An effective synthetic route to ortho-difluoromethyl arylphosphosphonates: Studies on the reactivity of phosphorus- and fluorine-containing functions

Article abstract of DOI:10.1016/j.tet.2011.03.076

Herein, we report a new and convenient methodology for the synthesis of ortho-XCF₂ arylphosphonates via Diels-Alder reaction of selected 1,3-butadienes with XCF₂-≡-P(O)(OEt)₂, followed by the aromatization of the cyclic vi

Full text of DOI:10.1016/j.tet.2011.03.076

Tetrahedron 67 (2011) 3887e3903
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An effective synthetic route to ortho-difluoromethyl arylphosphosphonates:
studies on the reactivity of phosphorus- and fluorine-containing functions
,
b
,
a
c
a,
Sergey N. Tverdomed a , Jacek Kolanowski , Enno Lork , Gerd-Volker Roschenthaler
*
*
€
a School of Engineering and Science, Jacobs University Bremen gGmbH, Campus Ring 1, 28759 Bremen, Germany
b Department of Organic Chemistry, St. Petersburg State Institute of Technology (Technical University), Moskovskii pr. 26, St. Petersburg 190013, Russia
c Institute of Inorganic & Physical Chemistry, University of Bremen, Leobener Strasse, 28359 Bremen, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Herein, we report a new and convenient methodology for the synthesis of ortho-XCF2 arylphosphonates
via DielseAlder reaction of selected 1,3-butadienes with XCF2eheP(O)(OEt)2, followed by the aroma-
tization of the cyclic vinylphosphonates obtained using the KMnO4/Al2O3 system. The reactivity of ortho-
XCF2 arylphosphonates was then examined to give the respective dichlorides that were converted to the
corresponding phosphonic acids, phosphine oxides or a carboxylic acid (upon hydrolysis of the CF2Br
group). When ortho-XCF2 arylphosphonates (X¼Br) were treated with Zn/CuBr and an electrophile, the
dimeric product ArCF]CFAr was isolated only. The lithiation of the CF2H group (X¼H) allowed however
to obtain products of nucleophilic substitution with various electrophiles.
Received 9 February 2011
Received in revised form 19 March 2011
Accepted 22 March 2011
Available online 30 March 2011
Keywords:
Cyclization
Aromatization
Alkynes
Ó 2011 Elsevier Ltd. All rights reserved.
Arylphosphonates
Regioselectivity
1. Introduction
For many years, the participation of organic phosphates in var-
ious enzymatic processes in living systems has been known.1 These
compounds have found practical application in medicine,2 agri-
culture,3 industry4 and organic synthesis.5 The incorporation of
fluorinated substituents into such molecules dramatically alters
their physical, chemical and biological properties.6 Recently, there
has been a growing interest in the synthesis of fluorine-containing
arylphosphonates. Some of these compounds have found wide-
spread use as effective additives in acrylic elastomer compositions
(A),7a as photostabilizers in polymer composites (B)7b or as building
blocks towards the synthesis of catalysts for ethylene polymeriza-
tion (C).7c Moreover, their benzimidazole derivatives show high
biological activity towards AMP-protein kinase, useful for diabetes
prevention (D) (Fig. 1).7d Their applications as herbicides, plant-
growth regulators,7e as well as monomers for synthesis of fluo-
rescent semiconductive polymers,7f for fireproof and crosslinking
agents7g or for photovoltaic cells7h have been also established.
The majority of the known methods for the synthesis of per-
fluoroarylphosphonates is based up on catalytic, thermal or
Fig. 1. Some fluorine-containing arylphosphonates with practical application.
organometallic substitution of an appropriate (perfluoroalkyl)aryl
halide with a phosphorus-containing reagent (Fig. 2). While several
methods have been developed for this purpose, none is available for
the synthesis of arylphosphonates, bearing partially fluorinated
groups, such as CF2H,8a CF2Cl8b,c and CF2Br.8d,e In the case of tri-
fluoromethylated para- or meta-aryl halides, the Michaelis-Becker
reaction with dialkyl phosphites proceeds smoothly in the presence
of Pd(PPh3)4/Et3N9a,b or Pd(OAc)2/i-Pr2NEt.9c To produce poly-
fluorinated aromatic compounds, an example of a non-catalytic
reaction with dialkyl phosphites has been described, however, this
method has met with only limited success due to the very low yield
of the target products.9d Other possible synthetic routes for these
compounds could be the catalytic Arbuzov reaction between aryl
* Corresponding authors. Tel.: þ49 421 200 3267; fax: þ49 421 200 3229 (S.N.T.);
tel.: þ49 421 200 3138; fax: þ49 421 200 3229 (G.-V.R.); e-mail addresses:
s.tverdomed@jacobs-university.de (S.N. Tverdomed), g.roeschenthaler@jacobs-
€
university.de (G.-V. Roschenthaler).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.03.076

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S.N. Tverdomed et al. / Tetrahedron 67 (2011) 3887e3903
Fig. 2. General methods for the preparation of CF3-substituted arylphosphonates.
halides and trialkyl phosphites, that proceeds in the presence of
hand, the synthetic route to other XCF2-acetylenephosphonates
(X¼Br, H) has not been reported beforehand. In this work, we used
the aforementioned method, but with some essential improvements
that included the use of strictly 1 equiv of n-BuLi, the decrease of the
temperature of the addition of lithiated methylphosphonate 1 to the
fluoroalkanoate to ꢀ90 to ꢀ100 ꢁC and azeotropic drying of the crude
product in boiling benzene, that finally produced a mixture of
10a
NiCl2 and Pd(OAc)2/PPh3,10b or under radical initiation,10c with
non-activated aryl halides. With activated aryl halides, bearing
10d
strong electron-withdrawing groups, e.g., eNO2
or eF,10e this
reaction occurs exclusively upon heating, however requiring very
harsh reaction conditions. In some cases, para- or meta-aryl-
phosphonates could be obtained by the oxidation of the corre-
sponding phosphonites using tetracyanoquinodimethane (TCNQ)10f
or NO2.10g
b-ketophosphonate/enol 2:3 in almost quantitative yield (93e98%)
and sufficiently pure to be used in the next step without purification.
When carrying out the dehydration process of this mixture using the
(CF3SO2)2O/i-Pr2NEt system at ꢀ40 ꢁC and extending the reaction
time up to 6e7 h (Method A), alkynephosphonates 4aee were
obtained in excellent yields 82e95% (Scheme 1).
In contrast to para- and meta-derivatives, methods for the prep-
aration of ortho-fluorine-containing arylphosphonates have been
rarely studied and only recently Heinicke et al. demonstrated for the
first time the synthesis of these class of compounds.7c Nevertheless,
this method including ortho-lithiation of 3,5-bis(trifluoromethyl)
arylphosphonates with subsequent migration of the phosphoryl
group in ortho-position to CF3-moiety (anionic phospho-Fries rear-
rangement), allows us to obtain hydroxyphosphonates only and is
limited by the availability of starting materials.7c In our previous
work, we have successfully demonstrated the synthesis of some 1,4-
cyclohexadienyl-1,2-perfluoroalkylphosphonates via DielseAlder
reaction of perfluoroacetylenephosphonates (RFeheP(O)(OEt)2)
bearing only inert and highly electron-withdrawing substituents,
such as CF3 and C2F5. In addition, no other transformations of the
obtained adducts were performed.11 For such reasons, we propose
herein a new and effective method for the synthesis of ortho-XCF2
arylphosphonates, including the formation of six-membered rings
andorthosubstitutionof fluorineandphosphorus functions viadiene
synthesis starting from XCF2-acetylenephosphonates and sub-
sequent aromatization of the corresponding carbocyclic adducts.
Further functionalization of phosphonate and fluorine functions of
these novel arenes upon treatment with some nucleophilic and
metalloorganic reagents was also investigated.
Scheme 1. Synthetic strategy to fluorine-containing alkynephosphonates 4aee.
An important factor influencing the dehydration process of the
ketone/enol 2:3 mixture was the amount of base (i-Pr2NEt). In
general, an increased amount of the base from 3.612f,g to 5.5 equiv
improved theyield and purity of the targeted alkynes 4aee (Table 1).
Acetylenes 4aee could be also successfully obtained via the de-
hydration of enols 3aee using P2O5/Et3N in CH2Cl2 at ꢀ20 ꢁC
(Method B). However, the best results were only achieved using
a large excess of the base (up to 6.5 equiv for alkyne 4d).
2. Results and discussion
A
convenient method for the synthesis of some per-
As is already known, the construction of six-membered carbo-
cyclic rings in the classical form of the DielseAlder reaction could
be realized according to the following scheme: (dien-
eedonor)e(acetyleneeacceptor).13 Some cycloadditions of alkynes
bearing perfluoroalkyl14 or dialkyl phosphonate15 substituents,
with 1,3-alkadienes were previously described in the literature.
However, there is only one example involving alkynes possessing
difluoromethylene, halodifluoromethylene functions14d,e and both
perfluoroalkyl- and phosphonate11 groups in such reactions.
fluoroacetylenephosphonates with CF3 and C2F5 substituents has
been reported before based on the lithiation of dialkyl methyl-
phosphonate using n-BuLi or LDA and subsequent reaction of the
pregenerated LiCH2P(O)(OAlk)2 with fluorinated ethyl or methyl
alkanoates to give thecorresponding ketoeenol mixtures,12aef which
were dehydrated subsequently.12f,g A similar methodology was
reported for preparing the ClCF2-acetylenephosphonate 4c, however
without full characterization of the targeted product.12e On the other

S.N. Tverdomed et al. / Tetrahedron 67 (2011) 3887e3903
3889
Table 1
Generally, we observed that the use of higher temperatures (up
to 160e165 ꢁC) and reduced reaction time (up to 2e2.5 h) gave
better results (Table 3). On the other hand, the temperature ele-
vation during the diene synthesis was limited by the thermal
stability of the final adducts 5cee, 6e and 7e that underwent retro-
DielseAlder reaction above 180 ꢁC. This process was additionally
monitored by the 31P and 19F NMR for the system (alkyne 4d)/
(adduct 5d). It was found that at temperatures up to 170 ꢁC adduct
5d is stable. However, upon heating the reaction mixture above
180 ꢁC, the retro-DielseAlder reaction occurred (Table 3).
Synthesis of fluorine-containing alkynephosphonates through the dehydration of
a b-ketophosphonate/enol mixture (2:3)
Substrate ratioa
(2:3, mol %)
2a:3a (81:19)f
2b:3b (69:31)
2c:3c (93:7)g
2d:3d (94:6)
2e:3e (93:7)
X
i-Pr2NEtb
(equiv)
Et3Nc (equiv)
Yieldd (%)
Bpe (ꢁC)
F
4.0
4.0
5.0
5.5
4.5
4.5
4.5
6.0
6.5
5.0
95/70 (4a)
92/67 (4b)
85/65 (4c)
82/60 (4d)
88/68 (4e)
35
41
56
64
71
CF3
Cl
Br
H
a
According to 31P, 19F and 1H NMR analysis in CDCl3.
b
c
d
e
f
For (CF3SO2)2O (1 equiv)/i-Pr2NEt (x equiv) system, Method A.
For (1 equiv) P2O5/Et3N (x equiv) system, Method B.
Isolated yield, Method A/Method B.
At 0.1 mmHg.
Table 3
Screening Diels- and retro-DielseAlder reaction conditions for 4de5d
86:14 (mol %).12e
Entry
Temperature (ꢁC)
Duration (h)
Composition of
g
78:22 (mol %).12e
reaction mixturea (% mol)
4d
5d
Otherb
Similarly to perfluoroacetylenephosphonates 4aeb difluorinated
alkynephosphonates 4cee reacted also smoothly with donor 1,3-
alkadienes, such as 2,3-dimethyl-1,3-butadiene or isoprene, and
formed the corresponding cyclohexo-1,4-dienyl-1-phosphonates
5cee, 6e and 7e in excellent yields (90e98%) (Scheme 2).
1
2
3
4
5
6
120
140
160
180
200
235
10
2
5
2
1.5
0.5
0
0
0
15
55
73
80
96
92
77
32
0
20
4
8
8
13
27
a
Due to 31P NMR data.
b
Decomposition products of 4d (31P NMR
d 3.6, 8.1, 32.5, 54.5) and a mixture of
isomeric 1,3-cyclohexadienes (31P NMR
d
w14.9e15.1).
The regioselectivity of such DielseAlder cycloadditions was in-
vestigated by reacting diethyl 3,3-difluoroprop-1-ynylphosphonate
4e with unsymmetrical 2-substituted-1,3-dienes, such as isoprene.
This reaction proceeded under harsh conditions (Table 2) giving
a
mixture of 4-methyl- and 5-methyl-substituted (2-difluor-
ocyclohexa-1,4-dien-1-yl) phosphonates 6e and 7e (Scheme 3).
Scheme 2. Synthesis of carbocyclic phosphonates 5aee via DielseAlder reaction and
their aromatization to 8aee.
This reaction was conducted at 110e160 ꢁC for 1.5e3 h using
10e15 mol % excess of 1,3-alkadiene, anhydrous toluene as solvent
and 0.001 mol % of BHT as polymerization inhibitor. We also ob-
served a significant reactivity decrease of the halodifluoroalkyne
phosphonates 4c,d (X¼Cl, Br) towards 2,3-dimethyl-1,3-butadiene,
compared to their perfluoroalkyl counterparts 4a,b (X¼F, CF3).
Alkynephosphonate 4e (X¼H) was even a less active dienophile
and fully reacted with 15 mol % excess of 2,3-dimethyl-1,3-buta-
diene for 2.5 h at 150 ꢁC and with isoprene at 160 ꢁC for 3 h, re-
spectively (Table 2). This could be best explained by the weaker
electron-withdrawing effect of CF2X groups of 4c,d (X¼Cl, Br) and
4e (X¼H) in comparison to perfluoroacetylenephosphonates 4a,b
(X¼F, CF3).
Scheme 3. Regioselectivity of DielseAlder reactions: synthesis of adducts 6e, 7e and
their aromatization to 9e, 10e.
The predominant formation of isomer 6e corresponded to the
polarization of the parent compounds16 and provided evidence for
the electronic control of the reaction. The ratio of regioisomers (6e
and 7e), according to 31P, 19F and 1H NMR spectra, was found to be
59:41 mol %, respectively. It should be however noted, that isomers
6e and 7e cannot be resolved using physical methods. Hence, their
structure was established, taking into account the characteristic
patterns of C3, C6 and C4, C5 signals for regioisomers 6e and 7e in
the 13C NMR spectra and respective data of previously reported
examples.11
It is known, that cyclohexa-1,4-dienes serve as convenient
synthons in the preparation of the corresponding substituted aro-
matic systems.17a In some cases, where the elimination of CO2,17b,c
CO17d,e or C2H417f is possible, the aromatization usually occurs upon
heating. Otherwise, for aromatization the use of oxidizing14a,18aec
Table 2
Fluorine-containing alkynylphosphonates in DielseAlder reaction: synthesis of
carbocyclic adducts 5aee
Cycloadduct(s) Reaction conditions
Temperature (ꢁC) Duration (h) 1,3-Dienea (equiv)
Yieldb (%)
5a
5b
5c
5d
5e
110
115
125
140
150
0.5
0.5
1.5
2.0
2.5
3.0
1.05
1.1
1.1
1.15
1.15
1.15
97
95
98
96
93
90
6eþ7e (59:41)c 160
a
For alkyne 4aee (1 equiv):1,3-alkadiene system (x equiv).
Isolated yields.
b
c
Ratio of isomers (mol %), according to 31P, 19F and 1H NMR data.

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S.N. Tverdomed et al. / Tetrahedron 67 (2011) 3887e3903
agents and catalytic dehydrohalogenation18d,e is required. In this
work, KMnO4/Al2O3 system was used for the oxidative de-
hydrogenation of novel XCF2-containing cyclohexa-1,4-dien-
ylphosphonates 5aee, 6e and 7e to obtain the ortho-XCF2
arylphosphonates 8aee, 9e and 10e (Schemes 2 and 3). The best
results were obtained upon mixing the substrates in dry acetone
under an inert atmosphere at ꢀ20 to 5 ꢁC. The reagent was added in
portions (0.1 equiv each) until the complete disappearance of sig-
nals of carbocyclic phosphonates 5aee, 6e and 7e at w15 ppm in
the 31P spectra, and simultaneous appearance of new ones at
17e18 ppm, attributable to arylphosphonates 8aee, 9e and 10e.
Our studies have shown that an excess of potassium permanganate
was also necessary. The temperature and the reaction time required
for the complete conversion of substrates 5aee, 6e and 7e, were
depending on the structure of adducts and on the electron-with-
drawing properties of CF2X groups (Table 4). In general, 4,5-di-
methyl-1,2-disubstituted cyclohexadienes 5aee show markedly
higher susceptibility for aromatization compared with 4- or 5-
metyl derivatives 6e and 7e. The position of substituents had little
effect on the aromatization process and similar reactivity has been
observed for isomers 6e and 7e. During the reaction course, the
product ratio 9e:10e (61:39 mol %) did not change and was similar
to that of the starting mixture 6e:7e (59:41 mol %).
1,4-quinone, chromatographic methods of isolation were essential
for isolation and purification of product 8a, preventing us from
using this system on
a preparative scale. Taking N-chlor-
osuccinimide (NCS) for the preparation of 8a was also ineffective as
a result of a competitive double bond isomerization in the carbo-
cyclic framework of 5a and their subsequent polychlorination.
Table 5
Other systems used for dehydrogenation of carbocyclic adduct 5a to form arene 8a
Entry
Reagents, aromatization conditions and
Yield of 8ab (%)
purification methoda
1
2
3
4
DDQ (1.5 equiv), CH2Cl2, 4 h, 25 ꢁC,
flash column chromatography.
p-Chloranil (2.0 equiv), toluene, 12 h, 100 ꢁC,
column chromatography.
60
50
28
15
NCS (1.1 equiv), methyl acetate, 5 h, 90 ꢁC,
column chromatography.
Activated MnO2 (25.0 equiv),
1,4-dioxane, 24 h, 101 ꢁC,
column chromatography.
5
Powdered KOH (2.0 equiv), 1,4-dioxane,
24 hefew min, 5e101 ꢁC.
0
a
Based on known literature procedures14a,c,18aee and per 1 equiv of 5a.
Isolated yield of 8a with ꢂ95 mol % purity.
b
In addition, product 8a was isolated after column chromatog-
Table 4
raphy in 28% yield (Table 5, entry 3). Similarly, activated MnO2
showed low activity and selectivity in the dehydration of 5a to 8a
resulting in a conversion less than 50 mol % of 5a. Hence, aryl-
phosphonate 8a was isolated with only 15% yield (Table 5, entry 4).
An approach to dehydrate cyclohexa-1,4-diene phosphonate 5a
with a suspension of KOH in 1,4-dioxane, did not lead to the desired
product 8a. Monitoring the reaction mixture by 31P and 19F NMR
showed no significant difference in spectral pattern upon mixing at
5 ꢁC to ambient temperature within 24 h although, heating the KOH
suspension to 50 ꢁC led to noticeable decomposition of substrate 5a
that proceeded fully within few minutes in refluxing 1,4-dioxane
(not even traces of 8a were detected) (Table 5, entry 5). Summa-
rizing the results of testing various oxidizingedehydration systems
(Tables 4 and 5) it could be deduced, that for the aromatization of
cyclohexa-1,4-diene phosphonates 5aee, 6e and 7e, which is a key
step in the synthesis of the corresponding ortho-XCF2 aryl-
phosphonates 8aee, 9e and 10e, the use of KMnO4 passivated with
dehydrated Al2O3 gave optimum results. In contrast to other re-
agents checked, KMnO4/Al2O3 in dry acetone is a mild and very
selective oxidizing agent for fluorine and phosphorus-containing
carbocycles 5aee, 6e and 7e, even at low temperatures.
In the next part of this work, we demonstrate the synthetic
utility of novel ortho-XCF2 arylphosphonates 8aee, 9e and 10e by
the modification and functionalization of phosphorus and fluorine-
containing moieties to access various phosphorus-containing are-
nes, which were not previously available. The functionalization of
a phosphonate group could be best achieved by the replacement of
the alkoxy groups with halogens19a, e.g., chlorine or bromine, in the
first step, followed by the addition of a nucleophile. Dichlor-
ophosphonates are usually obtained by treating the appropriate
The synthesis of ortho-CF2 arylphosphonates by aromatization of the corresponding
carbocyclic adducts 5aee, 6e and 7e
Arene(s)
Aromatization conditions
Yieldb (%)
a
KMnO4 (equiv) Duration (h) Temperature (ꢁC)
8a
8b
8c
8d
8e
2.0
2.0
2.05
2.05
2.1
3.0
3.5
5.0
6.0
6.5
ꢀ20
ꢀ15
ꢀ5
0
0
15
96
94
87
85
80
60
9eþ10e (61:39)c 2.6
10.0
a
Per potassium permanganate for cyclohexa-1,4-diene 5aee, 6e and 7e system
(1 equiv)/KMnO4/Al2O3 (1:1 weight ratio).
b
Isolated yield.
c
Ratio of isomers (mol %), according to 31P, 19F and 1H NMR data.
We also found, that an increased electron-withdrawing ability
of CF2X groups influenced the efficiency and selectivity of the
aromatization of cyclohexadienes 5aee. As summarized in Table 4,
in the case of X¼F and CF3 (5a,b) the appropriate ortho-fluorinated
arylphosphonates 8a,b were produced in almost quantitative yields
when using a stoichiometric amount of the oxidizing agent (Table
4). Due to the lower reactivity of 5c,d (X¼Cl, Br), compounds 8c,d
were obtained in lower yields even after temperature elevation and
reaction time extension (Table 4). For compound 5e with X¼H, the
ability for the aromatization and selectivity of the process was
significantly lower as shown by an 80% loss of yield for benzene 8e
by the need to use a large excess of KMnO4 (Table 4). It should be
however noted, that using KMnO4 for aromatization without Al2O3,
lower yields of the desired products (30e40%), higher consumption
of KMnO4 (up to 3.5 equiv) and the formation of larger amounts of
resinous by-products were observed. The effectiveness of aroma-
tization for 5a was also examined with other reagents using dif-
ferent systems known from the literature for other carbocyclic
systems, such as DDQ in dichloromethane,18a 2,3,4,5-tetra-
chlorobenzo-1,4-quinone in toluene,14a activated MnO2 in 1,4-
dioxane,18c NCS in methylacetate18e and KOH in 1,4-dioxane.14c The
best results (Table 5) were obtained using DDQ and 2,3,5,6-tetra-
chloro-p-benzoquinone (p-chloranil), giving rise to arene 8a in
60e50% yield (Table 5, entries 1 and 2). However due to the
formation of by-products and corresponding hydroquinones,
obtained from the reduction of DDQ and 2,3,4,5-tetrachlorobenzo-
phosphonic or thiophosphonic acid and their alkyl esters with
19e
SOCl2,19b,c oxalyl chloride19d and seldom with PCl5
in the pre-
sence (or absence) of activators, such as DMF, pyridine or
N-formylpiperidine.
During our investigations we observed, that diethyl aryl-
phosphonates 8aed underwent chlorination easily using
a PCl5ePOCl3 mixture forming the corresponding ortho-XCF2 aryl-
phosphonic dichlorides 11aed in good to excellent yields (85e94%)
(Scheme 4). The optimal reaction conditions were achieved with
the ratio of 2.3 equiv PCl5, 2.1 equiv POCl3 and 1.0 equiv of 8aed
(Method C).

