New α-substituted alkylbenzene- and dialkylbenzene-1,2-diphosphonates: side-chain metalation of tetraethyl 4-methyl- and 4,5-dimethylbenzene-1,2-diphosphonates

Article abstract of DOI:10.1016/j.tet.2008.03.020

Carbocyclic 1,2-diphosphonates (1a, 1b) are prepared by the Diels-Alder reaction of classical donor alka-1,3-dienes (isoprene and 2,3-dimethyl-1,3-butadiene) with tetraethyl acetylene bisphosphonate. Their aromatization by the KMnO₄-Al₂

Full text of DOI:10.1016/j.tet.2008.03.020

Tetrahedron 64 (2008) 5306–5313
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
New a-substituted alkylbenzene- and dialkylbenzene-1,2-diphosphonates:
side-chain metalation of tetraethyl 4-methyl- and
4,5-dimethylbenzene-1,2-diphosphonates
,
b
,
b
b
Sergey N. Tverdomed a , Gerd-Volker Ro¨schenthaler , Nataliya Kalinovich , Enno Lork ,
*
*
Alla V. Dogadina a, Boris I. Ionin a
a Department of Organic Chemistry, St. Petersburg State Institute of Technology (Technical University), Moskovskii pr. 26, St. Petersburg 190013, Russia
b Institute of Inorganic and Physical Chemistry, University of Bremen, Leobener Strasse, D-28334 Bremen, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Carbocyclic 1,2-diphosphonates (1a, 1b) are prepared by the Diels–Alder reaction of classical donor alka-
1,3-dienes (isoprene and 2,3-dimethyl-1,3-butadiene) with tetraethyl acetylene bisphosphonate. Their
aromatization by the KMnO4–Al2O3 system affords 4-methyl and 4,5-dimethylbenzene-1,2-diphospho-
nates (2a, 2b), used as precursor for the generation of benzyl-type carbanions (3a, 3b) by lithiation with
lithium isopropylamide in THF at ꢀ80 ꢁC. The carbanions react with electrophilic reagents (chloro-
trimethylsilane, p-fluorobenzaldehyde, and ethyl trifluoroacetate) in situ to form corresponding
a-substituted monoalkyl- and dialkylbenzenediphosphonates in good yields.
Received 23 January 2008
Received in revised form 18 February 2008
Accepted 7 March 2008
Available online 12 March 2008
Keywords:
Diels–Alder condensation
Aromatization
Ó 2008 Elsevier Ltd. All rights reserved.
o-Phenylenbisphosphonate
a-Metalation
1. Introduction
o-phenylenebisphosphonate alkyl derivatives,9 although the pres-
ence of the rigidly fixed o-phenylenebisphosphonate chelating
In recent years the synthesis and properties of various tolue-
nephosphonates substituted in the methyl group attracted in-
creased attention. a-Uraciltoluenephosphonate derivatives were
considered as prospective AMPA or Kainate receptor antagonists.1
Corresponding b-aminocarboxylic derivatives in a-position of
toluenephosphonates are interesting building blocks in the con-
struction of biologically active phosphopeptides.2 Toluenephosph-
onate a-styryl derivatives were examined as prospective electronic
luminescence materials3 and as ligands for asymmetric catalysis.4
a-Vinyl5 and a-O,N,P derivatives were used in the synthesis of
polydentate ligands,6 and a-OAlk derivatives as precursors in the
synthesis of Zn or Mg-porphyrins containing phenylphosphonate
groups, which are interesting materials possessing dielectric
properties for recording and saving information.7 a-Methyl-
enecyclopropyl toluenephosphonate derivatives due to their ability
of stabilization of the radical center by the phosphonate group were
used as model compounds for the radical isomerization mechanism
study of the methylcyclopropyl ring.8 Till now, only one example
has been published concerning the synthesis of a-functionalized
fragment is considered to be promising in pharmacological aspect.9
This situation is caused by the fact that synthetic approaches to
synthesize a-functionalized toluenephosphonates are rather poor.
The main method for the preparation of such compounds is either
photocatalyzed,10 or Ni(II),11 Cu(II),12 and Pd(II)13-catalyzed in-
sertion of the phosphoryl fragment by halide substitution in p- and
o-halotoluenes followed by a-functionalization of the alkyl group,14
or metal-catalyzed aromatic halide substitution by the phospho-
nate group in the a-functionalized p-halotoluene.15 Another ap-
proach to this class of compounds is based on electrophilic
phosphorylation of toluene followed by functionalization at the
aromatic methyl group.16 However, these methods are not suitable
for the introduction of two phosphonate groups into the aromatic
ring in ortho-position to each other, and thus restrict the application
of this synthetic strategy.
An alternative approach, allowing a predetermined synthesis of
aromatic o-diphosphonates is a Diels–Alder ring formation. In the
classical mode ‘donor diene–acceptor acetylene’, this method has
been applied to the reactions of acetylenediphosphonate with
some activated cyclic dienes, a-pyrone17 and its derivatives,18 or
1,3-cyclohexadiene19 (with fixed cis-configuration).20 The reaction
is accompanied by thermal elimination of low molecular weight
compounds (respectively, CO2 and C2H4) resulting in aromatization
* Corresponding authors. Tel.: þ49 421 218 2493; fax: þ49 421 218 4267 (G.-V.R).
E-mail addresses: tverd1975@mail.ru (S.N. Tverdomed), gvr@chemie.uni-
bremen.de (G.-V. Ro¨schenthaler).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.03.020

S.N. Tverdomed et al. / Tetrahedron 64 (2008) 5306–5313
5307
of cyclic 1,2-diphosphonates. In all examples mentioned above, the
initial cycloaddition product was not registered, only the aromatic
compounds were described. Earlier was reported21 that tetra-
methyl acetylenediphosphonate is an active dienophile in Diels–
Alder reactions with donor 1,3-alkadienes such as 1,3-butadiene,
isoprene, 2,3-dimethyl-1,3-butadiene, and piperylene. In this way,
the synthesis of earlier inaccessible tetramethylcyclohexa-1,4-
diene-1,2-diphosphonates readily capable to aromatization,21 was
achieved.
13C NMR spectra of compounds 1a, 1b doublet-doublet signals of
the C1,2 carbon nuclei in the region of d 138–139 with spin–spin
splitting constants of 1JCPw190 Hz and 2JCPw3 Hz are typical, as
well as dd signals of carbon atoms C4,5 and C3,6 at d 110–130
(3JCPw6–7 Hz) and d 31–35 (2JCPw13–14 Hz). The 31P NMR spectra
show signals in the region of d 17–18. We noted that heating of the
carbocyclic diphosphonate 1a to 230–250 ꢁC leads to the migration
of the C4]C5 double bond with formation of an isomeric cyclo-1,4-,
cyclo-1,3-, cyclo-1,5-dienyldiphosphonates (1H NMR: Me d 1.53,
1.01, and 1.62; ]CH– 5.2, 5.61 and 5.52, 5.34) (Scheme 2).
Aromatic o-diphosphonates containing alkyl substituents in the
ring,22 such as 3-methyl, 4-methyl-, and 4,5-dimethylbenzene-
1,2-diphosphonates are a new class of organophosphorus com-
pounds, appropriate for further functionalization. It is known, that
the presence of a heteroatom substituent in ortho-position of
toluene promotes metalation of both the aromatic ring and the
alkyl group.23 Treatment of such benzyl-type organolithium in-
termediate with an electrophilic reagent in situ leads to formation
of polyfunctional a-substituted products.24 With meta- and para-
isomer the substitution is more complicated and less selective.25
As far as we know, there are no examples of side-chain metalation
of o-phenylenebisphosphonate, and only a few and not fully in-
vestigated examples are known for toluenephosphonates26 and
phosphates.27 In this publication we report the successful appli-
cation of the earlier proposed methodology22 for the synthesis of
o-diphosphonates of the toluene and xylene series, which are
interesting from the pharmacological point of view,28 showing the
ability of their predetermined functionalization via regioselective
metalation at the exocyclic methyl groups leading to various
a-alkyl- and a,a-dialkyl-substituted benzene o-diphosphonates.
(EtO)2(O)P
CH3
CH3
(EtO)2(O)P
(EtO)2(O)P
CH3
(EtO)2(O)P
(EtO)2(O)P
1a
(EtO)2(O)P
KMnO4 / Al2O3
(EtO)2(O)P
(EtO)2(O)P
CH3
2a
Scheme 2.
