Synthesis of (α,α-Difluoroallyl)phosphonates from alkenyl halides or acetylenes

Full text of DOI:10.1021/jo960896j

J . Org. Chem. 1996, 61, 7207-7211
7207
Ta ble 1. Cou p lin g Rea ction of â-Ha logen ostyr en es w ith
Syn th esis of
Cop p er Rea gen t 3 in THF or DMF
(r,r-Diflu or oa llyl)p h osp h on a tes fr om
time %yield
Alk en yl Ha lid es or Acetylen es
entry
substrate (E:Z)
solvent (h) of 4a a E:Zb
1
2
3
4
(E)-â-bromostyrene (86:14)c THF
(E)-â-bromostyrene (86:14)c DMF
60
60
15
60
55
67
85
50
86:14
86:14
98:2
Tsutomu Yokomatsu, Kenji Suemune,
Tetsuo Murano, and Shiroshi Shibuya*
(E)-â-iodostyrene (98:2)d
DMF
(Z)-â-bromostyrene (26:74)e DMF
32:68
School of Pharmacy, Tokyo University of Pharmacy and Life
Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-03, J apan
a
b
Yield based on alkenyl halide. Determined by NMR (1H and/
or 31P) analysis. c Purchased from Wako Pure Chemical Industry
Ltd. Prepared from phenylacetylene according to the method of
Received May 15, 1996
d
Zweifel: Zweifel, G.; Whitney, C. C. J . Am. Chem. Soc. 1967, 89,
2753. e Prepared as described in the literature: Matsumoto, M.;
Kuroda, K. Tetrahedron Lett. 1980, 21, 4021.
In tr od u ction
Phosphonic acids often exhibit important biological
properties by virtue of their similarity to phosphate,1
while substitution of a fluorine atom in a biological
molecule often leads to pronounced enhancement in the
activity.2 Recently, (difluoromethylene)phosphonates as
hydrolytically stable analogues of naturally occurring
phosphate esters have attracted attention because they
mimic parental biophosphate more accurately than analo-
gous nonfluorinated phosphonates in their isosteric and
isopolar properties.3 Although the concept of (difluoro-
methylene)phosphonate as analogues of phosphate esters
has been much argued,4 this replacement has provided
several natural product analogues with significant ac-
tivites.5
Previous approaches to prepare these compounds have
included a variety of bond-forming reactions. A carbon-
carbon bond formation using ionic displacement of elec-
trophiles such as halides or primary triflates with
metalated dialkyl (difluoromethyl)phosphonates has been
applied as a convergent methods for introduction of the
(difluoromethylene)phosphonate moiety.6-9 The radical-
mediated addition of (iodo- or (bromodifluoromethyl)-
phosphonates across alkenes has also been reported.10,11
Alternatively, electrophilic fluorinations of phosphonate-
stabilized carbanions12 and nucleophilic fluorination of
benzilic R-oxophosphonates to the corresponding benzilic
R,R-difluorophosphonate with (diethylamido)sulfur tri-
fluoride (DAST)13 have been developed. Although these
methods exhibit great utility for construction of a variety
of (difluoromethylene)phosphonates,14 there is a con-
spicuous lack of methods for the preparation of the
compounds in which (difluoromethylene)phosphonate
moiety is directly attached to an olefinic carbon atom
such as (R,R-difluoroallyl)phosphonates.15,16 These com-
pounds would be highly useful as conformationally
restricted analogues of phosphate monoesters,15a but also
as versatile synthetic intermediates toward a new type
of (difluoromethylene)phosphonates through conversion
of the double bond to other functional groups.15b
As a part of our program designed to explore the utility
of (difluoromethylene)phosphonates for the synthesis of
new (difluoromethylene)phosphonates of biological inter-
est, we have examined the stereoselective synthesis of
(R,R-difluoroallyl)phosphonates through copper(I)-cata-
lyzed coupling or the addition reaction of [(diethoxyphos-
phinyl)difluoromethyl]zinc bromide (2)7 with alkenyl
halides and terminal acetylenes in dimethylformamide
(DMF).
Resu lts a n d Discu ssion
Cop p er (I)-Ca ta lyzed Cou p lin g Rea ction of [(Di-
eth oxyp h osp h in yl)d iflu or om eth yl]zin c Br om id es 2
w ith Alk en yl Ha lid es. Among various possible meth-
ods for synthesis of (R,R-difluoroallyl)phosphonates, direct
carbon-carbon bond formation using a coupling reaction
of alkenyl halides with metalated dialkyl difluorometh-
ylphosphonates17 such as [(diethoxyphosphinyl)difluoro-
methyl]zinc bromide (2)7 and [(diethoxyphosphinyl)-
difluoromethyl]copper complex 3 would be desirable.18
However such direct carbon-carbon formation has not
been extensively studied previously.19 Consequently, we
have examined the possibility of coupling reaction of (E)-
and (Z)-â-halogenostyrenes with zinc reagent 2 and
(1) (a) Engel, R. Chem. Rev. 1977, 77, 349. (b) Engel, R. The Role of
Phosphonates in Living Systems; Hilderbrand, R. L., Ed., CRC Press:
Boca Raton, FL, 1983; pp 93-138.
