Attempts at asymmetric electrosynthesis of α-fluorinated cyclopropylphosphonamides

Article abstract of DOI:10.1039/b008906k

Variously N,N-disubstituted chiral dibromofluoromethylphosphonamides 3 were easily prepared and used for the asymmetric electrosynthesis, in the presence of tert-butyl acrylate, of α-fluorinated cyclopropylphosphonamides 7. The diastereoisomeric excesses

Full text of DOI:10.1039/b008906k

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Attempts at asymmetric electrosynthesis of ꢀ-fluorinated
cyclopropylphosphonamides
Sophie Goumain,a Hassan Oulyadi,b Philippe Jubault,a Christian Feassona and
Jean-Charles Quiriona
1
a Laboratoire d’Hétérochimie Organique, INSA de Rouen, IRCOF, 1 rue Tesnière,
76130 Mont-Saint-Aignan Cedex, France
b Laboratoire de Chimie Organique et Biologie Structurale de l’IRCOF, Université de Rouen,
1 rue Tesnière, 76130 Mont-Saint-Aignan Cedex, France
Received (in Cambridge, UK) 6th November 2000, Accepted 19th February 2001
First published as an Advance Article on the web 14th March 2001
Variously N,N-disubstituted chiral dibromofluoromethylphosphonamides 3 were easily prepared and used for the
asymmetric electrosynthesis, in the presence of tert-butyl acrylate, of α-fluorinated cyclopropylphosphonamides 7.
The diastereoisomeric excesses are moderate (up to 40%). Moreover, the identification of the trans and cis
stereoisomers has been deduced from analysis of 2D 1H–19F HOESY spectra.
The cyclopropane moiety can be found in a number of natural
and unnatural substances, and some of these have received par-
ticular attention due to their biological properties.1,2 Hence, this
group continues to attract a lot of attention in synthetic organic
chemistry as well as in medicinal and agricultural chemistry.
Furthermore, it is known for biologically active compounds
that the replacement of a C–H bond with a C–F bond can lead
to dramatic effects on their physiological properties.3 Therefore,
Results and discussion
Synthesis of dibromofluoromethylphosphonamides 3 derived from
(R,R)-1,2-bis(N-alkylamino)cyclohexanes 4
the development of new synthetic approaches to fluorinated
compounds is an important field of research.4 Moreover, phos-
phonic acids exhibit important biological properties because of
their similarity to phosphates.5 The carbon–phosphorus bond
in phosphonates, unlike that in phosphates, is not susceptible to
the hydrolytic action of phosphatases, thereby imparting
greater stability under physiological conditions. In pioneering
work, Blackburn et al. established that α-fluorination of phos-
phonates is a successful strategy for the design of phosphonate
analogues of phosphate esters.6
Firstly, in this study, we investigated the synthesis of
dibromofluoromethylphosphonic dichloride 5. Several methods
have been described for the synthesis of such phosphonic
dichlorides. In our case, none of the previously reported
methods [PCl3, AlCl3, CFBr3, H2O);12 (iPrO)2P(O)CFBr2, PCl5,
P(O)Cl3);13 (iPrO)2P(O)CFBr2, SOCl2, DMF14] allowed the
preparation of the expected compound. Finally we successfully
applied the methodology developed by Bergstrom15 based
on the reaction between diisopropyl dibromofluoromethyl-
phosphonate 1, thionyl chloride (10.3 eq.) and pyridine (0.15
eq.). We then obtained in quantitative yield dibromofluoro-
methylphosphonic dichloride 5 (Scheme 2). The (R,R)-1,2-
We recently described the first synthesis7 of α-fluorinated
cyclopropylphosphonates 2 from the readily available8 diiso-
propyl dibromofluoromethylphosphonate 1 (Scheme 1). A
Scheme 1 Electrosynthesis of α-fluorinated cyclopropylphosphonates.
Scheme 2 Synthesis of dibromofluoromethylphosphonic dichloride 5.
novel method for the asymmetric synthesis of fully functional-
ized cyclopropanes has been found based on Hanessian’s phos-
phonamide technology9 using C2-symmetric diamines. This
process has been also applied, for example, to the asymmetric
synthesis of aziridines10 and to asymmetric alkylations.11 With
a good methodology to achieve the synthesis of 2 in hand, we
became interested in the asymmetric version of these elec-
trosyntheses using chiral dibromofluoromethylphosphon-
amides of type 3, the synthesis of which can be easily achieved
from the corresponding diamine and phosphonic dichloride 5.
bis(N-alkylamino)cyclohexanes 4a–e have been prepared by
known procedures9c from the readily available (R,R)-1,2-
diaminocyclohexane.16 The coupling reaction between 4a–e and
5 was carried out in toluene using triethylamine (Scheme 3).
