Synthetic application of fluorinated vinamidinium salts: Synthesis of fluorinated 1,3-butadienylphosphonates by the reaction with Horner-Wadsworth-Emmons reagents

Article abstract of DOI:10.1016/j.jfluchem.2006.07.001

The reaction of β-fluoro vinamidinium salt 1 with Horner-Wadsworth-Emmons reagents (HWE) such as diethyl(ethoxycarbonyl)methylphosphonate (2a), diethyl(methoxycarbonyl)methylphosphonate (2b), diethyl-2-oxopropylphosphonate (2c), diethyl benzylphosphonate (2d), tetraethyl methylenediphosphonate (2e) and diethyl cyanomethylphosphonate (2f) under basic conditions gave the fluorinated 1,3-butadienylphosphonates 3 in moderate to good yields. The phosphonates 3 could be hydrolyzed with a 10% HCl aqueous solution to afford the corresponding γ-(diethylphosphono)-α-fluoro-α,β-unsaturated aldehydes 7 in good yields. The treatment of the phosphonate 3c with an NH₃ aqueous solution at 70 °C produced the pyridine derivative 8 in 60% yield.

Full text of DOI:10.1016/j.jfluchem.2006.07.001

Journal of Fluorine Chemistry 127 (2006) 1235–1241
www.elsevier.com/locate/fluor
Synthetic application of fluorinated vinamidinium salts: Synthesis of
fluorinated 1,3-butadienylphosphonates by the reaction with
Horner–Wadsworth–Emmons reagents
*
Satoru Arimitsu a, Tsutomu Konno a, John T. Gupton b, Takashi Ishihara a,
,
Hiroki Yamanaka a,
*
a Department of Chemistry and Materials Technology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan
b Department of Chemistry, University of Richmond, Richmond, VA 23173, USA
Received 16 May 2006; received in revised form 28 June 2006; accepted 2 July 2006
Available online 5 July 2006
Abstract
The reaction of b-fluoro vinamidinium salt 1 with Horner–Wadsworth–Emmons reagents (HWE) such as diethyl(ethoxycarbonyl)methylpho-
sphonate (2a), diethyl(methoxycarbonyl)methylphosphonate (2b), diethyl-2-oxopropylphosphonate (2c), diethyl benzylphosphonate (2d), tetraethyl
methylenediphosphonate (2e) and diethyl cyanomethylphosphonate (2f) under basic conditions gave the fluorinated 1,3-butadienylphosphonates 3 in
moderatetogoodyields. Thephosphonates3couldbehydrolyzedwitha10%HClaqueoussolutiontoaffordthecorrespondingg-(diethylphosphono)-
a-fluoro-a,b-unsaturated aldehydes 7 in good yields. The treatment of the phosphonate 3c with an NH3 aqueous solution at 70 8C produced the
pyridine derivative 8 in 60% yield.
# 2006 Elsevier B.V. All rights reserved.
Keywords: Fluorinated vinamidinium salt; Horner–Wadsworth–Emmons reagents; Fluorinated 1,3-butadienylphosphonates; g-(Diethylphosphono)-a-fluoro-a,b-
unsaturated aldehydes; Phosphonated pyridine
1. Introduction
fluorinated vinamidinium salts as key building blocks. We have
already reported on the preparation of b-fluoro, b-trifluor-
omethyl and b-polyfluoroalkoxy vinamidinium salts and their
applications to the synthesis of regioselectively fluorinated
compounds through the reactions with hetero and carbon
nucleophiles [13–15]. Herein we wish to report the results of
the reaction of a b-fluoro vinamidinium salt with Horner–
Wadsworth–Emmons reagents (HWE), which provides a new
means for synthesizing useful organophosphorous compounds
containing a fluorine substituent [16].
Vinamidinium (1,5-diazapentadienium) salts are very useful
synthons in organic synthesis because of their versatile
reactivities. Therefore, much efforts have been made to prepare
many kinds of vinamidinium salts having various substituents
and to apply them in organic synthesis [1–4]. Recently, the
Merck research group has actively investigated the preparation
of a variety of vinamidinium salts and successfully applied
them to the synthesis of a highly potent, specific COX-2
inhibitor [5–9]. Although the availability of fluorine-containing
vinamidinium salts should open new routes to various kinds of
fluorinated compounds of biological and materials science
interest, there were few reports on fluorinated vinamidinium
salts [10–12] prior to our research concerning this area. One of
our primary goals is to uncover useful synthetic methodologies
for obtaining various organofluorine compounds by use of the
2. Results and discussion
We first examined the reaction of 1,1,5,5-tetraethyl-1,5-
diaza-2-fluoro-1,3-pentadienium iodide (b-fluoro vinamidi-
nium salt) (1) with diethyl(ethoxycarbonyl)methylphosphonate
(2a) under various conditions (Scheme 1). The results are
summarized in Table 1. Thus, to a suspension of sodium
hydride (NaH) (1.1 equiv.) in tetrahydrofuran (THF) was added
2a (1.1 equiv.) at room temperature, and the mixture was stirred
* Corresponding authors. Tel.: +81 75 724 7504; fax: +81 75 724 7580.
E-mail address: ishihara@kit.ac.jp (T. Ishihara).
