Synthesis and reactivity studies of α,α-difluoromethylphosphinates

Article abstract of DOI:10.1016/j.tet.2010.04.036

The preparation and reactivity of some α,α-difluorophosphinates are investigated. Alkylation of H-phosphinates with LiHMDS and ClCF₂H gives the corresponding α,α-difluorophosphinates in good yield. Deprotonation of these reagents with alkyllithium or LDA is then studied. Subtle electronic effects translate into significant differences in the deprotonation/alkylation of the two 'Ciba-Geigy reagents' (EtO)₂CRP(O)(OEt)H (R=H, Me). On the other hand, attempted methylation of difluoromethyl-octyl-phosphinic acid butyl ester resulted in the exclusive alkylation of the octyl chain. Finally, reaction with carbonyl compounds results in the formation of 1,1-difluoro-2-phosphinoyl compounds.

Full text of DOI:10.1016/j.tet.2010.04.036

Tetrahedron 66 (2010) 4434e4440
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis and reactivity studies of
a,
a-difluoromethylphosphinates
*
Isabelle Abrunhosa-Thomas, Laëtitia Coudray, Jean-Luc Montchamp
Department of Chemistry, Box 298860, Texas Christian University, Fort Worth, TX 76129, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The preparation and reactivity of some
phosphinates with LiHMDS and ClCF2H gives the corresponding a,a
a
,
a
-difluorophosphinates are investigated. Alkylation of H-
-difluorophosphinates in good yield.
Received 1 March 2010
Received in revised form 5 April 2010
Accepted 6 April 2010
Deprotonation of these reagents with alkyllithium or LDA is then studied. Subtle electronic effects
translate into significant differences in the deprotonation/alkylation of the two ‘Ciba-Geigy reagents’
(EtO)2CRP(O)(OEt)H (R¼H, Me). On the other hand, attempted methylation of difluoromethyl-octyl-
phosphinic acid butyl ester resulted in the exclusive alkylation of the octyl chain. Finally, reaction with
carbonyl compounds results in the formation of 1,1-difluoro-2-phosphinoyl compounds.
Ó 2010 Elsevier Ltd. All rights reserved.
Available online 10 April 2010
Keywords:
Phosphinate
Phosphonate
Fluorine
Conformational analysis
Pyrophosphate analogs
1. Introduction
a GABA analog (Scheme 1).4 Two GABA analogs H2NCH2CH(X)CH2P
(O)(OH)CF2H (X¼H, OH) were also studied, but these were less potent
a
-Fluorophosphorus compounds have gained popularity as
agonists in a GABAB binding assay than the corresponding non-fluo-
rinated methyl phosphinate by a factor of w3e5.4 Phosphonate H2N
(CH2)3P(O)(OH)2 behaves instead as an antagonist.4 The deprotection
of the acetal followed by functionalization was also reported in this
work (Scheme 1). A few years ago, we reported a general alkylation of
potential pharmacophores. In the case of phosphonates, the fluorine
substituent(s) is known to modulate the pKa of the phosphonic acid
group, sometimes improving the mimicry of a natural phosphate
monoester, and the inhibitory potency of the resulting analog.1
a,a-
Difluorophosphinates have been much less studied, and in their case,
the effect of fluorine on the pKa is unimportant since the phosphinic
monoacidsarealways deprotonatedatphysiologicalpH. Nonetheless,
the CF2 moiety is a known mimic of an oxygen atom. Usingour radical
hydrophosphinylation reaction (NaH2PO2, Et3B/air)2 Piettre and co-
H-phosphinates, and the preparation of a few a,a-difluoro-
methylphosphinates.5 Herein, we report a study of the alkylation of
these and other precursors, which expands upon the Hall precedent.4
workers have pioneered the synthesis of a,a-difluorophosphinates,
O
P
O
P
O
P
EtO
EtO
EtO
EtO
TMSCl
OEt
1) BuLi
OEt
OEt
from 1,1-difluoro-2,2-disubstituted olefins (Eq. 1).3
H
CF2Pr
EtOH, CH2Cl2
99%
2) n-PrBr
66%
CF2Pr
CF2H
R1
H2N
O
P
NC
CN
NH3, Ra-Ni
O
P
OEt
CF2Pr
F2C
R2
OH
O
P
O
P
R2
R1
H
ONa
EtOH
75%
EtONa, EtOH
4 oC to rt, 24 h
41%
CF2Pr
(1)
NaO
CF2
H
H
Et3B/air or t-BuOOPiv
degassed MeOH, reflux
63-85%
Scheme 1. Hall’s synthesis and elaboration of an a,a
-difluorophosphinate.4
2. Results and discussion
Fifteen years ago, Hall and co-workers reported the only example
we could find of the base-promoted alkylation of a difluoromethylp
hosphinateRP(O)(OEt)CF2H, aswellasitssubsequentelaborationinto
2.1. Synthesis of difluoromethylphosphinate RP(O)(OEt)CF2H
precursors
Three precursors 1e3 were synthesized previously (Eq. 2).5
A
* Corresponding author. E-mail address: j.montchamp@tcu.edu (J.-L. Montchamp).
fourth compound 4 was synthesized similarly from (EtO)2CHP(O)
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.04.036

I. Abrunhosa-Thomas et al. / Tetrahedron 66 (2010) 4434e4440
4435
Table 3
(OEt)H. We have been referring to (EtO)2CRP(O)(OEt)H (R¼H, Me)
Reactions of phosphinate 3 with some electrophiles
as the ‘Ciba-Geigy reagents’, after their development in that com-
pany. As will be discussed below, significant differences exist be-
tween compounds 3 and 4.
