Synthesis of (α,α-difluoropropargyl)phosphonates via aldehyde-to-alkyne homologation

Article abstract of DOI:10.1021/jo400198a

An efficient synthetic methodology to a series of novel alkynes bearing a difluoromethylenephosphonate function via a Corey-Fuchs-type sequence starting from (diethoxyphosphoryl)difluoroacetic aldehyde is described. Dehydrobromination of the intermediate (3,3-dibromodifluoroallyl)phosphonate with potassium tert-butoxide gave rise to the corresponding bromoalkyne, whereas upon treatment with lithium base, the generation of ((diethoxyphosphoryl) difluoropropynyl)lithium has been achieved for the first time. The synthetic potential of this lithium reagent was further demonstrated by its reactions with selected electrophiles such as aldehydes, ketones, triflates, chlorophosphines, and chlorosilanes, leading to the corresponding propargyl phosphonates in good to excellent yields. However, in the case, of sterically hindered aldehydes, (α-fluoroallenyl)phosphonates were the solely isolated products.

Full text of DOI:10.1021/jo400198a

Article
pubs.acs.org/joc
Synthesis of (α,α-Difluoropropargyl)phosphonates via Aldehyde-to-
Alkyne Homologation
Romana Pajkert* and Gerd-Volker Roschenthaler
̈
School of Engineering and Science, Jacobs University Bremen, Campus Ring 1, 28759 Bremen, Germany
S
* Supporting Information
ABSTRACT: An efficient synthetic methodology to a series of novel alkynes bearing a difluoromethylenephosphonate function
via a Corey−Fuchs-type sequence starting from (diethoxyphosphoryl)difluoroacetic aldehyde is described. Dehydrobromination
of the intermediate (3,3-dibromodifluoroallyl)phosphonate with potassium tert-butoxide gave rise to the corresponding
bromoalkyne, whereas upon treatment with lithium base, the generation of ((diethoxyphosphoryl)difluoropropynyl)lithium has
been achieved for the first time. The synthetic potential of this lithium reagent was further demonstrated by its reactions with
selected electrophiles such as aldehydes, ketones, triflates, chlorophosphines, and chlorosilanes, leading to the corresponding
propargyl phosphonates in good to excellent yields. However, in the case, of sterically hindered aldehydes, (α-
fluoroallenyl)phosphonates were the solely isolated products.
molecules,9 the attachment of the difluoromethylenephospho-
nato function onto unsaturated sp carbon centers still remains a
nontrivial synthetic problem. Moreover, relatively few reports
involving their preparations have appeared in the literature
1. INTRODUCTION
The interest in the synthesis and application of gem-
difluoromethylenephosphates (DFMP) as phosphate mimics
is unquestionable. The electronic and structural similarities of
citations to date. The first one, reported by Hammond, involves
the C−CF2−P moiety in DFMP to the C−O−P group in
the Pfitzner−Moffatt oxidation of diethyl α-hydroxyalkyne-
phosphates are attractive. In addition, the relative resistance of
phosphonate, prepared by the nucleophilic attack of diethyl
fluorinated phosphates to metabolic transformations has great
potential.1 Indeed, the importance of difluoromethylene-
phosphite on the corresponding aldehyde, followed by the
DAST fluorination of the resulting α-ketophosphonate.10
phosphonates as phosphate analogues and enzyme inhibitors
has been well established, and they are still of interest in
Further approaches included the one-pot Shibuya−Yokomatsu
type coupling of (EtO)2P(O)CF2ZnBr with the appropriate 1-
biochemical and pharmaceutical investigations. Recently, the
haloalkynes in the presence of copper(I) halide,11 nucleophilic
applications of DFMP derivatives in the treatment of infections,
substitution of TIPS−difluoropropargyl bromide with diethyl
inflammations, and respiratory, dermatological, autoimmune
phosphite,12 electrophilic fluorination of TIPS−propargyl
phosphonate using N-fluorobenzenesulfonimide (NFSI), fol-
lowed by its additional functionalization upon treatment with
water or benzaldehyde in the presence of (tetrabutylammonium
fluoride) TBAF,13a and the copper-mediated oxidative cross-
coupling reaction of terminal alkynes with α-silyldifluorome-
thylphosphonates13b (Scheme 1). It should be noted, however,
that these strategies have been generally restricted by the choice
of substrates, the requirement of multiple steps, or the use of
diseases (TLR modulators),2 in psychotic, anxiety, and
movement disorders and/or neurological disorders (PDE10
inhibitors),3 as antidiabetic agents (PTP 1B inhibitors),4 as
targets for cancer chemotherapy (IMPDH and Stat inhibitors),5
as agonists for purinergic receptors,6 and as gene expression
inhibitors7 have been established. Considering these benefits,
numerous synthetic methodologies have been investigated for
the introduction of the difluoromethylenephosphonate function
into a variety of organic compounds.1d,8
Despite the unique biological and physical properties
imparted by the CF2P(O)(OR)2 group, and the obvious
versatility of alkynes as valuable scaffolds for more functional
Received: January 29, 2013
© XXXX American Chemical Society
A
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Scheme 1. Previous Synthetic Routes to (α,α-Difluoropropargyl)phosphonates
Scheme 2. Preparation of (α,α-Difluoroacetic) Aldehyde (3)
reagents of limited stability, which could hamper their synthetic
application.
aqueous workup.16 However, the authors isolated only a
masked form of an aldehyde (dihydrate 2) in 80% yield and no
details on the preparation and characterization of the desired
aldehyde 3 have been reported. We thus re-examined this
synthetic procedure and found that after distillation of the
dihydrate 2 over phosphorus pentoxide under an inert
atmosphere, the corresponding aldehyde was formed in good
yield (Scheme 2).
According to the reported procedure for the Ramirez
olefination,17 we attempted to prepare the corresponding
dibromo(difluoroallyl)phosphonate 4 starting from 3. To our
delight, the slow addition of 3 to a CH2Cl2 solution of
tetrabromomethane and triphenylphosphine at 0 °C resulted in
a total consumption of 3 and quantitative conversion into gem-
dibromo(difluoroallyl)phosphonate (4) upon mixing the
suspension for 1 h at ambient temperature (Scheme 3).
Further workup and purification by distillation in vacuo
furnished the expected dibromide 4 in very good yield.
We have further studied the appropriate conditions leading
to HBr elimination on compound 4. We speculated that the
increased acidity of the vinylic hydrogen of 4, arising from the
proximity of the strong electron-withdrawing CF2P(O)(OEt)2
group, would facilitate the dehydrobromination process.
As an alternative approach to obtaining (difluoropropargyl)-
phosphonates, we were interested in an aldehyde-to-alkyne
homologation process, commonly known as the Ramirez−
Corey−Fuchs reaction. In its classical form, this high-yielding
two-step procedure involves the transformation of an aldehyde
to the homologated dibromoalkene (Ramirez olefination),14a
followed by the base-promoted, in situ formation of lithium
acetylide, whose hydrolysis or treatment with an electrophile
furnishes the corresponding terminal or internal acetylenic
compound.14b As a result of the high compatibility of a wide
range of aldehydes as well as various electrophiles, this method
has been widely applied recently, using nonfluorinated
substrates in their original or modified form.15 With this in
mind, we report herein the first general application of the
aldehyde-to-alkyne procedure in the synthesis of a new class of
(α,α-difluoropropargyl)phosphonates, as well as the generation
of ((diethoxyphosphoryl)difluoropropargyl)lithium from
(diethoxyphosphoryl)difluoroacetic aldehyde. Systematic inves-
tigations on the reactivity of the difluoropropargyl carbanion
toward selected electrophiles are also discussed.
