Nucleophilic additions of [(diethoxyphosphoryl)difluoromethyl]lithium to α,β-unsaturated compounds

Article abstract of DOI:10.1016/j.jfluchem.2012.02.003

The presence of HMPA leads to an increase of 1,4- versus 1,2-additions of [(diethoxyphosphoryl)difluoromethyl]lithium onto α,β-unsaturated ketones and provides products of conjugated addition in moderate to good yields. In the absence of HMPA, benzylidine

Full text of DOI:10.1016/j.jfluchem.2012.02.003

Journal of Fluorine Chemistry 137 (2012) 34–43
Contents lists available at SciVerse ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Nucleophilic additions of [(diethoxyphosphoryl)difluoromethyl]lithium
to
a,b-unsaturated compounds
*
Prabhakar Cherkupally, Petr Beier
´
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo nam. 2, 166 10 Prague, Czech Republic
A R T I C L E I N F O
A B S T R A C T
Article history:
The presence of HMPA leads to an increase of 1,4- versus 1,2-additions of [(diethoxyphosphoryl)di-
Received 18 January 2012
Received in revised form 3 February 2012
Accepted 7 February 2012
Available online 22 February 2012
fluoromethyl]lithium onto
a,b-unsaturated ketones and provides products of conjugated addition in
moderate to good yields. In the absence of HMPA, benzylidine or alkylidine 1,3-diones, malononitriles or
malonates as well as nitroalkenes and other Michael acceptors give products of 1,4-addition in good to
high yields.
ß 2012 Elsevier B.V. All rights reserved.
Keywords:
1,4-Addition
Nucleophilic addition
Difluoromethylphosphonate
1. Introduction
example was later described as limited only to nitrostyrene
derivatives and requiring excess of 1, while the presence of
a
-Fluorinated alkyl phosphonates have emerged as important
anhydrous CeCl3 allowed the reaction with aliphatic nitroalkenes
(as well as with nitrostyrene) in moderate yields [7]. Michael
addition of 1 to unsaturated esters or nitriles has not been
described, with the exception of reported low yields of inseparable
1:1 mixtures of 1,2- and 1,4-adducts in the reaction of 1 with ethyl
acrylate or 5H-furan-2-one in the presence of CeCl3 [3b].
Additionally, the literature described the reaction of 1 with
non-hydrolyzable phosphate mimics in many aspects of bio-
organic chemistry [1]. One class of such compounds is
a,a-
difluorophosphonates, which are isoelectronic and isosteric
analogs of natural phosphates. A wide range of biologically active
difluorophosphonates have been synthesized and used as enzyme
inhibitors or probes for the elucidation of mechanisms of biological
processes involving phosphates. The synthesis and transforma-
tions of difluoromethylphosphonates has been widely explored
and recently reviewed [2]. The common method for the introduc-
tion of the difluoromethylenephosphonate moiety is by organo-
metallic reagents such as MCF2P(O)(OEt)2, where M can be Li, CdBr,
ZnBr or SiR3. Typical electrophilic substrates for the reaction of
[(diethoxyphosphoryl)difluoromethyl]lithium (1) are aldehydes
and ketones, primary alkyl halides or triflates and activated imines
(such as N-sulfanylimines). Modification of reactivity of 1 can be
achieved by the addition of anhydrous CeCl3 and the resulting
reagent is able to transfer the difluoromethylenephosphonate
moiety to esters and lactones [3], DMF [3a,3b,4], vinylsulfoxides
[5], vinylsulfones [6], and nitroalkenes [7]. Two exceptions to this
reactivity profile have been reported. t-Bu ester of protected 4,5-
dihydroxy-2-pentenoate was reported to undergo addition of 1 at
À78 8C in THF to give the Michael adduct in 81% yield [8] and 1,4-
various
a,b-unsaturated aldehydes and ketones as exclusive 1,2-
addition on the carbonyl group [1,2,10].
[(Dialkoxyphosphoryl)difluoromethyl]lithium salts available
by the reaction of MeSCF2P(O)(RO)2 (R = Et or i-Pr) with t-BuLi
add to a wide range of elecrophiles including nitroalkenes and DMF
without the need of Ce3+ additives. The sulfide reagent allows
access to difluoromethylphosphonates avoiding the use of
environmentally problematic HCFCs and CFCs [11].
Another way to introduce the difluoromethylphosphonate
moiety is by free radical additions of the phosphonodifluoromethyl
radical generated from XCF2P(O)(OR)2. Various precursors and free
radical initiators have been used: (a) Co3+ (cat.)/Zn system for
X = Br in addition onto both electron-rich and electron-deficient
alkenes [12], (b) Pd(PPh3)4 (cat.) for X = I in addition onto electron
rich alkenes [13], (c) Na2S2O4 for X = I in addition onto electron-
rich alkenes [14] and alkynes [15], (d) Et3B for X = I in addition onto
electron-deficient alkenes such as cyclohexenone, cyclopentenone
and vinyl alkyl ketones (but not onto electron-deficient alkenes
with substituted double bond) [14], and (e) Bu3SnH/AIBN for
X = SMe or SePh in addition onto electron-rich alkenes [16].
Although, by intuition, electrophilic electronic character of the
phosphonodifluoromethyl radical can be expected, experimental
addition of 1 to 4-chloro-b-nitrostyrene under the same condi-
tions gave the adduct in 78% yield [9]. However, the second
* Corresponding author. Tel.: +420 739002221.
E-mail address: beier@uochb.cas.cz (P. Beier).
0022-1139/$ – see front matter ß 2012 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2012.02.003

P. Cherkupally, P. Beier / Journal of Fluorine Chemistry 137 (2012) 34–43
35
Table 1
The addition of [(diethoxyphosphoryl)difluoromethyl]lithium (1) to 2-cyclohexenone (2a).
O
P
F
F
HO
OEt
OEt
O
O
O
LDA (1.2 equiv.)
-78 °C, 1 h
O
EtO P CHF
OEt
+
+
2
P OEt
OEt
F
4a
F
2a (1.5 equiv.)
3a
Entry
Solvent
Additive (equiv.)
3a, Yield (%)a
4a, Yield (%)a
1
2
THF
–
91b [17a]
32
0
5
THF
15-Crown-5 (2)
12-Crown-4 (2)
DMPU (7)
HMPA (1.3)
HMPA (5)
HMPA (8.2)
HMPA (1.3)
HMPA (5)
HMPA (5)
3
THF
78
5
4
THF
26
13
21
47b
38
10
26
30
5
THF
73
6
THF
52
7
THF
30
8
DME
DME
Diglyme
70
9
41
10
54
a
19F NMR yield using PhCF3 as internal standard.
Isolated yield.
b
evidence shows that the radical can display significant nucleophil-
ic character and reacts with both electron-rich and deficient
alkenes, depending on reaction conditions (mainly nature of the
free radical initiator used).
We have been interested in developing fluoroalkylation
methodologies starting from fluorinated phosphonates [17] and
have also described 1,4-addition of tetraethyl fluoromethylenebi-
dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) [20]
significantly increased the product 4a:3a ratio, however, the
yields were only moderate (entry 4) and number of unidentified
products were formed presumably coming from the reaction of 1
with DMPU. Good results were obtained in the presence of
hexamethylphosphoramide (HMPA); the highest isolated yield
(47%) of 4a was achieved using 5 equiv. of HMPA in THF (entry 6).
Moving from THF solvent to DME or diglyme gave similar results.
In all cases, significant amounts of the product of 1,2-addition (3a)
were present in reaction mixtures. Employment of other lithium
ion-coordinating additives such as DMF or N-methyl-2-pyrroli-
done (NMP) did not give any 1,4-addition product. It appears from
these results that addition of HMPA increases the rate of conjugate
addition, mainly by increasing solvent polarity and modification of
aggregates of 1 in solution. It is interesting to compare our results
of the addition of 1 to 2a with the addition of the apparently softer
nucleophile PhSO2CF2Li, where the presence of HMPA reverses
selectivity from 1,2- to almost exclusive 1,4-addition [21].
sphosphonate to various
sulfoxides and phosphonates [18]. This led us to investigations of
nucleophilic additions of 1 to carbon–carbon double bonds of
unsaturated carbonyl compounds and other Michael acceptors.
a,b-unsaturated ketones, esters, sulfones,
a,b-
A number of factors can increase the ratio of conjugate versus
1,2-addition of an organolithium reagent to a given enone: (a)
increased size and charge delocalization (softness) of the nucleo-
phile, (b) increased solvent polarity, and (c) the addition of lithium-
coordinating additives. In the absence of these additives,
organolithium reagents form contact ion pairs (CIP), while
solvent-separated ion pairs (SSIP) are formed in the presence of
lithium-coordinating additives. CIP and SSIP rapidly interconvert
and, generally, SSIP species favor conjugate addition. Lithium
coordinating additives also affect the 1,4:1,2 ratio by decreasing or
preventing lithium catalysis (i.e. lithium coordination to carbonyl
which favors 1,2-addition by increasing its LUMO coefficient) [19].
Furthermore, alkyl lithium reagents are stabilized in solution by
the formation of aggregates. Lithium coordinating additives may
modify the structure of these aggregates such as break-down
tetramer to dimer and thus influence reactivity of the nucleophilic
reagent.
Reaction of 1 with
a,b-unsaturated aldehydes such as trans-
cinnamaldehyde and acrolein provided only 1,2-addition products
even in the presence of excess HMPA.
The scope of the 1,4-addition of 1 to various
Michael acceptors was explored (Table 2). In case of
a
,
b
a,b
-enones or
-enones
the reaction was performed in the presence of HMPA (5 equiv.).
Cyclic ketone 2b gave a good yield of the 1,4-addition product 4b,
while the acyclic 3-buten-2-one (2c) reacted in lower efficiency.
