlorophenyl)propyl
diethyl phosphate (5ab)
(1.875 g, 94%): 1H NMR:
d
0.07 (s, 9H, SiMe3), 1.26 (t, 3H,
Solution of TBAT (11 mg, 21 mmol) in DMF (0.5 mL) was added
3
3JHH = 7.1 Hz, CH3), 1.37 (t, 3H, JHH = 7.1 Hz, CH3), 4.04–4.31 (m,
4H, 2 Â CH2), 5.08–5.14 (m, 1H, CHO), 7.33–7.36 (m, 3H, CArH),
to a solution of 1 (535 mg, 2.06 mmol) and benzaldehyde (218 mg,
2.06 mmol) in DMF (3 mL) at 0 8C. The mixture was warmed up to
rt, after 4 h of stirring it was added dropwise to a mixture of TBAF
(333 mg, 0.62 mmol) and 4-chlorobenzaldehyde (578 mg,
4.11 mmol) in DMF (3 mL). After 3 h of stirring three drops of
distilled water were added and the mixture was stirred for further
2 h. Saturated NH4Cl (3 mL) was added and the product was
extracted into ethyl acetate (3 Â 30 mL). The combined organic
extract was washed with brine (10 mL), dried (MgSO4), filtered,
concentrated under reduced pressure, and purified on silica gel to
yield separately anti and syn products. Anti-5ab (mixture of
7.43–7.46 (m, 2H, CArH); 13C NMR:
CH3), 64.1–64.3 (m, CH2), 74.1–74.7 (m, CHO), 118.3 (ddd,
1J = 273.0, 262.6, 208.1 Hz, CF2), 127.8, 128.5, 128.6, 135.8–135.9
d
À0.1 (SiMe3), 16.1–16.3 (m,
(m); 19F NMR:
d
À124.5 (ddd, 1F, JFF = 304.6 Hz, JFP = 104.4 Hz,
2
2
3JFH = 18.9 Hz),–115.6 (ddd, 1F, JFF = 304.6 Hz, JFP = 102.1 Hz,
2 2
3JFH = 7.3 Hz); 31P NMR:
d
6.47 (dd, JPF = 104.4, 102.1 Hz); FTIR
2
(film, nmax cmÀ1) 2983 (w), 1455 (w), 1268 (m), 1253 (m), 1182
(m), 1016 (s), 842 (s), 752 (m); GC–MS (EI) m/z 73 (30%), 155 (20),
179 (100), 180 (15), 233 (10), 260 (40), 351 [M–Me]+ (5); HRMS
(ESI+) calculated for C15H26F2O4PSi: 367.13006, found: 367.12940.
isomeric phosphates 61:39): pale yellow oil (378 mg, 42%): Rf (30%
3
EtOAc/petrol ether) 0.29; 1H NMR:
d
1.30 (dt, 3H, JHH = 7.1 Hz,
3
4
4.2.2. Diethyl 1,1-difluoro-2-n-hexyl-2-
4JHP = 1.1 Hz, CH3major), 1.30 (dt, 3H, JHH = 7.1 Hz, JHP = 1.0 Hz,
CH3minor), 1.34–1.38 (m, 3H + 3H, CH3major+minor), 3.78–3.99 (m,
4H, 2 Â CH2minor), 4.13–4.28 (m, 4H, 2 Â CH2major), 5.14–5.21 (m,
1H + 1H, CHOHmajor+minor), 5.35–5.41 (m, 1H, OHminor), 5.60 (br s,
(trimethylsilyloxy)ethylphosphonate (3e)
Solution of TBAT (20 mg, 37
mmol) in DMF (1.5 mL) was added
dropwise to a solution of 1 (966 mg, 3.71 mmol) and n-heptanal
(466 mg, 4.08 mmol) in DMF (2.5 mL) at À50 8C. The mixture was
warmed up to rt, after 4 h of stirring, brine (3 mL) was added and
the product was extracted into petrol ether (3 Â 30 mL). The
combined organic extract was dried (MgSO4), filtered, concen-
trated under reduced pressure. After removal of impurities under
vacuum (50 8C, 0.1 torr, 3 h) pure product was obtained as a
1H, OHmajor), 5.73–5.82 (m, 1H + 1H, CHOPmajor+minor), 7.30–7.48
3
(m, 9H + 9H, CArHmajor+minor); 13C NMR:
d
15.7 (d, JCP = 6.7 Hz,
3
CH3), 15.8 (d, JCP = 7.1 Hz, CH3), 16.0–16.1 (m, CH3), 64.9 (d,
2JCP = 6.3 Hz, CH2), 65.0 (d, 2JCP = 6.4 Hz, CH2), 65.1 (d, 2JCP = 6.1 Hz,
CH2), 65.1 (d, JCP = 6.1 Hz, CH2), 70.3 (dd, JCF = 29.9, 25.4 Hz,
CHOH), 70.9 (dd, 2JCF = 29.6, 25.4 Hz, CHOH), 74.8–75.7 (m, CHOP),
119.2 (dt, JCF = 252.8 Hz, JCP = 7.5 Hz, CF2), 127.9, 128.1, 128.2,
128.4, 128.5, 129.4, 129.5, 129.8, 131.4 (d, 3JCP = 2.9 Hz, CArCHOP),