Entry
Base
(1.1 equiv)
Electrophile
Isolated
yield (%)
1
2
3
4
t-BuLi
t-BuLi
t-BuLi
Br
0.5 equiv
0.5 equiv
1.05 equiv
69a
Br
Br
Br
Ph
1) LiHMDS, THF
-78 oC,
Br
Br
62a
65
O
P
O
P
deoxygenation
OR'
OR'
H
(2)
R
R
CF2H
2) HCF2Cl (excess)
-78 oC to rt
t-BuLi
t-BuLi
Cl
1.0 equiv
1.0 equiv
70
52
O
5
Geranyl bromide
a
Disubstitution.
O
P
O
O
O
BuO
OEt
OEt
OEt
OEt
BuO
EtO
EtO
P
P
P
Oct
Alkylation with a carbohydrate-derived iodide also gave satis-
factory results but the product was obtained as the fully hydrolyzed
H-phosphinic acid (Eq. 3). It is interesting to note that 3 was suc-
cessful in this reaction, but 4 was not, under otherwise identical
conditions. In fact, the reactions of compound 4 are typically very
different from that of 3. Table 4 summarizes the results with methyl
iodide and 4 (compare with Table 1). It is expected that the elec-
tron-donating methyl substituent in compound 3 will somewhat
deactivate the phosphorus atom toward nucleophilic attack.
However, the subtle electronic effects translate into significant
differences when compared to compound 4.
HF2C
HF2C
HF2C
HF2C
1 (72%)
2 (78%)
3 (71%)
4 (72%)
The alkylation of H-phosphinate esters with lithium hexame-
thyldisilazide (LiHMDS)5 and F2CHCl (R-22) and mild de-
oxygenation gives good yields of products 1e4 (71e78%). As we
have reported previously, moderate deoxygenation is necessary to
achieve good yields of product (this is because the P(III) anion is
easily oxidized).5,6
OMe
OBn
2.2. Functionalization of the difluoromethylphosphinates
O
P
OEt
R
OEt
F
F
O
1) t-BuLi
EtO
O
P
Although the P(O)CF2H group is acidic, electrophilicity of the
phosphorus atom is also increased so that P-substitution is an
expected competitive pathway. Table 1 shows the outcome of the
deprotonationealkylation process with compound 3 (and methyl
iodide as electrophile) as a function of the base employed. t-BuLi
gives the best results because it is a strong base and less nucleo-
philic than other butyllithium reagents.
HO
H
HF2C
OBn
OMe
O
2)
(3)
OBn
OBn
OBn
R = CH3, 3
R = H, 4
63% from 3
I
OBn
Table 1
Table 4
Role of the base in the alkylation of 4 with CH3I
Role of the base in the alkylation of 3 with CH3I
Conditionsa
Crude NMR
Isolated
yield (%)
Entry
Base (equiv)
Conditionsa
Crude NMR yield, 31
and 19F (%)
P
Isolated
yield (%)
Entry
Base
(1.1 equiv)
yield, 31P and 19F (%)
1
2
3
4a
4b
LDA (1.0)
Deoxygenated
Deoxygenated
Deoxygenated
Deoxygenated
Without
20
0
80
100
53
d
d
d
91
d
1
2
3
LDA
BuLi
t-BuLi
Deoxygenated
Deoxygenated
Deoxygenated
100
62
d
d
LiHMDS (1.0)
t-BuLi (1.0)
t-BuLi (1.1)
Some addition to P
Addition to P major
a
All reactions were deoxygenated for 30 min to 1 h prior to adding the base.
deoxygenation
Compounds RP(O)(OEt)CF2R0 are hydrolyzed very easily during
chromatography on silica gel, even in the presence of some base
(like Et3N) in the eluent. This is not surprising due to the increased
electrophilicity of the phosphorus atom with the powerful elec-
tron-withdrawing CF2H group. Thus, products are often isolated
and/or characterized as the corresponding H-phosphinic esters or
acids. H-Phosphinate esters RP(O)(OEt)H are typically hydrolyzed
rather easily, and the difluoro-substituted compounds RCF2P(O)
(OEt)H are even more prone to further hydrolysis to the corre-
sponding H-phosphinic acids RCF2P(O)(OH)H.
a
Unless otherwise noted, all reactions were deoxygenated for 30 min to 1 h prior
to adding the base.
The role of electrophile was also investigated (Table 2). Not sur-
prisingly, the less reactive electrophilesgavea loweralkylationyield.
Table 2
Role of the Electrophile in the Alkylation of 3 with t-BuLia
Entry
Electrophile
Crude NMR, 31
P and 19F (%)
Isolated yield (%)
1
2
4
3
OctI
100
100
45
85
82
d
d
OctBr
OctOTs
OctCl
2.4. Alkylation of 2
30
a
Conditions: (1) deoxygenation, (2) addition of RX at ꢀ78 ꢁC, 30 min after the
base, (3) ꢀ78 ꢁC to 15 ꢁC, 1.5 h, (4) extractive work-up.
Alkylation of compound 2 resulted in an unexpected chain
functionalization, as opposed to the difluoromethyl deprotonation/
alkylation (Eq. 4).
2.3. Scope of the alkylation
O
1) base
2) CH3I
O
P
BuO
BuO
P
(4)
Compound 3 was treated with several electrophiles (Table 3).
The yields are moderate to good. When 0.5 equiv of a dielectrophile
is employed, the disubstituted product is obtained.