0022-1139/$ – see front matter # 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2006.07.001

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S. Arimitsu et al. / Journal of Fluorine Chemistry 127 (2006) 1235–1241
Scheme 1.
for 30 min. To the resultant mixture was added a THF solution
of the salt 1 at room temperature, and the whole was stirred for
3 h at room temperature. The 19F NMR spectra (CF3COOH as
the external reference) of the reaction mixture showed two
peaks at ꢀ76 and ꢀ81 ppm for the products, along with a peak
for unreacted salt 1. After the usual workup, the products were
isolated by column chromatography and identified as diethyl-4-
(N,N-diethylamino)-1-ethoxycarbonyl-3-fluoro-(1E,3Z)-buta-
dienylphosphonate (3a) (36% yield) and ethyl-5-(N,N-diethy-
lamino)-4-fluoro-(2E,4Z)-pentadienate (4) (5% yield) (entry 1).
A slight increase in the product yield was observed for the
reaction at reflux temperature for 2 h (entry 2). When 2.2 equiv.
each of 2a and NaH were employed, the yields of 3a and 4
increased to 51% and 26%, respectively (entry 3). The use of
dimethylformamide (DMF) as the solvent gave better result
than that of THF; the reaction of 1 with 2.2 equiv. each of 2a
and NaH in DMF at room temperature for 3 h afforded 3a in
72% yield without formation of 4 (entry 4).
peak for the product 3a appeared at ꢀ76 ppm (entries 6 and
7). Unfortunately the product corresponding to the large peak
could not be isolated, but these observations allowed us to
assume that the large peak was due to an intermediate (Int-X)
formed at the initial addition step. When NaH (1.1 equiv.)
was added to the reaction mixture employing 2.2 equiv. of
t-BuOK in DMF for 3 h, followed by stirring for 5 h, the
intermediate Int-X was smoothly converted to 3a in 78%
yield (entry 8). On adding acetic acid (3.3 equiv.) as the
additive, the starting salt 1 was recovered in 77% yield
along with 3a (21% yield) (entry 9). Et2O and 1,2-
dimethoxyethane (DME) as the solvents and lithium
diisopropylamide (LDA) as the base were not so effective
in producing 3a (entries 10–12).
The reactions of 1 with other HWE reagents 2 were
attempted under the optimized conditions (2.2 equiv. of
t-BuOK, 1.1 equiv. of NaH, DMF, room temperature) described
above (Scheme 2). The results are summarized in Table 2.
Diethyl (methoxycarbonyl)methylphosphonate (2b) and tetra-
ethyl methylenediphosphonate (2e) gave diethyl 4-(N,N-
diethylamino)-3-fluoro-1-methoxycarbonyl-(1E,3Z)-butadie-
nylphosphonate (3b) and tetraethyl-4-(N,N-diethylamino)-3-
fluoro-(1E,3Z)-butadienylbisphosphonate (3e) in 85% and 92%
yields, respectively (entries 2 and 9).
Interestingly, the use of potassium t-butoxide (t-BuOK) as
the base in place of NaH led to the different results. The 19F
NMR analysis for the reaction of 2.2 equiv. of 2a with t-
BuOK in DMF for 1 h showed a large peak at ꢀ74 ppm for a
new product and a small peak due to 1 (entry 5). As the
reaction time was extended, the large peak decreased and the
Table 1
Investigation of the reaction conditions
Entry
Eq of 2a
Solvent
Base (equiv.)
Time (h)
Temp
Additive (equiv.)
Yield of products (%)a
3a
4
Int-X
1
1.1
1.1
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
THF
THF
THF
DMF
DMF
DMF
DMF
DMF
DMF
Et2O
DME
THF
NaH (l.1)
3
r.t.
Ref.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
–
36
48
51
72
0
5
ND
ND
ND
ND
94
2
NaH (l.1)
2
–
10
26
0
3
NaH (2.2)
3
–
4
NaH (2.2)
3
–
5
t-BuOK (2.2)
t-BuOK (2.2)
t-BuOK (2.2)
t-BuOK (2.2)
t-BuOK (2.2)
t-BuOK (2.2)
t-BuOK (2.2)
LDA (2.2)
1
–
0
6
3
–
10
24
78
21
15
20
0
0
85
7
12
3 + 5b
3+0.5c
–
0
69
8
NaH (l.1)
0
ND
NDd
23e
26e
NDe
9
AcOH (3.3)
0
10
11
12
3
3
3
–
–
–
0
0
0
Determined by 19F NMR.
a
b
c
d
e
After addition of NaH, the mixture was stirred for 5 h.
After addition of acetic acid, the mixture was stirred for 0.5 h.
The salt 1 was recovered in 77% yield.
Recovery of the salt 1 was more than 50%.

S. Arimitsu et al. / Journal of Fluorine Chemistry 127 (2006) 1235–1241
1237
Scheme 2.
Table 2
Results of the reaction of 1 with various HWE reagents 2 in DMF
Entry
R of 2
Time A (h)
Additive (equiv.)