(2) Biochemical Aspects of Fluorine Chemistry; Filler, R., Kobayashi,
Y., Eds.; Kodansha/Elsevier: New York, 1982.
(3) (a) Blackburn, G. M. Chem. Ind. 1981, 134. (b) Blackburn, G.
M.; Kent, D. E. Kolkmann, F. J . Chem. Soc., Perkin Trans. 1 1984,
1119.
(4) (a) Thatcher, G. R. J .; Campbell, A. S. J . Org. Chem. 1993, 58,
2272. (b) Nieschalk, J .; O’Hagan, D. J . Chem. Soc., Chem. Commun.
1995, 719.
(5) (a) Chambers, R. D.; J aouhari, R.; O’Hagan, D. Tetrahedron
1989, 45, 5101. (b) Blackburn, G. M.; J akeman, D. L.; Ivory, A. J .;
Williamson, M. P. Bioorg. Med. Chem. Lett. 1994, 4, 2753. (c) Burke,
T. R., J r.; Smyth, M. S.; Otaka, A.; Nomizu, M.; Roller, P. P.; Wolf. G.;
Case, R.; Shoelson, S. E. Biochemistry 1994, 33, 6490.
(6) (a) Obayashi, M.; Ito, E.; Matsui, K.; Kondo, K. Tetrahedron Lett.
1982, 23, 2323. (b) Bigge, C. F.; Drummond, J . T.; J ohnson, G.
Tetrahedron Lett. 1989, 30, 7013. (c) Martin, S. F.; Dean, D. W.;
Wagman, A. S. Tetrahedron Lett., 1992, 33, 1839. (d) Berkowitz, D.
B.; Eggen, M.; Shen, Q.; Sloss, D. G. J . Org. Chem. 1993, 58, 6174. (e)
Berkowitz, D. B.; Shen, Q.; Maeng, J .-H. Tetrahedron Lett. 1994, 35,
6445. (f) Berkowitz, D. B.; Sloss, D. G. J . Org. Chem. 1995, 60, 7047.
(7) Burton, D. J .; Sprague, L. G. J . Org. Chem. 1989, 54, 613.
Chambers, R. D.; O’Hagan, D.; Lamount, R. B.; J ain, S. C. J . Chem.
Soc., Chem. Commun. 1990, 1053.
(8) (a) Burton, D. J .; Takei, R.; Shin-ya, S. J . Fluorine Chem. 1981,
18, 197. (b) Chambers, R. D.; J aouhari, R.; O’Hagan, D. J . Chem. Soc.,
Chem. Commun. 1988, 1169.
(9) (a) Lequeux, T. P.; Percy, J . M. Synlett 1995, 361. (b) Idem. J .
Chem. Soc., Chem. Commun. 1995, 2111.
(10) (a)Yang, Z.-Y.; Burton, D. J . Tetrahedron Lett. 1991, 32, 1019.
(b) Idem. J . Org. Chem. 1992, 57, 4676.
(11) Hu, C.-M.; Chen, J . J . Chem. Soc., Perkin Trans. 1 1993, 327
(12) Differding, E. Duthaler, R. O.; Krieger, A.; Ru¨egg, G. M; Schmit,
C. Synlett 1991, 395.
(13) Smyth, M. S.; Burke, T. R., J r. Tetrahedron Lett. 1994, 35, 551.
(14) Recently, radical mediated C-P bond formations have been
applied to the synthesis of (difluoromethylene)phosphonates: (a)
Herpin, T. F.; Houlton, J . S.; Motherwell, W. B.; Roberts, B. P.; Weibel,
J .-M. J . Chem. Soc., Chem. Commun. 1996, 613. (b) Piettre, S. R.
Tetrahedron Lett. 1996, 37, 2233.
(15) (a) Halazy, S.; Gross-Berge`s, V. J . Chem. Soc., Chem. Commun.
1992, 743. (b) Blades, K.; Lequeux, T. P.; Percy, J . M. J . Chem. Soc.,
Chem. Commun. 1996, 1457 and references cited therein.
(16) For the selective synthesis of (R-monofluoroallyl)phospho-
nates: Sanders, T. C.; Hammond, G. B. J . Org. Chem. 1993, 58, 5598.
(17) For review of metalated (difluoromethyl)phosphonate: Burton,
D. J .; Yang, Z.-Y. Tetrahedron 1992, 48, 189.
(18) Sprague, L. G.; Burton, D. J .; Guneratne, R. D.; Bennett, W.