We failed to separate the isomers due to their similar boiling
points and the sorption characteristics, but further aromatization
of the compounds in the mixture afforded one expected
o-diphosphonate 2a.
2. Results and discussion
2.1. The Diels–Alder reaction of tetraethyl acetylene-
diphosphonate with classical donor 1,3-alkadienes
Like tetramethyl acetylenediphosphonate,22 its tetraethyl ana-
log29 is an effective dienophile in diene synthesis with such clas-
sical 1,3-dienes as isoprene30 and 2,3-dimethyl-1,3-butadiene.31
The reaction starts even at room temperature, but the complete
conversion of the parent acetylenediphosphonate occurs during
heating of the reaction mixture for 5 h at 140–145 ꢁC. The reaction
was conducted in a sealed ampoule under dry argon atmosphere
with an excess of 1,3-diene as a solvent and catalytic amount of 1,4-
hydroquinone as a polymerization inhibitor (Scheme 1). Due to the
good solubility of tetraethyl acetylenediphosphonate in excess of
the 1,3-diene the reaction mixture is homogenous. This fact and the
absence of traces of oxygen resulted in an effective diene synthesis
and supression of diene polymerization, thus the yields of carbo-
cyclic diphosphonate ethyl esters 1a, 1b are noticeably higher than
tetramethyl analogs.22 Compounds 1a, 1b are stable colorless oily
liquids. The structures of the synthesized compounds were con-
firmed by 1H, 31P, 13C NMR spectroscopy, and mass spectrometry. In
the 1H NMR spectra typical signals of the methylene ring protons
occur at d 2.8–3.0 and methyl groups at dz1.5, for compound 1a
also the signal of the ring olefinic proton is observed at d 5.2. In the
2.2. Synthesis of methyl- and dimethylbenzene-1,2-
diphosphonates substituted at alkyl groups
For elaboration of a general procedure for side-chain metalation
and functionalization, we have initially investigated tetraethyl
4,5-dimethylbenzene-1,2-diphosphonate 2b. The benzyl-type
carbanion formed upon deprotonation of this compound should be
destabilized due to the electron-donor effect of the neighboring
methyl group. As for the metalating reagents, we tested n-butyl-
lithium (LinBu), tert-butyllithium (LitBu), and lithium diisopropyl-
amide (LDA), which were used in 1 or 2 equiv amounts. For the
limitation of a possible nucleophilic attack of these highly basic
compounds at the diethylphosphonate groups, the reaction with
diphosphonate 2b was carried out at temperatures below ꢀ80 ꢁC in
THF for 30 min, then the less reactive electrophile, namely p-fluo-
robenzaldehyde, was added. After acidic hydrolysis, the crude
products were studied by 31P and 19F NMR spectroscopy. The results
obtained are listed in Table 1, showing the advantage of using LDA
instead of other metalating agents. Reduction of the diethyl-
phosphonate groups of compound 2b observed in the cases of LinBu
P(O)(OEt)2
C3
C6
R2
R1
(EtO)2(O)P
R2
(EtO)2(O)P
(EtO)2(O)P
R2
R1
C3
C6
C2
C1
C4
C5
C2
C1
C4
C5
KMnO4 / Al2O3
70-80%
+
85-90%
(EtO)2(O)P
R1
P (O)(OEt)2
2a-b
1a-b
1a: R1 = H, R2 = CH3
1b: R1 = R2 = CH3
2a: R1 = H, R2 = CH3
2b: R1 = R2 = CH3
Scheme 1.

5308
S.N. Tverdomed et al. / Tetrahedron 64 (2008) 5306–5313
Table 1
which underwent quantitative dehydration leading to the forma-
tion of the corresponding stilbene derivative 5a (Scheme 3). The 1H
NMR spectrum of the crude product showed the presence of the
carbinol in 7–8% yield only (1H NMR, dw3.16 and 2.82) and the
presence of stilbene 5a in 82–85%, respectively (dw7.05). The re-
sidual carbinol was completely dehydrated in the process of the
column chromatography. This fact probably explains the low yield
of carbinol 5b. The metalation of benzenediphosphonates 2a, 2b in
the presence of 2 equiv of LDA proceeds chemoselectively enough.
Products of a,a-diaddition for compound 2a or a,a0-diaddition for
compound 2b at carbonyl group were not observed.
Composition of the reaction mixture for metalation of diphosphonate 2b after
treatment with p-fluorobenzaldehyde and hydrolysisa
Entry
Metalating system
2b (%)
5b (%)
Others (%)
1
2
3
4
5
6
LinBu (1 equiv), THF, ꢀ90 ꢁ
C
C
C
C
C
C
64
41
62
36
56
13
2
3
d
d
42
84
34b
LinBu (2 equiv), THF, ꢀ90 ꢁ
56b
LitBu (1 equiv), THF, ꢀ100 ꢁ
28,c 10b
52,c 12b
2d
LitBu (2 equiv), THF, ꢀ100 ꢁ
LDA (1 equiv), THF, ꢀ80 ꢁ
LDA (2 equiv), THF, ꢀ80 ꢁ
3d
a
1H, 31P, 19F NMR analysis of integral intensity of the corresponding signals.
b
Not identified mixture of phosphinates and phosphine oxides (31P NMR, dw44–
The process of C-metalation is known33 to obey kinetic control
and equilibrium between initial and deprotonated forms of the
substrate. The shift of this equilibrium to the desired direction
occurs when the generated carbanion reacts with an electrophile
and does not react with the parent organometallic compound. It is
probable that during the metalation of the diphosphonates 2a, 2b
this equilibrium is shifted considerably to the parent reagents’ side
(Scheme 3), as it has been shown by the reaction with bromine as
an electrophile, which leads quantitatively to diphosphonates 2a,
2b and N,N-diisopropylhydroxylamine. The attempted reactions of
carbanions 3a, 3b with weak electrophiles such as benzyl bromide
and methyl iodide also failed. Only in the reaction with BzBr, traces
(2–3%) of the product of a-substitution (multiplet at d 2.87) were
registered by 1H NMR analysis of the crude product, while the main
products were parent diphosphonates 2a, 2b with a small content
(8–10%) of isomeric benzyl- and methylphosphinates (31P NMR,
singlet dw45–48) and phosphine oxides (31P NMR, singlet dw39–
42) formed by the permetalation of the corresponding alkyl halides
followed by the reduction of diethylphosphonate groups. In a sec-
ond set of experiments, we studied reactions of lithiated carbanions
3a, 3b with chlorotrimethylsilane (Scheme 4). The high reactivity of
trimethylsilyl chlorides in reactions with carbanions even at low
temperature is well known and is widely used for the character-
ization of organolithium compounds.34 Like in the case of the
reaction with p-fluorobenzaldehyde, this reaction also required for
the metalation of diphosphonates (2a, 2b) 2 equiv of LDA per
methyl group, when only 1 equiv of LDA was added, the crude
product, as follows from 31P NMR analysis, contained a significant
fraction of the parent diphosphonates 2a, 2b: 48% for 2a and 63%
for 2b. This probably resulted from the propensity of the
a-substituted benzyl carbon to further lithiation on account of the
generated carbanion 3a or 3b, respectively (Scheme 4). Thus,
metalation of diphosphonates 2a, 2b using 2 equiv of LDA and the
following reactions of the generated carbanions 3a, 3b with 1 equiv
of Me3SiCl gave the corresponding mono-a-silylated methyl- and
dimethylbenzene-1,2-diphosphonates 7a and 8b in tolerable yields
(52 and 45%, respectively). The known enhanced activity of chloro-
trimethylsilane in reactions with carbanions34 was confirmed by
the reaction of tetraethyl 4,5-dimethylbenzene-1,2-diphosphonate
2b with 4 equiv of LDA. After the addition of 2 equiv of Me3SiCl
followed by the hydrolysis, the major product was a,a0-disilylated
4,5-dimethylbenzene-1,2-diphosphonate 9b, which was isolated in
30% yield.