Time B (h)
Yielda/% of Int-X
Yielda/% of 3
1
2
CO2Et (2a)
CO2Me (2b)
COMe (2c)
COMe (2c)
COMe (2c)
Ph (2d)
Ph (2d)
Ph (2d)
P(O)(OEt)2 (2e)
CN (2f)d
CN (2f)
3
3
1
3
5c
6
6
6
6
1
3
NaH (l.l)
5
0
0
78
NaH (l.l)
5
85
3
–
–
0
86
4
–
–
0
52 (17b)
0(81b)
0
5
–
–
0
6
–
–
91
90
0
7
NaH (l.l)
5
0
8
AcOH (3.3)
0.5
5
88
9
NaH (l.l)
0
92
10
11
–
–
–
0
85
6(85e)
–
0
a
Determined by 19F NMR.
b
c
d
e
The yield of diethyl(3-acetyl-5-fluoro-2-methyl)phenylphosphonate (5).
The mixture was stirred at room temperature for 1 h and then heated at 50 8C for 4 h.
1.1 equiv. each of base and 2f was used.
The yield of l,5-bis(diethylphosphono)-3-fluoro-l,5-dicyano-(lE,3Z)-pentadiene (6f)
.
Diethyl(2-oxopropyl)phosphonate (2c) participated in the
2.2 equiv. each of 2f and t-BuOK led to the formation of
tetraethyl-3-fluoro-1,5-dicyano-(1E,3Z)-pentadiene-1,5-bispho-
sphonate (6f) in 85% yield, together with a small amount of 3f
(6% yield) (entry 11).
reaction without NaH to produce the expected product, which
was unstable for isolation with column chromatography but
was presumed to be diethyl-1-acetyl-4-(diethylamino)-3-
fluoro-(1E,3Z)-butadienylphosphonate (3c) (86% 19F NMR
yield) by comparison with fluorine chemical shifts of other 3
(entry 3). Interestingly, the reaction with 2c at room
temperature for 3 h led to the cyclization product, diethyl(3-
acetyl-5-fluoro-2-methyl)phenylphosphonate (5), in 17% yield
as the by-product (entry 4). When this reaction was conducted
for 1 h at room temperature, followed by heating at 50 8C for
4 h, the cyclization product 5 was obtained in high yield as the
sole product (entry 5).
The stereochemical assignment of 3 was made on the basis
of the relative magnitudes for the H–F and H–P vicinal
couplings. The 1H and 19F NMR spectra of the 1,3-
butadienylphosphonates 3 showed the coupling constants of
30.0–35.5 Hz for Ha–F and 24.0–35.5 Hz for Hb–F, which
indicate that the Ha–F and Hb–F relationships are in a transoid
and trans geometry, respectively (Fig. 1) [17]. The Ha–Px and
The reaction with diethyl benzylphosphonate (2d) did not
give the corresponding product 3d without or with addition of
NaH as the additive (entries 6 and 7). However, when acetic
acid was added as the additive and the whole was stirred for
0.5 h, the expected product, diethyl-4-(N,N-diethylamino)-3-
fluoro-1-phenyl-(1E,3Z)-butadienylphosphonate (3d) was
obtained in 88% yield (entry 8).
The treatment of 1 with diethyl cyanomethylphosphonate (2f)
(1.1 equiv.) and t-BuOK (1.1 equiv.) in DMF at ambient
temperature for 1 h proceeded readily to give diethyl-1-cyano-
4-(N,N-diethylamino)-3-fluoro-(1E,3Z)-butadienylphosphonate
(3f) in 85% yield as the sole product (entry 10). The use of
Fig. 1. The coupling constants of 3.

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S. Arimitsu et al. / Journal of Fluorine Chemistry 127 (2006) 1235–1241
Scheme 3.
Ha–Py coupling constants of 3e are 42.0 and 27.5 Hz,
respectively, strongly suggesting that the Ha–Px relationship
is trans and the Ha–Py is cis [18]. Based on the fact that the Ha–
Py coupling constants of other phosphonates 3 are in a range of
18.5–27.5 Hz, the Ha–Py relationship in 3 was assigned as cis.
A possible mechanism for the reaction of 1 with 2 is outlined
in Scheme 3. Nucleophilic attack of the anion of 2 occurs at the
iminium carbon (C1) of the salt 1 to form the intermediate
Int-X, which subsequently undergoes the b-elimination of
diethylamine to give the 1,3-butadienylphosphonate 3. The
exclusive formation of the E isomer (at the C1–C2 double bond)
of 3 may be explained by an anti-elimination pathway as
follows. With the two possible intermediates Int-X1 and Int-
X2, in which the hydrogen and diethylamino group occupy the
antiperiplanar position, the intermediate Int-X2 may have
much larger gauche repulsion than Int-X1. Therefore, the b-
elimination of diethylamine can occur more readily through
Int-X1 than Int-X2, leading exclusively to the E isomer of 3
[19].
The findings that the intermediate Int-X was detected in the
reaction using t-BuOK as the base but not in the reaction using
NaH seem to be explained as follows. In the reaction with NaH,
the a-hydrogen adjacent to the phosphonate group of Int-X
may be activated by coordination of sodium cation with
carbonyl and phosphonate groups, and this activation facilitates
the elimination of diethylamine from Int-X leading to the
product 3. In the case of the reaction using t-BuOK, potassium
cation may not sufficiently exert the effect of such activation of
the a-hydrogen [20], Int-X remaining to be detected. The steric
bulk of the base will be considered as another factor; the a-
hydrogen of Int-X is sterically crowded and, therefore, it can be
abstracted with a small hydride ion but not with a bulky
butoxide ion effectively.