The results for the synthesized phosphonamides 3a–e and their
characteristics are collected in Table 1. These chiral phos-
phonamides are generally obtained in good yields (except for
3c, probably because of the steric hindrance of the two
neopentyl substituents).
DOI: 10.1039/b008906k
J. Chem. Soc., Perkin Trans. 1, 2001, 701–705
This journal is © The Royal Society of Chemistry 2001
701

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Table 1 Synthesis and physical and analytical data of phosphonamides 3
Yield
(%)a
31P (CDCl3)b
19F (CDCl3)b
δ (ppm)
Product
R1
δ (ppm) [2JPF/Hz]
Mp/ЊC
3a
3b
3c
3d
3e
CH2Ph
CH3
CH2C(CH3)3
(CH2)2C(CH3)3
CH2CH2OCH3
52
47
24
55
41
23.1 [67.2]
24.2 [67.9]
21.2 [61.6]
22.7 [68.4]
22.7 [69.3]
Ϫ68.5
133
84
112
122
118
Ϫ69.4
Ϫ62.8
Ϫ69.2
Ϫ69.1
a Product purified by flash chromatography over silica gel (see Experimental for eluents) and characterized by 1H and 13C NMR spectroscopy.
Satisfactory microanalyses were obtained. b Each signal appeared as a doublet.
Table 2 Electrosynthesis of α-fluorinated cyclopropylphosphonamides 7–12 from chiral phosphonamides 3
Chiral
phosphonamide 3
Yield
(%)a
trans : cis
trans de
cis de
Entry
Product
R2
ratiob
(%)b
(%)b
1
3a
3a
3a
3b
3c
3d
3e
7
7
Me
Me
tBu
tBu
tBu
tBu
tBu
62
65
54
30
—
—
70 : 30
95 : 5
63 : 37
78 : 22
90 : 10
72 : 28
70 : 30
36
36
32
20
40
27
22
24
70
20
42
95
12
18
2c
3
8
4
5
6
7
9
d
10
11
12
d
35
a Product purified by flash chromatography over silica gel (see Experimental for eluents) and characterized by 1H and 13C NMR spectroscopy.
b Measured by 19F NMR spectroscopy on the crude product. c The electrolysis was performed at 0 ЊC. d Unpurified product.
Electrosynthesis of ꢀ-fluorinated cyclopropylphosphonamides
from chiral dibromofluoromethylphosphonamides 3 and Michael
acceptors
the diastereoisomeric excess (de: 70%) of the cis-7 products.
Nevertheless, the main problem encountered with methyl
acrylate was that we were unable to separate the two trans
diastereoisomers from the two cis. For this reason, we then
decided to use tert-butyl acrylate 6b, instead of 6a. With this
Michael acceptor, the two trans products could be easily
separated from the two cis ones by flash chromatography
on silica gel. This feature was very important in terms of
stereochemical assignments (see NMR part below). The dif-
ferent results obtained using tert-butyl acrylate 6b and various
dibromofluoromethylphosphonamides 3a–e are collected in
Table 2. In each case, we observed the presence of four
diastereoisomers. The selectivity observed by Hanessian, based
on the hypothesis that, for steric and stereoelectronic reasons,
the electrophile would approach the α-carbanion derived from
(R,R)-alkylphosphonamides from the ‘left cleft’ (diastereo-
facial approach), did not occur in our case. It seemed that
under the conditions of electrosynthesis, the diastereofacial
discrimination was low. Using N,N-dibenzylphosphonamide
3a, the trans : cis ratio as well as the diastereoisomeric
excesses were low (Table 2, entry 3). Using the N,N-dimethyl-
phosphonamide 3b, similar results were obtained. Increasing
the steric hindrance on the two nitrogens, by using the neo-
pentyl moiety (3c), enhanced the trans : cis ratio as well as the
diastereoisomeric excesses of the trans mixture and, more
importantly, of the cis mixture (Table 2, entry 5). This last
result indicates that steric hindrance on the two nitrogens is
The main part of this study was concerned with the electrolysis
of dibromofluoromethylphosphonamides 3a–e in the presence
of Michael acceptors 6 (Scheme 4). Electroreductions of 3a–e,
in DMF between a carbon-felt cathode and a magnesium
sacrificial anode in a one-compartment cell,17 performed in
the presence of two equivalents of Michael acceptor, afforded
α-fluorinated cyclopropylphosphonamides 7–12. In this study,
we started our investigations with methyl acrylate 6a as Michael
acceptor (Table 2, entry 1). α-Fluorinated cyclopropylphos-
phonamide 7 was obtained in a good isolated yield (62%) as a
mixture of four diastereoisomers. The trans : cis ratio was
70 : 30 and the diastereoisomeric excesses were low (trans-7 de:
36%, cis-7 de: 24%). Performing the electrolysis at 0 ЊC (Table 2,
entry 2) enhanced not only the trans : cis ratio (95 : 5), but also
Scheme 3 Synthesis of dibromomethylphosphonamides 3a–e.