48 and dw40–43).
c
Diethyl (4-fluorophenyl)(hydroxy)methylphosphonate (31P NMR, d 22.52 and 19
F
NMR, d ꢀ115.35).
d
Phosphonostilbene (31P NMR, d 22.34 and 1H NMR, d 6.92).
and LitBu is connected with the high nucleophilicity of these re-
agents,23 and therefore unlike in the case of toluenephospho-
nates,26 they cannot be applied as metalating agents for this class of
compounds. Besides, with LitBu we observed ipso-substitution of
one diethylphosphonate group by a tBu group with formation of the
diethylphosphite anion; the latter reacted with the carbonyl group
of p-fluorobenzaldehyde affording diethyl (4-fluorphenyl)hydroxy-
methyl phosphonate as a major product, which was isolated in 30%
yield by column chromatography (eluent EtOAc–EtOH 12:1). Its
spectral characteristics and constants corresponded completely
with the published data.32 As seen from the data listed in Table 1, the
use of 1 equiv of LDA resulted, as seen from 13P and 19F NMR spectra,
in the formation of the expected carbinol 5b in the reaction mixture
in 42% yield only, while 56% of the parent compound 2b was not
consumed. This can be explained in a term of deprotonation of
compounds 4a, 4b by carbanions 3a, 3b. Therefore we used 2 equiv
of LDA, one for the deprotonation of 2a, 2b and the second for
deprotonation of the compounds 4a, 4b formed (Scheme 3).
The hydrolysis of the carbanion formed and the chromato-
graphic isolation yielded the carbinol 5b in 30% yield. Under the
same reaction conditions carbanion 3a gave the expected carbinol,
Li
(EtO)2(O)P
(EtO)2(O)P
CH3
R1
CH2
(EtO)2(O)P
(EtO)2(O)P
2
equiv. LDA
THF
R1
2a-b
3a-b
2a: R1 = H
2b: R1 = CH3
3a: R1 = H
3b: R1 = CH3
p-F-C6H4-CHO
F
F
HO
LiO
H+
(EtO)2(O)P
(EtO)2(O)P
(EtO)2(O)P
(EtO)2(O)P
CH3
R1
5b
4a-b
30%
The structure of silylated diphosphonates 7a, 8b, 9b were
evidenced by 1H, 31P, 13C NMR spectroscopy, and MS.
H+
- H2O
In our final experiments, the carbanions 3a, 3b generated by
using the metalating system based on LDA were tested in the
reaction with electrophile such as ethyl trifluoroacetate (Scheme 5).
The 31P and 19F NMR analysis of the crude reaction mixtures,
showed the presence of parent diphosphonates 2a, 2b in 7–10%
only, and 90–93% of the desired reaction products. The reaction
proceeded with high chemoselectivity affording tetraethyl
4-mono- and 4,5-bis(3,3,3-trifluoro-2,2-dihydroxypropyl)benzene-
1,2-diphosphonates 11a, 11b formed by the addition of water to the
corresponding trifluorobenzoyl derivatives. We found that this
F
(EtO)2(O)P
(EtO)2(O)P
5a
45%
Scheme 3.

S.N. Tverdomed et al. / Tetrahedron 64 (2008) 5306–5313
5309
SiMe3
Li
SiMe3
Li
CH2
(EtO)2(O)P
(EtO)2(O)P
CH3
(EtO)2(O)P
(EtO)2(O)P
(EtO)2(O)P
(EtO)2(O)P
(EtO)2(O)P
(EtO)2(O)P
H+
2
equiv. LDA
THF
Me3SiCl
2a
6a
3a
7a
52%
SiMe3
Li
SiMe3
Li
CH2
(EtO)2(O)P
(EtO)2(O)P
CH3
(EtO)2(O)P
(EtO)2(O)P
(EtO)2(O)P
(EtO)2(O)P
(EtO)2(O)P
(EtO)2(O)P
H+
2
equiv. LDA
THF
Me3SiCl
CH3
CH3
CH3
CH3
2b
6b
H+
3b
8b
45%
2
equiv. LDA
Me3SiCl
SiMe3
(EtO)2(O)P
(EtO)2(O)P
SiMe3
9b
30%
Scheme 4.
HO
CF3
OH
LiO
CF
3
Li
CH2
(EtO)2(O)P
(EtO)2(O)P
(EtO)2(O)P
(EtO)2(O)P
(EtO)2(O)P
(EtO)2(O)P
CF3C(O)OEt
H+
+H2O
R1
R1
11a
70%
3a-b
10a-b
H+
1 equiv. LDA
THF
-H2O
+H2O
(EtO)2(O)P
(EtO)2(O)P
CH3
R1
HO
CF3
OH
CF3
HO
CF3
O
(EtO)2(O)P
(EtO)2(O)P
(EtO)2(O)P
(EtO)2(O)P
(EtO)2(O)P
(EtO)2(O)P
2a-b
+
2a: R1 = H
2b: R1 = CH3
3a: R1 = H
3b: R1 = CH3
CH3
11b
55%
12a
13a
85%
Scheme 5.
reaction can be conducted effectively with 1 equiv of LDA per
methyl group. With 2 equiv occurred extra tarring of reaction
mixture and a decrease in the yield of the target compounds. We
explain this fact assuming the initial formation of the benzoyl
derivatives in the form of isomeric lithium enolate (Scheme 5) with
the a-position not capable to a further metalation. In the process of
hydrolysis probably an equilibrium of ketone and enol forms is
established whose shift to the ketone is promoted by nucleophilic
addition of water at the carbonyl group of the latter, resulting in the
formation of the final hydrates 11a, 11b, isolated in 70 and 55%
yields, respectively. The structures of these compounds were con-
firmed by X-ray diffraction data (Figs. 1 and 2).35,36 The principal
geometrical parameters of 11a, 11b are within the range of standard
values.
DMSO-d6 and CDCl3 showed a content of the ketone form up to 96
and 85.5%, respectively (19F NMR, d ꢀ79.65,1H NMR, d 3.24), while in
deuterobenzene the ketoneenol equilibrium falls to ketone/enol
ratio 62%:38%. Dehydration of compound 11b under the same con-
ditions does not lead to the expected products. Even after 2 h in
refluxing toluene, using a Dean–Stark trap the reaction mixture
contained (19F, 1H NMR) approximately 18% of the parent hydrate
11b. The products of dehydration under these conditions exerted
practically complete thermal destruction, thus analysis by 19F, 1H
NMR allowed register of only trace amounts (w5%). In the case of
metalation of compound 2b with 2 or more equiv of LDA and sub-
sequent treatment with 2 equiv of ethyl trifluoroacetate no traces of
theproductof a,a0-substitutionwereregistered inthe crudereaction
mixture, thus attesting chemoselectivity of this electrophile.
Compounds 11a, 11b were subjected to thermal dehydration in
toluene with azeotropic removing of water. With hydrate 11a this
process proceeds smoothly enough, for 15 min at 110 ꢁC. A mixture
of ketone 12a and enol 13a is formed rather pure (94%, according to
31P, 19F, 1H, 13C NMR, MS-analysis) even without additional purifi-
cation. As expected, ketone 12a/enol 13a ratio depends considerably
on the solvent polarity. The 19F, 1H NMR analysis of solutions in
The comparison of the results of the metalation–electrophilic
substitution of diphosphonates 2a, 2b under the same general
conditions, showed higher reactivity of the diphosphonate 2a,
probably resulting from resonance stabilization of generated
benzyl-type carbanion by phosphonate groups in para- and meta-
positions. The lack of destabilization by the methyl group in ortho-
position, unlike diphosphonate 2b, leads to the equilibrium shift to

5310
S.N. Tverdomed et al. / Tetrahedron 64 (2008) 5306–5313
1,2-diphosphonates functionalized at a-position of alkyl groups
based on the following reactions.
(i) Diels–Alder condensation of classical donor 1,3-alkadienes
with tetraethyl acetylenediphosphonate; (ii) aromatization of the
carbocyclic 1,2-diphosphonates formed; (iii) side-chain metalation
of the formed tetraethyl 4-methyl- and 4,5-dimethylbenzene-
1,2-diphosphonates; (iv) in situ reaction of the generated benzyl-
type carbanions with electrophilic reagents. We improved steps (i)
and (ii) as compared with a procedure for the synthesis of related
tetramethyl esters earlier proposed by us22 and prepared a series
of earlier unknown carbocyclic and aromatic 1,2-diphosphonates.
For steps (iii) and (iv), we revealed experimentally reagents and
conditions for effective metalation at methyl groups attached to an
aromatic ring and selected appropriate electrophilic reagents for
the fixation of the formed carbanions. Using this general strategy
we synthesized a series of a-functionalized 4-alkylbenzene-1,2-
diphosphonates and a,a0-difunctionalized 4,5-dialkylbenzene-1,2-
bisphosphonates, with fluoro- and silicon-containing functional
groups, which are prospective as synthones and intermediates for
new materials and bioactive compounds.