S.N. Tverdomed et al. / Tetrahedron 67 (2011) 3887e3903
3891
and 11c:11c0:11c00 with 70:15:15 mol %, with no change in the ratio
even after repeated fractional distillation. However, the significant
difference in the 1H, 31P, 19F NMR and MS characteristics for 11a,
11a0 and 11a00 (as well as for 11c, 11c0 and 11c00) allowed us to de-
termine the structure of these by-products.
In the 1H NMR spectra of 11a0,c0 and 11a00,c00 typical singlets19f of
o-AreCH2Cl and o-AreCH3 at w4.7 and w2.6 ppm and doublets
4
from protons HA and HB at w7.75 ppm with JHP w8.8 Hz and
w8.3 ppm with 3JHP w20.5 Hz for isomers 11a0,c0 and at w7.9 ppm
(4JHP w8.8 Hz) and w8.2 ppm (3JHP w20.5 Hz) for isomers 11a00,c00
could be distinguished. In the MS spectra, peaks from molecular
ions from [M]þ of 11a0þ11a00 (m/e¼324) and 11c0þ11c00 (m/e¼340)
were also observed. It should be noted that this phenomenon has
not been previously described in the literature and the mechanism
for their formation is not completely clear.
Reactions of phosphorus dichlorides with various nucleophiles
allowed us to modify the phosphorus function.20a Metalloorganic
reagents, such as lithioorganic20b,c or Grignard reagents20d,e offer an
broad access to phosphine oxides21a or tertiary phosphines,21b,c that
serve as valuable ligands in metallocomplex synthesis.21def At the
same time, these transformations using fluorinated organometallic
reagents have never been explored. As a part of our studies designed
to examine the utility of ortho-XCF2 arylphosphonic dichlorides, we
have found that compounds 11aed reacted smoothly in a solution of
dry THF with 2.1 equiv of Grignard reagent, e.g., methylmagnesium
bromide, at ꢀ30 ꢁC to give appropriate ortho-XCF2 phenyl(dimethyl)-
phosphine oxides 12aed in good yields (51e78%) (Scheme 5).
Scheme 4. Chlorination of diethyl phosphonates 8aee with PCl5ePOCl3: synthesis of
arylphosphonic dichlorides 11aed.
Phosphonic dichlorides 11aed could also be produced via direct
chlorination of cyclohexa-1,4-dienylphosphonates 5aed (1.0 equiv)
with phosphorus pentachloride (3.5 equiv) in the presence of
phosphorus oxychloride (3.0 equiv) (Method D). However for this
process rather harsh reaction conditions were required (10e12 h at
106 ꢁC) to give arenes 11aed with significantly lower yield (Table 6,
entries 1e4).
Table 6
The synthesis of ortho-XCF2 arylphosphonic dichlorides from phosphonates 8aee
with PCl5ePOCl3
Entry
Starting
arylphosphonate
Product
Yielda (%)
Method C
Bpb (ꢁC)
Method Dc
1
2
3
4
5
8a or 5a
8b or 5b
8c or 5c
8d or 5d
8e
11a
11b
11c
11d
11c
94
93
87
85
25
40
32
37
30
d
99
108
135
142
135
a
Isolated yield with ꢂ95% purity.
At 0.1 mmHg.
After three distillations.
b
c
Chlorination of phosphonates 8e, 9e and 10e with PCl5/POCl3
resulted in the chlorination of the CF2H moiety, instead of the
formation of the expected phosphonic dichlorides. In the case of 8e,
we isolated product 11c in 25% yield as the sole product (Scheme 4,
Table 6, entry 5). The treatment of isomeric arylphosphonates
9eþ10e with PCl5/POCl3 led to the decomposition of the HCF2 group
and to the formation of a non-separable mixture of chlorinated
products. Interestingly, upon treatment of 8a and 8c with PCl5/
POCl3 (Method D) in the presence of a small amount of FeCl3
Scheme 5. Reaction of arylphosphonic dichlorides 11aed with metallorganic re-
agents: synthesis of phosphine oxides 12aed and phosphinic acid 13.
Screening of the reaction conditions and spectral analysis of the
crude product showed no significant influence of the CF2X-function
onto the reactivity of the dichlorophosphonic group. Similarly, re-
actions with 11aec were carried out under standard conditions and
gave similar results, namely high regioselectivity and comparable
yields of phosphine oxides 12aec (75, 73 and 78%). However, in the
case of 11d this reaction did not take place selectively and oligo-
meric autocondensated by-products (approx. 15%) were obtained
(<0.01%), a monochlorination of a-methyl groups of the benzene
ring occurred (Fig. 3) to give compounds 11a0þ11a00 and 11c0þ11c00
as a mixture of regioisomers in a 1:1 (mol) ratio with 20% and 15%
yield, respectively, according to the 1H NMR data. The isolation of
11a0, 11a00 and 11c0, 11c00, as well as the separation from the major
product 11a and 11c, was not possible due to formation of a three-
component azeotropic system 11a:11a0:11a00 with 60:20:20 mol %
and determined as broad multiplets from d
52 to 61 in the 31P and at
ꢀ44 to ꢀ46 in 19F NMR spectra. In the mass spectrum a group of
molecular ions with m/e¼600e850 was also observed. These olig-
omeric by-products contained some fragments of substrate 11d
(ortho-xylene, phosphonate and CF2Br units) what could be de-
duced from their subsequent defragmentation probably explaining
the ability of the CF2Br group to form organometallic inter-
mediates22a,b and to undergo various coupling reactions22c as well
as hydrolysis (Scheme 6). As a result, phosphine oxide 12d was
isolated with only moderate 51% yield. To examine the possibility of
selective substitution at phosphorus with C-nucleophiles in CF2Br-
containing compounds 11d, the reaction with poor nucleophilic
Fig. 3.
a-Chloromethyl-containing by-products from the reaction of arylphosphonates
11a, 11c with PCl5ePOCl3 in the presence of FeCl3.

3892
S.N. Tverdomed et al. / Tetrahedron 67 (2011) 3887e3903
and highly selective species [C2F5Li],22d generated in situ from n-
BuLi and C2F5H, was carried out. This process was conducted in
anhydrous THF at ꢀ78 ꢁC using 1.1, 2.3 or 3.2 equiv of [C2F5Li], prior
to hydrolysis with 10% HCl. Interestingly, in all cases, a sole product
of monosubstitution at phosphorus atom of 11d was formed
(Scheme 5). This process occurred smoothly, without any formation
of other by-products and allowed us to obtain arylphosphonic acid
13 in 85% yield (Scheme 5). Substitution of chlorine proceeded
probably via an additioneelimination mechanism22e already
known for phosphonic dichlorides (Scheme 5) however its high
selectivity upon treatment with [C2F5Li] could be best explained by
the steric factors of CF2Br and C2F5 groups. To the best of our
knowledge, only one previous example of an effective introduction
of two isopropyl groups onto phosphorus in AreP(O)Cl2 has been
described.22f In the case of [C2F5Li], low nucleophilicity of the
carbanion and enhanced electrophilicity after addition of a first
equivalent of C2F5Li and elimination of Clꢀ prevented the phos-
phorus centre from subsequent addition due to the presence of the
sterically demanding CF2Br group in ortho-position. In a similar
manner, the stability of this moiety upon the reaction conditions
could be explained. Nevertheless, the spectral analysis revealed
interesting features. In the 1H NMR spectra of compounds 12aed,
a characteristic doublet of triplets (quartets) was detected from
substitution at phosphorus. This reaction usually takes place under
mild conditions23a and has found widespread application due to
the fact that the products of hydrolysisdphosphonic acidsdplay an
important role in modern medicine,23c agriculture23d and tech-
nology.23e On the other hand, perfluoroalkyl groups attached to the
aromatic ring undergo hydrolysis only if an acidic proton (e.g., OH,
SH and NH) is located in an ortho-position to fluorinated sub-
stituent.23f,g Moreover, there is a lack of literature protocols con-
sidering the hydrolysis of XCF2-aromatic compounds, where X¼Cl
or Br. For these reasons, hydrolysis of ortho-XCF2 arylphosphonic
dichlorides 11aed has been carried out under basic (5% aq NaOH),
acidic (10% HCl) and neutral conditions (Scheme 6).
For compounds 11aed, aqueous acetonitrile (70e90%) was used.
The full conversion of starting materials was determined by the
complete homogenization of the reaction mixture. Results of these
studies have shown that perfluoro-substituted phosphonic dichlor-
ides 11a,b easily and selectively undergo hydrolysis at pH 1e12 with
the formation of the corresponding ortho-XCF2 arylphosphonic acids
14a,b in good yields (75e80%) (Scheme 6). The prolongated reaction
time was however necessary for 11b due to its poorer solubility
compared to 11a, and for 11a,b under acidic conditions in contrast to
the reaction under basic conditions, which did not provide to the loss
of yield. Furthermore, no decomposition of difluoroalkyl groups has
occurred. In contrast, CF2Cl (11c) and particularly CF2Br (11d) groups
proved to be moisture and pH sensitive. Hence, under basic condi-
tions the hydrolysis of P(O)Cl2 groups for 11c,d proceeded smoothly
(Table 7), simultaneously with the hydrolysis of CF2X-moiety, which
at pH¼12 run quantitatively within 0.5 h and produced 4,5-di-
methyl-2-phosphonobenzoic acid 15 in 95% yield (Scheme 6).
At pH ꢃ7, the CF2Cl group was quite resistant to water. When 10%
HCl/CH3CN was used, the hydrolysis of the dichlorophosphonic group
of 11c proceeded within 2.5 h and the corresponding phosphonic acid
14c was isolated in 85% yield (Table 7). In addition, our efforts showed
thatphosphonicacid 14d cannot be obtained upon selective hydrolysis
of 11d. Therefore, compound 14d was synthesized using TMSeBr.24 In
the first step diethyl phosphonate 8d was converted into the corre-
sponding silyl phosphonic ester 16, followed by methanolysis giving
the desired acid in a 65% overall yield (Scheme 6). The above-
mentioned experiments showed that the ability of the CF2X-moiety to
undergo hydrolysis decreases in the order: CF2Br>CF2Cl>>CF3zC2F5.
Mechanistically, the key step in the hydrolysis of the CF2X group
should be the formation of intermediate 14dIV,25a that spontaneously
undergoes defragmentationwith the elimination of HF to give 14dV25b
and after the subsequent additioneelimination and protonation of
14dVI provides the acid 15 (Fig. 5).
2
CH3eP(O) group at 2.0 ppm with JHP w14 Hz and 6JHF w2 Hz.
Scheme 6. Hydrolysis of arylphosphonic dichlorides 11aed: synthesis of phosphonic
acids 14aed.
However the mechanism of the [CF2OH] formation of the in-
termediate 14dIV, as well as hydrolysis of CF2X-containing com-
pounds, is not yet clear.25c For some vinyl difluoromethyl bromides,
the mechanism includes 1,4-dehydrobromination (CF2Xe]e/
CF2]e]) with the formation of an intermediate of quinoid type,
prior to the addition of water to the gem-difluorovinyl derivative has
been reported.25d Although for compound 14d this explanation
seems to be rather weak since it requires the dehydration of a ben-
zene ring in the 6-position using 5% aq NaOH with the destruction of
aromaticity, that is, thermodynamically unfavourable and was not
confirmed experimentally. From this perspective, we propose an
alternative route involving a single electron transfer chain process
(SRN1) that has been already proved for some perfluoroalkyl iodid-
es25e and is in agreement with our experimental data (Fig. 5).
As well as the reactivity in 1994 Burton et al. for the first time
reported the synthesis of organometallic reagents from aromatic-
CF2Br, such as CF2eCd, CF2eCdeCF2 and CF2-Cu.26a Later, other
reagents with In,26b Zn,26c and Mg26d were also obtained and their
further reactions with electrophiles were investigated.26bed An
interesting example of the application of Zn, Cu and Al derivates of
para-bis[CF2Br(Cl)] benzene has been described, which includes
In the 13C NMR, a doublet of triplets (quartets) for methyl group
carbons directly attached to phosphorus was observed at
1
5
w18.5 ppm with JCP w75 Hz and JCF w5 Hz. Similar coupling
constants (6JFH w2 Hz) were recorded in multiplets from 12aed in
the 19F NMR spectra. The existence of spinespin couplings between
proton and carbon nuclei of MeeP and fluorines from the AreXCF2
moiety and anomalous large coupling constants (6JHF, 5JCF) indicated
the through-space character of these interactions. This hypothesis
was confirmed by the analysis of the 19F NMR spectrum of com-
pound 13 (Fig. 4). As presented, the CF2Br group connected to
phosphorus is detected as a doublet of triplets at ꢀ124.6 ppm with
2JFP 88.3 Hz what is in agreement with the 31P NMR data (
d: t, 24.4,
2JPF¼88.3 Hz), and 6JFF¼13.8 Hz. On the other hand, the ortho-BrCF2
group is observed as a triplet at ꢀ42.8 ppm with a coupling constant
6
4
of JFF¼13.8 Hz while JFP from phosphorus is not observed. This
phenomenon confirms strongly intramolecular electronespatial
interactions in structures of 12aed,13 attracting special attention to
further studies on ortho-XCF2 arylphosphonic compounds.
Another synthetic modification of the dichlorophosphonic
moiety, is its hydrolysis,23a,b also considered as a nucleophilic

S.N. Tverdomed et al. / Tetrahedron 67 (2011) 3887e3903
3893
Fig. 4. 19F NMR spectrum of 2-[bromo(difluoro)methyl]-4,5-dimethyl phenyl(pentafluoroethyl)phosphinic acid 13.
Table 7
Screening the reaction conditions for the hydrolysis of arylphosphonic dichlorides
11aed at pH 1e12
Entry
Starting
phosphonic
dichloride
Spectral yield of
Target
product
target product by (conditions) (%)a
Basicb
Acidicc
Neutrald
1
2
3
4
11a
11b
11c
11d
98
100
0
95
97
96
98
14a
14b
14c
14d
95
90
0
10e
w5f
a
Due to 31P and 19F NMR analysis.
5% aq NaOHeCH3CN (30%:70%), rt, 0.5 h.
10% aq HCleCH3CN (20%:80%), rt, 2.5 h.
H2OeCH3CN (10%:90%), rt, 1 h.
In the presence of 70 mol % of 15.
In the presence of 90 mol % of 15.
b
c
d
e
f
Scheme 7. Synthesis of Zn- and Cu-derivatives of 8d: reaction pathway to dimers 17
and 18.
This reaction was observed to proceed exothermically for 3 h and
gave additionally small amounts (w4 mol %) of CF2H-phosphonate
8e, as a result of the hydrolysis of organozinc reagents 8dI and 8dII26a
2
according to 19F NMR (doublet at ꢀ105.4 ppm with JFH 55.6 Hz).
Reagents 8dI and 8dII were identified in a DMF solution by 19F NMR
Fig. 5. Probable mechanism for hydrolysis of CF2Br-moiety of arylphosphonic acid 14d.
spectroscopyassinglets at
d
ꢀ92.2 andsinglet at ꢀ91.7in a 3:1 ratio,
d
in agreement with other analogues.26a,27c As it has been known,
difluoromethylene zinc bromides form stable solutions28a and their
dimerization occur only under harsh conditions.28b However, in the
case of 8d and Zn, immediately after the completion of reaction, the
19Fand 31P NMR analysis showed the existence of dimer 17 (dF ꢀ95.3,
dF 22.8)andm/e¼582for[M]þ atMS(EI)in10%NMRyield(Scheme7).
The dimer 17 ispossibly formed as a by-product, simultaneously with
8dI and 8dII resulting from the thermal decomposition of 8dI to give
the difluoromethyl radical27c 8dIII, which subsequently dimerizes to
form 17d. This synchronic route could be best explained by the ob-
servation that the filtrated solution of 8dI, 8dII and 17 may be stored
without significant changes up to 24 h at rt while the ratio of 8dI, 8dII
and 17 (3:1:0.5) remains unchanged. The obtained organozinc
di-, tri- and tetramerization to give industrially important cyclo-
phanes, macrocyclic systems formed from AreCF2eCF2eAr uni-
ts.27a,b However, it should be noted that these reactions proceed
often with low selectivity and yield. There are also no examples of
aromatic CF2Br(Cl)-arene bearing other EWG-groups, such as car-
bonyl- or phosphonic-substituents in the literature. To prove the
reactivity of the CF2Br-benzyl moiety in the presence of an ortho-
phosphonic substituent, diethyl 2-[bromo(difluoro)methyl]-4,5-
dimethylphenylphosphonate 8d was studied in the reaction with
acid-washed zinc to produce the corresponding organozinc re-
agent. This experiment showed that arylphosphonate 8d gave
a mixture of CF2ZnBr 8dI and AreCF2ZnCF2eAr 8dII at rt in dry DMF
with an 80% overall yield (Scheme 7).