High 1,2-addition selectivity observed with chalcone (2d) did not
seem to be the result of steric hindrance, but rather insufficient
activation of the carbon–carbon double bond. This statement was
supported by the fact that 2-benzylidene-1,3-diphenylpropane-
1,3-dione (2e) gave preferentially 1,4-addition product 4e and 2-
alkylidene derivative 2f provided exclusively 1,4-addition product
4f in high yield. The reactivity of 2e was the same in the presence or
the absence of HMPA suggesting that substrate electronic effects
(the presence of second carbonyl group) increase the reactivity of
the C55C bond to the extent that the effect of HMPA is relatively
insignificant.
2. Results and discussion
Nucleophilic addition of 1 to 2-cyclohexenone (2a) as a model
a
,b
-unsaturated ketone in THF provided the initial focus. Similar
to other -unsaturated aldehydes and ketones, 2-cyclohexenone
a,b
is known to react exclusively in 1,2-addition fashion (attack to
carbonyl group) providing alcohol 3a in a high yield, as shown in
entry 1, Table 1. Crown ethers were added to the reaction mixture
to solvate the lithium ions to prevent complexation to the carbonyl
group of 2a. Indeed, the formation of small amounts of 1,4-addition
product 4a was observed (entries 2 and 3), which suggests that
lithium catalysis plays only a small role in affecting chemoselec-
tivity of this nucleophilic addition. The addition of excess 1,3-
To our surprise, various other Michael acceptors also under-
went the 1,4-addition reactions. Here, the presence of HMPA
additive did not have any positive influence on the yield of Michael
adducts 4 (HMPA could influence reaction rates, however, the
kinetics were not investigated). On the other hand, the use of a

36
P. Cherkupally, P. Beier / Journal of Fluorine Chemistry 137 (2012) 34–43
Table 2
The additions of [(diethoxyphosphoryl)difluoromethyl]lithium (1) to
a,b-unsaturated compounds (2).
O
LDA (1.2 equiv.)
THF, -78 °C, 1 h
+
Substrate
EtO P CHF
OEt
+
4
3
2
2
Entry
1a
2
Substrate (equiv.)
Products and yields (%)b
2a
1.5
3a
51c
35c
4a
4b
47
41
O
P
F
O
O
O
O
O
F
HO
OEt
OEt
0.67
O
P OEt
OEt
F
F
2a
2b
1.5
3b
40
36
53
45
O
P
F
F
OEt
OEt
0.67
HO
HO
O
P OEt
OEt
F
F
3a
4a
5
2c
2d
2e
1.5
3c
3d
3e
21c
28c
4c
4d
4e
7c
O
P
F
F
F
O
O
P
F
F
OEt
OEt
0.67
27
OEt
OEt
F
F
1.5
58c
<2c
O
O
O
P
Ph
O
P
O
OEt
OEt
Ph
OEt
OEt
HO
Ph
Ph
Ph
Ph
Ph
F
F
0.67
40
57
Ph
O
P
O
O
P
F
OEt
OEt
Ph
OEt
OEt
HO
Ph
Ph
O
Ph
Ph
F
F
Ph
O
Ph
O
Ph
O
6
2f
0.67
3f
0c
4f
85
F
O
P
F
OEt
OEt
HO
O
O
P
Ph
OEt
OEt
Ph
Ph
O
F
F
Ph
O
Ph
O
7
2g
1.5
4g
32d
8c
O
EtO P
EtO
O
EtO P
EtO
O
0.67
P OEt
OEt
F
F
8
9
2h
2i
1.5
4h
4i
31
39
O O
O
P
O O
0.67
S
S
OEt
OEt
Ph
Ph
F
F
1.5
61
62
O
O
O
0.67
S
P OEt
OEt
S
Ph
Ph
F
F
10
11
2j
1.5
4j
61
83
Ph
O2N
Ph
NO
O
2
0.67
P OEt
OEt
F
F
2k
1.5
4k
70
81
MeO
O N
2
O
0.67
P OEt
OEt
NO2
NO
F
F
MeO
12
2l
0.67
4l
74
O2N
2
O
P
OEt
OEt
F
F

P. Cherkupally, P. Beier / Journal of Fluorine Chemistry 137 (2012) 34–43
37
Table 2 (Continued )
Entry
13
2
Substrate (equiv.)
Products and yields (%)b
2m
1.5
4m
4n
0c
0c
NC
Ph
Ph
CN
O
0.67
P OEt
OEt
F
F
14
2n
1.5
<3c
<3c
NC
CN
O2N
O
OEt
OEt
CN
CN
0.67
P
F
F
O2N
NC
15
16
2o
2p
1.5
4o
4p
78
97
CN
CN
O
0.67
Ph
CN
P OEt
OEt
Ph
F
F
1.5
74
96
NC
CN
MeO
O
CN
CN
0.67
P OEt
OEt
F
F
MeO
NC
17
2q
0.67
4q
97
CN
CN
CN
O
P OEt
OEt
F
F
a
In the presence of HMPA (5 equiv.).
b
c
Isolated yield calculated on deficient component.
19F NMR yield using PhCF3 as internal standard.
GC/MS yield.
d
slight excess of nucleophile 1 gave generally higher yields than
running reactions with excess of 2. Vinyl phosphonate 2g and
sulfone 2h gave products in rather low yields (no formation of any
oligomeric addition product by 19F NMR was observed), but
sulfoxide 2i provided the adduct 4i in a reasonable 62% yield. In
analogous Michael additions of tetraethyl fluoromethylenebispho-
no CeCl3 was needed to obtain high yields of Michael adducts. Our
reactions were reproducible and no special precautions in terms of
high purity and low salt content of the used n-BuLi (for the
preparation of LDA) were needed.
Reactivities of
a,b-unsaturated nitriles were also investigated.
3-Phenylacrylonitrile (2m) was found to be an insufficiently
activated substrate; only traces of products were observed in the
case of (4-nitrobenzylidine)malononitrile (2n) although in both
cases, the formation of a deep red reaction mixture was observed
upon the addition of 2m or 2n to the THF solution of 1 suggesting
the formation of some type of resonance-stabilized carbanionic
adduct. However, benzylidinemalononitrile (2o), its p-methoxy
derivative 2p as well as 2-isobutylidenemalononitrile (2q) showed
excellent reactivities.
sphonate [18] or diethyl (a-fluoro-a-phenylsulfonylmethyl)pho-
sphonate (McCarthy’s reagent) [22], the sulfone 2h was more
reactive than the sulfoxide 2i. It should be mentioned that sulfone
2h and sulfoxide 2i were reported to undergo conjugate addition
with 1 to give adducts 4h and 4i in 47% and 52% yields,
respectively, but only in the presence of at least equimolar
amounts of CeCl3 [5,6]. Similarly, with both nitrostyrenes and
nitroalkenes, we observed – in contrast to the literature [7] – that
Table 3
The additions of [(diethoxyphosphoryl)difluoromethyl]lithium (1) to
a,b-unsaturated esters (2).
O
LDA (1.2 equiv.)
THF, -78 °C, 1 h
2 (0.67 equiv.)
+
+
5
EtO P CHF
OEt
Ester
4
2
Entry
1
2
Ester
Products and yields (%)a
2r
4r
38
40
O
CO Et
2
EtO2C
P OEt
OEt
F
F
2
2s
4s
O
P
CO2Bu-n
n-BuO2C
OEt
OEt
F
F

38
P. Cherkupally, P. Beier / Journal of Fluorine Chemistry 137 (2012) 34–43
Table 3 (Continued )
Entry
3b
2
Ester
Products and yields (%)a
2t
5t
51
53
O
O
P
OEt
OEt
CO Me
2
F
F
4
5
6
2u
2v
5u
O
O
Ph
Ph
CO Et
2
P OEt
OEt
Ph
F
F
4v
17c
O
Ph
F
CO2Bu-t
P OEt
OEt
t-BuO C
2
F
2w
4w
71
CO2Et
CO2Et
CO Et
2
O
EtO C
2
P OEt
OEt
F
F
7
2x
4x
5x
4y
64
13c + 10c
56
CO2Et
CO2Et
CO2Et
O
EtO2C
Ph
Ph
P OEt
OEt
F
F
O
O
OEt
OEt
P
Ph
F
F
CO Et
2
8
2y
CO Et
MeO
2
EtO C
2
CO2Et
CO2Et
O
P OEt
OEt
F
F
MeO
MeO
5y
26c + 10c
O
O
OEt
OEt
P
F
F
CO Et
2
a
Isolated yield.
b
In the presence of HMPA (5 equiv.).
19F NMR yield using PhCF3 as internal standard.
c
Next, attention was turned to the additions of 1 to
a
,
b
-
reaction pathway back to conjugate addition. In case of arylidi-
unsaturated esters (Table 3). Alkyl acrylates 2r and 2s undergo 1,4-
nemalonates 2x and 2y the crude product mixture was accompa-
addition in moderate yields. This conjugate addition pathway is
nied by small amounts of a,a-difluoro-b-ketophosphonates 5
sensitive toward substitutions in
methyl methacrylate (2t) or ethyl cinnamate (2u) did not yield
products of conjugate additions, but provided -difluoro-
a
or
b
positions. For example,
(mixture of E and Z isomers).
a
,
a
b
-
3. Conclusions
ketophosphonates 5t and 5u, respectively, resulting from the
attack of 1 to the oxycarbonyl group followed by the departure of
the alkoxy group. A similar reactivity profile was reported for
methyl or ethyl esters in reactions with 1 in the presence of CeCl3
[3]. The employment of Ce3+ salts represents preferred conditions
for the preparation of ketones 5 from esters. The presence of tert-
butyl group in 2v prohibited the attack of 1 to the oxycarbonyl
group, probably due to steric reasons; however, the substrate was
not activated enough for efficient conjugate addition and the crude
product mixture contained a number of fluorinated products (all
formed in low 19F NMR yields), including 4v. In contrast, the
presence of the second oxycarbonyl group in alkylidine and
arylidinemalonates 2w–2y caused a switch of the dominant
In summary, conjugate additions of [(diethoxyphosphoryl)di-
fluoromethyl]lithium (1) to various -unsaturated carbonyl
compounds and other Michael acceptors led to number of new,
structurally diverse compounds, having an -difluorophospho-
nate moiety attached to a primary or secondary carbon center. In
cyclic -unsaturated ketones the reactivity can be varied from
exclusive 1,2-addition in the absence of HMPA to cca 1:1 1,2/1,4-
addition in the presence of excess HMPA. 1,4-Addition became the
main reaction pathway (and the effect of HMPA became
insignificant) for substrates containing two electron-acceptor
groups on the C55C bond. Good yields of products of conjugate
additions were obtained with phenyl vinyl sulfoxide, nitroalkenes,
a,b
a,a
a,b

P. Cherkupally, P. Beier / Journal of Fluorine Chemistry 137 (2012) 34–43
39
acrylates, and alkylidene and arylidene-1,3-diphenylpropane-1,3-
dione, malononitriles and malonates.
m/z [M+Na]+ calcd for C10H17F2NaO4P: 293.07247, found:
293.07248.