E. J . Fluorine Chem. 1990, 49, 75.
(19) The similar strategy have been applied to an efficient synthesis
of (R,R-difluroallyl)carboxylates: Taguchi, T.; Kitagawa, O.; Morikawa,
T.; Nishiwaki, T.; Uehara, H.; Endo, H.; Kobayashi, Y. Tetrahedron
Lett. 1986, 27, 6103.
S0022-3263(96)00896-1 CCC: $12.00 © 1996 American Chemical Society

7208 J . Org. Chem., Vol. 61, No. 20, 1996
Ta ble 2. Cou p lin g Rea ction of 3 w ith Alk en yl Ha lid es in DMF
Notes
copper reagent 3, prepared from diethyl (bromodifluoro-
methyl)phosphonate 1, zinc, and CuBr according to
method of Burton7,18 (eq 1 and Table 1). Although the
F igu r e 1.
was found to vary slightly owing to loss of starting
geometry during the coupling reaction20 (entry 4).
The stereochemistry of (E)-4a was determined on the
basis of the occurrence of a larger vicinal alkenyl coupling
constant (J ) 16.2 Hz). On the other hand, the alterna-
tive isomer showed a vicinal coupling of J ) 12.9 Hz
which is consistent with that of a Z-isomer. The stereo-
chemistry of (E)-4a was further confirmed by relatively
strong NOEs between protons on the phenyl ring and
C(2)-H as shown in Figure 1.
To explore the scope and applicability of the method,
the reaction was further examined with a variety of
alkenyl halides. The results of this exploratory study are
summarized in Table 2. Introduction of a methoxy group
onto the 4-position of â-bromostyrene was found to lower
the yield, as compared with the reaction on â-bromosty-
rene (entry 1 vs entry 2 of Table 1). Both (E)- and (Z)-
alkenyl halides possessing aliphatic substituents at the
â position were found to proceed with complete retention
of the starting geometry (entries 2-5), and both (E)-4d
and (Z)-4d could be prepared stereospecifically (entries
3 and 4). Nonterminal alkenyl iodides also reacted with
reagent 2 by itself did not react with (E)-â-bromostyrene,
the coupling reaction was found to proceed successfully
with retention of the starting olefinic geometry after the
transmetalation to 3 with a stoichiometric amount of
CuBr. Treatment of 2 with CuBr, followed by the
reaction with (E)-â-bromostyrene (E:Z ) 86:14) at room
temperature for 60 h in THF, gave (R,R-difluoroallyl)-
phosphonates (E)-4a and (Z)-4a in a ratio of 86:14 in 55%
yield (entry 1). The yield increased to 67% with the same
product ratio of E- and Z-isomers when the reaction was
carried out in DMF instead of THF (entry 2). The
coupling reaction of (E)-â-iodostyrene (E:Z ) 98:2) with
the copper reagent 3 in DMF was found to proceed more
rapidly (15 h), and (E)-4a of configurationally high purity
(98%) was obtained in high yield (entry 3). (Z)-â-Bromo-
styrene (E:Z ) 26:74) reacted with the copper reagent 3
in DMF to give (E)-4a and (Z)-4a in a ratio of 32:68 in
50% yield. Although the Z-enriched (R,R-difluoroallyl)-
phosphonate was produced in this reaction, the E/Z ratio
(20) The loss of starting olefinic geometry might arise from nonste-
reospecific radical addition of 3 to phenylacetylene, a contamination
product during the preparation of (Z)-â-bromostyrene.

Notes
Ta ble 3. 31P NMR Da ta of P h osp h on a te Rea gen ts in
J . Org. Chem., Vol. 61, No. 20, 1996 7209
DMF a n d Mon oglym e
MCF2P(O)(OEt)2
δ in DMFa
δ in monoglymea,b
2
2
M ) Br (1)
-1.0 (t, J F-P ) 93.2 Hz) -1.1 (t, J F-P ) 93 Hz)
2
2
M ) BrZn (2)
14.1 (t, J F-P ) 92.5 Hz) 14.1 (t, J F-P ) 89 Hz)
2 2
M ) Br2Zn‚Cu (3) 12.8 (t, J F-P ) 97.6 Hz) 13.0 (t, J F-P ) 99 Hz)
a
b
Relative values to 85% H3PO4. Values reported by Burton
(ref 18).
F igu r e 2.
3 to give the corresponding adducts 4f and 4g in good
yields (entries 6 and 7). However, the vinyl triflate
derived from cyclohexanone proved to be a very poor
reactant with 3 (entry 8).