3894
S.N. Tverdomed et al. / Tetrahedron 67 (2011) 3887e3903
reagents in their active form26a 8dI, proved to be very weak nucleo-
philes. Their reactivity was examined in reactions with MeI, allyl
bromide, benzaldehyde and trimethylsilyl chloride at temperatures
ranging from 20 to 100 ꢁC. Only allyl bromide and TMSeCl gave the
desired products of substitution (dF ꢀ91.4 and ꢀ85) in traces
(3e5 mol %). This decreased nucleophilicity of the organozinc
derivative26a,b could be best explained by the strong electron-with-
drawing properties of the dialkylphosphonic moiety and two fluo-
rine atoms directly connected to the carboanionic centre. Even lower
reactivity with electrophiles has been observed for the organocopper
reagent (CF2Cu/ZnBr2) 8dIV, obtained by the addition of Cu(I)Br to
the solution of (8dIþ8dII) at ꢀ30 ꢁC.26a Although, at this temperature
in the presence or absence of an electrophile (allylbromide, benzal-
dehyde or trimethylsilyl chloride), a fast and spontaneous di-
merization of the organocopper reagent occurred with the formation
of difluorstilbene 18 in very good 80% NMR yield (Scheme 7).
Moreover, the 19F, 31P and 1H NMR analysis of the crude product did
not show any substitution products with the concentration of the
dimer 17 not changing (w10%). This means that the second electron
chain decomposition of 8dIV with the predominant formation of
fluorocarbene27c 8dV occurred and finally gave the conjugated 18,
which was isolatedin 71% yield(Scheme 7). Probably, thesteric factor
of ortho-phosphonate groups played also an important role in the
dimerization, promoting more the compact, coplanar trans-stilbene
18 (Fig. 6). A similar dimerization process of aromatic CF2-orga-
nocuprates has never been reported and was only mentioned in
the Zn-mediated preparation of cyclophanes.28c The structure of
difluorostilbene 18 was determined by the 1H, 31P, 19F, 13C NMR,
MS(EI), HRMS and additionally confirmed by X-rayanalysis (Fig. 6).29
Another method for the functionalization of the CF2-moiety
included the lithiation of HCF2 group with the formation of the
difluoromethyl carbanion and its further interactions with various
electrophilic reagents.30a To the best of our knowledge, in a series of
difluoromethyl arenes this process is generally not known and only
few trials can be found in the literature. In these procedures, n-BuLi
was used as a base however due to the low acidity of AreCF2H
moiety, the reaction proceeded only via nucleophilic substitution of
aromatic halogen30b or the lithiation was observed to occur to the
para-position of benzene ring.30c Here we first demonstrated the
synthetic utility of ortho-CF2H groups of arylphosphonate 8e, 9e
and 10e in reactions with various strong organic bases and the
application of in situ generated difluorocarbanions in reactions
with some electrophiles. During our studies we found that ortho-
fluorine-containing arylphosphonate 8e, 9e and 10e could be easily
deprotonated by t-BuLi in THF to give the corresponding difluor-
ocarbanions 8eI, 9eI and 10eI (Scheme 8). The thermal stability of
8eI, 9eIþ10eI was tested by rapid hydrolysis of solutions of 8eI, 9eI
and 10eI with 10% HCl at ꢀ70, ꢀ40, 0 and 15 ꢁC and subsequent
analysis of the reaction mixture by the 19F and 31P NMR. These
experiments have shown that carbanions 8eI, 9eI and 10eI are
stable at ambient temperature up to 0e5 ꢁC and gave only starting
8e, 9e and 10e after hydrolysis. Although at 10e15 ꢁC, these carb-
anions decomposed with the elimination of Fꢀ, the phosphonic
group and the aromatic framework. The reactivity of carbanions
8eI, 9eI and 10eI was highly selective. Thus, difluorocarbanion 8eI,
obtained from 8e reacts smoothly with methyl iodide at ꢀ30 ꢁC to
give substitution product 19 in 74% yield (Scheme 8).
Scheme 8. Lithiation of CF2H moiety of compounds 8e, 9e, 10e and their reaction with
MeI and trimethylsilyl chloride: synthesis of arylphosphonates 19e21.
Fig. 6. ORTEP diagram of the single-crystal X-ray structure of compound 18.

S.N. Tverdomed et al. / Tetrahedron 67 (2011) 3887e3903
3895
A significantly lower reactivity of carbanion 8eI was observed in
reaction with trimethylsilyl chloride. Therefore, the final product 20
was isolated in 50% yield. Monitoring the progress of the reaction
by 19F and 31P NMR showed that prolonging the reaction time (up to
6e8 h) does not influence the product yield 20 but only increases
the concentration of decomposition products of 8eI (signals at
2aee and 2-hydroxyprop-1-enylphosphonates 3aee and their
subsequent dehydration with the formation of CF2X-containing
alkynephosphonates 4aee. (ii) The formation of six-membered
cyclic systems based on the DielseAlder cycloaddition of alkyne-
phosphonates 4aee with some classical 1,3-alkadienes (2,3-di-
methyl-1,3-butadiene and isoprene). (iii) Aromatization of the
obtained ortho-XCF2 cyclohexa-1,4-dienylphosphonates 5aee, 6e
and 7e using KMnO4/Al2O3 and synthesis of targeted arylphospho-
nates 8aee, 9e and 10e with excellent yield. The synthetic utility of
these compounds has been examined identifying possible routes
of their subsequent modification that includes reactivity studies of
phosphorus and fluorine-containing groups in some reactions by
their functionalization: (iv) the dialkyl phosphonate group has been
activated via its transformation into dichlorides 11aed, which were
further treated with metallorganic reagents to give appropriate
phosphine oxides 12aed or phosphinic acid 13, and their hydrolysis
gave arylphosphonic acids 14aed. (v) In the case of chloro- and
bromodifluoromethyl compounds the hydrolysis of fluorinated
group to ortho-phosphonobenzoic acid 15 under mild conditions
was firstly reported and by generating novel organozinc and copper
reagents and their dimerization product, E-(bis)aryl-difluor-
ostilbene 18 was obtained. For the first time the successful lithiation
of difluoromethyl moiety directly connected to aromatic ring was
performed and based on ortho-difluoromethyl arylphosphonates 8e
and 9e and 10e, novel ArCF2R 19e21 derivatives were obtained.
Applying the aforementioned strategies, a series of novel fluorine-
and phosphorus-containing aromatic compounds were synthesized
possibly serving as promising synthons for new materials,7g,h bio-
active substances7d,e and reagents in organic chemistry.7g
wꢀ138, ꢀ160 ppm in the 19F NMR and at w32, ꢀ2 ppm in the 31
P
NMR). The substitution of allyl and benzyl bromides and final
products were obtained in traces. When highly electrophilic car-
bonyl compounds, such as para-fluorbenzaldehyde or difluor-
ophosgene were reacted with 8eI, the expected products were not
formed even in traces and only starting material 8e was recovered.
When the mixture of regioisomers 9e and 10e (61:39 mol %) was
lithiated with t-BuLi followed by the addition of 1.1 equiv of MeI at
ꢀ25 ꢁC within 4 h and hydrolysis with 10% HCl, the 19F and 31P NMR
spectra showed w80% conversion of diethyl 2-(difluoromethyl)-4-
methylphenyl-phosphonate 9e and the formation of the corre-
sponding substituted 4-methylphenylphosphonate 21 in 73% (45%
overall) yield. Interestingly, the starting 5-methyl regioisomer 10e
was recovered after reaction and remaining unchanged in the same
proportion (35 mol %). After purification by column chromatogra-
phy, diethyl 2-(1,1-difluoroethyl)-4-methylphenylphosphonate 21
was isolated in 62% (38% overall) yield and substrate 10e was re-
covered in 27% yield. The reason for such low reactivity of 5-methyl
carbanion 10eI in comparison to 4-methyl 9eI is not yet clear but
the general reactivity of 8eI, 9eI is probably associated with the
strong EWG-effect of ortho-phosphonic moiety, that increases the
acidity of the CF2H group and facilitates deprotonation of this unit.
On the other hand, it deactivates and stabilizes the negative charge
through delocalization and hence determines the high regiospeci-
ficity and thermal stability of carbanions 9eI and 10eI. In order to
optimize the reaction conditions and check the effectiveness of
other bases, the reaction of 8e with MeI was carried out using
various metalating agents. The results are summarized in Table 8.
As observed, only a very strong and sterically hindered base, such as
t-BuLi is sufficiently powerful to generate the carbanion, especially
in dry THF (Table 8, entries 1 and 2). n-BuLi is basic enough to
deprotonate the CF2H moiety but is also sufficiently nucleophilic for
the substitution on tetrahedral phosphorus, leading to the forma-
tion of an unidentified mixture of phosphine oxides and phosphinic
4. Experimental section
4.1. General
All reagents were obtained from commercial suppliers and
were used without further purification. All solvents used in re-
actions were freshly distilled from appropriate drying agents be-
fore use. THF was distilled from sodium/benzophenone
immediately before use. Zinc was activated by washing four times
with 1% HCl and subsequently with water, acetone and diethyl
ether. All other reagents were recrystallized or distilled as nec-
essary. All glassware was oven-dried at 140 ꢁC, and reactions were
performed under an atmosphere of dry nitrogen. Analytical TLCs
were performed with Merck silica gel 60 F254 plates. Visualization
was accomplished using UV light or spraying by Ce(SO4)2 solution
in 5% H2SO4. Column chromatography was carried out using
Merck silica gel 60 (230e400 mesh ASTM). Melting points were
determined with an Electrothermal IA9100 Digital Melting Point
Apparatus and are uncorrected. NMR spectra were obtained on
a Bruker DPX-200 spectrometer operating at 200.13 MHz for
1H(TMS), 188.31 MHz for 19F (CFCl3), 80.99 MHz for 31P (H3PO4),
esters (31P NMR,
d w46e50 and d w40e43) and significantly re-
ducing the yield of targeted 19 (Table 8, entries 3).
Other bases such, as (LDA, LiN(SiMe3)2), were too weak to
deprotonate
the
CF2H
group
thus
the
equilibrium
8eþLDA$8eIþN,N-diisopropylamine was strongly shifted to the
left. Whereas in the case of LDA, product 19 was isolated in 10% yield,
forLiN(SiMe3)2 wasdetectedspectroscopicallyonlyintraces (Table 8,
entries 4 and 5).
Table 8
Examination of some metalating systems for 8e after treatment with MeI and hy-
drolysis to arylphosphonate 19
50.32 MHz 13C (TMS) and recorded at 25 ꢁC. Chemical shifts (
d) are
Entry
Metallating system and reaction conditionsa
Yieldb (%)
reported in parts per million and coupling constants (J) in Hertz.
13C NMR and 31P NMR spectra were broadband decoupled from
hydrogen nuclei. MS and HRMS spectra were obtained on a Varian
MAT CH7A instrument at 70 eV.
1
2
3
4
5
t-BuLi (1.1 equiv), THF, ꢀ80 to ꢀ30 ꢁC, 3 h
t-BuLi (1.1 equiv), Ether, ꢀ80 to ꢀ20 ꢁC, 4 h
n-BuLi (1.05 equiv), THF, ꢀ100 to ꢀ25 ꢁC, 3 h
LDA (1.1 equiv), THF, ꢀ70 to 0 ꢁC, 5 h
74
60
21
10
LiN (SiMe3)2 (1.15 equiv), THF, ꢀ50 to 10 ꢁC, 5 h
Trace
a
4.1.1. Diethyl 3,3,3-trifluoro-2-oxopropylphosphonate (2a). n-BuLi
(2.5 M solution in n-hexane, 0.15 mol) was added at ꢀ100 ꢁC to dry
THF (240 mL). Subsequently diethyl methylphosphonate 131
(22.8 g, 0.15 mol) was added dropwise and the mixture was stir-
red for 1 h at ꢀ95 ꢁC. Next, ethyl trifluoroacetate (21.3 g, 0.15 mol)
was added slowly and the solution was kept for 1 h below ꢀ90 ꢁC.
Then, the mixture was warmed to ꢀ20 ꢁC, followed by the addition
of 6 N HCl (40 mL). After warming to rt both layers were separated
water phase was extracted with diethyl ether (2ꢄ100 mL, 3ꢄ75 mL)
For 1.0 equiv of 8e, and further addition of 1.1 equiv of MeI followed by hy-
drolysis with 10% HCl.
b
Isolated yield of compound 19.
3. Conclusions
In this work, we have demonstrated a new methodology towards
the synthesis of ortho-XCF2-containing arylphosphonates that in-
cludes the following steps: (i) synthesis of
b-ketophosphonates

