The amination of difluoro(diethoxyphosphoryl)acetyl chloride: Facile synthetic route to novel amides containing difluoromethylenephosphonate moiety

Article abstract of DOI:10.1016/j.jfluchem.2009.05.001

A convenient route for the synthesis of novel amides containing at least one β-keto-α,α-difluoromethylenephosphonate group has been elaborated. The procedure requires simple stirring of an amine and difluoro(diethoxyphosphoryl)acetyl chloride in THF in th

Full text of DOI:10.1016/j.jfluchem.2009.05.001

Journal of Fluorine Chemistry 130 (2009) 695–701
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
The amination of difluoro(diethoxyphosphoryl)acetyl chloride: Facile synthetic
route to novel amides containing difluoromethylenephosphonate moiety
Romana Pajkert a, Magdalena Milewska a, Gerd-Volker Ro¨schenthaler b, Henryk Koroniak a,
*
a Adam Mickiewicz University, Faculty of Chemistry, Grunwaldzka 6, 60-780 Poznan, Poland
b Institute for Inorganic and Physical Chemistry, The University of Bremen, Leobener Str, D-28334, Germany
A R T I C L E I N F O
A B S T R A C T
convenient route for the synthesis of novel amides containing at least one
Article history:
A
b-keto-a,a-
Received 24 September 2008
Received in revised form 27 April 2009
Accepted 3 May 2009
difluoromethylenephosphonate group has been elaborated. The procedure requires simple stirring of
an amine and difluoro(diethoxyphosphoryl)acetyl chloride in THF in the presence of a catalytic amount
of DMAP. A wide range of amines has been accepted, including aliphatic and aromatic diamines,
diaminobenzidine or amine derivatives, such as Ciprofloxacin.
Available online 12 May 2009
ß 2009 Elsevier B.V. All rights reserved.
Keywords:
Difluoromethylenephosphonates
Fluorinated phosphonamides
Acylation
Difluoro(diethoxyphosphoryl)acetyl
chloride
1. Introduction
3 was considered as an inhibitor of aspartate transcarbamylase
(ATCase)(Fig. 1) [6].
The phosphate moiety is one of the most popular functionality
that can be found in living systems and which plays an essential
role in metabolic pathways, regulation processes or in the creation
of the genetic information [1]. However, in spite of its significance,
this functional group easily undergoes hydrolysis in the presence
of enzymes (phosphatases). On the other hand, the ubiquity of the
phosphate group in various biochemical processes has stimulated
intensive researches on the synthesis of various phosphate
analogues in which the labile P–O bond is replaced by phosphatase
resistant P–C bond [2]. One of these strategies, proposed by
Blackburn and McKenna in 1981, includes the substitution of the
bridging oxygen in phosphate moiety by the difluoromethylene
substituent [3]. This conception has been especially attractive due
to the electronic and steric similarity of the CF2 group to the oxygen
Although, despite interesting properties that could exhibit
difluorinated phosphonamides 1, 2 and 3, there is only a limited
number of synthetic pathways for the preparation of such
compounds [6]. These methods often requires the use of some
expensive reagents (e.g. benzotriazol-1-yloxy(dimethylamino)-
phosphonium hexafluorophosphate) or permits to obtain
products with moderate yields (50–80%). Therefore, we would
like to report an easy and high-yielding route to fluorinated
phosphonamides by the reaction of difluoro(diethoxyphosphor-
yl)acetyl chloride with various amines and amine derivatives, in
the presence of a catalytic amount of 4-dimethylaminopyridine
(DMAP).
2. Results and discussion
atom [4]. Indeed, the importance of
a,a-difluoromethylenepho-
sphonates as hydrolytically stable phosphate mimics and enzyme
inhibitors has been already well-established giving rise to the
synthesis of several analogues of natural products with enhanced
biological activity [5]. For example, compounds 1 and 2 are
analogues of 1,3-bisphosphoglyceric acid with micromolar binding
affinity for yeast phosphoglycerate kinase (PGK) while compound
The key substrate, difluoro(diethoxyphosporyl)acetyl chloride
5, was prepared by the treatment of difluoro(diethoxyphosphor-
yl)acetic acid 4 with an excess of oxalyl chloride (3 equiv.) in dry
benzene (Scheme 1).
This method, which is
a modification of the procedure
developed by Blackburn and Burton [7], afforded 4 in excellent
yield. Moreover, 5 though hydrolytically unstable, has been easily
isolated without decomposition. First trap-to-trap distillation of
the remaining excess of oxalyl chloride, followed by the distillation
of the product in vacuo (0.04 mmHg) gave 98% of pure 5 as a clear,
yellowish liquid. We have also observed, that produced by this
* Corresponding author.
E-mail addresses: gvr@chemie.uni-bremen.de (G.-V. Ro¨schenthaler),
koroniak@amu.edu.pl (H. Koroniak).