Oct
HF2C
HF2C
CH3
2

4436
I. Abrunhosa-Thomas et al. / Tetrahedron 66 (2010) 4434e4440
Table 5 shows the results. Even with excess t-BuLi, no alkylation
2.5. Anion reactivity with carbonyl compounds
of the difluoromethyl group is taking place (indicating that the
dianion could not be formed). A possible explanation for this ini-
tially surprising result (the lower pKa of the methylene group over
that of the CF2H group in 2, Eq. 4) might be due to the general
anomeric effect (negative hyperconjugation, HOMOeLUMO in-
teractions): the carbanion lone pair must be antiperiplanar to P]O
(4PþeOꢀ) to take advantage of stabilization (lone pair
Another unexpected reaction was uncovered when the anion
derived from (EtO)2CRP(O)(OEt)CF2H (3, 4) was treated with car-
bonyl compounds (Table 6).
A possible mechanism for the formation of 5 is shown in
Scheme 3. The first step is the expected 1,2-addition of anion 6 to
produce 7. At this point, formation of oxaphosphetane 8 can take
place (as in olefination reactions), and this intermediate collapses to
form a strong PeO bond and to cleave the PeCF2 bond to produce 9.
The driving force for this rearrangement is easily understood
with the more accurate semi-polar representation of P]O as
PþeOꢀ: the CF2 moiety enhances the electrophilicity of the phos-
phorus (destabilizes Pþ) toward nucleophilic attack by the alkoxide
7, and in oxaphosphetane 8, the CeF bonds cannot be antiperiplanar
n/
s
(PþeOꢀ)), whereas the P]O bond might instead prefer to be
*
antiperiplanar to CeF (
s
(PþeOꢀ)/
*
s (CeF), dipole minimization).
Table 5
Alkylation of compound 2 with CH3I (Eq. 4)
Entry
Base
Crude NMR yield,
Isolated
yield (%)
31P and 19F (%)
[s
(PþeOꢀ)/
s (CeF) interaction discussed earlier]. Hydrolysis of 9
*
1
2
3
LDA
t-BuLi
t-BuLi
1.1 equiv
1.1 equiv
2.2 equiv
100
100
100
87
85
d
(or possibly 8) gives the rearrangement product 5. It is interesting to
note that the 1,1-difluoroolefin 10 or phosphonate monoester 11
were not observed, although the reaction mixtures were not heated
(since the formation of 10 would not be competitive with other
synthetic methods). It is known that unactivated phosphonates/
phosphinates are generally poor olefination reagents. Obayashi and
In order to better understand these effects, a brief computational
investigation on the two possible anions derived from CH3P(O)
(OMe)CF2H as simplified models (conformational search followed
by optimization at the 6-311þG** level) was conducted
(Scheme 2).7 It revealed that, in fact, all conformers of the CF2 anion
B are always higher in energy than the corresponding CH2 anion A,
thereby supporting the experimental results (Eq. 4 and Table 5).7 In
the case of B, the energy difference between the three rotamers
B1eB3 is small, indicating that the intensities of the competing
stereoelectronic effects are similar.8 Interestingly, the conformation
in which the anion’s lone-pair is antiperiplanar to P]O (lone pair
Table 6
Reaction with carbonyl compounds
O
P
EtO
R
EtO
O
P
EtO
R
EtO
OEt
O
1) base
O
OEt
CF2H
R1
CF2H
2)
R2
3 R = CH3
4 R = H
R1
R2
5
n/
accepting ability decreases in the following order:
(PeOR)>
(PþeOꢀ), as shown in the stability order A1>A2>A3.
Experimentally, the (same) fact that HCF2 is more electron-with-
drawing (lower lying ) than OR can easily be established: the
s
*
(PþeOꢀ)) is higher in energy even for A. This is because the
(CeCF2H)>
s
*
Reagent Base
Carbonyl compound Crude NMR yield, 31P Isolated
s
*
s
*
19
(1.1 equiv) (1.1 equiv)
and F (%)
yield (%)
s
*
3
4
t-BuLi
100
100
80
77
O
second pKa of (HO)2P(O)CF2H is 5.4 versus 7.2 for (HO)3P(O) [and 7.6
for (HO)2P(O)CH3]; or the pKa of HCF2COOH is 1.24 versus 3.6 for
HOCOOH and 10.6 for HOCOOꢀ.1c,9 The pKa of phosphinate’s 2
methylene group should thus be a little lower than that in a phos-
phonate diester RCH2P(O)(OR0)2, whereas that of the CF2H is sig-
nificantly higher.
LDA
CHO
3
t-BuLi
85
48
N
MeO
O
MeO
F2C
O
A CH2-anion
B CF2-anion
P
P
HF2C
CH2
CH3
O
F
O
F
O
O
O
O
H
H
F
F
F
F
H
HF2C
H
OR
Me
OR
Me
OR
HF2C
OR HF2C
OR
Me
OR
H
H
0.0 kcal/mol
A1
+1.6
A2
+5.7
A3
+9.3
B1
+10
B2
+11.5
B3
Scheme 2. Computed relative energies (kcal/mol) for anions A and B (6-311þG**). The P]O group is represented as P(þ)eO(ꢀ) with only O(ꢀ) visible. Rotamers of the CF2H group
in A are not shown. As expected, anion B is much more pyramidalized than anion A.