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S.N. Tverdomed et al. / Tetrahedron 67 (2011) 3887e3903
2
2
and organic layers were combined, dried over MgSO4 and con-
centrated under reduced pressure. The resulting mixture was dis-
solved in dry benzene (250 mL) and refluxed with a DeaneStark
trap until complete removal of water. The evaporation of benzene
under reduced pressure yielded yellowish oil 2a (in mixture with
3a). Yield (together with isomer 3a) 36.5 g (98%); content 81 mol %,
bp 58e60 ꢁC (0.1 mmHg). 1H, 13C, 31P, 19F NMR and MS (HRMS) data
are consistent with the literature.12aed
NMR (50 MHz, CDCl3):
d
¼164.2 (td, JC,F¼29.8 Hz, JC,P¼3.7 Hz, 1C,
1
3
2-C), 116.7 (td, JC,F¼292.9 Hz, JC,P¼14.7 Hz, 1C, CF2Cl), 82.3 (dt,
1JC,P¼181.1 Hz, JC,F¼3.1 Hz, 1C, 1-C), 63.3 (d, JC,P¼6.2 Hz, 2C, i-C),
3
2
16.5 (d, JC,P¼6.1 Hz, 2C, j-C) ppm. 31P NMR (81 MHz, CDCl3):
3
d
¼23.9 (br s, 1P) ppm. 19F NMR (188 MHz, CDCl3):
¼ꢀ63.7 (br s, 2F,
d
CF2Cl) ppm. MS (EI, 70 eV): m/z (%)¼264 (8) [M]þ, 237 (50), 235 (21)
[MꢀEt]þ, 229 (10) [MꢀCl]þ, 179 (100) [MꢀCF2Cl]þ, 151 (33)
[MꢀC(O)CF2Cl]þ, 137 (14) [P(O)(OEt)2]þ. HRMS (EI) for
C7H12ClF2O4P [M]þ calcd 264.0130; found 264.0129.
4.1.2. Diethyl 3,3,3-trifluoro-2-hydroxyprop-1-enylphosphonate (3a). In
mixture with 2a; content 19 mol %. 1H NMR (200 MHz, CDCl3):
4.1.7. Diethyl 3-bromo-3,3-difluoro-2-oxopropylphosphonate (2d).
Prepared similarly to 2a from 1 (15.2 g, 0.1 mol), n-BuLi (2.5 M so-
lution in n-hexane, 0.1 mol) and ethyl bromo(difluoro)acetate
(30.0 g, 0.1 mol). In mixture with 3d; yield (together with isomer
3d) 28.7 g (93%); content 94 mol %, bp 84e86 ꢁC (0.1 mmHg). 1H
2
d
¼11.39 (br s, 1H, OH), 4.92 (d, JH,P¼8.3 Hz, 1H, C]CeH), 3.96e4.15
(m, 4H, OeCH2), 1.23 (t, 3JH,H¼7.1 Hz, 3H, CH3) ppm. 13C NMR (50 MHz,
2
2
CDCl3):
d
¼160.1 (qd, JC,F¼31.8 Hz, JC,P¼2.9 Hz, 1C, 2-C), 118.6 (qd,
1JC,F¼275.5 Hz, 3JC,P¼26.0 Hz, 1C, CF3), 84.9 (d, 1JC,P¼183.0 Hz, 1C, 1-C),
62.9 (d, JC,P¼5.8 Hz, 2C, i-C), 16.0 (d, JC,P¼5.8 Hz, 2C, j-C) ppm. 31P
NMR (200 MHz, CDCl3):
d
¼4.06e4.20 (m, 4H, OeCH2), 3.37 (d,
2
3
4
3 4
NMR (81 MHz, CDCl3):
d
¼23.3 (q, JP,F¼2.5 Hz, 1P) ppm. 19F NMR
2JH,P¼21.7 Hz, 2H, PeCH2), 1.31 (td, JH,H¼6.8 Hz, JH,P¼2.0 Hz, 6H,
2
(188 MHz, CDCl3):
d
¼ꢀ76.1 (br s, 3F, CF3) ppm.
CH3) ppm. 13C NMR (50 MHz, CDCl3):
d
¼184.0 (td, JC,F¼28.5 Hz,
2JC,P¼7.4 Hz, 1C, 2-C), 113.7 (td, JC,F¼319.5 Hz, JC,P¼6.2 Hz, 1C,
1
3
4.1.3. Diethyl 3,3,4,4,4-pentafluoro-2-oxobutylphosphonate (2b)12b
.
CF2Br), 63.5 (d, JC,P¼6.7 Hz, 2C, i-C), 34.8 (d, 1JC,P¼134.6 Hz, 1C, 1-
2
3
Prepared similarly to 2a from 1 (19.8 g, 0.13 mol), n-BuLi (2.5 M
solution in n-hexane, 0.13 mol) and ethyl pentafluoropropanoate
(25.1 g, 0.13 mol). In mixture with 3b; yield (together with isomer
3b) 36.8 g (95%); content 69 mol %, bp 64e65 ꢁC (0.1 mmHg). 1H
C), 16.6 (d, JC,P¼6.2 Hz, 2C, j-C) ppm. 31P NMR (81 MHz, CDCl3):
d
¼17.5 (s, 1P) ppm. 19F NMR (188 MHz, CDCl3):
¼ꢀ66.3 (s, 2F,
d
CF2Br) ppm.
NMR (200 MHz, CDCl3):
d
¼4.07e4.21 (m, 4H, OeCH2), 3.38 (d,
4.1.8. Diethyl 3-bromo-3,3-difluoro-2-hydroxyprop-1-enylphospho-
3
2JH,P¼22.5 Hz, 2H, PeCH2), 1.30 (t, JH,H¼6.9 Hz, 6H, CH3) ppm. 13
C
nate (3d). In mixture with 2d; content 6 mol %. 1H NMR (200 MHz,
2
2
2
NMR (50 MHz, CDCl3):
d
¼186.6 (td, JC,F¼28.5 Hz, JC,P¼8.1 Hz, 1C,
CDCl3):
d
¼11.53 (br s, 1H, OH), 4.89 (d, JH,P¼8.8 Hz, 1H, C]CeH),
1
2
3
4
2-C), 118.0 (qt, JC,F¼286.6 Hz, JC,F¼34.1 Hz, 1C, CF3), 106.7 (tqd,
4.07e4.21 (m, 4H, OeCH2), 1.30 (td, JH,H¼7.0 Hz, JH,P¼1.9 Hz, 6H,
2
3
2
1JC,F¼268.0 Hz, JC,F¼38.5 Hz, JC,P¼4.3 Hz, 1C, CF2), 63.7 (d,
CH3) ppm. 13C NMR (50 MHz, CDCl3):
d
¼165.1 (td, JC,F¼28.2 Hz,
2JC,P¼6.8 Hz, 2C, i-C), 37.1 (d, JC,P¼133.4 Hz, 1C, 1-C), 16.4 (d,
2JC,P¼4.3 Hz, 1C, 2-C), 124.8 (td, JC,F¼314.8 Hz, JC,P¼20.2 Hz, 1C,
1
1
3
3JC,P¼6.2 Hz, 2C, j-C) ppm. 31P NMR (81 MHz, CDCl3):
d
¼16.9 (s, 1P)
CF2Br), 81.4 (dt, JC,P¼182.4 Hz, JC,F¼3.7 Hz, 1C, 1-C), 63.2 (d,
1
3
ppm. 19F NMR (188 MHz, CDCl3):
CF3) ppm.
d
¼ꢀ123.6 (s, 2F, CF2), ꢀ83.0 (s, 3F,
2JC,P¼6.2 Hz, 2C, i-C), 16.5 (d, JC,P¼6.5 Hz, 2C, j-C) ppm. 31P NMR
3
(81 MHz, CDCl3):
d
d
¼23.8 (br s, 1P) ppm. 19F NMR (188 MHz, CDCl3):
¼ꢀ59.5 (d, 4JF,P¼2.3 Hz, 2F, CF2Br) ppm. MS (CI, positive): m/z (%)¼
4.1.4. Diethyl 3,3,4,4,4-pentafluoro-2-hydroxybut-1-enylphosphonate
309 (48) [MþH]þ, 282 (12), 248 (100), 231 (48), 196 (20), 179 (18)
[MþHꢀCF2Br]þ. MS (CI, negative): m/z (%)¼307 (29) [MꢀH]ꢀ, 228
(9) [MꢀHꢀBr]ꢀ, 224 (16), 210 (100). HRMS (CI) for C7H12BrF2O4P
[M]þ calcd 307.9625; found 307.9644; for C7H12F2O4P [MꢀBr]þ
calcd 229.0441; found 229.0442.
(3b). In mixture with 2b; content 31 mol %. 1H NMR (200 MHz,
2
CDCl3):
d
¼11.55 (br s, 1H, OH), 5.04 (d, JH,P¼8.8 Hz, 1H, C]CeH),
4.01e4.13 (m, 4H, OeCH2), 1.28 (t, JH,H¼6.8 Hz, 6H, CH3) ppm. 13
C
3
2
2
NMR (50 MHz, CDCl3):
d
¼161.1 (td, JC,F¼27.0 Hz, JC,P¼3.7 Hz, 1C,
2-C), 120.9 (tqd, 1JC,F¼283.2 Hz, 2JC,F¼37.5 Hz, 3JC,P¼2.8 Hz, 1C, CF2),
1
2
118.6 (qt, JC,F¼282.8 Hz, JC,F¼30.4 Hz, 1C, CF3), 86.5 (dt,
4.1.9. Diethyl 3,3-difluoro-2-oxopropylphosphonate (2e)12f. Prepared
similarly to 2a from 1 (22.8 g, 0.15 mol), n-BuLi (2.5 M solution in n-
hexane, 0.15 mol) and ethyl difluoroacetate (18.6 g, 0.15 mol). In
mixture with 3e; yield (together with isomer 3e) 33.5 g (97%);
1JC,P¼181.7 Hz, JC,F¼4.7 Hz, 1C, 1-C), 63.4 (d, JC,P¼5.0 Hz, 2C, i-C),
3
2
16.3 (d, JC,P¼5.9 Hz, 2C, j-C) ppm. 31P NMR (81 MHz, CDCl3):
3
4
d
d
¼23.2 (t, JP,F¼2.0 Hz, 1P) ppm. 19F NMR (188 MHz, CDCl3):
¼ꢀ123.9 (s, 2F, CF2), ꢀ84.7 (s, 3F, CF3) ppm. MS (EI, 70 eV): m/z
content 93 mol %, bp 70e72 ꢁC (0.1 mmHg). 1H NMR (200 MHz,
(%)¼298 (2) [M]þ, 271 (9), 253 (2) [MꢀOEt]þ, 243 (32), 225 (18), 179
(100) [MꢀC2F5]þ, 151 (38), 137 (8) [P(O)(OEt)2]þ, 123 (97). HRMS
(EI) for C8H12F5O4P [M]þ calcd 298.0393; found 298.0388.
CDCl3):
d
¼5.85 (t, JH,F¼53.8 Hz, 1H, CF2eH), 4.02e4.17 (m, 4H,
2
2
4
OeCH2), 3.27 (dt, JH,P¼22.5 Hz, JH,F¼1.2 Hz, 2H, PeCH2), 1.27 (td,
3JH,H¼7.1 Hz, 4JH,P¼0.8 Hz, 6H, CH3) ppm. 13C NMR (50 MHz, CDCl3):
2
2
d
¼191.2 (td, JC,F¼19.3 Hz, JC,P¼7.7 Hz, 1C, 2-C), 108.9 (td,
4.1.5. Diethyl 3-chloro-3,3-difluoro-2-oxopropylphosphonate (2c).
Prepared similarly to 2a from 1 (19.7 g, 0.13 mol), n-BuLi (2.5 M
solution in n-hexane, 0.13 mol) and ethyl chloro(difluoro)acetate
(20.0 g, 0.13 mol). In mixture with 3c; yield (together with isomer
3c) 33.0 g (96%); content 93 mol %, bp 68e69 ꢁC (0.1 mmHg). 1H
1JC,F¼251.4 Hz, 3JC,P¼2.8 Hz, 1C, CF2H), 62.6 (d, 2JC,P¼6.4 Hz, 2C, i-C),
36.4 (d, 1JC,P¼130.1 Hz, 1C, 1-C), 15.8 (d, JC,P¼4.3 Hz, 2C, j-C) ppm.
3
31P NMR (81 MHz, CDCl3):
d
¼18.3 (s, 1P) ppm. 19F NMR (188 MHz,
2
CDCl3):
d
¼ꢀ129.6 (d, JF,H¼54.3 Hz, 2F, CF2H) ppm.
NMR (200 MHz, CDCl3):
d
¼4.04e4.19 (m, 4H, OeCH2), 3.33 (d,
4.1.10. Diethyl 3,3-difluoro-2-hydroxyprop-1-enylphosphonate (3e). In
3
2JH,P¼21.5 Hz, 2H, PeCH2), 1.28 (t, JH,H¼6.9 Hz, 6H, CH3) ppm. 13
C
mixture with 2e; content 7 mol %.1H NMR (200 MHz, CDCl3):
d
¼11.18
2
2
2
NMR (50 MHz, CDCl3):
d
¼183.9 (td, JC,F¼31.6 Hz, JC,P¼7.5 Hz, 1C,
(br s, 1H, OH), 5.81 (t, JH,F¼53.6 Hz, 1H, CF2eH), 4.80 (d,
1
3
2-C), 119.6 (td, JC,F¼305.2 Hz, JC,P¼5.6 Hz, 1C, CF2Cl), 63.6 (d,
2JH,P¼10.3 Hz, 1H, C]CeH), 3.97e4.11 (m, 4H, OeCH2), 1.26 (t,
2JC,P¼6.8 Hz, 2C, i-C), 35.3 (d, JC,P¼134.0 Hz, 1C, 1-C), 16.5 (d,
3JH,H¼7.1 Hz, 6H, CH3) ppm. 13C NMR (50 MHz, CDCl3):
¼165.2 (td,
d
1
3JC,P¼6.3 Hz, 2C, j-C) ppm. 31P NMR (81 MHz, CDCl3):
d
¼17.4 (s, 1P)
2JC,F¼25.1 Hz, JC,P¼2.9 Hz, 1C, 2-C), 109.6 (td, JC,F¼241.8 Hz,
2
1
ppm. 19F NMR (188 MHz, CDCl3):
d
¼ꢀ69.5 (s, 2F, CF2Cl) ppm.
3JC,P¼22.2 Hz, 1C, CF2H), 82.1 (dt, 1JC,P¼182.1 Hz, 3JC,F¼4.8 Hz,1C,1-C),
62.3 (d, JC,P¼5.4 Hz, 2C, i-C), 15.9 (d, JC,P¼5.6 Hz, 2C, j-C) ppm. 31P
2
3
4
4.1.6. Diethyl 3-chloro-3,3-difluoro-2-hydroxyprop-1-enylphospho-
NMR (81 MHz, CDCl3):
(188 MHz, CDCl3):
d
¼24.9 (t, JP,F¼1.4 Hz, 1P) ppm. 19F NMR
nate (3c). In mixture with 2c; content 7 mol %. 1H NMR (200 MHz,
d
¼ꢀ126.5 (dd, JF,H¼54.7 Hz, JF,P¼1.3 Hz, 2F,
2
4
2
CDCl3):
d
¼11.51 (br s, 1H, OH), 4.90 (d, JH,P¼9.2 Hz, 1H, C]CeH),
CF2H) ppm. MS (EI, 70 eV): m/z (%)¼230 (5) [M]þ, 179 (100)
4.05e4.20 (m, 4H, OeCH2), 1.27 (t, 3JH,H¼6.9 Hz, 6H, CH3) ppm. 13
C
[MꢀCF2H]þ, 151 (30) [MꢀC(O)CF2H]þ, 137 (20) [P(O)(OEt)2]þ, 123

S.N. Tverdomed et al. / Tetrahedron 67 (2011) 3887e3903
3897
3
(65), 109 (50). HRMS (EI) for C7H13F2O4P [M]þ calcd 230.0520; found
230.0519.
CDCl3):
d
¼100.8 (td, 1JC,F¼292.2 Hz, JC,P¼6.2 Hz, 1C, CF2Br), 86.6 (dt,
2JC,P¼47.1 Hz, JC,F¼39.7 Hz, 1C, 2-C), 79.9 (dt, JC,P¼277.3 Hz,
2
1
2
3JC,F¼5.6 Hz, 1C, 1-C), 64.8 (d, JC,P¼5.6 Hz, 2C, i-C), 16.4 (d,
4.1.11. Diethyl 3,3,3-trifluoroprop-1-ynylphosphonate (4a). Method
A: N,N-Diisopropylethylamine (62.0 g, 0.48 mol) was added quickly
under nitrogen to a solution of ketoneeenol 2a:3a (24.8 g, 0.1 mol)
mixture in dry methylene chloride (180 mL) cooled to ꢀ45 ꢁC. The
resulting solution was stirred at this temperature for 10 min and
trifluoromethanesulfonic anhydride (33.9 g, 0.12 mol) was then
added dropwise at ꢀ40 ꢁC. The suspension was kept for 7 h at
ꢀ40 ꢁC and then 2 h at 5e7 ꢁC. The reaction mixture was diluted
with anhydrous ether (1000 mL) and left overnight at ꢀ30 ꢁC. The
resulting precipitate was filtered off and washed with cold diethyl
ether (3ꢄ75 mL). Then, the filtrate was washed with diluted solu-
tion of HCl (1ꢄ500 mL 1%, 3ꢄ300 mL 3%), organic layer was dried
over MgSO4 and solvents were removed under reduced pressure to
give crude product, which was distilled under reduced pressure
yielding 21.9 g (95%) of pure 4a as a colourless oil.
Method B: To a suspension of P2O5 (15.6 g, 0.11 mol) in 200 mL of
anhydrous methylene chloride cooled to ꢀ20 to ꢀ25 ꢁC under dry
nitrogen atmosphere at vigorous stirring was added dropwise
a solution of ketoneeenol mixture 2a:3a (24.8 g, 0.1 mol) and
triethylamine (50.1 g, 0.5 mol) in 100 mL of anhydrous methylene
chloride maintaining the reaction mixture temperature below
ꢀ20 ꢁC. The suspension was stirred for 6 h at this temperature and
then 2 h at the temperature 5e7 ꢁC. Then the reaction mixture was
diluted with anhydrous ether (1000 mL) and left overnight at
ꢀ30 ꢁC. The product was isolated according to Method A yielding
16.1 g (70%) of 4a. Bp 34e36 ꢁC (0.1 mmHg). 1H, 13C, 31P, 19F NMR
and MS (HRMS) data are consistent with the literature.11
3JC,P¼6.8 Hz, 2C, j-C) ppm. 31P NMR (81 MHz, CDCl3):
d
¼ꢀ9.6 (t,
4JP,F¼4.0 Hz, 1P) ppm. 19F NMR (188 MHz, CDCl3):
d
¼ꢀ38.8 (d,
4JF,P¼3.9 Hz, 2F, CF2Br) ppm. MS (EI, 70 eV): m/z (%)¼289 (8) [MꢀH]þ,
235 (19), 211 (15) [MꢀBr]þ, 183 (100),139 (30),103 (28). HRMS (EI) for
C7H9BrF2O3P [MꢀH]þ calcd 288.9441; found 288.9440.
4.1.15. Diethyl 3,3-difluoroprop-1-ynylphosphonate (4e). Prepared
similarly to 4a from 2e:3e (18.4 g, 0.08 mol), N,N-diisopropyle-
thylamine (58.2 g, 0.45 mol) and trifluoromethanesulfonic anhy-
dride (27.1 g, 0.1 mol); yield 14.9 g (88%) (Method A) or from 2e:3e
(23.0 g, 0.1 mol), triethylamine (55.7 g, 0.55 mol) and phosphorus
pentoxide (15.6 g, 0.11 mol); yield 14.4 g (68%) (Method B), bp
71e72 ꢁC (0.1 mmHg). 1H NMR (200 MHz, CDCl3):
d¼6.23 (td,
2JH,F¼53.1 Hz, 4JH,P¼2.2 Hz, 1H, CF2eH), 4.07e4.22 (m, 4H, OeCH2),
1.33 (t, JH,H¼7.1 Hz, 6H, CH3) ppm. 13C NMR (50 MHz, CDCl3):
3
1
3
d
¼103.1 (td, JC,F¼235.7 Hz, JC,P¼5.0 Hz, 1C, CF2H), 87.8 (dt,
2JC,P¼47.3 Hz, JC,F¼34.6 Hz, 1C, 2-C), 78.8 (dt, JC,P¼281.3 Hz,
2
1
2
3JC,F¼6.8 Hz, 1C, 1-C), 64.5 (d, JC,P¼5.6 Hz, 2C, i-C), 16.3 (d,
3JC,P¼6.8 Hz, 2C, j-C) ppm. 31P NMR (81 MHz, CDCl3):
d
¼ꢀ8.9 (t,
4JP,F¼6.4 Hz, 1P) ppm. 19F NMR (188 MHz, CDCl3):
d
¼ꢀ111.4 (dd,
1JF,H¼53.1 Hz, 4JF,P¼6.5 Hz, 2F, CF2H) ppm. MS (EI, 70 eV): m/z (%)¼
211 (22) [MꢀH]þ, 185 (60), 164 (40), 157 (100), 139 (58). HRMS (EI)
for C7H10F2O3P [MꢀH]þ calcd 211.0336; found 211.0337.
4.1.16. Diethyl 4,5-dimethyl-2-(trifluoromethyl)cyclohexa-1,4-dien-1-
ylphosphonate (5a). To a dry ampoule flushed with nitrogen and
charged withdrytoluene(50 mL)wereadded:acetylenephosphonate
4a (20.7 g, 0.09 mol), 2,3-dimethyl-1,3-butadiene (7.8 g, 0.095 mol)
and small amount (20e25 mg, ca. 0.001 mol %) of 2,6-di-tert-butyl-p-
cresol (BHT). The ampoule was sealed and heated at the temperature
110 ꢁC for 0.5 h. Then all volatiles were removed under reduced
pressure and the residue was dried overnight under vacuum yielding
27.3 g (97%) of 5a, which can be additionally purified by distillation in
avacuum. Yellowishoil; bp 84e86 ꢁC (0.1 mmHg).1H,13C, 31P, 19F NMR
and MS (HRMS) data are consistent with the literature.11
4.1.12. Diethyl 3,3,4,4,4-pentafluorobut-1-ynylphosphonate (4b).
Prepared similarly to 4a from 2b:3b (23.9 g, 0.08 mol), N,N-diiso-
propylethylamine (51.7 g, 0.4 mol) and trifluoromethanesulfonic
anhydride (27.1 g, 0.1 mol); yield 20.6 g (92%) (Method A) or from
2b:3b (29.8 g, 0.1 mol), triethylamine (50.1 g, 0.5 mol), phosphorus
pentoxide (15.6 g, 0.11 mol); yield 18.8 g (67%) (Method B), bp
40e41 ꢁC (0.1 mmHg). 1H, 13C, 31P, 19F NMR and MS (HRMS) data are
consistent with the literature.11
4.1.17. Diethyl 4,5-dimethyl-2-(pentafluoroethyl)cyclohexa-1,4-dien-
1-ylphosphonate (5b). Prepared similarly to 5a from 4b (19.6 g,
0.07 mol), 2,3-dimethyl-1,3-butadiene (6.3 g, 77 mmol) at 115 ꢁC
for 0.5 h; yield 24.1 g (95%) as a yellowish oil, bp 89e91 ꢁC
(0.1 mmHg). 1H, 13C, 31P, 19F NMR and MS (HRMS) data are consis-
tent with the literature.11
4.1.13. Diethyl 3-chloro-3,3-difluoroprop-1-ynylphosphonate (4c). Pre-
pared similarly to 4a from 2c:3c (15.9 g, 0.06 mol), N,N-diisopropyle-
thylamine (45.2 g, 0.35 mol) and trifluoromethanesulfonic anhydride
(20.3 g, 0.07 mol); yield 12.6 g (85%) (Method A) or from 2c:3c (26.5 g,
0.1 mol), triethylamine (66.8 g, 0.7 mol), phosphorus pentoxide
(15.6 g, 0.11 mol); yield 16.0 g (65%) (Method B), bp 56e57 ꢁC
(0.1 mmHg).1H NMR (200 MHz, CDCl3):
d
¼4.08e4.23 (m, 4H, OeCH2),
4.1.18. Diethyl 2-[chloro(difluoro)methyl]-4,5-dimethylcyclohexa-1,4-
dien-1-ylphosphonate (5c). Prepared similarly to 5a from 4c (22.2 g,
0.09 mol), 2,3-dimethyl-1,3-butadiene (8.1 g, 0.1 mol) at 125 ꢁC for
1.5 h; yield 29.0 g (98%) as a yellowish oil, bp 95e97 ꢁC (0.1 mmHg).
1.33 (t, 3JH,H¼6.9 Hz, 6H, CH3) ppm. 13C NMR (50 MHz, CDCl3):
¼112.7
d
1
3
2
(td, JC,F¼279.1 Hz, JC,P¼5.6 Hz, 1C, CF2Cl), 85.7 (td, JC,F¼46.5 Hz,
2JC,P¼44.1 Hz, 1C, 2-C), 78.7 (dt, 1JC,P¼277.9 Hz, JC,F¼5.0 Hz, 1C, 1-C),
3
64.8 (d, JC,P¼6.2 Hz, 2C, i-C), 16.3 (d, JC,P¼6.2 Hz, 2C, j-C) ppm. 31P
1H NMR (200 MHz, CDCl3):
d
¼4.06e4.22 (m, 4H, OeCH2), 2.96e3.01
2
3
4
NMR (81 MHz, CDCl3):
d
¼ꢀ9.7 (t, JP,F¼5.1 Hz, 1P) ppm. 19F NMR
(m, 4H, CH2),1.65 (s, 6H, CH3),1.33 (t, 3JH,H¼6.9 Hz, 6H, CH3) ppm.13
C
4
2
2
(188 MHz, CDCl3):
d
¼ꢀ41.7 (d, JF,P¼5.1 Hz, 2F, CF2Cl) ppm. MS (EI,
NMR (50 MHz, CDCl3):
d
¼141.6 (td, JC,F¼25.4 Hz, JC,P¼3.7 Hz, 1C,
1
3
70 eV): m/z(%)¼211 (21) [MꢀCl]þ,191 (90),183 (100),173 (42),109 (20)
[MꢀP(O)(OEt)2]þ. MS(CI,positive):m/z(%)¼247 (100) [MþH]þ.MS(CI,
negative): m/z (%)¼281 (10) [MþCl]ꢀ, 217 (100) [MꢀEt]ꢀ, 182 (60).
HRMS (EI) for C7H10F2O3P [MꢀCl]þ calcd 211.0336; found 211.0335.
2-C), 128.2 (dt, JC,P¼179.3 Hz, JC,F¼2.5 Hz, 1C, 1-C), 125.2 (td,
3
1JC,F¼292.8 Hz, JC,P¼9.9 Hz, 1C, 7-C), 121.2 (t, 4JC,F¼1.2 Hz, 1C, 4-C),
122.4 (d, 3JC,P¼9.9 Hz, 1C, 5-C), 62.8 (d, 2JC,P¼6.2 Hz, 2C, i-C), 37.5 (d,
2JC,P¼8.7 Hz, 1C, 6-C), 33.6 (dt, JC,P¼13.0 Hz, JC,F¼3.7 Hz, 1C, 3-C),
3
3
18.1 (d, 4JC,P¼1.2 Hz, 1C, 8-C), 16.7 (d, 3JC,P¼6.8 Hz, 2C, j-C) ppm. 31
P
4
4.1.14. Diethyl 3-bromo-3,3-difluoroprop-1-ynylphosphonate (4d).
Prepared similarly to 4a from 2d:3d (37.1 g, 0.12 mol), N,N-diisopro-
pylethylamine (99.5 g, 0.77 mol) and trifluoromethanesulfonic an-
hydride (40.6 g, 0.14 mol); yield 28.6 g (82%) (Method A) or from
2d:3d (30.9 g, 0.1 mol), triethylamine (72.3 g, 0.72 mol) and phos-
phorus pentoxide (15.6 g, 0.11 mol); yield 21.0 g (60%) (Method B), bp
NMR (81 MHz, CDCl3):
d
¼15.2 (t, JP,F¼3.0 Hz, 1P) ppm. 19F NMR
(188 MHz, CDCl3):
d¼ꢀ51.5 (br s, 2F, CF2Cl) ppm. MS (EI, 70 eV): m/z
(%)¼327 (4) [MꢀH]þ, 291 (100) [MꢀClꢀH2]þ, 263 (40), 35 (79), 215
(81), 201 (21). HRMS (EI) for C13H18F2O3P [MꢀClꢀH2]þ 291.0961;
found 291.0962.
64e66 ꢁC (0.1 mmHg). 1H NMR (200 MHz, CDCl3):
d
¼4.08e4.24 (m,
4.1.19. Diethyl 2-[bromo(difluoro)methyl]-4,5-dimethylcyclohexa-1,4-
dien-1-ylphosphonate (5d). Prepared similarly to 5a from 4d
3
4H, OeCH2), 1.34 (t, JH,H¼6.9 Hz, 6H, CH3) ppm. 13C NMR (50 MHz,