The formation of the cyclization product 5 and bispho-
sphonate 6f is explained as follows (Scheme 4). The anion
derived from 2c or 2f attacks on the C4 carbon of 3 to form an
intermediate Int-Y, which similarly undergoes the b-elimination
of diethylamine to yield 6c and 6f, respectively. The diketone
6c thus formed may undergo the intramolecular Horner–
Wadsworth–Emmons reaction to produce the product 5.
It was found that the 1,3-butadienylphosphonates 3a, 3d and
3e were subjected tohydrolysis with a10%HClaqueoussolution
at room temperature for 1 h, giving rise to the corresponding
a,b-unsaturated aldehydes 7 in 61–76% yields (Scheme 5).
The formation of 4 observed in the reaction in THF
(Table 1, entries 1–3) would be caused by the elimination of
phosphoramidate (Et2NP(O)(OEt)2) from an azaphosphatane
species which results from an effectual interaction between N
and P of Int-X in THF, a less polar solvent, compared to
DMF.
Scheme 4.

S. Arimitsu et al. / Journal of Fluorine Chemistry 127 (2006) 1235–1241
1239
1 was prepared according to the method reported by us [22]. All
reactions were carried out under an atmosphere of argon.
4.2. General procedure of the reaction of vinamidinium
salt 1 with HWE reagent 2
To a solution of t-BuOK (0.13 g, 1.1 mmol) in DMF
(1.5 mL) was gradually added a solution of HWE reagent 2
(1.1 mmol) in DMF (1.5 mL) at 0 8C. After stirring at room
temperature for 0.5 h, a solution of the salt 1 (0.164 g,
0.5 mmol) in DMF (2.0 mL) was slowly added, and then the
whole mixture was stirred at room temperature for the time
shown in Table 2. To the reaction mixture was added C6F6 for
determining 19F NMR yields of the products. In the cases of
entries 1, 2 and 7–9 in Table 2, NaH (0.013 g, 0.55 mmol) or
acetic acid (0.099 g, 1.65 mmol) was added and then the
mixture was stirred at room temperature for 5 or 0.5 h,
respectively. When NaH was used as the additive, the reaction
was quenched with EtOH (20 mL). The reaction mixture was
poured into brine (40 mL), followed by extraction with
dichloromethane (5ꢁ 20 mL). The combined extracts were
dried over sodium sulfate and concentrated under reduced
pressure. Column chromatography (silica gel, hexane/ethyl
acetate = 2/3) of the residue gave the corresponding 1,3-
butadienylphosphonate 3.
Scheme 5.
Scheme 6.
Additionally, on treatment of 3c with a 25% NH3 aqueous
solution at 70 8C for 2 h, the pyridine derivative 8 was afforded
in 60% yield (Scheme 6).
3. Conclusion
In summary, we demonstrated that the fluorinated 1,3-
butadienylphosphonates 3 were easily synthesized in moderate
to good yields by the reaction of the vinamidinium salt 1 with
4.2.1. Diethyl-4-(N,N-diethylamino)-1-ethoxycarbonyl-3-
fluoro-(1E,3Z)-butadienylphosphonate (3a)
various Horner–Wadsworth–Emmons reagents
2 in the
presence of base at room temperature. When the reaction of
1 with diethyl(2-oxopropyl)phosphonate 2c was conducted at
50 8C, the benzene derivative 5 was obtained in good yield
through the intramolecular Horner–Wadsworth–Emmons reac-
tion. Furthermore, the phosphonates 3 thus obtained could
easily be hydrolyzed with 10% HCl aqueous solution to give the
corresponding phosphonate-containing fluorinated a,b-unsa-
turated aldehydes 7 in good yields. The phosphonate 3c could
readily be converted to the phosphonated pyridine derivative 8
by treatment with aqueous ammonia solution at 70 8C.
IR (neat): n 2989, 1717, 1643, 1574, 1420, 1362, 1265, 1234,
1204, 1180, 1130, 1096, 1053, 1026, 964, 768 cmꢀ1; 1H NMR:
d 1.21 (t, J = 7.0 Hz, 6H), 1.30 (t, J = 7.0 Hz, 3H), 1.32 (t,
J = 7.0 Hz, 6H), 3.30 (q, J = 7.0 Hz, 4H), 4.05–4.13 (m, 4H),
4.23 (q, J = 7.0 Hz, 2H), 5.98 (d, J = 27.5 Hz, 1H), 6.80 (dd,
J = 32.5, 22.5 Hz, 1H); 13C NMR: d 14.00, 14.40, 16.09 (d,
J = 7.0 Hz), 47.70, 60.57, 61.73 (d, J = 4.8 Hz), 102.12 (d,
J = 190.0 Hz), 133.54 (d, J = 4.9 Hz), 136.86 (dd, J = 232.6,
22.6 Hz), 141.50 (dd, J = 14.1, 10.1 Hz), 166.80 (d,
J = 12.2 Hz); 19F NMR: d ꢀ151.68 (dd, J = 32.5, 27.5 Hz,
1F); MS (EI) m/z (rel intensity) 351 (M+, 100), 336 (9), 306
(84), 214 (86); HRMS (EI) calcd for C15H27FNO5P: 351.1595,
found: 351.1589.