Scheme 4 Electrolysis of α-fluorinated cyclopropylphosphonamides.
702
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Fig. 1 Part of 1H–19F NMR HOESY spectra obtained in CDCl3 at 298 K, with the 1D 1H and 19F spectra along the side and the top. The
experiment was recorded with a mixing time of 300 ms. (A) cyclopropylphosphonamides trans-8 (B) cyclopropylphosphonamides cis-8.
Table 3 19F and 1H chemical shifts (in ppm) of the cyclopropane
important for the level of diastereoselectivity. The homolo-
gation of the neopentyl group (phosphonamide 3d) induced
fragment of cyclopropylphosphonamides 8a
a spectacular drop of the diastereoisomeric excesses (Table 2,
entry 6).
Finally, we tested phosphonamide 3e, which contains a
Product
19F
Ha
Hb
Hc
trans-8b
trans-8c
cis-8b
Ϫ212.61
Ϫ212.01
Ϫ183.65
Ϫ187.31
2.39
2.33
2.33
2.37
1.16
1.59
1.53
1.20
1.64
1.92
1.84
1.46
methoxy group (we assumed that it could induce chelation
between the oxygen atom and the Mg2ϩ cations to stabilize
the carbanion and also to fix its conformation), but
phosphonamide 3e led to very low diastereoisomeric
excesses.
In summary, the diastereoisomeric excesses obtained for the
asymmetric electrosynthesis of α-fluorinated cyclopropyl-
phosphonamides 7–12 were generally low. The best result was
obtained using phosphonamide 3c, for which a 90 : 10 trans-
10 : cis-10 ratio and 40 and 95% de of trans-10 and cis-10,
respectively were observed. The diastereoisomeric excesses were
measured by 31P NMR after the complete identification of the
four diastereoisomers by HMQC, 1H–19F HETEROCOSY and
1H–19F HOESY NMR experiments.
cis-8c
a Values of 1H and 19F chemical shifts are, respectively, referred
to external TMS and CFCl3. b Major diastereoisomer. c Minor
diastereoisomer.
phosphonamides 8, assignment of protons Ha, Hb and Hc was
performed by using 2D NMR experiments.
In the first step, identification of the Ha, Hb and Hc proton
resonances in the 1H NMR spectrum of each sample was
achieved by using a combination of two-dimensional NMR
experiments: H–1H COSY18 and H–13C HMQC.19 In a sec-
ond step, cross peak connectivities observed in the 1H–19F
hetero-COSY20 spectrum allowed us to associate these
protons, previously identified, with the corresponding
diastereoisomers. The chemical shift values of protons of the
cyclopropane and fluorine resonances at 298 K are summarized
in Table 3.
1
1
Stereochemical assignments using HMQC, 1H–19F
HETEROCOSY and 1H–19F HOESY NMR experiments
An NMR investigation of the stereochemical structure of
cyclopropylphosphonamides 8 was carried out after separation
Identification of the trans or cis stereoisomers was deduced
from the analysis of 2D 1H–19F HOESY21 spectra. The 1H–19F
HOESY spectra of cyclopropylphosphonamides 8 (Fig. 1)
exhibited an interesting set of cross peaks between the fluorine
and the protons Ha, Hb, and Hc. For the trans-8 stereoisomer
(Fig. 1A), a strong correlation was observed between the
fluorine and proton Hc, indicating that this proton is spatially
close to the fluorine, while for the cis-8 stereoisomer (Fig. 1b)
the correlation between the fluorine and protons Ha and Hb
were much stronger than with Hc. The first type of connectivity
is encountered in trans stereoisomers, while the other two
characterize cis stereoisomers.