3898
S.N. Tverdomed et al. / Tetrahedron 67 (2011) 3887e3903
2
4
(23.3 g, 0.08 mol), 2,3-dimethyl-1,3-butadiene (7.6 g, 0.092 mol) at
NMR (188 MHz, CDCl3):
d
¼ꢀ121.7 (dd, JF,H¼55.6 Hz, JF,P¼4.7 Hz,
140 ꢁC for 2.0 h; yield 28.7 g (96%) as a yellowish oil, bp 110e112 ꢁC
2F, CF2H) ppm. MS (EI, 70 eV): m/z (%)¼279 (5) [MꢀH]þ, 259 (100)
[MꢀH2F]þ, 231 (25), 203 (30), 183 (35), 123 (40)
[MꢀHFꢀP(O)(OEt)2]þ. HRMS (EI) for C12H18F2O3P [MꢀH]þ calcd
279.0962; found 279.0949; for C12H17FO3P [MꢀH2F]þ calcd
259.0899; found 259.0892.
(0.1 mmHg). 1H NMR (200 MHz, CDCl3):
d
¼4.04e4.18 (m, 4H,
OeCH2), 2.95 (br s, 4H, CH2), 1.65 (s, 6H, CH3), 1.34 (t, 3JH,H¼6.8 Hz,
6H, CH3) ppm. 13C NMR (50 MHz, CDCl3):
d
¼142.8 (td, 2JC,F¼22.3 Hz,
2JC,P¼3.7 Hz, 1C, 2-C), 127.5 (dt, 1JC,P¼179.4 Hz, 3JC,F¼2.4 Hz, 1C, 1-C),
3
4
122.4 (d, JC,P¼9.9 Hz, 1C, 5-C), 121.1 (t, JC,F¼1.2 Hz, 1C, 4-C), 117.5
(td, 1JC,F¼306.4 Hz, 3JC,P¼9.9 Hz, 1C, 7-C), 62.8 (d, 2JC,P¼6.2 Hz, 2C, i-
C), 37.5 (d, 2JC,P¼8.7 Hz,1C, 6-C), 33.5 (dt, 3JC,P¼12.4 Hz, 3JC,F¼3.7 Hz,
4.1.23. Diethyl 4,5-dimethyl-2-(trifluoromethyl)phenylphosphonate
(8a). To a suspension of KMnO4/Al2O3 (49.3 g, 156 mmol) in dry
acetone (350 mL) a solution of adduct 5a (24.3 g, 78 mmol) in dry
acetone (250 mL) was added dropwise at ꢀ20 ꢁC over 1.5 h under
vigorous stirring. Afterwards, the mixture was left for 3 h at the
same temperature and warm up to rt. The precipitate was filtered
off and washed with a hot acetone (3ꢄ200 mL). Combined filtrates
were filtered through a 10e15 cm layer of CeliteÒ, concentrated and
dried under vacuum yielding 23.2 g (96%) of 8a as a colourless oil,
4
1C, 3-C), 18.3 (s, 1C, 9-C), 18.1 (d, JC,P¼1.2 Hz, 1C, 8-C), 16.7 (d,
3JC,P¼6.2 Hz, 2C, j-C) ppm. 31P NMR (81 MHz, CDCl3):
¼15.3 (t,
d
4JP,F¼3.2 Hz, 1P) ppm. 19F NMR (188 MHz, CDCl3):
¼ꢀ46.4 (s, 2F,
d
CF2Br) ppm. MS (EI, 70 eV): m/z (%)¼293 (100) [MꢀBr]þ, 237 (55),
235 (31) [MꢀHꢀP(O)(OEt)2]þ, 215 (46). MS (CI, positive): m/z (%)¼
373 (100) [MþH]þ, 293 (72), 237 (10) [MꢀP(O)(OEt)2þH]þ. HRMS
(EI) for C13H20F2O3P [MꢀBr]þ calcd 293.1118; found 293.1110.
bp 118e119 ꢁC (0.1 mmHg). 1H NMR (200 MHz, CDCl3):
d¼7.98 (d,
4
4.1.20. Diethyl 2-(difluoromethyl)-4,5-dimethylcyclohexa-1,4-dien-
1-ylphosphonate (5e). Prepared similarly to 5a from 4e (21.2 g,
0.1 mol), 2,3-dimethyl-1,3-butadiene (9.4 g, 0.115 mol) at 150 ꢁC for
3JH,P¼15.7 Hz, 1H, AreH), 7.53 (d, JH,P¼5.9 Hz, 1H, AreH),
4.04e4.18 (m, 4H, OeCH2), 2.33 (s, 6H, AreCH3), 1.30 (t,
3JH,H¼6.9 Hz, 6H, CH3) ppm. 13C NMR (50 MHz, CDCl3):
¼142.1 (d,
d
2.5 h; yield 27.4 g (93%) as
a
yellowish oil, bp 98e100 ꢁC
4JC,P¼3.1 Hz, 1C, 4-C), 140.8 (dq, 2JC,P¼14.3 Hz, 4JC,F¼1.2 Hz, 1C, 6-C),
137.9 (d, 3JC,P¼8.7 Hz, 1C, 5-C), 130.0 (qd, 2JC,F¼32.2 Hz, 2JC,P¼6.8 Hz,
2
(0.1 mmHg). 1H NMR (200 MHz, CDCl3):
d¼7.41 (t, JH,F¼55.3 Hz,
3
3
1H, CF2eH), 3.92e4.12 (m, 4H, OeCH2), 2.80 (s, 4H, CH2), 1.60 (br s,
1C, 2-C), 129.1 (dq, JC,P¼12.1 Hz, JC,F¼5.9 Hz, 1C, 3-C), 124.0 (dq,
3 1
6H, CH3), 1.26 (t, JH,H¼7.1 Hz, 6H, CH3) ppm. 13C NMR (50 MHz,
1JC,P¼185.5 Hz, JC,F¼1.6 Hz, 1C, 1-C), 123.9 (qd, JC,F¼273.6 Hz,
3
2
2
2
CDCl3):
d
¼143.7 (td, JC,F¼24.2 Hz, JC,P¼9.3 Hz, 1C, 2-C), 128.3 (dt,
3JC,P¼4.3 Hz, 1C, 7-C), 62.8 (d, JC,P¼5.6 Hz, 2C, i-C), 20.2 (d,
1JC,P¼175.2 Hz, 3JC,F¼8.9 Hz, 1C, 1-C), 121.9 (d, 3JC,P¼9.9 Hz, 1C, 5-C),
121.8 (d, 4JC,P¼2.2 Hz, 1C, 4-C), 112.1 (td, 1JC,F¼234.5 Hz, 3JC,P¼7.8 Hz,
1C, 7-C), 62.3 (d, 2JC,P¼5.9 Hz, 2C, i-C), 35.2 (d, 2JC,P¼7.8 Hz, 1C, 6-C),
29.9 (dt, 3JC,P¼14.9 Hz, 3JC,F¼3.4 Hz,1C, 3-C),18.3 (d, 5JC,P¼1.2 Hz,1C,
4JC,P¼1.2 Hz, 1C, 8-C), 19.9 (s, 1C, 9-C), 16.5 (d, 3JC,P¼6.8 Hz, 2C, j-C)
ppm. 31P NMR (81 MHz, CDCl3):
d
¼17.0 (q, 4JP,F¼1.5 Hz, 1P) ppm. 19
F
NMR (188 MHz, CDCl3):
d
¼ꢀ59.7 (s, 3F, CF3) ppm. MS (EI, 70 eV): m/
z (%)¼310 (42) [M]þ, 254 (100), 231 (25), 205 (15). HRMS (EI) for
4
3
9-C), 18.2 (d, JC,P¼1.2 Hz, 1C, 8-C), 16.5 (d, JC,P¼6.2 Hz, 2C, j-C)
C13H18F3O3P [M]þ calcd 310.0946; found 310.0938.
ppm. 31P NMR (81 MHz, CDCl3):
NMR (188 MHz, CDCl3):
d
¼16.7 (t, 4JP,F¼5.0 Hz, 1P) ppm. 19
F
2
4
d
¼ꢀ121.7 (dd, JF,H¼55.4 Hz, JF,P¼4.8 Hz,
4.1.24. Diethyl 4,5-dimethyl-2-(pentafluoroethyl)phenylphosphonate
(8b). Prepared similarly to 8a from 5b (26.1 g, 72 mmol), KMnO4/
Al2O3 reagent (45.5 g, 144 mmol) at ꢀ15 ꢁC for 3.5 h; yield 24.4 g
2F, CF2H) ppm. MS (EI, 70 eV): m/z (%)¼293 (10) [MꢀH]þ, 273 (100),
245 (16), 217 (20), 197 (45). HRMS (EI) for C13H20F2O3P [MꢀH]þ
calcd 293.1118; found 293.1105.
(94%) as a colourless oil, bp 121e122 ꢁC (0.1 mmHg). 1H NMR
3
(200 MHz, CDCl3):
d
¼8.05 (d, JH,P¼14.7 Hz, 1H, AreH), 7.39 (d,
4.1.21. Diethyl 2-(difluoromethyl)-4-methylcyclohexa-1,4-dien-1-yl-
phosphonate (6e). Prepared similarly to 5a from 4e (19.1 g,
90 mmol), 2-methyl-1,3-butadiene (7.1 g, 104 mmol) at 160 ꢁC for
3.0 h; in mixture with 7e; yield (together with isomer 7e) 22.7 g
4JH,P¼5.9 Hz, 1H, AreH), 3.97e4.17 (m, 4H, OeCH2), 2.30 (s, 6H,
AreCH3), 1.26 (t, JH,H¼6.9 Hz, 6H, CH3) ppm. 13C NMR (50 MHz,
3
CDCl3):
d
¼141.9 (d, 4JC,P¼2.8 Hz, 1C, 4-C), 140.9 (d, 2JC,P¼14.3 Hz, 1C,
3
3
6-C), 138.1 (d, JC,P¼8.1 Hz, 1C, 5-C), 131.0 (dtq, JC,P¼12.4 Hz,
4
2
(90%) as a yellowish oil; content 59 mol %, bp 95e96 ꢁC (0.1 mmHg).
3JC,F¼7.5 Hz, JC,F¼1.9 Hz, 1C, 3-C), 128.5 (td, JC,F¼24.2 Hz,
1H NMR (200 MHz, CDCl3):
d
¼7.46 (t, JH,F¼55.5 Hz, 1H, CF2eH),
2JC,P¼6.2 Hz, 1C, 2-C), 125.3 (dt, 1JC,P¼187.3 Hz, 3JC,F¼1.9 Hz, 1C, 1-C),
2
1
2
5.34e5.36 (m, 1H, C]CeH), 3.94e4.12 (m, 4H, OeCH2), 2.80 (s, 2H,
CH2), 2.85e2.93 (m, 2H, CH2), 1.65 (br s, 6H, CH3), 1.26 (t,
119.5 (qt, JC,F¼287.2 Hz, JC,F¼39.1 Hz, 1C, CF3), 114.1 (tqd,
2 3
1JC,F¼256.2 Hz, JC,F¼38.5 Hz, JC,P¼3.7 Hz, 1C, 7-C), 62.8 (d,
2JC,P¼6.2 Hz, 2C, i-C), 20.1 (d, 4JC,P¼1.2 Hz, 1C, 8-C), 19.9 (s, 1C, 9-C),
3JH,H¼6.9 Hz, 6H, CH3) ppm. 13C NMR (50 MHz, CDCl3):
¼143.3 (td,
d
2JC,F¼23.9 Hz, JC,P¼9.6 Hz, 1C, 2-C), 129.9 (d, JC,P¼1.6 Hz, 1C, 4-C),
16.5 (d, 3JC,P¼6.2 Hz, 2C, j-C) ppm. 31P NMR (81 MHz, CDCl3):
d
¼17.5
2
4
1
3
4
128.2 (dt, JC,P¼175.8 Hz, JC,F¼9.0 Hz, 1C, 1-C), 117.0 (d,
3JC,P¼10.2 Hz, 1C, 5-C), 112.2 (td, 1JC,F¼234.2 Hz, 3JC,P¼8.1 Hz, 1C, 7-
C), 62.4 (d, 2JC,P¼5.3 Hz, 2C, i-C), 29.6 (d, 2JC,P¼7.4 Hz, 1C, 6-C), 27.9
(t, JP,F¼2.0 Hz, 1P) ppm. 19F NMR (188 MHz, CDCl3):
d
¼ꢀ108.1 (s,
2F, CF2), ꢀ84.3 (s, 3F, CF3) ppm. MS (EI, 70 eV): m/z (%)¼360 (26)
[M]þ, 304 (50), 288 (43), 241 (100), 213 (40). HRMS (EI) for
C14H18F5O3P [M]þ calcd 360.0914; found 360.0903.
(dt, 3JC,P¼14.9 Hz, 3JC,F¼3.7 Hz, 1C, 3-C), 22.9 (d, JC,P¼1.6 Hz, 1C, 9-
5
C), 16.5 (d, JC,P¼6.5 Hz, 2C, j-C) ppm. 31P NMR (81 MHz, CDCl3):
3
4
d
d
¼16.9 (t, JP,F¼5.0 Hz, 1P) ppm. 19F NMR (188 MHz, CDCl3):
4.1.25. Diethyl 2-[chloro(difluoro)methyl]-4,5-dimethylphenylphosp-
honate (8c). Prepared similarly to 8a from 5c (29.6 g, 90 mmol),
KMnO4/Al2O3 (58.3 g, 185 mmol) at ꢀ5 ꢁC for 5 h; yield 25.6 g (87%)
as a yellowish oil, bp 134e135 ꢁC (0.1 mmHg). 1H NMR (200 MHz,
¼ꢀ122.1 (dd, 2JF,H¼55.2 Hz, JF,P¼3.9 Hz, 2F, CF2H) ppm.
4
4.1.22. Diethyl 2-(difluoromethyl)-5-methylcyclohexa-1,4-dien-1-yl-
3
4
phosphonate (7e). In mixture with 6e; content 41 mol %. 1H NMR
CDCl3):
d
¼7.98 (d, JH,P¼15.7 Hz, 1H, AreH), 7.53 (d, JH,P¼6.9 Hz,
2
(200 MHz, CDCl3):
d
¼7.44 (t, JH,F¼55.5 Hz, 1H, CF2eH), 5.33e5.35
1H, AreH), 4.05e4.27 (m, 4H, OeCH2), 2.35 (s, 6H, AreCH3), 1.35 (t,
(m, 1H, C]CeH), 3.95e4.14 (m, 4H, OeCH2), 2.75 (s, 2H, CH2),
3JH,H¼6.9 Hz, 6H, CH3) ppm. 13C NMR (50 MHz, CDCl3):
¼142.3 (d,
d
2.87e2.95 (m, 2H, CH2), 1.65 (br s, 6H, CH3), 1.27 (t, 3JH,H¼7.1 Hz, 6H,
4JC,P¼3.1 Hz, 1C, 4-C), 140.3 (dt, 2JC,P¼14.0 Hz, 4JC,F¼0.9 Hz, 1C, 6-C),
137.7 (d, 3JC,P¼8.1 Hz, 1C, 5-C), 136.3 (td, 2JC,F¼27.3 Hz, 2JC,P¼6.8 Hz,
CH3) ppm. 13C NMR (50 MHz, CDCl3):
d
¼143.5 (td, JC,F¼24.5 Hz,
2
2JC,P¼8.9 Hz, 1C, 2-C), 128.1 (dt, 1JC,P¼175.2 Hz, 3JC,F¼8.7 Hz, 1C, 1-C),
130.0 (d, 3JC,P¼9.6 Hz, 1C, 5-C), 116.8 (d, 4JC,P¼2.2 Hz, 1C, 4-C), 112.1
(td, 1JC,F¼233.8 Hz, 3JC,P¼7.8 Hz, 1C, 7-C), 62.4 (d, 2JC,P¼5.6 Hz, 2C, i-
C), 33.1 (d, 2JC,P¼7.4 Hz, 1C, 6-C), 24.4 (dt, 3JC,P¼14.6 Hz, 3JC,F¼3.7 Hz,
1C, 3-C), 22.8 (d, 4JC,P¼1.6 Hz, 1C, 8-C), 16.6 (d, 3JC,P¼6.2 Hz, 2C, j-C)
1C, 2-C), 128.7 (dt, JC,P¼12.2 Hz, JC,F¼7.1 Hz, 1C, 3-C), 126.0 (td,
3 1
3
3
1JC,F¼292.2 Hz, JC,P¼4.3 Hz, 1C, 7-C), 122.5 (dt, JC,P¼186.7 Hz,
3JC,F¼1.9 Hz, 1C, 1-C), 62.9 (d, JC,P¼6.2 Hz, 2C, i-C), 20.3 (d,
2
4JC,P¼1.2 Hz, 1C, 8-C), 19.9 (s, 1C, 9-C), 16.7 (d, 3JC,P¼6.8 Hz, 2C, j-C)
ppm. 31P NMR (81 MHz, CDCl3):
NMR (188 MHz, CDCl3):
d
¼17.3 (t, 4JP,F¼2.0 Hz, 1P) ppm. 19
F
ppm. 31P NMR (81 MHz, CDCl3):
d
¼16.7 (t, 4JP,F¼4.9 Hz, 1P) ppm. 19
F
d
¼ꢀ46.9 (s, 2F, CF2Cl) ppm. MS (EI, 70 eV):