4. Experimental
4.1. General
4.2.2. Diethyl-4-(N,N-diethylamino)-1-methoxycarbonyl-3-
fluoro-(1E,3Z)-butadienylphosphonate (3b)
IR (neat): n 2986, 2931, 1713, 1651, 1574, 1435, 1400, 1366,
1311, 1346, 1311, 1269, 1230, 1177, 1130, 872, 799, 748 cmꢀ1
;
Infrared spectra (IR) were recorded in a liquid film or KBr
disk method on a Shimadzu FTIR-8200A (PC) spectro-
1
photometer. H NMR spectra were measured with a Bruker
DRX (500.13 MHz) spectrometer in a chloroform-d (CDCl3)
solution with tetramethylsilane (TMS) as an internal
reference. 13C NMR spectra were recorded on a Bruker
DRX (125.77 MHz) spectrometer. A JEOL JNM EX90
(84.21 MHz, FT) spectrometer was used to obtain 19F NMR
spectra in CDCl3 with trichlorofluoromethane (CCl3F) as an
internal reference. C6F6 was used for determining the 19F NMR
yield as an internal standard. High resolution mass spectra
(HRMS) were taken on a JEOL JMS-700 mass spectrometer.
All chemicals are of reagent grade and, if necessary, were
purified in the usual manner prior to use. The vinamidinium salt
1H NMR: d 1.21 (t, J = 7.0 Hz, 6H), 1.32 (t, J = 7.0 Hz, 6H),
3.31 (q, J = 7.0 Hz, 4H), 3.77 (s, 3H), 4.05–4.13 (m, 4H), 6.00
(d, J = 27.5 Hz, 1H), 6.81 (dd, J = 32.5, 22.5 Hz, 1H); 19F
NMR: d ꢀ152.12 (dd, J = 32.5, 27.5Hz, 1F); MS (EI) m/z (rel
intensity) 337 (M+, 56), 306 (100); HRMS (EI) calcd for
C14H25FNO5P: 337.1454, found: 337.1453.
4.2.3. Diethyl-4-(N,N-diethylamino)-3-fluoro-1-phenyl-
(1E,3Z)-butadienylphosphonate (3d)
IR (neat): n 3025, 2978, 2900, 1643, 1585, 1416, 1342, 1261,
1234, 1184, 1123, 1096, 1030, 976, 798, 763 cmꢀ1; 1H NMR: d

1240
S. Arimitsu et al. / Journal of Fluorine Chemistry 127 (2006) 1235–1241
1.11 (t, J = 7.5 Hz, 6H), 1.22 (t, J = 7.0 Hz, 6H), 3.16 (q,
J = 7.5 Hz, 4H), 3.97–4.05 (m, 4H), 5.72 (d, J = 28.0 Hz, 1H),
6.80 (dd, J = 31.8, 23.8 Hz, 1H), 7.21–7.29 (m, 5H); 13C NMR:
d 14.46, 16.20 (d, J = 6.6 Hz), 47.23, 61.39 (d, J = 5.2 Hz),
102.52 (d, J = 182.3 Hz), 126.33, 127.23, 129.6 (d, J = 2.4 Hz),
129.60 (d, J = 5.9 Hz), 129.90 (d, J = 5.4 Hz), 136.62 (dd,
J = 25.3, 12.8 Hz), 138.01 (dd, J = 235.1, 25.7 Hz); 19F NMR: d
ꢀ150.86 (dd, J = 31.8, 28.0 Hz, 1F); MS (EI) m/z (rel intensity)
356 (M+, 25), 340 (100), 285 (30), 155 (8); HRMS (EI) calcd for
C18H28FNO3P: 356.1793, found: 356.1794.
J = 15.5, 8.3, 3.0 Hz, 1H); 13C NMR: d 16.26 (d, J = 7.2 Hz),
17.69 (d, J = 4.0 Hz), 30.45, 62.44 (d, J = 5.8 Hz), 118.13
(d, J = 22.1 Hz), 123.10 (dd, J = 22.4, 10.6 Hz), 131.83
(dd, J = 184.7, 5.3 Hz), 135.60 (dd, J = 10.4, 4.0 Hz), 142.90
(dd, J = 17.0, 4.8 Hz), 159.63 (dd, J = 249.2, 21.5 Hz), 201.67;
19F NMR: d ꢀ116.83 (dd, J = 15.5, 8.3 Hz, 1F); MS (FAB)
m/z (rel intensity) 289 (M+ + H0, 100), 233 (19), 154 (14);
HRMS (FAB) calcd for C13H19FO4P: 289.1005, found:
289.1007.
4.2.8. Tetraethyl-1,5-dicyano-3-fluoro-5-phosphono-
(1E,3Z)pentadienylphosphonate (6f)
IR (neat): n 2990, 2912, 2218, 1655, 1593, 1547, 1477, 1447,
4.2.4. Tetraethyl-4-(N,N-diethylamino)-3-fluoro-(1E,3Z)-
butadienylidenediphosphonate (3e)
1
IR (neat): n 2982, 2936, 2905, 1636, 1551, 1427, 1396, 1362,
1300, 1269, 1226, 1184, 1134, 1026, 964, 798 cmꢀ1; 1H NMR:
d 1.32 (t, J = 7.0 Hz, 6H), 1.33 (t, J = 6.5 Hz, 6H), 3.36 (q,
J = 7.0 Hz, 4H), 4.04–4.25 (m, 8H), 6.18 (d, J = 24.0 Hz, 1H),
7.23 (ddd, J = 42.0, 35.5, 27.5 Hz, 1H); 19F NMR: d ꢀ148.44
(dd, J = 35.5, 24.0 Hz, 1F); MS (EI) m/z (rel intensity) 416 (M+,
100), 308 (5), 142 (6); HRMS (EI) calcd for C16H32FNO6P2:
416.1767, found: 416.1765.