4. Experimental
ꢁ
Figure 1. Molecular structure of compound 11a; bond length in pm, bond angle in
[C(17)–F(3) 132.3(3), C(17)–C(16) 153.2(3), C(16)–O(7) 138.9(3), C(5)–C(4) 138.0(3),
C(1)–P(1) 179.7(2), C(7)–O(2) 146.2(3), C(7)–C(8) 149.1(3), C(13)–C(14) 135.7(6), O(1)–
P(1) 147.40(17), O(2)–P(1) 157.8(2); O(7)–C(16)–O(8) 114.8(2), O(8)–C(16)–C(15)
108.1(2), C(4)–C(5)–C(6) 118.1(2), C(4)–C(5)–C(15) 122.0(2), C(6)–C(1)–P(1) 115.6(2),
C(2)–C(1)–P(1) 125.4(2), C(3)–C(2)–P(2) 117.6(2), C(4)–C(3)–C(2) 121.8(2), C(7)–O(2)–
P(1) 121.7(1), O(1)–P(1)–O(3) 116.13(10), O(1)–P(1)–O(2) 113.81(9), O(3)–P(1)–O(2)
101.6(9)].
4.1. General methods
All reagents were obtained from commercial suppliers and were
used without further purification. All solvents used in reactions
were freshly distilled from appropriate drying agents before use.
THF was distilled from sodium–benzophenone and used immedi-
ately. All other reagents were recrystallized or distilled when nec-
essary. Reactions were performed under dry nitrogen atmosphere.
Analytical TLC was performed with Merck silica gel 60 F254 plates.
Visualization was accomplished by UV light or by spraying Ce(SO4)2
solution in 5% H2SO4. Column chromatography was carried out
using Merck silica gel 60 (230–400 mesh ASTM). Melting points
were determined with an Electrothermal IA9100 Digital Melting
Point Apparatus without correction. NMR spectra were obtained on
a Bruker DPX-200 spectrometer operating at 200.13 MHz for
1H(TMS), 188.31 MHz for 19F (CFC13), 80.99 MHz for 31P (H3PO4)
and 50.32 MHz for 13C (TMS). MS and HRMS spectra were obtained
on a Varian MAT CH7A instrument at 70 eV.
4.2. Typical procedure of the diene synthesis
To a 50 ml ampoule preliminary cooled to ꢀ30 ꢁC was given
0.1 molof tetraethylacetylenediphosphonate, 0.4 molof substituted
1,3-butadiene, and 3–5 mg of hydroquinone. Then the ampoule was
heated at 140–145 ꢁC for 5 h. After cooling, the reaction completion
was verified by NMR spectroscopy on the absence of the acetyl-
enediphosphonate precursor. The excess of 1,3-alkadiene was then
distilled off at reduced pressure and the residue was distilled in
vacuo.
ꢁ
Figure 2. Molecular structure of compound 11b; bond length in pm, bond angle in
[C(18)–F(3) 133.4(3), C(4)–C(15) 151.1(3), C(17)–O(8) 139.3(3), C(1)–C(6) 139.9(3),
C(1)–P(1) 179.6(2), O(2)–C(7) 145.9(3), C(7)–C(8) 149.2(4), C(2)–C(3) 139.8(3), O(1)–
P(1) 146.87(16), P(1)–O(3) 156.3(2); O(8)–C(17)–O(7) 114.4(2), O(2)–C(7)–C(8)
107.6(2), C(6)–C(1)–C(2) 118.5(2), C(6)–C(1)–P(1) 116.5 (2), C(2)–C(1)–P(1) 125.0(2),
C(3)–C(2)–P(2) 117.5(2), C(4)–C(3)–C(2) 123.1(2), C(7)–O(2)–P(1) 121.2(2), O(1)–P(1)–
O(3) 115.15(9), O(1)–P(1)–O(2) 113.9(9), O(3)–P(1)–O(2) 101.9(9)].
4.2.1. Tetraethyl 4-methylcyclohexa-1,4-diene-1,2-diphos-
phonate (1a)
Bp 148–151 ꢁC (0.1 mmHg). Yield 87%. 31P NMR spectrum,
d (CDCl3): 14.55 s. 13C NMR spectrum, d (CDCl3): 138.96 (dd, C1, 1JCP
2
1
2
188.70 Hz, JCP 2.5 Hz), 138.74 (dd, C2, JCP 188.23 Hz, JCP 3.5 Hz),
129.92 (dd, C5, 3JCP 7.05 Hz, 4JCP 1.00 Hz), 116.93 (dd, C4, 3JCP 6.5 Hz,
4JCP 1.0 Hz), 62.45 (d, Ci, 2JCP 4.02 Hz), 35.15 (dd, C6, 2JCP 14.1 Hz, 3JCP
11.5 Hz), 31.84 (dd, C3, 2JCP 14.1 Hz, 3JCP 13.6 Hz), 22.70 (s, C7), 16.50
(d, Cj, 3JCP 4.53 Hz). 1H NMR spectrum, d (CDCl3): 5.21 (m, 1H), 4.01
the side of the deprotonated form and higher yield of final reaction
products.
3
3. Summary
(m, 8H), 2.88 (m, 2H), 2.82 (m, 2H), 1.51 (s, 3H), 1.19 (t, 6H, JHH
3
7.2 Hz), 1.18 (t, 6H, JHH 7.1 Hz). MS (EI) m/e¼365 (Mþ, 100%), 337
In conclusion, we have demonstrated a new methodology for
the synthesis of tetraethyl 4-methyl- and 4,5-dimethylbenzene-
(18), 319 (10), 309 (12), 281 (6); HRMS m/e ([MꢀH]þ) calculated for
C15H27O6P2 365.32725, found 365.32762.

S.N. Tverdomed et al. / Tetrahedron 64 (2008) 5306–5313
5311
4.2.2. Tetraethyl 4,5-dimethylcyclohexa-1,4-diene-1,2-
diphosphonate (1b)
solution of sodium hydrocarbonate (2ꢂ50 ml), and dried over
Na2SO4. Then solvent was removed at reduced pressure and
residual crude product was used for analysis by 31P, 19F, and 1H NMR
spectroscopy and further purification by column chromatography.
Bp 165–169 ꢁC (0.1 mmHg). Yield 85%. 31P NMR spectrum,
d (CDCl3): 14.83 s. 13C NMR spectrum, d (CDCl3): 139.12 (dd, C1,2, 1JCP
191.25 Hz, 2JCP 3.52 Hz),121.92 (d, C4,5, 3JCP 4.02 Hz), 62.47 (d, Ci, 2JCP
3.52 Hz), 37.35 (dd, C3,6
,
2JCP 13.09 Hz, 3JCP 13.09 Hz), 18.13 (s, C7,8),
4.4.1. (E)-Tetraethyl 4-(4-fluorostyryl)benzene-1,2-diphos-
phonate (5a)
16.66 (d, Cj, 3JCP 3.02 Hz). 1H NMR spectrum, d (CDCl3): 4.02 (m, 8H),
2.84 (m, 4H), 1.49 (s, 6H), 1.20 (t, 12H, 3JHH 6.0 Hz). MS (EI) m/e¼379
(Mþ, 100%), 351 (14), 333 (11), 305 (10), 249 (45); HRMS m/e
([MꢀH]þ) calculated for C16H29O6P2 379.35334, found 379.35373.
Prepared according to the general procedure from 2a (2.0 g,
5.5 mmol), 2 M LDA solution (5.8 ml, 11.5 mmol), and p-fluo-
robenzaldehyde (0.7 g, 5.5 mmol). Crude product was purified by
column chromatography (EtOAc/EtOH 12:1 as eluent), white crys-
tals (1.16 g, yield 45%, mp 57 ꢁC). Rf (EtOAc/EtOH 12:1) 0.43. 31P
NMR spectrum, d (CDCl3): 22.53 m, 22.43 m. 19F NMR spectrum,
4.3. Typical procedure for the aromatization of carbocyclic
diphosphonates
d (CDCl3): ꢀ113.77 m. 13C NMR spectrum, d: 163.26 (d, C12
,
1JCF
To a solution of 0.05 mol of carbocyclic diphosphonate in 300 ml
of acetone under vigorous stirring 0.1 mol of KMnO4–Al2O3 (1:1)
mixture was added in portions, maintaining temperature of
reaction mixture at 0–3 ꢁC. Then stirring was continued for 12 h
at room temperature. The final suspension was filtered through a
3–5 mm layer of CeliteÒ, the precipitate was washed carefully with
acetone and ether, combined filtrate was evaporated at reduced
pressure, residue was distilled in vacuo.