2. RESULTS AND DISCUSSION
Scheme 3. Preparation of Diethyl (3,3-Dibromo-1,1-
difluoroallyl)phosphonate (4)
Initially, our attention was focused on finding an appropriate
method for the synthesis of the key substrate, (diethoxyphos-
phoryl)difluoroacetic aldehyde (3). Preliminary results of Percy
et al. indicated that compound 3 could be obtained by reacting
the lithium salt of diethyl difluoromethylenephosphonate (1)
with N,N-dimethylformamide (DMF) at −78 °C, prior to an
B
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Table 1. Dehydrobromination of 4 under Various Conditions
a
a
entry
base
TEA
solvent
conditions
yield of 5 (%)
yield of 11a (%)
1
2
3
4
5
6
7
8
9
Et2O
0 °C to room temp
0 °C to room temp
0 °C to room temp
0 °C to room temp
0 °C to room temp
0 °C to room temp
−78 °C to room temp
−78 °C to room temp
b
DIPEA
DBU
Et2O
b
DMSO
CH3CN
CH2Cl2
THF
59
53
25
49
62
63
36
30
19
18
38
37
DBU
DBU
DBU
NaHMDS
LDA
KOtBu
THF
THF
c
THF
-20 °C to room temp
96
a
b
c
Yield determined by 19F NMR analysis. Starting material was recovered. Isolated yield.
Scheme 4. Suggested Mechanism for the Formation of P−F Derivative D
Therefore, various bases, solvents, and temperatures were
examined in depth. Table 1 summarizes a screening of the
various reaction conditions for the dehydrobromination of
compound 4. Among the variety of bases, non-nucleophilic
tertiary amines such as triethylamine (TEA) and N,N-
diisopropyl-N-ethylamine (DIPEA) were shown not to be
sufficiently strong to promote the dehydrobromination process,
and only starting materials were recovered (Table 1, entries 1
and 2). Better results were obtained when a stronger base, 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU), was used. It is well-
known that bicyclic amidines such as DBU serve as powerful
reagents in organic chemistry and have been extensively applied
to dehydrohalogation in organic synthesis under mild
conditions. However, its basicity depends strongly on the
solvent used and decreases in the order DMSO > DMF >
CH3CN ≫ THF.18a,b Indeed, upon treating dibromo olefin 4
with 1 equiv of DBU dissolved in DMSO, CH3CN, CH2Cl2, or
THF and stirring the resulting mixture for a further 1 h at 0 °C,
the 19F NMR analysis indicated the formation of the desired 1-
bromoalkyne 5 (Table 1, entries 3−5, respectively). Depending
on the polarity of the solvent, the corresponding bromoalkyne
5 was obtained in moderate to good yields (Table 1, entries 3−
6). As predicted, the highest yield of the desired product 5 was
achieved in the solvent of highest polarity (DMSO) and the
lowest yield in the solvent of lowest polarity (THF). In all cases
the dehydrobromination of 4 was accompanied by the
additional formation of the terminal alkyne 11a (δF −98.6
propargyl anions A and B. We speculated that F− eliminated
from A could then cleave the CF2−P bond of 5 and 11a to
form phosphofluoridate D and the other byproducts C and E
(Scheme 4).
Therefore, we looked for a base more selective than DBU for
the preparation of 5. Attempts to perform this process using
sodium bis(trimethylsilyl)amide (NaHMDS) or lithium
diisopropylamide (LDA) in dry THF gave better yields of
the expected bromoalkyne 5. However, the formation of a
terminal alkyne as a byproduct was still observed during the
reaction. Changing the base to the weaker potassium tert-
butoxide (KOtBu) promoted the dehydrobromination process
remarkably well, giving cleanly and selectively the bromoalkyne
5 in excellent yield (Table 1, entry 9). Moreover, no P−CF2
cleavage was surveyed during this process, in contrast to the
case for DBU. Compound 5 possesses a bromoalkyne moiety
suitable for various cross-coupling reactions.18c,d
We next examined the potential of vinyl dibromide 4 as a
(diethoxyphosphoryl)difluoropropynyl anion precursor and its
reactivity toward selected electrophiles. To the best of our
knowledge, there are no literature citations containing the
generation of ((diethoxyphosphoryl)difluoropropynyl)lithium
(6) or functionalization of this synthon. To date, only TIPS−
difluoropropargylphosphonate has been described as a source
of carbanion in a TBAF-mediated preparation of terminal
difluoropropargylphosphonate 11a and γ-substituted hydroxy
difluorophosphonate 7a.13a
2
3
ppm, JFP = 104.4 Hz, JFH = 5.8 Hz) as well as
1
In order to find a viable method for the generation of
((diethoxyphosphoryl)difluoropropynyl)lithium 6, we first
examined the behavior of dibromo olefin 4 upon treatment
with common lithium bases such as n-BuLi, t-BuLi, and LDA at
−78 °C, followed by the addition of a representative
electrophile, in this case benzaldehyde. After quenching with
phosphofluoridate D (approximately 5%, δF −80.8 ppm, JFP
= 979.8 Hz) as a result of a nucleophilic substitution of the
fluoride anion on phosphorus center. The formation of a
fluoride anion could be explained as follows. Under the existing
basic conditions, difluoropropargylphosphonate 11a would
undergo deprotonation to give a resonance-stabilized allenyl−
C
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Table 2. Screening of Various Bases for Alkynylation of Benzaldehyde
a
a
entry
base
temp (°C)
yield (%) of 7a
yield (%) of 8
1
2
3
4
n-BuLi
n-BuLi
t-BuLi
LDA
−78
−100
−78
46
59
59
99
40
22
34
−78
a
Determined by 19F NMR analysis.
Scheme 5. Plausible Mechanism for the in Situ Generation of ((Diethoxyphosphoryl)difluoropropynyl)lithium 6 using Various
Bases and Product Distribution after Addition of Benzaldehyde
Table 3. Stability of the Lithium Reagent 6 at Various Temperatures
a
a
a
a
entry
temp (°C)
yield (%) of F
yield (%) of G
yield (%) of D
yield (%) of H
1
2
3
4
5
6
−78
−40
−20
0
99
99
99
91
16
8
78
93
10
6
4
20
2
a
Determined by 19F NMR analysis.
PhCHO, the product distribution was analyzed by 19F NMR
spectroscopy and the results are given in Table 2.
hindered t-BuLi at −78 °C and 1 equiv of benzaldehyde
resulted in the formation of fluoroallenylphosphonate 8 in 34%
yield (59% of 7a). Taking into consideration the obtained
results, we then attempted to generate ((diethoxyphosphoryl)-
difluoropropynyl)lithium (6) using a base milder than n-BuLi
or t-BuLi, such as LDA. In a typical reaction, a solution of 2.1
equiv of LDA was added to the stirred solution of
dibromoalkene 4 in THF at −78 °C, giving subsequent capture
by an electrophile (PhCHO) of the anionic species generated
in situ. The mixture was warmed to ambient temperature over 1
h and conveniently monitored by 19F NMR spectroscopy,
When the reaction was carried out with 2.1 equiv of n-BuLi at
−78 °C, followed by trapping with an electrophile, the alkyne
7a was formed in good yield (Table 2, entry 1). However, a
partial decomposition of the lithium reagent to fluoroallene 8 in
40% yield occurred. By lowering the temperature to −100 °C,
we were able to slightly suppress the decomposition of the
lithium reagent, which inevitably occurs using n-BuLi as a base
(59% of 7a). On the other hand, the treatment of a solution of
dibromoalkene 4 with 2.1 equiv of the more basic and sterically
D
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Scheme 6. Proposed Decomposition Pathway of Lithium Reagent 6
Table 4. Reactions of in Situ Prepared Acetylide 6 with Selected Aldehydes
a
Isolated yield.