1393,1369, 1261, 1211, 1165, 1018, 980, 799, 733 cmꢀ1; H
NMR: d 1.40 (t, J = 7.0 Hz, 12H), 4.16–4.33 (m, 9H), 5.61 (ddd,
J = 28.5, 10.0, 6.0 Hz, 1H), 7.34 (dd, J = 25.5, 20.1 Hz, 1H);
19F NMR: d ꢀ112.23 (dddd, J = 28.5, 25.5, 11.0, 4.4 Hz, 1F);
MS (EI) m/z (rel intensity) 408 (M+, 4), 299 (100), 272 (3), 167
(63); HRMS (EI) calcd for C15H23FN2O6P2: 408.1020, found:
408.1022.
4.3. General procedure for the synthesis of phosphonated
a,b-unsaturated aldehydes 7
4.2.5. Diethyl-1-cyano-4-(N,N-diethylamino)-3-fluoro-
(1E,3Z)butadienylphosphonate (3f)
IR (neat): n 2986, 2191, 1639, 1562, 1427, 1396, 1358, 1308,
1234, 1184, 1138, 1022, 964, 802, 768 cmꢀ1; 1H NMR: d 1.27
(t, J = 7.0 Hz, 6H), 1.37 (t, J = 7.0 Hz, 6H), 3.40 (q, J = 7.0 Hz,
4H), 4.09–4.16 (m, 4H), 6.18 (d, J = 26.5 Hz, 1H), 6.98 (dd,
J = 30.0, 18.5 Hz, 1H); 13C NMR: d 14.48, 16.18 (d,
J = 6.7 Hz), 47.45, 62.60 (d, J = 5.7 Hz), 75.68 (d,
J = 208.6 Hz), 117.70 (d, J = 10.9 Hz), 136.71 (d,
J = 3.5 Hz), 137.99 (dd, J = 232.7, 20.2 Hz), 147.86 (dd,
J = 11.3, 10.8 Hz); 19F NMR: d ꢀ152.06 (ddd, J = 30.0, 26.5,
5.5 Hz, 1F); MS (EI) m/z (rel intensity) 304 (M+, 100), 289 (28),
167 (63); HRMS (EI) calcd for C13H22FN2O5P: 304.1352,
found: 304.1351.
To a solution of 3 (0.5 mmol) in DMF (2 mL) was gradually
added 10% aqueous HCl (50 mL), and the mixture was stirred
for 1 h at room temperature. To the resulting mixture was added
C6F6 for determining 19F NMR yields of the products. The
reaction mixture was poured into brine (40 mL) and extracted
with diethyl ether (3ꢁ 30 mL). The combined diethyl ether
extracts were dried over sodium sulfate and concentrated under
reduced pressure. Column chromatography (silica gel, hexane/
ethyl acetate = 1/3) of the residue gave the corresponding
aldehydes 7.
4.3.1. 4-Ethoxycarbonyl-4-(diethylphosphono)-2-fluoro-
2(Z)-butenal (7a)
4.2.6. Ethyl-5-(diethylamino)-4-fluoro-(2E,4Z)-
pentadienoate (4)
IR (neat): n 3395, 2912, 2874, 1736, 1701, 1670, 1447, 1258,
1211, 1161, 1022, 976, 883 cmꢀ1; 1H NMR: d 1.33 (td, J = 7.0,
0.8 Hz, 6H), 1.32 (t, J = 7.0 Hz, 3H), 4.13–4.29 (m, 4H), 4.26
(q, J = 7.0 Hz, 2H), 4.30 (dd, J = 25.0, 10.5 Hz, 1H), 6.26 (ddd,
J = 30.5, 10.5, 6.0 Hz, 1H), 9.30 (d, J = 18.5 Hz, 1H); 13C
NMR: d 13.96, 16.21 (d, J = 5.2 Hz), 43.41 (d, J = 127.9 Hz),
62.59, 63.75 (d, J = 6.2 Hz), 63.80 (d, J = 6.3 Hz), 119.89 (dd,
J = 10.9, 9.3 Hz), 155.98 (dd, J = 268.7, 11.8 Hz), 165.26 (d,
J = 7.7 Hz), 182.76 (d, J = 24.7 Hz); 19F NMR: d ꢀ128.77
(ddd, J = 30.5, 18.50, 11.5 Hz, 1F); MS (FAB) m/z (rel
intensity) 297 (M+ + H0, 100), 251 (9), 224 (3), 136 (40);
HRMS (FAB) calcd for C11H19FO6P: 297.0903, found:
297.0802.