Cop p er (I)-Ca ta lyzed Ad d ition Rea ction of [(Di-
eth oxyp h osp h in yl)d iflu or om eth yl]zin c Br om id es 2
to Ter m in a l Acetylen es. The carbometalation reaction
of copper reagent 3 with hexafluoro-2-butyne was briefly
reported by Burton.17 As described above, we have
observed that the copper reagent 3 in DMF decomposed
at room temperature to form the dimeric product 5 of
[(diethoxyphosphinyl)difluoromethyl] radical 7 by means
of 19F NMR spectroscopy. On the basis of these findings
and the report of Burton,17 if the addition reaction of 3
to terminal acetylenes proceeds via carbometalation or
radical addition, synthesis of (R,R-difluoroally)phospho-
nates of either types I or II, respectively, would be
feasible as shown in eq 2.
Mech a n istic Discu ssion . The formation of 2, the
subsequent transmetalation with CuBr, and the thermal
stability of the prepared organometallic species in DMF
were monitored by means of 31P- and 19F-NMR spectros-
copy in order to gain insights into the mechanism for the
coupling reaction of CuBr-catalyzed organozinc 2 with
alkeny halides (Table 3). The signals due to diethyl
2
(bromodifluoromethyl)phosphonate (1) (δ -1.0, t, J P-F
) 93.2 Hz) disappeared within 3 h at room temperature
after addition of zinc in DMF. New signals appeared at
2
δ 14.1 (t, J P-F ) 92.5 Hz), which are consistent with a
reported δ value of organozinc 2 prepared in mono-
glyme.18 The transmetalation with CuBr required 30 min
to give a organocopper species, the signals of which
appeared at δ 12.8 (t, 2J P-F ) 97.6 Hz), closely related to
those of [diethoxyphosphinyl)difluoromethyl]copper com-
plex 3 in monoglyme as reported by Burton.18 Thus, it
was comfirmed that organocopper reagent 3 can be
prepared even in DMF. The copper reagent 3 in DMF
decomposed slowly to give many products at room tem-
perature, and two signals corresponding to the dimeric
decomposition products 511 and 618 were detected in the
19F NMR spectrum.21 The phosphonates 5 and 6 could
e
In keeping with this strategy for the synthesis of (R,R-
difluoroallyl)phosphonates, CuBr-catalyzed addition of 2
to terminal acetylenes was examined in DMF or THF
under the given conditions in Table 4. It was found that
all reactions gave (R,R-difluoroallyl)phosphonates of type
II, and no regioisomers of type I as shown in eq 2 were
detected. The reaction of phenylacetylene with 2 gave
(E)-4a and (Z)-4a in 62% yield in a ratio of 83:17 (entry
2). The stereoselectivity slightly increased to 86:14 upon
conducting the reaction at 0 °C (entry 1). The reaction
on (4-methoxyphenyl)acetylene under similar conditions
gave the corresponding (E)-(R,R-difluoroallyl)phosphonate
(E)-4b in a high stereoselectivity (E/Z ) 95:5), but in low
yield (entry 5). 1-Hexyne also reacted with 2 under the
same conditions to give 4c without stereroselctivity in
modest yield (entry 6). Moreover, it was found that a
stoichiometric amount of CuBr was necessary to achieve
the addition reaction effectively (entry 4). We also
observed that DMF was superior to THF for these
reactions (entries 2 vs 3).
arise via [(diethoxyphosphinyl)difluoromethyl] radical 7
and fluoro(diethoxyphosphinyl)carbene 8, respectively.11,18
Burton has reported that organocopper reagent 3 in
monoglyme decomposed slowly to yield the dimeric
product 6 in 50% yield but not to yield 5.18 Thus, it is
noteworthy that the decomposition process of 3 in DMF
remarkably differs from that in monoglyme.
To gain further insights into the mechanism, the
coupling reaction of 2 with â-bromostyrene (E:Z ) 86:
14) in the presence of a catalytic amount (10 mol %
relative to 2) of CuBr in DMF was carried out to give 4a
(E:Z ) 86:14) in 41% yield. The reaction was found to
involve a catalytic cycle with CuBr.
Based on the above results, the following mechanism
is proposed (Figure 2). Smooth transmetalation of zinc
reagent 2 to 3, followed by oxidative addition to alkenyl
halides, gave presumable intermediate 9 which reduc-
tively eliminates CuBr to give the coupling product with
retention of stereochemistry.