0022-1139/$ – see front matter ß 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2009.05.001

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R. Pajkert et al. / Journal of Fluorine Chemistry 130 (2009) 695–701
Fig. 1.
Scheme 1.
Scheme 2.
method 5, can be stored under nitrogen in a freezer for months
without any change [9].
expected products in good to excellent yield (Table 1). It should be
noted, that the acylation proceeds also without the addition of
DMAP but we found, that the yield of the desired products was
significantly lower (up to 68%, entries 1 and 4).
The reactivity of difluoro(diethoxyphosphoryl)acetyl chloride 5
has been then investigated toward some simple primary amines.
As shown in Scheme 2, the typical procedure was performed by
adding 5 (1 equiv.) to the mixture of an appropriate amine
(1 equiv.), pyridine (1 equiv.) and DMAP (5 mol%) in dry THF at
0 8C. The reaction was completed after 2 h of stirring at room
Based on the results with simple primary amines, we next
explored
a similar experiments to incorporate b-keto-a,a-
difluorophosphonate moiety into di- and tetraamines or into
amine derivatives showing interesting biological activity, such as L-
temperature (the progress of the conversion was monitored by 19
F
aspartic acid, 2,2,4,4-tetramethylpiperidine and Ciprofloxacin1—a
highly potent and orally active antibacterial agent [10]. We
NMR). Subsequently, an acidic work-up and purification gave the
Table 1
Fluorinated phosphonamides produced via Scheme 2.
Entry
Amine
5
Product (6)
Yield (%)a
1
1 equiv.
66b
2
1 equiv.
96
3
4
1 equiv.
1 equiv.
93
68b

R. Pajkert et al. / Journal of Fluorine Chemistry 130 (2009) 695–701
697
Table 1 (Continued )
Entry
Amine
5
Product (6)
Yield (%)a
92
5
1 equiv.
6
1 equiv.
98
7
2 equiv.
97
8
2 equiv.
93
9
2 equiv.
93
10
2 equiv.
98
11
2 equiv.
92

698
R. Pajkert et al. / Journal of Fluorine Chemistry 130 (2009) 695–701
Table 1 (Continued )
Entry
Amine
5
Product (6)
Yield (%)a
12
1 equiv.
96
13
14
1 equiv.
20
1 equiv.
30c
15
4 equiv.
90
a
Isolated yields, based on the total amount of 5 used in the reaction.
The reaction was conducted without addition of DMAP.
The mixture of two conformers was obtained.
b
c
suppose, that the modification of these compounds by the
introduction of -keto- -difluorophosphonate group, may
represent a simple way in the designing of molecules with
interesting biological activity.
As expected, aliphatic and aromatic diamines and diamino-
benzidine, when mixing with twofold excess of 5 and pyridine in
the presence of DMAP, react also smoothly giving corresponding
fluorinated tetraethyl diphosphonate and octaethyl tetrapho-
sphonate in very good yields (Table 1).
vary, which is due to the different surrounding for each
CF2P(O)(OEt)2 functionality (caused by dissimilar conformation
on the piperazine ring of Ciprofloxacin1).
b
a,a
On the other hand, when chloride 5 was used in the acylation of
1,6-diaminohexane or cystamine (entry 8 and 9, Table 1), acetylated
products 6h, 6i were obtained as mixtures of amidic 6 and imidic
forms7(ratio50:50), whichcould bededuced fromthetautomerism
observed for this group of compounds (Scheme 3).
The presence of these two forms was detected by 1H, 19F and 31
P
We observed however, that for entries 13 and 14 the yield of the
acylation decreased, which can be probably explained by the bad
NMR spectra of crude products 6h and 6i in CDCl3 at room
temperature. The ratio of 6–7 increased with the addition of protic
solvent, CD3OD, to the solution of 6h or 6i in CDCl3. Only the amide
structure 6 was finally observed when 1H, 19F and 31P NMR spectra
were measured in CD3OD. What is more, the purification of crude
products 6h and 6i by column chromatography on silica gel
changes the amidic/imidic equilibrium, giving pure amidic forms
of 6h and 6i as sole products.
solubility of L
-aspartic acid and Ciprofloxacin1 in common organic
solvents. Besides, compound 6n has been obtained as a mixture of
two structural conformers A and B (in a ratio of 70:30, as
determined by 19F NMR) as schematically presented at Fig. 2.
What is more, chemical shifts of difluoromethylene moieties, as
well as phosphonate groups of each conformers (A and B, Fig. 2)
Scheme 3.

R. Pajkert et al. / Journal of Fluorine Chemistry 130 (2009) 695–701
699
Fig. 2.