Mp 56.5–57.5 8C; IR (Kbr) n 2978, 2936, 1736, 1697, 1589,
1419, 1362, 1258, 1157, 1076, 833, 659 cmꢀ1; 1H NMR: d 1.18
(t, J = 7.1 Hz, 6H), 1.27 (t, J = 7.1 Hz, 3H), 3.26 (q, J = 7.1 Hz,
4H), 4.17 (q, J = 7.1 Hz, 2H), 5.54 (d, J = 14.8 Hz, 1H), 5.65 (d,
J = 29.5 Hz, 1H), 6.95 (dd, J = 29.9, 14.8 Hz, 1H); 13C NMR: d
14.46, 14.50, 47.42, 47.46, 59.55, 103.16 (d, J = 2.8 Hz),
128.47 (d, J = 4.9 Hz), 137.36 (d, J = 18.1 Hz), 137.41 (d,
J = 229.0 Hz), 168.30; 19F NMR: d ꢀ156.51 (dd, J = 29.9,
29.5 Hz, 1F); MS (EI) m/z (rel intensity) 215 (M+, 100), 200
(86), 186 (19), 170 (85); HRMS (EI) calcd for C11H18FNO2:
215.1307, found: 215.1295.
4.2.7. Diethyl(3-acetyl-5-fluoro-2-
methylphenyl)phosphonate (5)
4.3.2. 4-Phenyl-4-(diethylphosphono)-2-fluoro-2(Z)-
butenal (7d)
IR (neat): n 3074, 2986, 2989, 1701, 1593, 1435, 1393, 1358,
1
IR (neat): n 3036, 2986, 2864, 1701, 1666, 1496, 1391, 1238,
1020, 970, 883, 754, 698 cmꢀ1; 1H NMR: d 1.09 (t, J = 7.0 Hz,
3H), 1.30 (t, J = 7.0 Hz, 3H), 3.75–4.126 (m, 4H), 3.96 (m, 1H),
4.45 (dd, J = 23.5, 11.0, 1H), 6.36 (ddd, J = 29.5, 11.0, 7.5 Hz,
1293, 1246, 1165, 1088, 1022, 964, 822, 795, 741 cmꢀ1; H
NMR: d 1.33 (t, J = 7.0 Hz, 6H), 2.54 (s, 3H), 2.57 (s, 3H),
4.08–4.19 (m, 4H), 7.32 (dd, J = 8.3, 2.8 Hz, 1H), 7.76 (ddd,

S. Arimitsu et al. / Journal of Fluorine Chemistry 127 (2006) 1235–1241
1241
1H), 9.30 (d, J = 18.0 Hz, 1H); 13C NMR: d 16.13 (d,
J = 6.2 Hz), 16.31 (d, J = 5.8 Hz), 41.75 (d, J = 138.6 Hz),
62.88 (d, J = 7.3 Hz), 63.64 (d, J = 6.8 Hz), 125.06 (dd,
J = 10.1, 8.4 Hz), 128.10, 128.74 (d, J = 6.8 Hz), 129.11,
133.19, 156.23 (dd, J = 267.3, 11.2 Hz), 183.16 (d,
J = 25.4 Hz); 19F NMR: d 130.36 (ddd, J = 29.5, 18.0,
11.0 Hz, 1F); MS (FAB) m/z (rel intensity) 361 (M+ + H0,
100), 154 (68), 136 (55); HRMS (FAB) calcd for C14H19FO4P:
301.1005, found: 301.1004.
157.12 (dd, J = 256.4, 16.2 Hz), 201.67; 19F NMR: d ꢀ131.65
(dd, J = 8.5, 2.0 Hz, 1F); MS (FAB) m/z (rel intensity) 248
(M+ + H0, 100), 154 (47), 136 (36), 112 (1); HRMS (FAB) calcd
for C10H16FNO3P: 248.0852, found: 248.0857.
References
[1] D. Lyoyd, H. McNab, Angew. Chem. Int. Ed. Engl. 15 (1976) 459–468,
and references therein.
[2] J.T. Gupton, S.W. Riesnger, A.S. Shah, J.E. Gall, K.M. Bevirt, J. Org.
Chem. 56 (1991) 976–980.
4.3.3. 4,4-Bis(diethylphosphono)-2-fluoro-2(Z)-butenal
(7e)
IR (neat): n 2990, 2885,1693, 1663, 1443, 1393, 1350, 1250,
[3] A. Ehmann, R. Gompper, H. Hartmann, T.J.J. Muller, K. Polborn, R.
Schutz, Angew. Chem. Int. Ed. Engl. 33 (1994) 572–575.
[4] N.J. Tom, E.M. Ruel, Synthesis (2001) 1351–1355.
[5] I.W. Davies, M. Taylor, J.-F. Marcoux, J. Wu, P.G. Dormer, D. Hughes, P.J.
Reider, J. Org. Chem. 66 (2001) 251–255.
1
1165, 1022, 976, 933, 876, 791 cmꢀ1; H NMR: d 1.33 (dt,
J = 7.0, 2.5 Hz, 12H), 3.85 (td, J = 22.5, 11.5 Hz, 1H), 4.20 (dq,
J = 17.0, 7.0 Hz, 8H), 6.08 (ddt, J = 28.8, 11.5, 6.5 Hz, 1H),
9.29 (d, J = 18.0 Hz, 1H); 13C NMR: d 16.26 (d, J = 5.6 Hz),
36.72 (t, J = 133.7 Hz), 63.55 (d, J = 5.6 Hz), 63.68 (d,
J = 6.1 Hz), 119.19 (dt, J = 10.1, 8.7 Hz), 156.89 (dt,
J = 268.0, 11.2 Hz), 182.61 (d, J = 24.4 Hz); 19F NMR: d
ꢀ129.64 (ddt, J = 28.8, 18.0, 8.8 Hz, 1F); MS (FAB) m/z (rel
intensity) 361 (M+ + H0, 100), 231 (17), 197 (15), 136 (52);
HRMS (FAB) calcd for C12H24FO7P2: 361.0981, found:
361.0985.