In conclusion, we have described our first attempts at the
asymmetric electrosynthesis of α-fluorinated cyclopropyl-
phosphonamides using chiral dibromofluoromethylphosphon-
amides. The influence of different parameters (solvent,
temperature, nature of the chiral inductor) on the diastereo-
selectivity during the electrochemical process is under study
within our laboratory and will be reported in due course.
of the two trans diastereoisomers from the two cis. The 600
1
MHz H and 19F NMR spectra of trans-8 and cis-8 show that
all the proton and fluorine resonances split in two signals
corresponding to the two diastereoisomers (Fig. 1). In order
to identify the stereochemical structure of cyclopropyl-
J. Chem. Soc., Perkin Trans. 1, 2001, 701–705
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92.8 (dd, J 147.3 and J 339, O᎐P-C-F), 126.18, 126.2, 126.3,
126.8, 127.3, 127.4 (6s, Carom.), 136.5 (d, J 5.7, Cipso), 138.3 (d,
J 4,3, Cipso).
Experimental
General
᎐
Solvents were purified by conventional methods prior to use.
N,N-Dimethylformamide was purified by distillation under
reduced pressure on BaO. The cathodes, purchased from Le
Carbone Lorraine, were carbon-felt plates (45 × 35 mm, depth:
Dibromofluoromethylphosphonamide 3b. Pale yellow solid,
mp 84 ЊC, purified by chromatography over silica gel and elu-
tion with dichloromethane–methanol (98 : 2) (Rf = 0.5);
[α]D20 = Ϫ46 (c = 0.56, CHCl3) (Found: C, 28.77; H, 4.35; N, 7.56.
C9H16Br2FN2OP requires C, 28.60; H, 4.27; N, 7.41); δP 24.2
(d, J 67.9); δF Ϫ69.4 (d, J 67.9); δH 1.2–1.3 (m, 2H, CH2CH2-
CHN ϩ 2H, CH2CH2CHN), 1.8–2.0 (m, 2H, CH2CH2CHN ϩ
2H, CH2CH2CHN), 2.72–2.75 (2d, J 7.8, 6H, CH3 ϩ m, 1H,
CH2CH2CHN), 3.0 (m, 1H, CH2CH2CHN); δC 24.6 (d, J 1.0,
CH2CH2CHN), 24.7 (d, J 1.1, CH2CH2CHN), 28.2 (d, J 7.4,
CH2CH2CHN), 28.7 (d, J 9.5, CH2CH2CHN), 29.1 (d, J 4.0,
N-CH3), 31.7 (d, J 1.2, N-CH3), 63.6 (dd, J 8.9 and J 1.8,
CH2CH2CHN), 66.0 (d, J 7.0, CH2CH2CHN), 93.6 (dd, J 144.3
5 mm, specific area: 0.3 m2
g
Ϫ1). The magnesium anodes,
purchased from Prolabo, were rods (diameter: 15 mm). TLC
was performed on Merck 60F-250 silica gel plates and column
chromatography over silica gel SI 60 (230–240 mesh). Mps were
taken on a Kofler apparatus and are uncorrected. Elemental
analyses were carried out on a Carlo Erba EA 1100 analyser.
Optical rotations were measured on a Perkin-Elmer 341 polari-
meter and are reported in units of 10Ϫ1 deg cm2 gϪ1. NMR
spectra were recorded on a Bruker DXP 300 spectrometer
operating at 300 MHz for proton, 75.4 MHz for carbon, 121.5
MHz for phosphorus and 282 MHz for fluorine. All 2D
NMR spectra were collected on a Bruker Advance DMX
600 spectrometer. NMR spectra were obtained using a 5 mm
Bruker triple resonance 19F/13C/1H probe with channels pre-
tuned to the 19F (564.68 MHz), 13C (150.90 MHz) and 1H
(600.123 MHz) frequencies. This probe is equipped with pulsed-
field (z) gradients. Chemical shifts (δ) are expressed in ppm
and J 339, O᎐P-C-F).
᎐
Dibromofluoromethylphosphonamide 3c. White solid, mp
112 ЊC, purified by chromatography over silica gel and elution
with cyclohexane–diethyl ether (90 : 10) (Rf = 0.2); [α]D20 = Ϫ51
(c = 0.35, CHCl3) (Found: C, 41.92; H, 6.75; N, 5.82.