132.5 (d, JCP = 2.9 Hz, CArCHOP), 134.1, 134.5, 135.4, 135.7; 19F
d 0.26 (sminor), 0.39
(smajor); GC–MS (EI) m/z 77 (10%), 99 (8), 140 (100), 155 (10), 173
(65), 274 (9); FTIR (film, n
max cmÀ1) 3329 (m), 3092 (w), 3067 (w),
2
2
colorless liquid (1.298 g, 93%): 1H NMR:
d
0.16 (s, 9H, SiMe3), 0.87–
1
3
0.90 (m, 3H, CH3(CH2)5), 1.24–1.34 (m, 7H, CH3(CH2)3CH2CHaHb),
1.36–1.40 (m, 6H, 2 Â CH3CH2O), 1.41–1.58 (m, 1H,
CH3(CH2)4CHaHb), 1.65–1.80 (m, 2H, CH2), 3.93–4.04 (m, 1H,
3
NMR:
d
À122.3 to À122.2 (m); 31P NMR:
CHO), 4.20–4.34 (m, 4H, 2 Â CH2O); 13C NMR:
d
0.2 (SiMe3), 14.0
3
(CH3(CH2)5), 16.3 (d, JCP = 5.7 Hz, CH3CH2O), 22.6 (CH2), 25.6
(CH2), 29.0 (CH2), 30.8 (CH2), 31.7 (CH2), 64.2–64.4 (m, CH2O),
3035 (w), 2986 (m), 1598 (w), 1493 (m), 1256 (m), 1164 (m), 1036
(s); HRMS (ESI+) calculated for C19H22ClF2NaO5P: 457.0752, found:
457.0754. Syn-5ab (mixture of isomeric phosphates 69:31): white
gummy solid (373 mg, 42%): Rf (30% EtOAc/petrol ether) 0.14; 1H
73.0–73.7 (m, CHO), 116.0–123.3 (m, CF2); 19F NMR:
d
–119.5 (ddd,
2
2
3
1F, JFF = 303.8 Hz, JFP = 103.8 Hz, JFH = 16.0 Hz),–116.8 (ddd, 1F,
2JFF = 303.8 Hz, 2JFP = 105.2 Hz, 3JFH = 9.3 Hz); 31P NMR:
2JPF = 105.2, 103.8 Hz); FTIR (film, nmax cmÀ1) 1273 (s), 1253 (s),
1164 (m), 1025 (s), 845 (s), 754 (m); GC–MS (EI) m/z 55 (15%), 73
d 6.63 (dd,
NMR:
3H, 3JHH = 7.1 Hz, 4JHP = 1.0 Hz, CH3minor), 1.23 (dt, 3H,
d
1.03 (dt, 3H, 3JHH = 7.1 Hz, 4JHP = 1.1 Hz, CH3major), 1.08 (dt,

A.V. Alexandrova, P. Beier / Journal of Fluorine Chemistry 130 (2009) 493–500
497
4
3
3
3JHH = 7.1 Hz, JHP = 1.1 Hz, CH3major), 1.24 (dt, 3H, JHH = 7.1 Hz,
4JHP = 1.1 Hz, CH3minor), 3.67–3.80 (m, 2H + 2H, 2 Â CH2major+minor),
3.96–4.09 (m, 2H + 2H, 2 Â CH2major+minor), 4.42–4.49 (m, 1H + 1H,
15.8 (d, JCP = 7.1 Hz, CH3CH2), 21.1 (s, CArCH3), 21.2 (s, CArCH3),
2
2
63.7 (d, JCP = 5.8 Hz, CH2), 64.1 (d, JCP = 5.7 Hz, CH2), 64.2 (d,
2JCP = 5.6 Hz, CH2), 72.0–72.7 (m, CHOH), 77.6–78.2 (m, CHOP),
117.1–122.3 (m, CF2), 127.8, 127.9, 128.0, 128.4, 128.5, 128.6,
128.7, 129.1, 129.3, 130.8, 130.8–130.9 (m), 132.4, 133.2, 133.9–
3
CHOHmajor+minor), 4.72 (d, JHH = 5.0 Hz, OHminor), 4.96 (d,
3JHH = 5.1 Hz, OHmajor), 5.93–6.03 (m, 1H + 1H, CHOPmajor+minor),
7.25–7.31 (m, CArH), 7.34–7.42 (m, CArH), 7.58–7.64 (m, CArH); 13
C
134.0 (m), 136.3, 138.2, 139.2; 19F NMR:
2JFF = 250.4 Hz, 3JFH = 19.4,
6.9 Hz),–122.7
d
À124.0 (ddd, 1Fminor
,
,
NMR:
d
15.7 (d, 3JCP = 7.3 Hz, CH3), 15.9 (d, 3JCP = 7.1 Hz, CH3), 63.9
(dd, 1Fminor
2
2
(d, JCP = 6.0 Hz, CH2), 64.4 (d, JCP = 6.1 Hz, CH2), 71.8 (dd,
2JCF = 30.4, 23.6 Hz, CHOH), 72.4 (dd, JCF = 29.8, 24.2 Hz, CHOH),
77.6–78.2 (m, CHOP), 117.1–122.2 (m, CF2), 128.0, 128.1, 128.15,
2JFF = 250.4 Hz, 3JFH = 16.8 Hz),–123.9 (ddd, 1Fmajor, 2JFF = 250.7 Hz,
3JFH = 19.5,
3JFH = 17.3 Hz); 31P NMR:
6.9 Hz),–122.6
(dd,
1Fmajor
,
2JFF = 250.7 Hz,
2
d
À0.95 (sminor),–0.93 (smajor); GC–MS
128.5, 128.6, 128.7, 128.8, 129.5, 130.1, 132.4–132.5 (m), 133.7–
(EI) m/z 77 (10%), 91 (10), 119 (12), 140 (100), 154 (60); FTIR (film,
nmax cmÀ1) 3330 (m), 3091 (w), 3065 (w), 3034 (m), 2983 (m),
1614 (w), 1580 (w), 1516 (m), 1263 (s), 1162 (s), 1030 (s); HRMS
(ESI+) calculated for C20H25F2NaO5P: 437.1300, found: 437.1303.