In conclusion, a simple and high-yielding procedure for the
preparation and amination of difluoro(diethoxyphosphoryl)acetyl
chloride with various amines under mild conditions has been
accomplished. The reaction accepts a wide range of substrates,
including aliphatic and aromatic amines, diamines and amine
derivatives. Produced by this methodology functionalized phos-
phonamides are often of interest, due to their potential biological
activity [6]. They can also serve as convenient precursors for the
preparation of novel heterocycles containing difluoromethylene-
phosphonate moiety (e.g. oxazolines) [11] or as substrates in the
give 11.24 g of pure 5, as a clear, yellowish oil. Yield: 98%; b.p. 55 8C/
0.04 mmHg; 19F NMR (CDCl3):
d
ꢀ112.3 (d, 2JFP 93.1 Hz); 31P NMR
2
(CDCl3):
d
1.83 (t, JPF 93.6 Hz); 1H NMR (CDCl3):
d
d
1.40 (t, 6H,
OCH2CH3), 4.35 (q, 4H, OCH2CH3); 13C NMR (CDCl3):
5.65 Hz, OCH2CH3), 66.75 (d, 2JCP 6.70 Hz, OCH2CH3), 111.9 (td, 1JCF
278.3 Hz, JCP 204.2 Hz, CF2), 166.3 (td, JCF 33.8 Hz, JCP 22.6 Hz,
O).
16.63 (d, 3JCP
1
2
2
C
3.2. Typical procedure for the synthesis of fluorinated
phosphonamides (6)
synthesis of fluorinated
b-amino acid derivatives [12].
To a stirred solution of an amine (1 equiv.) and pyridine
(1 equiv. 6b–f and 6l–n; 2 equiv. 6g–k; 4 equiv. 6o) in dry
THF (15 ml) at 0 8C, an appropriate amount of difluoro(diethox-
yphosphoryl)acetyl chloride was added, followed by addition
of DMAP (5 mol%). The resulting suspension was then stirred for
2 h at room temperature. An aqueous solution of HCl was
added (pH ꢁ 5) and the mixture was stirred for additional
10 min. The reaction mixture was extracted three times
with CH2Cl2, combined organic layers were washed with brine
and dried over Na2SO4. The solvent was removed in vacuo, to give
crude product which was purified by flash column chromato-
graphy on silica gel (eluent: petroleum ether: ethyl acetate 1:1 or
ethyl acetate). Compounds 6b, 6j, 6k and 6n were additionally
recrystallized from chloroform–petroleum ether).
3. Experimental
All reactions were carried out under an atmosphere of dry
nitrogen. THF was freshly distilled from sodium benzophenone
ketyl. Difluoro(diethoxyphosphoryl)acetic acid was prepared
according to the procedure described by Blackburn [7], with
following an aqueous acid–base work-up by Hamilton and Roberts
[8]. All other reagents were distilled or recrystallized, if necessary.
Flash chromatography was performed using Merck silica gel 60
(230–400 mesh ASTM) and TLCs using Merck silica gel 60 F254
.
Visualization was achieved by UV light or by spraying with
Ce(SO4)2 solution in 5% H2SO4. 1H (200.13 MHz), 13C (50.32 MHz),
19F (188.31 MHz) and 31P NMR (80.99 MHz) have been achieved on
a Bruker Avance DPX-200 spectrometer in CDCl3 as a solvent. TMS
was the internal standard in 1H NMR, CFCl3 was used as a reference
3.2.1. Diethyl 2-(benzylamino)-1,1-difluoro-2-oxoethylphosphonate
for 19F NMR and 85% H3PO4 in 31P NMR. Chemical shifts (
d
) are
(6a)
2
reported in ppm and coupling constants (J) in Hz. 31P NMR spectra
were broadband decoupled from hydrogen nuclei. Mass spectra
were recorded on a Varian MAT CH7A instrument at 70 eV. Melting
points were determined with an Electrothermal IA9100 Digital
Melting Point Apparatus and are uncorrected.
Yield: 66%; Yellow oil; 19F NMR (CDCl3):
d
ꢀ118.4 (d, JFP
96.4 Hz); 31P NMR (CDCl3):
1.38 (t, 6H, OCH2CH3), 4.31 (q, 4H, OCH2CH3), 4.54 (d, 2H, CH2), 7.0
(br. s., NH), 7.31(m, 5H, HAr);13C NMR (CDCl3): 16.9(d, 3JCP 5.65 Hz,
d d
4.67 (t, 2JPF 96.4 Hz); 1H NMR (CDCl3):
d
OCH2CH3), 44.2 (s, CH2), 66.3 (d, 2JCP 6.70 Hz, OCH2CH3), 112.7 (td,
1JCF 271.6 Hz, 1JCP 200.9 Hz, CF2), 128.2 (s, CAr), 129.3 (s, CAr), 129.4 (s,
CAr), 137.5 (s, CAr), 162.0 (td, 2JCF 24.3 Hz, 2JCP 16.9 Hz, C O); MS (EI)
m/z (%): 321 [M]+ꢂ (25), 187 [MꢀC7H7NHCO]+ (10), 106
[MꢀC(O)CF2P(O)(OEt)2]+ (88), 91 [C7H7]+(100).