C17H32Br2FN2OP requires C, 41.65; H, 6.58; N, 5.71); δP 21.2
(d, J 61.6); δF Ϫ62.8 (d, J 61.6); δH 0.9, 1.0 (2s, 18H, C(CH3)3),
1.26 (m, 2H, CH2CH2CHN ϩ 2H, CH2CH2CHN), 1.8 (m, 2H,
CH2CH2CHN), 1.93 (m, 1H, CH2CH2CHN), 2.16 (m, 1H,
CH2CH2CHN), 2.48 (m, 1H, NCH2C(CH3)3), 2.87 (m, 1H,
NCH2C(CH3)3), 3.2 (m, 1H, NCH2C(CH3)3 ϩ 2H CH2CH2-
CHN), 3.45 (m, 1H, NCH2C(CH3)3); δC 24.7 (d, J 1.4, CH2CH2-
CHN), 25.2 (s, CH2CH2CHN), 28.6 (d, J 6.8, CH2CH2CHN),
28.7 (s, C(CH3)3), 29.7 (s, C(CH3)3), 31.0 (d, J 8.3, CH2CH2-
CHN), 32.2 (d, J 0.96, C(CH3)3), 33.9 (s, C(CH3)3), 54.0 (d,
J 3.3, NCH2C(CH3)3), 54.5 (dd, J 2.8 and J 0.9, NCH2-
C(CH3)3), 62.4 (d, J 9.9, CH2CH2CHN), 65.9 (dd, J 10.4 and
1
relative to TMS for H and 13C nuclei, to H3PO4 for 31P nuclei
and to CFCl3 for 19F nuclei; coupling constants (J) are given
in hertz; coupling multiplicities are reported using conven-
tional abbreviations. All the C2-symmetric diamines 3a–e were
prepared by literature procedures (refs. 9a–c).
Synthesis of dibromofluoromethylphosphonic dichloride 5
An excess of thionyl chloride (52.3 cm3, 0.716 mol, 10.3 eq.)
was added dropwise to a round-bottom flask containing diiso-
propyl dibromofluoromethylphosphonate (24.8 g, 0.696 mol,
1 eq.) and pyridine (0.85 cm3). The reaction mixture was pro-
tected from moisture and refluxed for 3 days. Thionyl chloride
was removed by fractional distillation and the crude product 5
was directly used in the next step. Orange oil (quantitative yield,
evaluated by 31P NMR spectrospcopy); δP 26.7 (d, J 107.8);
δF Ϫ75.3 (d, J 107.8); δC 89.7 (dd, J 334.2, 164.6).
J 3.2, CH CH CHN), 96.2 (dd, J 126.0 and J 342.7, O᎐P-C-F).
᎐
2
2
Dibromofluoromethylphosphonamide 3d. White solid, mp
122 ЊC, purified by chromatography over silica gel and elution
with cyclohexane–ethyl acetate (70 : 30) (Rf = 0.6); [α]D20 = Ϫ43
(c = 0.59, CHCl3) (Found: C, 43.72; H, 6.89; N, 5.54.
C19H36Br2FN2OP requires C, 44.03; H, 7.00; N, 5.40); δP 22.7 (d,
J 68.4); δF Ϫ69.2 (d, J 68.4); δH 0.9 (s, 18H, C(CH3)3), 1.33 (m,
2H, CH2CH2CHN ϩ 2H, CH2CH2CHN), 1.9 (m, 4H, NCH2-
CH2C(CH3)3), 1.84 (m, 2H, CH2CH2CHN), 2.05 (m, 2H,
CH2CH2CHN), 3.0 (m, 2H, CH2CH2CHN), 3.1–3.4 (m, 4H,
NCH2CH2C(CH3)3); δC 24.6 (s, CH2CH2CHN), 24.8 (s,
CH2CH2CHN), 28.8 (d, J 6.8, CH2CH2CHN), 29.6 (d, J 6.6,
CH2CH2CHN), 29.66 (s, C(CH3)3), 29.67 (s, C(CH3)3), 38.7 (d,
J 4.5, CH2-C(CH3)3), 41.4 (d, J 2.0, CH2-C(CH3)3), 42.8 (s,
N-CH2CH2C(CH3)3), 43.1 (d, J 3.4, N-CH2CH2C(CH3)3), 62.3
(d, J 9.65, CH2CH2CHN), 64.4 (d, J 8.2, CH2CH2CHN), 95.5
Typical procedure for the synthesis of dibromofluoromethyl-
phosphonamides 3
To a solution of diamine 4a–e (1 eq.) in toluene (50 cm3) was
added triethylamine (2 eq.) and the mixture was stirred at 25 ЊC.