4.2.3. Diethyl (1,1-difluoro-2-hydroxy-2-methylbut-3-en-1-
4. Experimental
yl)phosphonate (3c) [23]
Not isolated; 19F NMR (376 MHz, CDCl3): 28% yield,
d
= À120.7
4.1. General
(dd, 1F, 2JFF = 302.0 Hz, 2JFP = 107.9 Hz), À118.3 (dd, 1F,
2
2JFF = 302.0 Hz, JFP = 99.5 Hz); MS (EI): m/z (rel. int.) = 243 (3),
NMR spectra were recorded at room temperature in on Bruker
188 (49), 161 (55), 132 (100), 81 (12), 71 (12), 55 (6), 43 (11).
Avance 400 or 500 MHz instruments. Chemical shifts (d) are
reported in ppm. 13C and 31P NMR spectra were proton decoupled.
GCMS spectra were recorded on an Agilent 7890A gas chromato-
graph coupled with a 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
ionization (ESI). Infrared spectra were measured on a IR instrument.
Reactions were conducted under Ar. THF and DME were dried by
distillation from Na/benzophenone. Concentration of n-BuLi solu-
tion was determined by titration using diphenylacetic acid. All other
chemicals were used as received. Purifications of products were
performed by flash chromatography using silica gel 60.
4.2.4. (E)-Diethyl (1,1-difluoro-2-hydroxy-2,4-diphenylbut-3-en-1-
yl)phosphonate (3d) [10]
Not isolated; 19F NMR (376 MHz, CDCl3): 58% yield,
d
= À116.0
2
2
(dd, 1F, JFF = 302.2 Hz, JFP = 100.6 Hz), À117.8 (dd, 1F, 2JFF = 302.2
2
Hz, JFP = 106.0 Hz); 31P NMR (162 MHz, CDCl3):
d = 7.61 (dd,
2JPF = 106.0 Hz, 2JPF = 100.6 Hz).
4.2.5. (Z)-Diethyl (3-benzoyl-1,1-difluoro-2-hydroxy-2,4-diphenyl-
3-en-1-yl)phosphonate (3e)
Isolated as a colorless oil (188 mg, 40% yield); Rf = 0.40 (EtOAc-
PE, 30:70); IR (film):
1596, 1580, 1495, 1235, 1164, 1025; 1H NMR (400 MHz, CDCl3):
n
max (cmÀ1) = 3361, 3061, 3027, 1703, 1668,
3
4
4.2. General procedure for the preparation of compounds 3–5 (in the
d = 1.13 (dt, 3H, JHH = 7.1 Hz, JHP = 0.5 Hz), 1.31 (dt, 3H,
4
presence of 5 equiv. of HMPA and with 1.5 equiv. of
compound)
a
,b
-unsaturated
3JHH = 7.1 Hz, JHP = 0.5 Hz), 3.68–3.78 (m, 1H), 3.91–4.00 (m,
1H), 4.15–4.31 (m, 2H), 5.67 (brs, 1H), 7.03–7.06 (m, 3H), 7.09–7.12
(m, 2H), 7.17–7.21 (m, 2H), 7.24 (s, 1H), 7.31–7.36 (m, 2H), 7.38–
7.42 (m, 2H), 7.77–7.79 (m, 4H); 13C NMR (125.7 MHz, CDCl3):
A solution of n-BuLi (2 M, 0.56 mL, 1.11 mmol) in cyclohex-
ane was added dropwise to stirred solution of i-Pr2NH
3
3
a
d = 16.1 (d, JCP = 5.8 Hz), 16.3 (d, JCP = 5.7 Hz), 64.6 (d,
2
(0.16 mL, 1.11 mmol) in dry THF (3 mL) cooled to À78 8C. The
resulting solution was stirred at 0 8C for 10 min and then cooled
to À78 8C. A solution of diethyl difluoromethylphosphonate
(174.3 mg, 0.93 mmol) in dry THF (1 mL) was added dropwise
and the mixture was stirred at À78 8C for 45 min. HMPA (0.8 mL,
2JCP = 6.8 Hz), 65.2 (d, JCP = 6.8 Hz), 80.4–80.9 (m), 119.7 (dt,
1JCF = 276.4 Hz, JCP = 202.8 Hz), 127.8, 127.9, 128.0, 128.1, 128.3,
1
128.4, 129.0, 129.7, 133.0, 134.7, 136.4, 137.0, 137.7 (d,
3JCF = 6.6 Hz), 199.0; 19F NMR (470.4 MHz, CDCl3):
d
= À109.6 (d,
2
2F, JFP = 101.9 Hz); 31P NMR (162 MHz, CDCl3):
d
= 6.75 (t,
4.6 mmol) was added followed by the addition of
a
,
b
-
2JPF = 101.9 Hz); MS (ESI+): m/z (rel. int.) = 524 (30), 523 (100)
[M+Na]+, 483 (15), 315 (25); HRMS (ESI+): m/z [M+Na]+ calcd for
unsaturated compound 2 (1.4 mmol) in dry THF (0.5 mL). The
reaction mixture was stirred at À78 8C for 1 h and then saturated
aqueous NH4Cl (10 mL) was added. The product was extracted
into diethyl ether (3Â 15 mL), the combined organic phase was
washed with water (20 mL), brine (20 mL), dried (MgSO4) and
concentrated under reduced pressure. Purification by silica gel
flash chromatography afforded the pure product.
C27H27F2NaO5P: 523.14564, found: 523.14547.
4.2.6. Diethyl (difluoro(3-oxocyclohexyl)methyl)phosphonate (4a)
[11]
Isolated as a colorless oil (127 mg, 47% yield); Rf = 0.32 (EtOAc-
PE, 50:50); IR (film): nmax (cmÀ1) = 1716, 1269, 1166, 1028; 1H
NMR (400 MHz, CDCl3):d
= 1.39 (t, 6H, 3JHH = 7.1 Hz), 1.63–1.77 (m,
4.2.1. Diethyl (difluoro(1-hydroxycyclohex-2-en-1-
yl)methyl)phosphonate (3a) [16a]
2H), 2.13–2.60 (m, 6H), 2.65–2.69 (m, 1H), 4.25–4.33 (m, 4H); 13
C
3
NMR (100 MHz, CDCl3):
d
= 16.2 (d, JCP = 5.5 Hz), 23.5–23.6 (m),
Not isolated; 19F NMR (470.4 MHz, CDCl3): 51% yield,
24.1, 39.6–39.7 (m), 40.9, 42.7 (dt, JCF = 20.5 Hz, JCP = 15.4 Hz),
64.5 (d, 2JCP = 6.5 Hz), 64.6 (d, 2JCP = 6.5 Hz), 120.3 (dt,
2
2
2
2
d
= À119.1 (dd, 1F, JFF = 302.7 Hz, JFP = 103.9 Hz), À119.8 (dd,
2 2
1
1F, JFF = 302.7 Hz, JFP = 105.1 Hz); MS (EI): m/z (rel. int.) = 188
1JCF = 263.3 Hz, JCP = 212.2 Hz), 208.5; 19F NMR (470.4 MHz,
2
2
(78), 161 (76), 109 (18), 132 (100), 97 (84), 79 (17), 65 (12).
CDCl3):
d
= À115.6 (ddd, 1F, JFF = 301.5 Hz, JFP = 107.6 Hz,
3JFH = 13.8 Hz), À117.6 (ddd, 1F, JFF = 301.5 Hz, JFP = 108.9 Hz,
2 2
4.2.2. Diethyl (difluoro(1-hydroxycyclopent-2-en-1-
yl)methyl)phosphonate (3b)
Isolated as a colorless oil (104 mg, 40% yield); Rf = 0.30
(EtOAc-PE, 50:50); IR (film): nmax (cmÀ1) = 3366, 3054, 1622,
3JFH = 16.4 Hz); 31P NMR (162 MHz, CDCl3):
d
= 6.30 (dd,
2JPF = 108.9 Hz, JPF = 107.6 Hz); MS (EI): m/z (rel. int.) = 264
(100), 236 (16), 208 (15), 188 (36), 161 (56), 146 (84), 132 (66),
111 (47), 97 (79), 81 (31), 77 (31); HRMS (ESI+): m/z [M+Na]+ calcd
for C11H19F2NaO4P: 307.08812, found: 307.08802.