The regiochemical results of the reaction of 2 with
terminal acetylenes in the presence of CuBr may be
attributed to an addition of [(diethoxyphosphinyl)diflu-
oromethyl]radical 7 at the terminal alkyne positions.22
(22) Evidence consistent with the proposed mechanism is that the
reaction of diallyl ether with 2 in DMF in the presence of CuBr
proceeded in a 5-exo-trig mode to give radical-cyclization products i [δ
0.96 (d, J ) 7.1 Hz); HRMS m/z 286.1143 (calcd for C11H21O4FP:
286.1145)] in low yield.23
(21) Characteristic signals were observed at δ -87.4, -82.8, and
-65.1 in the 19F NMR spectrum; these signals are consistent with those
of (E)-6, 5, and (Z)-6, respectively, as reported by Burton and Hu.11,18

7210 J . Org. Chem., Vol. 61, No. 20, 1996
Ta ble 4. Cop p er (I) Br om id e-Ca ta lyzed Ad d ition of 2 to Ter m in a l Acetylen es
Notes
entrya
acetylenes
temp (°C)
time (h)
CuBr (equiv)b
solvent
product
yield (%)c
ratio (E/Z)d
1
2
3
4
5
6
C6H5-t-Η
C6H5-t-Η
C6H5-t-Η
C6H5-t-Η
4-MeOC6H4-t-H
n-Bu-t-H
0
25
25
25
25
25
48
15
15
15
15
24
1.0
1.0
1.0
0.1
1.0
1.0
DMF
DMF
THF
DMF
DMF
DMF
4a
4a
4a
4a
4b
4c
55
62
18
<5
23
54
86:14
83:17
83:17
NDf
95:5
50:50
a
b
d
Two equivalents of 2 was utilized. Equivalent to 2. c Yield based on acetylene. Determined by NMR (1H and 31P) analysis of crude
products. f Not determined.
Anal. Calcd for C13H17O3PF2: C, 53.78, H, 5.91. Found: C,
53.39, H, 5.86.
Con clu sion
In conclusion we have developed an efficient method
for the stereoselective synthesis of (R,R-difluoroallyl)-
phosphonates through the coupling reaction of [(di-
ethoxyphosphinyl)difluoromethyl]zinc bromide 2 with
alkenyl halides in the presence of cuprous bromide in
DMF. In addition, we have found that this reagent
system is applicable to radical addition of the (difluoro-
methylene)phosphonate moiety to terminal acetylenes.
Further works on applications to the synthesis of poly-
functionalized (difluoromethylene)phosphonates of bio-
logical interest are now in progress.
Dieth yl (Z)-(3-p h en yl-1,1-d iflu or o-2-p r op en yl)p h osp h o-
n a te (Z)-4a : obtained as an oil of a mixture of (Z)- and (E)-
isomers in ratio of 68:32; These isomers could not be separated
by column chromatography on silica gel. Spectroscopic data
corresponding to (Z)-4a contaminated with the E-isomer: 1H
NMR (CDCl3, 300 MHz) δ 7.52-7.28 (5H, m), 7.07 (0.32H, ddt,
J H-H ) 16.2, J H-P ) 3.0, J H-F ) 2.8 Hz), 6.95 (0.68H, dt, J H-H
) 12.9, J H-F ) 3.5 Hz), 6.30 (0.32H, ddt, J H-H ) 16.2, J H-F
)
12.9, J H-P ) 2.9 Hz), 5.76 (0.68H, ddt, J H-H ) 12.9, J H-P ) 2.1,
J H-F ) 17.4 Hz), 4.37-4.17 (4H, m), 1.38 (1.92H, t, J ) 7.1 Hz),
1.34 (4.08H, t, J ) 7.0 Hz); 13C NMR (CDCl3, 100 MHz) δ 138.9
(dt J C-P ) 7.2, J C-F ) 6.5 Hz)*, 134.6*, 129.1*, 128.2*, 127.8*,
119.9 (dt, J C-P ) 13.8, J C-F ) 21.3 Hz)*, 117.3 (dt, J C-P ) 219.2,
J C-F ) 259.8 Hz)*, 64.6 (d, J C-P ) 6.4 Hz)*, 16.2 (d, J C-P ) 5.5
Hz)* (*: signals corresponding to (Z)-4a ); 19F NMR (CDCl3, 376
MHz) δ -45.6 (0.64F, dd, J P-F ) 114.3, J H-F ) 12.9 Hz), -41.09
(2.04F, dd, J H-F ) 17.4 Hz, J P-F ) 112.1 Hz), 31P NMR (CDCl3,
160 MHz) δ 6.42 (0.68P, t, J P-F ) 111.8 Hz), 6.19 (0.32P, t, J P-F
) 114.3 Hz); IR (neat) 1271, 1038 cm-1; MS(EI) m/ z 290 (M+).
High-resolution MS calcd for C13H17O3PF2: 290.0883. Found:
290.0883. Anal. Calcd for C13H17O3PF2: C, 53.78; H, 5.91.
Found: C, 53.95; H, 6.14.
Exp er im en ta l Section
Gen er a l. All reactions were carried out under nitrogen
atmosphere. DMF was dried over molecular sieves (4 Å). THF
was distilled from sodium benzophenone ketyl. Diethyl (bro-
modifluoromethyl)phosphonate (1) was prepared according to ref
24. 1H NMR spectra were recorded at 300 or 400 MHz in CDCl3
using TMS or residual CHCl3 (7.26 ppm) as an internal refer-
ences. 13C NMR(100 or 75 MHz) and 31P NMR (160 MHz) were
taken in CDCl3 using CDCl3 (77.0 ppm) as an internal standard
and 85% H3PO4 as an external standard, respectively, with
broad-band 1H decoupling. 19F NMR spectra (376 MHz) was
measured in CDCl3 using benzotrifluoride (BTF) as an internal
standard.