which clearly indicated the selective formation of the desired
product 7a in nearly quantitative yield (Table 2, entry 3). A
plausible explanation for the product distribution upon
treatment with different bases could be best explained by the
initial formation of the thermally unstable vinyllithium Int-A
(Scheme 5). Depending on the base used, two competing
reaction pathways could be speculated. When the reactions
were carried out with stronger bases such as n-BuLi and t-BuLi
at −78 °C, partial decomposition of unstable Int-A took place
as a consequence of lithium fluoride elimination via a concerted
E2 or E1cB mechanism19 and the formation of fluoroallenyl-
phosphonate 8 as a byproduct was detected (Scheme 5, path
A). In contrast, using a milder base such as LDA, rapid
construction of a triple bond would be afforded by loss of
E
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Scheme 7. Plausible Mechanism of the Formation of (α-Fluoroallenyl)phosphonate 9b
Table 5. Reactions of in Situ Prepared 6 with Selected Ketones
a
Isolated yield.
F
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Table 6. Reaction of Lithium Reagent 6 with Other Electrophiles
a
b
c
Isolated yield. Terminal alkyne 11a was obtained after aqueous workup. A stoichiometric amount of HMPA was added as an additive.
lithium bromide in a first step, followed by the lithium−halogen
exchange (Scheme 5, path B). Since the treatment of vinyl
dibromide 4 with various bases resulted in different product
distributions in the same solvent (THF), the aggregation state
of RLi species might also affect the reaction course
significantly.20
It should also be noted that efforts to isolate
((diethoxyphosphoryl)difluoropropynyl)lithium (6) were un-
successful. Additional information concerning the stability of
the lithium reagent was therefore obtained by quenching the
dibromoalkene 4/LDA mixture with D2O at various temper-
atures. The product distribution was then conveniently
monitored by 19F NMR spectroscopy, which revealed that the
reagent obtained in this fashion is stable when held below 0 °C
and decomposes above this temperature. The decomposition
process of 6 could be observed by a gradual loss of the doublet
associated with product F at −99.0 ppm and the concomitant
development of a singlet at δF −183 (LiF), a doublet at δF
−160 (G), a doublet at δF −81 (D), and a doublet at δF −167
(H) (Table 3).
Due to the thermal instability of 6 at above 0 °C, β-
elimination of lithium fluoride from the carbanion 6 is assumed
and leads to the formation of compound B. This fluoride anion
formed in situ could then cleave the carbon−phosphorus bond
of B to furnish fluoroallene H and phosphofluoridate D
(Scheme 6).
With the optimized reaction conditions established, the
reactivity of in situ generated ((diethoxyphosphoryl)-
difluoropropynyl)lithium (6) toward selected electrophiles
was continuously investigated. Initially, we turned our attention
to screening various aldehydes under the conditions given in
Table 3. A wide range of aromatic aldehydes were suitable for
this transformation, regardless of the electronic effects of
substituents attached to the aromatic ring (Table 4, entries 1−
7). However, these aldehydes highly affected the stability of the
final products 7a−g. In the case of benzaldehyde (entry 1) and
its derivatives bearing an electron-donating methoxy group in
ortho, meta, and para positions (entries 2−4), the desired
propargyl alcohols 7a,b,d,f were obtained and isolated in
excellent yields after purification by column chromatography.
Aldehydes containing electron-withdrawing substituents such as
o-chloro-, m-chloro-, and p-nitrobenzaldehyde after treatment
with lithium reagent 6 also produced the desired propargyl
alcohols in excellent yield: 7c (92%), 7e (95%), and 7g (91%),
respectively (according to the 19F and 31P NMR analysis of the
crude reaction mixture). However, their isolation was rather
cumbersome, since they decomposed during the purification
process to an oligomeric material that contained fragments of
CF2H, α-fluoroallenyl, and 1,1-difluoroallylphosphonate
groups. Therefore, we were not able to isolate and fully
characterize compounds 7c,e,g. In the same manner, the linear
aliphatic aldehyde 1-heptanal underwent an addition reaction to
give the corresponding alcohol 7h in very good yield (entry 5).
On the other hand, branched aldehydes such as 2-
methylpropanal (entry 6) and pivalaldehyde (entry 7), upon
treatment with pregenerated carbanion 6, followed by an
aqueous hydrolysis at −40 °C, selectively produced allenic
alcohols 9a,b as a 1:1 mixture of diastereoisomers.
This unexpected selectivity of the propargylic reagent 6 in
SE2′ addition to a prochiral aldehyde possessing bulky
substituents could be dependent on the geometrical preferences
of substrates upon orientation in the transition state C to avoid
the steric repulsion between reagents (elimination of a fluoride
anion after capture of 6 with an aldehyde) (Scheme 7, path A).
It may also be a result of a thermodynamic preference of a
propargyl anion to isomerize into the unsymmetrical allenyl
species Int-B under the reaction conditions used, prior to the
addition to a sp2 carbon atom of an aldehyde to form
G
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homoallenyl alcohol 9b as a mixture of diastereoisomers
(Scheme 7, path B).
electrophilic source under standard reaction conditions (Table
6, entry 5).
To obtain more details on the selectivity of ((diethoxyphos-
phoryl)difluoropropargyl)lithium (6), we next applied our
procedure to various acyclic, cyclic, aromatic, and α,β-
unsaturated ketones. Interestingly, ketones regardless of their
steric and electronic properties underwent the addition of the
lithium reagent smoothly, providing access to tertiary propargyl
alcohols 10a−h in excellent yields (Table 5). In contrast to the
case for aromatic aldehydes, acetophenones bearing electron-
donating (entry 6) or electron-withdrawing (entry 7) groups
attached to the aromatic ring also participated in alkynyl
addition, giving rise to products 10e,g, respectively, in very
good yields. Moreover, these compounds were easily purified
by column chromatography without any decomposition. When
a sterically hindered ketone such as diisopropyl ketone was
used as an electrophile, an excellent isolated product yield was
afforded and no obvious influence of steric factors on the
distribution of the reaction product was observed (entry 2). In
addition, we also attempted the reaction of 6 with the α,β-
unsaturated ketone cyclohexenone, which gave only the
product of 1,2-nuclephilic addition to the carbonyl group and
no Michael addition adducts were formed under the reaction
conditions, even in the presence of additives such as
hexamethylphosphortriamide (HMPA) and cerium chloride,
which have been known to promote Michael addition toward
conjugated carbonyl compounds in the case of difluorinated
lithium reagents (Table 5, entry 4).21
In our quest for a viable route to the synthesis of novel (α,α-
difluoropropargyl)phosphonates, we extended our method to
other electrophiles to gain further information concerning the
selectivity of the lithium reagent 6. From our results in Table 6,
it is seen that the (diethoxyphosphoryl)difluoropropynyl anion
of 6 reacts readily in the usual manner with a limited range of
electrophilic centers to afford the respective CF2P(O)(OEt)2-
containing alkynes, typically in good to very good yields. These
include mostly phosphorus and silyl chlorides (Table 6, entries
2−7) as well as organic triflates (entries 8 and 9). Moreover,
the hydrolysis of the lithium acetylide at −40 °C furnished the
terminal propargylphosphonate 11a in near-quantitative yield
(Table 6, entry 1). Smooth and quantitative conversion of 6
into the silyl derivative 11b was also detected when
trimethylsilyl chloride (TMSCl) was used as an electrophilic
source (Table 6, entry 2), whereas a lower yield of the expected
difluoropropargyl phosphonate 11c was obtained in the case of
tert-butyldimethylsilyl chloride (TBDMSCl) as a result of the
steric bulkiness of a tert-butyl group in proximity to an
electrophilic center (Table 6, entry 3). Bearing in mind the high
susceptibility of the phosphorus−halogen linkage to nucleo-
philic displacement, chlorophosphines were also examined as
substrates in the reaction with lithium acetylide 6 to furnish the
corresponding propargylphosphonates 11d−f. In this series,
however, a significant substituent electronic effect occurred: the
more electron-deficient the chlorophosphines, the higher the
conversions. Therefore, the highest conversion of substrates
was observed in the case of electron-deficient diphenylchlor-
ophosphine (Table 6, entry 4), whereas no satisfactory results
were obtained in an attempt with bis(diethylamino)-
chlorophosphine. Only the terminal alkyne 11a was isolated
as the sole product after aqueous workup (Table 6, entry 6). In
our further attempt, it was also found that lithium reagent 6
afforded a good yield of bis(propargylphosphonate) 11e when
1 equiv of dichloro(isopropyl)phosphine was used as an
Finally, we examined the ability of organic triflates to
undergo nucleophilic displacement with preformed ((diethoxy-
phosphoryl)difluoropropynyl)lithium 6. Unfortunately, no
significant product derived from nucleophilic substitution of
methyl triflate with 6 was detected in the reaction mixture.