2
1258, 1165, 1060, 1023; 1H NMR (500 MHz, CDCl3):
d = 1.39 (dt,
3
4
3
3H, JHH = 7.1 Hz, JHP = 0.6 Hz), 1.40 (dt, 3H, JHH = 7.1 Hz,
4JHP = 0.6 Hz), 1.90–1.95 (m, 1H), 2.38–2.44 (m, 1H), 2.47–2.59
(m, 2H), 3.53 (brs, 1H), 4.25–4.35 (m, 4H), 5.85–5.87 (m, 1H),
6.15–6.17 (m, 1H); 13C NMR (125.7 MHz, CDCl3):
4.2.7. Diethyl (difluoro(3-oxocyclopentyl)methyl)phosphonate (4b)
[13]
d
= 16.2 (d,
Isolated as a colorless oil (134 mg, 53% yield); Rf = 0.23 (EtOAc-
PE, 50:50); IR (film): nmax (cmÀ1) = 1746, 1265, 1136, 1024; 1H
3
2
3JCP = 4.9 Hz), 31.2, 32.4 (d, JCF = 1.7 Hz), 64.8 (d, JCP = 6.8 Hz),
2
2
1
3
87.4 (dt, JCF = 23.6 Hz, JCP = 13.7 Hz), 119.3 (dt, JCF = 269.0 Hz,
NMR (400 MHz, CDCl3):
d
= 1.36 (t, 6H, JHH = 7.1 Hz), 2.03–2.47
1JCP = 202.4 Hz), 129.2 (d, JCF = 2.2 Hz), 138.7; 19F NMR
(m, 6H), 2.85–3.02 (m, 1H), 4.22–4.30 (m, 4H); 13C NMR (100 MHz,
= 16.3 (d, JCP = 5.5 Hz), 21.9–22.1 (m), 37.5, 37.8–38.0
(m), 40.5 (dt, JCF = 21.2 Hz, JCP = 15.3 Hz), 64.5 (d, JCP = 6.6 Hz),
3
3
(470.4 MHz, CDCl3):
d
= À117.4 (dd, 1F, 2JFF = 302.4 Hz,
CDCl3):
d
2JFP = 104.5 Hz), À118.4 (dd, 1F, JFF = 302.4 Hz, JFP = 104.7 Hz);
2
2
2
2
2
31P NMR (162 MHz, CDCl3):
d
= 7.54 (dd, JPF = 104.7 Hz,
64.6 (d, JCP = 6.6 Hz), 120.3 (dt, JCF = 261.7 Hz, JCP = 214.6 Hz),
2
2
1
1
2JPF = 104.5 Hz); MS (EI): m/z (rel. int.) = 188 (52), 161 (56),
215.4; 19F NMR (376 MHz, CDCl3):
d
= À116.8 (ddd, 1F,
132 (100), 115 (17), 83 (47), 65 (13), 55 (9), 39 (6); HRMS (ESI+):
2JFF = 299.8 Hz, JFP = 107.8 Hz, JFH = 17.0 Hz), À118.7 (ddd, 1F,
2
3

40
P. Cherkupally, P. Beier / Journal of Fluorine Chemistry 137 (2012) 34–43
2JFF = 299.9 Hz, 2JFP = 108.7 Hz, 3JFH = 15.1 Hz); 31P NMR (162 MHz,
4.2.11. Tetraethyl (1,1-difluoropropane-1,3-diyl)bis(phosphonate)
2
2
CDCl3):
d
= 6.52 (dd, JPF = 108.7 Hz, JPF = 107.8 Hz); MS (EI): m/z
(4g) [11]
(rel. int.) = 270 (3) [M]+, 250 (74), 269 (08), 222 (09), 188 (41), 161
(69), 132 (100), 111 (30), 83 (61), 77 (33); HRMS (ESI+): m/z
[M+Na]+ calcd for C10H17F2NaO4P: 293.07247, found: 293.07250.
Not isolated; 19F NMR (470.4 MHz, CDCl3): 8% yield,
d
= À114.0
(dt, 2JFP = 107.0 Hz, 3JFH = 18.9 Hz); MS (EI): m/z (rel. int.) = 325 (6),
307 (9), 223 (31), 215 (52), 165 (100), 137 (20), 109 (29), 81 (16), 55
(13).
4.2.8. Diethyl (1,1-difluoro-4-oxopentyl)phosphonate (4c) [11]
Isolated as a colorless oil (69 mg, 27% yield); Rf = 0.14 (EtOAc-
PE, 30:70); IR (film): nmax (cmÀ1) = 2987, 2922, 2854, 1722,
4.2.12. Diethyl (1,1-difluoro-3-(phenylsulfonyl)propyl)phosphonate
(4 h) [6]
1269, 1166, 1020; 1H NMR (400 MHz, CDCl3):
d
= 1.37 (t, 6H,
3JHH = 7.1 Hz), 2.18 (s, 3H), 2.28–2.43 (m, 2H), 2.73–2.77 (m, 2H),
4.22–4.29 (m, 4H); 13C NMR (125.7 MHz, CDCl3):
= 16.3 (d,
3JCP = 5.5 Hz), 28.0 (dt, JCF = 21.1 Hz, JCP = 15.6 Hz), 29.9, 34.8–
Isolated as a colorless oil (131 mg, 39% yield); Rf = 0.57 (EtOAc-
PE, 70:30); IR (film): n
max (cmÀ1) = 3066, 2988, 2934, 1585, 1480,
d
1323, 1149, 1291, 1020; 1H NMR (400 MHz, CDCl3):
d = 1.34 (t, 6H,
2
2
3JHH = 7.1 Hz), 2.42–2.57 (m, 2H), 3.33–3.37 (m, 2H), 4.18–4.27 (m,
2
1
34.9 (m), 64.5 (d, JCP = 6.8 Hz), 120.3 (dt, JCF = 259.4 Hz,
2JCP = 216.2 Hz), 205.8; 19F NMR (376 MHz, CDCl3):
= À112.4
(dt, JFP = 107.9 Hz, JFH = 19.7 Hz); 31P NMR (162 MHz, CDCl3):
= 6.82 (t, 2JPF = 107.9 Hz); MS (EI): m/z (rel. int.) = 258 (2) [M]+,
4H), 7.56–7.70 (m, 3H), 7.89–7.92 (m, 2H); 13C NMR (125.7 MHz,
3
2
d
CDCl3): d = 16.3 (d, JCP = 5.4 Hz), 27.8 (dt, JCF = 21.8 Hz,
2
3
2
2JCP = 16.3 Hz), 48.6–48.7 (m), 64.8 (d, JCP = 6.8 Hz), 118.8 (dt,
1JCF = 261.8 Hz, JCP = 217.2 Hz), 128.0, 129.5, 134.1, 138.4; 19F
NMR (376 MHz, CDCl3):
3JFH = 18.3 Hz); 31P NMR (162 MHz, CDCl3):
2JPF = 104.7 Hz); MS (EI): m/z (rel. int.) = 311 (12), 283 (10), 215
(18), 187 (25), 159 (100), 140 (15), 125 (25), 109 (34), 104 (41), 91
(17), 81 (23), 77 (74); HRMS (ESI+): m/z [M+Na]+ calcd for
1
d
216 (44), 187 (41), 161 (59), 138 (100), 132 (83), 109 (38), 120
d
= À112.4 (dt, 2JFP = 104.7 Hz,
(24), 109 (38), 93 (35), 81 (48), 65 (30), 43 (55); HRMS (ESI+): m/
d = 5.72 (t,
z
[M+Na]+ calcd for C9H17F2NaO4P: 281.07247, found:
281.07248.
4.2.9. Diethyl (3-benzoyl-1,1-difluoro-4-oxo-2,4-
C13H19F2NaO5PS: 379.05511, found: 379.05500.
diphenylbutyl)phosphonate (4e)
Isolated as a colorless oil (273 mg, 57% yield); Rf = 0.21
(EtOAc-PE, 30:70); IR (film): nmax (cmÀ1) = 3064, 3036, 1701,
1670, 1596, 1581, 1497, 1265, 1162, 1044; 1H NMR (500 MHz,
4.2.13. Diethyl (1,1-difluoro-3-(phenylsulfinyl)propyl)phosphonate
(4i) [5]
Isolated as a colorless oil (197 mg, 62% yield); Rf = 0.26
(EtOAc-PE, 70:30); IR (film): nmax (cmÀ1) = 3058, 1583, 1479,
CDCl3):
d
= 1.08 (dt, 3H, 3JHH = 7.1 Hz, 4JHP = 0.6 Hz), 1.12 (dt, 3H,
4
3JHH = 7.1 Hz, JHP = 0.5 Hz), 3.73–4.06 (m, 4H), 4.95–5.04 (m,
1271, 1163, 1040; 1H NMR (400 MHz, CDCl3):
d
= 1.29 (t, 3H,
3
3
1H), 6.56 (d, 1H, JHH = 10.5 Hz), 7.12–7.17 (m, 3H), 7.25–7.29
3JHH = 7.1 Hz), 1.32 (t, 3H, JHH = 7.1 Hz), 2.08–2.27 (m, 1H),
2.45–2.63 (m, 1H), 2.85–2.93 (m, 1H), 3.13–3.20 (m, 1H), 4.14–
4.25 (m, 4H), 7.48–7.59 (m, 3H), 7.61–7.63 (m, 2H); 13C NMR
(m, 2H), 7.39–7.42 (m, 3H), 7.44–7.48 (m, 2H), 7.52–7.56 (m,
1H), 7.75–7.78 (m, 2H), 8.14–8.16 (m, 2H); 13C NMR (125.7 MHz,
3
3
CDCl3):
d
= 15.9 (d, JCP = 5.9 Hz), 16.0 (d, JCP = 5.7 Hz), 50.9–
(125.7 MHz, CDCl3):
d
= 16.2 (d, 3JCP = 5.3 Hz), 16.3 (d,
2
2
2
51.3 (m), 55.8–56.0 (m), 64.1 (d, JCP = 6.8 Hz), 64.4 (d,
2JCP = 6.8 Hz), 121.3 (ddd, 1JCF = 269.1 Hz, 1JCF = 266.1 Hz,
1JCP = 212.0 Hz), 127.9, 128.0, 128.4, 128.5, 128.7, 128.9, 132.9
(d, JCF = 6.9 Hz) 133.2, 133.3, 136.6, 136.8, 192.1, 192.7; 19F
3JCP = 5.4 Hz), 26.2 (dt, JCF = 21.7 Hz, JCP = 16.1 Hz), 47.6–47.7
2
2
(m), 64.6 (d, JCP = 6.9 Hz), 64.7 (d, JCP = 6.9 Hz), 119.6 (dt,
1
1JCF = 261.4 Hz, JCP = 216.3 Hz), 123.9, 129.3, 131.2, 142.5; 19F
3
2
NMR (470.4 MHz, CDCl3):
d
= À111.4 (dddd, 1F, JFF = 296.7 Hz,
2
3
3
NMR (470.4 MHz, CDCl3):
d
= À101.7 (dd, 1F, JFF = 300.0 Hz,
2JFP = 105.9 Hz, JFH = 21.3 Hz, JFH = 16.0 Hz), À112.1 (dddd, 1F,
2JFP = 105.5 Hz), À115.0 (ddd, 1F, JFF = 300.0 Hz, JFP = 102.7 Hz,
2JFF = 296.7 Hz, JFP = 106.3 Hz, JFH = 21.4 Hz, JFH = 16.3 Hz); 31P
2
2
2
3
3
3JFH = 24.5 Hz); 31P NMR (162 MHz, CDCl3):
d
= 5.25 (dd,
NMR (162 MHz, CDCl3):
d
= 6.12 (dd, 2JPF = 106.3 Hz,
2JPF = 105.4 Hz, JPF = 102.7 Hz); MS (ESI+): m/z (rel. int.) = 502
(27) [M+Na]+, 501 (100) [M+Na]+, 479 (9) [M+H]+; HRMS (ESI+):
m/z [M+Na]+ calcd for C27H27F2NaO5P: 523.14564, found:
523.14541.