Gen er a l Exp er im en ta l P r oced u r e for Cu Br -Ca ta lyzed
Rea ction of 2 w ith Alk en yl Ha lid es or Acetylen es. To a
stirred suspension of Zn dust (1.3 g, 20 mmol) in dry DMF (10
mL) was slowly added a solution of 1 (5.34 g, 20 mmol) in DMF
(10 mL). During the addition, an exothermic reaction occurred.
The addition was controlled so that the internal temperature
was maintained at 50-60 °C. After addition was completed,
the solution was stirred at room temperature for an additional
3 h, and then CuBr (3.02 g, 20 mmol) was added in one portion.
The mixture was stirred at the same temperature for 30 min to
give organocopper reagent 3 in DMF. Alkenyl halide or acety-
lene (10 mmol) was added dropwise at room temperature
(exothermic reaction occurred). After the mixture was stirred
at room temperature for the time indicated in Tables 1 and 2,
HCl 2% was added to quench the reaction. Biphasic mixture
was passed through Celite and extracted with Et2O. The extract
was washed with saturated NaHCO3 and brine and dried over
MgSO4. Evaporation of the solvent, followed by chromatographic
purification on silica gel (hexane:EtOAc ) 5:1 to 3:1) gave (R,R-
difluoroallyl)phosphonate 4.
Dieth yl (E)-[3-(4′-m eth oxyp h en yl)-1,1-d iflu or o-2-p r op e-
1
n yl]p h osp h on a te (E)-4b: an oil; H NMR (CDCl3, 400 MHz)
δ 7.37 (2H, d, J ) 8.7 Hz), 6.99 (1H, ddt, J ) 16.1, J ) 2.9, 2.9
Hz), 6.86 (2H, d, J ) 8.7 Hz), 6.13 (1H, ddt, J H-H ) 13.0, J H-P
) 2.9, J H-F ) 16.1 Hz), 4.30-4.20 (4H, m), 3.78 (3H, s), 1.34
(6H, t, J ) 7.1 Hz); 13C-NMR (CDCl3, 100 MHz) δ 160.6, 136.4
(dt J C-P ) 6.1, 10.6 Hz), 128.8, 126.9, 117.6 (dt, J ) 221.7, 259.5
Hz), 116.1 (dt, J ) 21.3, 12.8 Hz), 114.1, 64.5 (d, J C-P ) 6.3 Hz),
55.2, 16.3 (d, J C-P ) 4.9 Hz); 19F NMR (CDCl3, 376 MHz) δ
-44.93 (dd, J H-F ) 13.0 Hz, J P-F ) 116.4 Hz), 31P NMR (CDCl3,
160 MHz) 6.33 (t, J P-F ) 116.4 Hz); IR (neat) 1269, 1035 cm-1
;
MS(EI) m/ z 320 (M+). High-resolution MS calcd for C14H19O4-
PF2: 320.0962. Found: 320.0989.
Dieth yl (E)-(1,1-d iflu or o-2-h exen yl)p h osp h on a te (E)-4c:
1
an oil; H NMR (CDCl3, 300 MHz) δ 6.37-6.21 (1H, m), 5.75-
5.57 (1H, m), 4.33-4.18 (4H, m), 2.22-2.10 (2H, m), 1.49-1.27-
(4H, m), 1.36 (6H, t, J ) 7.1 Hz), 0.90 (3H, t, J ) 7.2 Hz): 13C
NMR (CDCl3, 75 MHz) δ 140.2 (dt, J ) 5.9, 9.9 Hz), 120.6 (dt,
J ) 13.1, 21.1 Hz), 116.9 (dt, J ) 219.2, 256.9 Hz), 64.4 (d, J )
6.7 Hz), 31.7, 30.2, 22.0, 16.3 (d, J ) 5.4 Hz), 13.7; 19F NMR
(CDCl3, 376 MHz) δ -45.3 (dd, J H-F ) 12.4, J P-F ) 115.3 Hz);
31P NMR (CDCl3, 160 MHz) δ 6.52 (t, J P-F ) 115.3 Hz); IR (neat)
1273, 1040 cm-1; MS(EI) m/ z 270 (M+). Anal. Calcd for
C
11H21O3PF2: C, 48.87; H, 7.84. Found: C, 48.60; H, 7.76.