133.8 (m), 134.4, 135.0, 135.5, 136.2; 19F NMR:
d
À123.9 (ddd,
3
1Fmajor
,
2JFF = 251.1 Hz, JFH = 19.3, 6.5 Hz),–122.7 (dd, 1Fmajor
,
2JFF = 251.1 Hz, 3JFH = 17.3 Hz),–123.8 (ddd, 1Fminor, 2JFF = 251.1 Hz,
3JFH = 18.1, 2JFF = 250.6 Hz,
7.9 Hz),–123.0 (dd, 1Fminor
3JFH = 15.4 Hz); 31P NMR:
À1.02 (sminor),–0.98 (smajor); GC–MS
(EI) m/z 77 (15%), 99 (10), 140 (100), 155 (25), 174 (75); FTIR (film,
max cmÀ1) 3312 (m), 3067 (w), 3037 (w), 2985 (w), 1599 (w), 1493
(m), 1254 (m), 1162 (m), 1025 (s); HRMS (ESI+) calculated for
19H22ClF2NaO5P: 457.0752, found: 457.0754.
,
d
4.3.3. 1-(4-Chlorophenyl)-2,2-difluoro-3-hydroxy-3-(4-
methoxyphenyl)propyl diethyl phosphate (5bd)
n
Solution of TBAT (10 mg, 19 mmol) in DMF (0.5 mL) was added
to a solution of 1 (484 mg, 1.86 mmol) and 4-chlorobenzaldehyde
(261 mg, 1.86 mmol) in DMF (3 mL) at 0 8C. The mixture was
warmed up to rt, after 4 h of stirring it was added dropwise to a
mixture of CsF (141 mg, 0.93 mmol) and 4-methoxybenzaldehyde
(506 mg, 3.72 mmol) in DMF (2.5 mL). After additional 1.5 h of
stirring three drops of distilled water were added and the mixture
was stirred for further 2 h. Saturated NH4Cl (4 mL) was added and
the product was extracted into ethyl acetate (3 Â 30 mL). The
combined organic extract was washed with brine (10 mL), dried
(MgSO4), filtered, concentrated under reduced pressure, and
purified on silica gel to yield separately anti and syn products.
Anti-5bd (mixture of isomeric phosphates 67:33): colorless oil
C
4.3.2. 1-Phenyl-2,2-difluoro-3-hydroxy-3-(4-methylphenyl)propyl
diethyl phosphate (5ac)
Solution of TBAT (8 mg, 15
mmol) in DMF (0.5 mL) was added to
a solution of 1 (405 mg, 1.56 mmol) and benzaldehyde (165 mg,
1.56 mmol) in DMF (3 mL) at 0 8C. The mixture was warmed up to
rt, after 4 h of stirring it was added dropwise to a mixture of CsF
(118 mg, 0.78 mmol) and 4-methylbenzaldehyde (374 mg,
3.12 mmol) in DMF (2.5 mL). After additional 1 h of stirring three
drops of distilled water were added and the mixture was stirred for
further 2 h. Saturated NH4Cl (3 mL) was added and the product was
extracted into ethyl acetate (3 Â 30 mL). The combined organic
extract was washed with brine (10 mL), dried (MgSO4), filtered,
concentrated under reduced pressure, and purified on silica gel to
yield separately anti and syn products. Anti-5ac (mixture of
isomeric phosphates 50:50): colorless oil (239 mg, 37%): Rf (30%
(296 mg, 34%): Rf (30% EtOAc/petrol ether) 0.14; 1H NMR:
d 1.09–
1.16 (m, 6H, CH3CH2major+minor), 1.35–1.39 (m, 6H, CH3CH2major+-
minor), 3.77 (s, 3H, OCH3minor), 3.78 (s, 3H, OCH3major), 3.80–3.97 (m,
4H, 2 Â CH2minor), 4.13–4.25 (m, 4H, 2 Â CH2major), 5.08–5.21 (m,
3H, CHOHmajor+minor + OHminor), 5.55 (d, 1H, 3JHH = 4.9 Hz, OHmajor),
5.68–5.80 (m, 2H, CHOPmajor+minor), 6.86–6.90 (m, CArH), 7.30–7.43
(m, CArH); 13C NMR:
EtOAc/petrol ether) 0.24; 1H NMR:
d
1.06–1.12 (m, 6H,
d
15.7 (d, JCP = 6.7 Hz, CH3CH2), 15.8 (d,
3
3
4
3
2 Â CH3CH2), 1.35 (dt, 3H, JHH = 7.1 Hz, JHP = 1.0 Hz, CH3CH2),
3JCP = 6.4 Hz, CH3CH2), 15.9 (d, JCP = 6.7 Hz, CH3CH2), 55.1 (s,
OCH3), 55.2 (s, OCH3), 64.8–65.0 (m, CH2), 70.0–70.7 (m, CHOH),
74.5–75.4 (m, CHOP), 116.5–121.6 (m, CF2), 124.4 (d, 3JCP = 3.1 Hz),
127.9, 128.4, 128.7, 129.1, 129.3, 129.7, 130.8, 131.3 (d,
3JCP = 2.9 Hz), 132.4, 134.0, 134.4, 135.3, 159.6, 160.4, 167.7; 19F
3
4
1.36 (dt, 3H, JHH = 7.1 Hz, JHP = 1.0 Hz, CH3CH2), 2.32 (s, 3H,
ArCH3), 2.33 (s, 3H, CArCH3), 3.81–3.87 (m, 2H, CH2), 3.89–3.97 (m,
C
2H, CH2), 4.10–4.27 (m, 4H, 2 Â CH2), 5.10–5.18 (m, 2H, 2 Â CHOH),
5.22 (d, 1H, 3JHH = 5.6 Hz, OH), 5.35 (d, 1H, 3JHH = 5.3 Hz, OH), 5.71–