A solution of dibromofluoromethylphosphonic dichloride 5
(1 eq.) in toluene (50 cm3) was added dropwise over a period of
30 min, and the reaction mixture was stirred for two hours
(monitored by 31P NMR spectroscopy). The resulting precipi-
tate was filtered over a Celite pad and washed with ethyl acetate.
The solvent was evaporated and the residue was purified by
silica gel chromatography to give the desired dibromofluoro-
phosphonamide 3a–e.
(dd, J 145.9 and J 339.5, O᎐P-C-F).
᎐
Dibromofluoromethylphosphonamide 3e. Brown oil, purified
by chromatography over silica gel and elution with dichloro-
methane–methanol (98 : 2) (Rf = 0.2); [α]D20 = Ϫ37 (c = 0.68,
CHCl3) (Found: C, 33.55; H, 5.22; N, 6.23. C13H24Br2FN2O3P
requires C, 33.50; H, 5.19; N, 6.02); δP 22.7 (d, J 69.3); δF Ϫ69.1
(d, J 69.3); δH 1.25 (m, 2H, CH2CH2CHN ϩ 2H, CH2CH2-
CHN), 1.8 (m, 2H, CH2CH2CHN), 2.1 (m, 2H, CH2CH2CHN),
2.9 (m, 1H, CH2CH2CHN), 3.1–3.6 (m, 15 H: 1H, CH2CH2-
CHN ϩ 6H, OCH3 (3.3, s) ϩ 4H, CH2OCH3 ϩ 4H, NCH2-
CH2OCH3); δC 24.6 (s, CH2CH2CHN), 24.7 (s, CH2CH2CHN),
28.8 (d, J 6.6, CH2CH2CHN), 29.3 (d, J 9.4, CH2CH2CHN),
41.4 (d, J 4.7, NCH2CH2OCH3), 43.9 (s, NCH2CH2OCH3),
59.2 (s, NCH2CH2OCH3), 59.3 (s, NCH2CH2OCH3), 63.5 (d,
J 9.2, CH2CH2CHN), 64.9 (d, J 8.1, CH2CH2CHN), 72.3
(s, NCH2CH2OCH3), 72.6 (d, J 3.8, NCH2CH2OCH3), 95.0
Dibromofluoromethylphosphonamide 3a. Pale yellow solid,
mp 133 ЊC, purified by chromatography over silica gel and elu-
tion with dichloromethane (Rf = 0.2); [α]D20 = Ϫ62 (c = 0.67,
CHCl3) (Found: C, 47.57; H, 4.56; N, 5.28. C21H24Br2FN2OP
requires C, 47.27; H, 4.57; N, 5.16); δP 23.1 (d, J 67.2); δF Ϫ68.5
(d, J 67.2); δH 0.84 (m, 1H, CH2CH2CHN), 1.04 (m, 2H,
CH2CH2CHN ϩ 1H, CH2CH2CHN), 1.56 (m, 2H, CH2CH2-
CHN ϩ 2H, CH2CH2CHN), 2.75 (m, 1H, CH2CH2CHN), 3.30
(m, 1H, CH2CH2CHN), 4.1 (dd, J 16.2 and J 7.7, 1H, CH2Ph),
4.3 (dd, J 16.2 and J 4.6, 1H, CH2Ph), 4.6 (dd, J 14.9 and J 14.9,
1H, CH2Ph), 4.8 (dd, J 16.2 and J 9.2, 1H, CH2Ph), 7.25–7.45
(m, 10H, Harom.); δC 23.0 (s, CH2CH2CHN), 23.2 (s, CH2CH2-
CHN), 28.4 (d, J 2.2, CH2CH2CHN), 28.5 (d, J 4.7, CH2CH2-
CHN), 45.7 (d, J 4.6, CH2Ph), 48.4 (d, J 2.4, CH2Ph), 65.7 (dd,
J 9.2 and J 1.1, CH2CH2CHN), 63.7 (d, J 7.7, CH2CH2CHN),
(dd, J 146.6 and J 338.6, O᎐P-C-F).