(E)-4-(Dieth ylp h osp h on o)-4,4-d iflu or o-2-bu ten -1-ol THP
1
eth er (E)-4d : an oil; H NMR (CDCl3, 400 MHz) δ 6.40-6.26
(1H, m), 6.04-5.86 (1H, m), 4.26 (1H, t, J ) 3.2 Hz), 4.40-4.28
(1H, m), 4.28-4.16 (4H, m), 4.13-3.98 (1H, m), 3.86-3.74 (1H,
m), 3.54-3.42 (1H, m), 1.90-1.45 (6H, m), 1.43-1.30 (6H, m);
13C NMR (CDCl3, 75 MHz) 135.9 (dt, J C-P ) 5.8 Hz, J C-F ) 9.9
Hz), 121.0 (dt, J C-P ) 13.3 Hz, J C-F ) 21.5 Hz), 116.9 (dt, J C-P
) 219.1, J C-F ) 256.8 Hz), 98.0, 65.3, 64.6 (d, J C-P ) 6.7 Hz),
61.9, 30.3, 25.3, 19.1, 16.3 (d, J C-P ) 5.4 Hz); 19F NMR (CDCl3,
376 MHz) δ -45.9 (d, J P-F ) 113.4 Hz); 31P NMR (CDCl3, 160
Dieth yl (E)-(3-p h en yl-1,1-d iflu or op r op -2-en yl)p h osp h o-
n a te (E)-4a : an oil; 1H NMR (CDCl3, 300 MHz) δ 7.53-7.29
(5H, m), 7.07 (1H, ddt, J H-H ) 16.2, J H-P ) 3.0, J H-F ) 2.8 Hz),
6.30 (1H, ddt, J H-H ) 16.2, J H-F ) 12.9, J H-P ) 2.9 Hz), 4.38-
4.19 (4H, m), 1.38 (6H, t, J ) 7.1 Hz); 13C NMR (CDCl3, 75 MHz)
δ 136.9 (dt, J C-F ) 10.5, J C-P ) 5.9 Hz), 134.2, 129.4, 128.7,
127.3, 118.6 (dt, J C-F ) 21.1, J C-P ) 12.9 Hz), 117.4 (dt, J C-F
257.9, J C-P ) 221.0 Hz), 64.7 (d, J C-P ) 6.7 Hz), 16.3 (d, J C-P
)
)
5.3 Hz); 19F NMR (CDCl3, 376 MHz,) δ -45.6 (dd, J P-F ) 114.3,
MHz) δ 6.20 (t, J P-F ) 113.4 Hz); IR (neat) 1270, 1034 cm-1
;
J H-F ) 12.9 Hz); 31P NMR (CDCl3, 160 MHz) δ 6.19 (t, J P-F
)
MS(EI) m/ z 329 (M+ + 1). Anal. Calcd for C13H23O5PF2: C,-
47.54; H, 7.06. Found: C, 47.15; H, 6.99.
114.3 Hz); IR (neat) 1270, 1039 cm-1; MS(EI) m/ z 290 (M+).
(Z)-4-(Dieth ylp h osp h on o)-4,4-d iflu or o-2-bu ten -1-ol THP
1
eth er (Z)-4d : an oil; H NMR (CDCl3, 300 MHz) δ 6.20-6.08
(23) Hu, C.-M.; Chen, J . J . Fluorine Chem. 1994, 69, 79.
(24) Burton, D. J .; Flynn, R. M. J . Fluorine Chem. 1977, 10, 329.
Mahmood, T.; Shreeve, J . M. Synth. Commun. 1987, 17, 71.
(1H, m), 5.71-5.52 (1H, m), 4.64-4.60 (1H, m), 4.59-4.46 (1H,
m), 4.43-4.20 (5H, m), 3.90-3.80 (1H, m), 3.56-3.46 (1H, m),

Notes
J . Org. Chem., Vol. 61, No. 20, 1996 7211
1.90-1.48 (6H, t, J ) 7.1 Hz); 13C NMR (CDCl3, 100 MHz) 139.3
MHz) δ -46.9 (d, J P-F ) 114.5 Hz); 31P NMR (CDCl3, 160 MHz))
δ 6.24 (t, J P-F ) 114.5 Hz); IR (neat) 1273, 1024 cm-1; MS m/ z
299 (M+ + 1). Anal. Calcd for C13H25O3PF2: C,52.32; H, 8.45.
Found: C, 51.83; H, 8.24.