S.N. Tverdomed et al. / Tetrahedron 67 (2011) 3887e3903
3899
3
4
2
m/z (%)¼326 (18) [M]þ, 241 (100) [MꢀCF2Cl]þ, 235 (82), 215 (90),
187 (20). HRMS (EI) for C13H18ClF2O3P [M]þ calcd 326.0650; found
326.0650.
7.59 (dd, JH,H¼8.3 Hz, JH,P¼5.0 Hz, 1H, AreH), 7.28 (t, JH,F¼54.5 Hz,
1H, CF2eH), 3.94e4.12 (m, 4H, OeCH2), 2.37 (s, 3H, AreCH3), 1.26 (t,
3JH,H¼6.9 Hz, 6H, CH3) ppm. 13C NMR (50 MHz, CDCl3):
d¼140.9 (dt,
2JC,P¼14.0 Hz, JC,F¼1.8 Hz, 1C, 6-C), 134.7 (td, JC,F¼23.3 Hz,
4
2
3
4.1.26. Diethyl 2-[bromo(difluoro)methyl]-4,5-dimethylphenylphos-
phonate (8d). Prepared similarly to 8a from 5d (31.4 g, 84 mmol),
KMnO4/Al2O3 reagent (54.4 g, 172 mmol) at 0e5 ꢁC for 6 h; yield
2JC,P¼9.9 Hz, 1C, 2-C), 134.4 (d, JC,P¼8.7 Hz, 1C, 5-C), 133.8 (dt,
4JC,P¼2.8 Hz, JC,F¼0.8 Hz, 1C, 4-C), 126.7 (dt, JC,P¼180.8 Hz,
4
1
3JC,F¼5.6 Hz, 1C, 1-C), 126.5 (dt, JC,P¼13.6 Hz, JC,F¼5.9 Hz, 1C, 3-C),
3
3
26.5 g (85%) as a yellow-orange oil, bp 143e145 ꢁC (0.1 mmHg). 1H
112.5 (td, 1JC,F¼236.4 Hz, 3JC,P¼3.4 Hz,1C, 7-C), 62.7 (d, 2JC,P¼5.4 Hz, 2C,
3
4
3
NMR (200 MHz, CDCl3):
d
¼7.94 (d, JH,P¼15.7 Hz, 1H, AreH), 7.49
i-C), 21.7 (d, JC,P¼1.6 Hz, 1C, 8-C), 16.3 (d, JC,P¼6.5 Hz, 2C, j-C) ppm.
4
(d, 4JH,P¼5.9 Hz, 1H, AreH), 4.05e4.26 (m, 4H, OeCH2), 2.32 (s, 6H,
31P NMR (81 MHz, CDCl3):
d
¼17.9 (t, JP,F¼2.5 Hz, 1P) ppm. 19F NMR
AreCH3), 1.33 (t, JH,H¼6.9 Hz, 6H, CH3) ppm. 13C NMR (50 MHz,
(188 MHz, CDCl3):
d
¼ꢀ110.9 (dd, 2JF,H¼54.7 Hz, 4JF,P¼2.4 Hz, 2F, CF2H)
3
CDCl3):
d
¼142.3 (d, 4JC,P¼3.1 Hz, 1C, 4-C), 140.4 (d, 2JC,P¼14.1 Hz, 1C,
ppm. MS (EI, 70 eV): m/z (%)¼277 (30) [MꢀH]þ, 227 (95) [MꢀCF2H]þ,
222 (80), 185 (100), 169 (60). HRMS (EI) for C12H16F2O3P [MꢀH]þ calcd
277.0805; found 277.0807.
2
2
6-C), 138.1 (td, JC,F¼24.2 Hz, JC,P¼6.5 Hz, 1C, 2-C), 137.5 (d,
3JC,P¼8.1 Hz, 1C, 5-C), 128.6 (dt, 3JC,P¼12.1 Hz, 3JC,F¼6.9 Hz, 1C, 3-C),
1
3
121.8 (dt, JC,P¼187.3 Hz, JC,F¼1.9 Hz, 1C, 1-C), 117.4 (td,
1JC,F¼305.8 Hz, JC,P¼4.3 Hz, 1C, 7-C), 62.9 (d, JC,P¼5.6 Hz, 2C, i-C),
4.1.30. 4,5-Dimethyl-2-(trifluoromethyl)phenylphosphonic dichloride
(11a). To arylphosphonate 8a (5.52 g, 17.8 mmol) freshly distilled
phosphorus oxychloride (3.5 mL, 37.4 mmol) was added and the
mixture was cooled to 0 ꢁC. Then, phosphorus pentachloride
(8.52 g, 40.9 mmol) was added in small portions and the mixture
was stirred under reflux for 4 h (Method C). The excess of phos-
phorus oxychloride was removed under reduced pressure and the
resulting crude product was distilled in a vacuum yielding 4.9 g
3
2
20.3 (d, 4JC,P¼1.2 Hz, 1C, 8-C), 19.9 (s, 1C, 9-C), 16.7 (d, 3JC,P¼6.2 Hz,
2C, j-C) ppm. 31P NMR (81 MHz, CDCl3):
d
¼17.3 (t, 4JP,F¼2.0 Hz, 1P)
ppm. 19F NMR (188 MHz, CDCl3):
d
¼ꢀ41.6 (s, 2F, CF2Br) ppm. MS (EI,
70 eV): m/z (%)¼291 (75) [MꢀBr]þ, 254 (42), 241 (45), 235 (80), 215
(100). HRMS (EI) for C13H18F2O3P [MꢀBr]þ calcd 291.0962; found
291.0942.
4.1.27. Diethyl 2-(difluoromethyl)-4,5-dimethylphenylphosphonate
(8e). Prepared similarly to 8a from 5e (14.7 g, 50 mmol), KMnO4/
Al2O3 reagent (33.2 g, 105 mmol) at 0e5 ꢁC for 6.5 h; yield 11.7 g
(94%) of 11a as a yellowish oil, bp 98e100 ꢁC (0.1 mmHg). 1H NMR
3
(200 MHz, CDCl3):
d
¼8.10 (d, JH,P¼20.6 Hz, 1H, AreH), 7.67 (d,
4JH,P¼8.8 Hz, 1H, AreH), 2.44 (s, 6H, AreCH3) ppm. 13C NMR
(80%) as a yellowish oil, bp 115e117 ꢁC (0.1 mmHg). 1H NMR
(50 MHz, CDCl3):
d
¼145.6 (d, JC,P¼3.7 Hz, 1C, 4-C), 141.9 (d,
4
3
3
(200 MHz, CDCl3):
d
¼7.63 (d, JH,P¼14.4 Hz, 1H, AreH), 7.48 (d,
2JC,P¼16.8 Hz, 1C, 6-C), 136.8 (d, JC,P¼11.8 Hz, 1C, 5-C), 130.1 (dq,
4JH,P¼4.9 Hz, 1H, AreH), 7.21 (t, JH,F¼55.0 Hz, 1H, CF2eH),
3JC,P¼14.3 Hz, JC,F¼5.6 Hz, 1C, 3-C), 129.4 (dq, JC,P¼152.0 Hz,
3JC,F¼1.2 Hz, 1C, 1-C), 129.2 (qd, 2JC,F¼33.5 Hz, 2JC,P¼9.3 Hz, 1C, 2-C),
123.4 (qd, 1JC,F¼274.2 Hz, 3JC,P¼5.0 Hz, 1C, 7-C), 20.5 (d, 4JC,P¼1.9 Hz,
2
3
1
3.88e4.11 (m, 4H, OeCH2), 2.22 (s, 6H, AreCH3), 1.20 (t,
3JH,H¼7.1 Hz, 6H, CH3) ppm. 13C NMR (50 MHz, CDCl3):
¼142.7 (d,
d
4JC,P¼3.1 Hz, 1C, 4-C), 139.7 (dt, 2JC,P¼14.3 Hz, 4JC,F¼1.9 Hz, 1C, 6-C),
135.1 (d, 3JC,P¼8.9 Hz, 1C, 5-C), 135.0 (td, 2JC,F¼22.6 Hz, 2JC,P¼9.3 Hz,
1C, 8-C), 20.3 (s, 1C, 9-C) ppm. 31P NMR (81 MHz, CDCl3):
d¼32.7 (s,
1P) ppm. 19F NMR (188 MHz, CDCl3):
d
¼ꢀ57.2 (s, 3F, CF3) ppm. MS
3
3
1C, 2-C), 127.8 (dt, JC,P¼13.6 Hz, JC,F¼5.6 Hz, 1C, 3-C), 123.5 (dt,
(EI, 70 eV): m/z (%)¼290 (100) [M]þ, 270 (22) [MꢀHF]þ, 255 (40)
[MꢀCl]þ, 170 (43). HRMS (EI) for C9H8Cl2F3OP [M]þ calcd 289.9642;
found 289.9646.
1JC,P¼183.6 Hz, JC,F¼6.5 Hz, 1C, 1-C), 112.7 (td, JC,F¼236.3 Hz,
3
1
3JC,P¼3.1 Hz, 1C, 7-C), 62.6 (d, JC,P¼5.3 Hz, 2C, i-C), 20.2 (d,
2
4JC,P¼0.9 Hz, 1C, 8-C), 19.8 (s, 1C, 9-C), 16.5 (d, 3JC,P¼6.5 Hz, 2C, j-C)
ppm. 31P NMR (81 MHz, CDCl3):
NMR (188 MHz, CDCl3):
d
¼18.4 (t, 4JP,F¼2.5 Hz, 1P) ppm. 19
F
4.1.31. 4,5-Dimethyl-2-(perfluoroethyl)phenylphosphonic dichloride
(11b). Prepared similarly to 11a from 8b (4.94 g, 13.7 mmol), POCl3
(2.7 mL, 28.8 mmol) and PCl5 (6.56 g, 31.5 mmol); yield 4.4 g (93%)
d
¼ꢀ110.8 (d, 2JF,H¼55.1 Hz, 2F, CF2H) ppm.
MS (EI, 70 eV): m/z (%)¼292 (100) [M]þ, 241 (70) [MꢀCF2H]þ, 224
(40), 199 (90), 183 (60). HRMS (EI) for C13H19F2O3P [M]þ calcd
292.1040; found 292.1033.
as a yellowish solid, mp 49 ꢁC, bp 108e110 ꢁC (0.1 mmHg). 1H NMR
3
(200 MHz, CDCl3):
d
¼8.21 (d, JH,P¼20.5 Hz, 1H, AreH), 7.56 (d,
4JH,P¼9.3 Hz, 1H, AreH), 2.44 (s, 6H, AreCH3) ppm. 13C NMR
4
4.1.28. Diethyl 2-(difluoromethyl)-4-methylphenylphosphonate (9e).
Prepared similarly to 8a from 6e:7e (16.8 g, 60 mmol), KMnO4/Al2O3
reagent (49.3 g, 156 mmol) at 10e15 ꢁC for 10 h; purified by distil-
lation in vacuo using Vigreux column; in mixture with 10e; yield
(together with isomer 10e) 10.0 g (60%) as a yellowish oil; content
61 mol %, bp 110e112 ꢁC (0.1 mmHg). 1H NMR (200 MHz, CDCl3):
(50 MHz, CDCl3):
d
¼144.9 (d, JC,P¼4.3 Hz, 1C, 4-C), 142.2 (dt,
2JC,P¼16.8 Hz, 4JC,F¼1.2 Hz, 1C, 6-C), 136.6 (d, 3JC,P¼11.8 Hz, 1C, 5-C),
3
3
4
131.9 (dtq, JC,P¼14.3 Hz, JC,F¼8.1 Hz, JC,F¼1.9 Hz, 1C, 3-C), 127.6
(td, 2JC,F¼24.8 Hz, 2JC,P¼8.7 Hz, 1C, 2-C), 130.7 (d, 1JC,P¼151.4 Hz, 1C,
1
2
1-C), 119.3 (qt, JC,F¼287.2 Hz, JC,F¼39.1 Hz, 1C, CF3), 114.1 (tqd,
1JC,F¼257.4 Hz, JC,F¼39.1 Hz, JC,P¼3.7 Hz, 1C, 7-C), 20.4 (d,
2
3
3
3
d
¼7.93 (dd, JH,P¼14.2 Hz, JH,H¼7.9 Hz, 1H, AreH), 7.64 (d,
4JC,P¼1.9 Hz, 1C, 8-C), 20.3 (s, 1C, 9-C) ppm. 31P NMR (81 MHz,
4JH,P¼5.4 Hz, 1H, AreH), 7.40 (dd, JH,H¼8.0 Hz, JH,P¼4.7 Hz, 1H,
CDCl3):
d
¼33.6 (s, 1P) ppm. 19F NMR (188 MHz, CDCl3):
¼ꢀ104.4
d
3 4
AreH), 7.31 (t, 2JH,F¼54.8 Hz, 1H, CF2eH), 4.02e4.18 (m, 4H, OeCH2),
(s, 2F, CF2), ꢀ83.5 (s, 3F, CF3) ppm. MS (EI, 70 eV): m/z (%)¼340 (65)
[M]þ, 305 (15) [MꢀCl]þ, 271 (100), 167 (18), 103 (10). HRMS (EI) for
C10H8Cl2F5OP [M]þ calcd 339.9610; found 339.9610.
2.38 (s, 3H, AreCH3), 1.25 (t, JH,H¼7.1 Hz, 6H, CH3) ppm. 13C NMR
3
4
4
(50 MHz, CDCl3):
d
¼144.0 (dt, JC,P¼3.1 Hz, JC,F¼0.9 Hz, 1C, 4-C),
137.5 (td, 2JC,F¼22.6 Hz, 2JC,P¼9.9 Hz, 1C, 2-C), 134.0 (d, 3JC,P¼8.7 Hz,
2
4
1C, 5-C), 131.2 (dt, JC,P¼14.6 Hz, JC,F¼1.8 Hz, 1C, 6-C), 127.0 (dt,
4.1.32. 2-[Chloro(difluoro)methyl]-4,5-dimethylphenylphosphonic
dichloride (11c). Prepared similarly to 11a from 8c (4.05 g,
12.4 mmol), POCl3 (2.4 mL, 26.0 mmol) and PCl5 (5.94 g,
28.5 mmol); yield 3.3 g (87%) as a yellowish solid, mp 64 ꢁC, bp
3
1
3JC,P¼13.7 Hz, JC,F¼6.2 Hz, 1C, 3-C), 123.7 (dt, JC,P¼184.5 Hz,
3JC,F¼6.2 Hz, 1C, 1-C), 112.4 (td, 1JC,F¼236.6 Hz, 3JC,P¼3.7 Hz, 1C, 7-C),
2
5
62.6 (d, JC,P¼5.6 Hz, 2C, i-C), 21.3 (d, JC,P¼0.6 Hz, 1C, 9-C), 16.3 (d,
3JC,P¼6.5 Hz, 2C, j-C) ppm. 31P NMR (81 MHz, CDCl3):
d
¼18.0 (t,
134e135 ꢁC (0.1 mmHg). 1H NMR (200 MHz, CDCl3):
d¼8.09 (d,
4JP,F¼2.6 Hz, 1P) ppm. 19F NMR (188 MHz, CDCl3):
2JF,H¼55.2 Hz, 4JF,P¼2.3 Hz, 2F, CF2H) ppm.
d
¼ꢀ111.6 (dd,
3JH,P¼20.6 Hz, 1H, AreH), 7.64 (d, JH,P¼8.8 Hz, 1H, AreH), 2.43 (s,
4
6H, AreCH3) ppm. 13C NMR (50 MHz, CDCl3):
d
¼145.2 (d,
4JC,P¼3.7 Hz, 1C, 4-C), 141.4 (dt, 2JC,P¼16.8 Hz, 4JC,F¼1.2 Hz, 1C, 6-C),
4.1.29. Diethyl 2-(difluoromethyl)-5-methylphenylphosphonate (10e).
In mixture with 9e; content 39 mol %. 1H NMR (200 MHz, CDCl3):
135.9 (d, 3JC,P¼11.8 Hz,1C, 5-C),135.5 (td, 2JC,F¼27.9 Hz, 2JC,P¼9.3 Hz,
3
3
1C, 2-C), 129.6 (dt, JC,P¼14.3 Hz, JC,F¼6.5 Hz, 1C, 3-C), 127.8 (dt,
3
1
d
¼7.67 (d, 3JH,H¼8.2 Hz, 1H, AreH), 7.64 (d, 3JH,P¼14.7 Hz, 1H, AreH),
1JC,P¼153.2 Hz, JC,F¼1.4 Hz, 1C, C-1), 125.3 (td, JC,F¼290.9 Hz,