However, we tweaked the synthetic procedure and found that
upon generation of the anion 6 from dibromide 4 (1 equiv)
with LDA (2.1 equiv) in the presence of a stoichiometric
amount of lithium-complexing reagent, such as hexamethyl-
phosphortriamide (HMPA, 1 equiv), at −78 °C, followed by
the addition of methyl triflate, the displacement reaction
proceeded in excellent yield. The effect of a polar cosolvent
(HMPA) on the subsequent reactions of the organolithium
reagents, e.g., increasing rates of SN2 reactions, has already been
described elsewhere.22
It should also be noted that other electrophiles such as
iodomethane, dimethyl sulfate, benzoyl chloride, ethyl
benzoate, benzyl chloride, and oxiranes were examined under
the same reaction conditions, but no addition or substitution
products were obtained, even in the presence of lithium-
complexing reagents such as HMPA, TMEDA, and Lewis acids.
The terminal alkyne 11a was mostly obtained after an aqueous
workup. The problem may be in the relatively weak
nucleophilicity of lithium reagent 6, caused by the presence
of strongly electron-withdrawing difluoromethylene as well as
phosphonate groups that affects its nucleophilicity. Therefore,
anion 6 was observed only to react with very good
electrophiles.
In each case, the formation of the (diethoxyphosphoryl)-
difluoropropynyl function was confirmed by the presence of a
doublet resonance in the 19F NMR spectrum in the region of
−97 to −99 ppm with the typical coupling constant 1JFP ≈ 105
Hz (with respect to CFCl3). This is characteristic of an alkynic
CF2P(O)(OEt)2 group. Additional confirmation of the alkynic
CF2P(O)(OEt)2 was supported by 13C NMR spectroscopy, in
which CF2P(O)(OEt)2 was clearly resolved as a triplet of
doublets in the region of 109 ppm with coupling constants JCF
= 253 Hz and JCP = 229 Hz, respectively. Two further triplet of
doublets and doublet of triplets resonances, corresponding to
the carbon nuclei Csp α and β to CF2 group, were observed at
δC 71 (JCF = 33.8, JCP = 17.2 Hz) and 98 ppm (JCF = 7.8, JCP
=
6.7 Hz), respectively. For compound 10g (S isomer) additional
information was acquired from single X-ray diffraction studies.
This represents the first crystallographic structure of any
(diethoxyphosphoryl)difluoropropargyl compound (Figure 1;
see the Supporting Information).23
3. CONCLUSIONS
A novel and efficient strategy for the synthesis of a class of (α,α-
difluoropropargyl)phosphonates via modification of the
Corey−Fuchs methodology starting from (diethoxyphos-
phoryl)difluoroacetic aldehyde25 has been described. By the
action of appropriate bases on the intermediate 3,3-dibromo-
1,1-difluoroalkene, the synthesis of bromoalkyne and the
generation of (diethoxyphosphoryl)difluoromethyllithium
have been achieved for the first time. This anion reacted
readily with a limited range of electrophiles such as aldehydes,
ketones, chlorophosphines, trialkylsilyl chlorides, and organic
triflates to furnish the corresponding CF2P(O)(OEt)2-contain-
ing alkynes in excellent yield. When aldehydes with sterically
demanding substituents were reacted with the anion generated
H
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= 96.8, 3.4 Hz); 31P NMR (CDCl3, 161 MHz) δ 3.1 (t, J = 96.8 Hz);
HRMS (ESI) calcd for [M + H]+ C6H12F2O4P 217.0441, found
217.0448.
Diethyl 3,3-Dibromo-1,1-difluoroallylphosphonate (4). To a
solution of triphenylphosphine (19.9 g, 76 mmol) in dry dichloro-
methane (130 mL) at 0 °C was added carbon tetrabromide (12.7 g, 38
mmol) in one portion. The resulting mixture was stirred for 20 min,
and then (diethoxyphosphoryl)difluoroacetic aldehyde (3; 7.8 g, 36
mmol) was added slowly via syringe. After it was stirred for 1 h at 0
°C, the reaction mixture was warmed to room temperature. Pentane
(200 mL) was then added to the resulting mixture, and the precipitate
that formed was then filtered off. The filtrate was concentrated in
vacuo, and cyclohexane was added to the residue. The precipitate was
filtered off, the filtrate was concentrated by rotary evaporation, and the
crude product was distilled, yielding vinyl dibromide 4 (11.4 g, 85%)
as a colorless oil (bp 98−100 °C/0.1 mmHg): 1H NMR (CDCl3, 400
MHz) δ 1.37 (t, J = 7.1 Hz, 6H), 4.11−4.41 (m, 4H), 6.78 (td, J =
13.3, 2.2 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 16.5 (d, J = 5.2
Hz), 65.2 (d, J = 6.8 Hz), 98.8 (dt, J = 9.3, 9.2 Hz), 115.6 (td, J =
263.7 Hz, 221.9 Hz), 128.4 (td, J = 23.7, 14.4 Hz); 19F NMR (CDCl3,
376 MHz) δ −108.1 (dd, J = 108.8, 13.3 Hz); 31P NMR (CDCl3, 161
MHz) δ 4.9 (t, J = 108.4 Hz); HRMS (ESI) calcd for [M + Na]+
C7H11Br2F2NaO3P 392.8660, found 392.8673.
Figure 1. Solid-state molecular structure of compound 10g (H atoms
are omitted for clarity).
in situ, respective fluoroallenyl alcohols were isolated. Detailed
investigations on the stability of the pregenerated anion, as well
as mechanistic considerations including the reactivity of the
preformed lithium acetylide, were also discussed in this paper.
Further studies, including the application of novel (α,α-
difluoropropargyl)phosphonates as building blocks in the
synthesis of more complex molecules, will be reported in due
course.