2JPF = 105.9 Hz); MS (EI): m/z (rel. int.) = 252 (11), 250 (59),
184 (16), 141 (40), 125 (100), 109 (49), 77 (82), 65 (38), 51 (38);
HRMS (ESI+): m/z [M+H]+ calcd for C13H20F2O4PS: 341.07825,
found: 341.07823.
2
4.2.10. Diethyl (2-(1,3-dioxo-1,3-diphenylpropan-2-yl)-1,1-
difluorohex-5-en-1-yl)phosphonate (4f)
4.2.14. Diethyl (1,1-difluoro-3-nitro-2-phenylpropyl)phosphonate
(4j) [7]
Isolated as a colorless oil (381 mg, 85% yield); Rf = 0.28 (EtOAc-
Isolated as a colorless oil (265 mg, 83% yield); Rf = 0.38
(EtOAc-PE, 30:70); IR (film): nmax (cmÀ1) = 3067, 3036, 2987,
PE, 30:70); IR (film):
1581, 1268, 1164, 1024; 1H NMR (500 MHz, CDCl3):
3JHH = 7.1 Hz), 1.68–1.75 (m, 1H), 1.99–2.06 (m, 1H), 2.09–2.17
(m, 2H), 3.48–3.60 (m, 1H), 4.18–4.29 (m, 4H), 4.82–4.89 (m, 2H),
5.57–5.65 (m, 1H), 6.33 (d, 1H, 3JHH = 6.8 Hz), 7.39–7.58 (m, 6H),
8.01–8.03 (m, 2H), 8.08–8.10 (m, 2H); 13C NMR (125.7 MHz,
n
max (cmÀ1) = 3066, 1704, 1674, 1642, 1596,
d
= 1.33 (t, 6H,
2932, 1604, 1561, 1498, 1379, 1271, 1166, 1045; 1H NMR
3
(400 MHz, CDCl3):
d
= 1.17 (t, 3H, JHH = 7.1 Hz), 1.26 (t, 3H,
3JHH = 7.1 Hz), 3.82–3.92 (m, 1H), 3.97–4.06 (m, 1H), 4.09–4.22
2
(m, 2H), 4.29–4.42 (m, 1H), 4.87 (dd, 1H, JHH = 13.7 Hz,
3JHH = 10.0 Hz), 5.19 (dd, 1H, JHH = 13.7 Hz, JHH = 4.7 Hz),
2
3
CDCl3):
d
= 16.2 (d, 3JCP = 5.4 Hz), 16.3 (d, 3JCP = 5.3 Hz), 24.9–25.0
7.35–7.39 (m, 5H); 13C NMR (125.7 MHz, CDCl3):
d
= 16.0 (d,
2
2
3
(m), 32.4, 43.2 (dt, JCF = 18.9 Hz, JCP = 15.9 Hz), 53.2–53.3 (m),
3JCP = 6.3 Hz), 16.1 (d, JCP = 6.1 Hz), 48.0–48.4 (m), 64.4 (d,
2
2
2
64.8 (d, JCP = 6.9 Hz), 64.9 (d, JCP = 7.3 Hz), 115.2, 122.1 (ddd,
2JCP = 7.0 Hz), 65.0 (d, JCP = 6.7 Hz), 74.0–74.2 (m), 119.4 (ddd,
1JCF = 267.2 Hz, JCF = 264.0 Hz, JCP = 210.2 Hz), 128.6, 128.7,
1JCF = 269.7 Hz, JCF = 264.5 Hz, JCP = 213.3 Hz), 128.8, 129.0,
1
1
1
1
128.8, 133.3, 133.6, 136.1, 137.0, 137.5, 193.8, 194.2; 19F NMR
129.7, 131.0; 19F NMR (376 MHz, CDCl3):
d
= À110.5 (ddd, 1F,
2
3
(376 MHz, CDCl3):
d
= À106.5 (ddd, 1F, 2JFF = 303.2 Hz,
2JFF = 303.2 Hz, JFP = 105.3 Hz, JFH = 13.8 Hz), À114.9 (ddd, 1F,
2JFP = 106.4 Hz, JFH = 18.4 Hz), À109.1 (ddd, 1F, JFF = 303.2 Hz,
2JFF = 303.2 Hz,
2JFP = 98.6 Hz,
3JFH = 19.9 Hz);
31P
NMR
3
2
2JFP = 108.8 Hz, JFH = 15.8 Hz); 31P NMR (162 MHz, CDCl3):
(162 MHz, CDCl3): d = 4.72 (dd, JPF = 105.3 Hz, JPF = 98.6 Hz);
3
2
2
2
2
d
= 6.35 (dd, JPF = 108.8 Hz, JPF = 106.4 Hz); MS (ESI+): m/z (rel.
MS (EI): m/z (rel. int.) = 337 (3) [M]+, 291 (94), 242 (46), 214
(60), 153 (91), 133 (73), 109 (100), 104 (93), 91 (78), 81 (57), 65
(28), 77 (34); HRMS (ESI+): m/z [M+Na]+ calcd for
C13H18F2NNaO5P: 360.07829, found: 360.07809.
int.) = 524 (30) [M+Na]+, 523 (100) [M+Na]+, 501 (3) [M+H]+;
HRMS (ESI+): m/z [M+H]+ calcd for C25H30F2O5P: 479.17934,
found: 479.17926.

P. Cherkupally, P. Beier / Journal of Fluorine Chemistry 137 (2012) 34–43
41
4.2.15. Diethyl (1,1-difluoro-2-(4-methoxyphenyl)-3-
nitropropyl)phosphonate (4k)
2843, 2258, 1613, 1584, 1518, 1259, 1167, 1044; 1H NMR
3
(400 MHz, CDCl3):
d
= 1.11 (t, 3H, JHH = 7.1 Hz), 1.28 (t, 3H,
Isolated as a colorless oil (277 mg, 81% yield); Rf = 0.22 (EtOAc-
3JHH = 7.1 Hz), 3.72–3.82 (m, 1H), 3.78 (s, 3H), 3.88–3.99 (m, 2H),
3
PE, 30:70); IR (film):
n
max (cmÀ1) = 2986, 2935, 2841, 1613, 1561,
4.14–4.25 (m, 2H), 4.79 (d, 1H, JHH = 5.2 Hz), 6.96–6.98 (m, 2H),
7.46–7.48 (m, 2H); 13C NMR (100 MHz, CDCl3):
3JCP = 5.7 Hz), 16.1 (d, JCP = 5.5 Hz), 24.1–24.2 (m), 48.7–49.3
(m), 55.1, 64.7 (d, 2JCP = 7.1 Hz), 65.5 (d, 2JCP = 6.8 Hz), 110.9, 111.2,
114.4, 118.7 (ddd, 1JCF = 273.8 Hz, 1JCF = 265.3 Hz, 1JCP = 212.0 Hz),
120.6–120.6 (m), 131.3, 160.8; 19F NMR (470.4 MHz, CDCl3):
1516, 1379, 1255, 1166, 1046; 1H NMR (400 MHz, CDCl3):
d
= 1.19
d
= 15.9 (d,
3
4
3
3
(dt, 3H, JHH = 7.1 Hz, JHP = 0.4 Hz), 1.28 (dt, 3H, JHH = 7.1 Hz,
4JHP = 0.5 Hz), 3.78 (s, 3H), 3.85–3.96 (m, 1H), 3.99–4.08 (m, 1H),
4.11–4.23 (m, 2H), 4.24–4.36 (m, 1H), 4.83 (dd, 1H, 2JHH = 13.5 Hz,
3JHH = 10.2 Hz), 5.15 (dd, 1H, JHH = 13.5 Hz, JHH = 4.7 Hz), 6.87–
2
3
6.90 (m, 2H), 7.28–7.30 (m, 2H); 13C NMR (100 MHz, CDCl3):
d
= À107.6 (ddd, 1F, JFF = 302.7 Hz, JFP = 102.6 Hz, JFH = 9.5 Hz),
2
2
3
3
3
2
d
= 15.9 (d, JCP = 5.8 Hz), 16.0 (d, JCP = 5.8 Hz), 47.5 (dt,
À116.0 (ddd, 1F, JFF = 302.7 Hz, 2JFP = 94.0 Hz, 3JFH = 21.8 Hz); 31P
2
2
2JCF = 20.0 Hz, JCP = 16.5 Hz), 55.0, 64.3 (d, JCP = 7.2 Hz), 64.8 (d,
NMR
(162 MHz,
CDCl3):
d
= 3.81
(dd,
2JPF = 102.6 Hz,
2JCP = 7.1 Hz), 74.1–74.2 (m), 114.0, 119.3 (ddd, JCF = 269.2 Hz,
2JPF = 94.0 Hz); MS (EI): m/z (rel. int.) = 372 (42) [M]+, 307 (33),
279 (25), 251 (42), 231 (25), 188 (50), 170 (71), 155 (33), 132 (33),
109 (100), 91 (18), 81 (37); HRMS (ESI+): m/z [M+Na]+ calcd for
1
1JCF = 264.2 Hz, 1JCP = 213.0 Hz), 122.6–122.7 (m), 130.7, 160.0; 19
F
2
NMR (470.4 MHz, CDCl3):
d
= À110.4 (ddd, 1F, JFF = 302.3 Hz,
3
2
2JFP = 105.5 Hz, JFH = 13.6 Hz), À115.1 (ddd, 1F, JFF = 302.3 Hz,
C16H19F2N2NaO4P: 395.09427, found: 395.09413.