3900
S.N. Tverdomed et al. / Tetrahedron 67 (2011) 3887e3903
3JC,P¼4.3 Hz, 1C, 7-C), 20.5 (d, 4JC,P¼1.3 Hz, 1C, 8-C), 20.2 (s, 1C, 9-C)
285 (35) [MꢀCH3]þ, 215 (10), 181 (30) [MꢀC2F5]þ. HRMS (EI) for
ppm. 31P NMR (81 MHz, CDCl3):
d
¼33.3 (s, 1P) ppm. 19F NMR
C12H14F5OP [M]þ calcd 300.0702; found 300.0700.
(188 MHz, CDCl3):
d
¼ꢀ44.8 (s, 2F, CF2Cl) ppm. MS (EI, 70 eV): m/z
(%)¼306 (13) [M]þ, 273 (60), 271 (100) [MꢀCl]þ,167 (15). HRMS (EI)
4.1.36. {2-[Chloro(difluoro)methyl]-4,5-dimethylphenyl}(dimethyl)
phosphine oxide (12c). Prepared similarly to 12a from 11c (3.04 g,
9.9 mmol), methylmagnesium bromide (20.8 mmol) in dry THF
for C9H8Cl3F2OP [M]þ calcd 305.9346; found 305.9340.
4.1.33. 2-[Bromo(difluoro)methyl]-4,5-dimethylphenylphosphonic
dichloride (11d). Prepared similarly to 11a from 8d (4.68 g,
12.6 mmol), POCl3 (2.5 mL, 26.5 mmol) and PCl5 (6.04 g,
29.0 mmol); yield 3.8 g (85%), yellowish solid, mp 70 ꢁC, bp
(60 mL); yield 2.1 g (78%) as a yellowish solid, mp 175 ꢁC. 1H NMR
3
(200 MHz, CDCl3):
d
¼8.29 (d, JH,P¼13.7 Hz, 1H, AreH), 7.51 (d,
4JH,P¼4.9 Hz, 1H, AreH), 2.35 (s, 3H, AreCH3), 2.32 (s, 3H, AreCH3),
2.07 (dt, JH,P¼13.7 Hz, JH,F¼1.9 Hz, 6H, PeCH3) ppm. 13C NMR
2
6
142e144 ꢁC (0.1 mmHg). 1H NMR (200 MHz, CDCl3):
d
¼8.05 (d,
(50 MHz, CDCl3):
d
¼142.4 (d, JC,P¼2.1 Hz, 1C, 4-C), 141.8 (d,
4
4
3
3JH,P¼20.6 Hz, 1H, AreH), 7.61 (d, JH,P¼8.8 Hz, 1H, AreH), 2.42 (s,
2JC,P¼10.6 Hz, 1C, 6-C), 136.4 (d, JC,P¼6.8 Hz, 1C, 5-C), 134.6 (td,
6H, AreCH3) ppm. 13C NMR (50 MHz, CDCl3):
d
¼145.2 (d,
2JC,F¼26.7 Hz, JC,P¼8.1 Hz, 1C, 2-C), 129.0 (dt, JC,P¼90.6 Hz,
2
1
2
3
3
4JC,P¼3.7 Hz, 1C, 4-C), 141.4 (d, JC,P¼16.1 Hz, 1C, 6-C), 135.9 (d,
3JC,F¼2.9 Hz, 1C, 1-C), 129.0 (dt, JC,P¼8.9 Hz, JC,F¼6.4 Hz, 1C, 3-C),
127.7 (td, 1JC,F¼269.2 Hz, 3JC,P¼1.9 Hz, 1C, 7-C), 20.1 (d, 4JC,P¼1.0 Hz,
1C, 8-C), 20.0 (s, 1C, 9-C), 19.3 (dt, 1JC,P¼73.8 Hz, 5JC,F¼5.0 Hz, 2C, i-
3JC,P¼11.8 Hz,1C, 5-C),135.6 (td, 2JC,F¼29.2 Hz, 2JC,P¼8.7 Hz,1C, 2-C),
3
3
129.6 (dt, JC,P¼14.0 Hz, JC,F¼7.1 Hz, 1C, 3-C), 127.8 (dt,
1JC,P¼153.2 Hz, JC,F¼2.1 Hz, 1C, 1-C), 125.4 (td, JC,F¼290.9 Hz,
C) ppm. 31P NMR (81 MHz, CDCl3):
d
¼44.3 (s, 1P) ppm. 19F NMR
3
1
3JC,P¼4.4 Hz, 1C, 7-C), 20.5 (d, 4JC,P¼1.9 Hz, 1C, 8-C), 20.2 (s, 1C, 9-C)
(188 MHz, CDCl3):
d
¼ꢀ43.9 (s, 2F, CF2Cl) ppm. MS (EI, 70 eV): m/z
ppm. 31P NMR (81 MHz, CDCl3):
d
¼33.4 (s, 1P) ppm. 19F NMR
(%)¼266 (100) [M]þ, 251 (10) [MꢀCH3]þ, 231 (50) [MꢀCH2Cl]þ, 215
(30). HRMS (EI) for C11H14ClF2OP [M]þ calcd 266.0439; found
266.0432.
(188 MHz, CDCl3):
d
¼ꢀ40.2 (s, 2F, CF2Br) ppm. MS (EI, 70 eV): m/z
(%)¼271 (100) [MꢀBr]þ, 167 (12), 139 (8), 103 (10). HRMS (EI) for
C9H8Cl2F2OP [MꢀBr]þ calcd 270.9658; found 270.9653.
4.1.37. {2-[Bromo(difluoro)methyl]-4,5-dimethylphenyl}(dimethyl)
phosphine oxide (12d). Prepared similarly to 12a from 11d (3.29 g,
9.35 mmol), methylmagnesium bromide (19.6 mmol) in dry THF
(55 mL); yield 1.5 g (51%) as a yellow-orange solid, mp 184 ꢁC. 1H
4.1.34. [4,5-Dimethyl-2-(trifluoromethyl)phenyl](dimethyl)phos-
phine oxide (12a). To a solution of phosphonic dichloride 11a
(2.74 g, 9.4 mmol) in a dry THF (65 mL) at ꢀ30 ꢁC methyl-
magnesium bromide (3.2 M solution in THF, 19.8 mmol) was added
dropwise, the mixture was stirred for 3 h at ꢀ30 ꢁC and left over-
night to warm to rt. Next, 10% HCl (15 mL) was added at ꢀ30 ꢁC and
stirred for 1 h at rt. The water phase was separated, extracted with
diethyl ether (3ꢄ30 mL), organic layers were combined, dried over
MgSO4 and solvent evaporated under reduced pressure giving
crude product then was purified by sublimation in vacuo
(0.1 mmHg) yielding 1.77 g (75%) of 12a as a white solid; mp 104 ꢁC,
NMR (200 MHz, CDCl3):
d
¼8.10 (d, 3JH,P¼13.8 Hz,1H, AreH), 7.98 (d,
4JH,P¼5.1 Hz, 1H, AreH), 2.33 (s, 3H, AreCH3), 2.31 (s, 3H, AreCH3),
2
6
2.04 (dt, JH,P¼14.2 Hz, JH,F¼1.6 Hz, 6H, PeCH3) ppm. 13C NMR
4
(50 MHz, CDCl3):
d
¼142.0 (d, JC,P¼3.4 Hz, 1C, 4-C), 141.2 (d,
2JC,P¼10.6 Hz,1C, 6-C),136.4 (td, 2JC,F¼24.1 Hz, 2JC,P¼6.7 Hz,1C, 2-C),
135.8 (d, 3JC,P¼5.9 Hz, 1C, 5-C), 129.8 (dt, 1JC,P¼85.7 Hz, 3JC,F¼2.4 Hz,
3
3
1C, 1-C), 128.7 (dt, JC,P¼15.4 Hz, JC,F¼6.7 Hz, 1C, 3-C), 124.9 (td,
3
4
1JC,F¼274.5 Hz, JC,P¼3.0 Hz, 1C, 7-C), 20.0 (d, JC,P¼1.8 Hz, 1C, 8-C),
bp 116e117 ꢁC (0.1 mmHg). 1H NMR (200 MHz, CDCl3):
d
¼8.16 (d,
19.7 (s, 1C, 9-C), 18.7 (dt, JC,P¼73.2 Hz, JC,F¼4.7 Hz, 2C, i-C) ppm.
1
5
4
3JH,P¼13.7 Hz, 1H, AreH), 7.58 (d, JH,P¼4.9 Hz, 1H, AreH), 2.40 (s,
31P NMR (81 MHz, CDCl3):
CDCl3):
d
¼42.8 (s, 1P) ppm. 19F NMR (188 MHz,
5
3H, AreCH3), 2.37 (d, JH,P¼0.5 Hz, 3H, AreCH3), 1.96 (dq,
d
¼ꢀ38.1 (s, 2F, CF2Br) ppm. MS (EI, 70 eV): m/z (%)¼310
6
2JH,P¼13.7 Hz, JH,F¼1.7 Hz, 6H, PeCH3) ppm. 13C NMR (50 MHz,
(25) [M]þ, 295 (20) [MꢀCH3]þ, 231 (100) [MꢀBr]þ, 181 (50)
[MꢀCF2Br]þ. HRMS (EI) for C11H14BrF2OP [M]þ calcd 310.0347;
found 310.0342.
4
2
CDCl3):
d
¼142.3 (d, JC,P¼2.5 Hz, 1C, 4-C), 142.1 (dq, JC,P¼10.5 Hz,
4JC,F¼1.2 Hz, 1C, 6-C), 136.4 (d, JC,P¼6.5 Hz, 1C, 5-C), 129.2 (dq,
3
3JC,P¼8.7 Hz, JC,F¼5.6 Hz, 1C, 3-C), 128.24 (qd, JC,F¼31.9 Hz,
2JC,P¼7.4 Hz, 1C, 2-C), 127.8 (dq, 1JC,P¼90.6 Hz, 3JC,F¼1.9 Hz, 1C, 1-C),
124.5 (qd, 1JC,F¼272.9 Hz, 3JC,P¼2.5 Hz,1C, 7-C), 20.2 (d, 4JC,P¼0.9 Hz,
1C, 8-C), 20.1 (s, 1C, 9-C), 18.7 (dq, 1JC,P¼72.0 Hz, 5JC,F¼3.7 Hz, 2C, i-
3
2
4.1.38. 2-[Bromo(difluoro)methyl]-4,5-dimethylphenyl(penta-
fluoroethyl) phosphinic acid (13). To a solution of pentafluoroethane
(1.61 g, 13.4 mmol) in dry THF (50 mL), cooled to ꢀ90 ꢁC, n-BuLi
(12.9 mmol, 2.5 M solution in hexane) was added dropwise keeping
the temperature below ꢀ80 ꢁC. The resulting mixture was stirred
for 1 h at that temperature and a solution of 11d (1.97 g, 5.6 mmol)
in dry THF (10 mL) was added slowly at ꢀ80 ꢁC and stirred at that
temperature for 4 h. The reaction was warmed slowly to rt, cooled
to ꢀ20 ꢁC and 10% HCl (15 mL) was added. Next, water phase was
separated and washed with diethyl ether (3ꢄ20 mL), organic layers
were combined and dried over MgSO4. After removal of volatiles
under reduced pressure the crude product was purified by sub-
limation in vacuum (0.1 mmHg) yielding 2.0 g (85%) of 13 as a white
C) ppm. 31P NMR (81 MHz, CDCl3):
d
¼43.9 (s, 1P) ppm. 19F NMR
(188 MHz, CDCl3):
d
¼ꢀ56.9 (s, 3F, CF3) ppm. MS (EI, 70 eV): m/z
(%)¼250 (100) [M]þ, 235 (20) [MꢀCH3]þ, 187 (50), 181 (10)
[MꢀCF3]þ. HRMS (EI) for C11H14F3OP [M]þ calcd 250.0734; found
250.0721.
4.1.35. [4,5-Dimethyl-2-(pentafluoroethyl)phenyl](dimethyl)phos-
phine oxide (12b). Prepared similarly to 12a from 11b (3.1 g,
9.1 mmol), methylmagnesium bromide (19.1 mmol) in dry THF
(70 mL); yield 2.0 g (73%) as a white solid, mp 232 ꢁC. 1H NMR
3
(200 MHz, CDCl3):
d
¼8.14 (d, JH,P¼14.2 Hz, 1H, AreH), 7.42 (d,
solid; mp 133 ꢁC. 1H NMR (200 MHz, CDCl3):
d
¼10.37 (s, 1H, OH),
4JH,P¼4.9 Hz, 1H, AreH), 2.37 (s, 3H, AreCH3), 2.35 (s, 3H, AreCH3),
7.92 (d, JH,P¼14.7 Hz, 1H, AreH), 7.59 (d, JH,P¼5.9 Hz, 1H, AreH),
3
4
2.00 (dt, JH,P¼13.2 Hz, JH,F¼1.9 Hz, 6H, PeCH3) ppm. 13C NMR
2.42 (s, 3H, AreCH3), 2.40 (s, 3H, AreCH3) ppm. 13C NMR (50 MHz,
2
6
4
(50 MHz, CDCl3):
d
¼142.7 (d, JC,P¼2.0 Hz, 1C, 4-C), 142.5 (dt,
CDCl3):
d
¼145.1 (d, 4JC,P¼3.1 Hz, 1C, 4-C), 141.0 (d, 3JC,P¼13.8 Hz, 1C,
2JC,P¼11.2 Hz, JC,F¼1.6 Hz, 1C, 6-C), 136.6 (d, JC,P¼7.4 Hz, 1C, 5-C),
5-C), 140.0 (td, JC,F¼24.5 Hz, JC,P¼7.7 Hz, 1C, 2-C), 138.5 (dt,
4
3
2
2
131.0 (dt, 3JC,P¼7.8 Hz, 3JC,F¼7.3 Hz, 1C, 3-C), 127.8 (d, 1JC,P¼93.7 Hz,
2JC,P¼7.7 Hz, JC,F¼0.7 Hz, 1C, 6-C), 128.5 (dt, JC,P¼12.3 Hz,
4
3
2
2
1
2
1C, 1-C), 126.8 (td, JC,F¼24.8 Hz, JC,P¼6.8 Hz, 1C, 2-C), 119.2 (qt,
3JC,F¼7.7 Hz, 1C, 3-C), 118.7 (qtd, JC,F¼369.7 Hz, JC,F¼49.1 Hz,
1JC,F¼287.2 Hz, JC,F¼39.1 Hz, 1C, CF3), 114.9 (tqd, JC,F¼255.0 Hz,
2JC,P¼17.3 Hz,1C, CF3),117.1 (dt, 1JC,P¼146.4 Hz, 3JC,F¼2.1 Hz,1C, C-1),
2
1
2JC,F¼38.5 Hz, JC,P¼1.9 Hz, 1C, 7-C), 20.2 (s, 2C, 8,9-C), 18.8 (dt,
115.4 (td, JC,F¼304.4 Hz, JC,P¼2.9 Hz, 1C, C-7), 111.6 (tdq,
1 2
3
1
3
1JC,P¼75.6 Hz, 5JC,F¼5.6 Hz, 2C, i-C) ppm. 31P NMR (81 MHz, CDCl3):
1JC,F¼279.4 Hz, JC,P¼147.4 Hz, JC,F¼39.5 Hz, 1C, PeCF2), 20.6 (d,
d
¼49.1 (s, 1P) ppm. 19F NMR (188 MHz, CDCl3):
d
¼ꢀ105.6 (s, 2F,
4JC,P¼0.9 Hz, 1C, 8-C), 20.0 (s, 1C, 9-C) ppm. 31P NMR (81 MHz,
CF2), ꢀ84.1 (s, 3F, CF3) ppm. MS (EI, 70 eV): m/z (%)¼300 (100) [M]þ,
CDCl3):
d
¼24.4 (t, JP,F¼88.3 Hz, 1P) ppm. 19F NMR (188 MHz,
2