3.1. General procedure for the synthesis of
difluoro(diethoxyphosphoryl)acetyl chloride (5)
The mixture of 1 equiv. (10.6 g, 45.7 mmole) of (diethoxypho-
sphoryl)difluoroacetic acid 4, in dry benzene was put in the flask,
equipped with magnetic stirrer, nitrogen in–out system, bubble-
counter and septum. Then, 3 equiv. (17.4 g, 137 mmole) of oxalyl
chloride were added dropwise at room temperature. Stirring at r.t.
was continued overnight. Afterwards, all volatiles were condensed
off in vacuo. Brown residue was distilled under reduced pressure to
3.2.2. Diethyl 1,1-difluoro-2-oxo-2-(2,2,6,6,-tetramethylpiperidin-4-
ylamino) ethylphosphonate (6b)
Yield: 96%; yellowish crystals; m.p. 104–109 8C; 19F NMR
(CDCl3):
d
ꢀ118.2 (d, 2JFP 96.5 Hz); 31P NMR (CDCl3):
d
4.92 (td, 2JPF
96.2 Hz); 1H NMR (CDCl3):
d 1.02 (t, 2H, CH2), 1.12 (s, 6H, CH3), 1.23
(br. s., 1H, NH), 1.25 (s, 6H, CH3), 1.39 (t, 6H, OCH2CH3), 1.91 (dd,

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R. Pajkert et al. / Journal of Fluorine Chemistry 130 (2009) 695–701
2H, CH2), 4.29 (m, 1H, CH), 4.32 (q, 4H, OCH2CH3), 8.36 (br. d., 1H,
OCH2CH3), 39.0 (s, CH2), 66.3 (d, 2JCP 6.70 Hz, OCH2CH3), 112.7 (td,
3
1
1
2
2
NH); 13C NMR (CDCl3):
d
16.8 (d, JCP 5.65 Hz, OCH2CH3), 28.9 (s,
CF2, JCF 273.3 Hz, JCP 273.3 Hz), 162.9 (td, JCF 24.4 Hz, JCP
CH3), 35.3 (s, CH), 44.1 (s, CH2), 44.9 (s, CH2), 51.5 (s, C-CH3), 66.0 (d,
2JCP 6.70 Hz, OCH2CH3), 112.3 (td, CF2, 1JCF 273.3 Hz, 1JCP 273.3 Hz),
16.9 Hz,
C
O); MS (EI) m/z (%): 488 [M]+ꢂ (28), 301
[MꢀCF2P(O)(OEt)2]+, 245 [301ꢀCH2NHCO]+ (100).
2
2
160.9 (td, JCF 24.4 Hz, JCP 16.9 Hz, C = O); MS (EI) m/z (%): 370
[M]+ꢂ (2), 355 [MꢀCH3]+ (33), 124 [MꢀC6H12NO4PF2]+ (100);
HRMS: Calculated for C15H29N2O4PF2 (M+ꢂ) 370. 18330, found
370.18458.
3.2.8. Tetraethyl 2,20-(hexane-1,6-diylbis(azanediyl)bis(1,1-difluoro-
2-oxoethane-2,1-diyl)diphosphonate (6h)
Yield: 93%; yellowish oil; 19F NMR (CDCl3):
d
ꢀ117.9 (d, 2F, 2JFP
98.1 Hz); 31P NMR (CDCl3):
d
4.21 (t, 1P, JPF 97.1 Hz); 1H NMR
2
3.2.3. Diethyl 1,1-difluoro-2-(4-methylpiperazin-1-ylamino)-2-
(CDCl3):
d 1.30 (m, 2H, CH2), 1.34 (t, 12H, OCH2CH3), 1.52 (t, 4H,
oxoethylphosphonate(6c)
CH2), 3.27 (dd, 4H, CH2), 4.28 (q, 8H, OCH2CH3), 8.63 (br. s., 2H, NH);
2
3
Yield: 98%; yellowish oil; 19F NMR (CDCl3):
d
ꢀ118.6 (d, JFP
13C NMR (CDCl3):
d 16.9 (t, JCP 5.65 Hz, OCH2CH3), 26.4 (s, CH2),
96.5 Hz); 31P NMR (CDCl3): 4.28 (t, 2JPF 96.2 Hz); 1H NMR (CDCl3):
d
29.1 (s, CH2), 40.1 (s, CH2), 66.5 (t, 2JCP 6.70 Hz, OCH2CH3), 112.6 (td,
1
1
2
2
d
1.36 (t, 6H, OCH2CH3), 2.27 (s, 3H, CH3), 2.57 (t, 4H, CH2), 2.91 (t,
CF2, JCF 272.8 Hz, JCP 202.2 Hz), 176.8 (td, JCF 19.8 Hz, JCP
4H, CH2), 4.30 (q, 4H, OCH2CH3), 7.65 (br. s., 1H, NH); 13C NMR
16.8 Hz,
C
O); MS (EI) m/z (%): 544 [M]+ꢂ (10), 357
3
(CDCl3):
d
16.8 (d, JCP 5.65 Hz, OCH2CH3), 45.8 (s, CH3), 49.5 (s,
[MꢀCF2P(O)(OEt)2]+ (98), 188 (81), 132 (100).