While in compound 2 the side-chain methylene is more easily
deprotonated than the difluoromethyl group, in the case of com-
pound 4, deprotonation at the difluoromethylene moiety is clearly
preferred but then steric effects (steric hindrance for acetal
deprotonation) also exist (Table 4).10 Electrophiles other than MeI
have not been tried, but the nature of the electrophile should not
affect the regioselectivity.
co-workers reported a similar rearrangement producing 1,1-
difluoro-2-phosphonyl esters 12 (R¼OR3¼OEt, Scheme 3) or 17
(Scheme 4) in the reaction of (EtO)2P(O)CF2H and (EtO)2P(O)
CF2SiMe3 with carbonyl compounds, although 17 is only a minor
side-reaction, with either 1,2-addition product 16 or difluoroolefin
10 as the major products (Scheme 4).11 These authors also reported
the base-dependent isomerization of 16 into 17.11

I. Abrunhosa-Thomas et al. / Tetrahedron 66 (2010) 4434e4440
4437
O
O
P
OR3
O
O
P
O
P
EtO
R
EtO
EtO
R
EtO
OEt
CF2
R
O
P
R1
R2
EtO
R
EtO
OEt
CF2
O
R1
R1
CF2H
O
R2
R2
6
8
7
12
O
P
EtO
R
EtO
O
P
EtO
R
EtO
F
F
OEt
OEt
O
O
P
H3O
EtO
R
EtO
OEt
CF2
+
O
R1
R1
R2
O
R1
CF2H
R2
5
9
10
11
R2
Scheme 3. Postulated mechanism of the CF2/O rearrangement.
1) LDA, THF -78 o
or CsF, THF, rt
C
F
F
O
P
O
O
P
O
P
EtO
EtO
R1
R2
EtO
EtO
EtO
EtO
+
heat
O
CF2Y
R1
R2
O
F
F
2)
15
13 Y = H
10 (54 - 75%)
14 Y = SiMe3
R1
R2
H3O
O HF2C
O
P
OH
R1
R2
EtO
R1
R2
base
EtO
EtO
P
EtO
O
F
F
17 (0 - 27%)
16 (38 - 90%)
Scheme 4. Obayashi’s reactions with phosphonate reagents.11
Again, stereoelectronic effects could explain the much greater
propensity for rearrangement in phosphinates 7 over phospho-
nates 15. In the case of phosphonate 15, an additional oxygen lone-
pair in the second ethoxy group [antiperiplanar lone pair
Unfortunately, attempts at deprotecting acetal 18 were not
successful at delivering a clean product after chromatography, even
though the desired (EtO)2P(O)CF2P(O)(OEt)H product was major. A
similar reaction with 3 also worked, but was not as clean and gave
even more uncontrolled hydrolysis (the MeC(OEt)2 group is much
more labile) during attempted purification. On the other hand,
reaction of 3 with ClP(BH3)(OEt)2 gave a rather clean pyrophos-
phate analog 19 (>90%, Eq. 6), but once again, attempts at further
elaboration of 19 to the corresponding intermediate (EtO)2P(BH3)
CF2P(O)(OEt)H were largely unsuccessful, and although hydrolysis
is even more facile, we were unable to secure any pure product.
This line of research would require more work to produce the
synthetically useful pyrophosphate analog precursors, since the
novel products (EtO)2P(O)CF2P(O)(OEt)H and (EtO)2P(BH3)CF2P(O)
(OEt)H could be very useful compounds for potential medicinal
applications. Perhaps crude deprotected 18 and 19 might be used,
but this was not attempted in the present work. A current literature
approach to the corresponding pyrophosphate analog 20 is shown
in Scheme 5, and relies on the conversion of a phosphonate diester
into the phosphonochloridate, followed by displacement with the
well-known anion 21.14
n/
s
(PþeOꢀ)] decreases the electrophilicity at phosphorus com-
*
pared to the acetal group in phosphinates 7. Thus, it is perhaps not
surprising that our case gives rearrangement to 5, whereas the
phosphonate 15 only gives small amounts of 17.
There is only a handful of reported compounds having structure
12 (R¼C, Scheme 3).12 They are generally synthesized by phos-
phonylation of the corresponding fluorinated alcohol using PeCl
containing reagents.12
2.6. Pyrophosphate analogs
Pyrophosphate analogs are medicinally important in the treat-
ment of bone and other diseases. For example, bisphosphonates
constitute a major class of drugs against osteoporosis.13 Thus, we
briefly investigated the preparation of novel PCF2P building blocks.
Alkylation of 4 with ClP(O)(OEt)2 gave the corresponding difluor-
ophosphonate/phosphinate 18 quite cleanly (>90%) after a simple
work-up (Eq. 5).
O
EtO
P
21
CF2Li
O
P
F
O
O
P
1) aq. KOH, ROH
O
P
EtO
EtO
EtO
RO
RO
RO
Cl
R1
P
R1
O
P
O
P
F
O
R1
OEt
OEt
OEt
OEt
1) LDA
EtO
EtO
EtO
30-58%
F
20
OR
2) (COCl)2, cat. DMF
P
(5)
R = Me, Et
HF2C
2) ClP(O)(OEt)2
F
OEt
Scheme 5. Literature approach to some pyrophosphate analogs.14
4
18
Difluorophosphinates, like their phosphonate counterparts,15
could become useful in chemical biology. For example, difluoro-
phosphonate analogs of phosphorylated isoprenoids and hexoses
have tremendous current interest. Since H-phosphinates are also
versatile functional groups for the synthesis of other organophos-
phorus functionalities,16 the chemistry described above could be
employed to synthesize various biologically active analogs of
phosphates.