[6] I.W. Davies, J.-F. Marcoux, J.D.O. Taylor, P.G. Dormer, R.J. Deeth, F.-A.
Marcotte, D.L. Hughes, P.J. Reider, Org. Lett. 4 (2002) 439–441.
[7] I.W. Davies, J.-F. Marcoux, J. Wu, M. Palucki, E.G. Corley, M.A. Robbins,
N. Tsou, R.G. Ball, P.G. Dormer, R.D. Larsen, P.J. Reider, J. Org. Chem.
65 (2000) 4571–4574.
[8] J.-F. Marcoux, E.G. Corley, K. Rossen, P. Pye, J. Wu, M.A. Robbins, I.W.
Davies, R.D. Larsen, P.J. Reider, Org. Lett. 2 (2000) 2339–2341.
[9] I. Davies, J.-F. Marcoux, E.G. Corley, M. Journet, D.-W. Cai, M. Palucki,
J. Wu, R.D. Larsen, K. Rossen, P.L. Pye, L. DiMichele, P. Dormer, P.J.
Reider, J. Org. Chem. 65 (2000) 8415–8420.
[10] C. Reichardt, K. Halbritter, Justus Liebigs Ann. Chem. 737 (1970) 99–
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[11] C. Reichardt, K. Halbritter, Justus Liebigs Ann. Chem. (1975) 470–483.
[12] V.J. Saloutin, Z.E. Skryabina, Y.V. Burgart, O.N. Chupakhin, M. Font-
Altaba, X. Solans, M. Font-Bardia, J. Fluorine Chem. 69 (1994) 25–29.
[13] H. Yamanaka, T. Ishihara, J. Fluorine Chem. 105 (2000) 295–303, and
references therein.
4.4. Synthesis of the phosphonated pyridine 8
To the mixture, prepared by the reaction of the salt 1
(0.164 g, 0.50 mmol) with 2a (0.214 g, 1.1 mmol) and t-BuOK
(0.123 g, 1.1 mmol) in DMF (3.5 mL) for 1 h at room
temperature, was gradually added 25% NH3 aqueous solution
(30 mL). The whole mixture was stirred for 2 h at 70 8C. The
reaction mixture was extracted with diethyl ether (3ꢁ 30 mL)
and the combined organic layers were washed with brine
(50 mL), followed by drying over sodium sulfate and
concentration under reduced pressure. The residual oil was
purified by silica gel column chromatography (hexane/ethyl
acetate 1/3) to afford pure 2-acetyl-3-(diethoxyphosphono)-5-
fluoropyridine 8 (0.075 g, 0.3 mmol, 60% yield).
[14] S. Shibayama, T. Konno, T. Ishihara, H. Yamanaka, J. Fluorine Chem. 111
(2001) 91–100.
[15] K. Kase, M. Katayama, T. Konno, T. Ishihara, H. Yamanaka, J.T. Gupton,
J. Fluorine Chem. 120 (2003) 33–39.
[16] G. Zhang, B. Song, W. Xue, L. Jin, D. Hu, Q. Wan, P. Lu, H. Wang, S.
Yang, Q. Li, G. Liu, J. Fluorine Chem. 127 (2006) 48–53, and references
therein.
[17] R.M. Silverstein, R.X. Webster, Spectrometric Identification of Organic
Compounds, 6th ed., John Wiley & Sons, Inc., New York, 1998.
[18] E.F. Mooney (Ed.), Annual Reports on NMR Spectroscopy, vol. 5B,
Academic Press, 1973.
[19] However, the possibility of thermodynamic conversion of the Z isomer to
more stable E isomer through the conjugation of double bond cannot be
ruled out.
4.4.1. 2-Acetyl–3-(diethoxyphosphono)-5-fluoropyridine 8
IR (neat): n 3491, 2986, 2936, 2874, 1840, 1593, 1570, 1439,
1393, 1254, 1165, 1022, 968, 795, 748, 725, 683 cmꢀ1; H
[20] The effect of metal cation on activation of the a-hydrogen of HWE
reagents by coordination of metal cation with carbonyl and phosphonate
groups in generating enolates has been investigated and it has been found
that such activation effect of sodium cation is stronger than that of
potassium cation [21].
1
NMR: d 1.32 (t, J = 7.0 Hz, 6H), 2.72 (s, 3H), 4.08–4.20 (m,
4H), 7.88 (ddd, J = 15.5, 8.5, 3.0 Hz, 1H), 8.44 (dd, J = 3.0,
2.0 Hz, 1H); 13C NMR: d 16.22 (d, J = 6.4 Hz), 23.62, 62.58 (d,
J = 5.4 Hz), 124.49 (d, J = 183.4 Hz), 128.31 (dd, J = 19.6,
9.1 Hz), 140.10 (d, J = 22.1 Hz), 156.98 (dd, J = 10.9, 4.6 Hz),
[21] K. Ando, T. Oishi, M. Hirama, H. Ohno, T. Ibuka, J. Org. Chem. 65 (2000)
4745–4749, and references therein.
[22] H. Yamanaka, S. Yamashita, T. Ishihara, Tetrahedron Lett. 33 (1992) 357–
360.