2
CH2), 60.9 (s, CH2), 66.0 (d, JCP 6.70 Hz, OCH2CH3), 112.3 (td, CF2,
Imidic form (7h): 19F NMR (CDCl3):
d
ꢀ118.7 (d, 2F, 2JFP 97.4 Hz),
1
2
2
1JCF 273.3 Hz, JCP 273.3 Hz), 160.9 (td, JCF 24.4 Hz, JCP 16.9 Hz,
C = O); MS (EI) m/z (%): 329 [M]+ꢂ (5), 314 [MꢀCH3]+ (33), 142
[MꢀCF2P(O)(OEt)2]+ (100).
31P NMR (CDCl3): 4.62 (t, 1P, 2JPF 97.5 Hz), 1H NMR (CDCl3):
d d 1.30
(m, 2H, CH2), 1.34 (t, 12H, OCH2CH3), 1.52 (t, 4H, CH2), 3.27 (dd, 4H,
CH2), 4.28 (q, 8H, OCH2CH3), 7.30 (br. t., 2H, OH); 13C NMR (CDCl3):
d
16.9 (t, 3JCP 5.65 Hz, OCH2CH3), 26.4 (s, CH2), 29.1 (s, CH2), 40.1 (s,
2
1
3.2.4. Diethyl 1,1-difluoro-2-(hydroxyethylamino)-2-
CH2), 66.5 (t, JCP 6.70 Hz, OCH2CH3), 112.6 (td, CF2, JCF 272.8 Hz,
1JCP 202.2 Hz), 178.4 (td, JCF 19.8 Hz, JCP 16.8 Hz, C O).
2
2
oxoethylphosphonate (6d)
Yield: 68%; colorless oil; 19F NMR (CDCl3):
d
ꢀ118.9 (d, JFP
2
96.6 Hz); 31P NMR (CDCl3):
d
4.69 (t, JPF 96.5 Hz); 1H NMR
3.2.9. Tetraethyl 2,20-(2,20-disulfanediylbis(ethane-2,1-
diyl)bis(azanediyl)bis(1,1-difluoro-2-oxoethane-2,1-
diyl)diphosphonate (6i)
2
(CDCl3):
OH), 3.70 (t, 2H, CH2), 4.31 (q, 4H, OCH2CH3), 7.52 (br. s., 1H,
NH); 13C NMR (CDCl3): 16.7 (d, 3JCP 5.65 Hz, OCH2CH3), 42.8 (s,
CH2), 60.9 (s, CH2), 66.3 (d, 2JCP 6.70 Hz, OCH2CH3), 112.5 (td, CF2,
d 1.37 (t, 6H, OCH2CH3), 3.46 (t, 2H, CH2), 3.50 (br. s.,
d
Yield: 93%; colorless oil; 19F NMR (CDCl3):
d
ꢀ117.9 (d, 2F, 2JFP
2
97.7 Hz); 31P NMR (CDCl3):
d
4.26 (t, 1P, JPF 97.5 Hz); 1H NMR
1
2
2
1JCF 273.3 Hz, JCP 273.3 Hz), 162.3 (td, JCF 24.4 Hz, JCP 16.9 Hz,
(CDCl3): d 1.38 (t, 12H, OCH2CH3), 2.89 (t, 4H, CH2), 3.65 (dd, 4H,
C
O); MS (EI) m/z (%): 257 [MꢀH2O]+ꢂ (2), 187 [257ꢀC3H4NO]+
CH2), 4.33 (q, 8H, OCH2CH3), 7.49 (br. t., 2H, NH); 13C NMR (CDCl3):
16.8 (d, 3JCP 5.65 Hz, OCH2CH3), 37.3 (s, CH2), 39.0 (s, CH2), 66.1 (d,
2JCP 6.70 Hz, OCH2CH3), 112.4 (td, CF2, 1JCF 272.7 Hz, 1JCP 201.3 Hz),
(100).