Diethyl (3-Bromo-1,1-difluoroprop-2-yn-1-yl)phosphonate
(5). To a mixture of vinyl dibromide 4 (1 g, 2.7 mmol) in dry THF
(10 mL) at −20 °C was slowly added a solution of potassium tert-
butoxide (0.3 g, 2.7 mmol) in THF (2 mL). The resulting mixture was
stirred for 1 h at room temperature, prior to hydrolysis with water (5
mL) and extraction with diethyl ether. After evaporation of the solvent,
the crude product was purified by flash column chromatography, with
1
n-pentane−ethyl acetate as eluent: colorless oil (890 mg, 96%); H
NMR (CDCl3, 400 MHz) δ 1.38 (t, J = 7.1 Hz, 6H), 4.20−4.41 (m,
4H); 13C NMR (CDCl3, 100 MHz) δ 16.4 (d, J = 4.8 Hz), 56.6 (td, J
= 10.1, 8.4 Hz), 65.7 (d, J = 6.7 Hz), 70.6 (td, J = 35.5, 18.2 Hz), 109.1
(td, J = 253.1, 229.1 Hz); 19F NMR (CDCl3, 376 MHz) δ −96.8 (d, J
= 105.5 Hz); 31P NMR (CDCl3, 161 MHz) δ 3.4 (t, J = 105.5 Hz);
HRMS (ESI) calcd for [M + Na]+ C7H10BrF2NaO3P 312.9416, found
312.9420.
4. EXPERIMENTAL SECTION
General Considerations. All reactions were carried out under an
atmosphere of dry argon. THF was freshly distilled from sodium
benzophenone ketyl. Reagents, obtained from commercial sources,
were used without further purification. All other reagents were distilled
or recrystallized, if necessary. Diethyl difluoromethylphosphonate (1)
was prepared according to the known procedure.24 Column
chromatography was performed using silica gel 60 (230−400 mesh
ASTM) and TLCs using silica gel 60 F254. Visualization was achieved
General Procedure for the Synthesis of α,α-Difluoropropar-
gylphosphonates (7a−h, 10a−h, and 11a−g). To a solution of
dibromide (500 mg, 1.4 mmol, 1 equiv) in dry THF (30 mL) at −78
°C was slowly added LDA (6.8 mL, 2 M solution in THF/n-heptane/
ethylbenzene, 2.5 equiv). The resulting mixture was stirred at this
temperature for 5 min, and then an appropriate electrophile (1 equiv)
was added. After the mixture was stirred for 30 min, it was quenched
with 3 M HCl (10 mL). After the organic layer was separated, the
additional extraction with diethyl ether was repeated twice. The
solvent was evaporated, and the crude product was purified by column
chromatography with n-pentane−ethyl acetate as eluent.
1
by UV light or by spraying with Ce(SO4)2 solution in 5% H2SO4. H
(400 MHz), 13C (100 MHz), 19F (376 MHz), and 31P NMR (161
MHz) spectra were measured on a 400 MHz spectrometer at room
1
temperature using 5 mm tubes. TMS was the internal standard in H
NMR; CFCl3 was used as a reference for 19F NMR and 85% H3PO4 in
31P NMR. Chemical shifts (δ) are reported in ppm and coupling
constants (J) in Hz. 31P NMR spectra were broadband decoupled from
hydrogen nuclei. High-resolution mass spectra were recorded on an
ESI-Qq-TOF mass spectrometer. Melting points are uncorrected.
(Diethoxyphosphoryl)difluoroacetic Aldehyde (3). To a
solution of LDA (41 mL, 2.0 M solution in THF/n-heptane/
ethylbenzene) in dry THF at −78 °C was added freshly dried
cerium(III) chloride (21 g, 82 mmol) in one portion. The resulting
suspension was stirred vigorously at −78 °C for 20 min. Diethyl
difluoromethylphosphonate (1; 15 g, 80 mmol) was added dropwise
over 15 min, and the mixture was stirred for 1 h. Freshly distilled N,N-
dimethylformamide (6.2 mL, 6 g, 82 mmol) was slowly added to the
pale yellow-orange suspension, and after the mixture was stirred for 1
h further, aqueous hydrochloric acid was added until complete
dissolution of cerium salts and the solution was warmed to room
temperature. The aqueous layer was extracted with dichloromethane,
and the combined organic layers were washed with brine, dried over
MgSO4, and concentrated in vacuo. The residue was distilled over
phosphorus pentoxide to afford the desired aldehyde 3 (11.0 g, 65%)
Diethyl (1,1-difluoro-4-hydroxy-4-phenylbut-2-yn-1-yl)-
1
phosphonate (7a): yellow oil (421 mg, 98%); H NMR (400 MHz,
CDCl3) δ 1.34 (t, J = 7.1 Hz, 6H), 3.1 (bs, 1H), 4.22−4.31 (m, 4H),
5.08 (s, 1H), 7.21−7.29 (m, 5H); 13C NMR (100 MHz, CDCl3) δ
16.4 (d, J = 5.4 Hz), 65.8 (d, J = 6.7 Hz), 69.6 (td, J = 2.0, 1.1 Hz),
74.0 (td, J = 33.9, 17.4 Hz), 96.3 (dt, J = 7.6, 6.9 Hz), 109.3 (td, J =
253.1, 229.1 Hz), 124.8, 128.1, 128.5, 150.1; 19F NMR (376 MHz,
CDCl3) δ −98.2 (d, J = 104.5 Hz); 31P NMR (161 MHz, CDCl3) δ
3.9 (t, J = 105.6 Hz); HRMS (ESI) calcd for [M + H]+ C14H17F2O4P
318.0832, found 318.0838. The observed data were in accord with
those reported in the literature.13a
Diethyl (1,1-difluoro-4-hydroxy-4-(2-methoxyphenyl)but-2-yn-1-
1
yl)phosphonate (7b): colorless oil (440 mg, 94%); H NMR (400
MHz, CDCl3) δ 1.29 (t, J = 7.1 Hz, 6H), 3.83 (s, 3H), 4.12−4.29 (m,
4H), 5.74 (s, 1H), 6.67 (d, J = 8.3 Hz, 1H), 6.94 (td, J = 7.5, 0.9 Hz,
1H), 7.2−7.21 (m, 1H), 7.47 (dd, J = 7.5, 1.7 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 16.3 (d, J = 5.5 Hz), 55.6, 60.1, 65.7 (d, J = 6.3 Hz),
74.4 (td, J = 33.8, 17.4 Hz), 92.9 (dt, J = 7.6, 6.7 Hz), 110.9 (td, J =
253.2, 229.5 Hz), 120.9, 127.2, 127.8, 130.1, 156.6; 19F NMR (376
MHz, CDCl3) δ −97.5 (dd, J = 106.7, 5.0 Hz); 31P NMR (161 MHz,
1
as a colorless oil: bp 74−77 °C/0.1 mmHg; H NMR (CDCl3, 400
MHz) δ 1.34 (t, J = 7.1 Hz, 6H), 4.27 (quint, J = 7.1 Hz, 4H), 9.54 (dt,
JHF = JHP = 3.7 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 16.3 (d, J =
5.1 Hz), 65.6 (d, J = 6.7 Hz), 112.2 (td, J = 269.3, 192.7 Hz), 187.9
(td, J = 29.7, 14.4 Hz); 19F NMR (CDCl3, 376 MHz) δ −123.6 (dd, J
I
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CDCl3) δ 3.7 (t, J = 106.6 Hz); HRMS (ESI) calcd for [M + H]+
C15H19F2O5P 349.1016, found 349.1021.
(dt, J = 7.6, 6.7 Hz), 108.8 (td, J = 253.1, 230.0 Hz), 128.9, 130.9; 19
F
NMR (376 MHz, CDCl3) δ −97.3 (d, J = 106.9 Hz); 31P NMR (161
MHz, CDCl3) δ 3.9 (t, J = 108.4 Hz); HRMS (ESI) calcd for [M +
H]+ C13H20F2O4P 309.1067, found 309.1071.