5.82 (m, 2H, 2 Â CHOP), 7.13–7.17 (m, CArH), 7.29–7.39 (m, CArH),
NMR:
d
À122.5 to À122.2 (m); 31P NMR:
d 0.35 (sminor), 0.59
7.44–7.49 (m, CArH); 13C NMR:
d
15.7 (d, JCP = 6.7 Hz, CH3CH2),
(smajor); FTIR (film, n
max cmÀ1) 3329 (m), 3072 (w), 3038 (w), 2983
3
15.8 (d, 3JCP = 6.6 Hz, CH3CH2), 16.0 (d, 3JCP = 6.7 Hz, CH3CH2), 21.1
(m), 2840 (w), 1614 (m), 1587 (w), 1516 (m), 1253 (s), 1164 (m),
1033 (s); HRMS (ESI+) calculated for C20H24ClF2NaO6P: 487.0859,
found: 487.0860. Syn-5bd (mixture of isomeric phosphates 71:29):
colorless oil (297 mg, 34%): Rf (30% EtOAc/petrol ether) 0.06; 1H
2
(s, CArCH3), 21.2 (s, CArCH3), 64.8 (d, JCP = 6.3 Hz, CH2), 64.9 (d,
2JCP = 6.3 Hz, CH2), 65.0 (d, JCP = 6.1 Hz, CH2), 70.6–71.2 (m,
2
CHOH), 75.1–75.9 (m, CHOP), 119.3 (dt, 1JCF = 252.9 Hz,
3JCP = 7.6 Hz, CF2), 127.9, 127.9, 128.0, 128.1, 128.2, 128.3, 128.4,
128.7, 129.3, 129.7 (d, 3JCP = 3.0 Hz), 132.7–132.8 (m), 135.8, 138.0,
NMR:
d 1.03–1.09 (m, 6H, CH3CH2major+minor), 1.21–1.26 (m, 6H,
CH3CH2major+minor), 3.70 (s, 3H, OCH3minor), 3.84 (s, 3H, OCH3major),
3.96–4.07 (m, 4H, CH2major+minor), 4.17–4.25 (m, 4H, CH2major+mi-
nor), 4.36–4.47 (m, 2H, CHOHmajor+minor), 5.01–5.34 (br s, OHma-
jor+minor), 5.91–6.00 (m, 2H, CHOPmajor+minor), 6.82 (d, 1H,
3JHH = 8.8 Hz, CArH), 6.91–6.94 (m, CArH), 7.24–7.31 (m, CArH),
139.2; 19F NMR:
d
À122.4 to À122.2 (m); 31P NMR:
d 0.45 (s), 0.58
(s); GC–MS (EI) m/z 77 (10%), 91 (10), 119 (12), 140 (100), 154 (80);
FTIR (film, nmax cmÀ1) 3345 (m), 3092 (w), 3065 (w), 3034 (w),
2986 (m), 1617 (w), 1516 (w), 1496 (w), 1255 (m), 1164 (m), 1029
(s); HRMS (ESI+) calculated for C20H25F2NaO5P: 437.1300, found:
437.1302. Syn-5ac (mixture of isomeric phosphates 53:47):
colorless oil (232 mg, 36%): Rf (30% EtOAc/petrol ether) 0.09; 1H
7.37–7.40 (m, CArH), 7.50–7.59 (m, CArH), 7.68–7.70 (m, CArH); 13
C
3
3
NMR:
d 15.6 (d, JCP = 7.1 Hz, CH3CH2), 15.7 (d, JCP = 7.0 Hz,
CH3CH2), 55.0 (s, OCH3), 55.1 (s, OCH3), 63.7 (d, 2JCP = 5.9 Hz, CH2),
2
2
NMR:
d
1.02–1.07 (m, 6H, CH3CH2major+minor), 1.21–1.24 (m, 6H,
63.8 (d, JCP = 5.9 Hz, CH2), 64.1 (d, JCP = 5.9 Hz, CH2), 64.2 (d,
2JCP = 6.0 Hz, CH2), 71.3–72.1 (m, CHOH), 77.2–77.8 (m, CHOP),
CH3CH2major+minor), 2.31 (s, 3H, CArCH3minor), 2.73 (s, 3H, CArCH3-
major), 3.68–3.81 (m, 4H, 2 Â CH2minor), 3.97–4.10 (m, 4H,
2 Â CH2major), 4.19–4.23 (m, 2H, OHmajor+minor), 4.43–4.53 (m,
2H, CHOHmajor+minor), 5.91–6.02 (m, 2H, CHOPmajor+minor), 7.10 (d,
3
117.0–122.3 (m, CF2), 125.7 (d, JCP = 3.1 Hz), 127.9, 128.5, 128.6,
3
129.2, 129.4, 129.9, 130.8, 132.3, 132.4 (d, JCP = 2.9 Hz), 134.1,
135.1, 135.3, 159.7, 160.3, 167.6; 19F NMR:
d
À123.9 (ddd, 1Fmajor
,
,
3
3
2H, JHH = 8.0 Hz, CArHminor), 7.20 (d, 2H, JHH = 8.1 Hz, CArHmajor),
2JFF = 250.5 Hz,
3JFH = 17.7,
8.0 Hz),–123.1 (dd, 1Fmajor
3
7.23 (d, 2H, JHH = 8.1 Hz, CArHmajor), 7.27–7.29 (m, CArH), 7.34–
2JFF = 250.5 Hz, 3JFH = 16.0 Hz),–124.1 (ddd, 1Fminor, 2JFF = 249.8 Hz,
7.36 (m, CArH), 7.39–7.40 (m, CArH), 7.50–7.53 (m, CArH); 13C NMR:
3JFH = 17.7,
3JFH = 15.2 Hz); 31P NMR:
d
7.6 Hz),–123.2
(dd,
1Fminor
,
2JFF = 249.8 Hz,
3
3
d
15.6 (d, JCP = 7.1 Hz, CH3CH2), 15.7 (d, JCP = 7.1 Hz, CH3CH2),
À1.00 (sminor),–0.92 (smajor); FTIR (film,

498
A.V. Alexandrova, P. Beier / Journal of Fluorine Chemistry 130 (2009) 493–500
3
3
n
max cmÀ1) 3320 (m), 3071 (w), 1614 (m), 1585 (m), 1515 (s), 1253
CH3CH2O), 16.0 (d, JCP = 6.7 Hz, CH3CH2O), 16.1 (d, JCP = 6.9 Hz,
CH3CH2O), 22.4, 22.5, 25.0, 25.6, 28.0–28.1 (m), 28.5–28.6 (m),
(s), 1163 (m), 1031 (s); HRMS (ESI+) calculated for
2
C
20H24ClF2NaO6P: 487.0859, found: 487.0859.