2
2
3.2.5. Diethyl 2-(2-bromoethylamino)-1,1-difluoro-2-
162.1 (td, JCF 24.3 Hz, JCP 17.0 Hz, C O); MS (EI) m/z (%): 580
[M]+ꢂ (15), 290 [MꢀSC2H4NHCOCF2P(O)(OEt)2]+ (93), 258 [290ꢀS]+
oxoethylphosphonate (6e)
Yield: 92%; colorless oil; 19F NMR (CDCl3):
d
ꢀ118.5 (d, JFP
4.44 (t, 2JPF 98.8 Hz); 1H NMR (CDCl3):
1.32 (t, 6H, OCH2CH3), 3.42 (t, 2H, CH2), 3.68 (t, 2H, CH2), 4.28 (q,
4H, OCH2CH3), 7.55 (br. s., 1H, NH); 13C NMR (CDCl3): 16.7 (d, 3JCP
5.65 Hz, OCH2CH3), 30.8 (s, CH2), 41.8 (s, CH2), 66.2 (d, 2JCP 6.70 Hz,
(100).
2
97.0 Hz); 31P NMR (CDCl3):
d
Imidic form (7i): 19F NMR (CDCl3):
d
ꢀ118.5 (d, 2F, JFP
2
2
d
97.2 Hz),); 31P NMR (CDCl3): 4.39 (t, 1P, JPF 97.9 Hz); 1H NMR
d
(CDCl3): 1.38 (t, 12H, OCH2CH3), 2.89 (t, 4H, CH2), 3.65 (dd, 4H,
d
CH2), 4.33 (q, 8H, OCH2CH3), 7.64 (br. t., 2H, OH); 13C NMR (CDCl3):
16.8 (d, 3JCP 5.65 Hz, OCH2CH3), 37.3 (s, CH2), 39.0 (s, CH2), 66.1 (d,
2JCP 6.70 Hz, OCH2CH3), 112.4 (td, CF2, 1JCF 272.7 Hz, 1JCP 201.3 Hz),
1
1
OCH2CH3), 112.2 (td, CF2, JCF 272.3 Hz, JCP 201.1 Hz), 162.0 (td,
2
2JCF 24.4 Hz, JCP 16.9 Hz, C O); MS (EI) m/z (%): 337 [M+H]+ꢂ (6),
188 [338ꢀC3H5NOBr]+ (100).
162.1 (td, JCF 24.3 Hz, JCP 17.0 Hz, C O).
2
2
3.2.6. Diethyl 2-(2,4-difluorophenylamino)-1,1-difluoro-2-
3.2.10. Tetraethyl 2,20-(pyridine-2,6-diylbis(azanediyl)bis(1,1-
difluoro-2-oxoethane-2,1-diyl)diphosphonate (6j)
oxoethylphosphonate (6f)
Yield: 98%; colorless oil; 19F NMR (CDCl3):
d
ꢀ116.7 (m, 1F),
Yield: 98%; colorless crystals; m.p. 109–110 8C; 19F NMR (CDCl3):
ꢀ118.4 (d, 2F, 2JFP 95.6 Hz), ꢀ136.4 (m, 1F); 31P NMR (CDCl3);
d
4.58
d
ꢀ118.5(d, 2JFP 95.2 Hz);31PNMR (CDCl3):
d
4.32(t, 2JPF 95.4 Hz);1H
(t, 2JPF 96.0); 1H NMR (CDCl3):
d
1.39 (dt, 6H, OCH2CH3), 4.36 (m, 4H,
NMR (CDCl3): d1.42 (dt, 12H, OCH2CH3), 4.38 (q, 8H, OCH2CH3), 7.78
OCH2CH3), 6.81 (m, 1H, HAr), 7.06 (m, 1H, HAr), 8.07 (m, 1H, HAr), 8.65
(br. s., 1H, NH); 13C NMR (CDCl3): 16.9 (d, 3JCP 5.65 Hz, OCH2CH3),
(dd, 1H, HAr), 7.96 (d, 2H, HAr), 8.86 (br. s., 2H, NH); 13C NMR (CDCl3):
3
2
d
d 16.8 (d, JCP 5.65 Hz, OCH2CH3), 66.4 (d, JCP 6.70 Hz, OCH2CH3),
66.7 (d, 2JCP 6.70 Hz, OCH2CH3), 109.9 (dd, JCF 30.9 Hz, JCF 0.9 Hz, CAr),
112.7 (dd, JCF 24.5 Hz, JCF 10.3 Hz, CAr), 112.9 (td, CF2, 1JCF 272.9 Hz,
1JCP 200.4 Hz), 116.4 (dd, JCF 21.6 Hz, JCF 9.5 Hz, CAr), 126.0 (t, JCF
12.4 Hz, CAr), 149.5 (dd, JCF 241.4 Hz, JCF 3.1 Hz, CAr), 159.1 (dd, JCF
242.4 Hz, JCF 2.5 Hz, CAr), 159.8 (td, 2JCF 25.1 Hz, 2JCP 17.9 Hz, C = O);
MS (EI) m/z (%): 343 [M]+ꢂ (27), 188 [MꢀC7H4F2NO]+, 161
[188ꢀCO]+, 132 (100), 84 (83); HRMS: Calculated for C12H14NO4PF4
(M+ꢂ) 343.05966, found 343.06065.