249.13 Hz),140.86 (dd, C4, 3JCP 11.06 Hz, 4JCP 2.01 Hz), 136.35 (dd, C3,
3
2
3
2JCP 13.08 Hz, JCP 10.54 Hz), 133.97 (dd, C6, JCP 13.09 Hz, JCP
1
11.07 Hz), 133.04 (d, C10,14
,
3JCF 3.52 Hz), 132.51 (dd, C1, JCP
188.23 Hz, 2JCP 11.07 Hz), 131.56 (s, C7), 130.16 (dd, C2, 1JCP 191.76 Hz,
2JCP 10.08 Hz), 129.15 (d, C9, 4JCF 1.51 Hz), 128.92 (d, C5, 3JCP 8.05 Hz),
2
126.63 (s, C8), 116.25 (d, C11,13
,
2JCF 22.15 Hz), 62.03 (d, Ci, JCP
2
3
4.04 Hz), 62.91 (d, Ci, JCP 4.02 Hz), 16.79 (d, Cj, JCP 2.52 Hz), 16.69
(d, Cj, 3JCP 2.58 Hz). 1H NMR spectrum, d (CDCl3): 8.30 (dd, 1H, 3JHP
3
3
4
14.01 Hz, JHH 8.00 Hz), 8.11 (dd, 1H, JHP 14.00 Hz, JHP 6.05 Hz),
7.67 (dd, 1H, 3JHH 8.00 Hz, 4JHP 2.08 Hz), 7.49 (dd, 2H, 3JHH 10.00 Hz,
4.3.1. Tetraethyl 4-methyl-1,2-diphosphonate (2a)
Bp 155–157 ꢁC (0.1 mmHg). Yield 73%. 31P NMR spectrum,
d (CDCl3): 17.63 s, 17.56 s. 13C NMR spectrum, d (CDCl3): 142.38 (d,
C4, 3JCP 10.57 Hz), 136.44 (dd, C6, 2JCP 13.09 Hz, 3JCP 10.07 Hz), 135.74
3JHF 6.02 Hz), 7.13 (d, 2H, JHH 12.34 Hz), 7.05 (AB-system, 2H, JHH
3
3
3
3
19.68 Hz), 4.18 (m, 8H), 1.36 (t, 6H, JHH 8.09 Hz), 1.35 (t, 6H, JHH
8.05 Hz). MS (EI) m/e¼470 (Mþ, 60%), 425 (15), 361 (95), 333 (100),
305 (40), 259 (5); HRMS m/e ([M]þ) calculated for C22H29FO6P2
470.14234, found 470.14252.
2
3
3
(dd, C3, JCP 13.59 Hz, JCP 10.05 Hz), 132.31 (d, C5, JCP 11.07 Hz),
1
2
1
131.75 (dd, C2, JCP 188.23 Hz, JCP 11.07 Hz), 128.64 (dd, C1, JCP
191.76 Hz, 2JCP 10.07 Hz), 62.64 (d, Ci, 2JCP 5.54 Hz), 62.54 (d, Ci, 2JCP
5.53 Hz), 21.62 (s, C7), 16.56 (d, Cj, 3JCP 5.03 Hz). 1H NMR spectrum,
d (CDCl3): 7.85 (dd, 1H, 3JHP 19.96 Hz, 3JHH 7.98 Hz), 7.81 (d, 1H, 3JHP
17.98 Hz), 7.23 (d, 1H, 3JHH 8.01 Hz), 3.99 (m, 8H), 2.24 (s, 3H), 1.17 (t,
4.4.2. Tetraethyl 4-methyl-5-[2-(4-fluorophenyl)-2-hydroxy-
ethyl]benzene-1,2-diphosphonate (5b)
Prepared according to the general procedure from 2b (2.1 g,
5.5 mmol), 2 M LDA solution (5.8 ml, 11.5 mmol), and p-fluo-
robenzaldehyde (0.7 g, 5.5 mmol). The crude compound was puri-
fied by column chromatography (EtOAc/EtOH 10:1 as eluent),
colorless oil (0.84 g, yield 30%). Rf (EtOAc/EtOH 10:1) 0.33. 31P NMR
spectrum, d (CDCl3): 18.06 m, 17.88 m. 19F NMR spectrum, d (CDCl3):
6H, JHH 8.00 Hz), 1.16 (t, 6H, JHH 8.00 Hz). MS (EI) m/e¼364 (Mþ,
3
3
30%), 319 (100), 291 (27), 255 (29), 227 (80); HRMS m/e ([M]þ)
calculated for
C15H26O6P2 364.12047, found 364.12162, m/e
([MꢀH]þ) calculated for C15H25O6P2 363.11264, found 363.11285.
4.3.2. Tetraethyl 4,5-dimethyl-1,2-diphosphonate (2b)
ꢀ116.57 m. 13C NMR spectrum, d: 162.42 (d, C13
,
1JCF 245.61 Hz),
Bp 174–177 ꢁC (0.1 mmHg). Yield 78%. 31P NMR spectrum,
d (CDCl3): 17.65 s. 13C NMR spectrum, d (CDCl3): 140.80 (dd, C4,5, 3JCP
11.07 Hz, 4JCP 5.54 Hz), 137.03 (dd, C3,6, 2JCP 12.08 Hz, 3JCP 12.08 Hz),
141.58 (dd, C5, JCP 10.07 Hz, JCP 1.48 Hz), 141.15 (dd, C4, JCP
3
4
3
11.07 Hz, 4JCP 1.51 Hz), 140.53 (d, C10
,
4JCF 3.02 Hz), 137.36 (dd, C3,6
,
3
1
2
2JCP 12.08 Hz, JCP 12.08 Hz), 129.18 (dd, C1, JCP 190.25 Hz, JCP
2
2
1
2
128.63 (dd, C1,2
,
1JCP 190.25 Hz, JCP 10.07 Hz), 62.34 (d, Ci, JCP
10.09 Hz), 128.36 (dd, C2, JCP 191.25 Hz, JCP 10.57 Hz), 127.94 (d,
5.54 Hz), 19.76 (s, C7,8), 16.44 (d, Cj, 3JCP 3.02 Hz). 1H NMR spectrum,
C11,15
,
3JCF 8.05 Hz), 115.32 (d, C12,14
,
2JCF 21.64 Hz), 73.66 (s, C9),
3
4
2
2
d (CDCl3): 7.78 (dd, 2H, JHP 10.00 Hz, JHP 8.00 Hz), 4.01 (m, 8H),
62.71 (d, Ci, JCP 3.52 Hz), 62.64 (d, Ci, JCP 3.39 Hz), 43.34 (s, C8),
20.03 (s, C7), 16.69 (d, Cj, 3JCP 2.50 Hz), 16.62 (d, Cj, 3JCP 2.53 Hz). 1H
NMR spectrum, d (CDCl3): 7.86 (dd, 1H, 3JHP 13.21 Hz, 3JHH 9.78 Hz),
7.74 (dd, 1H, 3JHP 14.03 Hz, 4JHP 10.00 Hz), 7.15 (dd, 2H, 3JHH 8.08 Hz,
4JHF 3.08 Hz), 6.85 (dd, 2H, 3JHH 10.00 Hz, 3JHF 10.00 Hz), 4.86 (t, 1H,
2.17 (s, 6H), 1.19 (t, 12H, JHH 6.00 Hz). MS (EI) m/e¼378 (Mþ, 7%),
3
333 (75), 305 (28), 277 (20), 249 (55), 241 (100); HRMS m/e ([M]þ)
calculated for
C16H28O6P2 378.13612, found 378.13717, m/e
([MꢀH]þ) calculated for C16H27O6P2 377.12829, found 377.12778.
3JHH 6.24 Hz), 4.04 (m, 8H), 3.13 (dd, 1H, JHH 14.05 Hz, JHH
2
3
4.4. General procedure for the generation of benzyl-type
carbanions (3a, 3b) and conducting their reactions with
electrophilic reagents
8.00 Hz), 2.90 (dd, 1H, 2JHH 14.67 Hz, 3JHH 7.86 Hz), 2.27(s, 3H), 1.27
3
(t, 12H, JHH 7.79 Hz). MS (EI) m/e¼502 (Mþ, 100%), 501 ([MꢀH]þ,
20), 487 (10), 378 (35), 365 (10), 247 (15); HRMS m/e ([M]þ)
calculated for C23H33FO7P2 502.16856, found 502.16596.