28.9, 29.1, 31.5, 31.7, 64.8 (d, JCP = 6.2 Hz, OCH2), 64.9 (d,
2JCP = 6.2 Hz, OCH2), 64.9 (d, JCP = 6.2 Hz, OCH2), 65.0 (d,
2
2
4.3.4. 1-n-Hexyl-2,2-difluoro-3-hydroxy-3-phenylpropyl diethyl
phosphate (5ea)
2JCP = 5.7 Hz, OCH2), 68.8 (dd, JCF = 29.7, 26.4 Hz, CHOH), 69.7
2
(dd, JCF = 31.0, 24.6 Hz, CHOH), 73.9–74.6 (m, CHOP), 74.9 (ddd,
2JCF = 36.9, 27.8 Hz, JCP = 5.8 Hz, CHOP), 117.5–122.6 (m, CF2),
2
Solution of phosphonate 3e (527.9 mg, 1.41 mmol) in DMF
(2 mL) was added dropwise to a mixture of benzaldehyde (299 mg,
2.82 mmol) and CsF (107 mg, 0.71 mmol) in DMF (1.5 mL) at rt.
After additional 3 h of stirring three drops of distilled water were
added and the mixture was stirred for 1 h. Saturated NH4Cl (4 mL)
was added and the product was extracted into ethyl acetate
(3 Â 30 mL). The combined organic extract was washed with brine
(10 mL), dried (MgSO4), filtered, concentrated under reduced
pressure, and purified on silica gel to yield separately anti and syn
products. Anti-5ea: colorless oil (179 mg, 31%): Rf (30% EtOAc/
1
3
119.9 (dt, JCF = 252.9 Hz, JCP = 4.7 Hz, CF2), 127.9, 128.4, 129.4,
129.6, 131.4 (d, 3JCP = 3.3 Hz), 133.9, 134.4 (d, 3JCP = 3.2 Hz), 135.3;
19F NMR:
123.5 (ddd, 1Fmajor
d
À124.4 (dd, 1Fmajor
,
2JFF = 263.7 Hz, JFH = 19.3 Hz),–
2JFF = 263.9 Hz, JFH = 17.3, 5.3 Hz);–125.8
3
3
,
3
(ddd, 1Fminor
,
2JFF = 262.9 Hz, JFH = 16.9, 7.0 Hz),–125.0 (ddd,
2JFF = 263.0 Hz, JFH = 17.8, 5.9 Hz); 31P NMR:
3
1Fminor
,
d
0.55
(sminor), 0.99 (smajor); FTIR (film, nmax cmÀ1) 3330 (m), 3073 (w),
1598 (w), 1493 (m), 1251 (m), 1169 (m), 1032 (s); GC–MS (EI) m/z
99 (50%), 127 (40), 141 (10), 155 (100), 174 (15); HRMS (ESI+)
calculated for C19H30ClF2NaO5P: 465.1380, found: 465.1375. Syn-
5eb (mixture of isomeric phosphates 80:20): white solid (170 mg,
31%): m.p. 77–78 8C, Rf (25% EtOAc/petrol ether) 0.26, 0.16; 1H
petrol ether) 0.19; 1H NMR:
d 0.86–0.90 (m, 4H, n-C6H13), 1.08 (dt,
3
4
3H, JHH = 7.0 Hz, JHP = 0.8 Hz, CH3CH2O), 1.26–1.41 (m, 14H, n-
C6H13, CH3CH2O), 1.61–1.67 (m, 2H, n-C6H13), 3.76–3.86 (m, 1H,
CHaHbO), 3.88–3.97 (m, 1H, CHaHbO), 3.98–4.08 (m, 1H, CHOH),
4.10–4.25 (m, 2H, CH2O), 4.70 (d, 1H, 3JHH = 5.8 Hz, OH), 5.61–5.70
NMR:
d 0.84–0.91 (m, 3H +3H, n-C6H13major+minor), 1.09 (dt, 3H,
3JHH = 7.1 Hz, JHP = 0.7 Hz, CH3CH2Ominor), 1.24–1.32 (m, 7H + 7H
n-C6H13major+minor, 6H CH3CH2Omajor, 3H CH3CH2Ominor), 1.40–1.60
(m, 1H +1H, n-C6H13major+minor), 1.81–1.87 (m, 2H +2H, n-
C6H13major+minor), 3.30–3.39 (m, 1H, CHOHminor), 3.60 (d, 1H,
3JHH = 8.5 Hz, OHminor), 3.75-3.84 (m, 2H, CH2Ominor), 3.99–4.15 (m,
4H + 2H, CH2Omajor+minor), 4.79–4.95 (m, 2H, CHOH, CHOPmajor),
5.01 (d, 1H, 3JHH = 5.5 Hz, OHmajor), 5.77–5.86 (m, CHOPminor), 7.31–
7.33 (m, 2H, CArHmajor), 7.34–7.37 (m, 2H, CArHminor), 7.42 (d, 2H,
4
(m, 1H, CHOP), 7.38–7.41 (m, 3H, CArH), 7.42–7.47 (m, 2H, CArH);
13C NMR:
d