112.1 (td, CF2, JCF 273.8 Hz, 1JCP 200.6 Hz), 114.0 (s, CAr), 141.6 (s,
CAr), 148.5 (s, CAr), 160.1 (td, 2JCF 25.0 Hz, 2JCP 17.7 Hz, C O); MS (EI)
m/z (%): 537 [M]+ꢂ (5), 492 [MꢀOEt]+ (51), 350 [MꢀCF2P(O)(OEt)2]+
(100), 322 [350ꢀCO]+ (14); HRMS: Calculated for C17H24N3O8P2F4
([MꢀH]+) 536.09748, found 536.09797.
1
3.2.11. Tetraethyl 2,20-(4,40-methylenebis(4,1-
phenylene)bis(azanediyl)bis(1,1-difluoro-2-oxoethane-2,1-
diyl)diphosphonate (6k)
3.2.7. Tetraethyl 2,20-(ethane-1,2-diylbis(azanediyl)bis(1,1-difluoro-
Yield: 90%; white crystals; m.p. 112–114 8C; 19F NMR (CDCl3):
d
2
2
2-oxoethane-2,1-diyl)diphosphonate (6g)
ꢀ118.0 (d, JFP 96.5 Hz); 31P NMR (CDCl3):
d 4.79 (t, JPF 96.5 Hz);
Yield: 97%; white crystals; 19F NMR (CDCl3):
d
ꢀ120.5 (d, JFP
1H NMR (CDCl3):
d 1.41 (t, 12H, OCH2CH3), 3.94 (s, 2H, CH2), 4.37 (q,
2
95.9 Hz); 31P NMR (CDCl3):
d
5.19 (t, 2JPF 95.6 Hz); 1H NMR (CDCl3):
8H, OCH2CH3), 7.14 (d, 4H, HAr), 7.50 (d, 4H, HAr), 8.45 (br. s., 2H,
3
d
1.40 (dt, 12H, OCH2CH3), 3.51 (t, 4H, CH2), 4.34 (q, 8H, OCH2CH3),
NH); 13C NMR (CDCl3):
d 16.7 (d, JCP 5.65 Hz, OCH2CH3), 41.2 (s,
3
7.85 (br. s., 2H, NH); 13C NMR (CDCl3):
d 16.7 (d, JCP 5.65 Hz,
CH2), 66.4 (d, 2JCP 6.70 Hz, OCH2CH3), 112.8 (td, CF2, 1JCF 273.3 Hz,

R. Pajkert et al. / Journal of Fluorine Chemistry 130 (2009) 695–701
701
1JCP 273.3 Hz), 121.0 (s, CAr), 129.0 (s, CAr), 129.9 (s, CAr), 138.8 (s,
CAr), 159.4 (td, 2JCF 24.4 Hz, 2JCP 16.9 Hz, C O); MS (EI) m/z (%): 626
[M]+ꢂ (5), 439 [MꢀCF2P(O)(OEt)2]+ (100).
2P, 2JFP 96.2 Hz); 1H NMR (CDCl3):
d
1.41 (tdd, 24H, 4xOCH2CH3),
4.41 (dq, 16H, 4xOCH2CH3), 7.23 (dd, 2H, HAr), 7.49 (d, 2H, HAr),
7.55 (d, 2H, HAr), 9.53 (br. d., 4H, NH); 13C NMR (CDCl3):
16.8
(d, JCP 5.65 Hz, OCH2CH3), 66.4 (dd, JCP 6.70 Hz, OCH2CH3),
d
3
2
1
1
3.2.12. (S)-di-tert-butyl 2-(2-(diethoxyphosphoryl)-2,2-
difluoroacetamido)succinate (6l)
Yield: 96%; yellow oil; All NMR and MS analysis were consistent
with the literature data [6d].
115.8 (td, CF2, JCF 273.3 Hz, JCP 200.2 Hz), 124.3 (s, CAr), 126.2
(s, CAr), 128.5 (s, CAr), 128.7 (s, CAr), 128.9 (s, CAr), 138.4 (s, CAr),
2
2
161.4 (td, JCF 24.4 Hz, JCP 16.9 Hz, C O); MS (ESI, CH3CN) m/z
1070 [MꢀH]ꢀ.
3.2.13. (S)-2-(2-(diethoxyphosphoryl)-2,2-difluoro
acetamido)succinic acid (6m)
Acknowledgements
Yield: 20%; yellowish oil; All NMR and MS analysis were
consistent with the literature data [6d].
The Deutschen Forschungsgemeinschaft (Grant 436 POL 113/
120/0-1) is greatly acknowledged for the financial support of this
work. We would like also to express our gratitude to Dr. T. Duelcks
and D. Kemken (University of Bremen) for recording MS and HRMS
spectra.