Diethyl (1,1-difluoro-4-hydroxy-4-(3-methoxyphenyl)but-2-yn-1-
1
yl)phosphonate (7d): colorless oil (430 mg, 93%); H NMR (400
MHz, CDCl3) δ 1.29 (t, J = 7.1 Hz, 6H), 3.83 (s, 3H), 4.18−4.30 (m,
4H), 4.69 (bs, 1H), 5.49 (s, 1H), 6.67 (d, J = 8.3 Hz, 1H), 6.94 (td, J =
7.5, 0.9 Hz, 1H), 7.2−7.21 (m, 1H), 7.47 (dd, J = 7.5, 1.7 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 16.3 (d, J = 5.5 Hz), 55.3, 63.7, 65.9 (d, J
= 6.3 Hz), 75.3 (td, J = 33.8, 17.4 Hz), 93.0 (dt, J = 7.6, 6.7 Hz), 108.7
(td, J = 253.2, 229.5 Hz), 114.4, 118.9, 129.8, 140.5, 159.8; 19F NMR
(376 MHz, CDCl3) δ −97.9 (dd, J = 106.7, 4.9 Hz); 31P NMR (161
MHz, CDCl3) δ 3.7 (t, J = 106.2 Hz); HRMS (ESI): calcd for [M +
H]+ C15H19F2O5P 349.1010, found 349.1012.
Diethyl (1,1-difluoro-4-hydroxy-4-phenylpent-2-yn-1-yl)-
phosphonate (10e): yellow oil (384 mg, 92%); 1H NMR (400
MHz, CDCl3) δ 1.32 (dt, J = 7.1, 6.7 Hz, 6H), 1.77 (s, 3H), 4.21−4.27
(m, 4H), 4.48 (bs, 1H), 7.25−7.36 (m, 3H), 7.57 (dd, J = 7.6, 1.2 Hz,
2H); 13C NMR (100 MHz, CDCl3) δ 16.4 (d, J = 5.4 Hz), 32.5, 65.8
(d, J = 6.7 Hz), 69.5 (td, J = 2.0, 1.1 Hz), 74.1 (td, J = 33.9, 17.4 Hz),
96.3 (dt, J = 7.6, 6.9 Hz), 109.1 (td, J = 253.1, 229.1 Hz), 124.9, 128.0,
128.5, 143.9; 19F NMR (376 MHz, CDCl3) δ −97.7 (d, J = 106.5 Hz);
31P NMR (161 MHz, CDCl3) δ 3.8 (t, J = 105.6 Hz); HRMS (ESI)
calcd for [M + H]+ C15H20F2O4P 333.1067, found 333.1069.
Diethyl (1,1-difluoro-4-hydroxy-4-(4-methoxyphenyl)but-2-yn-1-
1
yl)phosphonate (7f): colorless oil (451 mg, 97%); H NMR (400
Diethyl (1,1-difluoro-4-hydroxy-4-(4-methoxyphenyl)pent-2-yn-
1-yl)phosphonate (10f): colorless oil (450 mg, 92%); 1H NMR
(400 MHz, CDCl3) δ 1.32 (dt, J = 7.3, 6.8 Hz, 6H), 1.75 (s, 3H), 3.77
(s, 3H), 4.22−4.29 (m, 4H), 4.30 (s, 1H), 6.8 (d, J = 9.2 Hz, 2H), 7.5
(d, J = 8.7 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 16.4 (d, J = 5.8
Hz), 32.3, 55.4, 65.8 (d, J = 6.7 Hz), 69.2, 73.9 (td, J = 33.6, 17.3 Hz),
96.4 (dt, J = 7.6, 6.7 Hz), 109.1 (td, J = 253.1, 229.1 Hz), 113.7, 126.2,
136.1, 159.4; 19F NMR (376 MHz, CDCl3) δ −96.8 (d, J = 109.0 Hz);
31P NMR (161 MHz, CDCl3) δ 4.1 (t, J = 109.0 Hz); HRMS (ESI)
MHz, CDCl3) δ 1.34 (td, J = 7.1, 1.4 Hz, 6H), 3.79 (s, 3H), 4.21−4.34
(m, 4H), 5.48 (td, J = 4.8, 2.2 Hz, 1H), 6.88 (d, J = 8.8 Hz, 2H), 7.41
(d, J = 8.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 16.4 (d, J = 5.5
Hz), 55.4, 63.6, 65.8 (d, J = 6.3 Hz), 75.5 (td, J = 33.8, 17.4 Hz), 93.1
(dt, J = 7.6, 6.7 Hz), 106.4 (td, J = 253.2, 229.5 Hz), 114.4, 128.2,
131.2, 159.9; 19F NMR (376 MHz, CDCl3) δ −97.9 (dd, J = 106.0, 4.9
Hz); 31P NMR (161 MHz, CDCl3) δ 3.9 (t, J = 106.2 Hz); HRMS
(ESI) calcd for [M + H]+ C15H19F2O5P 349.1010, found 349.1015.
Diethyl (1,1-difluoro-4-hydroxydec-2-yn-1-yl)phosphonate (7h):
colorless oil (382 mg, 93%); 1H NMR (400 MHz, CDCl3) δ 0.87 (t, J
= 6.6 Hz, 3H), 1.28−1.33 (m, 6H), 1.39 (t, J = 7.1 Hz, 6H), 1.41−1.47
(m, 2H), 3.00 (bs, 1H), 1.68−1.81 (m, 2H), 4.18−4.30 (m, 4H), 4.47
(tt, J = 6.7, 2.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 14.1, 16.3 (d,
J = 5.5 Hz), 22.6, 24.9, 28.9, 31.7, 36.9, 62.0, 55.3, 65.6 (d, J = 6.7 Hz),
65.7 (d, J = 6.7 Hz), 74.3 (dt, J = 17.4, 16.3 Hz), 93.0 (dt, J = 7.6, 6.7
Hz), 108.6 (td, J = 253.2, 229.5 Hz); 19F NMR (376 MHz, CDCl3) δ
−97.3 (dd, J = 106.7, 4.9 Hz); 31P NMR (161 MHz, CDCl3) δ 3.9 (t, J
= 106.6 Hz); HRMS (ESI) calcd for [M + H]+ C12H26F2O4P
303.1536, found 303.1540.
Diethyl (1,1-difluoro-4-hydroxy-4-methylpent-2-yn-1-yl)-
phosphonate (10a): colorless oil (357 mg, 98%); 1H NMR (400
MHz, CDCl3) δ 1.28 (t, J = 7.1 Hz, 6H), 1.43 (s, 6H), 4.17−4.26 (m,
4H), 4.65 (bs, 1H); 13C NMR (100 MHz, CDCl3) δ 16.2 (d, J = 5.5
Hz), 30.3, 64.4, 65.7 (d, J = 6.7 Hz), 71.2 (td, J = 33.8, 17.2 Hz), 97.8
(dt, J = 7.6, 6.7 Hz), 108.9 (td, J = 253.2, 229.5 Hz); 19F NMR (376
MHz, CDCl3) δ −97.4 (d, J = 106.9 Hz); 31P NMR (161 MHz,
CDCl3) δ 3.7 (t, J = 107.4 Hz); HRMS (ESI) calcd for [M + H]+
C10H18F2O4P 271.0905, found 271.0908.
calcd for [M + H]+ C16H22F2O5P 363.1173, found 363.1180.