O
P
H3B
EtO
F
F
O
OEt
OEt
OEt
OEt
1) t-BuLi
EtO
P
P
(6)
HF2C
2) ClP(BH3)(OEt)2 EtO
OEt
3
19

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I. Abrunhosa-Thomas et al. / Tetrahedron 66 (2010) 4434e4440
3. Conclusions
J¼1.0 Hz, 1H, (EtO)2CHeP), 4.29e4.41 (m, 2H, eCH2eOeP),
3.85e3.98 (m, 2H, eCH2eOeC), 3.68e3.79 (m, 2H, eCH2eOeC),
1.41 (t, J¼7.0 Hz, 3H, CH3eCeOeP), 1.28 (t, J¼7.0 Hz, 6H,
In conclusion, the synthesis and reactivity of difluoro-
methylphosphinates were investigated under basic conditions.
a
,
a
-
CH3eCeOeCꢂ2); 13C NMR (75.45 MHz, CDCl3)
d: 112.6 (td,
Difluoro substituted compounds can be obtained easily through
deprotonation with LiHMDS followed by alkylation with HCF2Cl.
The resulting products could have value as biologically active
phosphate analogs. In alkylation reactions of reagents 3 and 4,
significant differences are observed in spite of the relatively subtle
electronic effect at phosphorus. The resulting products are easily
hydrolyzed sometimes complicating purification. On the other
hand, alkylation of reagent 2 gives substitution on the alkyl chain,
and an explanation for this observation is provided.
An interesting rearrangement was uncovered when difluoro-
methylphosphinate anions were treated with carbonyl compounds.
Attempts were also made at preparing reagents for the synthesis of
pyrophosphate analogs. Although promising, the results require
additional investigations in order to obtain pure reagents and to
investigate their associated reactivities.
JCF¼262.0 Hz, JCP¼129.5 Hz), 99.2 (d, JCP¼152.5 Hz), 66.2 (d,
JCOCP¼10.0 Hz), 65.8 (d, JCOCP¼10.0 Hz), 63.9 (d, JCOP¼7.0 Hz), 16.6
(d, JCCOP¼4.5 Hz), 15.2, 15.1; 31P NMR (121.47 MHz, CDCl3)
d: 23.64
: ꢀ136.5 (ddd,
(t, JPCF¼76.0 Hz); 19F NMR (282.3 MHz, CDCl3)
d
JFF¼354.5 Hz,
JFCP¼76.0 Hz,
JFCH¼49.0 Hz),
ꢀ138.5 (ddd,
JFF¼354.5 Hz, JFCP¼76.0 Hz, JFCH¼49.0 Hz); HRMS (Chem Ion, NH3)
calcd for C8H17F2O4P, ([MþNH3]þ) 264.1176, found 264.1168.
4.4. Representative procedure for the alkylation of 3
(Tables 1e3): (1,1-diethoxy-ethyl)-(1,1-difluoro-ethyl)-
phosphinic acid ethyl ester
(1,1-Diethoxy-ethyl)-difluoromethyl-phosphinic acid ethyl ester
3 (0.52 g, 2.0 mmol) was placed under vacuum in a dry two-neck
flask 10 min before use. Anhydrous THF (6.7 mL, 0.3 M) was then
added under N2. The flask was cooled to ꢀ78 ꢁC and deoxygenated
under vacuum for 5 min. The reaction flask was back-filled with N2,
then t-BuLi (1.7 M in pentane, 1.3 mL, 2.2 mmol, 1.1 equiv) was
added at ꢀ78 ꢁC. After 30 min, iodomethane (2.0 mmol, 1.0 equiv)
was added under N2. After addition, the temperature of the solution
was kept at ꢀ78 ꢁC for 10 min, then slowly allowed to warm to 0 ꢁC
over 2 h. The reaction mixture was quenched with brine (10 mL).
The aqueous layer was extracted with ethyl acetate (3ꢂ). The
combined organic layer was dried over anhydrous MgSO4 and
concentrated to afford the product as a slightly yellow oil (0.5 g, 91%
Compounds RP(O)(OH)(CF2H) might also be useful analogs of
phosphonic acids but with a reduced charge, and this has appar-
ently not been investigated beyond the two GABA analogs in Hall’s
seminal work.4 Work to study this class of compounds as possible
phosphonate mimics is currently underway our laboratory.
4. Experimental section
4.1. General chemistry
1H NMR spectra were recorded on a 300-MHz spectrometer.
Chemical shifts for 1H NMR spectra are reported (in parts per
million) relative to internal tetramethylsilane (Me4Si,
yield). 1H NMR (300 MHz, CDCl3)
d: 4.27e4.40 (m, 2H, eCH2eOeP),
3.66e3.93 (m, 4H, eCH2eOeCꢂ2), 1.86 (td, JHCF¼21.5 Hz,
JHCCP¼7.5 Hz, 3H, PeCF2eCH3), 1.61 (d,,JHCP¼12.0 Hz, 3H,
PeCeCH3), 1.39 (t, J¼7.0 Hz, 3H, CH3eCeOeP), 1.20e1.25 (m, 6H,
d
¼0.00 ppm)
with CDCl3 or H2O (
d
¼4.75 ppm) in D2O. 13C NMR spectra were
recorded at 75 MHz. Chemical shifts for 13C NMR spectra are
CH3eCeOeCꢂ2); 13C NMR (75.45 MHz, CDCl3)
d: 122.2 (td,
reported (in parts per million) relative to CDCl3
(d
¼77.0 ppm). 31P
JCF¼262.5 Hz, JCP¼126.0 Hz), 101.6 (d, JCP¼145.0 Hz), 63.5 (d,
JCOP¼8.0 Hz), 58.9 (d, JCOCP¼5.0 Hz), 58.2 (d, JCOCP¼8.0 Hz), 21.6 (dt,
JFCC¼22.0 Hz, JPCC¼14.0 Hz), 20.9 (dt, JPCC¼12.5 Hz, JFCPCC¼3.0 Hz),
NMR spectra were recorded at 121 MHz, and chemical shifts are
reported (in parts per million) relative to external 85% phosphoric
acid (
d
¼0.0 ppm). 19F NMR spectra were recorded at 282 MHz, and
16.8 (d, JCCOP¼5.0 Hz), 15.6, 15.3; 31P NMR (121.47 MHz, CDCl3)
d:
chemical shifts are reported (in parts per million) relative to ex-
29.11 (t, JPCF¼90.0 Hz); 19F NMR (282.3 MHz, CDCl3)
: ꢀ101.9 (dq,
d
ternal CFCl3
(d¼0.0 ppm).