3.2.14. 1-cyclopropyl-7-(4-(2-(diethoxyphosphoryl)-2,2-
difluoroacetyl)piperazin-1-yl)-6-fluoro-4-oxo-1,4-dihydroquinoline-
3-carboxylic acid (6n)
Yield: 30%; yellowish solid; m.p. 159–162 8C;
Conformer A: 19F NMR (CDCl3):
d
ꢀ110.4 (d, 2F, CF2 JFP 94.0 Hz),
2
ꢀ122.2 (m, 1F, FAr); 31P NMR (CDCl3):
d
4.39 (t, 1P, 2JPF 94.2 Hz); 1H
References
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OCH2CH3), 7.28 (s, 1H, Hvinyl), 7.38 (d, 1H, HAr), 8.02 (d, 1H, HAr),
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8.76 (br. s., 1H, COOH); 13C NMR (CDCl3):
d 8.72 (s), 16.8 (dd,
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OCH2CH3), 35.9 (s), 43.5 (s), 46.1 (t), 49.8 (d), 50.3 (d), 66.3 (dd,
1
OCH2CH3), 105.7 (s), 108.5 (s), 112.7 (d), 112.9 (td, CF2, JCF
1
275.5 Hz, JCP 208.0 Hz), 139.4 (s), 120.7 (d), 145.6 (d), 160.4 (td,
2JCF 24.1 Hz, 2JCP 18.6 Hz, C O), 148.0 (s), 151.5 (s), 156.5 (s), 167.6
(s), 177.4 (s); MS (EI) m/z (%): 545 [M]+ꢂ (8), 329
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[MꢀCOCF2P(O)(OEt)2]+ (100).
2
Conformer B:
d
ꢀ117.9 (d, 2F, CF2, JFP 96.4 Hz), ꢀ122.4 (m, 1F,
FAr); 31P NMR (CDCl3): 4.44 (t, 1P, 2JFP 96.2 Hz); 1H NMR (CDCl3):
d d
(d) C. Grison, P. Coutrot, C. Comoy, L. Balas, S. Joliez, G. Lavecchia, P. Oliger, B.
Penverne, V. Serre, G. Herve, Eur. J. Med. Chem. (2004) 333.
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[8] C.J. Hamilton, S.M. Roberts, J. Chem. Soc., Perkin Trans. 1 (1999) 1051.
1.36 (m, 4H, CH2), 1.41 (m, 8H, OCH2CH3), 3.41 (m, 4H, CH2), 3.58
(m, 1H, CH), 4.0 (dm, 4H, CH2), 4.35 (m, 4H, OCH2CH3), 7.28 (s, 1H,
Hvinyl), 7.38 (d, 1H, HAr), 8.02 (d, 1H, HAr), 8.76 (br. s., 1H, COOH);
13C NMR (CDCl3):
d
8.72 (s), 16.8 (dd, OCH2CH3), 35.9 (s), 43.5 (s),
[9] M. Milewska, Ph.D. Dissertation, Adam Mickiewicz University, Poznan, 2003.
´
ˇ ´
ˇ ´
´
´
ˇ
´
´
[10] (a) Z.B. Tomisic, N. Kujundzic, M. Bukvic Krajacic, A. Visnjevac, B. Kojic-Prodic, J.
46.1 (t), 49.8 (d), 50.3 (d), 66.3 (dd, OCH2CH3), 105.7 (s), 108.5 (s),
1
1
Mol. Struct. 611 (2002) 73;
(b) M.J. Nieto, F. Del Lujan Alovero, R.H. Manzo, M.R. Mazzieri, Eur. J. Med. Chem.
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1451 (and references cited therein).
112.7 (d), 112.9 (td, CF2, JCF 275.5 Hz, JCP 208.0 Hz), 139.4 (s),
120.7 (d), 145.6 (d), 160.7 (td, 2JCF 26.7 Hz, 2JCP 17.8 Hz, C O), 148.0
(s), 151.5 (s), 156.5 (s), 167.6 (s), 177.4 (s).
3.2.15. Octaethyl 2,20,200,2000-(biphenyl-3,30,4,40-
tetrayltetrakis(azanediyl)tetrakis(1,1-difluoro-2-oxoethane-2,1-
diyl)tetraphosphonate (6o)
[11] N. Ishikawa, A. Sekiya, Eur. Pat. Appl. 151449 (1985).
[12] S.P. Stanforth, Tetrahedron 57 (2001) 1833.
Yield: 92%; viscosous oil; 19F NMR (CDCl3):
2JFP 96.4 Hz); 31P NMR (CDCl3):
d
ꢀ118.4 (d, 8F,
d
4.14 (t, 2P, 2JPF 96.2 Hz), 4.25 (t,