᎐
704
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General procedure for the electrosynthesis of ꢀ-fluorinated
cyclopropylphosphonamides 7–12
ꢀ-Fluorinated cyclopropylphosphonamides 9. Obtained as a
mixture of four diastereoisomers. Yellow oil. Purified by
chromatography over silica gel and elution with cyclohexane–
ethyl acetate (40 : 60). trans-9: Rf = 0.16; δP 34.4 (d, J 67.8,
major), 33.5 (d, J 64.9, minor); δF Ϫ213.8 (d, J 67.8, major),
Ϫ213.5 (d, J 64.9, minor). cis-9: Rf = 0.22; δP 35.0 (d, J 67.8,
major), 33.1 (d, J 64.9, minor); δF Ϫ188.6 (d, J 67.8, major),
Ϫ186.3 (d, J 64.9, minor).
In a purged one-compartment cell, equipped with a carbon-felt
cathode (S = 16 cm2), a magnesium rod as anode and a mag-
netic stirrer, a solution of 3 (4 mmol, 1 eq.) and Michael
acceptor (8 mmol, 2 eq.) in DMF (35 cm3) containing Et4NBr
(0.02 mol dmϪ3) was introduced. A 100 mA constant current
was applied. The electrolysis was continued until total con-
sumption of 3 was achieved (monitored by 31P NMR spec-
troscopy). The reaction mixture was poured into THF (100
cm3), then basified with a solution of saturated aqueous sodium
hydrogen carbonate (500 cm3), and extracted with ether
(3 × 100 cm3). The organic layers were washed with NaHCO3
(2 × 200 cm3) and dried. The solvents were evaporated in vacuo
to give 7–12.
ꢀ-Fluorinated cyclopropylphosphonamides 10. Obtained as a
mixture of four diastereoisomers. Yellow oil. Unpurified
product. trans-10: δF Ϫ214.3 (d, J 67.8, major), Ϫ214 (d, J 64.9,
minor). cis-10: δF Ϫ185.6 (d, J 67.8, major).
ꢀ-Fluorinated cyclopropylphosphonamides 11. Obtained as a
mixture of four diastereoisomers. Yellow oil. Unpurified
product. trans-11: δF Ϫ212.9 (d, J 64.9, major), Ϫ211.3 (d,
J 64.9, minor). cis-11: δF Ϫ184.1 (d, J 64.9, major), Ϫ184.3
(d, J 64.9, minor).
ꢀ-Fluorinated cyclopropylphosphonamides 7. Obtained as an
inseparable mixture of four diastereoisomers. Pale yellow oil.
Purified by chromatography over silica gel and elution with
cyclohexane–ethyl acetate (70 : 30) (Rf = 0.3). trans-7: δP 32 (d,
J 64.9, major), 31.9 (d, J 64.9, minor); δF Ϫ211.5 (d, J 64.9,
major), Ϫ211.1 (d, J 64.9, minor). cis-7: δP 32.5 (d, J 64.9,
major), 30.5 (d, J 64.9, minor); δF Ϫ188.5 (d, J 64.9, major),
Ϫ185.9 (d, J 64.9, minor).
ꢀ-Fluorinated cyclopropylphosphonamides 12. Obtained as a
mixture of four diastereoisomers. Yellow oil. Purified by chrom-
atography over silica gel and elution with cyclohexane–ethyl
acetate (40 : 60). trans-12: Rf = 0.26; δP 30.1 (d, J 64.9, minor),
31.0 (d, J 67.8, major); δF Ϫ212.4 (d, J 67.8, major), Ϫ212.2 (d,
J 64.9, minor). cis-12: Rf = 0.20; δP 29.2 (d, J 64.9, minor), 30.6
(d, J 67.8, major); δF Ϫ185.3 (d, J 67.8, major), Ϫ183.3 (d,
J 64.9, minor).