To a stirred solution of diphosphonate 2a (2 g, 5.5 mmol) or 2b
(2.1 g, 5.5 mmol) in 25 ml of THF at ꢀ80 ꢁC was added dropwise
2 M solution of lithium diisopropylamide in hexane–THF (5.8 ml,
11.5 mmol). The reaction mixture temperature was increased to
ꢀ70 ꢁC and the mixture was stirred for 30 min, therewith it became
dark-red in color. Then the mixture was again cooled to ꢀ80 ꢁC and
corresponding electrophilic reagent was added slowly at vigorous
stirring. After 2 h at ꢀ70 ꢁC the reaction mixture color changed
to orange; the mixture was allowed to reach room temperature
and was treated with freshly prepared acetate buffer (60 ml).
The emulsion formed was extracted with methylene chloride
(3ꢂ30 ml), combined organic layer was washed with saturated
4.4.3. Tetraethyl 4-(trimethylsilylmethyl)benzene-1,2-
diphosphonate (7a)
Prepared in accordance with the general procedure from 2a
(2.0 g, 5.5 mmol), 2 M LDA solution (5.8 ml, 11.5 mmol), and
chlorotrimethylsilane (0.6 g, 5.5 mmol). Crude product was purified
by column chromatography (EtOAc/EtOH 14:1 as eluent), colorless
oil (1.24 g, yield 52%). Rf (EtOAc/EtOH 14:1) 0.26. 31P NMR spectrum,
d (CDCl3): 22.34 m, 22.73 m. 13C NMR spectrum, d (CDCl3): 145.71
(dd, C4, 3JCP 13.59 Hz, 4JCP 3.02 Hz), 135.70 (dd, C6, 2JCP 14.09 Hz, 3JCP
2
3
9.56 Hz), 135.21 (dd, C3, JCP 14.09 Hz, JCP 9.57 Hz), 130.89 (dd, C5,
3JCP 13.59 Hz, JCP 2.52 Hz), 131.08 (dd, C2, JCP 188.24 Hz, JCP
4
1
2

5312
S.N. Tverdomed et al. / Tetrahedron 64 (2008) 5306–5313
2
10.57 Hz), 127.28 (dd, C1, 1JCP 194.27 Hz, JCP 9.56 Hz), 62.61 (d, Ci,
2JCP 6.04 Hz), 62.55 (d, Ci, 2JCP 5.54 Hz), 27.95 (s, C7), 16.61 (d, Cj, 3JCP
6.54 Hz), ꢀ1.73 (s, C8). 1H NMR spectrum, d (CDCl3): 7.82 (dd, 1H,
4.4.7. Tetraethyl 4-methyl-5-(3,3,3-trifluoro-2,2-dihydroxy-
propyl)benzene-1,2-diphosphonate (11b)
Prepared according to the general procedure from 2b (2.1 g,
5.5 mmol), 2 M LDA solution (2.9 ml, 5.7 mmol), and ethyl tri-
fluoroacetate (0.80 g, 5.6 mmol). Crude product was purified by
recrystallization from 1,4-dioxane–H2O 2:1, colorless crystals
(1.50 g, yield 55%, mp 188 ꢁC). 31PNMR spectrum, d(DMSO-d6): 17.34
m, 17.25 m. 19F NMR, d (DMSO-d6): ꢀ84.70 s. 13C NMR spectrum,
d (DMSO-d6): 143.17 (d, C5, 3JCP 9.56 Hz),139.18 (dd, C3, 2JCP 12.08 Hz,
3
3JHP 20.02 Hz, 3JHH 8.03 Hz), 7.62 (d, 1H, JHP 16.00 Hz), 7.05 (d, 1H,
3JHH 8.02 Hz), 4.03 (m, 8H), 2.02 (s, 2H), 1.19 (t, 12H, JHH 6.00 Hz),
3
ꢀ0.17 (s, 9H). MS (EI) m/e¼436 (Mþ, 100%), 408 (82), 380 (20), 352
(10), 319 (25), 290 (43); HRMS m/e ([M]þ) calculated for
C
18H34O6P2Si 436.15999, found 436.16127.
3
2
4.4.4. Tetraethyl 4-methyl-5-(trimethylsilylmethyl)benzene-1,2-
diphosphonate (8b)
3JCP 12.08 Hz), 138.34 (d, C4, JCP 10.07 Hz), 137.12 (dd, C6, JCP
12.58 Hz, 3JCP 12.58 Hz), 130.12 (dd, C1, 1JCP 188.74 Hz, 2JCP 11.07 Hz),
1
2
Prepared according to the general procedure from 2b (2.1 g,
5.5 mmol), 2 M LDA solution (5.8 ml, 11.5 mmol), and chloro-
trimethylsilane (0.6 g, 5.5 mmol). Crude product was purified by
column chromatography (EtOAc/EtOH 14:1 as eluent), colorless oil
(1.13 g, yield 45%). Rf (EtOAc/EtOH 14:1) 0.35. 31P NMR spectrum,
d (CDCl3): 18.66 m, 18.13 m. 13C NMR spectrum, d (CDCl3): 144.32
(dd, C5, 3JCP 13.58 Hz, 4JCP 2.52 Hz), 138.87 (dd, C4, 3JCP 13.59 Hz, 4JCP
3.02 Hz), 137.96 (dd, C6, 2JCP 14.59 Hz, 3JCP 10.01 Hz), 136.35 (dd, C3,
128.42 (dd, C2, JCP 190.25 Hz, JCP 10.67 Hz), 124.93 (q, C10,
1JCF
2
2
290.40 Hz), 94.00 (q, C9, JCF 30.70 Hz), 62.65 (d, Ci, JCP 4.03 Hz),
38.05 (s, C8), 20.59 (s, C7),16.96 (s, Cj),16.86 (s, Cj).1H NMR spectrum,
d (DMSO-d6): 7.97 (dd, 1H, 3JHP 16.04 Hz, 4JHP 6.01 Hz), 7.77 (dd, 1H,
3JHP 15.21 Hz, JHP 5.45 Hz), 6.94 (s, 2H), 4.01 (m, 8H), 3.04 (s, 2H),
4
2.39 (s, 3H), 1.24 (t,12H, 3JHH 6.24 Hz). MS (EI) m/e¼474 ([MꢀH2O]þ,
5%), 429 (100), 401 (25), 365 (30), 345 (65), 337 (95), 327 (20), 309
(38), 282 (8).
2JCP 14.60 Hz, JCP 10.07 Hz), 128.52 (dd, C2, JCP 190.75 Hz, JCP
3
1
2
10.08 Hz), 126.53 (dd, C1, 1JCP 193.27 Hz, 2JCP 10.57 Hz), 62.73 (d, Ci,
4.4.8. Tetraethyl 4-(3,3,3-trifluoro-2-oxopropyl)benzene-1,2-
diphosphonate (12a) and tetraethyl 4-(E,Z)-(3,3,3-trifluoro-2-
hydroxyprop-1-enyl)benzene-1,2-diphosphonate (13a)
2JCP 3.21 Hz), 62.61 (d, Ci, JCP 3.18 Hz), 24.92 (s, C8), 20.61 (s, C7),
2
16.82 (s, Cj), 16.69 (s, Cj), ꢀ0.96 (s, C9). 1H NMR spectrum, d (CDCl3):
7.90 (dd, 1H, 3JHP 14.02 Hz, 4JHP 6.01 Hz), 7.73 (dd, 1H, 3JHP 16.00 Hz,
4JHP 6.00 Hz), 4.17 (m, 8H), 2.29 (s, 3H), 2.19 (s, 2H), 1.36 (t, 6H, 3JHH
Prepared by dehydration of 11a (1.3 g) at reflux in anhydrous
toluene (20 ml) with a Dean–Stark trap for 15 min. To the cooled
solution at room temperature was added 2.0 g of anhydrous
silica gel (60 Å) and mixture was stirred at room temperature
for 1 h. The suspension was filtered; the filtrate was evaporated at
reduced pressure. The residual colorless oil (1.06 g, yield 85%)
consisted of practically pure ketone 12a and enol 13a mixture in
molar ratio 96:4 (DMSO), 85.5:14.5 (chloroform), and 62:38
(benzene).