14.0, 15.7 (d, JCP = 6.7 Hz, CH3CH2O), 16.0 (d,
3
3JCP = 6.6 Hz, CH3CH2O), 22.6, 25.7, 28.0–28.1 (m), 29.1, 31.7,
64.8 (d, 2JCP = 6.5 Hz, OCH2), 64.9 (d, 2JCP = 6.1 Hz, OCH2), 69.0 (dd,
2JCF = 29.5, 26.8 Hz, CHOH), 75.0 (ddd, JCF = 34.9, 29.2 Hz,
2
2JCP = 4.6 Hz, CHOP), 120.2 (ddd, 1JCF = 254.3, 252.6 Hz,
3JCP = 6.9 Hz, CF2), 128.2, 128.3, 129.2, 132.8 (d, JCP = 3.2 Hz);
3
19F NMR:
n
d
À125.4 to À125.3 (m); 31P NMR:
d
0.53 (s); FTIR (film,
3JHH = 8.4 Hz, CArHmajor), 7.49 (d, 2H, JHH = 8.4 Hz, CArHminor); 13C
3
max cmÀ1) 3377 (m), 3094 (w), 3068 (w), 3037 (w), 2983 (m), 1498
NMR:
d
14.0, 14.0, 15.8 (d, JCP = 7.0 Hz, CH3CH2O), 15.9–16.1 (m,
3
(w), 1259 (s), 1167 (m), 1037 (s); GC–MS (EI) m/z 91 (10%), 99 (15),
107 (20), 127 (10), 140 (100), 155 (35), 243 (18), 274 (10); HRMS
(ESI+) calculated for C19H31F2NaO5P: 431.1769, found: 431.1769.
Syn-5ea: colorless oil (187 mg, 33%): Rf (30% EtOAc/petrol ether)
CH3CH2O), 22.5, 22.6, 25.0, 25.3, 29.1, 29.2, 29.2–29.3 (m), 29.8–
29.9 (m), 31.7, 64.0–64.1 (m), 64.2 (d, 2JCP = 6.1 Hz, OCH2), 64.4 (d,
2JCP = 6.0 Hz, OCH2), 70.6 (dd, 2JCF = 29.4, 24.9 Hz, CHOH), 72.2 (dd,
2JCF = 30.8, 24.3 Hz, CHOH), 77.3–77.9 (m, CHOP), 120.0 (ddd,
3
1
0.40; 1H NMR:
d
0.87–0.91 (m, 4H, n-C6H13), 1.30–1.43 (m, 13H, n-
1JCF = 254.9, 248.7 Hz, JCP = 4.3 Hz, CF2), 120.7 (ddd, JCF = 258.5,
3
C6H13, CH3CH2O), 1.76–1.82 (m, 2H, n-C6H13), 4.17–4.27 (m, 4H,
2 Â CH2O), 4.74–4.85 (m, 1H, CHOH), 5.00–5.07 (m, 1H, CHOP),
5.58–5.59 (br s, 1H, OH), 7.32–7.38 (m, 3H, CArH), 7.46–7.48 (m, 2H,
252.3 Hz, JCP = 6.8 Hz, CF2), 128.2, 128.7, 129.5, 129.9, 132.5 (dd,
3J = 5.3, 2.2 Hz), 134.3, 135.3, 135.5; 19F NMR:
d
À126.1 (ddd,
3
1Fminor
,
2JFF = 249.9 Hz, JFH = 19.4, 6.7 Hz),–124.6 (dd, 1Fminor
,
,
,
C
ArH); 13C NMR: 14.0, 16.0–16.2 (m, CH3CH2O), 22.6, 25.0, 28.1–
2JFF = 250.4 Hz,
2JFF = 256.6 Hz,
3JFH = 16.3 Hz),
3JFH = 19.1,
6.7 Hz),–118.2
À121.1
(ddd,
(dd,
1Fmajor
1Fmajor
2
2
28.2, 29.1, 31.7, 64.9 (d, JCP = 6.1 Hz, OCH2), 65.0 (d, JCP = 5.7 Hz,
OCH2), 70.4 (dd, 2JCF = 31.0, 24.5 Hz, CHOH), 75.2 (ddd, 2JCF = 37.1,
27.7 Hz, 2JCP = 5.9 Hz, CHOP), 120.1 (dt, 1JCF = 252.7 Hz,
3JCP = 4.8 Hz, CF2), 127.9, 128.1–128.2 (m), 135.9–136.0 (m); 19F
2JFF = 256.6 Hz, JFH = 13.3 Hz); 31P NMR:
d
À1.03 (smajor),–0.83
3
(sminor); FTIR (film,
n
max cmÀ1) 3321 (m), 3073 (w), 1599 (w), 1580
(w), 1493 (m), 1253 (s), 1167 (m), 1036 (s); GC–MS (EI) m/z 99
(40%), 127 (45), 141 (30), 155 (100), 174 (40); HRMS (ESI+)
calculated for C19H30ClF2NaO5P: 465.1380, found: 465.1375.
NMR:
d
À124.4 (dd, 1F, 2JFF = 263.6 Hz, 3JFH = 19.5 Hz),–123.4 (ddd,
1F, JFF = 263.6 Hz, JFH = 17.3, 5.3 Hz); 31P NMR:
d 0.93 (s); FTIR
2
3
(film, nmax cmÀ1) 3343 (m), 3092 (w), 3066 (w), 3034 (w), 2983
(m), 1605 (w), 1496 (w), 1264 (s), 1032 (s); GC–MS (EI) m/z 99
(50%), 127 (33), 140 (25), 155 (100); HRMS (ESI+) calculated for
C19H31F2NaO5P: 431.1769, found: 431.1765.