JFCP¼90.0 Hz, JFCH¼21.5 Hz); HRMS (Chem Ion) calcd for
C10H21F2O4P, ([MþH]þ) 275.1224, found 275.0123.
4.2. Reagents and solvents
4.5. Representative procedure for the alkylation of 4
(Table 4): diethoxymethyl-(1,1-difluoro-ethyl)-phosphinic
acid ethyl ester
Tetrahydrofuran (THF) was distilled from sodium benzophe-
none ketyl under N2 just before reaction.
4.3. Diethoxymethyl-difluoromethyl-phosphinic acid ethyl
ester 4
To diisopropylamine (0.31 mL, 2.2 mmol,1.1 equiv) in anhydrous
THF (1.0 mL) at ꢀ20 ꢁC under N2 was added n-BuLi (1.6 M, 1.38 mL,
2.2 mmol, 1.1 equiv). After 30 min, the solution was cooled down to
ꢀ78 ꢁC and a solution of diethoxymethyl-difluoromethyl-phos-
phinic acid ethyl ester 4 (0.492 g, 2.0 mmol) in anhydrous THF
(4.0 mL) was added. After 30 min, iodomethane (0.124 mL,
2.0 mmol, 1.0 equiv) was added under N2. After addition, the tem-
perature of the solution was kept at ꢀ78 ꢁC for 10 min, then slowly
allowed to warm to 5 ꢁC over 1 h. The reaction mixture was
quenched with brine (10 mL). The aqueous layer was extracted with
ethyl acetate (3ꢂ). The combined organic layer was dried over
anhydrous MgSO4 and concentrated. The resulting oil was purified
by column chromatography over silica (hexanes/ethyl acetate, 1/1,
v/v) to afford the product as a slightly yellow oil (0.32 g, 62%). 1H
Neat diethoxymethyl-phosphinic acid ethyl ester (40.0 g,
204 mmol) was placed under vacuum in a dry two-neck flask
equipped with a cold finger 10 min before use. Anhydrous THF
(410 mL) was then added under N2. The flask was cooled to ꢀ78 ꢁC
and deoxygenated under vacuum for 5 min. The reaction flask was
back-filled with N2, then LiHMDS (1.0 M in THF, 224 mL, 224 mmol)
was added at ꢀ78 ꢁC. After 15 min, condensed chlorodifluoro-
methane (around 18 mL, 204 mmol) was added under N2. After
addition, the temperature of the solution was kept at ꢀ78 ꢁC for
10 min, then slowly allowed to warm to 0 ꢁC. After 10 min at 0 ꢁC,
the reaction mixture was quenched with a saturated solution of
NH4Cl/brine, extracted with ethyl acetate (3ꢂ), and then dried over
anhydrous MgSO4. Concentration in vacuo gave an oil, which was
purified by column chromatography over silica (hexanes/ethyl ac-
etate, 7/3, v/v to ethyl acetate 100%) to afford the ester 4 as a lightly
NMR (300 MHz, CDCl3)
d
: 4.94 (d, 1H, JHCP¼10.0 Hz, eCHeP),
4.29e4.42 (m, 2H, eCH2eOeP), 3.68e3.98 (m, 4H, eCH2eOeCꢂ2),
1.86 (td, JHCF¼21.5 Hz, JHCCP¼8.0 Hz, 3H, PeCF2eCH3), 1.40 (t,
J¼7.0 Hz, 3H, CH3eCeOeP), 1.27 (t, 6H, J¼7.0 Hz, CH3eCeOeCꢂ2);
yellow oil (36.0 g, 72% yield). 1H NMR (300 MHz, CDCl3)
JHCF¼49.0 Hz, JHCP¼26.5 Hz, 1H, PeCF2H), 4.90 (dt, JHCP¼9.0 Hz,
d
: 6.07 (td,
13C NMR (75.45 MHz, CDCl3)
d
:
122.2 (td, JCF¼262.5 Hz,
JCP¼126.0 Hz), 99.0 (d, JCP¼148.5 Hz), 65.8 (d, JCOP¼10.0 Hz), 65.6

I. Abrunhosa-Thomas et al. / Tetrahedron 66 (2010) 4434e4440
4439
(d, JCOCP¼9.0 Hz), 63.9 (d, JCOCP¼8.0 Hz), 21.3 (dt, JFCC¼22.0 Hz,
JPCC¼13.5 Hz), 16.8 (d, JCCOP¼5.0 Hz), 15.4, 15.3; 31P NMR
(s); 19F NMR (282.3 MHz, CDCl3)
d
: ꢀ133.6 (dd, JFCF¼285.5 Hz,
JFCH¼56.5 Hz), ꢀ132.0 (dd, JFCF¼285.5 Hz, JFCH¼56.5 Hz); HRMS
(121.47 MHz, CDCl3)
d
: 25.84 (t, JPCF¼93.5 Hz); 19F NMR (282.3 MHz,
(ESI) calcd for C15H29F2NaO5P, ([M]þ) 381.1618, found 381.1617.