Diethyl (1,1-difluoro-4-hydroxy-4-(4-nitrophenyl)pent-2-yn-1-yl)-
phosphonate (10g): colorless crystals (490 mg, 96%), mp 64−67 °C;
1H NMR (400 MHz, CDCl3) δ 1.3 (dt, J = 10.1, 6.8 Hz, 6H), 1.8 (s,
3H), 4.2 (m, 4H), 4.9 (bs, 1H), 7.8 (d, J = 8.7 Hz, 2H), 8.2 (d, J = 8.7
Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 16.4 (d, J = 3.8 Hz), 32.7,
65.9 (d, J = 6.7 Hz), 69.1, 74.8 (td, J = 33.6, 17.3 Hz), 94.7 (dt, J = 7.6,
6.7 Hz), 109.0 (td, J = 253.1, 229.1 Hz), 123.8, 126.1, 147.7, 150.1; 19F
NMR (376 MHz, CDCl3) δ −98.5 (d, J = 105.5 Hz); 31P NMR (161
MHz, CDCl3) δ 3.6 (t, J = 105.6 Hz); HRMS (ESI) calcd for [M +
H]+ C15H19F2NO6P 378.0918, found 378.0919.
Diethyl (1,1,5,5,5-pentafluoro-4-hydroxy-4-phenylpent-2-yn-1-
1
yl)phosphonate (10h): colorless oil (479 mg, 92%); H NMR (400
MHz, CDCl3) δ 1.33 (dt, J = 10.9, 6.8 Hz, 6H), 4.20−4.2 (m, 4H),
6.16 (s, 1H), 7.38−7.40 (m, 3H), 7.70 (dd, J = 5.5, 3.5 Hz, 2H); 13C
NMR (100 MHz, CDCl3) δ 16.2 (d, J = 5.6 Hz), 66.0 (d, J = 6.7 Hz),
66.1 (d, J = 6.7 Hz), 73.1 (m, 2C), 88.2 (dt, J = 7.6, 6.8 Hz), 108.2 (td,
J = 253.0, 228.9 Hz), 122.5 (q, J = 285.0 Hz), 127.2, 128.4, 129.8,
134.4; 19F NMR (376 MHz, CDCl3) δ −79.6 (s, 3F), −99.5 (d, J =
104.1 Hz, 2F); 31P NMR (161 MHz, CDCl3) δ 2.9 (t, J = 103.7 Hz);
HRMS (ESI) calcd for [M + H]+ C15H17F5O4P 387.0784, found
387.0788.
Diethyl (1,1-difluoro-4-hydroxy-4-isopropyl-5-methylhex-2-yn-1-
1
yl)phosphonate (10b): colorless oil (405 mg, 92%); H NMR (400
MHz, CDCl3) δ 0.94 (d, J = 6.8 Hz, 6H), 0.97 (d, J = 6.8 Hz, 6H),
1.32 (t, J = 6.8 Hz, 6H), 1.92 (sept, J = 6.8 Hz, 2H), 2.89 (bs, 1H),
4.25 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 16.1, 16.4 (d, J = 5.8
Hz), 17.8, 34.3, 65.3 (d, J = 6.7 Hz), 75.1 (td, J = 34.5, 16.3 Hz), 94.9
(dt, J = 7.6, 6.7 Hz), 109.0 (td, J = 252.1, 230.1 Hz); 19F NMR (376
MHz, CDCl3) δ −96.8 (d, J = 108.4 Hz); 31P NMR (161 MHz,
CDCl3) δ 4.1 (t, J = 109.4 Hz); HRMS (ESI) calcd for [M + H]+
C14H26F2O4P 327.1536, found 327.1538.
Diethyl (1,1-difluoro-3-(1-hydroxycyclohexyl)prop-2-yn-1-yl)-
phosphonate (10c): yellow oil (385 mg, 92%); 1H NMR (400
MHz, CDCl3) δ 1.17−1.25 (m, 1H), 1.34 (t, J = 6.8 Hz, 6H), 1.44−
1.68 (m, 9H), 1.89−1.93 (m, 2H), 4.22−4.34 (m, 4H); 13C NMR
(100 MHz, CDCl3) δ 16.4 (d, J = 5.8 Hz), 22.9, 25.0, 38.9, 65.7 (d, J =
6.7 Hz), 68.2, 73.5 (td, J = 33.4, 16.5 Hz), 97.1 (dt, J = 7.6, 6.7 Hz),
109.1 (td, J = 253.1, 230.0 Hz); 19F NMR (376 MHz, CDCl3) δ −97.2
(d, J = 106.9 Hz); 31P NMR (161 MHz, CDCl3) δ 4.0 (t, J = 107.4
Hz); HRMS (ESI) calcd for [M + H]+ C13H22F2O4P 311.1223, found
311.1228.
Diethyl (1,1-difluoroprop −2-yn-1-yl)phosphonate (11a): yellow-
ish oil (92%); 1H NMR (400 MHz, CDCl3) δ 1.26 (t, J = 7.1 Hz, 6H),
3.15 (td, J = 6.1, 3.1 Hz, 1H), 4.14−4.24 (m, 4H); 13C NMR (100
MHz, CDCl3) δ 16.2 (d, J = 5.8 Hz), 65.6 (d, J = 6.7 Hz), 73.0 (td, J =
33.6, 17.3 Hz), 80.7 (dt, J = 7.7, 6.7 Hz), 107.3 (td, J = 253.0, 228.1
Hz); 19F NMR (376 MHz, CDCl3) δ −99.1 (d, J = 104.1 Hz); 31P
NMR (161 MHz, CDCl3) δ 3.5 (t, J = 103.7 Hz); HRMS (ESI) calcd
for [M + H]+ C7H12F2O3P 213.0492, found 213.0494. The observed
data were in accord with those reported in the literature.13a
Diethyl 1,1-difluoro-3-(trimethylsilyl)prop-2-ynylphosphonate
1
(11b): colorless oil (353 mg, 92%); H NMR (CDCl3, 400 MHz) δ
0.21 (s, 9H), 1.37 (dt, J = 7.1, 0.7 Hz, 6H), 4.25−4.34 (m, 4H), 13C
NMR (CDCl3, 100 MHz) δ −0.8, 16.4 (d, J = 4.8 Hz), 65.5 (d, J = 6.6
Hz), 93.2 (td, J = 31.6, 16.3 Hz), 99.2 (dt, J = 5.6 Hz), 108.3 (td, J =
253.1, 228.1 Hz); 19F NMR (CDCl3, 376 MHz) δ −96.7 (d, J = 110.3
Hz); 31P NMR (CDCl3, 161 MHz) δ 3.8 (t, J = 106.2 Hz); HRMS
(ESI) calcd for [M + H]+ C10H20F2O3PSi 285.0882, found 285.0889.