4.3.6. 1,1-Dimethyl-2,2-difluoro-3-hydroxy-3-(4-
chlorophenyl)propyl diethyl phosphate (5fb)
Prepared in analogy to 5ea starting from 3f and 4-chloroben-
zaldehyde in 4 h reaction time yielding the product 5fb (mixture of
isomeric phosphates 67:33) as light yellow oil (566 mg, 56%): Rf
(30% EtOAc/petrol ether) 0.20. The spectroscopic characterization
data were identical to those published by us [5a].
4.3.5. 1-n-Hexyl-2,2-difluoro-3-hydroxy-3-(4-chlorophenyl)propyl
diethyl phosphate (5eb)
Prepared in analogy to 5ea starting from 4-chlorobenzaldehyde
yielding separately anti and syn products in 1:1 ratio. Anti-5eb
(mixture of isomeric phosphates 75:25): colorless oil (170 mg,
4.4. Preparation of ‘‘symmetrical’’ phosphates (5)
31%): Rf (30% EtOAc/petrol ether) 0.35, 0.50; 1H NMR:
d 0.88–0.91
(m, 3H + 3H, n-C6H13major+minor), 1.30–1.42 (m, 13H +13H,
CH3CH2Omajor+minor, n-C6H13major+minor), 1.54–1.61 (m, 1H +1H,
n-C6H13major+minor), 1.75–1.85 (m, 2H + 2H, n-C6H13major+minor),
3.76–3.86 (m, 1H + 1H, CH2Omajor+minor), 3.88–3.97 (m, 1H + 1H,
CH2Omajor+minor), 3.98–4.08 (m, 1H, CHOHmajor), 4.10–4.25 (m, 4H,
CH2Omajor+minor), 4.70 (d, 1H, 3JHH = 5.8 Hz, OHmajor), 4.71–4.83 (m,
1H, CHOHminor), 4.96–5.04 (m, 1H, CHOPminor), 5.61–5.70 (m, 1H,
4.4.1. 2,2-Difluoro-3-hydroxy-1,3-diphenylpropyl diethyl phosphate
(5aa) [5a]
Solution of TBAT (324 mg, 0.60 mmol) in DMF (1.5 mL) was
added dropwise to a solution of 1 (312 mg, 1.20 mmol) and
benzaldehyde (509 mg, 4.80 mmol) in DMF (3 mL) at 0 8C. The
mixture was warmed up to rt, after 5 h of stirring three drops of
distilled water were added and the mixture was stirred for further
2 h. Saturated NH4Cl (3 mL) was added and the product was
extracted into ethyl acetate (3 Â 30 mL). The combined organic
extract was washed with brine (10 mL), dried (MgSO4), filtered,
3
CHOPmajor), 5.96 (d, 1H, JHH = 3.3 Hz, OHminor), 7.36–7.42 (m, 4H,
C
ArHmajor+minor), 7.42–7.47 (m, 4H, CArHmajor+minor); 13C NMR:
d
3
3
13.9, 14.0, 15.7 (d, JCP = 6.6 Hz, CH3CH2O), 15.9 (d, JCP = 6.9 Hz,

A.V. Alexandrova, P. Beier / Journal of Fluorine Chemistry 130 (2009) 493–500
499
concentrated under reduced pressure, and purified on silica gel to
yield separately anti and syn products in 1:1 ratio and total 89%
yield. The spectroscopic characterization data were identical to
those published by us [5a].
4JHP = 1.1 Hz, CH3CH2), 3.76 (s, 3H, OCH3), 3.77 (s, 3H, OCH3), 3.81–
3.88 (m, 1H, CHaHb), 3.89–3.96 (m, 1H, CHaHb), 4.12–4.24 (m, 2H,
CH2), 5.06–5.13 (m, 1H, CHOH), 5.33 (br s, 1H, OH), 5.67–5.76 (m,
1H, CHOP), 6.86–6.89 (m, 4H, CArH), 7.36–7.40 (m, 4H, CArH); 13C
3
3
NMR:
d 15.8 (d, JCP = 6.8 Hz, CH3CH2), 16.0 (d, JCP = 6.7 Hz,
4.4.2. 1,3-Bis(4-chlorophenyl)-2,2-difluoro-3-hydroxypropyl diethyl
phosphate (5bb) [5a]
Prepared in analogy to 5aa in 2 h reaction time, yielding
separately anti and syn products in 1:1 ratio and total 77% yield.
The spectroscopic characterization data were identical to those
published by us [5a].