CDCl3)
d
: ꢀ104.0 (dq, JFCP¼93.5 Hz, JFCH¼22.0 Hz); HRMS (Chem
Ion) calcd for C9H19F2O4P, ([MþH]þ) 261.1067, found 261.1069.
Acknowledgements
4.6. Representative procedure for the alkylation of 2 (Table 5,
Eq. 4): difluoromethyl-(1-methyl-octyl)-phosphinic acid
butyl ester
We thank the National Institute of General Medical Sciences/
NIH (1R01 GM067610) for the financial support of this research.
Supplementary data
Difluoromethyl-octyl-phosphinic acid butyl ester 2 (0.426 g,
1.5 mmol) was placed under vacuum in a dry two-neck flask 10 min
before use. Anhydrous THF (5.0 mL, 0.3 M) was then added under
N2. The flask was cooled to ꢀ78 ꢁC and deoxygenated under vac-
uum for 5 min. The reaction flask was back-filled with N2, then
t-BuLi (1.7 M in pentane, 1.0 mL, 1.65 mmol, 1.1 equiv) was added
at ꢀ78 ꢁC. After 30 min, iodomethane (0.1 mmol, 1.65 mmol,
1.1 equiv) was added under N2. After addition, the temperature of
the solution was kept at ꢀ78 ꢁC for 30 min, then slowly allowed to
warm to rt over 1 h. The reaction mixture was quenched with
saturated solution of NH4Cl/brine (10 mL). The aqueous layer was
extracted with ethyl acetate (3ꢂ). The combined organic layer was
dried over anhydrous MgSO4 and concentrated. The resulting oil
was purified by column chromatography over silica (hexanes/ethyl
acetate, 8/2, v/v) to afford the product as a slightly yellow oil
Additional experimental and spectral data are provided. Sup-
plementary data associated with this article can be found, in the
online version, at doi:10.1016/j.tet.2010.04.036. These data include
MOL files and InChIKeys of the most important compounds
described in this article.
References and notes
1. For representative and general references, see: (a) O’Hagan, D. Chem. Soc. Rev.
2008, 37, 308; (b) Bégué, J.-P.; Bonnet-Delphon, D. Bioorganic and Medicinal
Chemistry of Fluorine; Wiley: Hoboken, NJ, 2008; (c) Romanenko, V. D.; Kukhar,
V. P. Chem. Rev. 2006, 106, 3868; (d) Lequeux, T. P. General Methods for the
Synthesis of Difluoromethylphosphonates In Fluorine-Containing Synthons. ACS
Symposium Series; 2005; Vol. 911, Chapter 26, pp 440e455; (e) Modern Fluo-
roorganic Chemistry; Kirsch, P., Ed.; Wiley-VCH: Weinheim, Germany, 2004; (f)
Savignac, P.; Iorga, B. Modern Phosphonate Chemistry; CRC: Boca Raton, FL, 2003.
2. Deprèle, S.; Montchamp, J.-L. J. Org. Chem. 2001, 66, 6745.
3. (a) Gautier, A.; Garipova, G.; Salcedo, C.; Balieu, S.; Piettre, S. R. Angew. Chem.,
Int. Ed. 2004, 43, 5963; (b) Our own studies using NaH2PO2 and Et3B/air on 1,1-
difluoro-2-monosubstituted olefins (unpublished results) showed that the re-
gioselectivity is poor (and small amounts of partially defluorinated products
also form). Thus, the use of R2C]CF2 appears important to form the tertiary
radical intermediate for complete regioselection (formation of PeCF2). There-
fore the present/Hall reaction provides a competing alternative to free radical
approaches.
4. (a) Froestl, W.; Mickel, S. J.; Hall, R. G.; von Sprecher, G.; Diel, P. J.; Strub, D.;
Baumann, P. A.; Brugger, F.; Gentsch, C.; Jaekel, J.; Olpe, H.-R.; Rihs, G.; Vassout,
A.; Waldmeier, P. C.; Bittiger, H. J. Med. Chem. 1995, 38, 3297; (b) Froestl, W.;
Mickel, S. J.; von Sprecher, G.; Diel, P. J.; Hall, R. G.; Maier, L.; Strub, D.; Melillo,
V.; Baumann, P. A.; Bernasconi, R.; Gentsch, C.; Hauser, K.; Jaekel, J.; Karlsson,
G.; Klebs, K.; Maitre, L.; Marescaux, C.; Pozza, M. F.; Schmutz, M.; Steinmann,
M. W.; van Riezen, H.; Vassout, A.; Mondadori, C.; Olpe, H.-R.; Waldmeier, P. C.;
Bittiger, H. J. Med. Chem. 1995, 38, 3313.