2JFP = 99.1 Hz, 3JFH = 20.3 Hz); 31P NMR (162 MHz, CDCl3):
d = 4.88
2
2
(dd, JPF = 105.5 Hz, JPF = 99.1 Hz); MS (EI): m/z (rel. int.) = 367
(15) [M]+, 320 (27), 293 (07), 265 (12), 245 (10), 184 (31), 170 (19),
134 (100), 121 (35), 109 (26), 91 (18), 81 (17); HRMS (ESI+): m/z
[M+Na]+ calcd for C14H20F2NNaO6P: 390.08885, found: 390.08879.
4.2.19. Diethyl (2-(dicyanomethyl)-1,1-difluoro-3-
methylbutyl)phosphonate (4q)
Isolated as a colorless oil (278 mg, 97% yield); Rf = 0.26 (EtOAc-
PE, 30:70); IR (film): n
max (cmÀ1) = 2985, 2293, 2915, 2258, 1397,
1372, 1269, 1164, 1086, 1027; 1H NMR (500 MHz, CDCl3):
d = 1.28–
4.2.16. Diethyl (1,1-difluoro-2-(nitromethyl)octyl)phosphonate (4l)
Isolated as a colorless oil (244 mg, 74% yield); Rf = 0.50 (EtOAc-PE,
1.30 (m, 6H), 1.41 (dt, 3H, 3JHH = 7.1 Hz, 4JHP = 0.7 Hz), 1.42 (dt, 3H,
3JHH = 7.1 Hz, 4JHP = 0.7 Hz), 2.54–2.61 (m, 1H), 2.64–2.71 (m, 1H),
3
4
30:70); IR (film):
n
max (cmÀ1) = 2959, 2931, 2860, 2873, 1560, 1381,
4.31–4.38 (m, 4H), 4.67 (dd, 1H, JHH = 2.8 Hz, JHF = 1.0 Hz); 13C
1273, 1167, 1024; 1H NMR (500 MHz, CDCl3):
d
= 0.88 (t, 3H,
NMR (125.7 MHz, CDCl3):
d
= 16.3 (d, JCP = 5.3 Hz), 19.9 (dt,
2JCF = 6.7 Hz, JCP = 2.5 Hz), 20.1 (d, JCF = 2.7 Hz), 21.2–21.3 (m),
3
3JHH = 6.9 Hz), 1.26–1.33 (m, 7H), 1.39 (dt, 3H, JHH = 7.0 Hz,
4JHP = 0.5 Hz), 1.40 (dt, 3H, JHH = 7.1 Hz, JHP = 0.5 Hz), 1.44–1.51
3
2
3
3
4
2
2
27.5, 49.0–49.4 (m), 65.5 (d, JCP = 7.3 Hz), 65.8 (d, JCP = 7.0 Hz),
111.6, 112.2, 120.0 (ddd, 1JCF = 270.4 Hz, 1JCF = 266.6 Hz,
(m, 1H), 1.87–1.94 (m, 1H), 3.08–3.21 (m, 1H), 4.26–4.33 (m, 4H),
2
3
4.38 (dd, 1H, JHH = 14.1 Hz, JHH = 6.4 Hz), 4.88 (dd, 1H,
1JCP = 211.1 Hz); 19F NMR (376 MHz, CDCl3):
d
= À111.3 (ddd, 1F,
2JHH = 14.2 Hz, JHH = 5.7 Hz); 13C NMR (125.7 MHz, CDCl3):
2JFF = 311.6, JFP = 103.8 Hz, JFH = 19.0 Hz), À112.9 (ddd, 1F,
3
2
3
3
d
= 13.9, 16.3 (d, JCP = 5.2 Hz), 22.4, 26.3, 26.5, 29.0, 31.4, 42.3 (dt,
2JFF = 311.6 Hz, 2JFP = 100.2 Hz, 3JFH = 13.9 Hz); 31P NMR
2JCF = 19.8 Hz, 2JCP = 16.3 Hz), 65.0 (d, JCP = 6.6 Hz), 73.4, 120.4 (dt,
(162 MHz, CDCl3): d = 4.61 (dd, JPF = 103.8 Hz, JPF = 100.2 Hz);
2
2
2
1JCF = 264.8 Hz, JCP = 211.8 Hz); 19F NMR (376 MHz, CDCl3):
MS (EI): m/z (rel. int.) = 265 (9), 209 (26), 137 (100), 109 (90), 81
(28), 65 (17), 43 (16); HRMS (ESI+): m/z [M+H]+ calcd for
C12H20F2N2O3P: 309.11741, found: 309.11736.
1
2
2
3
d
= À111.3 (ddd, 1F, JFF = 306.3 Hz, JFP = 105.0 Hz, JFH = 15.6 Hz),
À114.7 (ddd, 1F, 2JFF = 306.3 Hz, 2JFP = 105.2 Hz, 3JFH = 16.8 Hz); 31
P
NMR (162 MHz, CDCl3):d
= 5.50 (dd,2JPF = 105.2 Hz, 2JPF = 105.0 Hz);
MS (EI): m/z (rel. int.) = 265 (9), 215 (17), 187 (23), 159 (51), 127 (79),
109 (95), 99 (100), 81 (57), 55 (48), 41 (38); HRMS (ESI+): m/z
[M+Na]+ calcd for C13H26F2NNaO5P: 368.14089, found: 368.14085.
4.2.20. Ethyl 4-(diethoxy-phosphoryl)-4,4-difluorobutyrate (4r)
[3a,11,15]
Isolated as a colorless oil (106 mg, 38% yield); Rf = 0.22 (EtOAc-
PE, 30:70); IR (film): n
max (cmÀ1) = 2986, 2937, 2875, 1739, 1272,
4.2.17. Diethyl (3,3-dicyano-1,1-difluoro-2-
1165, 1021; 1H NMR (500 MHz, CDCl3):
d = 1.23 (t, 3H,
3
4
phenylpropyl)phosphonate (4o)
3JHH = 7.1 Hz), 1.36 (dt, 6H, JHH = 7.1 Hz, JHP = 0.6 Hz), 2.34–
3
Isolated as a pale yellow oil (312 mg, 97%yield); Rf = 0.15 (EtOAc-
PE, 30:70); IR (film): nmax (cmÀ1) = 3068, 3038, 2987, 2915, 2258,
1605, 1587, 1501, 1269, 1167, 1046; 1H NMR (400 MHz, CDCl3):
2.46 (m, 2H), 2.56–2.59 (m, 2H), 4.13 (q, 2H, JHH = 7.1 Hz), 4.22–
4.28 (m, 4H); 13C NMR (125.7 MHz, CDCl3):
d = 14.1, 16.3 (d,
3JCP = 5.4 Hz), 25.9–26.1 (m), 29.3 (dt, 2JCF = 21.1 Hz, 2JCP = 15.7 Hz),
60.8, 64.5 (d, 2JCP = 6.8 Hz), 119.9 (dt, 1JCF = 259.8 Hz,
3
3
d
= 1.13 (t, 3H, JHH = 7.1 Hz), 1.31 (t, 3H, JHH = 7.1 Hz), 3.73–3.83
(m, 1H), 3.91–4.04 (m, 2H), 4.18–4.29 (m, 2H), 4.82 (d, 1H,
3JHH = 5.3 Hz), 7.43–7.50 (m, 3H), 7.54–7.56 (m, 2H); 13C NMR
1JCP = 216.3 Hz), 171.7; 19F NMR (376 MHz, CDCl3):
d
= À113.3
(dt, JFP = 107.2 Hz, JFH = 19.4 Hz); 31P NMR (162 MHz, CDCl3):
2
3
3
3
2
(100 MHz, CDCl3):
d
= 15.9 (d, JCP = 5.6 Hz), 16.1 (d, JCP = 5.5 Hz),
d
= 6.74 (t, JPF = 107.2 Hz); MS (EI): m/z (rel. int.) = 243 (65), 182
2
23.9–24.1 (m), 49.5–50.1 (m), 64.8 (d, JCP = 7.2 Hz), 65.6 (d,
2JCP = 6.9 Hz), 110.8, 111.1, 118.7 (ddd, 1JCF = 273.9 Hz,
(100), 215 (37), 155 (58), 138 (26), 109 (57), 81 (39), 65 (19), 55
(15), 42 (16); HRMS (ESI+): m/z [M+H]+ calcd for C10H20F2O5P:
289.10109, found: 289.10105.
1JCF = 265.7 Hz, JCP = 212.2 Hz), 128.9–129.0 (m), 129.1, 130.0,
1
130.1; 19F NMR (376 MHz, CDCl3):
d
= À108.4 (ddd, 1F,
2JFF = 303.9 Hz, JFP = 102.5 Hz, JFH = 11.1 Hz), À115.4 (ddd, 1F,
4.2.21. n-Butyl 4-(diethoxy-phosphoryl)-4,4-difluorobutyrate (4s)
Isolated as a colorless oil (118 mg, 40% yield); Rf = 0.32 (EtOAc-
2
3
2
3
2JFF = 303.9 Hz, JFP = 93.4 Hz, JFH = 20.8 Hz); 31P NMR (162 MHz,
CDCl3):
d
= 3.68 (dd, 2JPF = 102.5 Hz, 2JPF = 93.4 Hz); MS (EI): m/z (rel.