Diet h yl (cycloh exen -1-yld iflu or om et h yl)p h osp h on a t e
(4g) an oil; 1H NMR (CDCl3, 300 MHz) 6.28-6.20 (1H, m), 4.32-
4.18 (4H, m), 2.26-2.09 (4H, m), 1.72-1.55 (4H, m), 1.36 (6H,
t, J ) 7.1 Hz); 13C NMR (CDCl3, 100 MHz) 130.7 (dt, J C-P ) 5.8
(dt, J C-P ) 6.3, J C-F ) 6.4 Hz), 120.2 (dt, J C-P ) 13.3, J C-F
)
22.8 Hz), 117.6 (dt, J C-P ) 219.1, J C-F ) 259.7 Hz), 98.5, 64.6
(d, J C-P ) 6.2 Hz), 63.8, 62.2, 30.5, 25.3, 19.3, 16.3 (d, J C-P
)
4.6 Hz); 19F NMR (CDCl3, 376 MHz) δ -43.3 (dd, J H-F ) 16.6,
J P-F ) 112.8 Hz); 31P NMR (CDCl3, 160 MHz) δ 6.20 (t, J P-F
112.8 Hz); IR (neat) 1273, 1034 cm-1; MS(EI) m/ z 329 (M+
)
+
1), 244 (MH+ - THP); high-resolution MS calcd for C8H15O4PF2
(MH+ - THP): 244.0696. Found: 244.0676. Anal. Calcd for
Hz, J C-F ) 9.3 Hz), 130.6, 118.4 (dt, J C-P ) 217.2 Hz, J C-F
)
C
13H23O5PF2: C,47.54; H, 7.06. Found: C, 48.01; H, 7.15.
216.0 Hz), 64.3 (d, J C-P ) 6.5 Hz) 24.8, 22.8, 21.8, 21.4, 16.3 (d,
J C-P ) 5.2 Hz); 19F NMR (CDCl3, 376 MHz) δ -47.7 (d, J P-F
)
(E)-5-(Dieth ylph osph on o)-7,7-diflu or o-5-h epten -1-ol THP
eth er (E)-4e: an oil; 1H-NMR (CDCl3, 300 MHz) δ 6.37-6.21
(1H, m), 5.77-5.59 (1H, m), 4.60-4.54 (1H, m), 4.34-4.19 (4H,
m), 3.90-3.80 (1H, m), 3.79-3.69 (1H, m), 3.55-3.45 (1H, m),
3.44-3.33 (1H, m), 2.28-2.14 (2H, m), 1.88-1.45 (10 H, m), 1.36
(6H, t, J ) 7.1 Hz); 13C NMR (CDCl3, 100 MHz) δ 139.8 (dt,
118.5 Hz); 31P NMR (CDCl3, 160 MHz) δ 6.60 (t, J P-F ) 118.5
Hz); IR (neat) 1665, 1270, 1045 cm-1; MS m/ z 269 (M+ + 1).
Anal. Calcd for C11H19O3PF2: C, 49.23; H, 7.14. Found: C,
48.85; H, 7.04.
J C-P ) 13.2, J C-F ) 10.0 Hz), 121.0 (dt, J C-P ) 13.2, J C-F
)
Ack n ow led gm en t. This work was supported in part
by Grant-in-Aid for Scientific Research (07672293,
08672449) from the Ministry of Education, Science and
Culture of J apan. Thanks are also due to F. TECH, Inc.
for kindly providing CBr2F2.
21.2 Hz), 116.9 (dt, J C-P ) 219.0, J C-F ) 256.8 Hz), 98.8, 67.0,
64.4 (d, J C-P ) 6.4 Hz), 62.2, 31.8, 30.7, 29.1, 25.4, 25.0, 19.6,
16.3; 19F NMR (CDCl3, 376 MHz) δ -45.4 (dd, J P-F ) 115.9, J H-F
) 12.4 Hz); 31P NMR (CDCl3, 160 MHz), 6.44 (t, J P-F ) 115.9
Hz); IR (neat) 1671, 1269, 1034 cm-1; MS m/ z 228, 138. Anal.
Calcd for C16H29O5 PF2: C, 51.89; H, 7.89. Found: C, 51.86; H,
7.81.
Su p p or tin g In for m a tion Ava ila ble: Photocopies of 1H
and 13C NMR spectra for (E)-4a -d , (Z)-4a ,c,d , and 4f,g (19
pages). This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masterhead page for ordering information.
Diet h yl (1,1-d iflu or o-2-h exyl-2-p r op en yl)p h osp h on a t e
(4f) an oil: 1H NMR (CDCl3, 300 MHz) δ 5.61-5.56 (1H, m),
5.34-5.30 (1H, m), 4.35-4.18 (4H, m), 2.28-2.18 (2H, m), 1.56-
1.23 (8H, m), 1.36 (6H, t, J ) 7.1 Hz), 0.88 (3H, t, J ) 6.8 Hz);
13C NMR (CDCl3, 100 MHz) 141.8 (dt, J C-P ) 12.4, J C-F ) 18.8
Hz), 118.5 (dt, J C-P ) 215.1, J C-F ) 262.4 Hz), 117.4 (dt, J C-P
)
4.8, J C-F ) 9.4 Hz), 64.5 (d, J C-P ) 6.5 Hz), 31.6, 29.7, 28.8,
27.7, 22.5, 16.3 (d, J P-C ) 4.5 Hz), 14.0; 19F NMR (CDCl3, 376
J O960896J