3
6.04 Hz), 1.35 (t, 6H, JHH 6.02 Hz), 0.01 (s, 9H). MS (EI) m/e¼450
(Mþ, 100%), 422 (85), 405 (5), 394 (15), 366 (5), 248 (20), 241 (15);
HRMS m/e ([M]þ) calculated for C19H36O6P2Si 450.17564, found
450.17753.
4.4.5. Tetraethyl 4,5-di(trimethylsilylmethyl)benzene-1,2-
diphosphonate (9b)
Prepared according to the general procedure from 2b (2.1 g,
5.5 mmol), 2 M LDA solution (11.6 ml, 23.0 mmol), and chloro-
trimethylsilane (1.2 g, 11.0 mmol). The crude compound was puri-
fied by column chromatography (EtOAc/EtOH 16:1 as eluent),
colorless oil (0.87 g, yield 30%). Rf (EtOAc/EtOH 16:1) 0.25. 31P NMR
spectrum, d (CDCl3): 18.69 m. 13C NMR spectrum, d (CDCl3): 141.99
4.4.8.1. Compound 12a. 31P NMR spectrum, d (DMSO-d6): 16.36 m,
16.26 m. 19F NMR spectrum, d (DMSO-d6): ꢀ79.65 s. 13C NMR
2
spectrum, d (DMSO-d6): 187.88 (q, C8, JCF 35.23 Hz), 138.29 (d, C4,
2
3
3JCP 13.08 Hz), 137.03 (dd, C6, JCP 13.09 Hz, JCP 11.07 Hz), 135.85
2
3
3
(dd, C3, JCP 13.09 Hz, JCP 10.07 Hz), 134.70 (d, C5, JCP 10.29 Hz),
4
2
1
2
1
(dd, C4,5
,
3JCP 10.11 Hz, JCP 4.32 Hz), 136.63 (dd, C3,6, JCP 12.08 Hz,
133.71 (dd, C2, JCP 187.73 Hz, JCP 10.57 Hz), 132.53 (dd, C1, JCP
190.26 Hz, 2JCP 10.07 Hz), 116.13 (q, C9, 1JCF 292.92 Hz), 62.69 (d, Ci,
2JCP 7.12 Hz), 62.48 (d, Ci, 2JCP 6.85 Hz), 42.01 (s, C7), 16.47 (d, Cj, 3JCP
1.01 Hz), 16.37 (d, Cj, 3JCP 1.06 Hz). 1H NMR spectrum, d (DMSO-d6):
8.15 (dd, 1H, 3JHP 20.06 Hz, 3JHH 8.02 Hz), 8.08 (dd, 1H, 3JHP 18.54 Hz,
4JHP 2.02 Hz), 6.80 (dd, 1H, 3JHH 8.02 Hz, 4JHP 2.01 Hz), 4.07 (m, 8H),
2
3JCP 12.08 Hz), 126.39 (dd, C1,2, 1JCP 191.76 Hz, JCP 10.08 Hz), 62.63
(d, Ci, 2JCP 5.01 Hz), 25.29 (s, C7,8), 16.76 (d, Cj, 3JCP 3.02 Hz), 0.95 (s,
C
9,10). 1H NMR spectrum, d (CDCl3): 7.69 (dd, 2H, 3JHP 14.01 Hz, 4JHP
10.00 Hz), 4.18 (m, 8H), 2.13 (s, 4H), 1.36 (t, 12H, 3JHH 6.01 Hz), 0.01
(s, 18H). MS (EI) m/e¼522 (Mþ, 15%), 479 (10), 450 (100), 422 (75),
394 (18), 333 (70), 241 (95); HRMS m/e ([M]þ) calculated for
3
3
3.24 (s, 2H), 1.10(t, 6H, JHH 7.23 Hz), 1.09 (t, 6H, JHH 7.14 Hz). MS
(EI) m/e¼460 (Mþ, 10%), 415 (100), 387 (20), 359 (18), 331 (65), 323
(70), 295 (30); HRMS m/e ([M]þ) calculated for C17H25 F3O7P2
460.10276, found 460.10067, m/e ([MꢀH]þ) calculated for C17H24
F3O7P2 459.09494, found 459.09448.
C
22H44O6P2Si2 522.21517, found 522.21537.
4.4.6. Tetraethyl 4-(3,3,3-trifluoro-2,2-dihydroxy-propyl)benzene-
1,2-diphosphonate (11a)
Prepared according to the general procedure from 2a (2.0 g,
5.5 mmol), 2 M LDA solution (2.9 ml, 5.7 mmol), and ethyl tri-
fluoroacetate (0.8 g, 5.6 mmol). Crude product was recrystallized
from benzene, colorless crystals (1.84 g, yield 70%, mp 132 ꢁC). 31P
NMR spectrum, d (DMSO-d6): 17.08 m, 16.83 m. 19F NMR spectrum,
d (DMSO-d6): ꢀ84.00 s. 13C NMR spectrum, d (DMSO-d6): 139.90 (d,
C5, 3JCP 10.57 Hz), 138.07 (dd, C6, 2JCP 13.09 Hz, 3JCP 10.07 Hz), 135.07
4.4.8.2. Compound 13a. 31P NMR spectrum, d (C6D6): 16.87 m,
16.70 m. 19F NMR spectrum, d (C6D6): ꢀ71.90 s. 13C NMR spectrum,
2
3
d (C6D6): 144.15 (q, C8, JCF 32.72 Hz), 138.07 (d, C4, JCP 14.11 Hz),
3
2
3
136.53 (d, C5, JCP 9.56 Hz), 135.92 (dd, C3, JCP 14.18 Hz, JCP
9.68 Hz), 134.87 (dd, C6, 2JCP 13.99 Hz, 3JCP 10.01 Hz), 134.16 (dd, C2,
2
1
2
1JCP 189.74 Hz, JCP 10.07 Hz), 132.45 (dd, C1, JCP 188.74 Hz, JCP
3
2
3
(d, C4, JCP 9.56 Hz), 135.01 (dd, C3, JCP 13.59 Hz, JCP 9.56 Hz),
11.58 Hz), 114.72 (q, C9, 1JCF 286.88 Hz), 104.58 (m, C7), 62.78 (d, Ci,
1
2
1
2
3
131.49 (dd, C2, JCP 187.23 Hz, JCP 11.07 Hz), 130.33 (dd, C1, JCP
2JCP 6.89 Hz), 62.73 (d, Ci, JCP 7.03 Hz), 16.33 (d, Cj, JCP 1.12 Hz),
16.30 (d, Cj, 3JCP 1.08 Hz). 1H NMR spectrum, d (C6D6): 11.50 (s, 1H),
9.07 (dd, 1H, 3JHP 14.04 Hz, 3JHH 6.01 Hz), 8.24 (dd, 1H, 3JHP 19.00 Hz,
189.24 Hz, 2JCP 10.57 Hz), 124.81 (q, C9, 1JCF 289.90 Hz), 93.56 (q, C8,
2JCF 29.69 Hz), 62.79 (d, Ci, JCP 6.03 Hz), 62.72 (d, Ci, JCP 6.04 Hz),
2
2
41.64 (s, C7), 16.97 (d, Cj, JCP 1.51 Hz), 16.87 (d, Cj, JCP 1.50 Hz). 1H
4JHP 2.02 Hz), 7.59 (dd, 1H, JHH 8.00 Hz, JHP 2.09 Hz), 5.94(s, 1H),
4.04 (m, 8H), 1.07(t, 12H, 3JHH 7.89 Hz). MS (EI) m/e¼460 (Mþ, 10%),
415 (100), 387 (20), 359 (18), 331 (65), 323 (70), 295 (30); HRMS
m/e ([M]þ) calculated for C17H25 F3O7P2 460.10276, found
460.10067, m/e ([MꢀH]þ) calculated for C17H24 F3O7P2 459.09494,
found 459.09448.
3
3
3
4
3
3
NMR spectrum, d (DMSO-d6): 7.95 (dd, 1H, JHP 22.01 Hz, JHH
6.02 Hz), 7.89 (d, 1H, 3JHP 20.06 Hz), 7.62 (d, 1H, JHH 8.00 Hz), 7.01
3
(s, 2H), 4.03 (m, 8H), 3.04 (s, 2H), 1.23 (t, 12H, 3JHH 8.04 Hz). MS (EI)
m/e¼460 ([MꢀH2O]þ, 5%), 415 (100), 387 (22), 359 (20), 331 (85),
323 (63), 295 (35).