Diethyl (3-(tert-butyldimethylsilyl)-1,1-difluoroprop-2-yn-1-yl)-
Diethyl (1,1-difluoro-3-(1-hydroxycyclohex-2-en-1-yl)prop-2-yn-
1
1
phosphonate (11c): colorless oil (405 mg, 92%); H NMR (CDCl3,
1-yl)phosphonate (10d): yellow oil (383 mg, 92%); H NMR (400
400 MHz) δ 0.13 (s, 6H), 0.92 (s, 9H), 1.34 (td, J = 7.1, 0.7 Hz, 6H),
4.17−4.36 (m, 4H), 13C NMR (CDCl3, 100 MHz) δ −5.3, 16.4 (d, J =
5.6 Hz), 16.5, 25.8, 65.3 (d, J = 6.6 Hz), 94.0 (td, J = 32.1, 16.6 Hz),
98.1 (dt, J = 5.9, 5.6 Hz), 108.3 (td, J = 253.2, 228.1 Hz); 19F NMR
(CDCl3, 376 MHz) δ −96.8 (d, J = 107.2 Hz); 31P NMR (CDCl3, 161
MHz, CDCl3) δ 1.36 (t, J = 6.8 Hz, 6H), 1.72−1.78 (m, 2H), 1.86−
1.92 (m, 1H), 1.99−2.07 (m, 3H), 4.11 (bs, 1H), 4.25−4.33 (m, 4H),
5.71 (dt, J = 9.9, 1.9 Hz, 1H), 5.85 (dt, J = 9.9, 3.7 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 16.4 (d, J = 5.8 Hz), 18.6, 24.6, 36.8, 64.9 (td, J
= 2.0, 1.0 Hz), 65.8 (d, J = 6.7 Hz), 72.9 (td, J = 33.6, 17.3 Hz), 96.7
J
dx.doi.org/10.1021/jo400198a | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
MHz) δ 3.9 (t, J = 107.2 Hz); HRMS (ESI) calcd for [M + H]+
C13H26F2O3PSi 327.1357, found 327.1362.
products. This material is available free of charge via the
Internet at http://pubs.acs.org.
Diethyl (3-(diphenylphosphino)-1,1-difluoroprop-2-yn-1-yl)-
1
phosphonate (11d): yellow oil (492 mg, 92%); H NMR (CDCl3,
AUTHOR INFORMATION
400 MHz) δ 1.29 (td, J = 7.1, 0.8 Hz, 6H), 4.16−4.31 (m, 4H), 7.32−
7.35 (m, 6H), 7.53−7.60 (m, 4H); 13C NMR (CDCl3, 100 MHz) δ
16.4 (d, J = 5.4 Hz), 65.6 (d, J = 6.5 Hz), 92.5 (ddt, J = 35.6, 7.1, 7.0
Hz), 95.8 (td, J = 33.5, 16.8 Hz), 108.8 (td, J = 254.0, 227.3 Hz),
128.9, 129.0, 129.8, 132.8, 133.1; 19F NMR (CDCl3, 376 MHz) δ
−97.3 (dd, J = 106.4, 10.8 Hz); 31P NMR (CDCl3, 161 MHz) δ 3.8
(td, J = 106.4, 3.1 Hz, 1P), −34.9 (td, J = 9.7, 2.8 Hz, 1P); HRMS
(ESI) calcd for [M + H]+ C19H21F2O3P2 397.0934, found 397.0939.
Tetraethyl ((isopropylphosphinediyl)bis(1,1-difluoroprop-2-yne-
3,1-diyl))bis(phosphonate) (11e): yellow oil (415 mg, 62%); 1H
NMR (CDCl3, 400 MHz) δ 1.28 (d, J = 7.0 Hz, 3H), 1.32 (d, J = 7.0
Hz, 3H), 1.38 (t, J = 7.1 Hz, 12H), 2.27 (sept, J = 7.0 Hz, 1H), 4.26−
4.36 (m, 8H), 13C NMR (CDCl3, 100 MHz) δ 16.4 (d, J = 5.4 Hz),
19.3 (d, J = 11.6 Hz), 27.8, 65.7 (d, J = 6.7 Hz), 65.8 (d, J = 6.7 Hz),
86.0−86.5 (m), 95.0 (td, J = 33.1, 16.6 Hz), 108.7 (td, J = 252.0, 231.1
Hz); 19F NMR (CDCl3, 376 MHz) δ −98.2 (dd, J = 106.6, 10.2 Hz);
31P NMR (CDCl3, 161 MHz) δ 3.4 (td, J = 104.7, 3.3 Hz, 2P), −51.5
■
Corresponding Author
*E-mail for R.P.: r.pajkert@jacobs-university.de.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge Dr. Max Braun and Dr. Johannes
Eicher (Solvay Fluor GmbH Hannover, Germany) for generous
gifts of chlorodifluoromethane. We also thank Dr. Bassem
Bassil (Jacobs University Bremen) for the X-ray measurements
and Ms. Anja Muller (Jacobs University Bremen) for measuring
̈
mass spectra.
REFERENCES
(quint t, J = 9.3, 3.1 Hz, 1P); HRMS (ESI) calcd for [M + H]+
C17H28F4O6P3 497.1035, found 497.1037.
■
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Diethyl (1,1-difluorobut-2-yn-1-yl)phosphonate (11g): yellow oil
1
(308 mg, 92%); H NMR (CDCl3, 400 MHz) δ 1.30 (t, J = 7.1 Hz,
6H), 1.91 (td, J = 6.3, 3.2 Hz, 3H), 4.17−4.27 (m, 4H), 13C NMR
(CDCl3, 100 MHz) δ 3.8, 16.3 (d, J = 5.4 Hz), 65.3 (d, J = 6.6 Hz),
69.9 (td, J = 33.2, 17.4 Hz), 90.3 (dt, J = 7.7, 6.9 Hz), 108.9 (td, J =
252.0, 231.1 Hz); 19F NMR (CDCl3, 376 MHz) δ −95.8 (dq, J =
108.8, 6.3 Hz); 31P NMR (CDCl3, 161 MHz) δ 4.1 (t, J = 108.6 Hz);
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Diethyl (1-fluoro-4-hydroxy-5-methylhexa-1,2-dien-1-yl)-
1
phosphonate (9a): yellow oil (310 mg, 88%); H NMR (400 MHz,
CDCl3) δ 0.69 (d, J = 6.9 Hz, 3H), 1.07 (d, J = 6.9 Hz, 3H), 1.24 (dt, J
= 7.1, 2.2 Hz, 6H), 1.96−2.16 (m, 1H), 3.38 (bs, 1H), 4.13−4.23 (m,
4H), 4.28 (dd, J = 2.1, 1.5 Hz, 1H), 6.45 (dd, J = 39.6, 8.6 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 14.9, 16.3 (d, J = 5.9 Hz), 19.9, 31.3,
64.3 (d, J = 6.0 Hz), 81.3, 116.3 (d, J = 26.0 Hz), 159.3 (dd, J = 309.4,
224.7 Hz), 198.6 (d, J = 13.1 Hz); 19F NMR (376 MHz, CDCl3) δ
−103.7 (dd, J = 98.7, 39.1 Hz); 31P NMR (161 MHz, CDCl3) δ 2.5 (d,
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Diethyl (1-fluoro-4-hydroxy-5,5-dimethylhexa-1,2-dien-1-yl)-
1
phosphonate (9b): yellow oil (400 mg, 86%); H NMR (400 MHz,
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J = 3.4 Hz, 1H), 4.00−4.25 (m, 4H), 6.57 (dd, J = 37.8, 8.8 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 16.2 (d, J = 5.5 Hz), 26.1, 36.1, 64.2
(d, J = 5.5 Hz), 84.1 (dd, J = 2.1, 1.5 Hz), 117.8 (d, J = 26.1 Hz), 157.7
(dd, J = 309.3, 225.3 Hz), 199.4 (d, J = 12.7 Hz); 19F NMR (376
MHz, CDCl3) δ −107.1 (dd, J = 98.7, 37.8 Hz); 31P NMR (161 MHz,
CDCl3) δ 2.8 (d, J = 98.9 Hz); HRMS (ESI) calcd for [M + H]+
C12H23FO4P 281.1318, found 281.1322.
ASSOCIATED CONTENT
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* Supporting Information
A CIF file giving X-ray structural data for compound 10g and
figures giving 1H, 13C, 19F, and 31P NMR spectra of the
K
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