S.N. Tverdomed et al. / Tetrahedron 67 (2011) 3887e3903
3901
CDCl3):
d
¼ꢀ124.6 (dtq, 2JF,P¼88.3 Hz, 6JF,F¼13.8 Hz, 3JF,F¼1.2 Hz, 2F,
3H, OH), 7.59 (d, 3JH,P¼21.0 Hz,1H, AreH), 7.56 (s,1H, AreH), 2.27 (s,
PeCF2), ꢀ81.4 (s, 3F, CF3), ꢀ42.8 (t, 6JF,F¼13.8 Hz, 2F, CF2Br) ppm. MS
(EI, 70 eV): m/z (%)¼337 (100) [MꢀBr]þ, 317 (20), 217 (83), 189 (30).
MS (CI, negative): m/z (%)¼415 (5) [MꢀH]ꢀ, 336 (100), 235 (20).
HRMS (EI) for C11H9F7O2P [MꢀBr]þ calcd 337.0228; found 337.0223.
6H, AreCH3) ppm. 13C NMR (50 MHz, DMSO-d6):
d
¼169.7 (d,
4
3JC,P¼4.8 Hz, 1C, COOH), 140.1 (d, JC,P¼2.9 Hz, 1C, 4-C), 139.7
2
3
(d, JC,P¼13.4 Hz, 1C, 6-C), 134.2 (d, JC,P¼8.6 Hz, 1C, 3-C), 133.5
3
2
(d, JC,P¼8.6 Hz, 1C, 5-C), 131.4 (d, JC,P¼12.5 Hz, 1C, 2-C), 129.9 (d,
1JC,P¼178.3 Hz, 1C, 1-C), 19.8 (br s, 1C, 8-C), 19.7 (s, 1C, 9-C) ppm. 31
P
4.1.39. 4,5-Dimethyl-2-(trifluoromethyl)phenylphosphonic acid (14a).
The solution of 11a (0.18 g, 0.62 mmol) in CH3CN (1 mL) was added
dropwise to a mixture of 5% aq solution of NaOH (8 mL) and aceto-
nitrile (18.6 mL) at rt and was stirred for 0.5 h at basic pH. RM was
acidified with concentrated HCl to pH 0e1 and the resulting pre-
cipitate was filtered off, washed with 1% HCl, dried and recrystallized
from 1,4-dioxane/EtOH (3:1) yielding 0.12 g (75%) of 14a as a white
NMR (81 MHz, DMSO-d6):
d
¼13.5 (s, 1P) ppm. MS (EI, 70 eV): m/z
(%)¼406 (10) [2Mꢀ3H2O]þ, 212 (100) [MꢀH2O]þ,148 (50),132 (95).
HRMS (EI) for C9H9O4P [MꢀH2O]þ calcd 212.0239; found 212.0233.
4.1.43. Bis(trimethylsilyl) 2-[bromo(difluoro)methyl]-4,5-dimethyl-
phenylphos-phonate (16). To a solution of 8d (1.7 g, 4.6 mmol) in dry
CH2Cl2 (20 mL), trimethylsilyl bromide (1.5 g, 9.7 mmol) was added
dropwise at 0 ꢁC; the mixture was stirred for 2 h at this temperature
and overnight at rt. Volatiles were evaporated and residue was dried
under vacuum (0.1 mmHg) yielding 2.1 g (98%) of 16 as a yellowish,
solid; mp 229e228 ꢁC (dec). 1H NMR (200 MHz, DMSO-d6):
d¼7.81 (d,
3JH,P¼14.7 Hz, 1H, AreH), 7.54 (d, JH,P¼4.9 Hz, 1H, AreH), 6.78 (br s,
4
2H, OH), 2.92 (s, 6H, AreCH3) ppm. 13C NMR (50 MHz, DMSO-d6):
d
¼141.1 (d, 2JC,P¼12.5 Hz, 1C, 6-C), 140.9 (d, 4JC,P¼2.5 Hz, 1C, 4-C), 136.4
viscous oil; 95 mol % purity. 1H NMR (200 MHz, CDCl3):
d
¼7.96 (d,
(d, 3JC,P¼7.5 Hz, 1C, 5-C), 129.0 (qd, 1JC,F¼305.2 Hz, 3JC,P¼2.5 Hz, 1C, 7-
3JH,P¼14.7 Hz,1H, AreH), 7.40 (d, 4JH,P¼4.9 Hz,1H, AreH), 2.26 (s, 6H,
2
2
C), 128.7 (qd, JC,F¼31.6 Hz, JC,P¼6.8 Hz, 1C, 2-C), 128.5 (dq,
AreCH3), 0.20 (s, 18H, SieCH3) ppm. 13C NMR (50 MHz, CDCl3):
3JC,P¼11.2 Hz, JC,F¼5.6 Hz, 1C, 3-C), 124.8 (dq, JC,P¼187.3 Hz,
d
¼141.3 (s, 1C, 4-C), 140.2 (d, JC,P¼14.3 Hz, 1C, 6-C), 137.2 (td,
3
1
2
3JC,F¼6.2 Hz, 1C, C-1), 20.1 (s, 1C, 9-C), 20.0 (d, JC,P¼0.9 Hz, 1C, 8-C)
2JC,F¼24.8 Hz, JC,P¼5.9 Hz, 1C, 2-C), 137.0 (d, JC,P¼8.4 Hz, 1C, 5-C),
4
2
3
ppm. 31P NMR (81 MHz, DMSO-d6):
d
¼10.5 (s, 1P) ppm. 19F NMR
128.4 (dt, JC,P¼11.2 Hz, JC,F¼6.5 Hz, 1C, 3-C), 125.4 (dt,
3 1
3
3
(188 MHz, DMSO-d6):
d
¼ꢀ57.5 (s, 3F, CF3) ppm. MS (EI, 70 eV): m/z
1JC,P¼195.1 Hz, JC,F¼5.6 Hz, 1C, 1-C), 117.8 (td, JC,F¼306.4 Hz,
3JC,P¼2.4 Hz,1C, 7-C), 20.2 (s,1C, 8-C),19.9 (s,1C, 9-C),1.4 (s, 6C, i-C)
(%)¼254 (100) [M]þ, 234 (17), 190 (22), 170 (30). HRMS (EI) for
C9H10F3O3P [M]þ calcd 254.0320; found 254.0315.
ppm. 31P NMR (81 MHz, CDCl3):
d
¼ꢀ1.2 (s, 1P) ppm. 19F NMR
(188 MHz, DMSO-d6):
d
¼ꢀ40.6 (s, 2F, CF2Br) ppm. MS (EI, 70 eV): m/
4.1.40. 4,5-Dimethyl-2-(pentafluoroethyl)phenylphosphonic acid (14b).
Prepared similarly to 14a from 11b (0.24 g, 0.72 mmol), 5% aq solution
of NaOH (8.6 mL) in acetonitrile (20.0 mL); yield 0.18 g (80%) as
a white solid, mp 206e207 ꢁC (dec) from 1,4-dioxane/EtOH (3:1). 1H
z (%)¼379 (100) [MꢀBr]þ, 291 (14), 195 (20), 147 (10). HRMS (EI) for
C15H26F2O3PSi2 [MꢀBr]þ calcd 379.0544; found 379.0548.
4.1.44. 2-[Bromo(difluoro)methyl]-4,5-dimethylphenylphosphonic
acid (14d). Methanol (20 mL) was added to 16 (2.0 g, 4.4 mmol) at
rt and the solution was stirred overnight. After the evaporation of
volatiles the resulting solid was washed with dry chloroform
(4ꢄ3 mL), dried in a vacuum and recrystallized from toluene/EtOH
NMR (200 MHz, DMSO-d6):
d
¼7.91 (d, 3JH,P¼14.7 Hz, 1H, AreH), 7.30
4
(d, JH,P¼5.9 Hz, 1H, AreH), 2.31 (s, 6H, AreCH3) ppm. 13C NMR
2
(50 MHz, DMSO-d6):
d
¼141.5 (d, JC,P¼12.4 Hz, 1C, 6-C), 141.0 (d,
4JC,P¼2.5 Hz, 1C, 4-C), 136.8 (d, JC,P¼7.5 Hz, 1C, 5-C), 131.3 (dt,
3
1JC,P¼178.6 Hz, JC,F¼2.4 Hz, 1C, 1-C), 130.3 (dt, JC,P¼9.8 Hz,
(5:1) yielding 0.92 g (66%) of 14d as a white solid; mp 197e199 ꢁC
3
3
3JC,F¼8.7 Hz, 1C, 3-C), 126.9 (td, JC,F¼24.2 Hz, JC,P¼6.8 Hz, 1C, 2-C),
(dec). 1H NMR (200 MHz, CD3OD):
d
¼7.87 (d, JH,P¼14.7 Hz, 1H,
2
2
3
1
2
4
119.5 (qt, JC,F¼288.1 Hz, JC,F¼39.5 Hz, 1C, CF3), 114.4 (tqd,
AreH), 7.52 (d, JH,P¼5.9 Hz, 1H, AreH), 2.34 (s, 6H, AreCH3) ppm.
1JC,F¼255.3 Hz, JC,F¼37.6 Hz, JC,P¼3.7 Hz, 1C, 7-C), 20.2 (s, 1C, 9-C),
13C NMR (50 MHz, CD3OD):
d
¼142.5 (d, 4JC,P¼1.9 Hz, 1C, 4-C), 141.3
2
3
20.0 (br s, 1C, 8-C) ppm. 31P NMR (81 MHz, DMSO-d6):
d
¼10.8 (s, 1P)
(d, JC,P¼13.7 Hz, 1C, 6-C), 138.6 (td, JC,F¼24.2 Hz, JC,P¼6.8 Hz, 1C,
2
2
2
ppm. 19F NMR (188 MHz, DMSO-d6):
d
¼ꢀ106.2 (s, 2F, CF2), ꢀ83.1 (s, 3F,
2-C), 136.6 (d, JC,P¼8.1 Hz, 1C, 5-C), 128.8 (dt, JC,P¼11.8 Hz,
3JC,F¼6.8 Hz, 1C, 3-C), 126.1 (dt, 1JC,P¼187.3 Hz, 3JC,F¼3.9 Hz, 1C, 1-C),
118.6 (td, 1JC,F¼304.6 Hz, 3JC,P¼4.4 Hz, 1C, 7-C), 19.8 (d, 4JC,P¼0.9 Hz,
3
3
CF3) ppm. MS (EI, 70 eV): m/z (%)¼304 (80) [M]þ, 215 (100), 187 (25),
173 (10). HRMS (EI) for C10H10F5O3P [M]þ calcd 304.0288; found
304.0286.
1C, 8-C),19.7 (s,1C, 9-C) ppm. 31P NMR (81 MHz, CD3OD):
d¼13.8 (s,
1P) ppm. 19F NMR (188 MHz, CD3OD):
d
¼ꢀ42.1 (s, 2F, CF2Br) ppm.
4.1.41. 2-[Chloro(difluoro)methyl]-4,5-dimethylphenylphosphonic
acid (14c). Prepared similarly to 14a from 11c (0.18 g, 0.59 mmol),
10% aq HCl (3.5 mL) in acetonitrile (14.0 mL) within 2.5 h; yield
MS (CI, negative): m/z (%)¼314 (9) [M]þ, 236 (26) [MꢀBr]þ, 214
(100), 187 (25). HRMS (CI) for C9H10BrF2O3P [M]þ calcd 313.9519;
found 313.9513.
0.14 g (85%) as a white solid, mp 209e210 ꢁC (dec) from benzene/
MeOH (6:1). 1H NMR (200 MHz, CD3CN):
d
¼7.24 (d, JH,P¼14.6 Hz,
4.1.45. (E)-Tetraethyl 6,60-(1,2-difluoroethene-1,2-diyl)bis(3,4-dimet-
hyl-6,1-phenylene)diphosphonate (18). To a suspension of freshly
activated Zn powder (0.3 g, 4.56 mmol) in dry DMF (10 mL) a solu-
tion of 8d (1.41 g, 3.8 mmol) in 3 mL dry DMF was added dropwise.
The mixture was stirred for 3 h at the temperature not exceeding
40 ꢁC and filtered under nitrogen. The filtrate was added slowly to
a solution of CuBr (0.55 g, 3.83 mmol) in a dry DMF (20 mL) at
ꢀ30 ꢁC. The mixture was stirred for 0.5 h at the same temperature
while 2% aq HCl (150 mL) was added under cooling with an ice bath.
The resulting mixture was extracted with diethyl ether (4ꢄ50 mL),
organic layers were combined, dried over MgSO4 and volatiles re-
moved under reduced. The crude product was purified by a re-
crystallization from a diethyl ether yielding 0.78 g (71%) of 18 as
3
4
1H, AreH), 6.96 (d, JH,P¼4.9 Hz, 1H, AreH), 1.74 (s, 3H, AreCH3),
1.72 (s, 3H, AreCH3) ppm. 13C NMR (50 MHz, DMSO-d6):
d
¼140.8
4
2
(d, JC,P¼2.9 Hz, 1C, 4-C), 140.3 (d, JC,P¼12.5 Hz, 1C, 6-C), 135.9 (d,
3JC,P¼7.7 Hz,1C, 5-C),134.0 (td, 2JC,F¼30.6 Hz, 2JC,P¼10.7 Hz,1C, 2-C),
1
3
131.2 (dt, JC,P¼178.9 Hz, JC,F¼3.4 Hz, 1C, 1-C), 127.8 (dt,
3JC,P¼10.5 Hz, JC,F¼7.7 Hz, 1C, 3-C), 123.6 (td, JC,F¼293.7 Hz,
3
1
3JC,P¼8.3 Hz, 1C, 7-C), 19.1 (s, 1C, 9-C), 19.0 (d, 4JC,P¼0.9 Hz, 1C, 8-C)
ppm. 31P NMR (81 MHz, CD3CN):
d
¼10.7 (s, 1P) ppm. 19F NMR
(188 MHz, CD3CN):
d
¼ꢀ45.0 (s, 2F, CF2Cl) ppm. MS (EI, 70 eV): m/z
(%)¼270 (20) [M]þ, 215 (100), 212 (90), 148 (40). HRMS (EI) for
C9H10ClF2O3P [M]þ calcd 270.0024; found 270.0025.
4.1.42. 4,5-Dimethyl-2-phosphonobenzoic acid (15). Prepared simi-
larly to 14a from 11d (0.31 g, 0.88 mmol) or 11c (0.26 g, 0.85 mmol),
5% aq solution of NaOH (10 mL) in acetonitrile (23.0 mL) within
0.5 h; yield 0.19 g (95%) as a white solid, mp 242e244 ꢁC (dec) from
white crystals; mp 137e138 ꢁC. 1H NMR (200 MHz, CDCl3):
d¼7.87
3
4
(d, JH,P¼14.2 Hz, 2H, AreH), 7.54 (d, JH,P¼5.4 Hz, 2H, AreH),
3.99e4.24 (m, 8H, OeCH2), 2.35 (s, 12H, AreCH3), 1.31 (t,
3JH,H¼6.9 Hz, 12H, CH3) ppm. 13C NMR (50 MHz, CDCl3):
¼147.4
d
1,4-dioxane/MeOH (5:1). 1H NMR (200 MHz, DMSO-d6):
d¼11.42 (s,
(ddd, JC,F¼297.1 Hz, JC,F¼112.0 Hz, JC,P¼5.3 Hz, 2C, 7,70-C), 142.1
1
2
3

3902
S.N. Tverdomed et al. / Tetrahedron 67 (2011) 3887e3903
(dd, 4JC,P¼3.4 Hz, 4JC,F¼1.2 Hz, 2C, 4,40-C), 139.2 (ddd, 2JC,P¼14.6 Hz,
61:39 mol %), t-BuLi (19.8 mmol) and MeI (1.2 mL, 19.8 mmol) in
dry THF (220 mL) at ꢀ25 ꢁC within 4 h; yield 2.0 g (62%, 38%
overall) as a colourless oil, eluent dichloromethane/ethylacetate
5
3
4JC,P¼1.2 Hz, JC,P¼1.2 Hz, 2C, 6,60-C), 136.3 (dd, JC,P¼9.3 Hz,
3
3
5JC,P¼1.0 Hz, 2C, 5,50-C), 133.5 (ddd, JC,P¼13.3 Hz, JC,F¼2.8 Hz,
2
3
4JC,F¼2.8 Hz, 2C, 3,30-C), 130.0 (ddd, JC,F¼10.2 Hz, JC,F¼10.2 Hz,
(15:1), Rf¼0.3. 1H NMR (200 MHz, CDCl3):
d
¼7.90 (dd, 3JH,P¼14.4 Hz,
2JC,P¼8.1 Hz, 2C, 2,20-C), 125.8 (dd, 1JC,P¼184.2 Hz, JC,F¼0.9 Hz, 2C,
3JH,H¼7.9 Hz, 1H, AreH), 7.44 (d, JH,P¼6.0 Hz, 1H, AreH), 7.27 (dd,
3
4
1,10-C), 62.5 (d, 2JC,P¼5.0 Hz, 4C, i,i0-C), 20.3 (d, 4JC,P¼1.2 Hz, 2C, 8,80-
3JH,H¼7.9 Hz, JH,P¼2.6 Hz, 1H, AreH), 4.05e4.24 (m, 4H, OeCH2),
4
C), 12.0 (s, 2C, 9,90-C), 16.7 (d, 3JC,P¼6.5 Hz, 4C, j,j0-C) ppm. 31P NMR
2.41 (s, 6H, AreCH3), 2.07 (t, JH,F¼18.8 Hz, 3H, CF2eCH3), 1.34 (t,
3
(81 MHz, CDCl3):
d
¼18.8 (dd, 4JP,F¼1.5 Hz, 5JP,F¼1.5 Hz, 2P) ppm. 19
F
3JH,H¼7.1 Hz, 6H, CH3) ppm. 13C NMR (50 MHz, CDCl3):
¼143.2 (dt,
2
d
4
NMR (188 MHz, CDCl3):
d
¼ꢀ131.4 (s, 2F, CF]CF) ppm. MS (EI,
4JC,P¼3.1 Hz, JC,F¼0.6 Hz, 1C, 4-C), 142.1 (td, JC,F¼27.0 Hz,
70 eV): m/z (%)¼544 (100) [M]þ, 448 (20), 392 (18), 269 (15), 216
(10). HRMS (EI) for C26H36F2O6P2 [M]þ calcd 544.1955; found
544.1965.
2JC,P¼9.6 Hz, 1C, 2-C), 135.3 (d, JC,P¼7.8 Hz, 1C, 5-C), 130.1 (dt,
3
2JC,P¼14.3 Hz, JC,F¼1.2 Hz, 1C, 6-C), 127.9 (dt, JC,P¼13.3 Hz,
3JC,F¼9.0 Hz, 1C, 3-C), 122.8 (dt, 1JC,P¼188.6 Hz, 3JC,F¼2.8 Hz, 1C, 1-C),
122.7 (td, 1JC,F¼241.8 Hz, 3JC,P¼3.6 Hz, 1C, 7-C), 62.7 (d, 2JC,P¼6.2 Hz,
2C, i-C), 27.1 (t, 2JC,F¼27.9 Hz, 1C, CF2eCH3), 21.9 (s, 1C, 8-C), 19.8 (s,
4
3
4.1.46. Diethyl 2-(1,1-difluoroethyl)-4,5-dimethylphenylphosphonate
(19). To a solution of 8e (0.6 g, 2.09 mmol) in dry THF (30 mL) at
ꢀ80 ꢁC, t-BuLi (1.6 M solution in n-pentane, 2.26 mmol) was added
dropwise and the RM was stirred for 0.5 h at the same temperature.
Then, the mixture was allowed to warm up to ꢀ30 ꢁC and methyl
iodide (0.14 mL, 2.26 mmol) was added dropwise under vigorous
stirring. Afterwards, the mixture was left for 3 h at ꢀ30 ꢁC and 10%
HCl (5 mL) was quickly added. The mixture was warmed to rt and
both layers were separated. Water phase was extracted with diethyl
ether (3ꢄ15 mL), organic layers were combined, dried over MgSO4
and all volatiles were evaporated under reduced pressure. The
crude product was purified by column chromatography (CH2Cl2/
1C, 9-C), 16.7 (d, JC,P¼6.5 Hz, 2C, j-C) ppm. 31P NMR (81 MHz,
3
CDCl3):
d
d
¼18.2 (t, 4JP,F¼2.0 Hz, 1P) ppm. 19F NMR (188 MHz, CDCl3):
3
4
¼ꢀ85.0 (qd, JF,H¼18.5 Hz, JF,P¼2.2 Hz, 2F, CF2CH3) ppm. MS (EI,
70 eV): m/z (%)¼2918 [MꢀH]þ, 272 (22) [MꢀHF]þ, 227 (45)
[MꢀCF2CH3]þ, 199 (100), 116 (25). HRMS (EI) for C13H18F2O3P
[MꢀH]þ calcd 291.0962; found 291.0961.
Acknowledgements
The Deutsche Forschungsgemeinschaft (436 RUS 113/961/0-1) is
greatly acknowledged for financial support of this work. We would
like also to express our gratitude to Dr. T. Duelcks (University of
Bremen) for recording MS and HRMS spectra and to Dr. Romana
Pajkert for valuable advices.
EtOAc; 20:1) yielding 0.46 g (74%) of pure 19 as a colourless oil;
3
Rf¼0.24. 1H NMR (200 MHz, CDCl3):
d
¼7.80 (d, JH,P¼14.7 Hz, 1H,
AreH), 7.39 (d, 4JH,P¼6.1 Hz, 1H, AreH), 4.07e4.25 (m, 4H, OeCH2),
3
2.32 (s, 6H, AreCH3), 2.06 (t, JH,F¼18.6 Hz, 3H, CF2eCH3), 1.35 (t,
3JH,H¼6.9 Hz, 6H, CH3) ppm. 13C NMR (50 MHz, CDCl3):
¼141.9 (dt,
2
d
Supplementary data
4JC,P¼3.1 Hz, JC,F¼0.7 Hz, 1C, 4-C), 139.5 (td, JC,F¼27.4 Hz,
2JC,P¼9.6 Hz, 1C, 2-C), 138.2 (dt, 2JC,P¼14.0 Hz, 4JC,F¼1.3 Hz, 1C, 6-C),
136.5 (d, 3JC,P¼8.4 Hz, 1C, 5-C), 128.6 (dt, 3JC,P¼13.7 Hz, 3JC,F¼8.8 Hz,
4
Characterization data includes 1H, 13C, 31P, 19F NMR spectra of all
new compounds and X-ray crystal data of 18. Supplementary data
associated with this article can be found in online version at
doi:10.1016/j.tet.2011.03.076. These data include MOL files and
InChIKeys of the most important compounds described in this
article.
1
3
1C, 3-C), 122.9 (td, JC,F¼241.9 Hz, JC,P¼3.7 Hz, 1C, 7-C), 122.8 (dt,
1JC,P¼187.0 Hz, JC,F¼2.5 Hz, 1C, 1-C), 62.7 (d, JC,P¼5.9 Hz, 2C, i-C),
3
2
2
4
27.2 (t, JC,F¼28.8 Hz, 1C, CF2eCH3), 20.3 (d, JC,P¼1.2 Hz, 1C, 8-C),
19.9 (s, 1C, 9-C), 16.7 (d, JC,P¼6.8 Hz, 2C, j-C) ppm. 31P NMR
3
4
(81 MHz, CDCl3):
(188 MHz, CDCl3):
d
¼18.7 (t, JP,F¼2.6 Hz, 1P) ppm. 19F NMR
3
4
d
¼ꢀ84.6 (qd, JF,H¼18.1 Hz, JF,P¼2.1 Hz, 2F,
References and notes
CF2CH3) ppm. MS (EI, 70 eV): m/z (%)¼306 (10) [M]þ, 286 (20)
[MꢀHF]þ, 241 (25) [MꢀCF2CH3]þ, 213 (100), 130 (30). HRMS (EI) for
C14H21F2O3P [M]þ calcd 306.1196; found 306.1193.
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€
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1216e1225; (d) Hosseini, S. H.; Khalkhali, R. A.; Noor, P. Monatsh. Chem. 2010,
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123e129.
4.1.47. Diethyl 2-[difluoro(trimethylsilyl)methyl]-4,5-dimethylphe-
nylphosphonate (20). Prepared similarly to 19 from 8e (1.13 g,
3.87 mmol), t-BuLi (4.26 mmol) and trimethylsilyl chloride (0.5 g,
4.64 mmol) in dry THF (50 mL) at 0e5 ꢁC within 4 h; yield 0.71 g
(50%) as a yellowish oil, eluent n-hexane/ethylacetate (4:1), Rf¼0.2.
1H NMR (200 MHz, CDCl3):
d
¼7.80 (d, 3JH,P¼14.2 Hz, 1H, AreH), 7.18
(d, 4JH,P¼6.6 Hz, 1H, AreH), 4.05e4.23 (m, 4H, OeCH2), 2.32 (s, 6H,
AreCH3), 1.34 (t, 3JH,H¼7.3 Hz, 6H, CH3), 0.18 (s, 9H, SiMe3) ppm. 13
C
4
NMR (50 MHz, CDCl3):
d
¼141.5 (d, JC,P¼3.1 Hz, 1C, 4-C), 140.2 (td,
2
2
2JC,F¼20.8 Hz, JC,P¼9.3 Hz, 1C, 2-C), 137.4 (dt, JC,P¼14.1 Hz,
4JC,F¼2.2 Hz, 1C, 6-C), 136.5 (dt, JC,P¼8.4 Hz, JC,F¼0.7 Hz, 1C, 5-C),
3
5
4. (a) Tarasova, N. P. Phosphorus, Sulfur Silicon Relat. Elem. 2008, 183, 300e305; (b)
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1
3
128.7 (td, JC,F¼266.7 Hz, JC,P¼2.8 Hz, 1C, 7-C), 128.5 (dt,
3
1
3JC,P¼13.6 Hz, JC,F¼9.6 Hz, 1C, 3-C), 122.5 (dt, JC,P¼188.3 Hz,
3JC,F¼3.2 Hz, 1C, 1-C), 62.5 (d, JC,P¼6.2 Hz, 2C, i-C), 20.3 (d,
2
€
5. (a) Warme, R.; Juhlin, L.; Trogen, L. Phosphorus, Sulfur Silicon Relat. Elem. 2008,
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1.5 (s, 3C, SieCH3) ppm. 31P NMR (81 MHz, CDCl3):
d¼19.2 (t,
4JP,F¼3.0 Hz, 1P) ppm. 19F NMR (188 MHz, CDCl3):
d
¼ꢀ102.8 (s, 2F,
CF2Si) ppm. MS (EI, 70 eV): m/z (%)¼363 (25) [MꢀH]þ, 313 (100)
[MꢀCF2H]þ, 285 (20), 273 (60), 215 (30). HRMS (EI) for
C16H26F2O3PSi [MꢀH]þ calcd 363.1357; found 363.1353.
4.1.48. Diethyl
2-(1,1-difluoroethyl)-4-methylphenylphosphonate
(21). Prepared similarly to 19 from 9e:10e (5.0 g, 18.0 mmol,

S.N. Tverdomed et al. / Tetrahedron 67 (2011) 3887e3903
3903
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