PE, 30:70); IR (film):
1165, 1021; 1H NMR (500 MHz, CDCl3):
n
max (cmÀ1) = 2963, 2936, 2876, 1739, 1273,
int.) = 342 (46) [M]+, 286 (6), 221 (9), 204 (19), 188 (66), 161 (68),
155 (46), 140(86), 132 (100), 109 (74), 91 (22), 81 (41);HRMS (ESI+):
m/z [M+Na]+ calcd for C15H17F2N2NaO3P: 365.08371, found:
365.08363.
d = 0.90 (t, 3H,
3
3JHH = 7.4 Hz), 1.31–1.38 (m, 2H), 1.35 (dt, 6H, JHH = 7.1 Hz,
4JHP = 0.6 Hz), 1.55–1.61 (m, 2H), 2.33–2.45 (m, 2H), 2.56–2.59
3
(m, 2H), 4.07 (t, 2H, JHH = 6.7 Hz), 4.25–4.32 (m, 4H); 13C NMR
(125.7 MHz, CDCl3):
d
= 13.6, 16.3 (d, 3JCP = 5.4 Hz), 19.0, 25.9–26.0
2
2
4.2.18. Diethyl (3,3-dicyano-1,1-difluoro-2-(4-
methoxyphenyl)propyl)phosphonate (4p)
(m), 29.3 (dt, JCF = 21.1 Hz, JCP = 15.7 Hz), 30.5, 64.5 (d,
2JCP = 6.8 Hz), 64.7, 119.9 (dt, JCF = 259.8 Hz, JCP = 216.3 Hz),
1
1
2
Isolated as a pale yellow oil (325 mg, 96% yield); Rf = 0.11
171.8; 19F NMR (376 MHz, CDCl3):
d
= À113.3 (dt, JFP = 107.2 Hz,
(EtOAc-PE, 30:70); IR (film):
n
max (cmÀ1) = 3068, 2986, 2915, 2935,
3JFH = 19.4 Hz); 31P NMR (162 MHz, CDCl3):
d = 6.74 (t,

42
P. Cherkupally, P. Beier / Journal of Fluorine Chemistry 137 (2012) 34–43
2JPF = 107.2 Hz); MS (EI): m/z (rel. int.) = 261 (7), 243 (100), 215
(51), 187 (98), 155 (80), 138 (17), 109 (27), 81 (20), 57 (11), 41 (12);
HRMS (ESI+): m/z [M+H]+ calcd for C12H24F2O5P: 317.13239, found:
317.13238.
(m, 1H), 6.81–6.84 (m, 2H), 7.29–7.32 (m, 2H); 13C NMR
3
(125.7 MHz, CDCl3):
d
= 13.5, 13.8, 16.0 (d, JCP = 5.7 Hz), 16.1 (d,
3JCP = 5.7 Hz), 48.2–48.7 (m), 52.0–52.2 (m), 55.1, 61.5, 61.9, 63.9
2
2
(d, JCP = 6.7 Hz), 64.5 (d, JCP = 6.5 Hz), 113.4, 120.6 (ddd,
1JCF = 271.1 Hz, 1JCF = 265.1 Hz, 1JCP = 213.8 Hz),
124.2(d,
3JCF = 8.5 Hz), 131.9, 159.5, 166.3, 167.3; 19F NMR (470.4 MHz,
4.2.22. t-Butyl 4-(diethoxy-phosphoryl)-4,4-difluoro-3-
2
2
phenylbutyrate (4v)
CDCl3):
d
= À105.3 (ddd, 1F, JFF = 301.2 Hz, JFP = 107.0 Hz,
Not isolated; 19F NMR (376 MHz, CDCl3): 17% yield,
d
= À111.0
3JFH = 4.4 Hz), À119.4 (ddd, 1F, JFF = 301.2 Hz, JFP = 101.5 Hz,
2 2
2
2
3
(ddd, 1F, JFF = 300.5 Hz, JFP = 109.8 Hz, JFH = 13.4 Hz), À116.0
(ddd, 1F, 2JFF = 300.5 Hz, 2JFP = 103.0 Hz, 3JFH = 21.4 Hz); MS (EI): m/
z (rel. int.) = 336 (21), 319 (12), 272 (22), 263 (16), 188 (10), 138
(100), 111 (24), 57 (36), 41 (23).
3JFH = 28.8 Hz); 31P NMR (162 MHz, CDCl3):
d
= 5.30 (dd,
2
2JPF = 107.0 Hz, JPF = 101.5 Hz); MS (EI): m/z (rel. int.) = 466 (10)
[M]+, 426 (16), 400 (12), 375 (13), 300 (23), 255 (100), 227 (28), 161
(45), 109 (14), 81 (9); HRMS (ESI+): m/z [M+Na]+ calcd for
C20H29F2NaO8P: 489.14603, found: 489.14571.
4.2.23. Diethyl 2-(1-((diethoxy-phosphoryl)-difluoro-methyl)-
pentyl)-malonate (4w)
4.2.26. Diethyl (1,1-difluoro-3-methyl-2-oxo-but-3-enyl)-
phosphonate (5t)
Isolated as a colorless oil (275 mg, 71% yield); Rf = 0.37 (EtOAc-
PE, 30:70); IR (film):
n
max (cmÀ1) = 2984, 2963, 2936, 2875, 1755,
Isolated as a colorless oil (121 mg, 51% yield); Rf = 0.34 (EtOAc-
1735, 1273, 1156, 1034; 1H NMR (400 MHz, CDCl3):
d
= 0.89 (t, 3H,
PE, 30:70); IR (film):
n
max (cmÀ1) = 1744, 1695, 1628, 1278, 1164,
3JHH = 7.2 Hz), 1.26–1.31 (m, 8H), 1.36–1.41 (m, 8H), 1.68–1.77 (m,
1022; 1H NMR (500 MHz, CDCl3):
d
= 1.37 (dt, 6H, JHH = 7.1 Hz,
3
1H), 1.83–1.92 (m, 1H), 3.00–3.15 (m, 1H), 3.94 (d, 1H,
4JHP = 0.7 Hz), 1.94–1.95 (m, 3H), 4.26–4.35 (m, 4H), 6.15–6.17 (m,
3
3JHH = 5.7 Hz), 4.21 (q, 4H, JHH = 7.1 Hz), 4.25–4.32 (m, 4H); 13C
1H), 6.43–6.44 (m, 1H); 13C NMR (125.7 MHz, CDCl3):
d = 16.3 (d,
NMR (125.7 MHz, CDCl3):
d
= 13.7, 13.8, 13.9, 16.2 (d, 3JCP = 5.4 Hz),
3JCP = 5.6 Hz), 18.3, 65.2 (d, 2JCP = 6.7 Hz), 114.7 (dt, 1JCF = 275.1 Hz,
1JCP = 200.4 Hz), 132.0 (t, 3JCP = 5.5 Hz), 139.1–139.2 (m), 188.9 (dt,
22.8, 25.4, 30.1, 43.0–43.3 (m), 49.8–49.9 (m), 61.3, 61.7, 64.5 (d,
2
1
2
2JCP = 7.5 Hz), 64.6 (d, JCP = 7.8 Hz), 121.4 (ddd, JCF = 266.3 Hz,
2JCF = 23.8 Hz, JCP = 15.0 Hz); 19F NMR (376 MHz, CDCl3):
1JCF = 265.0 Hz, JCP = 212.0 Hz), 167.5, 168.2; 19F NMR (376 MHz,
d
d
= À109.5 (d, JFP = 96.0 Hz); 31P NMR (162 MHz, CDCl3):
1
2
2
2
2
CDCl3):
d
= À108.5 (ddd, 1F, JFF = 303.6 Hz, JFP = 107.7 Hz,
= 3.83 (t, JPF = 96.0 Hz); MS (EI): m/z (rel. int.) = 228 (7), 211
3JFH = 14.0 Hz), À114.4 (ddd, 1F, JFF = 303.6 Hz, JFP = 107.5 Hz,
(6), 201 (7), 184 (7), 132 (14), 121 (13), 109 (5), 81 (10), 69 (100), 41
(41); HRMS (ESI+): m/z [M+Na]+ calcd for C9H15F2NaO4P:
279.05682, found: 279.05685.
2
2
3JFH = 21.4 Hz); 31P NMR (162 MHz, CDCl3):
d = 6.37 (dd,
2JPF = 107.7 Hz, JPF = 107.5 Hz); MS (EI): m/z (rel. int.) = 371 (20),
325 (22), 257 (100), 229 (48), 183 (48), 155 (22), 138 (28), 111 (21),
81 (21), 55 (14); HRMS (ESI+): m/z [M+Na]+ calcd for
2
4.2.27. Diethyl (1,1-difluoro-2-oxo-4-phenyl-but-3-enyl)-
phosphonate (5u) [3a,3b]
C
17H31F2NaO7P: 439.16677, found: 439.16659.