(0.79 g, 85%). Two diastereosisomers 1H NMR (300 MHz, CDCl3)
d:
6.03 (td, 1H, JHCF¼48.5 Hz, JHCP¼23.5 Hz, PeCF2H), 4.12e4.32 (m,
2H, eCH2eOeP), 2.01 (m, 1H, PeCHeCH2e), 1.67e1.85 (m, 3H,
PeCeCH3), 1.20e1.51 (m, 16H, eCH2e), 0.89e1.00 (m, 6H,
eCH2eCH3ꢂ2); 13C NMR (75.45 MHz, CDCl3)
d: 113.9 (2td,
JCF¼263.0 Hz, JCP¼122.0 Hz), 66.4 (2d, JCOP¼7.0 Hz), 32.7 (d,
JCCOP¼5.0 Hz), 31.8, 30.2 (d, JCP¼95.0 Hz) and 30.1 (d, JCP¼94.5 Hz),
29.3, 29.1, 28.2, 27.1 (2d, JCCP¼12.0 Hz), 22.6, 18.7, 14.1, 13.6, 11.6 (d,
JCCP¼14.5 Hz); 31P NMR (121.47 MHz, CDCl3)
d:
42.14 (t,
JPCF¼72.0 Hz), 41.75 (t, JPCF¼70.5 Hz); 19F NMR (282.3 MHz, CDCl3)
d
: ꢀ135.2 to ꢀ134.4 (m); HRMS (EI) calcd for C14H29F2O2P, ([M]þ)
298.1873, found 298.1875.
4.7. Representative procedure for the rearrangement with
carbonyl compounds (Table 6, entry 1): (1,1-diethoxy-ethyl)-
phosphonic acid 1-difluoromethyl-cyclohexyl ester ethyl ester
5. Abrunhosa-Thomas, I.; Sellers, C. E.; Montchamp, J.-L. J. Org. Chem. 2007, 72,
2851.
6. The ease of oxidation of P(III) compounds with oxygen is well-known. See for
example: (a) Lee, K.; Wiemer, D. F. J. Org. Chem. 1991, 56, 5556; (b) Fougère, C.;
Guénin, E.; Hardouin, J.; Lecouvey, M. Eur. J. Org. Chem. 2009, 6048.
7. Calculations were performed using the Spartan 08 molecular modeling soft-
ware (Wavefunction, Inc.). Although these are gas-phase computations, it is
reasonable to expect similar solvation of anions A and B. For interesting ref-
erences concerning conformational effects in phosphorus compounds, see: (a)
Thatcher, G. R. J.; Campbell, A. S. J. Org. Chem. 1993, 58, 2272; (b) Stewart, E. L.;
Nevins, N.; Allinger, N. L.; Bowen, J. P. J. Org. Chem. 1999, 64, 5350; (c) Grein, F. J.
Mol. Struct. (Theochem) 2001, 536, 87; (d) Vereshchagina, Y. A.; Ishmaeva, E. A.;
Zverev, V. V. Russ. Chem. Rev. 2005, 74, 297.
(1,1-Diethoxy-ethyl)-difluoromethyl-phosphinic acid ethyl ester
3 (0.52 g, 2.0 mmol) was placed under vacuum in a dry two-neck
flask 10 min before use. Anhydrous THF (6.7 mL, 0.3 M) was then
added under N2. The flask was cooled to ꢀ78 ꢁC and deoxygenated
under vacuum for 5 min. The reaction flask was back-filled with N2,
then t-BuLi (1.7 M in pentane, 1.3 mL, 2.2 mmol, 1.1 equiv) was
added at ꢀ78 ꢁC. After 30 min, cyclohexanone (2.2 mmol, 1.1 equiv)
was added under N2. After addition, the temperature of the solution
was kept at ꢀ78 ꢁC for 10 min, then slowly allowed to warm to 0 ꢁC
over 2 h. The reaction mixture was quenched with brine (10 mL).
The aqueous layer was extracted with ethyl acetate (3ꢂ). The
combined organic layer was dried over anhydrous MgSO4 and
concentrated. The crude oil was purified by chromatography over
silica (hexanes/ethyl Acetate, 8/2, v/v) to afford the product as
8. The preference for antiperiplanar CeF in carbonyl compounds is well known.
See for example Ref. 1a and references cited therein. In anions A1eA3, one of
the CeF bonds is always antiperiplanar to P]O.
9. Tossell, J. A. Environ. Sci. Technol. 2009, 43, 2575.
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(R)CH2R2, see: Pietrusiewicz, K. M.; Zablocka, M. Tetrahedron Lett. 1982, 30, 477.
11. (a) Obayashi, M.; Ito, E.; Matsui, K.; Kondo, K. Tetrahedron Lett. 1982, 23, 2323;
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a slightly yellow oil (0.61 g, 80% yield). 1H NMR (300 MHz, CDCl3)
d:
6.19 (t, 1H, JHCF¼56.5 Hz, eCF2H), 4.22 (m, 2H, eCH2eOeP),
3.64e3.76 (m, 4H, eCH2eOeCePꢂ2), 2.05e2.18 (m, 2H, eCHeꢂ2),
1.53e1.80 (m, 8H, eCHe), 1.55 (d, JHCP¼12.0 Hz, CH3eCeP), 1.34 (t,
J¼7.0 Hz, CH3eCeOeP), 1.21 (t, J¼7.0 Hz, CH3eCeOeC), 1.20 (t,
J¼7.0 Hz, CH3eCeOeC); 13C NMR (75.45 MHz, CDCl3)
d: 117.0 (d,
JCF¼248.0 Hz), 100.4 (d, JCP¼214.0 Hz), 84.3 (td, JCCF¼20.5 Hz,
JCOP¼10.0 Hz), 63.8 (d, JCOP¼7.0 Hz), 58.4 (d, JCOCP¼6.5 Hz), 57.9 (d,
JCOCP¼9.0 Hz), 29.9, 29.1, 25.3, 21.2 (d, JCCP¼10.0 Hz), 20.8, 20.7, 16.6
(d, JCCOP¼5.5 Hz), 15.6, 15.4; 31P NMR (121.47 MHz, CDCl3)
d: 15.49

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I. Abrunhosa-Thomas et al. / Tetrahedron 66 (2010) 4434e4440
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