ꢀ-Fluorinated cyclopropylphosphonamides 8. Obtained as a
mixture of four diastereoisomers. Yellow oil. Purified by chrom-
atography over silica gel and elution with cyclohexane–
diethylether (40 : 60). trans-8: Rf = 0.3; δP 31.6 (d, J 64.9,
minor), 32.9 (d, J 67.8, major); δF Ϫ212.6 (d, J 67.8, major),
Ϫ212.0 (d, J 64.9, minor); δH 1.1 (m, 1H, CH2CH2CHN), 1.2
(m, 2H, CH2CH2CHN ϩ 1H, CH2CH2CHN ϩ 1H, Hb, major),
1.35 (s, 9H, C(CH3)3, minor), 1.5 (2s, 9H, C(CH3)3, major),
1.65 (m, 2H, CH2CH2CHN ϩ 2H, CH2CH2CHN ϩ 1H, Hb,
minor ϩ 1H, Hc, major), 1.90 (m, 1H, Hc, minor), 2.3 (m, 1H,
Ha, minor), 2.4 (m, 1H, Ha, major), 3.1 (m, 2H, CH2CH2CHN),
4.0, 4.1, 4.45, 4.6, 4.75 (5m, 4H, CH2Ph), 7.35 (m, 10H,
Harom.); δC 14.2 (d, J 10.3, C3, major), 15.3 (d, J 10.4, C3,
minor), 24.4 (m, CH2CH2CHN), 24.6 (d, J 9.6, C2, minor), 25.6
References
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20 J. P. Macheteau, H. Oulyadi, B. Van Hemelryck, M. Bourdoneau
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21 C. Yu and G. Levy, J. Am. Chem. Soc., 1984, 106, 6533.
(d, J 10.3, C2, major), 27.1, 28.1, 28.3 (3s, O᎐COC(CH ) ), 29.8
᎐
3
3
(m, CH2CH2CHN), 46.6, 46.9 (2d, J 5.3, CH2Ph), 47.3, 47.6 (2s,
CH2Ph), 64.1, 64.7, 65.4 (3d, J 7.2, CH2CH2CHN), 75.5 (dd,
J 241.3 and 185.2, C1, major), 75.7 (dd, J 241.3 and 185.2, C1,
minor), 81.7 (s, O᎐COC(CH ) , minor), 81.8 (s, O᎐COC(CH ) ,
᎐
᎐
3
3
3 3
major), 127.2, 127.3, 127.4, 127.5, 127.6, 127.9, 128.5, 128.6
(8s, Carom.), 139.1, 139.3, 139.7, 140.0 (4d, J 5.7 and J 5.0,
Cipso), 166.5 (d, J 2.6, O᎐COC(CH ) ). cis-8: R = 0.25; δ 30.6
᎐
3
3
f
P
(d, J 64.9, minor), 33.3 (d, J 67.8, major); δF Ϫ187.4 (d, J 67.8,
major), Ϫ183.7 (d, J 64.9, minor); δH 0.90–1.23 (m, 2H,
CH2CH2CHN ϩ 1H, CH2CH2CHN ϩ 1H, Hb, major), 1.25–
1.35 (2s, 9H, C(CH3)3), 1.47 (1H, 1.65, Hc, major), 1.52–1.75
(m, 2H, CH2CH2CHN ϩ 2H, CH2CH2CHN ϩ 1H, Hb,
minor), 1.84 (m, 1H, Hc, minor), 2.33 (m, 1H, Ha, minor), 2.38
(m, 1H, Ha, major), 3.1 (m, 2H, CH2CH2CHN), 3.97, 4.05,
4.27, 4.6, 5.04 (5m, 4H, CH2Ph), 7.35 (m, 10H, Harom.);
δC 14.25 (d, J 9.5, C3, major), 15.6 (d, J 9.1, C3, minor), 24.6
(s, CH2CH2CHN), 27.8 (d, J 11.3, C2, minor), 28.1 (m,
O᎐COC(CH ) ϩ C2, major), 28.4 (s, O᎐COC(CH ) ), 30.1 (m,
᎐
᎐
3
3
3 3
CH2CH2CHN), 47.1 (m, CH2Ph), 63.8 (d, J 7.2, CH2CH2-
CHN), 64.6 (d, J 7.2, CH2CH2CHN), 65.2 (d, J 7.8, CH2-
CH2CHN), 65.9 (d, J 6.6, CH2CH2CHN), 74.6 (dd, J 241.3
and 185.2, C1), 74.8 (dd, J 241.3 and 185.2, C1), 82.0 (s,
O᎐COC(CH ) , minor), 82.2 (s, O᎐COC(CH ) , major), 127.3,
᎐
᎐
3
3
3 3
127.4, 127.6, 127.8, 127.9, 128.1, 128.3 (7s, Carom.), 139.6 (d,
J 5.1, Cipso), 139.8 (d, J 4.6, Cipso), 140.1 (d, J 5.1, Cipso), 140.6
(d, J 5.9, Cipso), 166.2, 166.5 (2s, O᎐COC(CH ) ).
᎐
3
3
J. Chem. Soc., Perkin Trans. 1, 2001, 701–705
705