Isolated as a colorless oil (171 mg, 53% yield); Rf = 0.32 (EtOAc-
4.2.24. Diethyl 2-(2-diethoxy-phosphoryl)-2,2-difluoro-1-phenyl-
ethyl-malonate (4x)
PE, 30:70); IR (film): n
max (cmÀ1) = 3063, 3030, 1705, 1609, 1599,
1577, 1496, 1277, 1164, 1088, 1021; 1H NMR (400 MHz, CDCl3):
3
Isolated as a colorless oil (260 mg, 64% yield); Rf = 0.35
(EtOAc-PE, 30:70); IR (film): nmax (cmÀ1) = 3065, 3036, 2985,
d
= 1.40 (t, 6H, JHH = 7.1 Hz), 4.30–4.38 (m, 4H), 7.21 (d, 1H,
3JHH = 15.9 Hz), 7.40–7.46 (m, 3H), 7.63–7.66 (m, 2H), 7.91 (d, 1H,
2936, 1761, 1738, 1605, 1590, 1498, 1273, 1158, 1030; 1H NMR
3JHH = 15.9 Hz); 13C NMR (125.7 MHz, CDCl3):
d = 16.2 (d,
3
2
1
(400 MHz, CDCl3):
d
= 0.87 (t, 3H, JHH = 7.1 Hz), 1.09 (dt, 3H,
3JCP = 5.6 Hz), 65.3 (d, JCP = 6.6 Hz), 113.7 (dt, JCF = 272.5 Hz,
3JHH = 7.1 Hz, 4JHP = 0.4 Hz), 1.18 (dt, 3H, 3JHH = 7.1 Hz,
4JHP = 0.5 Hz), 1.30 (t, 3H, JHH = 7.1 Hz), 3.65–3.75 (m, 1H),
1JCP = 197.0 Hz), 118.2, 129.0, 129.1, 131.7, 133.7, 147.9, 186.6 (dt,
3
2
2JCF = 23.6 Hz, JCP = 15.0 Hz); 19F NMR (376 MHz, CDCl3):
2
3.76–3.84 (m, 2H), 3.86–3.92 (m, 1H), 3.95–4.04 (m, 1H), 4.07–
4.15 (m, 1H), 4.20–4.30 (m, 3H), 4.35–4.47 (m, 1H), 7.27–7.32
(m, 3H), 7.37–7.41 (m, 2H); 13C NMR (125.7 MHz, CDCl3):
d
d
= À118.8 (d, JFP = 98.0 Hz); 31P NMR (162 MHz, CDCl3):
2
= 3.72 (t, JPF = 98.0 Hz); MS (EI): m/z (rel. int.) = 298 (7), 245
(2), 131 (100), 103 (26), 77 (12); HRMS (ESI+): m/z [M+Na]+ calcd
3
3
d
= 13.4, 13.9, 16.0 (d, JCP = 5.8 Hz), 16.1 (d, JCP = 5.8 Hz), 49.0–
for C14H17F2NaO4P: 341.07247, found: 341.07242.
2
49.6 (m), 52.0–52.2 (m), 61.5, 61.9, 63.9 (d, JCP = 6.9 Hz), 64.5
2
1
1
(d, JCP = 6.7 Hz), 120.5 (ddd, JCF = 271.5 Hz, JCF = 264.2 Hz,
4.2.28. Ethyl 2-benzylidene-4-(diethoxy-phosphoryl)-4,4-difluoro-3-
1JCP = 213.8 Hz), 128.0, 128.3, 130.8, 132.5 (d, JCF = 8.1 Hz),
oxo-butyrate (5x)
3
166.2, 167.3; 19F NMR (470.4 MHz, CDCl3):
d
= À105.7 (ddd, 1F,
Not isolated; 19F NMR (376 MHz, CDCl3): 13% yield,
d
= À110.5
2JFF = 302.2 Hz, JFP = 107.2 Hz, JFH = 4.6 Hz), À119.1 (ddd, 1F,
(d, 2F, JFP = 95.2 Hz), 10% yield,
d
= À113.9 (d, 2F, JFP = 97.4 Hz);
2
3
2
2
2JFF = 302.2 Hz, 2JFP = 100.9 Hz, 3JFH = 28.4 Hz); 31P NMR
MS (EI): both isomers m/z (rel. int.) = 370 (3), 345 (3), 203 (100),
2
2
(162 MHz, CDCl3):
d
= 5.15 (dd, JPF = 107.2 Hz, JPF = 100.9 Hz);
175 (9), 135 (19), 107 (12).
MS (EI): m/z (rel. int.) = 436 (12) [M]+, 396 (13), 370 (8), 345
(22), 317 (16), 299 (100), 253 (14), 203 (50), 138 (47), 111 (34),
91 (10), 81 (13); HRMS (ESI+): m/z [M+Na]+ calcd for
4.2.29. Ethyl 4-(diethoxy-phosphoryl)-4,4-difluoro-2-(4-methoxy-
benzylidene)-3-oxo-butyrate (5y)
C
19H27F2NaO7P: 459.13547, found: 459.13520.
Not isolated; 19F NMR (376 MHz, CDCl3): 26% yield,
d
= À110.2
2
2
(d, 2F, JFP = 95.7 Hz), 10% yield,
d
= À113.7 (d, 2F, JFP = 97.6 Hz);
4.2.25. Diethyl 2-(2-(diethoxy-phosphoryl)-2,2-difluoro-1-(4-
methoxy-phenyl)-ethyl)-malonate (4y)
MS (EI): both isomers m/z (rel. int.) = 375 (4), 345 (3), 233 (100),
205 (9), 165 (6), 137 (7), 117 (2).
Isolated as a colorless oil (243 mg, 56% yield); Rf = 0.18 (EtOAc-
PE, 30:70); IR (film):
1736, 1254, 1160, 1031; 1H NMR (500 MHz, CDCl3):
n
max (cmÀ1) = 3065, 2985, 2936, 2841, 1762,
Acknowledgments
d
= 0.92 (t, 3H,
3
4
3JHH = 7.1 Hz), 1.12 (dt, 3H, JHH = 7.1 Hz, JHP = 0.6 Hz), 1.21 (dt,
3
4
3
3H, JHH = 7.1 Hz, JHP = 0.7 Hz), 1.29 (t, 3H, JHH = 7.1 Hz), 3.72–
3.77 (m, 1H), 3.77 (s, 3H), 3.80–3.86 (m, 2H), 3.89–3.94(m, 1H),
3.98–4.06 (m, 1H), 4.10–4.17 (m, 2H), 4.19–4.30 (m, 2H), 4.31–4.41
This work was supported by the Grant Agency of the Czech
Republic (203/08/P310) and the Academy of Sciences of the Czech
Republic (Research Plan AVZ40550506).

P. Cherkupally, P. Beier / Journal of Fluorine Chemistry 137 (2012) 34–43
43
[9] W. Howson, J.M. Hills, Bioorg. Med. Chem. Lett. 1 (1991) 501–502.
[10] R. Pajkert, H. Koroniak, J. Fluorine Chem. 128 (2007) 1260–1263.
Appendix A. Supplementary data
[11] A. Henry-dit-Quesnel, L. Tupet, J.-C. Pommelet, T. Lequeux, Org. Biomol. Chem. 1
(2003) 2486–2491.
[12] C.M. Hu, J. Chen, J. Chem. Soc. Perkin Trans. 1 (1993) 327–330.
[13] Z.Y. Yang, D.J. Buton, J. Org. Chem. 57 (1992) 4676–4683.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.jfluchem.2012.02.003.
`
[14] A. Sene, S. Diab, A. Heinzsch, D. Cahard, T. Lequeux, Synlett (2009) 981–985.
[15] A.R. Li, Q.Y. Chen, Synthesis (1996) 606–608.
[16] T. Lequeux, F. Lebouc, C. Lopin, H. Yang, G. Gouhier, S.R. Piettre, Org. Lett. 3 (2001)
185–188.
References
[17] (a) P. Beier, A.V. Alexandrova, M. Zibinsky, G.K.S. Prakash, Tetrahedron 64 (2008)
10977–10985;
[1] V.D. Romanenko, V. Kukhar, Chem. Rev. 106 (2006) 3868–3935.
[2] K.S. Chunikhin, A.A. Kadyrov, P.V. Pasternak, N.D. Chkanikov, Russ. Chem. Rev. 79
(2010) 371–396.
[3] (a) T.P. Lequeux, J.M. Percy, J. Chem. Soc. Chem. Commun. (1995) 2111–2112;
(b) K. Blades, T.P. Lequeux, J.M. Percy, Tetrahedron 53 (1997) 10623–10632;
(c) D.B. Berkowitz, M. Eggen, Q. Shen, R.K. Shoemaker, J. Org. Chem. 61 (1996)
4666–4675;
(d) X. Li, A. Bhandari, C.P. Holmes, A.K. Szardenings, Bioorg. Med. Chem. Lett. 14
(2004) 4301–4306.
[4] (a) K. Blades, T.P. Lequeux, J.M. Percy, Chem. Commun. (1996) 1457–1458;
(b) K. Blades, A.H. Butt, G.S. Cockerill, H.J. Easterfield, T.P. Lequeux, J.M. Percy, J.
Chem. Soc. Perkin Trans. 1 (1999) 3609–3614.
(b) A.V. Alexandrova, P. Beier, J. Fluorine Chem. 130 (2009) 493–500;
(c) P. Beier, R. Pohl, A.V. Alexandrova, Synthesis (2009) 957–962;
(d) P. Cherkupally, P. Beier, Tetrahedron Lett. 51 (2010) 252–255;
(e) P. Cherkupally, A. Slazhnev, P. Beier, Synlett (2011) 331–334;
(f) P. Beier, S. Opekar, M. Zibinsky, I. Bychinskaya, G.K.S. Prakash, Org. Biomol.
Chem. 9 (2011) 4035–4038.
[18] S. Opekar, P. Beier, J. Fluorine Chem. 132 (2011) 363–366.
[19] (a) T. Cohen, W.D. Abraham, M. Myers, J. Am. Chem. Soc. 109 (1987) 7923–7924;
(b) H.J. Reich, W.H. Sikorski, J. Org. Chem. 64 (1999) 14–15;
(c) W.H. Sikorski, H.J. Reich, J. Am. Chem. Soc. 123 (2001) 6527–6535.
[20] T. Mukhopadhyay, D. Seebach, Helv. Chim. Acta 65 (1982) 385–391.
[21] C. Ni, L. Zhank, J. Hu, J. Org. Chem. 73 (2008) 5699–5713.
[22] S. Opekar, P. Beier, Unpublished results.
[5] K. Blades, J.M. Percy, Tetrahedron Lett. 39 (1998) 9085–9088.
[6] K. Blades, D. Lapoˆtre, J.M. Percy, Tetrahedron Lett. 38 (1997) 5895–5898.
[7] T.P. Lequeux, J.M. Percy, Synlett (1995) 361–362.
[23] S. Halazy, V. Grossberges, J. Chem. Soc. Chem. Commun. (1992) 743–745.
[8] T. Murano, S. Muroyama, T. Yokomatsu, S. Shibuya, Synlett (2002) 1657–1660.