CH3CH2), 55.1 (s, OCH3), 55.2 (s, OCH3), 64.8 (d, 2JCP = 6.3 Hz, CH2),
2
2
64.9 (d, JCP = 6.1 Hz, CH2), 70.6 (dd, JCF = 29.5, 25.8 Hz, CHOH),
1
75.1–75.7 (m, CHOP), 113.4, 113.7, 119.4 (dt, JCF = 252.2 Hz,
3JCP = 7.7 Hz, CF2), 124.8 (d, JCP = 2.5 Hz), 128.0, 129.3, 129.8,
3
159.7, 160.4; 19F NMR:
(s); FTIR (film,
d
À122.6 to À122.5 (m); 31P NMR:
d 0.74
n
max cmÀ1) 3342 (m), 3070 (w), 3039 (w), 2985 (m),
2840 (w), 1614 (m), 1587 (w), 1515 (s), 1252 (s), 1178 (m), 1165
(m), 1032 (s); HRMS (ESI+) calculated for C21H27F2NaO7P:
483.1355, found: 483.1354. Syn-5dd: colorless oil (260 mg,
4.4.3. 1,3-Bis(4-methylphenyl)-2,2-difluoro-3-hydroxypropyl diethyl
phosphate (5cc)
Solution of 1 (364 mg, 1.40 mmol) and 4-methylbenzaldehyde
(672 mg, 5.59 mmol) in DMF (2 mL) was added dropwise to a
suspension of CsF (106 mg, 0.70 mmol) in DMF (2 mL), cooled to
À5 8C. The mixture was warmed up to rt and after 2 h of stirring
three drops of distilled water were added. After 2 h of stirring
saturated NH4Cl (7 mL) was added and the product was extracted
into ethyl acetate (3 Â 30 mL). The combined organic extract was
washed with brine (10 mL), dried (MgSO4), filtered, concentrated
under reduced pressure, and purified on silica gel to yield
separately anti and syn products in 1:1 ratio. Anti-5cc: white solid
(838 mg, 42%): m.p. 94–95 8C, Rf (30% EtOAc/petrol ether) 0.20; 1H
40%): Rf (30% EtOAc/petrol ether) 0.06; 1H NMR:
d
1.05 (dt, 3H,
3JHH = 7.1 Hz, JHP = 1.0 Hz, CH3CH2), 1.23 (dt, 3H, JHH = 7.1 Hz,
4JHP = 1.1 Hz, CH3CH2), 3.69–3.79 (m, 2H, CH2), 3.76 (s, 3H, OCH3),
3.81 (s, 3H, OCH3), 3.96–4.09 (m, 2H, CH2), 4.25 (d, 1H,
3JHH = 5.0 Hz, OH), 4.39–4.47 (m, 1H, CHOH), 5.86–5.95 (m, 1H,
CHOP), 6.82 (d, 2H, 3JHH = 8.8 Hz, CArH), 6.92 (d, 2H,
4
3
3JHH = 8.8 Hz, CArH), 7.28 (d, 2H, JHH = 9.0 Hz, CArH), 7.54 (d, 2H,
3
3JHH = 8.6 Hz, CArH); 13C NMR:
d
15.8 (d, 3JCP = 7.1 Hz, CH3CH2), 15.9
3
(d, JCP = 7.1 Hz, CH3CH2), 55.2 (s, OCH3), 55.3 (s, OCH3), 63.8 (d,
2JCP = 5.8 Hz, CH2), 64.1 (d, 2JCP = 5.9 Hz, CH2), 72.1 (dd, 2JCF = 30.1,
23.8, CHOH), 77.5–78.0 (m, CHOP), 113.5, 113.9, 120.0 (ddd,
1JCF = 257.0, 250.4 Hz, JCP = 7.2 Hz, CF2), 126.0–126.1 (m), 128.6,
3
NMR:
d
1.12 (dt, 3H, 3JHH = 7.1 Hz, 4JHP = 1.0 Hz, CH3CH2), 1.38 (dt,
3H, 3JHH = 7.1 Hz, 4JHP = 1.1 Hz, CH3CH2), 2.33 (s, 3H, CArCH3), 2.34
(s, 3H, CArCH3), 3.81–3.91 (m, 1H, CHaHb), 3.91–4.01 (m, 1H,
CHaHb), 4.15–4.27 (m, 2H, CH2), 5.08–5.17 (m, 2H, OH, CHOH),
129.4, 130.1, 159.8, 160.4; 19F NMR:
d
À124.2 (ddd, 1F,
3
2
2JFF = 251.5 Hz, JFH = 18.8, 7.7 Hz),–122.4 (dd, 1F, JFF = 251.5 Hz,
3JFH = 16.4 Hz); 31P NMR (CDCl3)
d
À0.96 (s); FTIR (film,
n )
max cmÀ1
5.69–5.78 (m, 1H, CHOP), 7.14–7.18 (m, 4H, CArH), 7.33–7.37 (m,
3329 (s), 3071 (w), 3040 (w), 2985 (m), 2840 (m), 1614 (s), 1586
(m), 1515 (s), 1252 (s), 1178 (s), 1162 (m), 1032 (s); HRMS (ESI+)
calculated for C21H27F2NaO7P: 483.1355, found: 483.1354.
3
4H, CArH); 13C NMR:
d
15.7 (d, JCP = 6.7 Hz, CH3CH2), 15.9 (d,
3JCP = 6.7 Hz, CH3CH2), 21.1 (s, CArCH3), 21.1 (s, CArCH3), 64.7 (d,
2JCP = 6.4 Hz, CH2), 64.9 (d, 2JCP = 6.1 Hz, CH2), 70.7 (dd, 2JCF = 29.5,
25.7 Hz, CHOH), 75.1–75.7 (m, CHOP), 119.2 (ddd, JCF = 260.1,
252.8 Hz, JCP = 7.4 Hz, CF2), 127.9, 128.2, 128.6, 128.8, 129.7 (d,
3JCP = 3.0 Hz),132.7, 137.8, 139.1; 19F NMR:
1
Acknowledgements
3
d
À122.6 to À122.5
This work was supported by Research Plan AVZ40550506 from
the Academy of Sciences of the Czech Republic and the Grant
Agency of the Czech Republic (203/08/P310).
(m); 31P NMR:
d 0.68 (s); GC–MS (EI) m/z 91 (40%), 119 (12), 154
(100); FTIR (film, nmax cmÀ1) 3341 (s), 3100 (w), 3030 (m), 2986
(m), 1617 (w), 1516 (m), 1254 (m), 1163 (m), 1033 (s); HRMS (ESI+)
calculated for C21H27F2NaO5P: 451.1456, found: 451.1455. Syn-
5cc: white solid (827 mg, 41%): m.p. 93–94 8C, Rf (30% EtOAc/petrol
References
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d 1.07 (dt, 3H, JHH = 7.1 Hz, JHP = 1.0 Hz,
3
4
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250.7 Hz, JCP = 7.3 Hz, CF2), 127.9, 128.5, 128.8, 129.1, 130.8–
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À124.1 (ddd, 1F,
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2
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1.11
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