S.N. Tverdomed et al. / Tetrahedron 64 (2008) 5306–5313
5313
12. (a) Huang, C.; Tang, X.; Fu, H.; Jiang, Y.; Zhao, Y. J. Org. Chem. 2006, 71, 5020; (b)
Li, X.; Hewgley, J. B.; Mulrooney, C. A.; Yang, J.; Kozlowski, M. C. J. Org. Chem.
2003, 68, 5500; (c) Gelman, D.; Jiang, L.; Buchwald, S. L. Org. Lett. 2003, 5, 2315.
13. (a) Goossen, L. J.; Dezfuli, M. K. Synlett 2005, 445; (b) Maillet, C.; Praveen, T.;
Janvier, P.; Minguet, S.; Evain, M.; Saluzzo, C.; Tommasino, M. L.; Bujoli, B. J. Org.
Chem. 2002, 67, 8191.
14. Leblanc, Y.; Dufresne, C. Tetrahedron: Asymmetry 2001, 12, 3063.
15. Lui, W.-Q.; Vidal, M. J. Med. Chem. 2004, 47, 1223.
16. (a) Kim, M. K.; Wiemer, D. F. Tetrahedron Lett. 2005, 46, 7583; (b) Paruch, K.;
Vyklicky, L.; Wang, D. Z.; Katz, T. J.; Incarvito, C.; Zakharov, L.; Rheingold, A. L.
J. Org. Chem. 2003, 68, 8539; (c) Sime´on, F.; Jaffres, P.-A.; Villemin, D. Tetra-
hedron 1998, 54, 10111.
Acknowledgements
We thank the Deutschen Forschungsgemeinschaft (DFG No. 436
RUS 17/78/06) for financial support of this work. We also express
our gratitude to Dr. T. Duelcks (University of Bremen) and D.
Kemken (University of Bremen) for recording the MS and HRMS
spectra, also to H. Skarpos, M.Sc. (University of Bremen) for valuable
consultations on the purification of compounds.
References and notes
17. Kyba, E. P.; Steven, P. R. Tetrahedron Lett. 1981, 22, 1875.
18. Ziegler, T.; Layh, M. Chem. Ber. 1987, 120, 1347.
19. Seyferth, D.; Paetsch, J. D. H. J. Org. Chem. 1969, 34, 1483.
20. Behringer, H.; Heckmaier, P. Chem. Ber. 1969, 102, 2835.
21. Tverdomed, S. N.; Dogadina, A. V.; Ionin, B. I. Russ. J. Gen. Chem. 2001, 71,
1821.
22. Tverdomed, S. N.; Dogadina, A. V.; Ionin, B. I. Russ. J. Gen. Chem. 2006, 76,
885.
1. Dolman, N. P.; More, J. J. Med. Chem. 2006, 49, 2579.
2. (a) Suri, J. T.; Steiner, D. D.; Barbas, C. F. Org. Lett. 2005, 7, 3885; (b) Oishi, S.;
Karki, R. G.; Kang, S.-U.; Wang, X.; Worthy, K. M.; Bindu, L. K.; Nicklaus, M. C.;
Fisher, R. J.; Burke, T. R. J. Med. Chem. 2005, 48, 764; (c) Lui, W.-Q.; Carreaux, F.
Tetrahedron 1996, 52, 4411; (d) Oishi, O.; Kang, S.-U.; Liu, H.; Zhang, M.; Yang,
D.; Deschamps, J. R.; Burke, T. R. Tetrahedron 2004, 60, 2971; (e) Gasparini, F.;
Inderbitzin, W.; Francotte, E.; Lecis, G.; Richert, P.; Dragic, Z.; Kuhn, R.; Flor, P. J.
Bioorg. Med. Chem. Lett. 2000, 10, 1241.
23. The Chemistry of Organolithium Compounds; Wakefield, B. J., Ed.; Pergamon:
Oxford, 1974; p 30.
24. Watanabe, M.; Sahara, M. J. Org. Chem. 1984, 49, 742.
25. (a) Letsinger, R. L.; Schnizer, A. W. J. Org. Chem. 1951, 16, 869; (b) Watanabe, H.;
Hauser, C. R. J. Org. Chem. 1968, 33, 4278; (c) Ludt, R. E.; Griffiths, J. S. J. Org.
Chem. 1973, 38, 1668.
26. Boumekouez, A.; About-Jaudet, E. J. Organomet. Chem. 1994, 466, 89.
27. (a) Watanabe, M.; Date, M. Chem. Pharm. Bull. 1991, 39, 41; (b) Watanabe, M.;
Kawanishi, K. Chem. Pharm. Bull. 1991, 39, 3123.
28. Bayle-Lacoste, M.; Moulines, J. Tetrahedron 1990, 46, 7793.
29. Ionin, B. I.; Petrov, A. A. Zh. Obshch. Khim. 1965, 35, 1917.
30. Available commercially from Acros Organics, 2006.
31. Available commercially from Sigma-Aldrich, 2006.
32. Consiglio, G.; Failla, S.; Finocchiaro, P. Phosphorus, Sulfur Silicon Relat. Elem.
1996, 117, 37.
33. Broaddus, C. D. J. Am. Chem. Soc. 1966, 88, 4174.
34. The Chemistry of Organolithium Compounds; Wakefield, B. J., Ed.; Pergamon:
Oxford, 1974; p 260.
3. Katz, H. E.; Bent, S. F. J. Am. Chem. Soc. 1994, 116, 6631.
4. (a) Ngo, H. L.; Hu, A. J. Mol. Catal. A: Chem. 2004, 215, 177; (b) Ayyappan, P.;
Evans, O. R.; Cui, Y.; Wheeler, K. A.; Lin, W. Inorg. Chem. 2002, 41, 4978; (c)
Frantz, R.; Carre, F.; Durand, J.-O.; Lanneau, G. F. New J. Chem. 2001, 25, 188; (d)
Frantz, F.; Durand, J.-O.; Granier, M. Compt. Rendus. Chem. 2005, 8, 911.
5. Edwards, P. G.; Paisey, S. J. J. Chem. Soc., Perkin Trans. 1 2000, 3122.
6. (a) Jayasundera, K. P.; Watson, A. J.; Taylor, C. M. Tetrahedron Lett. 2005, 46,
4311; (b) Hu, A.; Lin, W. Org. Lett. 2005, 7, 455; (c) Hu, A.; Ngo, H. L.; Linx, W.
Angew. Chem., Int. Ed. 2003, 42, 6000; (d) Kalbitz, J.; Leissring, E. Z. Anorg. Allg.
Chem. 1994, 620, 2041.
7. (a) Muthukumaran, K.; Loewe, R. S. J. Org. Chem. 2004, 69, 1444; (b) Kuba´t, P.;
Lang, K.; Anzenbacher, P. Biochim. Biophys. Acta 2004, 1670, 40; (c) Ma¨rkl, G.;
Gschwendner, K.; Ro¨tzer, I. Helv. Chim. Acta 2004, 87, 825.
8. Creary, X.; Benage, B. Tetrahedron Lett. 1985, 26, 2383.
9. Lange, G.; Lesuisse, D.; Deprez, P.; Schoot, B.; Loenze, P.; Benard, D.; Marquette,
J.-P.; Broto, P.; Sarubbi, E.; Mandine, E. J. Med. Chem. 2003, 46, 5184.
10. (a) Bard, R. R.; Bunnett, J. F. J. Org. Chem. 1979, 44, 4918; (b) Obrycki, R.; Griffin,
C. E. Tetrahedron Lett. 1966, 31, 5049; (c) Jiao, X.-Y.; Bentrude, W. J. Org. Chem.
2003, 68, 3303.
11. (a) Picha, J.; Cibulka, R.; Liska, F.; Papik, P. Collect. Czech. Chem. Commun. 2004,
69, 2239; (b) Villemin, D.; Elbilali, A.; Simeon, F.; Jaffres, P.-A.; Maheut, G.;
Mosaddak, M.; Hakiki, A. J. Chem. Res., Synop. 2003, 436.
35. CCDC 669742 contains the supplementary crystallographic data of compound
11a. These data can be obtained free of charge from The Cambridge Crystal-
lographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
36. CCDC 669741 contains the supplementary crystallographic data of compound
11b. These data can be obtained free of charge from The Cambridge Crystal-
lographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.